Matrix-assisted Autologous Chondrocyte Implantation Research Articles

Fixation of the Membrane during Matrix-Induced Autologous Chondrocyte Implantation in the Knee: A Systematic Review.

It is unclear whether the type of membrane used for matrix-assisted autologous chondrocyte implantation (mACI) influences results. A systematic review was conducted to investigate the midterm results of the three most common types of membrane fixation for mACI. This systematic review was conducted according to the 2020 PRISMA checklist. PubMed, Google Scholar, Embase, and Scopus online databases were accessed in August 2022. All the prospective clinical trials reporting outcomes of mACI in the knee were considered. Studies that describe the modality of membrane fixation (glued, glued, and sutured, no fixation) used for mACI were eligible. Studies that conducted a minimum of 12 months of follow-up were considered. The outcomes of interest were the Tegner Activity Scale and International Knee Documentation Committee (IKDC) score. The rate of failure and revisions were also collected. Data from 26 studies (1539 procedures; 554 of 1539 (36%) were women) were retrieved. The mean follow-up was 42.6 (12 to 84) months. No difference between the groups was found in terms of mean duration of symptoms, age, BMI, gender, and defect size (P > 0.1). No difference was found in terms of the Tegner score (P = 0.3). When no fixation was used, a statistically significant higher IKDC compared to the other groups (P = 0.02) was evidenced. No difference was found in the rate of failure (P = 0.1). The no-fixation group evidenced a statistically significant lower rate of revisions (P = 0.02). No membrane fixation for mACI in the knee scored better than the fastening techniques at the midterm follow-up.

Evaluation of a co-culture of rapidly isolated chondrocytes and stem cells seeded on tri-layered collagen-based scaffolds in a caprine osteochondral defect model

Cartilage has poor regenerative capacity and thus damage to the joint surfaces presents a major clinical challenge. Recent research has focussed on the development of tissue-engineered and cell-based approaches for the treatment of cartilage and osteochondral injuries, with current clinically available cell-based approaches including autologous chondrocyte implantation and matrix-assisted autologous chondrocyte implantation. However, these approaches have significant disadvantages due to the requirement for a two-stage surgical procedure and an in vitro chondrocyte expansion phase which increases logistical challenges, hospital times and costs. In this study, we hypothesized that seeding biomimetic tri-layered scaffolds, with proven regenerative potential, with chondrocyte/infrapatellar fat pad stromal cell co-cultures would improve their regenerative capacity compared to scaffolds implanted cell-free. Rapid cell isolation techniques, without the requirement for long term in vitro culture, were utilised to achieve co-cultures of chondrocytes and stromal cells and thus overcome the limitations of existing cell-based techniques. Cell-free and cell-seeded scaffolds were implanted in osteochondral defects, created within the femoral condyle and trochlear ridge, in a translational large animal goat model. While analysis showed trends towards delayed subchondral bone healing in the cell-seeded scaffold group, by the 12 month timepoint the cell-free and cell-seeded groups yield cartilage and bone tissue with comparable quality and quantity. The results of the study reinforce the potential of the biomimetic tri-layered scaffold to repair joint defects but failed to demonstrate a clear benefit from the addition of the CC/FPMSC co-culture to this scaffold. Taking into consideration the additional cost and complexity associated with the cell-seeded scaffold approach, this study demonstrates that the treatment of osteochondral defects using cell-free tri-layered scaffolds may represent a more prudent clinical approach.

Articular cartilage delamination at eight years following cellular-based repair procedures: a case reports

This report describes two cases of late cartilage delamination in two young adults after two different autologous cell-based techniques for cartilage restoration: 1. Matrix-assisted autologous chondrocyte implantation (MACI) and 2. Hyaluronic acid-bone marrow aspirate concentrate (HA-BMAC). Both cases demonstrate that even in patients who do not present with any ongoing symptoms after primary surgery, a cellular-based graft’s subsequent delamination can occur later. It is possible that regardless of the technique used or the time passed since the surgery, a graft failure may occur at some level, causing delamination of a previously asymptomatic cartilage restoration graft and a traumatic event with long-term follow-up. Surgeons must be alert to this injury and describe histologic findings to determine where failure occurs.

