Next Article in Journal
Preparation, Corrosion Resistance, and Electrochemical Properties of MnO2/TiO2 Coating on Porous Titanium
Next Article in Special Issue
Powder Synthesized from Aqueous Solution of Calcium Nitrate and Mixed-Anionic Solution of Orthophosphate and Silicate Anions for Bioceramics Production
Previous Article in Journal
Wear Study of Coated Mills during Circumferential Milling of Carbon Fiber-Reinforced Composites and Their Influence on the Sustainable Quality of the Machined Surface
Previous Article in Special Issue
Advanced Biomaterials and Coatings
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Calcium Orthophosphate (CaPO4)-Based Bioceramics: Preparation, Properties, and Applications

by
Sergey V. Dorozhkin
Kudrinskaja sq. 1-155, 123242 Moscow, Russia
Coatings 2022, 12(10), 1380; https://doi.org/10.3390/coatings12101380
Submission received: 1 August 2022 / Revised: 19 August 2022 / Accepted: 14 September 2022 / Published: 21 September 2022
(This article belongs to the Special Issue Advanced Biomaterials and Coatings)

Abstract

:
Various types of materials have been traditionally used to restore damaged bones. In the late 1960s, a strong interest was raised in studying ceramics as potential bone grafts due to their biomechanical properties. A short time later, such synthetic biomaterials were called bioceramics. Bioceramics can be prepared from diverse inorganic substances, but this review is limited to calcium orthophosphate (CaPO4)-based formulations only, due to its chemical similarity to mammalian bones and teeth. During the past 50 years, there have been a number of important achievements in this field. Namely, after the initial development of bioceramics that was just tolerated in the physiological environment, an emphasis was shifted towards the formulations able to form direct chemical bonds with the adjacent bones. Afterwards, by the structural and compositional controls, it became possible to choose whether the CaPO4-based implants would remain biologically stable once incorporated into the skeletal structure or whether they would be resorbed over time. At the turn of the millennium, a new concept of regenerative bioceramics was developed, and such formulations became an integrated part of the tissue engineering approach. Now, CaPO4-based scaffolds are designed to induce bone formation and vascularization. These scaffolds are usually porous and harbor various biomolecules and/or cells. Therefore, current biomedical applications of CaPO4-based bioceramics include artificial bone grafts, bone augmentations, maxillofacial reconstruction, spinal fusion, and periodontal disease repairs, as well as bone fillers after tumor surgery. Prospective future applications comprise drug delivery and tissue engineering purposes because CaPO4 appear to be promising carriers of growth factors, bioactive peptides, and various types of cells.

1. Introduction

One of the most exciting and rewarding areas of the engineering discipline involves development of various devices for healthcare. Some of them are implantable. Examples comprise sutures, catheters, heart valves, pacemakers, breast implants, fracture fixation plates, nails and screws in orthopedics, various filling formulations, orthodontic wires, total joint replacement prostheses, etc. However, in order to be accepted by the living body without any unwanted side effects, all implantable items must be prepared from a special class of tolerable materials, called biomedical materials or biomaterials, in short. The physical character of the majority of the available biomaterials is solids [1,2].
From the material point of view, all types of solids are divided into four major groups: metals, polymers, ceramics, and various blends thereof, called composites. Similarly, all types of solid biomaterials are also divided into the same groups: biometals, biopolymers, bioceramics, and biocomposites. All of them play very important roles in both replacement and regeneration of various human tissues; however, setting biometals, biopolymers, and biocomposites aside, this review is focused on bioceramics only. In general, bioceramics comprise various polycrystalline materials, amorphous materials (glasses), and blends thereof (glass-ceramics). Nevertheless, the chemical elements used to manufacture bioceramics form just a small set of the periodic table; namely, bioceramics might be prepared from alumina, zirconia, magnesia, carbon, silica-contained, and calcium-contained compounds, as well as from a limited number of other compounds. All these compounds might be manufactured in both dense and porous forms in bulk, as well as in the forms of crystals, powders, particles, granules, scaffolds, and/or coatings [1,2,3].
As seen from the above, the entire subject of bioceramics is still rather broad. To specify it further, let me limit myself by a description of calcium orthophosphate (abbreviated as CaPO4)-based formulations only. If compared with other types of bioceramics (such as alumina, zirconia, calcium silicates, calcium sulfate, etc.), the main feature and superiority of CaPO4 is based on their chemical similarity to the composition of calcified tissues of mammals (bones, teeth, and deer antlers) and the need for versatile and risk-free bone substitute biomaterials immediately available without the constraint of bone grafts. One of the major properties of most types of CaPO4 is their osteoconductivity, an ability to favor bone healing and to bind firmly to bone tissues. In addition, some types of CaPO4 have been shown to be able to initiate bone formation de novo in nonosseous sites [1,2,3]. Therefore, CaPO4 bioceramics are widely used in a number of different applications throughout the body, covering all areas of the skeleton. The examples include healing of bone defects, fracture treatment, total joint replacement, bone augmentation, orthopedics, cranio-maxillofacial reconstruction, spinal surgery, otolaryngology, ophthalmology, and percutaneous devices [1,2,3], as well as dental fillings and periodontal treatments [4]. Furthermore, they are also used in nonosseous applications, such as ocular implants, allowing eye movements. Depending upon the required properties, different types of CaPO4 might be used. For example, Figure 1 displays some randomly chosen samples of the commercially available CaPO4 bioceramics for bone graft applications. One should note that the global bone grafts and substitutes market was valued at USD 2.65 billion in 2020 and is projected to reach USD 3.36 billion by 2028, registering a cumulative annual growth rate of ~4.3% from 2021 to 2028 [5]. This clearly demonstrates the biomedical perspectives of CaPO4-based bioceramics.
A list of the available CaPO4, including their standard abbreviations and major properties, is summarized in Table 1 [3,6]. To narrow the subject further, with a few important exceptions, bioceramics prepared from undoped and unsubstituted CaPO4 will be considered and discussed only. Due to this reason, CaPO4-based bioceramics prepared from biological resources, such as bones, teeth, corals, antlers, etc. [7,8,9,10,11,12,13,14], including food [15] and animal wastes [16], as well as various types of ion-substituted CaPO4 [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41], including rhenanite NaCaPO4 and chlorapatite Ca10(PO4)6Cl2, are not considered. The readers interested in both topics are advised to study the original publications.

2. General Knowledge and Definitions

A number of definitions have been developed for the term “biomaterials”. For example, by the end of the 20th century, the consensus developed by the experts was the following: biomaterials were defined as synthetic or natural materials to be used to replace parts of a living system or to function in intimate contact with living tissues [42]. In September 2009, a more advanced definition was introduced: “A biomaterial is a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure, in human or veterinary medicine” [43]. Further, in 2018, the term biomaterial was redefined as “a material designed to take a form that can direct, through interactions with living systems, the course of any therapeutic or diagnostic procedure” [44]. According to the Williams, “The two critical parts of this definition relate to the objectives of the systems in which a biomaterial is used and the fact that the material has to interact with living systems, in most cases parts of the human body, in order for these objectives to be realized. This definition, and indeed, the whole concept of biomaterials science, applies equally to situations involving implantable devices, artificial organs, tissue engineering templates, nonviral gene vectors, drug delivery systems and contrast agents” [45]. The definition alterations were accompanied by a shift in both the conceptual ideas and the expectations of biological performance, which mutually changed in time. However, one should stress that any artificial materials that are in contact with skin, such as hearing aids and wearable artificial limbs, are not included in the definition of biomaterials since the skin acts as a protective barrier between the body and the external world [1,2].
In general, the biomaterials discipline is founded in the knowledge of the synergistic interaction of material science, biology, chemistry, medicine, and mechanical science and it requires the input of comprehension from all these areas so that potential implants perform adequately in a living body and interrupt normal body functions as little as possible [46]. As biomaterials deal with all aspects of the material synthesis and processing, the knowledge in chemistry, material science, and engineering appears to be essential. On the other hand, since clinical implantology is the main purpose of biomaterials, biomedical sciences become the key part of the research. These include cell and molecular biology, histology, anatomy, and physiology. The final aim is to achieve the correct biological interaction of the artificial grafts with living tissues of a host. Thus, to achieve the goals, several stages have to be performed, such as material synthesis, design, and manufacturing of prostheses, followed by various types of tests. Furthermore, before clinical applications, any potential biomaterial must also pass all regulatory requirements [47].
The major difference between biomaterials and other classes of materials lays in their ability to remain in a biological environment while neither damaging the surroundings nor being damaged in that process. Therefore, biomaterials must be distinguished from biological materials because the former are the materials that are accepted by living tissues and, therefore, they might be used for tissue replacements, while the latter are just the materials being produced by various biological systems (wood, cotton, bones, chitin, etc.) [48]. Furthermore, there are biomimetic materials, which are not made by living organisms but have composition, structure, and properties similar to those of biological materials. Concerning the subject of the current review, bioceramics (or biomedical ceramics) are defined as biomaterials having a ceramic origin. Now, it is important to define the meaning of ceramics. According to Wikipedia, the free encyclopedia: “The word ceramic comes from the Greek word κεραμικός (keramikos), “of pottery” or “for pottery”, from κέραμος (keramos), “potter’s clay, tile, pottery”. The earliest known mention of the root “ceram-” is the Mycenaean Greek ke-ra-me-we, “workers of ceramics”, written in Linear B syllabic script. The word “ceramic” may be used as an adjective to describe a material, product or process, or it may be used as a noun, either singular, or, more commonly, as the plural noun “ceramics”. A ceramic material is an inorganic, nonmetallic, often crystalline oxide, nitride or carbide material. Some elements, such as carbon or silicon, may be considered ceramics. Ceramic materials are brittle, hard, strong in compression, weak in shearing and tension. They withstand chemical erosion that occurs in other materials subjected to acidic or caustic environments. Ceramics generally can withstand very high temperatures, such as temperatures that range from 1000 to 1600 °C (1800 to 3000 °F). Glass is often not considered a ceramic because of its amorphous (noncrystalline) character. However, glassmaking involves several steps of the ceramic process and its mechanical properties are similar to ceramic materials” [49]. Similar to any other type of biomaterials, bioceramics can have structural functions as joint or tissue replacements, and be used as coatings to improve the biocompatibility, as well as function as resorbable lattices, providing temporary structures and frameworks that are dissolved and/or replaced as the body rebuilds the damaged tissues [50,51,52,53]. Some types of bioceramics feature a drug-delivery capability [54,55,56,57].
In medicine, bioceramics are needed to alleviate pain and restore functions of diseased or damaged calcified tissues (bones and teeth) of the body. A great challenge facing its medical application is, first, to replace and, second, to regenerate old and deteriorating bones with a biomaterial that can be replaced by a new mature bone without transient loss of a mechanical support [1,2]. The excellent performance of the specially designed bioceramics that have survived these clinical conditions represents one of the most remarkable accomplishments of research, development, production, and quality assurance before the end of the past century [50]. Regarding CaPO4 bioceramics, a surface bioactivity appears to be its major feature. It contributes to a bone bonding ability and enhances new bone formation [58].

3. Bioceramics of CaPO4

3.1. History

The detailed history of HA and other types of CaPO4, including the subject of CaPO4 bioceramics, as well as description of their past biomedical applications, might be found elsewhere [59,60], where the interested readers are referred. One should just note that the earliest book devoted to CaPO4 bioceramics was published in 1983 [61].

3.2. Chemical Composition and Preparation

Currently, CaPO4 bioceramics can be prepared from various sources [7,8,9,10,11,12,13,14,15,16]. Nevertheless, up to now, all attempts to synthesize bone replacement materials for clinical applications featuring the physiological tolerance, biocompatibility, and a long-term stability have had only relative success; this clearly demonstrates both the superiority and a complexity of the natural structures [62].
In general, a characterization of CaPO4 bioceramics should be performed from various viewpoints such as the chemical composition (including stoichiometry and purity), homogeneity, phase distribution, morphology, grain sizes and shape, grain boundaries, crystallite size, crystallinity, pores, cracks, surface roughness, etc. From the chemical point of view, the vast majority of CaPO4 bioceramics are based on HA [63,64,65,66,67], both types of TCP [68,69,70,71,72,73,74,75,76,77,78], and various multiphasic formulations thereof [79]. Biphasic formulations (commonly abbreviated as BCP–biphasic calcium phosphate) are the simplest among the latter ones. They include β-TCP + HA [80,81,82,83,84,85,86,87,88], α-TCP + HA [89,90,91], and biphasic TCP (commonly abbreviated as BTCP), consisting of α-TCP and β-TCP [92,93,94,95,96,97]. In addition, triphasic formulations (HA + α-TCP + β-TCP) have been prepared as well [98,99,100,101]. Further details on this topic can be found in a special review [79]. Leaving aside a big subject of DCPD-forming self-setting formulations [102,103], one should note that just a few publications on bioceramics prepared from other types of CaPO4 are available [104,105,106,107,108,109,110,111,112].
The preparation techniques of various types of CaPO4 have been extensively reviewed in the literature [6,113,114,115,116,117], where the interested readers are referred. Briefly, when compared to both α- and β-TCP, HA is a more stable phase under the physiological conditions, as it has a lower solubility (Table 1) and, thus, slower resorption kinetics [118,119,120]. Therefore, the BCP concept is determined by the optimum balance of a more stable phase of HA and a more soluble TCP. Due to a higher biodegradability of the α- or β-TCP component, the reactivity of BCP increases with the TCP/HA ratio increasing. Thus, in vivo bioresorbability of BCP can be controlled through the phase composition [81]. Similar conclusions are also valid for the biphasic TCP (in which α-TCP is a more soluble phase), as well as for both triphasic (HA, α-TCP, and β-TCP) and yet more complex formulations [79].
As implants made of sintered HA are found in bone defects for many years after implantation (Figure 2, bottom), bioceramics made of more soluble types of CaPO4 [68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,121,122] are preferable for the biomedical purposes (Figure 2, top). Furthermore, the experimental results showed that BCP had a higher ability to adsorb fibrinogen, insulin, or type I collagen than HA [123]. Thus, according to both observed and measured bone formation parameters, CaPO4 bioceramics have been ranked as follows: low sintering temperature BCP (rough and smooth) ≈ medium sintering temperature BCP ≈ TCP > calcined low sintering temperature HA > non-calcined low sintering temperature HA > high sintering temperature BCP (rough and smooth) > high sintering temperature HA [124]. This sequence was developed in the year 2000 and, thus, neither multiphase formulations nor other CaPO4 are included.

3.3. Forming and Shaping

In order to fabricate CaPO4 bioceramics in progressively complex shapes, scientists are investigating the use of both old and new manufacturing techniques. These techniques range from an adaptation of the age-old pottery techniques to the newest manufacturing methods for high-temperature ceramic parts for airplane engines; namely, reverse engineering [125,126] and rapid prototyping [127,128,129] technologies have revolutionized a generation of physical models, allowing the engineers to efficiently and accurately produce physical models and customized implants with high levels of geometric intricacy. Combined with computer-aided design and manufacturing (CAD/CAM), complex physical objects of the anatomical structure can be fabricated in a variety of shapes and sizes. In a typical application, an image of a bone defect in a patient can be taken and used to develop a three-dimensional (3D) CAD computer model [130,131,132,133,134]. Then, a computer can reduce the model to slices or layers. Afterwards, 3D objects and coatings are constructed layer-by-layer using rapid prototyping techniques. The examples comprise fused deposition modeling [135,136], selective laser sintering [137,138,139,140,141,142], laser cladding [143,144,145,146], 3D printing and/or plotting [73,147,148,149,150,151,152,153], robocasting [154,155,156], solid freeform fabrication [157,158,159,160,161,162], stereolithography [163,164,165,166], and direct light processing [167]. More advanced techniques, such as 4D [168,169] and 5D [170] printing techniques, have been introduced as well. Three-dimensional printing of the CaPO4-based self-setting formulations is known as well [151]. Additional details of these techniques are available in the literature [171,172,173,174].
In the specific case of ceramic scaffolds, a sintering step is usually applied after printing the green bodies (see Section 3.4. Sintering and Firing below). Furthermore, a thermal printing process of melted CaPO4 was proposed [175], while, in some cases, laser processing might be applied as well [176,177]. A schematic of the 3D-printing technique as well as some 3D-printed items are shown in Figure 3 [56]. A custom-made implant of actual dimensions would reduce the time it takes to perform the medical implantation procedure and subsequently lower the risk to the patient. Another advantage of a prefabricated, exact-fitting implant is that it can be used more effectively and applied directly to the damaged site rather than a replacement, which is formulated during surgery from a paste or granular material [158,177,178,179].
In addition to the aforementioned modern techniques, classical forming and shaping approaches are still widely used. The selection of the desired technique depends greatly on the ultimate application of the bioceramic device, e.g., whether it is for a hard-tissue replacement or an integration of the device within the surrounding tissues. In general, three types of processing technologies might be used: (1) employment of a lubricant and a liquid binder with ceramic powders for shaping and subsequent firing; (2) application of self-setting and self-hardening properties of water-wet molded powders; (3) materials are melted to form a liquid and are shaped during cooling and solidification [180,181,182]. Since CaPO4 are either thermally unstable (MCPM, MCPA, DCPA, DCPD, OCP, ACP, CDHA) or have a melting point at temperatures exceeding ~1400 °C with a partial decomposition (α-TCP, β-TCP, HA, FA, TTCP), only the first and the second consolidation approaches are used to prepare bulk bioceramics and scaffolds. The methods include uniaxial compaction [154,183,184], isostatic pressing (cold or hot) [87,185,186,187,188,189,190,191], granulation [192,193,194,195,196,197,198], loose packing [199], slip casting [75,200,201,202,203,204,205], gel casting [163,206,207,208,209,210,211], pressure mold forming [212,213,214], injection molding [215,216,217,218], polymer replication [219,220,221,222,223,224,225,226], ultrasonic machining [227], extrusion [228,229,230,231,232,233,234], and slurry dipping and spraying [235]. In addition, to form ceramic sheets from slurries, tape casting [207,236,237,238,239,240], doctor blade [241], and colander methods can be employed [180,181,182]. In addition, flexible, ultrathin (of 1 to several microns thick), freestanding HA sheets were produced by a pulsed laser deposition technique, followed by thin film isolation technology [242]. Various combinations of several techniques are also possible [77,207,243,244,245]. Furthermore, some of those processes might be performed under the electromagnetic field, which helps crystal aligning [201,204,246,247,248,249]. Finally, the prepared CaPO4 bioceramics might be subjected to additional treatments (e.g., chemical, thermal, and/or hydrothermal ones) to convert one type of CaPO4 into another one [226].
To prepare bulk bioceramics, powders are usually pressed damp in metal dies or dry in lubricated dies at pressures high enough to form sufficiently strong structures to hold together until they are sintered [250]. An organic binder, such as polyvinyl alcohol, helps to bind the powder particles altogether. Afterwards, the binder is removed by heating in air to oxidize the organic phases to carbon dioxide and water. Since many binders contain water, drying at ~100 °C is a critical step in preparing damp-formed pieces for firing. Too much or too little water in the compacts can lead to blowing apart the ware on heating or crumbling, respectively [180,181,182,186]. Furthermore, removal of water during drying often results in subsequent shrinkage of the product. In addition, due to local variations in water content, warping and even cracks may be developed during drying. Dry pressing and hydrostatic molding can minimize these problems [182]. Finally, the manufactured green samples are sintered.
It is important to note that forming and shaping of any ceramic products require a proper selection of the raw materials in terms of particle sizes and size distribution; namely, tough and strong bioceramics consist of pure, fine, and homogeneous microstructures. To attain this, pure powders with small average size and high surface area must be used as the starting sources. However, for maximum packing and least shrinkage after firing, mixing of ~70% coarse and ~30% fine powders have been suggested [182]. Mixing is usually carried out in a ball mill for uniformity of properties and reaction during subsequent firing. Mechanical die forming or sometimes extrusion through a die orifice can be used to produce a fixed cross-section.
Finally, to produce the accurate shaping, necessary for the fine design of bioceramics, machine finishing might be essential [132,180,251,252]. Unfortunately, cutting tools developed for metals are usually useless for bioceramics due to their fragility; therefore, grinding and polishing appear to be the most convenient finishing techniques [132,180]. In addition, the surface of CaPO4 bioceramics might be modified by various supplementary treatments [253,254], and CaPO4 bioceramics might be subjected to post-processing actions, such as immersing into special solutions [255].

3.4. Sintering and Firing

After being formed and shaped, the CaPO4 bioceramics are commonly sintered. A sintering (or firing) procedure is a thermal process in which loosely bound particles are converted into a consistent solid mass under the influence of heat and/or pressure without melting the particles. This process is of great importance to manufacture bulk bioceramics with the required mechanical properties. Usually, this technique is carried out according to controlled temperature programs of electric furnaces in adjusted ambience of air with necessary additional gasses; however, always at temperatures below the melting points of the materials. The firing step can include temporary holds at intermediate temperatures to burn out organic binders [180,181,182]. The heating rate, sintering temperature, and holding time depend on the starting materials. For example, in the case of HA, these values are in the ranges of 0.5–3 °C/min, 1000–1250 °C, and 2–5 h, respectively [256]. In the majority of cases, sintering allows a structure to retain its shape. However, this process might be accompanied by a considerable degree of shrinkage [257,258,259], which must be accommodated in the fabrication process. For instance, in the case of FA sintering, a linear shrinkage was found to occur at ~715 °C and the material reached its final density at ~890 °C. Above this value, grain growth became important and induced an intra-granular porosity, which was responsible for density decrease. At ~1180 °C, a liquid phase was formed due to formation of a binary eutectic between FA and fluorite contained in the powder as impurity. This liquid phase further promoted the coarsening process and induced formation of large pores at high temperatures [260].
In general, sintering occurs only when the driving force is sufficiently high, while the latter relates to the decrease in surface and interfacial energies of the system by matter (molecules, atoms, or ions) transport, which can proceed by solid, liquid, or gaseous phase diffusion. Namely, when solids are heated to high temperatures, their constituents are driven to move to fill up pores and open channels between the grains of powders, as well as to compensate for the surface energy differences among their convex and concave surfaces (matter moves from convex to concave). At the initial stages, bottlenecks are formed and grow among the particles (Figure 4). Existing vacancies tend to flow away from the surfaces of sharply curved necks; this is an equivalent of a material flow towards the necks, which grow as the voids shrink. Small contact areas among the particles expand and, at the same time, a density of the compact increases and the total void volume decreases. As the pores and open channels are closed during a heat treatment, the particles become tightly bonded together, and density, strength, and fatigue resistance of the sintered object improve greatly. Grain boundary diffusion was identified as the dominant mechanism for densification [261]. Furthermore, strong chemical bonds are formed among the particles, and loosely compacted green bodies are hardened to denser materials [180,181,182]. Further knowledge on the ceramic sintering process can be found elsewhere [262].
In the case of CaPO4, the earliest paper on their sintering was published in 1971 [263]. Since then, numerous papers on this subject have been published, and several specific processes have been found to occur during CaPO4 sintering. Firstly, moisture, carbonates and all other volatile chemicals remaining from the synthesis stage, such as ammonia, nitrates, and any organic compounds, are removed as gaseous products. Secondly, unless powders are sintered, the removal of these gases facilitates production of denser ceramics with subsequent shrinkage of the samples (Figure 5). Thirdly, all chemical changes are accompanied by a concurrent increase in crystal size and a decrease in the specific surface area. Fourthly, a chemical decomposition of all acidic orthophosphates and their transformation into other phosphates (e.g., 2HPO42− → P2O74− + H2O) takes place. In addition, sintering causes toughening [66], densification [67,264], partial dehydroxylation (in the case of HA) [67], a partial evaporation and condensation of phosphates [265], and grain growth [261,266], as well as a mechanical strength increasing [267,268,269]. The latter events are due to presence of air and other gases filling gaps among the particles of unsintered powders. At sintering, the gases move towards the outside of powders, and green bodies shrink owing to decrease of distances among the particles. For example, sintering of biologically formed apatites was investigated [270,271] and the obtained products were characterized [272,273]. In all cases, the numerical value of the Ca/P ratio in sintered apatites of biological origin was higher than that of the stoichiometric HA. One should mention that in the vast majority of cases, CaPO4 with Ca/P ratio < 1.5 (Table 1) are not sintered, since these compounds are thermally unstable, while sintering of nonstoichiometric CaPO4 (CDHA and ACP) always leads to their transformation into various types of biphasic, triphasic, and multiphase formulations [79].
An extensive study on the effects of sintering temperature and time on the properties of HA bioceramics revealed a correlation between these parameters and density, porosity, grain size, chemical composition, and strength of the scaffolds [274]. Namely, sintering below ~1000 °C was found to result in initial particle coalescence, with little or no densification and a significant loss of the surface area and porosity. The degree of densification appeared to depend on the sintering temperature, whereas the degree of ionic diffusion was governed by the period of sintering [274]. To enhance sinterability of CaPO4, a variety of sintering additives might be added [275,276,277,278].
Solid-state pressureless sintering is the simplest procedure. For example, HA bioceramics can be pressurelessly sintered up to the theoretical density at 1000–1200 °C. Processing at even higher temperatures usually lead to exaggerated grain growth and decomposition because HA becomes unstable at temperatures exceeding ~1300 °C [6,113,114,115,116,117,279,280,281]. The decomposition temperature of HA bioceramics is a function of the partial pressure of water vapor. Moreover, processing under vacuum leads to an earlier decomposition of HA, while processing under high partial pressure of water prevents the decomposition. On the other hand, the presence of water in the sintering atmosphere was reported to inhibit densification of HA and accelerate grain growth [282]. Unexpectedly, an application of a magnetic field during sintering was found to influence the growth of HA grains [266]. A definite correlation between hardness, density, and a grain size in sintered HA bioceramics was found; despite exhibiting high bulk density, hardness started to decrease at a certain critical grain size limit [283,284,285].
Since grain growth occurs mainly during the final stage of sintering, to avoid this, a new method called ‘‘two-step sintering’’ (TSS) was proposed [286]. The method consists of suppressing grain boundary migration responsible for grain growth, while keeping grain boundary diffusion that promotes densification. The TSS approach was successfully applied to CaPO4 bioceramics [77,86,287,288,289,290]. For example, HA compacts prepared from nanodimensional powders were two-step sintered. The average grain size of near full dense (>98%) HA bioceramics made via conventional sintering was found to be ~1.7 μm, while that for TSS HA bioceramics was ~190 nm (i.e., ~9 times less) with simultaneous increasing of the fracture toughness of samples from 0.98 ± 0.12 to 1.92 ± 0.20 MPa m1/2. In addition, due to the lower second-step sintering temperature, no HA phase decomposition was detected in the TSS method [287].
Hot pressing [285,291,292,293,294,295,296,297], hot isostatic pressing [87,185,190,191], or hot pressing with post-sintering [298,299], as well as “cold sintering” (which is very similar to hot pressing) [300] processes make it possible to decrease the temperature of the densification process, diminish the grain size, and achieve higher densities. This leads to finer microstructures, higher thermal stability, and subsequently better mechanical properties of CaPO4 bioceramics. In addition, microwave [301,302,303,304,305,306], spark plasma [69,104,307,308,309,310,311,312,313,314,315], flash [316,317], and ultrafast high-temperature [318] sintering techniques are alternative methods to the conventional sintering, hot pressing, and hot isostatic pressing. Both alternative methods were found to be time- and energy-efficient densification techniques. Further developments are still possible. For example, a hydrothermal hot pressing method was developed to fabricate OCP [105], CDHA [319], HA/β-TCP [294], and HA [295,296,297,298,320] bioceramics with neither thermal dehydration nor thermal decomposition. Further details on the sintering and firing processes of CaPO4 bioceramics are available in the literature [115,321,322].
To conclude this section, one should note that the sintering stage is not always necessary. For example, CaPO4-based bulk bioceramics with the reasonable mechanical properties might be prepared by means of self-setting (self-hardening) formulations (see Section 6.1. Self-setting (Self-hardening) Formulations below). Furthermore, the reader’s attention is directed to an excellent review on various ceramic manufacturing techniques [323], in which various ceramic processing techniques are well described.

4. The Major Properties

4.1. Mechanical Properties

The modern generation of biomedical materials should stimulate the body’s own self-repairing abilities [324]. Therefore, during healing, a mature bone should replace the modern grafts and this process must occur without transient loss of the mechanical support. Unluckily for material scientists, a human body provides one of the most inhospitable environments for the implanted biomaterials. It is warm, wet, and both chemically and biologically active. For example, a diversity of body fluids in various tissues might have a solution pH varying from 1 to 9. In addition, a body is capable of generating quite massive force concentrations, and the variance in such characteristics among individuals might be enormous. Typically, bones are subjected to ~4 MPa loads, whereas tendons and ligaments experience peak stresses in the range of 40–80 MPa. The hip joints are subjected to an average load of up to three times the body weight (3000 N), and peak loads experienced during jumping can be as high as 10 times the body weight. These stresses are repetitive and fluctuating depending on the nature of the activities, which can include standing, sitting, jogging, stretching, and climbing. Therefore, all types of implants must sustain attacks of a great variety of aggressive conditions [325]. Regrettably, there is presently no artificial material fulfilling all these requirements.
Now it is important to mention that the mechanical behavior of any ceramics is rather specific; namely, ceramics is brittle, which is attributed to high-strength ionic bonds. Thus, it is not possible for plastic deformation to happen prior to failure, as a slip cannot occur. Therefore, ceramics fail in a dramatic manner. Namely, if a crack is initiated, its progress will not be hindered by the deformation of material ahead of the crack, as would be the case in a ductile material (e.g., a metal). In ceramics, the crack will continue to propagate, rapidly resulting in a catastrophic breakdown. In addition, the mechanical data typically have a considerable amount of scatter [181]. Alas, all of these are applicable to CaPO4 bioceramics.
For dense bioceramics, the strength is a function of the grain sizes. Namely, finer-grain-size bioceramics have smaller flaws at the grain boundaries and thus are stronger than ones with larger grain sizes. Thus, in general, the strength for ceramics is proportional to the inverse square root of the grain sizes [326]. In addition, the mechanical properties decrease significantly with increasing content of an amorphous phase, microporosity, and grain sizes, while a high crystallinity, a low porosity, and small grain sizes tend to give a higher stiffness, a higher compressive and tensile strength, and a greater fracture toughness. Furthermore, ceramics strength appears to be very sensitive to slow crack growth [327]. Accordingly, from the mechanical point of view, CaPO4 bioceramics appear to be brittle polycrystalline materials for which the mechanical properties are governed by crystallinity, grain size, grain boundaries, porosity, and composition [328]. Thus, it possesses poor mechanical properties (for instance, a low impact and fracture resistances) that do not allow CaPO4 bioceramics to be used in load-bearing areas, such as artificial teeth or bones [50,51,52,53]. For example, fracture toughness (this is a property that describes the ability of a material containing a crack to resist fracture and is one of the most important properties of any material for virtually all design applications) of HA bioceramics does not exceed the value of ~1.2 MPa·m1/2 [329] (human bone: 2–12 MPa·m1/2). It decreases exponentially with increasing porosity [330]. Generally, fracture toughness increases with grain size decreasing. However, in some materials, especially noncubic ceramics, fracture toughness reaches the maximum and rapidly drops with decreasing grain size. For example, a fracture toughness of pure hot-pressed HA with grain sizes between 0.2–1.2 µm was investigated. The authors found two distinct trends, where fracture toughness decreased with increasing grain size above ~0.4 µm and subsequently decreased with decreasing grain size. The maximum fracture toughness measured was 1.20 ± 0.05 MPa·m1/2 at ~0.4 µm [291]. Fracture energy of HA bioceramics is in the range of 2.3–20 J/m2, while the Weibull modulus (a measure of the spread or scatter in fracture strength) is low (~5–12) in wet environments, which means that HA behaves as a typical brittle ceramics and indicates a low reliability of HA implants [331]. Porosity has a great influence on the Weibull modulus [332,333]. In addition, the reliability of HA bioceramics was found to depend on deformation mode (bending or compression), along with pore size and pore size distribution: reliability was higher for smaller average pore sizes in bending but lower for smaller pore sizes in compression [334]. Interestingly, three peaks of internal friction were found at temperatures of about –40, 80, and 130 °C for HA but no internal friction peaks were obtained for FA in the measured temperature range; this effect was attributed to the differences of F and OH positions in FA and HA, respectively [335]. Differences in internal friction values were also found between HA and TCP [336].
Bending, compressive, and tensile strengths of dense HA bioceramics are in the ranges of 38–250, 120–900, and 38–300 MPa, respectively. Similar values for porous HA bioceramics are substantially lower: 2–11, 2–100, and ~3 MPa, respectively [331]. These wide variations in the properties are due to both structural variations (e.g., an influence of remaining microporosity, grain sizes, presence of impurities, etc.) and manufacturing processes, and they are also caused by a statistical nature of the strength distribution. Strength was found to increase with Ca/P ratio increasing, reaching the maximum value around Ca/P ~1.67 (stoichiometric HA) and decreasing suddenly when Ca/P > 1.67 [331]. Furthermore, strength decreases almost exponentially with increasing porosity [337,338]. However, by changing the pore geometry, it is possible to influence the strength of porous bioceramics. It is also worth mentioning that porous CaPO4 bioceramics are considerably less fatigue-resistant than dense ones (in materials science, fatigue is the progressive and localized structural damage that occurs when a material is subjected to cyclic loading). Both grain sizes and porosity are reported to influence the fracture path, which itself has little effect on the fracture toughness of CaPO4 bioceramics [328,339]. However, no obvious decrease in mechanical properties was found after CaPO4 bioceramics had been aged in the various solutions during the different periods of time [340].
Young’s (or elastic) modulus of dense HA bioceramics is in the range of 3–120 GPa [341,342], which is more or less similar to those of the most resistant components of the natural calcified tissues (dental enamel: ~74 GPa, dentine: ~21 GPa, compact bone: ~18–22 GPa). This value depends on porosity [343,344]. Nevertheless, dense bulk compacts of HA have mechanical resistances of the order of 100 MPa versus ~00 MPa of human bones, drastically diminishing their resistances in the case of porous bulk compacts [345]. Young’s modulus measured in bending is between 44 and 88 GPa. To investigate the subject in more detail, various types of modeling and calculations are increasingly used [346,347,348,349,350]. For example, the elastic properties of HA appeared to be significantly affected by the presence of vacancies, which softened HA via reducing its elastic modules [350]. In addition, a considerable anisotropy in the stress–strain behavior of the perfect HA crystals was found by ab initio calculations [347]. The crystals appeared to be brittle for tension along the z-axis with the maximum stress of ~9.6 GPa at 10% strain. Furthermore, the structural analysis of the HA crystal under various stages of tensile strain revealed that the deformation behavior manifested itself mainly in the rotation of PO4 tetrahedrons with concomitant movements of both the columnar and axial Ca ions [347]. Data for single crystals are also available [351]. Vickers hardness (a measure of the resistance to permanent indentation) of dense HA bioceramics is within 3–7 GPa, while the Poisson’s ratio (the ratio of the contraction or transverse strain to the extension or axial strain) for HA is about 0.27, which is close to that of bones (~0.3). At temperatures within 1000–1100 °C, dense HA bioceramics were found to exhibit superplasticity with a deformation mechanism based on grain boundary sliding [312,352,353]. Furthermore, both wear resistance and friction coefficient of dense HA bioceramics are comparable to those of dental enamel [331].
Due to a high brittleness (associated with a low crack resistance), the biomedical applications of CaPO4 bioceramics are focused on production of non-load-bearing implants, such as pieces for middle ear surgery, filling of bone defects in oral or orthopedic surgery, and coating of dental implants and metallic prosthesis (see below) [62,354,355]. Therefore, methods are continuously sought to improve the reliability of CaPO4 bioceramics. Namely, the mechanical properties of sintered bioceramics might be improved by changing the morphology of the initial CaPO4 [356]. In addition, diverse reinforcements (ceramics, metals, or polymers) have been applied to manufacture various biocomposites and hybrid biomaterials [357], but that is another story. However, successful hybrid formulations consisting of CaPO4 only [358,359,360,361,362,363,364,365] are within the scope of this review. Namely, bulk HA bioceramics might be reinforced by HA whiskers [359,360,361,362,363]. Furthermore, various biphasic apatite/TCP formulations were tested [358,364,365] and, for example, a superior superplasticity of HA/β-TCP biocomposites to HA bioceramics was detected [364].
Another method to improve the mechanical properties of CaPO4 bioceramics is to cover the items by polymeric coatings [366,367,368] or infiltrate porous structures by polymers [369,370,371]; however, this is another topic. Other approaches are also possible [154]. Further details on the mechanical properties of CaPO4 bioceramics are available elsewhere [330,331,372], where interested readers are referred.

4.2. Electric/Dielectric and Piezoelectric Properties

Recently, an interest in both electric/dielectric [301,373,374,375,376,377,378,379,380,381,382,383,384,385] and piezoelectric [386,387] properties of CaPO4 bioceramics has been expressed. In addition, some types of CaPO4 bioceramics (namely, HA) appear to be electrets [388,389]. An electret is a dielectric material that has a quasi-permanent electric charge or dipole polarization. An electret generates internal and external electric fields, and is the electrostatic equivalent of a permanent magnet [390]. For example, a surface ionic conductivity of both porous and dense HA bioceramics was examined for humidity sensor applications, since the room temperature conductivity was influenced by relative humidity [374]. Namely, the ionic conductivity of HA is a subject of research for its possible use as a gas sensor for alcohol [375], carbon dioxide [373,382], or carbon monoxide [378]. Electric measurements were also used as a characterization tool to study the evolution of microstructure in HA bioceramics [376]. More to the point, the dielectric properties of HA were examined to understand its decomposition to β-TCP [375]. In the case of CDHA, the electric properties, in terms of ionic conductivity, were found to increase after compression of the samples at 15 t/cm2, which was attributed to establishment of some order within the apatitic network [377]. The conductivity mechanism of CDHA appeared to be multiple [380]. Furthermore, there are attempts to develop HA and/or CDHA electrets for biomedical utilization [379,388,389].
The electric properties of CaPO4 bioceramics appear to influence their biomedical applications. For example, there is an interest in polarization of HA bioceramics to generate a surface charge by the applying a constant DC electric field of 0.5–10.0 kV/cm at elevated temperatures (300–1000 °C) to samples previously sintered at ~ 1000–1250 °C for ~2 h. This technique is called thermally stimulated polarization and its results indicated that the polarization effects were a consequence of electrical dipoles associated with the formation of defects inside crystal grains, such as thermally-induced OH vacancies, and of the space charge polarization that originated in the grain boundaries [391,392,393]. The presence of surface charges on HA was shown to have a significant effect on both in vitro and in vivo crystallization of biological apatite [394,395,396,397,398,399,400], as well as on an ability to adsorb various types of phosphate ions [393]. Furthermore, a growth of both biomimetic CaPO4 and bones was found to be accelerated on negatively charged surfaces and decelerated at positively charged surfaces [398,399,400,401,402,403,404,405,406,407]. A similar effect was found for adsorption of bovine serum albumin [408]. In addition, the electric polarization of CaPO4 was found to accelerate a cytoskeleton reorganization of osteoblast-like cells [409,410,411,412], extend bioactivity [413], enhance bone ingrowth through the pores of porous implants [414], and influence the cell activity [415,416]. The positive effect of electric polarization was found for carbonated apatite as well [417]. There is an interesting study on the interaction of a blood coagulation factor on electrically polarized HA surfaces [418]. Further details on the electric properties of CaPO4-based bioceramics are available in the literature [301,383,384,389].

4.3. Possible Transparency

Single crystals of all types of CaPO4 are optically transparent for the visible light. As bioceramics of CaPO4 have a polycrystalline nature with a random orientation of big amounts of small crystals, it is opaque and of white color, unless colored dopants have been added. However, in some cases, a transparency is convenient to provide some essential advantages (e.g., to enable direct viewing of living cells, their attachment, spreading, proliferation, and osteogenic differentiation cascade in a transmitted light). Thus, transparent CaPO4 bioceramics (Figure 6) [419] have been prepared and investigated [69,87,185,187,310,311,312,313,314,315,419,420,421,422,423,424,425,426,427]. They can exhibit an optical transmittance of ~66% at a wavelength of 645 nm [425]. The preparation techniques include a hot isostatic pressing [87,185,187,426], an ambient-pressure sintering [420], a gel casting coupled with a low-temperature sintering [421,424], and a pulse electric current sintering [422], as well as spark plasma [69,307,308,309,310,311,312,313,314,315] and flash [316,317] sintering techniques. Fully dense, transparent CaPO4 bioceramics are obtained at temperatures above ~800 °C. Depending on the preparation technique, the transparent bioceramics have a uniform grain size ranging from ~67 nm [87] to ~250 μm [421] and are always pore-free. Furthermore, translucent CaPO4 bioceramics are also known [87,263,428,429,430]. Concerning possible biomedical applications, the optically transparent in visible light CaPO4 bioceramics can be useful for direct viewing of other objects, such as cells, in some specific experiments [423]. In addition, the transparency for laser light CaPO4 bioceramics may appear to be convenient for minimal invasive surgery by allowing passing the laser beam through it to treat the injured tissues located underneath. However, due to a lack of both porosity and the necessity to have see-through implants inside the body, the transparent and translucent forms of CaPO4 bioceramics will hardly be extensively used in medicine, except for the aforementioned cases and possible eye implants.

4.4. Porosity

Porosity is defined as a percentage of voids in solids, and this morphological property is independent of the material. The surface area of porous bodies is much higher, which guarantees a good mechanical fixation in addition to providing sites on the surface that allow chemical bonding between the bioceramics and bones [431]. Furthermore, a porous material may have both closed (isolated) pores and open (interconnected) pores. The latter look similar to tunnels and are accessible by gases, liquids, and particulate suspensions [432]. The open-cell nature of porous materials (also known as reticulated materials) is a unique characteristic essential in many applications. In addition, pore dimensions are also important. Namely, the dimensions of open pores are directly related to bone formation, since such pores grant both the surface and space for cell adhesion and bone ingrowth [433,434,435]. On the other hand, pore interconnection provides the ways for cell distribution and migration, and it allows an efficient in vivo blood vessel formation suitable for sustaining bone tissue neo-formation and possibly remodeling [123,414,436,437,438,439,440]. Namely, porous CaPO4 bioceramics are colonized easily by cells and bone tissues [436,439,441,442,443,444,445,446]. Therefore, interconnecting macroporosity (pore size > 100 μm) [84,431,436,447,448] is intentionally introduced in solid bioceramics (Figure 7). Calcining of natural bones and teeth appears to be the simplest way to prepare porous CaPO4 bioceramics [7,8,9,10,11,12,13,14]. In addition, macroporosity might be formed artificially due to a release of various easily removable compounds and, for that reason, incorporation of pore-creating additives (porogens) is the most popular technique to create macroporosity. The porogens are crystals, particles, or fibers of either volatile (they evolve gases at elevated temperatures) or soluble substances. The popular examples comprise paraffin [449,450,451], naphthalene [328,452,453,454], sucrose [455,456], NaHCO3 [457,458,459], NaCl [460,461], polymethylmethacrylate [74,462,463,464], hydrogen peroxide [465,466,467,468], cellulose [469], and its derivatives [64]. Several other compounds [338,470,471,472,473,474,475,476,477], including carbon nanotubes [478], might be used as porogens as well. The ideal porogen should be nontoxic and be removed at ambient temperature, thereby allowing the bioceramic/porogen mixture to be injected directly into a defect site and allowing the scaffold to fit the defect [479]. Sintering particles, preferably spheres of equal size, is a similar way to generate porous 3D bioceramics of CaPO4; however, pores resulting from this method are often irregular in size and shape and not fully interconnected with one another. Schematic drawings of various types of the ceramic porosity are shown in Figure 8 [480]. One should note that 3D-printing techniques allow producing structures with tailored pore orientations by changing framework directions in a controlled, periodic pattern (Figure 9) [481].
Many other techniques, such as replication of polymer foams by impregnation [219,220,221,224,482,483,484,485,486] (Figure 7), various types of casting [202,203,207,209,468,487,488,489,490,491,492,493,494,495], suspension foaming [101], surfactant washing [496], microemulsions [497,498], and ice templating [499,500,501,502], as well as many other approaches [68,71,74,75,140,503,504,505,506,507,508,509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528], have been applied to fabricate porous CaPO4 bioceramics. Some of them are summarized in Table 2 [479]. In addition, both natural CaCO3 porous materials, such as coral skeletons [529,530], shells [530,531], and even wood [532], as well as artificially prepared ones [533], can be converted into porous CaPO4 under the hydrothermal conditions (250 °C, 24–48 h) with the microstructure undamaged. Porous HA bioceramics can also be obtained by hydrothermal hot pressing. This technique allows solidification of the HA powder at 100–300 °C (30 MPa, 2 h) [320]. In another approach, bi-continuous water-filled microemulsions are used as preorganized systems for the fabrication of needle-like frameworks of crystalline HA (2 °C, 3 weeks) [497,498]. In addition, porous CaPO4 might be prepared by a combination of gel casting and foam burn out methods [243,245], as well as by hardening of the self-setting formulations [450,451,458,459,460,461,520]. Lithography was used to print a polymeric material, followed by packing with HA and sintering [507]. Hot pressing was applied as well [292,293]. More to the point, an HA suspension can be cast into a porous CaCO3 skeleton, which is then dissolved, leaving a porous network [503]. A 3D periodic macroporous frame of HA was fabricated via a template-assisted colloidal processing technique [509,512]. In addition, porous HA bioceramics might be prepared by using different starting HA powders and sintering at various temperatures by a pressureless sintering [505]. Porous bioceramics with an improved strength might be fabricated from CaPO4 fibers or whiskers. In general, fibrous porous materials are known to exhibit an improved strength due to fiber interlocking, crack deflection, and/or pullout [534]. Namely, porous bioceramics with well-controlled open pores were processed by sintering of fibrous HA particles [504]. In another approach, porosity was achieved by firing apatite-fiber compacts mixed with carbon beads and agar. By varying the compaction pressure, firing temperature and carbon/HA ratio, the total porosity was controlled in the ranges from ~40% to ~85% [64]. Finally, a superporous (~85% porosity) HA bioceramic was developed as well [515,517,518]. Additional information on the processing routes to produce porous ceramics can be found in the literature [535].
Bioceramic microporosity (pore size < 10 μm), which is defined by its capacity to be impregnated by biological fluids [536], results from the sintering process, while the pore dimensions mainly depend on the material composition, thermal cycle, and sintering time. The microporosity provides both a greater surface area for protein adsorption and increased ionic solubility. For example, embedded osteocytes distributed throughout microporous rods might form a mechanosensory network, which would not be possible in scaffolds without microporosity [537,538]. CaPO4 bioceramics with nanodimensional (<100 nm) pores might be fabricated as well [539,540,541,542,543]. It is important to stress that differences in porogens usually influence the bioceramics’ macroporosity, while differences in sintering temperatures and conditions affect the percentage of microporosity. Usually, the higher the sintering temperature, the lower both the microporosity content and the specific surface area of bioceramics. Namely, HA bioceramics sintered at ~1200 °C show significantly less microporosity and a dramatic change in crystal sizes, if compared with those sintered at ~1050 °C (Figure 10) [544]. Furthermore, the average shape of pores was found to transform from strongly oblate to round at higher sintering temperatures [545]. The total porosity (macroporosity + microporosity) of CaPO4 bioceramics was reported to be ~70% [546] or even ~85% [515,517,518] of the entire volume. In the case of coralline HA or bovine-derived apatites, the porosity of the original biologic material (coral or bovine bone) is usually preserved during processing [547]. To finalize the production topic, creation of the desired porosity in CaPO4 bioceramics is a rather complicated engineering task and interested readers are referred to the additional publications on the subject [338,435,519,548,549,550,551,552,553].
Regarding the biomedical importance of porosity, studies revealed that increasing of both the specific surface area and pore volume of bioceramics might greatly accelerate the in vivo process of apatite deposition and, therefore, enhance the bone-forming bioactivity. More importantly, a precise control over the porosity, pore dimensions, and internal pore architecture of bioceramics on different length scales is essential for understanding the structure–bioactivity relationship and the rational design of better bone-forming biomaterials [551,554,555]. Namely, in antibiotic charging experiments, CaPO4 bioceramics with nanodimensional (<100 nm) pores showed a much higher charging capacity (1621 μg/g) than those of commercially available CaPO4 (100 μg/g), which did not contain nanodimensional porosity [549]. In other experiments, porous blocks of HA were found to be viable carriers with sustained release profiles for drugs [556] and antibiotics over 12 days [557] and 12 weeks [558], respectively. Unfortunately, porosity significantly decreases the strength of implants [334,339,372]. Thus, porous CaPO4 implants cannot be loaded and are used to fill only small bone defects; however, their strength increases gradually when bones ingrow into the porous network of CaPO4 implants [119,559,560,561,562]. For example, bending strengths of 4–60 MPa for porous HA implants filled with 50%–60% of cortical bone were reported [559], while in another study an ingrown bone increased strength of porous HA bioceramics by a factor of three to four [561].
Unfortunately, the biomedical effects of bioceramics’ porosity are not straightforward. For example, the in vivo response of CaPO4 to different porosity was investigated, and a hardly any effect of macropore dimensions (~150, ~260, ~510, and ~1220 μm) was observed [563]. In another study, a greater differentiation of mesenchymal stem cells was observed when cultured on ~200 μm pore size HA scaffolds when compared to those on ~500 μm pore size HA [564]. The latter finding was attributed to the fact that a higher pore volume in ~500 μm macropore scaffolds might contribute to a lack of cell confluency, leading to the cells proliferating before beginning differentiation. In addition, the authors hypothesized that bioceramics having less than the optimal pore dimensions induced quiescence in differentiated osteoblasts due to reduced cell confluency [564]. In still another study, the use of BCP (HA/TCP = 65/35 wt.%) scaffolds with cubic pores of ~500 μm resulted in the highest bone formation compared with the scaffolds with lower (~100 μm) or higher (~1000 μm) pore sizes [565]. Furthermore, CaPO4 bioceramics with greater strut porosity appeared to be more osteoinductive [566]. As early as 1979, Holmes suggested that the optimal pore range was 200–400 μm with the average human osteon size of ~223 μm [567]. In 1997, Tsurga and coworkers implied that the optimal pore size of bioceramics that supported ectopic bone formation was 300–400 μm [568]. Thus, there is no need to create CaPO4 bioceramics with very big pores; however, the pores must be interconnected [437,447,448,569]. Interconnectivity governs a depth of cells or tissue penetration into the porous bioceramics, and it allows development of blood vessels required for new bone nourishing and wastes removal [570,571]. Nevertheless, the total porosity of implanted bioceramics appears to be important. For example, 60% porous β-TCP granules achieved a higher bone fusion rate than 75% porous β-TCP granules in lumbar posterolateral fusion [537].
More details on the importance of CaPO4 bioceramics porosity on bone regeneration are available in a topical review [572].

5. Biological Properties and In Vivo Behavior

The most important differences between bioactive bioceramics and all other implanted materials comprise inclusion in the metabolic processes of the organism, adaptation of either surface or the entire material to the biomedium, integration of a bioactive implant with bone tissues at the molecular level, or the complete replacement of a resorbable bioceramics by healthy bone tissues. All of the enumerated processes are related to the effect of an organism on the implant. Nevertheless, another aspect of implantation is also important—the effect of the implant on the organism. For example, use of bone implants from corpses or animals, even after they have been treated in various ways, provokes a substantially negative immune reaction in the organism, which substantially limits the application of such implants. In this connection, it is useful to dwell on the biological properties of bioceramic implants, particularly those of CaPO4, which in the course of time may be resorbed completely [573].

5.1. Interactions with Surrounding Tissues and the Host Responses

All interactions between implants and the surrounding tissues are dynamic processes. Water, dissolved ions, various biomolecules, and cells surround the implant surface within the initial few seconds after the implantation. It is accepted that no foreign material placed inside a living body is completely compatible. The only substances that conform completely are those manufactured by the body itself (autogenous), while any other substance, which is recognized as foreign, initiates some types of reactions (a host-tissue response). The reactions occurring at the biomaterial/tissue interfaces lead to time-dependent changes in the surface characteristics of both the implanted biomaterials and the surrounding tissues [58,574].
In order to develop new biomaterials, it is necessary to understand the in vivo host responses. Similar to any other species, biomaterials and bioceramics react chemically with their environment and, ideally, they should neither induce any changes nor provoke undesired reactions in the neighboring or distant tissues. In general, living organisms can treat artificial implants as biotoxic (or bioincompatible [53]), bioinert (or biostable [47]), biotolerant (or biocompatible [53]; however, this term appears to be questionable [575]), and bioactive and bioresorbable materials [1,2,3,42,43,50,51,52,53,573,574,576]. Biotoxic (e.g., alloys containing cadmium, vanadium, lead, and other toxic elements) materials release to the body substances in toxic concentrations and/or trigger the formation of antigens that may cause immune reactions ranging from simple allergies to inflammation to septic rejection with the associated severe health consequences. They cause atrophy, pathological change, or rejection of living tissue near the material as a result of chemical, galvanic, or other processes. Bioinert (this term should be used with care, since it is clear that any material introduced into the physiological environment will induce a response; however, for the purposes of biomedical implants, the term can be defined as a minimal level of response from the host tissue), such as zirconia, alumina, carbon, and titanium, as well as biotolerant (e.g., polymethylmethacrylate, titanium, and Co–Cr alloy), materials do not release any toxic constituents but also do not show positive interaction with living tissue. They evoke a physiological response to form a fibrous capsule, thus isolating the material from the body. In such cases, thickness of the layer of fibrous tissue separating the material from other tissues of an organism can serve as a measure of bioinertness. Generally, both bioactivity and bioresorbability phenomena are fine examples of chemical reactivity, and CaPO4 (both nonsubstituted and ion-substituted ones) fall into these two categories of bioceramics [1,2,3,42,43,50,51,52,53,573,574,576]. A bioactive material will dissolve slightly but promote formation of a surface layer of biological apatite before interfacing directly with the tissue at the atomic level, that results in formation of direct chemical bonds to bones. Such implants provide a good stabilization for materials that are subject to mechanical loading. A bioresorbable material will dissolve over time (regardless of the mechanism leading to the material removal) and allow a newly formed tissue to grow into any surface irregularities, but may not necessarily interface directly with the material. Consequently, the functions of bioresorbable materials are to participate in dynamic processes of formation and reabsorption occurring in bone tissues; thus, bioresorbable materials are used as scaffolds or filling spacers, allowing the tissues their infiltration and substitution [180,576,577,578,579].
It is important to stress that a distinction between the bioactive and bioresorbable bioceramics might be associated with structural factors only. Namely, bioceramics made from nonporous, dense, and highly crystalline HA behave as bioinert (but a bioactive) materials and are retained in an organism for at least 5–7 years without noticeable changes (Figure 2 bottom), while highly porous bioceramics of the same composition can be resorbed approximately within a year. Furthermore, submicron-sized HA powders are biodegraded even faster than the highly porous HA scaffolds. Other examples of bioresorbable materials comprise porous bioceramic scaffolds made of biphasic, triphasic, or multiphasic CaPO4 formulations [79] or bone grafts (dense or porous) made of CDHA [121], TCP [74,580,581], and/or ACP [470,582]. One must note that at the beginning of the 2000s, the concepts of bioactive and bioresorbable materials were converged and bioactive materials were made bioresorbable, while bioresorbable ones were made bioactive [583].
Although in certain in vivo experiments inflammatory reactions were observed after implantation or injection of CaPO4 [584,585,586,587,588,589,590,591,592,593], the general conclusion on using CaPO4 with Ca/P ionic ratio within 1.0–1.7 is that all types of implants (bioceramics of various porosities and structures, powders, or granules) are not only nontoxic but also induce neither inflammatory nor foreign-body reactions [108,571,594]. The biological response to implanted CaPO4 follows a similar cascade to that observed in fracture healing. This cascade includes a hematoma formation, inflammation, neovascularization, osteoclastic resorption, and a new bone formation. An intermediate layer of fibrous tissue between the implants and bones has been never detected. Furthermore, CaPO4 implants display the ability to directly bond to bones [1,2,3,42,43,50,51,52,53,573,574,576]. For further details, interested readers are referred to a good review on cellular perspectives of bioceramic scaffolds for bone tissue engineering [479].
One should note that the aforementioned rare cases of the inflammatory reactions to CaPO4 bioceramics were often caused by “other” reasons. For example, a high rate of wound inflammation occurred when highly porous HA was used. In that particular case, the inflammation was explained by sharp implant edges, which irritated surrounding soft tissues [585]. To avoid this, only rounded material should be used for implantation (Figure 11) [595]. Another reason for inflammation produced by porous HA could be due to micro movements of the implants, leading to simultaneous disruption of a large number of microvessels, which grow into the pores of the bioceramics. This would immediately produce an inflammatory reaction. Additionally, problems could arise in clinical tests connected with migration of granules used for alveolar ridge augmentation, because it might be difficult to achieve a mechanical stability of implants at the implantation sites [585]. In addition, presence of calcium pyrophosphate impurity might be the reason for inflammation [588]. Additional details on inflammatory cell responses to CaPO4 can be found in a special review on this topic [589].

