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Between 1999 and 2002, 16 patients with osteochondral lesions on the central and posterior talar dome underwent osteochondral autografting. A new approach with temporary removal and replacement of a tibia! bone block from the anterior tibial plafond was adopted. Inclusion criteria were joint stability, an age between 18 and 50 years, and osteochondral lesions stages 3 and 4 according to the radiological classification of Loomer, for which previous arthroscopic treatment was not successful. All patients underwent clinical and MRI evaluation after 12, 35 and 59 months. The AOFAS Ankle Hindfoot score improved significantly between the preoperative period and 1 year (p < 0.001), between 1 and 3 years (p < 0.001), but not between 3 and 5 years postoperative (p = 0.37). The score was independent from patients gender (p=0.44) and age. The Spearman coefficient of correlation between clinical outcome and defect size was -0.79 (p = 0.01), indicating that patients with small lesions had the best results. Control radiographs and MRls showed no reduced joint space and good integration of the tibial bone block without incongruency. Osteochondral grafting with temporary removal of a tibial bone block is a successful technique with good midterm results in Osteochondral talar lesions for which arthroscopic excision, curettage and drilling has failed. [ABSTRACT FROM AUTHOR]

BACKGROUND: There have been no data in the literature reporting the influence of sports on the outcome of autologous chondrocyte implantation in chondral defects of the knee. HYPOTHESIS: Sports can improve the result of autologous chondrocyte implantation in postoperative follow-up. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Between 1997 and 2003, 118 patients with symptomatic isolated chondral lesions of the knee underwent autologous chondrocyte implantation. According to the sports activity level before the start of symptoms, patients were assigned to 2 groups: group II with no or rare sports involvement (1-3 times/month); group I with regular (1-3 times/week) or competitive sports (4-7 times/week). All patients underwent clinical and magnetic resonance imaging evaluation preoperative and 6, 18, and 36 months after autologous chondrocyte implantation. RESULTS: Group I patients showed significantly better results (<.01) in the International Cartilage Repair Society and Cincinnati scores than group II patients. Preoperative evaluation revealed no correlation between the sports activity levels and the clinical scores (P > .05). However, from the sixth month on, correlation was statistically significant, increasing from 6 to 18 months, and from 18 to 36 months postoperatively. CONCLUSION: Physical training improves long-term results after autologous chondrocyte implantation of the knee and should be carried out for at least 2 years after surgery. [ABSTRACT FROM AUTHOR]

Background: There have been limited data in the literature reporting the results of osteochondral autografting for osteochondral lesions of the talus that have failed arthroscopic treatment.Hypothesis: Osteochondral autografting can produce significant clinical improvement and a high rate of healing of osteochondral defects of the talus that have failed arthroscopic treatment.Study Design: Cohort study; Level of evidence, 4.Methods: Between 1998 and 2003, 35 patients (18 men, 17 women) with osteochondral talar lesions for which arthroscopic excision, curettage, and drilling had failed, underwent mosaicplasty with an osteochondral graft harvested from the ipsilateral talar articular facet. A malleolar osteotomy or a tibial wedge osteotomy was used for central or posterior lesions that could not otherwise be reached. The mean age of the patients was 30.9 years, and the mean follow-up was 48.9 months.Results: The American Orthopaedic Foot and Ankle Society Ankle Hindfoot scale score in patients without osteotomy rose by 39 points (P = .0001); with malleolar osteotomy, by 30.1 points (P = .017); with tibial wedge osteotomy, by 34.9 points (P = .0002); and with the posterolateral approach, by 32 points. The Wilcoxon test revealed a significant difference between patients without and with osteotomy (P .027) and between patients with malleolar and tibial wedge osteotomies (P = .046). There were no patients with nonunion or malunion in the osteotomy groups. The score values corresponded with the subjective patient evaluation. The Spearman coefficient of correlation was .89.Conclusion: Osteochondral autografting with tibial wedge osteotomy is a good alternative to malleolar osteotomy in osteochondral talar lesions that have failed arthroscopic treatment and that cannot be reached in spite of a forced plantar flexion of the ankle. Patients with small osteochondral lesions accessible through an anterior approach without additional osteotomy have the best prognostic factors. [ABSTRACT FROM AUTHOR]

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Abstract Background Complex cartilage lesions of the knee including large cartilage defects, kissing lesions, and osteoarthritis (OA) represent a common problem in orthopaedic surgery and a challenging task for the orthopaedic surgeon. As there is only limited data, we performed a prospective clinical study to investigate the benefit of autologous chondrocyte implantation (ACI) for this demanding patient population. Methods Fifty-one patients displaying at least one of the criteria were included in the present retrospective study: (1.) defect size larger than 10 cm2; (2.) multiple lesions; (3.) kissing lesions, cartilage lesions Outerbridge grade III-IV, and/or (4.) mild/moderate osteoarthritis (OA). For outcome measurements, the International Cartilage Society's International Knee Documentation Committee's (IKDC) questionnaire, as well as the Cincinnati, Tegner, Lysholm and Noyes scores were used. Radiographic evaluation for OA was done using the Kellgren score. Results and Discussion Patient's age was 36 years (13-61), defects size 7.25 (3-17.5) cm2, previous surgical procedures 1.94 (0-8), and follow-up 30 (12-63) months. Instruments for outcome measurement indicated significant improvement in activity, working ability, and sports. Mean ICRS grade improved from 3.8 preoperatively to grade 3 postoperatively, Tegner grade 1.4 enhanced to grade 3.39. The Cincinnati score enhanced from 25.65 to 66.33, the Lysholm score from 33.26 to 64.68, the Larson score from 43.59 to 79.31, and Noyes score from 12.5 to 46.67, representing an improvement from Cincinnati grade 3.65 to grade 2.1. Lysholm grade 4 improved to grade 3.33, and Larson grade 3.96 to 2.78 (Table 1), (p < 0.001). Patients with kissing cartilage lesions had similar results as patients with single cartilage lesions. Table 1 Mean scores and grades at surgery (Tx) and at follow-up Tx Follow-up Score Grade Score Grade ICRS 4 3 Tegner 1 3 Noyes 13 47 Cincinnati 26 4 66 2 Lysholm 33 4 65 3 Larson 44 4 79 3 Conclusion Our results suggest that ACI provides mid-term results in patients with complex cartilage lesions of the knee. If long term results will confirm our findings, ACI may be a considered as a valuable tool for the treatment of complex cartilage lesions of the knee.

