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Review

Liposomes for Intra-Articular Analgesic Drug Delivery in Orthopedics: State-of-Art and Future Perspectives. Insights from a Systematic Mini-Review of the Literature

by
Lucio Cipollaro
1,2,
Paolo Trucillo
3,4,
Nicola Luigi Bragazzi
5,6,
Giovanna Della Porta
2,3,
Ernesto Reverchon
3 and
Nicola Maffulli
1,2,7,8,*
1
Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via San Leonardo 1, 84131 Salerno, Italy
2
Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy
3
Department of Industrial Engineering, University of Salerno, Via Giovanni Paolo II, 84084 Salerno, Italy
4
Department of Chemical, Material and Industrial Production Engineering, University of Naples Federico II, Piazzale V. Tecchio, 80-80125 Napoli, Italy
5
Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada
6
Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, 16132 Genoa, Italy
7
Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital, Queen Mary University of London, 275 Bancroft Road, London E1 4DG, UK
8
School of Pharmacy and Bioengineering, Guy Hilton Research Centre, Keele University School of Medicine, Thornburrow Drive, Stoke on Trent ST4 7QB, UK
*
Author to whom correspondence should be addressed.
Medicina 2020, 56(9), 423; https://doi.org/10.3390/medicina56090423
Submission received: 10 June 2020 / Revised: 6 August 2020 / Accepted: 17 August 2020 / Published: 20 August 2020
(This article belongs to the Special Issue Nano-Biosciences in the Field of Health-Care)
Browse Figure
Versions Notes

Abstract

:
Background and objectives: Liposomal structures are artificial vesicles composed of one or several lamellae of phospholipids which surround an inner aqueous core. Given the amphoteric nature of phospholipids, liposomes are promising systems for drug delivery. The present review provides an updated synthesis of the main techniques for the production of liposomes for orthopedic applications, focusing on the drawbacks of the conventional methods and on the advantages of high pressure techniques. Materials and Methods: Articles published in any language were systematically retrieved from two major electronic scholarly databases (PubMed/MEDLINE and Scopus) up to March 2020. Nine articles were retained based on the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines. Results: Liposome vesicles decrease the rate of inflammatory reactions after local injections, and significantly enhance the clinical effectiveness of anti-inflammatory agents providing controlled drug release, reducing toxic side effects. Conclusions: This review presents an update on the improvement in musculoskeletal ailments using liposome treatment.

1. Introduction

Liposomal structures are artificial devices characterized by one or several lamellae of phospholipids which surround an inner aqueous core and form vesicles. Given the amphoteric nature of phospholipids, liposomes are promising systems for drug delivery [1].
Since their discovery by Dr. Alec Bangham over 40 years ago, liposomes have garnered considerable scholarly interest, and have been the topic of an extensive body of literature as drug delivery systems of bio-active molecules [2]. The original production of simple unilamellar vesicles resulted in low stability and easy early degradation immediately after exposure to heat. Second-generation liposomes were fabricated by coating the external lipidic surface using polyethylene glycol (PEG) [3]. PEG-based coating avoided degradation bio-processes, including phagocytosis induced by activation of the reticulo-endothelial system (RES), and, therefore, enabled to extend liposomes half-life.
Moreover, the possibility of delivering loaded drugs to specific, selected target sites thanks to the creation of biochemical bonds among lipids and antibodies fragments or ligands contributed to raise the interest of the scientific community on liposomes [4] for their applications to human health and diseases [5].
The properties of liposomes are affected by a range of parameters, including surface charge, lipid composition, mean size, and the technique of formulation [6]. Hydrophilic compounds and lipophilic therapeutics can be incorporated within the inner aqueous compartment and in the lipidic double layer. The latter is optimal for drug delivery to the human body tissues and cells, given its similarity with biological components [7]. Various approaches and technologies can be used for the preparation, leading to liposomes ranging between 50 nm and 100 μm, based on the chosen production method[7], lipid composition, post-production step, filtration strategy, and number of lipid bilayers produced around water droplets, among others [7,8].
Most conventional techniques to fabricate liposomes are thin layer hydration method (or Bangham method), the extrusion method, microfluidic channel, and ethanol injection; they are largely used for several commercial application.
For example, the microfluidic channel-based technique enables to produce homogeneous liposomes, given that the manufacturing of the channels size and shape of microsomes can be varied by varying flow rate and dilution in a microfluidic device. However, some authors described that some of these techniques have low replicability, low rate of encapsulation efficiency of the entrapped/loaded bio-compounds and high solvent residue in the final product [9]. For instance, in the microfluidic channel, the ethanol and the water phases are mixed together, and it is then quite difficult to remove the solvent from the solution.
For these reasons, several non-conventional, high pressure assisted processes have been devised to tackle these issues, including the “Depressurization of an Expanded Liquid Organic Solution” (DELOS), the “Supercritical Reverse Phase Evaporation” (scRPE), and the “Supercritical AntiSolvent” (SAS) production methods [10].
Despite these new technologies, there are still problems of high solvent residue, and encapsulation efficiencies are lower than 60% [11]. Therefore, a novel “supercritical assisted process” termed SuperLip (Supercritical assisted Liposome formation) has been recently designed and implemented to produce one-shot replicable vesicles at the nanometric level [12,13].
Liposomes have been largely employed in various fields, such as biomedical, pharmacological, and cosmetic ones. In particular, liposomes have been deployed to deliver chemotherapeutics to carcinogenic cells [14], cell signaling [15], vaccines to confer immunity [16], radiopharmaceuticals to improve and enhance diagnostic imaging [17], and gene therapy [18]. Several clinical trials have focused on liposomes, mostly for cancer and immunology applications [19,20].
This review will focus on the use of liposomes in the orthopedic field and in particular on a specific use as liposomes for “Intra-Articular Analgesic Drug Delivery”, as this is the only application actually present on the market.
A general description of the technologies for liposome design and fabrication will be also discussed. focusing on the applications in the orthopedic field. However, molecules presently employed for the treatment of musculoskeletal illnesses are encapsulated into liposomes only using Bangham method, which causes massive drug loss resulting in increased costs.
For this reason, a more successful process is needed to enhance drug loading for this application.

2. Materials and Methods

The article selection procedure was designed, carried out and reported adhering to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines [21].
A systematic search up to March 2020 was performed in PubMed/MEDLINE and Scopus scholarly databases evaluating the different applications of liposome formulations in the orthopedic field, with no language filter nor restriction in terms of the publication year.
We utilized the terms “liposome”, “musculoskeletal”, “orthopaedic”, “orthopedic”, “orthopaedics” and “orthopedics” (as different possible spelling variants) variously combined as key terms.
Articles designed as clinical case series or case reports, editorials, letters to the editor, brief reports, technical notes, commentaries, expert opinions, in vitro and animal studies, review articles (narrative and systematic) were excluded, even though the reference lists of the latter articles were scanned by hand to increase the chance to include all relevant articles.
An orthopedic resident (LC) carried out the literature search and assessed the studies aided by a PhD student and chemical engineer (PT). Three independent researchers (NLB, GDP and NM) with expertise in the field of systematic reviews solved doubtful cases. Initially, the examiner read the title and abstracts of all the articles, and, based on pre-determined inclusion/exclusion criteria, selected the relevant ones, and then compared the results with the findings obtained by the other examiner. The extent of agreement was assessed by means of the kappa statistics.
After initial familiarization, the same studies were read again two weeks later, to reach the consensus of the authors involved in the process of selection. No disagreements were observed among the investigators. Subsequently, the reviewers abstracted relevant information from the full-text articles to an ad hoc Excel structured spreadsheets to analyze each investigation. Possible discrepancies were discussed until they were solved.

3. Results

3.1. Analysis of Results

The initial literature search identified 273 records; with the exclusion of duplicates, 268 items were selected. The first inspection of the title and/or abstracts led to the exclusion of 159 articles. A further screening excluded 100 articles. A pool of 9 articles was retained and was selected for results synthesis and discussion (Figure 1).
The scholarly interest towards liposomes in the field of orthopedics has increased over time [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69]. Table 1 summarizes the major characteristics of the studies included in the present systematic review.

