Matrix-induced Autologous Chondrocyte Implantation Research Articles

PHP222 - Advanced Therapy Medicinal Products (Atmps) In Europe 8 Years On: What Is The Path To Market Access So Far?

To examine the current EU5 market access landscape for ATMPs. Assessed the regulatory path, HTA assessments and funding mechanisms for ATMPs with EMA approval as of May 2016. Eight ATMPs are EMA approved as of May 2016. Of these, one was suspended (matrix-induced autologous chondrocyte implantation) and another withdrawn (sipuleucel-T). Germany: All ATMPs need to be authorised by the Paul Ehrlich Institute (PEI). Furthermore, the GBA could classify an ATMP as a procedure rather than a drug thereby bypassing AMNOG (e.g. autologous human corneal epithelial cells). The two ATMPs assessed under AMNOG (alipogene tiparvovec and sipuleucel-T), were both assigned “non-quantifiable additional benefit”. Talimogene laherparepvec is currently undergoing assessment with a final decision expected in mid-Dec 2016. Currently, alipogene tiparvovec is a hospital use only drug with reimbursement negotiated by the hospital and sickness funds on a case by case basis. In France, HAS assessed only two ATMPs (autologous cultured chondrocytes and alipogene tiparvovec) with reimbursement not being granted for either. Autologous cultured chondrocytes is the only ATMP that hospitals in Italy can currently import while it is available for hospital use only in Spain. Preliminary UK recommendation for autologous cultured chondrocytes and matrix-induced autologous chondrocyte implantation was for use in research only. Draft guidance on talimogene laherparepvec issued by NICE in March 2016 did not recommend use in melanoma. No other ATMP is currently routinely commissioned. All EMA approved ATMPs to date have faced EU5 market access challenges, with Germany being particularly complex. HTA assessments have been unfavourable largely due to the uncertainty with available data and – possibly – costs. The ATMP landscape is beginning to form and evolve. It will need to solidify for AMTPs to be viable for the companies seeking to market them and the patients who will benefit.

A Prospective Clinical and Radiological Evaluation at 5 Years After Arthroscopic Matrix-Induced Autologous Chondrocyte Implantation

Background: While midterm outcomes after matrix-induced autologous chondrocyte implantation (MACI) are encouraging, the procedure permits an arthroscopic approach that may reduce the morbidity of arthrotomy and permit accelerated rehabilitation. Hypothesis: A significant improvement in clinical and radiological outcomes after arthroscopic MACI will exist through to 5 years after surgery. Study Design: Case series; Level of evidence, 4. Methods: We prospectively evaluated the first 31 patients (15 male, 16 female) who underwent MACI via arthroscopic surgery to address symptomatic tibiofemoral chondral lesions. MACI was followed by a structured rehabilitation program in all patients. Clinical scores were administered preoperatively and at 3 and 6 months as well as 1, 2, and 5 years after surgery. These included the Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm knee scale (LKS), Tegner activity scale (TAS), visual analog scale for pain, Short Form–36 Health Survey (SF-36), active knee motion, and 6-minute walk test. Isokinetic dynamometry was used to assess peak knee extension and flexion strength and limb symmetry indices (LSIs) between the operated and nonoperated limbs. High-resolution magnetic resonance imaging (MRI) was performed at 3 months and at 1, 2, and 5 years postoperatively to evaluate graft repair as well as calculate the MRI composite score. Results: There was a significant improvement (P < .05) in all KOOS subscale scores, LKS and TAS scores, the SF-36 physical component score, pain frequency and severity, active knee flexion and extension, and 6-minute walk distance. Isokinetic knee extension strength significantly improved, and all knee extension and flexion LSIs were above 90% (apart from peak knee extension strength at 1 year). At 5 years, 93% of patients were satisfied with MACI to relieve their pain, 90% were satisfied with improving their ability to undertake daily activities, and 80% were satisfied with the improvement in participating in sport. Graft infill (P = .033) and the MRI composite score (P = .028) significantly improved over time, with 90% of patients demonstrating good to excellent tissue infill at 5 years. There were 2 graft failures at 5 years after surgery. Conclusion: The arthroscopically performed MACI technique demonstrated good clinical and radiological outcomes up to 5 years, with high levels of patient satisfaction.

