Matrix-induced Autologous Chondrocyte Implantation Research Articles

Autologous Chondrocyte Implantation (ACI) for Knee Cartilage Defects: A Review of Indications, Technique, and Outcomes.

* Autologous chondrocyte implantation (ACI) was first developed in the late 1980s for the treatment of articular cartilage defects in the knee. The first generation of ACI utilized a periosteal patch to contain the cultured chondrocyte solution within the defect. Because of issues with periosteal graft hypertrophy, ACI with use of a collagen membrane patch (second-generation ACI) was developed. Finally, the application of chondrocytes within a matrix (third-generation ACI) was created to improve cell delivery, to allow for minimally invasive implantation, to better replicate normal cartilage architecture, and to accelerate patient rehabilitation. As of December 2016, only 1 third-generation ACI product (matrix-induced autologous chondrocyte implantation, or MACI) has been cleared for marketing by the U.S. Food and Drug Administration (FDA) and is available in the United States.* ACI (regardless of generation) is effective for the treatment of high-grade tibiofemoral cartilage defects. However, issues with coronal alignment, ligament laxity/instability, and meniscal deficiency must be addressed or the outcomes following ACI will be poor.* Because of the extended time that is required for graft maturation, special consideration must be given to return-to-play protocols as athletes can regain strength and neuromuscular coordination well before the graft has sufficiently matured.

Treatment of Articular Cartilage Defects: Focus on Tissue Engineering.

The treatment of articular cartilage defects seems to be one of the greatest challenges in modern orthopaedics. From a medical point of view there are 3 main goals to achieve for cartilage trauma treatment: restoration of the joints motion, pain relief and elimination/delay of the onset of osteoarthritis. Treatment can be divided into conservative (including pharmacotherapy, arthrocentesis and physiotherapy) and surgical. The last comprises reparative techniques, regenerative methods and symptomatic treatment. While both are focused on reconstruction of the damaged cartilage, the difference lies in the type of filling tissue. Reparative techniques include: drilling of the subchondral bone, spongiolisation, abrasion, mictrofracture, and autologous matrix induced chondrogenesis (AMIC). Regenerative methods contain: periosteal and perichondral grafts, mosaicplasty, autologous chondrocyte implantation and matrix-induced autologous chondrocyte implantation (MACI). Nowadays tissue engineering, including gene therapy, is emerging as one of the key approaches to cartilage treatment and holds promises for new achievements and better outcomes of many cartilage diseases and traumas.

Matrix-Induced Autologous Chondrocyte Implantation (MACI) Using a Cell-Seeded Collagen Membrane Improves Cartilage Healing in the Equine Model.

Autologous chondrocyte implantation (ACI) using a collagen scaffold (matrix-induced ACI; MACI) is a next-generation approach to traditional ACI that provides the benefit of autologous cells and guided tissue regeneration using a biocompatible collagen scaffold. The MACI implant also has inherent advantages including surgical implantation via arthroscopy or miniarthrotomy, the elimination of periosteal harvest, and the use of tissue adhesive in lieu of sutures. This study evaluated the efficacy of the MACI implant in an equine full-thickness cartilage defect model at 1 year. Autologous chondrocytes were seeded onto a collagen type-I/III membrane and implanted into one of two 15-mm defects in the femoral trochlear ridge of 24 horses. Control defects either were implanted with cell-free collagen type-I/III membrane (12 horses) or were left ungrafted as empty defects (12 horses). An additional 3 horses had both 15-mm defects remain empty as nonimplanted joints. The repair was scored by second-look arthroscopy (12 weeks), and necropsy examination (53 weeks). Healing was assessed by arthroscopic scoring, gross assessment, histology and immunohistology, cartilage matrix component assay, and gene expression determination. Toxicity was examined by prostaglandin E2 formation in joint fluid, and lymph node morphology combined with histologic screening of organs. MACI-implanted defects had improved gross healing and composite histologic scores, as well as increases in chondrocyte predominance, toluidine blue-stained matrix, and collagen type-II content compared with scaffold-only implanted or empty defects. There was minimal evidence of reaction to the implant in the synovial membrane (minor perivascular cuffing), subchondral bone, or cartilage. There were no adverse clinical effects, signs of organ toxicity, or evidence of chondrocytes or collagen type-I/III membrane in draining lymph nodes. The MACI implant appeared to improve cartilage healing in a critical-sized defect in the equine model compared with collagen matrix alone. These results indicate that the MACI implant is quick to insert, provides chondrocyte security in the defect, and improves cartilage healing compared with ACI.