5.2. Osteoinduction

Until recently, it was generally considered that, alone, no type of synthetic bioceramic possessed either osteogenic (osteogenesis is the process of laying down new bone material by osteoblasts [596]) or osteoinductive (the property of the material to induce bone formation de novo or ectopically (i.e., in non-bone-forming sites) [596]) properties, and they demonstrated a minimal immediate structural support. However, a number of reports have already shown the osteoinductive properties of certain types of CaPO4 bioceramics [544,566,597,598,599,600,601,602,603,604,605], and the amount of such publications is rapidly increasing. For example, bone formation was found to occur in dog muscle inside porous CaPO4 with surface microporosity, while bone was not observed on the surface of dense bioceramics [601]. Furthermore, implantation of porous β-TCP bioceramics appeared to induce bone formation in soft tissues of dogs, while no bone formation was detected in any α-TCP implants [598]. More to the point, titanium implants coated with a microporous layer of OCP were found to induce ectopic bone formation in goat muscles, while a smooth layer of carbonated apatite on the same implants was not able to induce bone formation there [599,600]. In another study, β-TCP powder, biphasic (HA + β-TCP) powder, and intact biphasic (HA + β-TCP) rods were implanted into leg muscles of mice and dorsal muscles of rabbits [606]. One month and three months after implantation, samples were harvested for biological and histological analysis. New bone tissues were observed in 10 of 10 samples for β-TCP powder, 3 of 10 samples for biphasic powder, and 9 of 10 samples for intact biphasic rods at the third month in mice, but not in rabbits. The authors concluded that the chemical composition was the prerequisite in osteoinduction, while porosity contributed to more bone formation [606]. Therefore, researchers had already discovered the methods to prepare osteoinductive CaPO4 bioceramics.
Unfortunately, the underlying mechanism(s) leading to bone induction by synthetic materials remains largely unknown. Nevertheless, besides the specific genetic factors [604] and chosen animals [606], the dissolution/precipitation behavior of CaPO4 [607], their particle size [608,609], microporosity [572,603,610,611,612,613,614], physicochemical properties [601,603], composition [606], the specific surface area [614], and nanostructure [605], as well as the surface topography and geometry [602,615,616,617,618,619,620,621] have been pointed out as the relevant parameters [617]. A positive effect of increased microporosity on the ectopic bone formation could be both direct and indirect. Firstly, an increased microporosity is directly related to the changes in surface topography, i.e., it increases surface roughness, which affects the cellular differentiation [619]. Secondly, an increased microporosity indirectly means a larger surface that is exposed to the body fluids, leading to elevated dissolution/precipitation phenomena, as compared to non-microporous surfaces. In addition, other hypotheses are also available, namely, Reddi explained the apparent osteoinductive properties as an ability of particular bioceramics to concentrate bone growth factors, which are circulating in biological fluids, and those growth factors induce bone formation [615]. Other researchers proposed a similar hypothesis, that the intrinsic osteoinduction by CaPO4 bioceramics is a result of adsorption of osteoinductive substances on their surface [602]. Moreover, Ripamonti [616] and Kuboki et al. [617] independently postulated that the geometry of CaPO4 bioceramics is a critical parameter in bone induction. Specifically, bone induction by CaPO4 was never observed on flat bioceramic surfaces. All osteoinductive cases were observed on either porous structures or structures that contained well-defined concavities. Furthermore, bone formation was never observed on the peripheries of porous implants and was always found inside the pores or concavities, aligning the surface [180]. Some researchers speculated that a low oxygen tension in the central region of implants might provoke a dedifferentiation of pericytes from blood microvessels into osteoblasts [622]. Finally, yet importantly, both nanostructured rough surfaces and a surface charge on implants were found to cause an asymmetrical division of the stem cells into osteoblasts, which is important for osteoinduction [613]. Additional details on this topic are available in the literature [623].
Nevertheless, to finalize this topic, it is worth citing a conclusion made by Boyan and Schwartz [624]: “Synthetic materials are presently used routinely as osteoconductive bone graft substitutes, but before purely synthetic materials can be used to treat bone defects in humans where an osteoinductive agent is required, a more complete appreciation of the biology of bone regeneration is needed. An understanding is needed of how synthetic materials modulate the migration, attachment, proliferation and differentiation of mesenchymal stem cells, how cells on the surface of a material affect other progenitor cells in the peri-implant tissue, how vascular progenitors can be recruited and a neovasculature maintained, and how remodeling of newly formed bone can be controlled.” (p. 9).

5.3. Biodegradation

Shortly after implantation, a healing process is initiated by compositional changes of the surrounding bio-fluids and adsorption of biomolecules. Following this, various types of cells reach the CaPO4 surface, and the adsorbed layer dictates the ways the cells respond. Further, a biodegradation (which can be envisioned as an in vivo process by which an implanted material breaks down into either simpler components or components of the smaller dimensions) of the implanted CaPO4 bioceramics begins. This process can occur by three possible ways: (1) physical: due to abrasion, fracture and/or disintegration; (2) chemical: due to physicochemical dissolution of the implanted phases of CaPO4 with a possibility of phase transformations into other phases of CaPO4, as well as their precipitation; and (3) biological: due to cellular activity (so called, bioresorption). In biological systems, all these processes take place simultaneously and/or in competition with each other. For example, authors of interesting in vivo studies on a rat calvarial repair model showed that HA bioceramics degraded first, followed by diffusion of the degraded product, which was reconstructed to form new HA to repair the bone defect [625].
Since the existing CaPO4 are differentiated by Ca/P ratio, basicity/acidity, and solubility (Table 1), in the first instance, their degradation kinetics and mechanisms depend on the chosen type of CaPO4 [626,627]. Given the fact that dissolution is a physical chemistry process, it is controlled by some factors, such as CaPO4 solubility, surface area to volume ratio, local acidity, fluid convection, and temperature. For HA and FA, the dissolution mechanism in acids has been described by a sequence of four successive chemical equations, in which several other CaPO4, such as TCP, DCPD/DCPA and MCPM/MCPA, appear as virtual intermediate phases [628,629].
With a few exceptions, dissolution rates of CaPO4 are inversely proportional to the Ca/P ratio (except for TTCP), phase purity, and crystalline size, and they are also directly related to both the porosity and the surface area. In addition, phase transformations might occur with DCPA, DCPD, OCP, α-TCP, β-TCP, and ACP because they are unstable in aqueous environments under the physiological conditions [630]. Bioresorption is a biological process mediated by cells (mainly osteoclasts and, to a lesser extent, macrophages) [631,632]. In vitro, this process may be followed up by various techniques, such as a spherical instrumented indentation [633]. Bioresorption depends on the response of cells to their environment. Osteoclasts attach firmly to the implant and dissolve CaPO4 by secreting an enzyme carbonic anhydrase or any other acid, leading to a local pH drop to ~4–5 [634]. Formation of multiple spine-like crystals at the exposed areas of β-TCP was discovered [635]. Furthermore, nanodimensional particles of CaPO4 can also be phagocytosed by cells, i.e., they are incorporated into cytoplasm and thereafter dissolved by acid attack and/or enzymatic processes [636]. A study is available [637] in which a comparison was made between the solubility and osteoclastic resorbability of three types of CaPO4 (DCPA, ACP, and HA) + β-calcium pyrophosphate (β-CPP) powders having the monodisperse particle size distributions. The authors discovered that with the exception of β-CPP, the difference in solubility among different calcium phosphates became neither mitigated nor reversed but augmented in the resorptive osteoclastic milieu. Namely, DCPA (the phase with the highest solubility) was resorbed more intensely than any other calcium phosphate, whereas HA (the phase with the lowest solubility) was resorbed the least. Β-CPP became retained inside the cells for the longest period of time, indicating hindered digestion of only this particular type of calcium phosphate. Genesis of osteoclasts was found to be mildly hindered in the presence of HA, ACP, and DCPA, but not in the presence of β-CPP. HA appeared to be the most viable compound with respect to the mitochondrial succinic dehydrogenase activity. The authors concluded that chemistry did have a direct effect on biology, while biology neither overrode nor reversed the chemical propensities of calcium phosphates with which it interacted, but rather augmented and took a direct advantage of them [637]. Similar conclusions on both the resorbability and dissolution behavior of OCP, β-TCP, and HA [630], as well as β-TCP, BCP (HA + β-TCP), and HA [638], were made by other researchers. In addition, in vivo biodegradation of MCPA was found to be faster than that of bovine HA [639]. Thus, one can conclude that in vivo biodegradation kinetics of CaPO4 seem to correlate well with their solubility. Nevertheless, one must keep in mind that this is a very complicated combination of various nonequilibrium processes, occurring simultaneously and/or in competition with each other [640].
Strictly speaking, the processes that happen in vitro do not necessarily represent the ones occurring in vivo and vice versa; nevertheless, in vitro experiments are widely performed. Usually, an in vitro biodegradation of CaPO4 bioceramics is simulated by suspending the material in a slightly acidic (pH~4) buffer and monitoring the release of major ions with time [627,641,642,643,644]. An acidic buffer, to some extent, mimics the acidic environment during osteoclastic activity. The authors of one study reviewed the available literature on acellular in vitro resorption of CaPO4 bioceramics and found the following [645]: “The materials were certainly processed under different conditions, but this dispersion of data is also due to the large variety of tests performed. In fact, each work differs from the others in the type of sample (i.e., composition, shape, porosity, dimension.), of immersion condition (i.e., kind of solution, quantity, stirring, refresh.) and of performed analysis (i.e., microstructural, physicochemical, mechanical) and testing conditions. However, all these aspects can affect the final results.” (p. 912). Further, the authors of that paper performed in vitro resorption of DCPD and β-TCP samples in TRIS and PBS solutions for different times with or without refresh of the medium and demonstrated the importance of choosing the appropriate immersion conditions according to the phenomenon being investigated (i.e., CaPO4 dissolution, precipitation of new phases, etc.) [645].
For example, in vivo behavior of porous β-TCP bioceramics prepared from rod-shaped particles and those prepared from non-rod-shaped particles in the rabbit femur was compared. Although the porosities of both types of β-TCP bioceramics were almost the same, a more active osteogenesis was preserved in the region where rod-shaped bioceramics were implanted [646]. Furthermore, the dimensions of both the particles [608] and the surface microstructure [607] were found to influence the osteoinductive potential of CaPO4 bioceramics. These results implied that the microstructure affected the activity of bone cells and subsequent bone replacement.
In addition, a quantitative and fast method was developed to measure the chemical changes occurring within the pores of β-TCP granules incubated in a simulated body fluid [647]. A factorial design of experiments revealed that the particle size, specific surface area, microporosity, and purity of the β-TCP granules influenced the chemical composition of the solution. Large pH, calcium, and phosphate concentration changes were observed inside the granules and lasted for several days. The kinetics and magnitude of these changes (up to 2 pH units) largely depended on the processing and properties of the granules. Small particles, low sintering temperature, high microporosity, and the presence of HA impurity magnified the intensity and duration of pH, calcium, and phosphate variations [647].
Regarding in vivo studies, terbium (Tb)-doped uniform nanodimensional CDHA crystals were implanted into bone tissue and compared with those of native bone apatite. The comparisons demonstrated an occurrence of compositional and structural alterations of the implanted CDHA crystals and their gradual degradation during bone reconstruction. They also revealed notable differences between implanted Tb-doped CDHA and bone apatite crystals in dimensions, distribution pattern, and state of existence in bone tissue. The authors concluded that although synthetic nanodimensional CDHA crystals could osteointegrate with bone tissue, they still seemed to be treated as foreign material and thus were gradually degraded [648].
The experimental results demonstrated that both the dissolution kinetics and in vivo biodegradation of biologically relevant CaPO4 proceed in the following decreasing order: β-TCP > bovine bone apatite (unsintered) > bovine bone apatite (sintered) > coralline HA > HA. In the case of biphasic (HA + TCP), triphasic, and multiphasic CaPO4 formulations, the biodegradation kinetics depend on the HA/TCP ratio: the higher the ratio, the lower the degradation rate. Similarly, the in vivo degradation rate of biphasic TCP (α-TCP + β-TCP) bioceramics appeared to be lower than that of α-TCP and higher than that of β-TCP bioceramics, respectively [93]. Furthermore, incorporation of doping ions can either increase (e.g., CO32−, Mg2+, or Sr2+) or decrease (e.g., F) the solubility (therefore, biodegradability) of CDHA and HA. Contrarily to apatites, solubility of β-TCP is decreased by incorporation of either Mg2+ or Zn2+ ions [544]. Here, one should remember that ion-substituted CaPO4 are not considered in this review; the interested readers are advised to read the original publications [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41].

5.4. Bioactivity

Generally, bioactive materials interact with surrounding bone, resulting in formation of a chemical bond to this tissue (bone bonding). The bioactivity phenomenon is determined by both chemical factors, such as crystal phases and molecular structures of a biomaterial, and physical factors, such as surface roughness and porosity. Currently, it is agreed that the newly formed bone bonds directly to biomaterials through a carbonated CDHA layer precipitating at the bone/biomaterial interface. Strangely enough, a careful search of the literature resulted in just a few publications [544,623,649,650,651] where the bioactivity mechanism of CaPO4 was briefly described. For example, the chemical changes occurring after exposure of a synthetic HA bioceramic to both in vivo (implantation in human) and in vitro (cell culture) conditions were studied. A small amount of HA was phagocytozed but the major remaining part behaved as a secondary nucleator, as evidenced by the appearance of a newly formed mineral [649]. In vivo, cellular activity (e.g., of macrophages or osteoclasts; however, this may depend on the cellular origin [652]) associated with an acidic environment was found to result in partial dissolution of CaPO4, causing liberation of calcium and orthophosphate ions to the microenvironment. The liberated ions increased the local supersaturation degree of the surrounding biologic fluids, causing precipitation of nanosized crystals of biological apatite with simultaneous incorporating of various ions present in the fluids. Infrared spectroscopic analyses demonstrated that these nanodimensional crystals were intimately associated with bioorganic components (probably proteins), which might also have originated from the biologic fluids, such as serum [544]. However, in 2019, the concept of a local supersaturation degree that caused CaPO4 precipitation was criticized: on the contrary, intrinsic osteoinduction was proposed to be the result of calcium and/or phosphate depletion (blood supply must be insufficient to maintain the physiological calcium and/or phosphate ion concentrations) [623].
Therefore, one should consider the bioactivity mechanism of other biomaterials, particularly of bioactive glasses—the concept introduced by Prof. Larry L. Hench [50,51]. The bonding mechanism of bioactive glasses to living tissues involves a sequence of 11 successive reaction steps (Figure 12), some of which comprise CaPO4. The initial five steps occurring on the surface of bioactive glasses are “chemistry” only, while the remaining six steps belong to “biology” because the latter include colonization by osteoblasts, followed by proliferation and differentiation of the cells to form a new bone that has a mechanically strong bond to the implant surface. Therefore, in the case of bioactive glasses, the border between “dead” and “alive” is postulated between stages 5 and 6. According to Hench, all bioactive materials “form a bone-like apatite layer on their surfaces in the living body and bond to bone through this apatite layer. The formation of bone-like apatite on artificial material is induced by functional groups, such as Si–OH (in the case of biological glasses), Ti–OH, Zr–OH, Nb–OH, Ta–OH, –COOH and –H2PO4 (in the case of other materials). These groups have specific structures revealing negatively charge and induce apatite formation via formations of an amorphous calcium compound, e.g., calcium silicate, calcium titanate and ACP” [50,51].
In addition, one should mention another set of 11 successive reaction steps for bonding mechanism of unspecified bioceramics, developed by Prof. Paul Ducheyne (Figure 13) [58]. One can see that the Ducheyne’s model is rather similar to that proposed by Hench; however, there are noticeable differences between them. For example, Ducheyne mentions ion exchange and structural rearrangement at the bioceramic/tissue interface (stage 3), as well as on interdiffusion from the surface boundary layer into bioceramics (stage 4) and deposition with integration into the bioceramics (stage 7), which are absent in the Hench’s model. On the other hand, Hench describes six biological stages (stages 6–11), while Ducheyne describes only four (stages 8–11). Both models were developed more than two decades ago and, to the best of my knowledge, remain unchanged since then. Presumably, both approaches have pro et contra of their own and, obviously, should be updated and/or revised. Furthermore, in the literature there are at least two other descriptions of the biological and cellular events occurring at the bone/implant interface [653,654]. Unfortunately, both of them comprise fewer stages. In 2010, one more hypothesis was proposed (Figure 14). For the first time, it describes reasonable surface transformations, happening with CaPO4 bioceramics (in that case, HA) shortly after the implantation [651]. However, one must note that the schemes displayed in Figure 12, Figure 13 and Figure 14 do not represent the real mechanisms, but are only descriptions of the observable events occurring at the CaPO4 interface after implantation. Furthermore, many events occur simultaneously; therefore, none of the schemes should be considered in terms of the strict time sequences.
An important study on formation of CaPO4 precipitates on various types of bioceramic surfaces in both simulated body fluid and rabbit muscle sites was performed [655]. The bioceramics were sintered porous solids, including bioglass, glass-ceramics, α-TCP, β-TCP, and HA. The ability to induce CaPO4 precipitation was compared among these types of bioceramics. The following conclusions were made: (1) OCP formation ubiquitously occurred on all types of bioceramic surfaces both in vitro and in vivo, except on β-TCP. (2) Apatite formation did not occur on every type of bioceramic surface; it was less likely to occur on the surfaces of HA and α-TCP. (3) Precipitation of CaPO4 on the bioceramic surfaces was more difficult in vivo than in vitro. (4) Differences in CaPO4 precipitation among the bioceramic surfaces were less noticeable in vitro than that in vivo. (5) β-TCP bioceramics showed poor ability of CaPO4 precipitation both in vitro and in vivo [655]. These findings clearly revealed that apatite formation in the physiological environments could not be confirmed as the common feature of bioceramics. Nevertheless, for want of anything better, currently, the bioactivity mechanism of CaPO4 bioceramics should be described by a reasonable combination of Figure 12, Figure 13 and Figure 14, e.g., by updating the Ducheyne’s and Hench’s models with the three initial stages taken from Figure 14. Additional details on this topic are available in the literature [656].
Interestingly, bioactivity of HA bioceramics might be enhanced by a high-energy ion irradiation [657]. The effect was attributed to formation of a unique 3D macroporous apatite layer of decreased crystallinity and crystal size on the irradiated surfaces. Obviously, to obtain further insights into the bioactivity phenomenon, the atomic and molecular processes occurring at the bioceramic surface in aqueous solutions and their effects on the relevant reaction pathways of cells and tissues must be elucidated in more details.

5.5. Cellular Response

Fixation of any implants in the body is a complex dynamic process that remodels the interface between the implants and living tissues at all dimensional levels, from the molecular up to the cell and tissue morphology level, and at all time scales, from the first second up to several years after implantation. Immediately following the implantation, a space filled with biological fluids appears next to the implant surface. With time, cells are adsorbed at the implant surface that will give rise to their proliferation and differentiation towards bone cells, followed by revascularization and eventual gap closing. Ideally, a strong bond is formed between the implants and surrounding tissues [53]. An interesting study on the interfacial interactions between calcined HA and substrates was performed [658], where the interested readers are referred for further details.
The aforementioned paragraph clearly demonstrates the importance of studies on cellular responses to CaPO4 bioceramics. Such investigations have been performed extensively for several decades [589,659,660,661,662,663,664,665,666,667,668,669,670,671]. For example, bioceramic discs made of seven different types of CaPO4 (TTCP, HA, carbonate apatite, β-TCP, α-TCP, OCP, and DCPD) were incubated in osteoclastic cell cultures for 2 days. In all cases, similar cell morphologies and good cell viability were observed; however, different levels of resorbability of various types of CaPO4 were detected [661]. Similar results were found for fluoridated HA coatings [663]. Chemical composition of CaPO4, which contributed to pH changes, and concentration of calcium ions in the medium were found to make up particularly significant factors for cellular responses; moreover, it was proved that the number of material types represented a further important aspect [670]. Experiments performed with human osteoblasts revealed that nanostructured bioceramics prepared from nanosized HA showed significant enhancement in mineralization compared to microstructured HA bioceramics [662]. In addition, the influence of lengths and surface areas of rod-shaped HA on cellular response were studied. Again, similar cell morphologies and good cell viability were observed; however, it was concluded that high surface area could increase cell–particle interaction [665]. Nevertheless, another study with cellular response to rod-shaped HA bioceramics revealed that some types of crystals might trigger a severe inflammatory response [666]. In addition, CaPO4-based sealers appeared to show fewer cytotoxicity and inflammatory mediators compared with other sealers [664]. More examples are available in the literature [589,659,660,661,662,663,664,665,666,667,668,669,670,671].
Cellular biodegradation of CaPO4 bioceramics is known to depend on its phases. For example, a higher solubility of β-TCP was shown to prevent L-929 fibroblast cell adhesion, thereby leading to damage and rupture of the cells [672]. A mouse ectopic model study indicated the maximal bone growth for the 80:20 β-TCP:HA biphasic formulations preloaded with human mesenchymal stem cells when compared to other CaPO4 [673]. The effects of substrate microstructure and crystallinity have been corroborated with an in vivo rabbit femur model, where rod-like crystalline β-TCP was reported to enhance osteogenesis when compared to non-rod-like crystalline β-TCP [649]. Additionally, using a dog mandibular defect model, a higher bone formation on a scaffold surface coated by nanodimensional HA was observed when compared to that coated by a microdimensional HA [674]. Furthermore, studies revealed a stronger stress signaling response by osteoblast precursor cells in 3D scaffolds when compared to 2D surfaces [675].
Mesenchymal stem cells are one of the most attractive cellular lines for application as bone grafts [676,677]. Early investigations by Okumura et al. indicated an adhesion, proliferation, and differentiation, which ultimately became new bone and integrated with porous HA bioceramics [660]. Later, a sustained coculture of endothelial cells and osteoblasts on HA scaffolds for up to 6 weeks was demonstrated [678]. Furthermore, a release of factors by endothelial and osteoblast cells in coculture-supported proliferation and differentiation was suggested to ultimately result in microcapillary-like vessel formation and supported a neo-tissue growth within the scaffold [479]. More to the point, investigation of rat calvaria osteoblasts cultured on transparent HA bioceramics, as well as the analysis of osteogenic-induced human bone marrow stromal cells at different time points of culturing, indicated a good cytocompatibility of HA bioceramics and revealed favorable cell proliferation [424]. Positive results for other types of cells were obtained in other studies [187,423,443,444,679,680,681]. In addition, CaPO4 are used for cell transfections [682].
Interestingly, HA scaffolds with marrow stromal cells in a perfused environment were reported to result in ~85% increase in mean core strength, a ~130% increase in failure energy, and a ~355% increase in post-failure strength. The increase in mineral quantity and promotion of the uniform mineral distribution in that study was suggested to be attributed to the perfusion effect [560]. Additionally, other investigators indicated mechanical properties increasing for other CaPO4 scaffolds after induced osteogenesis [559,562].
To finalize this subsection, one should note the recent developments to influence the cellular response. First, to facilitate interactions with cells, the CaPO4 surfaces could be functionalized [683,684,685,686]. Second, it appears that crystals of biological apatite of calcified tissues exhibit different orientations depending on the tissue; namely, in vertebrate bones and tooth enamel surfaces, the respective a, b-planes and c-planes of the apatite crystals are preferentially exposed. Therefore, ideally, this should be taken into account in artificial bone grafts. Recently, a novel process to fabricate dense HA bioceramics with highly preferred orientation to the a,b-plane was developed. The results revealed that increasing the a,b-plane orientation degree shifted the surface charge from negative to positive and decreased the surface wettability with simultaneous decreasing of cell attachment efficiency [687,688,689]. The latter finding resulted in further developments on preparation of oriented CaPO4 compounds [690,691,692].
Finally, to conclude the entire Biological Properties and in vivo Behavior section, let me quote several sentences from Ref. [265]: “Variations in surface chemistry resulting from variable thermal processing conditions of otherwise identical samples might thus explain inconsistencies in biological behavior reported in the literature. For instance, β-TCP has been reported to be both bioactive [693] and non-bioactive [655], non-osteoinductive [694] and highly osteoinductive [695,696], highly resorbable [694,697] and poorly resorbable [697]. Authors have related this dichotomous behavior with the effect of sintering temperature on specific surface area, bulk composition, and scaffold or pore topography.” (p. 6096). In addition, simple thermal treatment at 500 °C was found to reduce body reactions to irregular α- and β-TCP granules as foreign bodies, due to a partial evaporation of phosphate species during thermal treatment [698]. Thus, there are still many uncertainties in our understanding of the biological properties of CaPO4 bioceramics.

6. Biomedical Applications

Since Levitt et al. described a method of preparing FA bioceramics and suggested their possible use in medical applications in 1969 [699], CaPO4 bioceramics have been widely tested for clinical applications. Namely, over 400 forms, compositions, and trademarks (Table 3) are currently either in use or under consideration in many areas of orthopedics and dentistry [700], with even more in development. In addition, various formulations containing demineralized bone matrix (commonly abbreviated as DBM) are produced for bone grafting. For example, bulk materials, available in dense and porous forms, are used for alveolar ridge augmentation, immediate tooth replacement, and maxillofacial reconstruction [4,701]. Other examples comprise burr-hole buttons [702,703], cosmetic (nonfunctional) eye replacements such as Bio-Eye® [704,705,706,707,708,709], increment of the hearing ossicles [710,711,712], and spine fusion [713,714,715,716], as well as repair of bone [118,717,718], craniofacial [719], and dental [720] defects. In order to permit growth of new bone into defects, a suitable bioresorbable material should fill these defects. Otherwise, ingrowth of fibrous tissue might prevent bone formation within the defects.
In spite of the aforementioned serious mechanical limitations (see Section 4.1. Mechanical Properties), bioceramics of CaPO4 are available in various physical forms: powders, particles, granules (or granulates), dense blocks, porous scaffolds, self-setting formulations, implant coatings, and composite components of different origin (natural, biological, or synthetic), often with specific shapes, such as implants, prostheses, or prosthetic devices. In addition, CaPO4 are also applied as nonhardening injectable formulations [721,722,723,724,725,726] and pastes [726,727,728,729,730]. Generally, they consist of a mixture of CaPO4 powders or granules and a “glue”, which can be a highly viscous hydrogel. More to the point, custom-designed shapes such as wedges for tibial opening osteotomy, cones for spine and knee, and inserts for vertebral cage fusion are also available [546]. Various trademarks of the commercially available types of CaPO4-based bioceramics and biomaterials are summarized in Table 3, while their surgical applications are schematically shown in Figure 15 [731]. A long list of both trademarks and producers clearly demonstrates that CaPO4 bioceramics are easy to make and not very difficult to register for biomedical applications. There is an ISO standard for CaPO4-based bone substitutes [732].
One should note that among the existing CaPO4 (Table 1), only certain compounds are useful for biomedical applications, because those having a Ca/P ionic ratio less than 1 are not suitable for implantation due to their high solubility and acidity. Furthermore, due to its basicity, TTCP alone cannot be suitable either. Nevertheless, researchers try [141]. In addition, to simplify biomedical applications, these “of little use” CaPO4 can be successfully combined with either other types of CaPO4 or other chemicals.

6.1. Self-Setting (Self-Hardening) Formulations

The need for bioceramics for minimal invasive surgery has induced the concept of self-setting (or self-hardening) formulations consisting of CaPO4 only to be applied as injectable and/or moldable bone substitutes [102,103,124,507,733]. After hardening, they form bulk CaPO4 bioceramics. In addition, there are reinforced formulations that, in a certain sense, might be defined as CaPO4 concretes [102]. Furthermore, self-setting formulations able to produce porous bulk CaPO4 bioceramics are also available [450,451,458,459,460,461,507,520,733,734,735,736].
All types of the self-setting CaPO4 formulations belong to low-temperature bioceramics. They are divided into two major groups. The first one is a dry mixture of two different types of CaPO4 (a basic one and an acidic one), in which, after being wetted, the setting reaction occurs according to an acid–base reaction. The second group contains only one CaPO4, such as ACP with Ca/P molar ratio within 1.50–1.67 or α-TCP: both of them form CDHA upon contact with an aqueous solution [102,124]. Chemically, setting (= hardening, curing) is due to the succession of dissolution and precipitation reactions. Mechanically, it results from crystal entanglement and intergrowth (Figure 16) [737]. By influencing dimensions of forming CaPO4 crystals, it is possible to influence the mechanical properties of the hardened bulk bioceramics [738]. Sometimes, the self-set formulations are sintered to prepare high-temperature CaPO4 bioceramics [739]. Despite a large number of initial compositions, all types of self-setting CaPO4 formulations can form three products only: CDHA, DCPD, and, rarely, DCPA [102,103,124,507,733]. Special reviews on the topic are available in [102,103,739], where interested readers are referred for further details.

6.2. CaPO4 Deposits (Coatings, Films, and Layers)

For many years, the clinical application of CaPO4-based bioceramics has been largely limited to non-load-bearing parts of the skeleton due to their inferior mechanical properties. Therefore, materials with better mechanical properties appear to be necessary. For example, metallic implants are encountered in endoprostheses (total hip joint replacements) and artificial teeth sockets. As metals do not undergo bone bonding, i.e., they do not form a mechanically stable link between the implant and bone tissue, methods have been sought to improve contacts at the interface. One major method is to coat metals with CaPO4, which enables bonding ability between the metal and the bone [180,190,397,740,741,742].
A number of factors influence the properties of CaPO4 deposits (coatings, films, and layers). They include thickness (this will influence coating adhesion and fixation—the agreed optimum now seems to be within 50–100 µm), crystallinity (this affects the dissolution and biological behavior), phase and chemical purity, porosity, and adhesion. The coated implants combine the surface biocompatibility and bioactivity of CaPO4 with the core strength of strong substrates (Figure 17). Moreover, CaPO4 deposits decrease a release of potentially hazardous chemicals from the core implant and shield the substrate surface from environmental attack. In the case of porous implants, the CaPO4-coated surface enhances bone ingrowth into the pores [331]. The clinical results for CaPO4-deposited implants reveal that they have much longer lifetimes after implantation than uncoated devices and they are found to be particularly beneficial for younger patients. Further details on this topic are available in the special reviews [740,741,742].

6.3. Functionally Graded Bioceramics

In general, functionally gradient materials (FGMs) are defined as materials having either compositional or structural gradient from their surface to the interior. The idea of FGMs allows one device to possess two different properties. One of the most important combinations for the biomedical field is that of mechanical strength and biocompatibility. Namely, only surface properties govern a biocompatibility of the entire device. In contrast, the strongest material determines the mechanical strength of the entire device. Although this subject belongs to the previous section on coatings, films, and layers, in a certain sense, all types of implants covered by CaPO4 might be also considered as FGMs.
Within the scope of this review, functionally graded bioceramics consisting of CaPO4 are considered and discussed only. Such formulations have been developed [74,491,494,550,743,744,745,746,747,748,749,750,751,752,753]. For example, dense sintered bodies with gradual compositional changes from α-TCP to HA were prepared by sintering diamond-coated HA compacts at 1280 °C under a reduced pressure, followed by heating under atmospheric conditions [743]. The content of α-TCP gradually decreased, while the content of HA increased with increasing depth from the surface. This functionally gradient bioceramic consisting of HA core and α-TCP surface showed potential value as a bone-substituting biomaterial [743]. Two types of functionally gradient FA/β-TCP biocomposites were prepared in another study [744]. As shown in Figure 18, one of the graded biocomposites was in the shape of a disk and contained four different layers of about 1 mm thick. The other graded biocomposite was also in the shape of a disk but contained two sets of the four layers, each layer being 0.5 mm thick controlled by using a certain amount of the mixed powders. The final FA/β-TCP graded structures were formed at 100 MPa and sintered at 1300 °C for 2 h [744]. The same approach was used in yet another study, but HA was used instead of FA and CDHA was used instead of β-TCP [752]. CaPO4 coatings with graded crystallinity were prepared as well [748].
In addition, it is well known that a bone cross-section from cancellous to cortical bone is nonuniform in porosity and pore dimensions. Thus, in various attempts to mimic the porous structure of bones, CaPO4 bioceramics with graded porosity have been fabricated [74,432,478,491,494,550,743,744,745,746]. For example, graded porous CaPO4 bioceramics can be produced by means of tape casting and lamination (Figure 19, top). Other manufacturing techniques, such as a compression molding process (Figure 19, bottom) followed by impregnation and firing, are known as well [432]. In the first method, an HA slurry was mixed with a pore former. The mixed slurry was then cast into a tape. Using the same method, different tapes with different pore former sizes were prepared individually. The different tape layers were then laminated together. Firing was then performed to remove the pore formers and sinter the HA particle compacts, resulting in graded porous bioceramics [746]. This method was also used to prepare graded porous HA with a dense part (core or layer) in order to improve the mechanical strength, as dense ceramics are much stronger than porous ceramics. However, as in the pressure infiltration of mixed particles, this multiple tape casting also has the problem of poor connectivity of pores, although the pore size and the porosity are relatively easy to control. Furthermore, the lamination step also introduces additional discontinuity of the porosity on the interfaces between the stacked layers.
Since diverse biomedical applications require different configurations and shapes, the graded (or gradient) porous bioceramics can be grouped according to both the overall shape and the structural configuration [432]. The basic shapes include rectangular blocks and cylinders (or disks). For the cylindrical shape, there are configurations of dense core–porous layer, less porous core–more porous layer, dense layer–porous core, and less porous layer–more porous core. For the rectangular shape, in the gradient direction, i.e., the direction with varying porosity, pore size, or composition, there are configurations of porous top–dense bottom (same as porous bottom–dense top), porous top–dense center–porous bottom, dense top–porous center–dense bottom, etc. Concerning biomedical applications, a dense core–porous layer structure is suitable for implants of a high mechanical strength and with bone ingrowth for stabilization, whereas a less porous layer–more porous core configuration can be used for drug delivery systems. Furthermore, a porous top –dense bottom structure can be shaped into implants of articulate surfaces for wear resistance and with porous ends for bone ingrowth fixation, while a dense top–porous center–dense bottom arrangement mimics the structure of head skull. Further details on bioceramics with graded porosity can be found in the literature [432].

7. CaPO4 Bioceramics in Tissue Engineering

7.1. Tissue Engineering

Tissue/organ repair has been the ultimate goal of surgery from ancient times to nowadays [56,57]. The repair has traditionally taken two major forms: tissue grafting followed by organ transplantation, and alloplastic or synthetic material replacement. Both approaches, however, have limitations. Grafting requires second surgical sites with associated morbidity and is restricted by limited amounts of material, especially for organ replacement. Synthetic materials often integrate poorly with host tissue and fail over time due to wear and fatigue or adverse body response [754]. In addition, all modern artificial orthopedic implants lack three of the most critical abilities of living tissues: (i) self-repairing; (ii) maintaining of blood supply; (iii) self-modifying their structure and properties in response to external aspects such as a mechanical load [755]. It is needless to mention that bones not only possess all of these properties but, in addition, they are self-generating, hierarchical, multifunctional, nonlinear, composite, and biodegradable; therefore, the ideal artificial bone grafts must possess similar properties [62].
The last decades have seen a surge in creative ideas and technologies developed to tackle the problem of repairing or replacing diseased and damaged tissues, leading to the emergence of a new field in healthcare technology now referred to as tissue engineering, which might be defined as “the creation of new tissue for the therapeutic reconstruction of the human body, by the deliberate and controlled stimulation of selected target cells through a systematic combination of molecular and mechanical signals” [756]. Briefly, this is an interdisciplinary field that exploits a combination of living cells, engineering materials, and suitable biochemical factors (Figure 20) in a variety of ways to improve, replace, restore, maintain, or enhance living tissues and whole organs [757,758,759]. However, since two of three major components (namely, cells and biochemical factors) of the tissue engineering subject appear to be far beyond the scope of this review, the topic of bone tissue engineering that aims to mimic the in vivo bone regeneration processes in a laboratory environment is narrowed down to the engineering materials prepared from CaPO4 bioceramics only.
Regeneration, rather than a repair, is the central goal of any tissue engineering strategy; therefore, it aims to create tissues and organs de novo [758]. This field of science started more than two decades ago [760,761], and the famous publication by Langer and Vacanti [762] has greatly contributed to the promotion of tissue engineering research worldwide. The field of tissue engineering, particularly when applied to bone substitutes where tissues often function in a mechanically demanding environment [763,764,765], requires a collaboration of excellence in cell and molecular biology, biochemistry, material sciences, bioengineering, and clinical research [766]. For success, it is necessary that researchers with expertise in one area have an appreciation of the knowledge and challenges of the other areas. However, since the technical, regulatory, and commercial challenges might be substantial, the introduction of new products is likely to be slow [758].
Nowadays, tissue engineering is at full research potential due to the following key advantages: (i) the solutions it provides are long-term, much safer than other options, and cost-effective as well; (ii) the need for donor tissue is minimal, which eliminates the immunosuppression problems; (iii) the presence of residual foreign material is eliminated as well [767,768].

7.2. Scaffolds and Their Properties

It would be very convenient for both patients and physicians if devastated tissues or organs of patients could be regenerated by simple cell injections to the target sites, but such cases are rare. The majority of large-sized tissues and organs with distinct 3D form require a support for their formation from cells. The support is called a scaffold, template, and/or artificial extracellular matrix [127,128,534,760,763,764,765,766,767,768,769,770,771,772]. The major function of scaffolds is similar to that of the natural extracellular matrix that assists proliferation, differentiation, and biosynthesis of cells. In addition, scaffolds placed at the regeneration sites will prevent disturbing cells from invasion into the sites of action [771,772]. The role of scaffolds was perfectly described by a Spanish classical guitarist Andrés Segovia (1893–1987): “When one puts up a building one makes an elaborate scaffold to get everything into its proper place. But when one takes the scaffold down, the building must stand by itself with no trace of the means by which it was erected. That is how a musician should work”. However, for the future of tissue engineering, the term “template” might become more suitable because, according to David F. Williams, the term scaffold “conveys an old fashioned meaning of an inert external structure that is temporarily used to assist in the construction or repair of inanimate objects such as buildings, taking no part in the characteristics of the finished product.” [773] (p. 1129).
Therefore, the idea behind tissue engineering is to create or engineer autografts by either expanding autologous cells in vitro guided by a scaffold or implanting an acellular template in vivo and allowing the patient’s cells to repair the tissue guided by the scaffold. The first phase is the in vitro formation of a tissue constructed by placing the chosen cells and scaffolds in a metabolically and mechanically supportive environment with growth media (in a bioreactor), in which the cells proliferate and elaborate extracellular matrix. It is expected that cells infiltrate into the porous matrix and consequently proliferate and differentiate therein [774,775]. In the second phase, the construct is implanted in the appropriate anatomic location, where remodeling in vivo is intended to recapitulate the normal functional architecture of an organ or a tissue [776,777]. The key processes occurring during both in vitro and in vivo phases of the tissue formation and maturation are (1) cell proliferation, sorting, and differentiation, (2) extracellular matrix production and organization, (3) biodegradation of the scaffold, and (4) remodeling and potentially growth of the tissue [778].
To achieve the goal of tissue reconstruction, the scaffolds (templates) must meet a number of the specific requirements [127,128,769,770,771,772,773]. Five features of the scaffold’s architecture appear to influence the biological response: (1) a macroscopic shape, (2) a porous network, (3) pore dimensions and geometry, (4) surface microtopography, and (5) micro-, submicro-, and nanoporosities. In addition, scaffolds should be biodegradable. Among them, a reasonable surface roughness is necessary to facilitate cell seeding and fixation [619,779,780,781,782,783,784]. A high porosity and the adequate pore dimensions (Table 2 and Table 4) are very important to allow cell migration and vascularization, as well as a diffusion of nutrients [437,758]. A French architect, Robert le Ricolais (1894–1977), stated: “The art of structure is where to put the holes”. Therefore, to enable proper tissue ingrowth, vascularization, and nutrient delivery, scaffolds should have a highly interconnected porous network, formed by a combination of macro- and micropores, in which more than ~60% of the pores should have a size ranging from ~150 to ~400 μm and at least ~20% should be smaller than ~20 μm [437,442,443,448,529,530,536,538,544,563,564,565,566,567,568,569,570,572,754,785,786,787,788,789,790,791]. Furthermore, a sufficient mechanical strength and stiffness are mandatory to oppose contraction forces and later for the remodeling of damaged tissues [792,793]. In addition, scaffolds must be manufactured from the materials with controlled biodegradability and/or bioresorbability, such as CaPO4, so that a new bone will eventually replace the scaffold [763,786,794]. Furthermore, the degradation byproducts of scaffolds must be noncytotoxic. More to the point, the resorption rate has to coincide as much as possible with the rate of bone formation (i.e., between a few months and about 2 years) [795]. This means that while cells are fabricating their own natural matrix structure around themselves, the scaffold is able to provide a structural integrity within the body, and eventually it will break down, leaving the newly formed tissue that will take over the mechanical load. However, one should bear in mind that the scaffold’s architecture changes with the degradation process, and the degradation byproducts affect the biological response. In addition, scaffolds should be easily fabricated into a variety of shapes and sizes [796] and be malleable to fit irregularly shaped defects, while the fabrication processes should be effortlessly scalable for mass production. In many cases, ease of processability, as well as easiness of conformation and injectability, which self-setting CaPO4 formulations possess (see Section 6.1. Self-setting (Self-hardening) Formulations), can determine the choice of a certain biomaterial. Finally, sterilization with no loss of properties is a crucial step in scaffold production at both a laboratory and an industrial level [763,764,765]. Thus, each scaffold (template) should fulfill many functions before, during, and after implantation.
Many fabrication techniques are available to produce porous CaPO4 scaffolds (Table 2) with varying architectural features (see the aforementioned Section 3.3 and Section 4.4). In order to achieve the desired properties with the minimum expenses, the production process should be optimized [798]. The main goal is to develop a high potential synthetic bone substitute (so-called “smart scaffold”) which will not only promote osteoconduction, i.e., bone growth on a surface, but also osteopromotion, i.e., the ability to enhance osteoinduction [799]. In the case of CaPO4, a smart scaffold represents a biphasic (HA/β–TCP ratio of 20/80) formulation with a total porosity of ~73%, constituted of macropores (>100 µm), mesopores (10–100 µm), and a high content (~40%) of micropores (<10 µm) with the crystal dimensions within <0.5 to 1 µm and the specific surface area ~6m2/g [800]. With the advent of CaPO4 in tissue engineering, the search is on for the ultimate option consisting of a synthetic smart scaffold impregnated with cells and growth factors. Figure 21 schematically depicts a possible fabrication process of such item that, afterwards, will be implanted into a living organism to induce bone regeneration [47].
To finalize this topic, one should note the fundamental unfeasibility to create the so-called “ideal scaffold” for bone grafting. Since bones of the human skeleton have very different dimensions, shapes, and structures depending on their functions and locations, synthetic bone grafts of various sizes, shapes, porosity, mechanical strength, composition, and resorbability appear to be necessary. Therefore, HA bioceramics of 0 to 15% porosity are used as both ilium and intervertebral spacers, where a high strength is required, HA bioceramics of 30 to 40% porosity are useful as spinous process spacers for laminoplasty, where both bone formation and middle strength are necessary, while HA bioceramics of 40% to 60% porosity are useful for the calvarias plate, where a fast bone formation is needed (Figure 22) [518]. Furthermore, defining the optimum parameters for artificial scaffolds is, in fact, an attempt to find a reasonable compromise between various conflicting functional requirements. Namely, an increased mechanical strength of bone substitutes requires solid and dense structures, while colonization of their surfaces by cells requires interconnected porosity. Additional details and arguments on this subject are well described elsewhere [801], in which the authors concluded that “there is enough evidence to postulate that ideal scaffold architecture does not exist.” (p. 478).

7.3. Bioceramic Scaffolds from CaPO4

Philosophically, the increase in life expectancy requires biological solutions to all biomedical problems, including orthopedic ones, which were previously managed with mechanical solutions. Therefore, since the end of the 1990s, biomaterials research has focused on tissue regeneration instead of tissue replacement [802]. The alternatives include using hierarchical bioactive scaffolds to engineer in vitro living cellular constructs for transplantation or using bioresorbable bioactive particulates or porous networks to activate, in vivo, the mechanisms of tissue regeneration [803,804]. Thus, the aim of CaPO4 is to prepare artificial porous bioceramic scaffolds able to provide the physical and chemical cues to guide cell seeding, differentiation, and assembly into 3D tissues of a newly formed bone. Particle sizes, shape, and surface roughness of the scaffolds are known to affect cellular adhesion, proliferation, and phenotype [619,779,780,781,782,783,784]. Additionally, the surface energy might play a role in attracting particular proteins to the bioceramic surface and, in turn, this will affect the cells’ affinity to the material. More to the point, cells are exceedingly sensitive to the chemical composition, and their bone-forming functions can be dependent on grain morphology of the scaffolds. For example, osteoblast functions were found to increase on nanodimensional fibers when compared to nanodimensional spheres because the former more closely approximated the shape of biological apatite in bones [805]. In addition, a significantly higher osteoblast proliferation on HA bioceramics sintered at 1200 °C, compared to that on HA bioceramics sintered at 800 and 1000 °C, was reported [806]. Furthermore, since ions of calcium and orthophosphate are known to regulate bone metabolism, CaPO4 appears to be among the few bone graft substitute materials that can be considered as a drug. A schematic drawing of the key scaffold properties affecting a cascade of biological processes occurring after CaPO4 implantation is shown in Figure 23 [807].
Thus, to meet the tissue engineering requirements, much attention is devoted to further improvements of CaPO4 bioceramics [808,809,810]. From the chemical point of view, the developments include synthesis of novel ion-substituted CaPO4 [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. For example, a recent systematic review and meta-analysis indicated a significant positive effect on new bone formation by supplementing CaPO4-based bone substitutes with bioinorganics compared to those without dopants, especially when strontium, silicon, or magnesium were used [811]. A positive influence of CaPO4 doping by carbonates was also noticed [812]. From the material point of view, the major research topics include nanodimensional and nanocrystalline structures [813,814,815,816], amorphous compounds [817,818], (bio)organic/CaPO4 biocomposites and hybrid formulations [357,819,820], and biphasic, triphasic, and multiphasic formulations [79], as well as various types of structures, forms, and shapes. The latter comprise fibers, wires, whiskers, and filaments [135,231,821,822,823,824,825,826,827,828,829,830,831,832,833,834], macro-, micro-, and nanosized spheres, beads, and granules [833,834,835,836,837,838,839,840,841,842,843,844,845,846], tetrapods and pyramids [847], micro- and nanosized tubes [848,849,850,851,852], aerogels [853], “flowers” [854], porous 3D scaffolds [172] made of ACP [470,582,855], DCPD/DCPA [148,856,857,858,859], OCP [860,861], TCP [68,71,139,140,862,863,864,865], HA [147,447,448,487,513,514,798,852,866,867,868,869,870], TTCP [141] and biphasic formulations [245,474,491,531,836,843,865,871,872,873,874,875,876,877], structures with graded porosity [74,432,478,491,494,550,743,744,745,746], and hierarchically organized ones [877,878]. More advanced combined techniques are also possible. For example, to increase the degree of ossification and homogenization, the surface of porous CaPO4 scaffolds might be modified by generation of CaPO4 whiskers on their surface [879,880], followed by reinforcing with multiple layers of releasable nanodimensional CDHA particles [880]. Recently, research progress has been made in the deformable CaPO4-based biomaterials with a high flexibility, softness, and/or elasticity based on nanodimensional ultralong HA wires [881,882]. Furthermore, an addition of defects through an intensive milling [883,884] or their removal by a thermal treatment [885] can be used to modify the chemical reactivity of CaPO4. In addition, more attention should be paid to a crystallographically aligned CaPO4 bioceramics [687,688,689,690,691,692,886].
In general, there are three principal therapeutic strategies for treating diseased or injured tissues in patients: (i) implantation of freshly isolated or cultured cells; (ii) implantation of tissues assembled in vitro from cells and scaffolds; (iii) in situ tissue regeneration. For cellular implantation, individual cells or small cellular aggregates from the patient or a donor are either injected into the damaged tissue directly or are combined with a degradable scaffold in vitro and then implanted. For tissue implantation, a complete 3D tissue is grown in vitro using patient or donor cells and a bioresorbable scaffold and then is implanted into the patients to replace diseased or damaged tissues. For in situ regeneration, a scaffold implanted directly into the injured tissue stimulates the body’s own cells to promote local tissue repair [324,757]. In any case, simply trapping cells at the particular point on a surface is not enough: the cells must be encouraged to differentiate, which is impossible without the presence of suitable biochemical factors [887]. All previously mentioned points clearly indicate that, for the purposes of tissue engineering, CaPO4 bioceramics play an auxiliary role; namely, they acts as a suitable material to manufacture the appropriate 3D templates, substrates, or scaffolds to be colonized by living cells before the successive implantation [799,800,888,889,890]. The in vitro evaluation of potential CaPO4 scaffolds for tissue engineering is described elsewhere [891], while the data on the mechanical properties of CaPO4 bioceramics for use in tissue engineering are also available [892,893,894]. The effect of an HA-based biomaterial on gene expression in osteoblast-like cells was reported as well [895]. To conclude this part, the excellent biocompatibility of CaPO4 bioceramics, their possible osteoinductivity [544,566,597,598,599,600,601,602,603,604,605], and high affinity for drugs [54,55,56,57,896,897,898,899,900], proteins, and cells [897,901] make them very functional for the tissue engineering applications [902]. The feasible production of scaffolds with tailored structures and properties opens up a spectacular future for CaPO4 bioceramics [895,896,897,898,899,900,901,902,903].

7.4. A Clinical Experience

To date, there are just a few publications on clinical application of cell-seeded CaPO4 bioceramics for bone tissue engineering of humans. Namely, Quarto et al. [904] were the first to report a treatment of large (4–7 cm) bone defects of the tibia, ulna, and humerus in three patients aged from 16 to 41 years old, where the conventional surgical therapies had failed. The authors implanted a custom-made unresorbable porous HA scaffold seeded with in vitro expanded autologous bone marrow stromal cells. In all three patients, radiographs and computed tomographic scans revealed abundant callus formation along the implants and good integration at the interfaces with the host bones by the second month after surgery [904]. In the same year, Vacanti et al. [905] reported the case of a man who had a traumatic avulsion of the distal phalanx of a thumb. The phalanx was replaced with a specially treated natural coral (porous HA; 500-pore ProOsteon (see Table 3)) implant that was previously seeded with in vitro expanded autologous periosteal cells. The procedure resulted in the functional restoration of a stable and biomechanically sound thumb of normal length, without the pain and complications that are usually associated with harvesting a bone graft.
Morishita et al. [906] treated a defect resulting from surgery of benign bone tumors in three patients using HA scaffolds seeded with in vitro expanded autologous bone marrow stromal cells after osteogenic differentiation of the cells. Two bone defects in a tibia and one defect in a femur were treated. Although ectopic implants in nude mice were mentioned to show the osteogenicity of the cells, details such as the percentage of the implants containing bone and at what quantities were not reported. Furthermore, cell-seeded CaPO4 scaffolds were found to be superior to autograft, allograft or cell-seeded allograft in terms of bone formation at ectopic implantation sites [907]. In addition, it has been hypothesized that dental follicle cells combined with β-TCP bioceramics might become a novel therapeutic strategy to restore periodontal defects [908]. In yet another study, the behavior of human periodontal ligament stem cells on an HA-coated genipin-chitosan scaffold in vitro was studied followed by evaluation on bone repair in vivo [909]. The study demonstrated the potential of this formulation for bone regeneration.
A research group from Holland evaluated vascularization in relation to bone formation potential of adipose-stem-cells-containing stromal vascular fractions of adipose tissues, seeded on two types of CaPO4 carriers, within the human maxillary sinus floor elevation model, in a phase I study [910]. Autologous stromal vascular fractions were obtained from 10 patients and seeded on either β-TCP scaffolds with 60% porosity (n = 5) or BCP (HA + β-TCP) ones with 90% porosity (n = 5) and used for maxillary sinus floor elevations in a one-step surgical procedure. After 6 months, biopsies were obtained during dental implant placements and the quantifications of the number of blood vessels were performed using histomorphometric analysis and immunohistochemical stainings for blood vessel markers. Bone percentages seemed to correlate with blood vessel formation and were higher in the study versus control biopsies in the cranial area, in particular for β-TCP-treated patients. That study showed the safety, feasibility, and efficiency of using of adipose-stem-cells-seeded CaPO4 scaffolds for human maxillary sinus floor elevations and indicated a proangiogenic effect of stromal vascular fraction [910]. A brief description of several other cases is available in the literature [911].
To finalize this section, one must mention that CaPO4 bioceramics are also used in veterinary orthopedics for favoring animal bone healing in areas in which bony defects exist [912,913].

