Focal Cartilage Defects Research Articles

3D Bioprinted Implants for Cartilage Repair in Intervertebral Discs and Knee Menisci.

Cartilage defects pose a significant clinical challenge as they can lead to joint pain, swelling and stiffness, which reduces mobility and function thereby significantly affecting the quality of life of patients. More than 250,000 cartilage repair surgeries are performed in the United States every year. The current gold standard is the treatment of focal cartilage defects and bone damage with nonflexible metal or plastic prosthetics. However, these prosthetics are often made from hard and stiff materials that limits mobility and flexibility, and results in leaching of metal particles into the body, degeneration of adjacent soft bone tissues and possible failure of the implant with time. As a result, the patients may require revision surgeries to replace the worn implants or adjacent vertebrae. More recently, autograft – and allograft-based repair strategies have been studied, however these too are limited by donor site morbidity and the limited availability of tissues for surgery. There has been increasing interest in the past two decades in the area of cartilage tissue engineering where methods like 3D bioprinting may be implemented to generate functional constructs using a combination of cells, growth factors (GF) and biocompatible materials. 3D bioprinting allows for the modulation of mechanical properties of the developed constructs to maintain the required flexibility following implantation while also providing the stiffness needed to support body weight. In this review, we will provide a comprehensive overview of current advances in 3D bioprinting for cartilage tissue engineering for knee menisci and intervertebral disc repair. We will also discuss promising medical-grade materials and techniques that can be used for printing, and the future outlook of this emerging field.

Autologous chondrocyte implantation combined with anterior cruciate ligament reconstruction: similar short-term results in comparison with isolated cartilage repair in ligament intact joints

PurposeBoth acute ruptures of the anterior cruciate ligament (ACL) as well as chronic ACL insufficiency show a high association with focal cartilage defects of the knee. However, the results after combined ACL reconstruction and cartilage repair are not well investigated. The aim of the present study was to investigate the short-term outcomes after autologous chondrocyte implantation (ACI) in combination with ACL reconstruction and to compare the results with patients who underwent isolated ACI in ligament intact knees.MethodsAll patients who were registered in the German Cartilage Registry with ACI for focal cartilage defects in the knee joint in combination with ACL reconstruction and who completed the 24 month follow-up were included in the study group. A matched-pair procedure according to gender, defect location, defect size, and age was used to create a control group of patients with isolated ACI in ACL intact joints. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the numeric analog scale for pain (NAS) were used to assess the preoperative state as well as the clinical outcomes 12 and 24 months after surgery.ResultsA total of 34 patients were included in both the study group (age mean 33.3 ± SD 8.8 years) and the control group (33.6 ± 8.4 years) with a median defect size of 466 (25%-75% IQR 375–600) mm2 and 425 (IQR 375–600) mm2, respectively. In comparison with the preoperative state (median 67, IQR 52–75), the study group showed a significant increase of the total KOOS after 12 months (78, IQR 70–86; p = 0.014) and after 24 months (81, IQR 70–84; p = 0.001). The NAS for pain did not change significantly in the postoperative course. In comparison with the control group there was no significant difference for the total KOOS neither preoperative (control group median 67, IQR 52–73) nor at any postoperative time point (12 months: 82, IQR 67–93; 24 months: 81, IQR 71–91).ConclusionThe clinical short-term outcomes after ACI at the knee joint in combination with ACL reconstruction are good and similar to the results after isolated ACI in ligament intact knees.Level of evidenceIII.