Management of Osteochondral Lesions of the Talus Using Autologous Chondrocyte Implantation

Category: Arthroscopy Introduction/Purpose: Osteochondral lesions of the talus (OLT) are frequent occurrences when patients sustain both traumatic and atraumatic ankle injuries with a report rate of up to 70% OLT in patients who sustain an ankle sprain or fracture. Surgical treatment options for OLT is either reparative or replacement and are dictated by characteristics of the lesion, including size and presence or absence of cysts. Periosteal-autologous chondrocyte implantation (P-ACI) or MACI (matrix-induced autologous chondrocyte implantation) is useful for lesions with or without cysts under 2.5cm2. We hypothesize that MACI will have the lowest reoperation rate and highest patient satisfaction rate in treating OLT. Methods: A systematic review was registered with PROSPERO and performed with PRISMA guidelines using three publicly available free databases. Therapeutic clinical outcome investigations reporting OLT outcomes with levels of evidence I-IV were eligible for inclusion. All study, subject, and surgical technique demographics were analyzed and compared between continents and countries. Statistics were calculated using Student’s t-tests, one-way ANOVA, chi-squared, and two-proportion Z-tests. Results: Nineteen articles met our inclusion criteria, which resulted in a total of 343 patients. Six studies pertained to arthroscopic MACI, 8 to open MACI, and 5 studies to open PACI. All studies were Level IV evidence. Due to study quality, imprecise and sparse data, and potential for reporting bias, the quality of evidence is low. In comparison of open and arthroscopic MACI, we found both advantages favoring open MACI (AOFAS and MOCART score). However, open MACI had higher complication rates versus arthroscopic (18.18% vs 0.78%, p = 0.002). In addition, the rate of impingement was noted to be significantly higher for the open technique of MACI with a rate of 10.61% as opposed to 0.78% for the arthroscopic technique (p = 0.01). Conclusion: No procedure demonstrates superiority or inferiority between the combination of open or arthroscopic MACI and PACI in the management of OLT less than 2.5 cm2. Ultimately well-designed randomized trials are needed to address the limitation of the available literature and further our understanding of the optimal treatment options.

Repair Potential of Matrix-Induced Bone Marrow Aspirate Concentrate and Matrix-Induced Autologous Chondrocyte Implantation for Talar Osteochondral Repair

The low regenerative potential of cartilage contributed to the development of different cell therapies aimed to improve the clinical outcome in young patients with Osteochondral Lesions of the Talus (OLT). This study is designed to assess the regenerative potential of autologous matrix-induced Bone Marrow Aspirate Concentrate (mBMAC) and matrix-induced Autologous Chondrocyte Implantation (mACI) evaluating, on a small number of osteochondral biopsies, the expression of some catabolic, inflammatory, and pain mediators. Twenty-two patients with OLT were analyzed in this study; 7 were treated with mACI and 15 with mBMAC. Informed consent was obtained from all the patients. Clinical assessments were performed pre-operatively and at 12, 24, and 36 months after surgery using the American Orthopedic Foot and Ankle Society (AOFAS). Histology and immunohistochemistry were used to assess cartilage repair at 24 months. Data were analyzed using non-parametric Wilcoxon-Mann-Whitney and Spearman tests. A remarkable improvement in AOFAS score was noticed for both treatments up to 36 months; however, patients treated with mACI reported the best AOFAS score. Various degrees of tissue remodeling were observed by histological analysis for both cell strategies. However, mBMAC treatment showed a higher expression of some fibrous and hypertrophic markers compared to mACI group. A mild positivity for nerve growth factor, as pain mediator, was noticed for both treatments.M. Our findings demonstrated the best histological and clinical results following mACI treatment since different fibrotic and hypertrophic features were evident in the mBMAC group at 24-month follow-up.

258 - A Computer-Aided Meta-Dosimetry of Dose Distribution Analysis Using a Neural Network Model Reveal Accelerated Weightbearing Rehabilitation and Time-Dependent Differences Between the Clinical Outcomes Achieved by Microfracture and Mesenchymal Stem Cells Induced Implantation of PolyScaffolding Based Matrix-Induced Autologous Chondrocyte Implantation (POMACI) for Chondral Defects

Calculations of dose distributions using a neural network model. In order to master and optimize the dose distribution within the patient, dosimetric planning has to be carried out. Thus, for determining the most accurate dose distribution during treatment planning, a compromise must be found between the precision and the speed of calculation. Current techniques, using analytic methods, models and databases, are rapid but lack precision. Enhanced precision can be achieved by using calculation codes based, for example, on Monte Carlo methods. However, in spite of all efforts to optimize speed (methods and computer improvements), Monte Carlo based methods remain painfully slow. A newer way to handle all of these problems is to use a new approach in dosimetric calculation by employing neural networks. Neural networks (Wu and Zhu 2000 Phys. Med. Biol. 45 913-22) provide the advantages of those various approaches while avoiding their main inconveniences, i.e., time-consumption calculations. The first description of autologous chondrocyte implantation (ACI) in 1994 different methods and improvements were established for this regenerative treatment option of large chondral defects. This study analyzes safety and short-term clinical results from characterized ACI using a collagen based biphasic scaffold and evaluates prognostic factors utilizing a Computer-Aided meta-analysis reveal accelerating weightbearing rehabilitation and time-dependent differences between the clinical outcomes achieved by microfracture and mesenchymal stem cells induced implantation of PolyScaffolding based Matrix-induced autologous chondrocyte implantation (POMACI) for chondral defects in the patellofemoral joint after matrix-induced autologous chondrocyte implantation in the tibiofemoral joint.

