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Objective Patients undergoing articular cartilage paste grafting have been shown in studies to have significant improvement in pain and function in long-term follow-ups. We hypothesized that ex vivo impacting of osteochondral autografts results in higher chondrocyte matrix production versus intact osteochondral autograft plugs. Design This institutional review board–approved study characterizes the effects of impacting osteochondral plugs harvested from the intercondylar notch of 16 patients into a paste, leaving one graft intact as a control. Cell viability/proliferation, collagen type I/II, SOX-9, and aggrecan gene expression via qRT-PCR (quantitative reverse transcription-polymerase chain reaction) were analyzed at 24 and 48 hours. Matrix production and cell morphology were evaluated using histology. Results Paste samples from patients (mean age 39.7) with moderate (19%) to severe (81%) cartilage lesions displayed 34% and 80% greater cell proliferation compared to plugs at 24 and 48 hours post processing, respectively ( P = 0.015 and P = 0.021). qRT-PCR analysis yielded a significant ( P = 0.000) increase of aggrecan, SOX-9, collagen type I and II at both 24 and 48 hours. Histological examination displayed cell division throughout paste samples, with accumulation of aggrecan around multiple chondrocyte lacunae. Conclusions Paste graft preparation resulted in increased mobility of chondrocytes by matrix disruption without loss of cell viability. The impaction procedure stimulated chondrocyte proliferation resulting in a cellular response to reestablish native extracellular matrix. Analysis of gene expression supports a regenerative process of cartilage tissue formation and contradicts long-held beliefs that impaction trauma leads to immediate cell death. This mechanism of action translates into clinical benefit for patients with moderate to severe cartilage damage.

OBJECTIVE: Patients undergoing articular cartilage paste grafting have been shown in studies to have significant improvement in pain and function in long-term follow-ups. We hypothesized that ex vivo impacting of osteochondral autografts results in higher chondrocyte matrix production versus intact osteochondral autograft plugs. DESIGN: This institutional review board–approved study characterizes the effects of impacting osteochondral plugs harvested from the intercondylar notch of 16 patients into a paste, leaving one graft intact as a control. Cell viability/proliferation, collagen type I/II, SOX-9, and aggrecan gene expression via qRT-PCR (quantitative reverse transcription-polymerase chain reaction) were analyzed at 24 and 48 hours. Matrix production and cell morphology were evaluated using histology. RESULTS: Paste samples from patients (mean age 39.7) with moderate (19%) to severe (81%) cartilage lesions displayed 34% and 80% greater cell proliferation compared to plugs at 24 and 48 hours post processing, respectively (P = 0.015 and P = 0.021). qRT-PCR analysis yielded a significant (P = 0.000) increase of aggrecan, SOX-9, collagen type I and II at both 24 and 48 hours. Histological examination displayed cell division throughout paste samples, with accumulation of aggrecan around multiple chondrocyte lacunae. CONCLUSIONS: Paste graft preparation resulted in increased mobility of chondrocytes by matrix disruption without loss of cell viability. The impaction procedure stimulated chondrocyte proliferation resulting in a cellular response to reestablish native extracellular matrix. Analysis of gene expression supports a regenerative process of cartilage tissue formation and contradicts long-held beliefs that impaction trauma leads to immediate cell death. This mechanism of action translates into clinical benefit for patients with moderate to severe cartilage damage.

This review describes a novel method developed for processing porcine tendon and other ligament implants that enables in situ remodeling into autologous ligaments in humans. The method differs from methods using extracellular matrices (ECMs) that provide postoperative orthobiological support (i.e., augmentation grafts) for healing of injured ligaments, in that the porcine bone-patellar-tendon-bone itself serves as the graft replacing ruptured anterior cruciate ligament (ACL). The method allows for gradual remodeling of porcine tendon into autologous human ACL while maintaining the biomechanical integrity. The method was first evaluated in a preclinical model of monkeys and subsequently in patients. The method overcomes detrimental effects of the natural anti-Gal antibody and harnesses anti-non-gal antibodies for the remodeling process in two steps: Step 1. Elimination of α-gal epitopes-this epitope that is abundant in pigs (as in other nonprimate mammals) binds the natural anti-Gal antibody, which is the most abundant natural antibody in humans. This interaction, which can induce fast resorption of the porcine implant, is avoided by enzymatic elimination of α-gal epitopes from the implant with recombinant α-galactosidase. Step 2. Partial cross-linking of porcine tendon with glutaraldehyde-this cross-linking generates covalent bonds in the ECM, which slow infiltration of macrophages into the implant. Anti-non-gal antibodies are produced in recipients against the multiple porcine antigenic proteins and proteoglycans because of sequence differences between human and porcine homologous proteins. Anti-non-gal antibodies bind to the implant ECM, recruit macrophages, and induce the implant destruction by directing proteolytic activity of macrophages. Partial cross-linking of the tendon ECM decreases the extent of macrophage infiltration and degradation of the implant and enables concomitant infiltration of fibroblasts that follow the infiltrating macrophages. These fibroblasts align with the implant collagen fibers and secrete their own collagen and other ECM proteins, which gradually remodel the porcine tendon into human ACL. This ligamentization process lasts ∼2 years and the biomechanical integrity of the graft is maintained throughout the whole period. These studies are the first, and so far the only, to demonstrate remodeling of porcine tendon implants into permanently functional autologous ACL in humans.