Autologous osteochondral transplantation for focal femoral condyle defects: Comparison of mosaicplasty by arthrotomy vs. arthroscopy

BackgroundWhile many studies have reported the outcomes of open mosaicplasty, data on arthroscopic mosaicplasty are scarce. Only two cadaver studies have compared arthrotomy and arthroscopy. Moreover, the patello-femoral joint, which is the main donor site, has never been assessed using a specific functional score. The objective of this in vivo study was to compare arthrotomy and arthroscopy for mosaicplasty using both a global functional knee score and a specific score of the patello-femoral joint. HypothesisThe arthroscopic technique results in better functional patello-femoral outcomes. Material and methodsWe retrospectively compared two groups of 17 patients who underwent mosaicplasty for focal condylar cartilage defects, at our department between 2009 and 2019. Functional outcomes were assessed using the Kujala score and the Lysholm score, at least 1 year after surgery. The return to sports was assessed using the Tegner score. ResultsMean follow-up was 67.4±15.9 months in the arthrotomy group and 45.2±35.1 months in the arthroscopy group (p<0.01). Cartilage defect size was similar in the two groups (arthrotomy: 1.21±0.91cm2; arthroscopy: 0.92±1.23cm2; p=0.052). The mean Kujala score was 85±21.3 in the arthrotomy group and 91.9±13.7 in the arthroscopy group (p=0.064). The mean Lysholm score was 83.9±19.8 with arthrotomy and 89.5±14.9 with arthroscopy (p=0.1). The Kujala score was greater than 95 in 4 (26%) arthrotomy patients and 13 (81%) arthroscopy patients (p=0.003). The Lysholm score was higher than 95 in 4 (26%) arthrotomy patients and 12 (75%) arthroscopy patients (p=0.012). No patient underwent surgical revision for autograft failure. DiscussionThis is the first clinical study comparing arthrotomy and arthroscopy for mosaicplasty. Clinical outcomes were good with both techniques. The proportion of patients with excellent Lysholm and Kujala functional scores was significantly higher in the arthroscopy group than in the arthrotomy group. This result may be ascribable to decreased donor-site morbidity obtained with arthroscopy. Level of evidenceIV, retrospective observational comparative study.

A Systematic Review of Focal Cartilage Defect Treatments in Middle-Aged Versus Younger Patients.

Background:Focal cartilage defects are often debilitating, possess limited potential for regeneration, are associated with increased risk of osteoarthritis, and are predictive for total knee arthroplasty. Cartilage repair studies typically focus on the outcome in younger patients, but a high proportion of treated patients are 40 to 60 years of age (ie, middle-aged). The reality of current clinical practice is that the ideal patient for cartilage repair is not the typical patient. Specific attention to cartilage repair outcomes in middle-aged patients is warranted.Purpose:To systematically review available literature on knee cartilage repair in middle-aged patients and include studies comparing results across different age groups.Study Design:Systematic review; Level of evidence, 4.Methods:A systematic search was performed in EMBASE, MEDLINE, and the Cochrane Library database. Articles were screened for relevance and appraised for quality.Results:A total of 21 articles (mean Coleman Methodology Score, 64 points) were included. Two out of 3 bone marrow stimulation (BMS) studies, including 1 using the microfracture technique, revealed inferior clinical outcomes in middle-aged patients in comparison with younger patients. Nine cell-based studies were included showing inconsistent comparisons of results across age groups for autologous chondrocyte implantation (ACI). Bone marrow aspirate concentrate showed age-independent results at up to 8 years of follow-up. A negative effect of middle age was reported in 1 study for both ACI and BMS. Four out of 5 studies on bone-based resurfacing therapies (allografting and focal knee resurfacing implants [FKRIs]) showed age-independent results up to 5 years. One study in only middle-aged patients reported better clinical outcomes for FKRIs when compared with biological repairs.Conclusion:Included studies were heterogeneous and had low methodological quality. BMS in middle-aged patients seems to only result in short-term improvements. More research is warranted to elucidate the ameliorating effects of cell-based therapies on the aging joint homeostasis. Bone-based therapies seem to be relatively insensitive to aging and may potentially result in effective joint preservation. Age subanalyses in cohort studies, randomized clinical trials, and international registries should generate more evidence for the large but underrepresented (in terms of cartilage repair) middle-aged population in the literature.

Membrane scaffolds for matrix-induced autologous chondrocyte implantation in the knee: a systematic review.

