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Objective Hypertrophic cartilage formation is a major setback in mesenchymal stem cells (MSCs)–mediated cartilage repair, and overcoming it requires optimization of differentiation. Here, we tested the miR-140 activated collagen hydrogel for the chondrogenic differentiation of MSCs and to produce hyaline cartilage. Methods Bone marrow MSCs isolated from 3 patients were pretreated with miR-140 and then chondrogenic differentiated. The 3-dimensional (3D) transfection potential of 5 different transfection reagents (Polyethylenimine, Lipofectamine, TransIT-X2, Amide:Cholesterol-based liposomes [AmC] and AmC pegylated with Tocofersolan [AmCTOC]) was compared and the reagent that showed higher green fluorescent protein (GFP) expression was selected. Finally, the collagen hydrogel was activated using miR-140-transfection complex and sustained delivered to MSCs during chondrogenic differentiation. After differentiation, the outcome was assessed by reverse transcription–polymerase chain reaction (RT-PCR), histology, immunohistochemistry, and compared with scrambled miRNA treated control. Results Pretreatment of MSCs with miR-140 significantly increased the expression of cartilage-specific genes ( COL2A1, SOX9, and ACAN) with reduced hypertrophic chondrocyte ( COL10A1) marker expression and better safranin-O staining than the control. The AmCTOC liposome showed a significant increase in 3D transfection of GFP expressing plasmid than the others. Furthermore, the knockdown of GAPDH using siRNA in HEK cells and expression of GFP mRNA in human bone marrow MSCs confirmed the 3D-transfection efficiency of AmCTOC. The sustained delivery of miR-140 using activated matrix formed a hyaline cartilage-like tissue with minimal COL10A1 expression in RT-PCR and immunohistochemistry. Conclusion Our results demonstrated the therapeutic potential of miR-140-activated hydrogel for MSCs-based cartilage tissue engineering, which could also be used for endogenous stem cells–mediated cartilage repair.

Objective 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. Design 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. Results 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. Conclusions 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.

Objective The aim of this study was to investigate texture features from T2 maps as a marker for distinguishing the maturation of repair tissue after 2 different cartilage repair procedures. Design Seventy-nine patients, after either microfracture (MFX) or matrix-associated chondrocyte transplantation (MACT), were examined on a 3-T magnetic resonance (MR) scanner with morphological and quantitative (T2 mapping) MR sequences 2 years after surgery. Twenty-one texture features from a gray-level co-occurrence matrix (GLCM) were extracted. The texture feature difference between 2 repair types was assessed individually for the femoral condyle and trochlea/anterior condyle using linear regression models. The stability and reproducibility of texture features for focal cartilage were calculated using intra-observer variability and area under curve from receiver operating characteristics. Results There was no statistical significance found between MFX and MACT for T2 values ( P = 0.96). There was, however, found a statistical significance between MFX and MACT in femoral condyle in GLCM features autocorrelation ( P < 0.001), sum of squares ( P = 0.023), sum average ( P = 0.005), sum variance ( P = 0.0048), and sum entropy ( P = 0.05); and in anterior condyle/trochlea homogeneity ( P = 0.02) and dissimilarity ( P < 0.001). Conclusion Texture analysis using GLCM provides a useful extension to T2 mapping for the characterization of cartilage repair tissue by increasing its sensitivity to tissue structure. Some texture features were able to distinguish between repair tissue after different cartilage repair procedures, as repair tissue texture (and hence, probably collagen organization) 24 months after MACT more closely resembled healthy cartilage than did MFX repair tissue.

Objective Focal cartilage injuries are debilitating and difficult to treat. Biological cartilage repair procedures are used for patients younger than 40 years, and knee arthroplasties are generally reserved for patients older than 60 years. Resurfacing implants are well suited for patients in this treatment gap. The objective was to investigate the 10-year survival of resurfacing implants in the Danish Knee Arthroplasty Registry. Design In this retrospective cohort study, patients treated with resurfacing implants were followed longitudinally in the Danish Knee Arthroplasty Registry from 1997 to 2020. The primary endpoint was revision surgery. The survival of the resurfacing implants was analyzed by Kaplan-Meier method. Results A total of 379 resurfacing implant procedures were retrieved from the Danish Knee Arthroplasty Registry. The mean age and weight of patients were 50 years (SD = 11) and 84 kg (SD = 17), respectively. The indications for surgery were as follows: secondary osteoarthritis (42%), primary osteoarthritis (32%), and osteochondral lesions (20%). Within the follow-up period, 70 (19%) of the implants were revised to arthroplasties. The 1-, 5-, and 10-year revision-free survival estimation was 0.95 (95% CI 0.93-0.97), 0.84 (95% CI 0.80-0.88), and 0.80 (95% CI 0.75-0.84), respectively. The median time to revision was 2 years. Conclusion The 10-year revision-free survival rate for resurfacing implants was 80%. Based on the revision rates, this treatment offers a viable alternative to biological cartilage repair methods in patients aged 40 to 60 years with focal cartilage pathology. Improved patient selection could further improve the implant survival rate. Further studies are needed to investigate this treatment method.

After high fractures of the mandibular condyle, the insufficient blood supply to the condyle often leads to poor bone and cartilage repair ability and poor clinical outcome. Parathyroid hormone (PTH) can promote the bone formation and mineralization of mandibular fracture, but its effects on cartilage healing after the free reduction and internal fixation of high fractures of the mandibular condyle are unknown. In this study, a rabbit model of free reduction and internal fixation of high fractures of the mandibular condyle was established, and the effects and mechanisms of PTH on condylar cartilage healing were explored. Forty-eight specific-pathogen-free (SPF) grade rabbits were randomly divided into two groups. In the experimental group, PTH was injected subcutaneously at 20 µg/kg (PTH (1–34)) every other day, and in the control group, PTH was replaced with 1 ml saline. The healing cartilages were assessed at postoperative days 7, 14, 21, and 28. Observation of gross specimens, hematoxylin eosin staining and Safranin O/fast green staining found that every-other-day subcutaneous injection of PTH at 20 µg/kg promoted healing of condylar cartilage and subchondral osteogenesis in the fracture site. Immunohistochemistry and polymerase chain reaction showed that PTH significantly upregulated the chondrogenic genes Sox9 and Col2a1 in the cartilage fracture site within 7–21 postoperative days in the experimental group than those in the control group, while it downregulated the cartilage inflammation gene matrix metalloproteinase-13 and chondrocyte terminal differentiation gene ColX. In summary, exogenous PTH can stimulate the formation of cartilage matrix by triggering Sox9 expression at the early stage of cartilage healing, and it provides a potential therapeutic protocol for high fractures of the mandibular condyle.

Background: Microfracture augmentation can be a cost-effective single-step alternative to current cartilage repair techniques. Trypsin pretreatment combined with a growth factor–functionalized self-assembling KLD hydrogel (“functionalized hydrogel”) has been shown to improve overall cartilage repair and integration to surrounding tissue in small animal models of osteochondral defects. Hypothesis: Microfracture combined with trypsin treatment and a functionalized hydrogel will improve reparative tissue quality and integration as compared with microfracture alone in an equine model. Study Design: Controlled laboratory study. Methods: Bilateral cartilage defects (15-mm diameter) were created on the medial trochlear ridge of the femoropatellar joints in 8 adult horses (16 defects total). One defect was randomly selected to receive the treatment, and the contralateral defect served as the control (microfracture only). Treatment consisted of 2-minute trypsin pretreatment of the surrounding cartilage, subchondral bone microfracture, and functionalized hydrogel premixed with growth factors (platelet-derived growth factor and heparin-binding insulin-like growth factor 1). After surgery, all horses were subjected to standardized controlled exercise on a high-speed treadmill. Clinical evaluation was conducted monthly, and radiographic examinations were performed at 2, 16, 24, 32, 40, and 52 weeks after defect creation. After 12 months, all animals were euthanized. Magnetic resonance imaging, arthroscopy, gross pathologic evaluation of the joint, histology, immunohistochemistry, and biomechanical analyses were performed. Generalized linear mixed models (with horse as random effect) were utilized to assess outcome parameters. When P values were Results: Improved functional outcome parameters were observed for the treatment group, even though mildly increased joint effusion and subchondral bone sclerosis were noted on imaging. Microscopically, treatment resulted in improvement of several histologic parameters and overall quality of repaired tissue. Proteoglycan content based on safranin O–fast green staining was also significantly higher in the treated defects. Conclusion: Trypsin treatment combined with functionalized hydrogel resulted in improved microfracture augmentation. Clinical Relevance: Therapeutic strategies for microfracture augmentation, such as those presented in this study, can be cost-effective ways to improve cartilage healing outcomes, especially in more active patients.