Patellofemoral Cartilage Restoration: Indications, Techniques, and Outcomes of Autologous Chondrocytes Implantation, Matrix-Induced Chondrocyte Implantation, and Particulated Juvenile Allograft Cartilage.

Focal chondral defects are common in the patellofemoral (PF) joint and can significantly impair the quality of life. The autologous chondrocytes implantation (ACI) technique has evolved over the past 20 years: the first-generation technique involves the use of a periosteal patch, the second-generation technique (collagen-cover) uses a type I/III collagen membrane, and the newest third-generation technique seeds and cultivates the collagen membrane with chondrocytes prior to implantation and is referred to as matrix-induced autologous chondrocyte implantation. Particulated juvenile allograft cartilage (PJAC) (DeNovo NT) is minced cartilage allograft from juvenile donors. A thorough physical exam is important, especially for issues affecting the PF joint, to isolate the location and source of pain, and to identify associated pathologies. Imaging studies allow further characterization of the lesions and identification of associated pathologies and alignment. Conservative management should be exhausted before proceeding with surgical treatment. Steps of surgical treatment are diagnostic arthroscopy and biopsy, chondrocytes culture and chondrocyte implantation for the three generations of ACI, and diagnostic arthroscopy and implantation for PJAC. The techniques and their outcomes will be discussed in this article.

Examination of Knee Isokinetic Strength and Single-Leg Balance of Operated and Non-Operated Side of Patients with Unilateral Matrix-Induced Autologous Chondrocyte Implantation (MACI) Surgery : Pilot Study

Examination of Knee Isokinetic Strength and Single-Leg Balance of Operated and Non-Operated Side of Patients with Unilateral Matrix-Induced Autologous Chondrocyte Implantation (MACI) Surgery : Pilot Study

A Comparison of 2-Year Outcomes in Patients Undergoing Tibiofemoral or Patellofemoral Matrix-Induced Autologous Chondrocyte Implantation

Background: Matrix-induced autologous chondrocyte implantation (MACI) has demonstrated encouraging clinical results in the treatment of knee chondral defects. However, earlier studies suggested that chondrocyte implantation in the patellofemoral (PF) joint was less effective than in the tibiofemoral (TF) joint. Purpose: To compare the radiological and clinical outcomes of those undergoing MACI to either the femoral condyles or PF joint. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 194 patients were included in this analysis, including 127 undergoing MACI to the medial (n = 94) and lateral (n = 33) femoral condyle, as well as 67 to the patella (n = 35) or trochlea (n = 32). All patients were evaluated clinically (Knee injury and Osteoarthritis Outcome Score [KOOS], visual analog scale, Short Form–36) before surgery and at 3, 12, and 24 months after surgery, while magnetic resonance imaging (MRI) was undertaken at 3, 12, and 24 months, with the MOCART (magnetic resonance observation of cartilage repair tissue) scoring system employed to evaluate the quality and quantity of repair tissue, as well as an MRI composite score. Patient satisfaction was evaluated. Results: No significant group differences (P > .05) were seen in demographics, defect size, prior injury, or surgical history, while the majority of clinical scores were similar preoperatively. All clinical scores significantly improved over time (P < .05), with a significant group effect observed for KOOS activities of daily living (P = .008), quality of life (P = .008), and sport (P = .017), reflecting better postoperative scores in the TF group. While the PF group had significantly lower values at baseline for the KOOS activities of daily living and quality of life subscales, it actually displayed a similar net improvement over time compared with the TF group. At 24 months, 93.7% (n = 119) and 91.0% (n = 61) of patients were satisfied with the ability of MACI to relieve their knee pain, 74.0% (n = 94) and 65.7% (n = 44) with their ability to participate in sport, and 90.5% (n = 115) and 83.6% (n = 56) satisfied overall, in the TF and PF groups, respectively. MRI evaluation via the MOCART score revealed a significant time effect (P < .05) for the MRI composite score and graft infill over the 24-month period. While subchondral lamina scored significantly better (P = .002) in the TF group, subchondral bone scored significantly worse (P < .001). At 24 months, the overall MRI composite score was classified as good/excellent in 98 TF patients (77%) and 54 PF patients (81%). Conclusion: MACI in the PF joint with concurrent correction of PF maltracking if required leads to similar clinical and radiological outcomes compared with MACI on the femoral condyles.