Chondral defects of the knee are common and their management is challenging. Current scientific literature published in PubMed, Google scholar, Embase and Scopus. Membrane-induced autologous chondrocyte implantation (mACI) has been used to manage chondral defects of the knee. Hyaluronic acid membrane provides better outcomes than a collagenic membrane for mACI in the knee at midterm follow-up is controversial. To investigate whether hyaluronic acid membrane may provide comparable clinical outcomes than collagenic membranes for mACI in focal defects of the knee. Hyaluronic acid membrane yields a lower rate of failures and revision surgeries for mACI in the management of focal articular cartilage defects of the knee compared with collagenic scaffolds at midterm follow-up. No difference was found in patient reported outcome measures (PROMs). Further comparative studies are required to validate these results in a clinical setting.

Impact of Early Weightbearing After Ankle Arthroscopy and Bone Marrow Stimulation for Osteochondral Lesions of the Talus.

Background:Osteochondral lesion of the talus (OLT) may be caused by osteochondritis dissecans, osteochondral fractures, avascular necrosis, or focal arthritic changes. For certain focal cartilage defects, bone marrow stimulation (BMS) has been a widely used technique to restore a fibrocartilage substitute overlying the defect. There are various postoperative weightbearing protocols for this procedure, with no single gold standard method.Purpose:To retrospectively review the outcomes of patients undergoing ankle arthroscopy with concomitant BMS to determine outcomes based on postoperative weightbearing status.Study Design:Cohort study; Level of evidence, 3.Methods:We retrospectively reviewed the records of patients who underwent ankle arthroscopy with BMS for OLTs between 2015 and 2018. Patients were placed into 2 cohorts based on postoperative immobilization status: the nonweightbearing (NWB) group and the weightbearing-as-tolerated (WBAT) group. Patient characteristics obtained included age, sex, comorbidities, and etiology of talar pathology. Outcomes included the pain visual analog scale (VAS), range of motion (ROM), complications, time to first weightbearing, and the method and length of immobilization. Patients who were lost to follow-up before 30 days were excluded. The chi-square test was used to compare categorical variables between cohorts, and the t test was used for continuous variables.Results:A total of 69 patients met the inclusion criteria for this study, 18 in the WBAT group and 51 in the NWB group. The mean lesion size was 9.48 × 9.21 mm (range, 3-15 mm × 2-20 mm) for the NWB group and 9.36 × 9.72 mm (range, 5-14 mm × 6-20 mm) for the WBAT group (P > .05). The VAS scores improved from 4.40 to 0.67 for the WBAT group and from 6.33 to 2.55 for the NWB group, with the difference in final values reaching statistical significance (P = .0002). Postoperative ROM was not significantly different between the groups. There were 4 repeat operations within the NWB cohort.Conclusion:The surgical management of OLTs can be challenging, and the postoperative weightbearing protocol can be an extra obstacle for the patient to navigate. We found no difference in pain, ROM, or complications when allowing immediate, full WBAT.

Role of Matrix-Associated Autologous Chondrocyte Implantation with Spheroids in the Treatment of Large Chondral Defects in the Knee: A Systematic Review.

Autologous chondrocyte implantation (ACI) is a cell therapy for the treatment of focal cartilage defects. The ACI product that is currently approved for use in the European Union (EU) consists of spheroids of autologous matrix-associated chondrocytes. These spheroids are spherical aggregates of ex vivo expanded human autologous chondrocytes and their self-synthesized extracellular matrix. The aim is to provide an overview of the preclinical and nonclinical studies that have been performed to ensure reproducible quality, safety, and efficacy of the cell therapy, and to evaluate the clinical data on ACI with spheroids. A systematic review was performed to include all English publications on self-aggregated spheroids of chondrocytes cultured in autologous serum without other supplements. A total of 20 publications were included, 7 pre- and nonclinical and 13 clinical research publications. The pre- and nonclinical research publications describe the development from concept to in vivo efficacy and quality- and safety-related aspects such as biodistribution, tumorigenicity, genetic stability, and potency. The evaluation of clinical research shows short- to mid-term safety and efficacy for the ACI with spheroid-based treatment of cartilage defects in both randomized clinical trials with selected patients, as well as in routine treatment providing real-world data in more complex patients.