Current research on pharmacologic and regenerative therapies for osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disorder commonly encountered in clinical practice, and is the leading cause of disability in elderly people. Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers, OA is a challenging disease with limited treatment options. Traditional pharmacologic therapies such as acetaminophen, non-steroidal anti-inflammatory drugs, and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events. Current research focuses on the development of new OA drugs (such as sprifermin/recombinant human fibroblast growth factor-18, tanezumab/monoclonal antibody against β-nerve growth factor), which aims for more effectiveness and less incidence of adverse effects than the traditional ones. Furthermore, regenerative therapies (such as autologous chondrocyte implantation (ACI), new generation of matrix-induced ACI, cell-free scaffolds, induced pluripotent stem cells (iPS cells or iPSCs), and endogenous cell homing) are also emerging as promising alternatives as they have potential to enhance cartilage repair, and ultimately restore healthy tissue. However, despite currently available therapies and research advances, there remain unmet medical needs in the treatment of OA. This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations.

Early efficacy study of matrix induced autologous chondrocyte implantation repairing knee joint cartilage injury

Objective To study the feasibility and early efficacy of matrix-induced autologous chondrocyte implantation repairing knee joint cartilage injury. Methods The Matrix-induced autologous chondrocyte implantation was used to repair knee joint cartilage injury in 13 cases (11 males and 2 females) with knee joint cartilage injury from April 2012 to March 2013. The average age was 27.5 years old. All cases were suffering from unilateral focal cartilage defect of knee joint with International Cartilage Repair Society (ICRS) chondral defect classification system grade III or IV, visual analogue scale (VAS) >3, and all of which had corresponding pain symptoms. The average defect area was 4.2 cm2. Standardized rehabilitation exercise was carried out after matrix-induced autologous chondrocyte implantation. Patients were followed up for 1 years, and knee injury and use osteoarthritis outcome score (KOOS), International Knee Documentation Committee (IKDC), subjective knee form and Lysholm score were collected to assess the function. Meanwhile, magnetic resonance observation of cartilage repair tissue (MOCART) score was used to assess the magnetic resonance imaging. Results All patients had been followed-up for 1 year. One patient had meniscus repair under arthroscopy for the meniscus injury caused by downstairs sprain in 6.5 months postoperative, so the score of 12 months postoperative was excluded. The knee range of motion was decreased in 3 months postoperative (123.1°±8.0°) compared to preoperative one (135.4°±5.7°), and has no difference in 6 months (136.1°±6.1°) and 12 months postoperative (135.1°±3.6°) compared to preoperative one. The 5 subsets of KOOS score were decreased in 3 months compared to preoperative one, and were significantly increased in 6 months and 12 months. The IKDC has no difference in 3 months (26.1±3.9) compared to preoperative one (43.5± 6.5), and were significantly increased in 6 months (53.3±5.8) and 12 months (62.8±7.2) compared to preoperative one. The magnetic resonance observation of cartilage repair tissue (MOCART) score was increased in 12 month (73.3±17.9) compared to preoperative one (51.5±12.6). Conclusion MACI is a good technology for knee joint cartilage injury. It has a good clinical effect on re- pairing cartilage injury effectively and restoring the function of knee joint. Key words: Chondrocytes; Transplantation, autologous; knee joint

Nuestra experiencia con la técnica de implante de condrocitos autólogos para el tratamiento de lesiones condrales: resultados de 50 pacientes a 2 años de seguimiento