Background: Multiple cartilage repair techniques are available for chondral defects in the knee. Optimal treatment is controversial. Purpose: To evaluate change from baseline in the 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales among different cartilage repair techniques of the knee. Study Design: Systematic review and meta-analysis; Level of evidence, 1A. Methods: Medline and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for randomized controlled trials with minimum 1 year follow-up reporting change from baseline KOOS (delta KOOS) subscale values. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. A meta-analysis was performed on the following surgery types: microfracture (Mfx); augmented microfracture techniques (Mfx+Augment); and culture-based therapies, including autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI). A random-effects metaregression model was used. Results: A total of 14 randomized trials with a total of 775 patients were included. The KOOS Sport and Recreation (Sport) and KOOS Quality of Life (QOL) were the 2 most responsive subscales after operative intervention. Outcomes from Mfx and Mfx+Augment were not different in any of the 5 KOOS subscales (minimum P > .3). The mean delta KOOS Sport after ACI/MACI was 9.9 points greater than after Mfx ( P = .021) and 11.7 points greater than after Mfx+Augment ( P = .027). Longer follow-up time correlated with greater delta KOOS Sport ( P = .028). Larger body mass index led to greater delta KOOS QOL ( P = .045). Larger cartilage defect size correlated with greater delta KOOS Pain and KOOS Activities of Daily Living scores ( P = .023 and P = .002, respectively). Conclusion: The KOOS Sport and QOL were the most responsive subscales after cartilage restoration surgery of the knee. Culture-based therapies (ACI/MACI) led to clinically relevant improvements in the KOOS Sport score compared with marrow stimulation and may be a more appropriate treatment in younger and more active individuals. There were no benefits to Mfx+Augment over Mfx alone in any of the KOOS subscales.

Objective To analyze the effects of light therapy (LT) on cartilage repair for knee osteoarthritis (OA) treatment. Design The PubMed, Embase, Scopus, and Web of Science databases were searched up to August 31, 2020 to identify in vitro and in vivo studies that analyzed the effects of LT on knee cartilage for OA treatment. The study and sample characteristics, LT intervention parameters and posttreatment outcomes were analyzed. Risk of bias was assessed using the Risk of Bias Assessment for Non-randomized Studies (RoBANS) tool. Results Three in vitro and 30 in vivo studies were included. Most studies were judged as high risk of performance and detection bias. Biochemical outcomes were analyzed for both i n vitro and in vivo studies, and histological and behavioral outcomes were analyzed for in vivo studies. LT reduced extracellular matrix (ECM) degradation, inflammation, and OA progression, promoting ECM synthesis. LT improved pain-like behavior in animal models, having no apparent effect on gait performance. There were conflicting findings of some of the biochemical, histological, and behavioral outcomes. Conclusion The included studies presented different strategies and LT parameters. LT resulted in positive effects on cartilage repair and may be an adequate therapy for OA treatment.

Background: Long-term clinical evaluation of patient outcomes can steer treatment choices and further research for cartilage repair. Using mesenchymal stromal cells (MSCs) as signaling cells instead of stem cells is a novel approach in the field. Purpose: To report the 5-year follow-up of safety, clinical efficacy, and durability after treatment of symptomatic cartilage defects in the knee with allogenic MSCs mixed with recycled autologous chondrons in first-in-human study of 1-stage cartilage repair. Study Design: Case series; Level of evidence, 4. Methods: This study is an investigator-driven study aiming at the feasibility and safety of this innovative cartilage repair procedure. Between 2013 and 2014, a total of 35 patients (mean ± SD age, 36 ± 8 years) were treated with a 1-stage cartilage repair procedure called IMPACT (Instant MSC Product Accompanying Autologous Chondron Transplantation) for a symptomatic cartilage defect on the femoral condyle or trochlear groove. Subsequent follow-up after initial publication was performed annually using online patient-reported outcome measures with a mean follow-up of 61 months (range, 56-71 months). Patient-reported outcome measures included the KOOS (Knee injury and Osteoarthritis Outcome Score), visual analog scale for pain, and EuroQol–5 Dimensions. All clinical data and serious adverse events, including additional treatment received after IMPACT, were recorded. A failure of IMPACT was defined as a chondral defect of at least 20% of the index lesion with a need for a reintervention including a surgical procedure or an intra-articular injection. Results: Using allogenic MSCs, no signs of a foreign body response or serious adverse reactions were recorded after 5 years. The majority of patients showed statistically significant and clinically relevant improvement in the KOOS and all its subscales from baseline to 60 months: overall, 57.9 ± 16.3 to 78.9 ± 17.7 ( P < .001); Pain, 62.3 ± 18.9 to 79.9 ± 20.0 ( P = .03); Function, 61.6 ± 16.5 to 79.4 ± 17.3 ( P = .01); Activities of Daily Living, 69.0 ± 19.0 to 89.9 ± 14.9 ( P < .001); Sports and Recreation, 32.3 ± 22.6 to 57.5 ± 30.0 ( P = .02); and Quality of Life, 25.9 ± 12.9 to 55.8 ± 26.8 ( P < .001). The visual analog scale score for pain improved significantly from baseline (45.3 ± 23.6) to 60 months (15.4 ± 13.4) ( P < .001). Five cases required reintervention. Conclusion: This is the first study showing the midterm safety and efficacy of the proof of concept that allogenic MSCs augment 1-stage articular cartilage repair. The absence of serious adverse events and the clinical outcome support the longevity of this unique concept. These data support MSC-augmented chondron transplantation (IMPACT) as a safe 1-stage surgical solution that is considerably more cost-effective and a logistically advantageous alternative to conventional 2-stage cell-based therapy for articular chondral defects in the knee.

Objective Regulatory guidelines for preclinical cartilage repair studies suggest large animal models (e.g., sheep, goat, [mini]-pig, or horse) to obtain results representative for humans. However, information about the 3-dimensional thickness of articular cartilage at different implantation sites in these models is limited. Design To identify the most suitable site for experimental surgery, cartilage thickness at the medial femoral condyle (MFC), lateral femoral condyle (LFC), and trochlea in ovine, caprine, and porcine cadaver stifle joints was systematically measured using hematoxylin-eosin staining of 6 µm paraffin sections and software-based image analysis. Results Regarding all ventral-dorsal regions of the MFC, goat showed the thickest articular cartilage (maximal mean thickness: 1299 µm), followed by sheep (1096 µm) and mini-pig (604 µm), with the highest values in the most ventral and dorsal regions. Also for the LFC, the most ventral regions showed the thickest cartilage in goat (maximal mean thickness: 1118 µm), followed by sheep (678 µm) and mini-pig (607 µm). Except for the mini-pig, however, the cartilage thickness on the LFC was consistently lower than that on the MFC. The 3 species also differed along the transversal measuring points on the MFC and LFC. In contrast, there were no consistent differences for the regional cartilage thickness of the trochlea among goat and sheep (≥780 µm) and mini-pig (≤500 µm). Conclusions Based on their cartilage thickness, experimental defects on goat and sheep MFC may be viable options for preclinical cartilage repair studies, in addition to well-established horse models.

