Matrix-associated Autologous Chondrocyte Implantation Research Articles

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

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

Neutral to slightly undercorrected mechanical leg alignment provides superior long-term results in patients undergoing matrix-associated autologous chondrocyte implantation.

The aim of this study was to evaluate the role of leg alignment on long-term clinical outcomeafter matrix-associated autologous chondrocyte implantation (M-ACI) and to define an individualized target range to optimize clinical outcome. The present study examined patients who underwent M-ACI of the femoral condyle. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) were used to assess the results. Clinical outcomes were related to Patient Acceptable Symptomatic State (PASS). For intra- and interobserver reliability of mechanical tibiofemoral angle, mechanical medial proximal tibial angleand mechanical lateral distal femoral angle, we calculated intraclass correlation coefficientsusing a two-way mixed model with absolute agreement. A regression model and receiver-operating characteristics curve were used to identify an individual range of alignment where a favourable clinical outcome could be expected in the long term. Additional osteotomy was performed in 50% of patients with similar clinical outcomes as physiologically aligned patients (p > 0.05). The curve-fitting regression model identified a target range of -2.5° valgus to 4.5° varus for ideal postoperative alignment (R2 = 0.12, p = 0.01). Patients within this range were more likely to achieve PASS (70% vs. 27%, p = 0.001). In medially treated defects, a refined range of -2.5° valgus to 4° varus alignment was found (R2 = 0.15, p = 0.01). These patients were more likely to achieve PASS (67% vs. 30%, p = 0.01) and showed favourable postoperative KOOS and MOCART scores (p = 0.02). Patients with lateral defects were more likely to achieve PASS within a range of -2° valgus and 0.5° varus (90% vs. 45%, p = 0.03) and showed favourable postoperative KOOS and MOCART scores (p = not significant). An individual range of leg alignment-whether achieved by osteotomy or physiologic alignment-should be respected in M-ACI treatment. A neutral to slightly undercorrected alignment favours the postoperative outcome after M-ACI. When planning surgery for patients with focal cartilage defects of the femoral condyle, these ranges should be recognized as critical factors. Level III.

Hydrogel-Based Matrix-Associated Autologous Chondrocyte Implantation Shows Greater Substantial Clinical Benefit at 24 Months Follow-Up than Microfracture: A Propensity Score Matched-Pair Analysis.

To compare substantial clinical benefit (SCB) of a hydrogel-based, matrix-associated autologous chondrocyte implantation (M-ACI) method versus microfracture (MFx) in the treatment of knee cartilage defects. Propensity score matched-pair analysis, using the MFx control group of a phase III study as comparator for M-ACI treatment in a single-arm phase III study, resulting in 144 patients in the matched-pair set. Groups were comparable regarding baseline Knee Injury and Osteoarthritis Outcome Score (KOOS), sex, age, body mass index, symptom duration, smoking status, and previous knee surgeries. Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 cm2 vs. 3.7 cm2). Other differences concerned location, number, and etiology of defects that were not considered to influence the interpretation of results. At 24 months, significantly more patients in the M-ACI group achieved SCB in KOOS pain (72.2% vs. 48.6%; P = 0.0108), symptoms (84.7% vs. 61.1%, P = 0.0039), sports/recreation (84.7% vs. 56.9%, P = 0.0008), and quality of life (QoL; 72.2% vs. 44.4%, P = 0.0014). The SCBs for KOOS activities in daily living and International Knee Documentation Committee score were higher for M-ACI but not significantly different from MFx. The SCB rates consistently favored M-ACI from 3 months onward. The highest improvements from baseline at 24 months in patients with SCB were observed for KOOS sports/rec. (M-ACI: 60.8 points, MFx: 55.9 points) and QoL (M-ACI: 58.1, MFx: 57.4). Hydrogel-based M-ACI demonstrated superior SCB in KOOS pain, symptoms, sports/rec., and QoL compared with MFx in patients with knee cartilage defects through 2 years follow-up.

The role of autologous bone grafting in matrix-associated autologous chondrocyte implantation at the knee: Results from the German Cartilage Registry (KnorpelRegister DGOU).