3.2. Technologies for Liposome Design and Fabrication

Lipid nanocarriers can be used as smart nanomedicines able to provide site-specific targeting and delivery [22,23]. Nanomedicines are already present on the market [24], and represent a new frontier in modern therapeutics and clinical practice. This scenario is a solid evidence of the feasibility of suitable polymeric and/or lipid-based nanocarriers for the efficacious encapsulation and delivery of several drugs. The achievement of targeted drug delivery with high encapsulation efficiency and high cellular uptake of liposomes can be guaranteed only if the fabrication technique is solvent-free and has a 1-shot continuous configuration.
In the last few decades, several conventional and non-conventional techniques have been proposed in the literature [25] (Table 2, Table 3 and Table 4). A large number of clinical trials have used liposome formulations, mostly for cancer treatment (see Table 4). Most of these formulations have been also commercialized, after approval by the Food & Drug Administration (FDA) [19].
Recently, Supercritical assisted Liposome formation (SuperLip) technology-based approach using different compositions has been proposed to produce liposomes at namometric level, with potential applications in various industrial fields, such as the pharmacological, cosmetic and nutraceutical ones [15,38]. This technology allowed to fabricate Single Unilamellar Vesicles (SUV) optimizing particle size and distributions (both at nanometric and micrometric level) with high encapsulation efficiency in both lipid and water phase [39].
To favor ethanol extraction from liposome suspension, SuperLip uses dCO2 to improve lipid/ethanol/water mixing. Recently, phosphatidyl-choline (PC) small unilamellar vesicles with an average size of 0.2 ± 0.05 μm of were loaded with Fluorescein Iso-ThioCyanate (FITC), using a lipid concentration of at 8 μg/mgPC. Liposomes loaded bioavailability was monitored by incubation with human monocytes isolated from the blood of healthy donors’ by flow cytometer assay, which represents the only cell population that could properly internalize the carriers. An internalization of 96.1 ± 21% was obtained, at a dosage of 0.1 mg/mL for SuperLip fabricated nanocarriers, with a monocytes viability of almost 100% at all the concentrations studied after vesicles internalization. This result suggested the reliability of the dCO2 technologies, opening perspectives for future drug loading [40].

3.3. Liposomes for Intra-Articular (IA) Injections

The major obstacle for drug transport out of the joint space is represented by the synovium. In the joint cavity, molecules of soluble drugs released from the immobilized depot undergo various distribution processes and reactions [41]. For the transport of small molecules, the extra-cellular matrix is the main diffusional barrier, whereas the endothelium represents the major barrier for the diffusion and transport of proteins [41]. Therefore, the drug formulation sizes and their passage through the articulation determine their reliability for cellular uptake and tissue penetration.
That is why the dimension of the formulation is a key point in intra-articular (IA) drug delivery. Hence, IA injection of active molecules could be ineffective without the use of a drug carrier, since small molecules are rapidly cleared from these tissues. Native drugs are cleared from the joint space just in a couple of hours through lymphatic drainage [42]. For instance, the half-lives of methotrexate, ibuprofen and diclofenac are 0.59–2.9, 1.9 and 5.2 h, respectively [41]. IA drug delivery systems are expected to solve the issue of the low persistence times because of the quick uptake of the drugs injected within the synovial cavity, which determines adverse side effects and low bioavailability. Considering their structure, liposomes provide controlled drug release [43]. There are still no studies on human patients that demonstrate the efficacy of IA liposome treatment, but several studies on animal models have produced encouraging results [42,44,45,46,47]. Liposome vesicles reduce the incidence of inflammatory reactions after local injections compared to crystalline drug suspensions [48].
Furthermore, the IA delivery of several non steroidal anti-inflammatory drugs could avoid the risk of gastric side effects and cardiovascular problems intrinsic with their systemic administration [10].

3.4. Liposomes in Postsurgical Analgesia

Orthopedic surgery is frequently associated to remarkable postoperative pain [49], which may continue for 2 years or even longer [50]. About 50% of the patients who undergo joint arthroplasty experience intense postsurgical pain [51]. Inappropriate postsurgical pain management may cause development of chronic pain, thromboembolic or pulmonary complications, and decrease in health-related quality of life [52]. In orthopedic surgery patients, the inability to effectively control postsurgical pain has been associated with reduced capacity for exercise, delayed time to ambulation, and increased hospital length of stay [53,54]. A prolonged-release injectable liposomal formulation of bupivacaine, a local anesthetic, is available (Exparel®; Pacira Pharmaceuticals, Inc., Parsippany, NJ, USA) and can be injected at the surgical site to produce postsurgical analgesia [55,56].
The mechanism of action of Exparel is similar to that of marcaine and other local anesthetics, but its pharmaco-kinetic profile is unique [55]. With multiple aqueous chambers, Exparel is a multivesicular formulation enabling prolonged release and rapid absorption of bupivacaine when injected locally. To produce long-lasting effects, Exparel has a bimodal pharmacokinetic profile: after administration at the surgical site, bupivacaine diffuses slowly out of the chambers, with an initial peak in plasma concentration within the first hour after injection, and a second peak 12 to 36 h later [55]. Compared to placebo and bupivacaine hydrochloride (HCL), a single administration of liposome bupivacaine provided postsurgical analgesia for up to 72 h, reduced postsurgical opioid consumption, and delayed the use of rescue medication [57]. Liposome bupivacaine did not reduce postoperative pain when compared to other local anesthetics at 24 or 48 h after surgery [58], and did not reduce postoperative opioid uptake at different time-points (namely, at 24, 48, and 72 h) [59,60,61]. Liposome bupivacaine does not exhibit an analgesic advantage when compared to plain local anesthetics for patients undergoing surgical procedures. Premkumar et al. [62] evaluated whether the use of liposomal bupivacaine after anterior cruciate ligament (ACL) reconstruction would decrease opioid use and pain when compared with the same volume of 0.25% bupivacaine HCl. There were no significant differences in postoperative opioid use and postsurgical pain comparing patients receiving liposomal bupivacaine with those receiving 0.25% bupivacaine HCl [62]. Schroer et al [63], instead of standard bupivacaine in periarticular injections (PAI), used liposomal bupivacaine as part of a multimodal pain management, and did not evidence significant benefit after primary total knee arthroplasty (TKA). No significant differences in pain scores were found, as well as no differences in narcotic use during hospitalization, with no variations in hospital length of stay. Similar findings have been reported by Bagsby et al. [64]: in 150 patients, they found less pain relief in periarticular injection of liposomal bupivacaine compared to a combination of ropivacaine, epinephrine and morphine. The authors explained the unsatisfactory outcomes of the liposomal bupivacaine by the slow release of the drug from the liposomal structures, limiting the availability of free bupivacaine at the site of action [63,64].
Webb et al. [65], differently, found that after a TKA, healthier patients and those with a BMI <40 had a shorter hospital stay and used fewer narcotics with the use of liposomal bupivacaine. The same results were achieved by Mont et al [66], who in 140 patients showed reduced postsurgical pain, and decreased opioid uptake, and increased time to first opioid rescue after a TKA. Bramlett et al. [61] investigated 138 TKA patients comparing the effectiveness, safety profile, and pharmacokinetics of liposome bupivacaine with 150 mg of bupivacaine hydrochloride. Liposome bupivacaine was associated with statistically significantly greater analgesia while patients were at rest after surgery compared with bupivacaine hydrochloride. Alter et al. [55] compared the effect of Marcaine and Exparel in patients with distal radius fractures. Patients who received Exparel experienced less pain on the day of surgery but no difference in the following 5 days; they also consumed fewer opioids on the day of surgery, with no difference in the following days. An interesting effect noted comparing local anesthetics with liposome bupivacaine was the reduction of postoperative nausea [67]. The mechanism responsible for the antiemetic effect of liposome bupivacaine remains to be determined, but the reduction of postoperative nausea is an important goal in peri-operative patients [68]. In the largest case-control study to date, Barrington et al. [69] performed more than 2000 hip and knee joint arthroplasties adopting a standard multimodal pain care protocol with a periarticular injection, or a protocol including a periarticular injection of liposomal bupivacaine. In patients managed with liposomal bupivacaine, visual analog scale pain scores were found to be lower in a statistically significant fashion for both hip (1.67 versus 2.30; p < 0.0001) and knee (2.21 versus 2.52; p < 0.0001) procedures. Furthermore, the number of pain-free patients increased and the overall costs decreased [69].