Biological Augments for Acetabular Chondral Defects in Hip Arthroscopy-A Scoping Review of the Current Clinical Evidence.

A wide array of joint-preserving surgical techniques exists in the management of acetabular chondral defects (ACDs). The purpose of this review is to summarize the clinical outcomes of the recent biologics used to treat ACDs during hip arthroscopy. Increasing evidence is available for different biological solutions used in the hip. Studies have shown promising outcomes with minimal complications when using biologics as augmentation to microfracture (MF), including different scaffolds or stem cells, or to enhance autologous chondrocyte implantation (ACI). However, data so far is scarce, and more trials and longer follow-ups are needed to better delineate the appropriate indications and benefits for each technique. Presently, the level of evidence is low, but in general, biologics appear safe and trend toward beneficial compared to standard surgical techniques. Augmented MF is recommended for small to medium ACDs, and matrix-assisted ACI or three-dimensional ACI is recommended for medium to large defects.

Alginate-Agarose Hydrogels Improve the In Vitro Differentiation of Human Dental Pulp Stem Cells in Chondrocytes. A Histological Study.

Matrix-assisted autologous chondrocyte implantation (MACI) has shown promising results for cartilage repair, combining cultured chondrocytes and hydrogels, including alginate. The ability of chondrocytes for MACI is limited by different factors including donor site morbidity, dedifferentiation, limited lifespan or poor proliferation in vitro. Mesenchymal stem cells could represent an alternative for cartilage regeneration. In this study, we propose a MACI scaffold consisting of a mixed alginate-agarose hydrogel in combination with human dental pulp stem cells (hDPSCs), suitable for cartilage regeneration. Scaffolds were characterized according to their rheological properties, and their histomorphometric and molecular biology results. Agarose significantly improved the biomechanical behavior of the alginate scaffolds. Large scaffolds were manufactured, and a homogeneous distribution of cells was observed within them. Although primary chondrocytes showed a greater capacity for chondrogenic differentiation, hDPSCs cultured in the scaffolds formed large aggregates of cells, acquired a rounded morphology and expressed high amounts of type II collagen and aggrecan. Cells cultured in the scaffolds expressed not only chondral matrix-related genes, but also remodeling proteins and chondrocyte differentiation factors. The degree of differentiation of cells was proportional to the number and size of the cell aggregates that were formed in the hydrogels.

Reconstruction of Large Osteochondral Lesions in the Knee: Focus on Fixation Techniques.

Large (>3 cm2), focal osteochondral lesions (OCL) may result in poor functional outcomes and early secondary osteoarthritis of the knee. The surgical management of these OCL remains challenging. The treatment strategy must be tailored to various aspects, including lesion-specific (e.g., size, location, chronicity), joint-specific (e.g., instability, limb alignment, meniscal status), and patient-specific factors (e.g., age, activity level, comorbidities). Simple chondroplasty and bone marrow stimulation (BMS) techniques should be reserved for smaller lesions, as they only realize midterm clinical benefits, related to inferior wear characteristics of the induced fibrocartilage (type I collagen). Therefore, much attention has been focused on surgical restoration with hyaline cartilage (type II collagen), based on chondrocyte transplantation and matrix-assisted autologous chondrocyte implantation (MACI). Limited graft availability, staged procedures (MACI), and high treatment costs are limitations of these techniques. However, acute traumatic OCL of the femoral condyles and patellofemoral joint may also be suitable for preservation by surgical fixation. Early detection of the fragment facilitates primary repair with internal fixation. The surgical repair of the articular surface may offer promising clinical and cost-effective benefits as a first-line therapy but remains under-investigated and potentially under-utilized. As a unique characteristic, the fixation technique allows the anatomic restoration of the hyaline articular surface with native cartilage and the repair of the subchondral bone. In this manuscript, we present a case series of large OCL around the knee that were preserved by surgical fixation. Furthermore, various implants and techniques reported for this procedure are reviewed.