Methods: Peer-reviewed literature was analyzed regarding different topics relevant to osteochondral lesions of the talus (OLTs) treatment. This process concluded with a statement for each topic reflecting the best scientific evidence available for a particular diagnostic or therapeutic concept, including the grade of recommendation. Besides the scientific evidence, all group members rated the statements to identify possible gaps between literature and current clinical practice., Conclusion: In patients with minimal symptoms, OLT progression to ankle osteoarthritis is unlikely. Risk factors for progression are the depth of the lesion on MRI, subchondral cyst formation, and the extent of bone marrow edema. Conservative management is the adaptation of activities to the performance of the ankle joint. A follow-up imaging after 12 months helps not to miss any progression. It is impossible to estimate the probability of success of conservative management from initial symptoms and imaging. Cast immobilization is an option in OLTs in children, with a success rate of approximately 50%, although complete healing, estimated from imaging, is rare. In adults, improvement by conservative management ranges between 45% and 59%. Rest and restrictions for sports activities seem to be more successful than immobilization. Intra-articular injections of hyaluronic acid and platelet-rich plasma can improve pain and functional scores for more than 6 months. If 3 months of conservative management does not improve symptoms, surgery can be recommended.

The Working Group of the German Orthopedic and Trauma Society (DGOU) on Tissue Regeneration has published recommendations on the indication of different surgical approaches for treatment of full-thickness cartilage defects in the knee joint in 2004, 2013 and 2016. Based upon new scientific knowledge and new developments, this recommendation is an update based upon the best clinical evidence available. In addition to prospective randomised controlled clinical trials, this also includes studies with a lower level of evidence. In the absence of evidence, the decision is based on a consensus process within the members of the working group.The principle of making decision dependent on defect size has not been changed in the new recommendation either. The indication for arthroscopic microfracturing has been reduced up to a defect size of 2 cm 2 maximum, while autologous chondrocyte implantation is the method of choice for larger cartilage defects. Additionally, matrix-augmented bone marrow stimulation (mBMS) has been included in the recommendation for defects ranging from 1 to 4.5 cm 2 . For the treatment of smaller osteochondral defects, in addition to osteochondral transplantation (OCT), mBMS is also recommended. For larger defects, matrix-augmented autologous chondrocyte implantation (mACI/mACT) in combination with augmentation of the subchondral bone is recommended., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Orthoregeneration is defined as a solution for orthopedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and optimally, provide an environment for tissue regeneration. Options include: drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electro-magnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the knee, including symptomatic osteoarthritis and chondral injuries, as well as injuries to tendon, meniscus, and ligament, including the anterior cruciate ligament. Promising and established treatment modalities include hyaluronic acid (HA) in liquid or scaffold form; platelet-rich plasma (PRP); bone marrow aspirate (BMA) comprising mesenchymal stromal cells (MSCs), hematopoietic stem cells, endothelial progenitor cells, and growth factors; connective tissue progenitor cells (CTPs) including adipose-derived mesenchymal stem cells (AD-MSCs) and tendon-derived stem cells (TDSCs); matrix cell-based therapy including autologous chondrocytes or allograft; vitamin D; and fibrin clot. Future investigations should standardize solution preparations, because inconsistent results reported may be due to heterogeneity of HA, PRP, BMAC, or MSC preparations and regimens, which may inhibit meaningful comparison between studies to determine the true efficacy and safety for each treatment., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA., Competing Interests: One or more of the authors has declared a potential conflict of interest or source of funding: see supplemental material for details. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Background: Autologous matrix-induced chondrogenesis (AMIC) is a well-established treatment for full-thickness cartilage defects., Purpose: To evaluate the long-term clinical outcomes of AMIC for the treatment of chondral lesions of the knee., Study Design: Case series; Level of evidence, 4., Methods: A multisite prospective registry recorded demographic data and outcomes for patients who underwent repair of chondral defects. In total, 131 patients were included in the study. Lysholm, Knee injury and Osteoarthritis Outcome Score (KOOS), and visual analog scale (VAS) score for pain were used for outcome analysis. Across all patients, the mean ± SD age of patients was 36.6 ± 11.7 years. The mean body weight was 80.0 ± 16.8 kg, mean height was 176.3 ± 7.9 cm, and mean defect size was 3.3 ± 1.8 cm 2 . Defects were classified as Outerbridge grade III or IV. A repeated-measures analysis of variance was used to compare outcomes across all time points., Results: The median follow-up time for the patients in this cohort was 4.56 ± 2.92 years. Significant improvement ( P < .001) in all scores was observed at 1 to 2 years after AMIC, and improved values were noted up to 7 years postoperatively. Among all patients, the mean preoperative Lysholm score was 46.9 ± 19.6. At the 1-year follow-up, a significantly higher mean Lysholm score was noted, with maintenance of the favorable outcomes at 7-year follow-up. The KOOS also showed a significant improvement of postoperative values compared with preoperative data. The mean VAS had significantly decreased during the 7-year follow-up. Age, sex, and defect size did not have a significant effect on the outcomes., Conclusion: AMIC is an effective method of treating chondral defects of the knee and leads to reliably favorable results up to 7 years postoperatively., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Treating cartilage injuries and degenerations represents an open surgical challenge. The recent advances in cell therapies have raised the need for a potent off-the-shelf cell source. Intra-articular injections of TGF-β transduced polydactyly chondrocytes have been proposed as a chronic osteoarthritis treatment but despite promising results, the use of gene therapy still raises safety concerns. In this study, we characterized infant, polydactyly chondrocytes during in vitro expansion and chondrogenic re-differentiation. Polydactyly chondrocytes have a steady proliferative rate and re-differentiate in 3D pellet culture after up to five passages. Additionally, we demonstrated that polydactyly chondrocytes produce cartilage-like matrix in a hyaluronan-based hydrogel, namely transglutaminase cross-linked hyaluronic acid (HA-TG). We utilized the versatility of TG cross-linking to augment the hydrogels with heparin moieties. The heparin chains allowed us to load the scaffolds with TGF-β1, which induced cartilage-like matrix deposition both in vitro and in vivo in a subcutaneous mouse model. This strategy introduces the possibility to use infant, polydactyly chondrocytes for the clinical treatment of joint diseases.

