Allogenic platelet-rich plasma for treating cartilage injury: A systematic review of the evidence on the basic sciences for potential future applications.

It is apparent that whilst many reports are available regarding Platelet-Rich-Plasma (PRP), the larger majority of these have been mainly focused on autologous sources, and for good reason. Issues relating to allogenic source have been consciously avoided owing to concerns of cross infectivity and immune rejection. However, this topic today is now revisited and is of interest since progress over the year have demonstrated its safety, efficacy and its abundance of supply. The present systematic review was thus conducted to elucidate advances made in this area, with the aim to provide a wider and deeper understanding of studies relevant to the application of allogenic PRP in cartilage repair. Literature search was conducted systematically using Medline, ProQuest, Web of Science, Cochrane Central Register of Controlled Trials, and snowballing searching strategy to identify relevant studies using topic-specific keywords in various combinations including "allogenic, platelet, rich, plasma" OR "allogeneic, platelet, rich, plasma" OR "allogenic platelet-rich plasma" OR "allogeneic platelet-rich plasma" OR "allogenic platelet rich plasma" OR "allogeneic platelet rich plasma AND cartilage OR chondrocytes OR synoviocytes OR stem cells. Studies that used allogenic PRP in an attempt to facilitate cartilage repair were included. The risk of bias was assessed by the SYRCLE's checklist. Of 206 studies identified, 12 were found eligible. Only those studies that are clearly related and specific to allogenic PRP were included. Of these, nine investigated the efficacy of allogenic PRP in animal models, while three articles employed an in vitro model. Allogenic PRP promotes cell proliferation, cartilage matrix production and anti-inflammatory effects in vitro. The in vivo studies reported histological evidence of significant acceleration of cartilage repair in treated animals. Despite several conflicting findings, all studies agreed that allogenic PRP is safe and potentially efficacious for cartilage repair, with the advantages of allogenic sources apparent.

Small Extracellular Vesicles' miRNAs: Biomarkers and Therapeutics for Neurodegenerative Diseases.

Neurodegenerative diseases are critical in the healthcare system as patients suffer from progressive diseases despite currently available drug management. Indeed, the growing ageing population will burden the country's healthcare system and the caretakers. Thus, there is a need for new management that could stop or reverse the progression of neurodegenerative diseases. Stem cells possess a remarkable regenerative potential that has long been investigated to resolve these issues. Some breakthroughs have been achieved thus far to replace the damaged brain cells; however, the procedure's invasiveness has prompted scientists to investigate using stem-cell small extracellular vesicles (sEVs) as a non-invasive cell-free therapy to address the limitations of cell therapy. With the advancement of technology to understand the molecular changes of neurodegenerative diseases, efforts have been made to enrich stem cells' sEVs with miRNAs to increase the therapeutic efficacy of the sEVs. In this article, the pathophysiology of various neurodegenerative diseases is highlighted. The role of miRNAs from sEVs as biomarkers and treatments is also discussed. Lastly, the applications and delivery of stem cells and their miRNA-enriched sEVs for treating neurodegenerative diseases are emphasised and reviewed.

Early Alterations of Subchondral Bone in the Rat Anterior Cruciate Ligament Transection Model of Osteoarthritis.

OBJECTIVE: Advances in research have shown that the subchondral bone plays an important role in the propagation of cartilage loss and progression of osteoarthritis (OA), but whether the subchondral bone changes precede or lead to articular cartilage loss remains debatable. In order to elucidate the subchondral bone and cartilage changes that occur in early OA, an experiment using anterior cruciate ligament transection (ACLT) induced posttraumatic OA model of the rat knee was conducted. DESIGN: Forty-two Sprague Dawley rats were divided into 2 groups: the ACLT group and the nonoperated control group. Surgery was conducted on the ACLT group, and subsequently rats from both groups were sacrificed at 1, 2, and 3 weeks postsurgery. Subchondral bone was evaluated using a high-resolution peripheral quantitative computed tomography scanner, while cartilage was histologically evaluated and scored. RESULTS: A significant reduction in the subchondral trabecular bone thickness and spacing was found as early as 1 week postsurgery in ACLT rats compared with the nonoperated control. This was subsequently followed by a reduction in bone mineral density and bone fractional volume at week 2, and finally a decrease in the trabecular number at week 3. These changes occurred together with cartilage degeneration as reflected by an increasing Mankin score over all 3 weeks. CONCLUSIONS: Significant changes in subchondral bone occur very early in OA concurrent with surface articular cartilage degenerative change suggest that factors affecting bone remodeling and resorption together with cartilage matrix degradation occur very early in the disease.

Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine.