3.5. Liposomes Can Help Prevent Orthopedic Device-Associated Osteomyelitis

Osteomyelitis, caused by bacteria contamination at the time of surgery, systemic transmission, direct colonization, or orthopedic device implantation, remains a major challenge for orthopedic surgeons [70]. Post-arthroplasty infection still occurs in 1.2% of primary arthroplasties and 3–5% of revisions, despite antibiotics being commonly used for prophylaxis [71]. These complications often result in significantly worse patients outcomes.
Liu et al. [72] tried to devise a technique to counteract osteomyelitis associated with orthopedic arthroplasty. They successfully developed a novel alendronate-based binding liposome formulation to prevent orthopedic implant associated osteomyelitis. The alendronate-based binding portion was conjugated to cholesterol, demonstrating fast and strong binding capability to a model implant surface. The biomineral-binding liposome formulation added with oxacillin reliably prevented bacterial colonization compared to controls when challenged with a Staphylococcus aureus isolate [72].

3.6. Liposomes in Hirudo Therapy for OA

Non steroidal anti-inflammatory drugs are commonly used to relieve pain associated with osteoarthritis (OA). However, the incidence of adverse effects is high. Thus, researchers have attempted to use organic products, such as leech saliva, to achieve safe and alternative painkillers. The process of blood-letting and purification, in medicine practices like Leech therapy (LT) or Hirudotherapy, relieves a variety of chronic diseases such as blood disorders, gout, and skin disorders [73,74]. Introduced by the FDA, leech is a modern therapeutic agent and it contains different peptides and proteins such as histamine, steroid hormones and modulators, serotonin, enzymes, anti-microbial agent, and protease inhibitors. These substances exhibit analgesic, anti-inflammatory, thrombolytic, vasodilation, and anticoagulation effects, which improve blood circulation and relieve several ailments [75]. Leech saliva may block the cascade involved in certain steps of the modulation and regulation of pain via cytokines hindering from the anti-inflammatory agents present in the saliva [76].
Shakouri et al. [77] extracted the saliva of medical leech, and a nano liposomes-based gel was used to formulate the supplement to enhance skin absorption. Pain was relieved up to 50% after one month of administration of leech saliva liposomal gel. Also, given the reduction in stiffness and joint inflammation, the patients quality of life was enhanced (p < 0.001) and the range of motion was increased.

4. Discussion

Orthopedic surgery procedure can induce severe post-operative pain [78]. The general principle, common to all disciplines (not only the surgical ones), at the basis of the prevention and management of postoperative pain is represented by the combination of multiple techniques and therapeutic agents, which act at every level of the pain conduction pathways [79,80,81,82]. Enhancing the effect of these analgesic techniques and reducing the dose of drugs to be administered, consequently reducing adverse effects, are the main objectives of research in this area.
In this context, the development of long-lasting anesthetic or pain-relieving formulations are increasingly being used in clinical practice [83,84,85]. Liposomal formulations, which allow the encapsulation of pharmaceutical agents, prolong the residence time at their site of action [58]. However, the scholarly literature on the therapeutic superiority of liposomal formulations compared to standard analgesic formulations is conflicting [58]. Further studies should focus on what the optimal drug dose should be, in relation to the different types of surgery and the potential adverse effects of the drug. In terms of clinical practice and implications, the use of liposomal formulations is not yet widespread, and therefore developing research and studies on these formulations would be of paramount importance.
Liposomes are potentially highly efficient drug delivery systems, especially for biomedical and orthopedic applications. Liposomes exhibit high cell penetration and efficacy, particularly if they are produced at the nanometric level, using novel techniques and approaches such as the SuperLip technology. Liposomes loaded with molecules for OA treatment showed an enhanced half-life and provided controlled drug release, reducing toxic side effects. The major benefit of these formulations is the possibility to provide a delayed and controlled drug release, thus resulting in a substantial reduction in the number of administration procedures. Indeed, the main reason why liposomal formulation-based bupivacaine has not been widely adopted is its cost. At US$ 283.00 per 20 mL, it is significantly more expensive than 20 mL of 0.5% bupivacaine HCl: a 30 mL vial costs, indeed, US$ 1.24. For this reason, the higher costs of liposomal products should be compensated by greater efforts to reduce manufacturing cost. This is not particularly simple, since it depends also on the drug synthesis, production line, purification and quality control post-processing steps.
The current literature evidenced improved outcomes administrating liposomal formulations. Further statistically robust evidence of reasonable costs is warranted to draw solid and robust conclusions concerning the benefits of this approach. The relationship between cost and benefits not only arises from the price of the medication but also from other factors such as the use of pain pumps and opioids, operative time, hospitalization time, and readmissions. Even though the cost of liposomal bupivacaine is clearly higher than that of bupivacaine hydrochloride, information extrapolated from a retrospective study showed a clear reduction in hospitalization costs compared with standard care [78,79]. Very interesting indications are provided by a case-control study of more than 2000 joint arthroplasties conducted adopting a classical multimodal pain care protocol with periarticular injection versus targeted delivery of liposomal bupivacaine. This study showed a significant improvement in pain outcomes and a mean decrease in hospital overall direct cost of US$1,246 per patient using liposomal bupivacaine [69].
For this reason, liposomes appear promising drug delivery systems for orthopedic applications.

5. Conclusions

Liposomes are potentially highly efficient drug delivery systems, especially if they are produced at the nanometric level, using advanced and sophisticated techniques and approaches such as the SuperLip technology. Liposomes loaded with molecules for osteoarthritis (OA) treatment showed an enhanced half-life and provided controlled drug release, reducing toxic side effects and exhibiting cost-effectiveness. As such, liposomes could be powerful and cheaper drug delivery systems for orthopedic and, in general, biomedical application.

Author Contributions

Conceptualization, L.C., P.T., G.D.P., E.R. and N.M.; methodology, L.C., P.T., N.L.B., G.D.P., E.R. and N.M; validation, L.C. and N.M.; software, L.C., N.L.B., G.D.P. and N.M; validation, N.M.; formal analysis, L.C., N.L.B., G.D.P. and N.M.; investigation, L.C., P.T., G.D.P., E.R. and N.M.; resources, L.C., P.T., G.D.P., E.R. and N.M.; data curation, L.C., N.L.B., G.D.P. and N.M.; writing—original draft preparation, L.C., P.T., G.D.P., E.R. and N.M.; writing—review and editing, L.C., P.T., N.L.B., G.D.P., E.R. and M.M.; visualization, L.C. and N.M.; supervision, N.M.; project administration, G.D.P. and N.M.; funding acquisition, N.L.B., G.D.P. and N.M. All authors have read and agree to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

Professor Nicola Maffulli is supported by the UNISA-FARB 2019 “Assessment of cartilage regenerative capacity of infiltrations with hyaluronic acid loaded with liposomes containing ascorbic acid and/or thyroid hormone” for the years 2019-22. This study was partially funded by the American Orthopedic Foot & Ankle Society (AOFAS) Research Committee, Grant ID#: 2019-133-S, Grant Project Title: Nano-FT3C+: An Innovative Liposome-Based Formulation for Thyroid Hormone Controlled Delivery. An In Vitro Study on Tendinopathic Human Achilles Tendon Tenocytes”. Project responsible: Prof. Maffulli Nicola, Della Porta Giovanna.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

RES: Reticulo-Endothelial System, PEG: polyethylene glycol, scRPE: Supercritical Reverse Phase Evaporation, SAS: Supercritical Anti-Solvent, DELOS: Depressurization of an Expanded Liquid Organic Solution, DESAM: Depressurization of an Expanded Solution into Aqueous Media, SuperLip: Supercritical assisted Liposome formation, PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses, FDA: Food and Drug Administration, SUV: Single Unilamellar Vesicles; FITC: Fluorescein Iso-ThioCyanate; IA: Intra-Articular; PC: Phosphatidyl-Choline.