AimThe aim of this work was to evaluate the clinical results of the matrix-induced autologous chondrocyte implantation (MACI) technique on chondral defects of the knee and ankle. A study was conducted on 150 patients treated with MACI (performed by the same team of surgeons in all cases) during 2002-2007. MethodsThe lesion was evaluated by arthroscopy, and a cartilage biopsy was taken. The cellular implant was performed by arthroscopy in 53 patients, and by open surgery in the remaining cases. The results were measured following an in-house clinical protocol. Data corresponding to a mean follow-up period of 24 months were available in 50 out of the 150 implanted patients. Histological studies were performed in a second biopsy taken by arthroscopy in 5 patients 2 years after cell implantation. ResultsIn 89% of patients without previous surgeries, and in 66% of patients with previous surgeries, the results were good or excellent for pain and motion, and most of them were able to return to their previous physical activities, including professional sport. Histological studies performed on a second biopsy showed that the new tissue is hyaline-like cartilage with lower cell numbers and subjectively softer than normal cartilage. ConclusionArthroscopic MACI is a promising procedure to treat chondral lesions in the knee and ankle, although the histological analysis suggests that increasing cellular dosage would improve the results of the technique. Level of evidenceLevel III. Clinical relevanceThe importance of this study is that it presents an increased number of patients with chondral lesion treated with MACI. A high number of these patients were treated with arthroscopic MACI. In the present study it is shown that the treatment gives good results.

Incidence, Degree, and Development of Graft Hypertrophy 24 Months After Matrix-Induced Autologous Chondrocyte Implantation

Background: Graft hypertrophy is a common occurrence after periosteal, collagen-covered and matrix-induced autologous chondrocyte implantation (MACI). Purpose/Hypothesis: The purpose of this study was to investigate the incidence, development, and degree of graft hypertrophy at 24 months after MACI. The hypothesis was that graft hypertrophy would not be associated with clinical outcome at 24 months. Study Design: Case series, Level of evidence, 4. Methods: This study was undertaken in 180 consecutive patients (113 male, 67 female) after MACI in the knee. All patients were assessed clinically using the Knee injury and Osteoarthritis Outcome Score (KOOS) and underwent magnetic resonance imaging (MRI) at 3, 12, and 24 months after surgery. The incidence of hypertrophy relevant to anatomic graft site was investigated, as was the progressive change in hypertrophic studies postoperatively. The degree of tissue overgrowth in hypertrophic cases was investigated, as was its association with patient clinical outcome at 24 months after surgery. Results: Of the 180 patients, 50 demonstrated a hypertrophic graft at 1 or more postoperative time points. This included 9 grafts (5.0%) at 3 months and 32 grafts (18.7%) at 12 months. At 24 months, 47 grafts (26.1%)—43 (32.1%) tibiofemoral and 4 (8.7%) patellofemoral—were hypertrophic. Patients with hypertrophic grafts at 24 months (n = 47) were younger (P = .051), they had a lower body mass index (BMI; P = .069), and significantly fewer of them had patellofemoral grafts (P = .007) compared with patients who had grafts with full (100%) tissue infill (n = 61). There were no significant differences in any of the KOOS subscales between patients with graft hypertrophy or full (100%) tissue infill at 24 months after surgery, while the severity of graft hypertrophy was not associated with KOOS subscales at 24 months. Conclusion: Hypertrophic grafts after MACI were common and continued to develop through to 24 months after surgery. Hypertrophic growth was associated with being younger and having a lower BMI, was more common on the femoral condyles, and overall was not associated with clinical outcome at 24 months after surgery. However, further research with longer term follow-up is required to evaluate the effect of persistent hypertrophy on graft stability and to assess the use of early surgical intervention to prevent such failure.

Experimental articular cartilage repair in the Göttingen minipig: the influence of multiple defects per knee.

BackgroundA gold standard treatment for articular cartilage injuries is yet to be found, and a cost-effective and predictable large animal model is needed to bridge the gap between in vitro studies and clinical studies.Ideally, the animal model should allow for testing of clinically relevant treatments and the biological response should be reproducible and comparable to humans. This allows for a reliable translation of results to clinical studies.This study aimed at verifying the Göttingen minipig as a pre-clinical model for articular cartilage repair by testing existing clinical cartilage repair techniques and evaluating the use of two defects per knee.MethodsSixteen fully mature Göttingen minipigs were used. The minipigs received bilateral trochlear osteochondral drill-hole defects or chondral defects (Ø 6 mm), either one defect per knee or two defects per knee. The defects were treated with one of the following: Matrix-induced autologous chondrocyte implantation (MACI), microfracture (MFx), autologous-dual-tissue transplantation (ADTT), autologous bone graft, autologous cartilage chips. Empty chondral and osteochondral defects were used as controls. MRI and CT were performed 3 and 6 month, histology was performed 6 month postoperative.ResultsThe repair tissue varied in morphology from non-cartilaginous fibrous tissue to fibrocartilaginous tissue as seen on MRI, CT and histology at 6 month. The worst results were seen in the empty controls, while the best results were achieved with the MACI and ADTT treatment. The use of two defects per knee did not have any significant effect on the repair response.ConclusionThe outcomes of the applied treatments were consistent with the outcomes in clinical studies and it was possible to apply two defects per knee. The Göttingen minipig model was easy to handle, cost-effective and provided predictable outcome. Based on this study the use of two defects per knee, one in the medial and one in the lateral trochlear facet, in male Göttingen minipigs is recommended.