8. Non-Biomedical Applications of CaPO4

Due to their strong adsorption ability, surface acidity or basicity, and ion exchange abilities, some types of CaPO4 possess a catalytic activity [914,915,916,917,918,919,920,921,922,923,924,925,926]. As seen from the references, CaPO4 are able to catalyze oxidation and reduction reactions, as well as formation of C–C bonds. Namely, the application in oxidation reactions mainly includes oxidation of alcohol and dehydrogenation of hydrocarbons, while the reduction reactions include hydrogenolysis and hydrogenation. The formation of C–C bonds mainly comprises Claisen–Schmidt and Knoevenagel condensation reactions, Michael addition reaction, as well as Friedel–Crafts, Heck, Diels–Alder, and aldol reactions [921].
In addition, due to the chemical similarity to the inorganic part of mammalian calcified tissues, CaPO4 powders appear to be good solid carriers for chromatography of biological substances. Namely, high-value biological materials such as recombinant proteins, therapeutic antibodies, and nucleic acids are separated and purified [927,928,929,930,931,932,933]. Furthermore, some types of CaPO4 are used as a component of various sensors [373,374,378,379,382,934,935,936,937,938]. Finally, CaPO4 ceramics appear to be good adsorbents of fluorides [939]; however, since these subjects are almost irrelevant to bioceramics, they are not detailed further. Additional details and examples are available elsewhere [940].

9. Conclusions and Outlook

The available chronology of seeking suitable bioceramics for bone substitutes is as follows: since the 1950s, the first aim was to use bioinert bioceramics, which had no reaction with living tissues. They included inert and tolerant compounds, which were designed to withstand physiological stress without, however, stimulating any specific cellular responses. Later on, in the 1980s, the trend changed towards exactly the opposite: the idea was to implant bioceramics that reacted with the surrounding tissues by producing newly formed bone (a “responsive” bioceramic because it was able to elicit biological responses). These two stages are referred to as the first and the second generations of bioceramics, respectively [941] and, currently, both of them are extensively commercialized. Thus, the majority of the marketable products listed in Table 3 belong to the first and the second generations of bone substitute biomaterials. However, the progress has continued and, in the current century, scientists are searching for the third generation of bioceramics [324], which will be able to “instruct” the physiological environment toward desired biological responses (i.e., bioceramics will be able to regenerate bone tissues by stimulating specific responses at the molecular level) [47,942]. Since each generation represents an evolution of the requirements and properties of the biomaterials involved, one should stress that these three generations should not be interpreted as the chronological, but instead as the conceptual ones. This means that at present, research and development is still devoted to biomaterials and bioceramics that, according to their properties, could be considered to be of the first or the second generations, because the second generation of bioceramics with added porosity is one of the initial approaches in developing the third generation of bioceramics [943]. Furthermore, there is another classification of the history of biomaterials introduced by Prof. James M. Anderson. According to Anderson, from 1950–1975 the researchers studied bioMATERIALS, from 1975–2000 they studied BIOMATERIALS, and since 2000 the time for BIOmaterials has been approaching [944]. Here, the capital letters emphasis the major direction of the research efforts in the complex subject of biomaterials. As bioceramics are biomaterials of the ceramic origin (see Section 2. General Knowledge and Definitions), Anderson’s historical classification appears to be applicable to the bioceramics field as well.
The historical development of biomaterials informs that their widespread use experiences two major difficulties. The first is an incomplete understanding of the physical and chemical functioning of biomaterials and of the human response to these materials. Recent advances in material characterization and computer science, as well as in cell and molecular biology, are expected to play a significant role in the study of biomaterials. A second difficulty is that many biomaterials do not perform as desirably as we would like. This is not surprising, since many materials used in medicine were not designed for medical purposes. It needs to be mentioned here that biomaterials are expected to perform in our body’s internal environment, which is very aggressive. For example, solution pH of body fluids in various tissues varies in the range from 1 to 9. During daily activities, bones are subjected to a stress of ~4 MPa, whereas the tendons and ligaments experience peak stresses in the range of 40–80 MPa. The mean load on a hip joint is up to three times the body weight (3000 N) and peak load during jumping can be as high as ~10 times the body weight. More importantly, these stresses are repetitive and fluctuating, depending on the activities, such as standing, sitting, jogging, stretching, and climbing. All of these require careful designing of biomaterials in terms of composition, shape, physical, and biocompatibility properties. Therefore, a significant challenge is the rational design of human biomaterials based on a systematic evaluation of desired biological, chemical, and engineering requirements [945].
Nevertheless, the field of biomaterials is in the midst of a revolutionary change in which the life sciences are becoming equal in importance to materials science and engineering as the foundation of the field. Simultaneously, advances in engineering (for example, nanotechnology) are greatly increasing the sophistication with which biomaterials are designed and have allowed fabrication of biomaterials with increasingly complex functions [797]. Specifically, during the last ~50 years, CaPO4 bioceramics have become an integral and vital segment of our modern healthcare delivery system. In the modern fields of the third-generation bioceramics (Hench) or BIOceramics (Anderson), the full potential of CaPO4 has only begun to be recognized. Namely, CaPO4, which were intended as osteoconductive bioceramics in the past, represent materials to fabricate osteoinductive implants nowadays [544,566,597,598,599,600,601,602,603,604,605]. Some steps in this direction have been already made by fabricating scaffolds for bone tissue engineering through the design of controlled 3D-porous structures and increasing the biological activity through development of novel ion-substituted CaPO4 bioceramics [546,946]. The future of biosynthetic bone implants will point to better mimicking the autologous bone grafts. Therefore, the composition, structure, and molecular surface chemistry of various types of CaPO4 will be tailored to match the specific biological and metabolic requirements of tissues or disease states [947,948]. This new generation of CaPO4 bioceramics should enhance the quality of life of millions of people as they grow older.
However, in spite of the great progress, there is still a great potential for major advances to be made in the field of CaPO4 bioceramics. This includes requirements for [949]:
  • Improvement of the mechanical performance of existing types of bioceramics.
  • Enhanced bioactivity in terms of gene activation.
  • Improvement in the performance of biomedical coatings in terms of their mechanical stability and ability to deliver biological agents.
  • Development of smart biomaterials capable of combining sensing with bioactivity.
  • Development of improved biomimetic composites.
Furthermore, there is still need for a better understanding of the biological systems. For example, the bonding mechanism between the bone mineral and collagen remains unclear. It is also unclear whether a rapid repair that is elicited by the new generation of bioceramics is a result of the enhancement of mineralization, per se, or whether there is a more complex signaling process involving proteins in collagen. If we were able to understand the fundamentals of bone response to specific ions and the signals they activate, then we would be able to design better bioceramics for the future [949].
To finalize this review, it is completely obvious that the present status of research and development in the field of CaPO4 bioceramics is still at the starting point for the solution of new problems at the confluence of materials science, biology, and medicine, concerned with the restoration of damaged functions in the human organisms. A large increase in active elderly people has dramatically raised the need for load-bearing bone graft substitutes, for example, for bone reconstruction during revision arthroplasty or for the reinforcement of osteoporotic bones. Strategies applied in the last four decades towards this goal have failed, so new strategies, possibly based on self-assembling and/or nanofabrication, will have to be proposed and developed [950]. Angiogenesis (the process and stimulation of new blood vessel formation via sprouting from existing blood vessels) is also very important to the success of hard tissue regeneration, and CaPO4 seem to be useful for this purpose [951]. In addition, some CaPO4-containing formulations were tested with soft tissues [952,953], mainly for various types of soft-tissue augmentations [721,954,955,956] and eyeball replacements [704,705,706,707,708,709], as well as for cancer diagnostics and therapy [957,958,959], wound healing [960], as components of various cosmetic formulations [961], and vaccine adjuvants [962]. Recently, a concept of black bioceramics for Ca- and Mg-silicates, as well as for HA and TCP, was introduced [963]. The black bioceramics were prepared through a partial thermal reduction of traditional white ceramics (CaSiO3, MgSiO3, TCP, and HA) by magnesium. Due to the presence of oxygen vacancies and structural defects, the black bioceramics were found to possess a photothermal functionality while maintaining their initial high bioactivity and regenerative capacity. These black bioceramics showed excellent photothermal antitumor effects for both skin and bone tumors. At the same time, they significantly improved bioactivity for skin/bone tissue repair both in vitro and in vivo [963]. Bioceramics prepared from other types of calcium phosphates, such as calcium pyrophosphate, are worth investigating as well [964]. Additive manufacturing techniques will be further developed [965]. A bioinformatics approach to study the role of CaPO4 properties in bone regeneration might be promising as well [966].
In future, it should be feasible to design a new generation of gene-activating CaPO4-based scaffolds tailored for specific patients and disease states. In addition, further developments of 3D-printing technologies [967] will allow designing of personalized bone grafts, which will provide an accurate control of the geometry. The design of the implant shape, based on X-ray computed tomography data, will ensure the perfect fit between the graft and the anatomical defect [968]. Personalized implants will be produced with tailored characteristics better adapted to the patient-specific bone tissue regions/defects that need to be replaced/reinforced. To transfer these technologies to clinical practice, material science and tissue engineering need to be closely assisted by biomedical researchers in order to confer the safety risk assessment, as well as efficacy at high standards. In addition, the development of complex testing strategies will help to unveil the network of biological events elicited by CaPO4-based bioceramics as bulks, coatings, or nanodimensional forms, which are essential to ensure a longer and safer implant life in orthopedic and dentistry applications [969]. Perhaps, sometime-bioactive stimuli will be used to activate genes in a preventative treatment to maintain the health of aging tissues. Currently, all the aforementioned seem hardly possible. However, we need to remember that only ~50 years ago, the concept of a material that would not be rejected by living tissues also seemed impossible [583].