To investigate whether concomitant autologous bone grafting adversely affects clinical outcome and graft survival after matrix-associated autologous chondrocyte implantation (M-ACI). The present study examines registry data of patients who underwent M-ACI with or without autologous bone grafting for large-sized chondral or osteochondral defects. Propensity score matching was performed to exclude potential confounders. A total of 215 patients with similar baseline characteristics were identified. Clinical outcome was assessed at the time of surgery and at 6, 12, 24, 36 and 60 months using the Knee Injury and Osteoarthritis Outcome Score (KOOS). KOOS change, clinical response rate, KOOS subcomponents and failure rate were determined. Patients treated with M-ACI and autologous bone grafting achieved comparable clinical outcomes compared with M-ACI alone. At 24 months postoperatively, the patient-reported outcome (PRO) of patients treated with M-ACI and autologous bone grafting was even significantly better as measured by KOOS (74.9 ± 18.8 vs. 79.2 ± 15.4; p = 0.043). However, the difference did not exceed the minimal clinically important difference (MCID). In patients with M-ACI and autologous bone grafting, a greater change in KOOS relative to baseline was observed at 6 (9.3 ± 14.7 vs. 15.0 ± 14.7; p = 0.004) and 12 months (12.6 ± 17.2 vs. 17.7 ± 14.6; p = 0.035). Overall, a high clinical response rate was observed in both groups at 24 months (75.8% vs. 82.0%; p = n.s.). The estimated survival at the endpoint of reoperation for any reason was 82.1% (SD 2.8) at 8.4 years for isolated M-ACI and 88.7% (SD 2.4) at 8.2 years for M-ACI with autologous bone grafting (p = 0.039). Even in the challenging cohort of large osteochondral defects, the additional treatment with autologous bone grafting leads to remarkably good clinical outcomes in patients treated with M-ACI. In fact, they tend to benefit more from surgery, have lower revision rates and achieve clinical response rates earlier. Subchondral bone management is critical to the success of M-ACI and should be addressed in the treatment of borderline defects. Level III.

MR imaging after patellar MACI and MPFL reconstruction: a comparison of isolated versus combined procedures.

To qualitatively and quantitatively evaluate the 2.5-year MRI outcome after Matrix-associated autologous chondrocyte implantation (MACI) at the patella, reconstruction of the medial patellofemoral ligament (MPFL), and combined procedures. In 66 consecutive patients (age 22.8 ± 6.4years) with MACI at the patella (n = 16), MPFL reconstruction (MPFL; n = 31), or combined procedures (n = 19) 3T MRI was performed 2.5 years after surgery. For morphological MRI evaluation WORMS and MOCART scores were obtained. In addition quantitative cartilage T2 and T1rho relaxation times were acquired. Several clinical scores were obtained. Statistical analyses included descriptive statistics, Mann-Whitney-U-tests and Pearson correlations. WORMS scores at follow-up (FU) were significantly worse after combined procedures (8.7 ± 4.9) than after isolated MACI (4.3 ± 3.6, P = 0.005) and after isolated MPFL reconstruction (5.3 ± 5.7, P = 0.004). Bone marrow edema at the patella in the combined group was the only (non-significantly) worsening WORMS parameter from pre- to postoperatively. MOCART scores were significantly worse in the combined group than in the isolated MACI group (57 ± 3 vs 88 ± 9, P < 0.001). Perfect defect filling was achieved in 26% and 69% of cases in the combined and MACI group, respectively (P = 0.031). Global and patellar T2 values were higher in the combined group (Global T2: 34.0 ± 2.8ms) and MACI group (35.5 ± 3.1ms) as compared to the MPFL group (31.1 ± 3.2ms, P < 0.05). T2 values correlated significantly with clinical scores (P < 0.005). Clinical Cincinnati scores were significantly worse in the combined group (P < 0.05). After combined surgery with patellar MACI and MPFL reconstruction inferior MRI outcomes were observed than after isolated procedures. Therefore, patients with need for combined surgery may be at particular risk for osteoarthritis.

Treatment of cartilage defects in the patellofemoral joint with matrix-associated autologous chondrocyte implantation effectively improves pain, function, and radiological outcomes after 5-7 years.