References

  1. Allen, T.M.; Cullis, P.R. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev. 2013, 65, 36–48. [Google Scholar] [CrossRef] [PubMed]
  2. Bangham, A.; Standish, M.; Watkins, J. Diffusion of univalent ions across the lamellae of swollen phospholipids. J. Mol. Biol. 1965, 13, 238–252. [Google Scholar] [CrossRef]
  3. Immordino, M.L.; Dosio, F.; Cattel, L. Stealth liposomes: Review of the basic science, rationale, and clinical applications, existing and potential. Int. J. Nanomed. 2006, 1, 297–315. [Google Scholar]
  4. Goulart, L.R.; Dantas, N.; Silva, A.; Madurro, J.M.; Brito-Madurro, A.G.; Ueira-Vieira, C.; Fujimura, P.; Maia, Y.; Santos, P.S.; Freschi, A.P.; et al. Frontiers of biology in human diseases: Strategies for biomolecule’s discovery, nanobiotechnologies and biophotonics. BMC Proc. 2014, 8 (Suppl. 4). [Google Scholar] [CrossRef] [Green Version]
  5. Sahoo, S.K.; Parveen, S.; Panda, J. The present and future of nanotechnology in human health care. Nanomed. Nanotechnol. Biol. Med. 2007, 3, 20–31. [Google Scholar] [CrossRef] [PubMed]
  6. Kalaycioglu, G.D.; Aydogan, N. Preparation and investigation of solid lipid nanoparticles for drug delivery. Colloids Surf. Physicochem. Eng. Asp. 2016, 510, 77–86. [Google Scholar] [CrossRef]
  7. Trucillo, P.; Campardelli, R.; Reverchon, E. Supercritical CO 2 assisted liposomes formation: Optimization of the lipidic layer for an efficient hydrophilic drug loading. J. CO2 Util. 2017, 18, 181–188. [Google Scholar] [CrossRef]
  8. Campardelli, R.; Santo, I.E.; Cabral-Albuquerque, E.C.; De Melo, S.A.B.V.; Della Porta, G.; Reverchon, E. Efficient encapsulation of proteins in submicro liposomes using a supercritical fluid assisted continuous process. J. Supercrit. Fluids 2016, 107, 163–169. [Google Scholar] [CrossRef]
  9. Situ, W.; Song, X.; Luo, S.; Liang, Y. A nano-delivery system for bioactive ingredients using supercritical carbon dioxide and its release behaviors. Food Chem. 2017, 228, 219–225. [Google Scholar] [CrossRef]
  10. Patil, Y.P.; Jadhav, S. Novel methods for liposome preparation. Chem. Phys. Lipids 2014, 177, 8–18. [Google Scholar] [CrossRef]
  11. Mozafari, M.R. Liposomes: An overview of manufacturing techniques. Cell. Mol. Biol. Lett. 2005, 10, 711–719. [Google Scholar] [PubMed]
  12. Trucillo, P.; Campardelli, R.; Reverchon, E. A versatile supercritical assisted process for the one-shot production of liposomes. J. Supercrit. Fluids 2019, 146, 136–143. [Google Scholar] [CrossRef]
  13. Trucillo, P.; Campardelli, R.; Scognamiglio, M.; Reverchon, E. Control of liposomes diameter at micrometric and nanometric level using a supercritical assisted technique. J. CO2 Util. 2019, 32, 119–127. [Google Scholar] [CrossRef]
  14. Harrington, K.; Syrigos, K.; Vile, R.G. Liposomally targeted cytotoxic drugs for the treatment of cancer. J. Pharm. Pharmacol. 2002, 54, 1573–1600. [Google Scholar] [CrossRef]
  15. Lonez, C.; Vandenbranden, M.; Ruysschaert, J.-M. Cationic lipids activate intracellular signaling pathways. Adv. Drug Deliv. Rev. 2012, 64, 1749–1758. [Google Scholar] [CrossRef]
  16. Huang, W.-C.; Deng, B.; Lin, C.; Carter, K.A.; Geng, J.; Razi, A.; He, X.; Chitgupi, U.; Federizon, J.; Sun, B.; et al. A malaria vaccine adjuvant based on recombinant antigen binding to liposomes. Nat. Nanotechnol. 2018, 13, 1174–1181. [Google Scholar]
  17. Dearling, J.L.; Packard, A.B. Molecular imaging in nanomedicine – A developmental tool and a clinical necessity. J. Control. Release 2017, 261, 23–30. [Google Scholar] [CrossRef]
  18. De Lima, M.C.P.; Neves, S.; Filipe, A.; Duzgunes, N.; Simões, S. Cationic liposomes for gene delivery: From biophysics to biological applications. Curr. Med. Chem. 2003, 10, 1221–1231. [Google Scholar] [CrossRef]
  19. Slingerland, M.; Guchelaar, H.-J.; Gelderblom, H. Liposomal drug formulations in cancer therapy: 15 years along the road. Drug Discov. Today 2012, 17, 160–166. [Google Scholar] [CrossRef]
  20. Hoven, J.M.V.D.; Van Tomme, S.R.; Metselaar, J.M.; Nuijen, B.; Beijnen, J.H.; Storm, G. Liposomal Drug Formulations in the Treatment of Rheumatoid Arthritis. Mol. Pharm. 2011, 8, 1002–1015. [Google Scholar] [CrossRef]
  21. Knobloch, K.; Yoon, U.; Vogt, P.M. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication bias. J. Cranio Maxillofac. Surg. 2011, 39, 91–92. [Google Scholar] [CrossRef] [PubMed]
  22. Paolino, D.; Cosco, D.; Gaspari, M.; Celano, M.; Wolfram, J.; Voce, P.; Puxeddu, E.; Filetti, S.; Celia, C.; Ferrari, M.; et al. Targeting the thyroid gland with thyroid-stimulating hormone (TSH)-nanoliposomes. Biomaterials 2014, 35, 7101–7109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Celia, C.; Ferrati, S.; Bansal, S.; Van De Ven, A.L.; Ruozi, B.; Zabre, E.; Hosali, S.; Paolino, D.; Sarpietro, M.G.; Fine, D.; et al. Sustained zero-order release of intact ultra-stable drug-loaded liposomes from an implantable nanochannel delivery system. Adv. Health Mater. 2013, 3, 230–238. [Google Scholar] [CrossRef] [PubMed]
  24. Pasut, G.; Paolino, D.; Celia, C.; Mero, A.; Joseph, A.S.; Wolfram, J.; Cosco, D.; Schiavon, O.; Shen, H.; Fresta, M. Polyethylene glycol (PEG)-dendron phospholipids as innovative constructs for the preparation of super stealth liposomes for anticancer therapy. J. Control. Release 2015, 199, 106–113. [Google Scholar] [CrossRef] [PubMed]
  25. Wagner, A.; Uhl, K.; Katinger, H. Liposomes produced in a pilot scale: Production, purification and efficiency aspects. Eur. J. Pharm. Biopharm. 2002, 54, 213–219. [Google Scholar] [CrossRef]
  26. Bangham, A.D.; Hill, M.W.; Miller, N.G.A. Preparation and Use of Liposomes as Models of Biological Membranes. In Methods in Membrane Biology; Korn, E.D., Ed.; Springer: Boston, MA, USA, 1974; Volume 1, pp. 1–68. [Google Scholar] [CrossRef]
  27. Mui, B.; Chow, L.; Hope, M.J. Extrusion Technique to Generate Liposomes of Defined Size. Methods Enzymol. 2003, 367, 3–14. [Google Scholar]
  28. Andar, A.; Hood, R.R.; Vreeland, W.N.; DeVoe, D.L.; Swaan, P.W. Microfluidic Preparation of Liposomes to Determine Particle Size Influence on Cellular Uptake Mechanisms. Pharm. Res. 2013, 31, 401–413. [Google Scholar] [CrossRef]
  29. Charcosset, C.; Juban, A.; Valour, J.-P.; Urbaniak, S.; Fessi, H. Preparation of liposomes at large scale using the ethanol injection method: Effect of scale-up and injection devices. Chem. Eng. Res. Des. 2015, 94, 508–515. [Google Scholar] [CrossRef]
  30. Otake, K.; Shimomura, T.; Goto, T.; Imura, T.; Furuya, T.; Yoda, S.; Takebayashi, Y.; Sakai, H.; Abe, M. Preparation of Liposomes Using an Improved Supercritical Reverse Phase Evaporation Method. Langmuir 2006, 22, 2543–2550. [Google Scholar] [CrossRef]
  31. Meure, L.A.; Knott, R.; Foster, N.R.; Dehghani, F. The Depressurization of an Expanded Solution into Aqueous Media for the Bulk Production of Liposomes. Langmuir 2009, 25, 326–337. [Google Scholar] [CrossRef]
  32. Zhao, L.; Temelli, F. Preparation of liposomes using a modified supercritical process via depressurization of liquid phase. J. Supercrit. Fluids 2015, 100, 110–120. [Google Scholar] [CrossRef]
  33. Lesoin, L.; Crampon, C.; Boutin, O.; Badens, E. Preparation of liposomes using the supercritical anti-solvent (SAS) process and comparison with a conventional method. J. Supercrit. Fluids 2011, 57, 162–174. [Google Scholar] [CrossRef]
  34. Gabizon, A.; Shmeeda, H.; Barenholz, Y. Pharmacokinetics of Pegylated Liposomal Doxorubicin. Clin. Pharmacokinet. 2003, 42, 419–436. [Google Scholar] [CrossRef] [PubMed]
  35. Rivankar, S. An overview of doxorubicin formulations in cancer therapy. J. Cancer Res. Ther. 2014, 10, 853. [Google Scholar] [CrossRef] [PubMed]
  36. Petre, C.E.; Dittmer, D.P. Liposomal daunorubicin as treatment for Kaposi’s sarcoma. Int. J. Nanomed. 2007, 2, 277–288. [Google Scholar]