A novel strategy for cartilage tissue engineering: Collagenase-loaded cryogel scaffolds in a sheep model

ABSTRACTIn this study, we developed a novel strategy, through which cartilage tissue pieces were placed in a sheep cartilage defect model and covered with a collagenase incorporated cryogel scaffold (in vivo cartilage tissue engineering, IVCTE group). While applying this strategy, the chondrocytes could be isolated inside the body and the treatment could be accomplished in one session. To compare our strategy, to another group, in which we used cultured cells and Chondro-gide, standard matrix-induced autologous chondrocyte implantation (MACI) was applied. Although the MACI applied group demonstrated better healing than IVCTE, the type II collagen synthesis was better in the IVCTE group compared to MACI applied group. Collagenase did not have detrimental effect on surrounding cartilage in IVCTE group. The preliminary results of the novel strategy applied group (IVCTE) were promising.

The Use of Biological Approaches in the Treatment of Shoulder Pathology: A Critical Analysis Review.

* The major pathological conditions affecting the shoulder that are treated with use of biological applications include focal cartilage lesions and rotator cuff tears. Biological modalities that previously have been used or investigated include platelet-rich plasma (PRP), growth factors, progenitor cells, bone-marrow stimulation, autologous chondrocyte implantation (ACI), matrix-induced ACI (MACI), and biological scaffolds.* Marrow-stimulating procedures have been reported to yield positive results when used for the treatment of focal cartilage lesions of the glenoid or humeral head. Limited data are available on the use of PRP, ACI, and MACI for the treatment of chondral lesions involving the shoulder, and therefore no conclusions can be drawn regarding the efficacy of these modalities.* Preclinical and in vitro studies have demonstrated that modulation of growth factors may be helpful for rotator cuff tear healing; however, the optimal modulation and delivery vehicle remain to be elucidated. PRP has received much research attention; however, most studies have been hindered by study setup and conflicting results. Therefore, the use of PRP to enhance rotator cuff healing remains controversial. Progenitor cells have shown positive results in a small number of preclinical and clinical studies, but further research is needed before conclusions can be drawn.* In summary, basic-science studies investigating biological factors to enhance healing in the shoulder have shown potential. However, clinical data are still limited, contradictory, and controversial. Additional research is needed. Most importantly, robust, consistent, well-powered clinical trials are necessary to definitively determine which methods improve clinical outcomes.

RNA Interference and BMP-2 Stimulation Allows Equine Chondrocytes Redifferentiation in 3D-Hypoxia Cell Culture Model: Application for Matrix-Induced Autologous Chondrocyte Implantation.

As in humans, osteoarthritis (OA) causes considerable economic loss to the equine industry. New hopes for cartilage repair have emerged with the matrix-associated autologous chondrocyte implantation (MACI). Nevertheless, its limitation is due to the dedifferentiation occurring during the chondrocyte amplification phase, leading to the loss of its capacity to produce a hyaline extracellular matrix (ECM). To enhance the MACI therapy efficiency, we have developed a strategy for chondrocyte redifferentiation, and demonstrated its feasibility in the equine model. Thus, to mimic the cartilage microenvironment, the equine dedifferentiated chondrocytes were cultured in type I/III collagen sponges for 7 days under hypoxia in the presence of BMP-2. In addition, chondrocytes were transfected by siRNA targeting Col1a1 and Htra1 mRNAs, which are overexpressed during dedifferentiation and OA. To investigate the quality of the neo-synthesized ECM, specific and atypical cartilage markers were evaluated by RT-qPCR and Western blot. Our results show that the combination of 3D hypoxia cell culture, BMP-2 (Bone morphogenetic protein-2), and RNA interference, increases the chondrocytes functional indexes (Col2a1/Col1a1, Acan/Col1a1), leading to an effective chondrocyte redifferentiation. These data represent a proof of concept for this process of application, in vitro, in the equine model, and will lead to the improvement of the MACI efficiency for cartilage tissue engineering therapy in preclinical/clinical trials, both in equine and human medicine.

