Large Articular Cartilage Defects Research Articles

Effectiveness and Safety of Matrix-Associated Autologous Chondrocyte Implantation for the Treatment of Articular Cartilage Defects: A Real-World Data Analysis in Japan

Background: The effectiveness and safety of matrix-associated autologous chondrocyte implantation with an autologous periosteal flap (pMACI) remain unclear. The Japanese Ministry of Health, Labor, and Welfare requires postmarketing surveillance of all patients undergoing pMACI using the tissue-engineered product JACC. Purpose: To evaluate the effectiveness and safety of pMACI for large articular cartilage defects (≥4 cm2) in the knee joint using real-world data analysis. Study Design: Case series; Level of evidence, 4. Methods: Data were collected from patients who underwent pMACI between 2012 and 2019, with 2 years of follow-up. The primary outcomes were the Lysholm knee score and Knee injury and Osteoarthritis Outcome Score (KOOS) at 6, 12, and 24 months. Adverse events were assessed by physical examination, magnetic resonance imaging, and/or arthroscopy. Results: Overall, 232 knees in 225 patients who presented with trauma (198 knees) or osteochondritis dissecans (34 knees) in the medial (132 knees) and lateral (44 knees) femoral condyle, patella (25 knees), trochlea (86 knees), and tibial plateau (4 knees) were included. The mean age of the patients was 40.9 ± 15.0 years, with mean cartilage defects of 5.6 ± 2.4 cm2 in size. Concomitant surgeries, such as osteotomy (50 knees), ligament reconstruction (27 knees), meniscal procedures (28 knees), osteochondral autograft transplantation (24 knees), and microfracture (14 knees), were performed in 113 (48.7%) knees. The minimal clinically important difference in the Lysholm knee score and KOOS Symptoms subscale was achieved in 79.7% and 63.5% of patients, respectively, and the Patient Acceptable Symptom State was achieved in 90.1% and 73.7%, respectively. Substantial clinical benefit was achieved in the KOOS Sports/Recreation and Quality of Life subscales at 39.6% and 37.8%, respectively. Knees that underwent concomitant microfracture had significantly worse KOOS values than the remainder of the cohort. Complications, including effusion (16.8%), graft delamination (14.7%), knee contracture (9.1%), graft hypertrophy (8.2%), and ossification (3.4%), were observed in 86 (37.1%) knees. Osteochondritis dissecans was significantly associated with graft hypertrophy and ossification, whereas concomitant surgery was significantly associated with delamination and contracture. Treatment failure required additional cartilage procedures in 11 (4.7%) knees. Conclusion: Treatment of large cartilage defects (≥4 cm2) with pMACI resulted in improved outcome scores in approximately 75% of patients. However, complications occurred in one-third of patients, and 4.7% required reoperation.

Articular Cartilage Injury; Current Status and Future Direction.

Today, treatments of cartilage and osteochondral lesions are routine clinical procedures. The avascular and hard-to-self-repair nature of cartilage tissue has posed a clinical challenge for the replacement and reconstruction of damaged cartilage. Treatment of large articular cartilage defects is technically difficult and complex, often accompanied by failure. Articular cartilage cannot repair itself after injury due to a lack of blood vessels, lymph, and nerves. Various treatments for cartilage regeneration have shown encouraging results, but unfortunately, none have been the perfect solution. New minimally invasive and effective techniques are being developed. The development of tissue engineering technology has created hope for articular cartilage reconstruction. This technology mainly supplies stem cells with various sources of pluripotent and mesenchymal stem cells. This article describes the treatments in detail, including types, grades of cartilage lesions, and immune mechanisms in cartilage injuries.

Hydrogel-based and spheroid-based autologous chondrocyte implantation of the knee show similar 2-year functional outcomes: An analysis based on the German Cartilage Registry (KnorpelRegister DGOU).