Background: CARGEL (Smith & Nephew Inc.), a chitosan-based polymer scaffolding biomaterial, has been used since 2012 for treating articular cartilage lesions. Limited data are available on patient outcomes following CARGEL treatment. This study aimed to describe short-term clinical and radiographic outcomes in a cohort of patients treated with CARGEL and microfracture surgery for articular cartilage defects in the knee., Methods: A retrospective cohort study was conducted of consecutive patients with articular cartilage defects who had undergone microfracture surgery with CARGEL, or in patellar lesions microfracture and CARGEL plus Chondro-Gide (at SportsClinic Zurich). Study outcomes included reoperations, infections, allergic reactions, pain, swelling, range of motion, and tissue quality and quantity. Ethics approval was obtained from the local ethics committee on 05/09/2017 (Basec. Nr: 2017-01441)., Results: A total of 91 participants, with 93 treated lesions, consenting to chart review were included. No participants required reoperation due to complications on the index lesion. Fifteen participants had second-look surgery on the index knee for other reasons, allowing for visual confirmation of cartilage repair. No study participants experienced a post-surgical infection or suffered an allergic reaction. No significant changes in range of motion or T2 values were observed from pre-treatment to post-treatment follow-up. However, significant decreases were found in pain (P < 0.001) and swelling (P < 0.001), along with significant increases in MOCART II scores (P < 0.001). Similar results were found in a subgroup of patients with patellar lesions., Conclusions: Patients treated with CARGEL experienced few postoperative complications and reported promising reductions in pain and swelling after treatment., Level of Evidence: IV., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: Many studies have shown that local anesthetics may impede chondrocyte metabolism. However, the influence of a single-dose local anesthetics is controversial. The aim of this metaanalysis was to review the literature for studies investigating the cytotoxic effects of single-dose local anesthetics on chondrocytes and cartilage., Methods: A comprehensive literature search was performed using established search engines (Medline, Embase) to identify studies, investigating the influence of single-dose local anesthetics on cartilage. The systematic analysis included the influence on histology, cell viability, morphology, and matrix production depending upon dose, exposure time, and type of local anesthetics., Results: Twelve studies with four different local anesthetics were included in this metaanalysis. Bupivacaine and lidocaine were found to be more chondrotoxic than mepivacaine and ropivacaine. The amount of dead cells increased in a substance-, dose-, and time-dependent process. Osteoarthritic cartilage seems to be more vulnerable compared to intact cartilage. The toxic effects occur first in the superficial cartilage layers and include damage to membrane integrity, mitochondrial DNA, and nuclear changes. There is no study that could show a significant chondrotoxic effect with low concentrations of bupivacaine (0.0625%), ropivacaine (0.1 and 0.2%), and mepivacaine (0.5%)., Conclusions: The cytotoxicity of local anesthetics on chondrocytes is dependent on dose, time, and type of local anesthetics. Single-dose intra-articular administration of local anesthetics impede chondrocyte metabolism and should be performed only with low concentrations for selected diagnostic purposes and painful joints. The use of lidocaine should be avoided., Level of Evidence: II.

Degeneration of articular cartilage represents one of the most common causes of pain and disability in our aging society. Current treatments only address the symptoms of joint disease, but not their underlying causes which include oxidative stress and inflammation in cartilage and surrounding tissues. Sulfated biopolymers that mimic aspects of the native extracellular environment of cartilage are recently gaining interest as a means to slow the inflammatory events responsible for tissue degeneration. Here we show that the natural polysaccharide alginate and particularly its sulfated derivatives have potent anti-oxidant, anti-inflammatory and anti-immunogenic properties in vitro. We found that these polymers exert a free radical scavenging activity in a sulfation-dependent manner. In particular, the sulfation degree of substitution of alginate directly correlated with its ability to scavenge superoxide radicals and to chelate metal ions. We also studied the effect of sulfated alginate on the ability of IL-1β to stimulate inflammatory genes in human chondrocytes and found decreased expression of the pro-inflammatory markers IL-6 and CXCL8, which inversely correlated with the sulfation degree. Moreover, in studies testing the ability of the alginates to modulate macrophage polarization, we found that they decreased both the gene expression and synthesis of the proinflammatory cytokine TNF-α in human THP-1 macrophages with M1-like phenotype in a sulfation-dependent manner. To conclude, sulfated alginates effectively protect against oxidative stress and inflammation in vitro and are a promising biomaterial to be explored for treatment of osteoarthritis.

Loss of articular cartilage from ageing, injury or degenerative disease is commonly associated with inflammation, causing pain and accelerating degradation of the cartilage matrix. Sulphated glycosaminoglycans (GAGs) are involved in the regulation of immune responses in vivo, and analogous polysaccharides are currently being evaluated for tissue engineering matrices to form a biomimetic environment promoting tissue growth while suppressing inflammatory and catabolic activities. Here, we characterise physical properties of sulphated alginate (S-Alg) gels for use in cartilage engineering scaffolds, and study their anti-inflammatory effects on encapsulated chondrocytes stimulated with IL-1β. Sulphation resulted in decreased storage modulus and increased swelling of alginate gels, whereas mixing highly sulphated alginate with unmodified alginate resulted in improved mechanical properties compared to gels from pure S-Alg. S-Alg gels showed extensive anti-inflammatory and anti-catabolic effects on encapsulated chondrocytes induced by IL-1β. Cytokine-stimulated gene expression of pro-inflammatory markers IL-6, IL-8, COX-2 and aggrecanase ADAMTS-5 were significantly lower in the sulphated gels compared to unmodified alginate gels. Moreover, sulphation of the microenvironment suppressed the protein expression of COX-2 and NF-κB as well as the activation of NF-κB and p38-MAPK. The sulphated alginate matrices were found to interact with IL-1β, and proposed to inhibit inflammatory induction by sequestering cytokines from their receptors. This study shows promising potential for sulphated alginates in biomimetic tissue engineering scaffolds, by reducing cytokine-mediated inflammation and providing a protective microenvironment for encapsulated cells.