Topical Review: MACI as an Emerging Technology for the Treatment of Talar Osteochondral Lesions.

Level V, expert opinion.

Seven-Year Follow-up of Matrix-Induced Autologous Implantation in Talus Articular Defects.

Osteochondral lesions of the talus (OLT) are difficult to treat because of the poor intrinsic healing capability of articular cartilage. Matrix-induced autologous chondrocyte implantation (MACI) has been shown to be a reliable method for treating cartilage lesions that fail to respond to traditional microfracture and debridement. The purpose of this study was to assess 7-year clinical follow-up data of this technique and demonstrate midterm success of this implant. A prospective investigation of MACI was performed on 10 patients with OLTs who had failed previous arthroscopic treatment. In all, 5 male and 5 female patients were included in the study. Of the 10 patients, 9 were available for 7-year follow-up. Functional and clinical evaluations were done at 7 years postoperatively using the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot evaluation and the Short Form Health Survey (SF-36) and compared with preoperative values. SF-36 data at 7 years showed significant improvements in Physical Functioning (P < .01), Lack of Bodily Pain (P < .1), and Social Functioning (P < .001) compared with preoperative data. The mean AOFAS hindfoot scores of the 9 patients at 7 years was 78.3 ± 18.1 (P = .05) compared with their preoperative mean of 61.8 ± 14.3. MACI provides a stable midterm chondral replacement strategy for osteochondral lesions that fail initial microfracture. Level IV: Prospective case series.

How to Manage a Failed Cartilage Repair: A Systematic Literature Review.

Purpose The aims of this paper are to report the rate and risk factors for the failure of the most common cartilage repair technique, and analyze the most important factors that could influence the choice of a specific surgical treatment to revise a failed cartilage repair. Methods A review of the literature was performed focusing on failed cartilage repair and related treatments. Two of the authors independently screened articles. Conflicts about the inclusion of a paper was resolved by further evaluation by the senior author. Review articles, articles written in languages different from/other than English, case reports, and papers that did not evaluate the outcomes of interest were excluded. Full-text version of each included paper was obtained and relevant data were extracted and collected in a database. Results At the end of the screening process, 31 articles were included. Microfractures and mosaicplasty showed a nonnegligible failure rate at short- and midterm. Better results, especially in terms of time to failure or revision, were reported with the use of autologous chondrocyte implantation (ACI) and osteochondral allograft (OCA) transplantation. Regarding the treatment of failed cartilage repair, the use of OCA transplantation in patients with previous failed cartilage repair may be a safe option. The revision of failed OCA transplantation with further OCA seems to have a greater failure rate. Patients with previous failed ACI or matrix-induced autologous chondrocyte implantation (MACI) who underwent further MACI or ACI reported acceptable results. Otherwise, ACI in patients with history of previous subchondral marrow stimulation (SMS) demonstrated a greater failure rate. Conclusion From the analysis of the literature, OCA transplantation seems to be the most reliable treatment of a failed SMS. ACI or MACI showed acceptable results in patients with previously failed MACI or ACI. Level of Evidence Level IV, systematic review of level I-IV studies.

Two year comparison of clinical and graft outcomes in patients undergoing tibiofemoral or patellofemoral Matrix-Induced Autologous Chondrocyte Implantation (MACI)

Two year comparison of clinical and graft outcomes in patients undergoing tibiofemoral or patellofemoral Matrix-Induced Autologous Chondrocyte Implantation (MACI)

Cartilage Repair Tissue Composition Assessed with 3-T MRI Correlates with Trabecular Bone Remodeling in Patients with Spongiosa-augmented Matrix-induced Autologous Chondrocyte Implantation

Cartilage Repair Tissue Composition Assessed with 3-T MRI Correlates with Trabecular Bone Remodeling in Patients with Spongiosa-augmented Matrix-induced Autologous Chondrocyte Implantation

Surgical management of large talar osteochondral defects using autologous chondrocyte implantation