To compare short-term patient-reported outcomes (PRO) of two contemporary matrix-associated autologous chondrocyte implantation (M-ACI) products for the treatment of large articular cartilage defects of the knee. A retrospective, registry-based, matched-pair analysis was performed, comparing PRO ofpatients undergoing isolated M-ACI with either Spherox™, a spheroid-based ACI (Sb-ACI), or NOVOCART™Inject, a hydrogel-based ACI product (Hb-ACI), for a focal full-thickness cartilage defect of the knee ≥4 cm2. Matching parameters included age, sex, body mass index, defect size, defect localization, symptom duration and previous surgeries. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC) score were obtained up to the 24-month follow-up. The total KOOS response rate and percentage of patients attaining a substantial clinical benefit (SCB) in KOOS subscores were calculated. A total of 45 patients per group were matched. The response rate after 24 months was not significantly different between the groups (Sb-ACI 64.4% vs. Hb-ACI 82.2%, p = 0.057). The number of patients with a SCB at 24 months was not significantly different in any KOOS subscore, despite significantly higher improvement of the total KOOS (14.8 ± 16.2 vs. 21.5 ± 15.4, p = 0.047) and KOOS pain in the Hb-ACI group (12.2 ± 18.6 vs. 20.6 ± 19.1, p = 0.037). The IKDC score in the Hb-ACI group was significantly higher at the 12-and 24-month follow-up (60.7 ± 20.2 vs. 70.9 ± 18.0, p = 0.013). The response rate and number of patients achieving an SCB were not significantly different between patients treated with Sb-ACI or Hb-ACI. Both procedures can achieve favourable 2-year PRO. Hb-ACI was associated with better PRO between 1 and 2 years postoperatively;however, the clinical relevance of this benefit is yet to be proven. III, Retrospective comparative study.

Responsiveness of Patient-Reported Outcome Measures After Large Knee Articular Cartilage Transplantation: A Systematic Review and Meta-analysis

Background: Cartilage transplantation is commonly used to treat large (>4 cm2) articular cartilage defects of the knee. The 2 most common transplants are osteochondral allograft transplantation and autologous chondrocyte implantation. Several patient-reported outcome measures (PROMs) have been used to determine the efficacy of treatment, but it is unknown which measures are the most effective. Purpose: To report the multiple PROMs used after large knee articular cartilage transplantation surgery and to compare the responsiveness between them. Study Design: Meta-analysis; Level of evidence, 4. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search of the PubMed/MEDLINE and Web of Science databases was performed. A total of 181 articles met inclusion criteria. Patient and study characteristics were extracted, including pre- and postoperative means for PROMs. From the articles that met inclusion criteria for responsiveness analysis (2+ PROMs reported, 1-year minimum follow-up, reported pre- and postoperative means and standard deviations; n = 131), the authors compared the responsiveness between PROM instruments using effect size and relative efficiency (RE) if a PROM could be compared with another in ≥10 articles. Results: A total of 10,015 patients (10,093 knees; mean age, 34.8 years; mean body mass index, 26.1) were included in this study. The mean follow-up time was 58.3 months (range, 1.5-247.2 months), imaging findings were reported in 80 articles (44.2%), patient satisfaction was reported in 39 articles (21.5%), and range of motion was reported in 10 articles (5.5%). There were 58 unique PROM instruments identified, with the most used being the International Knee Documentation Committee (IKDC) score (n = 118; 65.2%), followed by Knee injury and Osteoarthritis Outcome Score (KOOS) Pain (n = 58; 32.0%), KOOS Sport and Recreation (n = 58; 32.0%), KOOS Quality of Life (n = 57; 31.5%), KOOS Activities of Daily Living (n = 57; 31.5%), and KOOS Symptoms (n = 57; 31.5%). Overall, IKDC was found to have the greatest effect size (1.68) and the best responsiveness of the other PROMs, which include KOOS Pain (RE, 1.38), KOOS Symptoms (RE, 3.06), KOOS Activities of Daily Living (RE, 1.65), KOOS Sport and Recreation (RE, 1.44), Lysholm (RE, 1.76), and Tegner (RE, 1.56). Conclusion: The IKDC is the most responsive PROM after large knee articular cartilage transplantation surgery. The IKDC score is recommended for assessing outcomes after cartilage transplantation surgery.

Current Advances in Regenerative Medicine for Articular Cartilage Injury: Progress and Market Trends

Today, treatments of cartilage and osteochondral lesions are routine clinical procedures. Treatment of large Articular Cartilage (AC) defects is technically difficult and complex, often accompanied by failure. Articular cartilage is a highly specialized connective tissue with limited ability to repair itself after injury due to a lack of blood vessels, lymph, and nerves. Therefore, without sufficient and potent intervention, cartilage lesions can easily lead to progressive tissue degeneration, disabling joint pain, and eventually the degenerative disease, Osteoarthritis (OA). Various treatments for cartilage regeneration have shown encouraging results, but unfortunately, none of them have been the perfect solution. New minimally invasive and effective techniques are being developed. The development of tissue engineering technology has created strong promise to engineer or regenerate functional and healthy articular cartilage. In this technology, potential stem cell sources are mainly supplied with pluripotent stem cells and mesenchymal stem cells from various sources. In the meantime, some such as BioSeed®-C and NOVOCART® have been marketed. In this review, the common techniques of articular cartilage reconstruction and the clinical application of articular cartilage tissue engineering are described in detail.