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Ratner, B.D.; Hoffman, A.S.; Schoen, F.J.; Lemons, J.E. (Eds.) Biomaterials Science: An Introduction to Materials in Medicine, 3rd ed.; Academic Press: Oxford, UK, 2013; p. 1573. [Google Scholar]
  2. Ducheyne, P.; Healy, K.; Hutmacher, D.E.; Grainger, D.W.; Kirkpatrick, C.J. (Eds.) Comprehensive Biomaterials II, 2nd ed.; Seven-Volume Set; Elsevier: Amsterdam, The Netherlands, 2017; p. 4858. [Google Scholar]
  3. Dorozhkin, S.V. Calcium Orthophosphate-Based Bioceramics and Biocomposites; Wiley-VCH: Weinheim, Germany, 2016; p. 405. [Google Scholar]
  4. Dorozhkin, S.V. Dental applications of calcium orthophosphates (CaPO4). J. Dent. Res. 2019, 1, 24–54. [Google Scholar]
  5. Available online: https://www.alliedmarketresearch.com/bone-graft-substitutes-market (accessed on 24 June 2022).
  6. Dorozhkin, S.V. Calcium Orthophosphates: Applications in Nature, Biology, and Medicine; Pan Stanford: Singapore, 2012; p. 850. [Google Scholar]
  7. Balazsi, C.; Weber, F.; Kover, Z.; Horvath, E.; Nemeth, C. Preparation of calcium-phosphate bioceramics from natural resources. J. Eur. Ceram. Soc. 2007, 27, 1601–1606. [Google Scholar] [CrossRef]
  8. Gergely, G.; Wéber, F.; Lukács, I.; Illés, L.; Tóth, A.L.; Horváth, Z.E.; Mihály, J.; Balázsi, C. Nano-hydroxyapatite preparation from biogenic raw materials. Cent. Eur. J. Chem. 2010, 8, 375–381. [Google Scholar] [CrossRef]
  9. Mondal, S.; Mahata, S.; Kundu, S.; Mondal, B. Processing of natural resourced hydroxyapatite ceramics from fish scale. Adv. Appl. Ceram. 2010, 109, 234–239. [Google Scholar] [CrossRef]
  10. Lim, K.T.; Suh, J.D.; Kim, J.; Choung, P.H.; Chung, J.H. Calcium phosphate bioceramics fabricated from extracted human teeth for tooth tissue engineering. J. Biomed. Mater. Res. B Appl. Biomater. 2011, 99B, 399–411. [Google Scholar] [CrossRef]
  11. Seo, D.S.; Hwang, K.H.; Yoon, S.Y.; Lee, J.K. Fabrication of hydroxyapatite bioceramics from the recycling of pig bone. J. Ceram. Proc. Res. 2012, 13, 586–589. [Google Scholar]
  12. Ho, W.F.; Hsu, H.C.; Hsu, S.K.; Hung, C.W.; Wu, S.C. Calcium phosphate bioceramics synthesized from eggshell powders through a solid state reaction. Ceram. Int. 2013, 39, 6467–6473. [Google Scholar] [CrossRef]
  13. González-Rodríguez, L.; López-Álvarez, M.; Astray, S.; Solla, E.L.; Serra, J.; González, P. Hydroxyapatite scaffolds derived from deer antler: Structure dependence on processing temperature. Mater. Charact. 2019, 155, 109805. [Google Scholar] [CrossRef]
  14. Arokiasamy, P.; Al Bakri Abdullah, M.M.; Abd Rahim, S.Z.; Luhar, S.; Sandu, A.V.; Jamil, N.H.; Nabiałek, M. Synthesis methods of hydroxyapatite from natural sources: A review. Ceram. Int. 2022, 48, 14959–14979. [Google Scholar] [CrossRef]
  15. Grigoraviciute-Puroniene, I.; Zarkov, A.; Tsuru, K.; Ishikawa, K.; Kareiva, A. A novel synthetic approach for the calcium hydroxyapatite from the food products. J. Sol-Gel Sci. Technol. 2019, 91, 63–71. [Google Scholar] [CrossRef]
  16. Tosun, G.U.; Sakhno, Y.; Jaisi, D.P. Synthesis of hydroxyapatite nanoparticles from phosphorus recovered from animal wastes. ACS Sustain. Chem. Eng. 2021, 9, 15117–15126. [Google Scholar] [CrossRef]
  17. Ergun, C.; Webster, T.J.; Bizios, R.; Doremus, R.H. Hydroxylapatite with substituted magnesium, zinc, cadmium, and yttrium. I. Structure and microstructure. J. Biomed. Mater. Res. 2002, 59, 305–311. [Google Scholar] [CrossRef]
  18. Webster, T.J.; Ergun, C.; Doremus, R.H.; Bizios, R. Hydroxylapatite with substituted magnesium, zinc, cadmium, and yttrium. II. Mechanisms of osteoblast adhesion. J. Biomed. Mater. Res. 2002, 59, 312–317. [Google Scholar] [CrossRef]
  19. Kim, S.R.; Lee, J.H.; Kim, Y.T.; Riu, D.H.; Jung, S.J.; Lee, Y.J.; Chung, S.C.; Kim, Y.H. Synthesis of Si, Mg substituted hydroxyapatites and their sintering behaviors. Biomaterials 2003, 24, 1389–1398. [Google Scholar] [CrossRef]
  20. Landi, E.; Celotti, G.; Logroscino, G.; Tampieri, A. Carbonated hydroxyapatite as bone substitute. J. Eur. Ceram. Soc. 2003, 23, 2931–2937. [Google Scholar] [CrossRef]
  21. Vallet-Regí, M.; Arcos, D. Silicon substituted hydroxyapatites. A method to upgrade calcium phosphate based implants. J. Mater. Chem. 2005, 15, 1509–1516. [Google Scholar] [CrossRef]
  22. Gbureck, U.; Thull, R.; Barralet, J.E. Alkali ion substituted calcium phosphate cement formation from mechanically activated reactants. J. Mater. Sci. Mater. Med. 2005, 16, 423–427. [Google Scholar] [CrossRef]
  23. Gbureck, U.; Knappe, O.; Grover, L.M.; Barralet, J.E. Antimicrobial potency of alkali ion substituted calcium phosphate cements. Biomaterials 2005, 26, 6880–6886. [Google Scholar] [CrossRef]
  24. Reid, J.W.; Tuck, L.; Sayer, M.; Fargo, K.; Hendry, J.A. Synthesis and characterization of single-phase silicon substituted α-tricalcium phosphate. Biomaterials 2006, 27, 2916–2925. [Google Scholar] [CrossRef]
  25. Tas, A.C.; Bhaduri, S.B.; Jalota, S. Preparation of Zn-doped β-tricalcium phosphate (β-Ca3(PO4)2) bioceramics. Mater. Sci. Eng. C 2007, 27, 394–401. [Google Scholar]
  26. Gibson, I.R. Silicon-containing apatites. In Comprehensive Biomaterials II; Chapter 1.20; Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2017; pp. 428–459. [Google Scholar]
  27. Jalota, S.; Bhaduri, S.B.; Tas, A.C. A new rhenanite (β-NaCaPO4) and hydroxyapatite biphasic biomaterial for skeletal repair. J. Biomed. Mater. Res. B Appl. Biomater. 2007, 80B, 304–316. [Google Scholar] [CrossRef]
  28. Kannan, S.; Ventura, J.M.G.; Ferreira, J.M.F. Synthesis and thermal stability of potassium substituted hydroxyapatites and hydroxyapatite/β-tricalcium phosphate mixtures. Ceram. Int. 2007, 33, 1489–1494. [Google Scholar] [CrossRef]
  29. Kannan, S.; Rebelo, A.; Lemos, A.F.; Barba, A.; Ferreira, J.M.F. Synthesis and mechanical behaviour of chlorapatite and chlorapatite/β-TCP composites. J. Eur. Ceram. Soc. 2007, 27, 2287–2294. [Google Scholar] [CrossRef]
  30. Kannan, S.; Goetz-Neunhoeffer, F.; Neubauer, J.; Ferreira, J.M.F. Ionic substitutions in biphasic hydroxyapatite and β-tricalcium phosphate mixtures: Structural analysis by Rietveld refinement. J. Am. Ceram. Soc. 2008, 91, 1–12. [Google Scholar] [CrossRef]
  31. Meejoo, S.; Pon-On, W.; Charnchai, S.; Amornsakchai, T. Substitution of iron in preparation of enhanced thermal property and bioactivity of hydroxyapatite. Adv. Mater. Res. 2008, 55–57, 689–692. [Google Scholar] [CrossRef]
  32. Kannan, S.; Goetz-Neunhoeffer, F.; Neubauer, J.; Ferreira, J.M.F. Synthesis and structure refinement of zinc-doped β-tricalcium phosphate powders. J. Am. Ceram. Soc. 2009, 92, 1592–1595. [Google Scholar] [CrossRef]
  33. Matsumoto, N.; Yoshida, K.; Hashimoto, K.; Toda, Y. Thermal stability of β-tricalcium phosphate doped with monovalent metal ions. Mater. Res. Bull. 2009, 44, 1889–1894. [Google Scholar] [CrossRef]
  34. Boanini, E.; Gazzano, M.; Bigi, A. Ionic substitutions in calcium phosphates synthesized at low temperature. Acta Biomater. 2010, 6, 1882–1894. [Google Scholar] [CrossRef] [PubMed]
  35. Habibovic, P.; Barralet, J.E. Bioinorganics and biomaterials: Bone repair. Acta Biomater. 2011, 7, 3013–3026. [Google Scholar] [CrossRef] [PubMed]
  36. Mellier, C.; Fayon, F.; Schnitzler, V.; Deniard, P.; Allix, M.; Quillard, S.; Massiot, D.; Bouler, J.M.; Bujoli, B.; Janvier, P. Characterization and properties of novel gallium-doped calcium phosphate ceramics. Inorg. Chem. 2011, 50, 8252–8260. [Google Scholar] [CrossRef] [PubMed]
  37. Ansar, E.B.; Ajeesh, M.; Yokogawa, Y.; Wunderlich, W.; Varma, H. Synthesis and characterization of iron oxide embedded hydroxyapatite bioceramics. J. Am. Ceram. Soc. 2012, 95, 2695–2699. [Google Scholar] [CrossRef]
  38. Shepherd, J.H.; Shepherd, D.V.; Best, S.M. Substituted hydroxyapatites for bone repair. J. Mater. Sci. Mater. Med. 2012, 23, 2335–2347. [Google Scholar] [CrossRef]
  39. Šupová, M. Substituted hydroxyapatites for biomedical applications: A review. Ceram. Int. 2015, 41, 9203–9231. [Google Scholar] [CrossRef]
  40. Ratnayake, J.T.B.; Mucalo, M.; Dias, G.J. Substituted hydroxyapatites for bone regeneration: A review of current trends. J. Biomed. Mater. Res. B Appl. Biomater. 2017, 105B, 1285–1299. [Google Scholar] [CrossRef]
  41. Cacciotti, I. Multisubstituted hydroxyapatite powders and coatings: The influence of the codoping on the hydroxyapatite performances. Int. J. Appl. Ceram. Technol. 2019, 16, 1864–1884. [Google Scholar] [CrossRef]
  42. Williams, D.F. The Williams Dictionary of Biomaterials; Liverpool University Press: Liverpool, UK, 1999; p. 368. [Google Scholar]
  43. Williams, D.F. On the nature of biomaterials. Biomaterials 2009, 30, 5897–5909. [Google Scholar] [CrossRef]
  44. Zhang, X.D.; Williams, D.F. (Eds.) Definitions of biomaterials for the twenty-first century. In Proceedings of the A Consensus Conference Held in Chengdu, Chengdu, China, 11–12 June 2018; Materials Today. Elsevier: Amsterdam, The Netherlands, 2019; p. 290. [Google Scholar]
  45. Williams, D.F. Specifications for innovative, enabling biomaterials based on the principles of biocompatibility mechanisms. Front. Bioeng. Biotechnol. 2019, 7, 255. [Google Scholar] [CrossRef]
  46. Mann, S. (Ed.) Biomimetic Materials Chemistry; Wiley-VCH: Weinheim, Germany, 1996; p. 400. [Google Scholar]
  47. Vallet-Regí, M. Bioceramics: Where do we come from and which are the future expectations. Key Eng. Mater. 2008, 377, 1–18. [Google Scholar] [CrossRef]
  48. Meyers, M.A.; Chen, P.Y.; Lin, A.Y.M.; Seki, Y. Biological materials: Structure and mechanical properties. Prog. Mater. Sci. 2008, 53, 1–206. [Google Scholar] [CrossRef]
  49. Available online: https://en.wikipedia.org/wiki/Ceramic (accessed on 24 June 2022).
  50. Hench, L.L. Bioceramics: From concept to clinic. J. Am. Ceram. Soc. 1991, 74, 1487–1510. [Google Scholar] [CrossRef]
  51. Hench, L.L.; Day, D.E.; Höland, W.; Rheinberger, V.M. Glass and medicine. Int. J. Appl. Glass Sci. 2010, 1, 104–117. [Google Scholar] [CrossRef]
  52. Pinchuk, N.D.; Ivanchenko, L.A. Making calcium phosphate biomaterials. Powder Metall. Metal Ceram. 2003, 42, 357–371. [Google Scholar]
  53. Heimann, R.B. Materials science of crystalline bioceramics: A review of basic properties and applications. CMU J. 2002, 1, 23–46. [Google Scholar]
  54. Tomoda, K.; Ariizumi, H.; Nakaji, T.; Makino, K. Hydroxyapatite particles as drug carriers for proteins. Colloid Surf. B 2010, 76, 226–235. [Google Scholar] [CrossRef]
  55. Zamoume, O.; Thibault, S.; Regnié, G.; Mecherri, M.O.; Fiallo, M.; Sharrock, P. Macroporous calcium phosphate ceramic implants for sustained drug delivery. Mater. Sci. Eng. C 2011, 31, 1352–1356. [Google Scholar] [CrossRef]
  56. Bose, S.; Tarafder, S. Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: A review. Acta Biomater. 2012, 8, 1401–1421. [Google Scholar] [CrossRef]
  57. Arcos, D.; Vallet-Regí, M. Bioceramics for drug delivery. Acta Mater. 2013, 61, 890–911. [Google Scholar] [CrossRef]
  58. Ducheyne, P.; Qiu, Q. Bioactive ceramics: The effect of surface reactivity on bone formation and bone cell function. Biomaterials 1999, 20, 2287–2303. [Google Scholar] [CrossRef]
  59. Dorozhkin, S.V. Calcium orthophosphates and human beings. A historical perspective from the 1770s until 1940. Biomatter 2012, 2, 53–70. [Google Scholar] [CrossRef]
  60. Dorozhkin, S.V. A detailed history of calcium orthophosphates from 1770-s till 1950. Mater. Sci. Eng. C 2013, 33, 3085–3110. [Google Scholar] [CrossRef] [PubMed]
  61. De Groot, K. (Ed.) Bioceramics of Calcium Phosphate; CRC Press; Taylor & Francis: Boca Raton, FL, USA, 1983; p. 146. [Google Scholar]
  62. Vallet-Regí, M.; González-Calbet, J.M. Calcium phosphates as substitution of bone tissues. Progr. Solid State Chem. 2004, 32, 1–31. [Google Scholar] [CrossRef]
  63. Layrolle, P.; Ito, A.; Tateishi, T. Sol-gel synthesis of amorphous calcium phosphate and sintering into microporous hydroxyapatite bioceramics. J. Am. Ceram. Soc. 1998, 81, 1421–1428. [Google Scholar] [CrossRef]
  64. Engin, N.O.; Tas, A.C. Manufacture of macroporous calcium hydroxyapatite bioceramics. J. Eur. Ceram. Soc. 1999, 19, 2569–2572. [Google Scholar] [CrossRef]
  65. Ahn, E.S.; Gleason, N.J.; Nakahira, A.; Ying, J.Y. Nanostructure processing of hydroxyapatite-based bioceramics. Nano Lett. 2001, 1, 149–153. [Google Scholar] [CrossRef]
  66. Khalil, K.A.; Kim, S.W.; Dharmaraj, N.; Kim, K.W.; Kim, H.Y. Novel mechanism to improve toughness of the hydroxyapatite bioceramics using high-frequency induction heat sintering. J. Mater. Process. Technol. 2007, 187–188, 417–420. [Google Scholar] [CrossRef]
  67. Laasri, S.; Taha, M.; Laghzizil, A.; Hlil, E.K.; Chevalier, J. The affect of densification and dehydroxylation on the mechanical properties of stoichiometric hydroxyapatite bioceramics. Mater. Res. Bull. 2010, 45, 1433–1437. [Google Scholar] [CrossRef]
  68. Kitamura, M.; Ohtsuki, C.; Ogata, S.; Kamitakahara, M.; Tanihara, M. Microstructure and bioresorbable properties of α-TCP ceramic porous body fabricated by direct casting method. Mater. Trans. 2004, 45, 983–988. [Google Scholar] [CrossRef]
  69. Kawagoe, D.; Ioku, K.; Fujimori, H.; Goto, S. Transparent β-tricalcium phosphate ceramics prepared by spark plasma sintering. J. Ceram. Soc. Jpn. 2004, 112, 462–463. [Google Scholar] [CrossRef]
  70. Wang, C.X.; Zhou, X.; Wang, M. Influence of sintering temperatures on hardness and Young’s modulus of tricalcium phosphate bioceramic by nanoindentation technique. Mater. Character. 2004, 52, 301–307. [Google Scholar] [CrossRef]
  71. Ioku, K.; Kawachi, G.; Nakahara, K.; Ishida, E.H.; Minagi, H.; Okuda, T.; Yonezawa, I.; Kurosawa, H.; Ikeda, T. Porous granules of β-tricalcium phosphate composed of rod-shaped particles. Key Eng. Mater. 2006, 309–311, 1059–1062. [Google Scholar] [CrossRef]
  72. Kamitakahara, M.; Ohtsuki, C.; Miyazaki, T. Review paper: Behavior of ceramic biomaterials derived from tricalcium phosphate in physiological condition. J. Biomater. Appl. 2008, 23, 197–212. [Google Scholar] [CrossRef]
  73. Vorndran, E.; Klarner, M.; Klammert, U.; Grover, L.M.; Patel, S.; Barralet, J.E.; Gbureck, U. 3D powder printing of β-tricalcium phosphate ceramics using different strategies. Adv. Eng. Mater. 2008, 10, B67–B71. [Google Scholar] [CrossRef]
  74. Descamps, M.; Duhoo, T.; Monchau, F.; Lu, J.; Hardouin, P.; Hornez, J.C.; Leriche, A. Manufacture of macroporous β-tricalcium phosphate bioceramics. J. Eur. Ceram. Soc. 2008, 28, 149–157. [Google Scholar] [CrossRef]
  75. Liu, Y.; Kim, J.H.; Young, D.; Kim, S.; Nishimoto, S.K.; Yang, Y. Novel template-casting technique for fabricating β-tricalcium phosphate scaffolds with high interconnectivity and mechanical strength and in vitro cell responses. J. Biomed. Mater. Res. A 2010, 92A, 997–1006. [Google Scholar]
  76. Carrodeguas, R.G.; de Aza, S. α-tricalcium phosphate: Synthesis, properties and biomedical applications. Acta Biomater. 2011, 7, 3536–3546. [Google Scholar] [CrossRef]
  77. Kim, I.Y.; Wen, J.; Ohtsuki, C. Fabrication of α-tricalcium phosphate ceramics through two-step sintering. Key Eng. Mater. 2015, 631, 78–82. [Google Scholar] [CrossRef]
  78. Bohner, M.; Santoni, B.L.G.; Döbelin, N. β-tricalcium phosphate for bone substitution: Synthesis and properties. Acta Biomater. 2020, 113, 23–41. [Google Scholar] [CrossRef]
  79. Dorozhkin, S.V. Multiphasic calcium orthophosphate (CaPO4) bioceramics and their biomedical applications. Ceram. Int. 2016, 42, 6529–6554. [Google Scholar] [CrossRef]
  80. LeGeros, R.Z.; Lin, S.; Rohanizadeh, R.; Mijares, D.; LeGeros, J.P. Biphasic calcium phosphate bioceramics: Preparation, properties and applications. J. Mater. Sci. Mater. Med. 2003, 14, 201–209. [Google Scholar] [CrossRef]
  81. Daculsi, G.; Laboux, O.; Malard, O.; Weiss, P. Current state of the art of biphasic calcium phosphate bioceramics. J. Mater. Sci. Mater. Med. 2003, 14, 195–200. [Google Scholar] [CrossRef]
  82. Dorozhkina, E.I.; Dorozhkin, S.V. Mechanism of the solid-state transformation of a calcium-deficient hydroxyapatite (CDHA) into biphasic calcium phosphate (BCP) at elevated temperatures. Chem. Mater. 2002, 14, 4267–4272. [Google Scholar] [CrossRef]
  83. Daculsi, G. Biphasic calcium phosphate granules concept for injectable and mouldable bone substitute. Adv. Sci. Technol. 2006, 49, 9–13. [Google Scholar]
  84. Lecomte, A.; Gautier, H.; Bouler, J.M.; Gouyette, A.; Pegon, Y.; Daculsi, G.; Merle, C. Biphasic calcium phosphate: A comparative study of interconnected porosity in two ceramics. J. Biomed. Mater. Res. B Appl. Biomater. 2008, 84B, 1–6. [Google Scholar] [CrossRef]
  85. Daculsi, G.; Baroth, S.; LeGeros, R.Z. 20 years of biphasic calcium phosphate bioceramics development and applications. Ceram. Eng. Sci. Proc. 2010, 30, 45–58. [Google Scholar]
  86. Lukić, M.; Stojanović, Z.; Škapin, S.D.; Maček-Kržmanc, M.; Mitrić, M.; Marković, S.; Uskoković, D. Dense fine-grained biphasic calcium phosphate (BCP) bioceramics designed by two-step sintering. J. Eur. Ceram. Soc. 2011, 31, 19–27. [Google Scholar] [CrossRef]
  87. Descamps, M.; Boilet, L.; Moreau, G.; Tricoteaux, A.; Lu, J.; Leriche, A.; Lardot, V.; Cambier, F. Processing and properties of biphasic calcium phosphates bioceramics obtained by pressureless sintering and hot isostatic pressing. J. Eur. Ceram. Soc. 2013, 33, 1263–1270. [Google Scholar] [CrossRef]
  88. Owen, R.G.; Dard, M.; Larjava, H. Hydoxyapatite/beta-tricalcium phosphate biphasic ceramics as regenerative material for the repair of complex bone defects. J. Biomed. Mater. Res. B Appl. Biomater. 2018, 106B, 2493–2512. [Google Scholar]
  89. Li, Y.; Kong, F.; Weng, W. Preparation and characterization of novel biphasic calcium phosphate powders (α-TCP/HA) derived from carbonated amorphous calcium phosphates. J. Biomed. Mater. Res. B Appl. Biomater. 2009, 89B, 508–517. [Google Scholar] [CrossRef]
  90. Sureshbabu, S.; Komath, M.; Varma, H.K. In situ formation of hydroxyapatite –alpha tricalcium phosphate biphasic ceramics with higher strength and bioactivity. J. Am. Ceram. Soc. 2012, 95, 915–924. [Google Scholar]
  91. Radovanović, Ž.; Jokić, B.; Veljović, D.; Dimitrijević, S.; Kojić, V.; Petrović, R.; Janaćković, D. Antimicrobial activity and biocompatibility of Ag+- and Cu2+-doped biphasic hydroxyapatite/α-tricalcium phosphate obtained from hydrothermally synthesized Ag+- and Cu2+-doped hydroxyapatite. Appl. Surf. Sci. 2014, 307, 513–519. [Google Scholar]
  92. Oishi, M.; Ohtsuki, C.; Kitamura, M.; Kamitakahara, M.; Ogata, S.; Miyazaki, T.; Tanihara, M. Fabrication and chemical durability of porous bodies consisting of biphasic tricalcium phosphates. Phosphorus Res. Bull. 2004, 17, 95–100. [Google Scholar] [CrossRef] [Green Version]
  93. Kamitakahara, M.; Ohtsuki, C.; Oishi, M.; Ogata, S.; Miyazaki, T.; Tanihara, M. Preparation of porous biphasic tricalcium phosphate and its in vivo behavior. Key Eng. Mater. 2005, 59, 281–284. [Google Scholar] [CrossRef]
  94. Wang, R.; Weng, W.; Deng, X.; Cheng, K.; Liu, X.; Du, P.; Shen, G.; Han, G. Dissolution behavior of submicron biphasic tricalcium phosphate powders. Key Eng. Mater. 2006, 309–311, 223–226. [Google Scholar] [CrossRef]
  95. Li, Y.; Weng, W.; Tam, K.C. Novel highly biodegradable biphasic tricalcium phosphates composed of α-tricalcium phosphate and β-tricalcium phosphate. Acta Biomater. 2007, 3, 251–254. [Google Scholar] [CrossRef]
  96. Zou, C.; Cheng, K.; Weng, W.; Song, C.; Du, P.; Shen, G.; Han, G. Characterization and dissolution–reprecipitation behavior of biphasic tricalcium phosphate powders. J. Alloys Compd. 2011, 509, 6852–6858. [Google Scholar] [CrossRef]
  97. Xie, L.; Yu, H.; Deng, Y.; Yang, W.; Liao, L.; Long, Q. Preparation and in vitro degradation study of the porous dual alpha/beta-tricalcium phosphate bioceramics. Mater. Res. Inn. 2016, 20, 530–537. [Google Scholar] [CrossRef]
  98. Albuquerque, J.S.V.; Nogueira, R.E.F.Q.; da Silva, T.D.P.; Lima, D.O.; da Silva, M.H.P. Porous triphasic calcium phosphate bioceramics. Key Eng. Mater. 2004, 254–256, 1021–1024. [Google Scholar] [CrossRef]
  99. Mendonça, F.; Lourom, L.H.L.; de Campos, J.B.; da Silva, M.H.P. Porous biphasic and triphasic bioceramics scaffolds produced by gelcasting. Key Eng. Mater. 2008, 361–363, 27–30. [Google Scholar]
  100. Vani, R.; Girija, E.K.; Elayaraja, K.; Parthiban, P.S.; Kesavamoorthy, R.; Narayana Kalkura, S. Hydrothermal synthesis of porous triphasic hydroxyapatite/(α and β) tricalcium phosphate. J. Mater. Sci. Mater. Med. 2009, 20 (Suppl. 1), S43–S48. [Google Scholar] [CrossRef]
  101. Ahn, M.K.; Moon, Y.W.; Koh, Y.H.; Kim, H.E. Production of highly porous triphasic calcium phosphate scaffolds with excellent in vitro bioactivity using vacuum-assisted foaming of ceramic suspension (VFC) technique. Ceram. Int. 2013, 39, 5879–5885. [Google Scholar] [CrossRef]
  102. Dorozhkin, S.V. Self-setting calcium orthophosphate (CaPO4) formulations and their biomedical applications. Adv. Nano-Bio. Mater. Dev. 2019, 3, 321–421. [Google Scholar]
  103. Tamimi, F.; Sheikh, Z.; Barralet, J. Dicalcium phosphate cements: Brushite and monetite. Acta Biomater. 2012, 8, 474–487. [Google Scholar] [CrossRef]
  104. Drouet, C.; Largeot, C.; Raimbeaux, G.; Estournès, C.; Dechambre, G.; Combes, C.; Rey, C. Bioceramics: Spark plasma sintering (SPS) of calcium phosphates. Adv. Sci. Technol. 2006, 49, 45–50. [Google Scholar]
  105. Ishihara, S.; Matsumoto, T.; Onoki, T.; Sohmura, T.; Nakahira, A. New concept bioceramics composed of octacalcium phosphate (OCP) and dicarboxylic acid-intercalated OCP via hydrothermal hot-pressing. Mater. Sci. Eng. C 2009, 29, 1885–1888. [Google Scholar] [CrossRef]
  106. Barinov, S.M.; Komlev, V.S. Osteoinductive ceramic materials for bone tissue restoration: Octacalcium phosphate (review). Inorg. Mater. Appl. Res. 2010, 1, 175–181. [Google Scholar] [CrossRef]
  107. Moseke, C.; Gbureck, U. Tetracalcium phosphate: Synthesis, properties and biomedical applications. Acta Biomater. 2010, 6, 3815–3823. [Google Scholar] [CrossRef]
  108. Morimoto, S.; Anada, T.; Honda, Y.; Suzuki, O. Comparative study on in vitro biocompatibility of synthetic octacalcium phosphate and calcium phosphate ceramics used clinically. Biomed. Mater. 2012, 7, 045020. [Google Scholar] [CrossRef]
  109. Tamimi, F.; Nihouannen, D.L.; Eimar, H.; Sheikh, Z.; Komarova, S.; Barralet, J. The effect of autoclaving on the physical and biological properties of dicalcium phosphate dihydrate bioceramics: Brushite vs. monetite. Acta Biomater. 2012, 8, 3161–3169. [Google Scholar] [CrossRef]
  110. Suzuki, O. Octacalcium phosphate (OCP)-based bone substitute materials. Jpn. Dent. Sci. Rev. 2013, 49, 58–71. [Google Scholar] [CrossRef]
  111. Komlev, V.S.; Barinov, S.M.; Bozo, I.I.; Deev, R.V.; Eremin, I.I.; Fedotov, A.Y.; Gurin, A.N.; Khromova, N.V.; Kopnin, P.B.; Kuvshinova, E.A.; et al. Bioceramics composed of octacalcium phosphate demonstrate enhanced biological behavior. ACS Appl. Mater. Interf. 2014, 6, 16610–16620. [Google Scholar] [CrossRef]
  112. Zhou, H.; Yang, L.; Gbureck, U.; Bhaduri, S.B.; Sikder, P. Monetite, an important calcium phosphate compound–its synthesis, properties and applications in orthopedics. Acta Biomater. 2021, 127, 41–55. [Google Scholar] [CrossRef] [PubMed]
  113. LeGeros, R.Z. Calcium phosphates in oral biology and medicine. In Monographs in Oral Science; Karger: Basel, Switzerland, 1991; Volume 15, p. 201. [Google Scholar]
  114. Narasaraju, T.S.B.; Phebe, D.E. Some physico-chemical aspects of hydroxylapatite. J. Mater. Sci. 1996, 31, 1–21. [Google Scholar] [CrossRef]
  115. Elliott, J.C. Structure and chemistry of the apatites and other calcium orthophosphates. In Studies in Inorganic Chemistry; Elsevier: Amsterdam, The Netherlands, 1994; Volume 18, p. 389. [Google Scholar]
  116. Brown, P.W.; Constantz, B. (Eds.) Hydroxyapatite and Related Materials; CRC Press: Boca Raton, FL, USA, 1994; p. 343. [Google Scholar]
  117. Amjad, Z. (Ed.) Calcium Phosphates in Biological and Industrial Systems; Kluwer Academic Publishers: Boston, MA, USA, 1997; p. 529. [Google Scholar]
  118. Da Silva, R.V.; Bertran, C.A.; Kawachi, E.Y.; Camilli, J.A. Repair of cranial bone defects with calcium phosphate ceramic implant or autogenous bone graft. J. Craniofac. Surg. 2007, 18, 281–286. [Google Scholar] [CrossRef] [PubMed]
  119. Okanoue, Y.; Ikeuchi, M.; Takemasa, R.; Tani, T.; Matsumoto, T.; Sakamoto, M.; Nakasu, M. Comparison of in vivo bioactivity and compressive strength of a novel superporous hydroxyapatite with beta-tricalcium phosphates. Arch. Orthop. Trauma Surg. 2012, 132, 1603–1610. [Google Scholar] [CrossRef]
  120. Draenert, M.; Draenert, A.; Draenert, K. Osseointegration of hydroxyapatite and remodeling-resorption of tricalciumphosphate ceramics. Microsc. Res. Tech. 2013, 76, 370–380. [Google Scholar] [CrossRef]
  121. Okuda, T.; Ioku, K.; Yonezawa, I.; Minagi, H.; Gonda, Y.; Kawachi, G.; Kamitakahara, M.; Shibata, Y.; Murayama, H.; Kurosawa, H.; et al. The slow resorption with replacement by bone of a hydrothermally synthesized pure calcium-deficient hydroxyapatite. Biomaterials 2008, 29, 2719–2728. [Google Scholar] [CrossRef]
  122. Daculsi, G.; Bouler, J.M.; LeGeros, R.Z. Adaptive crystal formation in normal and pathological calcifications in synthetic calcium phosphate and related biomaterials. Int. Rev. Cytol. 1997, 172, 129–191. [Google Scholar]
  123. Zhu, X.D.; Zhang, H.J.; Fan, H.S.; Li, W.; Zhang, X.D. Effect of phase composition and microstructure of calcium phosphate ceramic particles on protein adsorption. Acta Biomater. 2010, 6, 1536–1541. [Google Scholar] [CrossRef]
  124. Bohner, M. Calcium orthophosphates in medicine: From ceramics to calcium phosphate cements. Injury 2000, 31 (Suppl. 4), D37–D47. [Google Scholar] [CrossRef]
  125. Ahato, I. Reverse engineering the ceramic art of algae. Science 1999, 286, 1059–1061. [Google Scholar]
  126. Popişter, F.; Popescu, D.; Hurgoiu, D. A new method for using reverse engineering in case of ceramic tiles. Qual. Access Success 2012, 13 (Suppl. 5), 409–412. [Google Scholar]
  127. Yang, S.; Leong, K.F.; Du, Z.; Chua, C.K. The design of scaffolds for use in tissue engineering. Part II. Rapid prototyping techniques. Tissue Eng. 2002, 8, 1–11. [Google Scholar] [CrossRef]
  128. Yeong, W.Y.; Chua, C.K.; Leong, K.F.; Chandrasekaran, M. Rapid prototyping in tissue engineering: Challenges and potential. Trends Biotechnol. 2004, 22, 643–652. [Google Scholar] [CrossRef]
  129. Ortona, A.; D’Angelo, C.; Gianella, S.; Gaia, D. Cellular ceramics produced by rapid prototyping and replication. Mater. Lett. 2012, 80, 95–98. [Google Scholar] [CrossRef]
  130. Eufinger, H.; Wehniöller, M.; Machtens, E.; Heuser, L.; Harders, A.; Kruse, D. Reconstruction of craniofacial bone defects with individual alloplastic implants based on CAD/CAM-manipulated CT-data. J. Cranio Maxillofac. Surg. 1995, 23, 175–181. [Google Scholar] [CrossRef]
  131. Klein, M.; Glatzer, C. Individual CAD/CAM fabricated glass-bioceramic implants in reconstructive surgery of the bony orbital floor. Plastic Reconstruct. Surg. 2006, 117, 565–570. [Google Scholar] [CrossRef]
  132. Yin, L.; Song, X.F.; Song, Y.L.; Huang, T.; Li, J. An overview of in vitro abrasive finishing & CAD/CAM of bioceramics in restorative dentistry. Int. J. Machine Tools Manufact. 2006, 46, 1013–1026. [Google Scholar]
  133. Li, J.; Hsu, Y.; Luo, E.; Khadka, A.; Hu, J. Computer-aided design and manufacturing and rapid prototyped nanoscale hydroxyapatite/polyamide (n-HA/PA) construction for condylar defect caused by mandibular angle ostectomy. Aesthetic Plast. Surg. 2011, 35, 636–640. [Google Scholar] [CrossRef]
  134. Ciocca, L.; Donati, D.; Fantini, M.; Landi, E.; Piattelli, A.; Iezzi, G.; Tampieri, A.; Spadari, A.; Romagnoli, N.; Scotti, R. CAD-CAM-generated hydroxyapatite scaffold to replace the mandibular condyle in sheep: Preliminary results. J. Biomater. Appl. 2013, 28, 207–218. [Google Scholar] [CrossRef]
  135. Janek, M.; Žilinská, V.; Kovár, V.; Hajdúchová, Z.; Tomanová, K.; Peciar, P.; Veteška, P.; Gabošová, T.; Fialka, R.; Feranc, J.; et al. Mechanical testing of hydroxyapatite filaments for tissue scaffolds preparation by fused deposition of ceramics. J. Eur. Ceram. Soc. 2020, 40, 4932–4938. [Google Scholar] [CrossRef]
  136. Esslinger, S.; Grebhardt, A.; Jaeger, J.; Kern, F.; Killinger, A.; Bonten, C.; Gadow, R. Additive manufacturing of β-tricalcium phosphate components via fused deposition of ceramics (FDC). Materials 2021, 14, 156. [Google Scholar] [CrossRef] [PubMed]
  137. Tan, K.H.; Chua, C.K.; Leong, K.F.; Cheah, C.M.; Cheang, P.; Abu Bakar, M.S.; Cha, S.W. Scaffold development using selective laser sintering of polyetheretherketone-hydroxyapatite biocomposite blends. Biomaterials 2003, 24, 3115–3123. [Google Scholar] [CrossRef]
  138. Wiria, F.E.; Leong, K.F.; Chua, C.K.; Liu, Y. Poly-ε-caprolactone/hydroxyapatite for tissue engineering scaffold fabrication via selective laser sintering. Acta Biomater. 2007, 3, 1–12. [Google Scholar] [CrossRef]
  139. Shuai, C.J.; Li, P.J.; Feng, P.; Lu, H.B.; Peng, S.P.; Liu, J.L. Analysis of transient temperature distribution during the selective laser sintering of β-tricalcium phosphate. Laser Eng. 2013, 26, 71–80. [Google Scholar]
  140. Shuai, C.; Zhuang, J.; Hu, H.; Peng, S.; Liu, D.; Liu, J. In vitro bioactivity and degradability of β-tricalcium phosphate porous scaffold fabricated via selective laser sintering. Biotechnol. Appl. Biochem. 2013, 60, 266–273. [Google Scholar] [CrossRef] [PubMed]
  141. Qin, T.; Li, X.; Long, H.; Bin, S.; Xu, Y. Bioactive tetracalcium phosphate scaffolds fabricated by selective laser sintering for bone regeneration applications. Materials 2020, 13, 2268. [Google Scholar] [CrossRef]
  142. Bulina, N.V.; Titkov, A.I.; Baev, S.G.; Makarova, S.V.; Khusnutdinov, V.R.; Bessmeltsev, V.P.; Lyakhov, N.Z. Laser sintering of hydroxyapatite for potential fabrication of bioceramic scaffolds. Mater. Today Proc. 2021, 37, 4022–4026. [Google Scholar] [CrossRef]
  143. Lusquiños, F.; Pou, J.; Boutinguiza, M.; Quintero, F.; Soto, R.; León, B.; Pérez-Amor, M. Main characteristics of calcium phosphate coatings obtained by laser cladding. Appl. Surf. Sci. 2005, 247, 486–492. [Google Scholar] [CrossRef]
  144. Wang, D.G.; Chen, C.Z.; Ma, J.; Zhang, G. In situ synthesis of hydroxyapatite coating by laser cladding. Colloid Surf. B 2008, 66, 155–162. [Google Scholar] [CrossRef]
  145. Comesaña, R.; Lusquiños, F.; del Val, J.; Malot, T.; López-Álvarez, M.; Riveiro, A.; Quintero, F.; Boutinguiza, M.; Aubry, P.; de Carlos, A.; et al. Calcium phosphate grafts produced by rapid prototyping based on laser cladding. J. Eur. Ceram. Soc. 2011, 31, 29–41. [Google Scholar] [CrossRef]
  146. Jing, Z.; Cao, Q.; Jun, H. Corrosion, wear and biocompatibility of hydroxyapatite bio-functionally graded coating on titanium alloy surface prepared by laser cladding. Ceram. Int. 2021, 47, 24641–24651. [Google Scholar] [CrossRef]
  147. Leukers, B.; Gülkan, H.; Irsen, S.H.; Milz, S.; Tille, C.; Schieker, M.; Seitz, H. Hydroxyapatite scaffolds for bone tissue engineering made by 3D printing. J. Mater. Sci. Mater. Med. 2005, 16, 1121–1124. [Google Scholar] [CrossRef]
  148. Gbureck, U.; Hölzel, T.; Klammert, U.; Würzler, K.; Müller, F.A.; Barralet, J.E. Resorbable dicalcium phosphate bone substitutes prepared by 3D powder printing. Adv. Funct. Mater. 2007, 17, 3940–3945. [Google Scholar] [CrossRef]
  149. Seitz, H.; Deisinger, U.; Leukers, B.; Detsch, R.; Ziegler, G. Different calcium phosphate granules for 3-D printing of bone tissue engineering scaffolds. Adv. Eng. Mater. 2009, 11, B41–B46. [Google Scholar] [CrossRef]
  150. Butscher, A.; Bohner, M.; Roth, C.; Ernstberger, A.; Heuberger, R.; Doebelin, N.; von Rohr, R.P.; Müller, R. Printability of calcium phosphate powders for three-dimensional printing of tissue engineering scaffolds. Acta Biomater. 2012, 8, 373–385. [Google Scholar] [CrossRef]
  151. Akkineni, A.R.; Luo, Y.; Schumacher, M.; Nies, B.; Lode, A.; Gelinsky, M. 3D plotting of growth factor loaded calcium phosphate cement scaffolds. Acta Biomater. 2015, 27, 264–274. [Google Scholar] [CrossRef]
  152. Trombetta, R.; Inzana, J.A.; Schwarz, E.M.; Kates, S.L.; Awad, H.A. 3D printing of calcium phosphate ceramics for bone tissue engineering and drug delivery. Ann. Biomed. Eng. 2017, 45, 23–44. [Google Scholar] [CrossRef]
  153. Ma, H.; Feng, C.; Chang, J.; Wu, C. 3D-printed bioceramic scaffolds: From bone tissue engineering to tumor therapy. Acta Biomater. 2018, 79, 37–59. [Google Scholar] [CrossRef]
  154. Miranda, P.; Pajares, A.; Saiz, E.; Tomsia, A.P.; Guiberteau, F. Mechanical behaviour under uniaxial compression of robocast calcium phosphate scaffolds. Eur. Cells Mater. 2007, 14 (Suppl. 1), 79. [Google Scholar]
  155. Maazouz, Y.; Montufar, E.B.; Guillem-Marti, J.; Fleps, I.; Öhman, C.; Persson, C.; Ginebra, M.P. Robocasting of biomimetic hydroxyapatite scaffolds using self-setting inks. J. Mater. Chem. B 2014, 2, 5378–5386. [Google Scholar] [CrossRef] [Green Version]
  156. Liu, Q.; Lu, W.F.; Zhai, W. Toward stronger robocast calcium phosphate scaffolds for bone tissue engineering: A mini-review and meta-analysis. Biomater. Adv. 2022, 134, 112578. [Google Scholar] [CrossRef]
  157. Porter, N.L.; Pilliar, R.M.; Grynpas, M.D. Fabrication of porous calcium polyphosphate implants by solid freeform fabrication: A study of processing parameters and in vitro degradation characteristics. J. Biomed. Mater. Res. 2001, 56, 504–515. [Google Scholar] [CrossRef]
  158. Leong, K.F.; Cheah, C.M.; Chua, C.K. Solid freeform fabrication of three-dimensional scaffolds for engineering replacement tissues and organs. Biomaterials 2003, 24, 2363–2378. [Google Scholar] [CrossRef]
  159. Shanjani, Y.; de Croos, J.N.A.; Pilliar, R.M.; Kandel, R.A.; Toyserkani, E. Solid freeform fabrication and characterization of porous calcium polyphosphate structures for tissue engineering purposes. J. Biomed. Mater. Res. B Appl. Biomater. 2010, 93B, 510–519. [Google Scholar] [CrossRef] [PubMed]
  160. Kim, J.; Lim, D.; Kim, Y.H.; Koh, Y.H.; Lee, M.H.; Han, I.; Lee, S.J.; Yoo, O.S.; Kim, H.S.; Park, J.C. A comparative study of the physical and mechanical properties of porous hydroxyapatite scaffolds fabricated by solid freeform fabrication and polymer replication method. Int. J. Precision Eng. Manuf. 2011, 12, 695–701. [Google Scholar] [CrossRef]
  161. Shanjani, Y.; Hu, Y.; Toyserkani, E.; Grynpas, M.; Kandel, R.A.; Pilliar, R.M. Solid freeform fabrication of porous calcium polyphosphate structures for bone substitute applications: In vivo studies. J. Biomed. Mater. Res. B Appl. Biomater. 2013, 101B, 972–980. [Google Scholar] [CrossRef] [PubMed]
  162. Kwon, B.J.; Kim, J.; Kim, Y.H.; Lee, M.H.; Baek, H.S.; Lee, D.H.; Kim, H.L.; Seo, H.J.; Lee, M.H.; Kwon, S.Y.; et al. Biological advantages of porous hydroxyapatite scaffold made by solid freeform fabrication for bone tissue regeneration. Artif. Organs 2013, 37, 663–670. [Google Scholar] [CrossRef] [PubMed]
  163. Li, X.; Li, D.; Lu, B.; Wang, C. Fabrication of bioceramic scaffolds with pre-designed internal architecture by gel casting and indirect stereolithography techniques. J. Porous Mater. 2008, 15, 667–671. [Google Scholar] [CrossRef]
  164. Ronca, A.; Ambrosio, L.; Grijpma, D.W. Preparation of designed poly(D,L-lactide)/nanosized hydroxyapatite composite structures by stereolithography. Acta Biomater. 2013, 9, 5989–5996. [Google Scholar] [CrossRef]
  165. Wei, Y.; Zhao, D.; Cao, Q.; Wang, J.; Wu, Y.; Yuan, B.; Li, X.; Chen, X.; Zhou, Y.; Yang, X.; et al. Stereolithography-based additive manufacturing of high-performance osteoinductive calcium phosphate ceramics by a digital light-processing system. ACS Biomater. Sci. Eng. 2020, 6, 1787–1797. [Google Scholar] [CrossRef]
  166. Ullah, I.; Cao, L.; Cui, W.; Xu, Q.; Yang, R.; Tang, K.L.; Zhang, X. Stereolithography printing of bone scaffolds using biofunctional calcium phosphate nanoparticles. J. Mater. Sci. Technol. 2021, 88, 99–108. [Google Scholar]
  167. Paredes, C.; Martínez-Vázquez, F.J.; Elsayed, H.; Colombo, P.; Pajares, A.; Miranda, P. Evaluation of direct light processing for the fabrication of bioactive ceramic scaffolds: Effect of pore/strut size on manufacturability and mechanical performance. J. Eur. Ceram. Soc. 2021, 41, 892–900. [Google Scholar] [CrossRef]
  168. Gladman, A.S.; Matsumoto, E.A.; Nuzzo, R.G.; Mahadevan, L.; Lewis, J.A. Biomimetic 4D printing. Nat. Mater. 2016, 15, 413–418. [Google Scholar] [CrossRef]
  169. Hwangbo, H.; Lee, H.; Roh, E.J.; Kim, W.; Joshi, H.P.; Kwon, S.Y.; Choi, U.Y.; Han, I.B.; Kim, G.H. Bone tissue engineering via application of a collagen/hydroxyapatite 4D-printed biomimetic scaffold for spinal fusion. Appl. Phys. Rev. 2021, 8, 021403. [Google Scholar] [CrossRef]
  170. Haleem, A.; Javaid, M.; Vaishya, R. 5D printing and its expected applications in orthopaedics. J. Clin. Orthop. Trauma. 2019, 10, 809–810. [Google Scholar] [CrossRef]
  171. Du, X.; Fu, S.; Zhu, Y. 3D printing of ceramic-based scaffolds for bone tissue engineering: An overview. J. Mater. Chem. B 2018, 6, 4397–4412. [Google Scholar] [CrossRef]
  172. Kumar, A.; Kargozar, S.; Baino, F.; Han, S.S. Additive manufacturing methods for producing hydroxyapatite and hydroxyapatite-based composite scaffolds: A review. Front. Mater. 2019, 6, 313. [Google Scholar] [CrossRef]
  173. Chen, Z.; Li, Z.; Li, J.; Liu, C.; Lao, C.; Lao, C.; Fu, Y.; Liu, C.; Li, Y.; Wang, P.; et al. 3D printing of ceramics: A review. J. Eur. Ceram. Soc. 2019, 39, 661–687. [Google Scholar] [CrossRef]
  174. Qu, H. Additive manufacturing for bone tissue engineering scaffolds. Mater. Today Commun. 2020, 24, 101024. [Google Scholar] [CrossRef]
  175. Saber-Samandari, S.; Gross, K.A. The use of thermal printing to control the properties of calcium phosphate deposits. Biomaterials 2010, 31, 6386–6393. [Google Scholar] [CrossRef]
  176. De Meira, C.R.; Gomes, D.T.; Braga, F.J.C.; de Moraes Purquerio, B.; Fortulan, C.A. Direct manufacture of hydroxyapatite scaffolds using blue laser. Mater. Sci. Forum 2015, 805, 128–133. [Google Scholar] [CrossRef]
  177. Narayan, R.J.; Jin, C.; Doraiswamy, A.; Mihailescu, I.N.; Jelinek, M.; Ovsianikov, A.; Chichkov, B.; Chrisey, D.B. Laser processing of advanced bioceramics. Adv. Eng. Mater. 2005, 7, 1083–1098. [Google Scholar] [CrossRef]
  178. Nather, A. (Ed.) Bone Grafts and Bone Substitutes: Basic Science and Clinical Applications; World Scientific: Singapore, 2005; p. 592. [Google Scholar]
  179. Bártolo, P.; Bidanda, B. (Eds.) Bio-Materials and Prototyping Applications in Medicine; Springer: New York, NY, USA, 2008; p. 216. [Google Scholar]
  180. Kokubo, T. (Ed.) Bioceramics and Their Clinical Applications; Woodhead Publishing: Cambridge, UK, 2008; p. 784. [Google Scholar]
  181. Narayan, R. (Ed.) Biomedical Materials; Springer: New York, NY, USA, 2009; p. 566. [Google Scholar]
  182. Park, J. Bioceramics: Properties, Characterizations, and Applications; Springer: New York, NY, USA, 2008; p. 364. [Google Scholar]
  183. Rodríguez-Lorenzo, L.M.; Vallet-Regí, M.; Ferreira, J.M.F. Fabrication of hydroxyapatite bodies by uniaxial pressing from a precipitated powder. Biomaterials 2001, 22, 583–588. [Google Scholar] [CrossRef]
  184. Indra, A.; Putra, A.B.; Handra, N.; Fahmi, H.; Nurzal; Asfarizal; Perdana, M.; Anrinal; Subardi, A.; Affi, J.; et al. Behavior of sintered body properties of hydroxyapatite ceramics: Effect of uniaxial pressure on green body fabrication. Mater. Today Sustain. 2022, 17, 100100. [Google Scholar] [CrossRef]
  185. Uematsu, K.; Takagi, M.; Honda, T.; Uchida, N.; Saito, K. Transparent hydroxyapatite prepared by hot isostatic pressing of filter cake. J. Am. Ceram. Soc. 1989, 72, 1476–1478. [Google Scholar] [CrossRef]
  186. Itoh, H.; Wakisaka, Y.; Ohnuma, Y.; Kuboki, Y. A new porous hydroxyapatite ceramic prepared by cold isostatic pressing and sintering synthesized flaky powder. Dent. Mater. 1994, 13, 25–35. [Google Scholar] [CrossRef]
  187. Takikawa, K.; Akao, M. Fabrication of transparent hydroxyapatite and application to bone marrow derived cell/hydroxyapatite interaction observation in-vivo. J. Mater. Sci. Mater. Med. 1996, 7, 439–445. [Google Scholar] [CrossRef]
  188. Gautier, H.; Merle, C.; Auget, J.L.; Daculsi, G. Isostatic compression, a new process for incorporating vancomycin into biphasic calcium phosphate: Comparison with a classical method. Biomaterials 2000, 21, 243–249. [Google Scholar] [CrossRef]
  189. Tadic, D.; Epple, M. Mechanically stable implants of synthetic bone mineral by cold isostatic pressing. Biomaterials 2003, 24, 4565–4571. [Google Scholar] [CrossRef]
  190. Onoki, T.; Hashida, T. New method for hydroxyapatite coating of titanium by the hydrothermal hot isostatic pressing technique. Surf. Coat. Technol. 2006, 200, 6801–6807. [Google Scholar] [CrossRef]
  191. Ehsani, N.; Ruys, A.J.; Sorrell, C.C. Hot isostatic pressing (HIPing) of fecralloy-reinforced hydroxyapatite. J. Biomimet. Biomater. Tissue Eng. 2013, 17, 87–102. [Google Scholar] [CrossRef]
  192. Irsen, S.H.; Leukers, B.; Höckling, C.; Tille, C.; Seitz, H. Bioceramic granulates for use in 3D printing: Process engineering aspects. Materwiss. Werksttech. 2006, 37, 533–537. [Google Scholar] [CrossRef]
  193. Hsu, Y.H.; Turner, I.G.; Miles, A.W. Fabrication and mechanical testing of porous calcium phosphate bioceramic granules. J. Mater. Sci. Mater. Med. 2007, 18, 1931–1937. [Google Scholar] [CrossRef]
  194. Zyman, Z.Z.; Glushko, V.; Dedukh, N.; Malyshkina, S.; Ashukina, N. Porous calcium phosphate ceramic granules and their behaviour in differently loaded areas of skeleton. J. Mater. Sci. Mater. Med. 2008, 19, 2197–2205. [Google Scholar] [CrossRef]
  195. Viana, M.; Désiré, A.; Chevalier, E.; Champion, E.; Chotard, R.; Chulia, D. Interest of high shear wet granulation to produce drug loaded porous calcium phosphate pellets for bone filling. Key Eng. Mater. 2009, 396–398, 535–538. [Google Scholar] [CrossRef]
  196. Chevalier, E.; Viana, M.; Cazalbou, S.; Chulia, D. Comparison of low-shear and high-shear granulation processes: Effect on implantable calcium phosphate granule properties. Drug Dev. Ind. Pharm. 2009, 35, 1255–1263. [Google Scholar] [CrossRef]
  197. 197 Lakevics, V.; Locs, J.; Loca, D.; Stepanova, V.; Berzina-Cimdina, L.; Pelss, J. Bioceramic hydroxyapatite granules for purification of biotechnological products. Adv. Mater. Res. 2011, 284–286, 1764–1769. [Google Scholar] [CrossRef]
  198. Camargo, N.H.A.; Franczak, P.F.; Gemelli, E.; da Costa, B.D.; de Moraes, A.N. Characterization of three calcium phosphate microporous granulated bioceramics. Adv. Mater. Res. 2014, 936, 687–694. [Google Scholar] [CrossRef]
  199. Reikerås, O.; Johansson, C.B.; Sundfeldt, M. Bone ingrowths to press-fit and loose-fit implants: Comparisons between titanium and hydroxyapatite. J. Long-Term Eff. Med. Implant. 2006, 16, 157–164. [Google Scholar] [CrossRef]
  200. Rao, R.R.; Kannan, T.S. Dispersion and slip casting of hydroxyapatite. J. Am. Ceram. Soc. 2001, 84, 1710–1716. [Google Scholar] [CrossRef]
  201. Sakka, Y.; Takahashi, K.; Matsuda, N.; Suzuki, T.S. Effect of milling treatment on texture development of hydroxyapatite ceramics by slip casting in high magnetic field. Mater. Trans. 2007, 48, 2861–2866. [Google Scholar] [CrossRef] [Green Version]
  202. Zhang, Y.; Yokogawa, Y.; Feng, X.; Tao, Y.; Li, Y. Preparation and properties of bimodal porous apatite ceramics through slip casting using different hydroxyapatite powders. Ceram. Int. 2010, 36, 107–113. [Google Scholar] [CrossRef]
  203. Zhang, Y.; Kong, D.; Yokogawa, Y.; Feng, X.; Tao, Y.; Qiu, T. Fabrication of porous hydroxyapatite ceramic scaffolds with high flexural strength through the double slip-casting method using fine powders. J. Am. Ceram. Soc. 2012, 95, 147–152. [Google Scholar] [CrossRef]
  204. Hagio, T.; Yamauchi, K.; Kohama, T.; Matsuzaki, T.; Iwai, K. Beta tricalcium phosphate ceramics with controlled crystal orientation fabricated by application of external magnetic field during the slip casting process. Mater. Sci. Eng. C 2013, 33, 2967–2970. [Google Scholar] [CrossRef] [PubMed]
  205. Marçal, R.L.S.B.; da Rocha, D.N.; da Silva, M.H.P. Slip casting used as a forming technique for hydroxyapatite processing. Key Eng. Mater. 2017, 720, 219–222. [Google Scholar] [CrossRef]
  206. Sepulveda, P.; Ortega, F.S.; Innocentini, M.D.M.; Pandolfelli, V.C. Properties of highly porous hydroxyapatite obtained by the gel casting of foams. J. Am. Ceram. Soc. 2000, 83, 3021–3024. [Google Scholar] [CrossRef]
  207. Sánchez-Salcedo, S.; Werner, J.; Vallet-Regí, M. Hierarchical pore structure of calcium phosphate scaffolds by a combination of gel-casting and multiple tape-casting methods. Acta Biomater. 2008, 4, 913–922. [Google Scholar] [CrossRef]
  208. Chen, B.; Zhang, T.; Zhang, J.; Lin, Q.; Jiang, D. Microstructure and mechanical properties of hydroxyapatite obtained by gel-casting process. Ceram. Int. 2008, 34, 359–364. [Google Scholar] [CrossRef]
  209. Marcassoli, P.; Cabrini, M.; Tirillò, J.; Bartuli, C.; Palmero, P.; Montanaro, L. Mechanical characterization of hydroxiapatite micro/macro-porous ceramics obtained by means of innovative gel-casting process. Key Eng. Mater. 2010, 417–418, 565–568. [Google Scholar] [CrossRef]
  210. Dash, S.R.; Sarkar, R.; Bhattacharyya, S. Gel casting of hydroxyapatite with naphthalene as pore former. Ceram. Int. 2015, 41, 3775–3790. [Google Scholar] [CrossRef]
  211. Ramadas, M.; Ferreira, J.M.F.; Ballamurugan, A.M. Fabrication of three dimensional bioactive Sr2+ substituted apatite scaffolds by gel-casting technique for hard tissue regeneration. J. Tissue Eng. Regen. Med. 2021, 15, 577–585. [Google Scholar] [CrossRef]
  212. Fomin, A.S.; Barinov, S.M.; Ievlev, V.M.; Smirnov, V.V.; Mikhailov, B.P.; Belonogov, E.K.; Drozdova, N.A. Nanocrystalline hydroxyapatite ceramics produced by low-temperature sintering after high-pressure treatment. Dokl. Chem. 2008, 418, 22–25. [Google Scholar] [CrossRef]
  213. Zhang, J.; Yin, H.M.; Hsiao, B.S.; Zhong, G.J.; Li, Z.M. Biodegradable poly(lactic acid)/hydroxyl apatite 3D porous scaffolds using high-pressure molding and salt leaching. J. Mater. Sci. 2014, 49, 1648–1658. [Google Scholar] [CrossRef]
  214. Zhang, J.; Liu, H.; Ding, J.X.; Wu, J.; Zhuang, X.; Chen, X.; Wang, J.; Yin, J.; Li, Z. High-pressure compression-molded porous resorbable polymer/hydroxyapatite composite scaffold for cranial bone regeneration. ACS Biomater. Sci. Eng. 2016, 2, 1471–1482. [Google Scholar] [CrossRef]
  215. Kankawa, Y.; Kaneko, Y.; Saitou, K. Injection molding of highly-purified hydroxylapatite and TCP utilizing solid phase reaction method. J. Ceram. Soc. Jpn. 1991, 99, 438–442. [Google Scholar] [CrossRef]
  216. Cihlář, J.; Trunec, M. Injection moulded hydroxyapatite ceramics. Biomaterials 1996, 17, 1905–1911. [Google Scholar] [CrossRef]
  217. Jewad, R.; Bentham, C.; Hancock, B.; Bonfield, W.; Best, S.M. Dispersant selection for aqueous medium pressure injection moulding of anhydrous dicalcium phosphate. J. Eur. Ceram. Soc. 2008, 28, 547–553. [Google Scholar] [CrossRef]
  218. McNamara, S.L.; McCarthy, E.M.; Schmidt, D.F.; Johnston, S.P.; Kaplan, D.L. Rheological characterization, compression, and injection molding of hydroxyapatite-silk fibroin composites. Biomaterials 2021, 269, 120643. [Google Scholar] [CrossRef]
  219. Kwon, S.H.; Jun, Y.K.; Hong, S.H.; Lee, I.S.; Kim, H.E.; Won, Y.Y. Calcium phosphate bioceramics with various porosities and dissolution rates. J. Am. Ceram. Soc. 2002, 85, 3129–3131. [Google Scholar] [CrossRef]
  220. Fooki, A.C.B.M.; Aparecida, A.H.; Fideles, T.B.; Costa, R.C.; Fook, M.V.L. Porous hydroxyapatite scaffolds by polymer sponge method. Key Eng. Mater. 2009, 396–398, 703–706. [Google Scholar] [CrossRef]
  221. Sopyan, I.; Kaur, J. Preparation and characterization of porous hydroxyapatite through polymeric sponge method. Ceram. Int. 2009, 35, 3161–3168. [Google Scholar] [CrossRef]
  222. Bellucci, D.; Cannillo, V.; Sola, A. Shell scaffolds: A new approach towards high strength bioceramic scaffolds for bone regeneration. Mater. Lett. 2010, 64, 203–206. [Google Scholar] [CrossRef]
  223. Cunningham, E.; Dunne, N.; Walker, G.; Maggs, C.; Wilcox, R.; Buchanan, F. Hydroxyapatite bone substitutes developed via replication of natural marine sponges. J. Mater. Sci. Mater. Med. 2010, 21, 2255–2261. [Google Scholar] [CrossRef]
  224. Sung, J.H.; Shin, K.H.; Koh, Y.H.; Choi, W.Y.; Jin, Y.; Kim, H.E. Preparation of the reticulated hydroxyapatite ceramics using carbon-coated polymeric sponge with elongated pores as a novel template. Ceram. Int. 2011, 37, 2591–2596. [Google Scholar] [CrossRef]
  225. Mishima, F.D.; Louro, L.H.L.; Moura, F.N.; Gobbo, L.A.; da Silva, M.H.P. Hydroxyapatite scaffolds produced by hydrothermal deposition of monetite on polyurethane sponges substrates. Key Eng. Mater. 2012, 493–494, 820–825. [Google Scholar] [CrossRef]
  226. Hannickel, A.; da Silva, M.H.P. Novel bioceramic scaffolds for regenerative medicine. Bioceram. Dev. Appl. 2015, 5, 1000082. [Google Scholar]
  227. Das, S.; Kumar, S.; Doloi, B.; Bhattacharyya, B. Experimental studies of ultrasonic machining on hydroxyapatite bio-ceramics. Int. J. Adv. Manuf. Tech. 2016, 86, 829–839. [Google Scholar] [CrossRef]
  228. Velayudhan, S.; Ramesh, P.; Sunny, M.C.; Varma, H.K. Extrusion of hydroxyapatite to clinically significant shapes. Mater. Lett. 2000, 46, 142–146. [Google Scholar] [CrossRef]
  229. Yang, H.Y.; Thompson, I.; Yang, S.F.; Chi, X.P.; Evans, J.R.G.; Cook, R.J. Dissolution characteristics of extrusion freeformed hydroxyapatite–tricalcium phosphate scaffolds. J. Mater. Sci. Mater. Med. 2008, 19, 3345–3353. [Google Scholar] [CrossRef]
  230. Yang, S.; Yang, H.; Chi, X.; Evans, J.R.G.; Thompson, I.; Cook, R.J.; Robinson, P. Rapid prototyping of ceramic lattices for hard tissue scaffolds. Mater. Des. 2008, 29, 1802–1809. [Google Scholar] [CrossRef]
  231. Yang, H.Y.; Chi, X.P.; Yang, S.; Evans, J.R.G. Mechanical strength of extrusion freeformed calcium phosphate filaments. J. Mater. Sci. Mater. Med. 2010, 21, 1503–1510. [Google Scholar] [CrossRef]