Hip Chondral Defects: Arthroscopic Treatment With the Needle and Curette Technique and ChondroFiller

Management of symptomatic focal cartilage defects of the hip can be challenging. Cells, scaffold therapies, and injectable agents have emerged as an adjunctive modality to improve clinical outcomes. Long and malleable needles that can be bent are used to release these kinds of biological products. Distance between the tip of the needle and the area to be filled should be minimal to ensure full contact with the chondral lesion to avoid losing material inside the hip cavity and to increase the efficiency of the release of the product. Nevertheless in many cases the accessibility is not easy, and the distance between the tip of the needle and the area to be treated is such that the efficiency of the release is difficult, if not impossible. We aim to describe a simple, inexpensive, and reproducible technique to facilitate the implantation of biologic and injectable materials in hip chondral defects during arthroscopy: the use of a combination of a curette and a needle inside the tip of the curette. Additionally we describe the use of ChondroFiller liquid, a liquid cell-free collagen matrix, for the treatment of symptomatic full-thickness chondral defects of the hip in a 1-step arthroscopic procedure.

Update on the Operative Treatment of Cartilage Defects

Focal cartilage defects lead to swelling, significant pain and loss of function of the affected joint. Additionally, they are linked to early onset of osteoarthritis. Often young and active patients are especially susceptible due to the high stress placed on their joints. A vast amount of treatment options is available to orthopaedic surgeons to cure cartilage defects of the knee, hip, shoulder, elbow and ankle joints. This article serves to give an overview of these available treatment options and to explain the expected outcomes.

Overlapping Allografts Provide Superior and More Reliable Surface Topography Matching Than Oblong Allografts: A Computer-Simulated Model Study

Background: Osteochondral allograft transplantation is 1 treatment option for focal articular cartilage defects of the knee. Large irregular defects, which can be treated using an oblong allograft or multiple overlapping allografts, increase the procedure’s technical complexity and may provide suboptimal cartilage and subchondral surface matching between donor grafts and recipient sites. Purpose: To quantify and compare cartilage and subchondral surface topography mismatch and cartilage step-off for oblong and overlapping allografts using a 3-dimensional simulation model. Study Design: Controlled laboratory study. Methods: Human cadaveric medial femoral hemicondyles (n = 12) underwent computed tomography and were segmented into cartilage and bone components using 3-dimensional reconstruction and modeling software. Segments were then exported into point-cloud models. Modeled defect sizes of 17 × 30 mm were created on each recipient hemicondyle. There were 2 types of donor allografts from each condyle utilized: overlapping and oblong. Grafts were virtually harvested and implanted to optimally align with the defect to provide minimal cartilage surface topography mismatch. Least mean squares distances were used to measure cartilage and subchondral surface topography mismatch and cartilage step-off. Results: Cartilage and subchondral topography mismatch for the overlapping allograft group was 0.27 ± 0.02 mm and 0.80 ± 0.19 mm, respectively. In comparison, the oblong allograft group had significantly increased cartilage (0.62 ± 0.43 mm; P < .001) and subchondral (1.49 ± 1.10 mm; P < .001) mismatch. Cartilage step-off was also found to be significantly increased in the oblong group compared with the overlapping group (P < .001). In addition, overlapping allografts more reliably provided a significantly higher percentage of clinically acceptable (0.5- and 1-mm thresholds) cartilage surface topography matching (overlapping: 100% for both 0.5 and 1 mm; oblong: 90% for 1 mm and 56% for 0.5 mm; P < .001) and cartilage step-off (overlapping: 100% for both 0.5 and 1 mm; oblong: 86% for 1 mm and 12% for 0.5 mm; P < .001). Conclusion: This computer simulation study demonstrated improved topography matching and decreased cartilage step-off with overlapping osteochondral allografts compared with oblong osteochondral allografts when using grafts from donors that were not matched to the recipient condyle by size or radius of curvature. These findings suggest that overlapping allografts may be superior in treating large, irregular osteochondral defects involving the femoral condyles with regard to technique. Clinical Relevance: This study suggests that overlapping allografts may provide superior articular cartilage surface topography matching compared with oblong allografts and do so in a more reliable fashion. Surgeons may consider overlapping allografts over oblong allografts because of the increased ease of topography matching during placement.