Poster 365: Initial outcomes after unicompartmental tibiofemoral bipolar osteochondral and meniscus allograft transplantation in the knee using high-viability tissues

Objectives: To report initial outcomes for unicompartmental tibiofemoral bipolar osteochondral allograft transplantation (OCAT) with meniscus allograft transplantation (MAT) using fresh high-cell- viability tissues for treatment of knee articular cartilage defects with meniscus deficiency. The study was designed to test the hypothesis that primary OCAT and MAT using high-viability tissues will be associated with successful short-term (2 to 6 years) outcomes based on statistically significant and clinically meaningful improvements in pain and function in the majority of patients. Methods: With IRB approval and documented informed consent, patients who underwent primary OCAT and MAT for large articular cartilage defects with meniscus deficiency involving at least one femoral condyle, tibial plateau, and meniscus, all of which were opposing (bipolar). Surgeries were defined as Uni when patients underwent OCAT and MAT involving one femoral condyle, tibial plateau, and meniscus in the same compartment or Uni-Plus when patients underwent Uni OCAT and MAT with at least one other OCA transplant to treat a large (>2.5cm2) grade III or IV focal articular cartilage defect of the patella, trochlea, femoral condyle, or tibial plateau. Patients who had at least 2-year follow up data regarding complications, failures, adherence, and patient reported outcome measures (PROMs) were analyzed. Patients who required OCA and/or MAT revision or artificial arthroplasty were defined as treatment failures. Patient reported outcome measures (PROMs) including VAS pain, IKDC, SANE, PROMIS Global Health and Physical Function, were collected at 3 and 6 months and then yearly after transplantation. Outcomes were compared based on patient sex, age, and BMI, tobacco use, previous and concurrent procedures, differences in number of surfaces transplanted (Uni vs Uni-Plus), and adherence. Significance was set at P < 0.05. Differences in PROMs were also assessed for minimum clinically important differences. Results: Seventy-six patients (n=52 males; 68%) met inclusion criteria (mean followup = 52 months; median = 56 months; range, 24-70 months). Mean age was 41.1 years (range, 15-69 years) and mean body mass index (BMI) was 28.9 kg/m2 (range, 17-46). Forty-eight patients underwent OCAT(s) in addition to Uni (Uni-Plus). Eight patients (10.5%) underwent concurrent ACL reconstruction, and 28 patients (36.8%) underwent ipsilateral lower extremity osteotomy in order to address co-morbidities. Twenty-three patients (30.3%) were documented to be non-adherent during the first year after transplantation. Initial (>2-year) success rate was 77.6% with 8 patients (10.5%) undergoing OCA and/or MAT revision and 9 patients (11.8%) converted to arthroplasty. Variables associated with increased risk for treatment failure (revision or arthroplasty) included ipsilateral osteotomy (p = .046; OR = 3.3), ipsilateral concurrent procedure (p = .0057; OR = 5.5), and non-adherence (p = .0009; OR = 7.2). None of the patients undergoing OCA and/or MAT revision surgery in the present study required arthroplasty at the time of data analysis such that overall success rate for primary and revision unicompartmental bipolar OCA plus MAT was 88.2%. There were statistically significant (p < .0001) and clinically important improvements from preoperative levels for all patient reported outcomes at each annual follow-up time point. Conclusions: Unicompartmental tibiofemoral bipolar osteochondral and meniscus allograft transplantation can result in successful short-term (2 to 6 years) outcomes and satisfaction in the majority (78%) of patients. Primary MOPS-preserved OCAT and MAT for treatment of femoral condyle and tibial plateau articular cartilage defects with concurrent meniscus deficiency was associated with statistically significant and clinically meaningful improvements in patient-reported measures of pain and function.

Engineering large, anatomically shaped osteochondral constructs with robust interfacial shear properties

Despite the prevalence of large (>5 cm2) articular cartilage defects involving underlying bone, current tissue-engineered therapies only address small defects. Tissue-engineered, anatomically shaped, native-like implants may address the need for off-the-shelf, tissue-repairing therapies for large cartilage lesions. This study fabricated an osteochondral construct of translationally relevant geometry with robust functional properties. Scaffold-free, self-assembled neocartilage served as the chondral phase, and porous hydroxyapatite served as the osseous phase of the osteochondral constructs. Constructs in the shape and size of an ovine femoral condyle (31 × 14 mm) were assembled at day 4 (early) or day 10 (late) of neocartilage maturation. Early osteochondral assembly increased the interfacial interdigitation depth by 244%, interdigitation frequency by 438%, interfacial shear modulus by 243-fold, and ultimate interfacial shear strength by 4.9-fold, compared to late assembly. Toward the development of a bioprosthesis for the repair of cartilage lesions encompassing up to an entire condylar surface, this study generated a large, anatomically shaped osteochondral construct with robust interfacial mechanical properties and native-like neocartilage interdigitation.

