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OBJECTIVE: Realignment osteotomy performed concomitantly with cartilage restoration typically requires early restricted weightbearing and can add significant morbidity, potentially leading to an increased risk of early perioperative complications. The purpose of this study was to compare the 30-day complication rates after isolated cartilage restoration (ICR) versus concomitant cartilage restoration and osteotomy (CRO) using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. DESIGN: NSQIP registries between 2006 and 2019 were queried using Current Procedural Terminology codes to identify patients undergoing ICR (autologous chondrocyte implantation, osteochondral autograft transfer, or osteochondral allograft transplantation) and CRO (with concomitant high tibial osteotomy, distal femoral osteotomy, and/or tibial tubercle osteotomy). Complications rates between treatment groups were compared using multivariate logistic regression analyses adjusted for sex, age, steroid use, and respiratory status. RESULTS: A total of 773 ICR and 97 CRO surgical procedures were identified. Mean patient ages were 35.9 years for the ICR group and 31.2 years for the CRO group. Operative time was significantly longer in the CRO group (170.8 min) compared with the ICR group (97.8 min). Multivariate analysis demonstrated no significant differences in rates of PE, VTE, and all-cause readmission between the ICR and CRO groups. No events of wound disruption, SSI and reoperation were found in the CRO group, while the ICR group was characterized by low rates of wound disruption, reoperation, and SSI (

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

The purpose of this study was to assess the long-term clinical efficacy of first-generation autologous chondrocyte implantation (ACI) technique for osteochondral lesions of the ankle joint. Eleven patients with symptomatic OLTs underwent ACI from December 1997 to October 2002. A total of 9 patients (5 men, 4 women, age 25.2 ± 6.3) were evaluated at baseline and at 1, 3, 10 years, and at final follow-up of minimum 20 years with AOFAS ankle-hindfoot score, NRS for pain, and with the Tegner score. The AOFAS score improved significantly from the baseline value of 40.4 ± 19.8 to 82.7 ± 12.9 at the final follow-up (p < 0.0005). The NRS for pain improved significantly from 7.8 ± 0.7 at baseline to 4.8 ± 2.1 at the final follow-up (p < 0.0005). Moreover, the Tegner score underwent a modification from the pre-operative median value of 1 (range: 1–3) and from a pre-injury value of 5 (range: 3–7) to 3 (range: 2–4) at the final follow-up (p < 0.0005). ACI has proven to be an effective treatment option for patients suffering from OLTs, leading to a long-lasting clinical improvement even beyond 20 years of follow-up. Level IV [ABSTRACT FROM AUTHOR]

Background: Matrix-induced autologous chondrocyte implantation (MACI), the third-generation of the technique, is an established procedure for the treatment of focal cartilage defects in the knee. However, the literature lacks long-term results of MACI with good statistical power. Purpose: To determine long-term survival and patient-reported outcomes (PROs) in a representative cohort and to identify patient- and surgery-related parameters that may influence long-term clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: A total of 103 patients were clinically evaluated at the current follow-up of 8.1 years (range, 5-11.9 years). PRO measures (PROMs) included the Knee injury and Osteoarthritis Outcome Score (KOOS), EQ-5D, visual analog scale for pain, and Tegner Activity Scale. Magnetic resonance imaging results were evaluated by using the AMADEUS (area measurement and depth and underlying structures) and MOCART (magnetic resonance observation of cartilage repair tissue) 2.0 knee score classification systems. Potential factors influencing PROs were first identified univariately and investigated in a multivariate regression model. Results: The defects had a mean size of 4.8 cm2 (range, 1.2-12 cm2) and were predominantly femorotibial (66%). The mean Kaplan-Meier survival rate of revision for any reason was 97.2% ± 1.6% at 10 years. In comparison to preoperative values, all PROMs were significantly improved at the current follow-up (P <.05). The MOCART 2.0 score peaked at 12 months (mean, 80.2 ± 15.3 months) and showed no significant change at 96 months (mean, 76.1 ± 19.5 months; P =.142). The linear multivariate regression model identified an association of body mass index (BMI), MOCART 2.0 score, and number of previous knee surgeries with KOOS (R 2 = 0.41; f 2 = 0.69). Further analysis of the individual determinants revealed an optimal BMI range of 20 to 29 for favorable PROs at 96 months. Significant correlations of MOCART subscores with the overall KOOS were found for graft surface and structure, bony reaction, and subchondral detectable changes. Only 30% of patients with2 previous surgeries and 20% of patients with 3 previous surgeries achieved a Patient Acceptable Symptom State (χ2 = 10.93; P =.012). Conclusion: The present study shows consistently good long-term clinical outcomes after MACI with a low revision rate and high patient satisfaction. BMI and number of previous knee surgeries may influence clinical outcomes and should be considered in patient selection and education. There is a correlation between graft structure, subchondral bone changes on magnetic resonance imaging, and long-term PROMs. [ABSTRACT FROM AUTHOR]

Background: Multiple chondral lesions in the knee are difficult to manage. A few treatment options are available. Considering the number of lesions, size, location, and total surface area, the autologous cultured chondrocytes on porcine collagen membrane (MACI) technique can effectively treat multiple defects simultaneously. Indications: The MACI procedure is indicated for multiple chondral lesions in the knee with large surface areas when other technologies are hard to implement or lack sufficient follow-up. Technique Description: The chondral defects are debrided to subchondral bone with vertical walls. Concomitant procedures are to be completed before MACI implantation. Each defect is treated as an isolated lesion. Irregular and uncontained lesions require a unique approach. A single membrane can treat multiple lesions; however, careful presurgery analysis is necessary to analyze the requirement of an additional membrane. Results: The MACI technique for multiple lesions in the knee has a good response rate and high satisfaction scores over mid- to long-term follow-up. Discussion/Conclusions: Multiple chondral lesions of the knee can effectively be treated with MACI, providing patients with additional improved quality of life, increasing level of function, and possibly delaying total knee arthroplasty procedures. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication. [ABSTRACT FROM AUTHOR]

Introduction: Cartilage lesions and osteoarthritis are very prevalent and imply a significant clinical and economic burden. Objectives: To review treatments for cartilage lesions in a time life sequence and its particularities. Methods: We performed a broad PUBMED database review with a sensitive systematized strategy without restriction to article date or type. Results: This review brings us to the aspects of chondral and osteochondral lesions throughout the different age groups of patients. Focusing mainly on surgical treatment, we present here the most widely used techniques. To facilitate discussion, patients have been divided into 3 groups: children and adolescents with open physes, adults until the fifth decade, and adult patients over the fifth decade. For open physes patients, their capacity for healing is of important consideration in both conservative and operative management. In those with closed physes, most patients are treated surgically. While marrow stimulation is the most common cartilage treatment procedure, there is a growing use of other techniques such as osteochondral autograft transplantation and osteochondral allograft transplantation. Patients over 50 years old commonly present with more severe chondral lesions, which influences the treatment decision-making process. Conclusion: When attempting to optimize cartilage restoration in these 3 groups, it is important to weigh the physiologic age, the extent of the cartilage lesion, and the stage of the degenerative and osteoarthritic processes.

