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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Orthopedics".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 24114

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Prof. Dr. Peter V. Giannoudis

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Academic Department of Trauma & Orthopaedic Surgery, School of Medicine, University of Leeds, Leeds, UK
Interests: pelvic instability; pelvic reconstruction; non-union; bone regeneration; post fracture fixation complications
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Special Issue Information

Dear Colleagues,

One of the amost important complications post fracture fixation continues to be an impaired fracture healing response leading to non-union. Non-union, delayed union, bone voids, bone defects, and avascular necrosis represent different clinical expressions of the problem.

The incidence of non-union depends on patient characteristics, severity of injury, location of injury, and method of treatment applied. Different rates have been reported in the literature ranging from 1 to 30%. In the United States, for instance, at least 100,000 procedures of non-union per year have been recorded.

While this phenomenon is considered to be multifactorial, dysfunction in the biological component of the evolution of the bone repair process has been reported to affect angiogenesis, the osteogenic matrix, osteoprogenitor cells, presence and potency of inductive molecules, availiability of molecular mediators, and defects in the local immunoregulation environment.

Different strategies have been implemented to provide solutions to this clinical complication, including cellular therapy treatment, implantation of growth factors and scaffolds, autologous bone grafting, and combinatory approaches in general within the context of tissue enginnering.

In this special issue focusing on bone regeneration, both clinical and basic science manuscripts are invited to be submitted. The overarching objective is to gather and to disseminate the latest advances made in terms of the aetiopathogenesis and treatent modalities of this unique clinical entity to the scientific community.

Prof. Dr. Peter V. Giannoudis
Guest Editor

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Keywords

Bone regeneration
Non-union
Growth factors
Osteoprogenitor cells
Scaffolds
Tissue engineering

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Published Papers (7 papers)

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Research

16 pages, 1959 KiB

Open AccessArticle

Regulation of Angiogenesis Discriminates Tissue Resident MSCs from Effective and Defective Osteogenic Environments

by R. J. Cuthbert, E. Jones, C. Sanjurjo-Rodríguez, A. Lotfy, P. Ganguly, S. M. Churchman, P. Kastana, H. B. Tan, D. McGonagle, E. Papadimitriou and P. V. Giannoudis

J. Clin. Med. 2020, 9(6), 1628; https://doi.org/10.3390/jcm9061628 - 28 May 2020

Cited by 12 | Viewed by 3733

Abstract

Background: The biological mechanisms that contribute to atrophic long bone non-union are poorly understood. Multipotential mesenchymal stromal cells (MSCs) are key contributors to bone formation and are recognised as important mediators of blood vessel formation. This study examines the role of MSCs in tissue formation at the site of atrophic non-union. Materials and Methods: Tissue and MSCs from non-union sites (n = 20) and induced periosteal (IP) membrane formed following the Masquelet bone reconstruction technique (n = 15) or bone marrow (n = 8) were compared. MSC content, differentiation, and influence on angiogenesis were measured in vitro. Cell content and vasculature measurements were performed by flow cytometry and histology, and gene expression was measured by quantitative polymerase chain reaction (qPCR). Results: MSCs from non-union sites had comparable differentiation potential to bone marrow MSCs. Compared with induced periosteum, non-union tissue contained similar proportion of colony-forming cells, but a greater proportion of pericytes (p = 0.036), and endothelial cells (p = 0.016) and blood vessels were more numerous (p = 0.001) with smaller luminal diameter (p = 0.046). MSCs showed marked differences in angiogenic transcripts depending on the source, and those from induced periosteum, but not non-union tissue, inhibited early stages of in vitro angiogenesis. Conclusions: In vitro, non-union site derived MSCs have no impairment of differentiation capacity, but they differ from IP-derived MSCs in mediating angiogenesis. Local MSCs may thus be strongly implicated in the formation of the immature vascular network at the non-union site. Attention should be given to their angiogenic support profile when selecting MSCs for regenerative therapy. Full article

(This article belongs to the Special Issue Latest Clinical And Basic Science Advances In Bone Regeneration)