Cartilage Repair Capacity within a Single Full-Thickness Chondral Defect in a Porcine Autologous Matrix-Induced Chondrogenesis Model Is Affected by the Location within the Defect.

Large articular cartilage defects are a challenge to regenerative surgery. Biomaterial scaffolds might provide valuable support for restoration of articulating surface. The performance of a composite biomaterial scaffold was evaluated in a large porcine cartilage defect. Cartilage repair capacity of a biomaterial combining recombinant human type III collagen (rhCo) and poly-(l/d)-lactide (PLA) was tested in a porcine model. A full-thickness chondral defect covering the majority of the weightbearing area was inflicted to the medial femoral condyle of the right knee. Spontaneous cartilage repair and nonoperated healthy animals served as controls. The animals were sacrificed after a 4-month follow-up. The repair tissue was evaluated with the International Cartilage Repair Society (ICRS) macroscopic score, ICRS II histological score, and with micro-computed tomography. Additionally, histopathological evaluation of lymph nodes and synovial samples were done for toxicological analyses. The lateral half of the cartilage defect in the operated groups showed better filling than the medial half. The mean overall macroscopic score for the rhCo-PLA, spontaneous, and nonoperated groups were 5.96 ± 0.33, 4.63 ± 0.42, and 10.98 ± 0.35, respectively. The overall histological appearance of the specimens was predominantly hyaline cartilage in 3 of 9 samples of the rhCo-PLA group, 2 of 8 of the spontaneous group, and 9 of 9 of the nonoperated group. The use of rhCo-PLA scaffold did not differ from spontaneous healing. The repair was affected by the spatial properties within the defect, as the lateral part of the defect showed better repair than the medial part, probably due to different weightbearing conditions.

Magnetic nanocarriers as a therapeutic drug delivery strategy for promoting pain-related motor functions in a rat model of cartilage transplantation

Cartilage is an avascular tissue with low cellularity and insufficient self-repair response. In clinical practice, a large articular cartilage defect is usually fixed by cartilage transplantation. Importantly, the fast repair process has been demanded postoperatively in the area between the host cartilage and the transplanted cartilage. In the past few years, magnetic nanoparticles have drawn great attention due to their biocompatible, biodegradable, and nontoxic properties. In addition, the nanoparticles can easily pass through the cell plasma membrane and increase the cellular uptake efficiency. Here, a therapeutic drug delivery strategy was proposed for cartilage repair. The prepared kartogenin (KGN)-conjugated magnetic nanocarriers (KGN@NCs) promoted the viability of chondrocytes in vitro. In a rat model of cartilage transplantation, intra-articularly delivered KGN@NCs generated cartilage with a flat surface and a high level of aggrecan in vivo. Notably, KGN@NCs were also capable of improving the pain-related motor functions. They promoted the motor functional parameters including the print area and intensity to restore to a normal level compared with the single KGN. Therefore, these therapeutic drug nanocarriers provided the potential for cartilage repair.

The effect of cryoprotectant vehicle solution on cartilage cell viability following vitrification.

Osteochondral allografts are often used to repair large articular cartilage defects to prevent or delay the onset of osteoarthritis. This approach is limited by the timely acquisition and use of allograft tissue since standard hypothermic protocols allow for a maximum storage of 4weeks. Vitrification is a proven technique for the long-term preservation of cells and tissues, but requires careful determination of parameters to be successful, particularly for articular cartilage. One parameter that is infrequently considered is the choice of cryoprotectant vehicle solution. The aim of this study was to evaluate the impact of a subset of vehicle solutions on an established vitrification protocol for articular cartilage. These solutions were phosphate-buffered saline (PBS), Dulbecco's Modified Eagle's Medium: Nutrient Mixture F-12 (DMEM), X-VIVO, and Unisol-CV (UCV). Both the solution pH at various points throughout vitrification and the cell viability of porcine articular cartilage slices following vitrification were measured. Using randomized block ANOVA, it was found that the normalized cell viability of articular cartilage vitrified in UCV was significantly greater than that of PBS (p < 0.05) and may be greater than those of DMEM and X-VIVO (p < 0.1). There was no correlation between pH parameters and cell viability, although significant differences between calculated pH parameters were identified. These results provide information to guide the design of effective vitrification protocols for articular cartilage.

Use of Osteochondral and Meniscal Allografts from Bone Cuts of Total Knee Arthroplasty for the Treatment of Tibial Plateau Malunions: A Case Series of Four Patients Showing Early Results.