Preclinical safety and efficacy of juvenile cartilage-derived chondrocyte sheets for treating focal chondral injury

Purpose: Cartilage lacks an innate repair capability after traumatic injury. As such, focal cartilage defects have been implicated as a potential initiator of early osteoarthritic disease, and early treatment of chondral defects may prevent or delay the development of osteoarthritis and improve patient quality of life. Cell sheet technology using temperature responsive cultureware allows production of confluently cultured cells as sheets. Harvested sheets are readily patched on tissue lesions and adhere without suture, fibrin glue or other adhesion techniques.

Regeneration of hyaline cartilage in response to a single injection of LNA043, an ANGPTL3 mimetic, in the knee of patients with a focal cartilage defect

Purpose: LNA043 is a modified human angiopoietin-like 3 (ANGPTL3) protein that induces chondrogenesis and cartilage repair. In a first-in-human trial (FIH), it displayed a favorable safety profile while eliciting a chondro-anabolic response as supported by the modulation of several pathways in chondrocytes involved in osteoarthritis (OA) at the RNA level. The primary objective of this trial (NCT 03334812) was to assess the efficacy of a single intra-articular (i.a.) injection of LNA043 in the regeneration of hyaline cartilage tissue at the donor site of patients undergoing autologous chondrocyte implantation (ACI).

The partial femoral condyle focal resurfacing (HemiCAP-UniCAP) for treatment of full-thickness cartilage defects, systematic review and meta-analysis

Knee osteochondral defects are a common problem among people, especially young and active patients. So effective joint preserving surgeries is essential to prevent or even delay the onset of osteoarthritis for these group of patients. This study aims to critically appraise and evaluate the evidence for the results and effectiveness of femoral condyle resurfacing (HemiCAP/ UniCAP) in treatment of patients with focal femoral condyle cartilage defect. Using the search terms : HemiCAP, UniCAP, Episurf, focal, femoral, condyle, inlay and resur-facing, we reviewed the PubMed and EMBASE and the Cochrane Database of Systematic Reviews (CDSR) to find any articles published up to March 2020. The short term follow-up of the HemiCAP shows (6.74 %) revision rate. However, 29.13 % loss of follow up let us consider these results with caution especially if the revision rate progressively increased with time to 19.3 % in 5-7 years with no enough evidence for the long term results except the data from the Australian Joint Registry 2018, where the cumulative revision rate was 40.6 % (33.5, 48.4) at ten years. The UniCAP that used for defect more than 4 cm 2 has a high revision rate (53.66 %) which is considered unacceptable revision rate in com-parison to another similar prosthesis such as Uni-Knee Arthroplasty (UKA). The evidence from published studies and our meta- analysis suggests that partial resurfacing of the femoral condyle (HemiCAP) doesn't support its usage as a tool to treat the focal cartilage defect in middle- aged patients. The UniCAP as femoral condyle resurfacing has very high revision rate at 5-7 years (53.66 %) which make us recommend against its usage.

Algorithm for Treatment of Focal Cartilage Defects of the Knee: Classic and New Procedures.