Background:In patients undergoing cartilage restoration of the knee, limited information is available regarding clinically important difference (CID) and Patient Acceptable Symptomatic State (PASS) estimates for commonly used patient-reported outcome measures (PROMs).Purpose:The objective of this study was to determine the CID and PASS in the population with knee cartilage restoration for the Knee injury and Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee Subjective Knee Form (IKDC) score, and the Lysholm score.Study Design:Cohort study (Diagnosis); Level of evidence, 2.Methods:Between 2012 and 2017, patients who underwent a cartilage restoration procedure were prospectively enrolled. Patients completed the KOOS, IKDC, and Lysholm, all of which were scored from 0 to 100, and completed relevant anchor questions at baseline and 1 year postoperatively. Receiver operating characteristic curve analyses were conducted to determine CID and PASS cutoff points. Multivariable regression analyses were performed to determine the effect of age, sex, and baseline score on likelihood of achieving CID and PASS.Results:Of the 113 patients enrolled, 53 (47%) were male, and the mean age was 36 years. The CID values for the PROMs were 10.7 for KOOS Symptoms, 8.3 for KOOS Pain, 8.8 for KOOS Activities of Daily Living (ADL), 30.0 for KOOS Sports and Recreation, 18.8 for KOOS Quality of Life (QOL), 9.2 for IKDC, and 13.0 for Lysholm. The PASS values were 71.5 for KOOS Symptoms, 72.2 for KOOS Pain, 86.8 for KOOS ADL, 43.8 for KOOS Sports and Recreation, 50.0 for KOOS QOL, 62.1 for IKDC, and 70.0 for Lysholm. Patients with higher baseline scores were more likely to achieve PASS for the IKDC (odds ratio, 2.28; P = .03). Baseline score did not have an effect on the likelihood of achieving CID. Younger age was an independent predictor of achieving PASS and CID across all outcomes ( P < .05), but sex did not have such an effect.Conclusion:This study determined CID and PASS values for the KOOS, IKDC, and Lysholm scores among patients treated with knee cartilage restoration. Younger age was a positive prognostic variable, and higher baseline scores implied achieving PASS for the IKDC. The information in this study can be used in designing randomized controlled trials, counseling individual patients as to anticipated outcomes, and conducting responder analyses when evaluating new cartilage technology from a regulatory perspective.

Objective To determine potential predictive associations between patient-/lesion-specific factors, clinical outcome and anterior ankle impingement in patients that underwent isolated autologous matrix-induced chondrogenesis (AMIC) for an osteochondral lesion of the talus (OLT). Design Thirty-five patients with a mean age of 34.7 ± 15 years who underwent isolated cartilage repair with AMIC for OLTs were evaluated at a mean follow-up of 4.5 ± 1.9 years. Patients completed AOFAS (American Orthopaedic Foot and Ankle Society) scores at final follow-up, as well as Tegner scores at final follow-up and retrospectively for preinjury and presurgery time points. Pearson correlation and multivariate regression models were used to distinguish associations between patient-/lesion-specific factors, the need for subsequent surgery due to anterior ankle impingement and patient-reported outcomes. Results At final follow-up, AOFAS and Tegner scores averaged 92.6 ± 8.3 and 5.1 ± 1.8, respectively. Both body mass index (BMI) and duration of symptoms were independent predictors for postoperative AOFAS and Δ preinjury to postsurgery Tegner with positive smoking status showing a trend toward worse AOFAS scores, but this did not reach statistical significance ( P = 0.054). Nine patients (25.7%) required subsequent surgery due to anterior ankle impingement. Smoking was the only factor that showed significant correlation with postoperative anterior ankle impingement with an odds ratio of 10.61 when adjusted for BMI and duration of symptoms (95% CI, 1.04-108.57; P = 0.047). Conclusion In particular, patients with normal BMI and chronic symptoms benefit from AMIC for the treatment of OLTs. Conversely, smoking cessation should be considered before AMIC due to the increased risk of subsequent surgery and possibly worse clinical outcome seen in active smokers.

Objective Treatments for steroid-induced osteonecrosis of the knee remains challenging, and there has not been sufficient evidence to support joint preservation surgery. This study evaluated long-term outcomes of osteochondral autologous transplantation (OAT) for steroid-induced osteonecrosis of the knee. Design This retrospective case series included patients who underwent OAT for steroid-induced osteonecrosis of the knee from 1998 to 2008. The survivorship and need for secondary surgery were evaluated, and the clinical outcome was evaluated with the International Knee Documentation Committee (IKDC) subjective score. Preoperative and final Kellgren-Lawrence (KL) grade of the femorotibial and patellofemoral joints were individually evaluated. Results Fourteen knees of 10 patients whose mean age was 32.5 (95%CI 26.4-38.6) years were included and followed for 14.0 (12.4-15.7) years. The mean lesion size of 6.9 (5.3-8.5) cm2 was repaired using 4 median (minimum 2, maximum 5) osteochondral plugs. No revision surgeries were performed for transplanted osteochondral plugs. The IKDC subjective score improved from 32.9 (24.5-41.3) to 74.2 (61.9-88.5) ( P < 0.001). Knee flexion was improved at the final follow-up, and Seiza sitting was finally possible in 9 knees in 7 patients. Although the osteoarthritic change did not progress in femorotibial joint, patellofemoral joint showed early osteoarthritic changes at the final follow-up (mean KL grade: 0.8 [0.5-1.1]). Conclusions Prosthetic joint replacement was successfully avoided for at least the first decade by OAT in young patients with steroid-induced osteonecrosis of the knee. The progression of KL grade of the patellofemoral joint is of concern.

Objective The main purpose of the present study was to assess the risk for major revision surgery after perichondrium transplantation (PT) at a minimum of 22 years postoperatively and to evaluate the influence of patient characteristics. Design Primary outcome was treatment success or failure. Failure of PT was defined as revision surgery in which the transplant was removed, such as (unicondylar) knee arthroplasty or patellectomy. The functioning of nonfailed patients was evaluated using the International Knee Documentation Committee (IKDC) score. In addition, the influence of patient characteristics was evaluated. Results Ninety knees in 88 patients, aged 16 to 55 years with symptomatic cartilage defects, were treated by PT. Eighty knees in 78 patients were eligible for analysis and 10 patients were lost to follow-up. Twenty-eight knees in 26 patients had undergone major revision surgery. Previous surgery and a longer time of symptoms prior to PT were significantly associated with an increased risk for failure of cartilage repair. Functioning of the remaining 52 patients and influence of patient characteristics was analyzed using their IKDC score. Their median IKDC score was 39.08, but a relatively young age at transplantation was associated with a higher IKDC score. Conclusions This 22-year follow-up study of PT, with objective outcome parameters next to patient-reported outcome measurements in a unique group of patients, shows that overall 66% was without major revision surgery and patient characteristics also influence long-term outcome of cartilage repair surgery.

Objective Chondroprogenitors have recently gained prominence due to promising results seen in in vitro and animal studies as a potential contender in cell-based therapy for cartilage repair. Lack of consensus regarding nomenclature, isolation techniques, and expansion protocols create substantial limitations for translational research, especially given the absence of distinct markers of identification. The objective of this systematic review was to identify and collate information pertaining to hyaline cartilage–derived chondroprogenitors, with regard to their isolation, culture, and outcome measures. Design As per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a web-based search of Scopus and PubMed databases was performed from January 2000 to May 2020, which yielded 509 studies. A total of 65 studies were identified that met the standardized inclusion criteria which comprised of, but was not limited to, progenitors derived from fibronectin adhesion, migrated subpopulation from explant cultures, and single-cell sorting. Result Literature search revealed that progenitors demonstrated inherent chondrogenesis and minimal tendency for hypertrophy. Multiple sources also demonstrated significantly better outcomes that bone marrow–derived mesenchymal stem cells and comparable results to chondrocytes. With regard to progenitor subgroups, collated evidence points to better and consistent outcomes with the use of migratory progenitors when compared to fibronectin adhesion assay–derived progenitors, although a direct comparison between the two cell populations is warranted. Conclusion Since chondroprogenitors exhibit favorable properties for cartilage repair, efficient characterization of progenitors is imperative, to complete their phenotypic profile, so as to optimize their use in translational research for neocartilage formation.