Marrow Stimulation Has Relatively Inferior Patient-Reported Outcomes in Cartilage Restoration Surgery of the Knee: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: Multiple cartilage repair techniques are available for chondral defects in the knee. Optimal treatment is controversial. Purpose: To evaluate change from baseline in the 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales among different cartilage repair techniques of the knee. Study Design: Systematic review and meta-analysis; Level of evidence, 1A. Methods: Medline and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for randomized controlled trials with minimum 1 year follow-up reporting change from baseline KOOS (delta KOOS) subscale values. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. A meta-analysis was performed on the following surgery types: microfracture (Mfx); augmented microfracture techniques (Mfx+Augment); and culture-based therapies, including autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI). A random-effects metaregression model was used. Results: A total of 14 randomized trials with a total of 775 patients were included. The KOOS Sport and Recreation (Sport) and KOOS Quality of Life (QOL) were the 2 most responsive subscales after operative intervention. Outcomes from Mfx and Mfx+Augment were not different in any of the 5 KOOS subscales (minimum P > .3). The mean delta KOOS Sport after ACI/MACI was 9.9 points greater than after Mfx (P = .021) and 11.7 points greater than after Mfx+Augment (P = .027). Longer follow-up time correlated with greater delta KOOS Sport (P = .028). Larger body mass index led to greater delta KOOS QOL (P = .045). Larger cartilage defect size correlated with greater delta KOOS Pain and KOOS Activities of Daily Living scores (P = .023 and P = .002, respectively). Conclusion: The KOOS Sport and QOL were the most responsive subscales after cartilage restoration surgery of the knee. Culture-based therapies (ACI/MACI) led to clinically relevant improvements in the KOOS Sport score compared with marrow stimulation and may be a more appropriate treatment in younger and more active individuals. There were no benefits to Mfx+Augment over Mfx alone in any of the KOOS subscales.

Anteriorization of the Tibial Tubercle With Osteotomy, Combined With Cartilage Restoration in the Patellofemoral Joint: A Surgical Technique

Left untreated, cartilage defects of the knee are responsible for substantial patient morbidity and may lead to osteoarthritis. This has led to the development of several techniques to improve healing potential, including microfracture, osteochondral autograft, osteochondral allografts, autologous chondrocyte implantation, and matrix-assisted autologous chondrocyte implantation. Of paramount importance when addressing patellofemoral (PF) cartilage defects is treating associated PF malalignment. We describe a surgical technique for tibial tubercle anteriorization in conjunction with autologous chondrocyte implantation for the treatment of PF cartilage lesions. In our opinion, a distal realignment procedure should be routinely performed for any cartilage restoration procedure of the PF joint as it may delay the onset of osteoarthritis.

Management of the Failed OCD.

Osteochondritis dissecans (OCD) is a pathologic condition of subchondral bone most frequently occurring in the medial femoral condyle of the knee in children and adolescents. Salvage techniques are necessary when either nonoperative or typical operative treatments fail, or the OCD presents in an unsalvageable state. The purpose of this review is to describe the evaluation and management of failed OCDs. Thorough preoperative planning is essential to the treatment of failed OCDs. Radiographs and advanced imaging such as MRI and CT allow for a detailed assessment of subchondral bone and cartilage. Long-leg alignment radiographs are critical to assess for malalignment which may increase the contact forces on the affected condyle. Malalignment can be corrected with hemiepiphysiodesis or an osteotomy depending on the skeletal maturity of the patient. Osteochondral allografts and autologous chondrocyte implantation treat the defect in both bone and cartilage or solely cartilage and have good short to moderate term outcomes, particularly as compared to the inferior outcomes of microfracture of larger OCDs. Osteochondritis dissecans of the knee that fails to heal with initial operative measures can result in a large defect of bone and cartilage in the knee of adolescents. Treatment of the bone and cartilage defect can be accomplished with either osteochondral allograft transplantation or matrix-assisted autologous chondrocyte implantation can be performed with good outcomes. Assessment and correction of lower extremity malalignment is a critical component of treatment. Durable long-term solutions are necessary for the treatment of these difficult lesions.