Intra-articular malunion of tibial plateau fracture is a complex problem to treat. We are presenting outcomes of our series of patients of malunited tibial plateau fractures treated with osteo-chondro-meniscal allograft from lateral tibial plateau harvested from patients undergoing total knee arthroplasty (TKA). The technique was used in four patients. Preoperative computed tomography (CT) scan was used to match donor and recipient graft dimensions and to measure any malalignment. Patients were evaluated for Visual analogue Scale (VAS) for pain (scale 1-10cm), WOMAC (Western Ontario McMaster Osteo-Arthritis Index) score, knee range of motion, and limb alignment. There were three medial tibial plateau malunions and one lateral tibial plateau malunion. Articular comminution with depression was seen in all of them. One patient underwent concurrent high tibial osteotomy for the elevation of the medial tibial plateau and posterior cruciate ligament reconstruction was performed concurrently in one patient. All patients showed improvement in knee range of motion, WOMAC score, and VAS score for knee pain. Limb alignment improved in all cases. Radiologically there was consolidation of the allograft in all the cases at 6months. The mean follow-up was 15.2months (range 12-18months). Osteochondral allograft can be a good choice for reconstructing large articular cartilage defects in tibial plateau malunions. Osteo-chondro-meniscal grafts obtained during TKA can be a viable alternative for reconstructing such defects with excellent early clinical, functional, and radiological outcomes. IV.

Effect of quercetin on chondrocyte phenotype and extracellular matrix expression

Due to the poor repair ability of cartilage tissue, regenerative medicine still faces great challenges in the repair of large articular cartilage defects. Quercetin is widely applied as a traditional Chinese medicine in tissue regeneration including liver, bone and skin tissues. However, the evidence for its effects and internal mechanisms for cartilage regeneration are limited. In the present study, the effects of quercetin on chondrocyte function were systematically evaluated by CCK8 assay, PCR assay, cartilaginous matrix staining assays, immunofluorescence assay, and western blotting. The results showed that quercetin significantly up-regulated the expression of chondrogenesis genes and stimulated the secretion of GAG (glycosaminoglycan) through activating the ERK, P38 and AKT signalling pathways in a dose-dependent manner. Furthermore, in vivo experiments revealed that quercetin-loaded silk protein scaffolds dramatically stimulated the formation of new cartilage-like tissue with higher histological scores in rat femoral cartilage defects. These data suggest that quercetin can effectively stimulate chondrogenesis in vitro and in vivo, demonstrating the potential application of quercetin in the regeneration of cartilage defects.

Efficacy of one-stage cartilage repair using allogeneic mesenchymal stromal cells and autologous chondron transplantation (IMPACT) compared to nonsurgical treatment for focal articular cartilage lesions of the knee: study protocol for a crossover randomized controlled trial

BackgroundArticular cartilage defects in the knee have poor intrinsic healing capacity and may lead to functional disability and osteoarthritis (OA). “Instant MSC Product accompanying Autologous Chondron Transplantation” (IMPACT) combines rapidly isolated recycled autologous chondrons with allogeneic MSCs in a one-stage surgery. IMPACT was successfully executed in a first-in-man investigator-driven phase I/II clinical trial in 35 patients. The purpose of this study is to compare the efficacy of IMPACT to nonsurgical treatment for the treatment of large (2–8 cm2) articular cartilage defects in the knee.MethodsSixty patients will be randomized to receive nonsurgical care or IMPACT. After 9 months of nonsurgical care, patients in the control group are allowed to receive IMPACT surgery. The Knee Injury and Osteoarthritis Outcome Score (KOOS), pain (numeric rating scale, NRS), and EuroQol five dimensions five levels (EQ5D-5 L) will be used to compare outcomes at baseline and 3, 6, 9, 12, and 18 months after inclusion. Cartilage formation will be assessed at baseline, and 6 and 18 months after inclusion using MRI. An independent rheumatologist will monitor the onset of a potential inflammatory response. (Severe) adverse events will be recorded. Lastly, the difference between IMPACT and nonsurgical care in terms of societal costs will be assessed by monitoring healthcare resource use and productivity losses during the study period. A health economic model will be developed to estimate the incremental cost-effectiveness ratio of IMPACT vs. nonsurgical treatment in terms of costs per quality adjusted life year over a 5-year time horizon.DiscussionThis study is designed to evaluate the efficacy of IMPACT compared to nonsurgical care. Additionally, safety of IMPACT will be assessed in 30 to 60 patients. Lastly, this study will evaluate the cost-effectiveness of IMPACT compared to nonsurgical care.Trial registrationNL67161.000.18 [Registry ID: CCMO]2018#003470#27 [EU-CTR; registered on 26 March 2019]NCT04236739 [ClinicalTrials.gov] [registered after start of inclusion; 22 January 2020]

Mesenchymal Stem/Progenitor Cells Derived from Articular Cartilage, Synovial Membrane and Synovial Fluid for Cartilage Regeneration: Current Status and Future Perspectives.