Cartilage defects in the knee are being diagnosed with increased frequency and are treated with a variety of techniques. The aim of any cartilage repair procedure is to generate the highest tissue quality, which might correlate with improved clinical outcomes, return-to-sport, and long-term durability. Minced cartilage implantation (MCI) is a relatively simple and cost-effective technique to transplant autologous cartilage fragments in a single-step procedure. Minced cartilage has a strong biologic potential since autologous, activated non-dedifferentiated chondrocytes are utilized. It can be used both for small and large cartilage lesions, as well as for osteochondral lesions. As it is purely an autologous and homologous approach, it lacks a significant regulatory oversight process and can be clinically adopted without such limitations. The aim of this narrative review is to provide an overview of the current evidence supporting autologous minced cartilage implantation.

Objectives Chondral fractures are focal cartilage lesions without osseous attachment, most commonly seen in adolescent knees. They have limited capacity for intrinsic healing and traditional treatment has been removal of loose fragments. However, case reports of successful healing after fixation indicate that repair of the joint surface is possible. We wanted to evaluate the outcome in a cohort of patients who underwent fixation of acute chondral fractures in the knee. Design Patients treated with fixation of a chondral fracture in the knee at our institution were invited to participate in a follow-up study. The mechanism of injury, fragment properties and complications were registered. Patients completed KOOS (Knee Injury and Osteoarthritis Outcome Score) and Lysholm questionnaires and performed a validated single leg hop test. Magnetic resonance imaging (MRI) was used to assess healing of the defect and the quality of the cartilage. Results Ten patients with a median age at surgery of 15 years (12-17 years) and median follow-up of 5 years (2-9 years) were assessed. The lesions were located on the patella ( n = 7), the trochlea ( n = 2), and the lateral femoral condyle ( n = 1). Median lesion size was 250 mm2 (1.9-6.0 cm2) All patients were treated within 2 months of injury (4-58 days). All patients returned to preinjury level of sports and MRI showed retained fragments that integrated well with surrounding cartilage at follow-up. Mean Lysholm score at follow-up was 90 (73-100). Conclusion Fixation of traumatic chondral-only fragments using bioabsorbable implants may result in successful healing in adolescent patients and should be considered a treatment option in acute injuries.

Objective To prospectively assess the efficacy of GelrinC in the treatment of chondral and osteochondral femoral cartilage lesions using morphological (Magnetic Resonance Observation of Cartilage Repair Tissue [MOCART]) and quantitative (T2-mapping) magnetic resonance imaging (MRI). Design This study was designed as a prospective single-arm, open label, multicenter study. Morphological magnetic resonance imaging (MRI) for MOCART assessment and T2 mapping was performed 1 week and 6, 12, 18, and 24 months after GelrinC implantation. Evaluation of T2 mapping was based on the assessment of global T2 indices (T2 of the repair tissue [RT] divided by T2 of healthy reference cartilage) and zonal variation. Results Fifty-six (20 female) patients were prospectively enrolled. The mean MOCART score significantly increased from baseline to the 24-month follow-up with 88.8 (95% CI, 85.8-91.9; P < 0.001) for all lesions combined as well as 86.8 (95% CI, 83.0-90.6) for chondral lesions and 94.1 (95% CI, 68.55-100) for osteochondral lesions. Furthermore, based on T2 mapping, significant zonal variation of the RT was observed at 24 months ( P = 0.039), which did not differ significantly from healthy reference cartilage ( P = 0.6). Conclusion Increasing MOCART scores were observed throughout the follow-up period, indicative of maturation of the cartilage repair. Significant zonal variation of the RT at 24 months might indicate the transformation into hyaline cartilage–like RT. Slightly differing morphological outcome between chondral and osteochondral lesions, but similar global and zonal T2 indices at 24 months, support the potential of GelrinC as a treatment option for both lesion types.

The goal was to examine gender differences of patient characteristics and outcome after cartilage repair based on a collective of nearly 5,000 patients. Patient characteristics, accompanying therapies, and outcome (Knee Injury and Osteoarthritis Outcome Score [KOOS], reoperations, patient satisfaction) of 4,986 patients of the German cartilage register DGOU were assessed by t test for possible gender differences. P values

Objective To compare the efficacy and safety of costal chondrocyte–derived pellet-type autologous chondrocyte implantation (CCP-ACI) with microfracture (MFx) for repair of articular cartilage defects of the knee. Design Thirty subjects with an International Cartilage Repair Society (ICRS) grade 3 to 4 chondral defect (2-10 cm2 in area; ≤4 cm3 in volume) were randomized at a ratio of 2:1 (CCP-ACI:MFx). Twenty patients were allocated in the CCP-ACI group and 10 patients in the MFx group. CCP-ACI was performed by harvesting costal cartilage at least 4 weeks before surgery. Implantation was performed without any marrow stimulation. Efficacy and safety were assessed at weeks 8, 24, and 48 after surgery according to the magnetic resonance observation of cartilage repair tissue (MOCART) score and clinical outcomes. Results MOCART scores improved from baseline to 24 and 48 weeks postoperatively in both treatment groups. The improvement in MOCART scores in the CCP-ACI group was significantly greater than that in the MFx group at 24 and 48 weeks (39.1 vs 21.8 and 43.0 vs 24.8, respectively). The proportions of complete defect repair and complete integration were significantly higher in the CCP-ACI group than the MFx group at 48 weeks. Improvement in Lysholm score and KOOS subscores, including Function (Sports and Recreational Activity) and knee-related quality of life was significantly greater in the CCP-ACI group than the MFx group at 48 weeks (35.4 vs 31.5, 35.7 vs 28.5, and 27.9 vs 11.6, respectively). Conclusion Treatment of cartilage defects with CCP-ACI yielded satisfactory cartilage tissue repair outcomes, with good structural integration with native cartilage tissue shown by magnetic resonance imaging at 24 and 48 weeks after surgery. Level of Evidence Level 1: Randomized controlled study.

Objective. To evaluate minimum biosecurity parameters (MBP) for arthroscopic matrix-encapsulated autologous chondrocyte implantation (AMECI) based on patients’ clinical outcomes, magnetic resonance imaging (MRI) T2-mapping, Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, and International Cartilage Repair Society (ICRS) second-look arthroscopic evaluation, laying the basis for a future multicenter study. Design. Pilot clinical study. We analyzed the logistics to perform AMECI to treat focal chondral lesions in different hospitals following strict biosecurity parameters related to tissue and construct transportation, chondrocyte isolation, and cell expansion. Patient progress was analyzed with patient-reported outcome measures, MRI T2-mapping, MOCART, and ICRS arthroscopic second-look evaluation. Results. Thirty-five lesions in 30 patients treated in 7 different hospitals were evaluated. Cell viability before implantation was >90%. Cell viability in construct remnants was 87% ± 11% at 24 hours, 75% ± 17.1% at 48 hours, and 60% ± 8% at 72 hours after implantation. Mean final follow-up was 37 months (12-72 months). Patients showed statistically significant improvement in all clinical scores and MOCART evaluations. MRI T2-mapping evaluation showed significant decrease in relaxation time from 61.2 ± 14.3 to 42.9 ± 7.2 ms ( P < 0.05). Arthroscopic second-look evaluation showed grade II “near normal” tissue in 83% of patients. Two treatment failures were documented. Conclusions. It was feasible to perform AMECI in 7 different institutions in a large metropolitan area following our biosecurity measures without any implant-related complication. Treated patients showed improvement in clinical, MRI T2-mapping, and MOCART scores, as well as a low failure rate and a favorable ICRS arthroscopic evaluation at a mid-term follow-up. Level of Evidence. 2b.

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.