  232. Cortez, P.P.; Atayde, L.M.; Silva, M.A.; da Silva, P.A.; Fernandes, M.H.; Afonso, A.; Lopes, M.A.; Maurício, A.C.; Santos, J.D. Characterization and preliminary in vivo evaluation of a novel modified hydroxyapatite produced by extrusion and spheronization techniques. J. Biomed. Mater. Res. B Appl. Biomater. 2011, 99B, 170–179. [Google Scholar] [CrossRef]
  233. Lim, S.; Chun, S.; Yang, D.; Kim, S. Comparison study of porous calcium phosphate blocks prepared by piston and screw type extruders for bone scaffold. Tissue Eng. Regen. Med. 2012, 9, 51–55. [Google Scholar] [CrossRef]
  234. Blake, D.M.; Tomovic, S.; Jyung, R.W. Extrusion of hydroxyapatite ossicular prosthesis. Ear Nose Throat J. 2013, 92, 490–494. [Google Scholar] [CrossRef]
  235. Muthutantri, A.I.; Huang, J.; Edirisinghe, M.J.; Bretcanu, O.; Boccaccini, A.R. Dipping and electrospraying for the preparation of hydroxyapatite foams for bone tissue engineering. Biomed. Mater. 2008, 3, 25009. [Google Scholar] [CrossRef]
  236. Roncari, E.; Galassi, C.; Pinasco, P. Tape casting of porous hydroxyapatite ceramics. J. Mater. Sci. Lett. 2000, 19, 33–35. [Google Scholar] [CrossRef]
  237. Tian, T.; Jiang, D.; Zhang, J.; Lin, Q. Aqueous tape casting process for hydroxyapatite. J. Eur. Ceram. Soc. 2007, 27, 2671–2677. [Google Scholar] [CrossRef]
  238. Tanimoto, Y.; Shibata, Y.; Murakami, A.; Miyazaki, T.; Nishiyama, N. Effect of varying HAP/TCP ratios in tape-cast biphasic calcium phosphate ceramics on responcce in vitro. J. Hard Tiss. Biol. 2009, 18, 71–76. [Google Scholar] [CrossRef]
  239. Tanimoto, Y.; Teshima, M.; Nishiyama, N.; Yamaguchi, M.; Hirayama, S.; Shibata, Y.; Miyazaki, T. Tape-cast and sintered β-tricalcium phosphate laminates for biomedical applications: Effect of milled Al2O3 fiber additives on microstructural and mechanical properties. J. Biomed. Mater. Res. B Appl. Biomater. 2012, 100B, 2261–2268. [Google Scholar] [CrossRef]
  240. Khamkasem, C.; Chaijaruwanich, A. Effect of binder/plasticizer ratios in aqueous-based tape casting on mechanical properties of bovine hydroxyapatite tape. Ferroelectrics 2013, 455, 129–135. [Google Scholar] [CrossRef]
  241. Suzuki, S.; Itoh, K.; Ohgaki, M.; Ohtani, M.; Ozawa, M. Preparation of sintered filter for ion exchange by a doctor blade method with aqueous slurries of needlelike hydroxyapatite. Ceram. Int. 1999, 25, 287–291. [Google Scholar] [CrossRef]
  242. Nishikawa, H.; Hatanaka, R.; Kusunoki, M.; Hayami, T.; Hontsu, S. Preparation of freestanding hydroxyapatite membranes excellent biocompatibility and flexibility. Appl. Phys. Express 2008, 1, 088001. [Google Scholar] [CrossRef]
  243. Padilla, S.; Roman, J.; Vallet-Regí, M. Synthesis of porous hydroxyapatites by combination of gel casting and foams burn out methods. J. Mater. Sci. Mater. Med. 2002, 13, 1193–1197. [Google Scholar] [CrossRef]
  244. Yang, T.Y.; Lee, J.M.; Yoon, S.Y.; Park, H.C. Hydroxyapatite scaffolds processed using a TBA-based freeze-gel casting/polymer sponge technique. J. Mater. Sci. Mater. Med. 2010, 21, 1495–1502. [Google Scholar] [CrossRef] [PubMed]
  245. Baradararan, S.; Hamdi, M.; Metselaar, I.H. Biphasic calcium phosphate (BCP) macroporous scaffold with different ratios of HA/β-TCP by combination of gel casting and polymer sponge methods. Adv. Appl. Ceram. 2012, 111, 367–373. [Google Scholar] [CrossRef]
  246. Inoue, K.; Sassa, K.; Yokogawa, Y.; Sakka, Y.; Okido, M.; Asai, S. Control of crystal orientation of hydroxyapatite by imposition of a high magnetic field. Mater. Trans. 2003, 44, 1133–1137. [Google Scholar] [CrossRef]
  247. Iwai, K.; Akiyama, J.; Tanase, T.; Asai, S. Alignment of HAp crystal using a sample rotation in a static magnetic field. Mater. Sci. Forum. 2007, 539–543, 716–719. [Google Scholar] [CrossRef]
  248. Iwai, K.; Akiyama, J.; Asai, S. Structure control of hydroxyapatite using a magnetic field. Mater. Sci. Forum. 2007, 561–565, 1565–1568. [Google Scholar] [CrossRef]
  249. Sakka, Y.; Takahashi, K.; Suzuki, T.S.; Ito, S.; Matsuda, N. Texture development of hydroxyapatite ceramics by colloidal processing in a high magnetic field followed by sintering. Mater. Sci. Eng. A 2008, 475, 27–33. [Google Scholar] [CrossRef]
  250. Fleck, N.A. On the cold compaction of powders. J. Mech. Phys. Solids 1995, 43, 1409–1431. [Google Scholar] [CrossRef]
  251. Kang, J.; Hadfield, M. Parameter optimization by Taguchi methods for finishing advanced ceramic balls using a novel eccentric lapping machine. Proc. Inst. Mech. Eng. B 2001, 215, 69–78. [Google Scholar] [CrossRef]
  252. Kulkarni, S.S.; Yong, Y.; Rys, M.J.; Lei, S. Machining assessment of nano-crystalline hydroxyapatite bio-ceramic. J. Manuf. Processes 2013, 15, 666–672. [Google Scholar] [CrossRef]
  253. Kurella, A.; Dahotre, N.B. Surface modification for bioimplants: The role of laser surface engineering. J. Biomater. Appl. 2005, 20, 5–50. [Google Scholar] [CrossRef]
  254. Moriguchi, Y.; Lee, D.S.; Chijimatsu, R.; Thamina, K.; Masuda, K.; Itsuki, D.; Yoshikawa, H.; Hamaguchi, S.; Myoui, A. Impact of non-thermal plasma surface modification on porous calcium hydroxyapatite ceramics for bone regeneration. PLoS ONE 2018, 13, e0194303. [Google Scholar]
  255. Bertol, L.S.; Schabbach, R.; dos Santos, L.A.L. Different post-processing conditions for 3D bioprinted α-tricalcium phosphate scaffolds. J. Mater. Sci. Mater. Med. 2017, 28, 168. [Google Scholar] [CrossRef]
  256. Oktar, F.N.; Genc, Y.; Goller, G.; Erkmen, E.Z.; Ozyegin, L.S.; Toykan, D.; Demirkiran, H.; Haybat, H. Sintering of synthetic hydroxyapatite compacts. Key Eng. Mater. 2004, 264–268, 2087–2090. [Google Scholar] [CrossRef]
  257. Georgiou, G.; Knowles, J.C.; Barralet, J.E. Dynamic shrinkage behavior of hydroxyapatite and glass-reinforced hydroxyapatites. J. Mater. Sci. 2004, 39, 2205–2208. [Google Scholar] [CrossRef]
  258. Fellah, B.H.; Layrolle, P. Sol-gel synthesis and characterization of macroporous calcium phosphate bioceramics containing microporosity. Acta Biomater. 2009, 5, 735–742. [Google Scholar] [CrossRef]
  259. Kutty, M.G.; Bhaduri, S.B.; Zhou, H.; Yaghoubi, A. In situ measurement of shrinkage and temperature profile in microwave- and conventionally-sintered hydroxyapatite bioceramic. Mater. Lett. 2015, 161, 375–378. [Google Scholar] [CrossRef]
  260. Ben Ayed, F.; Bouaziz, J.; Bouzouita, K. Pressureless sintering of fluorapatite under oxygen atmosphere. J. Eur. Ceram. Soc. 2000, 20, 1069–1076. [Google Scholar] [CrossRef]
  261. He, Z.; Ma, J.; Wang, C. Constitutive modeling of the densification and the grain growth of hydroxyapatite ceramics. Biomaterials 2005, 26, 1613–1621. [Google Scholar] [CrossRef] [PubMed]
  262. Rahaman, M.N. Sintering of Ceramics; CRC Press: Boca Raton, FL, USA, 2007; p. 388. [Google Scholar]
  263. Monroe, E.A.; Votava, W.; Bass, D.B.; McMullen, J. New calcium phosphate ceramic material for bone and tooth implants. J. Dent. Res. 1971, 50, 860–861. [Google Scholar] [CrossRef] [PubMed]
  264. Landi, E.; Tampieri, A.; Celotti, G.; Sprio, S. Densification behaviour and mechanisms of synthetic hydroxyapatites. J. Eur. Ceram. Soc. 2000, 20, 2377–2387. [Google Scholar] [CrossRef]
  265. Döbelin, N.; Maazouz, Y.; Heuberger, R.; Bohner, M.; Armstrong, A.A.; Wagoner Johnson, A.J.; Wanner, C. A thermodynamic approach to surface modification of calcium phosphate implants by phosphate evaporation and condensation. J. Eur. Ceram. Soc. 2020, 40, 6095–6106. [Google Scholar] [CrossRef]
  266. Chen, S.; Wang, W.; Kono, H.; Sassa, K.; Asai, S. Abnormal grain growth of hydroxyapatite ceramic sintered in a high magnetic field. J. Cryst. Growth 2010, 312, 323–326. [Google Scholar] [CrossRef]
  267. Ruys, A.J.; Wei, M.; Sorrell, C.C.; Dickson, M.R.; Brandwood, A.; Milthorpe, B.K. Sintering effect on the strength of hydroxyapatite. Biomaterials 1995, 16, 409–415. [Google Scholar] [CrossRef]
  268. Van Landuyt, P.; Li, F.; Keustermans, J.P.; Streydio, J.M.; Delannay, F.; Munting, E. The influence of high sintering temperatures on the mechanical properties of hydroxylapatite. J. Mater. Sci. Mater. Med. 1995, 6, 8–13. [Google Scholar] [CrossRef]
  269. Pramanik, S.; Agarwal, A.K.; Rai, K.N.; Garg, A. Development of high strength hydroxyapatite by solid-state-sintering process. Ceram. Int. 2007, 33, 419–426. [Google Scholar] [CrossRef]
  270. Haberko, K.; Bućko, M.M.; Brzezińska-Miecznik, J.; Haberko, M.; Mozgawa, W.; Panz, T.; Pyda, A.; Zarebski, J. Natural hydroxyapatite–its behaviour during heat treatment. J. Eur. Ceram. Soc. 2006, 26, 537–542. [Google Scholar] [CrossRef]
  271. Haberko, K.; Bućko, M.M.; Mozgawa, W.; Pyda, A.; Brzezińska-Miecznik, J.; Carpentier, J. Behaviour of bone origin hydroxyapatite at elevated temperatures and in O2 and CO2 atmospheres. Ceram. Int. 2009, 35, 2537–2540. [Google Scholar] [CrossRef]
  272. Janus, A.M.; Faryna, M.; Haberko, K.; Rakowska, A.; Panz, T. Chemical and microstructural characterization of natural hydroxyapatite derived from pig bones. Mikrochim. Acta 2008, 161, 349–353. [Google Scholar] [CrossRef]
  273. Bahrololoom, M.E.; Javidi, M.; Javadpour, S.; Ma, J. Characterisation of natural hydroxyapatite extracted from bovine cortical bone ash. J. Ceram. Process. Res. 2009, 10, 129–138. [Google Scholar]
  274. Mostafa, N.Y. Characterization, thermal stability and sintering of hydroxyapatite powders prepared by different routes. Mater. Chem. Phys. 2005, 94, 333–341. [Google Scholar] [CrossRef]
  275. Suchanek, W.; Yashima, M.; Kakihana, M.; Yoshimura, M. Hydroxyapatite ceramics with selected sintering additives. Biomaterials 1997, 18, 923–933. [Google Scholar] [CrossRef]
  276. Kalita, S.J.; Bose, S.; Bandyopadhyay, A.; Hosick, H.L. Oxide based sintering additives for HAp ceramics. Ceram. Trans. 2003, 147, 63–72. [Google Scholar]
  277. Kalita, S.J.; Bose, S.; Hosick, H.L.; Bandyopadhyay, A. CaO–P2O5–Na2O-based sintering additives for hydroxyapatite (HAp) ceramics. Biomaterials 2004, 25, 2331–2339. [Google Scholar] [CrossRef]
  278. Safronova, T.V.; Putlyaev, V.I.; Shekhirev, M.A.; Tretyakov, Y.D.; Kuznetsov, A.V.; Belyakov, A.V. Densification additives for hydroxyapatite ceramics. J. Eur. Ceram. Soc. 2009, 29, 1925–1932. [Google Scholar] [CrossRef]
  279. Eskandari, A.; Aminzare, M.; Hassani, H.; Barounian, H.; Hesaraki, S.; Sadrnezhaad, S.K. Densification behavior and mechanical properties of biomimetic apatite nanocrystals. Curr. Nanosci. 2011, 7, 776–780. [Google Scholar] [CrossRef]
  280. Ramesh, S.; Tolouei, R.; Tan, C.Y.; Aw, K.L.; Yeo, W.H.; Sopyan, I.; Teng, W.D. Sintering of hydroxyapatite ceramic produced by wet chemical method. Adv. Mater. Res. 2011, 264–265, 1856–1861. [Google Scholar]
  281. Ou, S.F.; Chiou, S.Y.; Ou, K.L. Phase transformation on hydroxyapatite decomposition. Ceram. Int. 2013, 39, 3809–3816. [Google Scholar] [CrossRef]
  282. Bernache-Assollant, D.; Ababou, A.; Champion, E.; Heughebaert, M. Sintering of calcium phosphate hydroxyapatite Ca10(PO4)6(OH)2 I. Calcination and particle growth. J. Eur. Ceram. Soc. 2003, 23, 229–241. [Google Scholar] [CrossRef]
  283. Ramesh, S.; Tan, C.Y.; Bhaduri, S.B.; Teng, W.D.; Sopyan, I. Densification behaviour of nanocrystalline hydroxyapatite bioceramics. J. Mater. Process. Technol. 2008, 206, 221–230. [Google Scholar] [CrossRef]
  284. Wang, J.; Shaw, L.L. Grain-size dependence of the hardness of submicrometer and nanometer hydroxyapatite. J. Am. Ceram. Soc. 2010, 93, 601–604. [Google Scholar] [CrossRef]
  285. Kobayashi, S.; Kawai, W.; Wakayama, S. The effect of pressure during sintering on the strength and the fracture toughness of hydroxyapatite ceramics. J. Mater. Sci. Mater. Med. 2006, 17, 1089–1093. [Google Scholar] [CrossRef]
  286. Chen, I.W.; Wang, X.H. Sintering dense nanocrystalline ceramics without final-stage grain growth. Nature 2000, 404, 168–170. [Google Scholar] [CrossRef]
  287. Mazaheri, M.; Haghighatzadeh, M.; Zahedi, A.M.; Sadrnezhaad, S.K. Effect of a novel sintering process on mechanical properties of hydroxyapatite ceramics. J. Alloys Compd. 2009, 471, 180–184. [Google Scholar] [CrossRef]
  288. Panyata, S.; Eitssayeam, S.; Rujijanagul, G.; Tunkasiri, T.; Pengpat, K. Property development of hydroxyapatite ceramics by two-step sintering. Adv. Mater. Res. 2012, 506, 190–193. [Google Scholar] [CrossRef]
  289. Esnaashary, M.; Fathi, M.; Ahmadian, M. The effect of the two-step sintering process on consolidation of fluoridated hydroxyapatite and its mechanical properties and bioactivity. Int. J. Appl. Ceram. Technol. 2014, 11, 47–56. [Google Scholar] [CrossRef]
  290. Feng, P.; Niu, M.; Gao, C.; Peng, S.; Shuai, C. A novel two-step sintering for nano-hydroxyapatite scaffolds for bone tissue engineering. Sci. Rep. 2014, 4, 5599. [Google Scholar] [CrossRef]
  291. Halouani, R.; Bernache-Assolant, D.; Champion, E.; Ababou, A. Microstructure and related mechanical properties of hot pressed hydroxyapatite ceramics. J. Mater. Sci. Mater. Med. 1994, 5, 563–568. [Google Scholar] [CrossRef]
  292. Kasuga, T.; Ota, Y.; Tsuji, K.; Abe, Y. Preparation of high-strength calcium phosphate ceramics with low modulus of elasticity containing β-Ca(PO3)2 fibers. J. Am. Ceram. Soc. 1996, 79, 1821–1824. [Google Scholar] [CrossRef]
  293. Suchanek, W.L.; Yoshimura, M. Preparation of fibrous, porous hydroxyapatite ceramics from hydroxyapatite whiskers. J. Am. Ceram. Soc. 1998, 81, 765–767. [Google Scholar] [CrossRef]
  294. Kim, Y.; Kim, S.R.; Song, H.; Yoon, H. Preparation of porous hydroxyapatite/TCP composite block using a hydrothermal hot pressing method. Mater. Sci. Forum 2005, 486–487, 117–120. [Google Scholar] [CrossRef]
  295. Li, J.G.; Hashida, T. In situ formation of hydroxyapatite-whisker ceramics by hydrothermal hot-pressing method. J. Am. Ceram. Soc. 2006, 89, 3544–3546. [Google Scholar] [CrossRef]
  296. Li, J.G.; Hashida, T. Preparation of hydroxyapatite ceramics by hydrothermal hot-pressing method at 300 °C. J. Mater. Sci. 2007, 42, 5013–5019. [Google Scholar] [CrossRef]
  297. Petrakova, N.V.; Lysenkov, A.S.; Ashmarin, A.A.; Egorov, A.A.; Fedotov, A.Y.; Shvorneva, L.I.; Komlev, V.S.; Barinov, S.M. Effect of hot pressing temperature on the microstructure and strength of hydroxyapatite ceramic. Inorg. Mater. Appl. Res. 2013, 4, 362–367. [Google Scholar] [CrossRef]
  298. Nakahira, A.; Murakami, T.; Onoki, T.; Hashida, T.; Hosoi, K. Fabrication of porous hydroxyapatite using hydrothermal hot pressing and post-sintering. J. Am. Ceram. Soc. 2005, 88, 1334–1336. [Google Scholar] [CrossRef]
  299. Auger, M.A.; Savoini, B.; Muñoz, A.; Leguey, T.; Monge, M.A.; Pareja, R.; Victoria, J. Mechanical characteristics of porous hydroxyapatite/oxide composites produced by post-sintering hot isostatic pressing. Ceram. Int. 2009, 35, 2373–2380. [Google Scholar] [CrossRef]
  300. Guo, N.; Shen, H.Z.; Jin, Q.; Shen, P. Hydrated precursor-assisted densification of hydroxyapatite and its composites by cold sintering. Ceram. Int. 2020, 47, 14348–14353. [Google Scholar] [CrossRef]
  301. Silva, C.C.; Graça, M.P.F.; Sombra, A.S.B.; Valente, M.A. Structural and electrical study of calcium phosphate obtained by a microwave radiation assisted procedure. Phys. Rev. B Condens. Matter 2009, 404, 1503–1508. [Google Scholar] [CrossRef]
  302. Veljović, D.; Zalite, I.; Palcevskis, E.; Smiciklas, I.; Petrović, R.; Janaćković, D. Microwave sintering of fine grained HAP and HAP/TCP bioceramics. Ceram. Int. 2010, 36, 595–603. [Google Scholar] [CrossRef]
  303. Veljović, D.; Palcevskis, E.; Dindune, A.; Putić, S.; Balać, I.; Petrović, R.; Janaćković, D. Microwave sintering improves the mechanical properties of biphasic calcium phosphates from hydroxyapatite microspheres produced from hydrothermal processing. J. Mater. Sci. 2010, 45, 3175–3183. [Google Scholar] [CrossRef]
  304. Tarafder, S.; Balla, V.K.; Davies, N.M.; Bandyopadhyay, A.; Bose, S. Microwave-sintered 3D printed tricalcium phosphate scaffolds for bone tissue engineering. J. Tissue Eng. Regen. Med. 2013, 7, 631–641. [Google Scholar] [CrossRef]
  305. Thuault, A.; Savary, E.; Hornez, J.C.; Moreau, G.; Descamps, M.; Marinel, S.; Leriche, A. Improvement of the hydroxyapatite mechanical properties by direct microwave sintering in single mode cavity. J. Eur. Ceram. Soc. 2014, 34, 1865–1871. [Google Scholar] [CrossRef]
  306. Sikder, P.; Ren, Y.; Bhaduri, S.B. Microwave processing of calcium phosphate and magnesium phosphate based orthopedic bioceramics: A state-of-the-art review. Acta Biomater. 2020, 111, 29–53. [Google Scholar] [CrossRef]
  307. Nakamura, T.; Fukuhara, T.; Izui, H. Mechanical properties of hydroxyapatites sintered by spark plasma sintering. Ceram. Trans. 2006, 194, 265–272. [Google Scholar]
  308. Grossin, D.; Rollin-Martinet, S.; Estournès, C.; Rossignol, F.; Champion, E.; Combes, C.; Rey, C.; Geoffroy, C.; Drouet, C. Biomimetic apatite sintered at very low temperature by spark plasma sintering: Physico-chemistry and microstructure aspects. Acta Biomater. 2010, 6, 577–585. [Google Scholar] [CrossRef] [Green Version]
  309. Ortali, C.; Julien, I.; Vandenhende, M.; Drouet, C.; Champion, E. Consolidation of bone-like apatite bioceramics by spark plasma sintering of amorphous carbonated calcium phosphate at very low temperature. J. Eur. Ceram. Soc. 2018, 38, 2098–2109. [Google Scholar] [CrossRef]
  310. Chesnaud, A.; Bogicevic, C.; Karolak, F.; Estournès, C.; Dezanneau, G. Preparation of transparent oxyapatite ceramics by combined use of freeze-drying and spark-plasma sintering. Chem. Comm. 2007, 1550–1552. [Google Scholar] [CrossRef]
  311. Eriksson, M.; Liu, Y.; Hu, J.; Gao, L.; Nygren, M.; Shen, Z. Transparent hydroxyapatite ceramics with nanograin structure prepared by high pressure spark plasma sintering at the minimized sintering temperature. J. Eur. Ceram. Soc. 2011, 31, 1533–1540. [Google Scholar] [CrossRef]
  312. Yoshida, H.; Kim, B.N.; Son, H.W.; Han, Y.H.; Kim, S. Superplastic deformation of transparent hydroxyapatite. Scripta Mater. 2013, 69, 155–158. [Google Scholar] [CrossRef]
  313. Kim, B.N.; Prajatelistia, E.; Han, Y.H.; Son, H.W.; Sakka, Y.; Kim, S. Transparent hydroxyapatite ceramics consolidated by spark plasma sintering. Scripta Mater. 2013, 69, 366–369. [Google Scholar] [CrossRef]
  314. Yun, J.; Son, H.; Prajatelistia, E.; Han, Y.H.; Kim, S.; Kim, B.N. Characterisation of transparent hydroxyapatite nanoceramics prepared by spark plasma sintering. Adv. Appl. Ceram. 2014, 113, 67–72. [Google Scholar] [CrossRef]
  315. Li, Z.; Khor, K.A. Transparent hydroxyapatite obtained through spark plasma sintering: Optical and mechanical properties. Key Eng. Mater. 2015, 631, 51–56. [Google Scholar] [CrossRef]
  316. Frasnelli, M.; Sglavo, V.M. Flash sintering of tricalcium phosphate (TCP) bioceramics. J. Eur. Ceram. Soc. 2018, 38, 279–285. [Google Scholar] [CrossRef]
  317. Hwang, C.; Yun, J. Flash sintering of hydroxyapatite ceramics. J. Asian Ceram. Soc. 2021, 9, 281–288. [Google Scholar] [CrossRef]
  318. Biesuz, M.; Galotta, A.; Motta, A.; Kermani, M.; Grasso, S.; Vontorová, J.; Tyrpekl, V.; Vilémová, M.; Sglavo, V.M. Speedy bioceramics: Rapid densification of tricalcium phosphate by ultrafast high-temperature sintering. Mater. Sci. Eng. C 2021, 127, 112246. [Google Scholar] [CrossRef]
  319. Yanagisawa, K.; Kim, J.H.; Sakata, C.; Onda, A.; Sasabe, E.; Yamamoto, T.; Matamoros-Veloza, Z.; Rendón-Angeles, J.C. Hydrothermal sintering under mild temperature conditions: Preparation of calcium-deficient hydroxyapatite compacts. Z. Naturforsch. B 2010, 65, 1038–1044. [Google Scholar] [CrossRef]
  320. Hosoi, K.; Hashida, T.; Takahashi, H.; Yamasaki, N.; Korenaga, T. New processing technique for hydroxyapatite ceramics by the hydrothermal hot-pressing method. J. Am. Ceram. Soc. 1996, 79, 2771–2774. [Google Scholar] [CrossRef]
  321. Champion, E. Sintering of calcium phosphate bioceramics. Acta Biomater. 2013, 9, 5855–5875. [Google Scholar] [CrossRef]
  322. Indurkar, A.; Choudhary, R.; Rubenis, K.; Locs, J. Advances in sintering techniques for calcium phosphates ceramics. Materials 2021, 14, 6133. [Google Scholar]
  323. Evans, J.R.G. Seventy ways to make ceramics. J. Eur. Ceram. Soc. 2008, 28, 1421–1432. [Google Scholar] [CrossRef]
  324. Hench, L.L.; Polak, J.M. Third-generation biomedical materials. Science 2002, 295, 1014–1017. [Google Scholar] [CrossRef]
  325. Black, J. Biological Performance of Materials: Fundamentals of Biocompatibility, 4th ed.; CRC Press: Boca Raton, FL, USA, 2005; p. 520. [Google Scholar]
  326. Carter, C.B.; Norton, M.G. Ceramic Materials: Science and Engineering, 2nd ed.; Springer: New York, NY, USA, 2013; p. 766. [Google Scholar]
  327. Benaqqa, C.; Chevalier, J.; Saädaoui, M.; Fantozzi, G. Slow crack growth behaviour of hydroxyapatite ceramics. Biomaterials 2005, 26, 6106–6112. [Google Scholar] [CrossRef]
  328. Pecqueux, F.; Tancret, F.; Payraudeau, N.; Bouler, J.M. Influence of microporosity and macroporosity on the mechanical properties of biphasic calcium phosphate bioceramics: Modelling and experiment. J. Eur. Ceram. Soc. 2010, 30, 819–829. [Google Scholar] [CrossRef]
  329. Ramesh, S.; Tan, C.Y.; Sopyan, I.; Hamdi, M.; Teng, W.D. Consolidation of nanocrystalline hydroxyapatite powder. Sci. Technol. Adv. Mater. 2007, 8, 124–130. [Google Scholar] [CrossRef]
  330. Wagoner Johnson, A.J.; Herschler, B.A. A review of the mechanical behavior of CaP and CaP/polymer composites for applications in bone replacement and repair. Acta Biomater. 2011, 7, 16–30. [Google Scholar] [CrossRef]
  331. Suchanek, W.L.; Yoshimura, M. Processing and properties of hydroxyapatite-based biomaterials for use as hard tissue replacement implants. J. Mater. Res. 1998, 13, 94–117. [Google Scholar] [CrossRef]
  332. Fan, X.; Case, E.D.; Ren, F.; Shu, Y.; Baumann, M.J. Part I: Porosity dependence of the Weibull modulus for hydroxyapatite and other brittle materials. J. Mech. Behav. Biomed. Mater. 2012, 8, 21–36. [Google Scholar] [CrossRef]
  333. Fan, X.; Case, E.D.; Gheorghita, I.; Baumann, M.J. Weibull modulus and fracture strength of highly porous hydroxyapatite. J. Mech. Behav. Biomed. Mater. 2013, 20, 283–295. [Google Scholar] [CrossRef]
  334. Cordell, J.; Vogl, M.; Johnson, A. The influence of micropore size on the mechanical properties of bulk hydroxyapatite and hydroxyapatite scaffolds. J. Mech. Behav. Biomed. Mater. 2009, 2, 560–570. [Google Scholar] [CrossRef]
  335. Suzuki, S.; Sakamura, M.; Ichiyanagi, M.; Ozawa, M. Internal friction of hydroxyapatite and fluorapatite. Ceram. Int. 2004, 30, 625–627. [Google Scholar] [CrossRef]
  336. Suzuki, S.; Takahiro, K.; Ozawa, M. Internal friction and dynamic modulus of polycrystalline ceramics prepared from stoichiometric and Ca-deficient hydroxyapatites. Mater. Sci. Eng. B 1998, 55, 68–70. [Google Scholar] [CrossRef]
  337. Bouler, J.M.; Trecant, M.; Delecrin, J.; Royer, J.; Passuti, N.; Daculsi, G. Macroporous biphasic calcium phosphate ceramics: Influence of five synthesis parameters on compressive strength. J. Biomed. Mater. Res. 1996, 32, 603–609. [Google Scholar] [CrossRef]
  338. Tancret, F.; Bouler, J.M.; Chamousset, J.; Minois, L.M. Modelling the mechanical properties of microporous and macroporous biphasic calcium phosphate bioceramics. J. Eur. Ceram. Soc. 2006, 26, 3647–3656. [Google Scholar] [CrossRef]
  339. Le Huec, J.C.; Schaeverbeke, T.; Clement, D.; Faber, J.; le Rebeller, A. Influence of porosity on the mechanical resistance of hydroxyapatite ceramics under compressive stress. Biomaterials 1995, 16, 113–118. [Google Scholar] [CrossRef]
  340. Hsu, Y.H.; Turner, I.G.; Miles, A.W. Mechanical properties of three different compositions of calcium phosphate bioceramic following immersion in Ringer’s solution and distilled water. J. Mater. Sci. Mater. Med. 2009, 20, 2367–2374. [Google Scholar] [CrossRef]
  341. Torgalkar, A.M. Resonance frequency technique to determine elastic modulus of hydroxyapatite. J. Biomed. Mater. Res. 1979, 13, 907–920. [Google Scholar] [CrossRef]
  342. Gilmore, R.S.; Katz, J.L. Elastic properties of apatites. J. Mater. Sci. 1982, 17, 1131–1141. [Google Scholar] [CrossRef]
  343. Fan, X.; Case, E.D.; Ren, F.; Shu, Y.; Baumann, M.J. Part II: Fracture strength and elastic modulus as a function of porosity for hydroxyapatite and other brittle materials. J. Mech. Behav. Biomed. Mater. 2012, 8, 99–110. [Google Scholar] [CrossRef]
  344. Garcia-Prieto, A.; Hornez, J.C.; Leriche, A.; Pena, P.; Baudín, C. Influence of porosity on the mechanical behaviour of single phase β-TCP ceramics. Ceram. Int. 2017, 43, 6048–6053. [Google Scholar] [CrossRef]
  345. De Aza, P.N.; de Aza, A.H.; de Aza, S. Crystalline bioceramic materials. Bol. Soc. Esp. Ceram. V 2005, 44, 135–145. [Google Scholar] [CrossRef]
  346. Fritsch, A.; Dormieux, L.; Hellmich, C.; Sanahuja, J. Mechanical behavior of hydroxyapatite biomaterials: An experimentally validated micromechanical model for elasticity and strength. J. Biomed. Mater. Res. A 2009, 88A, 149–161. [Google Scholar] [CrossRef] [PubMed]
  347. Ching, W.Y.; Rulis, P.; Misra, A. Ab initio elastic properties and tensile strength of crystalline hydroxyapatite. Acta Biomater. 2009, 5, 3067–3075. [Google Scholar] [CrossRef]
  348. Fritsch, A.; Hellmich, C.; Dormieux, L. The role of disc-type crystal shape for micromechanical predictions of elasticity and strength of hydroxyapatite biomaterials. Philos. Trans. R. Soc. Lond. A 2010, 368, 1913–1935. [Google Scholar]
  349. Menéndez-Proupin, E.; Cervantes-Rodríguez, S.; Osorio-Pulgar, R.; Franco-Cisterna, M.; Camacho-Montes, H.; Fuentes, M.E. Computer simulation of elastic constants of hydroxyapatite and fluorapatite. J. Mech. Behav. Biomed. Mater. 2011, 4, 1011–1120. [Google Scholar] [CrossRef]
  350. Sun, J.P.; Song, Y.; Wen, G.W.; Wang, Y.; Yang, R. Softening of hydroxyapatite by vacancies: A first principles investigation. Mater. Sci. Eng. C 2013, 33, 1109–1115. [Google Scholar] [CrossRef]
  351. Sha, M.C.; Li, Z.; Bradt, R.C. Single-crystal elastic constants of fluorapatite, Ca5F(PO4)3. J. Appl. Phys. 1994, 75, 7784–7787. [Google Scholar] [CrossRef]
  352. Wakai, F.; Kodama, Y.; Sakaguchi, S.; Nonami, T. Superplasticity of hot isostatically pressed hydroxyapatite. J. Am. Ceram. Soc. 1990, 73, 457–460. [Google Scholar] [CrossRef]
  353. Tago, K.; Itatani, K.; Suzuki, T.S.; Sakka, Y.; Koda, S. Densification and superplasticity of hydroxyapatite ceramics. J. Ceram. Soc. Jpn. 2005, 113, 669–673. [Google Scholar] [CrossRef]
  354. Burger, E.L.; Patel, V. Calcium phosphates as bone graft extenders. Orthopedics 2007, 30, 939–942. [Google Scholar]
  355. Guillaume, B. Filling bone defects with β-TCP in maxillofacial surgery: A review.|Comblement osseux par β-TCP en chirurgie maxillofaciale: Revue des indications. Morphologie 2017, 101, 113–119. [Google Scholar] [CrossRef]
  356. Song, J.; Liu, Y.; Zhang, Y.; Jiao, L. Mechanical properties of hydroxyapatite ceramics sintered from powders with different morphologies. Mater. Sci. Eng. A 2011, 528, 5421–5427. [Google Scholar] [CrossRef]
  357. Dorozhkin, S.V. Calcium orthophosphate-containing biocomposites and hybrid biomaterials for biomedical applications. J. Funct. Biomater. 2015, 6, 708–832. [Google Scholar] [CrossRef]
  358. Bouslama, N.; Ben Ayed, F.; Bouaziz, J. Sintering and mechanical properties of tricalcium phosphate–fluorapatite composites. Ceram. Int. 2009, 35, 1909–1917. [Google Scholar] [CrossRef]
  359. Suchanek, W.; Yashima, M.; Kakihana, M.; Yoshimura, M. Processing and mechanical properties of hydroxyapatite reinforced with hydroxyapatite whiskers. Biomaterials 1996, 17, 1715–1723. [Google Scholar] [CrossRef]
  360. Suchanek, W.; Yashima, M.; Kakihana, M.; Yoshimura, M. Hydroxyapatite/hydroxyapatite-whisker composites without sintering additives: Mechanical properties and microstructural evolution. J. Am. Ceram. Soc. 1997, 80, 2805–2813. [Google Scholar] [CrossRef]
  361. Simsek, D.; Ciftcioglu, R.; Guden, M.; Ciftcioglu, M.; Harsa, S. Mechanical properties of hydroxyapatite composites reinforced with hydroxyapatite whiskers. Key Eng. Mater. 2004, 264–268, 1985–1988. [Google Scholar] [CrossRef]
  362. Bose, S.; Banerjee, A.; Dasgupta, S.; Bandyopadhyay, A. Synthesis, processing, mechanical, and biological property characterization of hydroxyapatite whisker-reinforced hydroxyapatite composites. J. Am. Ceram. Soc. 2009, 92, 323–330. [Google Scholar] [CrossRef]
  363. Lie-Feng, L.; Xiao-Yi, H.; Cai, Y.X.; Weng, J. Reinforcing of porous hydroxyapatite ceramics with hydroxyapatite fibres for enhanced bone tissue engineering. J. Biomim. Biomater. Tissue Eng. 2011, 1314, 67–73. [Google Scholar]
  364. Shiota, T.; Shibata, M.; Yasuda, K.; Matsuo, Y. Influence of β-tricalcium phosphate dispersion on mechanical properties of hydroxyapatite ceramics. J. Ceram. Soc. Jpn. 2009, 116, 1002–1005. [Google Scholar] [CrossRef] [Green Version]
  365. Shuai, C.; Feng, P.; Nie, Y.; Hu, H.; Liu, J.; Peng, S. Nano-hydroxyapatite improves the properties of β-tricalcium phosphate bone scaffolds. Int. J. Appl. Ceram. Technol. 2013, 10, 1003–1013. [Google Scholar] [CrossRef]
  366. Dorozhkin, S.V.; Ajaal, T. Toughening of porous bioceramic scaffolds by bioresorbable polymeric coatings. Proc. Inst. Mech. Eng. H 2009, 223, 459–470. [Google Scholar] [CrossRef]
  367. Dorozhkin, S.V.; Ajaal, T. Strengthening of dense bioceramic samples using bioresorbable polymers–a statistical approach. J. Biomim. Biomater. Tissue Eng. 2009, 4, 27–39. [Google Scholar] [CrossRef]
  368. Dressler, M.; Dombrowski, F.; Simon, U.; Börnstein, J.; Hodoroaba, V.D.; Feigl, M.; Grunow, S.; Gildenhaar, R.; Neumann, M. Influence of gelatin coatings on compressive strength of porous hydroxyapatite ceramics. J. Eur. Ceram. Soc. 2011, 31, 523–529. [Google Scholar] [CrossRef]
  369. Martinez-Vazquez, F.J.; Perera, F.H.; Miranda, P.; Pajares, A.; Guiberteau, F. Improving the compressive strength of bioceramic robocast scaffolds by polymer infiltration. Acta Biomater. 2010, 6, 4361–4368. [Google Scholar] [CrossRef]
  370. Fedotov, A.Y.; Bakunova, N.V.; Komlev, V.S.; Barinov, S.M. High-porous calcium phosphate bioceramics reinforced by chitosan infiltration. Dokl. Chem. 2011, 439, 233–236. [Google Scholar] [CrossRef]
  371. Martínez-Vázquez, F.J.; Pajares, A.; Guiberteau, F.; Miranda, P. Effect of polymer infiltration on the flexural behavior of β-tricalcium phosphate robocast scaffolds. Materials 2014, 7, 4001–4018. [Google Scholar] [CrossRef] [PubMed]
  372. He, L.H.; Standard, O.C.; Huang, T.T.; Latella, B.A.; Swain, M.V. Mechanical behaviour of porous hydroxyapatite. Acta Biomater. 2008, 4, 577–586. [Google Scholar] [CrossRef] [PubMed]
  373. Yamashita, K.; Owada, H.; Umegaki, T.; Kanazawa, T.; Futagamu, T. Ionic conduction in apatite solid solutions. Solid State Ionics 1988, 28–30, 660–663. [Google Scholar] [CrossRef]
  374. Nagai, M.; Nishino, T. Surface conduction of porous hydroxyapatite ceramics at elevated temperatures. Solid State Ionics 1988, 28–30, 1456–1461. [Google Scholar] [CrossRef]
  375. Valdes, J.J.P.; Rodriguez, A.V.; Carrio, J.G. Dielectric properties and structure of hydroxyapatite ceramics sintered by different conditions. J. Mater. Res. 1995, 10, 2174–2177. [Google Scholar] [CrossRef]
  376. Fanovich, M.A.; Castro, M.S.; Lopez, J.M.P. Analysis of the microstructural evolution in hydroxyapatite ceramics by electrical characterisation. Ceram. Int. 1999, 25, 517–522. [Google Scholar] [CrossRef]
  377. Bensaoud, A.; Bouhaouss, A.; Ferhat, M. Electrical properties in compressed poorly crystalline apatite. J. Solid State Electrochem. 2001, 5, 362–365. [Google Scholar]
  378. Mahabole, M.P.; Aiyer, R.C.; Ramakrishna, C.V.; Sreedhar, B.; Khairnar, R.S. Synthesis, characterization and gas sensing property of hydroxyapatite ceramic. Bull. Mater. Sci. 2005, 28, 535–545. [Google Scholar] [CrossRef]
  379. Tanaka, Y.; Takata, S.; Shimoe, K.; Nakamura, M.; Nagai, A.; Toyama, T.; Yamashita, K. Conduction properties of non-stoichiometric hydroxyapatite whiskers for biomedical use. J. Ceram. Soc. Jpn. 2008, 116, 815–821. [Google Scholar] [CrossRef]
  380. Tanaka, Y.; Nakamura, M.; Nagai, A.; Toyama, T.; Yamashita, K. Ionic conduction mechanism in Ca-deficient hydroxyapatite whiskers. Mater. Sci. Eng. B 2009, 161, 115–119. [Google Scholar] [CrossRef]
  381. Wang, W.; Itoh, S.; Yamamoto, N.; Okawa, A.; Nagai, A.; Yamashita, K. Electrical polarization of β-tricalcium phosphate ceramics. J. Am. Ceram. Soc. 2010, 93, 2175–2177. [Google Scholar] [CrossRef]
  382. Mahabole, M.P.; Mene, R.U.; Khairnar, R.S. Gas sensing and dielectric studies on cobalt doped hydroxyapatite thick films. Adv. Mater. Lett. 2013, 4, 46–52. [Google Scholar] [CrossRef]
  383. Suresh, M.B.; Biswas, P.; Mahender, V.; Johnson, R. Comparative evaluation of electrical conductivity of hydroxyapatite ceramics densified through ramp and hold, spark plasma and post sinter hot isostatic pressing routes. Mater. Sci. Eng. C 2017, 70, 364–370. [Google Scholar] [CrossRef]
  384. Das, A.; Pamu, D. A comprehensive review on electrical properties of hydroxyapatite based ceramic composites. Mater. Sci. Eng. C 2019, 101, 539–563. [Google Scholar] [CrossRef] [PubMed]
  385. Prezas, P.R.; Dekhtyar, Y.; Sorokins, H.; Costa, M.M.; Soares, M.J.; Graça, M.P.F. Electrical charging of bioceramics by corona discharge. J. Electrost. 2022, 115, 103664. [Google Scholar] [CrossRef]
  386. Gandhi, A.A.; Wojtas, M.; Lang, S.B.; Kholkin, A.L.; Tofail, S.A.M. Piezoelectricity in poled hydroxyapatite ceramics. J. Am. Ceram. Soc. 2014, 97, 2867–2872. [Google Scholar] [CrossRef]
  387. Bystrov, V.S. Piezoelectricity in the ordered monoclinic hydroxyapatite. Ferroelectrics 2015, 475, 148–153. [Google Scholar] [CrossRef]
  388. Horiuchi, N.; Madokoro, K.; Nozaki, K.; Nakamura, M.; Katayama, K.; Nagai, A.; Yamashita, K. Electrical conductivity of polycrystalline hydroxyapatite and its application to electret formation. Solid State Ion. 2018, 315, 19–25. [Google Scholar] [CrossRef]
  389. Saxena, A.; Pandey, M.; Dubey, A.K. Induced electroactive response of hydroxyapatite: A review. J. Indian I. Sci. 2019, 99, 339–359. [Google Scholar] [CrossRef]
  390. Available online: https://en.wikipedia.org/wiki/Electret (accessed on 24 June 2022).
  391. Nakamura, S.; Takeda, H.; Yamashita, K. Proton transport polarization and depolarization of hydroxyapatite ceramics. J. Appl. Phys. 2001, 89, 5386–5392. [Google Scholar] [CrossRef]
  392. Gittings, J.P.; Bowen, C.R.; Turner, I.G.; Baxter, F.R.; Chaudhuri, J.B. Polarisation behaviour of calcium phosphate based ceramics. Mater. Sci. Forum. 2008, 587–588, 91–95. [Google Scholar] [CrossRef]
  393. Rivas, M.; del Valle, L.J.; Armelin, E.; Bertran, O.; Turon, P.; Puiggalí, J.; Alemán, C. Hydroxyapatite with permanent electrical polarization: Preparation, characterization, and response against inorganic adsorbates. ChemPhysChem 2018, 19, 1746–1755. [Google Scholar] [CrossRef]
  394. Itoh, S.; Nakamura, S.; Kobayashi, T.; Shinomiya, K.; Yamashita, K.; Itoh, S. Effect of electrical polarization of hydroxyapatite ceramics on new bone formation. Calcif. Tissue Int. 2006, 78, 133–142. [Google Scholar] [CrossRef]
  395. Iwasaki, T.; Tanaka, Y.; Nakamura, M.; Nagai, A.; Hashimoto, K.; Toda, Y.; Katayama, K.; Yamashita, K. Rate of bonelike apatite formation accelerated on polarized porous hydroxyapatite. J. Am. Ceram. Soc. 2008, 91, 3943–3949. [Google Scholar] [CrossRef]
  396. Itoh, S.; Nakamura, S.; Kobayashi, T.; Shinomiya, K.; Yamashita, K. Enhanced bone ingrowth into hydroxyapatite with interconnected pores by electrical polarization. Biomaterials 2006, 27, 5572–5579. [Google Scholar] [CrossRef]
  397. Kobayashi, T.; Itoh, S.; Nakamura, S.; Nakamura, M.; Shinomiya, K.; Yamashita, K. Enhanced bone bonding of hydroxyapatite-coated titanium implants by electrical polarization. J. Biomed. Mater. Res. A 2007, 82A, 145–151. [Google Scholar] [CrossRef]
  398. Bodhak, S.; Bose, S.; Bandyopadhyay, A. Role of surface charge and wettability on early stage mineralization and bone cell-materials interactions of polarized hydroxyapatite. Acta Biomater. 2009, 5, 2178–2188. [Google Scholar] [CrossRef]
  399. Sagawa, H.; Itoh, S.; Wang, W.; Yamashita, K. Enhanced bone bonding of the hydroxyapatite/β-tricalcium phosphate composite by electrical polarization in rabbit long bone. Artif. Organs 2010, 34, 491–497. [Google Scholar] [CrossRef]
  400. Ohba, S.; Wang, W.; Itoh, S.; Nagai, A.; Yamashita, K. Enhanced effects of new bone formation by an electrically polarized hydroxyapatite microgranule/platelet-rich plasma composite gel. Key Eng. Mater. 2013, 529–530, 82–87. [Google Scholar] [CrossRef]
  401. Yamashita, K.; Oikawa, N.; Umegaki, T. Acceleration and deceleration of bone-like crystal growth on ceramic hydroxyapatite by electric poling. Chem. Mater. 1996, 8, 2697–2700. [Google Scholar] [CrossRef]
  402. Teng, N.C.; Nakamura, S.; Takagi, Y.; Yamashita, Y.; Ohgaki, M.; Yamashita, K. A new approach to enhancement of bone formation by electrically polarized hydroxyapatite. J. Dent. Res. 2001, 80, 1925–1929. [Google Scholar] [CrossRef]
  403. Kobayashi, T.; Nakamura, S.; Yamashita, K. Enhanced osteobonding by negative surface charges of electrically polarized hydroxyapatite. J. Biomed. Mater. Res. 2001, 57, 477–484. [Google Scholar] [CrossRef]
  404. Kato, R.; Nakamura, S.; Katayama, K.; Yamashita, K. Electrical polarization of plasma-spray-hydroxyapatite coatings for improvement of osteoconduction of implants. J. Biomed. Mater. Res. A 2005, 74A, 652–658. [Google Scholar] [CrossRef]
  405. Nakamura, S.; Kobayashi, T.; Nakamura, M.; Itoh, S.; Yamashita, K. Electrostatic surface charge acceleration of bone ingrowth of porous hydroxyapatite/β-tricalcium phosphate ceramics. J. Biomed. Mater. Res. A 2010, 92A, 267–275. [Google Scholar] [CrossRef] [PubMed]
  406. Tarafder, S.; Bodhak, S.; Bandyopadhyay, A.; Bose, S. Effect of electrical polarization and composition of biphasic calcium phosphates on early stage osteoblast interactions. J. Biomed. Mater. Res. B Appl. Biomater. 2011, 97B, 306–314. [Google Scholar] [CrossRef] [PubMed]
  407. Ohba, S.; Wang, W.; Itoh, S.; Takagi, Y.; Nagai, A.; Yamashita, K. Acceleration of new bone formation by an electrically polarized hydroxyapatite microgranule/platelet-rich plasma composite. Acta Biomater. 2012, 8, 2778–2787. [Google Scholar] [CrossRef] [PubMed]
  408. Tarafder, S.; Banerjee, S.; Bandyopadhyay, A.; Bose, S. Electrically polarized biphasic calcium phosphates: Adsorption and release of bovine serum albumin. Langmuir 2010, 26, 16625–16629. [Google Scholar] [CrossRef]
  409. Itoh, S.; Nakamura, S.; Nakamura, M.; Shinomiya, K.; Yamashita, K. Enhanced bone regeneration by electrical polarization of hydroxyapatite. Artif. Organs 2006, 30, 863–869. [Google Scholar] [CrossRef]
  410. Nakamura, M.; Nagai, A.; Ohashi, N.; Tanaka, Y.; Sekilima, Y.; Nakamura, S. Regulation of osteoblast-like cell behaviors on hydroxyapatite by electrical polarization. Key Eng. Mater. 2008, 361–363, 1055–1058. [Google Scholar]
  411. Nakamura, M.; Nagai, A.; Tanaka, Y.; Sekilima, Y.; Yamashita, K. Polarized hydroxyapatite promotes spread and motility of osteoblastic cells. J. Biomed. Mater. Res. A 2010, 92A, 783–790. [Google Scholar] [CrossRef]
  412. Nakamura, M.; Nagai, A.; Yamashita, K. Surface electric fields of apatite electret promote osteoblastic responses. Key Eng. Mater. 2013, 529–530, 357–360. [Google Scholar] [CrossRef]
  413. Nakamura, S.; Kobayashi, T.; Yamashita, K. Extended bioactivity in the proximity of hydroxyapatite ceramic surfaces induced by polarization charges. J. Biomed. Mater. Res. 2002, 61, 593–599. [Google Scholar] [CrossRef]
  414. Wang, W.; Itoh, S.; Tanaka, Y.; Nagai, A.; Yamashita, K. Comparison of enhancement of bone ingrowth into hydroxyapatite ceramics with highly and poorly interconnected pores by electrical polarization. Acta Biomater. 2009, 5, 3132–3140. [Google Scholar] [CrossRef]
  415. Cartmell, S.H.; Thurstan, S.; Gittings, J.P.; Griffiths, S.; Bowen, C.R.; Turner, I.G. Polarization of porous hydroxyapatite scaffolds: Influence on osteoblast cell proliferation and extracellular matrix production. J. Biomed. Mater. Res. A 2014, 102A, 1047–1052. [Google Scholar] [CrossRef]
  416. Nakamura, M.; Kobayashi, A.; Nozaki, K.; Horiuchi, N.; Nagai, A.; Yamashita, K. Improvement of osteoblast adhesion through polarization of plasma-sprayed hydroxyapatite coatings on metal. J. Med. Biol. Eng. 2014, 34, 44–48. [Google Scholar] [CrossRef]
  417. Nagai, A.; Tanaka, K.; Tanaka, Y.; Nakamura, M.; Hashimoto, K.; Yamashita, K. Electric polarization and mechanism of B-type carbonated apatite ceramics. J. Biomed. Mater. Res. A 2011, 99A, 116–124. [Google Scholar] [CrossRef]
  418. Nakamura, M.; Niwa, K.; Nakamura, S.; Sekijima, Y.; Yamashita, K. Interaction of a blood coagulation factor on electrically polarized hydroxyapatite surfaces. J. Biomed. Mater. Res. B Appl. Biomater. 2007, 82B, 29–36. [Google Scholar] [CrossRef]
  419. Ioku, K. Tailored bioceramics of calcium phosphates for regenerative medicine. J. Ceram. Soc. Jpn. 2010, 118, 775–783. [Google Scholar] [CrossRef]
  420. Fang, Y.; Agrawal, D.K.; Roy, D.M.; Roy, R. Fabrication of transparent hydroxyapatite ceramics by ambient-pressure sintering. Mater. Lett. 1995, 23, 147–151. [Google Scholar] [CrossRef]
  421. Varma, H.; Vijayan, S.P.; Babu, S.S. Transparent hydroxyapatite ceramics through gel-casting and low-temperature sintering. J. Am. Ceram. Soc. 2002, 85, 493–495. [Google Scholar] [CrossRef]
  422. Watanabe, Y.; Ikoma, T.; Monkawa, A.; Suetsugu, Y.; Yamada, H.; Tanaka, J.; Moriyoshi, Y. Fabrication of transparent hydroxyapatite sintered body with high crystal orientation by pulse electric current sintering. J. Am. Ceram. Soc. 2005, 88, 243–245. [Google Scholar] [CrossRef]
  423. Kotobuki, N.; Ioku, K.; Kawagoe, D.; Fujimori, H.; Goto, S.; Ohgushi, H. Observation of osteogenic differentiation cascade of living mesenchymal stem cells on transparent hydroxyapatite ceramics. Biomaterials 2005, 26, 779–785. [Google Scholar] [CrossRef]
  424. John, A.; Varma, H.K.; Vijayan, S.; Bernhardt, A.; Lode, A.; Vogel, A.; Burmeister, B.; Hanke, T.; Domaschke, H.; Gelinsky, M. in vitro investigations of bone remodeling on a transparent hydroxyapatite ceramic. Biomed. Mater. 2009, 4, 015007. [Google Scholar] [CrossRef]
  425. Wang, J.; Shaw, L.L. Transparent nanocrystalline hydroxyapatite by pressure-assisted sintering. Scripta Mater. 2010, 63, 593–596. [Google Scholar] [CrossRef]
  426. Boilet, L.; Descamps, M.; Rguiti, E.; Tricoteaux, A.; Lu, J.; Petit, F.; Lardot, V.; Cambier, F.; Leriche, A. Processing and properties of transparent hydroxyapatite and β tricalcium phosphate obtained by HIP process. Ceram. Int. 2013, 39, 283–288. [Google Scholar] [CrossRef]
  427. Han, Y.H.; Kim, B.N.; Yoshida, H.; Yun, J.; Son, H.W.; Lee, J.; Kim, S. Spark plasma sintered superplastic deformed transparent ultrafine hydroxyapatite nanoceramics. Adv. Appl. Ceram. 2016, 115, 174–184. [Google Scholar] [CrossRef]
  428. Kobune, M.; Mineshige, A.; Fujii, S.; Iida, H. Preparation of translucent hydroxyapatite ceramics by HIP and their physical properties. J. Ceram. Soc. Jpn. 1997, 105, 210–213. [Google Scholar] [CrossRef]
  429. Barralet, J.E.; Fleming, G.J.P.; Campion, C.; Harris, J.J.; Wright, A.J. Formation of translucent hydroxyapatite ceramics by sintering in carbon dioxide atmospheres. J. Mater. Sci. 2003, 38, 3979–3993. [Google Scholar] [CrossRef]
  430. Chaudhry, A.A.; Yan, H.; Gong, K.; Inam, F.; Viola, G.; Reece, M.J.; Goodall, J.B.M.; ur Rehman, I.; McNeil-Watson, F.K.; Corbett, J.C.W.; et al. High-strength nanograined and translucent hydroxyapatite monoliths via continuous hydrothermal synthesis and optimized spark plasma sintering. Acta Biomater. 2011, 7, 791–799. [Google Scholar] [CrossRef]
  431. Tancred, D.C.; McCormack, B.A.; Carr, A.J. A synthetic bone implant macroscopically identical to cancellous bone. Biomaterials 1998, 19, 2303–2311. [Google Scholar] [CrossRef]
  432. Miao, X.; Sun, D. Graded/gradient porous biomaterials. Materials 2010, 3, 26–47. [Google Scholar] [CrossRef]
  433. Schliephake, H.; Neukam, F.W.; Klosa, D. Influence of pore dimensions on bone ingrowth into porous hydroxylapatite blocks used as bone graft substitutes. A histometric study. Int. J. Oral Maxillofac. Surg. 1991, 20, 53–58. [Google Scholar] [CrossRef]
  434. Otsuki, B.; Takemoto, M.; Fujibayashi, S.; Neo, M.; Kokubo, T.; Nakamura, T. Pore throat size and connectivity determine bone and tissue ingrowth into porous implants: Three-dimensional micro-CT based structural analyses of porous bioactive titanium implants. Biomaterials 2006, 27, 5892–5900. [Google Scholar] [CrossRef]
  435. Hing, K.A.; Best, S.M.; Bonfield, W. Characterization of porous hydroxyapatite. J. Mater. Sci. Mater. Med. 1999, 10, 135–145. [Google Scholar] [CrossRef]
  436. Lu, J.X.; Flautre, B.; Anselme, K.; Hardouin, P.; Gallur, A.; Descamps, M.; Thierry, B. Role of interconnections in porous bioceramics on bone recolonization in vitro and in vivo. J. Mater. Sci. Mater. Med. 1999, 10, 111–120. [Google Scholar] [CrossRef]
  437. Karageorgiou, V.; Kaplan, D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials 2005, 26, 5474–5491. [Google Scholar] [CrossRef]
  438. Tamai, N.; Myoui, A.; Kudawara, I.; Ueda, T.; Yoshikawa, H. Novel fully interconnected porous hydroxyapatite ceramic in surgical treatment of benign bone tumor. J. Orthop. Sci. 2010, 15, 560–568. [Google Scholar] [CrossRef]
  439. Panzavolta, S.; Torricelli, P.; Amadori, S.; Parrilli, A.; Rubini, K.; Della Bella, E.; Fini, M.; Bigi, A. 3D interconnected porous biomimetic scaffolds: In vitro cell response. J. Biomed. Mater. Res. A 2013, 101A, 3560–3570. [Google Scholar] [CrossRef]
  440. Jin, L.; Feng, Z.Q.; Wang, T.; Ren, Z.; Ma, S.; Wu, J.; Sun, D. A novel fluffy hydroxylapatite fiber scaffold with deep interconnected pores designed for three-dimensional cell culture. J. Mater. Chem. B 2014, 2, 129–136. [Google Scholar] [CrossRef]
  441. Flautre, B.; Descamps, M.; Delecourt, C.; Blary, M.C.; Hardouin, P. Porous HA ceramic for bone replacement: Role of the pores and interconnections–experimental study in the rabbits. J. Mater. Sci. Mater. Med. 2001, 12, 679–682. [Google Scholar] [CrossRef]
  442. Mastrogiacomo, M.; Scaglione, S.; Martinetti, R.; Dolcini, L.; Beltrame, F.; Cancedda, R.; Quarto, R. Role of scaffold internal structure on in vivo bone formation in macroporous calcium phosphate bioceramics. Biomaterials 2006, 27, 3230–3237. [Google Scholar] [CrossRef]
  443. Okamoto, M.; Dohi, Y.; Ohgushi, H.; Shimaoka, H.; Ikeuchi, M.; Matsushima, A.; Yonemasu, K.; Hosoi, H. Influence of the porosity of hydroxyapatite ceramics on in vitro and in vivo bone formation by cultured rat bone marrow stromal cells. J. Mater. Sci. Mater. Med. 2006, 17, 327–336. [Google Scholar] [CrossRef]
  444. Li, X.; Liu, H.; Niu, X.; Fan, Y.; Feng, Q.; Cui, F.Z.; Watari, F. Osteogenic differentiation of human adipose-derived stem cells induced by osteoinductive calcium phosphate ceramics. J. Biomed. Mater. Res. B Appl. Biomater. 2011, 97B, 10–19. [Google Scholar] [CrossRef]
  445. Hong, M.H.; Kim, S.M.; Han, M.H.; Kim, Y.H.; Lee, Y.K.; Oh, D.S. Evaluation of microstructure effect of the porous spherical β-tricalcium phosphate granules on cellular responses. Ceram. Int. 2014, 40, 6095–6102. [Google Scholar] [CrossRef]
  446. De Godoy, R.F.; Hutchens, S.; Campion, C.; Blunn, G. Silicate-substituted calcium phosphate with enhanced strut porosity stimulates osteogenic differentiation of human mesenchymal stem cells. J. Mater. Sci. Mater. Med. 2015, 26, 54. [Google Scholar] [CrossRef]
  447. Omae, H.; Mochizuki, Y.; Yokoya, S.; Adachi, N.; Ochi, M. Effects of interconnecting porous structure of hydroxyapatite ceramics on interface between grafted tendon and ceramics. J. Biomed. Mater. Res. A 2006, 79A, 329–337. [Google Scholar] [CrossRef]
  448. Yoshikawa, H.; Tamai, N.; Murase, T.; Myoui, A. Interconnected porous hydroxyapatite ceramics for bone tissue engineering. J. R. Soc. Interface 2009, 6, S341–S348. [Google Scholar] [CrossRef]
  449. Ribeiro, G.B.M.; Trommer, R.M.; dos Santos, L.A.; Bergmann, C.P. Novel method to produce β-TCP scaffolds. Mater. Lett. 2011, 65, 275–277. [Google Scholar] [CrossRef]
  450. Silva, T.S.N.; Primo, B.T.; Silva, A.N., Jr.; Machado, D.C.; Viezzer, C.; Santos, L.A. Use of calcium phosphate cement scaffolds for bone tissue engineering: In vitro study. Acta Cir. Bras. 2011, 26, 7–11. [Google Scholar] [CrossRef]
  451. De Moraes MacHado, J.L.; Giehl, I.C.; Nardi, N.B.; dos Santos, L.A. Evaluation of scaffolds based on α-tricalcium phosphate cements for tissue engineering applications. IEEE Trans. Biomed. Eng. 2011, 58, 1814–1819. [Google Scholar] [CrossRef] [PubMed]
  452. Li, S.H.; de Wijn, J.R.; Layrolle, P.; de Groot, K. Novel method to manufacture porous hydroxyapatite by dual-phase mixing. J. Am. Ceram. Soc. 2003, 86, 65–72. [Google Scholar] [CrossRef]
  453. De Oliveira, J.F.; de Aguiar, P.F.; Rossi, A.M.; Soares, G.D.A. Effect of process parameters on the characteristics of porous calcium phosphate ceramics for bone tissue scaffolds. Artif. Organs 2003, 27, 406–411. [Google Scholar] [CrossRef]
  454. Swain, S.K.; Bhattacharyya, S. Preparation of high strength macroporous hydroxyapatite scaffold. Mater. Sci. Eng. C 2013, 33, 67–71. [Google Scholar] [CrossRef]
  455. Maeda, H.; Kasuga, T.; Nogami, M.; Kagami, H.; Hata, K.; Ueda, M. Preparation of bonelike apatite composite sponge. Key Eng. Mater. 2004, 254–256, 497–500. [Google Scholar] [CrossRef]
  456. Le Ray, A.M.; Gautier, H.; Bouler, J.M.; Weiss, P.; Merle, C. A new technological procedure using sucrose as porogen compound to manufacture porous biphasic calcium phosphate ceramics of appropriate micro- and macrostructure. Ceram. Int. 2010, 36, 93–101. [Google Scholar] [CrossRef]
  457. Li, S.H.; de Wijn, J.R.; Layrolle, P.; de Groot, K. Synthesis of macroporous hydroxyapatite scaffolds for bone tissue engineering. J. Biomed. Mater. Res. 2002, 61, 109–120. [Google Scholar]
  458. Hesaraki, S.; Sharifi, D. Investigation of an effervescent additive as porogenic agent for bone cement macroporosity. Biomed. Mater. Eng. 2007, 17, 29–38. [Google Scholar]