To create a treatment algorithm for focal grade 3 or 4 cartilage defects of the knee using both classic and novel cartilage restoration techniques. A comprehensive review of the literature was performed highlighting classic as well as novel cartilage restoration techniques supported by clinical and/or basic science research and currently being employed by orthopedic surgeons. There is a high level of evidence to support the treatment of small to medium size lesions (<2-4 cm2) without subchondral bone involvement with traditional techniques such as marrow stimulation, osteochondral autograft transplant (OAT), or osteochondral allograft transplant (OCA). Newer techniques such as autologous matrix-induced chondrogenesis and bone marrow aspirate concentrate implantation have also been shown to be effective in select studies. If subchondral bone loss is present OAT or OCA should be performed. For large lesions (>4 cm2), OCA or matrix autologous chondrocyte implantation (MACI) may be performed. OCA is preferred over MACI in the setting of subchondral bone involvement while cell-based modalities such as MACI or particulated juvenile allograft cartilage are preferred in the patellofemoral joint. Numerous techniques exist for the orthopedic surgeon treating focal cartilage defects of the knee. Treatment strategies should be based on lesion size, lesion location, subchondral bone involvement, and the level of evidence supporting each technique in the literature.

Hydrogel-Guided, rAAV-Mediated IGF-I Overexpression Enables Long-Term Cartilage Repair and Protection against Perifocal Osteoarthritis in a Large-Animal Full-Thickness Chondral Defect Model at One Year In Vivo.

The regeneration of focal articular cartilage defects is complicated by the reduced quality of the repair tissue and the potential development of perifocal osteoarthritis (OA). Biomaterial-guided gene therapy may enhance cartilage repair by controlling the release of therapeutic sequences in a spatiotemporal manner. Here, the benefits of delivering a recombinant adeno-associated virus (rAAV) vector coding for the human insulin-like growth factor I (IGF-I) via an alginate hydrogel (IGF-I/AlgPH155) to enhance repair of full-thickness chondral defects following microfracture surgery after one year in minipigs versus control (lacZ/AlgPH155) treatment are reported. Sustained IGF-I overexpression is significantly achieved in the repair tissue of defects treated with IGF-I/AlgPH155 versus those receiving lacZ/AlgPH155 for one year and in the cartilage surrounding the defects. Administration of IGF-I/AlgPH155 significantly improves parameters of cartilage repair at one year relative to lacZ/AlgPH155 (semiquantitative total histological score, cell densities, matrix deposition) without deleterious or immune reactions. Remarkably, delivery of IGF-I/AlgPH155 also significantly reduces perifocal OA and inflammation after one year versus lacZ/AlgPH155 treatment. Biomaterial-guided rAAV gene transfer represents a valuable clinical approach to promote cartilage repair and to protect against OA.

Longitudinal T2 Mapping and Texture Feature Analysis in the Detection and Monitoring of Experimental Post-Traumatic Cartilage Degeneration.

Background: Traumatic cartilage injuries predispose articulating joints to focal cartilage defects and, eventually, posttraumatic osteoarthritis. Current clinical-standard imaging modalities such as morphologic MRI fail to reliably detect cartilage trauma and to monitor associated posttraumatic degenerative changes with oftentimes severe prognostic implications. Quantitative MRI techniques such as T2 mapping are promising in detecting and monitoring such changes yet lack sufficient validation in controlled basic research contexts. Material and Methods: 35 macroscopically intact cartilage samples obtained from total joint replacements were exposed to standardized injurious impaction with low (0.49 J, n = 14) or high (0.98 J, n = 14) energy levels and imaged before and immediately, 24 h, and 72 h after impaction by T2 mapping. Contrast, homogeneity, energy, and variance were quantified as features of texture on each T2 map. Unimpacted controls (n = 7) and histologic assessment served as reference. Results: As a function of impaction energy and time, absolute T2 values, contrast, and variance were significantly increased, while homogeneity and energy were significantly decreased. Conclusion: T2 mapping and texture feature analysis are sensitive diagnostic means to detect and monitor traumatic impaction injuries of cartilage and associated posttraumatic degenerative changes and may be used to assess cartilage after trauma to identify “cartilage at risk”.