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11 pages, 3661 KiB

Open AccessArticle

Multifunctional Properties of Quercitrin-Coated Porous Ti-6Al-4V Implants for Orthopaedic Applications Assessed In Vitro

by Maria Antonia Llopis-Grimalt, Aina Arbós, Maria Gil-Mir, Aleksandra Mosur, Prathamesh Kulkarni, Armando Salito, Joana M. Ramis and Marta Monjo

J. Clin. Med. 2020, 9(3), 855; https://doi.org/10.3390/jcm9030855 - 20 Mar 2020

Cited by 21 | Viewed by 3410

Abstract

(1) One strategy to improve the outcome of orthopedic implants is to use porous implants with the addition of a coating with an antibacterial biomolecule. In this study, we aimed to produce and test the biocompatibility, the osteopromotive (both under normal conditions and under a bacterial challenge with lipopolysaccharide (LPS)) and antibacterial activities of a porous Ti-6Al-4V implant coated with the flavonoid quercitrin in vitro. (2) Porous Ti-6Al-4V implants were produced by 3D printing and further functionalized with quercitrin by wet chemistry. Implants were characterized in terms of porosity and mechanical testing, and the coating with quercitrin by fluorescence staining. Implant biocompatibility and bioactivity was tested using MC3T3-E1 preosteoblasts by analyzing cytotoxicity, cell adhesion, osteocalcin production, and alkaline phosphatase (ALP) activity under control and under bacterial challenging conditions using lipopolysaccharide (LPS). Finally, the antibacterial properties of the implants were studied using Staphylococcus epidermidis by measuring bacterial viability and adhesion. (3) Porous implants showed pore size of about 500 µm and a porosity of 52%. The coating was homogeneous over all the 3D surface and did not alter the mechanical properties of the Young modulus. Quercitrin-coated implants showed higher biocompatibility, cell adhesion, and osteocalcin production compared with control implants. Moreover, higher ALP activity was observed for the quercitrin group under both normal and bacterial challenging conditions. Finally, S. epidermidis live/dead ratio and adhesion after 4 h of incubation was lower on quercitrin implants compared with the control. (4) Quercitrin-functionalized porous Ti-6Al-4V implants present a great potential as an orthopedic porous implant that decreases bacterial adhesion and viability while promoting bone cell growth and differentiation. Full article

(This article belongs to the Special Issue Latest Clinical And Basic Science Advances In Bone Regeneration)

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16 pages, 3542 KiB

Open AccessArticle

Dynamics of Early Signalling Events during Fracture Healing and Potential Serum Biomarkers of Fracture Non-Union in Humans

by Agata N. Burska, Peter V. Giannoudis, Boon Hiang Tan, Dragos Ilas, Elena Jones and Frederique Ponchel

J. Clin. Med. 2020, 9(2), 492; https://doi.org/10.3390/jcm9020492 - 11 Feb 2020

Cited by 18 | Viewed by 2980

Abstract

To characterise the dynamic of events during the early phases of fracture repair in humans, we investigated molecular events using gene expression profiling of bone fragments from the fracture site at different time points after trauma and immune/stromal cells recruitment at the fracture site using flow cytometry. Bone and inflammatory markers were expressed at low levels at homeostasis, while transcripts for bone constituent proteins were consistently detected at higher levels. Early after fracture (range 2–4 days), increased expression of CXCL12, suggested recruitment of immune cells associated with a change in the balance of degradation enzymes and their inhibitors. At intermediate time after fracture (4–8 days), we observed high expression of inflammatory cytokines (IL1-beta, IL6), CCL2, the T-cell activation marker CD69. Late after fracture (8–14 days), high expression of factors co-operating towards the regulation of bone turnover was detected. We identified potential soluble factors and explored circulating levels in patients for whom a union/non-union (U/NU) outcome was known. This showed a clear difference for PlGF (p = 0.003) at day 1. These findings can inform future studies further investigating the cascade of molecular events following fractures and for the prediction of fracture non-union. Full article

(This article belongs to the Special Issue Latest Clinical And Basic Science Advances In Bone Regeneration)

