Full-thickness Articular Cartilage Research Articles

Co-culture of hWJMSCs and pACs in double biomimetic ACECM oriented scaffold enhances mechanical properties and accelerates articular cartilage regeneration in a caprine model

BackgroundThe dedifferentiation of chondrocytes and the unstable chondrogenic differentiation status of pluripotent mesenchymal stem cells (MSCs) are immense issues in cell-based articular cartilage repair and regenerative strategies. Here, to improve the cartilage characteristics of seed cells, a double biomimetic acellular cartilage extracellular matrix (ACECM)-oriented scaffold was used to mimic the cartilage microenvironment for human umbilical cord Wharton’s jelly-derived MSCs (hWJMSCs) and primary cartilage cells (pACs) to regenerate hyaline cartilage.MethodsA double biomimetic ACECM-oriented scaffold was created from the cartilage extracellular matrix of pig articular cartilage using pulverization decellularization freeze-drying procedures. hWJMSCs and pACs were co-cultured at ratios of 50:50 (co-culture group, ACCC), 0:100 (ACAC group) and 100:0 (ACWJ group) in the ACECM-oriented scaffold, and the co-culture system was implanted in a caprine model for 6 months or 9 months to repair full-thickness articular cartilage defects. The control groups, which had no cells, comprised the blank control (BC) group and the ACECM-oriented scaffold (AC) group. Gross morphology and magnetic resonance imaging (MRI) as well as histological and biomechanical evaluations were used to characterize the cartilage of the repair area.ResultsRelative to the control groups, both the gross morphology and histological staining results demonstrated that the neotissue of the ACCC group was more similar to native cartilage and better integrated with the surrounding tissue. Measurements of glycosaminoglycan content and Young’s modulus showed that the repair areas had more abundant cartilage-specific content and significantly higher mechanical strength in the ACCC group than in the control groups, especially at 9 months. On MRI, the T2-weighted signal of the repair area was homogeneous, and the oedema signal disappeared almost completely in the ACCC group at 9 months. HLA-ABC immunofluorescence staining demonstrated that hWJMSCs participated in the repair and regeneration of articular cartilage and escaped surveillance and clearance by the caprine immune system.ConclusionThe structure and components of double biomimetic ACECM-oriented scaffolds provided a cartilage-like microenvironment for co-cultured seed cells and enhanced the biomechanics and compositions of neotissue. This co-culture system has the potential to overcome the dedifferentiation of passage chondrocytes and the unstable chondrogenic differentiation status of MSCs.

Tissue-Adhesive Paint of Silk Microparticles for Articular Surface Cartilage Regeneration.

Current biomaterials and tissue engineering techniques have shown a promising efficacy on full-thickness articular cartilage defect repair in clinical practice. However, due to the difficulty of implanting biomaterials or tissue engineering constructs into a partial-thickness cartilage defect, it remains a challenge to provide a satisfactory cure in joint surface regeneration in the early and middle stages of osteoarthritis. In this study, we focused on a ready-to-use tissue-adhesive joint surface paint (JS-Paint) capable of promoting and enhancing articular surface cartilage regeneration. The JS-Paint is mainly composed of N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide (NB)-coated silk fibroin microparticles and possess optimal cell adhesion, migration, and proliferation properties. NB-modified silk fibroin microparticles can directly adhere to the cartilage and form a smooth layer on the surface via the photogenerated aldehyde group of NB reacting with the -NH2 groups of the cartilage tissue. JS-Paint treatment showed a significant promotion of cartilage regeneration and restored the smooth joint surface at 6 weeks postsurgery in a rabbit model of a partial-thickness cartilage defect. These findings revealed that silk fibroin can be utilized to bring about a tissue-adhesive paint. Thus, the JS-Paint strategy has some great potential to enhance joint surface regeneration and revolutionize future therapeutics of early and middle stages of osteoarthritis joint ailments.

Cartilage repair by various concentrations of placenta-derived mesenchymal stem cells and hyaluronic acid hydrogels in a rabbit model