Cell therapy involves the transplantation of human cells to replace or repair the damaged tissues and modulate the mechanisms underlying disease initiation and progression in the body. Nowadays, many different types of cell-based therapy are developed and used to treat a variety of diseases. In the past decade, cell-free therapy has emerged as a novel approach in regenerative medicine after the discovery that the transplanted cells exerted their therapeutic effect mainly through the secretion of paracrine factors. More and more evidence showed that stem cell-derived secretome, i.e., growth factors, cytokines, and extracellular vesicles, can repair the injured tissues as effectively as the cells. This finding has spurred a new idea to employ secretome in regenerative medicine. Despite that, will cell-free therapy slowly replace cell therapy in the future? Or are these two modes of treatment still needed to address different diseases and conditions? This review provides an indepth discussion about the values of stem cells and secretome in regenerative medicine. In addition, the safety, efficacy, advantages, and disadvantages of using these two modes of treatment in regenerative medicine are also critically reviewed.

Mechanical compression controls the biosynthesis of human osteoarthritic chondrocytes in vitro.

BACKGROUND: Cartilage damage, which can potentially lead to osteoarthritis, is a leading cause of morbidity in the elderly population. Chondrocytes are sensitive to mechanical stimuli and their matrix-protein synthesis may be altered when chondrocytes experience a variety of in vivo loadings. Therefore, a study was conducted to evaluate the biosynthesis of isolated osteoarthritic chondrocytes which subjected to compression with varying dynamic compressive strains and loading durations. METHODS: The proximal tibia was resected as a single osteochondral unit during total knee replacement from patients (N = 10). The osteoarthritic chondrocytes were isolated from the osteochondral units, and characterized using reverse transcriptase-polymerase chain reaction. The isolated osteoarthritic chondrocytes were cultured and embedded in agarose, and then subjected to 10% and 20% uniaxial dynamic compression up to 8-days using a bioreactor. The morphological features and changes in the osteoarthritic chondrocytes upon compression were evaluated using scanning electron microscopy. Safranin O was used to detect the presence of cartilage matrix proteoglycan expression while quantitative analysis was conducted by measuring type VI collagen using an immunohistochemistry and fluorescence intensity assay. FINDINGS: Gene expression analysis indicated that the isolated osteoarthritic chondrocytes expressed chondrocyte-specific markers, including BGN, CD90 and HSPG-2. Moreover, the compressed osteoarthritic chondrocytes showed a more intense and broader deposition of proteoglycan and type VI collagen than control. The expression of type VI collagen was directly proportional to the duration of compression in which 8-days compression was significantly higher than 4-days compression. The 20% compression showed significantly higher intensity compared to 10% compression in 4- and 8-days. INTERPRETATION: The biosynthetic activity of human chondrocytes from osteoarthritic joints can be enhanced using selected compression regimes.

Factors Influencing the Successful Isolation and Expansion of Aging Human Mesenchymal Stem Cells.

Most studies highlight mesenchymal stem cells (MSCs) extracted primarily from bone marrow (BM), very few report the use of peripheral blood (PB), often due to the associated low seeding density and difficulties with extraction techniques. As ageing populations are becoming more predominant globally, together with escalating demands for MSC transplantation and tissue regeneration, obtaining quality MSCs suitable for induced differentiation and biological therapies becomes increasingly important. In this study, BM and PB were obtained from elderly patients and extracted MSCs grown in vitro to determine their successful isolation and expansion. Patients' socio-demographic background and other medical information were obtained from medical records. Successful and failed cultures were correlated with key demographic and medical parameters. A total of 112 samples (BM or PB) were used for this study. Of these, 50 samples (44.6%) were successfully cultured according to standardised criteria with no signs of contamination. Our comparative analyses demonstrated no statistical correlation between successful MSC cultures and any of the six demographic or medical parameters examined, including sample quantity, age, sex, race, habits and underlying comorbidities of sample donors. In conclusion, the present study demonstrates that typical demographics and comorbidities do not influence successful MSC isolation and expansion in culture.

Chondrogenic potential of physically treated bovine cartilage matrix derived porous scaffolds on human dermal fibroblast cells.

Extracellular matrices have drawn attention in tissue engineering as potential biomaterials for scaffold fabrication because of their bioactive components. Noninvasive techniques of scaffold fabrication and cross-linking treatments are believed to maintain the integrity of bioactive molecules while providing proper architectural and mechanical properties. Cartilage matrix derived scaffolds are designed to support the maintenance of chondrocytes and provide proper signals for differentiation of chondroinducible cells. Chondroinductive potential of bovine articular cartilage matrix derived porous scaffolds on human dermal fibroblasts and the effect of scaffold shrinkage on chondrogenesis were investigated. An increase in sulfated glycosaminoglycans production along with upregulation of chondrogenic genes confirmed that physically treated cartilage matrix derived scaffolds have chondrogenic potential on human dermal fibroblasts.

Human peripheral blood derived mesenchymal stem cells demonstrate similar characteristics and chondrogenic differentiation potential to bone marrow derived mesenchymal stem cells.