Mechanical characterization of matrix-induced autologous chondrocyte implantation (MACI®) grafts in an equine model at 53 weeks

There has been much interest in using autologous chondrocytes in combination with scaffold materials to aid in cartilage repair. In the present study, a total of 27 animals were used to compare the performance of matrix-assisted chondrocyte implantation (MACI®) using a collagen sponge as a chondrocyte delivery vehicle, the sponge membrane alone, and empty controls. A total of three distinct types of mechanical analyses were performed on repaired cartilage harvested from horses after 53 weeks of implantation: (1) compressive behavior of samples to measure aggregate modulus (HA) and hydraulic permeability (k) in confined compression; (2) local and global shear modulus using confocal strain mapping; and (3) boundary friction coefficient using a custom-built tribometer. Cartilage defects receiving MACI® implants had equilibrium modulus values that were 70% of normal cartilage, and were not statistically different than normal tissue. Defects filled with Maix™ membrane alone or left empty were only 46% and 51–63% of control, respectively. The shear modulus of tissue from all groups of cartilage defects were between 4 and 10 times lower than control tissue, and range from 0.2 to 0.4MPa. The average values of boundary mode friction coefficients of control tissue from all groups ranged from 0.42 to 0.52. This study represents an extensive characterization of the mechanical performance of the MACI® grafts implant in a large animal model at 53 weeks. Collectively, these data demonstrate a range of implant performance, revealing similar compressive and frictional properties to native tissue, with inferior shear properties.

Prospective Clinical and Radiologic Evaluation of Patellofemoral Matrix-Induced Autologous Chondrocyte Implantation

Background: While matrix-induced autologous chondrocyte implantation (MACI) has demonstrated encouraging outcomes in the treatment of knee chondral defects, there remains little available research specifically investigating its use in the patellofemoral joint. Purpose: To prospectively evaluate the clinical and radiologic outcome of MACI in the patellofemoral joint. Study Design: Case series; Level of evidence, 4. Methods: In 47 consecutive patients undergoing patellofemoral MACI, clinical (Knee injury and Osteoarthritis Outcome Score, 36-Item Short Form Health Survey, visual analog scale for pain, 6-minute walk test, knee range of motion, and strength assessment) and magnetic resonance imaging (MRI) assessments were undertaken before and 3, 12, and 24 months after surgery. The MRI was performed to assess graft infill and determine an overall MRI composite score. Results were analyzed according to (1) the patient sample overall and (2) after stratification into 4 subgroups per implant location (patella or trochlea) as well as whether or not adjunct tibial tubercle transfer for patellofemoral malalignment was required. Results: The overall patient sample, as well as each of the 4 procedural subgroups, demonstrated clinically and statistically significant (P < .05) improvements over time for all clinical scores. Graft infill and the MRI composite score also demonstrated statistically significant (P < .05) improvements over time, with no evidence of a main effect for procedure group or interaction between procedure group and time. At 24 months after surgery, 40.4% (n = 19) of patients exhibited complete graft infill comparable with the adjacent native cartilage, with a further 6.4% (n = 3) demonstrating a hypertrophic graft. A further 31.9% (n = 15) of patients exhibited 50% to 100% tissue infill, and 17% (n = 8) demonstrated <50% tissue infill. Two patients (4.3%) demonstrated graft failure. At 24 months after surgery, 85% (n = 40) of patients were satisfied with the results of their MACI surgery. Conclusion: These results demonstrate that MACI provides improved clinical and radiologic outcomes to 24 months in patients undergoing treatment specifically for articular cartilage defects on the patella or trochlea, with and without concurrent realignment of the extensor mechanism if required.