  459. Hesaraki, S.; Moztarzadeh, F.; Sharifi, D. Formation of interconnected macropores in apatitic calcium phosphate bone cement with the use of an effervescent additive. J. Biomed. Mater. Res. A 2007, 83A, 80–87. [Google Scholar] [CrossRef]
  460. Tas, A.C. Preparation of porous apatite granules from calcium phosphate cement. J. Mater. Sci. Mater. Med. 2008, 19, 2231–2239. [Google Scholar] [CrossRef]
  461. Şahin, E.; Çiftçioğlu, M. Compositional, microstructural and mechanical effects of NaCl porogens in brushite cement scaffolds. J. Mech. Behav. Biomed. Mater. 2021, 116, 104363. [Google Scholar] [CrossRef]
  462. Yao, X.; Tan, S.; Jiang, D. Improving the properties of porous hydroxyapatite ceramics by fabricating methods. J. Mater. Sci. 2005, 40, 4939–4942. [Google Scholar] [CrossRef]
  463. Song, H.Y.; Youn, M.H.; Kim, Y.H.; Min, Y.K.; Yang, H.M.; Lee, B.T. Fabrication of porous β-TCP bone graft substitutes using PMMA powder and their biocompatibility study. Korean J. Mater. Res. 2007, 17, 318–322. [Google Scholar] [CrossRef]
  464. Indra, A.; Hadi, F.; Mulyadi, I.H.; Affi, J.; Gunawarman. A novel fabrication procedure for producing high strength hydroxyapatite ceramic scaffolds with high porosity. Ceram. Int. 2021, 47, 26991–27001. [Google Scholar] [CrossRef]
  465. Almirall, A.; Larrecq, G.; Delgado, J.A.; Martínez, S.; Planell, J.A.; Ginebra, M.P. Fabrication of low temperature macroporous hydroxyapatite scaffolds by foaming and hydrolysis of an α-TCP paste. Biomaterials 2004, 25, 3671–3680. [Google Scholar] [CrossRef]
  466. Huang, X.; Miao, X. Novel porous hydroxyapatite prepared by combining H2O2 foaming with PU sponge and modified with PLGA and bioactive glass. J. Biomater. Appl. 2007, 21, 351–374. [Google Scholar] [CrossRef]
  467. Li, B.; Chen, X.; Guo, B.; Wang, X.; Fan, H.; Zhang, X. Fabrication and cellular biocompatibility of porous carbonated biphasic calcium phosphate ceramics with a nanostructure. Acta Biomater. 2009, 5, 134–143. [Google Scholar] [CrossRef] [PubMed]
  468. Cheng, Z.; Zhao, K.; Wu, Z.P. Structure control of hydroxyapatite ceramics via an electric field assisted freeze casting method. Ceram. Int. 2015, 41, 8599–8604. [Google Scholar] [CrossRef]
  469. Lyu, Y.; Asoh, T.A.; Uyama, H. Facile synthesis of a three-dimensional hydroxyapatite monolith for protein adsorption. J. Mater. Chem. B 2021, 9, 9711–9719. [Google Scholar] [CrossRef] [PubMed]
  470. Tadic, D.; Beckmann, F.; Schwarz, K.; Epple, M. A novel method to produce hydroxylapatite objects with interconnecting porosity that avoids sintering. Biomaterials 2004, 25, 3335–3340. [Google Scholar] [CrossRef]
  471. Sepulveda, P.; Binner, J.G.; Rogero, S.O.; Higa, O.Z.; Bressiani, J.C. Production of porous hydroxyapatite by the gel-casting of foams and cytotoxic evaluation. J. Biomed. Mater. Res. 2000, 50, 27–34. [Google Scholar] [CrossRef]
  472. Chevalier, E.; Chulia, D.; Pouget, C.; Viana, M. Fabrication of porous substrates: A review of processes using pore forming agents in the biomaterial field. J. Pharm. Sci. 2008, 97, 1135–1154. [Google Scholar] [CrossRef]
  473. Tang, Y.J.; Tang, Y.F.; Lv, C.T.; Zhou, Z.H. Preparation of uniform porous hydroxyapatite biomaterials by a new method. Appl. Surf. Sci. 2008, 254, 5359–5362. [Google Scholar] [CrossRef]
  474. Abdulqader, S.T.; Rahman, I.A.; Ismail, H.; Ponnuraj Kannan, T.; Mahmood, Z. A simple pathway in preparation of controlled porosity of biphasic calcium phosphate scaffold for dentin regeneration. Ceram. Int. 2013, 39, 2375–2381. [Google Scholar] [CrossRef]
  475. Wen, F.H.; Wang, F.; Gai, Y.; Wang, M.T.; Lai, Q.H. Preparation of mesoporous hydroxylapatite ceramics using polystyrene microspheres as template. Appl. Mech. Mater. 2013, 389, 194–198. [Google Scholar] [CrossRef]
  476. Sari, M.; Hening, P.; Chotimah; Ana, I.D.; Yusuf, Y. Bioceramic hydroxyapatite-based scaffold with a porous structure using honeycomb as a natural polymeric porogen for bone tissue engineering. Biomater. Res. 2021, 25, 2. [Google Scholar] [CrossRef]
  477. Castillo-Paz, A.M.; Cañon-Davila, D.F.; Londoño-Restrepo, S.M.; Jimenez-Mendoza, D.; Pfeiffer, H.; Ramírez-Bon, R.; Rodriguez-Garcia, M.E. Fabrication and characterization of bioinspired nanohydroxyapatite scaffolds with different porosities. Ceram. Int. 2022, in press. [Google Scholar] [CrossRef]
  478. Cho, S.; Kim, J.; Lee, S.B.; Choi, M.; Kim, D.H.; Jo, I.; Kwon, H.; Kim, Y. Fabrication of functionally graded hydroxyapatite and structurally graded porous hydroxyapatite by using multi-walled carbon nanotubes. Compos. A 2020, 139, 106138. [Google Scholar] [CrossRef]
  479. Guda, T.; Appleford, M.; Oh, S.; Ong, J.L. A cellular perspective to bioceramic scaffolds for bone tissue engineering: The state of the art. Curr. Top. Med. Chem. 2008, 8, 290–299. [Google Scholar] [CrossRef]
  480. Habraken, W.J.E.M.; Wolke, J.G.C.; Jansen, J.A. Ceramic composites as matrices and scaffolds for drug delivery in tissue engineering. Adv. Drug Deliv. Rev. 2007, 59, 234–248. [Google Scholar] [CrossRef]
  481. Lee, J.B.; Maeng, W.Y.; Koh, Y.H.; Kim, H.E. Porous calcium phosphate ceramic scaffolds with tailored pore orientations and mechanical properties using lithography-based ceramic 3D printing technique. Materials 2018, 11, 1711. [Google Scholar] [CrossRef]
  482. Tian, J.; Tian, J. Preparation of porous hydroxyapatite. J. Mater. Sci. 2001, 36, 3061–3066. [Google Scholar] [CrossRef]
  483. Swain, S.K.; Bhattacharyya, S.; Sarkar, D. Preparation of porous scaffold from hydroxyapatite powders. Mater. Sci. Eng. C 2011, 31, 1240–1244. [Google Scholar] [CrossRef]
  484. Zhao, K.; Tang, Y.F.; Qin, Y.S.; Luo, D.F. Polymer template fabrication of porous hydroxyapatite scaffolds with interconnected spherical pores. J. Eur. Ceram. Soc. 2011, 31, 225–229. [Google Scholar] [CrossRef]
  485. Sung, J.H.; Shin, K.H.; Moon, Y.W.; Koh, Y.H.; Choi, W.Y.; Kim, H.E. Production of porous calcium phosphate (CaP) ceramics with highly elongated pores using carbon-coated polymeric templates. Ceram. Int. 2012, 38, 93–97. [Google Scholar] [CrossRef]
  486. Morejón, L.; Delgado, J.A.; Ribeiro, A.A.; de Oliveira, M.V.; Mendizábal, E.; García, I.; Alfonso, A.; Poh, P.; van Griensven, M.; Balmayor, E.R. Development, characterization and in vitro biological properties of scaffolds fabricated from calcium phosphate nanoparticles. Int. J. Mol. Sci. 2019, 20, 1790. [Google Scholar] [CrossRef]
  487. Deville, S.; Saiz, E.; Tomsia, A.P. Freeze casting of hydroxyapatite scaffolds for bone tissue engineering. Biomaterials 2006, 27, 5480–5489. [Google Scholar] [CrossRef]
  488. Lee, E.J.; Koh, Y.H.; Yoon, B.H.; Kim, H.E.; Kim, H.W. Highly porous hydroxyapatite bioceramics with interconnected pore channels using camphene-based freeze casting. Mater. Lett. 2007, 61, 2270–2273. [Google Scholar] [CrossRef]
  489. Fu, Q.; Rahaman, M.N.; Dogan, F.; Bal, B.S. Freeze casting of porous hydroxyapatite scaffolds. I. Processing and general microstructure. J. Biomed. Mater. Res. B Appl. Biomater. 2008, 86B, 125–135. [Google Scholar] [CrossRef]
  490. Impens, S.; Schelstraete, R.; Luyten, J.; Mullens, S.; Thijs, I.; van Humbeeck, J.; Schrooten, J. Production and characterisation of porous calcium phosphate structures with controllable hydroxyapatite/β-tricalcium phosphate ratios. Adv. Appl. Ceram. 2009, 108, 494–500. [Google Scholar] [CrossRef]
  491. Macchetta, A.; Turner, I.G.; Bowen, C.R. Fabrication of HA/TCP scaffolds with a graded and porous structure using a camphene-based freeze-casting method. Acta Biomater. 2009, 5, 1319–1327. [Google Scholar] [CrossRef]
  492. Potoczek, M.; Zima, A.; Paszkiewicz, Z.; Ślósarczyk, A. Manufacturing of highly porous calcium phosphate bioceramics via gel-casting using agarose. Ceram. Int. 2009, 35, 2249–2254. [Google Scholar] [CrossRef]
  493. Zuo, K.H.; Zeng, Y.P.; Jiang, D. Effect of polyvinyl alcohol additive on the pore structure and morphology of the freeze-cast hydroxyapatite ceramics. Mater. Sci. Eng. C 2010, 30, 283–287. [Google Scholar] [CrossRef]
  494. Soon, Y.M.; Shin, K.H.; Koh, Y.H.; Lee, J.H.; Choi, W.Y.; Kim, H.E. Fabrication and compressive strength of porous hydroxyapatite scaffolds with a functionally graded core/shell structure. J. Eur. Ceram. Soc. 2011, 31, 13–18. [Google Scholar] [CrossRef]
  495. Hesaraki, S. Freeze-casted nanostructured apatite scaffold obtained from low temperature biomineralization of reactive calcium phosphates. Key Eng. Mater. 2014, 587, 21–26. [Google Scholar] [CrossRef]
  496. Ng, S.; Guo, J.; Ma, J.; Loo, S.C.J. Synthesis of high surface area mesostructured calcium phosphate particles. Acta Biomater. 2010, 6, 3772–3781. [Google Scholar] [CrossRef]
  497. Walsh, D.; Hopwood, J.D.; Mann, S. Crystal tectonics: Construction of reticulated calcium phosphate frameworks in bicontinuous reverse microemulsions. Science 1994, 264, 1576–1578. [Google Scholar] [CrossRef] [PubMed]
  498. Walsh, D.; Mann, S. Chemical synthesis of microskeletal calcium phosphate in bicontinuous microemulsions. Chem. Mater. 1996, 8, 1944–1953. [Google Scholar] [CrossRef]
  499. Zhao, K.; Tang, Y.F.; Qin, Y.S.; Wei, J.Q. Porous hydroxyapatite ceramics by ice templating: Freezing characteristics and mechanical properties. Ceram. Int. 2011, 37, 635–639. [Google Scholar] [CrossRef]
  500. Zhou, K.; Zhang, Y.; Zhang, D.; Zhang, X.; Li, Z.; Liu, G.; Button, T.W. Porous hydroxyapatite ceramics fabricated by an ice-templating method. Scripta Mater. 2011, 64, 426–429. [Google Scholar] [CrossRef]
  501. Flauder, S.; Gbureck, U.; Muller, F.A. TCP scaffolds with an interconnected and aligned porosity fabricated via ice-templating. Key Eng. Mater. 2013, 529–530, 129–132. [Google Scholar] [CrossRef]
  502. Zhang, Y.; Zhou, K.; Bao, Y.; Zhang, D. Effects of rheological properties on ice-templated porous hydroxyapatite ceramics. Mater. Sci. Eng. C 2013, 33, 340–346. [Google Scholar] [CrossRef]
  503. White, E.; Shors, E.C. Biomaterial aspects of Interpore-200 porous hydroxyapatite. Dent. Clin. North Am. 1986, 30, 49–67. [Google Scholar] [CrossRef]
  504. Aizawa, M.; Howell, S.F.; Itatani, K.; Yokogawa, Y.; Nishizawa, K.; Toriyama, M.; Kameyama, T. Fabrication of porous ceramics with well-controlled open pores by sintering of fibrous hydroxyapatite particles. J. Ceram. Soc. Jpn. 2000, 108, 249–253. [Google Scholar] [CrossRef]
  505. Nakahira, A.; Tamai, M.; Sakamoto, K.; Yamaguchi, S. Sintering and microstructure of porous hydroxyapatite. J. Ceram. Soc. Jpn. 2000, 108, 99–104. [Google Scholar] [CrossRef]
  506. Koh, Y.H.; Kim, H.W.; Kim, H.E.; Halloran, J.W. Fabrication of macrochannelled-hydroxyapatite bioceramic by a coextrusion process. J. Am. Ceram. Soc. 2002, 85, 2578–2580. [Google Scholar] [CrossRef]
  507. Charriere, E.; Lemaitre, J.; Zysset, P. Hydroxyapatite cement scaffolds with controlled macroporosity: Fabrication protocol and mechanical properties. Biomaterials 2003, 24, 809–817. [Google Scholar] [CrossRef]
  508. Gonzalez-McQuire, R.; Green, D.; Walsh, D.; Hall, S.; Chane-Ching, J.Y.; Oreffo, R.O.C.; Mann, S. Fabrication of hydroxyapatite sponges by dextran sulphate/amino acid templating. Biomaterials 2005, 26, 6652–6656. [Google Scholar] [CrossRef]
  509. Eichenseer, C.; Will, J.; Rampf, M.; Wend, S.; Greil, P. Biomorphous porous hydroxyapatite-ceramics from rattan (Calamus Rotang). J. Mater. Sci. Mater. Med. 2010, 21, 131–137. [Google Scholar] [CrossRef]
  510. Walsh, D.; Boanini, E.; Tanaka, J.; Mann, S. Synthesis of tri-calcium phosphate sponges by interfacial deposition and thermal transformation of self-supporting calcium phosphate films. J. Mater. Chem. 2005, 15, 1043–1048. [Google Scholar] [CrossRef]
  511. Song, H.Y.; Islam, S.; Lee, B.T. A novel method to fabricate unidirectional porous hydroxyapatite body using ethanol bubbles in a viscous slurry. J. Am. Ceram. Soc. 2008, 91, 3125–3127. [Google Scholar] [CrossRef]
  512. Zhou, L.; Wang, D.; Huang, W.; Yao, A.; Kamitakahara, M.; Ioku, K. Preparation and characterization of periodic porous frame of hydroxyapatite. J. Ceram. Soc. Jpn. 2009, 117, 521–524. [Google Scholar] [CrossRef]
  513. Xu, S.; Li, D.; Lu, B.; Tang, Y.; Wang, C.; Wang, Z. Fabrication of a calcium phosphate scaffold with a three dimensional channel network and its application to perfusion culture of stem cells. Rapid Prototyp. J. 2007, 13, 99–106. [Google Scholar] [CrossRef]
  514. Saiz, E.; Gremillard, L.; Menendez, G.; Miranda, P.; Gryn, K.; Tomsia, A.P. Preparation of porous hydroxyapatite scaffolds. Mater. Sci. Eng. C 2007, 27, 546–550. [Google Scholar] [CrossRef]
  515. Sakamoto, M.; Nakasu, M.; Matsumoto, T.; Okihana, H. Development of superporous hydroxyapatites and their examination with a culture of primary rat osteoblasts. J. Biomed. Mater. Res. A 2007, 82A, 238–242. [Google Scholar] [CrossRef] [PubMed]
  516. Wang, H.; Zhai, L.; Li, Y.; Shi, T. Preparation of irregular mesoporous hydroxyapatite. Mater. Res. Bull. 2008, 43, 1607–1614. [Google Scholar] [CrossRef]
  517. Sakamoto, M. Development and evaluation of superporous hydroxyapatite ceramics with triple pore structure as bone tissue scaffold. J. Ceram. Soc. Jpn. 2010, 118, 753–757. [Google Scholar] [CrossRef]
  518. Sakamoto, M.; Matsumoto, T. Development and evaluation of superporous ceramics bone tissue scaffold materials with triple pore structure a) hydroxyapatite, b) beta-tricalcium phosphate. In Bone Regeneration; Tal, H., Ed.; InTech Open: Rijeka, Croatia, 2012; pp. 301–320. [Google Scholar]
  519. Deisinger, U. Generating porous ceramic scaffolds: Processing and properties. Key Eng. Mater. 2010, 441, 155–179. [Google Scholar] [CrossRef]
  520. Ishikawa, K.; Tsuru, K.; Pham, T.K.; Maruta, M.; Matsuya, S. Fully-interconnected pore forming calcium phosphate cement. Key Eng. Mater. 2012, 493–494, 832–835. [Google Scholar]
  521. Yoon, H.J.; Kim, U.C.; Kim, J.H.; Koh, Y.H.; Choi, W.Y.; Kim, H.E. Fabrication and characterization of highly porous calcium phosphate (CaP) ceramics by freezing foamed aqueous CaP suspensions. J. Ceram. Soc. Jpn. 2011, 119, 573–576. [Google Scholar] [CrossRef] [Green Version]
  522. Ahn, M.K.; Shin, K.H.; Moon, Y.W.; Koh, Y.H.; Choi, W.Y.; Kim, H.E. Highly porous biphasic calcium phosphate (BCP) ceramics with large interconnected pores by freezing vigorously foamed BCP suspensions under reduced pressure. J. Am. Ceram. Soc. 2011, 94, 4154–4156. [Google Scholar] [CrossRef]
  523. Schlosser, M.; Kleebe, H.J. Vapor transport sintering of porous calcium phosphate ceramics. J. Am. Ceram. Soc. 2012, 95, 1581–1587. [Google Scholar] [CrossRef]
  524. Zheng, W.; Liu, G.; Yan, C.; Xiao, Y.; Miao, X.G. Strong and bioactive tri-calcium phosphate scaffolds with tube-like macropores. J. Biomim. Biomater. Tissue Eng. 2014, 19, 65–75. [Google Scholar] [CrossRef]
  525. Tsuru, K.; Nikaido, T.; Munar, M.L.; Maruta, M.; Matsuya, S.; Nakamura, S.; Ishikawa, K. Synthesis of carbonate apatite foam using β-TCP foams as precursors. Key Eng. Mater. 2014, 587, 52–55. [Google Scholar] [CrossRef]
  526. Chen, Z.C.; Zhang, X.L.; Zhou, K.; Cai, H.; Liu, C.Q. Novel fabrication of hierarchically porous hydroxyapatite scaffolds with refined porosity and suitable strength. Adv. Appl. Ceram. 2015, 114, 183–187. [Google Scholar] [CrossRef]
  527. Swain, S.K.; Bhattacharyya, S.; Sarkar, D. Fabrication of porous hydroxyapatite scaffold via polyethylene glycol-polyvinyl alcohol hydrogel state. Mater. Res. Bull. 2015, 64, 257–261. [Google Scholar] [CrossRef]
  528. Charbonnier, B.; Laurent, C.; Marchat, D. Porous hydroxyapatite bioceramics produced by impregnation of 3D-printed wax mold: Slurry feature optimization. J. Eur. Ceram. Soc. 2016, 36, 4269–4279. [Google Scholar] [CrossRef]
  529. Roy, D.M.; Linnehan, S.K. Hydroxyapatite formed from coral skeletal carbonate by hydrothermal exchange. Nature 1974, 247, 220–222. [Google Scholar] [CrossRef]
  530. Zhang, X.; Vecchio, K.S. Conversion of natural marine skeletons as scaffolds for bone tissue engineering. Front. Mater. Sci. 2013, 7, 103–117. [Google Scholar] [CrossRef]
  531. Yang, Y.; Yao, Q.; Pu, X.; Hou, Z.; Zhang, Q. Biphasic calcium phosphate macroporous scaffolds derived from oyster shells for bone tissue engineering. Chem. Eng. J. 2011, 173, 837–845. [Google Scholar] [CrossRef]
  532. Tampieri, A.; Sprio, S.; Ruffini, A.; Celotti, G.; Lesci, I.G.; Roveri, N. From wood to bone: Multi-step process to convert wood hierarchical structures into biomimetic hydroxyapatite scaffolds for bone tissue engineering. J. Mater. Chem. 2009, 19, 4973–4980. [Google Scholar] [CrossRef]
  533. Thanh, T.N.X.; Maruta, M.; Tsuru, K.; Matsuya, S.; Ishikawa, K. Three–dimensional porous carbonate apatite with sufficient mechanical strength as a bone substitute material. Adv. Mater. Res. 2014, 891–892, 1559–1564. [Google Scholar] [CrossRef]
  534. Moroni, L.; de Wijn, J.R.; van Blitterswijk, C.A. Integrating novel technologies to fabricate smart scaffolds. J. Biomater. Sci. Polymer Edn. 2008, 19, 543–572. [Google Scholar] [CrossRef]
  535. Studart, A.R.; Gonzenbach, U.T.; Tervoort, E.; Gauckler, L.J. Processing routes to macroporous ceramics: A review. J. Am. Ceram. Soc. 2006, 89, 1771–1789. [Google Scholar] [CrossRef]
  536. Hing, K.; Annaz, B.; Saeed, S.; Revell, P.; Buckland, T. Microporosity enhances bioactivity of synthetic bone graft substitutes. J. Mater. Sci. Mater. Med. 2005, 16, 467–475. [Google Scholar] [CrossRef]
  537. Wang, Z.; Sakakibara, T.; Sudo, A.; Kasai, Y. Porosity of β-tricalcium phosphate affects the results of lumbar posterolateral fusion. J. Spinal Disord. Tech. 2013, 26, E40–E45. [Google Scholar] [CrossRef]
  538. Lan Levengood, S.K.; Polak, S.J.; Wheeler, M.B.; Maki, A.J.; Clark, S.G.; Jamison, R.D.; Wagoner Johnson, A.J. Multiscale osteointegration as a new paradigm for the design of calcium phosphate scaffolds for bone regeneration. Biomaterials 2010, 31, 3552–3563. [Google Scholar] [CrossRef]
  539. Ruksudjarit, A.; Pengpat, K.; Rujijanagul, G.; Tunkasiri, T. The fabrication of nanoporous hydroxyapatite ceramics. Adv. Mater. Res. 2008; 47–50, 797–800. [Google Scholar]
  540. Li, Y.; Tjandra, W.; Tam, K.C. Synthesis and characterization of nanoporous hydroxyapatite using cationic surfactants as templates. Mater. Res. Bull. 2008, 43, 2318–2326. [Google Scholar] [CrossRef]
  541. El Asri, S.; Laghzizil, A.; Saoiabi, A.; Alaoui, A.; El Abassi, K.; M’hamdi, R.; Coradin, T. A novel process for the fabrication of nanoporous apatites from Moroccan phosphate rock. Colloid Surf. A 2009, 350, 73–78. [Google Scholar] [CrossRef]
  542. Raksujarit, A.; Pengpat, K.; Rujijanagul, G.; Tunkasiri, T. Processing and properties of nanoporous hydroxyapatite ceramics. Mater. Des. 2010, 31, 1658–1660. [Google Scholar] [CrossRef]
  543. Ramli, R.A.; Adnan, R.; Bakar, M.A.; Masudi, S.M. Synthesis and characterisation of pure nanoporous hydroxyapatite. J. Phys. Sci. 2011, 22, 25–37. [Google Scholar]
  544. LeGeros, R.Z. Calcium phosphate-based osteoinductive materials. Chem. Rev. 2008, 108, 4742–4753. [Google Scholar] [CrossRef] [PubMed]
  545. Prokopiev, O.; Sevostianov, I. Dependence of the mechanical properties of sintered hydroxyapatite on the sintering temperature. Mater. Sci. Eng. A 2006, 431, 218–227. [Google Scholar] [CrossRef]
  546. Daculsi, G.; Jegoux, F.; Layrolle, P. The micro macroporous biphasic calcium phosphate concept for bone reconstruction and tissue engineering. In Advanced Biomaterials: Fundamentals, Processing and Applications; Basu, B., Katti, D.S., Kumar, A., Eds.; American Ceramic Society: Columbus, OH, USA; Wiley: Hoboken, NJ, USA, 2009; p. 768. [Google Scholar]
  547. Shipman, P.; Foster, G.; Schoeninger, M. Burnt bones and teeth: An experimental study of color, morphology, crystal structure and shrinkage. J. Archaeol. Sci. 1984, 11, 307–325. [Google Scholar] [CrossRef]
  548. Rice, R.W. Porosity of Ceramics; Marcel Dekker: New York, NY, USA, 1998; p. 560. [Google Scholar]
  549. Fan, J.; Lei, J.; Yu, C.; Tu, B.; Zhao, D. Hard-templating synthesis of a novel rod-like nanoporous calcium phosphate bioceramics and their capacity as antibiotic carriers. Mater. Chem. Phys. 2007, 103, 489–493. [Google Scholar] [CrossRef]
  550. Hsu, Y.H.; Turner, I.G.; Miles, A.W. Fabrication of porous bioceramics with porosity gradients similar to the bimodal structure of cortical and cancellous bone. J. Mater. Sci. Mater. Med. 2007, 18, 2251–2256. [Google Scholar] [CrossRef] [PubMed]
  551. Munch, E.; Franco, J.; Deville, S.; Hunger, P.; Saiz, E.; Tomsia, A.P. Porous ceramic scaffolds with complex architectures. JOM 2008, 60, 54–59. [Google Scholar] [CrossRef]
  552. Naqshbandi, A.R.; Sopyan, I.; Gunawan. Development of porous calcium phosphate bioceramics for bone implant applications: A review. Rec. Pat. Mater. Sci. 2013, 6, 238–252. [Google Scholar]
  553. Jodati, H.; Yılmaz, B.; Evis, Z. A review of bioceramic porous scaffolds for hard tissue applications: Effects of structural features. Ceram. Int. 2020, 46, 15725–15739. [Google Scholar] [CrossRef]
  554. Yan, X.; Yu, C.; Zhou, X.; Tang, J.; Zhao, D. Highly ordered mesoporous bioactive glasses with superior in vitro bone-forming bioactivities. Angew. Chem. Int. Ed. Engl. 2004, 43, 5980–5984. [Google Scholar] [CrossRef] [PubMed]
  555. Barba, A.; Maazouz, Y.; Diez-Escudero, A.; Rappe, K.; Espanol, M.; Montufar, E.B.; Öhman-Mägi, C.; Persson, C.; Fontecha, P.; Manzanares, M.C.; et al. Osteogenesis by foamed and 3D-printed nanostructured calcium phosphate scaffolds: Effect of pore architecture. Acta Biomater. 2018, 79, 135–147. [Google Scholar] [CrossRef] [PubMed]
  556. Cosijns, A.; Vervaet, C.; Luyten, J.; Mullens, S.; Siepmann, F.; van Hoorebeke, L.; Masschaele, B.; Cnudde, V.; Remon, J.P. Porous hydroxyapatite tablets as carriers for low-dosed drugs. Eur. J. Pharm. Biopharm. 2007, 67, 498–506. [Google Scholar] [CrossRef]
  557. Uchida, A.; Shinto, Y.; Araki, N.; Ono, K. Slow release of anticancer drugs from porous calcium hydroxyapatite ceramic. J. Orthop. Res. 1992, 10, 440–445. [Google Scholar] [CrossRef]
  558. Shinto, Y.; Uchida, A.; Korkusuz, F.; Araki, N.; Ono, K. Calcium hydroxyapatite ceramic used as a delivery system for antibiotics. J. Bone. Joint. Surg. Br. 1992, 74, 600–604. [Google Scholar] [CrossRef]
  559. Martin, R.B.; Chapman, M.W.; Sharkey, N.A.; Zissimos, S.L.; Bay, B.; Shors, E.C. Bone ingrowth and mechanical properties of coralline hydroxyapatite 1 yr after implantation. Biomaterials 1993, 14, 341–348. [Google Scholar] [CrossRef]
  560. Kazakia, G.J.; Nauman, E.A.; Ebenstein, D.M.; Halloran, B.P.; Keaveny, T.M. Effects of in vitro bone formation on the mechanical properties of a trabeculated hydroxyapatite bone substitute. J. Biomed. Mater. Res. A 2006, 77A, 688–699. [Google Scholar] [CrossRef]
  561. Hing, K.A.; Best, S.M.; Tanner, K.E.; Bonfield, W.; Revell, P.A. Mediation of bone ingrowth in porous hydroxyapatite bone graft substitutes. J. Biomed. Mater. Res. A 2004, 68A, 187–200. [Google Scholar] [CrossRef]
  562. Vuola, J.; Taurio, R.; Goransson, H.; Asko-Seljavaara, S. Compressive strength of calcium carbonate and hydroxyapatite implants after bone marrow induced osteogenesis. Biomaterials 1998, 19, 223–227. [Google Scholar] [CrossRef]
  563. Von Doernberg, M.C.; von Rechenberg, B.; Bohner, M.; Grünenfelder, S.; van Lenthe, G.H.; Müller, R.; Gasser, B.; Mathys, R.; Baroud, G.; Auer, J. In vivo behavior of calcium phosphate scaffolds with four different pore sizes. Biomaterials 2006, 27, 5186–5198. [Google Scholar] [CrossRef]
  564. Mygind, T.; Stiehler, M.; Baatrup, A.; Li, H.; Zou, X.; Flyvbjerg, A.; Kassem, M.; Bunger, C. Mesenchymal stem cell ingrowth and differentiation on coralline hydroxyapatite scaffolds. Biomaterials 2007, 28, 1036–1047. [Google Scholar] [CrossRef]
  565. Mankani, M.H.; Afghani, S.; Franco, J.; Launey, M.; Marshall, S.; Marshall, G.W.; Nissenson, R.; Lee, J.; Tomsia, A.P.; Saiz, E. Lamellar spacing in cuboid hydroxyapatite scaffolds regulates bone formation by human bone marrow stromal cells. Tissue Eng. A 2011, 17, 1615–1623. [Google Scholar] [CrossRef]
  566. Chan, O.; Coathup, M.J.; Nesbitt, A.; Ho, C.Y.; Hing, K.A.; Buckland, T.; Campion, C.; Blunn, G.W. The effects of microporosity on osteoinduction of calcium phosphate bone graft substitute biomaterials. Acta Biomater. 2012, 8, 2788–2794. [Google Scholar] [CrossRef]
  567. Holmes, R.E. Bone regeneration within a coralline hydroxyapatite implant. Plast. Reconstr. Surg. 1979, 63, 626–633. [Google Scholar] [CrossRef]
  568. Tsuruga, E.; Takita, H.; Wakisaka, Y.; Kuboki, Y. Pore size of porous hydoxyapatite as the cell-substratum controls BMP-induced osteogenesis. J. Biochem. 1997, 121, 317–324. [Google Scholar] [CrossRef]
  569. LeGeros, R.Z.; LeGeros, J.P. Calcium phosphate bioceramics: Past, present, future. Key Eng. Mater. 2003, 240–242, 3–10. [Google Scholar] [CrossRef]
  570. Woodard, J.R.; Hilldore, A.J.; Lan, S.K.; Park, C.J.; Morgan, A.W.; Eurell, J.A.C.; Clark, S.G.; Wheeler, M.B.; Jamison, R.D.; Wagoner Johnson, A.J. The mechanical properties and osteoconductivity of hydroxyapatite bone scaffolds with multi-scale porosity. Biomaterials 2007, 28, 45–54. [Google Scholar] [CrossRef] [PubMed]
  571. Jacovella, P.F.; Peiretti, C.B.; Cunille, D.; Salzamendi, M.; Schechtel, S.A. Long-lasting results with hydroxylapatite (Radiesse) facial filler. Plast. Reconstr. Surg. 2006, 118, 15S–21S. [Google Scholar] [CrossRef] [PubMed]
  572. Rustom, L.E.; Poellmann, M.J.; Wagoner Johnson, A.J. Mineralization in micropores of calcium phosphate scaffolds. Acta Biomater. 2019, 83, 435–455. [Google Scholar] [CrossRef] [PubMed]
  573. Dubok, V.A. Bioceramics–yesterday, today, tomorrow. Powder Metall. Met. Ceram. 2000, 39, 381–394. [Google Scholar] [CrossRef]
  574. Heness, G.; Ben-Nissan, B. Innovative bioceramics. Mater. Forum 2004, 27, 104–114. [Google Scholar]
  575. Williams, D.F. There is no such thing as a biocompatible material. Biomaterials 2014, 35, 10009–10014. [Google Scholar] [CrossRef]
  576. Punj, S.; Singh, J.; Singh, K. Ceramic biomaterials: Properties, state of the art and future prospectives. Ceram. Int. 2021, 47, 28059–28074. [Google Scholar] [CrossRef]
  577. Greenspan, D.C. Bioactive ceramic implant materials. Curr. Opin. Solid State Mater. Sci. 1999, 4, 389–393. [Google Scholar] [CrossRef]
  578. Blokhuis, T.J.; Termaat, M.F.; den Boer, F.C.; Patka, P.; Bakker, F.C.; Haarman, H.J.T.M. Properties of calcium phosphate ceramics in relation to their in vivo behavior. J. Trauma 2000, 48, 179–189. [Google Scholar] [CrossRef]
  579. Kim, H.M. Bioactive ceramics: Challenges and perspectives. J. Ceram. Soc. Jpn. 2001, 109, S49–S57. [Google Scholar] [CrossRef]
  580. Seeley, Z.; Bandyopadhyay, A.; Bose, S. Tricalcium phosphate based resorbable ceramics: Influence of NaF and CaO addition. Mater. Sci. Eng. C 2008, 28, 11–17. [Google Scholar] [CrossRef]
  581. Descamps, M.; Richart, O.; Hardouin, P.; Hornez, J.C.; Leriche, A. Synthesis of macroporous β-tricalcium phosphate with controlled porous architectural. Ceram. Int. 2008, 34, 1131–1137. [Google Scholar] [CrossRef]
  582. Cushnie, E.K.; Khan, Y.M.; Laurencin, C.T. Amorphous hydroxyapatite-sintered polymeric scaffolds for bone tissue regeneration: Physical characterization studies. J. Biomed. Mater. Res. A 2008, 84A, 54–62. [Google Scholar] [CrossRef]
  583. Hench, L.L.; Thompson, I. Twenty-first century challenges for biomaterials. J. R. Soc. Interface 2010, 7, S379–S391. [Google Scholar] [CrossRef]
  584. Nagase, M.; Baker, D.G.; Schumacher, H.R. Prolonged inflammatory reactions induced by artificial ceramics in the rat pouch model. J. Rheumatol. 1988, 15, 1334–1338. [Google Scholar]
  585. Rooney, T.; Berman, S.; Indersano, A.T. Evaluation of porous block hydroxylapatite for augmentation of alveolar ridges. J. Oral Maxillofac. Surg. 1988, 46, 15–18. [Google Scholar] [CrossRef]
  586. Prudhommeaux, F.; Schiltz, C.; Lioté, F.; Hina, A.; Champy, R.; Bucki, B.; Ortiz-Bravo, E.; Meunier, A.; Rey, C.; Bardin, T. Variation in the inflammatory properties of basic calcium phosphate crystals according to crystal type. Arthritis Rheum. 1996, 39, 1319–1326. [Google Scholar] [CrossRef]
  587. Ghanaati, S.; Barbeck, M.; Orth, C.; Willershausen, I.; Thimm, B.W.; Hoffmann, C.; Rasic, A.; Sader, R.A.; Unger, R.E.; Peters, F.; et al. Influence of β-tricalcium phosphate granule size and morphology on tissue reaction in vivo. Acta Biomater. 2010, 6, 4476–4487. [Google Scholar] [CrossRef]
  588. Lin, K.; Yuan, W.; Wang, L.; Lu, J.; Chen, L.; Wang, Z.; Chang, J. Evaluation of host inflammatory responses of β-tricalcium phosphate bioceramics caused by calcium pyrophosphate impurity using a subcutaneous model. J. Biomed. Mater. Res. B Appl. Biomater. 2011, 99B, 350–358. [Google Scholar] [CrossRef]
  589. Velard, F.; Braux, J.; Amedee, J.; Laquerriere, P. Inflammatory cell response to calcium phosphate biomaterial particles: An overview. Acta Biomater. 2013, 9, 4956–4963. [Google Scholar] [CrossRef] [PubMed]
  590. Rydén, L.; Molnar, D.; Esposito, M.; Johansson, A.; Suska, F.; Palmquist, A.; Thomsen, P. Early inflammatory response in soft tissues induced by thin calcium phosphates. J. Biomed. Mater. Res. A 2013, 101A, 2712–2717. [Google Scholar] [CrossRef] [PubMed]
  591. Chatterjea, A.; van der Stok, J.; Danoux, C.B.; Yuan, H.; Habibovic, P.; van Blitterswijk, C.A.; Weinans, H.; de Boer, J. Inflammatory response and bone healing capacity of two porous calcium phosphate ceramics in a critical size cortical bone defects. J. Biomed. Mater. Res. A 2014, 102A, 1399–1407. [Google Scholar] [CrossRef]
  592. Friesenbichler, J.; Maurer-Ertl, W.; Sadoghi, P.; Pirker-Fruehauf, U.; Bodo, K.; Leithner, A. Adverse reactions of artificial bone graft substitutes: Lessons learned from using tricalcium phosphate geneX®. Clin. Orthop. Relat. Res. 2014, 472, 976–982. [Google Scholar] [CrossRef] [PubMed]
  593. Chang, T.Y.; Pan, S.C.; Huang, Y.H.; Hsueh, Y.Y. Blindness after calcium hydroxylapatite injection at nose. J. Plast. Reconstr. Aesthet. Surg. 2014, 67, 1755–1757. [Google Scholar] [CrossRef]
  594. Ghanaati, S.; Barbeck, M.; Detsch, R.; Deisinger, U.; Hilbig, U.; Rausch, V.; Sader, R.; Unger, R.E.; Ziegler, G.; Kirkpatrick, C.J. The chemical composition of synthetic bone substitutes influences tissue reactions in vivo: Histological and histomorphometrical analysis of the cellular inflammatory response to hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate ceramics. Biomed. Mater. 2012, 7, 015005. [Google Scholar]
  595. Draenert, K.; Draenert, M.; Erler, M.; Draenert, A.; Draenert, Y. How bone forms in large cancellous defects: Critical analysis based on experimental work and literature. Injury 2011, 42 (Suppl. 2), S47–S55. [Google Scholar] [CrossRef]
  596. Albrektsson, T.; Johansson, C. Osteoinduction, osteoconduction and osseointegration. Eur. Spine. J. 2001, 10, S96–S101. [Google Scholar]
  597. Yuan, H.; Kurashina, K.; de Bruijn, D.J.; Li, Y.; de Groot, K.; Zhang, X. A preliminary study of osteoinduction of two kinds of calcium phosphate bioceramics. Biomaterials 1999, 20, 1799–1806. [Google Scholar] [CrossRef]
  598. Yuan, H.P.; de Bruijn, J.D.; Li, Y.B.; Feng, J.Q.; Yang, Z.J.; de Groot, K.; Zhang, X.D. Bone formation induced by calcium phosphate ceramics in soft tissue of dogs: A comparative study between porous α-TCP and β-TCP. J. Mater. Sci. Mater. Med. 2001, 12, 7–13. [Google Scholar] [CrossRef]
  599. Barrere, F.; van der Valk, C.M.; Dalmeijer, R.A.; Meijer, G.; van Blitterswijk, C.A.; de Groot, K.; Layrolle, P. Osteogenecity of octacalcium phosphate coatings applied on porous metal implants. J. Biomed. Mater. Res. A 2003, 66A, 779–788. [Google Scholar] [CrossRef]
  600. Habibovic, P.; van der Valk, C.M.; van Blitterswijk, C.A.; de Groot, K.; Meijer, G. Influence of octacalcium phosphate coating on osteoinductive properties of biomaterials. J. Mater. Sci. Mater. Med. 2004, 15, 373–380. [Google Scholar] [CrossRef]
  601. Ripamonti, U.; Richter, P.W.; Nilen, R.W.; Renton, L. The induction of bone formation by smart biphasic hydroxyapatite tricalcium phosphate biomimetic matrices in the non human primate Papio ursinus. J. Cell. Mol. Med. 2008, 12, 2609–2621. [Google Scholar] [CrossRef]
  602. Cheng, L.; Ye, F.; Yang, R.; Lu, X.; Shi, Y.; Li, L.; Fan, H.; Bu, H. Osteoinduction of hydroxyapatite/β-tricalcium phosphate bioceramics in mice with a fractured fibula. Acta Biomater. 2010, 6, 1569–1574. [Google Scholar] [CrossRef]
  603. Yuan, H.; Fernandes, H.; Habibovic, P.; de Boer, J.; Barradas, A.M.C.; de Ruiter, A.; Walsh, W.R.; van Blitterswijk, C.A.; de Bruijn, J.D. Osteoinductive ceramics as a synthetic alternative to autologous bone grafting. Proc. Natl. Acad. Sci. USA 2010, 107, 13614–13619. [Google Scholar] [CrossRef]
  604. Barradas, A.M.; Yuan, H.; van der Stok, J.; le Quang, B.; Fernandes, H.; Chaterjea, A.; Hogenes, M.C.; Shultz, K.; Donahue, L.R.; van Blitterswijk, C.; et al. The influence of genetic factors on the osteoinductive potential of calcium phosphate ceramics in mice. Biomaterials 2012, 33, 5696–5705. [Google Scholar] [CrossRef]
  605. Li, B.; Liao, X.; Zheng, L.; Zhu, X.; Wang, Z.; Fan, H.; Zhang, X. Effect of nanostructure on osteoinduction of porous biphasic calcium phosphate ceramics. Acta Biomater. 2012, 8, 3794–3804. [Google Scholar] [CrossRef]
  606. Cheng, L.; Shi, Y.; Ye, F.; Bu, H. Osteoinduction of calcium phosphate biomaterials in small animals. Mater. Sci. Eng. C 2013, 33, 1254–1260. [Google Scholar] [CrossRef]
  607. Davison, N.L.; Gamblin, A.L.; Layrolle, P.; Yuan, H.; de Bruijn, J.D.; Barrère-de Groot, F. Liposomal clodronate inhibition of osteoclastogenesis and osteoinduction by submicrostructured beta-tricalcium phosphate. Biomaterials 2014, 35, 5088–5097. [Google Scholar] [CrossRef]
  608. Wang, L.; Barbieri, D.; Zhou, H.; de Bruijn, J.D.; Bao, C.; Yuan, H. Effect of particle size on osteoinductive potential of microstructured biphasic calcium phosphate ceramic. J. Biomed. Mater. Res. A 2015, 103A, 1919–1929. [Google Scholar] [CrossRef]
  609. He, Y.; Peng, Y.; Liu, L.; Hou, S.; Mu, J.; Lan, L.; Cheng, L.; Shi, Z. The relationship between osteoinduction and vascularization: Comparing the ectopic bone formation of five different calcium phosphate biomaterials. Materials 2022, 15, 3440. [Google Scholar] [CrossRef]
  610. Yuan, H.; Barbieri, D.; Luo, X.; van Blitterswijk, C.A.; de Bruijn, J.D. Calcium phosphates and bone induction. In Comprehensive Biomaterials II; Chapter 1.14; Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2017; pp. 339–349. [Google Scholar]
  611. Murata, M.; Hino, J.; Kabir, M.A.; Yokozeki, K.; Sakamoto, M.; Nakajima, T.; Akazawa, T. Osteoinduction in novel micropores of partially dissolved and precipitated hydroxyapatite block in scalp of young rats. Materials 2021, 14, 196. [Google Scholar] [CrossRef]
  612. Iaquinta, M.R.; Torreggiani, E.; Mazziotta, C.; Ruffini, A.; Sprio, S.; Tampieri, A.; Tognon, M.; Martini, F.; Mazzoni, E. In vitro osteoinductivity assay of hydroxylapatite scaffolds, obtained with biomorphic transformation processes, assessed using human adipose stem cell cultures. Int. J. Mol. Sci. 2021, 22, 7092. [Google Scholar] [CrossRef]
  613. Habibovic, P.; Yuan, H.; van der Valk, C.M.; Meijer, G.; van Blitterswijk, C.A.; de Groot, K. 3D microenvironment as essential element for osteoinduction by biomaterials. Biomaterials 2005, 26, 3565–3575. [Google Scholar] [CrossRef]
  614. Habibovic, P.; Sees, T.M.; van den Doel, M.A.; van Blitterswijk, C.A.; de Groot, K. Osteoinduction by biomaterials–physicochemical and structural influences. J. Biomed. Mater. Res. A 2006, 77A, 747–762. [Google Scholar] [CrossRef] [PubMed]
  615. Reddi, A.H. Morphogenesis and tissue engineering of bone and cartilage: Inductive signals, stem cells and biomimetic biomaterials. Tissue Eng. 2000, 6, 351–359. [Google Scholar] [CrossRef] [PubMed]
  616. Ripamonti, U. The morphogenesis of bone in replicas of porous hydroxyapatite obtained by conversion of calcium carbonate exoskeletons of coral. J. Bone Joint Surg. A 1991, 73, 692–703. [Google Scholar] [CrossRef]
  617. Kuboki, Y.; Takita, H.; Kobayashi, D. BMP-induced osteogenesis on the surface of hydroxyapatite with geometrically feasible and nonfeasible structures: Topology of osteogenesis. J. Biomed. Mater. Res. 1998, 39, 190–199. [Google Scholar] [CrossRef]
  618. Zhang, J.; Luo, X.; Barbieri, D.; Barradas, A.M.C.; de Bruijn, J.D.; van Blitterswijk, C.A.; Yuan, H. The size of surface microstructures as an osteogenic factor in calcium phosphate ceramics. Acta Biomater. 2014, 10, 3254–3263. [Google Scholar] [CrossRef]
  619. Zhang, J.; Barbieri, D.; Ten Hoopen, H.; de Bruijn, J.D.; van Blitterswijk, C.A.; Yuan, H. Microporous calcium phosphate ceramics driving osteogenesis through surface architecture. J. Biomed. Mater. Res. A 2015, 103A, 1188–1199. [Google Scholar] [CrossRef]
  620. Xiao, D.; Zhang, J.; Zhang, C.; Barbieri, D.; Yuan, H.; Moroni, L.; Feng, G. The role of calcium phosphate surface structure in osteogenesis and the mechanisms involved. Acta Biomater. 2020, 106, 22–33. [Google Scholar] [CrossRef]
  621. Daskalova, A.; Angelova, L.; Trifonov, A.; Lasgorceix, M.; Hocquet, S.; Minne, M.; Declercq, H.; Leriche, A.; Aceti, D.; Buchvarov, I. Development of femtosecond laser-engineered β-tricalcium phosphate (β-TCP) biomimetic templates for orthopaedic tissue engineering. Appl. Sci. 2021, 11, 2565. [Google Scholar] [CrossRef]
  622. Diaz-Flores, L.; Gutierrez, R.; Lopez-Alonso, A.; Gonzalez, R.; Varela, H. Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. Clin. Orthop. Relat. Res. 1992, 275, 280–286. [Google Scholar] [CrossRef]
  623. Bohner, M.; Miron, R.J. A proposed mechanism for material-induced heterotopic ossification. Mater. Today 2019, 22, 132–141. [Google Scholar] [CrossRef]
  624. Boyan, B.D.; Schwartz, Z. Are calcium phosphate ceramics ‘smart’ biomaterials? Nat. Rev. Rheumatol. 2011, 7, 8–9. [Google Scholar] [CrossRef]
  625. Li, X.; Ma, B.; Li, J.; Shang, L.; Liu, H.; Ge, S. A method to visually observe the degradation-diffusion-reconstruction behavior of hydroxyapatite in the bone repair process. Acta Biomater. 2020, 101, 554–564. [Google Scholar] [CrossRef]
  626. Lu, J.; Descamps, M.; Dejou, J.; Koubi, G.; Hardouin, P.; Lemaitre, J.; Proust, J.P. The biodegradation mechanism of calcium phosphate biomaterials in bone. J. Biomed. Mater. Res. Appl. Biomater. 2002, 63, 408–412. [Google Scholar] [CrossRef]
  627. Wang, H.; Lee, J.K.; Moursi, A.; Lannutti, J.J. Ca/P ratio effects on the degradation of hydroxyapatite in vitro. J. Biomed. Mater. Res. A 2003, 67A, 599–608. [Google Scholar] [CrossRef]
  628. Dorozhkin, S.V. Inorganic chemistry of the dissolution phenomenon, the dissolution mechanism of calcium apatites at the atomic (ionic) level. Comments Inorg. Chem. 1999, 20, 285–299. [Google Scholar] [CrossRef]
  629. Dorozhkin, S.V. Dissolution mechanism of calcium apatites in acids: A review of literature. World J. Methodol. 2012, 2, 1–17. [Google Scholar] [CrossRef]
  630. Sakai, S.; Anada, T.; Tsuchiya, K.; Yamazaki, H.; Margolis, H.C.; Suzuki, O. Comparative study on the resorbability and dissolution behavior of octacalcium phosphate, β-tricalcium phosphate, and hydroxyapatite under physiological conditions. Dent. Mater. J. 2016, 35, 216–224. [Google Scholar] [CrossRef] [PubMed]
  631. Wenisch, S.; Stahl, J.P.; Horas, U.; Heiss, C.; Kilian, O.; Trinkaus, K.; Hild, A.; Schnettler, R. In vivo mechanisms of hydroxyapatite ceramic degradation by osteoclasts: Fine structural microscopy. J. Biomed. Mater. Res. A 2003, 67A, 713–718. [Google Scholar] [CrossRef] [PubMed]
  632. Riihonen, R.; Nielsen, S.; Väänänen, H.K.; Laitala-Leinonen, T.; Kwon, T.H. Degradation of hydroxyapatite in vivo and in vitro requires osteoclastic sodium-bicarbonate co-transporter NBCn1. Matrix Biol. 2010, 29, 287–294. [Google Scholar] [CrossRef] [PubMed]
  633. Meille, S.; Gallo, M.; Clément, P.; Tadier, S.; Chevalier, J. Spherical instrumented indentation as a tool to characterize porous bioceramics and their resorption. J. Eur. Ceram. Soc. 2019, 39, 4459–4472. [Google Scholar] [CrossRef]
  634. Teitelbaum, S.L. Bone resorption by osteoclasts. Science 2000, 289, 1504–1508. [Google Scholar] [CrossRef]
  635. Matsunaga, A.; Takami, M.; Irié, T.; Mishima, K.; Inagaki, K.; Kamijo, R. Microscopic study on resorption of β-tricalcium phosphate materials by osteoclasts. Cytotechnology 2015, 67, 727–732. [Google Scholar] [CrossRef]
  636. Narducci, P.; Nicolin, V. Differentiation of activated monocytes into osteoclast-like cells on a hydroxyapatite substrate: An in vitro study. Ann. Anat. 2009, 191, 349–355. [Google Scholar] [CrossRef]
  637. Wu, V.M.; Uskoković, V. Is there a relationship between solubility and resorbability of different calcium phosphate phases in vitro? Biochim. Biophys. Acta 2016, 1860, 2157–2168. [Google Scholar] [CrossRef]
  638. Stastny, P.; Sedlacek, R.; Suchy, T.; Lukasova, V.; Rampichova, M.; Trunec, M. Structure degradation and strength changes of sintered calcium phosphate bone scaffolds with different phase structures during simulated biodegradation in vitro. Mater. Sci. Eng. C 2019, 100, 544–553. [Google Scholar] [CrossRef]
  639. Tamimi, F.; Torres, J.; Bassett, D.; Barralet, J.; Cabarcos, E.L. Resorption of monetite granules in alveolar bone defects in human patients. Biomaterials 2010, 31, 2762–2769. [Google Scholar] [CrossRef]
  640. Sheikh, Z.; Abdallah, M.N.; Hanafi, A.A.; Misbahuddin, S.; Rashid, H.; Glogauer, M. Mechanisms of in vivo degradation and resorption of calcium phosphate based biomaterials. Materials 2015, 8, 7913–7925. [Google Scholar] [CrossRef]
  641. Raynaud, S.; Champion, E.; Lafon, J.P.; Bernache-Assollant, D. Calcium phosphate apatites with variable Ca/P atomic ratio. III. Mechanical properties and degradation in solution of hot pressed ceramics. Biomaterials 2002, 23, 1081–1089. [Google Scholar] [CrossRef]
  642. Barrère, F.; van der Valk, C.M.; Dalmeijer, R.A.J.; van Blitterswijk, C.A.; de Groot, K.; Layrolle, P. In vitro and in vivo degradation of biomimetic octacalcium phosphate and carbonate apatite coatings on titanium implants. J. Biomed. Mater. Res. A 2003, 64A, 378–387. [Google Scholar] [CrossRef]
  643. Souto, R.M.; Laz, M.M.; Reis, R.L. Degradation characteristics of hydroxyapatite coatings on orthopaedic TiAlV in simulated physiological media investigated by electrochemical impedance spectroscopy. Biomaterials 2003, 24, 4213–4221. [Google Scholar] [CrossRef]
  644. Dellinger, J.G.; Wojtowicz, A.M.; Jamison, R.D. Effects of degradation and porosity on the load bearing properties of model hydroxyapatite bone scaffolds. J. Biomed. Mater. Res. A 2006, 77A, 563–571. [Google Scholar] [CrossRef]
  645. Gallo, M.; Tadier, S.; Meille, S.; Chevalier, J. Resorption of calcium phosphate materials: Considerations on the in vitro evaluation. J. Eur. Ceram. Soc. 2018, 38, 899–914. [Google Scholar] [CrossRef]
  646. Okuda, T.; Ioku, K.; Yonezawa, I.; Minagi, H.; Kawachi, G.; Gonda, Y.; Murayama, H.; Shibata, Y.; Minami, S.; Kamihara, S.; et al. The effect of the microstructure of β-tricalcium phosphate on the metabolism of subsequently formed bone tissue. Biomaterials 2007, 28, 2612–2621. [Google Scholar] [CrossRef]
  647. Maazouz, Y.; Rentsch, I.; Lu, B.; Santoni, B.L.G.; Doebelin, N.; Bohner, M. In vitro measurement of the chemical changes occurring within β-tricalcium phosphate bone graft substitutes. Acta Biomater. 2020, 102, 440–457. [Google Scholar] [CrossRef]
  648. Li, X.; Zou, Q.; Chen, H.; Li, W. In vivo changes of nanoapatite crystals during bone reconstruction and the differences with native bone apatite. Sci. Adv. 2019, 5, eaay6484. [Google Scholar] [CrossRef]
  649. Orly, I.; Gregoire, M.; Menanteau, J.; Heughebaert, M.; Kerebel, B. Chemical changes in hydroxyapatite biomaterial under in vivo and in vitro biological conditions. Calcif. Tissue Int. 1989, 45, 20–26. [Google Scholar] [CrossRef]
  650. Sun, L.; Berndt, C.C.; Gross, K.A.; Kucuk, A. Review: Material fundamentals and clinical performance of plasma sprayed hydroxyapatite coatings. J. Biomed. Mater. Res. Appl. Biomater. 2001, 58, 570–592. [Google Scholar] [CrossRef]
  651. Bertazzo, S.; Zambuzzi, W.F.; Campos, D.D.P.; Ogeda, T.L.; Ferreira, C.V.; Bertran, C.A. Hydroxyapatite surface solubility and effect on cell adhesion. Colloid Surf. B 2010, 78, 177–184. [Google Scholar] [CrossRef]
  652. Arbez, B.; Manero, F.; Mabilleau, G.; Libouban, H.; Chappard, D. Human macrophages and osteoclasts resorb β-tricalcium phosphate in vitro but not mouse macrophages. Micron 2019, 125, 102730. [Google Scholar] [CrossRef]
  653. Schwartz, Z.; Boyan, B.D. Underlying mechanisms at the bone-biomaterial interface. J. Cell. Biochem. 1994, 56, 340–347. [Google Scholar] [CrossRef]
  654. Puleo, D.A.; Nanci, A. Understanding and controlling the bone-implant interface. Biomaterials 1999, 20, 2311–2321. [Google Scholar] [CrossRef]
  655. Xin, R.; Leng, Y.; Chen, J.; Zhang, Q. A comparative study of calcium phosphate formation on bioceramics in vitro and in vivo. Biomaterials 2005, 26, 6477–6486. [Google Scholar] [CrossRef]
  656. Knabe, C.; Adel-Khattab, D.; Ducheyne, P. Bioactivity: Mechanisms. In Comprehensive Biomaterials II; Chapter 1.12; Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2017; pp. 291–310. [Google Scholar]
  657. Girija, E.K.; Parthiban, S.P.; Suganthi, R.V.; Elayaraja, K.; Joshy, M.I.A.; Vani, R.; Kularia, P.; Asokan, K.; Kanjilal, D.; Yokogawa, Y.; et al. High energy irradiation–a tool for enhancing the bioactivity of hydroxyapatite. J. Ceram. Soc. Jpn. 2008, 116, 320–324. [Google Scholar] [CrossRef]
  658. Okada, M.; Furukawa, K.; Serizawa, T.; Yanagisawa, Y.; Tanaka, H.; Kawai, T.; Furuzono, T. Interfacial interactions between calcined hydroxyapatite nanocrystals and substrates. Langmuir 2009, 25, 6300–6306. [Google Scholar] [CrossRef]
  659. Callis, P.D.; Donaldson, K.; McCord, J.F. Early cellular responses to calcium phosphate ceramics. Clin. Mater. 1988, 3, 183–190. [Google Scholar] [CrossRef]
  660. Okumura, M.; Ohgushi, H.; Tamai, S. Bonding osteogenesis in coralline hydroxyapatite combined with bone marrow cells. Biomaterials 1990, 12, 28–37. [Google Scholar] [CrossRef]
  661. Doi, Y.; Iwanaga, H.; Shibutani, T.; Moriwaki, Y.; Iwayama, Y. Osteoclastic responses to various calcium phosphates in cell cultures. J. Biomed. Mater. Res. 1999, 47, 424–433. [Google Scholar] [CrossRef]
  662. Guo, X.; Gough, J.E.; Xiao, P.; Liu, J.; Shen, Z. Fabrication of nanostructured hydroxyapatite and analysis of human osteoblastic cellular response. J. Biomed. Mater. Res. A 2007, 82A, 1022–1032. [Google Scholar] [CrossRef] [PubMed]
  663. Wang, Y.; Zhang, S.; Zeng, X.; Ma, L.L.; Weng, W.; Yan, W.; Qian, M. Osteoblastic cell response on fluoridated hydroxyapatite coatings. Acta Biomater. 2007, 3, 191–197. [Google Scholar] [CrossRef] [PubMed]
  664. Bae, W.J.; Chang, S.W.; Lee, S.I.; Kum, K.Y.; Bae, K.S.; Kim, E.C. Human periodontal ligament cell response to a newly developed calcium phosphate-based root canal sealer. J. Endod. 2010, 36, 1658–1663. [Google Scholar] [CrossRef] [PubMed]
  665. Zhao, X.; Heng, B.C.; Xiong, S.; Guo, J.; Tan, T.T.Y.; Boey, F.Y.C.; Ng, K.W.; Loo, J.S.C. In vitro assessment of cellular responses to rod-shaped hydroxyapatite nanoparticles of varying lengths and surface areas. Nanotoxicology 2011, 5, 182–194. [Google Scholar] [CrossRef] [PubMed]
  666. Liu, X.; Zhao, M.; Lu, J.; Ma, J.; Wei, J.; Wei, S. Cell responses to two kinds of nanohydroxyapatite with different sizes and crystallinities. Int. J. Nanomed. 2012, 7, 1239–1250. [Google Scholar] [CrossRef] [PubMed]
  667. Lobo, S.E.; Glickman, R.; da Silva, W.N.; Arinzeh, T.L.; Kerkis, I. Response of stem cells from different origins to biphasic calcium phosphate bioceramics. Cell Tiss. Res. 2015, 361, 477–495. [Google Scholar] [CrossRef] [PubMed]
  668. Oliveira, H.L.; da Rosa, W.L.O.; Cuevas-Suárez, C.E.; Carreño, N.L.V.; da Silva, A.F.; Guim, T.N.; Dellagostin, O.A.; Piva, E. Histological evaluation of bone repair with hydroxyapatite: A systematic review. Calcif. Tissue Int. 2017, 101, 341–354. [Google Scholar] [CrossRef]
  669. Sadowska, J.M.; Wei, F.; Guo, J.; Guillem-Marti, J.; Lin, Z.; Ginebra, M.P.; Xiao, Y. The effect of biomimetic calcium deficient hydroxyapatite and sintered β-tricalcium phosphate on osteoimmune reaction and osteogenesis. Acta Biomater. 2019, 96, 605–618. [Google Scholar] [CrossRef]
  670. Šupová, M.; Suchý, T.; Sucharda, Z.; Filová, E.; der Kinderen, J.N.L.M.; Steinerová, M.; Bačáková, L.; Martynková, G.S. The comprehensive in vitro evaluation of eight different calcium phosphates: Significant parameters for cell behavior. J. Amer. Ceram. Soc. 2019, 102, 2882–2904. [Google Scholar] [CrossRef]
  671. Wang, X.; Yu, Y.; Ji, L.; Geng, Z.; Wang, J.; Liu, C. Calcium phosphate-based materials regulate osteoclast-mediated osseointegration. Bioact. Mater. 2021, 6, 4517–4530. [Google Scholar] [CrossRef]
  672. Suzuki, T.; Ohashi, R.; Yokogawa, Y.; Nishizawa, K.; Nagata, F.; Kawamoto, Y.; Kameyama, T.; Toriyama, M. Initial anchoring and proliferation of fibroblast L-929 cells on unstable surface of calcium phosphate ceramics. J. Biosci. Bioeng. 1999, 87, 320–327. [Google Scholar] [CrossRef]
  673. Arinzeh, T.L.; Tran, T.; McAlary, J.; Daculsi, G. A comparative study of biphasic calcium phosphate ceramics for human mesenchymal stem-cell-induced bone formation. Biomaterials 2005, 26, 3631–3638. [Google Scholar] [CrossRef]
  674. Oh, S.; Oh, N.; Appleford, M.; Ong, J.L. Bioceramics for tissue engineering applications–a review. Am. J. Biochem. Biotechnol. 2006, 2, 49–56. [Google Scholar] [CrossRef]
  675. Appleford, M.; Oh, S.; Cole, J.A.; Carnes, D.L.; Lee, M.; Bumgardner, J.D.; Haggard, W.O.; Ong, J.L. Effects of trabecular calcium phosphate scaffolds on stress signaling in osteoblast precursor cells. Biomaterials 2007, 28, 2747–2753. [Google Scholar] [CrossRef]
  676. Gamie, Z.; Tran, G.T.; Vyzas, G.; Korres, N.; Heliotis, M.; Mantalaris, A.; Tsiridis, E. Stem cells combined with bone graft substitutes in skeletal tissue engineering. Expert Opin. Biol. Ther. 2012, 12, 713–729. [Google Scholar] [CrossRef]