The use of mesenchymal stem cells (MSCs) for cartilage repair has generated much interest owing to their multipotentiality. However, their significant presence in peripheral blood (PB) has been a matter of much debate. The objectives of this study are to isolate and characterize MSCs derived from PB and, compare their chondrogenic potential to MSC derived from bone marrow (BM). PB and BM derived MSCs from 20 patients were isolated and characterized. From 2 ml of PB and BM, 5.4 ± 0.6 million and 10.5 ± 0.8 million adherent cells, respectively, were obtained by cell cultures at passage 2. Both PB and BM derived MSCs were able to undergo tri-lineage differentiation and showed negative expression of CD34 and CD45, but positively expressed CD105, CD166, and CD29. Qualitative and quantitative examinations on the chondrogenic potential of PB and BM derived MSCs expressed similar cartilage specific gene (COMP) and proteoglycan levels, respectively. Furthermore, the s-GAG levels expressed by chondrogenic MSCs in cultures were similar to that of native chondrocytes. In conclusion, this study demonstrates that MSCs from PB maintain similar characteristics and have similar chondrogenic differentiation potential to those derived from BM, while producing comparable s-GAG expressions to chondrocytes.

Treatment outcomes of alginate-embedded allogenic mesenchymal stem cells versus autologous chondrocytes for the repair of focal articular cartilage defects in a rabbit model.

BACKGROUND: Mesenchymal stem cells (MSCs) represent a promising alternative form of cell-based therapy for cartilage injury. However, the capacity of MSCs for chondrogenesis has not been fully explored. In particular, there is presently a lack of studies comparing the effectiveness of MSCs to conventional autologous chondrocyte (autoC) treatment for regeneration of full-thickness cartilage defects in vivo. HYPOTHESIS: Treatment with allogenic undifferentiated MSCs (alloMSCs) results in superior cartilage tissue regeneration profiles when compared with autoC for repair of focal articular cartilage defects. STUDY DESIGN: Controlled laboratory study. METHODS: Full-thickness articular cartilage defects were created on the weightbearing surface of the medial femoral condyles in both knees of New Zealand White rabbits (N = 30). Six weeks after the defect was induced, the right knee was treated with either alloMSCs (n = 12) or autoC (n = 18), while the left knee remained untreated (control). The rabbits were sacrificed at 6 months after treatment for assessment of cartilage tissue regeneration, which included the Brittberg morphologic score, histologic grading by O'Driscoll score, and quantitative analysis of glycosaminoglycans per total protein content. RESULTS: Apart from significantly higher Brittberg scores in the alloMSC treatment group (8.8 ± 0.8) versus the autoC treatment group (6.6 ± 0.8) (P = .04), both treatments showed similar cartilage regenerative profiles. All outcome measures were significantly higher in the treatment groups compared with their respective controls (P < .05). CONCLUSION: AlloMSCs have similar effectiveness as autoC for repair of focal cartilage defects. Both treatments resulted in superior tissue regeneration compared with untreated defects. CLINICAL RELEVANCE: The results have an implication of supporting the potential use of MSCs for cartilage repair after sports injuries or diseases, in view of similar efficacy but less patient morbidity and potential cost savings as compared with conventional autoC therapy.

A preliminary study comparing the use of allogenic chondrogenic pre-differentiated and undifferentiated mesenchymal stem cells for the repair of full thickness articular cartilage defects in rabbits.

Chondrogenic differentiated mesenchymal stem cells (CMSCs) have been shown to produce superior chondrogenic expression markers in vitro. However, the use of these cells in vivo has not been fully explored. In this study, in vivo assessment of cartilage repair potential between allogenic-derived chondrogenic pre-differentiated mesenchymal stem cells and undifferentiated MSCs (MSCs) were compared. Bilateral full thickness cartilage defects were created on the medial femoral condyles of 12 rabbits (n = 12). Rabbits were divided into two groups. In one group, the defects in the right knees were repaired using alginate encapsulated MSCs while in the second group, CMSCs were used. The animals were sacrificed and the repaired and control knees were assessed at 3 and 6 months after implantation. Quantitative analysis was performed by measuring the Glycosaminoglycans (GAGs)/total protein content. The mean Brittberg score was higher in the transplanted knees as compared to the untreated knee at 6 months (p < 0.05). Quantitative analysis of GAGs was consistent with these results. Histological and immunohistochemical analysis demonstrated hyaline-like cartilage regeneration in the transplanted sites. Significant differences between the histological scores based on O'Driscoll histological grading were observed between contralateral knees at both 3 and 6 months (p < 0.05). No significant differences were observed between the Britberg, O'Driscoll scores, and GAGs/total protein content when comparing defect sites treated with MSC and CMSC (p > 0.05). This study demonstrates that the use of either MSC or CMSC produced superior healing when compared to cartilage defects that were untreated. However, both cells produced comparable treatment outcomes.