The aim of the present study was to evaluate midterm outcomes 5-7years after matrix-associated autologous chondrocyte implantation (MACI) in the patellofemoral joint. Twenty-six patients who had undergone MACI using the Novocart® 3D scaffold were prospectively evaluated. Clinical outcomes were determined by measuring the 36-Item Short-Form Health Survey (SF-36) and International Knee Documentation Committee (IKDC) scores and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) values preoperatively and 3, 6, and 12months, and a mean of 6years postoperatively. At the final follow-up, the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score was evaluated. Twenty-two patients with 23 focal cartilage defects (19 patella and four trochlea) were available for the final follow-up. The mean defect size was 4.0 ± 1.9 cm2 (range 2.4-9.4 cm2). All clinical outcome scores improved significantly until 5-7 years after MACI (SF-36 score, 61.2 ± 19.6 to 83.2 ± 11.6; P = 0.001; IKDC score, 47.5 ± 20.6 to 74.7 ± 15.5; P < 0.001; and WOMAC, 29.8 ± 15.7 to 8.2 ± 10.3; P < 0.001). The mean MOCART score was 76.0 ± 11.0 at the final follow-up. Nineteen of the 22 patients (86.4%) were satisfied with the outcomes after 5-7 years and responded that they would undergo the procedure again. MACI in the patellofemoral joint demonstrated good midterm clinical results with a significant reduction in pain, improvement in function, and high patient satisfaction. These clinical findings are supported by radiological evidence from MOCART scores. IV-case series.

All-Arthroscopic Matrix-Associated Autologous Chondrocyte Implantation for a Trochlear Defect

Matrix-associated autologous chondrocyte implantation (MACI) is a 2-step technique designed to treat symptomatic full-thickness articular cartilage defects of the knee. In this technique article, MACI (autologous cultured chondrocytes on porcine collagen membrane) is used to treat a femoral trochlear defect of the knee. Treating a defect with this technique leads to improved clinical outcomes by restoring the native chondral surface architecture and biomechanics of the knee. In addition, it has the potential to prevent or delay further progressive degeneration of the joint. It is a 2-stage procedure consisting of an initial arthroscopic cartilage biopsy, followed by 4 to 6 weeks of in vitro chondrocyte expansion and, finally, re-implantation. We recommend performing the MACI procedure arthroscopically for the second stage to treat a femoral trochlear defect. During the second surgical procedure, we examine and prepare the recipient site, followed by graft introduction in an all-arthroscopic manner via dry scoping, secured by a thin layer of fibrin glue.

Comparison of Hydrogel-Based Autologous Chondrocyte Implantation Versus Microfracture: A Propensity Score Matched-Pair Analysis.

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. 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. Cohort study; Level of evidence, 3. 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. 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). 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.

Poster 288: The Effect of Time Delay From Biopsy to Second-Stage Implantation on Return to Sport and Clinical Outcomes following Autologous Chondrocyte Implantation

Objectives: Expansion of chondral defect size and clinical outcomes in patients with cartilage lesions are thought to be modulated by several risk factors. Previous studies suggest that time delay until implantation may be a risk factor for an increase in the number and size of chondral lesions at the time of implantation. Reports on the effect of time delay on clinical outcomes, however, remain limited. Therefore, the purpose of this study was to evaluate the effect of time delay from cartilage biopsy to implantation on patient satisfaction, return to sport (RTS), and clinical outcomes following autologous chondrocyte implantation. Methods: A retrospective review was performed among patient who underwent autologous chondrocyte implantation (ACI) and matrix-associated autologous chondrocyte implantation (MACI) at a single institution between the years 2012 to 2020 with minimum 2-year clinical follow-up. Clinical outcomes were measured using the Visual Analog Scale (VAS) for pain and satisfaction and the Knee Injury and Osteoarthritis Outcome Score (KOOS; subscores: symptoms, pain, sport, and quality of life (QOL)). Time delay was calculated as the elapsed time between cartilage biopsy and implantation. Cartilage lesions were categorized based on the Outerbridge classification of chondral lesions. The number of high-grade lesions (Outerbridge grade 3 or 4) and size of lesions were analyzed at time of biopsy and implantation. T-tests or non-parametric tests and Chi-squared tests were used to analyze continuous variables and categorical variables, respectively. A one-way ANOVA was used to compare outcomes based on RTS status, using a post-hoc Tukey’s HSD test for multiple comparisons. Bivariate linear regression was used to determine the impact of the time interval from biopsy to implantation on the change in size of the largest high-grade lesion and RTS. Results: A total of 36 patients, mainly female (55.6%) aged 29.25 (± 9.49) with a mean follow-up of 6.51 ± 2.5 years were included in our analysis. Thirteen patients (36.1%) did not RTS. Of the 23 patients (63.9%) who returned to sport, 11 (30.6%) returned at their preoperative level or higher, and 12 (33.3%) returned at a lower level. VAS pain scores were significantly higher in patients who did not RTS vs those who did (42.85 vs. 9.35, p &lt;0.001). All KOOS subscores (Symptom: 56.54 vs. 81.96, Pain: 72.22 vs. 91.74, Sports: 40.38 vs. 79.3, QOL: 35.58 vs. 70.38, p &lt;0.001) were significantly lower in patients who did not RTS compared to those who returned. Increase in time delay from biopsy to implantation was associated with an increase in VAS pain score (OR [95% CI]; 1.42 [0.16 to 2.69], p=0.02) and inversely related to KOOS pain scores (OR [95% CI]; -1.01 [-1.83 to -0.01], p= 0.01. Furthermore, when comparing time from biopsy to implantation and expansion of the largest highgrade lesion, it was found that for every month increase in time, lesion surface area increased by 0.588 cm2; however, this correlation did not reach significance (p=0.09). The number of high-grade lesions at time of implantation were significantly higher in those that returned to sport at a lower level than those who did not return (1.67 vs. 1.23, p=0.02). The average surface area of the defect at biopsy and implantation were 3.13 cm2 and 4.38 cm2 respectively. The number of patients who had an increase in the number of high-grade lesions from biopsy to implantation was significantly higher in those who returned to sport at a lower level compared to those who did not return (4 vs. 1, p=0.05). Logistic regression demonstrated no significant relationship between time interval and rate of return to sport (p=3.59). No other associations were observed between time from biopsy to implantation and clinical outcomes. Conclusions: An increase in time delay from biopsy to graft implantation is associated with worse pain after surgery. Both the number of high-grade lesions at the time of implantation and an increase in time delay were not associated with lower rates of return to sport. Further studies are needed to evaluate the effects of time delay until implantation and its potential role as a risk factor for worse clinical outcomes in patients undergoing autologous chondrocyte implantation procedures. [Table: see text]