Background Revision of failed surgical treatments of osteochondritis dissecans (OCD) lesions remains a challenge without an obvious solution. The aim of this study was to evaluate seven consecutive patients undergoing osteochondral grafting of a failed OCD repair. Methods The mean time from surgery to the latest evaluation was 7.0 years. IKDC, WOMAC, Tegner, and MRI studies were collected both preoperatively and during follow-up. Evaluation of the graft was assessed using the magnetic resonance observation of cartilage repair tissue (MOCART) grading system. Results Over the course of the study period, five patients required additional surgery with a study median of one additional surgery (range, zero to 3). At most recent follow-up, there was significant improvement from preoperative values in median IKDC (p = 0.004), WOMAC (p = 0.030), and Tegner (p = 0.012). Complete cartilage fill and adjacent tissue integration of the paste graft were observed by MRI evaluation in five of the seven (71.4%) patients. Definitive correlation between clinical outcomes and MRI scores was not observed. Conclusions This study shows promising results of osteochondral grafting as a viable option for the revision of failed OCD lesion repairs; however, more patients are needed to fully support its efficacy in these challenging failed revision cases.

The purpose of this study was to evaluate the efficacy of meniscus allograft transplantation in an active patient population with moderate to severe cartilage damage and the procedure’s ability to allow sports participation postoperatively. Forty-nine patients with moderate to severe cartilage damage who underwent meniscus allograft transplantation were included in this study; those with symptoms related to articular cartilage damage also underwent articular cartilage repair. Kaplan–Meier (KM) survival estimate, potential hazards to survival, and subjective clinical outcomes were analyzed. For KM survival, failure was defined as progression to knee arthroplasty, surgical removal of the meniscus transplant without revision, a self-reported follow-up pain level that was more than preoperative level, or constant moderate pain with no relief from non-operative treatment. The mean follow-up time was 8.6 ± 4.2 years. The mean age at surgery was 45.3 ± 12.9 years. Meniscus transplantation was performed in 37 medial cases and 12 lateral cases. There were 41 patients with Outerbridge Grade IV and 8 with Grade III. Thirty-six (73.5 %) patients were able to participate in sporting activities postoperatively. Eleven (22.4 %) meniscus transplants failed at an average of 5.2 ± 4.4 years. The KM mean estimated survival time was 12.6 ± 0.7 years. No tested risks were found to affect sports participation or procedure success. Meniscus transplantation is a viable surgical option for patients with severe cartilage damage and missing or irreparable menisci to provide significant improvements in pain and function levels in the medium to long term with the majority of patients achieving their goal of participation in sporting activities. These results indicate that symptomatic patients may be able to participate in sports activities for an average of 12.6 years following meniscus transplantation. Case series, Level IV.

Background. Understanding anti-non-gal antibody response is of significance for success in xenotransplantation. Long-term anti-non-gal response in humans was studied in patients transplanted with porcine patellar tendon (PT) lacking -gal epitopes, for replacing ruptured anterior cruciate ligament (ACL). Methods. Porcine PTs were treated with recombinant -galactosidase to eliminate -gal epitopes and with glutaraldehyde for moderate cross-linking of collagen fibers. The processed pig PTs were implanted to replace ruptured ACL in patients. Results. In five of six evaluable subjects, the xenografts have continued to function for over two years and passed all functional stability assessments. Thus, processed porcine PT seems to be appropriate for replacing ruptured human ACL.Enzyme-linkedimmunosorbentassayandWesternblotstudiesindicatedthatallsubjectsproducedanti-non-gal antibodies against multiple pig xenoproteins, but not against human ligament proteins. Production of anti-non-gal antibodies peaked two to six months posttransplantation and disappeared after two years. Conclusions. These antibodies contribute to a low-level inflammatory process that aids in gradual xenograft replacement by infiltrating host fibroblasts that align with the pig collagen “scaffold” and secrete collagen matrix. The assays monitoringanti-non-galantibodieswillhelptodeterminewhetherlong-termsurvivalofliveorganxenograftsrequires complete suppression of this antibody response.