Background & Aim The placenta-derived mesenchymal stem cells have great interest as a promising cell source for regenerative medicine due to non-invasive collection, readily availability, high expansion capacity, and low immunogenicity. We investigated the feasibility of transplanting placenta-derived MSCs and a hyaluronic acid (HA) hydrogel composite to repair full-thickness articular cartilage defects and determine whether the transplantation of various concentrations of placenta-derived MSCs with 4% hyaluronic acid (HA) hydrogel promoted articular cartilage repair in a rabbit model. Methods, Results & Conclusion Methods Critical-sized osteochondral defects (5mm diameter × 5mm depth) were created in the center of the trochlear groove of femur. The Four experimental groups were as follows: group A, defect only (left knee)/ 4% HA hydrogel without placenta-MSCs (right knee), n=6; group B, 0.01 × 107 cells/ml with 4% HA hydrogel (left knee)/ 0.1 × 107 cells/ml with 4% HA hydrogel (right knee), n=8; group C, 0.1 × 107 cells/ml with 4% HA hydrogel (left knee)/ 0.5 × 107 cells/ml with 4% HA hydrogel (right knee), n=8; group D, 0.5 × 107 cells/ml with 4% HA hydrogel (left knee)/ 1 × 107 cells/ml with 4% HA hydrogel (right knee) were transplantation in a rabbit model. At 8 weeks after transplantation, the degree of cartilage repair was evaluated grossly and histologically using the International Cartilage Repair Society macroscopic score, the modified O'Driscoll score for histologic grading. Results Transplanting placenta-derived MSCs and a HA hydrogel composite resulted in overall superior cartilage repair tissue with better quality than no treatment and hyaluronic acid (HA) only treatment group. Interestingly, The 0.5 × 106 cells/ml group showed the highest cartilage repair at 8 weeks post transplantation. Conclusions The results of this study suggest that transplantation of the composite of placenta-derived MSCs and HA is promoting for cartilage repair. In addition, this study shows that optimal MSC concentration needs to be determined for better cartilage repair.

Treatment of Full-Thickness Cartilage Defects with Pedunculated and Free Synovial Grafts: A Comparative Study in an Animal Model.

The purpose of this study was to compare the potential effects of pedunculated and free synovial grafts in the repair of full-thickness articular cartilage defects on an animal model with histological and immunohistochemical analysis. A comparative study in an animal model was performed with 24 rabbits, divided into two groups. Full-thickness cartilage defects were created bilaterally on the knees of all rabbits. Pedunculated and free synovial grafts were applied to the right knees of Group 1 and Group 2, respectively. Left knees were left as the control group. Six rabbits from each group were randomly selected for euthanasia 4 and 8 weeks postoperatively. All samples were examined histologically with a cartilage scoring system. For immunohistochemical analysis, the degree of collagen 2 staining was determined using a staging system. All data were statistically compared between the study groups with Student's t-test or Mann-Whitney U-test. The correlations between categorical variables were analyzed with Fisher's exact test and Chi-square test. In Group 1, the mean defect size had significantly decreased at 8 weeks postsurgery. It was also significantly smaller than that of Group 2. Both pedunculated and free synovial grafts had significantly better histological and immunohistochemical outcomes compared with the controls. Contrastingly, the results of comparison between the study groups (Group 1 vs. 2) at the 4th and 8th week were not statistically significant with regard to histological scores and immunohistochemical staining. Synovial tissue, whether pedunculated or free, provided much better cartilage recovery compared with the control. It can be used as a mesenchymal stem cell (MSC) source, and synovium-derived MSCs have the chondrogenic potential for the in vivo treatment of full-thickness cartilage defects.

The time-dependent effects of bipolar radiofrequency energy on bovine articular cartilage

PurposeThe purpose of this study was to compare the effect of bipolar radiofrequency energy (bRFE) on chondroplasty at the different time durations in an in vitro experiment that simulated an arthroscopic procedure.MethodsSix fresh bovine knees were used in our study. Six squares were marked on both the medical and lateral femoral condyles of each femur. Each square was respectively treated with bRFE for 0 s, 10 s, 20 s, 30 s, 40 s and 50 s. Full-thickness articular cartilage specimens were harvested from the treatment areas. Each specimen was divided into three distinct parts: one for hematoxylin/eosin staining histology, another for cartilage surface contouring assessment via scanning electron microscopy (SEM), and the last one for glycosaminoglycan (GAG) content measurement.ResultsbRFE caused time-correlated damage to chondrocytes, and GAG content in the cartilage was negatively correlated to exposure time. bRFE caused time-correlated damage to chondrocytes. The GAG content in the cartilage negatively correlated with the exposure time. The sealing effect positively correlated with the exposure time. Additionally, it took at least 20 s of radiofrequency exposure to render a smooth cartilage surface and a score of 2 (normal) in the scoring system used.ConclusionbRFE usage in chondroplasty could effectively trim and polish the cartilage lesion area; however, it induces a dose-dependent detrimental effect on chondrocytes and metabolic activity that negatively correlated with the treatment time. Therefore, cautions should be taken in the use of bRFE for treatment of articular cartilage injury.