Background: There is an unmet need for a single-stage cartilage repair treatment that is cost-effective and chondrocyte-based. Purpose: To evaluate the safety and preliminary efficacy of autologous freshly isolated primary chondrocytes and bone marrow mononucleated cells (MNCs) seeded into a PolyActive scaffold in patients with symptomatic cartilage lesions of the knee. Study Design: Case series; Level of evidence, 4. Methods: A total of 40 patients with symptomatic knee cartilage lesions were treated with freshly isolated autologous chondrocytes combined with bone marrow MNCs delivered in a biodegradable load-bearing scaffold. The treatment requires only 1 surgical intervention and is potentially a cost-effective alternative to autologous chondrocyte implantation. The primary chondrocytes and bone marrow MNCs were isolated, washed, counted, mixed, and seeded into a load-bearing scaffold in the operating room. Patients were followed up at 3, 6, 12, 18, and 24 months. Primary endpoints were treatment-related adverse events up to 3 months, adverse implant effects between 3 and 24 months, and the implant success rate at 3 months as measured by lesion filling. Results: Successful lesion filling (≥67% on magnetic resonance imaging) was found in 40 patients at 3 months and in 32 of the 32 patients analyzed at 24 months. Significant improvement over baseline was found for visual analog scale for pain from 3 months onward; Knee injury and Osteoarthritis Outcome Score (KOOS)-Pain and KOOS-Activities of Daily Living from 6 months onward; for KOOS-Symptoms and Stiffness, KOOS-Quality of Life and International Knee Documentation Committee from 12 months onward; and for KOOS-Sport and Recreation from 18 months onward. Hyaline-like repair tissue was found in 22 of 31 patients available for biopsy. Arthralgia and joint effusion were the most common adverse events. Scaffold delamination and adhesions led to removal of the implant in 2 patients. Conclusion: The treatment of knee cartilage lesions with autologous primary chondrocytes and bone marrow MNCs, both isolated and seeded into a load-bearing PolyActive scaffold within a single surgical intervention, is safe and clinically effective. Good lesion fill and sustained clinically important and statistically significant improvement in all patient-reported outcome scores were found throughout the 24-month study. Hyaline-like cartilage was observed on biopsy specimen in at least 22 of the 40 patients. Registration: NCT01041885 (ClinicalTrials.gov identifier)

Background: In the field of cartilage repair, cell-based therapy, employing the use of mesenchymal stem cells and chondrocytes maybe a propitious treatment option. Once transferred, success of transplanted cells is determined by their immunogenicity making assessment imperative. Another contender in the field, may be articular chondroprogenitors (CPs) shown to possess chondrogenic potential and reduced expression of hypertrophy markers. Our aim was to assess immunogenic properties of CPs (non-diseased and osteoarthritic (OA)) and compare them with chondrocytes since it may be a good alternative for cell-based therapy and data regarding its immunogenic profile is limited. Methods: Human chondrocytes and CPs from the same cartilage source were isolated. Passage 0 cells characterized by fluorescence-activated cell sorting against human surface antigen were human leucocyte antigen class I (HLA-A2 and HLA-B7), HLA-DR and its costimulatory molecules (CD80 and CD86) and macrophage/monocyte marker (CD14). Results and conclusion: Our observations indicated that CPs isolated from human non-diseased and OA cartilage showed similar immunogenic properties to chondrocytes isolated from the same source with no significant difference in expression. High-to-moderate expression of MHC class I (HLA-A2 and HLA-B7) and moderate-to-low expression of MHC class II (HLA-DR and its co-stimulatory molecules CD80 and CD86) were observed. This is the first report to shed insight on the immunogenic properties of human cartilage-derived progenitors, a potential contender in the field of regenerative therapy for formation of genuine hyaline cartilage.

Objectives. The purpose of this study was to examine whether patients with diagnosed hypertension have an increased risk of graft failure following cartilage repair with either autologous chondrocyte implantation (ACI) or osteochondral allograft transplantation (OCA). We hypothesized that hypertension is related to higher ACI and OCA graft failure. Design. Patients who underwent ACI or OCA transplantation between February 2009 and December 2016 were included in this study. Inclusion criteria were (1) at least 2 years’ follow-up, (2) available information related to the living habits (smoking and medication status), and (3) available information related to the presence of hypertension, diabetes mellitus, or hyperlipidemia. To identify potential independent risk factors of graft failure, univariate screening was performed and factors with significance at a level of P < 0.1 were entered in multivariate logistic regression models. Results. A total of 368 patients (209 ACI and 159 OCA) were included into our study. In the ACI group, 61 patients’ (29.1%) graft failed. Univariate screening identified older age, female gender, defect size, higher prevalence of hypertension, and smoking as a predictor of graft failure. Following, multivariate logistic regression revealed female gender (odds ratio [OR] 1.02, P = 0.048), defect size (OR 1.07, P = 0.035), and hypertension (OR 3.73, P = 0.023) as significant independent risk factors predicting graft failure after ACI. In the OCA group, 29 patients’ (18.2%) graft failed and none of the included factors demonstrated to be a potential risk factor for graft failure. Conclusion. Hypertension, defect size, and female gender seem to predict ACI graft failure but not OCA failure.

Objective Fibrin has been used as a standard material for scaffold fixation during cartilage repair surgery. Most of the commercially available fibrin preparations need an additional method for scaffold fixation, most often with sutures, thus damaging the surrounding healthy cartilage. There is therefore a need to find alternatives to this method. In our study, we have investigated the potential possibility to use mussel adhesive protein as such an alternative. Methods In this study, hydrophobic plastic was coated with the mussel adhesive protein Mefp-1 as well as with other cell adhesives (poly-lysine, fibronectin, and collagen). Human keratinocytes and chondrocytes were seeded on these substrates at 37°C in culture medium, followed by analysis of attachment and proliferation by crystal violet staining and metabolic labelling. Performance of Mefp-1 and fibrin as tissue glues were estimated by tensional force resistance measurement of moist porcine dermis (as a correlate to scaffold) glued to dermis, cartilage, or bone at 37°C. Results Mefp-1 supported maximal cell attachment at a coating density of approximately 1 µg/cm2. This was at least as good as the other adhesives tested. In addition, it supported cell proliferation at least as good as regular tissue culture plastic over a 7-day period. Measurement of tensional force resistance showed that Mefp-1 performed equally well as fibrin when porcine dermis was glued to cartilage and bone at the same concentration. Separation of the moist tissues after 15-minute incubation required a force of approximately 1 N/cm2 for both compounds. Conclusions Mefp-1 show properties that qualify it as a compound that potentially could replace fibrin as a tissue glue for scaffold fixation. Given the possibilities to modify this protein by bioengineering, it is likely that the properties can be further improved.

Background: The use of bone marrow–derived mesenchymal stem cells (BMSCs) in cartilage repair procedures circumvents some of the limitations of autologous chondrocyte implantation (ACI), but long-term outcomes for this newer procedure are lacking. The authors previously reported comparable outcomes for the 2 procedures at 2-year follow-up. Purpose/Hypothesis: The purpose was to compare the long-term clinical outcomes of ACI versus BMSCs. It was hypothesized that there would be no significant difference between the groups in terms of patient-reported outcome scores and safety outcomes at 10-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Seventy-two patients who underwent either ACI or BMSC implantation—matched in terms of age and lesion site— were followed up to a median of at least 10 years. Patients were assessed with the 36-item Short Form Health Survey (SF-36), the International Knee Documentation Committee knee evaluation form, the Lysholm Knee Score, and the Tegner Activity Scale. In addition, information was obtained regarding any additional surgical procedures as well as safety data, with particular attention to infection and tumor formation. Results: There was an improvement in all patient-reported outcomes scores apart from the Mental Component Summary of the SF-36 after cartilage repair surgery. There was no significant difference in any of the patient-reported outcomes between cohorts at any time point. Six and 5 patients in the ACI and BMSC groups, respectively, underwent subsequent surgical procedures, including 1 total knee replacement in the BMSC group. None of the patients in either group developed any deep infection or tumor within the follow-up period. Conclusion: BMSC implantation used for the treatment of chondral defects of the knee appears to result in equivalent clinical outcomes to first-generation ACI at up to 10 years, with no apparent increased tumor formation risk.