Poster 267: Psychological Readiness and Return to Sport and Work Following Autologous Chondrocyte Implantation

Objectives: Return to preinjury function in work and sport is dependent on both postoperative physical function and psychological readiness. Kinesiophobia has been studied following various orthopedic surgeries, but data remains scant in patients undergoing cartilage restoration procedures. The purpose of our investigation is to evaluate the effect of fear of reinjury on return to sport (RTS), return to work (RTW), and clinical outcomes following autologous chondrocyte implantation. Methods: A retrospective review of patients who underwent autologous chondrocyte implantation (ACI) and matrix-associated autologous chondrocyte implantation (MACI) at a single institution between 2012 – 2020 with a minimum of 2 year clinical follow-up was conducted. Patient-reported outcomes were measured using the Visual Analog Scale (VAS) for pain and satisfaction and the Knee Injury and Osteoarthritis Outcome Score (KOOS; subscores: symptoms, pain, sport, and quality of life (QOL)). Kinesiophobia was assessed using the Tampa Scale of Kinesiophobia-11 (TSK-11). The Pain Catastrophizing Scale (PCS) was used to analyze individuals’ response to pain. T-tests or non-parametric tests and Chi-squared tests were used to analyze continuous variables and categorical variables, respectively. A one-way ANOVA was used to compare outcomes based on RTS status, using a post-hoc Tukey’s HSD test for multiple comparisons. Logistic regression controlling for age, sex, and BMI was used to determine if TSK-11 scores is predictive of RTS. Results: Forty-nine patients, mainly male (55.1%) aged 29.35 (± 6.28) with a mean follow-up of 5.7 ± 3.2 years were included in our analysis. Sixteen patients (32.7%) did not RTS. Of the 33 patients (67.3%) who returned to sport, 16 (32.7%) returned at their preoperative level or higher, and 17 (34.7%) returned at a lower level. TSK-11 scores (26.44 vs. 20.62, p=0.019) and VAS pain scores (47.94 vs. 6.88, p&lt;0.001) were significantly greater in patients that that did not return to sport compared to those who return at the same level or higher. All KOOS subscores (Symptom: 59.69 vs. 85.62, Pain: 71.35 vs. 94.97, Sports: 37.19 vs. 86.56, QOL: 29.69 vs. 82.42, p &lt;0.001) were significantly lower in patients who did not RTS compared to those who returned at the same level or higher. Patients who returned to sport, but at a lower level, had significantly greater KOOS-QOL (58.82 vs. 29.69, p&lt;0.001) and KOOS-pain subscores (89.22 vs. 71.35, p&lt;0.001) compared to patients who did not RTS. There were no significant differences in PCS scores between all three groups (p = 0.08). Increasing TSK-11 scores were inversely related to probability of RTS (OR [95% CI]; -0.19 [0.36 to 0.06], p=0.01). Of the 40 (81.6%) patients employed prior to injury, 100% (n=40) returned to work. Thirty-six (90%) patients returned to modified work within six months of surgery and had significantly lower TSK-11 scores (23.00 vs. 30.50, p=0.01) compared to patients who returned to work &gt;6 months postoperatively. Conclusions: Fear of reinjury decreases the likelihood that patients will return to preinjury level of sport or higher after autologous chondrocyte implantation. Those who did not return to work had significantly worse KOOS scores. [Table: see text]