Background: Autologous chondrocyte implantation (ACI) is an established and well-accepted procedure for the treatment of localised full-thickness cartilage defects of the knee., Methods: The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU) describes the biology and function of healthy articular cartilage, the present state of knowledge concerning therapeutic consequences of primary cartilage lesions and the suitable indication for ACI., Results: Based on best available scientific evidence, an indication for ACI is given for symptomatic cartilage defects starting from defect sizes of more than three to four square centimetres; in the case of young and active sports patients at 2.5cm(2), while advanced degenerative joint disease needs to be considered as the most important contraindication., Conclusion: The present review gives a concise overview on important scientific background and the results of clinical studies and discusses the advantages and disadvantages of ACI., Level of Evidence: Non-systematic Review., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In recent years treatment of early osteoarthritis came more and more into focus of orthopaedic research. In particular regenerative therapy options seem to have a high potential to fill the existing treatment gap for patients with early osteoarthritic changes. This article focuses on basic science, recent developments and available clinical data in the important field of operative regeneration procedures for treatment of chondral and osteochondral defects in early degenerative joints. It highlights current knowledge and perspectives of treatment options like microfracture, autologous or allogenous osteochondral transplantations and autologous chondrocyte transplantation. Further the role of biomaterials in a degenerative joint environment is illuminated. First clinical data of regenerative therapy in early osteoarthritis are encouraging to intensify research efforts in this important field. Future treatment perspectives for patients who suffer from early degenerative cartilage changes are discussed.

There is an increasing awareness on the importance in identifying early phases of the degenerative processes in knee osteoarthritis (OA), the crucial period of the disease when there might still be the possibility to initiate treatments preventing its progression. Early OA may show a diffuse and ill-defined involvement, but also originate in the cartilage surrounding a focal lesion, thus necessitating a separate assessment of these two entities. Early OA can be considered to include a maximal involvement of 50 % of the cartilage thickness based on the macroscopic ICRS classification, reflecting an OARSI grade 4. The purpose of this paper was to provide an updated review of the current status of the diagnosis and definition of early knee OA, including the clinical, radiographical, histological, MRI, and arthroscopic definitions and biomarkers. Based on current evidence, practical classification criteria are presented. As new insights and technologies become available, they will further evolve to better define and treat early knee OA.

During a specialised orthopedic meeting held on 'the state of the art in cartilage defect repair', all previously fully-registered participants were requested to participate in an electronic survey by the use of a moderator-presented "Power Point Presentation-based" 9-item questionnaire. The aim of this survey was to assess indication, approach, and treatment execution of cartilage defect debridement prior to planned microfracture (MFX) or autologous chondrocyte implantation (ACI). All participants completed the questionnaire (n = 146) resulting in a return rate of 100 %. An uncertainty exists as to whether the removal of the calcifying layer prior to cartilage repair must be carried out or not. The same was true for the acceptability of subchondral bleeding prior to microfracturing and its handling prior to autologous chondrocyte implantation. There is a degree of unanimity among experts regarding the management of osteophytes and bone marrow edema. In a homogenous society collective of consultants that frequently deal with cartilage defective pathologies, there still remain a significant heterogeneity in selected topics of defect debridement.

Objective: An attempt to define pre-osteoarthritis (OA) versus early OA and definitive osteoarthritis., Methods: A group of specialists in the field of cartilage science and treatment was formed to consider the nature of OA onset and its possible diagnosis., Results: Late-stage OA, necessitating total joint replacement, is the end stage of a biological process, with many previous earlier stages. Early-stage OA has been defined and involves structural changes identified by arthroscopy or radiography. The group argued that before the "early-stage OA" there must exist a stage where cellular processes, due to the presence of risk factors, have kicked into action but have not yet resulted in structural changes. The group suggested that this stage could be called "pre-osteoarthritis" (pre-OA)., Conclusions: The group suggests that defining points of initiation for OA in the knee could be defined, for example, by traumatic episodes or surgical meniscectomy. Such events may set in motion metabolic processes that could be diagnosed by modern MRI protocols or arthroscopy including probing techniques before structural changes of early OA have developed. Preventive measures should preferably be applied at this pre-OA stage in order to stop the projected OA "epidemic."

Objectives: Knee cartilage damage is a common cause of referral for orthopedic surgery. Treatment aims to reduce pain and symptoms by repairing cartilage. Microfracture, the current standard of care, yields good short-term clinical outcomes; however, treatment might fail after 2-3 years. A Chitosan-Beta glycerolphosphate-based medical device (BST-CarGel) is used as an adjunct to microfracture and demonstrates improvements in quantity and quality of repaired tissue, potentially reducing the risk of treatment failure. This study aimed to establish the economic value of BST-CarGel vs microfracture alone in knee cartilage repair from the societal perspective, using Germany as the reference market., Methods: A decision tree with a 20-year time-horizon was constructed, in which undesirable clinical events were inferred following initial surgery. These events consisted of pain management, surgery, and total knee replacement. Clinical outcomes were taken from the pivotal clinical trial, supplemented by other literature. Data and assumptions were validated by a Delphi panel. All relevant resource use and costs for procedures and events were considered., Results: In a group of patients with all lesion sizes, the model inferred that BST-CarGel yields a positive return on investment at year 4 (with 20-year cumulative cost savings of €6448). Reducing the incremental risk of treatment failure gap between the device and microfracture by 25-50% does not alter this conclusion. Cost savings are greatest for patients with large lesions; results for patients with small lesions are more modest., Limitations: Clinical evidence for microfracture and other interventions varies in quality. Comparative long-term data are lacking. The comparison is limited to microfracture and looks only at costs without considering quality-of-life., Conclusion: BST-CarGel potentially represents a cost-saving alternative for patients with knee cartilage injury by reducing the risk of clinical events through regeneration of chondral tissue with hyaline characteristics. Since the burden of this condition is high, both to the patient and society, an effective and economically viable alternative is of importance.