A cell-free therapy for articular cartilage repair based on synergistic delivery of SDF-1 & KGN with HA injectable scaffold

Co-encapsulation of SDF-1/KGN within microsphere for synergistic cartilage repair. • Co-encapsulation of a chemokine & a chondroinductive molecule within individual microsphere. • Synergistic release profiles of SDF-1& KGN for efficient cartilage regeneration. • An injectable scaffold based cell free therapy for articular cartilage repair. This study was to co-encapsulate a chemokine (stromal cell-derived factor-1, SDF-1) and a chondroinductive molecule (kartogenin, KGN) within microspheres via microfluidics, and to incorporate them into a hyaluronic acid (HA) injectable scaffold for articular cartilage defect repair. HA injectable scaffold, as a cartilage-friendly microenvironment, was prepared by crosslinking HA with 1,4-butanediol diglycidyl ether. A microfluidic device was set up to prepare monodisperse PLGA microspheres (49 μm) to load SDF-1 and KGN. An in vivo model of full-thickness articular cartilage defects in rabbits was applied to evaluate the reparative capacity of the current package. The SDF-1 and KGN were co-encapsulated simultaneously within the core and shell area of the microsphere with high loading efficiency and sustained release profiles of more than 2 months. The release profiles of them were highly matched and well fitted to a first-order mathematical model. These microspheres when incorporated into HA injectable scaffold were demonstrated to heal the full-thickness articular cartilage defects in rabbits. The regenerated tissue had the typical cartilage histological characters and integrated well with the surrounding tissue at 12w. This developed cell-free system could serve as an efficient therapy for articular cartilage defects treatment, serving as a supplementary way to cell based therapies.

Findings on repaired full-thickness acetabular articular cartilage defects during revision hip arthroscopy allowing a second look.

Full-thickness acetabular articular cartilage defects (FAACD) are found on most hips with femoroacetabular impingement (FAI) with a wave sign in the acetabulum. When not repaired it can produce pain and catching sensation. Multiple arthroscopic techniques for repairing this chondral lesion exist, but only few show the quality of the repair on a second look. The purpose of this study is to evaluate the quality of the repaired cartilage during revision hip arthroscopy (RHA) allowing a second look in patients treated of FAACD. A total of 13 hips with FAACD repaired in the past underwent RHA for ongoing pain. Signs of persistent chondral defects or the ability to elevate the articular cartilage from subchondral bone were evaluated by zones. Those with persistent defects were re-repaired. All patients had FAACD lesions in zones I, II and III diagnosed in the index hip arthroscopy. The most common finding at the RHA was the presence of bone growth or residual impingement. Before FAACD repair, 11 (85%) hips had the wave sign, while 2 (15%) hips had it in RHA. Five (38%) hips had residual delamination in the second look, these patients had residual FAI, were ≥58 years or waited >6 months to be revised. The wave sign was not observed in 85% of the revised hips, indicating the technique was successful in most cases and was not the principal cause of their ongoing pain. This technique achieved the stated goal of stabilizing the articular cartilage seen in the wave sign.

No effect of platelet-rich plasma as adjuvant to bone marrow stimulation for the treatment of chondral defects in a large animal model.

Bone marrow stimulation (BMS) remains a dominant treatment strategy for symptomatic full thickness articular cartilage defects. Autologous platelet-rich plasma (PRP), may improve biological cartilage repair as an adjunct to BMS. To assess the histological quality of cartilage repair after BMS with and without repeated local injections of PRP for the treatment of full-thickness focal chondral defects of the knee. Two full-thickness chondral defects (Ø = 6mm) were surgically performed in the medial and lateral trochlea of each knee in skeletally mature Göttingen minipigs. The two treatment groups with 12 defect for each groups were (1) BMS with one weekly PRP injection for 4weeks, and (2) BMS alone. The animals were euthanized after 6months. Samples of both whole blood and PRP were analysed with an automated hematology analyzer to determine the concentrations of platelets and nucleated cells. The composition of cartilage repair tissue was assessed using gross appearance assessment, histomorphometry and semi-quantitative scoring (ICRS II). The average fold increase in platelets was 10.2 ± 2.2. Leukocyte concentration increased in PRP samples by an average fold change of 7.2 ± 1.3. Our macroscopic findings showed that the defects in the BMS + PRP-treated group, were filled with an irregular, partially rough tissue similar to the BMS-treated group. No significant difference in amount of hyalin cartilage, fibrocartilage or fibrous tissue content and ICRS II scores was found between the groups. Four repeated local injections of leukocyte-rich PRP after BMS in the treatment of full-thickness cartilage injuries demonstrated no beneficial effects in terms of macroscopic and histological cartilage repair tissue quality.