Cost-effectiveness of a new ACI technique for the treatment of articular cartilage defects of the knee compared to regularly used ACI technique and microfracture

AimsFor patients with cartilage defects of the knee, a new biocompatible and in situ cross-linkable albumin-hyaluronan-based hydrogel has been developed for matrix-associated autologous chondrocyte implantation (M-ACI) – NOVOCART Inject plus (Ninject; TETEC AG, Reutlingen, Germany). We aimed to estimate the potential cost-effectiveness of NInject, that is not available on the market, yet compared to spheroids of human autologous matrix-associated chondrocytes (Spherox; CO.DON GmbH, Leipzig, Germany) and microfracture.Materials and methodsAn early Markov model was developed to estimate the cost-effectiveness in the United Kingdom (UK) from the payer perspective. Transition probabilities, response rates, utility values and costs were derived from literature. Since NInject has not yet been launched and no prices are available, its costs were assumed equal to those of Spherox. Cycle length was set at one year and the time horizon chosen was notional patients’ remaining lifetime. Model robustness was evaluated with deterministic and probabilistic sensitivity analyses (DSA; PSA) and value of information analysis (VOIA). The Markov model was built using TreeAge Pro Healthcare.ResultsNInject was cost-effective compared to microfracture (ICER: ₤5,147) while Spherox was extendedly dominated. In sensitivity analyses, the ICER exceeded conventional WTP threshold of ₤20,000 only when the utility value after successful first treatment with NInject was decreased by 20% (ICER: ₤69,620). PSA corroborated the cost-effectiveness findings of NInject, compared to both alternatives, with probabilities of 60% of NInject undercutting the aforementioned WTP threshold and being the most cost-effective alternative. The VOIA revealed that obtaining additional evidence on the new technology will likely not be cost-effective for the UK National Health Service.Limitations and conclusionThis early Markov model showed that NInject is cost-effective for the treatment of articular cartilage defects in the knee, compared to Spherox and microfracture. However, as the final price of NInject has yet to be determined, the cost-effectiveness analysis performed in this study is provisional, assuming equal prices for NInject and Spherox.

Utilization of Autologous Chondrocyte Implantation in the Knee Is Increasing While Reoperation Rates Are Decreasing Despite Increasing Preoperative Comorbidities

The primary purpose of this study was to assess the use of autologous chondrocyte implantation (ACI) procedures in the knee during last decade, and the secondary aims of the study were to determine reoperation rates after ACI and to identify associated risk factors. A retrospective cohort study from 2010-2020 was performed using the PearlDiver database. The database was queried for the Current Procedural Terminology (CPT) code for ACI performed in any knee location, including the patellofemoral and tibiofemoral joints. Reoperation was defined as interventional knee procedures or total knee arthroplasty after ACI. Reoperations were identified using CPT and International Classification of Diseases codes. Univariate and multivariate logistic regression were used to identify risk factors for reoperation. Significance was defined as P < .05. Among the 2010 patients included in this study, there were 90-day and overall reoperation rates of 2.24% and 30.4%, respectively, with an average follow up of 4.8 ± 3.3 years. The most common reoperations included chondroplasty, meniscectomy, and microfracture. There was an increased rate of ACI performed from 2017-2019 (5.53/100,000) compared to 2014-2016 (4.16/100,000; P < .001). ACI surgeries performed in2017-2019 were associated with decreased risk of reoperation within 2 years relative to 2014-2016 (odds ratio [OR]= 0.70; 95% confidence interval [CI], 0.52-0.94; P= .019). In the entire ACI cohort, older age (OR= 1.07; 95% CI, 1.05-1.09; P < .001) and tobacco use (OR= 2.13; 95% CI, 1.06-3.94; P= .022) were associated with increased risk of conversion to arthroplasty. Male sex was associated with decreased overall reoperation rates (OR= 0.73; 95% CI, 0.60-0.89; P= .002). There has been increasing use of ACI in the knee with decreased risk of reoperation since 2017 and the introduction of matrix-associated autologous chondrocyte implantation. Older age and tobacco use were predictors of increased risk of conversion to arthroplasty. Male sex was associated with decreased risk of reoperation. Level IV, retrospective cohort design; database study.