Objective Functional cartilage repair requires the new formation of organized hyaline cartilaginous matrix to avoid the generation of fibrous repair tissue. The potential of mesenchymal progenitors was used to assemble a 3-dimensional structure in vitro, reflecting the zonation of collagen matrix in hyaline articular cartilage. Design The 3-dimensional architecture of collagen alignment in pellet cultures of chondroprogenitors (CPs) was assessed with Picrosirius red staining analyzed under polarized light. In parallel assays, the trilineage capability was confirmed by calcium deposition during osteogenesis by alizarin S staining and alkaline phosphatase staining. Using reverse transcription–quantitative polymerase chain reaction (RT-qPCR), mRNA levels of ALP, RUNX2, and BGLAP were assessed after 21 days of osteoinduction. Lipid droplets were stained with oil red O and adipogenic differentiation was confirmed by RT-qPCR analysis of PPARG and LPL gene expression. Results Under conditions promoting the chondrogenic signature in self-assembling constructs, CPs formed an aligned extracellular matrix, positive for glycosaminoglycans and collagen type II, showing developing zonation of birefringent collagen fibers along the cross section of pellets, which reflect the distribution of collagen fibers in hyaline cartilage. Induced osteogenic and adipogenic differentiation confirmed the trilineage potential of CPs. Conclusion This model promotes the differentiation and self-organization of postnatal chondroprogenitors, resulting in the formation of zonally organized engineered hyaline cartilage comparable to the 3 zones of native cartilage.

Background: Autologous chondrocyte implantation (ACI) is a well-established cartilage repair procedure; however, numerous studies have shown higher ACI graft failure rates after prior marrow stimulation techniques (MSTs). Purpose: To identify which factors may predict decreased graft survival after ACI among patients who underwent a prior MST. A secondary aim was to investigate the specificity of these predictors. Study Design: Case-control study; Level of evidence, 3. Methods: In this review of prospectively collected data, the authors analyzed 38 patients who had failed prior MST surgery and subsequently underwent collagen-covered ACI (case group). The case group was divided into graft failure ACI (n = 8, 21%) and successful ACI (n = 30, 79%). Fourteen clinical variables were categorized and analyzed to determine predictors for failure of the ACI graft: age, body mass index, sex, defect characteristics (number, size, location, etiology, type), presence of kissing lesion, intraoperative presence of intralesional osteophyte, time between an MST and ACI, previous surgery, duration of the symptoms, and concomitant surgical procedure. Preoperative magnetic resonance imaging (MRI) was used to evaluate the severity of subchondral bone marrow edema (BME), graded I (absent) to IV (severe), and the presence of subchondral cyst, hypertrophic sclerosis, and intralesional osteophyte. The effects of these MRI findings on the graft survivor were also investigated. Concurrently, a control group without a prior MST was matched to investigate the specificity of the previously determined predictors. These patients were matched individually according to age, sex, body mass index, and outcome of the procedure (failure [n = 8] or successful [n = 30] per the case group). Results: In the case group, the presence of preoperative severe BME was significantly higher among patients with failed ACI as compared with patients with successful ACI ( P < .001). In the control group, the presence of severe BME was not significantly different between the failure and successful groups ( P = .747). The ACI graft failure rate among patients with a prior MST and preoperative grade IV BME was 83.7% at 5 years postoperatively, resulting in a significantly lower survival rate as compared with patients with a prior MST and without severe BME (5-year graft failure rate, 6.5%; P < .001). All the other parameters did not differ significantly. Conclusion: After a prior MST, the presence of grade IV BME by MRI was a predictive factor for graft failure among patients who then underwent second-generation ACI.

Background:Cell-based cartilage repair performed as a single-stage procedure is an important advancement in the treatment of full-thickness cartilage injury and has potential for widespread clinical use.Purpose:To investigate the long-term clinical outcomes of cartilage repair in the knee with a hyaluronic acid–based scaffold embedded with bone marrow aspirate concentrate (HA-BMAC) for the treatment of full-thickness cartilage injury.Study Design:Case series; Level of evidence, 4.Methods:Patients underwent treatment of full-thickness chondral injury in the knee with HA-BMAC and were followed prospectively for a minimum of 6 years. Clinical outcomes were examined with patient-reported scoring instruments that consisted of the Tegner Activity Scale, International Knee Documentation Committee (IKDC) subjective score, visual analog scale, and Knee injury and Osteoarthritis Outcome Score (KOOS). Comparative analysis of pre- and postoperative scores was performed, and the effects of patient age, body mass index, lesion size, number of treated lesions, and concurrent treatment with associated procedures were examined.Results:Twenty-three patients (mean age, 48.5 years) were followed prospectively for a mean 8 years (range, 6-10 years). Median cartilage lesion size was 6.5 cm2(range, 2-27 cm2). At final follow-up, median Tegner, visual analog scale, and IKDC subjective scores were 4, 0.3, and 85, respectively. Final median KOOS subset scores were as follows: Pain, 94; Symptoms, 89; Activities of Daily Living, 99; Sports/Recreation, 85; and Quality of Life, 85. All scores were significantly increased at final follow-up ( P < .001). Comparable median outcome scores were demonstrated after categorization of patients by age, lesion size, treatment of multiple lesions, treatment of multiple knee compartments, and treatment by associated procedures. Rank correlation analysis demonstrated a negative correlation between patient age and final outcome scores of the IKDC, Tegner, and KOOS subsets of Pain, Activities of Daily Living, and Sports/Recreation. No associations were identified between body mass index or lesion size and outcome scores.Conclusion:Repair of full-thickness cartilage injury in the knee with a HA-BMAC provides good to excellent clinical outcomes at long-term follow-up in the treatment of small to large lesions. Cartilage repair with HA-BMAC leads to comparatively successful long-term outcomes in the treatment of small or large lesions, single or multiple lesions, and lesions in 1 or 2 compartments, as well as in cases of associated lesion treatment. While good outcomes can be expected among treated patients >45 years of age, outcomes may be comparatively more successful in younger patients.

Background: Recent studies demonstrated a 5% increase in cartilage repair procedures annually in the United States. There is currently no consensus regarding a superior technique, nor has there been a comprehensive evaluation of postoperative clinical outcomes with respect to a minimal clinically important difference (MCID). Purpose: To determine the proportion of available cartilage repair studies that meet or exceed MCID values for clinical outcomes improvement over short-, mid-, and long-term follow-up. Study Design: Systematic review and meta-analysis. Methods: A systematic review was performed via the Medline, Scopus, and Cochrane Library databases. Available studies were included that investigated clinical outcomes for microfracture (MFX), osteoarticular transfer system (OATS), osteochondral allograft transplantation, and autologous chondrocyte implantation/matrix-induced autologous chondrocyte implantation (ACI/MACI) for the treatment of symptomatic knee chondral defects. Cohorts were combined on the basis of surgical intervention by performing a meta-analysis that utilized inverse-variance weighting in a DerSimonian-Laird random effects model. Weighted mean improvements in International Knee Documentation Committee (IKDC), Lysholm, and visual analog scale for pain (VAS pain) scores were calculated from preoperative to short- (1-4 years), mid- (5-9 years), and long-term (≥10 years) postoperative follow-up. Mean values were compared with established MCID values per 2-tailed 1-sample Student t tests. Results: A total of 89 studies with 3894 unique patients were analyzed after full-text review. MFX met MCID values for all outcome scores at short- and midterm follow-up with the exception of VAS pain in the midterm. OATS met MCID values for all outcome scores at all available time points; however, long-term data were not available for VAS pain. Osteochondral allograft transplantation met MCID values for IKDC at short- and midterm follow-up and for Lysholm at short-term follow-up, although data were not available for other time points or for VAS pain. ACI/MACI met MCID values for all outcome scores (IKDC, Lysholm, and VAS pain) at all time points. Conclusion: In the age of informed consent, it is important to critically evaluate the clinical outcomes and durability of cartilage surgery with respect to well-established standards of clinical improvement. MFX failed to maintain VAS pain improvements above MCID thresholds with follow-up from 5 to 9 years. All cartilage repair procedures met MCID values at short- and midterm follow-up for IKDC and Lysholm scores; ACI/MACI and OATS additionally met MCID values in the long term, demonstrating extended maintenance of clinical benefits for patients undergoing these surgical interventions as compared with MFX.