3D Bioprinted Integrated Osteochondral Scaffold-Mediated Repair of Articular Cartilage Defects in the Rabbit Knee

To demonstrate that a 3D-bioprinted integrated osteochondral scaffold can provide improved repair of articular cartilage defects in the rabbit knee compared to that reported for traditional tissue-engineering methods. Bone marrow mesenchymal stem cells were differentiated into osteoblasts and chondrocytes as seed cells and mixed with the corresponding bone and cartilage scaffold materials. An integrated osteochondral biphasic scaffold was fabricated via 3D-bioprinting technology through successive natural overlays of the printed material and used to repair full-thickness articular cartilage defects in the rabbit knee. Histological and biomechanical assessment of repaired tissue at 6 months post-transplantation showed almost complete repair of injured articular surfaces and presence of hyaline cartilage. A boundary existed between the transition and repair zones. The Wakitani histological score was 5.50 ± 2.07 points; maximum load was 183.11 ± 35.20 N. Repaired cartilage was integrated firmly with the subchondral bone and almost assimilated with surrounding cartilage and bone tissues. The 3D bioprinted integrated osteochondral scaffold achieved double bionic effects on the scaffold composition and structure, and it is expected to offer a new strategy for articular cartilage repair and regeneration.

Xenotransplantation of human dental pulp stem cells in platelet-rich plasma for the treatment of full-thickness articular cartilage defects in a rabbit model.

Stem cells in platelet-rich plasma (PRP) scaffolds may be a promising treatment for cartilage repair. Human dental pulp stem cell (hDPSC) subpopulations have been identified to have substantial angiogenic, neurogenic and regenerative potential when compared with other stem cell sources. The present study evaluated the potential of hDPSCs in a PRP scaffold to regenerate full-thickness cartilage defects in rabbits. Full-thickness articular cartilage defects were created in the patellar groove of the femur of 30 rabbits allocated into three experimental groups: Those with an untreated critical defect (CTL), those treated with PRP (PRP) and those treated with stem cells in a PRP scaffold (PRP+SC). The patellar grooves of the femurs from the experimental groups were evaluated macroscopically and histologically at 6 and 12 weeks post-surgery. The synovial membranes were also collected and evaluated for histopathological analysis. The synovial lining cell layer was enlarged in the CTL group compared with the PRP group at 6 weeks (P=0.037) but not with the PRP+SC group. All groups exhibited low-grade synovitis at 6 weeks and no synovitis at 12 weeks. Notably, macroscopic grades for the area of articular cartilage repair for the PRP+SC group were significantly improved compared with those in the CTL (P=0.001) and PRP (P=0.049) groups at 12 weeks. Furthermore, histological scores (modified O'Driscoll scoring system) of the patellar groove articular cartilage in the PRP+SC and PRP groups, in which the articular cartilage was primarily hyaline-like, were significantly higher compared with those in the CTL group at 12 weeks (P=0.002 and P=0.007, respectively). The present results support the therapeutic use of hDPSCs for the treatment of full-thickness articular cartilage defects.

Genetic correlations in recombinant inbred mouse strains suggest that cartilage repair is positively correlated with protection from osteoarthritis