Background: Advancements have been made in the realm of cartilage-regenerative techniques in the past decades. However, their comparative advantage has not yet been fully studied. Objectives: To comparatively analyze the functional, radiological and histological outcomes, and complications of various procedures available for the treatment of cartilage defects. Data sources: PubMed, Embase, Web of Science, Cochrane, and Scopus. Study eligibility criteria, participants, and interventions: Randomized controlled trials reporting functional, radiological, histological outcomes, or complications of various methods were utilized in the management of cartilage defects. Patients with cartilage defects. Treatment methods include microfracture (MFX), autologous chondrocyte implantation (ACI), osteochondral allograft/autograft transplantation (OAT), mosaicplasty, or acellular implants. Study appraisal and synthesis methods: Cochrane’s Confidence in Network meta-analysis approach. Network meta-analysis was conducted in Stata. Random effects model was used for forest plots. Results: Three thousand one hundred ninety-three patients from 54 randomized controlled trials were included in the analysis. The mean age of included patients was 37.9 (±9.46) years. MFX-I was used as a constant comparator. Among the restorative methods, OAT-II offered significantly better functional outcome at 5 years (weighted mean difference [WMD] = 16.00, 95% confidence interval [CI] [11.66, 20.34], P

Background: Costal chondrocyte–derived pellet-type autologous chondrocyte implantation (CCP-ACI) has been introduced as a new therapeutic option for the treatment of articular cartilage defects. We had previously conducted a randomized controlled trial comparing CCP-ACI versus microfracture at 1 year postoperatively. Purpose: To compare the efficacy and safety of CCP-ACI versus microfracture for the treatment of articular cartilage defects of the knee at 5 years postoperatively. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: This study describes the mean 5-year follow-up of a previously published prospective clinical trial. The previous prospective trial compared the results of CCP-ACI versus microfracture until 1 year of follow-up. Of the 30 patients who were included in the previous study, 25 were followed up for 5 years. Patients were evaluated based on clinical outcome scores (Lysholm score, International Knee Documentation Committee score, Knee injury and Osteoarthritis Outcome Score [KOOS], and visual analog scale for pain), magnetic resonance imaging findings, and rates of treatment failure at last follow-up. Results: The MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score in the CCP-ACI group was significantly higher than that in the microfracture group at 5 years (62.3 vs 26.7, respectively; P <.0001). The Lysholm score and KOOS score in the CCP-ACI group were significantly higher than those in the microfracture group at 5 years (84.5 vs 64.9, respectively, and 390.9 vs 303.0, respectively; P =.023 and P =.017, respectively). There was 1 case of treatment failure that occurred in the microfracture group. Conclusion: The present randomized controlled trial indicated that the results of both procedures clinically and statistically significantly improved at 1 and 5 years' follow-up in treating cartilage defects, but the results of CCP-ACI were superior to those of microfracture. Magnetic resonance imaging conducted at 1 year and 5 years after CCP-ACI revealed statistically significant superior structural integration with native cartilage tissue compared with microfracture. Registration: NCT03545269 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Recently, various types of engineered autologous chondrocyte implantation (ACI) have been developed. Atelocollagen-associated ACI (A-ACI) is the only ACI procedure covered by Japanese Health Insurance since 2013. The indications of the A-ACI are traumatic cartilage defects and osteochondral dissecans (OCD) for knee joints. To evaluate midterm clinical results after A-ACI for the treatment for full-thickness cartilage defects of the knee. Thirteen consecutive patients who underwent A-ACI between 2014 and 2018 had been prospectively enrolled in this study. There were 11 men and 2 women with a mean age of 34 years at the time of surgery. The causes of the cartilage defect were trauma in 10 knees and OCD in 3 knees. The total number of lesions was 15, which were comprised of the medial femoral condyle in 5 knees, the lateral femoral condyle in 5 knees, and the femoral trochlea in 5 knees. The mean size of the lesion was 5.3 cm2. Each knee was clinically and radiologically evaluated preoperatively and postoperatively. The mean Lysholm score improved significantly from 74.0 points to 94.0 points (p = 0.008) and each subscale in Knee injury and Osteoarthritis Outcome Score improved significantly (p < 0.001) at the mean final follow-up period of 51 months (range, 36–84 months). The magnetic resonance observation of cartilage repair tissue 2.0 score at the mean follow-up of 38 months was significantly higher than that at 2 months postoperatively (p = 0.014). According to the International Cartilage Repair Society (ICRS) grading scale, 3 knees were graded as normal, 3 knees as nearly normal, and 1 knee as severely abnormal in second-look arthroscopic evaluation at a mean of 22 months (range, 8–41 months) after A-ACI. The present study showed a significant subjective and objective clinical improvement in the A-ACI for large cartilage defects of the knee at a mean follow-up of 51 months (range, 36–84 months). [ABSTRACT FROM AUTHOR]

Purpose: The optimal treatment approach for the complex pathology of meniscal insufficiency and coexisting full‐thickness cartilage defects remains unclear. The purpose of this study was to evaluate the viability, safety, and efficacy of this combined surgical approach at medium‐term follow‐up. Methods: This is a single‐centre longitudinal study with blinded outcome assessment. All consecutive patients treated with combined all‐arthroscopic meniscal allograft transplantation (MAT) with bone bridge fixation and ACI using chondrospheres at our institution between 2001 and 2021 were eligible for inclusion. Twenty patients with an average follow‐up of 72.6 ± 34.4 months were included in the statistical analysis. Clinical outcomes were assessed pre‐ and postoperatively using the IKDC Subjective Knee Form, Lysholm Score, Tegner Activity Scale, KOOS, and Visual Analog Scale (VAS) for patient satisfaction. Failure and reoperation rates were assessed, and cartilage regeneration tissue was evaluated on postoperative MRI. Results: IKDC scores significantly improved from 52.1 ± 16.9 to 68.5 ± 16.3 (p = 0.003). Lysholm scores improved from 61.5 ± 21.7 to 78.5 ± 12.9 (p = 0.004). Tegner scores improved from 3.5 (1–4) to 4.0 (2–6) (p = 0.014). KOOS scores improved significantly across all subcategories, except 'symptoms', where improvements did not reach statistical significance. VAS for overall patient satisfaction showed improvements but did not reach statistical significance. The combined procedure was successful in 17 patients (85%). Eight patients had to undergo reoperation (40%), comprising mostly small, arthroscopic procedures. Seven reoperations were directly attributable to meniscal allograft transplantation (46.7%). Postoperative Magnetic Resonance Observation of Cartilage Repair Tissue scores were 68.9 ± 16.8 (n = 14). Conclusion: Combined arthroscopic MAT and autologous chondrocyte implantation (ACI) is a viable, safe, and effective treatment approach for younger patients with meniscal insufficiency and coexisting full‐thickness cartilage damage, where alternative treatment options are limited. The combined surgical procedure achieved significant improvements in clinical outcome measures and patient satisfaction with acceptable failure and high arthroscopic reoperation rates. MAT is the limiting part of this combined procedure, with most failures and reoperations being attributable to MAT, as opposed to ACI. Level of Evidence: Level III. [ABSTRACT FROM AUTHOR]

Background: Osteochondral lesions of the knee are difficult to manage. Such lesions can be effectively treated with the matrix-induced autologous chondrocyte implantation (MACI) "sandwich" technique using autologous chondrocytes on porcine collagen membrane in conjuction with autologous cancellous bone grafting (ABG). Few studies have examined this technique to restore the osteochondral unit. Indications: The MACI "Sandwich" procedure is indicated when osteochondral lesions are larger than 2 cm2 in size and deeper than 8 to 10 mm, with symptoms consistent with the location of the lesion. Technique Description: The chondral defect is radically debrided back to healthy bone and cartilage tissue. The base of the bony cavity is drilled to enhance the vascular supply and promote healing. Next, the bony cavity is prepared to slightly undermine the subchondral bone surface around the articular margins, with the depth of the cavity wider than the opening, similar to a dental amalgam. The autologous cancellous bone is subsequently morselized and impacted up to the level of the native subchondral bone plate. The first MACI membrane with the cells facing up is placed directly onto the bone graft site and compressed with a neural patty. The neural patty is removed, and the second MACI membrane is then placed with the cells facing down. The edges are then micro-sutured to ensure stability. Results: The "sandwich" technique has superior survival rates compared with autologous bone grafting alone, with patients reporting decreased pain, improved function, and high satisfaction scores over a mid-term to long-term follow-up. Discussion/Conclusion: The MACI "sandwich" technique is an effective surgical intervention to restore the osteochondral unit and preserve the patient's native knee joint. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the risk of reoperation following autologous chondrocyte implantation (ACI) of the knee utilizing third-generation ACI products in a time-to-event analysis and report on the associated patient-reported outcome measures (PROM) in case of reoperation. Methods: Patients undergoing ACI were included from a longitudinal database. Patient age, sex, body mass index (BMI), number of previous surgeries, lesion localization, lesion size, symptom duration, as well as time and type of reoperation was extracted. A cox proportional-hazards model was applied to investigate the influence of baseline variables on risk of reoperation. Reoperation was defined as any type of subsequent ipsilateral knee surgery, excluding hardware removal. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was utilized to compare PROM between patients with and without reoperation. Results: A total of 2039 patients were included with 1359 (66.7%) having a minimum follow-up of 24 months. There were overall 243 reoperations (prevalence 17.9%). Minor arthroscopic procedures (n = 96, 39.5%) and revision cartilage repair procedures (n = 78, 32.1%) were the most common reoperations. Nineteen patients (0.9%) reported conversion arthroplasty at 17.7 (10.4) months after ACI. Female sex (HR 1.5, 95% CI [1.2, 2.0], p = 0.002) and the presence of 1–2 previous surgeries (HR 1.5, 95% CI [1.1, 2.0], p = 0.010), or more than 2 previous surgeries (HR 1.9, 95% CI [1.2, 2.9], p = 0.004) were significantly associated with increased risk of reoperation following ACI. Significantly less patients surpassed the minimal clinically important difference (MCID) in the reoperation group at 24 months regarding the KOOS subscores pain (OR 1.6, 95% CI [1.1, 2.2]), quality of life (OR 2.2, 95% CI [1.6, 3.2]), symptoms (OR 2.0 [1.4, 2.9]), and sports (OR 2.0 [1.4, 2.8]). Conclusion: Female patients and individuals with a history of previous surgeries face an elevated risk of requiring reoperation after undergoing ACI, which is associated with failure to attain clinically relevant improvements. A thorough evaluation of the indications for ACI is paramount, particularly when patients have a history of previous surgeries. Level of evidence: Level III. [ABSTRACT FROM AUTHOR]