  37. Bomgaars, L.R.; Geyer, J.; Franklin, J.; Dahl, G.; Park, J.; Winick, N.; Klenke, R.; Berg, S.L.; Blaney, S.M. Phase I Trial of Intrathecal Liposomal Cytarabine in Children with Neoplastic Meningitis. J. Clin. Oncol. 2004, 22, 3916–3921. [Google Scholar] [CrossRef] [PubMed]
  38. Della Porta, G.; Ciardulli, M.C.; Maffulli, N. Microcapsule Technology for Controlled Growth Factor Release in Musculoskeletal Tissue Engineering. Sports Med. Arthrosc. Rev. 2018, 26, e2–e9. [Google Scholar] [CrossRef]
  39. Santo, I.E.; Campardelli, R.; Cabral-Albuquerque, E.C.; De Melo, S.A.B.V.; Della Porta, G.; Reverchon, E. Liposomes preparation using a supercritical fluid assisted continuous process. Chem. Eng. J. 2014, 249, 153–159. [Google Scholar] [CrossRef]
  40. Ciaglia, E.; Montella, F.; Trucillo, P.; Ciardulli, M.; Di Pietro, P.; Amodio, G.; Remondelli, P.; Vecchione, C.; Reverchon, E.; Maffulli, N.; et al. A bioavailability study on microbeads and nanoliposomes fabricated by dense carbon dioxide technologies using human-primary monocytes and flow cytometry assay. Int. J. Pharm. 2019, 570, 118686. [Google Scholar] [CrossRef]
  41. Larsen, C.; Østergaard, J.; Larsen, S.W.; Jensen, H.; Jacobsen, S.; Lindegaard, C.; Andersen, P.H. Intra-articular depot formulation principles: Role in the management of postoperative pain and arthritic disorders. J. Pharm. Sci. 2008, 97, 4622–4654. [Google Scholar] [CrossRef]
  42. Maudens, P.; Jordan, O.; Allémann, E. Recent advances in intra-articular drug delivery systems for osteoarthritis therapy. Drug Discov. Today 2018, 23, 1761–1775. [Google Scholar] [CrossRef] [PubMed]
  43. Akbarzadeh, A.; Rezaei-Sadabady, R.; Davaran, S.; Joo, S.W.; Zarghami, N.; Hanifehpour, Y.; Samiei, M.; Kouhi, M.; Nejati-Koshki, K. Liposome: Classification, preparation, and applications. Nanoscale Res. Lett. 2013, 8, 102. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Cho, H.; Stuart, J.M.; Magid, R.; Danila, D.C.; Hunsaker, T.; Pinkhassik, E.; Hasty, K.A. Theranostic immunoliposomes for osteoarthritis. Nanomed. Nanotechnol.Biol. Med. 2014, 10, 619–627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Vanniasinghe, A.S.; Bender, V.; Manolios, N. The Potential of Liposomal Drug Delivery for the Treatment of Inflammatory Arthritis. Semin. Arthritis Rheum. 2009, 39, 182–196. [Google Scholar] [CrossRef] [PubMed]
  46. Dong, J.; Jiang, D.; Wang, Z.; Wu, G.; Miao, L.; Huang, L. Intra-articular delivery of liposomal celecoxib–hyaluronate combination for the treatment of osteoarthritis in rabbit model. Int. J. Pharm. 2013, 441, 285–290. [Google Scholar] [CrossRef] [PubMed]
  47. Zhang, P.; Zhong, Z.-H.; Yu, H.-T.; Liu, B. Exogenous expression ofIL-1RaandTGF-β1promotes in vivo repair in experimental rabbit osteoarthritis. Scand. J. Rheumatol. 2015, 44, 404–411. [Google Scholar] [CrossRef]
  48. Bonanomi, M.H.; Velvart, M.; Stimpel, M.; Roos, K.M.; Fehr, K.; Weder, H.G. Studies of pharmacokinetics and therapeutic effects of glucocorticoids entrapped in liposomes after intraarticular application in healthy rabbits and in rabbits with antigen-induced arthritis. Rheumatol. Int. 1987, 7, 203–212. [Google Scholar] [CrossRef]
  49. Accreditata, X.C.N.S.S.I.C.O.D.P.; Cipollaro, L.; Aicale, R.; Maccauro, G.; Maffulli, N. Single- versus double-integrated screws in intramedullary nailing systems for surgical management of extracapsular hip fractures in the elderly: A systematic review. J. Biol. Regul. Homeost. Agents 2019, 33, 175–182. [Google Scholar]
  50. Hutchinson, H.L. Local infiltration of liposome bupivacaine in orthopedic trauma patients: Case-based reviews. Am. J. Orthop. 2014, 43, S13–S16. [Google Scholar]
  51. Nota, S.P.; Spit, S.A.; Voskuyl, T.; Bot, A.G.; Hageman, M.G.; Ring, D. Opioid Use, Satisfaction, and Pain Intensity After Orthopedic Surgery. Psychosomatics 2015, 56, 479–485. [Google Scholar] [CrossRef]
  52. Wu, C.L.; Naqibuddin, M.; Rowlingson, A.J.; Lietman, S.A.; Jermyn, R.M.; Fleisher, L.A. The Effect of Pain on Health-Related Quality of Life in the Immediate Postoperative Period. Anesth. Analg. 2003, 97, 1078–1085. [Google Scholar] [CrossRef] [PubMed]
  53. Capdevila, X.; Dadure, C.; Bringuier, S.; Bernard, N.; Biboulet, P.; Gaertner, E.; Macaire, P. Effect of Patient-controlled Perineural Analgesia on Rehabilitation and Pain after Ambulatory Orthopedic Surgery. Anesthesiology 2006, 105, 566–573. [Google Scholar] [CrossRef] [PubMed]
  54. Ranawat, A.S.; Ranawat, C.S. Pain Management and Accelerated Rehabilitation for Total Hip and Total Knee Arthroplasty. J. Arthroplast. 2007, 22, 12–15. [Google Scholar] [CrossRef] [PubMed]
  55. Alter, T.; Liss, F.E.; Ilyas, A.M. A Prospective Randomized Study Comparing Bupivacaine Hydrochloride Versus Bupivacaine Liposome for Pain Management After Distal Radius Fracture Repair Surgery. J. Hand Surg. 2017, 42, 1003–1008. [Google Scholar] [CrossRef] [PubMed]
  56. Burbridge, M.; Jaffe, R.A. Exparel: A New Local Anesthetic with Special Safety Concerns. Anesth. Analg. 2015, 121, 1113–1114. [Google Scholar] [CrossRef]
  57. Lonner, J.H.; Scuderi, G.R.; Lieberman, J.R. Potential utility of liposome bupivacaine in orthopedic surgery. Am. J. Orthop. 2015, 44, 111–117. [Google Scholar]
  58. Kendall, M.C.; Alves, L.J.C.; De Oliveira, G. Liposome Bupivacaine Compared to Plain Local Anesthetics to Reduce Postsurgical Pain: An Updated Meta-Analysis of Randomized Controlled Trials. Pain Res. Treat. 2018, 2018, 1–10. [Google Scholar] [CrossRef] [Green Version]
  59. Barrington, J.W.; Emerson, R.H.; Lovald, S.T.; Lombardi, A.V.; Berend, K.R. No Difference in Early Analgesia Between Liposomal Bupivacaine Injection and Intrathecal Morphine After TKA. Clin. Orthop. Relat. Res. 2016, 475, 94–105. [Google Scholar] [CrossRef] [Green Version]
  60. Amundson, A.W.; Johnson, R.L.; Abdel, M.P.; Mantilla, C.B.; Panchamia, J.K.; Taunton, M.J.; Kralovec, M.E.; Hebl, J.R.; Schroeder, D.R.; Pagnano, M.W.; et al. A Three-arm Randomized Clinical Trial Comparing Continuous Femoral Plus Single-injection Sciatic Peripheral Nerve Blocks versus Periarticular Injection with Ropivacaine or Liposomal Bupivacaine for Patients Undergoing Total Knee Arthroplasty. Anesthesiology 2017, 126, 1139–1150. [Google Scholar] [CrossRef]
  61. Bramlett, K.; Onel, E.; Viscusi, E.R.; Jones, K. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee 2012, 19, 530–536. [Google Scholar] [CrossRef]
  62. Premkumar, A.; Samady, H.; Slone, H.; Hash, R.; Karas, S.; Xerogeanes, J. Liposomal Bupivacaine for Pain Control After Anterior Cruciate Ligament Reconstruction. Am. J. Sports Med. 2016, 44, 1680–1686. [Google Scholar] [CrossRef] [PubMed]
  63. Schroer, W.C.; Diesfeld, P.G.; Lemarr, A.R.; Morton, D.J.; Reedy, M.E. Does Extended-Release Liposomal Bupivacaine Better Control Pain Than Bupivacaine After Total Knee Arthroplasty (TKA)? A Prospective, Randomized Clinical Trial. J. Arthroplast. 2015, 30, 64–67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Bagsby, D.T.; Ireland, P.H.; Meneghini, R.M. Liposomal Bupivacaine Versus Traditional Periarticular Injection for Pain Control After Total Knee Arthroplasty. J. Arthroplast. 2014, 29, 1687–1690. [Google Scholar] [CrossRef] [PubMed]
  65. Webb, B.T.; Spears, J.R.; Smith, L.S.; Malkani, A.L. Periarticular injection of liposomal bupivacaine in total knee arthroplasty. Arthroplast. Today 2015, 1, 117–120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Mont, M.A.; Beaver, W.B.; Dysart, S.H.; Barrington, J.W.; Del Gaizo, D.J. Local Infiltration Analgesia with Liposomal Bupivacaine Improves Pain Scores and Reduces Opioid Use After Total Knee Arthroplasty: Results of a Randomized Controlled Trial. J. Arthroplast. 2018, 33, 90–96. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Barrington, J.W. Opioid-Sparing Pain Control in Outpatient Total Joint Arthroplasty. Am. J. Orthop. 2016, 45, S2–S5. [Google Scholar]