Purpose: The etiology of osteoarthritis (OA) is unknown, however, there appears to be a significant contribution from genetics. We have identified recombinant inbred strains of mice derived from LG/J (large) and SM/J (small) that vary significantly in their susceptibility to post-traumatic OA due to their genetic composition. While in the past, it was considered that articular cartilage could not undergo repair, we have demonstrated that a number of mouse strains, considered “healer” mice, are able to repair articular cartilage. Here we report cartilage repair phenotypes in the same strains of mice in which OA susceptibility was analyzed. We demonstrate that protection from OA is positively correlated with the ability to repair cartilage. These results suggest a shift in the risk paradigm for OA from degeneration to regeneration. Methods: All procedures were approved by the Institutional Animal Care and Use Committee. We used 12 recombinant inbred (RI) strains of mice generated from LG/J by SM/J intercross to test three phenotypes: ear wound healing, articular cartilage repair, and post-traumatic OA. (1) A 2 mm hole was created in the external ears using a biopsy punch (n = 263) at 6 weeks of age and healing outcome was measured at 30-day post-punch. (2) An acute full-thickness articular cartilage injury was introduced in the trochlear groove of 8-week-old mice (n = 126) through microsurgery and healing outcomes were measured at 16 weeks after surgery. (3) OA was induced in 10-week-old mice (n = 53) by destabilization of medial meniscus (DMM). Maximum OARSI score (representing the highest score within all sectioned levels of the knee), summed OARSI score (representing whole joint changes) and synovitis score (representing synovial cell proliferation) were measured 8 weeks post-DMM. Genetic correlations between various traits were calculated as Pearson correlation coefficients of strain means using GraphPad Prism. Results: We found a significant positive correlation between ear wound healing and knee articular cartilage regeneration (r = 0.74, P = 0.006) (Fig. 1A). We observed a strong linear correlation between cartilage regeneration and protection from OA based on summed OARSI (r = 0.49, P = 0.106) as well as maximum OARSI scores (r = 0.50, P = 0.097) (Fig. 1B). Summed and maximum OARSI scores were also significantly associated with each other (r = 0.92, P < 0.0001) (Fig. 1C). While synovitis was not significantly correlated with knee cartilage healing, it showed highly significant positive correlation with maximum OARSI score (r = 0.63, P = 0.028) and summed OARSI score (r = 0.70, P = 0.011) (Fig. 1D). Despite strong significant correlation between ear wound healing and knee cartilage regeneration, there was a weak correlation between ear wound healing and OA. Conclusions: Our study allows, for the first time, the measurement of genetic correlations of regeneration phenotypes with the degeneration phenotypes that are characteristics of PTOA. These results demonstrate a linear relationship between the resistance to OA after DMM surgery in mouse strains of different genotypes in recombinant inbred strains of a “healer” mouse, LG/J and a “non-healer” mouse, SM/J and the ability to heal an articular cartilage defect in the same mouse strains. While cartilage degeneration and regeneration were the phenotypes of primary interest in these studies, we also assessed synovitis in the OA study and thus could correlate synovitis with OA. The correlation between synovitis and OA ranged from 0.63-0.70, which is consistent with reports of patients with OA. Consequently, we have confidence that our correlation of OA with cartilage repair of 0.5 will be reflective of human cartilage degeneration and repair. We predict that the human population will also demonstrate this genetic variability in cartilage repair for which there is already some data derived from the ability to differentiate cartilage from stem cells. Thus, in the future the ability to repair cartilage may be a powerful indicator of the future susceptibility to OA after injury. Lastly, gene variants involved in cartilage repair may be informative as potential treatments for OA.

The Use of Bone Marrow Concentrate in the Treatment of Full-Thickness Chondral Defects

This article is a critical analysis of a study, "Minimally Manipulated Bone Marrow Concentrate Compared with Microfracture Treatment of Full-Thickness Chondral Defects: A One-Year Study in an Equine Model," by Chu et al. (J Bone Joint Surg Am. 100(2):138-146, 2018). The investigation compared two interventions in the management of full-thickness chondral defects in an equine model: autologous bone marrow concentrate without concomitant microfracture treatment versus microfracture treatment alone. This review analyzes the methodology and results of their investigation and examines how their findings may influence the continued development of therapeutic options for full-thickness cartilage injuries. The study utilized in vitro analysis, arthroscopic assessment, magnetic resonance imaging (MRI) evaluation, and histological analysis to compare the treatments and their influence on the quality of cartilage repair. Although Chu et al. reported similar results between groups, their findings offer insight into the role of arthroscopy, MRI, and histology in the evaluation of repair quality. We compare their findings to those of similar investigations, highlighting the limited therapeutic options and variable clinical outcomes related to the treatment of full-thickness articular cartilage defects.

Microfracture for cartilage repair in the knee: a systematic review of the contemporary literature.

To systematically review and evaluate novel clinical data following microfracture treatment of knee articular cartilage defects. A systematic review was performed by searching PubMed, ScienceDirect, and Cochrane Library databases for clinical trials on microfracture treatment, published between 2013 and 2018. Titles, abstracts, and articles were reviewed, and data concerning patient demographics, study design, pre-, intra-, and postoperative findings were extracted. PRISMA guidelines were applied. The methodological quality of the included studies was analyzed by the modified Coleman Methodology Score (CMS), and aggregate data were generated. Eighteen studies including 1830 defects (1759 patients) were included. Of them, 8 (59% of patients) were cohort studies without a comparison group. Overall study quality was moderate (mean total CMS: 64 points), mainly due to low patient numbers, short follow-up periods, lack of control groups and structural repair tissue evaluation, and inhomogeneity in outcome parameters. Microfracture treatment of full-thickness articular cartilage defects (3.4 ± 2.1cm2) was performed at 43.4 ± 68.0months of symptom duration. Postoperative assessment at 79.5 ± 27.2months revealed failure rates of 11-27% within 5years and 6-32% at 10years. Imaging analysis was conducted in 10 studies, second-look arthroscopies were reported twice (n = 205 patients) and revealed well integrated fibrocartilaginous repair tissue. Microfracture provides good function and pain relief at the mid-term and clinically largely satisfying results thereafter. Standardized, high-quality future study designs will better refine optimal indications for microfracture in the context of cartilage repair strategies. This systematic review is based on studies with levels of evidence ranging between I and IV (see results section and Table). Therefore, and according to this journals Instructions for Authors (SYSTEMATIC REVIEWS AND META-ANALYSES are assigned a level of evidence equivalent to the lowest level of evidence used from the manuscripts analysed), level of evidence is IV.