Osteochondritis dissecans can result in significant limitations in activity, pain, and early osteoarthritis. There are various treatment modalities to address these defects. The purpose of this study was to provide a qualitative summary of the various treatment options for unstable osteochondritis dissecans in the knee. A literature search was performed on osteochondritis dissecans in the knee using PubMed (MEDLINE), Embase, and Cochrane electronic databases. The search was completed using a combination of the following terms: 'osteochondritis dissecans,' 'OCD,' 'osteochondral,' 'articular cartilage,' 'repair,' 'surgery,' 'treatment,' 'osteochondral allograft,' 'autologous chondrocyte implantation,' 'unstable,' 'knee,' 'clinical studies.' A total of 682 studies were found, of which 24 were included in the qualitative analysis. The quality score ranged from 46 to 80, and the mean follow-up ranged from 2 to 17 years. The most common surgical procedures were internal fixation (n = 7 studies), ACI (n = 6), fragment excision (n = 3), MACI (n = 2), bone graft + ACI (n = 2), OCA (n = 2), mosaicplasty/OAT (n = 2), and scaffold (n = 2). Overall, the reported outcome measures were heterogeneous in nature. Post-operative International Knee Documentations Committee (IKDC) scores ranged from 75 to 85 and Lysholm scores ranged from 70 to 93.5. Tegner scores ranged from 4 to 5. Rates of failure, complication, and revision were highly variable across studies and surgical techniques. There are a variety of surgical options for the treatment of unstable osteochondritis dissecans. In skeletally immature patients, internal fixation demonstrated acceptable rates of radiographic union and patient reported outcome measures. In skeletally mature patients with large lesions, MACI and OCA transplantation provided similar patient reported outcomes. [ABSTRACT FROM AUTHOR]

Imaging, particularly magnetic resonance imaging, and cartilage restoration surgery have both made substantial progress since the beginning of the 21st century. This era has seen high-field (3 T) magnets become ubiquitous in large centers, the development of novel quantitative imaging tools, and the advent of new generations of autologous cartilage implantation techniques. Here, we provide an update on postoperative imaging after cartilage restoration surgeries.Postoperative magnetic resonance imaging of cartilage restorative procedures is used for both confirming the success of the repair and identifying potential complications. There are no standard protocols for postoperative imaging following cartilage restorative procedures; however, in general, imaging can be routinely used 3 to 6 months postoperatively to assess for integration of repair and, depending on the technique, at approximately 6 to 12 months to assess for defect filling, integration with the host, and maturation of repair tissue. Imaging permits longitudinal assessments of cartilage repair and the adjacent osteochondral unit and is essential to assess the success of cartilage restoration.

BackgroundCell-based cartilage restoration with autologous chondrocyte implantation (ACI) is a safe and effective treatment for symptomatic cartilage lesions. Many patients undergoing ACI have a history of prior surgery, including bone marrow stimulation (BMS). There is mounting evidence that a history of prior BMS may impede healing of the ACI graft.Purpose/hypothesisThe purpose of this study was to compare the failure rates of primary ACI with ACI after prior BMS. We hypothesized that ACI after BMS would have a significantly higher failure rate (defined as reoperation, conversion to arthroplasty, and/or imaging-based failure) compared with primary ACI.Study designSystematic review; Level of evidence, 4.MethodsA literature search was performed by use of PubMed and Embase databases for relevant articles published through October 2, 2020, to identify studies evaluating outcomes and failures rates of ACI after prior BMS in the knee.ResultsIncluded were 11 studies comprising 1479 ACI procedures. The mean age at surgery ranged from 18.3 to 39.1 years, and the mean follow-up ranged from 3 to 20.6 years. All studies reported failure rates. The overall failure rate was significantly higher in the patients who underwent ACI after BMS, at 26.4% compared with 14.8% in the ACI group (P

Introduction: Cartilage restoration in the middle-aged population (40-60 years) is understudied. Objectives: The purpose of this study is to report the clinical outcomes and satisfaction of patients over the age of 40 years old who underwent autologous cultured chondrocytes on porcine collagen membrane (MACI) for the treatment of degenerative articular cartilage lesions in the knee. Methods: The study included 30 patients who were over 40 years of age (mean 48.6 ± 5.5 years, range 41-60 years). Patients included were treated by a single surgeon from 2017 to 2020. Clinical outcome data was available for 29 patients at a minimum 2-year follow-up (mean 39.6 ± 9.6 months). All patients with intact MACI grafts completed a satisfaction questionnaire. The mean lesion surface area transplanted was 11.5 ± 6.6 cm2. The mean number of defects transplanted was 2.5 ± 1.0. Treatment failure was defined as delamination of the MACI graft with associated clinical symptoms and/or progression of osteoarthritis. Results: Of the 29 patients, 6 (21%) had a graft failure. Three patients went on to osteochondral allograft transplantation, 1 patient experienced symptomatic improvement with debridement, and 2 patients underwent total knee arthroplasty. Twenty-seven of the 29 patients (93%) maintained their native knee. Of those with intact MACI grafts, 17 out of 23 (74%) rated their knee as “good” or “excellent” and 16 out of 23 (70%) were satisfied with their surgery. Conclusions: MACI is effective in the short-term in patients over the age of 40 years old with degenerative articular cartilage lesions to maintain their native knee. A moderate degree of satisfaction was achieved in most patients.

Purpose: To evaluate clinical, radiographic, and magnetic resonance (MR) results of costal chondrocyte-derived pellet-type scaffold-free autologous chondrocyte implantation (CCP-ACI) in osteochondral defects (ODs) up to 10-mm depth during 5 years of follow-up. Methods: Ten patients with CCP-ACI performed in ODs with depth up to 10 mm were retrospectively analyzed. The minimum follow-up period was 5 years. The median age was 36.5 (range 20–55) years. The median size and the depth of the OD lesion were 4.25 cm2 (range 2–6) and 7.0 mm (6–9), respectively. Clinically, the International Knee Documentation Committee, Lysholm, and visual analog scale pain scores were evaluated. Radiographically, the hip‒knee‒ankle (HKA) angle and the Kellgren‒Lawrence (K‒L) grade were assessed. On MR imaging, the magnetic resonance observation of cartilage repair tissue (MOCART) 2.0 score and the defect depth were evaluated. Results: All average clinical scores improved significantly by 1, 2, and 5 years postoperatively. The average HKA angle and the proportion of K‒L grade did not change significantly within 5 years. The median total MOCART scores were 50 (range 45–65), 50 (35–90), 57.5 (40–90), and 65 (50–85) at 6 months, 1 year, 2 years, and 5 years postoperatively, respectively (p = 0.001), with significant improvement at 2 years compared to that at 6 months postoperatively. The signal intensity of the repair tissue and subchondral change significantly improved from 10 (range 10–10) to 12.5 (10–15) (p = 0.036), and from 10 (10–10) to 17.5 (0–20) (p = 0.017), respectively. Significant improvements were seen at 5 years postoperatively for the former and at 2 years postoperatively for the latter. The average depths on MR imaging were 6.7, 6.7, 6.8, 6.6, and 6.6 mm preoperatively and at 6 months, 1 year, 2 years, and 5 years postoperatively with no significant changes (n.s). Conclusion: CCP-ACI provided acceptable mid-term outcomes in ODs up to 10-mm in depth without bone grafting despite of no scaffold. The procedure can be one of minimally invasive treatment options for ODs without scaffold-related problems. Level of evidence: IV. [ABSTRACT FROM AUTHOR]