The Predictive Value of Early Postoperative MRI-Based Bone Marrow Parameters for Mid-Term Outcome after MACI with Autologous Bone Grafting at the Knee.

ObjectiveThe aim of this study was to longitudinally determine the prognostic value of early postoperative quantitative 3T-MRI (magnetic resonance imaging) parameters of subchondral bone marrow for 2-year clinical and MRI outcome after matrix-associated autologous chondrocyte implantation (MACI) with autologous bone grafting (ABG) at the knee.DesignConsecutive subjects who received MACI with ABG for treatment of focal osteochondral defects received MRI follow-up 3, 6, 12, and 24 months postoperatively. Quantitative MRI included bone marrow edema-like lesion (BMEL) volume measurements and single-voxel magnetic resonance spectroscopy (MRS; n = 9) of the subchondral bone marrow. At 2-year follow-up, morphological MRI outcome included MOCART (magnetic resonance observation of cartilage repair tissue) 2.0 scores. Clinical outcomes were assessed using Lysholm scores.ResultsAmong a total of 18 subjects (mean age: 28.7 ± 8.4 years, n = 14 males) with defects at the medial or lateral (n = 15 and n = 3, respectively) condyle, mean BMEL volume decreased from 4.9 cm3 at 3 months to 2.0 cm3 at 2-year follow-up (P = 0.040). MRS-based bone marrow water T2 showed a decrease from 20.7 ms at 1-year follow-up to 16.8 ms at 2-year follow-up (P = 0.040). Higher BMEL volume at 6 months correlated with lower 2-year Lysholm (R = −0.616, P = 0.015) and MOCART 2.0 scores (R = −0.567, P = 0.027). Larger early postoperative BMEL volumes at 3 months (R = −0.850, P = 0.007) and 6 months (R = −0.811, P = 0.008) correlated with lower MRS-based unsaturated lipid fractions at 2-year follow-up. Furthermore, patients with early postoperative bony defects showed worse MOCART 2.0 (P = 0.044) and Lysholm scores (P = 0.017) after 24 months.ConclusionLow subchondral BMEL volume and optimal restoration of the subchondral bone at early postoperative time points predict better 2-year clinical and MRI outcomes after MACI with ABG.

Recent Developments in Hyaluronic Acid-Based Hydrogels for Cartilage Tissue Engineering Applications.

Articular cartilage lesions resulting from injurious impact, recurring loading, joint malalignment, etc., are very common and encompass the risk of evolving to serious cartilage diseases such as osteoarthritis. To date, cartilage injuries are typically treated via operative procedures such as autologous chondrocyte implantation (ACI), matrix-associated autologous chondrocyte implantation (MACI) and microfracture, which are characterized by low patient compliance. Accordingly, cartilage tissue engineering (CTE) has received a lot of interest. Cell-laden hydrogels are favorable candidates for cartilage repair since they resemble the native tissue environment and promote the formation of extracellular matrix. Various types of hydrogels have been developed so far for CTE applications based on both natural and synthetic biomaterials. Among these materials, hyaluronic acid (HA), a principal component of the cartilage tissue which can be easily modified and biofunctionalized, has been favored for the development of hydrogels since it interacts with cell surface receptors, supports the growth of chondrocytes and promotes the differentiation of mesenchymal stem cells to chondrocytes. The present work reviews the various types of HA-based hydrogels (e.g., in situ forming hydrogels, cryogels, microgels and three-dimensional (3D)-bioprinted hydrogel constructs) that have been used for cartilage repair, specially focusing on the results of their preclinical and clinical assessment.

Long-term cost-effectiveness of matrix-associated chondrocyte implantation in the German health care system: a discrete event simulation

IntroductionCartilage 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 methodsWe 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.ResultsThe 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.ConclusionM-ACI is projected to be a highly cost‐effective treatment for chondral defects of the knee in the German healthcare setting.