BackgroundTalar osteochondral lesions (OLT) occur frequently in ankle sprains and fractures. We hypothesize that matrix-induced autologous chondrocyte implantation (MACI) will have a low reoperation rate and high patient satisfaction rate in treating OLT less than 2.5cm2. MethodsA systematic review was registered with PROSPERO and performed with PRISMA guidelines using three publicly available free databases. 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. Statistics were calculated using Student’s t-tests, one-way ANOVA, chi-squared, and two-proportion Z-tests. ResultsNineteen 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 periosteal ACI (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. However, open MACI had higher complication rates. ConclusionsNo procedure demonstrates superiority or inferiority between the combination of open or arthroscopic MACI and PACI in the management of OLT less than 2.5cm2. Ultimately, well-designed randomized trials are needed to address the limitation of the available literature and further our understanding of the optimal treatment options.

Matrix-induced autologous chondrocyte implantation for treatment of femoral trochlea cartilage injury

To determine the short-term effectiveness of matrix-induced autologous chondrocyte implantation (MACI) for femoral trochlea cartilage injury. A retrospective analysis was performed on the clinical data of 10 patients with femoral trochlea cartilage injury treated with MACI between June 2012 and October 2014. There were 6 males and 4 females, aged from 15 to 48 years (mean, 33 years). The left knee was involved in 3 cases and the right knee in 7 cases. Nine patients had a history of trauma, and 1 case suffered from osteochondritis dissecans. Combined injuries included meniscus injury in 1 case, anterior cruciate ligament injury in 3 cases, and lateral collateral ligament tear in 2 cases. The mean lesion depth was 2.80 mm (range, 2-7 mm), with the mean defect size of 84.85 mm 2 (range, 28.26-153.86 mm 2). The mean duration of definite diagnosis was 14 days (range, 5 days to 3 months). By using arthroscopic biopsy, 200-300 mg healthy articular cartilage at non weight-bearing area of the knee femoral trochlea was collected as a source of seed cells, which were isolated and cultured to prepare MACI membrane. The adhesion activity, growth rate, and mechanical properties of the chondrocytes on the Bio-gide collagen scaffold were evaluated. In addition, the stretch rate, tensile strength, and suture strength of scaffold were tested. MACI membrane was implanted after 2 weeks to 6 months. The visual analogou scale (VAS), Lysholm score, and Tegner movement level score at preoperation and last follow-up were used to assess the function. The MACI membrane was successfully prepared, and the human chondrocytes adhered and grew well on the Bio-gide collagen scaffold. Mechanical test showed that MACI membrane had the stretch rate of 65.27%, the tensile strength of 26.81 MPa, and the suture strength of 6.49 N, indicating good mechanical properties. MACI membrane was successfully implanted. The mean operation time was 58.5 minutes (range, 43-99 minutes), and the mean hospitalization time was 7 days (range, 6-15 days). All incisions healed well. Ten cases were followed up 9 to 16 months (mean, 12 months). Four cases underwent iliac bone graft surgery. The mean healing time was 14 weeks (range, 12-16 weeks). No complications of osteochondrolysis, knee pain, nerve and vascular injury, deep vein thrombosis, and knee adhesion occurred during follow-up. The VAS score, Lysholm score, and Tegner score at last follow-up were significantly improved when compared with preoperative scores ( t=12.060, P=0.000; t=-9.200, P=0.000; t=-14.000, P=0.000). MACI for femoral trochlea cartilage injury has good short-term effectiveness, with less injury and fast function recovery.

Arthroscopic treatment of chondral defects in the hip: AMIC, MACI, microfragmented adipose tissue transplantation (MATT) and other options.

Chondral lesions are currently considered in the hip as a consequence of trauma, osteonecrosis, dysplasia, labral tears, loose bodies, dislocation, previous slipped capital femoral epiphysis and Femoro-Acetabular-Impingement (FAI). The management of chondral lesions is debated and several techniques are described. The physical examination must be carefully performed, followed by radiographs and magnetic resonance imaging (MRI). Differential diagnosis with other pathologies must be considered. Debridement is indicated in patients younger than 50 years with a chondropathy of 1st or 2nd degree. Microfractures are indicated in patients younger than 50 years with a chondropathy of 3rd or 4th degree less than 2 cm2. Matrix-Induced Autologous Chondrocyte Implantation (MACI) and Autologous Matrix-Induced Chondrogenesis (AMIC) procedures are indicated in patients with full-thickness symptomatic 3rd–4th degree chondral defects, extended 2 cm2 or more. The AMIC procedure has the advantage of a one-step procedure and much less expense. Microfragmented adipose tissue transplantation (MATT) is indicated for the treatment of delamination and 1st and 2nd degree chondral lesions, regardless of the age of the patient. Chondral defects are effective when the joint space is not compromised. When the Tonnis classification is two or greater, treatment of chondral lesions should be considered ineffective.