  677. Manfrini, M.; di Bona, C.; Canella, A.; Lucarelli, E.; Pellati, A.; d’Agostino, A.; Barbanti-Bròdano, G.; Tognon, M. Mesenchymal stem cells from patients to assay bone graft substitutes. J. Cell. Physiol. 2013, 228, 1229–1237. [Google Scholar] [CrossRef]
  678. Unger, R.E.; Sartoris, A.; Peters, K.; Motta, A.; Migliaresi, C.; Kunkel, M.; Bulnheim, U.; Rychly, J.; Kirkpatrick, C.J. Tissue-like self-assembly in cocultures of endothelial cells and osteoblasts and the formation of microcapillary like structures on three-dimensional porous biomaterials. Biomaterials 2007, 28, 3965–3976. [Google Scholar] [CrossRef]
  679. Nazir, N.M.; Dasmawati, M.; Azman, S.M.; Omar, N.S.; Othman, R. Biocompatibility of in house β-tricalcium phosphate ceramics with normal human osteoblast cell. J. Eng. Sci. Technol. 2012, 7, 169–176. [Google Scholar]
  680. Tan, F.; O’Neill, F.; Naciri, M.; Dowling, D.; Al-Rubeai, M. Cellular and transcriptomic analysis of human mesenchymal stem cell response to plasma-activated hydroxyapatite coating. Acta Biomater. 2012, 8, 1627–1638. [Google Scholar] [CrossRef]
  681. Arbez, B.; Libouban, H. Behavior of macrophage and osteoblast cell lines in contact with the β-TCP biomaterial (beta-tricalcium phosphate)|Comportement de lignées cellulaires de macrophages et d’ostéoblastes en contact avec le biomatériau β-TCP (phosphate bêta tricalcique).]. Morphologie 2017, 101, 154–163. [Google Scholar] [CrossRef] [PubMed]
  682. Frayssinet, P.; Rouquet, N.; Vidalain, P.O. Calcium phosphates for cell transfection. In Comprehensive Biomaterials II; Chapter 1.15.; Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2017; pp. 350–359. [Google Scholar]
  683. Teixeira, S.; Fernandes, M.H.; Ferraz, M.P.; Monteiro, F.J. Proliferation and mineralization of bone marrow cells cultured on macroporous hydroxyapatite scaffolds functionalized with collagen type I for bone tissue regeneration. J. Biomed. Mater. Res. A 2010, 95A, 1–8. [Google Scholar] [CrossRef] [PubMed]
  684. Treccani, L.; Klein, T.Y.; Meder, F.; Pardun, K.; Rezwan, K. Functionalized ceramics for biomedical, biotechnological and environmental applications. Acta Biomater. 2013, 9, 7115–7150. [Google Scholar] [CrossRef] [PubMed]
  685. Bigi, A.; Boanini, E. Functionalized biomimetic calcium phosphates for bone tissue repair. J. Appl. Biomater. Funct. Mater. 2017, 15, e313–e325. [Google Scholar] [CrossRef] [PubMed]
  686. Dorozhkin, S.V. Functionalized calcium orthophosphates (CaPO4) and their biomedical applications. J. Mater. Chem. B 2019, 7, 7471–7489. [Google Scholar] [CrossRef]
  687. Zhuang, Z.; Yoshimura, H.; Aizawa, M. Synthesis and ultrastructure of plate-like apatite single crystals as a model for tooth enamel. Mater. Sci. Eng. C 2013, 33, 2534–2540. [Google Scholar] [CrossRef] [PubMed]
  688. Zhuang, Z.; Fujimi, T.J.; Nakamura, M.; Konishi, T.; Yoshimura, H.; Aizawa, M. Development of a,b-plane-oriented hydroxyapatite ceramics as models for living bones and their cell adhesion behavior. Acta Biomater. 2013, 9, 6732–6740. [Google Scholar] [CrossRef]
  689. Aizawa, M.; Matsuura, T.; Zhuang, Z. Syntheses of single-crystal apatite particles with preferred orientation to the a- and c-axes as models of hard tissue and their applications. Biol. Pharm. Bull. 2013, 36, 1654–1661. [Google Scholar] [CrossRef]
  690. Lin, K.; Wu, C.; Chang, J. Advances in synthesis of calcium phosphate crystals with controlled size and shape. Acta Biomater. 2014, 10, 4071–4102. [Google Scholar] [CrossRef]
  691. Chen, W.; Long, T.; Guo, Y.J.; Zhu, Z.A.; Guo, Y.P. Hydrothermal synthesis of hydroxyapatite coatings with oriented nanorod arrays. RSC Adv. 2014, 4, 185–191. [Google Scholar] [CrossRef]
  692. Guan, J.J.; Tian, B.; Tang, S.; Ke, Q.F.; Zhang, C.Q.; Zhu, Z.A.; Guo, Y.P. Hydroxyapatite coatings with oriented nanoplate arrays: Synthesis, formation mechanism and cytocompatibility. J. Mater. Chem. B 2015, 3, 1655–1666. [Google Scholar] [CrossRef]
  693. Ribeiro, C.; Rigo, E.C.S.; Sepúlveda, P.; Bressiani, J.C.; Bressiani, A.H.A. Formation of calcium phosphate layer on ceramics with different reactivities. Mater. Sci. Eng. C 2004, 24, 631–636. [Google Scholar] [CrossRef]
  694. Barba, A.; Diez-Escudero, A.; Maazouz, Y.; Rappe, K.; Espanol, M.; Montufar, E.B.; Bonany, M.; Sadowska, J.M.; Guillem-Marti, J.; Öhman-Mägi, C.; et al. Osteoinduction by foamed and 3D-printed calcium phosphate scaffolds: Effect of nanostructure and pore architecture. ACS Appl. Mater. Interfaces 2017, 9, 41722–41736. [Google Scholar] [CrossRef]
  695. Tsukanaka, M.; Fujibayashi, S.; Otsuki, B.; Takemoto, M.; Matsuda, S. Osteoinductive potential of highly purified porous β-TCP in mice. J. Mater. Sci. Mater. Med. 2015, 26, 132. [Google Scholar] [CrossRef]
  696. Duan, R.; Barbieri, D.; Luo, X.; Weng, J.; Bao, C.; de Bruijn, J.D.; Yuan, H. Variation of the bone forming ability with the physicochemical properties of calcium phosphate bone substitutes. Biomater. Sci. 2018, 6, 136–145. [Google Scholar] [CrossRef]
  697. Davison, N.L.; ten Harkel, B.; Schoenmaker, T.; Luo, X.; Yuan, H.; Everts, V.; Barrère-de Groot, F.; de Bruijn, J.D. Osteoclast resorption of beta-tricalcium phosphate controlled by surface architecture. Biomaterials 2014, 35, 7441–7451. [Google Scholar] [CrossRef]
  698. Al-Maawi, S.; Barbeck, M.; Vizcaíno, C.H.; Egli, R.; Sader, R.; Kirkpatrick, C.J.; Bohner, M.; Ghanaati, S. Thermal treatment at 500 °C significantly reduces the reaction to irregular tricalcium phosphate granules as foreign bodies: An in vivo study. Acta Biomater. 2021, 121, 621–636. [Google Scholar] [CrossRef]
  699. Levitt, G.E.; Crayton, P.H.; Monroe, E.A.; Condrate, R.A. Forming methods for apatite prosthesis. J. Biomed. Mater. Res. 1969, 3, 683–685. [Google Scholar] [CrossRef]
  700. Fukuba, S.; Okada, M.; Nohara, K.; Iwata, T. Alloplastic bone substitutes for periodontal and bone regeneration in dentistry: Current status and prospects. Materials 2021, 14, 1096. [Google Scholar] [CrossRef]
  701. Roca-Millan, E.; Jané-Salas, E.; Marí-Roig, A.; Jiménez-Guerra, Á.; Ortiz-García, I.; Velasco-Ortega, E.; López-López, J.; Monsalve-Guil, L. The application of beta-tricalcium phosphate in implant dentistry: A systematic evaluation of clinical studies. Materials 2022, 15, 655. [Google Scholar] [CrossRef]
  702. Easwer, H.V.; Rajeev, A.; Varma, H.K.; Vijayan, S.; Bhattacharya, R.N. Cosmetic and radiological outcome following the use of synthetic hydroxyapatite porous-dense bilayer burr-hole buttons. Acta Neurochir. 2007, 149, 481–485. [Google Scholar] [CrossRef] [PubMed]
  703. Kashimura, H.; Ogasawara, K.; Kubo, Y.; Yoshida, K.; Sugawara, A.; Ogawa, A. A newly designed hydroxyapatite ceramic burr-hole button. Vasc. Health Risk Manag. 2010, 6, 105–108. [Google Scholar] [CrossRef]
  704. Jordan, D.R.; Gilberg, S.; Bawazeer, A. Coralline hydroxyapatite orbital implant (Bio-Eye): Experience with 158 patients. Ophthal. Plast. Reconstr. Surg. 2004, 20, 69–74. [Google Scholar] [CrossRef]
  705. Yoon, J.S.; Lew, H.; Kim, S.J.; Lee, S.Y. Exposure rate of hydroxyapatite orbital implants. A 15-year experience of 802 cases. Ophthalmology 2008, 115, 566–572. [Google Scholar] [CrossRef] [PubMed]
  706. Tabatabaee, Z.; Mazloumi, M.; Rajabi, T.M.; Khalilzadeh, O.; Kassaee, A.; Moghimi, S.; Eftekhar, H.; Goldberg, R.A. Comparison of the exposure rate of wrapped hydroxyapatite (Bio-Eye) versus unwrapped porous polyethylene (Medpor) orbital implants in enucleated patients. Ophthal. Plast. Reconstr. Surg. 2011, 27, 114–118. [Google Scholar] [CrossRef] [PubMed]
  707. Ma, X.Z.; Bi, H.S.; Zhang, X. Effect of hydroxyapatite orbital implant for plastic surgery of eye in 52 cases. Int. Eye Sci. 2012, 12, 988–990. [Google Scholar]
  708. Baino, F.; Vitale-Brovarone, C. Bioceramics in ophthalmology. Acta Biomater. 2014, 10, 3372–3397. [Google Scholar] [CrossRef]
  709. Thiesmann, R.; Anagnostopoulos, A.; Stemplewitz, B. Long-term results of the compatibility of a coralline hydroxyapatite implant as eye replacement|Langzeitergebnisse zur Verträglichkeit eines korallinen Hydroxylapatitimplantats als Bulbusersatz. Ophthalmologe 2018, 115, 131–136. [Google Scholar] [CrossRef]
  710. Wehrs, R.E. Hearing results with incus and incus stapes prostheses of hydroxylapatite. Laryngoscope 1991, 101, 555–556. [Google Scholar] [CrossRef]
  711. Smith, J.; Gardner, E.; Dornhoffer, J.L. Hearing results with a hydroxylapatite/titanium bell partial ossicular replacement prosthesis. Laryngoscope 2002, 112, 1796–1799. [Google Scholar] [CrossRef]
  712. Doi, T.; Hosoda, Y.; Kaneko, T.; Munemoto, Y.; Kaneko, A.; Komeda, M.; Furukawa, M.; Kuriyama, H.; Kitajiri, M.; Tomoda, K.; et al. Hearing results for ossicular reconstruction using a cartilage-connecting hydroxyapatite prosthesis with a spearhead. Otol. Neurotol. 2007, 28, 1041–1044. [Google Scholar] [CrossRef]
  713. Thalgott, J.S.; Fritts, K.; Giuffre, J.M.; Timlin, M. Anterior interbody fusion of the cervical spine with coralline hydroxyapatite. Spine 1999, 24, 1295–1299. [Google Scholar] [CrossRef]
  714. Mashoof, A.A.; Siddiqui, S.A.; Otero, M.; Tucci, J.J. Supplementation of autogenous bone graft with coralline hydroxyapatite in posterior spine fusion for idiopathic adolescent scoliosis. Orthopedics 2002, 25, 1073–1076. [Google Scholar] [CrossRef]
  715. Liu, W.Y.; Mo, J.W.; Gao, H.; Liu, H.L.; Wang, M.Y.; He, C.L.; Tang, W.; Ye, Y.J. Nano-hydroxyapatite artificial bone serves as a spacer for fusion with the cervical spine after bone grafting. Chin. J. Tissue Eng. Res. 2012, 16, 5327–5330. [Google Scholar]
  716. Litak, J.; Czyzewski, W.; Szymoniuk, M.; Pastuszak, B.; Litak, J.; Litak, G.; Grochowski, C.; Rahnama-Hezavah, M.; Kamieniak, P. Hydroxyapatite use in spine surgery–molecular and clinical aspect. Materials 2022, 15, 2906. [Google Scholar] [CrossRef]
  717. Silva, R.V.; Camilli, J.A.; Bertran, C.A.; Moreira, N.H. The use of hydroxyapatite and autogenous cancellous bone grafts to repair bone defects in rats. Int. J. Oral Maxillofac. Surg. 2005, 34, 178–184. [Google Scholar] [CrossRef]
  718. Damron, T.A. Use of 3D β-tricalcium phosphate (Vitoss®) scaffolds in repairing bone defects. Nanomedicine 2007, 2, 763–775. [Google Scholar] [CrossRef]
  719. Zaed, I.; Cardia, A.; Stefini, R. From reparative surgery to regenerative surgery: State of the art of porous hydroxyapatite in cranioplasty. Int. J. Mol. Sci. 2022, 23, 5434. [Google Scholar] [CrossRef]
  720. Alsahafi, R.A.; Mitwalli, H.A.; Balhaddad, A.A.; Weir, M.D.; Xu, H.H.K.; Melo, M.A.S. Regenerating craniofacial dental defects with calcium phosphate cement scaffolds: Current status and innovative scope review. Front. Dent. Med. 2021, 2, 743065. [Google Scholar] [CrossRef]
  721. Bass, L.S.; Smith, S.; Busso, M.; McClaren, M. Calcium hydroxylapatite (Radiesse) for treatment of nasolabial folds: Long-term safety and efficacy results. Aesthetic Surg. J. 2010, 30, 235–238. [Google Scholar] [CrossRef]
  722. Low, K.L.; Tan, S.H.; Zein, S.H.S.; Roether, J.A.; Mouriño, V.; Boccaccini, A.R. Calcium phosphate-based composites as injectable bone substitute materials. J. Biomed. Mater. Res. B Appl. Biomater. 2010, 94B, 273–286. [Google Scholar] [CrossRef] [PubMed]
  723. Daculsi, G.; Uzel, A.P.; Weiss, P.; Goyenvalle, E.; Aguado, E. Developments in injectable multiphasic biomaterials. The performance of microporous biphasic calcium phosphate granules and hydrogels. J. Mater. Sci. Mater. Med. 2010, 21, 855–861. [Google Scholar] [CrossRef] [PubMed]
  724. Suzuki, K.; Anada, T.; Honda, Y.; Kishimoto, K.N.; Miyatake, N.; Hosaka, M.; Imaizumi, H.; Itoi, E.; Suzuki, O. Cortical bone tissue response of injectable octacalcium phosphate-hyaluronic acid complexes. Key Eng. Mater. 2013; 529–530, 296–299. [Google Scholar]
  725. Pastorino, D.; Canal, C.; Ginebra, M.P. Drug delivery from injectable calcium phosphate foams by tailoring the macroporosity-drug interaction. Acta Biomater. 2015, 12, 250–259. [Google Scholar] [CrossRef] [PubMed]
  726. Moussi, H.; Weiss, P.; le Bideau, J.; Gautier, H.; Charbonnier, B. Injectable macromolecules-based calcium phosphate bone substitutes. Mater. Adv. 2022, 3, 6125–6141. [Google Scholar] [CrossRef]
  727. Bohner, M.; Baroud, G. Injectability of calcium phosphate pastes. Biomaterials 2005, 26, 1553–1563. [Google Scholar] [CrossRef]
  728. Laschke, M.W.; Witt, K.; Pohlemann, T.; Menger, M.D. Injectable nanocrystalline hydroxyapatite paste for bone substitution: In vivo analysis of biocompatibility and vascularization. J. Biomed. Mater. Res. B Appl. Biomater. 2007, 82B, 494–505. [Google Scholar] [CrossRef]
  729. Lopez-Heredia, M.A.; Barnewitz, D.; Genzel, A.; Stiller, M.; Peters, F.; Huebner, W.D.; Stang, B.; Kuhr, A.; Knabe, C. In vivo osteogenesis assessment of a tricalcium phosphate paste and a tricalcium phosphate foam bone grafting materials. Key Eng. Mater. 2015, 631, 426–429. [Google Scholar] [CrossRef]
  730. Torres, P.M.C.; Gouveia, S.; Olhero, S.; Kaushal, A.; Ferreira, J.M.F. Injectability of calcium phosphate pastes: Effects of particle size and state of aggregation of β-tricalcium phosphate powders. Acta Biomater. 2015, 21, 204–216. [Google Scholar] [CrossRef]
  731. Salinas, A.J.; Esbrit, P.; Vallet-Regí, M. A tissue engineering approach based on the use of bioceramics for bone repair. Biomater. Sci. 2013, 1, 40–51. [Google Scholar] [CrossRef]
  732. ISO 13175-3:2012 Implants for Surgery—Calcium Phosphates—Part 3: Hydroxyapatite and Beta-Tricalcium Phosphate Bone Substitutes. Available online: https://www.iso.org/obp/ui/#iso:std:iso:13175:-3:ed-1:v1:en (accessed on 24 June 2022).
  733. Chow, L.C. Next generation calcium phosphate-based biomaterials. Dent. Mater. J. 2009, 28, 1–10. [Google Scholar] [CrossRef]
  734. Victor, S.P.; Kumar, T.S.S. Processing and properties of injectable porous apatitic cements. J. Ceram. Soc. Jpn. 2008, 116, 105–107. [Google Scholar] [CrossRef]
  735. Hesaraki, S.; Nemati, R.; Nosoudi, N. Preparation and characterisation of porous calcium phosphate bone cement as antibiotic carrier. Adv. Appl. Ceram. 2009, 108, 231–240. [Google Scholar] [CrossRef]
  736. Stulajterova, R.; Medvecky, L.; Giretova, M.; Sopcak, T. Structural and phase characterization of bioceramics prepared from tetracalcium phosphate–monetite cement and in vitro osteoblast response. J. Mater. Sci. Mater. Med. 2015, 26, 183. [Google Scholar] [CrossRef]
  737. Bohner, M. Resorbable biomaterials as bone graft substitutes. Mater. Today 2010, 13, 24–30. [Google Scholar] [CrossRef]
  738. Moussa, H.; Jiang, W.; Alsheghri, A.; Mansour, A.; Hadad, A.E.; Pan, H.; Tang, R.; Song, J.; Vargas, J.; McKee, M.D.; et al. High strength brushite bioceramics obtained by selective regulation of crystal growth with chiral biomolecules. Acta Biomater. 2020, 106, 351–359. [Google Scholar] [CrossRef]
  739. Schröter, L.; Kaiser, F.; Stein, S.; Gbureck, U.; Ignatius, A. Biological and mechanical performance and degradation characteristics of calcium phosphate cements in large animals and humans. Acta Biomater. 2020, 117, 1–20. [Google Scholar] [CrossRef]
  740. Paital, S.R.; Dahotre, N.B. Calcium phosphate coatings for bio-implant applications: Materials, performance factors, and methodologies. Mater. Sci. Eng. R 2009, 66, 1–70. [Google Scholar] [CrossRef]
  741. León, B.; Jansen, J.A. (Eds.) Thin Calcium Phosphate Coatings for Medical Implants; Springer: New York, NY, USA, 2009; p. 326. [Google Scholar]
  742. Dorozhkin, S.V. Calcium orthophosphate deposits: Preparation, properties and biomedical applications. Mater. Sci. Eng. C 2015, 55, 272–326. [Google Scholar] [CrossRef]
  743. Kon, M.; Ishikawa, K.; Miyamoto, Y.; Asaoka, K. Development of calcium phosphate based functional gradient bioceramics. Biomaterials 1995, 16, 709–714. [Google Scholar] [CrossRef]
  744. Wong, L.H.; Tio, B.; Miao, X. Functionally graded tricalcium phosphate/fluoroapatite composites. Mater. Sci. Eng. C 2002, 20, 111–115. [Google Scholar] [CrossRef]
  745. Tampieri, A.; Celotti, G.; Sprio, S.; Delcogliano, A.; Franzese, S. Porosity-graded hydroxyapatite ceramics to replace natural bone. Biomaterials 2001, 22, 1365–1370. [Google Scholar] [CrossRef]
  746. Werner, J.; Linner-Krcmar, B.; Friess, W.; Greil, P. Mechanical properties and in vitro cell compatibility of hydroxyapatite ceramics with graded pore structure. Biomaterials 2002, 23, 4285–4294. [Google Scholar] [CrossRef]
  747. Watanabe, T.; Fukuhara, T.; Izui, H.; Fukase, Y.; Okano, M. Properties of HAp/β-TCP functionally graded material by spark plasma sintering. Trans. Jpn. Soc. Mech. Eng. A 2009, 75, 612–618. [Google Scholar] [CrossRef]
  748. Bai, X.; Sandukas, S.; Appleford, M.R.; Ong, J.L.; Rabiei, A. Deposition and investigation of functionally graded calcium phosphate coatings on titanium. Acta Biomater. 2009, 5, 3563–3572. [Google Scholar] [CrossRef]
  749. Tamura, A.; Asaoka, T.; Furukawa, K.; Ushida, T.; Tateishi, T. Application of α-TCP/HAp functionally graded porous beads for bone regenerative scaffold. Adv. Sci. Technol. 2013, 86, 63–69. [Google Scholar]
  750. Gasik, M.; Keski-Honkola, A.; Bilotsky, Y.; Friman, M. Development and optimisation of hydroxyapatite-β-TCP functionally gradated biomaterial. J. Mech. Behav. Biomed. Mater. 2014, 30, 266–273. [Google Scholar] [CrossRef]
  751. Zhou, C.; Deng, C.; Chen, X.; Zhao, X.; Chen, Y.; Fan, Y.; Zhang, X. Mechanical and biological properties of the micro-/nano-grain functionally graded hydroxyapatite bioceramics for bone tissue engineering. J. Mech. Behav. Biomed. Mater. 2015, 48, 1–11. [Google Scholar] [CrossRef]
  752. Marković, S.; Lukić, M.J.; Škapin, S.D.; Stojanović, B.; Uskoković, D. Designing, fabrication and characterization of nanostructured functionally graded HAp/BCP ceramics. Ceram. Int. 2015, 41, 2654–2667. [Google Scholar] [CrossRef]
  753. Salimi, E. Functionally graded calcium phosphate bioceramics: An overview of preparation and properties. Ceram. Int. 2020, 46, 19664–19668. [Google Scholar] [CrossRef]
  754. Hollister, S.J. Porous scaffold design for tissue engineering. Nat. Mater. 2005, 4, 518–524. [Google Scholar] [CrossRef]
  755. Jones, J.R.; Hench, L.L. Regeneration of trabecular bone using porous ceramics. Curr. Opin. Solid State Mater. Sci. 2003, 7, 301–307. [Google Scholar] [CrossRef]
  756. Williams, D.F. To engineer is to create; the link between engineering and regeneration. Trends Biotech. 2006, 24, 4–8. [Google Scholar] [CrossRef] [PubMed]
  757. Griffith, L.G.; Naughton, G. Tissue engineering–current challenges and expanding opportunities. Science 2002, 295, 1009–1014. [Google Scholar] [CrossRef] [PubMed]
  758. Goldberg, V.M.; Caplan, A.I. Orthopedic Tissue Engineering Basic Science and Practice; Marcel Dekker: New York, NY, USA, 2004; p. 338. [Google Scholar]
  759. Bahraminasab, M.; Janmohammadi, M.; Arab, S.; Talebi, A.; Nooshabadi, V.T.; Koohsarian, P.; Nourbakhsh, M.S. Bone scaffolds: An incorporation of biomaterials, cells, and biofactors. ACS Biomater. Sci. Eng. 2021, 7, 5397–5431. [Google Scholar] [CrossRef]
  760. Ikada, Y. Challenges in tissue engineering. J. R. Soc. Interface 2006, 3, 589–601. [Google Scholar] [CrossRef]
  761. Cima, L.G.; Langer, R. Engineering human tissue. Chem. Eng. Prog. 1993, 89, 46–54. [Google Scholar]
  762. Langer, R.; Vacanti, J.P. Tissue engineering. Science 1993, 260, 920–926. [Google Scholar] [CrossRef] [Green Version]
  763. El-Ghannam, A. Bone reconstruction: From bioceramics to tissue engineering. Expert Rev. Med. Dev. 2005, 2, 87–101. [Google Scholar] [CrossRef]
  764. Kneser, U.; Schaefer, D.J.; Polykandriotis, E.; Horch, R.E. Tissue engineering of bone: The reconstructive surgeon’s point of view. J. Cell. Mol. Med. 2006, 10, 7–19. [Google Scholar] [CrossRef]
  765. Boyan, B.D.; Cohen, D.J.; Schwartz, Z. Bone tissue grafting and tissue engineering concepts. In Comprehensive Biomaterials II; Chapter 7.17.; Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2017; pp. 298–313. [Google Scholar]
  766. Koons, G.L.; Diba, M.; Mikos, A.G. Materials design for bone-tissue engineering. Nat. Rev. Mater. 2020, 5, 584–603. [Google Scholar] [CrossRef]
  767. Lutolf, M.P.; Hubbell, J.A. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat. Biotechnol. 2005, 23, 47–55. [Google Scholar] [CrossRef]
  768. Ma, P.X. Biomimetic materials for tissue engineering. Adv. Drug. Deliv. Rev. 2008, 60, 184–198. [Google Scholar] [CrossRef]
  769. Yang, S.; Leong, K.F.; Du, Z.; Chua, C.K. The design of scaffolds for use in tissue engineering. Part, I. Traditional factors. Tissue Eng. 2001, 7, 679–689. [Google Scholar] [CrossRef]
  770. Ma, P.X.; Elisseeff, J. (Eds.) Scaffolding in Tissue Engineering; CRC Press: Boca Raton, FL, USA, 2006; p. 638. [Google Scholar]
  771. Alvarez-Urena, P.; Kim, J.; Bhattacharyya, S.; Ducheyne, P. Bioactive ceramics and bioactive ceramic composite-based scaffolds. In Comprehensive Biomaterials II; Chapter 6.1.; Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2017; pp. 1–19. [Google Scholar]
  772. Baldwin, J.; Henkel, J.; Hutmacher, D.W. Engineering the organ bone. In Comprehensive Biomaterials II; Chapter 6.3.; Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2017; pp. 54–74. [Google Scholar]
  773. Williams, D.F. The biomaterials conundrum in tissue engineering. Tissue Eng. A 2014, 20, 1129–1131. [Google Scholar] [CrossRef]
  774. Freed, L.E.; Guilak, F.; Guo, X.E.; Gray, M.L.; Tranquillo, R.; Holmes, J.W.; Radisic, M.; Sefton, M.V.; Kaplan, D.; Vunjak-Novakovic, G. Advanced tools for tissue engineering: Scaffolds, bioreactors, and signaling. Tissue Eng. 2006, 12, 3285–3305. [Google Scholar] [CrossRef]
  775. Gandaglia, A.; Bagno, A.; Naso, F.; Spina, M.; Gerosa, G. Cells, scaffolds and bioreactors for tissue-engineered heart valves: A journey from basic concepts to contemporary developmental innovations. Eur. J. Cardiothorac. Surg. 2011, 39, 523–531. [Google Scholar] [CrossRef]
  776. Hui, J.H.P.; Buhary, K.S.; Chowdhary, A. Implantation of orthobiologic, biodegradable scaffolds in osteochondral repair. Orthop. Clin. North Am. 2012, 43, 255–261. [Google Scholar] [CrossRef]
  777. Vanderleyden, E.; Mullens, S.; Luyten, J.; Dubruel, P. Implantable (bio)polymer coated titanium scaffolds: A review. Curr. Pharm. Des. 2012, 18, 2576–2590. [Google Scholar] [CrossRef]
  778. Service, R.F. Tissue engineers build new bone. Science 2000, 289, 1498–1500. [Google Scholar] [CrossRef]
  779. Deligianni, D.D.; Katsala, N.D.; Koutsoukos, P.G.; Missirlis, Y.F. Effect of surface roughness of hydroxyapatite on human bone marrow cell adhesion, proliferation, differentiation and detachment strength. Biomaterials 2001, 22, 87–96. [Google Scholar] [CrossRef]
  780. Fini, M.; Giardino, R.; Borsari, V.; Torricelli, P.; Rimondini, L.; Giavaresi, G.; Aldini, N.N. In vitro behaviour of osteoblasts cultured on orthopaedic biomaterials with different surface roughness, uncoated and fluorohydroxyapatite-coated, relative to the in vivo osteointegration rate. Int. J. Artif. Organs 2003, 26, 520–528. [Google Scholar] [CrossRef] [PubMed]
  781. Kumar, G.; Waters, M.S.; Farooque, T.M.; Young, M.F.; Simon, C.G. Freeform fabricated scaffolds with roughened struts that enhance both stem cell proliferation and differentiation by controlling cell shape. Biomaterials 2012, 33, 4022–4030. [Google Scholar] [CrossRef] [PubMed]
  782. Holthaus, M.G.; Treccani, L.; Rezwan, K. Osteoblast viability on hydroxyapatite with well-adjusted submicron and micron surface roughness as monitored by the proliferation reagent WST2-1. J. Biomater. Appl. 2013, 27, 791–800. [Google Scholar] [CrossRef] [PubMed]
  783. Bianchi, M.; Edreira, E.R.U.; Wolke, J.G.C.; Birgani, Z.T.; Habibovic, P.; Jansen, J.A.; Tampieri, A.; Marcacci, M.; Leeuwenburgh, S.C.G.; van den Beucken, J.J.J.P. Substrate geometry directs the in vitro mineralization of calcium phosphate ceramics. Acta Biomater. 2014, 10, 661–669. [Google Scholar] [CrossRef]
  784. Sadowska, J.M.; Wei, F.; Guo, J.; Guillem-Marti, J.; Ginebra, M.P.; Xiao, Y. Effect of nano-structural properties of biomimetic hydroxyapatite on osteoimmunomodulation. Biomaterials 2018, 181, 318–332. [Google Scholar] [CrossRef]
  785. Ebaretonbofa, E.; Evans, J.R. High porosity hydroxyapatite foam scaffolds for bone substitute. J. Porous Mater. 2002, 9, 257–263. [Google Scholar] [CrossRef]
  786. Hing, K.A. Bioceramic bone graft substitutes: Influence of porosity and chemistry. Int. J. Appl. Ceram. Technol. 2005, 2, 184–199. [Google Scholar] [CrossRef]
  787. Malmström, J.; Adolfsson, E.; Arvidsson, A.; Thomsen, P. Bone response inside free-form fabricated macroporous hydroxyapatite scaffolds with and without an open microporosity. Clin. Implant. Dent. Rel. Res. 2007, 9, 79–88. [Google Scholar]
  788. Lew, K.S.; Othman, R.; Ishikawa, K.; Yeoh, F.Y. Macroporous bioceramics: A remarkable material for bone regeneration. J. Biomater. Appl. 2012, 27, 345–358. [Google Scholar] [CrossRef]
  789. Ren, L.M.; Todo, M.; Arahira, T.; Yoshikawa, H.; Myoui, A. A comparative biomechanical study of bone ingrowth in two porous hydroxyapatite bioceramics. Appl. Surf. Sci. 2012, 262, 81–88. [Google Scholar] [CrossRef]
  790. Guda, T.; Walker, J.A.; Singleton, B.; Hernandez, J.; Oh, D.S.; Appleford, M.R.; Ong, J.L.; Wenke, J.C. Hydroxyapatite scaffold pore architecture effects in large bone defects in vivo. J. Biomater. Appl. 2014, 28, 1016–1027. [Google Scholar] [CrossRef]
  791. Shao, R.; Quan, R.; Zhang, L.; Wei, X.; Yang, D.; Xie, S. Porous hydroxyapatite bioceramics in bone tissue engineering: Current uses and perspectives. J. Ceram. Soc. Jpn. 2015, 123, 17–20. [Google Scholar] [CrossRef]
  792. Zhou, Y.; Chen, F.; Ho, S.T.; Woodruff, M.A.; Lim, T.M.; Hutmacher, D.W. Combined marrow stromal cell-sheet techniques and high-strength biodegradable composite scaffolds for engineered functional bone grafts. Biomaterials 2007, 28, 814–824. [Google Scholar] [CrossRef]
  793. Vitale-Brovarone, C.; Baino, F.; Verné, E. High strength bioactive glass-ceramic scaffolds for bone regeneration. J. Mater. Sci. Mater. Med. 2009, 20, 643–653. [Google Scholar] [CrossRef]
  794. Stevens, M.M. Biomaterials for bone tissue engineering. Mater. Today 2008, 11, 18–25. [Google Scholar] [CrossRef]
  795. Artzi, Z.; Weinreb, M.; Givol, N.; Rohrer, M.D.; Nemcovsky, C.E.; Prasad, H.S.; Tal, H. Biomaterial resorbability and healing site morphology of inorganic bovine bone and beta tricalcium phosphate in the canine: A 24-month longitudinal histologic study and morphometric analysis. Int. J. Oral Max. Impl. 2004, 19, 357–368. [Google Scholar]
  796. Burg, K.J.L.; Porter, S.; Kellam, J.F. Biomaterial developments for bone tissue engineering. Biomaterials 2000, 21, 2347–2359. [Google Scholar] [CrossRef]
  797. Huebsch, N.; Mooney, D.J. Inspiration and application in the evolution of biomaterials. Nature 2009, 462, 426–432. [Google Scholar] [CrossRef]
  798. Ajaal, T.T.; Smith, R.W. Employing the Taguchi method in optimizing the scaffold production process for artificial bone grafts. J. Mater. Process. Technol. 2009, 209, 1521–1532. [Google Scholar] [CrossRef]
  799. Daculsi, G. Smart scaffolds: The future of bioceramic. J. Mater. Sci. Mater. Med. 2015, 26, 154. [Google Scholar] [CrossRef]
  800. Daculsi, G.; Miramond, T.; Borget, P.; Baroth, S. Smart calcium phosphate bioceramic scaffold for bone tissue engineering. Key Eng. Mater. 2013, 529–530, 19–23. [Google Scholar] [CrossRef]
  801. Bohner, M.; Loosli, Y.; Baroud, G.; Lacroix, D. Commentary: Deciphering the link between architecture and biological response of a bone graft substitute. Acta Biomater. 2011, 7, 478–484. [Google Scholar] [CrossRef]
  802. Peppas, N.A.; Langer, R. New challenges in biomaterials. Science 1994, 263, 1715–1720. [Google Scholar] [CrossRef] [PubMed]
  803. Hench, L.L. Biomaterials: A forecast for the future. Biomaterials 1998, 19, 1419–1423. [Google Scholar] [CrossRef]
  804. Barrère, F.; Mahmood, T.A.; de Groot, K.; van Blitterswijk, C.A. Advanced biomaterials for skeletal tissue regeneration: Instructive and smart functions. Mater. Sci. Eng. R 2008, 59, 38–71. [Google Scholar] [CrossRef]
  805. Liu, H.; Webster, T.J. Nanomedicine for implants: A review of studies and necessary experimental tools. Biomaterials 2007, 28, 354–369. [Google Scholar] [CrossRef] [PubMed]
  806. Wang, C.; Duan, Y.; Markovic, B.; Barbara, J.; Howlett, C.R.; Zhang, X.; Zreiqat, H. Proliferation and bone-related gene expression of osteoblasts grown on hydroxyapatite ceramics sintered at different temperature. Biomaterials 2004, 25, 2949–2956. [Google Scholar] [CrossRef] [PubMed]
  807. Samavedi, S.; Whittington, A.R.; Goldstein, A.S. Calcium phosphate ceramics in bone tissue engineering: A review of properties and their influence on cell behavior. Acta Biomater. 2013, 9, 8037–8045. [Google Scholar] [CrossRef]
  808. Matsumoto, T.; Okazaki, M.; Nakahira, A.; Sasaki, J.; Egusa, H.; Sohmura, T. Modification of apatite materials for bone tissue engineering and drug delivery carriers. Curr. Med. Chem. 2007, 14, 2726–2733. [Google Scholar] [CrossRef]
  809. Chai, Y.C.; Carlier, A.; Bolander, J.; Roberts, S.J.; Geris, L.; Schrooten, J.; van Oosterwyck, H.; Luyten, F.P. Current views on calcium phosphate osteogenicity and the translation into effective bone regeneration strategies. Acta Biomater. 2012, 8, 3876–3887. [Google Scholar] [CrossRef]
  810. Denry, I.; Kuhn, L.T. Design and characterization of calcium phosphate ceramic scaffolds for bone tissue engineering. Dent. Mater. 2016, 32, 43–53. [Google Scholar] [CrossRef]
  811. Lodoso-Torrecilla, I.; Gunnewiek, R.K.; Grosfeld, E.C.; de Vries, R.B.M.; Habibović, P.; Jansen, J.A.; van den Beucken, J.J.J.P. Bioinorganic supplementation of calcium phosphate-based bone substitutes to improve in vivo performance: A systematic review and meta-analysis of animal studies. Biomater. Sci. 2020, 8, 4792–4809. [Google Scholar] [CrossRef]
  812. Ishikawa, K.; Miyamoto, Y.; Tsuchiya, A.; Hayashi, K.; Tsuru, K.; Ohe, G. Physical and histological comparison of hydroxyapatite, carbonate apatite, and β-tricalcium phosphate bone substitutes. Materials 2018, 11, 1993. [Google Scholar] [CrossRef]
  813. Traykova, T.; Aparicio, C.; Ginebra, M.P.; Planell, J.A. Bioceramics as nanomaterials. Nanomedicine 2006, 1, 91–106. [Google Scholar] [CrossRef]
  814. Kalita, S.J.; Bhardwaj, A.; Bhatt, H.A. Nanocrystalline calcium phosphate ceramics in biomedical engineering. Mater. Sci. Eng. C 2007, 27, 441–449. [Google Scholar] [CrossRef]
  815. Dorozhkin, S.V. Nanometric calcium orthophosphates (CaPO4): Preparation, properties and biomedical applications. Adv. Nano-Bio. Mater. Dev. 2019, 3, 422–513. [Google Scholar]
  816. Šupová, M. Isolation and preparation of nanoscale bioapatites from natural sources: A review. J. Nanosci. Nanotechnol. 2014, 14, 546–563. [Google Scholar] [CrossRef]
  817. Zhao, J.; Liu, Y.; Sun, W.B.; Zhang, H. Amorphous calcium phosphate and its application in dentistry. Chem. Cent. J. 2011, 5, 40. [Google Scholar] [CrossRef]
  818. Dorozhkin, S.V. Synthetic amorphous calcium phosphates (ACPs): Preparation, structure, properties, and biomedical applications. Biomater. Sci. 2021, 9, 7748–7798. [Google Scholar] [CrossRef]
  819. Venkatesan, J.; Kim, S.K. Nano-hydroxyapatite composite biomaterials for bone tissue engineering–A review. J. Biomed. Nanotechnol. 2014, 10, 3124–3140. [Google Scholar] [CrossRef]
  820. Holzmeister, I.; Schamel, M.; Groll, J.; Gbureck, U.; Vorndran, E. Artificial inorganic biohybrids: The functional combination of microorganisms and cells with inorganic materials. Acta Biomater. 2018, 74, 17–35. [Google Scholar] [CrossRef]
  821. Wu, Y.; Hench, L.L.; Du, J.; Choy, K.L.; Guo, J. Preparation of hydroxyapatite fibers by electrospinning technique. J. Am. Ceram. Soc. 2004, 87, 1988–1991. [Google Scholar] [CrossRef]
  822. Ramanan, S.R.; Venkatesh, R. A study of hydroxyapatite fibers prepared via sol-gel route. Mater. Lett. 2004, 58, 3320–3323. [Google Scholar] [CrossRef]
  823. Aizawa, M.; Porter, A.E.; Best, S.M.; Bonfield, W. Ultrastructural observation of single-crystal apatite fibres. Biomaterials 2005, 26, 3427–3433. [Google Scholar] [CrossRef]
  824. Park, Y.M.; Ryu, S.C.; Yoon, S.Y.; Stevens, R.; Park, H.C. Preparation of whisker-shaped hydroxyapatite/β-tricalcium phosphate composite. Mater. Chem. Phys. 2008, 109, 440–447. [Google Scholar] [CrossRef]
  825. Aizawa, M.; Ueno, H.; Itatani, K.; Okada, I. Syntheses of calcium-deficient apatite fibres by a homogeneous precipitation method and their characterizations. J. Eur. Ceram. Soc. 2006, 26, 501–507. [Google Scholar] [CrossRef]
  826. Seo, D.S.; Lee, J.K. Synthesis of hydroxyapatite whiskers through dissolution-reprecipitation process using EDTA. J. Cryst. Growth 2008, 310, 2162–2167. [Google Scholar] [CrossRef]
  827. Tas, A.C. Formation of calcium phosphate whiskers in hydrogen peroxide (H2O2) solutions at 90°C. J. Am. Ceram. Soc. 2007, 90, 2358–2362. [Google Scholar] [CrossRef]
  828. Neira, I.S.; Guitián, F.; Taniguchi, T.; Watanabe, T.; Yoshimura, M. Hydrothermal synthesis of hydroxyapatite whiskers with sharp faceted hexagonal morphology. J. Mater. Sci. 2008, 43, 2171–2178. [Google Scholar] [CrossRef]
  829. Yang, H.Y.; Yang, S.F.; Chi, X.P.; Evans, J.R.G.; Thompson, I.; Cook, R.J.; Robinson, P. Sintering behaviour of calcium phosphate filaments for use as hard tissue scaffolds. J. Eur. Ceram. Soc. 2008, 28, 159–167. [Google Scholar] [CrossRef]
  830. Junginger, M.; Kübel, C.; Schacher, F.H.; Müller, A.H.E.; Taubert, A. Crystal structure and chemical composition of biomimetic calcium phosphate nanofibers. RSC Adv. 2013, 3, 11301–11308. [Google Scholar] [CrossRef]
  831. Cui, Y.S.; Yan, T.T.; Wu, X.P.; Chen, Q.H. Preparation and characterization of hydroxyapatite whiskers. Appl. Mech. Mater. 2013, 389, 21–24. [Google Scholar] [CrossRef]
  832. Lee, J.H.; Kim, Y.J. Hydroxyapatite nanofibers fabricated through electrospinning and sol-gel process. Ceram. Int. 2014, 40, 3361–3369. [Google Scholar] [CrossRef]
  833. Zhang, H.; Zhu, Q. Synthesis of nanospherical and ultralong fibrous hydroxyapatite and reinforcement of biodegradable chitosan/hydroxyapatite composite. Modern Phys. Lett. B 2009, 23, 3967–3976. [Google Scholar] [CrossRef]
  834. Wijesinghe, W.P.S.L.; Mantilaka, M.M.M.G.P.G.; Premalal, E.V.A.; Herath, H.M.T.U.; Mahalingam, S.; Edirisinghe, M.; Rajapakse, R.P.V.J.; Rajapakse, R.M.G. Facile synthesis of both needle-like and spherical hydroxyapatite nanoparticles: Effect of synthetic temperature and calcination on morphology, crystallite size and crystallinity. Mater. Sci. Eng. C 2014, 42, 83–90. [Google Scholar] [CrossRef] [PubMed]
  835. Zhou, W.Y.; Wang, M.; Cheung, W.L.; Guo, B.C.; Jia, D.M. Synthesis of carbonated hydroxyapatite nanospheres through nanoemulsion. J. Mater. Sci. Mater. Med. 2008, 19, 103–110. [Google Scholar] [CrossRef]
  836. Lim, J.H.; Park, J.H.; Park, E.K.; Kim, H.J.; Park, I.K.; Shin, H.Y.; Shin, H.I. Fully interconnected globular porous biphasic calcium phosphate ceramic scaffold facilitates osteogenic repair. Key Eng. Mater, 2008; 361–363, 119–122. [Google Scholar]
  837. Kawai, T.; Sekikawa, H.; Unuma, H. Preparation of hollow hydroxyapatite microspheres utilizing poly(divinylbenzene) as a template. J. Ceram. Soc. Jpn. 2009, 117, 340–343. [Google Scholar] [CrossRef]
  838. Cho, J.S.; Ko, Y.N.; Koo, H.Y.; Kang, Y.C. Synthesis of nano-sized biphasic calcium phosphate ceramics with spherical shape by flame spray pyrolysis. J. Mater. Sci. Mater. Med. 2010, 21, 1143–1149. [Google Scholar] [CrossRef]
  839. Ye, F.; Guo, H.; Zhang, H.; He, X. Polymeric micelle-templated synthesis of hydroxyapatite hollow nanoparticles for a drug delivery system. Acta Biomater. 2010, 6, 2212–2218. [Google Scholar] [CrossRef]
  840. Itatani, K.; Tsugawa, T.; Umeda, T.; Musha, Y.; Davies, I.J.; Koda, S. Preparation of submicrometer-sized porous spherical hydroxyapatite agglomerates by ultrasonic spray pyrolysis technique. J. Ceram. Soc. Jpn. 2010, 118, 462–466. [Google Scholar] [CrossRef] [Green Version]
  841. Xiao, W.; Fu, H.; Rahaman, M.N.; Liu, Y.; Bal, B.S. Hollow hydroxyapatite microspheres: A novel bioactive and osteoconductive carrier for controlled release of bone morphogenetic protein-2 in bone regeneration. Acta Biomater. 2013, 9, 8374–8383. [Google Scholar] [CrossRef]
  842. Rahaman, M.N.; Fu, H.; Xiao, W.; Liu, Y. Bioactive ceramic implants composed of hollow hydroxyapatite microspheres for bone regeneration. Ceram. Eng. Sci. Proc. 2014, 34, 67–76. [Google Scholar]
  843. Ito, N.; Kamitakahara, M.; Ioku, K. Preparation and evaluation of spherical porous granules of octacalcium phosphate/hydroxyapatite as drug carriers in bone cancer treatment. Mater. Lett. 2014, 120, 94–96. [Google Scholar] [CrossRef]
  844. Li, Z.; Wen, T.; Su, Y.; Wei, X.; He, C.; Wang, D. Hollow hydroxyapatite spheres fabrication with three-dimensional hydrogel template. CrystEngComm 2014, 16, 4202–4209. [Google Scholar] [CrossRef]
  845. Kovach, I.; Kosmella, S.; Prietzel, C.; Bagdahn, C.; Koetz, J. Nano-porous calcium phosphate balls. Colloid Surf. B 2015, 132, 246–252. [Google Scholar] [CrossRef]
  846. He, F.; Tian, Y.; Fang, X.; Xu, Y.; Ye, J. Porous calcium phosphate composite bioceramic beads. Ceram. Int. 2018, 44, 13430–13433. [Google Scholar] [CrossRef]
  847. Hettich, G.; Schierjott, R.A.; Epple, M.; Gbureck, U.; Heinemann, S.; Mozaffari-Jovein, H.; Grupp, T.M. Calcium phosphate bone graft substitutes with high mechanical load capacity and high degree of interconnecting porosity. Materials 2019, 12, 3471. [Google Scholar] [CrossRef]
  848. Chandanshive, B.; Dyondi, D.; Ajgaonkar, V.R.; Banerjee, R.; Khushalani, D. Biocompatible calcium phosphate based tubes. J. Mater. Chem. 2010, 20, 6923–6928. [Google Scholar] [CrossRef]
  849. Kamitakahara, M.; Takahashi, H.; Ioku, K. Tubular hydroxyapatite formation through a hydrothermal process from α-tricalcium phosphate with anatase. J. Mater. Sci. 2012, 47, 4194–4199. [Google Scholar] [CrossRef]
  850. Ustundag, C.B.; Kaya, F.; Kamitakahara, M.; Kaya, C.; Ioku, K. Production of tubular porous hydroxyapatite using electrophoretic deposition. J. Ceram. Soc. Jpn. 2012, 120, 569–573. [Google Scholar] [CrossRef]
  851. Li, C.; Ge, X.; Li, G.; Lu, H.; Ding, R. In situ hydrothermal crystallization of hexagonal hydroxyapatite tubes from yttrium ion-doped hydroxyapatite by the Kirkendall effect. Mater. Sci. Eng. C 2014, 45, 191–195. [Google Scholar] [CrossRef] [PubMed]
  852. Zhang, Y.G.; Zhu, Y.J.; Chen, F.; Sun, T.W. Biocompatible, ultralight, strong hydroxyapatite networks based on hydroxyapatite microtubes with excellent permeability and ultralow thermal conductivity. ACS Appl. Mater. Interfaces 2017, 9, 7918–7928. [Google Scholar]
  853. Zhang, Y.G.; Zhu, Y.J.; Xiong, Z.C.; Wu, J.; Chen, F. Bioinspired ultralight inorganic aerogel for highly efficient air filtration and oil-water separation. ACS Appl. Mater. Interfaces 2018, 10, 13019–13027. [Google Scholar] [CrossRef]
  854. Dadhich, P.; Dhara, S. Calcium phosphate flowers: A bone filler substitute. Mater. Today 2017, 20, 657–658. [Google Scholar] [CrossRef]
  855. Nonoyama, T.; Kinoshita, T.; Higuchi, M.; Nagata, K.; Tanaka, M.; Kamada, M.; Sato, K.; Kato, K. Arrangement techniques of proteins and cells using amorphous calcium phosphate nanofiber scaffolds. Appl. Surf. Sci. 2012, 262, 8–12. [Google Scholar] [CrossRef]
  856. Galea, L.G.; Bohner, M.; Lemaître, J.; Kohler, T.; Müller, R. Bone substitute: Transforming β-tricalcium phosphate porous scaffolds into monetite. Biomaterials 2008, 29, 3400–3407. [Google Scholar] [CrossRef] [PubMed]
  857. Tamimi, F.; Torres, J.; Gbureck, U.; Lopez-Cabarcos, E.; Bassett, D.C.; Alkhraisat, M.H.; Barralet, J.E. Craniofacial vertical bone augmentation: A comparison between 3D printed monolithic monetite blocks and autologous onlay grafts in the rabbit. Biomaterials 2009, 30, 6318–6326. [Google Scholar] [CrossRef] [PubMed]
  858. Sheikh, Z.; Drager, J.; Zhang, Y.L.; Abdallah, M.N.; Tamimi, F.; Barralet, J. Controlling bone graft substitute microstructure to improve bone augmentation. Adv. Healthc. Mater. 2016, 5, 1646–1655. [Google Scholar] [CrossRef]
  859. Oryan, A.; Alidadi, S.; Bigham-Sadegh, A. Dicalcium phosphate anhydrous: An appropriate bioceramic in regeneration of critical-sized radial bone defects in rats. Calcif. Tissue Int. 2017, 101, 530–544. [Google Scholar] [CrossRef]
  860. Sugiura, Y.; Ishikawa, K. Fabrication of pure octacalcium phosphate blocks from dicalcium hydrogen phosphate dihydrate blocks via a dissolution–precipitation reaction in a basic solution. Mater. Lett. 2019, 239, 143–146. [Google Scholar] [CrossRef]
  861. Kim, J.S.; Jang, T.S.; Kim, S.Y.; Lee, W.P. Octacalcium phosphate bone substitute (Bontree®): From basic research to clinical case study. Appl. Sci. 2021, 11, 7921. [Google Scholar] [CrossRef]
  862. Sohier, J.; Daculsi, G.; Sourice, S.; de Groot, K.; Layrolle, P. Porous beta tricalcium phosphate scaffolds used as a BMP-2 delivery system for bone tissue engineering. J. Biomed. Mater. Res. A 2010, 92A, 1105–1114. [Google Scholar] [CrossRef]
  863. Stähli, C.; Bohner, M.; Bashoor-Zadeh, M.; Doebelin, N.; Baroud, G. Aqueous impregnation of porous β-tricalcium phosphate scaffolds. Acta Biomater. 2010, 6, 2760–2772. [Google Scholar] [CrossRef]
  864. Lin, K.; Chen, L.; Qu, H.; Lu, J.; Chang, J. Improvement of mechanical properties of macroporous β-tricalcium phosphate bioceramic scaffolds with uniform and interconnected pore structures. Ceram. Int. 2011, 37, 2397–2403. [Google Scholar] [CrossRef]
  865. Wójtowicz, J.; Leszczyńska, J.; Chróścicka, A.; Ślósarczyk, A.; Paszkiewicz, Z.; Zima, A.; Rozniatowski, K.; Jeleń, P.; Lewandowska-Szumieł, M. Comparative in vitro study of calcium phosphate ceramics for their potency as scaffolds for tissue engineering. Bio-Med. Mater. Eng. 2014, 24, 1609–1623. [Google Scholar] [CrossRef]
  866. Simon, J.L.; Michna, S.; Lewis, J.A.; Rekow, E.D.; Thompson, V.P.; Smay, J.E.; Yampolsky, A.; Parsons, J.R.; Ricci, J.L. In vivo bone response to 3D periodic hydroxyapatite scaffolds assembled by direct ink writing. J. Biomed. Mater. Res. A 2007, 83A, 747–758. [Google Scholar] [CrossRef] [PubMed]
  867. Yoshikawa, H.; Myoui, A. Bone tissue engineering with porous hydroxyapatite ceramics. J. Artif. Organs 2005, 8, 131–136. [Google Scholar] [CrossRef]
  868. Min, S.H.; Jin, H.H.; Park, H.Y.; Park, I.M.; Park, H.C.; Yoon, S.Y. Preparation of porous hydroxyapatite scaffolds for bone tissue engineering. Mater. Sci. Forum, 2006; 510–511, 754–757. [Google Scholar]
  869. Deville, S.; Saiz, E.; Nalla, R.K.; Tomsia, A.P. Strong biomimetic hydroxyapatite scaffolds. Adv. Sci. Technol. 2006, 49, 148–152. [Google Scholar]
  870. Buckley, C.T.; O’Kelly, K.U. Fabrication and characterization of a porous multidomain hydroxyapatite scaffold for bone tissue engineering investigations. J. Biomed. Mater. Res. B Appl. Biomater. 2010, 93B, 459–467. [Google Scholar] [CrossRef]
  871. Ramay, H.R.R.; Zhang, M. Biphasic calcium phosphate nanocomposite porous scaffolds for load-bearing bone tissue engineering. Biomaterials 2004, 25, 5171–5180. [Google Scholar] [CrossRef]
  872. Chen, G.; Li, W.; Zhao, B.; Sun, K. A novel biphasic bone scaffold: β-calcium phosphate and amorphous calcium polyphosphate. J. Am. Ceram. Soc. 2009, 92, 945–948. [Google Scholar] [CrossRef]
  873. Guo, D.; Xu, K.; Han, Y. The in situ synthesis of biphasic calcium phosphate scaffolds with controllable compositions, structures, and adjustable properties. J. Biomed. Mater. Res. A 2009, 88A, 43–52. [Google Scholar] [CrossRef] [PubMed]
  874. Sarin, P.; Lee, S.J.; Apostolov, Z.D.; Kriven, W.M. Porous biphasic calcium phosphate scaffolds from cuttlefish bone. J. Am. Ceram. Soc. 2011, 94, 2362–2370. [Google Scholar] [CrossRef]
  875. Kim, D.H.; Kim, K.L.; Chun, H.H.; Kim, T.W.; Park, H.C.; Yoon, S.Y. In vitro biodegradable and mechanical performance of biphasic calcium phosphate porous scaffolds with unidirectional macro-pore structure. Ceram. Int. 2014, 40, 8293–8300. [Google Scholar] [CrossRef]
  876. Marques, C.F.; Perera, F.H.; Marote, A.; Ferreira, S.; Vieira, S.I.; Olhero, S.; Miranda, P.; Ferreira, J.M.F. Biphasic calcium phosphate scaffolds fabricated by direct write assembly: Mechanical, anti-microbial and osteoblastic properties. J. Eur. Ceram. Soc. 2017, 37, 359–368. [Google Scholar] [CrossRef]
  877. Furuichi, K.; Oaki, Y.; Ichimiya, H.; Komotori, J.; Imai, H. Preparation of hierarchically organized calcium phosphate-organic polymer composites by calcification of hydrogel. Sci. Technol. Adv. Mater. 2006, 7, 219–225. [Google Scholar] [CrossRef]
  878. Wei, J.; Jia, J.; Wu, F.; Wei, S.; Zhou, H.; Zhang, H.; Shin, J.W.; Liu, C. Hierarchically microporous/macroporous scaffold of magnesium-calcium phosphate for bone tissue regeneration. Biomaterials 2010, 31, 1260–1269. [Google Scholar] [CrossRef]
  879. Ye, X.; Zhou, C.; Xiao, Z.; Fan, Y.; Zhu, X.; Sun, Y.; Zhang, X. Fabrication and characterization of porous 3D whisker-covered calcium phosphate scaffolds. Mater. Lett. 2014, 128, 179–182. [Google Scholar] [CrossRef]
  880. Zhao, R.; Shang, T.; Yuan, B.; Yang, X.; Zhu, X.; Zhang, X. Osteoporotic bone recovery by a bamboo-structured bioceramic with controlled release of hydroxyapatite nanoparticles. Bioact. Mater. 2022, 17, 379–393. [Google Scholar] [CrossRef]
  881. Zhu, Y.J.; Lu, B.Q. Deformable biomaterials based on ultralong hydroxyapatite nanowires. ACS Biomater. Sci. Eng. 2019, 5, 4951–4961. [Google Scholar] [CrossRef]
  882. Huang, G.J.; Yu, H.P.; Wang, X.L.; Ning, B.B.; Gao, J.; Shi, Y.Q.; Zhu, Y.J.; Duan, J.L. Highly porous and elastic aerogel based on ultralong hydroxyapatite nanowires for high-performance bone regeneration and neovascularization. J. Mater. Chem. B 2021, 9, 1277–1287, Erratum J. Mater. Chem. B 2021, 9, 7566. [Google Scholar] [CrossRef]
  883. Gbureck, U.; Grolms, O.; Barralet, J.E.; Grover, L.M.; Thull, R. Mechanical activation and cement formation of β-tricalcium phosphate. Biomaterials 2003, 24, 4123–4131. [Google Scholar] [CrossRef]
  884. Gbureck, U.; Barralet, J.E.; Hofmann, M.; Thull, R. Mechanical activation of tetracalcium phosphate. J. Am. Ceram. Soc. 2004, 87, 311–313. [Google Scholar] [CrossRef]
  885. Bohner, M.; Luginbühl, R.; Reber, C.; Doebelin, N.; Baroud, G.; Conforto, E. A physical approach to modify the hydraulic reactivity of α-tricalcium phosphate powder. Acta Biomater. 2009, 5, 3524–3535. [Google Scholar] [CrossRef]
  886. Hagio, T.; Tanase, T.; Akiyama, J.; Iwai, K.; Asai, S. Formation and biological affinity evaluation of crystallographically aligned hydroxyapatite. J. Ceram. Soc. Jpn. 2008, 116, 79–82. [Google Scholar] [CrossRef]
  887. Blawas, A.S.; Reichert, W.M. Protein patterning. Biomaterials 1998, 19, 595–609. [Google Scholar] [CrossRef]
  888. Kasai, T.; Sato, K.; Kanematsu, Y.; Shikimori, M.; Kanematsu, N.; Doi, Y. Bone tissue engineering using porous carbonate apatite and bone marrow cells. J. Craniofac. Surg. 2010, 21, 473–478. [Google Scholar] [CrossRef]
  889. Wang, L.; Fan, H.; Zhang, Z.Y.; Lou, A.J.; Pei, G.X.; Jiang, S.; Mu, T.W.; Qin, J.J.; Chen, S.Y.; Jin, D. Osteogenesis and angiogenesis of tissue-engineered bone constructed by prevascularized β-tricalcium phosphate scaffold and mesenchymal stem cells. Biomaterials 2010, 31, 9452–9461. [Google Scholar] [CrossRef]
  890. Wijnhoven, I.B.; Vallejos, R.; Santibanez, J.F.; Millán, C.; Vivanco, J.F. Analysis of cell-biomaterial interaction through cellular bridge formation in the interface between hGMSCs and CaP bioceramics. Sci. Rep. 2020, 10, 16493. [Google Scholar] [CrossRef]
  891. Sánchez-Salcedo, S.; Izquierdo-Barba, I.; Arcos, D.; Vallet-Regí, M. In vitro evaluation of potential calcium phosphate scaffolds for tissue engineering. Tissue Eng. 2006, 12, 279–290. [Google Scholar] [CrossRef]
  892. Meganck, J.A.; Baumann, M.J.; Case, E.D.; McCabe, L.R.; Allar, J.N. Biaxial flexure testing of calcium phosphate bioceramics for use in tissue engineering. J. Biomed. Mater. Res. A 2005, 72A, 115–126. [Google Scholar] [CrossRef] [PubMed]
  893. Case, E.D.; Smith, I.O.; Baumann, M.J. Microcracking and porosity in calcium phosphates and the implications for bone tissue engineering. Mater. Sci. Eng. A 2005, 390, 246–254. [Google Scholar] [CrossRef]
  894. Tripathi, G.; Basu, B. A porous hydroxyapatite scaffold for bone tissue engineering: Physico-mechanical and biological evaluations. Ceram. Int. 2012, 38, 341–349. [Google Scholar] [CrossRef]
  895. Sibilla, P.; Sereni, A.; Aguiari, G.; Banzi, M.; Manzati, E.; Mischiati, C.; Trombelli, L.; del Senno, L. Effects of a hydroxyapatite-based biomaterial on gene expression in osteoblast-like cells. J. Dent. Res. 2006, 85, 354–358. [Google Scholar] [CrossRef]
  896. Verron, E.; Bouler, J.M. Calcium phosphate ceramics as bone drug-combined devices. Key Eng. Mater. 2010, 441, 181–201. [Google Scholar] [CrossRef]
  897. Kolmas, J.; Krukowski, S.; Laskus, A.; Jurkitewicz, M. Synthetic hydroxyapatite in pharmaceutical applications. Ceram. Int. 2016, 42, 2472–2487. [Google Scholar] [CrossRef]
  898. Parent, M.; Baradari, H.; Champion, E.; Damia, C.; Viana-Trecant, M. Design of calcium phosphate ceramics for drug delivery applications in bone diseases: A review of the parameters affecting the loading and release of the therapeutic substance. J. Control. Release 2017, 252, 1–17. [Google Scholar] [CrossRef]
  899. Mondal, S.; Pal, U. 3D hydroxyapatite scaffold for bone regeneration and local drug delivery applications. J. Drug Deliv. Sci. Tec. 2019, 53, 101131. [Google Scholar] [CrossRef]
  900. Zhao, Q.; Zhang, D.; Sun, R.; Shang, S.; Wang, H.; Yang, Y.; Wang, L.; Liu, X.; Sun, T.; Chen, K. Adsorption behavior of drugs on hydroxyapatite with different morphologies: A combined experimental and molecular dynamics simulation study. Ceram. Int. 2019, 45, 19522–19527, Correction Ceram. Int. 2020, 46, 27909. [Google Scholar] [CrossRef]
  901. Rapoport, A.; Borovikova, D.; Kokina, A.; Patmalnieks, A.; Polyak, N.; Pavlovska, I.; Mezinskis, G.; Dekhtyar, Y. Immobilisation of yeast cells on the surface of hydroxyapatite ceramics. Process. Biochem. 2011, 46, 665–670. [Google Scholar] [CrossRef]