  68. Tateosian, V.; Gan, T.J. Another quest for the holy grail of abolishing post operative nausea and vomiting. J. Clin. Anesthes. 2017, 41, 58–59. [Google Scholar] [CrossRef]
  69. Barrington, J.W.; Olugbode, O.; Lovald, S.T.; Ong, K.; Watson, H.; Emerson, R. Liposomal Bupivacaine: A Comparative Study of More Than 1000 Total Joint Arthroplasty Cases. Orthop. Clin. N. Am. 2015, 46, 469–477. [Google Scholar] [CrossRef]
  70. Calhoun, J.H.; Manring, M.; Shirtliff, M. Osteomyelitis of the Long Bones. Semin. Plast. Surg. 2009, 23, 59–72. [Google Scholar] [CrossRef] [Green Version]
  71. Lamagni, T. Epidemiology and burden of prosthetic joint infections. J. Antimicrob. Chemother. 2014, 69, i5–i10. [Google Scholar] [CrossRef] [Green Version]
  72. Liu, X.-M.; Zhang, Y.; Chen, F.; Khutsishvili, I.; Fehringer, E.V.; Marky, L.A.; Bayles, K.W.; Wang, D. Prevention of orthopedic device-associated osteomyelitis using oxacillin-containing biomineral-binding liposomes. Pharm. Res. 2012, 29, 3169–3179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Hildebrandt, J.-P.; Lemke, S. Small bite, large impact–saliva and salivary molecules in the medicinal leech, Hirudo medicinalis. Naturwissenschaften 2011, 98, 995–1008. [Google Scholar] [CrossRef] [PubMed]
  74. Koeppen, D.; Aurich, M.; Rampp, T. Medicinal leech therapy in pain syndromes: A narrative review. Wien. Med. Wochenschr. 2013, 164, 95–102. [Google Scholar] [CrossRef] [PubMed]
  75. Liu, C.; Barkley, T.W. Medicinal leech therapy. Nursing 2015, 45, 25–30. [Google Scholar] [CrossRef] [PubMed]
  76. Rai, P.K.; Singh, A.K.; Singh, O.P.; Rai, N.P.; Dwivedi, A.K. Efficacy of leech therapy in the management of osteoarthritis (Sandhivata). Selendang Ayu Oil Spill Lessons Learn. 2011, 32, 213–217. [Google Scholar] [CrossRef]
  77. Shakouri, A.; Adljouy, N.; Balkani, S.; Mohamadi, M.; Hamishehkar, H.; Abdolalizadeh, J.; Shakouri, S.K. Effectiveness of topical gel of medical leech(Hirudo medicinalis)saliva extract on patients with knee osteoarthritis: A randomized clinical trial. Complement. Ther. Clin. Pract. 2018, 31, 352–359. [Google Scholar] [CrossRef]
  78. Beaussier, M.; Sciard, D.; Sautet, A. New modalities of pain treatment after outpatient orthopaedic surgery. Orthop. Traumatol. Surg. Res. 2016, 102, S121–S124. [Google Scholar] [CrossRef]
  79. Li, C.; Qu, J.; Pan, S.; Qu, Y. Local infiltration anesthesia versus epidural analgesia for postoperative pain control in total knee arthroplasty: A systematic review and meta-analysis. J. Orthop. Surg. Res. 2018, 13, 112. [Google Scholar] [CrossRef]
  80. Elvir-Lazo, O.L.; White, P.F. The role of multimodal analgesia in pain management after ambulatory surgery. Curr. Opin. Anaesthesiol. 2010, 23, 697–703. [Google Scholar] [CrossRef]
  81. Elvir-Lazo, O.L.; White, P.F. Postoperative Pain Management After Ambulatory Surgery: Role of Multimodal Analgesia. Anesthesiol. Clin. 2010, 28, 217–224. [Google Scholar] [CrossRef]
  82. Dahl, J.B.; Møiniche, S. Pre-emptive analgesia. Br. Med. Bull. 2004, 71, 13–27. [Google Scholar] [CrossRef] [PubMed]
  83. Cummings, I.K.; Chahar, P. Liposomal bupivacaine: A review of a new bupivacaine formulation. J. Pain Res. 2012, 5, 257–264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Asche, C.V.; Ren, J.; Kim, M.; Gordon, K.; McWhirter, M.; Kirkness, C.S.; Maurer, B.T. Local infiltration for postsurgical analgesia following total hip arthroplasty: A comparison of liposomal bupivacaine to traditional bupivacaine. Curr. Med. Res. Opin. 2017, 33, 1283–1290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Kirkness, C.S.; Asche, C.V.; Ren, J.; Kim, M.; Rainville, E.C. Cost–benefit evaluation of liposomal bupivacaine in the management of patients undergoing total knee arthroplasty. Am. J. Heal. Pharm. 2016, 73, e247–e254. [Google Scholar] [CrossRef] [PubMed]
Medicina 56 00423 g001 550
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
Medicina 56 00423 g001
Table
Table 1. Summary of the studies included in this review.
Table 1. Summary of the studies included in this review.
Authors (Year)Study DesignSample SizeAgeGenderDisorderProceduresTreatmentResultAdverse Outcomes
Alter et al. (2017) [55] Prospective, randomized, single-blinded, single-center clinical trial, sample size a priori computed, systematic recruitment41, 20 receiving Exparel, 21 receiving marcaine63 ± 15 years receiving Exparel, 57 ± 15 years receiving marcaine16 women (80%) receiving Exparel, 17 (81%) receiving marcaineDistal Radius Fracture Distal Radius Fracture Repair SurgeryExparel 20 mL+ 10 mL 0.5% MarcaineExparel use resulted in decreased pain (4.0 versus 6.0, p < 0.05) and opioid consumption (1.2 versus 2.0 pills, 7.3 versus 12.5 oral morphine equivalents) only on the day of surgery and not thereafter16/20 receiving Exparel and 11/21 receiving marcaine experienced hand numbness, 1/20 receiving Exparel and 4/21 receiving marcaine reported itching, nausea, drowsiness/dizziness, and lack of energy
Amundson et al. (2017) [60]Three-arm, parallel, single blinded (outcome adjudicator-blinded), superiority, randomized-controlled, single-center clinical trial, sample size a priori computed, systematic recruitment157 (out of an initial list of 165 patients), 52 receiving Exparel, 55 receiving Ropivacaine, 50 receiving peripheral nerve block67 ± 8 years receiving Exparel, 68 ± 8 years receiving Ropivacaine, 67 ± 9 years receiving peripheral nerve block 27 women (52%) receiving Exparel, 34 (62% receiving Ropivacaine), 25 (50%) receiving peripheral nerve blockPatients needing total knee arthroplastyElective, Unilateral, Primary, Total Knee ArthroplastyExparel 20 mL (266 mg) + 100 mL Saline +120 mL (300 mg) RopivacaineNo significant benefit of liposomal bupivacaine over ropivacaine in periarticular injections for total knee arthroplasty (post-operative day 1 median maximal pain score was lower for peripheral nerve blockade, p = 0.016, median difference -1 [95%CI -2 to 0]), patients receiving Exparel exhibited improved physical quality of life (p = 0.048), as well as those receiving Ropivacaine (p = 0.001), but not those receiving peripheral nerve block6 patients fell (2 receiving peripheral nerve block, 1 receiving Ropivacaine, 1 receiving Exparel), 6 patients had a wound infection (2 for each group)
Bramlett et al. (2012) [61]Phase 2, randomized, parallel-group, double-blinded, dose-ranging, multi-center clinical trial, sample size a priori computed, systematic recruitment138 (out of an initial list of 164 screened patients and of 144 randomized patients), four discontinued the trial, two experienced serious adverse events, one died, one left for other reasons, 27 receiving DepoFoam 133 mg, 25 receiving DepoFoam 266 mg, 26 receiving DepoFoam 399 mg, 24 receiving DepoFoam 532 mg, 32 receiving Bupivacaine61.4 ± 7.0 years receiving DepoFoam 133 mg; 61.1 ± 8.7 years receiving DepoFoam 266 mg; 61.8 ± 6.3 years receiving DepoFoam 399 mg, 64.9 ± 7.3 years receiving DepoFoam 532 mg, 62.2 ± 7.2 years receiving Bupivacaine 150 mg15 women (53.6%) receiving DepoFoam 133 mg; 12 women (48.0%) receiving DepoFoam 266 mg; 15 women (57.7%) receiving DepoFoam 399 mg; 20 women (80.0%) receiving DepoFoam 532 mg; 23 women (67.6%) receiving Bupivacaine 150 mgPatients needing total knee arthroplastyUnilateral, Primary, Total Knee ArthroplastyExparel 20 mL (266 mg) + 40 mL Saline + 50% Bupivacaine 30 mL + 30 mL NSExparel was associated with statistically significantly greater analgesia compared with bupivacaine HCl in terms of pain at rest and pain with activityOverall 112 (81.2%) experienced at least one side-effect (79.8% receiving DepoFoam versus 85.3% receiving Bupivacaine)