Purpose: We present meniscus allograft survival data at least 2 years from surgery for 45 patients (47 allografts) with significant arthrosis to determine if the meniscus can survive in an arthritic joint. Type of Study: Prospective, longitudinal survival study. Methods: Data were collected for 31 men and 14 women, mean age 48 years (range, 14 to 69 years), with preoperative evidence of significant arthrosis and an Outerbridge classification greater than II. Failure is established by previous studies as allograft removal. No patient was lost to follow-up. Results: The success rate was 42 of 47 allografts (89.4%) with a mean failure time of 4.4 years as assessed by Kaplan-Meier survival analysis. Statistical power is greater than 0.9, with α = 0.05 and N=47. There was significant mean improvement in preoperative versus postoperative self-reported measures of pain, activity, and functioning, with P = .001, P = .004, and P = .001, respectively, as assessed by a Wilcoxon rank-sum test with P = .05. Conclusions: Meniscus allografts can survive in a joint with arthrosis, challenging the contraindications of age and arthrosis severity. These results compare favorably with those in previous reports of meniscus allograft survival in patients without arthrosis. Level of Evidence: Level IV.

Focal arthritic defects in the knee lead to pain, swelling, and dysfunction. Treatment of the defects has includeddrilling, abrasion, and grafting. This report describes our surgical technique of autogenous articular cartilage grafting of arthritic and traumatic articular cartilage lesions. Articular cartilage grafting can be performed as a single arthroscopic outpatient procedure. The mixture of articular cartilage and cancellous bone appears to provide a supportive matrix for cartilage formation. Pain relief is excellent if careful surgical technique and a defined rehabilitation program is followed. Further collagen typing data and additional biopsies will reveal more about the durability of the newly formed cartilage.

We describe 119 meniscal allograft transplantations performed concurrently with articular cartilage repair in 115 patients with severe articular cartilage damage. In all, 53 (46.1%) of the patients were over the age of 50 at the time of surgery. The mean follow-up was for 5.8 years (2 months to 12.3 years), with 25 procedures (20.1%) failing at a mean of 4.6 years (2 months to 10.4 years). Of these, 18 progressed to knee replacement at a mean of 5.1 years (1.3 to 10.4). The Kaplan-Meier estimated mean survival time for the whole series was 9.9 years (sd 0.4). Cox’s proportional hazards model was used to assess the effect of covariates on survival, with age at the time of surgery (p = 0.026) and number of previous operations (p = 0.006) found to be significant. The survival of the transplant was not affected by gender, the severity of cartilage damage, axial alignment, the degree of narrowing of the joint space or medial versus lateral allograft transplantation. Patients experienced significant improvements at all periods of follow-up in subjective outcome measures of pain, activity and function (all p-values < 0.05), with the exception of the seven-year Tegner index score (p = 0.076).

The meniscus performs as a knee joint stabilizer and shock absorber as the femoral condyle bears weight on the tibia, translating and rotating on the tibial plateau. A damaged meniscus is often partially removed rather than repaired. Patients without an intact meniscus have few choices: live with the pain, select joint debridement procedures, undergo meniscus allograft transplantation or undergo artifi cial joint replacement. Despite this, meniscus transplantation has been, until recently, a technique in its infancy. The procedure can be surgically demanding; however, recent studies suggest that meniscus transplantation is a rewarding soft tissue reconstruction that can be useful for arthritic as well as pristine knees to alleviate pain, restore function, and ultimately, delay or avoid joint arthroplasty.