Cartiform Implantation for focal cartilage defects in the knee: A 2-year clinical and magnetic resonance imaging follow-up study

The purpose of this study was to evaluate clinical and magnetic resonance imaging (MRI) outcomes in patients who underwent cryopreserved viable osteochondral allograft (CVOCA) implantation for focal cartilage defects in the knee at a minimum of 2-years postoperatively. This is a retrospective follow-up study of twelve patients who underwent CVOCA implantation from 2013 to 2015 by a single surgeon for a International Cartilage Repair Society (ICRS) grade 3 or 4 chondral defect. Patient-reported outcome (PRO) measurements and MRI were obtained 2-years postoperatively. Collected PRO measures included: International Knee Documentation Committee (IKDC) form; Visual Analog Scale (VAS) pain score; Veterans RAND 12-Item Health Survey (VR-12); Knee Injury and Osteoarthritis Outcome Score (KOOS); and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Patients completed a standard return to work and sports/recreation survey. A blinded, fellowship-trained musculoskeletal radiologist independently evaluated each MRI to determine the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score. Mean follow-up was 2.1 years (2.0–2.3). There were 6 women and 6 men with a mean age of 46.2 ± 11.9 years. Mean PRO scores were: IKDC 72.6 ± 17.4; VAS 2.9 ± 2.8; WOMAC 84.2 ± 15.1; KOOS- Pain 83.8 ± 18.5, Symptoms 77.6 ± 16.0, ADL 88.0 ± 16.9, Sports/Rec 67.7 ± 33.3, QOL 54.8 ± 24.2; and VR-12 PCS 45.0 ± 8.5 and MCS 51.1 ± 9.5. The mean MOCART score was 59.5 ± 12.9. To our knowledge, this is the largest study to report clinical and MRI outcomes of CVOCA implantation in the knee. With positive functional outcomes and lack of failures at 2-year follow-up, CVOCA is a promising treatment option for focal chondral defects in the knee. Study designRetrospective case series, Level of evidence 4.

Enhancing the potential of aged human articular chondrocytes for high-quality cartilage regeneration.

Autologous chondrocyte implantation (ACI) is a regenerative procedure used to treat focal articular cartilage defects in knee joints. However, age has been considered as a limiting factor and ACI is not recommended for patients older than 40-50years of age. One reason for this may be due to the reduced capacity of aged chondrocytes in generating new cartilage. Currently, the underlying mechanism contributing to aging-associated functional decline in chondrocytes is not clear and no proven approach exists to reverse chondrocyte aging. Given that chondrocytes in healthy hyaline cartilage typically display a spherical shape, believed to be essential for chondrocyte phenotype stability, we hypothesize that maintaining aged chondrocytes in a suspension culture that forces the cells to adopt a round morphology may help to "rejuvenate" them to a younger state, thus, leading to enhanced cartilage regeneration. Chondrocytes isolated from aged donors displayed reduced proliferation potential and impaired capacity in generating hyaline cartilage, compared to cells isolated from young donors, indicated by increased hypertrophy and cellular senescence. To test our hypothesis, the "old" chondrocytes were seeded as a suspension onto an agarose-based substratum, where they maintained a round morphology. After the 3-day suspension culture, aged chondrocytes displayed enhanced replicative capacity, compared to those grown adherent to tissue culture plastic. Moreover, chondrocytes subjected to suspension culture formed new cartilage in vitro with higher quality and quantity, with enhanced cartilage matrix deposition, concomitant with lower levels of hypertrophy and cellular senescence markers. Mechanistic analysis suggested the involvement of the RhoA and ERK1/2 signaling pathways in the "rejuvenation" process. In summary, our study presents a robust and straightforward method to enhance the function of aged human chondrocytes, which can be conveniently used to generate a large number of high-quality chondrocytes for ACI application in the elderly.