Premkumar et al. (2016) [62]Prospective, double-blinded, randomized, positive-controlled, single-center clinical trial, systematic recruitment32 (out of an initial list of 35 patients), follow-up rate of 90.6%, 16 receiving Exparel, 16 receiving Bupivacaine24.1 ± 7.3 years receiving Exparel, 25.5 ± 6.8 years receiving Bupivacaine 33% women receiving Exparel, 47% women receiving BupivacaineInjury of the anterior cruciate ligamentAnterior Cruciate Ligament Reconstruction with a soft tissue quadriceps tendon autograftExparel/Bupivacaine 20 mL + 20 mL 0.9% SalineNo significant differences in postoperative pain, recovery time, mobility, pain location or opioid use between patients receiving liposomal bupivacaine or 0.25% bupivacaine HClNot reported
Schroer et al. (2015) [63]Prospective, randomized, clinical trial, systematic (consecutive) recruitment111, 58 receiving Exparel, 53 receving Bupivacaine67 ± 8.8 (48–86) years receiving Exparel, 68.6 ± 9.2 (52-89) receiving Bupivacaine34 women (59%) receiving Exparel, 32 women (60%) receiving Bupivacaine Patients undergoing a total knee arthroplastyUnilateral, Cemented Total Knee Arthroplasty through a mini-subvastus approach, anteriorly stabilized, with resurfacing of patelleExparel 20 mL (266 mg) + 30 mL 0.25% Bupivacaine + 0.25% Bupivacaine 60 mLLiposomal bupivacaine did not demonstrate improved pain scores, lower narcotic use, or better knee motion during hospitalization3 cases (5%) and 2 controls (4%) had post-operatve nausea
Bagsby et al. (2014) [64]Retrospective, cohort study, systematic (consecutive) recruitment150; 65 receiving Exparel, 85 receiving Ropivacaine63.13 ± 10.32 years receiving Exparel, 65.19 ± 9.21 years receiving Ropivacaine47 (72.3%) women receiving Exparel, 61 (70.9%) women receiving RopivacainePatients undergoing total knee arthroplastyTotal Knee ArthroplastyExparel 20 cc + 30 cc Saline + 30 cc 0.5% MarcaineExparel provided inferior pain control compared to Ropivacaine (p = 0.04), being more expensiveIn the Exparel group, 3/65 patients (4.6%) reported a wound drainage at 3–4 weeks post-surgery and an acute postoperative methicillin sensitive staphilococcal infection requiring reoperation
Webb et al. (2015) [65]Retrospective, case-control study, systematic (consecutive) recruitment100; 50 receiving Exparel, 50 serving as controls64 (46–88) years receiving Exparel, 64 (38–85) years serving as controls34 (68%) women receiving Exparel, 32 (64%) serving as controlsPatients undergoing total knee arthroplastyTotal Knee ArthroplastyExparel 20 mL (266 mg) + 40 mL SalineUse of Exparel resulted in decreased narcotic usage (60.97 mg oral morphine equivalent versus 89.74 mg, p = 0.009). Periarticular Total Knee Arthroplasty injection using liposomal bupivacaine in patients with a Body Mass Index less than 40 kg/m2 and few co-morbidities lead to earlier hospital discharge ((2.64 days versus 3.06 days, p = 0.004) and decreased narcotic usage over 24–48 h (110.66 mg versus 182.47 mg, p = 0.013), and over 48–72 h (49.61 mg versus 112.65 mg, p = 0.004)Not reported
Mont et al. (2018) [66]Phase 4, randomized, double-blinded, active-controlled, parallel-group, multi-center clinical trial, sample size a priori computed, systematic recruitment139 (out of an initial list of 140 patients), 70 receiving Exparel, 69 receiving Bupivacaine66 ± 8.61 years receiving Exparel, 66 ± 7.21 years receiving Bupivacaine43 women (61.4%) receiving Exparel, 39 women (56.5%) receiving BupivacainePatients with degenerative knee osteoarthritis undergoing total knee arthroplastyPrimary, Unilateral, Tricompartimental, Total Knee ArthroplastyExparel 20 mL (266 mg) + 40 mL Saline + 50% Bupivacaine 20 mLExparel provides significantly reduced postsurgical pain (area under the curve of visual analog scale pain intensity score 12–48 h post-surgery 180.8 versus 209.3, p = 0.0381), reduced opioid consumption (18.7 mg versus 84.9, p = 0.0048), percentage of patients (p < 0.01), and time to first opioid rescue (p = 0.0230)64.3% receiving Exparel versus 56.5% receiving Bupivacaine experienced mild-to-modest adverse events
Barrington et al. (2015) [69]Prospective, randomized clinical trial, sample size power calculated a posteriori, systematic (consecutive) recruitment2248; 1124 receiving a classical, well-established multimodal analgesia, including peri-articular injection, 1124 receiving Exparel (pre-post design)63.1 (19.0–95.0) years receiving the multimodal analgesia, 65.8 (32.0–96.0) years receiving Exparel, for hip procedures, 66.7 (36.0–93.0) years receiving the multimodal analgesia, 66.7 (38.0–97.0) years for receiving Exparel, for knee procedures56.5% women receiving the multimodal analgesia, 57.2% receiving Exparel, for hip procedures, 58.7% women receiving the multimodal analgesia, 57.5% receiving Exparel, for knee procedures Patients undergoing knee/hip arthroplastyKnee/Hip Arthroplasty (primary knee, 48%, revision knee, 45%, unicompartmental knee, 56%, bilateral knee, 46%, primary hip, 50%, revision hip, 47%, and bilateral hip, 50%)Exparel versus multimodal analgesiaImproved overall mean VAS pain scores for hip (1.67 versus 2.30, p < 0.0001) and for knee (2.21 versus 2.52, p < 0.0001) procedures, an increased number of pain-free patients, decreased hospital length of stay (p < 0.0001), trends toward decreased falls (p = 0.021), and decreased overall costNot reported
Table
Table 2. List of techniques for liposomes fabrication and their disadvantages.
Table 2. List of techniques for liposomes fabrication and their disadvantages.
TechniquesDisadvantagesAuthor (Year)
Bangham method
(1)
Large particle size distribution, that means production of large vesicles (mean size > 10 µm), that are not compatible with pharmaceutical applications
(2)
Low replicability, i.e., production of heterogeneous vesicles, that are not applicable to industrial production
(3)
High solvent residue, i.e., high toxicity and low biocompatibility to human tissues
(4)
Low encapsulation efficiency (<30%), i.e., low loading efficacy of drugs, resulting in a high percentage of drug waste
Bangham et al. (1974) [26]
Extrusion methodMui et al. (2003) [27]
Microfluidic channelAndar et al. (2014) [28]
Ethanol InjectionCharcosset et al. (2015) [29]
Table
Table 3. List of non-conventional techniques for liposomes’ fabrication.
Table 3. List of non-conventional techniques for liposomes’ fabrication.
TechniquesDisadvantagesAuthor (Year)
Supercritical reverse phase evaporation
(1)
Semi-continuous processes, meaning that the process cannot be replicated at large scale, for example for the massive fabrication of liposomes for vaccine delivery
(2)
Encapsulation Efficiency of drugs <60%. Higher than conventional methods, but still too low to obtain a large profitability from the process
(3)
Low stability, i.e., vesicles are not stable over a long observation time
(4)
Difficult control of particle size distribution linked to problems of replicability
Otake et al. (2006) [30]
Depressurization of an Expanded Solution into Aqueous MediaMeure et al. (2009) [31]
Depressurization of an Expanded Liquid Organic SolutionZhao, Tamelli (2015) [32]
Supercritical Anti-SolventLesoin et al. (2011) [33]
Table
Table 4. List of the most commercialized liposome formulations.
Table 4. List of the most commercialized liposome formulations.
Commercialized Liposomes FormulationCommercial NameAuthor (Year)
PEGylated liposomal doxorubicin(Doxil/Caelyx)Gabizon et al. (2003) [34]
Non-PEGylated liposomal doxorubicin (Myocet)Rivankar (2014) [35]
Liposomal daunorubicin(DaunoXome)Petre, Dittmer (2007) [36]
Liposomal cytarabine (DepoCyt)Bomgaars et al. (2004) [37]