Background: Autologous chondrocyte implantation (ACI) represents an established surgical therapy for large cartilage defects of the knee joint. Although various studies report satisfying midterm results, little is known about long-term outcomes., Purpose: To evaluate long-term clinical and magnetic resonance imaging (MRI) outcomes after ACI., Study Design: Case series; Level of evidence, 4., Methods: Between January 1997 and June 2001, a total of 86 patients were treated with ACI for isolated cartilage defects of the knee. The mean patient age at the time of surgery was 33.3 ± 10.2 years, and the mean defect size was 6.5 ± 4.0 cm(2). Thirty-four defects were located on the medial femoral condyle and 13 on the lateral femoral condyle, while 6 patients were treated for cartilage defects of the trochlear groove and 17 for patellar lesions. At a mean follow-up of 10.9 ± 1.1 years, 70 patients (follow-up rate, 82%) treated for 82 full-thickness cartilage defects of the knee were available for an evaluation of knee function using standard instruments, while 59 of these patients were additionally evaluated by 1.5-T MRI to quantify the magnetic resonance observation of cartilage repair tissue (MOCART) score. Clinical function at follow-up was assessed by means of the Lysholm score, the International Knee Documentation Committee (IKDC) score, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Patient activity was assessed by the Tegner score. In addition, pain on a visual analog scale (VAS) and patient satisfaction were evaluated separately., Results: At follow-up, 77% reported being "satisfied" or "very satisfied." The mean IKDC score at follow-up was 74.0 ± 17.3. The mean Lysholm score improved from 42.0 ± 22.5 before surgery to 71.0 ± 17.4 at follow-up (P < .01). The mean pain score on the VAS decreased from 7.2 ± 1.9 preoperatively to 2.1 ± 2.1 postoperatively. The mean MOCART score was 44.9 ± 23.6. Defect-associated bone marrow edema was found in 78% of the cases. Nevertheless, no correlation between the MOCART score and clinical outcome (IKDC score) could be found (Pearson coefficient, r = 0.173)., Conclusion: First-generation ACI leads to satisfying clinical results in terms of patient satisfaction, reduction of pain, and improvement in knee function. Nevertheless, full restoration of knee function cannot be achieved. Although MRI reveals lesions in the majority of the cases and the overall MOCART score seems moderate, this could not be correlated with long-term clinical outcomes.

Background: Autologous chondrocyte implantation (ACI) has been associated with satisfying results. Still, it remains unclear when success or failure after ACI can be estimated., Purpose: To evaluate the clinical outcomes of cell-seeded collagen matrix-supported ACI (ACI-Cs) for the treatment of cartilage defects of the knee at 36 months and to determine a time point after ACI-Cs at which success or failure can be estimated., Study Design: Cohort study; Level of evidence, 3., Methods: A total of 80 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI-Cs were prospectively assessed before surgery as well as postoperatively by use of the International Knee Documentation Committee (IKDC) score and Lysholm knee score., Results: Preoperative IKDC and Lysholm scores increased from 49.6 and 59.5, respectively, to 79.1 and 83.5, respectively, at 36 months. Only half the patients (46.6%) with poor IKDC scores (ie, <70) at 6 months postoperatively showed continued poor or fair scores at 36 months' follow-up. The probability of poor scores at 36 months after surgery further increased to 0.61 and 0.81, respectively, when scores were persistent at 12 and 24 months. All 3 patients (100%) with good IKDC scores (ie, 81-90) at 6 months after surgery showed constant or even improved scores at 36 months' follow-up. Ninety-one percent of patients with good and excellent scores at 12 months and 83% of patients with good and excellent scores at 24 months (a total of 23 and 37 patients, respectively) were able to maintain these scores at 36 months' follow-up. Similar results were obtained for the Lysholm score., Conclusion: With regard to the improvements in functional outcomes after ACI-Cs at 36 months after surgery, the technique described here appears to lead to satisfying and stable clinical results. This study helps the treating physician to predict the likeliness of further clinical improvements or constant unsatisfactory results after ACI. In patients with good/excellent scores shortly after surgery, deterioration of the knee's condition is rarely found. For patients with poor and fair postoperative scores, clinical outcomes are more difficult to predict, especially during the first year after the procedure.

Purpose: Although traumatic osteochondral fractures of the knee represent a common pathology of the knee joint, there is no general agreement concerning specific treatment of this entity. This meta-analysis was initiated in order to evaluate scientific evidence on different treatment options for acute osteochondral fractures of the knee., Methods: For this purpose an OVID-based systematic literature search was performed including the following databases: MEDLINE, MEDLINE preprints, Embase, CINAHL, Life Science Citations, British National Library of Health and Cochrane Central Register of Controlled Trials. The literature search period was from 1946 to January 2012, which led to the identification of 1,226 articles. After applying study-specific inclusion criteria a total of 19 studies with clinical follow-up of 638 patients were included. The methodology of these studies was systematically analysed by means of the Coleman Methodology Score. Outcome and success rates were evaluated depending on treatment applied., Results: All studies (n = 19) identified represent case series (evidence-based medicine level IV) and included a total of 638 patients. The average post-operative follow-up was 46 ± 27 months (range 3.75-108). The mean number of study subjects per study was 33 ± 44 patients (range 4-169). The average Coleman Methodology Score was 29 ± 17 points (range 5-72). Six different scoring systems were used for clinical assessment. The overall clinical success rate was 83% and varied between 45 and 100%., Conclusions: This meta-analysis reveals a significant lack of scientific evidence for treatment of osteochondral fractures of the knee. No valid conclusion can be drawn from this study concerning the recommendation of a specific treatment algorithm. Nevertheless, the overall failure rate of 17% underlines that an acute osteochondral fracture of the knee represents an important pathology which is not a self-limiting injury and needs further investigation.