Objective The limits of the microfracture (MFX) treatment in terms of lesion size and long-term tissue functionality makes it necessary to investigate different alternatives to repair focal cartilage lesions. The present study aims at evaluating the efficacy of a minimally invasive approach against the conventional MFX to repair a chondral defect in rabbits. An injectable scaffold of BMP-2 pre-encapsulated in PLGA microspheres dispersed in a Pluronic F-127 solution is proposed as support of cells and controlled delivery system for the growth factor. Design MFX was compared versus the injectable system seeded with mesenchymal stem cells (MSCs), both without BMP-2 and under controlled release of BMP-2 at 2 different doses (3 and 12 µg/scaffold). The different treatments were evaluated on a 4-mm diameter chondral defect model using 9 experimental groups of 4 rabbits (8 knees) each, throughout 24 weeks. Results Histologically, all the treated groups, except MFX treated, responded significantly better than the control group (nontreated defect). Although no significant differences were found between the treated groups, only BMP(12), MSC-BMP(12), and MFX-BMP(3) groups showed nonsignificant differences when compared with the normal cartilage. Conclusions The hydrogel system proposed to control the release rate of the BMP-2 was safe, easily injectable, and also provided good support for cells. Treatments with MSCs or BMP-2 repaired efficiently the chondral lesion created in rabbits, being less invasive than MFX treatment.

Objective Osteochondral allograft transplantation (OCA) is a well-established procedure for patients with symptomatic cartilage defects in the knee. Revision to OCA after prior failed cartilage repair has shown similar clinical outcomes as primary OCA; however, most of the failed procedures were arthroscopic procedures for smaller defects. There is no literature investigating the clinical outcomes after OCA for prior failed autologous chondrocyte implantation (ACI) for the treatment of large chondral defects of the knee. The purpose of this study was therefore to determine clinical outcomes of patients undergoing revision to OCA after prior failed ACI as compared with a matched cohort of patients undergoing OCA as a primary cartilage repair procedure (primary OCA). Design In this review of prospectively collected data, we analyzed data from 26 patients with at least 2 years follow-up. Thirteen patients who underwent revision to OCA after prior failed ACI by a single surgeon were compared with a matched group of patients who underwent primary OCA. The patients were matched per age, gender, body mass index, and defect size. Patient-reported outcomes, reoperations, and survival rates were compared between groups. Results There were no significant differences in patient-reported clinical outcome scores between the groups at final follow-up. Moreover, there was no significant difference in reoperation rates and survival rates between the groups. Conclusion The present study demonstrates that revision to OCA is a viable treatment option with favorable functional outcomes and similar reoperation and survival rate as primary OCA even for revision of large chondral defects previously treated with ACI.

Objective The study aims were to determine whether BST-CarGel, a chitosan scaffold for cartilage repair, can be mixed with bone marrow aspirate concentrate (BMAC) to create a cell seeded implant with comparative properties to standard BST-CarGel mixed with blood. Design Whole blood and bone marrow were harvested from 12 patients who underwent cartilage repair surgery using BMAC after informed consent. A validated in vitro testing model was used to assess the following 6 conditions: (1) BST-CarGel mixed with whole blood (CG-WB), (2) BST-CarGel mixed with bone marrow (CG-BM), (3) BST-CarGel mixed with bone marrow concentrate (CG-BMAC), (4) whole blood (WB), (5) bone marrow (BM), and (6) bone marrow concentrate and batroxobin (BMAC-BTX). Cell retention and viability within the BST-CarGel/BMAC clots were investigated. Results In our study, BM and BMAC (processed using the Harvest, SmartPrep2 system and reactivated with batroxibin) when combined with BST-CarGel produced a product that had similar clot contraction, macroscopic properties, and histological appearance to standard BSTCarGel mixed with blood. Mononucleated cells from the BMAC were retained within the scaffold and remained viable until clot dissolution in vitro. Conclusions By combining BST-CarGel with BMAC in the manner described, bone marrow–derived mononucleated cells can be retained within the chondral defect potentially negating the need for microfracture. Further in vivo work is required to confirm these potential benefits and determine if this combination will result in more durable cartilage repair and improved clinical outcomes.

Background: One of the most important limitations of osteochondral autograft transplant is the adverse effect on donor sites in the knee. Ultrapurified alginate (UPAL) gel is a novel biomaterial that enhances hyaline-like cartilage repair for articular defects. To avoid the need for knee cartilage autografting when treating osteochondritis dissecans (OCD) of the capitellum, we developed a surgical procedure involving a bone marrow stimulation technique (BMST) augmented by implantation of UPAL gel. Hypothesis: BMST augmented by UPAL gel implantation improves the cartilage repair capacity and provides satisfactory clinical outcomes in OCD of the capitellum. Study Design: Case series; Level of evidence, 4. Methods: A total of 5 athletes with advanced capitellar OCD in the dominant elbow underwent BMST augmented by implantation of UPAL gel. The osteochondral defects were filled with UPAL gel after BMST. At a mean follow-up of 97 weeks, all patients were evaluated clinically and radiographically. Results: At final follow-up, all 5 patients had returned to competitive-level sports, and 4 patients were free from elbow pain. The mean Timmerman-Andrews score significantly improved from 100 to 194 points. Radiographically, all patients exhibited graft incorporation and a normal contour of the subchondral cortex. Magnetic resonance imaging showed that the preoperative heterogeneity of the lesion had disappeared, and the signal intensity had returned to normal. Arthroscopic examinations consistently exhibited improvement in the International Cartilage Regeneration and Joint Preservation Society (ICRS) grade of lesions from 3 or 4 to 1 or 2 in 4 patients at 85 weeks postoperatively. Histologic analysis of biopsy specimens revealed an average total ICRS Visual Assessment Scale II histologic score of 1060. Conclusion: The acellular cartilage repair technique using UPAL gel for advanced capitellar OCD provided satisfactory clinical and radiographic results. The present results suggest that this novel technique is a useful, minimally invasive approach for treating cartilaginous lesions in athletes.

Purpose To evaluate autologous matrix-induced chondrogenesis (AMIC) for isolated focal retropatellar cartilage lesions and the influence of patellofemoral (PF) anatomy on clinical outcomes at a minimum of 2-year follow-up. Methods Twenty-nine consecutive patients (31 knees) who underwent retropatellar AMIC with a mean age of 27.9 ± 11.0 years were evaluated at a follow-up averaging 4.1 ± 1.9 years (range, 2-8 years). Patient factors, lesion morphology, and patient-reported outcome measures, including Knee Injury and Osteoarthritis Outcome Score (KOOS), Tegner, Kujula score, and visual analogue scale (VAS) score were collected. PF anatomy was assessed on pre- and postoperative imaging, and subsequently correlated to outcome scores and failure to determine risk factors for poor outcome. Results At final follow-up, the AMIC graft failed in 4 cases (12.9%) at a mean follow-up of 21 ± 14.1 months. Patients with failed grafts had a significantly smaller patellar and Laurins’s PF angle than patients whose graft did not fail ( P = 0.008 and P = 0.004, respectively). Concomitant corrective surgery for patellar instability was performed in 29 knees (93.5%). Grafts that did not fail presented with an average Kujala score of 71.3 ± 16.9, KOOS Pain of 76.2 ± 16.6 and Tegner scores of 4.2 ± 1.8. The patellar angle was significantly associated with the patient’s satisfaction level ( r = 0.615; P < 0.001). Conclusion AMIC for retropatellar cartilage lesions in combination with concomitant corrective surgery for patellar instability results in low failure rate with satisfactory clinical outcome and patient satisfaction of almost 80% at mid-term follow-up. As most failures occurred in patients without concurrent tibial tubercle osteotomy and both a smaller patellar and Laurins’s PF angle were associated with less favorable outcome, this study supports the growing evidence for the need of unloading retropatellar cartilage repair, when indicated. Level of Evidence Case series; level of evidence, 4.