Large articular cartilage defects remain an immense challenge in the field of regenerative medicine because of their poor intrinsic repair capacity. Currently, the available medical interventions can relieve clinical symptoms to some extent, but fail to repair the cartilaginous injuries with authentic hyaline cartilage. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stem/progenitor cells with or without scaffolds. Mesenchymal stem/progenitor cells are promising graft cells for tissue regeneration, but the most suitable source of cells for cartilage repair remains controversial. The tissue origin of mesenchymal stem/progenitor cells notably influences the biological properties and therapeutic potential. It is well known that mesenchymal stem/progenitor cells derived from synovial joint tissues exhibit superior chondrogenic ability compared with those derived from non-joint tissues; thus, these cell populations are considered ideal sources for cartilage regeneration. In addition to the progress in research and promising preclinical results, many important research questions must be answered before widespread success in cartilage regeneration is achieved. This review outlines the biology of stem/progenitor cells derived from the articular cartilage, the synovial membrane, and the synovial fluid, including their tissue distribution, function and biological characteristics. Furthermore, preclinical and clinical trials focusing on their applications for cartilage regeneration are summarized, and future research perspectives are discussed.

OCA Transplantation Outcomes for Replacing Large Bipolar Defects in the Knee using Novel Techniques

Objectives:Osteochondral allograft (OCA) transplantation can functionally restore large articular cartilage defects in the knee, shoulder, hip and ankle. Studies have reported 10-year survivorship between 71% and 85% and up to 74% survivorship at 15 years. Outcomes after OCA treatment have been good to excellent, even in the athletic population in which 88% of patients returned to sport, including 79% returning to preinjury level of sport. However, OCA transplantations for bipolar defects in the knee have traditionally had less favorable results. With the advent of improved allograft preservation methods and refined surgical techniques, OCA transplantations for bipolar defects in the knee have shown a trend toward better outcomes. Therefore, the objective of this study was to report early functional outcomes associated with OCA transplantations to replace large (>4 cm2) bipolar articular cartilage defects in the knee using novel techniques for graft preservation, enhancing bone ingrowth, and implantation.Methods:With IRB approval, patients were enrolled in a dedicated registry for prospective assessment of outcomes after OCA surgery. Demographic and operative data were collected. Outcomes assessments including VAS pain, VAS level of function, IKDC, SANE and PROMIS Mobility are prospectively collected at 6 months and yearly after surgery. All complications and re-operations are recorded. OCA survival is determined based on maintenance of acceptable levels of pain and function and/or need for revision surgery. Data are compared to pre-operative and/or pre-injury levels using repeated measures analyses with significance set at p<0.05.Results:Large bipolar OCA transplantations were performed in 23 knees: femorotibial (n=19), patellofemoral (n=4). Mean age of patients was 34.6 years. Mean pre-operative pain, function, IKDC, SANE and PROMIS Mobility scores were 4.7, 4.1, 40.8, 40.1 and 42.1, respectively. At 6 months postop (n=17), mean scores improved to 1.3, 6, 56.2, 71.8 and 46.1, respectively. At 1 year (n=11), mean scores further improved to 0.4, 8.4, 76.7, 80.6 and 58.4, respectively (Table). Two (8.7%) meniscotibial grafts failed in the first 6 months after surgery and were successfully revised by a second OCA transplantation, making initial survival 91.3%. Five (21.7%) other patients required minor reoperations for lysis of adhesions to restore range of motion and/or screw removal. All subjects are enrolled in the registry and outcomes assessments are ongoing and will be updated for presentation.Conclusion:Bipolar osteochondral allograft transplantation surgeries for treatment of large (>4 cm2) femorotibial or patellofemoral articular cartilage defects in the knee using novel techniques are associated with significant improvements in levels of pain and function at 1 year after surgery.Table – Summary of Outcomes for Large Bipolar OCA Transplantation in Knees Time Point Pain Function IKDC SANE PROMIS Mobility Pre-Operative 4.74.140.840.142.1 6 months 1.3*6.056.271.8*46.1 1 year 0.4*8.4*76.7*80.6*58.4** denotes statistically significant (p<0.05) improvement from pre-op

Articular cartilage: injury, healing, and regeneration

Treatment of large articular cartilage defects is technically demanding, and healing is a complicated process often associated with failure. The aim of treatment of articular cartilage injuries is to induce an acceptable healing process. Invasive and noninvasive treatments usually have good short- to mid-term outcomes; however, long-term results have been disappointing probably due to scar formation. Thus, current options are more palliative than curative. Tissue engineering and regenerative medicine (TERM) that includes scaffolds, healing factors, stem cells, and genetic engineering was introduced to orthopaedic research in the last 2 decades. Although TERM has demonstrated utility, the expected goals are not necessarily realistic. Despite advancements, several problems still exist and must be solved. This review discusses articular cartilage structure and function, injury types, the healing process, and factors that influence the healing response. Current treatment modalities, including TERM-based strategies, and their limitations are reviewed to provide future directions for treatment.