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16 pages, 2183 KiB

Open AccessArticle

Towards Understanding Therapeutic Failures in Masquelet Surgery: First Evidence that Defective Induced Membrane Properties are Associated with Clinical Failures

by Marjorie Durand, Laure Barbier, Laurent Mathieu, Thomas Poyot, Thomas Demoures, Jean-Baptiste Souraud, Alain-Charles Masquelet and Jean-Marc Collombet

J. Clin. Med. 2020, 9(2), 450; https://doi.org/10.3390/jcm9020450 - 6 Feb 2020

Cited by 27 | Viewed by 2850

Abstract

The two-stage Masquelet induced-membrane technique (IMT) consists of cement spacer-driven membrane induction followed by an autologous cancellous bone implantation in this membrane to promote large bone defect repairs. For the first time, this study aims at correlating IMT failures with physiological alterations of the induced membrane (IM) in patients. For this purpose, we compared various histological, immunohistochemical and gene expression parameters obtained from IM collected in patients categorized lately as successfully (Responders; n = 8) or unsuccessfully (Non-responders; n = 3) treated with the Masquelet technique (6 month clinical and radiologic post-surgery follow-up). While angiogenesis or macrophage distribution pattern remained unmodified in non-responder IM as compared to responder IM, we evidenced an absence of mesenchymal stem cells and reduced density of fibroblast-like cells in non-responder IM. Furthermore, non-responder IM exhibited altered extracellular matrix (ECM) remodeling parameters such as a lower expression ratio of metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinases (TIMP-1) mRNA as well as an important collagen overexpression as shown by picrosirius red staining. In summary, this study is the first to report evidence that IMT failure can be related to defective IM properties while underlining the importance of ECM remodeling parameters, particularly the MMP-9/TIMP-1 gene expression ratio, as early predictive biomarkers of the IMT outcome regardless of the type of bone, fracture or patient characteristics. Full article

(This article belongs to the Special Issue Latest Clinical And Basic Science Advances In Bone Regeneration)

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15 pages, 1434 KiB

Open AccessArticle

Inflammatory Profile and Osteogenic Potential of Fracture Haematoma in Humans

by Ippokratis Pountos, Gavin Walters, Michalis Panteli, Thomas A. Einhorn and Peter V. Giannoudis

J. Clin. Med. 2020, 9(1), 47; https://doi.org/10.3390/jcm9010047 - 24 Dec 2019

Cited by 14 | Viewed by 3062

Abstract

Fracture haematoma forms immediately after fracture and is considered essential for the bone healing process. Its molecular composition has been briefly investigated with our current understanding being based on animal studies. This study aims to analyse the inflammatory cytokine content of fracture haematoma in humans and determine its effect on osteoprogenitor cells. Twenty-three patients were recruited following informed consent. Peripheral blood, fracture haematoma and bone were collected. A Luminex assay on the levels of 34 cytokines was performed and autologous peripheral blood samples served as control. Mesenchymal Stem Cells (MSCs) were isolated following collagenase digestion and functional assays were performed. Gene expression analysis of 84 key osteogenic molecules was performed. Thirty-three inflammatory cytokines were found to be significantly raised in fracture haematoma when compared to peripheral serum (p < 0.05). Amongst the most raised molecules were IL-8, IL-11 and MMP1, -2 and -3. Fracture haematoma did not significantly affect MSC proliferation, but ALP activity and calcium deposition were significantly increased in the MSCs undergoing osteogenic differentiation. Medium supplementations with fracture haematoma resulted in a statistically significant upregulation of osteogenic genes including the EGF, FGF2 and VEGFA. This seems to be the pathway involved in the osteogenic effect of fracture haematoma on bone cells. In conclusion, fracture haematoma is found to be a medium rich in inflammatory and immunomodulatory mediators. At the same time, it contains high levels of anti-inflammatory molecules, regulates osteoclastogenesis, induces angiogenesis and the production of the extracellular matrix. It appears that fracture haematoma does not affect osteoprogenitor cells proliferation as previously thought, but induces an osteogenic phenotype. Full article