Chondrocyte Culture Parameters for Matrix-Assisted Autologous Chondrocyte Implantation Affect Catabolism and Inflammation in a Rabbit Model.

Cartilage defects represent an increasing pathology among active individuals that affects the ability to contribute to sports and daily life. Cell therapy, such as autologous chondrocyte implantation (ACI), is a widespread option to treat larger cartilage defects still lacking standardization of in vitro cell culture parameters. We hypothesize that mRNA expression of cytokines and proteases before and after ACI is influenced by in vitro parameters: cell-passage, cell-density and membrane-holding time. Knee joint articular chondrocytes, harvested from rabbits (n = 60), were cultured/processed under varying conditions: after three different cell-passages (P1, P3, and P5), cells were seeded on 3D collagen matrices (approximately 25 mm3) at three different densities (2 × 105/matrix, 1 × 106/matrix, and 3 × 106/matrix) combined with two different membrane-holding times (5 h and two weeks) prior autologous transplantation. Those combinations resulted in 18 different in vivo experimental groups. Two defects/knee/animal were created in the trochlear groove (defect dimension: ∅ 4 mm × 2 mm). Four identical cell-seeded matrices (CSM) were assembled and grouped in two pairs: One pair giving pre-operative in vitro data (CSM-i), the other pair was implanted in vivo and harvested 12 weeks post-implantation (CSM-e). CSMs were analyzed for TNF-α, IL-1β, MMP-1, and MMP-3 via qPCR. CSM-i showed higher expression of IL-1β, MMP-1, and MMP-3 compared to CSM-e. TNF-α expression was higher in CSM-e. Linearity between CSM-i and CSM-e values was found, except for TNF-α. IL-1β expression was higher in CSM-i at higher passage and longer membrane-holding time. IL-1β expression decreased with prolonged membrane-holding time in CSM-e. For TNF-α, the reverse was true. Lower cell-passages and lower membrane-holding time resulted in stronger TNF-α expression. Prolonged membrane-holding time resulted in increased MMP levels among CSM-i and CSM-e. Cellular density was of no significant effect. We demonstrated cytokine and MMP expression levels to be directly influenced by in vitro culture settings in ACI. Linearity of expression-patterns between CSM-i and CSM-e may predict ACI regeneration outcome in vivo. Cytokine/protease interaction within the regenerate tissue could be guided via adjusting in vitro culture parameters, of which membrane-holding time resulted the most relevant one.

An in vitro and in vivo comparison of cartilage growth in chondrocyte-laden matrix metalloproteinase-sensitive poly(ethylene glycol) hydrogels with localized transforming growth factor β3