Many patients, particularly those aged above 40, experience knee joint pain, which hampers both sports activities and daily living. Treating isolated chondral and osteochondral defects in the knee poses a significant clinical challenge, particularly in younger patients who are not typically recommended partial or total knee arthroplasty as alternatives. Several surgical approaches have been developed to address focal cartilage defects. The treatment strategies are characterized as palliation (e.g., chondroplasty and debridement), repair (e.g., drilling and microfracture), or restoration (e.g., autologous chondrocyte implantation, osteochondral autograft, and osteochondral allograft). This review offers an overview of the commonly employed clinical methods for treating articular cartilage defects, with a specific focus on the clinical trials conducted in the last decade. Our study reveals that, currently, no single technology fully meets the essential requirements for effective cartilage healing while remaining easily applicable during surgical procedures. Nevertheless, numerous methods are available, and the choice of treatment should consider factors such as the location and size of the cartilage lesion, patient preferences, and whether it is chondral or osteochondral in nature. Promising directions for the future include tissue engineering, stem cell therapies, and the development of pre-formed scaffolds from hyaline cartilage, offering hope for improved outcomes. [ABSTRACT FROM AUTHOR]

Cytotherapies are often necessary for the management of symptomatic large knee (osteo)-chondral defects. While autologous chondrocyte implantation (ACI) has been clinically used for 30 years, allogeneic cells (clinical-grade FE002 primary chondroprogenitors) have been investigated in translational settings (Swiss progenitor cell transplantation program). The aim of this study was to comparatively assess autologous and allogeneic approaches (quality, safety, functional attributes) to cell-based knee chondrotherapies developed for clinical use. Protocol benchmarking from a manufacturing process and control viewpoint enabled us to highlight the respective advantages and risks. Safety data (telomerase and soft agarose colony formation assays, high passage cell senescence) and risk analyses were reported for the allogeneic FE002 cellular active substance in preparation for an autologous to allogeneic clinical protocol transposition. Validation results on autologous bioengineered grafts (autologous chondrocyte-bearing Chondro-Gide scaffolds) confirmed significant chondrogenic induction (COL2 and ACAN upregulation, extracellular matrix synthesis) after 2 weeks of co-culture. Allogeneic grafts (bearing FE002 primary chondroprogenitors) displayed comparable endpoint quality and functionality attributes. Parameters of translational relevance (transport medium, finished product suturability) were validated for the allogeneic protocol. Notably, the process-based benchmarking of both approaches highlighted the key advantages of allogeneic FE002 cell-bearing grafts (reduced cellular variability, enhanced process standardization, rationalized logistical and clinical pathways). Overall, this study built on our robust knowledge and local experience with ACI (long-term safety and efficacy), setting an appropriate standard for further clinical investigations into allogeneic progenitor cell-based orthopedic protocols. [ABSTRACT FROM AUTHOR]

Hyaline cartilage's inability to self-repair can lead to osteoarthritis and joint replacement. Various treatments, including cell therapy, have been developed for cartilage damage. Autologous chondrocyte implantation (ACI) is considered the best option for focal chondral lesions. In this article, we aimed to create a narrative review that highlights the evolution and enhancement of our chondrocyte implantation technique: High-Density-ACI (HD-ACI) Membrane-assisted Autologous Chondrocyte Implantation (MACI) improved ACI using a collagen membrane as a carrier. However, low cell density in MACI resulted in softer regenerated tissue. HD-ACI was developed to improve MACI, implanting 5 million chondrocytes per cm2, providing higher cell density. In animal models, HD-ACI formed hyaline-like cartilage, while other treatments led to fibrocartilage. HD-ACI was further evaluated in patients with knee or ankle defects and expanded to treat hip lesions and bilateral defects. HD-ACI offers a potential solution for cartilage defects, improving outcomes in regenerative medicine and cell therapy. HD-ACI, with its higher cell density, shows promise for treating chondral defects and advancing cartilage repair in regenerative medicine and cell therapy. [ABSTRACT FROM AUTHOR]

Background: Few studies exist for large defects comparing matrix-associated autologous chondrocyte implantation (M-ACI) with other cartilage repair methods due to the limited availability of suitable comparator treatments. Purpose: To compare the clinical efficacy of a novel hydrogel-based M-ACI method (NOVOCART Inject plus) versus microfracture (MFx) in patients with knee cartilage defects. Study Design: Cohort study; Level of evidence, 3. Methods: Propensity score matched-pair analysis was used to compare the 24-month outcomes between the M-ACI treatment group from a previous single-arm phase 3 study and the MFx control group from another phase 3 study. Patients were matched based on preoperative Knee injury and Osteoarthritis Outcomes Score (KOOS), symptom duration, previous knee surgeries, age, and sex, resulting in 144 patients in the matched-pair set (72 patients per group). The primary endpoint was the change in least-squares means (ΔLSmeans) for the KOOS from baseline to the 24-month assessment. Results: Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 versus 3.7 cm2). Other differences included defect location (no patellar or tibial defects in the MFx group), number of defects (33.3% with 2 defects in the M-ACI group versus 9.7% in the MFx group), and defect cause (more patients with degenerative lesions in the M-ACI group). The M-ACI group had higher posttreatment KOOS (M-ACI versus MFX: 81.8 ± 16.8 versus 73.0 ± 20.6 points) and KOOS ΔLSmeans from baseline to 24 months posttreatment (M-ACI versus MFX: 36.9 versus 26.9 points). Treatment contrasts in KOOS ΔLSmeans from baseline indicated statistical significance in favor of M-ACI from 3 to 24 months posttreatment (P =.0026). Significant and clinically meaningful differences in favor of M-ACI at 24 months were also found regarding International Knee Documentation Committee (IKDC) score ΔLSmeans from baseline (37.8 versus 30.4 points; P =.0334), KOOS responder rates at 24 months (≥10-point improvement from baseline; 94.4% versus 65.3%; P <.0001), IKDC responder rates at 24 months (>20.5-point improvement from baseline; 83.3% versus 61.1%, P =.0126) and MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score in a subgroup of patients (LS means, 86.9 versus 69.1; P =.0096). Conclusion: In this exploratory analysis, M-ACI using an in situ crosslinked hydrogel demonstrated superior clinical and structural (MOCART) 24-month outcomes compared with MFx in patients with knee cartilage defects. [ABSTRACT FROM AUTHOR]

Autologous chondrocyte implantation (ACI) for the treatment of articular cartilage defects remains challenging in terms of maintaining chondrogenic phenotype during in vitro chondrocyte expansion. Growth factor supplementation has been found supportive in improving ACI outcomes by promoting chondrocyte redifferentiation. Here, we analysed the chondrogenic growth factor concentrations in the human blood-derived secretome of Hypoxia Preconditioned Serum (HPS) and assessed the effect of HPS-10% and HPS-40% on human articular chondrocytes from osteoarthritic cartilage at different time points compared to normal fresh serum (NS-10% and NS-40%) and FCS-10% culture conditions. In HPS, the concentrations of TGF-beta1, IGF-1, bFGF, PDGF-BB and G-CSF were found to be higher than in NS. Chondrocyte proliferation was promoted with higher doses of HPS (HPS-40% vs. HPS-10%) and longer stimulation (4 vs. 2 days) compared to FCS-10%. On day 4, immunostaining of the HPS-10%-treated chondrocytes showed increased levels of collagen type II compared to the other conditions. The promotion of the chondrogenic phenotype was validated with quantitative real-time PCR for the expression of collagen type II (COL2A1), collagen type I (COL1A1), SOX9 and matrix metalloproteinase 13 (MMP13). We demonstrated the highest differentiation index (COL2A1/COL1A1) in HPS-10%-treated chondrocytes on day 4. In parallel, the expression of differentiation marker SOX9 was elevated on day 4, with HPS-10% higher than NS-10/40% and FCS-10%. The expression of the cartilage remodelling marker MMP13 was comparable across all culture conditions. These findings implicate the potential of HPS-10% to improve conventional FCS-based ACI culture protocols by promoting the proliferation and chondrogenic phenotype of chondrocytes during in vitro expansion. [ABSTRACT FROM AUTHOR]