Rapid Chondrocyte Isolation for Tissue Engineering Applications: The Effect of Enzyme Concentration and Temporal Exposure on the Matrix Forming Capacity of Nasal Derived Chondrocytes.

Laboratory based processing and expansion to yield adequate cell numbers had been the standard in Autologous Disc Chondrocyte Transplantation (ADCT), Allogeneic Juvenile Chondrocyte Implantation (NuQu®), and Matrix-Induced Autologous Chondrocyte Implantation (MACI). Optimizing cell isolation is a key challenge in terms of obtaining adequate cell numbers while maintaining a vibrant cell population capable of subsequent proliferation and matrix elaboration. However, typical cell yields from a cartilage digest are highly variable between donors and based on user competency. The overall objective of this study was to optimize chondrocyte isolation from cartilaginous nasal tissue through modulation of enzyme concentration exposure (750 and 3000 U/ml) and incubation time (1 and 12 h), combined with physical agitation cycles, and to assess subsequent cell viability and matrix forming capacity. Overall, increasing enzyme exposure time was found to be more detrimental than collagenase concentration for subsequent viability, proliferation, and matrix forming capacity (sGAG and collagen) of these cells resulting in nonuniform cartilaginous matrix deposition. Taken together, consolidating a 3000 U/ml collagenase digest of 1 h at a ratio of 10 ml/g of cartilage tissue with physical agitation cycles can improve efficiency of chondrocyte isolation, yielding robust, more uniform matrix formation.

Two-Year Outcomes of a Randomized Trial Investigating a 6-Week Return to Full Weightbearing After Matrix-Induced Autologous Chondrocyte Implantation

Background: Matrix-induced autologous chondrocyte implantation (MACI) has demonstrated encouraging outcomes in treating patients with knee cartilage defects. Postoperatively, the time required to attain full weightbearing (WB) remains conservative. Hypothesis: We hypothesized that patients would have no significant clinical or radiological differences or graft complications after an 8-week or 6-week return to full WB after MACI. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 37 knees (n = 35 patients) were randomly allocated to either an 8-week return to full WB that we considered current best practice based on the existing literature (CR group; n = 19 knees) or an accelerated 6-week WB approach (AR group; n = 18 knees). Patients were evaluated preoperatively and at 1, 2, 3, 6, 12, and 24 months after surgery, using the Knee Injury and Osteoarthritis Outcome Score, 36-Item Short Form Health Survey, visual analog pain scale, 6-minute walk test, and active knee range of motion. Isokinetic dynamometry was used to assess peak knee extension and flexion strength and limb symmetry indices (LSIs) between the operated and nonoperated limbs. Magnetic resonance imaging (MRI) was undertaken to evaluate the quality and quantity of repair tissue as well as to calculate an MRI composite score. Results: Significant improvements (P < .05) were observed in all subjective scores, active knee flexion and extension, 6-minute capacity, peak knee extensor torque in the operated limb, and knee extensor LSI, although no group differences existed. Although knee flexor LSIs were above 100% for both groups at 12 and 24 months after surgery, LSIs for knee extensor torque at 24 months were 93.7% and 87.5% for the AR and CR groups, respectively. The MRI composite score and pertinent graft parameters significantly improved over time (P < .05), with some superior in the AR group at 24 months. All patients in the AR group (100%) demonstrated good to excellent infill at 24 months, compared with 83% of patients in the CR group. Two cases of graft failure were observed, both in the CR group. At 24 months, 83% of patients in the CR group and 88% in the AR group were satisfied with the results of their MACI surgery. Conclusion: Patients in the AR group who reduced the length of time spent ambulating on crutches produced comparable outcomes up to 24 months, without compromising graft integrity.

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.