While matrix-assisted autologous chondrocyte implantation has emerged as a promising therapy to treat focal chondral defects, matrices that support regeneration of hyaline cartilage remain challenging. The goal of this work was to investigate the potential of a matrix metalloproteinase (MMP)-sensitive poly(ethylene glycol) (PEG) hydrogel containing the tethered growth factor, transforming growth factor β3 (TGF-β3), and compare cartilage regeneration in vitro and in vivo. The in vitro environment comprised chemically-defined medium while the in vivo environment utilized the subcutaneous implant model in athymic mice. Porcine chondrocytes were isolated and expanded in 2D culture for 10 days prior to encapsulation. The presence of tethered TGF-β3 reduced cell spreading. Chondrocyte-laden hydrogels were analyzed for total sulfated glycosaminoglycan and collagen contents, MMP activity, and spatial deposition of aggrecan, decorin, biglycan, and collagens type II and I. The total amount of extracellular matrix (ECM) deposited in the hydrogel constructs was similar in vitro and in vivo. However, the in vitro environment was not able to support long-term culture up to 64 days of the engineered cartilage leading to the eventual breakdown of aggrecan. The in vivo environment, on the other hand, led to more elaborate ECM, which correlated with higher MMP activity, and an overall higher quality of engineered tissue that was rich in aggrecan, decorin, biglycan and collagen type II with minimal collagen type I. Overall, the MMP-sensitive PEG hydrogel containing tethered TGF-β3 is a promising matrix for hyaline cartilage regeneration in vivo. Statement of SignificanceRegenerating hyaline cartilage remains a significant clinical challenge. The resultant repair tissue is often fibrocartilage, which long-term cannot be sustained. The goal of this study was to investigate the potential of a synthetic hydrogel matrix containing peptide crosslinks that can be degraded by enzymes secreted by encapsulated cartilage cells (i.e., chondrocytes) and tethered growth factors, specifically TGF-β3, to provide localized chondrogenic cues to the cells. This hydrogel led to hyaline cartilage-like tissue growth in vitro and in vivo, with minimal formation of fibrocartilage. However, the tissue formed in vitro, could not be maintained long-term. In vivo this hydrogel shows great promise as a potential matrix for use in regenerating hyaline cartilage.

Hip Cartilage Restoration: Available Evidence and Current Trends

AbstractTreatment of cartilage pathology is controversial. In the hip, it is even more so as identification and treatment of early cartilage disease are relatively new and little evidence exists. With the advent and more widespread use of hip arthroscopy, easier access to the hip joint is available, and adequate treatment is possible with less morbidity. Many treatment options exist for cartilage lesions including nonoperative treatment, debridement, microfracture, acetabuloplasty, cartilage fixation, cartilage scaffolds, autologous chondrocyte implantation, and osteochondral grafting. While far from definitive, the current evidence suggests that smaller cartilage lesions (< 4 cm2) have good results with most treatments while larger lesions fare better with treatments that produce hyaline-like cartilage. The most cost-effective arthroscopic treatments of smaller cartilage lesions include acetabuloplasty and microfracture, while larger lesions should be considered for autologous matrix-induced chondrogenesis or matrix-assisted autologous chondrocyte implantation. Larger cartilage lesions with bone disease are more adequately treated with open procedures such as osteochondral grafting or total hip arthroplasty.

In Vitro Analysis of Cartilage Regeneration Using a Collagen Type I Hydrogel (CaReS) in the Bovine Cartilage Punch Model.

Limitations of matrix-assisted autologous chondrocyte implantation to regenerate functional hyaline cartilage demand a better understanding of the underlying cellular/molecular processes. Thus, the regenerative capacity of a clinically approved hydrogel collagen type I implant was tested in a standardized bovine cartilage punch model. Cartilage rings (outer diameter 6 mm; inner defect diameter 2 mm) were prepared from the bovine trochlear groove. Collagen implants (± bovine chondrocytes) were placed inside the cartilage rings and cultured up to 12 weeks. Cartilage-implant constructs were analyzed by histology (hematoxylin/eosin; safranin O), immunohistology (aggrecan, collagens 1 and 2), and for protein content, RNA expression, and implant push-out force. Cartilage-implant constructs revealed vital morphology, preserved matrix integrity throughout culture, progressive, but slight proteoglycan loss from the "host" cartilage or its surface and decreasing proteoglycan release into the culture supernatant. In contrast, collagen 2 and 1 content of cartilage and cartilage-implant interface was approximately constant over time. Cell-free and cell-loaded implants showed (1) cell migration onto/into the implant, (2) progressive deposition of aggrecan and constant levels of collagens 1 and 2, (3) progressively increased mRNA levels for aggrecan and collagen 2, and (4) significantly augmented push-out forces over time. Cell-loaded implants displayed a significantly earlier and more long-lasting deposition of aggrecan, as well as tendentially higher push-out forces. Preserved tissue integrity and progressively increasing cartilage differentiation and push-out forces for up to 12 weeks of cultivation suggest initial cartilage regeneration and lateral bonding of the implant in this in vitro model for cartilage replacement materials.