A chondrocyte infiltrated collagen type I/III membrane (MACI® implant) improves cartilage healing in the equine patellofemoral joint model

Autologous chondrocyte implantation (ACI) has improved outcome in long-term studies of joint repair in man. However, ACI requires sutured periosteal flaps to secure the cells, which precludes minimally-invasive implantation, and introduces complications with arthrofibrosis and graft hypertrophy. This study evaluated ACI on a collagen type I/III scaffold (matrix-induced autologous chondrocyte implantation; MACI(®)) in critical sized defects in the equine model. Chondrocytes were isolated from horses, expanded and seeded onto a collagen I/III membrane (ACI-Maix™) and implanted into one of two 15-mm defects in the femoral trochlear ridge of six horses. Control defects remained empty as ungrafted debrided defects. The animals were examined daily, scored by second look arthroscopy at 12 weeks, and necropsy examination 6 months after implantation. Reaction to the implant was determined by lameness, and synovial fluid constituents and synovial membrane histology. Cartilage healing was assessed by arthroscopic scores, gross assessment, repair tissue histology and immunohistochemistry, cartilage glycosaminoglycan (GAG) and DNA assay, and mechanical testing. MACI(®) implanted defects had improved arthroscopic second-look, gross healing, and composite histologic scores, compared to spontaneously healing empty defects. Cartilage GAG and DNA content in the defects repaired by MACI implant were significantly improved compared to controls. Mechanical properties were improved but remained inferior to normal cartilage. There was minimal evidence of reaction to the implant in the synovial fluid, synovial membrane, subchondral bone, or cartilage. The MACI(®) implant appeared to improve cartilage healing in a critical sized defect in the equine model evaluated over 6 months.

Matrix-Induced Autologous Chondrocyte Implantation versus Multipotent Stem Cells for the Treatment of Large Patellofemoral Chondral Lesions: A Nonrandomized Prospective Trial.

ObjectiveTo compare the outcome of matrix-induced autologous chondrocyte implantation (MACI) and bone marrow aspirate concentrate (BMAC)–derived multipotent stem cells (MSCs) implantation in patellofemoral chondral lesions, using the same HYAFF11 scaffold.MethodsFrom January 2005 to December 2010, 37 patients with patellofemoral chondral lesions were prospectively followed up, for a minimum of 3 years; 19 of these patients were treated with MACI and 18 with BMAC. Radiographs, magnetic resonance imaging, and clinical scores (International Knee Documentation Committee, Knee Injury and Osteoarthritis Outcome Score, visual analog scale, and Tegner) were collected preoperatively, at 2-year and final follow-up. Five patients of MACI and 6 of the BMAC group underwent second-look arthroscopy; 4 patients of each group consented to a concomitant biopsy.ResultsNo adverse reactions or postoperative infections were noted. Baseline characteristics were similar in both groups (P > 0.05). Both groups showed significant improvement in all scores, from preoperative to final follow-up (P = 0.001), but there was no significant difference in improvement between the 2 groups, except for the IKDC subjective score (P = 0.015), which favored the BMAC group. Deterioration in MACI and improvement in BMAC group scores were noticed, from 2-year to final follow-up, but was nonsignificant. MACI patients with trochlear lesions showed better results than patellar lesions, while location was not a prognostic factor in the BMAC group. MRI showed complete filling of the defects in 76% of patients in MACI and 81% of patients in BMAC, and histological analysis revealed hyaline-like features.ConclusionBoth techniques are viable and effective for large patellofemoral chondral lesions at minimum 3-year follow-up.

Matrix-induced autologous chondrocyte implantation for the treatment of chondral defects of the knees in Chinese patients.

Articular cartilage injury is the most common type of damage seen in clinical orthopedic practice. The matrix-induced autologous chondrocyte implant (MACI) was developed to repair articular cartilage with an advance on the autologous chondrocyte implant procedure. This study aimed to evaluate whether MACI is a safe and efficacious cartilage repair treatment for patients with knee cartilage lesions. The primary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS) domains and magnetic resonance imaging (MRI) results, compared between baseline and postoperative months 3, 6, 12, and 24. A total of 15 patients (20 knees), with an average age of 33.9 years, had a mean defect size of 4.01 cm2. By 6-month follow-up, KOOS results demonstrated significant improvements in symptoms and knee-related quality of life. MRI showed significant improvements in four individual graft scoring parameters at 24 months postoperatively. At 24 months, 90% of MACI grafts had filled completely and 10% had good-to-excellent filling of the chondral defect. Most (95%) of the MACI grafts were isointense and 5% were slightly hyperintense. Histologic evaluation at 15 and 24 months showed predominantly hyaline cartilage in newly generated tissue. There were no postoperative complications in any patients and no adverse events related to the MACI operation. This 2-year study has confirmed that MACI is safe and effective with the advantages of a simple technique and significant clinical improvements. Further functional and mechanistic studies with longer follow-up are needed to validate the efficacy and safety of MACI in patients with articular cartilage injuries.

Matrix-induced autologous chondrocyte implantation (MACI) in the knee: clinical outcomes and challenges.