Background: There are several techniques for knee exposure in treating chondral defects with restorative procedures. The medial subvastus knee exposure is often overlooked when choosing the surgical approach. When properly performed, the medial subvastus approach can allow for the treatment of a wide range of pathology while preserving the extensor mechanism. Indications: We present a case of an active 40-year-old man with persistent left knee pain noted to have a full-thickness medial femoral condylar articular cartilage defect in an otherwise healthy appearing knee. Technique Description: The rationale and considerations for the medial subvastus knee exposure in treating a chondral defect with an autologous chondrocyte implant are discussed. Careful consideration of the approach, intra-articular exposure, and closure are emphasized to achieve optimal outcomes. Results: At 18 months postoperative, the patient reported no knee pain with improvements made in Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm, and International Knee Documentation Committee (IKDC) scores. These results are consistent with our institutions larger cohort of 26 patients undergoing matrix-induced autologous chondrocyte implantation (MACI) using the subvastus approach. These improvements in patient-reported outcomes are maintained at 2 years postoperative and are consistent with other published outcomes of the MACI procedure. Discussion/Conclusion: Excellent results in addressing chondral pathology about the knee can be achieved by selecting the appropriate surgical access. The subvastus approach has several advantages such as preserving the quadriceps mechanism, improving postoperative quadriceps muscle strength, conservation of the patellar genicular blood supply and possibly reducing postoperative pain that can result in a faster rehabilitation. When performed systematically and carefully, complete exposure of the knee can be achieved to facilitate a wide variety of surgical interventions. In patients undergoing cartilage restoration procedures, the medial subvastus approach should be considered in the surgeon's armamentarium. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication. [ABSTRACT FROM AUTHOR]

Research on the long-term outcomes following surgical therapy for osteochondritis dissecans (OCD) of the knee is scarce. A single-center retrospective cohort study was conducted to investigate surgically treated patients for knee OCD between 1993 and 2007. A total of 37 patients with an average follow-up duration of 14 years (range 8–18) were in the final cohort. IKDC and Lysholm scores were assessed. The duration and types of sport activity were reported. Long-term results were compared with existing midterm data. Knee scores showed a very good outcome with a mean of 91.3 in the IKDC score and 91.7 in the Lysholm score. Compared to midterm outcomes, both IKDC (p = 0.028) and Lysholm scores (p = 0.01) improved on final follow-up. Patients with open physes showed a significantly better Lysholm score compared to patients with closed physes (p = 0.034). Defect localization and size did not influence the outcome, but a defect depth of <0.8 cm2 achieved significantly better scores than ≥0.8 cm2. Of all surgical interventions, refixation achieved the best outcome. Long-term results significantly improved compared to midterm results with a follow-up of 40 months (p = 0.01). Thirty-six out of 37 patients were physically active, with 56% of sports being knee-straining activities. Long-term results following surgically treated OCD fragments show excellent function and a good athletic level. Patients with open physes potentially have better knee outcomes. Midterm results are sustainable and could improve further in the long term. [ABSTRACT FROM AUTHOR]

Purpose: This systematic review evaluated the efficacy and safety of autologous chondrocyte implantation (ACI) for chondral defects of the knee in skeletally immature patients. Current available data from patients reported outcome measures (PROMs) and complications were collected, analyzed, and discussed. Methods: This systematic review was conducted according to the PRISMA guidelines. The following databases were accessed in May 2022: PubMed, Google scholar, Embase, and Scopus. All the clinical studies investigating the efficacy of ACI to manage chondral defects of the knee in skeletally immature patients were accessed. Articles treating patients with surgical procedures other than ACI were not eligible, nor were studies with a follow-up shorter than 12 months. Results: Data from 9 studies (251 procedures) were collected. 32% (80 of 251) of patients were females. The mean length of follow-up was 44.2 ± 29.4 (range, 12–115) months. The mean age of the patients was 16.4 ± 0.7 (range, 15–17) years. The Knee injury and Osteoarthritis Outcome Score (KOOS) and International Knee Document Committee (IKDC) increased of + 41.9/100 (P = 0.003) and + 33.2/100 (P = < 0.0001) points, respectively. The Lysholm Knee Score improved of + 20.6/100 (P = 0.02) points. The Visual Analogue Scale (VAS) for pain reduced of − 3.6/10 (P = 0.004) points. The Tegner scale did not show any statistically significant improvement from baseline to follow-up (P = n.s.). The rate of graft hypertrophy was 12.5% (5 of 40 patients), and the rate of failure 5.6% (8 of 142 patients). Conclusion: ACI for chondral defects of the knee is effective to improve PROMs in skeletally immature patients. The safety profile of ACI still remains controversial. Level of evidence: III. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and efficacy of matrix-associated autologous chondrocyte implantation (ACI) using spheroids in comparison to arthroscopic microfracture for the treatment of symptomatic cartilage defects of the knee. Methods: In a prospective multicenter-controlled trial, patients aged between 18 and 50 years, with single symptomatic focal cartilage defects between 1 and 4 cm2 (mean 2.6 ± 0.8, median 2.75, range 1.44–5.00) in the knee were randomized to treatment with ACI with spheroids (n = 52) or microfracture (n = 50). Primary clinical outcome was assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS). Analyses were performed in a defined hierarchical manner where outcomes of ACI were first compared to baseline values followed by a comparison to the microfracture group with repeated-measures ANCOVA with a non-inferiority approach. Subgroup analyses were performed to investigate the influence of age and defect size on the overall KOOS. Secondary clinical outcomes were the magnetic resonance observation of cartilage repair tissue (MOCART), modified Lysholm score and International Knee Documentation Committee (IKDC) examination form. Safety data focused on adverse events. Here the 5 years results are presented at which there were 33 observed cases in the ACI group and 30 in the microfracture group. Results: The overall KOOS and its five subscores were significantly improved compared to baseline for both the ACI and microfracture group. Non-inferiority of ACI to microfracture was confirmed for the overall KOOS and the subscores, while for the subscores activities of daily living, quality of life and sports and recreation of the threshold for superiority was passed. In the ACI group, a notably more rapid initial improvement of the KOOS was found at three months for the older age group compared to the younger age group and the microfracture group. No other differences were found based on age or defect size. In addition, clinical improvement was found for the MOCART, modified Lysholm and IKDC examination form both the ACI and microfracture group. No safety concern related to either treatment was observed. Conclusion: This study confirms the safety and efficacy of matrix-associated ACI with spheroids at a mid to long-term follow-up. Non-inferiority of ACI to microfracture was confirmed for the overall KOOS and all subscores, while superiority was reached for the subscores activities of daily living, quality of life and sports and recreation in the ACI group. This underlines the importance of ACI for the young and active patients. Level of evidence.: I. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the mid- and long-term efficacy of autologous chondrocyte implantation (ACI) and matrix-assisted chondrocyte implantation (MACI) to treat patients with knee cartilage defects in the presence of osteoarthritis (OA). Methods: PubMed and Cochrane databases were systematically searched for studies describing the treatment of knee OA with ACI or MACI (Kellgren–Lawrence (KL) ≥ 1, minimum follow-up 36 months). Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines and included Lysholm, Western Ontario McMaster University and International Knee Documentation Committee scores. Results: Of the 127 full-text articles assessed for eligibility, only five studies were selected based on inclusion/exclusion criteria (2 on ACI and 3 on MACI). In both groups, the defects were mainly located at femoral level, size 2.2–15.1 cm2 in the ACI and 2.0–7.6 cm2 in the MACI group. ACI was mostly used for patients affected by KL I, whereas MACI for patients with KL II–IV. The data obtained from 235 patients (161 ACI, 74 MACI) showed that ACI and MACI sustained stable clinical improvements up to 11 and 15 years, respectively, with a failure rate of about 10% up to 11 years. Scarce biological details regarding chondrocyte implantation were reported. Conclusions: ACI and MACI procedures for the treatment of knee cartilage lesions associated to OA showed long-term success and allowed delaying arthroplasty. Additional trials reporting homogenous data and precise patient characterization are needed to conduct an effective literature meta-analysis and identify the clinical relevance of these procedures. Level of evidence: IV. [ABSTRACT FROM AUTHOR]