Autologous Matrix-Induced Chondrogenesis: A Systematic Review of the Clinical Evidence

Background: The addition of a type I/III collagen membrane in cartilage defects treated with microfracture has been advocated for cartilage repair, termed “autologous matrix-induced chondrogenesis” (AMIC). Purpose: To examine the current clinical evidence regarding AMIC for focal chondral defects. Study Design: Systematic review. Methods: A systematic review was performed by searching PubMed, ScienceDirect, and Cochrane Library databases. Inclusion criteria were clinical studies of AMIC for articular cartilage repair, written in English. Relative data were extracted and critically analyzed. PRISMA guidelines were applied, the methodological quality of the included studies was assessed by the modified Coleman Methodology Score (CMS), and aggregate data were generated. Results: Twenty-eight clinical articles were included: 12 studies (245 patients) of knee cartilage defects, 12 studies (214 patients) of ankle cartilage defects, and 4 studies (308 patients) of hip cartilage defects. The CMS demonstrated a suboptimal study design in the majority of published studies (knee, 57.8; ankle, 55.3; hip, 57.7). For the knee, 1 study reported significant clinical improvements for AMIC compared with microfracture for medium-sized cartilage defects (mean defect size 3.6 cm2) after 5 years (level of evidence, 1). No study compared AMIC with matrix-assisted autologous chondrocyte implantation (ACI) in the knee. For the ankle, no clinical trial was available comparing AMIC versus microfracture or ACI. In the hip, only one analysis (level of evidence, 3) compared AMIC with microfracture for acetabular lesions. For medium-sized acetabular defects, one study (level of evidence, 3) found no significant differences between AMIC and ACI at 5 years. Specific aspects not appropriately discussed in the currently available literature include patient-related factors, membrane fixation, and defect properties. No treatment-related adverse events were reported. Conclusion: This systematic review reveals a paucity of high-quality, randomized controlled studies testing the AMIC technique versus established procedures such as microfracture or ACI. Evidence is insufficient to recommend joint-specific indications for AMIC. Additional nonbiased, high-powered, randomized controlled clinical trials will provide better clinical and structural long-term evidence, thus helping to define possible indications for this technique.

Correlation Analysis of SOX9, -5, and -6 as well as COL2A1 and Aggrecan Gene Expression of Collagen I Implant-Derived and Osteoarthritic Chondrocytes.

ObjectiveMatrix-assisted autologous chondrocyte implantation is frequently applied to replace damaged cartilage in order to support tissue regeneration or repair and to prevent progressive cartilage degradation and osteoarthritis. Its application, however, is limited to primary defects and contraindicated in the case of osteoarthritis that is partially ascribed to dedifferentiation and phenotype alterations of chondrocytes obtainable from patients’ biopsies. The differentiation state of chondrocytes is reflected at the level of structural gene (COL2A1, ACAN, COL1A1) and transcription factor (SOX9, 5, 6) expression.Methods/DesignWe determined the mRNA abundances of COL2A1, ACAN, and COL1A1as well as SOX9, -5, and -6 of freshly isolated and passaged collagen I implant–derived and osteoarthritic chondrocytes via reverse transcription–polymerase chain reaction. Moreover, we analyzed the correlation of structural and transcription factor gene expression. Thus, we were able to evaluate the impact of the mRNA levels of transcription factors on the expression of cartilage-specific structural genes.ResultsSignificant differences were obtained (1) for freshly isolated osteoarthritic versus collagen I implant–derived chondrocytes, (2) due to passaging of the respective cell sources, (3) for osteoarthritic versus nonosteoarthritic chondrocytes, and (4) for COL2A1 versus ACAN expression with respect to the coherence with SOX9, -5, and -6 transcript levels.ConclusionOur results might contribute to a better understanding of the transcriptional regulation of structural gene expression of chondrocytes with implications for their use in matrix-assisted autologous chondrocyte implantation.