Safety and Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroids for Patellofemoral or Tibiofemoral Defects: A 5-Year Follow-up of a Phase 2, Dose-Confirmation Trial.

Background:Matrix-associated autologous chondrocyte implantation (ACI) is a well-established treatment for cartilage defects. High-level evidence at midterm follow-up is limited, especially for ACI using spheroids (spherical aggregates of ex vivo expanded human autologous chondrocytes and self-synthesized extracellular matrix).Purpose:To assess the safety and efficacy of 3-dimensional matrix-associated ACI using spheroids to treat medium to large cartilage defects on different locations in the knee joint (patella, trochlea, and femoral condyle) at 5-year follow-up.Study Design:Cohort study; Level of evidence, 2.Methods:A total of 75 patients aged 18 to 50 years with medium to large (4-10 cm2), isolated, single cartilage defects, International Cartilage Repair Society grade 3 or 4, were randomized on a single-blind basis to treatment with ACI at 1 of 3 dose levels: 3 to 7, 10 to 30, or 40 to 70 spheroids/cm2 of defect size. Outcomes were assessed via changes from baseline Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee score, and modified Lysholm assessments at 1- and 5-year follow-up. Structural repair was evaluated using MOCART (magnetic resonance observation of cartilage repair tissue) score. Treatment-related adverse events were assessed up to 5 years for all patients. The overall KOOS at 12 months was assessed for superiority versus baseline in a 1-sample, 2-sided t test.Results:A total of 73 patients were treated: 24 in the low-dose group, 25 in the medium-dose group, and 24 in the high-dose group. The overall KOOS improved from 57.0 ± 15.2 at baseline to 73.4 ± 17.3 at 1-year follow-up (P < .0001) and 76.9 ± 19.3 at 5-year follow-up (P < .0001), independent of the applied dose. The different defect locations (patella, trochlea, and weightbearing part of the femoral condyles; P = .2216) and defect sizes (P = .8706) showed comparable clinical improvement. No differences between the various doses were observed. The overall treatment failure rate until 5 years was 4%. Most treatment-related adverse events occurred within the first 12 months after implantation, with the most frequent adverse reactions being joint effusion (n = 71), arthralgia (n = 14), and joint swelling (n = 9).Conclusion:ACI using spheroids was safe and effective for defect sizes up to 10 cm2 and showed maintenance of efficacy up to 5 years for all 3 doses that were investigated.Registration:NCT01225575 (ClinicalTrials.gov identifier); 2009-016816-20 (EudraCT number).

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

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

Clinical evaluation after matrix-associated autologous chondrocyte transplantation : a comparison of four different graft types.

AimsThe aim of this retrospective study was to determine if there are differences in short-term clinical outcomes among four different types of matrix-associated autologous chondrocyte transplantation (MACT).MethodsA total of 88 patients (mean age 34 years (SD 10.03), mean BMI 25 kg/m2 (SD 3.51)) with full-thickness chondral lesions of the tibiofemoral joint who underwent MACT were included in this study. Clinical examinations were performed preoperatively and 24 months after transplantation. Clinical outcomes were evaluated using the International Knee Documentation Committee (IKDC) Subjective Knee Form, the Brittberg score, the Tegner Activity Scale, and the visual analogue scale (VAS) for pain. The Kruskal-Wallis test by ranks was used to compare the clinical scores of the different transplant types.ResultsThe mean defect size of the tibiofemoral joint compartment was 4.28 cm2 (SD 1.70). In total, 11 patients (12.6%) underwent transplantation with Chondro-Gide (matrix-associated autologous chondrocyte implantation (MACI)), 40 patients (46.0%) with Hyalograft C (HYAFF), 21 patients (24.1%) with Cartilage Regeneration System (CaReS), and 15 patients (17.2%) with NOVOCART 3D. The mean IKDC Subjective Knee Form score improved from 35.71 (SD 6.44) preoperatively to 75.26 (SD 18.36) after 24 months postoperatively in the Hyalograft group, from 35.94 (SD 10.29) to 71.57 (SD 16.31) in the Chondro-Gide (MACI) group, from 37.06 (SD 5.42) to 71.49 (SD 6.76) in the NOVOCART 3D group, and from 45.05 (SD 15.83) to 70.33 (SD 19.65) in the CaReS group. Similar improvements were observed in the VAS and Brittberg scores.ConclusionTwo years postoperatively, there were no significant differences in terms of outcomes. Our data demonstrated that MACT, regardless of the implants used, resulted in good clinical improvement two years after transplantation for localized tibiofemoral defects.Cite this article: Bone Joint Res 2021;10(7):370–379.