Background: Current cartilage therapy modalities like microfracture, ACT/MACT, AMIC or osteochondral transplantation are important tools to treat symptomatic (osteo)chondral lesions of the knee joint. However, until now there exists no high-level evidence based accepted rehabilitation plan for the postoperative treatment., Hypothesis/purpose: This survey describes the predominantly used rehabilitation plan as implemented by expert musculoskeletal surgeons for operatively treated (osteo)chondral lesions., Study Design: Survey and systematic review., Methods: An electronic questionnaire covering general and specific items concerning aftercare following cartilage therapy in the knee joint was designed and disposed to analyze rehabilitation programs among a population of expert musculoskeletal surgeons of the AGA (Society of arthroscopy and joint surgery). All instructors (304 in 01/2011) were included into the survey. A total of 246 (80.9 %) instructors answered the questionnaire., Results: The predominant used therapy to treat cartilage lesions is microfracture and for osteochondral lesions the osteochondral transplantation. Physiotherapy starts directly after surgery and takes more than 6 weeks. Most surgeons do not immobilize patients after surgery and use partial weight-bearing for up to 5 weeks. The change from partial to full weight-bearing is done step-wise with a 20-kg/week increase. Free ROM is allowed by the majority of instructors (55 %) directly after surgery. A CPM-device is also used directly and up to 5 weeks. Swimming and biking are allowed after 6 weeks, running is allowed after 12 weeks and contact sports after 24 weeks. Most instructors do not use braces in the aftercare procedure, but nearly all (93 %) prescribe crutches. Typical drugs used during the aftercare are NSAID, Heparin and antibiotics. For most instructors (79 % respectively 75 %) knee stability and a straight leg axis are necessary for a successful cartilage therapy. If a concomitant therapy like ACL reconstruction or an osteotomy is performed, aftercare is mainly dependent on cartilage therapy (62 % respectively 59 % of instructors)., Conclusions: Today there exists no detailed rehabilitation program for treatment after a cartilage-related operation on the basis of an evidence-based level I study. The reason might be that many variables contribute to a specific aftercare procedure. Therefore, the survey of experienced surgeons may help to identify the most promising rehabilitation regime for today, at least until evidence-based level I studies are accomplished.

Objective: Autologous chondrocyte transplantation has become an established therapy for full-thickness cartilage defects. Cell-seeded collagen matrix-supported autologous chondrocyte transplantation (ACT-CS) has been introduced as a modification of conventional ACT, which allows easier handling and is intended to combine the advantages of using a cell suspension (i.e., cell viability and mitotic activity) with the stability and self-containment provided by a matrix of biomaterials. Unlike other techniques and products, this seeding step can be easily applied using a porcine collagen type I/III membrane and autologous chondrocytes in an operating room setting. Although some suturing is required, this technique provides the distinct advantage of not requiring a water-tight seal of the bilayer membrane, as is required using the classic cell suspension technique. Comparable to other modifications of ACT, the ACT-CS procedure requires a specific surgical technique that focuses on the following important details: (1) accurate debridement of the cartilage defect; (2) preparation of the cells, and seeding and containment of the cells within the transplantation site; and (3) sealing and suturing around the defect., Design: A consensus meeting of leading European orthopedic surgeons specializing in cartilage repair was convened to discuss and standardize the surgical aspects of this technique., Results & Conclusions: The present article describes and discusses the adoption of these best surgical practices for implementing the ACT-CS technique, including more detailed descriptions of each phase of the surgery in order to standardize and optimize patient outcomes.

Soccer players and athletes in high-impact sports are frequently affected by knee injuries. Injuries to the anterior cruciate ligament and menisci are frequently observed in soccer players and may increase the risk of developing an articular cartilage lesion. In high-level athletes, the overall prevalence of knee articular cartilage lesions has been reported to be 36% to 38%. The treatment for athletic patients with articular cartilage lesions is often challenging because of the high demands placed on the repair tissue by impact sports. Cartilage defects in athletes can be treated with microfracture, osteochondral grafting, and autologous chondrocyte implantation. There is increasing scientific evidence for cartilage repair in athletes, with more extensive information available for microfracture and autologous chondrocyte implantation than for osteochondral grafting. The reported rates and times to return to sport at the preinjury level are variable in recreational players, with the best results seen in younger and high-level athletes. Better return to sport is consistently observed for all repair techniques with early cartilage repair. Besides minimizing sensorimotor deficits and addressing accompanying pathologies, the quality of the repair tissue may be a significant factor for the return to sport.

Background: Participation in football can put both male and female players at an increased risk for knee osteoarthritis. There is a higher prevalence of focal chondral defects in the knee of athletes compared to nonathletes. The management of chondral defects in the football player is complex and multifactorial., Objective: The aim of this study is to provide an overview of the current strategies for rehabilitation after articular cartilage repair of the knee in the football player., Design: A review of current literature and the scientific evidence for rehabilitation after articular cartilage repair of the knee., Conclusions: Articular cartilage repair has been shown to allow return to sport but rehabilitation timescales are lengthy. Successful rehabilitation for a return to football after articular cartilage repair of the knee requires the player to be able to accept the load of the sport. This necessitates a multidisciplinary approach to rehabilitation, especially in the transition from therapy to performance care. It should be recognized that not all players will return to football after articular cartilage repair. The evidence base for rehabilitative practice after articular cartilage repair is increasing but remains sparse in areas.