Objective Cellular and molecular events occurring in cartilage regions close to injury are poorly investigated, but can possibly compromise the outcome of cell-based cartilage repair. In this study, key functional properties were assessed for cartilage biopsies collected from the central part of traumatic joint lesions ( central) and from regions surrounding the defect ( peripheral). These properties were then correlated with the quality of the initial cartilage biopsy and the inflammatory state of the joint. Design Cartilage samples were collected from knee joints of 42 patients with traumatic knee injuries and analyzed for cell phenotype (by reverse transcriptas-polymerase chain reaction), histological quality, cellularity, cell viability, proliferation capacity, and post-expansion chondrogenic capacity of chondrocytes (in pellet culture). Synovium was also harvested and analyzed for the expression of inflammatory cytokines. Results Cartilage quality and post-expansion chondrogenic capacity were higher in peripheral versus central samples. Differences between these 2 parameters were more pronounced in joints with high inflammatory features characterized by >100-fold difference in the mRNA levels of IL6 and IL8 in the corresponding synovium. Peripheral chondrocytes isolated from good- versus bad-quality biopsies expressed higher levels of collagen II/I and aggrecan/versican and lower levels of MMP13 and ADAMTS5. They also exhibited reduced proliferation and enhanced cartilage-forming capacity. Conclusions Chondrocytes at the periphery of traumatic lesions better maintain properties of healthy cartilage compared to those isolated from the center, even when derived from bad-quality tissues harvested from highly inflamed joints. Future studies are necessary to investigate the change of functional properties of peripheral chondrocytes over time.

Background: In December 2016, MACI (autologous cultured chondrocytes on porcine collagen membrane) received approval from the US Food and Drug Administration for the treatment of symptomatic articular cartilage defects of the knee with or without bone involvement in adults. Purpose: To describe the cartilage defects and patient characteristics for 1000 adult patients treated with MACI for knee cartilage repair in the United States. Study Design: Case series; Level of evidence, 4. Methods: Data collected by Vericel for adult patients treated for articular cartilage defects of the knee were reconciled and summarized. Data were collected for 1000 consecutive patients starting on July 1, 2017, when Carticel (the prior generation of autologous cultured chondrocytes) was no longer available. Patient names were removed for confidentiality, and patients were identified by MACI lot number and surgery date. Safety data were derived from the pharmacovigilance database. Patient demographics, cartilage defect characteristics, concomitant surgical procedures, and adverse events were summarized with descriptive statistics. Results: A total of 1000 adults and 1010 knee joints were implanted with MACI by 372 surgeons. The male (49.6%)-to-female (50.4%) ratio was evenly split, and the mean age was 34.0 years. The majority of patients (68.1%) had a single cartilage defect treated, and the mean treated defect size was 4.7 cm2. The mean total treated lesion size, including multiple defects, was 5.8 cm2. The patella was the most commonly treated joint surface (32.7%), followed by the medial femoral condyle (31.3%). Most patients (92.4%) had concomitant surgical procedures at the time of cartilage biopsy acquisition. The most common concomitant procedures at the time of biopsy procurement included cartilage debridement (83.7%) and meniscal resection (11.3%). The most common planned concomitant surgeries at the time of MACI implantation were anterior tibial tubercleplasty (7.8%) and reconstruction of dislocating patella (5.5%). Few patients (2.6%) had adverse events. Conclusion: Patient age and mean total MACI-treated defect size in the United States are similar to the findings of the pivotal European SUMMIT (Superiority of MACI Implant Versus Microfracture Treatment) trial and other studies from outside the United States. Treatment of multiple cartilage defects is more frequent in the United States than elsewhere.

Objective The aim of this study was to compare the clinical outcome of cartilage repair with autologous chondrocyte implantation (ACI) in patients with osteochondritis dissecans (OCD) lesions and full-thickness cartilage lesions. Design This study included a cohort of 115 consecutive patients with a cartilage lesion of the knee treated with ACI. Of the patients, 35 had an OCD lesion and 80 a full-thickness cartilage lesion. During a follow-up period from 2 to 13 years all treatment failures were identified. The failure rate between OCD lesions and full-thickness cartilage lesions was compared with Kaplan-Meier analysis. Patient-reported outcome was evaluated 2 years postoperatively with the Lysholm score. Results During the follow-up 21 out of 115 patients encountered a treatment failure. The failure rate for full-thickness cartilage lesions was 19.1% and for OCD lesions 43.3% over the 10-year follow-up. Patient-reported outcome improved from baseline to 2 years postoperatively. The improvement from baseline was statistically significant, and the Lysholm score improved more than the minimal clinically important difference. The patient-reported outcome showed no difference between lesion types at 2 years. Conclusions In the presented retrospective study, the failure rate of first-generation ACI was higher in OCD lesions than in large full-thickness cartilage lesions, suggesting that OCD lesions may associate with properties that affect the durability of repair tissue. Future prospective studies are needed to tell us how to best repair OCD lesions with biological tissue engineering.

The umbilical cord-mesenchymal stem cells (UC-MSC) has been shown to improve the viability of degenerated chondrocytes in knee osteoarthritis (KOA) in cellular level. Additional somatotropin injection also shown clinical improvement in patients. The present trial is conducted to assess the efficacy of umbilical cord mesenchymal stem cells (UC-MSC) in comparison to somatotropin and hyaluronic acid (HA) injection to treat and slow the progression of knee osteoarthritis. Methods: This study was conducted from January 2016 to April 2018 in Cipto Mangunkusumo General Hospital. A total of 28 knees from 15 patients with early KOA Kellgren Lawrence I-II were randomized into three groups. Group A was treated with 1x106 units of intra-articular UC-MSCs + 2 ml HA followed with 2 consecutive weeks of HA injection; group B was treated with the same dose of HA with additional 8 IU of Somatotropin; group C was treated as control. The International Knee Documentation Committee (IKDC) score, The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue score (VAS), were assessed on the 1st and 3rd month, then every 3rd month until 12 months. Cartilage evaluation using MRI cartigram were performed at pre-implantation, and after the 6th and 12th month after implantation Results: General improvement were observed in all groups after 6 and 12 months. The IKDC score improved significantly among groups after 12 months (69.43 [48.3-89.66], 79.31 [51.72-90.08], and 75.9 [67.82-97.7] in group A, B, and C, respectively, p =0.005). We did not find a significant difference between groups in VAS and WOMAC results. However, we observed a medial T2 improvement in group A (39.55 [32.65-67.85] initially and 45.64 [38.12-70.65] 12 months after implantation). Conclusion: Injection of UC-MSC could improve knee function and cartilage profile in early KOA. However, further multicenter studies with larger samples are required to investigate the efficacy of such treatment for treating knee osteoarthritis.

Objective Inflammation is known to negatively affect cartilage repair. However, it is unclear how inflammation influences the migration of mesenchymal stromal cells (MSCs) from the underlying bone marrow into the defect. We therefore aimed to investigate how synovial inflammation influences MSC migration, and whether modulation of inflammation with triamcinolone acetonide (TAA) may influence migration. Design Inflamed human osteoarthritic synovium, M(IFNγ+TNFα) pro-inflammatory macrophages, M(IL4) repair macrophages, M(IL10) anti-inflammatory macrophages, or synovial fibroblasts were cultured with/without TAA. Conditioned medium (CM) was harvested after 24 hours, and the effect on MSC migration was studied using a Boyden chamber assay. Inflammation was evaluated with gene expression and flow cytometry analysis. Results Synovium CM increased MSC migration. Modulation of synovial inflammation with TAA further increased migration 1.5-fold ( P < 0.01). TAA significantly decreased TNFA, IL1B, and IL6 gene expression in synovium explants and increased CD163, a gene associated with anti-inflammatory macrophages. TAA treatment decreased the percentage of CD14+/CD80+ and CD14+/CD86+ pro-inflammatory macrophages and increased the percentage of CD14+/CD163+ anti-inflammatory macrophages in synovium explants. Interestingly, MSC migration was specifically enhanced by medium conditioned by M(IL4) macrophages and by M(IL10) macrophages treated with TAA, and unaffected by CM from M(IFNγ+TNFα) macrophages and synovial fibroblasts. Conclusion Macrophages secrete factors that stimulate the migration of MSCs. Modulation with TAA increased specifically the ability of anti-inflammatory macrophages to stimulate migration, indicating that they play an important role in secreting factors to attract MSCs. Modulating inflammation and thereby improving migration could be used in approaches based on endogenous repair of full-thickness cartilage defects.