Intra-articular injection of N-acetylglucosamine and hyaluronic acid combined with PLGA scaffolds for osteochondral repair in rabbits.

Repairing damaged articular cartilage is particularly challenging because of the limited ability of cartilage to perform self-repair. Intra-articular injections of N-acetylglucosamine (GlcNAc) comprise a method of repairing full-thickness articular cartilage defects in the rabbit knee joint model. To date, the effects of administration of GlcNAc and hyaluronic acid (HA) have been investigated only in the context of osteoarthritis treatment. Therefore, we evaluated the therapeutic effects of using cell-free porous poly lactic-co-glycolic acid (PLGA) graft implants and intra-articular injections of GlcNAc or HA in a rabbit model of osteochondral regeneration to investigate whether they have the potential for inducing osteochondral regeneration when used alone or simultaneously. Twenty-four rabbits were randomized into one of four groups: the scaffold-only group (PLGA), the scaffold with intra-articular injections of GlcNAc (PLGA+G) group, twice per week for four weeks; the scaffold with intra-articular injections of HA group (PLGA+HA) group, once per week for three weeks; and the scaffold with intra-articular injections of GlcNAc and HA (PLGA+G+HA) group, once per week for three weeks. Knees were evaluated at 4 and 12 weeks after surgery. At the end of testing, only the PLGA+G+HA group exhibited significant bone reconstruction, chondrocyte clustering, and good interactions with adjacent surfaces at 4 weeks. Additionally, the PLGA+G+HA group demonstrated essentially original hyaline cartilage structures that appeared to have sound chondrocyte orientation, considerable glycosaminoglycan levels, and reconstruction of the bone structure at 12 weeks. Moreover, the PLGA+G+HA group showed organized osteochondral integration and significantly higher bone volume per tissue volume and trabecular thickness. However, there were no significant differences between the PLGA+G and PLGA+HA groups except for gap formation on subchondral bone in the PLGA+G group. This study demonstrated that PLGA implantation combined with intra-articular injections of GlcNAc and HA allowed for cartilage and bone regeneration and significantly promoted osteochondral regeneration in rabbits without supplementation of exogenous growth factors. And the combination of this two supplements with PLGA scaffold could also prolong injection interval and better performance than either of them alone for the reconstruction of osteochondral tissue in the knee joints of rabbits.

Cartilage Tissue Regeneration: The Roles of Cells, Stimulating Factors and Scaffolds.

Cartilage tissue engineering is an emerging technique for the regeneration of cartilage tissue damaged as a result of trauma or disease. As the propensity for healing and regenerative capabilities of articular cartilage are limited, its repair remains one of the most challenging issues of musculoskeletal medicine. Clinical treatments intended to promote the success and complete repair of partial- and fullthickness articular cartilage defects are still unpredictable. However, one of the most exciting theories is that treatment of damaged articular cartilage can be realized with cartilage tissue engineering. This notion has prompted tissue engineering research involving cells, stimulating factors and scaffolds, either alone or in combination. With these perspectives, this review aims to present a summary of cartilage tissue engineering including development, recent progress, and major steps taken toward the regeneration of functional cartilage tissue. In addition, we discussed the role of stimulating factors, including growth factors, gene therapies, biophysical stimuli, and bioreactors, as well as scaffolds, including natural, synthetic, and nanostructured scaffolds, in cartilage tissue regeneration. Special emphasis was placed on cell source, including chondrocytes, fibroblasts, and stem cells, as an important component of cartilage tissue engineering techniques. In conclusion, continued development of cartilage tissue engineering will support future applications for patients suffering from diseased cartilage tissue problems and osteoarthritis.

Review of an exploratory phase II FDA regulated clinical trial of a novel surgical innovation: completion of a prospective, randomized, controlled trial to compare NeoCart with the standard-of-care, microfracture, for articular cartilage repair

Background: Full thickness articular cartilage lesions cause significant morbidity, and surgical intervention is frequently applied to restore the joint surface. Current approaches of cartilage restoration have not proven to produce hyaline cartilage and have limited clinical longevity. The objective of the current study was to evaluate a novel autologous cartilage tissue implant, NeoCart, at the conclusion of the FDA-regulated exploratory phase II randomized, prospective clinical trial. The primary surgical standard-of-care, microfracture, was set by the FDA as the control. Objectives included parameter setting for the phase III trial while conducting a preliminary long-term evaluation of safety and efficacy. Methods: Patients were randomized 2:1 to NeoCart (n=21) or microfracture (n=9) surgical intervention at time of arthroscopy. Baseline demographics and patient-reported outcomes were established including: International Knee Documentation Committee (IKDC); Knee Injury and Osteoarthritis Outcome Score (KOOS) components including Pain, Activity of Daily Living, Quality of Life, Symptoms, Sports & Recreation; Short Form 36; and Visual Analog Scale Pain. Adverse events (AEs), range of motion, and patient reported outcomes were assessed annually for 5 years. Results: The treatment and control groups did not significantly differ in age, gender distribution, symptom duration, lesion size, or baseline patient reported outcomes aside from pre-surgical Visual Analog Scale Pain scores and KOOS Sports and Recreation. AE rates did not differ between treatments. The control group had greater loss to follow-up over a 5-year period. Change from baseline was significantly greater for NeoCart than for microfracture for primary end points; IKDC (1, 2 years) and KOOS Pain (1, 3, 4 years), and secondary end points; KOOS Quality of Life, Symptoms, and Sports & Recreation until 4 years. At 5 years, IKDC, KOOS Pain, Activities of Daily Living, and Quality of Life, and Short Form 36 Physical scores for both treatments improved significantly (P<0.05). Improvements for NeoCart were sustained earlier and throughout the entire study period. Conclusions: NeoCart implantation has a safety and efficacy profile supporting further consideration of this therapy in a confirmatory phase III trial for establishment as a primary cartilage injury treatment. While clinical trials for surgical interventions depend on comparison with a standard-of-care, the favorability of the control procedure, microfracture, varied over the study duration. The known short duration of microfracture’s therapeutic effect was likely associated with high loss to follow-up in the small control group. Although adequate for setting phase III parameters, this study is under-powered to clearly attribute differences in longer term efficacy. Nonetheless, preliminary results demonstrate that NeoCart may provide an alternative primary surgical option for cartilage injury with a more rapid onset of action than microfracture.

Return to Play Among Elite Basketball Players After Osteochondral Allograft Transplantation of Full-Thickness Cartilage Lesions.

Background:Osteochondral allograft transplantation (OCA) is a recognized option for full-thickness articular cartilage defects of the knee, especially in the setting of large lesions or those involving the subchondral bone. Previous heterogenous studies of athletes have shown a 75% to 79% rate of return to play after the procedure.Purpose:To define return-to-play rates in a cohort of elite collegiate and professional basketball players following osteochondral allograft of the knee.Study Design:Case series; Level of evidence, 4.Methods:Prospectively collected data from an institutional cartilage repair registry were retrospectively reviewed. Patients were eligible for inclusion if they were collegiate or professional basketball players at the time of surgery. Patient demographics, lesion size and location, and surgical details were collected. Postoperative magnetic resonance imaging scans were scored with the OCAMRISS system. Time to return to play and pre- versus postoperative player performance were determined with publicly available internet resources.Results:Eleven athletes (4 professional, 7 collegiate) with a total of 14 treated lesions (1 to the medial femoral condyle, 6 to the lateral femoral condyle, 5 to the trochlea, and 2 to the patella) were eligible for study inclusion. Mean lesion size was 509 mm2. All patients underwent OCA through an arthrotomy, with fresh grafts. The overall rate of return to play at the same level of competition was 80%. Median time to return to play was 14 months (range, 6-26 months). Among players with available statistics, there was no significant reduction in any performance category.Conclusion:OCA in elite basketball players results in an 80% return to previous level of competition, which is consistent with previous reports of athletes playing other sports. Osteochondral allografting is a reasonable option to consider for full-thickness cartilage lesions of the knee, even for elite jumping athletes.

Outcome of Autologous Bone Grafting with Preservation of Articular Cartilage to Treat Osteochondral Lesions of the Talus with Large Subchondral Cysts