Mechanostimulation changes the catabolic phenotype of human dedifferentiated osteoarthritic chondrocytes.

The treatment of cartilage defects with matrix-embedded autologous chondrocytes is a promising method to support the repair process and to foster reconstitution of full functionality of the joint. Human osteoarthritic chondrocytes were harvest from nine different patients (mean ± SD age 68 ± 8 years) who underwent total knee replacement. The chondrocytes were embedded after a precultivation phase into a collagen I hydrogel. Mid-term intermitted mechanostimulation on matrix-embedded dedifferentiated human osteoarthritic chondrocytes was performed by intermittently applying a cyclic sinusoid compression regime for 4 days (cycles of 1 h of sinusoidal stimulation (1 Hz) and 4 h of break; maximum compression 2.5%). Stimulated (Flex) and non-stimulated (No Flex) cell matrix constructs were analysed concerning the expression of genes involved in tissue metabolism, the content of sulphated glycosaminoglycans (sGAG) and the morphology of the chondrocytes. Gene expression analysis showed a high significant increase in collagen type II expression (p < 0.001), a significant increase in aggrecan expression (p < 0.04) and a high significant decrease in MMP-13 expression (p < 0.001) under stimulation condition compared with unstimulated controls. No significant changes were found in the gene expression rate of MMP-3. This positive effect of the mechanostimulation was confirmed by the analyses of sGAG. Mechanically stimulated cell-matrix constructs had nearly tripled sGAG content than the non-stimulated control (p < 0.002). In addition, histological examination showed that morphology of chondrocytes was altered from a spindle-shaped to a chondrocyte-characteristic rounded phenotype. Mid-term intermitted mechanical stimulation in vitro has the potential to improve the cell quality of cell matrix constructs prepared from dedifferentiated osteoarthritic chondrocytes. This observation may extend the inclusion criteria for matrix-assisted autologous chondrocyte implantation (MACI) and confirms the importance of moderate dynamic compression in clinical rehabilitation after MACI.

Infrapatellar fat pad-derived stem cells maintain their chondrogenic capacity in disease and can be used to engineer cartilaginous grafts of clinically relevant dimensions.

A therapy for regenerating large cartilaginous lesions within the articular surface of osteoarthritic joints remains elusive. While tissue engineering strategies such as matrix-assisted autologous chondrocyte implantation can be used in the repair of focal cartilage defects, extending such approaches to the treatment of osteoarthritis will require a number of scientific and technical challenges to be overcome. These include the identification of an abundant source of chondroprogenitor cells that maintain their chondrogenic capacity in disease, as well as the development of novel approaches to engineer scalable cartilaginous grafts that could be used to resurface large areas of damaged joints. In this study, it is first demonstrated that infrapatellar fat pad-derived stem cells (FPSCs) isolated from osteoarthritic (OA) donors possess a comparable chondrogenic capacity to FPSCs isolated from patients undergoing ligament reconstruction. In a further validation of their functionality, we also demonstrate that FPSCs from OA donors respond to the application of physiological levels of cyclic hydrostatic pressure by increasing aggrecan gene expression and the production of sulfated glycosaminoglycans. We next explored whether cartilaginous grafts could be engineered with diseased human FPSCs using a self-assembly or scaffold-free approach. After examining a range of culture conditions, it was found that continuous supplementation with both transforming growth factor-β3 (TGF-β3) and bone morphogenic protein-6 (BMP-6) promoted the development of tissues rich in proteoglycans and type II collagen. The final phase of the study sought to scale-up this approach to engineer cartilaginous grafts of clinically relevant dimensions (≥2 cm in diameter) by assembling FPSCs onto electrospun PLLA fiber membranes. Over 6 weeks in culture, it was possible to generate robust, flexible cartilage-like grafts of scale, opening up the possibility that tissues engineered using FPSCs derived from OA patients could potentially be used to resurface large areas of joint surfaces damaged by trauma or disease.