Importance of Donor Chondrocyte Viability for Osteochondral Allografts

Background: Osteochondral allograft (OCA) transplantation provides a biological treatment option for functional restoration of large articular cartilage defects in multiple joints. While successful outcomes after OCA transplantation have been linked to viable donor chondrocytes, the importance of donor cell viability has not been comprehensively validated. Purpose: To use a canine model to determine the importance of donor chondrocyte viability at the time of implantation with respect to functional success of femoral condylar OCAs based on radiographic, gross, cell viability, histologic, biochemical, and biomechanical outcome measures. Study Design: Controlled laboratory study. Methods: After approval was obtained from the institutional animal care and use committee, adult female dogs (N = 16) were implanted with 8-mm cylindrical OCAs from male dogs in the lateral and medial femoral condyles of 1 knee. OCAs were preserved for 28 or 60 days after procurement, and chondrocyte viability was quantified before implantation. Two different storage media, temperatures, and time points were used to obtain a spectrum of percentage chondrocyte viability at the time of implantation. A successful outcome was defined as an OCA that was associated with graft integration, maintenance of hyaline cartilage, lack of associated cartilage disorder, and lack of fibrillation, fissuring, or fibrous tissue infiltration of the allograft based on subjective radiographic, gross, and histologic assessments at 6 months after implantation. Results: Chondrocyte viability ranged from 23% to 99% at the time of implantation. All successful grafts had >70% chondrocyte viability at the time of implantation, and no graft with chondrocyte viability <70% was associated with a successful outcome. Live-dead stained sections and histologic findings with respect to cell morphological features suggested that successful grafts were consistently composed of viable chondrocytes in lacunae, while grafts that were not successful were composed of nonviable chondrocytes with infiltration of fibroblasts from the surrounding recipient tissues. In situ polymerase chain reaction (fluorescence in situ hybridization [FISH]) assays were performed in an attempt to distinguish donor (male) cells from recipient (female) cells. Unfortunately, this technique was exceptionally difficult to perform on intact articular cartilage sections, and consistent, repeatable data could not be obtained from this testing. However, the data did support histologic and live-dead data, which strongly suggested that successful grafts retained viable donor (male) chondrocytes and unsuccessful grafts degraded and were replaced by fibrous tissue populated with recipient (female) fibroblasts. Conclusion: Viable chondrocytes in OCAs at the time of transplantation are primarily responsible for maintenance of donor articular cartilage health in the long term. Clinical Relevance: Optimizing chondrocyte viability in all aspects of OCA transplantation—including procurement, processing, storage, transportation, and surgical implantation—needs to be a primary focus for OCA clinical use.

Importance Of Donor Chondrocyte Viability in Osteochondral Allografting

Objectives:Osteochondral allografting (OCA) provides a biologic treatment option for functional restoration of large articular cartilage defects in multiple joints. While successful outcomes after OCA have been linked to viable donor chondrocytes, the importance of donor cell viability has not been comprehensively validated. The purpose of this study was to use a canine model to determine the importance of donor chondrocyte viability at the time of implantation with respect to functional success of femoral condylar OCAs based on gross, cell viability, histologic, biochemical, and biomechanical outcome measures.Methods:With IACUC approval, adult female dogs (n = 16) were implanted with 8-mm cylindrical osteochondral allografts from male dogs in the lateral and medial femoral condyles of one knee. Osteochondral allografts were preserved for 28 or 60 days after procurement and chondrocyte viability was quantified prior to implantation. Two different storage media, temperatures and time points were used in order to obtain a spectrum of %chondrocyte viability at the time of implantation. A successful outcome was defined as an osteochondral allograft that was associated with graft integration, maintenance of hyaline cartilage, lack of associated cartilage disorder, and lack of fibrillation, fissuring, or fibrous tissue infiltration of the allograft based on subjective radiographic, arthroscopic, gross, and histologic assessments at 6 months after implantation.Results:Chondrocyte viability ranged from 23% to 99% at the time of implantation. All successful grafts had greater than 70% chondrocyte viability at the time of implantation and no graft with chondrocyte viability <70% was associated with a successful outcome. Live-dead stained sections and histologic findings with respect to cell morphology suggested that successful grafts were consistently comprised of viable chondrocytes in lacunae, while grafts that were not successful were comprised of non-viable chondrocytes with infiltration of fibroblasts from the surrounding recipient tissues. In situ PCR (FISH) assays were performed in an attempt to distinguish donor (male) cells from recipient (female) cells. Unfortunately, this technique was exceptionally difficult to perform on intact articular cartilage sections, and consistent, repeatable data could not be obtained from this testing. However, the data did support histologic and live-dead data, which strongly suggested that successful grafts retained viable donor (male) chondrocytes and unsuccessful grafts degraded and were replaced by fibrous tissue populated with recipient (female) fibroblasts.Conclusion:Viable chondrocytes in osteochondral allografts at the time of transplantation are primarily responsible for maintenance of donor articular cartilage health long term. Optimizing chondrocyte viability in all aspects of osteochondral allografting - including procurement, processing, storage, transportation, and surgical implantation - needs to be a primary focus for clinical use of OCA.