Matrix-induced autologous chondrocyte implantation (MACI) has demonstrated effectiveness in treating isolated cartilage defects of the knee but medium- and long-term evidence and information on the management of postoperative complications or partially successful cases are sparse. This study hypothesised that MACI is effective for up to 5 years and that patients with posttreatment problems may go on to obtain clinical benefit from other interventions. A follow-on, prospective case series of patients recruited into a previous controlled, randomised, prospective study or newly enroled. Patients were followed up 6, 12, 24 and 60 months after surgery. Outcome measures were Tegner (activity levels) and Lysholm (pain, stability, gait, clinical symptoms) scores. Zone-specific subgroups were analysed 6, 12 and 24 months postoperatively. Sixty-five patients were treated with MACI. Median Tegner score improved from II to IV at 12 months; an improvement maintained to 60 months. Mean Lysholm score improved from 28.5 to 76.6 points (±19.8) at 24 months, settling back to 75.5 points after 5 years (p > 0.0001). No significant differences were identified in the zone-specific analysis. Posttreatment issues (N = 12/18.5 %) were resolved with microfracture, debridement, OATS or bone grafting. MACI is safe and effective in the majority of patients. Patients in whom treatment is only partially successful can go on to obtain clinical benefit from other cartilage repair options. This study adds to the clinical evidence on the MACI procedure, offers insight into likely treatment outcomes, and highlights MACI's usefulness as part of an armamentarium of surgical approaches to the treatment of isolated knee defects. Prospective case control study with no control group, Level III.

Degree of Preoperative Subchondral Bone Edema Is Not Associated With Pain and Graft Outcomes After Matrix-Induced Autologous Chondrocyte Implantation

Background: Matrix-induced autologous chondrocyte implantation (MACI) is an established technique for the repair of knee chondral defects. While a number of factors may affect the clinical outcome, little is known about the influence of subchondral bone abnormalities at the time of surgery on pain and graft outcomes after MACI. Purpose: To investigate the association between subchondral bone marrow edema within 3 months before MACI surgery on preoperative and postoperative reported pain and symptoms as well as postoperative graft outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: This retrospective study was undertaken in 56 patients undergoing MACI with clinical and radiological assessments before surgery and at 3, 12, 24, and 60 months after surgery. Patients were assessed using the Pain and Symptoms subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS). High-resolution magnetic resonance imaging (MRI) was used to evaluate the severity of preoperative subchondral bone marrow edema, while graft infill and an MRI composite graft score were evaluated after surgery via the magnetic resonance observation of cartilage repair tissue (MOCART) scoring system. Linear regression utilizing generalized estimating equations was used to investigate the association between preoperative subchondral bone marrow edema scores and preoperative and postoperative KOOS subscores as well as postoperative MRI-based scores of graft repair. Results: The degree of preoperative subchondral bone marrow edema was not significantly associated with postoperative outcomes, whereby there was no evidence of a difference between edema subgroups over all time points for the KOOS-Pain subscore (P = .644), KOOS-Symptoms subscore (P = .475), or MRI composite score (P = .685) after adjustment for potential confounders of age, body mass index, defect size, and defect location. Conclusion: No association was demonstrated between the severity of preoperative subchondral bone marrow edema with postoperative patient-reported knee pain or symptoms or postoperative graft repair assessed via MRI.

Viability of chondrocytes seeded onto a collagen I/III membrane for matrix-induced autologous chondrocyte implantation.

Cell viability is crucial for effective cell-based cartilage repair. The aim of this study was to determine the effect of handling the membrane during matrix-induced autologous chondrocyte implantation surgery on the viability of implanted chondrocytes. Images were acquired under five conditions: (i) Pre-operative; (ii) Handled during surgery; (iii) Cut edge; (iv) Thumb pressure applied; (v) Heavily grasped with forceps. Live and dead cell stains were used. Images were obtained for cell counting and morphology. Mean cell density was 6.60 × 10(5) cells/cm(2) (5.74-7.11 × 10(5) ) in specimens that did not have significant trauma decreasing significantly in specimens that had been grasped with forceps (p < 0.001) or cut (p = 0.004). Cell viability on delivery grade membrane was 75.1%(72.4-77.8%). This dropped to 67.4%(64.1-69.7%) after handling (p = 0.002), 56.3%(51.5-61.6%) after being thumbed (p < 0.001) and 28.8%(24.7-31.2%) after crushing with forceps (p < 0.001). When cut with scissors there was a band of cell death approximately 275 µm in width where cell viability decreased to 13.7%(10.2-18.2%, p < 0.001). Higher magnification revealed cells without the typical rounded appearance of chondrocytes. We found that confocal laser-scanning microscope (CLSM) can be used to quantify and image the fine morphology of cells on a matrix-induced autologous chondrocyte implantation (MACI) membrane. Careful handling of the membrane is essential to minimise chondrocyte death during surgery.