  902. Ghiasi, B.; Sefidbakht, Y.; Mozaffari-Jovin, S.; Gharehcheloo, B.; Mehrarya, M.; Khodadadi, A.; Rezaei, M.; Siadat, S.O.R.; Uskoković, V. Hydroxyapatite as a biomaterial–a gift that keeps on giving. Drug Dev. Ind. Pharm. 2020, 46, 1035–1062. [Google Scholar] [CrossRef]
  903. Mastrogiacomo, M.; Muraglia, A.; Komlev, V.; Peyrin, F.; Rustichelli, F.; Crovace, A.; Cancedda, R. Tissue engineering of bone: Search for a better scaffold. Orthod. Craniofac. Res. 2005, 8, 277–284. [Google Scholar] [CrossRef]
  904. Quarto, R.; Mastrogiacomo, M.; Cancedda, R.; Kutepov, S.M.; Mukhachev, V.; Lavroukov, A.; Kon, E.; Marcacci, M. Repair of large bone defects with the use of autologous bone marrow stromal cells. N. Engl. J. Med. 2001, 344, 385–386. [Google Scholar] [CrossRef]
  905. Vacanti, C.A.; Bonassar, L.J.; Vacanti, M.P.; Shufflebarger, J. Replacement of an avulsed phalanx with tissue-engineered bone. N. Engl. J. Med. 2001, 344, 1511–1514. [Google Scholar] [CrossRef]
  906. Morishita, T.; Honoki, K.; Ohgushi, H.; Kotobuki, N.; Matsushima, A.; Takakura, Y. Tissue engineering approach to the treatment of bone tumors: Three cases of cultured bone grafts derived from patients’ mesenchymal stem cells. Artif. Organs 2006, 30, 115–118. [Google Scholar] [CrossRef]
  907. Eniwumide, J.O.; Yuan, H.; Cartmell, S.H.; Meijer, G.J.; de Bruijn, J.D. Ectopic bone formation in bone marrow stem cell seeded calcium phosphate scaffolds as compared to autograft and (cell seeded) allograft. Eur. Cell Mater. 2007, 14, 30–39. [Google Scholar] [CrossRef]
  908. Zuolin, J.; Hong, Q.; Jiali, T. Dental follicle cells combined with beta-tricalcium phosphate ceramic: A novel available therapeutic strategy to restore periodontal defects. Med. Hypotheses 2010, 75, 669–670. [Google Scholar] [CrossRef]
  909. Ge, S.; Zhao, N.; Wang, L.; Yu, M.; Liu, H.; Song, A.; Huang, J.; Wang, G.; Yang, P. Bone repair by periodontal ligament stem cell-seeded nanohydroxyapatite-chitosan scaffold. Int. J. Nanomed. 2012, 7, 5405–5414. [Google Scholar] [CrossRef]
  910. Farré-Guasch, E.; Bravenboer, N.; Helder, M.N.; Schulten, E.A.J.M.; Ten Bruggenkate, C.M.; Klein-Nulend, J. Blood vessel formation and bone regeneration potential of the stromal vascular fraction seeded on a calcium phosphate scaffold in the human maxillary sinus floor elevation model. Materials 2018, 11, 161. [Google Scholar] [CrossRef]
  911. Tanaka, T.; Komaki, H.; Chazono, M.; Kitasato, S.; Kakuta, A.; Akiyama, S.; Marumo, K. Basic research and clinical application of beta-tricalcium phosphate (β-TCP).|Recherche fondamentale et application clinique du bêta-tricalcium phosphate (β-TCP). Morphologie 2017, 101, 164–172. [Google Scholar] [CrossRef]
  912. Franch, J.; Díaz-Bertrana, C.; Lafuente, P.; Fontecha, P.; Durall, I. Beta-tricalcium phosphate as a synthetic cancellous bone graft in veterinary orthopaedics: A retrospective study of 13 clinical cases. Vet. Comp. Orthop. Traumatol. 2006, 19, 196–204. [Google Scholar]
  913. Vertenten, G.; Gasthuys, F.; Cornelissen, M.; Schacht, E.; Vlaminck, L. Enhancing bone healing and regeneration: Present and future perspectives in veterinary orthopaedics. Vet. Comp. Orthop. Traumatol. 2010, 23, 153–162. [Google Scholar]
  914. Freidlin, L.K.; Sharf, V.Z. Two paths for the dehydration of 1,4-butandiol to divinyl with a tricalcium phosphate catalyst. Bull. Acad. Sci. USSR Div. Chem. Sci. 1960, 9, 1577–1579. [Google Scholar] [CrossRef]
  915. Bett, J.A.S.; Christner, L.G.; Hall, W.K. Studies of the hydrogen held by solids. XII. Hydroxyapatite catalysts. J. Am. Chem. Soc. 1967, 89, 5535–5541. [Google Scholar] [CrossRef]
  916. Monma, H. Catalytic behavior of calcium phosphates for decompositions of 2-propanol and ethanol. J. Catal. 1982, 75, 200–203. [Google Scholar] [CrossRef]
  917. Tsuchida, T.; Yoshioka, T.; Sakuma, S.; Takeguchi, T.; Ueda, W. Synthesis of biogasoline from ethanol over hydroxyapatite catalyst. Ind. Eng. Chem. Res. 2008, 47, 1443–1452. [Google Scholar] [CrossRef]
  918. Tsuchida, T.; Kubo, J.; Yoshioka, T.; Sakuma, S.; Takeguchi, T.; Ueda, W. Reaction of ethanol over hydroxyapatite affected by Ca/P ratio of catalyst. J. Catal. 2008, 259, 183–189. [Google Scholar] [CrossRef]
  919. Xu, J.; White, T.; Li, P.; He, C.; Han, Y.F. Hydroxyapatite foam as a catalyst for formaldehyde combustion at room temperature. J. Am. Chem. Soc. 2010, 132, 13172–13173. [Google Scholar] [CrossRef] [PubMed]
  920. Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Which is the actual catalyst: Chiral phosphoric acid or chiral calcium phosphate? Angew. Chem. Int. Ed. Engl. 2010, 49, 3823–3826. [Google Scholar] [CrossRef]
  921. Zhang, D.; Zhao, H.; Zhao, X.; Liu, Y.; Chen, H.; Li, X. Application of hydroxyapatite as catalyst and catalyst carrier. Prog. Chem. 2011, 23, 687–694. [Google Scholar]
  922. Gruselle, M.; Kanger, T.; Thouvenot, R.; Flambard, A.; Kriis, K.; Mikli, V.; Traksmaa, R.; Maaten, B.; Tõnsuaadu, K. Calcium hydroxyapatites as efficient catalysts for the Michael C–C bond formation. ACS Catal. 2011, 1, 1729–1733. [Google Scholar] [CrossRef]
  923. Stošić, D.; Bennici, S.; Sirotin, S.; Calais, C.; Couturier, J.L.; Dubois, J.L.; Travert, A.; Auroux, A. Glycerol dehydration over calcium phosphate catalysts: Effect of acidic-basic features on catalytic performance. Appl. Catal. A 2012, 447–448, 124–134. [Google Scholar] [CrossRef]
  924. Ghantani, V.C.; Lomate, S.T.; Dongare, M.K.; Umbarkar, S.B. Catalytic dehydration of lactic acid to acrylic acid using calcium hydroxyapatite catalysts. Green Chem. 2013, 15, 1211–1217. [Google Scholar] [CrossRef]
  925. Chen, G.; Shan, R.; Shi, J.; Liu, C.; Yan, B. Biodiesel production from palm oil using active and stable K doped hydroxyapatite catalysts. Energ. Convers. Manage. 2015, 98, 463–469. [Google Scholar] [CrossRef]
  926. Gruselle, M. Apatites: A new family of catalysts in organic synthesis. J. Organomet. Chem. 2015, 793, 93–101. [Google Scholar] [CrossRef]
  927. Urist, M.R.; Huo, Y.K.; Brownell, A.G.; Hohl, W.M.; Buyske, J.; Lietze, A.; Tempst, P.; Hunkapiller, M.; de Lange, R.J. Purification of bovine bone morphogenetic protein by hydroxyapatite chromatography. Proc. Natl. Acad. Sci. USA 1984, 81, 371–375. [Google Scholar] [CrossRef] [Green Version]
  928. Kawasaki, T. Hydroxyapatite as a liquid chromatographic packing. J. Chromatogr. 1991, 544, 147–184. [Google Scholar] [CrossRef]
  929. Kuiper, M.; Sanches, R.M.; Walford, J.A.; Slater, N.K.H. Purification of a functional gene therapy vector derived from moloney murine leukaemia virus using membrane filtration and ceramic hydroxyapatite chromatography. Biotechnol. Bioeng. 2002, 80, 445–453. [Google Scholar] [CrossRef]
  930. Jungbauer, A.; Hahn, R.; Deinhofer, K.; Luo, P. Performance and characterization of a nanophased porous hydroxyapatite for protein chromatography. Biotechnol. Bioeng. 2004, 87, 364–375. [Google Scholar] [CrossRef]
  931. Wensel, D.L.; Kelley, B.D.; Coffman, J.L. High-throughput screening of chromatographic separations: III. Monoclonal antibodies on ceramic hydroxyapatite. Biotechnol. Bioeng. 2008, 100, 839–854. [Google Scholar] [CrossRef]
  932. Hilbrig, F.; Freitag, R. Isolation and purification of recombinant proteins, antibodies and plasmid DNA with hydroxyapatite chromatography. Biotechnol. J. 2012, 7, 90–102. [Google Scholar] [CrossRef]
  933. Cummings, L.J.; Frost, R.G.; Snyder, M.A. Monoclonal antibody purification by ceramic hydroxyapatite chromatography. Method Mol. Biol. 2014, 1131, 241–251. [Google Scholar]
  934. Nagai, M.; Nishino, T.; Saeki, T. A new type of CO2 gas sensor comprising porous hydroxyapatite ceramics. Sens. Actuator 1988, 15, 145–151. [Google Scholar] [CrossRef]
  935. Petrucelli, G.C.; Kawachi, E.Y.; Kubota, L.T.; Bertran, C.A. Hydroxyapatite-based electrode: A new sensor for phosphate. Anal. Commun. 1996, 33, 227–229. [Google Scholar] [CrossRef]
  936. Tagaya, M.; Ikoma, T.; Hanagata, N.; Chakarov, D.; Kasemo, B.; Tanaka, J. Reusable hydroxyapatite nanocrystal sensors for protein adsorption. Sci. Technol. Adv. Mater. 2010, 11, 045002. [Google Scholar] [CrossRef]
  937. Khairnar, R.S.; Mene, R.U.; Munde, S.G.; Mahabole, M.P. Nano-hydroxyapatite thick film gas sensors. AIP Conf. Proc. 2011, 1415, 189–192. [Google Scholar]
  938. López, M.S.P.; Redondo-Gómez, E.; López-Ruiz, B. Electrochemical enzyme biosensors based on calcium phosphate materials for tyramine detection in food samples. Talanta 2017, 175, 209–216. [Google Scholar] [CrossRef]
  939. Nijhawan, A.; Butler, E.C.; Sabatini, D.A. Hydroxyapatite ceramic adsorbents: Effect of pore size, regeneration, and selectivity for fluoride. J. Environ. Eng. 2018, 144, 04018117. [Google Scholar] [CrossRef]
  940. Ibrahim, M.; Labaki, M.; Giraudon, J.M.; Lamonier, J.F. Hydroxyapatite, a multifunctional material for air, water and soil pollution control: A review. J. Hazard. Mater. 2020, 383, 121139. [Google Scholar] [CrossRef]
  941. Hench, L.L.; Wilson, J. Surface-active biomaterials. Science 1984, 226, 630–636. [Google Scholar] [CrossRef]
  942. Bongio, M.; van den Beucken, J.J.J.P.; Leeuwenburgh, S.C.G.; Jansen, J.A. Development of bone substitute materials: From ‘biocompatible’ to ‘instructive’. J. Mater. Chem. 2010, 20, 8747–8759. [Google Scholar] [CrossRef]
  943. Navarro, M.; Michiardi, A.; Castano, O.; Planell, J.A. Biomaterials in orthopaedics. J. R. Soc. Interface 2008, 5, 1137–1158. [Google Scholar] [CrossRef] [PubMed]
  944. Anderson, J.M. The future of biomedical materials. J. Mater. Sci. Mater. Med. 2006, 17, 1025–1028. [Google Scholar] [CrossRef] [PubMed]
  945. Zadpoor, A.A. Meta-biomaterials. Biomater. Sci. 2020, 8, 18–38. [Google Scholar] [CrossRef]
  946. Sanchez-Sálcedo, S.; Arcos, D.; Vallet-Regí, M. Upgrading calcium phosphate scaffolds for tissue engineering applications. Key Eng. Mater. 2008, 377, 19–42. [Google Scholar] [CrossRef]
  947. Chevalier, J.; Gremillard, L. Ceramics for medical applications: A picture for the next 20 years. J. Eur. Ceram. Soc. 2009, 29, 1245–1255. [Google Scholar] [CrossRef]
  948. Salgado, P.C.; Sathler, P.C.; Castro, H.C.; Alves, G.G.; de Oliveira, A.M.; de Oliveira, R.C.; Maia, M.D.C.; Rodrigues, C.R.; Coelh, P.G.; Fuly, A.; et al. Bone remodeling, biomaterials and technological applications: Revisiting basic concepts. J. Biomater. Nanobiotechnol. 2011, 2, 318–328. [Google Scholar] [CrossRef]
  949. Vallet-Regí, M. Evolution of bioceramics within the field of biomaterials. C. R. Chimie 2010, 13, 174–185. [Google Scholar] [CrossRef]
  950. Hartgerink, J.D.; Beniash, E.; Stupp, S.I. Self-assembly and mineralization of peptide-amphiphile nanofibers. Science 2001, 294, 1684–1688. [Google Scholar] [CrossRef]
  951. Malhotra, A.; Habibovic, P. Calcium phosphates and angiogenesis: Implications and advances for bone regeneration. Trends Biotechnol. 2016, 34, 983–992. [Google Scholar] [CrossRef]
  952. Kim, J. Multilayered injection of calcium hydroxylapatite filler on ischial soft tissue to rejuvenate the previous phase of chronic sitting pressure sore. Clin. Cosmet. Investig. Dermatol. 2019, 12, 771–784. [Google Scholar] [CrossRef]
  953. Kargozar, S.; Singh, R.K.; Kim, H.W.; Baino, F. “Hard” ceramics for “soft” tissue engineering: Paradox or opportunity? Acta Biomater. 2020, 115, 1–28. [Google Scholar] [CrossRef]
  954. Jansen, D.A.; Graivier, M.H. Evaluation of a calcium hydroxylapatite-based implant (Radiesse) for facial soft-tissue augmentation. Plast. Reconstr. Surg. 2006, 118 (Suppl. 3), 22S–30S. [Google Scholar] [CrossRef]
  955. Wasylkowski, V.C. Body vectoring technique with Radiesse® for tightening of the abdomen, thighs, and brachial zone. Clin. Cosmet. Invest. Dermatol. 2015, 8, 267–273. [Google Scholar] [CrossRef]
  956. Shi, X.H.; Zhou, X.; Zhang, Y.M.; Lei, Z.Y.; Liu, T.; Fan, D.L. Complications from nasolabial fold injection of calcium hydroxylapatite for facial soft-tissue augmentation: A systematic review and meta-analysis. Aesthet. Surg. J. 2016, 36, 712–717. [Google Scholar] [CrossRef]
  957. Qi, C.; Lin, J.; Fu, L.H.; Huang, P. Calcium-based biomaterials for diagnosis, treatment, and theranostics. Chem. Soc. Rev. 2018, 47, 357–403. [Google Scholar] [CrossRef]
  958. Chyzhma, R.; Piddubnyi, A.; Danilchenko, S.; Kravtsova, O.; Moskalenko, R. Potential role of hydroxyapatite nanocrystalline for early diagnostics of ovarian cancer. Diagnostics 2021, 11, 1741. [Google Scholar] [CrossRef]
  959. Du, M.; Chen, J.; Liu, K.; Xing, H.; Song, C. Recent advances in biomedical engineering of nano-hydroxyapatite including dentistry, cancer treatment and bone repair. Composites B 2021, 215, 108790. [Google Scholar] [CrossRef]
  960. Yu, W.; Jiang, Y.Y.; Sun, T.W.; Qi, C.; Zhao, H.; Chen, F.; Shi, Z.; Zhu, Y.J.; Chen, D.; He, Y. Design of a novel wound dressing consisting of alginate hydrogel and simvastatin-incorporated mesoporous hydroxyapatite microspheres for cutaneous wound healing. RSC Adv. 2016, 106, 104375–104387. [Google Scholar] [CrossRef]
  961. Carella, F.; Esposti, L.D.; Adamiano, A.; Iafisco, M. The use of calcium phosphates in cosmetics, state of the art and future perspectives. Materials 2021, 14, 6398. [Google Scholar] [CrossRef]
  962. Masson, J.D.; Thibaudon, M.; Belec, L.; Crepeaux, G. Calcium phosphate: A substitute for aluminum adjuvants? Expert Rev. Vaccines 2017, 16, 289–299. [Google Scholar] [CrossRef]
  963. Wang, X.; Xue, J.; Ma, B.; Wu, J.; Chang, J.; Gelinsky, M.; Wu, C. Black bioceramics: Combining regeneration with therapy. Adv. Mater. 2020, 32, 2005140. [Google Scholar] [CrossRef]
  964. Safronova, T.; Kiselev, A.; Selezneva, I.; Shatalova, T.; Lukina, Y.; Filippov, Y.; Toshev, O.; Tikhonova, S.; Antonova, O.; Knotko, A. Bioceramics based on β-calcium pyrophosphate. Materials 2022, 15, 3105. [Google Scholar] [CrossRef]
  965. Germaini, M.M.; Belhabib, S.; Guessasma, S.; Deterre, R.; Corre, P.; Weiss, P. Additive manufacturing of biomaterials for bone tissue engineering–A critical review of the state of the art and new concepts. Prog. Mater. Sci. 2022, 130, 100963. [Google Scholar] [CrossRef]
  966. Galván-Chacón, V.P.; Vasilevich, A.; Yuan, H.; Groen, N.; de Boer, J.; Habibovic, P.; Vermeulen, S. A bioinformatics approach to study the role of calcium phosphate properties in bone regeneration. Eur. J. Mater. 2022. [Google Scholar] [CrossRef]
  967. Mohd, N.; Razali, M.; Ghazali, M.J.; Kasim, N.H.A. 3D-printed hydroxyapatite and tricalcium phosphates-based scaffolds for alveolar bone regeneration in animal models: A scoping review. Materials 2022, 15, 2621. [Google Scholar] [CrossRef]
  968. Ginebra, M.P.; Espanol, M.; Maazouz, Y.; Bergez, V.; Pastorino, D. Bioceramics and bone healing. EFORT Open Rev. 2018, 3, 173–183. [Google Scholar] [CrossRef]
  969. Albulescu, R.; Popa, A.C.; Enciu, A.M.; Albulescu, L.; Dudau, M.; Popescu, I.D.; Mihai, S.; Codrici, E.; Pop, S.; Lupu, A.R.; et al. Comprehensive in vitro testing of calcium phosphate-based bioceramics with orthopedic and dentistry applications. Materials 2019, 12, 3704. [Google Scholar] [CrossRef] [Green Version]
Figure 1. Several examples of the commercial CaPO4-based bioceramics.
Figure 1. Several examples of the commercial CaPO4-based bioceramics.
Coatings 12 01380 g001
Figure 2. Soft X-ray photographs of the operated portion of the rabbit femur. Four weeks (a), 12 weeks (b), 24 weeks (c), and 72 weeks (d) after implantation of CDHA; 4 weeks (e), 12 weeks (f), 24 weeks (g), and 72 weeks (h) after implantation of sintered HA. Reprinted from Ref. [121] with permission.
Figure 2. Soft X-ray photographs of the operated portion of the rabbit femur. Four weeks (a), 12 weeks (b), 24 weeks (c), and 72 weeks (d) after implantation of CDHA; 4 weeks (e), 12 weeks (f), 24 weeks (g), and 72 weeks (h) after implantation of sintered HA. Reprinted from Ref. [121] with permission.
Coatings 12 01380 g002
Figure 3. A schematic of 3D printing and some 3D-printed parts (fabricated at Washington State University) showing the versatility of 3D-printing technology for ceramic scaffolds fabrication with complex architectural features. Reprinted from Ref. [56] with permission.
Figure 3. A schematic of 3D printing and some 3D-printed parts (fabricated at Washington State University) showing the versatility of 3D-printing technology for ceramic scaffolds fabrication with complex architectural features. Reprinted from Ref. [56] with permission.
Coatings 12 01380 g003
Figure 4. A schematic diagram representing the changes occurring with spherical particles under sintering. Shrinkage is noticeable.
Figure 4. A schematic diagram representing the changes occurring with spherical particles under sintering. Shrinkage is noticeable.
Coatings 12 01380 g004
Figure 5. Linear shrinkage of the compacted ACP powders that were converted into β-TCP, BCP (50% HA + 50% β-TCP), and HA upon heating. According to the authors: “At 1300 °C, the shrinkage reached a maximum of approximately ~25, ~30 and ~35% for the compacted ACP powders that converted into HA, BCP 50/50 and β-TCP, respectively” [258]. Reprinted from Ref. [258] with permission.
Figure 5. Linear shrinkage of the compacted ACP powders that were converted into β-TCP, BCP (50% HA + 50% β-TCP), and HA upon heating. According to the authors: “At 1300 °C, the shrinkage reached a maximum of approximately ~25, ~30 and ~35% for the compacted ACP powders that converted into HA, BCP 50/50 and β-TCP, respectively” [258]. Reprinted from Ref. [258] with permission.
Coatings 12 01380 g005
Figure 6. Transparent HA bioceramics prepared by spark plasma sintering at 900 °C from nanosized HA single crystals. Reprinted from Ref. [419] with permission.
Figure 6. Transparent HA bioceramics prepared by spark plasma sintering at 900 °C from nanosized HA single crystals. Reprinted from Ref. [419] with permission.
Coatings 12 01380 g006
Figure 7. Photographs of commercially available porous CaPO4 bioceramics with different porosity (top) and a method of their production (bottom). For photos, the horizontal field width is 20 mm.
Figure 7. Photographs of commercially available porous CaPO4 bioceramics with different porosity (top) and a method of their production (bottom). For photos, the horizontal field width is 20 mm.
Coatings 12 01380 g007
Figure 8. Schematic drawings of various types of the ceramic porosity: (A)—nonporous, (B)—microporous, (C)—macroporous (spherical), (D)—macroporous (spherical) + micropores, (E)—macroporous (3D-printing), (F)— macroporous (3D-printing) + micropores. Reprinted from Ref. [480] with permission.
Figure 8. Schematic drawings of various types of the ceramic porosity: (A)—nonporous, (B)—microporous, (C)—macroporous (spherical), (D)—macroporous (spherical) + micropores, (E)—macroporous (3D-printing), (F)— macroporous (3D-printing) + micropores. Reprinted from Ref. [480] with permission.
Coatings 12 01380 g008
Figure 9. A schematic diagram showing the porous structures of various CaPO4 scaffolds with different pore orientations: (A) 0°/90°, (B) 0°/45°/90°/135°, and (C) 0°/30°/60°/90°/120°/150°, with their top-down view of the repeating CaPO4 frameworks. Reprinted from Ref. [481] with permission.
Figure 9. A schematic diagram showing the porous structures of various CaPO4 scaffolds with different pore orientations: (A) 0°/90°, (B) 0°/45°/90°/135°, and (C) 0°/30°/60°/90°/120°/150°, with their top-down view of the repeating CaPO4 frameworks. Reprinted from Ref. [481] with permission.
Coatings 12 01380 g009
Figure 10. SEM pictures of HA bioceramics sintered at (A) 1050 °C and (B) 1200 °C. Note the presence of microporosity in A and not in B. Reprinted from Ref. [544] with permission.
Figure 10. SEM pictures of HA bioceramics sintered at (A) 1050 °C and (B) 1200 °C. Note the presence of microporosity in A and not in B. Reprinted from Ref. [544] with permission.
Coatings 12 01380 g010
Figure 11. Rounded β-TCP granules 2.6–4.8 mm in size, providing no sharp edges for combination with bone cement. Reprinted from Ref. [595] with permission.
Figure 11. Rounded β-TCP granules 2.6–4.8 mm in size, providing no sharp edges for combination with bone cement. Reprinted from Ref. [595] with permission.
Coatings 12 01380 g011
Figure 12. A sequence of interfacial reactions involved in forming a bond between tissue and bioactive ceramics. Reprinted from Refs. [50,51] with permission.
Figure 12. A sequence of interfacial reactions involved in forming a bond between tissue and bioactive ceramics. Reprinted from Refs. [50,51] with permission.
Coatings 12 01380 g012
Figure 13. A schematic diagram representing the events which take place at the interface between bioceramics and the surrounding biological environment: (1) dissolution of bioceramics; (2) precipitation from solution onto bioceramics; (3) ion exchange and structural rearrangement at the bioceramic/tissue interface; (4) interdiffusion from the surface boundary layer into the bioceramics; (5) solution-mediated effects on cellular activity; (6) deposition of either the mineral phase (a) or the organic phase (b) without integration into the bioceramic surface; (7) deposition with integration into the bioceramics; (8) chemotaxis to the bioceramic surface; (9) cell attachment and proliferation; (10) cell differentiation; (11) extracellular matrix formation. All phenomena, collectively, lead to the gradual incorporation of a bioceramic implant into developing bone tissue. Reprinted from Ref. [58] with permission.
Figure 13. A schematic diagram representing the events which take place at the interface between bioceramics and the surrounding biological environment: (1) dissolution of bioceramics; (2) precipitation from solution onto bioceramics; (3) ion exchange and structural rearrangement at the bioceramic/tissue interface; (4) interdiffusion from the surface boundary layer into the bioceramics; (5) solution-mediated effects on cellular activity; (6) deposition of either the mineral phase (a) or the organic phase (b) without integration into the bioceramic surface; (7) deposition with integration into the bioceramics; (8) chemotaxis to the bioceramic surface; (9) cell attachment and proliferation; (10) cell differentiation; (11) extracellular matrix formation. All phenomena, collectively, lead to the gradual incorporation of a bioceramic implant into developing bone tissue. Reprinted from Ref. [58] with permission.
Coatings 12 01380 g013
Figure 14. A schematic diagram representing the phenomena that occur on the HA surface after implantation: (1) beginning of the implant procedure, where a solubilization of the HA surface starts; (2) continuation of the solubilization of the HA surface; (3) the equilibrium between the physiological solutions and the modified surface of HA has been achieved (changes in the surface composition of HA do not mean that a new phase of DCPA or DCPD forms on the surface); (4) adsorption of proteins and/or other bioorganic compounds; (5) cell adhesion; (6) cell proliferation; (7) beginning of a new bone formation; (8) new bone has been formed. Reprinted from Ref. [651] with permission.
Figure 14. A schematic diagram representing the phenomena that occur on the HA surface after implantation: (1) beginning of the implant procedure, where a solubilization of the HA surface starts; (2) continuation of the solubilization of the HA surface; (3) the equilibrium between the physiological solutions and the modified surface of HA has been achieved (changes in the surface composition of HA do not mean that a new phase of DCPA or DCPD forms on the surface); (4) adsorption of proteins and/or other bioorganic compounds; (5) cell adhesion; (6) cell proliferation; (7) beginning of a new bone formation; (8) new bone has been formed. Reprinted from Ref. [651] with permission.
Coatings 12 01380 g014
Figure 15. Different types of biomedical applications of CaPO4 bioceramics. Reprinted from Ref. [731] with permission.
Figure 15. Different types of biomedical applications of CaPO4 bioceramics. Reprinted from Ref. [731] with permission.
Coatings 12 01380 g015
Figure 16. A typical microstructure of a CaPO4 cement after hardening. The mechanical stability is provided by the physical entanglement of crystals. Reprinted from Ref. [737] with permission.
Figure 16. A typical microstructure of a CaPO4 cement after hardening. The mechanical stability is provided by the physical entanglement of crystals. Reprinted from Ref. [737] with permission.
Coatings 12 01380 g016
Figure 17. Shows how a plasma-sprayed HA coating on a porous titanium (dark bars), dependent on the implantation time, will improve the interfacial bond strength compared to uncoated porous titanium (light bars). Reprinted from Ref. [50] with permission.
Figure 17. Shows how a plasma-sprayed HA coating on a porous titanium (dark bars), dependent on the implantation time, will improve the interfacial bond strength compared to uncoated porous titanium (light bars). Reprinted from Ref. [50] with permission.
Coatings 12 01380 g017
Figure 18. A schematic diagram showing the arrangement of the FA/β-TCP biocomposite layers. (a) A nonsymmetric functionally gradient material (FGM); (b) symmetric FGM. Reprinted from Ref. [744] with permission.
Figure 18. A schematic diagram showing the arrangement of the FA/β-TCP biocomposite layers. (a) A nonsymmetric functionally gradient material (FGM); (b) symmetric FGM. Reprinted from Ref. [744] with permission.
Coatings 12 01380 g018
Figure 19. Schematic illustrations of fabrication of pore-graded bioceramics: top—lamination of individual tapes, manufactured by tape casting; bottom—a compression molding process. Reprinted from Ref. [432] with permission.
Figure 19. Schematic illustrations of fabrication of pore-graded bioceramics: top—lamination of individual tapes, manufactured by tape casting; bottom—a compression molding process. Reprinted from Ref. [432] with permission.
Coatings 12 01380 g019aCoatings 12 01380 g019b
Figure 20. A tissue engineering approach for developing an advanced bone scaffold. Reprinted from Ref. [759] with permission.
Figure 20. A tissue engineering approach for developing an advanced bone scaffold. Reprinted from Ref. [759] with permission.
Coatings 12 01380 g020
Figure 21. A schematic view of a third-generation biomaterial, in which porous CaPO4 bioceramic acts as a scaffold or a template for cells, growth factors, etc. Reprinted from Ref. [47] with permission.
Figure 21. A schematic view of a third-generation biomaterial, in which porous CaPO4 bioceramic acts as a scaffold or a template for cells, growth factors, etc. Reprinted from Ref. [47] with permission.
Coatings 12 01380 g021
Figure 22. A schematic drawing presenting the potential usage of HA with various degrees of porosity. Reprinted from Ref. [518] with permission.
Figure 22. A schematic drawing presenting the potential usage of HA with various degrees of porosity. Reprinted from Ref. [518] with permission.
Coatings 12 01380 g022
Figure 23. A schematic drawing of the key scaffold properties affecting a cascade of biological processes occurring after CaPO4 implantation. Reprinted from Ref. [807] with permission.
Figure 23. A schematic drawing of the key scaffold properties affecting a cascade of biological processes occurring after CaPO4 implantation. Reprinted from Ref. [807] with permission.
Coatings 12 01380 g023
Table 1. Existing calcium orthophosphates and their major properties [3,6].
Table 1. Existing calcium orthophosphates and their major properties [3,6].
Ca/P Molar RatioCompounds and Their Typical AbbreviationsChemical FormulaSolubility at
25 °C, -log(Ks)
Solubility at
25 °C, g/L
pH Stability Range in Aqueous Solutions at 25 °C
0.5Monocalcium phosphate monohydrate (MCPM)Ca(H2PO4)2·H2O1.14~180.0–2.0
0.5Monocalcium phosphate anhydrous (MCPA or MCP)Ca(H2PO4)21.14~17[c]
1.0Dicalcium phosphate dihydrate (DCPD), mineral brushiteCaHPO4·2H2O6.59~0.0882.0–6.0
1.0Dicalcium phosphate anhydrous (DCPA or DCP), mineral monetiteCaHPO46.90~0.048[c]
1.33Octacalcium phosphate (OCP)Ca8(HPO4)2(PO4)4·5H2O96.6~0.00815.5–7.0
1.5α-Tricalcium phosphate (α-TCP)α-Ca3(PO4)225.5~0.0025[a]
1.5β-Tricalcium phosphate (β-TCP)β-Ca3(PO4)228.9~0.0005[a]
1.2–2.2Amorphous calcium phosphates (ACP)CaxHy(PO4)z·nH2O,
n = 3–4.5; 15%–20% H2O
[b][b]~5–12 [d]
1.5–1.67Calcium-deficient hydroxyapatite (CDHA or Ca-def HA) [e]Ca10-x(HPO4)x(PO4)6−x(OH)2−x
(0 < x < 1)
~85~0.00946.5–9.5
1.67Hydroxyapatite (HA, HAp, or OHAp)Ca10(PO4)6(OH)2116.8~0.00039.5–12
1.67Fluorapatite (FA or FAp)Ca10(PO4)6F2120.0~0.00027–12
1.67Oxyapatite (OA, OAp, or OXA) [f], mineral voelckeriteCa10(PO4)6O~69~0.087[a]
2.0Tetracalcium phosphate (TTCP or TetCP), mineral hilgenstockiteCa4(PO4)2O38–44~0.0007[a]
[a] These compounds cannot be precipitated from aqueous solutions. [b] Cannot be measured precisely. However, the following values were found: 25.7 ± 0.1 (pH = 7.40), 29.9 ± 0.1 (pH = 6.00), 32.7 ± 0.1 (pH = 5.28). The comparative extent of dissolution in acidic buffer is ACP >> α-TCP >> β-TCP > CDHA >> HA > FA. [c] Stable at temperatures above 100 °C.[d] Always metastable. [e] Occasionally, it is called “precipitated HA (PHA)”. [f] Existence of OA remains questionable.
Table 2. The procedures used to manufacture porous CaPO4 scaffolds for tissue engineering [479].
Table 2. The procedures used to manufacture porous CaPO4 scaffolds for tissue engineering [479].
YearLocationProcessApatite from:SinteringCompressive StrengthPore SizePorosityMethod of Porosity Control
2006Deville et al., Berkeley, CAHA + ammonium methacrylate in polytetrafluoroethylene mold, freeze dried and sintered.HA #30Yes: 1300 °C16 MPa
65 MPa
145 MPa
Open unidirectional 50–150 μm.>60%
56%
47%
Porosity control: slurry conc. Structure controlled by physics of ice front formation.
2006Saiz et al., Berkeley, CAPolymer foams coated, compressed after infiltration, then calcined.HA powderYes: 700–1300 °C100–200 μm.Porosity control: extent of compression, HA loading.
2006Murugan et al., Singapore + USABovine bone cleaned, calcined.bovine boneYes: 500 °CRetention of nanosized pores.Porosity control: native porosity of bovine bone.
2006Xu et al., Gaithersburg, MDDirectly injectable CaPO4 cement, self-hardens, mannitol as porogen.nanocrystalline HANo2.2–4.2 MPa (flexural)0%–50% macroporous.65%–82%Porosity control: mannitol mass fraction in mixture.
2004Landi et al., Italy + IndonesiaSponge impregnation, isotactic pressing, sintering of HA in simulated body fluid.CaO + H3PO4Yes: 1250 °C for 1 h23 ± 3.8 MPaClosed 6%, open 60%.66%Porosity control: possibly by controlling HA particle size. Not suggested by authors.
2003Charriere et al., EPFL, SwitzerlandThermoplastic negative porosity by Inkjet printing, slip casting process for HA.DCPA + calciteNo: 90 °C for 1 day.12.5 ± 4.6 MPa44%Porosity control: negative printing.
2003Almirall et al., Barcelona, Spainα-TCP foamed with hydrogen peroxide at different conc., liq. Ratios, poured in polytetrafluoroethylene molds.A-TCP + (10% and 20% H2O2)No: 60 °C for 2 h.1.41 ± 0.27 MPa
2.69 ± 0.91 MPa
35.7% macro. 29.7% micro. 26.8% macro. 33.8% micro.65.5% 60.7%Porosity control: different concentration, α-TCP particle sizes.
2003Ramay et al., Seattle, WASlurries of HA prepared: gel-casting + polymer sponge technique, sintered.HA powderYes: 600 °C for 1 h 1350 °C for 2 h.0.5–5 MPa200–400 μm.70%–77%Porosity control: replicate of polymer sponge template.
2003Miao et al., SingaporeTTCP to CaPO4 cement. Slurry cast on polymer foam, sintered.TTCPYes: 1200 °C for 2 h.1 mm macro.
5 μm micro.
~70%Porosity control: Recoating time, polyurethane foam.
2003Uemura et al., China + JapanSlurry of HA with polyoxyethylene lauryl ether (cross-linked) and sintered.HA powdersYes: 1200 °C for 3 h.2.25 MPa (0 wk) 4.92 MPa (12 wk)
11.2 MPa (24 wx)
500 μm.
200 μm interconnects.
~77%Porosity control: polymer interconnects cross-linking.
2003Ma et al., Singapore + USAElectrophoretic deposition of HA, sintering.HA powdersYes: 1200 °C for 2 h.860 MPa0.5 μm.
130 μm.
~20%Porosity control: electrophoresis field.
2002Barralet et al., Birmingham, London, UKCaPO4 cement + sodium phosphate ice, evaporated.CaCO3 + DCPD1st step: 1400 °C for 1 day.0.6 ± 0.27 MPa2 μm.62% ± 9%Porosity control: porogen shape.
Table 3. Registered commercial trademarks (current and past) of CaPO4-based bioceramics and biomaterials.
Table 3. Registered commercial trademarks (current and past) of CaPO4-based bioceramics and biomaterials.
Calcium OrthophosphateTrade Name and Producer (When Available)
CDHACalcibon (Zimmer Biomet, IN, USA)
Cementek (Teknimed, France)
CHT Ceramic Hydroxyapatite (Bio-Rad, CA, USA)
nanoXIM (Fluidinova, Portugal)
OsteoGen (Impladent, NY, USA)
without trade name (Himed, NY, USA)
HAActifuse (ApaTech, UK)
Alveograf (Cooke-Waite Laboratories, USA)
Apaceram (HOYA Technosurgical, Japan)
Apafill-G (Habana, Cuba)
ApaPore (ApaTech, UK)
BABI-HAP (Berkeley Advanced Biomaterials, CA, USA)
Bio-Eye (Integrated Orbital Implants, CA, USA)
BIOGAP (Connectbiopharm, Russia)
BioGraft (IFGL BIO CERAMICS, India)
Bioroc (Depuy Bioland, France)
Blue Bone (Regener Biomateriais, Brazil)
Boneceram (Sumitomo Osaka Cement, Japan)
Bonefil (Pentax, Japan)
BoneSource (Stryker Orthopaedics, NJ, USA)
Bonetite (Pentax, Japan)
Bonfil (Mitsubishi Materials, Japan)
Bongros-HA (Daewoong Pharmaceutical, Korea)
CAFOS DT (Chemische Fabrik Budenheim, Germany)
Calcitite (Sulzer Calcitek, CA, USA)
CAMCERAM HA (CAM Implants, Netherlands)
CAPTAL (Plasma Biotal, UK)
CELLYARD (HOYA Technosurgical, Japan)
Cerapatite (Ceraver, France)
Ceros HA (Mathys, Switzerland)
CHT Ceramic Hydroxyapatite (Bio-Rad, CA, USA)
Durapatite (unknown producer)
ENGIpore (JRI Orthopaedics, UK)
G-Bone (Surgiwear, India)
GranuMas (GranuLab, Malaysia)
HA BIOCER (CHEMA – ELEKTROMET, Poland)
HAnano Surface (Promimic, Sweden)
HAP-91 (JHS Biomateriais, Brazil)
HAP-99 (Polystom, Russia)
HAP–Bionnovation (Bionnovation, Brazil)
IngeniOs HA (Zimmer Dental, CA, USA)
Micro Crystalline Hydroxyapatite Complex (MCHC) (Clarion Pharmaceutical, India)
nanoXIM (Fluidinova, Portugal)
Neobone (Covalent Materials, Japan)
Osbone (Curasan, Germany)
OsproLife HA (Lincotek Medical, Italy)
Ossein Hydroxyapatite (Clarion Pharmaceutical, India)
OssaBase-HA (Lasak, Czech Republic)
Ostegraf (Ceramed, CO, USA)
Ostim (Heraeus Kulzer, Germany)
Ovis Bone HA (DENTIS, Korea)
Periograf (Cooke-Waite Laboratories, USA)
PermaOS (Mathys, Switzerland)
PRINT3D Hydroxyapatite (Prodways, France)
Pro Osteon (Zimmer Biomet, IN, USA)
PurAtite (PremierBiomaterials, Ireland)
REGENOS (Kuraray, Japan)
SHAp (SofSera, Japan)
Synatite (SBM, France)
Synthacer (KARL STORZ Recon, Germany)
Theriridge (Therics, OH, USA)
without trade name (Cam Bioceramics, Netherlands)
without trade name (CaP Biomaterials, WI, USA)
without trade name (DinganTec, China)
without trade name (Ensail Beijing, China)
without trade name (Himed, NY, USA)
without trade name (MedicalGroup, France)
without trade name (SANGI, Japan)
without trade name (Shanghai Rebone Biomaterials, China)
without trade name (SigmaGraft, CA, USA)
without trade name (SkySpring Nanomaterials, TX, USA)
without trade name (SofSera, Japan)
without trade name (Taihei Chemical Industrial, Japan)
without trade name (Xpand Biotechnology, Netherlands)
Mg-HASINTlife (JRI Orthopaedics, UK)
HA powder suspended in waterOstibone (FH Orthopedics, France)
NANOSTIM (Medtronic Sofamor Danek, TN, USA)
n-IBS (Bioceramed, Portugal)
Skelifil (Osteotec, UK)
HA embedded or suspended in a gelBio-Gel HT hydroxyapatite (Bio-Rad, CA, USA)
Coaptite (Boston Scientific, MA, USA)
Facetem (Daewoong, Korea)
NanoBone (Artoss, Germany)
Nanogel (Teknimed, France)
Radiesse (Merz Aesthetics, Germany)
Renú Calcium Hydroxylapatite Implant (Cytophil, WI, USA)
HA/collagen, CDHA/collagen and/or carbonate apatite/collagenAUGMATRIX (Wright Medical Technology, TN, USA)
Bioimplant (Connectbiopharm, Russia)
Bio-Oss Collagen (Geitslich, Switzerland)
Boneject (Koken, Japan)
COL.HAP-91 (JHS Biomateriais, Brazil)
Collagraft (Zimmer and Collagen Corporation, USA)
CollaOss (SK Bioland, Korea)
CollapAn (Intermedapatite, Russia)
COLLAPAT (Symatese, France)
DualPor collagen (OssGen, Korea)
G-Graft (Surgiwear, India)
HAPCOL (Polystom, Russia)
Healos (DePuy Spine, USA)
LitAr (LitAr, Russia)
Ossbone Collagen (SK Bioland, Korea)
OssFill (Sewon Cellontech, Korea)
OssiMend (Collagen Matrix, NJ, USA)
Osteomatrix (Connectbiopharm, Russia)
OsteoTape (Impladent, NY, USA)
ReFit (HOYA Technosurgical, Japan
RegenOss (JRI Orthopaedics, UK)
RegenerOss Synthetic (Zimmer Dental, CA, USA)
Straumann XenoFlex (Straumann, Switzerland)
HA/sodium alginateBialgin (Biomed, Russia)
HA/poly-L-lactic acidBiosteon (Biocomposites, UK)
ReOss (ReOss, Germany)
OSTEOTRANS MX (Teijin Medical Technologies, Japan)
SuperFIXSORB30 (Takiron, Japan)
HA/polyethyleneHAPEX (Gyrus, TN, USA)
HA/CaSO4BioWrist Bone Void Filler (Skeletal Kinetics, CA, USA)
Bond Apatite (Augma Biomaterials, NJ, USA)
Hapset (LifeCore, MN, USA)
PerOssal (aap Implantate, Germany)
HA/CaSO4 powders suspended in a liquidCERAMENT (BONESUPPORT, Sweden)
Coralline HABiocoral (Bio Coral Calcium Bone, France)
BoneMedik-S (Meta Biomed, Korea)
Interpore (Interpore, CA, USA)
ProOsteon (Interpore, CA, USA)
Carbonate apatiteCytrans (GC, Japan)
Norian SRS (Norian, CA, USA)
Algae-derived HAAlgipore (AlgOss Biotechnologies, Austria)
Algisorb (AlgOss Biotechnologies, Austria)
FRIOS Algipore (DENTSPLY Implants, Sweden)
SIC nature graft (AlgOss Biotechnologies, Austria)
HA/glassBonelike (unknwn producer)
Bovine bone (unsintered)Unilab Surgibone (Unilab, NJ, USA)
Bovine bone (unsintered) + polymerAlpha-Bio’s Graft (Alpha-Bio Tec, Israel)
C-Graft Putty (unknwn producer)
Bovine bone apatite (unsintered)Apatos (OsteoBiol, Italy)
Bio-Oss (Geistlich Biomaterials, Switzerland)
Bonefill (Bionnovation, Brazil).
CANCELLO-PURE (Wright Medical Technology, TN, USA)
CenoBone (Tissue Regeneration Corporation, Iran)
CopiOs Cancellous Particulate Xenograft (Zimmer, IN, USA)
GenOs (OsteoBiol, Italy)
InterOss (SigmaGraft, CA, USA)
Laddec (Ost-Developpement, France)
Lubboc (Ost-Developpement, France)
MatrixCellect (Curasan, Germany)
Mega-Oss Bovine (Megagen Implant, Korea)
Orthoss (Geitslich, Switzerland)
OssiGuide (Collagen Matrix, NJ, USA)
Oxbone (Bioland biomateriaux, France)
Straumann XenoGraft (Straumann, Switzerland)
Surgibone (Surgibon, Ecuador)
Tutobone (Tutogen Medical, Germany)
Tutofix (Tutogen Medical, Germany)
Tutoplast (Tutogen Medical, Germany)
without trade name (MedicalGroup, France)
Porcine bone apatite (unsintered)A-OSS (Osstem Implant, Korea)
GEM Bone Graft (Lynch Biologics, USA)
Gen-Os (OsteoBiol, Italy)
MatrixOss (Collagen Matrix, NJ, USA)
OsteoBiol (OsteoBiol, Italy)
Symbios Xenograft (DENTSPLY Implants, Sweden)
THE Graft (Purgo Biologics, Korea)
Equine bone apatite (unsintered)BIO-GEN (BioTECK, Italy)
Sp-Block (OsteoBiol, Italy)
Bovine bone apatite (sintered)4Bone XBM (MIS Implants, Israel)
BonAP (unknown producer)
Cerabone (aap Implantate, Germany and botiss, Germany)
Endobon (Merck, Germany)
GenoxInorgânico (Baumer, SP, Brazil)
Iceberg oss (Global Medical Implants, Spain)
Navigraft (Zimmer Dental, USA)
Osteograf (Ceramed, CO, USA)
OVIS XENO (DENTIS, Korea)
PepGen P-15 (DENTSPLY Implants, Sweden)
Pyrost (Osteo AG, Germany)
Sinbone (Purzer Pharmaceutical, Taiwan)
SynOss (Collagen Matrix, NJ, USA)
Straumann cerabone (Straumann, Switzerland)
Human bone allograftALLOPURE (Wright Medical Technology, TN, USA)
Allosorb (Curasan, Germany)
CancellOss (Impladent, NY, USA)
CurOss (Impladent, NY, USA)
J Bone Block (Impladent, NY, USA)
maxgraft (botiss, Germany)
Mega-Oss (Megagen Implant, Korea)
NonDemin (Impladent, NY, USA)
Osnatal (aap Implantate, Germany)
OsteoDemin (Impladent, NY, USA)
OsteoWrap (Curasan, Germany)
OVIS ALLO (DENTIS, Korea)
PentOS OI (Citagenix, QC, Canada)
RAPTOS (Citagenix, QC, Canada)
Straumann AlloGraft (Straumann, Switzerland)
TenFUSE (Wright Medical Technology, TN, USA)
α-TCPBioBase (Biovision, Germany)
Tetrabone (unknown producer)
without trade name (Cam Bioceramics, Netherlands)
without trade name (DinganTec, China)
without trade name (Ensail Beijing, China)
without trade name (Himed, NY, USA)
without trade name (InnoTERE, Germany)
without trade name (PremierBiomaterials, Ireland)
without trade name (Taihei Chemical Industrial, Japan)
β-TCPAdboneTCP (Medbone Medical Devices, Portugal)
AFFINOS (Kuraray, Japan)
Allogran-R (Biocomposites, UK)
Antartik TCP (MedicalBiomat, France)
ArrowBone (Brain Base Corporation, Japan)
AttraX scaffold (NuVasive, CA, USA)
BABI-TCP (Berkeley Advanced Biomaterials, CA, USA)
Betabase (Biovision, Germany)
BioGraft (IFGL BIO CERAMICS, India)
Bioresorb (Sybron Implant Solutions, Germany)
Biosorb (SBM, France)
Bi-Ostetic (Berkeley Advanced Biomaterials, CA, USA)
Bonegraft (Bonegraft biomaterials, Turkey)
BoneSigma TCP (SigmaGraft, CA, USA)
C 13-09 (Chemische Fabrik Budenheim, Germany)
Calc-i-oss classic (Degradable Solutions, Switzerland)
Calciresorb (Ceraver, France)
CAMCERAM TCP (CAM Implants, Netherlands)
CAPTAL β-TCP (Plasma Biotal, UK)
CELLPLEX (Wright Medical Technology, TN, USA)
Cerasorb (Curasan, Germany)
Ceros TCP (Mathys, Switzerland)
ChronOS (Synthes, PA, USA)
Cidemarec (KERAMAT, Spain)
Conduit (DePuy Spine, USA)
cyclOS (Mathys, Switzerland)
ExcelOs (BioAlpha, Korea)
GenerOs (Berkeley Advanced Biomaterials, CA, USA)
HT BIOCER (CHEMA – ELEKTROMET, Poland)
Iceberg TCP (Global Medical Implants, Spain)
IngeniOs β-TCP (Zimmer Dental, CA, USA)
ISIOS+ (Kasios, France)
JAX (Smith and Nephew Orthopaedics, USA)
Keramedic (Keramat, Spain)
KeraOs (Keramat, Spain)
Mega-TCP (Megagen Implant, Korea)
microTCP (Conmed, USA)
nanoXIM (Fluidinova, Portugal)
Orthograft (DePuy Spine, USA)
Ossaplast (Ossacur, Germany)
Osferion (Olympus Terumo Biomaterials, Japan)
Osfill (Olympus Terumo Biomaterials, Japan)
OsproLife β-TCP (Lincotek Medical, Italy)
OsSatura TCP (Integra Orthobiologics, CA, USA)
Ossoconduct (SteinerBio, NV, USA)
Osteoblast (Galimplant, Spain)
Osteocera (Hannox, Taiwan)
Osteopore TCP (SpiteCraft, IL, USA)
OSTEOwelt (Biolot Medical, Turkey)
Periophil β-TCP (Cytophil, WI, USA)
Platon Pearl Bone (Platon, Japan)
PolyBone (Kyungwon Medical, Korea)
PORESORB-TCP (Lasak, Czech Republic)
Powerbone (Medical Expo Bonegraft Biomaterials, Spain)
PRINT3D Tricalcium Phosphate (Prodways, France)
Repros (JRI Orthopaedics, UK)
R.T.R. (Septodont, PA, USA)
SigmaOs TCP (SigmaGraft, CA, USA)
Socket Graft (SteinerBio, NV, USA)
Sorbone (Meta Biomed, Korea)
SUPERPORE (HOYA Technosurgical, Japan)
Suprabone TCP (BMT Group, Turkey)
Syncera (Oscotec, Korea)
SynthoGraft (Bicon, MA, USA)
Synthos (unknown producer)
Syntricer (KARL STORZ Recon, Germany)
TCP (Kasios, France)
Terufill (Olympus Terumo Biomaterials, Japan)
TKF-95 (Polystom, Russia)
TriCaFor (BioNova, Russia)
Triha+ (Teknimed, France)
TriOSS (Bioceramed, Portugal)
Vitomatrix (Orthovita, PA, USA)
Vitoss (Orthovita, PA, USA)
without trade name (CaP Biomaterials, WI, USA)
without trade name (Cam Bioceramics, Netherlands)
without trade name (DinganTec, China)
without trade name (Ensail Beijing, China)
without trade name (Himed, NY, USA)
without trade name (Shanghai Bio-lu Biomaterials, China)
without trade name (Shanghai Rebone Biomaterials, China)
without trade name (SigmaGraft, CA, USA)
without trade name (Taihei Chemical Industrial, Japan)
without trade name (Xpand Biotechnology, Netherlands)
β-TCP/CaSO4Fortoss vital (Biocomposites, UK)
Genex (Biocomposites, UK)
β-TCP/poly-lactic acidBilok (Biocomposites, UK)
Duosorb (SBM, France)
Matryx Interference Screws (Conmed, USA)
β-TCP/poly-lactic-co-glycolic acidEvolvemer TCP30PLGA (Arctic Biomaterials, Finland)
β-TCP/polymerAttraX putty (NuVasive, CA, USA)
Therigraft (Therics, OH, USA)
β-TCP/bone marrow aspirateInduce (Skeletal Kinetics, CA, USA)
β-TCP/collagenIntegra Mozaik (Integra Orthobiologics, CA, USA)
β-TCP/growth-factorGEM 21S (Lynch Biologics, USA)
β-TCP/rhPDGF-BB solutionAUGMENT Bone Graft (Wright Medical Group, TN, USA)
BCP (HA + β-TCP)4Bone BCH (MIS Implants, Israel)
adboneBCP (Medbone Medical Devices, Portugal)
Antartik (MedicalBiomat, France)
ARCA BONE (ARCA-MEDICA, Switzerland)
Artosal (aap Implantate, Germany)
BABI-HATCP (Berkeley Advanced Biomaterials, CA, USA)
Bicera (Hannox, Taiwan)
BCP BiCalPhos (Medtronic, MN, USA)
BIO-C (Cowellmedi, Korea)
BioActys (Graftys, France)
BioGraft (IFGL BIO CERAMICS, India)
Biosel (Depuy Bioland, France)
BonaGraft (Biotech One, Taiwan)
Boncel-Os (BioAlpha, Korea)
Bone Plus BCP (Megagen Implant, Korea)
Bone Plus BCP Eagle Eye (Megagen Implant, Korea)
BoneMedik-DM (Meta Biomed, Korea)
BoneSave (Stryker Orthopaedics, NJ, USA)
BoneSigma BCP (SigmaGraft, CA, USA)
BONITmatrix (DOT, Germany)
Calcicoat (Zimmer, IN, USA)
Calciresorb (Ceraver, France)
Calc-i-oss crystal (Degradable Solutions, Switzerland)
CellCeram (Scaffdex, Finland)
Ceraform (Teknimed, France)
Ceratite (NGK Spark Plug, Japan)
Cross.Bone (Biotech Dental, France)
CuriOs (Progentix Orthobiology BV, Netherlands)
DM-Bone (Meta Biomed, Korea)
Eclipse (Citagenix, QC, Canada)
Eurocer (FH Orthopedics, France)
Frabone (Inobone, Korea)
Genesis-BCP (DIO, Korea)
GenPhos HA TCP (Baumer, Brazil)
Graftys BCP (Graftys, France)
Hatric (Arthrex, Naples, FL, USA)
Hydroxyapol (Polystom, Russia)
Kainos (Signus, Germany)
MagnetOs (Kuros Biosciences, Switzerland)
MasterGraft (Medtronic Sofamor Danek, TN, USA)
Maxresorb (botiss, Germany)
MBCP (Biomatlante, France)
MimetikOss (Mimetis Biomaterials, Spain)
Neobone (Bioceramed, Portugal)
New Bone (GENOSS, Korea)
NT-BCP (OssGen, Korea)
NT-Ceram (Meta Biomed, Korea)
OdonCer (Teknimed, France)
OpteMX (Exactech, FL, USA)
OrthoCer HA TCP (Baumer, Brazil)
OsproLife HA-βTCP (Lincotek Medical, Italy)
OsSatura BCP (Integra Orthobiologics, CA, USA)
ossceram nano (bredent medical, Germany)
OSSEOPLUS (JHS Biomateriais, Brazil)
Osspol (Genewel, Korea)
OsteoFlux (VIVOS-Dental, Switzerland)
Osteon (GENOSS, Korea)
Osteosynt (Einco, Brazil)
Ostilit (Stryker Orthopaedics, NJ, USA)
Ovis Bone BCP (DENTIS, Korea)
Periophil biphasic (Cytophil, WI, USA)
Q-OSS+ (Osstem Implant, Korea)
ReproBone (Ceramisys, UK)
R.T.R.+ (Septodont, PA, USA)
SBS (Expanscience, France)
Scaffdex (Scaffdex Oy, Finland)
SigmaOs BCP (SigmaGraft, CA, USA)
SinboneHT (Purzer Pharmaceutical, Taiwan)
SkeliGraft (Osteotec, UK)
Straumann BoneCeramic (Straumann, Switzerland)
SYMBIOS Biphasic Bone Graft Material (DENTSPLY Implants, Sweden)
SynMax (BioHorizons, Spain)
Synergy (unknown producer)
TCH (Kasios, France)
Topgen-S (Toplan, Korea)
Tribone (Stryker, Europe)
Triosite (Zimmer, IN, USA)
without trade name (AlgOss Biotechnologies, Austria)
without trade name (Cam Bioceramics, Netherlands)
without trade name (CaP Biomaterials, WI, USA)
without trade name (Himed, NY, USA)
without trade name (MedicalGroup, France)
without trade name (SigmaGraft, CA, USA)
without trade name (Xpand Biotechnology, Netherlands)
BCP (HA + α-TCP)Skelite (Millennium Biologix, ON, Canada)
BCP (HA + β-TCP)/collagenAllograft (Zimmer, IN, USA)
collacone max (botiss, Germany)
Collagraft (Zimmer, IN, USA)
Cross.Bone Matrix (Biotech Dental, France)
Indost (Polystom, Russia)
MasterGraft (Medtronic Sofamor Danek, TN, USA)
MATRI BONE (Biom’Up, France)
Osteon III collagen (GENOSS, Korea)
SynergOss (Nobil Bio Ricerche, Italy)
without trade name (MedicalGroup, France)
BCP (HA + β-TCP)/hydrogel4MATRIX+ (MIS Implants, Israel)
Eclipse (Citagenix, QC, Canada)
BCP (HA + β-TCP)/polymerIn’Oss (Biomatlante, France)
Hydros (Biomatlante, France)
Osteocaf (Texas Innovative Medical Devices, TX, USA)
Osteotwin (Biomatlante, France)
BCP (HA + TTCP)OsproLife HA-TTCP (Lincotek Medical, Italy)
BCP (HA + β-TCP)/chitosank-IBS (Bioceramed, Portugal)
BCP (HA + β-TCP)/fibrinTricOS (Baxter BioScience, France)
BCP (HA + β-TCP)/siliconFlexHA (Xomed, FL, USA)
Bioglass + α-TCP + β-TCP + HA + polymersOsteoFlo NanoPutty (SurGenTec, FL, USA)
FAwithout trade name (CaP Biomaterials, WI, USA)
FA + BCP (HA + β-TCP)FtAP (Polystom, Russia)
DCPAwithout trade name (Himed, NY, USA)
without trade name (Shanghai Rebone Biomaterials, China)
DCPA + MgHPO4·3H2O + SiO2 + carboxymethyl celluloseNovogro (OsteoNovus, OH, USA)
DCPDwithout trade name (Himed, NY, USA)
DCPD/collagenCopiOs Bone Void Filler (Zimmer, IN, USA)
DCPD + β-TCP/CaSO4PRO-DENSE (Wright Medical Group, TN, USA)
DCPD + β-TCP/CaSO4 + collagenPRO-STIM (Wright Medical Group, TN, USA)
ACPCAPTAL ACP (Plasma Biotal, UK)
without trade name (Himed, NY, USA)
OCPBontree (HudensBio, Korea)
OctoFor (BioNova, Russia)
without trade name (Himed, NY, USA)
OCP/fibrinFibroFor (BioNova, Russia)
OCP/collagenBonarc (Toyobo, Japan)
TTCPwithout trade name (Ensail Beijing, China)
without trade name (Himed, NY, USA)
without trade name (Shanghai Rebone Biomaterials, China)
without trade name (Taihei Chemical Industrial, Japan)
Undisclosed CaPO4Arex Bone (Osteotec, UK)
Inno-CaP (Cowellmedi, Korea)
Undisclosed CaPO4 + biologicsi-FACTOR (Cerapedics, CO, USA)
MCPMPhosfeed MCP (OCP group, Morocco)
MCPM + DCPDPhosfeed MDCP (OCP group, Morocco)
Table 4. A hierarchical pore size distribution that an ideal scaffold should exhibit [797].
Table 4. A hierarchical pore size distribution that an ideal scaffold should exhibit [797].
Pore Sizes of a 3D ScaffoldA Biochemical Effect or Function
<1 μmInteraction with proteins
Responsible for bioactivity
1–20 μmType of cells attracted
Cellular development
Orientation and directionality of cellular ingrowth
100–1000 μmCellular growth
Bone ingrowth
Predominant function in the mechanical strength
>1000 μmImplant functionality
Implant shape
Implant esthetics
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Dorozhkin, S.V. Calcium Orthophosphate (CaPO4)-Based Bioceramics: Preparation, Properties, and Applications. Coatings 2022, 12, 1380. https://doi.org/10.3390/coatings12101380

AMA Style

Dorozhkin SV. Calcium Orthophosphate (CaPO4)-Based Bioceramics: Preparation, Properties, and Applications. Coatings. 2022; 12(10):1380. https://doi.org/10.3390/coatings12101380

Chicago/Turabian Style

Dorozhkin, Sergey V. 2022. "Calcium Orthophosphate (CaPO4)-Based Bioceramics: Preparation, Properties, and Applications" Coatings 12, no. 10: 1380. https://doi.org/10.3390/coatings12101380

APA Style

Dorozhkin, S. V. (2022). Calcium Orthophosphate (CaPO4)-Based Bioceramics: Preparation, Properties, and Applications. Coatings, 12(10), 1380. https://doi.org/10.3390/coatings12101380

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop