No Effect of Platelet-Rich Plasma Injections as an Adjuvant to Autologous Cartilage Chips Implantation for the Treatment of Chondral Defects.

BACKGROUND: Repair of chondral injuries using cartilage chips has recently demonstrated clinical feasibility. Autologous platelet-rich plasma (PRP) is a potential promising technique for improving healing response during cartilage repair. PURPOSE: To assess the cartilage repair tissue quality after autologous cartilage chips treatment (CC) with and without repeated local injections of PRP for the treatment of full-thickness focal chondral defects of the knee. MATERIALS AND METHODS: Two full-thickness chondral defects (Ø = 6 mm) were created in the medial and lateral trochlea facets of each knee in 6 skeletally mature Göttingen minipigs. The 2 treatment groups were (1) CC with 1 weekly PRP injection for 3 weeks (n = 12) and (2) CC alone (n = 12). The animals were euthanized after 6 months. Samples of whole blood and PRP were analyzed for concentrations of platelets and nucleated cells. The composition of the cartilage repair tissue was assessed using gross appearance assessment, histomorphometry, and semiquantitative scoring (ICRS II). RESULTS: Histological evaluation demonstrated no significant difference in the content of hyaline cartilage (CC + PRP: 18.7% vs. CC: 19.6%), fibrocartilage (CC + PRP: 48.1% vs. CC: 51.8%), or fibrous tissue (CC + PRP: 22.7% vs. CC: 21.8%) between the treatment groups. Macroscopic evaluation did not demonstrate any difference between groups. CONCLUSIONS: PRP injections after CC in the treatment of full-thickness cartilage injuries demonstrated no beneficial effects in terms of macroscopic and histologic composition of cartilage repair tissue.

Particulated Cartilage for Chondral and Osteochondral Repair: A Review.

INTRODUCTION: Injuries to articular cartilage have a poor spontaneous repair potential and no gold standard treatment exist. Particulated cartilage, both auto- and allograft, is a promising new treatment method that circumvents the high cost of scaffold- and cell-based treatments. MATERIALS AND METHODS: A comprehensive database search on particulated cartilage was performed. RESULTS: Fourteen animal studies have found particulated cartilage to be an effective treatment for cartilage injuries. Many studies suggest that juvenile cartilage has increased regenerative potential compared to adult cartilage. Sixteen clinical studies on 4 different treatment methods have been published. (1) CAIS, particulated autologous cartilage in a scaffold, (2) Denovo NT, juvenile human allograft cartilage embedded in fibrin glue, (3) autologous cartilage chips-with and without concomitant bone grafting, and (4) augmented autologous cartilage chips. CONCLUSION: Implantation of allogeneic and autologous particulated cartilage provides a low cost and effective treatment alternative to microfracture and autologous chondrocyte implantation. The methods are promising, but large randomized controlled studies are needed.

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

BACKGROUND: 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. OBJECTIVES: 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. METHODS: Two full-thickness chondral defects (Ø = 6 mm) 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 4 weeks, and (2) BMS alone. The animals were euthanized after 6 months. 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). RESULTS: 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. CONCLUSIONS: 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.

Age-Dependent Systemic Effects of a Systemic Intermittent Hypoxic Therapy In Vivo.

Introduction: The adaptive response to systemic intermittent hypoxic therapy (SIHT) may be used for therapeutic advances due to the activation of multiple pathways involved in angiogenesis, immunomodulation, and tissue homeostasis. The aim of this study was to investigate the early age-dependent systemic response of different exposures of SIHT in mice. Materials and Methods: Sixty-four C57BL/6NRj female mice in three different age groups, young (4-5 weeks), adolescent (8-10 weeks), and adults (23-32 weeks), were exposed to SIHT. Different algorithms for equal hypoxic challenges (oxygen-decrease*time) were investigated to allow examination of the role of absolute hypoxia (oxygen-decrease) compared with relative hypoxia (total oxygen depletion over time). The systemic effects of angiogenetic regulation were investigated using blood samples analyzed by ELISA, proteome profiles, and proximity extension immunoassay. One-way analysis of variance with post hoc Bonferroni analyses was performed. Results: The early systemic response to SIHT was dependent on the absolute hypoxia rather than relative hypoxia over time. Serum erythropoietin (EPO) levels were increased significantly in young mice receiving low-oxygen SIHT treatments (10% and 15% oxygen). The expression of angiogenic proteins differed between the different age groups indicating an age-dependent response to SIHT. Focusing on hypoxia-inducible factor-1 (HIF-1) signaling, there was a trend toward upregulated angiogenetic response with younger age. Furthermore, clustering of protein expression in low-oxygen SIHT algorithms were found between young and adolescent mice. In adult mice, the majority of the proteins were downregulated as a response to SIHT. The systemic response of metabolites expressions was most pronounced in young mice. Systemic levels of cardiac troponin I (Tnni3) was unaffected by SIHT independent of age groups. Conclusions: The systemic response to SIHT is dependent on the absolute hypoxic exposure rather than the relative hypoxic depletion over time. Age-dependent effects of a short-term SIHT were associated with an increase in EPO, upregulation of angiogenetic pathways, and select metabolic and cell-surface proteins.

Clinical Outcomes and Failure Rates of Osteochondral Allograft Transplantation in the Knee: A Systematic Review.

BACKGROUND: Cartilage lesions are a significant cause of morbidity and impaired knee function; however, cartilage repair procedures have failed to reproduce native cartilage to date. Thus, osteochondral allograft (OCA) transplantation represents a 1-step procedure to repair large chondral defects without the donor site morbidity of osteochondral autograft transplantation. PURPOSE: To perform a systematic review of clinical outcomes and failure rates after OCA transplantation in the knee at a minimum mean 2 years' follow-up. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review of the literature regarding the existing evidence for clinical outcomes and failure rates of OCA transplantation in the knee joint was performed using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed, and MEDLINE from studies published between 1980 and 2017. Inclusion criteria were as follows: clinical outcomes and failure rates of OCAs for the treatment of chondral defects in the knee joint, English language, mean follow-up of 2 years and minimum follow-up of 18 months, minimum study size of 20 patients, and human studies. The methodological quality of each study was assessed using a modified version of the Coleman methodology score. RESULTS: The systematic search identified 19 studies with a total of 1036 patients. The mean 5-year survival rate across the studies included in this review was 86.7% (range, 64.1%-100.0%), while the mean 10-year survival rate was 78.7% (range, 39.0%-93.0%). The mean survival rate was 72.8% at 15 years (range, 55.8%-84.0%) and 67.5% at 20 years (range, 66.0%-69.0%). The weighted mean patient age was 31.5 years (range, 10-82 years), and the weighted mean follow-up was 8.7 years (range, 2-32 years). The following outcome measures showed significant improvement from preoperatively to postoperatively: d'Aubigné-Postel, International Knee Documentation Committee, Knee Society function, and Lysholm scores. The weighted mean reoperation rate was 30.2% (range, 0%-63%). The weighted mean failure rate was 18.2% (range, 0%-31%). Of note, revision cases, patellar lesions, and bipolar lesions demonstrated worse survival rates. CONCLUSION: Improved patient-reported outcomes can be expected after OCA transplantation, with a survival rate of 78.7% at 10 years. Revision cases, patellar lesions, and bipolar lesions were associated with worse survival rates; therefore, utilization of the most appropriate index cartilage restoration procedure and proper patient selection are key to improving results.

Autologous Cartilage Chip Transplantation Improves Repair Tissue Composition Compared With Marrow Stimulation.

BACKGROUND: Repair of chondral injuries by use of cartilage chips has recently demonstrated clinical feasibility. PURPOSE: To investigate in vivo cartilage repair outcome of autologous cartilage chips compared with marrow stimulation in full-thickness cartilage defects in a minipig model. STUDY DESIGN: Controlled laboratory study. METHODS: Six Göttingen minipigs received two 6-mm chondral defects in the medial and lateral trochlea of each knee. The two treatment groups were (1) autologous cartilage chips embedded in fibrin glue (ACC) (n = 12) and (2) marrow stimulation (MST) (n = 12). The animals were euthanized after 6 months, and the composition of repair tissue was quantitatively determined using histomorphometry. Semiquantitative evaluation was performed by means of the International Cartilage Repair Society (ICRS) II score. Collagen type II staining was used to further evaluate the repair tissue composition. RESULTS: Significantly more hyaline cartilage was found in the ACC (17.1%) compared with MST (2.9%) group ( P < .01). Furthermore, the ACC group had significantly less fibrous tissue (23.8%) compared with the MST group (41.1%) ( P < .01). No significant difference in fibrocartilage content was found (54.7% for ACC vs 50.8% for MST). The ACC group had significantly higher ICRS II scores for tissue morphological characteristics, matrix staining, cell morphological characteristics, surface assessment, mid/deep assessment, and overall assessment ( P < .05). The ACC-treated defects had significantly more collagen type II staining (54.5%) compared with the MST-treated defects (28.1%) ( P < .05). CONCLUSION: ACC transplant resulted in improved quality of cartilage repair tissue compared with MST at 6 months postoperatively. CLINICAL RELEVANCE: Further studies are needed to investigate ACC as a possible alternative first-line treatment for focal cartilage injuries in the knee.

Implantation of Autologous Cartilage Chips Improves Cartilage Repair Tissue Quality in Osteochondral Defects: A Study in Göttingen Minipigs.

BACKGROUND: Osteochondral injuries have poor endogenous healing potential, and no standard treatment has been established. The use of combined layered autologous bone and cartilage chips for treatment of osteochondral defects has shown promising short-term clinical results. PURPOSE/HYPOTHESIS: This study aimed to investigate the role of cartilage chips by comparing combined layered autologous bone and cartilage chips with autologous bone implantation alone in a Göttingen minipig model. The hypothesis was that the presence of cartilage chips would improve the quality of the repair tissue. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve Göttingen minipigs received 2 osteochondral defects in each knee. The defects were randomized to autologous bone graft (ABG) combined with autologous cartilage chips (autologous dual-tissue transplantation [ADTT]) or ABG alone. Six animals were euthanized at 6 months and 6 animals were euthanized at 12 months. Follow-up evaluation consisted of histomorphometry, immunohistochemistry, semiquantitative scoring (International Cartilage Repair Society II), and computed tomography. RESULTS: There was significantly more hyaline cartilage in the ADTT group (25.8%) compared with the ABG group (12.8%) at 6 months after treatment. At 12 months, the fraction of hyaline cartilage in the ABG group had significantly decreased to 4.8%, whereas the fraction of hyaline cartilage in the ADTT group was unchanged (20.1%). At 6 and 12 months, there was significantly more fibrocartilage in the ADTT group (44% and 60.8%) compared with the ABG group (24.5% and 41%). The fraction of fibrous tissue was significantly lower in the ADTT group compared with the ABG group at both 6 and 12 months. The implanted cartilage chips stained >75% positive for collagen type 4 and laminin at both 6 and 12 months. Significant differences were found in a number of International Cartilage Repair Society II subcategories. The volume of the remaining bone defect significantly decreased from 6 to 12 months in both treatment groups; however, no difference in volume was found between the groups at either 6 or 12 months. CONCLUSION: The presence of cartilage chips in an osteochondral defect facilitated the formation of fibrocartilage as opposed to fibrous tissue at both 6 and 12 months posttreatment. The implanted chips were present in the defect and viable after 12 months. CLINICAL RELEVANCE: This study substantiates the chondrogenic role of cartilage chips in osteochondral defects.

Experimental articular cartilage repair in the Göttingen minipig: the influence of multiple defects per knee.

BACKGROUND: A gold standard treatment for articular cartilage injuries is yet to be found, and a cost-effective and predictable large animal model is needed to bridge the gap between in vitro studies and clinical studies. Ideally, the animal model should allow for testing of clinically relevant treatments and the biological response should be reproducible and comparable to humans. This allows for a reliable translation of results to clinical studies.This study aimed at verifying the Göttingen minipig as a pre-clinical model for articular cartilage repair by testing existing clinical cartilage repair techniques and evaluating the use of two defects per knee. METHODS: Sixteen fully mature Göttingen minipigs were used. The minipigs received bilateral trochlear osteochondral drill-hole defects or chondral defects (Ø 6 mm), either one defect per knee or two defects per knee. The defects were treated with one of the following: Matrix-induced autologous chondrocyte implantation (MACI), microfracture (MFx), autologous-dual-tissue transplantation (ADTT), autologous bone graft, autologous cartilage chips. Empty chondral and osteochondral defects were used as controls. MRI and CT were performed 3 and 6 month, histology was performed 6 month postoperative. RESULTS: The repair tissue varied in morphology from non-cartilaginous fibrous tissue to fibrocartilaginous tissue as seen on MRI, CT and histology at 6 month. The worst results were seen in the empty controls, while the best results were achieved with the MACI and ADTT treatment. The use of two defects per knee did not have any significant effect on the repair response. CONCLUSION: The outcomes of the applied treatments were consistent with the outcomes in clinical studies and it was possible to apply two defects per knee. The Göttingen minipig model was easy to handle, cost-effective and provided predictable outcome. Based on this study the use of two defects per knee, one in the medial and one in the lateral trochlear facet, in male Göttingen minipigs is recommended.