Purpose: The purpose of our study was to compare arthroscopic versus open measurement of cartilage defects and determination of defect grade according to the International Cartilage Repair Society (ICRS) classification., Methods: Arthroscopic determination of defect size and grade according to the ICRS classification of 450 focal cartilage defects in 407 patients who underwent autologous chondrocyte implantation was compared with definite findings at the time of open knee surgery. Results were analyzed based on defect location, defect size, and experience of the treating surgeon., Results: Open evaluation of all cartilage defects showed a mean size of 4.54 ± 2.11 cm², whereas arthroscopic determination resulted in a significantly larger mean defect size of 5.69 ± 1.81 cm² (P < .001, r = 0.757). This observation was found in all subgroups concerning defect location and experience of the treating surgeon (P < .001). Overestimation was pronounced among inexperienced surgeons (all P < .01) and in smaller defects (P < .01). Concerning grading of the defect according to the ICRS classification, there was a consensus in 80.9% of the cases when arthroscopic grading was compared with open grading. No differences were found based on defect location or experience of the treating surgeon (P > .05)., Conclusions: Although a high correlation was found between arthroscopic and open evaluation of the cartilage defect size, there is a significant overestimation of the cartilage defect size during arthroscopy. This observation is independent of defect location. Smaller defects and inexperienced surgeons are factors that make an overestimation of defect size more likely. Arthroscopic detection and estimation of the full-thickness cartilage defects according to the ICRS classification seem reliable., Level of Evidence: Level IV, therapeutic case series., (Copyright © 2011 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Autologous chondrocyte implantation (ACI) is an established therapy for the treatment of cartilage defects across the knee joint. Even though different techniques for initial biopsy have been described, the exact location, depth, and volume of the biopsy are chosen individually by the treating surgeon. This study evaluated 252 consecutive cartilage biopsies taken from the intercondylar notch with a standardized hollow cylinder system for the isolation and in vitro cultivation of human chondrocytes assigned to ACI. All biopsies were assessed for weight of total cartilage obtained, cartilage biopsy weight per cylinder, biopsy cylinder quality, and initial cell count after digestive cellular isolation as well as cell vitality. Parameters were correlated with individual patient parameters. Mean patient age was 35.1 years (median 35.9; range 14.7-56.4). Adequate amounts of cartilage assigned to chondrocyte in vitro cultivation could be harvested in all cases. The mean overall biopsy weight averaged 75.5 mg (SD +/- 44.9) and could be identified as main factor for initial cell number (mean 1.05E+05; SD +/- 7.44E+04). No correlation was found between the initial cell count and patient age (correlation coefficient r = 0.005) or grade of joint degeneration (r = 0.040). Concerning cell viability, a total of 4.4% (SD + 3.0) of the chondrocytes harvested were apoptotic. Cartilage biopsies from the intercondylar notch using a standardized hollow cylinder system provides a reliable, safe, and successful method to obtain articular cartilage for further in vitro cultivation of articular chondrocytes to achieve autologous chondrocyte transplantation.

Introduction: Since introduction of autologous chondrocyte implantation (ACI), various factors have been described that influence the clinical outcome. The present paper investigates the influence of bone marrow edema at time of treatment on clinical function before and in the early clinical course after ACI., Methods: 67 patients treated with ACI for cartilage defects of the knee joint were included. Presence of subchondral bone marrow edema was graded as absent (1), mild (2), moderate (3) or severe (4) using magnetic resonance (MR) imaging before surgery. All patients were assessed in terms of clinical function before surgery and 6 as well as 12 months after ACI using IKDC and Lysholm scores. Presence of subchondral edema was correlated with functional outcome., Results: In 18 patients edema on initial MRI was graded as "absent", while 17 patients had grade 2 edema, 19 patients had grade 3 edema and 13 patients had grade 4 edema. IKDC score increased significantly from 49.8 points (SD +/- 14.9) to 72.3 points (SD +/- 17.5) at 12 months (p < 0.01). At all time points investigated, patients of group "4" showed inferior results to all other groups (p < 0.05). In addition, in patients without any edema, better clinical function was detected compared to all other groups before surgery (p < 0.05) and compared to group 3 at 6 months following ACI (p < 0.05)., Conclusions: Presence of severe subchondral bone marrow edema seems to correlate with knee function in patients with cartilage defects and may be a reliable prognostic factor for the early clinical course after ACI.

Purpose: We report the 2-year clinical results and identify prognostic factors in patients treated with autologous chondrocyte transplantation by use of a collagen membrane to seed the chondrocytes (ACT-CS)., Methods: This is a prospective study of 59 patients who were treated with ACT-CS and followed up for 24 months. Clinical function was assessed by International Knee Documentation Committee (IKDC-2000), objective International Cartilage Repair Society, and Lysholm scores before surgery and at 6, 12, and 24 months after surgery., Results: On the basis of objective International Cartilage Repair Society (ICRS) rating, the percentage of patients rated A (normal) and B (nearly normal) increased from 33.9% preoperatively to 92.5% at 24 months after ACT-CS. IKDC and Lysholm scores increased from 50.1 points (SD, 13.4) and 60.5 points (SD, 9.4), respectively, to 76.1 points (SD, 15.2) (P < .001) and 82.5 points (SD, 13.7) (P < .001), respectively, at 24 months. The failure rate was highest, at 26.7% at 2 years' follow-up, in the subgroup of patients who underwent ACT-CS as a salvage procedure. The rate of failures in patients with isolated cartilage defects was 5.9%., Conclusions: ACT-CS represents a technical modification of membrane-associated autologous chondrocyte transplantation that combines easy handling and attractive application properties with reliable clinical results 24 months after surgery, especially in patients with isolated cartilage defects. Even though the failure rate was higher in patients with kissing lesions or mild osteoarthritis, ACT-CS also seems to improve function in a large proportion of such patients., Level of Evidence: Level IV, prospective case series., (2010 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Autologous chondrocyte transplantation/implantation (ACT/ACI) is becoming increasingly common for the treatment of large cartilage defects in the knee joint. The traditional ACT technique involves injection of a suspension of cells into the cartilage defect, which is covered with a periosteal flap or collagen membrane. The technique requires extensive suturing to create an effective seal; however, cell leakage remains a potential problem. Matrix-induced autologous chondrocyte implantation (MACI/MACT) avoids this potential problem by using a membrane on which chondrocytes are seeded and cultured for several days, before the membrane is cut to the correct size and shape of the defect. Time-consuming extensive suturing is unnecessary. However, cutting and repeated manipulation of the seeded membrane may result in the loss of critical chondrocytes. A modified technique termed ACT-collagen membrane seeding (ACT-Cs) has been developed in which expanded chondrocytes are applied to the collagen membrane after it has been cut to size, substantially reducing the risk of viable cell loss while retaining the ease and speed of the MACI/MACT procedure. In addition, the seeding of mitotically active chondrocytes onto the membrane after expansion and immediately before transplantation allows direct application of high cell concentrations.