Hyaline cartilage has very limited repair capability and cannot be rebuilt predictably using conventional treatments. This study presents Autologous Chondrocyte Implantation (ACI) on two different scaffolds for the treatment of lesions in hyaline cartilage in rabbits. The first one is a commercially available scaffold (Chondro–Gide) made of collagen type I/III and the second one is a polyethersulfone (PES) synthetic membrane, manufactured by phase inversion. The revolutionary idea in the present study is the fact that we used PES membranes, which have unique features and benefits that are desirable for the 3D cultivation of chondrocytes. Sixty-four White New Zealand rabbits were used in this research. Defects penetrating into the subchondral bone were filled with or without the placement of chondrocytes on collagen or PES membranes after two weeks of culture. The expression of the gene encoding type II procollagen, a molecular marker of chondrocytes, was evaluated. Elemental analysis was performed to estimate the weight of tissue grown on the PES membrane. The reparative tissue was analyzed macroscopically and histologically after surgery at 12, 25, and 52 weeks. RT-PCR analysis of the mRNA isolated from cells detached from the polysulphonic membrane revealed the expression of type II procollagen. The elementary analysis of polysulphonic membrane slices after 2 weeks of culture with chondrocytes revealed a concentration of 0.23 mg of tissue on one part of the membrane. Macroscopic and microscopic evaluation indicated that the quality of regenerated tissue was similar after the transplantation of cells placed on polysulphonic or collagen membranes. The established method for the culture and transplantation of chondrocytes placed on polysulphonic membranes resulted in the growth of the regenerated tissue, revealing the morphology of hyaline-like cartilage to be of similar quality to collagen membranes. [ABSTRACT FROM AUTHOR]

Purpose: To investigate postoperative complications and associated risk factors for failure following autologous chondrocyte transplantation ("ACT") as well as its long-term survival and clinical function. It was hypothesized that ACT is a safe technique for cartilage repair with a low incidence of postoperative complications and rare rates of revision surgery combined with a high long-term survival and good to excellent clinical outcome in long-term-follow-up. Methods: All patients undergoing ACT-Cs of the knee joint between 2006 and 2012 at the author's institution were included in this retrospective study. Concomitant procedures had been performed if necessary. Early postoperative complications, revision surgeries, failure and risk factors for those events were evaluated 6 months after the surgery. Long-term clinical outcome was assessed using the Lysholm Score, the Tegner Score, a 10-grade scale for satisfaction and the Visual Analogue Scale (VAS) at a minimum follow-up of 9 years postoperatively. Long-term survival was calculated using revision surgeries, clinical failures and conversion procedures to create a Kaplan–Meier analysis. A subgroup analysis for different defect locations was performed. 139 patients were included in this study (27% female/ 73%male; age 26.7 [21.7; 35.2] years). The median defect size was 4.0 [3.0; 6.0] cm2 (40% medial femoral condyle (MFC), 17% lateral femoral condyle (LFC), 36% patella, 19% trochlea). 97 (70%) of the patients had undergone previous surgery and 84 (60%) underwent concomitant procedures. Results: Postoperatively, 8% of patients had complications (4% bleeding, 2% arthrofibrosis, 2% infection), 7% of patients needed revision surgery. 12% of patients had a prolonged deficit in ROM, that did not require revision surgery. No significant difference in terms of complications was found between the patellofemoral and femorotibial group. Patients demonstrated good patient reported long-term outcomes 9–15 years after the index surgery (Tegner: 4.7 ± 1.8; VAS: 2.4 ± 2.1; Lysholm: 80 ± 14; satisfaction with operation: 7.3 ± 1.9). Survival rates were 88% at 9 years, 85% at 11 years, and 85% at 13 years after the index procedure. Reasons for failure included debridement of ACT (n = 4; 5%), revision ACT (n = 3, 3%), conversion to total knee arthroplasty (n = 3, 3%) and conversion to High tibial osteotomy (HTO) (n = 1; 1%)). Conclusion: The present study indicates ACT as an effective treatment option for femorotibial- as well as patellofemoral cartilage defects with a high long-term survival and low conversion rate as well as good long-term results regarding knee function and satisfaction. Postoperative complications needing revision surgery are rare. Prolongated deficits of range of motion appear frequently up to six months especially in patellofemoral defects, but can often be successfully addressed by intensified physiotherapy without requiring an arthrolysis. Level of evidence: Level III. [ABSTRACT FROM AUTHOR]

Background: Stratification is required to ensure that only patients likely to benefit receive autologous chondrocyte implantation (ACI). It would be advantageous to identify biomarkers to predict ACI outcome that are measurable in blood, avoiding the need for an invasive synovial fluid harvest. Purpose: To assess if proteomic analyses can be used to identify novel candidate blood biomarkers in individuals who respond well or poorly to ACI. Study Design: Controlled laboratory study. Methods: Isobaric tagging for relative and absolute quantitation (iTRAQ) mass spectrometry was used to assess the proteome in plasma pooled from ACI responders (mean Lysholm improvement after ACI, 33; n = 10) or nonresponders (mean, −13; n = 10), collected at the time of surgery for cartilage harvest (stage 1) or implantation of culture-expanded chondrocytes (stage 2). An alternative proteomic method, label-free quantitation liquid chromatography–tandem mass spectrometry, was used to analyze plasma samples (majority matched to iTRAQ) individually. Differentially abundant proteins (±2.0-fold) were analyzed from both proteomic data sets, and markers of interest identified via pooled iTRAQ were validated via immunoassay of individual samples. Results: Protein differences could be detected in the plasma preoperatively between ACI responders and nonresponders (16 proteins; ≥±2.0-fold change; P <.05) using iTRAQ proteomics. The most pronounced plasma proteome shift was evident in response to stage 1 surgery in ACI nonresponders, with 48 proteins being differentially abundant between the procedures. Label-free quantitation liquid chromatography–tandem mass spectrometry analysis of these same plasma samples (nonpooled) resulted in very few proteins being identified that were significantly differentially abundant. However, this work highlighted cartilage acidic protein 1 as being increased preoperatively in nonresponders as compared with responders. Conclusions: This study is the first to use proteomic techniques to profile the plasma of individuals treated with ACI. Despite iTRAQ analysis of pooled plasmas indicating that there are differences in the plasma proteome between responders and nonresponders to ACI, these findings were not replicated when assessed using an alternative nonpooled technique. This study highlights some of the difficulties in profiling the plasma proteome in an attempt to identify novel biomarkers. Regardless, cartilage acidic protein 1 has been identified as a protein candidate, which is detectable in plasma and can predict outcome to ACI before treatment. Clinical Relevance: Candidate plasma protein biomarkers identified in this study have the potential to help determine which patients will be best suited to treatment with ACI. [ABSTRACT FROM AUTHOR]

The purpose of this study is to analyze the epidemiology of children and adolescents undergoing osteochondral autograft transplantation (OAT), osteochondral allograft transplantation (OCA), and autologous chondrocyte implantation (ACI) in the United States. The Pediatric Health Information System, a national database consisting of 49 children's hospitals, was queried for all patients undergoing OAT, OCA, and ACI between 2012 and 2018. Demographic information was collected for each subject. United States Census guidelines were used to categorize hospitals geographically. Univariate analysis was followed by purposeful entry multivariate regression to adjust for confounding factors. A total of 809 subjects with a mean age of 15.4 ± 2.4 years were included in the analysis. Of these, 48.6% underwent OCA, 41.9% underwent OAT, and 9.5% underwent ACI. After adjusting for confounders in a multivariate model, ACI was 3.6 times more likely to be performed in patients with private insurance than those that were publicly insured (95% CI 1.6–8.0, p = 0.002). Furthermore, a patient in the Northeast was 33.1 times more likely to undergo ACI than in the West (95% CI 4.5–246.1, p = 0.001). OAT was performed most frequently in the West and Midwest (52.4% and 51.8% of the time, respectively; p < 0.001). In the United States, there is substantial variation in the procedures performed for cartilage restoration in children and adolescents. Though ACI is the least commonly selected operation overall, it is significantly more likely to be performed on patients with private insurance and those in the Northeast. [ABSTRACT FROM AUTHOR]