Evaluation of Patient Preference and Perception Regarding the Clinical Use of Autologous Versus Allogeneic Cell Therapy in Orthopedic Surgery.

Background: Cell therapy has become a hot topic in orthopedics, with significant research dedicated to improving physicians' understanding of its efficacy. However, little is known about patients' cell therapy knowledge. Questions/Purposes: The aims of this study were to (1) evaluate patients' perceptions of cell therapy in orthopedics, (2) determine whether patients have a preference for autologous or allogeneic cell therapy, and (3) assess patient concerns about cell therapy. Methods: Consecutive outpatients of an orthopedic clinic were surveyed from June 2019 to January 2020. All patients were 18 years old or older and being seen for an orthopedic intervention, including rotator cuff repair, anterior cruciate ligament (ACL) reconstruction, arthroscopic meniscectomy, or a cartilage repair procedure such as an osteochondral allograft transplantation or matrix-associated autologous chondrocyte implantation. Results: A total of 50 patients were surveyed (mean age: 53 years). The patients' average rating for likelihood to use autologous cells was 8.86 ± 2.2 out of 10 and the average rating for likelihood to use allogeneic cells was 6.24 ± 3.3; 46% of patients had no specific concerns about autologous cell therapy, while 28% expressed concerns about efficacy, and 12% had concerns about donor age. The top 2 "main concerns" about allogeneic cell therapy were disease transmission (30%) and immune reaction (24%). Conclusions: This survey found that patients asserted a preference for autologous cell therapy in orthopedics. Further research is necessary to further elucidate the factors related to cell therapy that are most important to patients.

Matrix-associated autologous chondrocyte implantation with autologous bone grafting of osteochondral lesions of the talus in adolescents: patient-reported outcomes with a median follow-up of 6 years

BackgroundThis study presents patient-reported outcome measures after combined matrix-associated autologous chondrocyte implantation and autologous bone grafting in high-stage osteochondral lesions of the talus in adolescents.MethodsA total of 12 adolescent patients (13 ankles) received matrix-associated autologous chondrocyte implantation and autologous bone grafting for a solitary osteochondral lesion of the talus at a single centre. The Foot and Ankle Outcome Score and Foot and Ankle Ability Measure were defined as outcome measures (median follow-up 80 months [range 22–107 months]). Pre- and postoperative ankle radiographs were evaluated according to the van Dijk ankle osteoarthritis scale.ResultsThe study population consisted of four male and nine female cases (mean age at the time of surgery, 17.7 ± 2.1 years). Eight lesions were classified as traumatic and five as idiopathic. Twelve lesions were located medial vs one lateral in the coronal plane and all central in the sagittal plane. The median lesion size and depth were 1.3 cm2 (range 0.9–3.2 cm2) and 5 mm (range 5–9 mm), respectively.There were no perioperative complications in any of the cases.In 9 cases patient-reported outcome measures were available. The results of the Foot and Ankle Outcome Score subscales were symptoms, 70 ± 14; pain, 83 ± 10; activities of daily living, 89 ± 12; sports/recreational activities, 66 ± 26; and quality of life, 51 ± 17. The mean overall Foot and Ankle Outcome Score was 78 ± 13.The results of the Foot and Ankle Ability Measure subscales were activities of daily living, 81 ± 20; function/activities of daily living, 84 ± 13; sports, 65 ± 29; and function/sports, 73 ± 27. According to the function overall subscale of the Foot and Ankle Ability Measure, in two cases, the patients assessed the ankle function as normal, in three as nearly normal, and in three as abnormal (missing data, n = 1).Preoperative van Dijk scale: stage 0 in five cases and stage I in eight cases; postoperative van Dijk scale: stage 0 in four cases, stage I in 9 casesConclusionsPatient-reported outcome measures following matrix-associated autologous chondrocyte implantation and autologous bone grafting for high-stage osteochondral lesions of the talus in adolescents show heterogeneous results. Long-term limitations mainly affect sports and recreational activities. Osteochondral lesions of the talus are associated with osteoarthritis, even preoperatively. However, we did not find significant osteoarthritis progression after matrix-associated autologous chondrocyte implantation and autologous bone grafting in the long term.