Category: Ankle Introduction/Purpose: Treatment options for osteochondral lesion of the talus (OLT) have substantially increased over the last decade. There are a wide variety of surgical treatments for OLT, and good clinical results have been reported. However, treatment for OLT with large subchondral bone cysts remains under discussion. The combination of autologous bone grafting for subchondral bone cyst with fixation of articular cartilage would be the desirable procedure for the repair of the large subchondral cyst preserving the original cartilage with native structure and geometry. The purpose of this study is to evaluate the clinical outcome of autologous cancellous bone graft and fixation of cartilage fragment for OLT with large subchondral cysts. Methods: Patients comprised seven men and five women, aged 14–70 (mean 35.9) years. All OLTs included full-thickness articular cartilage, extended through subchondral bone and were associated with subchondral cysts. The mean size of the cysts was 9 ×8.6 ×12.3 mm on preoperative CT. Medial lesions were exposed through an oblique medial malleolar osteotomy; lateral lesions through expansion of an anterolateral arthroscopic portal. After refreshed the subchondral cyst, it was grafted with autologous cancellous bone from the distal tibial metaphysis, then cartilage fragments were fixed with nylon suture to surrounding cartilage. Postoperative MRI and CT scans were acquired for all patients at one year after surgery. Seven patients requested screw removal although none had symptoms. The screws were removed and simultaneous arthroscopic examination was performed at 1.5–2 years after surgery with the patients’ permission. The cartilage repair was assessed according to the criteria of the International Cartilage Repair Society (ICRS). Results: Functional outcome was evaluated at 25.3 (15–50) months after surgery. Mean American Orthopedic Foot and Ankle Society ankle-hindfoot outcome score improved from 65.7 to 92 (90–100) postoperatively, with 100% patient satisfaction. All follow-up CT scans showed that the grafts were well consolidated with the surrounding subchondral bone. On MRI one year after surgery, no scans showed any signs of osteochondral graft instability. The mean ICRS arthroscopic score from follow-up arthroscopy was 11.1 (8–12) points, and represented nearly normal cartilage. Conclusion: Our study demonstrated good results of autologous bone grafting in preserving articular cartilage in cases of symptomatic OLT with subchondral cysts. In seven cases, we performed follow-up arthroscopy at 1.5–2 years after primary operation and the chondral fragment showed a smooth surface and good stability. The technique of autologous bone grafting with chondral fragment fixation could be a promising option for treatment of OLT with subchondral cysts.

Shape-memory collagen scaffold for enhanced cartilage regeneration: native collagen versus denatured collagen

Nowadays, it is still questionable whether denatured collagen (DCol) can replace the native collagen (Col) as a bioactive protein in cartilage engineering. We sought to study the advantages of Col with a triple-helical structure in the collagen-based composite materials for cartilage engineering. We presented new three-dimensional (3D) Col and DCol scaffolds with shape memory properties. The effects of Col and DCol scaffolds on rabbit chondrocytes' proliferation, adhesion, differentiation and interaction with matrix were investigated. Tissue compatibility was performed in a subcutaneous Sprague Dawley (SD) rat model. The repair ability of different scaffolds with chondrocytes for full-thickness articular cartilage defects in knee joints of New Zealand white rabbits were investigated. The results indicated that the Col scaffolds (with concentration 1.6wt% and 0.8wt%, respectively) promoted the proliferation, adhesion and redifferentiation of chondrocytes, as well as chondrocyte-matrix interaction, to a greater degree than the DCol scaffolds. In the animal experiment, the Col scaffolds filled in the defect hole significantly maintained chondrocytes function, promoted cartilage and subchondral bone regeneration, compared with the DCol scaffolds, and the scaffolds loaded with chondrocytes were better than the cell-free scaffolds, especially in the case of the Col scaffolds (1.6 wt%). Taken together, these insights suggest that the better proliferation, adhesion and redifferentiation of chondrocytes in Col scaffolds with the triple-helical structure may contribute to the greater cartilage repair ability. Col scaffolds may be more appropriate for repairing cartilage defects than DCol scaffolds, and DCol cannot as an alternative when using collagen-based materials for cartilage engineering applications.

Xenogenic Implantation of Equine Synovial Fluid-Derived Mesenchymal Stem Cells Leads to Articular Cartilage Regeneration.

Horses are widely used as large animal preclinical models for cartilage repair studies, and hence, there is an interest in using equine synovial fluid-derived mesenchymal stem cells (SFMSCs) in research and clinical applications. Since, we have previously reported that similar to bone marrow-derived MSCs (BMMSCs), SFMSCs may also exhibit donor-to-donor variations in their stem cell properties; the current study was carried out as a proof-of-concept study, to compare the in vivo potential of equine BMMSCs and SFMSCs in articular cartilage repair. MSCs from these two sources were isolated from the same equine donor. In vitro analyses confirmed a significant increase in COMP expression in SFMSCs at day 14. The cells were then encapsulated in neutral agarose scaffold constructs and were implanted into two mm diameter full-thickness articular cartilage defect in trochlear grooves of the rat femur. MSCs were fluorescently labeled, and one week after treatment, the knee joints were evaluated for the presence of MSCs to the injured site and at 12 weeks were evaluated macroscopically, histologically, and then by immunofluorescence for healing of the defect. The macroscopic and histological evaluations showed better healing of the articular cartilage in the MSCs' treated knee than in the control. Interestingly, SFMSC-treated knees showed a significantly higher Col II expression, suggesting the presence of hyaline cartilage in the healed defect. Data suggests that equine SFMSCs may be a viable option for treating osteochondral defects; however, their stem cell properties require prior testing before application.