The progression of isokinetic knee strength after matrix-induced autologous chondrocyte implantation: implications for rehabilitation and return to activity.

Matrix-induced autologous chondrocyte implantation (MACI) is an established technique for the repair of knee chondral defects. Despite the reported clinical improvement in knee pain and symptoms, little is known on the recovery of knee strength and its return to an appropriate level compared with the unaffected limb. To investigate the progression of isokinetic knee strength and limb symmetry after MACI. Prospective cohort. Private functional rehabilitation facility. 58 patients treated with MACI for full-thickness cartilage defects to the femoral condyles. MACI and a standardized rehabilitation protocol. Preoperatively and at 1, 2, and 5 y postsurgery, patients underwent a 3-repetition-maximum straight-leg raise test, as well as assessment of isokinetic knee-flexor and -extensor torque and hamstring:quadriceps (H:Q) ratios. Correlation analysis investigated the association between strength and pain, demographics, defect, and surgery characteristics. Linear-regression analysis estimated differences in strength measures between the operated and nonoperated limbs, as well as Limb Symmetry Indexes (LSI) over time. Peak knee-extension torque improved significantly over time for both limbs but was significantly lower on the operated limb preoperatively and at 1, 2, and 5 y. Mean LSIs of 77.0%, 83.0%, and 86.5% were observed at 1, 2, and 5 y, respectively, while 53.4-72.4% of patients demonstrated an LSI < or = 90% across the postoperative timeline. Peak knee-flexion torque was significantly lower on the operated limb preoperatively and at 1 year. H:Q ratios were significantly higher on the operated limb at all time points. While peak knee-flexion and hip-flexor strength were within normal limits, the majority of patients in this study still demonstrated an LSI for peak knee-extensor strength < or = 90%, even at 5 y. It is unknown how this prolonged knee-extensor deficit may affect long-term graft outcome and risk of reinjury after return to activity.

Correlation Between Clinical and Radiological Outcomes After Matrix-Induced Autologous Chondrocyte Implantation in the Femoral Condyles

Background: Matrix-induced autologous chondrocyte implantation (MACI) is an established technique for the repair of knee chondral defects, although the correlation between clinical and radiological outcomes after surgery is poorly understood. Purpose: To determine the correlation between clinical and radiological outcomes throughout the postoperative timeline to 5 years after MACI. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: This retrospective study was undertaken in 83 patients (53 male, 30 female) with complete clinical and radiological follow-up at 1, 2, and 5 years after MACI. The mean age of patients was 38.9 years (range, 13-62 years), with a mean body mass index (BMI) of 26.6 kg/m2 (range, 16.8-34.8 kg/m2), mean defect size of 3.3 cm2 (range, 1-9 cm2), and mean preoperative duration of symptoms of 9.2 years (range, 1-46 years). Patients indicated for MACI in this follow-up were 13 to 65 years of age, although they were excluded if they had a BMI >35 kg/m2, had undergone prior extensive meniscectomy, or had ongoing progressive inflammatory arthritis. Patients were assessed clinically using the Knee Injury and Osteoarthritis Outcome Score (KOOS). Magnetic resonance imaging (MRI) was used to evaluate the graft using a 1.5-T or 3-T clinical scanner; the MRI assessment included 8 parameters of graft repair (infill, signal intensity, border integration, surface contour, structure, subchondral lamina, subchondral bone, and effusion) based on the magnetic resonance observation of cartilage repair tissue (MOCART) score as well as an MRI composite score. The degree of an association between the MRI parameters and the KOOS subscales at each postoperative time point was assessed with the Spearman correlation coefficient (SCC), and significance was determined at P < .05. Ethics approval was obtained from the appropriate hospital and university Human Research Ethics Committees, and informed consent was gathered from all patients. Results: The only MRI parameter displaying consistent evidence of an association with the KOOS subscales was effusion, with a pattern of increasing strength of correlations over time and statistically significant associations at 5 years with KOOS-Pain (SCC, 0.25; P = .020), KOOS–Activities of Daily Living (SCC, 0.26; P = .018), and KOOS-Sport (SCC, 0.32; P = .003). Apart from a significant correlation between subchondral lamina and KOOS-Sport at 1 year (SCC, 0.27; P = .016), no further significant findings were observed. Conclusion: Apart from some consistent evidence of an association between the KOOS and effusion, this analysis demonstrated a limited correlative capacity between clinical and radiological outcomes up to 5 years after surgery.