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Cipollaro, L.; Trucillo, P.; Bragazzi, N.L.; Della Porta, G.; Reverchon, E.; Maffulli, N. Liposomes for Intra-Articular Analgesic Drug Delivery in Orthopedics: State-of-Art and Future Perspectives. Insights from a Systematic Mini-Review of the Literature. Medicina 2020, 56, 423. https://doi.org/10.3390/medicina56090423

AMA Style

Cipollaro L, Trucillo P, Bragazzi NL, Della Porta G, Reverchon E, Maffulli N. Liposomes for Intra-Articular Analgesic Drug Delivery in Orthopedics: State-of-Art and Future Perspectives. Insights from a Systematic Mini-Review of the Literature. Medicina. 2020; 56(9):423. https://doi.org/10.3390/medicina56090423

Chicago/Turabian Style

Cipollaro, Lucio, Paolo Trucillo, Nicola Luigi Bragazzi, Giovanna Della Porta, Ernesto Reverchon, and Nicola Maffulli. 2020. "Liposomes for Intra-Articular Analgesic Drug Delivery in Orthopedics: State-of-Art and Future Perspectives. Insights from a Systematic Mini-Review of the Literature" Medicina 56, no. 9: 423. https://doi.org/10.3390/medicina56090423

APA Style

Cipollaro, L., Trucillo, P., Bragazzi, N. L., Della Porta, G., Reverchon, E., & Maffulli, N. (2020). Liposomes for Intra-Articular Analgesic Drug Delivery in Orthopedics: State-of-Art and Future Perspectives. Insights from a Systematic Mini-Review of the Literature. Medicina, 56(9), 423. https://doi.org/10.3390/medicina56090423

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