(This article belongs to the Special Issue Latest Clinical And Basic Science Advances In Bone Regeneration)

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19 pages, 4567 KiB

Open AccessArticle

Biomimetic Biomolecules in Next Generation Xeno-Hybrid Bone Graft Material Show Enhanced In Vitro Bone Cells Response

by Giuseppe Perale, Marta Monjo, Joana M. Ramis, Øystein Øvrebø, Felice Betge, Petter Lyngstadaas and Håvard J. Haugen

J. Clin. Med. 2019, 8(12), 2159; https://doi.org/10.3390/jcm8122159 - 6 Dec 2019

Cited by 14 | Viewed by 3411

Abstract

Bone defects resulting from trauma, disease, surgery or congenital malformations are a significant health problem worldwide. Consequently, bone is the second most transplanted tissue just after blood. Although bone grafts (BGs) have been used for decades to improve bone repairs, none of the currently available BGs possesses all the desirable characteristics. One way to overcome such limitations is to introduce the feature of controlled release of active bone-promoting biomolecules: however, the administration of, e.g., recombinant Bone morphogenetic proteins (BMPs) have been used in concentrations overshooting physiologically occurring concentrations and has thus raised concerns as documented side effects were recorded. Secondly, most such biomolecules are very sensitive to organic solvents and this hinders their use. Here, we present a novel xeno-hybrid bone graft, SmartBonePep^®, with a new type of biomolecule (i.e., intrinsically disordered proteins, IDPs) that is both resistant to processing with organic solvent and both triggers bone cells proliferation and differentiation. SmartBonePep^® is an advanced and improved modification of SmartBone^®, which is a bone substitute produced by combining naturally-derived mineral bone structures with resorbable polymers and collagen fragments. Not only have we demonstrated that Intrinsically Disordered Proteins (IDPs) can be successfully and safely loaded onto a SmartBonePep^®, withstanding the hefty manufacturing processes, but also made them bioavailable in a tuneable manner and proved that these biomolecules are a robust and resilient biomolecule family, being a better candidate with respect to other biomolecules for effectively producing the next generation bone grafts. Most other biomolecules which enhances bone formation, e.g., BMP, would not have tolerated the organic solvent used to produce SmartBonePep^®. Full article

(This article belongs to the Special Issue Latest Clinical And Basic Science Advances In Bone Regeneration)

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18 pages, 4453 KiB

Open AccessArticle

Stimulation of Human Osteoblast Differentiation in Magneto-Mechanically Actuated Ferromagnetic Fiber Networks

by Galit Katarivas Levy, Mark A. Birch, Roger A. Brooks, Suresh Neelakantan and Athina E. Markaki

J. Clin. Med. 2019, 8(10), 1522; https://doi.org/10.3390/jcm8101522 - 22 Sep 2019

Cited by 11 | Viewed by 4041

Abstract

There is currently an interest in “active” implantable biomedical devices that include mechanical stimulation as an integral part of their design. This paper reports the experimental use of a porous scaffold made of interconnected networks of slender ferromagnetic fibers that can be actuated in vivo by an external magnetic field applying strains to in-growing cells. Such scaffolds have been previously characterized in terms of their mechanical and cellular responses. In this study, it is shown that the shape changes induced in the scaffolds can be used to promote osteogenesis in vitro. In particular, immunofluorescence, gene and protein analyses reveal that the actuated networks exhibit higher mineralization and extracellular matrix production, and express higher levels of osteocalcin, alkaline phosphatase, collagen type 1α1, runt-related transcription factor 2 and bone morphogenetic protein 2 than the static controls at the 3-week time point. The results suggest that the cells filling the inter-fiber spaces are able to sense and react to the magneto-mechanically induced strains facilitating osteogenic differentiation and maturation. This work provides evidence in support of using this approach to stimulate bone ingrowth around a device implanted in bone and can pave the way for further applications in bone tissue engineering. Full article

(This article belongs to the Special Issue Latest Clinical And Basic Science Advances In Bone Regeneration)

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