Surgical and tissue engineering strategies for articular cartilage and meniscus repair

Abstract

Injuries to articular cartilage and menisci can lead to cartilage degeneration that ultimately results in arthritis. Different forms of arthritis affect ~50 million people in the USA alone, and it is therefore crucial to identify methods that will halt or slow the progression to arthritis, starting with the initiating events of cartilage and meniscus defects. The surgical approaches in current use have a limited capacity for tissue regeneration and yield only short-term relief of symptoms. Tissue engineering approaches are emerging as alternatives to current surgical methods for cartilage and meniscus repair. Several cell-based and tissue-engineered products are currently in clinical trials for cartilage lesions and meniscal tears, opening new avenues for cartilage and meniscus regeneration. This Review provides a summary of surgical techniques, including tissue-engineered products, that are currently in clinical use, as well as a discussion of state-of-the-art tissue engineering strategies and technologies that are being developed for use in articular cartilage and meniscus repair and regeneration. The obstacles to clinical translation of these strategies are also included to inform the development of innovative tissue engineering approaches.

Figure 1.. Articular cartilage structure and treatment methods.

a| Articular cartilage consists of chondrocytes embedded in a defined structure of collagen fibres and glycosaminoglycans. Two main types of defects can occur; chondral defects, which only penetrate the cartilage and osteochondral defects, which also penetrate the subchondral bone. b| Currently used repair strategies for cartilage defects include microfracture, osteochondral autograft transfer, osteochondral allograft transplantation, implantation of processed allograft cartilage such as DeNovo NT, ProChondrix and Cartiform, and matrix-induced autologous chondrocyte implantation (MACI). The choice of treatment method depends on the size and type of the defect, the expertise and preferences of the surgeon and patient-specific factors such as age and activity level.

Figure 2.. Meniscus structure and treatment methods.

a| The meniscus consists of three main zones; red-red (R-R), red-white (R-W) and white-white (W-W). The R-R zone is fully vascularized and the W-W zone is avascular. b| A variety of different types of defects can occur in the meniscus, some of which are easier to repair than others owing to their intrusion into vascular or avascular zones. c| Reduction strategies in current use include defect closure with sutures or anchors and the trimming of torn pieces (partial or total meniscectomy). d| Replacement strategies in current use include allograft transplantation and the use of synthetic implants. As with articular cartilage, the size and type of defect, the expertise and preferences of the surgeon and patient-specific factors such as age and activity level affect the choice of treatment method.

Figure 3.. Advances in tissue engineering strategies for articular cartilage and meniscus.

Engineered implants go through several stages of development that can be modified or enhanced by the addition of appropriate stimuli. The source of cells is important as many cells dedifferentiate in culture; alternative cell sources currently being trialed include non-articular chondrocytes, tenocytes, fibrocytes, osteoarthritic chondrocytes and stem cells or progenitor cells. Growth factors such as TGFβs, PDGFs, FGFs, EGF, BMPs and GDFs are used to effectively expand and help to redifferentiate cells prior to neotissue formation. Scaffold-based and scaffold-free methods can be used to engineer articular cartilage and menisci, and biochemical and biophysical factors such as TGFβs, BMPs, IGFs, FGFs, chondroitinase ABC (c-ABC), lysyl-oxidase-like 2 (LOXL2), hyaluronic acid, matrilin 3, kartogenin and variations in oxygen tension are used to promote the maturation of engineered tissues. Similarly, biomechanical stimulation such as compression, tension, shear, hydrostatic pressure and biaxial loading can be used to improve the functional properties of the neotissue.

Figure 4.. Challenges to the clinical translation of engineered cartilage and meniscus products.

a| The main technical challenges to clinical translation include obtaining sufficient numbers of autologous cells, the effects of biological variability on the consistent production of high-quality engineered tissues and integration of the engineered tissues once implanted in vivo. Potential solutions and avenues of further investigation include; cells sourced from non-articulating cartilages (such as costal cartilage); allogeneic approaches, including extensive screening to identify appropriate donors; the fortification of engineered tissues to withstand immune-mediated degeneration within an inflamed joint; the priming of engineered tissues with chondroitinase ABC (c-ABC) and lysyl-oxidase-like 2 (LOXL2) for enhanced integration; and novel in vivo implantation methods that protect tissue-engineered implants. b| Regulatory challenges to clinical translation include the long time-frames and high costs associated with clinical trials. Solutions such as the Regenerative Medicine Advanced Therapy (RMAT) designation, other FDA programs that enable accelerated review and approval of applications and the use of surrogate endpoints are hoped to help overcome these challenges.