Hyaluronic Acid-Based Shape-Memory Cryogel Scaffolds for Focal Cartilage Defect Repair

Traumatic joint injuries can result in significant cartilage defects, which can greatly increase the risk of osteoarthritis development. Due to the limited self-healing capacity of avascular cartilage, tissue engineering approaches are required for filling defects and promoting cartilage regeneration. Current approaches utilize invasive surgical procedures for extraction and implantation of autologous chondrocytes; therefore, injectable biomaterials have gained interest to minimize the risk of infection as well as patient pain and discomfort. In this study, we engineered biomimetic, hyaluronic acid (HA)-based cryogel scaffolds that possess shape-memory properties as they contract and regain their shape after syringe injection to noninvasively fill cartilage defects. The cryogels, fabricated with HA and glycidyl methacrylate at -20°C, resulted in an elastic, macroporous, and highly interconnected network that provided a conducive microenvironment for chondrocytes to remain viable and metabolically active after injection through a syringe needle. Chondrocytes seeded within cryogels and cultured for 15 days exhibited enhanced cell proliferation, metabolism, and production of cartilage extracellular matrix glycosaminoglycans compared with HA-based hydrogels. Furthermore, immunohistochemical staining revealed production of collagen type II from chondrocyte-seeded cryogels, indicating the maintenance of cell phenotype. These results demonstrate the potential of chondrocyte-seeded, HA-based, injectable cryogel scaffolds to promote regeneration of cartilage tissue for nonsurgically invasive defect repair. Impact statement Hyaluronic acid-based shape-memory cryogels provide a conducive microenvironment for chondrocyte adhesion, proliferation, and matrix biosynthesis for use in repair of cartilage defects. Due to their sponge-like elastic properties, cryogels can fully recover their original shape back after injection while not impacting metabolism or viability of encapsulated cells. Clinically, they provide an opportunity for filling focal cartilage defects by using a single, minimally invasive injection of a cell encapsulating biocompatible three-dimensional scaffold that can return to its original structure to fit the defect geometry and enable matrix regeneration.

All-Arthroscopic Hydrogel-Based Autologous Chondrocyte Transplantation in the Knee Joint: Good Clinical and Magnetic Resonance Imaging Outcome After 24 Months

To evaluate subjective and objective clinical and magnetic resonance imaging-based radiologic outcomes after short-term follow-up in patients with focal full-size cartilage lesions of the knee joint treated with all-arthroscopic hydrogel-based autologous chondrocyte transplantation. A retrospective study on patients with isolated focal cartilage defects of the knee joint who were treated with arthroscopically conducted matrix-induced autologous chondrocyte transplantation was performed. Clinical scores were assessed at baseline and final follow-up using the Tegner Score, visual analog scale, the International Knee Documentation Committee, and the 5 subscales of the Knee Injury and Osteoarthritis Outcome Score. Magnetic resonance imaging scans of the treated knee joints were evaluated with the updated MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) 2.0 scoring system at follow-up. Twenty-nine consecutive patients were included in the study. Mean time to follow-up was 24.9 ± 1.1 months. Average visual analog scale decreased significantly from 6.5 ± 3.1 preoperatively to 2.3 ± 1.6 at follow-up (P < .0001). Tegner score increased from 3.1 ± 1.3 to 4.3 ± 1.2 (P < .0001) and the International Knee Documentation Committee from 43.8 ± 21.9 to 64.9 ± 18.9 (P < .0001). Also, all Knee Injury and Osteoarthritis Outcome Score subscales displayed significant improvements. Patients showed similar improvements of nearly all clinical scores independent of the defect size. Average MOCART2.0 score was 70.0 ± 13.6 and 20 patients scored ≥70 points. All 8 patients with large defects (>5 cm2) scored ≥75 points. In this small study, injectable matrix-induced autologous chondrocyte transplantation therapy in the knee joint led to favourable clinical and radiologic short-term results with significant improvements in all clinical scores and MOCART2.0 scores, confirming morphologic integrity of the transplanted chondrocytes. Therefore, this minimally invasive procedure represents a promising operative technique for cartilage regeneration, even for large-diameter lesions. IV, therapeutic case series.