Distal Femoral Fresh Osteochondral Allografts: Follow-up at a Mean of Twenty-two Years.

Osteochondral defects of the knee in young, active patients represent a challenge to the orthopaedic surgeon. Our study examined long-term outcomes of the use of fresh allograft for posttraumatic osteochondral and osteochondritis dissecans defects in the distal aspect of the femur. We reviewed the cases of sixty-three patients who underwent osteochondral allograft transplantation to the distal aspect of the femur between 1972 and 1995. Five patients who resided out of the country were lost to follow-up. Indications for the allograft procedure were an age of less than fifty years and a unipolar posttraumatic osteochondral or osteochondritis dissecans defect in the distal aspect of the femur that was larger than 3 cm in diameter and 1 cm in depth. Fifty-eight patients ages eleven to forty-eight years at the time of surgery (mean age, twenty-eight years) were followed for a mean of 21.8 years (range, fifteen to thirty-two years). Thirteen of the fifty-eight cases required further surgery; three underwent graft removal, nine were converted to total knee arthroplasty, and one underwent multiple debridements followed by above-the-knee amputation. Three patients died during the study due to unrelated causes. A Kaplan-Meier analysis of graft survival showed rates of 91%, 84%, 69%, and 59% at ten, fifteen, twenty, and twenty-five years, respectively. Patients with surviving grafts had good function, with a mean modified Hospital for Special Surgery (HSS) score of 86 at fifteen years or more following the allograft transplant surgery. Late osteoarthritic degeneration on radiographs was associated with lower HSS scores and poorer clinical outcomes. Fresh osteochondral allograft was found to provide a long-term solution for large articular cartilage defects in the distal aspect of the femur in young, active patients. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Treatment of Full-Thickness Chondral Defects of the Knee With Autologous Chondrocyte Implantation

Background: Autologous chondrocyte implantation (ACI) has been proven an effective method in treating large articular cartilage defects in short- or medium-term follow-up clinical studies. Hypothesis: First generation ACI of patients with large full-thickness chondral defects of the knee could yield reliable functional outcomes after a minimum follow-up of 5 years. Study Design: Case series; Level of evidence, 4. Methods: Between 1997 and 2005, 42 patients (45 knees) underwent first generation ACI for symptomatic chondral defects of the knee. All patients had moderate to large (mean, 5.33 cm2) full-thickness chondral defects. Patients were evaluated using the International Cartilage Repair Society (ICRS) score, the International Knee Documentation Committee (IKDC) Knee Examination Form, the Tegner activity score, the Lysholm score, the Stanmore functional rating score, and a visual analog scale (VAS) for pain. Results: The mean follow-up was 96 months (range, 62-144 months). At the final follow-up, a significant increase in all scores was recorded. Compared with preoperative findings, the median Lysholm score significantly improved, increasing from 56.0 to 89.0 (P < .05). The IKDC and the Tegner activity score showed significant improvement postoperatively, increasing from 45 and 5.5 to 69 and 6.5, respectively (P < .05). The mean ICRS improved from grade 3.8 preoperatively to grade 2.8 postoperatively (P < .05). The Stanmore functional rating score and the VAS pain score were decreased from 3.06 and 7.33 to 0.94 and 2, respectively (P < .05). Reoperation was required in 5 patients. In 2 of them graft failure was recorded due to degeneration or partial detachment, respectively. Conclusion: The long-term outcomes of our series support the effectiveness of first generation ACI in both pain relief and functional rehabilitation of patients with large full-thickness osteochondral defects of the knee.