Background: Although autologous chondrocyte implantation (ACI) is a well-established therapy for the treatment of isolated cartilage defects of the knee joint, little is known about typical complications and their treatment after ACI., Hypothesis: Unsatisfactory outcome after ACI is associated with technique-related typical complications., Study Design: Case series; Level of evidence, 4., Methods: A total of 309 consecutive patients with 349 ACI procedures of the knee joint were analyzed. Three different ACI techniques were used: periosteum-covered ACI in 52 cases (14.9%), Chondrogide (Geistlich Biomaterials, Wolhusen, Switzerland) membrane-covered ACI in 215 cases (61.6%), and a 3-dimensional matrix-associated ACI (BioSeed-C, Biotissue Technologies, Freiburg, Germany) in 82 cases (23.5%). In 52 patients, revision surgery was performed for persistent clinical problems. These patients were analyzed for defect size and location, technique of ACI, and intraoperative findings during revision surgery. The mean time of follow-up for patients after ACI was 4.5 years (standard deviation, +/- 1.5)., Results: Four typical major complications were identified: hypertrophy of the transplant, disturbed fusion of the regenerative cartilage and the healthy surrounding cartilage, insufficient regenerative cartilage, and delamination. These diagnoses covered a total of 88.5% of the patients who underwent revision surgery. The overall complication rate was highest in the group of patients treated with periosteum-covered ACI (P = .008). The incidence of symptomatic hypertrophy was 5.2% for all techniques and defect locations; the highest incidence was in patients treated with periosteum-covered ACI (15.4%) (P = .001). The incidence of disturbed fusion was highest in the Chondrogide-covered ACI (3.7%) and the matrix-associated ACI group (4.8%). Concerning the incidence of complications by defect location, there was a tendency for increased complications in patellar defects (P = .095). Within the patellar defects group, no correlation was found for the occurrence of delamination, insufficient regeneration, and disturbed fusion. As a statistical trend, an increased rate of hypertrophy was found for patellar defects (P = .091)., Conclusion: A major proportion of complications after ACI can be summarized by 4 major diagnoses (symptomatic hypertrophy, disturbed fusion, delamination, and graft failure). Among those, the overall complication rate and incidence of hypertrophy of the transplant were higher for periosteum-covered ACI. Furthermore, an increased rate of symptomatic hypertrophy was found for patellar defects. Therapeutic concepts need to be developed to treat these typical complications of ACI.

Introduction: Although autologous chondrocyte implantation (ACI) has become well established for the treatment of full-thickness cartilage defects of the knee joint, nevertheless clinical results of retropatellar lesions are still inferior compared to those of defects located on femoral condyles. We report the clinical results obtained in 70 patients treated with ACI for full-thickness defects of the patella, with special reference to defect location and size, age, body mass index and sports activity., Methods: At a follow-up of 38.4 months (range 14-64, follow-up rate 83.3%), patients' subjective functional knee scores (IKDC, Lysholm) were analysed, as were the results of objective examination (according to ICRS)., Results: Mean patient age at the time of surgery was 34.3 years (+/-10.1). The mean Lysholm score at the time of follow-up was 73.0 (+/-22.4) and the subjective IKDC score was 61.6 (+/-21.5); normal and nearly normal clinical results according to the objective criteria of the International Cartilage Research Society (ICRS) were achieved in 67.1% of the patients, while abnormal results were achieved in 20.0% of the patients and severely abnormal results, in 12.9%. While different surgical techniques did not seem to have any significant influence on the treatment results, both defect size and defect location within the patella were found to be significantly associated with clinical outcome. The corollaries to this are that larger cartilage lesions of the patella are associated with an inferior outcome (p = 0.007) and that cartilage defects located on the lateral patellar facet are correlated with a better clinical outcome than those located on the medial facet or those involving both facets (p = 0.017)., Conclusion: This study demonstrates that within a group of patients treated with ACI for retropatellar cartilage lesion there are significant differences in clinical outcome, which are important and should be taken into account of when a decision has to be made on whether or not ACI is indicated.

Due to the very low intrinsic activity of human adult cartilage, healing of chondral and osteochondral defects in patients cannot be expected. In treating symptomatic cartilage damage, marrow stimulation methods belong to the most frequently used methods, along with autologous chondrocyte transplantation (ACT) and mosaicplasty. These arthroscopic procedures are generally easy and the marrow stimulation treatment costs relatively little. In recent years, Pridie drilling has been increasingly replaced by the microfracture technique. This modification relies on the same biological principles of promoting resurfacing with the formation of fibro-cartilaginous repair tissue. For the treatment of smaller cartilage defects (<2.5 cm(2)), microfracture still remains the first choice for treatment. The clinical results after microfracture in the knee are age dependent. Younger and active patients (<40 years) with smaller isolated traumatic lesions on the femoral condyles have the best long-term results. The deterioration of the clinical results begins after 18 months and is significantly more pronounced in older patients with defects on the patella-femoral joint and tibia. The inferior quality of the repair tissue, partially incomplete defect filling and new bone formation in the defect area seem to be limitations of these methods. The AMIC (autologous matrix induced chondrogenesis) technique was developed to enable treatment of larger defects by the application of a collagen Type III/I membrane (Geistlich Pharma, Wolhusen, Switzerland), in particular when cell-engaged procedures such as ACT cannot be used for financial reasons or because it is not indicated. AMIC seems to be particularly suitable for treating damaged retropatellar cartilage, which is an advantage because these defects can be hard to treat with standard microfracturing alone. The results of the ongoing studies are awaited to establish whether better results with this technology are achievable in the long term.