Introduction: Cartilage defects in the knee can be caused by injury, various types of arthritis, or degeneration. As a long-term consequence of cartilage defects, osteoarthritis can develop over time, often leading to the need for a total knee replacement (TKR). The treatment alternatives of chondral defects include, among others, microfracture, and matrix-associated autologous chondrocyte implantation (M-ACI). The purpose of this study was to determine cost-effectiveness of M-ACI in Germany with available mid- and long-term outcome data, with special focus on the avoidance of TKR. Materials and methods: We developed a discrete-event simulation (DES) that follows up individuals with cartilage defects of the knee over their lifetimes. The DES was conducted with a status-quo scenario in which M-ACI is available and a comparison scenario with no M-ACI available. The model included 10,000 patients with articular cartilage defects. We assumed Weibull distributions for short- and long-term effects for implant failures. Model outcomes were costs, number of TKRs, and quality-adjusted life years (QALYs). All analyses were performed from the perspective of the German statutory health insurance. Results: The majority of patients was under 45 years old, with defect sizes between 2 and 7 cm2 (mean: 4.5 cm2); average modeled lifetime was 48 years. In the scenario without M-ACI, 26.4% of patients required a TKR over their lifetime. In the M-ACI scenario, this was the case in only 5.5% of cases. Thus, in the modeled cohort of 10,000 patients, 2700 TKRs, including revisions, could be avoided. Patients treated with M-ACI experienced improved quality of life (22.53 vs. 21.21 QALYs) at higher treatment-related costs (18,589 vs. 14,134 € /patient) compared to those treated without M-ACI, yielding an incremental cost‐effectiveness ratio (ICER) of 3376 € /QALY. Conclusion: M-ACI is projected to be a highly cost‐effective treatment for chondral defects of the knee in the German healthcare setting. [ABSTRACT FROM AUTHOR]

Background: The extent to which concomitant osteotomy provides an improvement in clinical outcomes after cartilage repair procedures is unclear. Purpose: To review the existing literature to compare clinical outcomes of patients undergoing cartilage repair of the tibiofemoral joint with versus without concomitant osteotomy. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines by searching PubMed, the Cochrane Library, and Embase to identify studies that directly compared outcomes between cartilage repair of the tibiofemoral joint alone (group A) versus cartilage repair with concomitant osteotomy (high tibial osteotomy [HTO] or distal femoral osteotomy [DFO]) (group B). Studies on cartilage repair of the patellofemoral joint were excluded. The search terms used were as follows: osteotomy AND knee AND ("autologous chondrocyte" OR "osteochondral autograft" OR "osteochondral allograft" OR microfracture). Outcomes in groups A and B were compared based on reoperation rate, complication rate, procedure payments, and patient-reported outcomes (Knee injury and Osteoarthritis Outcome Score [KOOS], visual analog scale [VAS] for pain, satisfaction, and WOMAC). Results: Included in the review were 5 studies (1 level 2 study, 2 level 3 studies, 2 level 4 studies) with 1747 patients in group A and 520 patients in group B. The mean patient ages were 34.7 and 37.5 years in groups A and B, respectively, and the mean lesion sizes were 4.0 and 4.5 cm2, respectively. The mean follow-up time was 44.6 months. The most common lesion location was the medial femoral condyle (n = 999). Preoperative alignment averaged 1.8° and 5.5° of varus in groups A and B, respectively. One study found significant differences between groups in KOOS, VAS, and satisfaction, favoring group B. The reoperation rates were 47.4% and 17.3% in groups A and B, respectively (P <.0001). Conclusion: Patients undergoing cartilage repair of the tibiofemoral joint with concomitant osteotomy might be expected to experience greater improvement in clinical outcomes with a lower reoperation rate compared with those undergoing cartilage repair alone. Surgeons preparing for cartilage procedures of the knee joint should pay particular attention to preoperative malalignment of the lower extremity to optimize outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background This systematic review investigated the efficacy and safety of surgical procedures augmented with cell therapies for chondral defects of the talus. Methods The present systematic review was conducted according to the 2020 PRISMA guidelines. PubMed, Google scholar, Embase, and Scopus databases were accessed in March 2022. All the clinical trials investigating surgical procedures for talar chondral defects augmented with cell therapies were accessed. The outcomes of interest were to investigate whether surgical procedures augmented with cell therapies promoted improvement in patients reported outcomes measures (PROMs) with a tolerable rate of complications. Results Data from 477 procedures were retrieved. At a mean follow-up of 34.8 ± 9.7 months, the Visual Analogic Scale (VAS) improved of 4.4/10 (P = 0.002) and the American Orthopaedic Foot and Ankle Score (AOFAS) of 31.1/100 (P = 0.0001) points. No improvement was found in Tegner score (P = 0.4). Few articles reported data on complications. At last follow-up, the rate of reoperation and failure were 0.06% and 0.03%, respectively. No graft delamination or hypertrophy was observed. Conclusion The current evidence suggests that cell therapies may be effective and safe to enhance surgical procedures for chondral defects of the talus. These results should be considered within the limitations of the present study. The current literature should be enriched with randomized controlled clinical trials with larger population size and longer follow-up.

Abstract Background Some authors secured the membrane during matrix-induced autologous chondrocyte implantation (mACI) with fibrin glue or did not use a formal fixation. The real impact of fibrin glue addition on chondrocytes migration and proliferation has not yet been clarified. This study evaluated the impact of fibrin glue on a chondrocyte loaded collagenic membrane. Methods A resorbable collagen I/III porcine derived membrane commonly employed in AMIC was used for all experiments. Chondrocytes from three difference donors were used. At 1-, 2-, 3-, 4-, 6-, and at 8-week the membranes were embedded in Mounting Medium with Dapi (ABCAM, Cambridge, UK). The Dapi contained in the mounting medium ties the DNA of the cell nucleus and emits a blue fluorescence. In this way, the spreading of the cells in the membrane can be easily monitored. The outcomes of interest were to evaluate (1) cell migration and (2) cell proliferation within the porous membrane layer. DAPI/nuclei signals were analysed with fluorescence microscope under a magnification of 100-fold. Results The no-fibrin group demonstrated greater migration of the cells within the membrane. Although migration resulted higher in the no-fibrin group at every follow-up, this difference was significant only at week 1 (P

Osteoarthritis is one of the most severe diseases of the human musculoskeletal system, and therefore, for many years, special attention has been paid to the search for effective methods of its treatment. However, even the most modern methods only in a limited number of cases in the early or intermediate stages of osteoarthritis lead to positive treatment results. In the later stages of development, osteoarthritis is practically incurable and most often ends with disability or the need for joint replacement for a large number of people. One of the main reasons hindering the development of osteoarthritis treatment methods is the peculiarities of articular cartilage, in which there is practically no vascular network and tissue homeostasis is carried out mainly due to the diffusion of nutrients present in the synovial fluid. In modern medicine, for the treatment of osteoarthritis, tissue engineering strategies have been developed based on the implantation of scaffolds populated with chondrogenic cells into the area of the defect. In vitro studies have established that these cells are highly mechanosensitive and, under the influence of mechanical stimuli of a certain type and intensity, their ability to proliferate and chondrogenesis increases. This property can be used to improve the efficiency of regenerative rehabilitation technologies based on the synergistic combination of cellular technologies, tissue engineering strategies, and mechanical tissue stimulation. In this work, using a regenerative rehabilitation mathematical model of local articular cartilage defects, numerical experiments were performed, the results of which indicate that the micro-and macro environment of the restored tissue, which changes during mechanical stimulation, has a significant effect on the formation of the extracellular matrix, and, consequently, cartilage tissue generally. The results obtained can be used to plan strategies for mechanical stimulation, based on the analysis of the results of cell proliferation experimental assessment after each stimulation procedure in vivo.