Revision cartilage cell transplantation for failed autologous chondrocyte transplantation in chronic osteochondral defects of the knee

The management of failed autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI) for the treatment of symptomatic osteochondral defects in the knee represents a major challenge. Patients are young, active and usually unsuitable for prosthetic replacement. This study reports the results in patients who underwent revision cartilage transplantation of their original ACI/MACI graft for clinical or graft-related failure. We assessed 22 patients (12 men and 10 women) with a mean age of 37.4 years (18 to 48) at a mean of 5.4 years (1.3 to 10.9). The mean period between primary and revision grafting was 46.1 months (7 to 89). The mean defect size was 446.6 mm(2) (150 to 875) and they were located on 11 medial and two lateral femoral condyles, eight patellae and one trochlea. The mean modified Cincinnati knee score improved from 40.5 (16 to 77) pre-operatively to 64.9 (8 to 94) at their most recent review (p < 0.001). The visual analogue pain score improved from 6.1 (3 to 9) to 4.7 (0 to 10) (p = 0.042). A total of 14 patients (63%) reported an 'excellent' (n = 6) or 'good' (n = 8) clinical outcome, 5 'fair' and one 'poor' outcome. Two patients underwent patellofemoral joint replacement. This study demonstrates that revision cartilage transplantation after primary ACI and MACI can yield acceptable functional results and continue to preserve the joint.

Matrix-induced autologous chondrocyte implantation for a large chondral defect in a professional football player: a case report

IntroductionMatrix-assisted autologous chondrocyte implantation is a well-known procedure for the treatment of cartilage defects, which aims to establish a regenerative milieu and restore hyaline cartilage. However, much less is known about third-generation autologous chondrocyte implantation application in high-level athletes. We report on the two-year follow-up outcome after matrix-assisted autologous chondrocyte implantation to treat a large cartilage lesion of the lateral femoral condyle in a male Caucasian professional football player.Case presentationA 27-year-old male Caucasian professional football player was previously treated for cartilage problems of his left knee with two failed microfracture procedures resulting in a 9 cm2 Outerbridge Grade 4 chondral lesion at his lateral femoral condyle. Preoperative Tegner-Lysholm and Brittberg-Peterson scores were 64 and 58, and by the second year they were 91 and 6. An evaluation with magnetic resonance imaging demonstrated filling of the defect with the signal intensity of the repair tissue resembling healthy cartilage. Second-look arthroscopy revealed robust, smooth cartilage covering his lateral femoral condyle. He returned to his former competitive level without restrictions or complaints one year after the procedure.ConclusionsThis case illustrates that robust cartilage tissue can be obtained with a matrix-assisted autologous chondrocyte implantation procedure even after two failed microfracture procedures in a large (9 cm2) cartilage defect. To the best of our knowledge, this is the first case report on the application of the third-generation cell therapy treatment technique, matrix-assisted autologous chondrocyte implantation, in a professional football player.

ACI and MACI

Regenerative procedures aim to recreate a hyaline-like tissue, thus restoring a biologically and biomechanically valid articular surface with durable clinical results. Autologous chondrocyte implantation (ACI) has been developed two decades ago, and both the production of a hyaline-like articular surface and a satisfactory clinical outcome have been documented at medium-long follow-up. Bioengineering technology further improved this regenerative treatment approach to include matrix-assisted ACI (MACI) techniques. These procedures have been introduced in the clinical practice one decade ago, showing similar results while at the same time overcoming most of the concerns related to the first-generation ACI. The use of scaffolds to create a cartilage-like tissue in a three-dimensional culture system allows for the optimization of the procedure from both the biological and surgical point of view. However, despite thousands of treated patients and many published studies suggesting good clinical results and durability of these procedures, the properties of healthy, normal articular cartilage are still unmatched by any available substitute. Both indications and results of these substitutes are still controversial. The role of many variables that may influence the final outcome still need to be clarified to further improve the potential benefits of these biological regenerative procedures.