Purpose: This study proposes treatment methods to provide a mechanically competent, immunocompatible, and sterile porcine graft for human knee ligament reconstruction. Methods: The anterior cruciate ligament (ACL) was reconstructed by using treated porcine patellar tendon grafts or controls of untreated porcine grafts or allografts in 20 rhesus monkeys. Animals were stratified into 2-, 6-, and 12-month postreconstruction cohorts. Serologic and histologic assessments were performed to evaluate host immunological and cellular response. Healing and functional integrity of the ACL reconstructions were assessed by tensile biomechanical testing. Results: Untreated porcine grafts were acutely resorbed and rejected, whereas treated porcine grafts and allografts were incorporated by the host as functional grafts. Temporal histologic assessment of treated porcine grafts and rhesus grafts revealed gradual host cellular infiltration and graft collagen remodeling through a similar mechanism of ligamentization. Biomechanical evaluations support graft functional integration with no difference between allograft and treated graft reconstructions. Conclusion: Rhesus allograft and treated porcine grafts presented with similar healing profiles in a long-term evaluation of ACL reconstruction. Clinical Relevance: Immunochemical modification and sterilization of porcine patellar tendon grafts may improve initial biocompatibility and long-term functionality of xenografts in musculoskeletal applications.

To prospectively assess clinical outcomes and regeneration of osteoarthritic cartilage lesions treated with an articular cartilage paste grafting technique.Prospective, longitudinal case series.We treated 125 patients (136 procedures; 34% female, 66% male; mean age, 46 years; range, 17 to 73 years) with an Outerbridge classification of grade IV lesions with an articular cartilage paste graft. Clinical data were recorded 2 to 12 years from surgery, with 20 of 145 patients lost to follow-up over 12 years (13.7%). Clinical outcomes were captured annually with validated Western Ontario and McMaster Universities Arthritis Index (WOMAC), International Knee Documentation Committee (IKDC), and Tegner subjective questionnaires. Regenerated cartilage biopsy specimens were obtained at second-look arthroscopy from 66 patients and evaluated as to quality and quantity of defect fill by a blinded, independent histopathology reviewer.Preoperative versus postoperative validated pain, functioning, and activity measures improved significantly (P.001). Clinically, 18 of the 125 patients were considered failures (14.4%), with 10 patients undergoing subsequent joint arthroplasty and 8 who reported worse pain after surgery. Regional histologic variation occurred. Forty-two of 66 biopsy specimens (63.6%) showed strong and consistent evidence of replacement of their articular surface, and 18 of 66 biopsy specimens (27.3%) showed development of areas of cartilage.Paste grafting is a low-cost, 1-stage arthroscopic treatment for patients with Outerbridge classification grade IV arthritic chondral lesions. The procedure offers excellent, long-lasting, pain relief, restored functioning, and possibility of tissue regeneration for patients with painful chondral lesions in both arthritic and traumatically injured knees.Level IV, case series.

Transplantation of discordant xenograft tissues usually results in antibody-mediated hyperacute rejection response. It has been speculated that because cartilage has a limited vascular, neural, and lymphatic supply, it might be immunologically privileged and may not undergo hyperacute or chronic rejection. Moreover, porcine and bovine cartilage were found to express very low amounts of alpha-galactosyl epitopes (Gal alpha1-3Gal beta1-4GlcNAc-R). To evaluate animal cartilage for possible human transplantation, xenograft meniscal cartilage was transplanted from pigs and cows into the suprapatellar pouches of six cynomolgus monkeys (group 1). In a second group of six monkeys (group 2), porcine meniscal cartilage and porcine articular cartilage plugs were evaluated. During the 2-month evaluation period in group 1, all monkeys displayed an extensive humoral response to the xenograft, as indicated by the increase in production of antibodies against bovine and porcine cartilage. Upon explant, all meniscal cartilage samples in this group demonstrated histological evidence of chronic rejection, including fibroplasia, encapsulation, mononuclear infiltrates, foreign body giant cells, and eosinophilic infiltrates. There was no difference between the response seen in untreated tissues and that seen in tissues treated with UV irradiation or ozone oxidation. In group 2, the menisci explanted after 1 month displayed extensive infiltration of eosinophils alone or eosinophils mixed with mononuclear cells. The mononuclear infiltrates consisted primarily of CD4+ and CD8+ T cells and of macrophages. The articular cartilage plugs demonstrated only a small area of fibrous encapsulation and leukocyte infiltration at the periphery. This study suggests that xenograft cartilage tissue does not appear to be immunoprivileged and is unsuitable for human implantation due to a chronic rejection mechanism, which is evident already within 1 month after transplantation. In addition, this study may serve as a general model for the primate immune response against xenografts in the absence of hyperacute rejection.