Introduction: Early results using injectable autologous chondrocyte implantation (ACI) for the treatment of full thickness acetabular cartilage defects have been promising. However, so far there is no information on radiological results after injectable ACI using spheroids. The purpose of this sturdy was to (1) investigate the quality of tissue repair on MRI and (2) investigate the correlation between the MRI results and clinical results at a minimum follow-up of 24 months after third generation ACI in full thickness acetabular cartilage defects. It was hypothesized that ACI shows good MRI results in patients with large full thickness acetabular cartilage defects 24 months after surgery. It was also hypothesized that there is a correlation between postoperative clinical and MRI morphological results at a minimum follow-up of 24 months. Study design: Retrospective case series. Materials and methods: Patients with ACI for full thickness acetabular cartilage defects > 2 cm2 were evaluated by preoperative and postoperative clinical scoring tools including the modified Harris Hip Score (mHHS), the International Hip Outcome Tool (iHOT-33), and the Subjective Hip Value (SHV) as well as a high resolution indirect arthro-MRI 24 months after surgery utilizing an identical imaging protocol for all patients. The magnetic resonance observation of cartilage repair tissue (MOCART) scoring system was used to classify the repair tissue on MRI. Demographic patient data was evaluated for influencing factors for pre- and postoperative clinical as well as radiological results. Results: Thirty six consecutive patients (5 women/31 men, average age 32.9 years) had undergone two stage ACI procedure. The average size of the cartilage defect was 5.0 (2–6) cm2. The average follow-up was 29.9 (24–42) months. Four patients were not available for the final follow-up (follow-up rate 89%). The postoperative average MOCART score was 82.2 (± 14.2). MOCART score showed medium correlation of the item defect fill and the postoperative mHHS (r = 0.384, p = 0.043). There was no correlation of the other items or the total score with postoperative results. The patients showed significant improvement in the outcome measurements between preoperative and postoperative in the mHHS, the iHOT-33, and the SHV. Conclusions: Despite the large acetabular cartilage defects included in this study, ACI showed good MRI results with complete defect fill in 87.5% after a minimum 24-month follow-up. Statistically significant correlation of MRI and clinical results could only be seen with the item defect fill. Further research with longer follow-up is needed to evaluate the long-term results of ACI in acetabular cartilage defects. [ABSTRACT FROM AUTHOR]

Autologous chondrocyte implantation (ACI) is a cell therapy to repair cartilage defects. In ACI a biopsy is taken from a non-load bearing area of the knee and expanded in-vitro. The expansion process provides the benefit of generating a large number of cells required for implantation; however, during the expansion these cells de-differentiate and lose their chondrocyte phenotype. In this review we focus on examining the de-differentiation phenotype from a mechanobiology and biophysical perspective, highlighting some of the nuclear mechanics and chromatin changes in chondrocytes seen during the expansion process and how this relates to the gene expression profile. We propose that manipulating chondrocyte nuclear architecture and chromatin organization will highlight mechanisms that will help to preserve the chondrocyte phenotype. [ABSTRACT FROM AUTHOR]

Background: Some authors secured the membrane during matrix-induced autologous chondrocyte implantation (mACI) with fibrin glue or did not use a formal fixation. The real impact of fibrin glue addition on chondrocytes migration and proliferation has not yet been clarified. This study evaluated the impact of fibrin glue on a chondrocyte loaded collagenic membrane. Methods: A resorbable collagen I/III porcine derived membrane commonly employed in AMIC was used for all experiments. Chondrocytes from three difference donors were used. At 1-, 2-, 3-, 4-, 6-, and at 8-week the membranes were embedded in Mounting Medium with Dapi (ABCAM, Cambridge, UK). The Dapi contained in the mounting medium ties the DNA of the cell nucleus and emits a blue fluorescence. In this way, the spreading of the cells in the membrane can be easily monitored. The outcomes of interest were to evaluate (1) cell migration and (2) cell proliferation within the porous membrane layer. DAPI/nuclei signals were analysed with fluorescence microscope under a magnification of 100-fold. Results: The no-fibrin group demonstrated greater migration of the cells within the membrane. Although migration resulted higher in the no-fibrin group at every follow-up, this difference was significant only at week 1 (P < 0.001), 2 (P = 0.004), and 3 (P = 0.03). No difference was found at week 3, 6, and 8. The no-fibrin group demonstrated greater proliferation of the chondrocytes within the membrane. These differences were significant at week 4 (P < 0.0001), 6 (P < 0.0001), 8 (P < 0.0001). Conclusion: The use of fibrin glue over a resorbable membrane leads to lower in vitro proliferation and migration of chondrocytes. [ABSTRACT FROM AUTHOR]

Background/objective: The purpose of this study was to report the outcomes of a clinical trial conducted in Japan to assess the safety and effectiveness of third-generation autologous chondrocyte implantation (ACI) using IK-01 (CaReS™), which does not require flap coverage, in the treatment of patients with focal cartilage injury of the knee. Methods: This was an open label, exploratory clinical trial. Patients were enrolled between June 2012 and September 2016. The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 52 weeks after implantation. The IKDC, Lysholm, and visual analog scale (VAS) scores were evaluated at the time of screening and at 4, 12, 24, 36, and 52 weeks after implantation. Improvements from the baseline scores were evaluated using the equation “(postoperative score) − (preoperative score).” Magnetic resonance imaging (MRI) was performed at 2, 12, 24, and 52 weeks after implantation, and MRI measurements were evaluated using T1 rho and T2 mapping. Results: Nine patients were enrolled in this study and were examined for safety. Product quality did not satisfy the specification in one patient, and bacterial joint infection occurred in one patient. As a result, seven patients were included in the outcome analyses. The mean IKDC score significantly improved from 36.4 preoperatively to 74.1% at 52 weeks after implantation (p

Hyaline cartilage’s inability to self-repair can lead to osteoarthritis and joint replacement. Various treatments, including cell therapy, have been developed for cartilage damage. Autologous chondrocyte implantation (ACI) is considered the best option for focal chondral lesions. In this article, we aimed to create a narrative review that highlights the evolution and enhancement of our chondrocyte implantation technique: High-Density-ACI (HD-ACI) Membrane-assisted Autologous Chondrocyte Implantation (MACI) improved ACI using a collagen membrane as a carrier. However, low cell density in MACI resulted in softer regenerated tissue. HD-ACI was developed to improve MACI, implanting 5 million chondrocytes per cm2, providing higher cell density. In animal models, HD-ACI formed hyaline-like cartilage, while other treatments led to fibrocartilage. HD-ACI was further evaluated in patients with knee or ankle defects and expanded to treat hip lesions and bilateral defects. HD-ACI offers a potential solution for cartilage defects, improving outcomes in regenerative medicine and cell therapy. HD-ACI, with its higher cell density, shows promise for treating chondral defects and advancing cartilage repair in regenerative medicine and cell therapy.

Cytotherapies are often necessary for the management of symptomatic large knee (osteo)-chondral defects. While autologous chondrocyte implantation (ACI) has been clinically used for 30 years, allogeneic cells (clinical-grade FE002 primary chondroprogenitors) have been investigated in translational settings (Swiss progenitor cell transplantation program). The aim of this study was to comparatively assess autologous and allogeneic approaches (quality, safety, functional attributes) to cell-based knee chondrotherapies developed for clinical use. Protocol benchmarking from a manufacturing process and control viewpoint enabled us to highlight the respective advantages and risks. Safety data (telomerase and soft agarose colony formation assays, high passage cell senescence) and risk analyses were reported for the allogeneic FE002 cellular active substance in preparation for an autologous to allogeneic clinical protocol transposition. Validation results on autologous bioengineered grafts (autologous chondrocyte-bearing Chondro-Gide scaffolds) confirmed significant chondrogenic induction (COL2 and ACAN upregulation, extracellular matrix synthesis) after 2 weeks of co-culture. Allogeneic grafts (bearing FE002 primary chondroprogenitors) displayed comparable endpoint quality and functionality attributes. Parameters of translational relevance (transport medium, finished product suturability) were validated for the allogeneic protocol. Notably, the process-based benchmarking of both approaches highlighted the key advantages of allogeneic FE002 cell-bearing grafts (reduced cellular variability, enhanced process standardization, rationalized logistical and clinical pathways). Overall, this study built on our robust knowledge and local experience with ACI (long-term safety and efficacy), setting an appropriate standard for further clinical investigations into allogeneic progenitor cell-based orthopedic protocols.