Considerations for translation of tissue engineered fibrocartilage from bench to bedside

Abstract

Fibrocartilage is found in the knee meniscus, the temporomandibular joint (TMJ) disc, the pubic symphysis, the annulus fibrosus of intervertebral disc, tendons, and ligaments. These tissues are notoriously difficult to repair due to their avascularity, and limited clinical repair and replacement options exist. Tissue engineering has been proposed as a route to repair and replace fibrocartilages. Using the knee meniscus and TMJ disc as examples, this review describes how fibrocartilages can be engineered toward translation to clinical use. Presented are fibrocartilage anatomy, function, epidemiology, pathology, and current clinical treatments because they inform design criteria for tissue engineered fibrocartilages. Methods for how native tissues are characterized histomorphologically, biochemically, and mechanically to set gold standards are described. Then, provided is a review of fibrocartilage-specific tissue engineering strategies, including the selection of cell sources, scaffold or scaffold-free methods, and biochemical and mechanical stimuli. In closing, the Food and Drug Administration paradigm is discussed to inform researchers of both the guidance that exists and the questions that remain to be answered with regard to bringing a tissue engineered fibrocartilage product to the clinic.

Figures

Fig. 1

Anatomy of the knee meniscus and TMJ disc. The anatomical structures of the knee are shown, with the menisci depicted between the femur and tibia. The transverse view is shown in the right panel, indicating the different vascular regions of each meniscus. The TMJ disc is shown from a sagittal view between the mandibular condyle and the articular eminence in an open jaw position. The disc from a transverse view is depicted in the right-hand panel.

Fig. 2

Clinical indications of the knee meniscus and TMJ disc. Different clinical indications for the meniscus are shown including five different tears: oblique, complex, vertical longitudinal, horizontal, and radial tears. For the TMJ disc, disc thinning and DP are the clinical indications presented.

Fig. 3

Tissue engineering of fibrocartilage. Tissue engineering requires characterization of native cartilage from which design criteria can be specified. Tissue engineering parameters such as selection of a cell source, choice of scaffold or scaffold-free methodology, and use of biochemical or mechanical stimuli results in tissue engineered fibrocartilage which is subsequently tested for appropriate properties. If design criteria are met, the tissue engineered fibrocartilage and methodology used may move to preclinical animal models or the tissue engineering process might be reiterated to obtain improved tissue engineered fibrocartilage.

Fig. 4

The FDA paradigm. The FDA paradigm is outlined from tissue engineering studies to the postmarketing phase with appropriate milestones for CBER and CDRH depicted.

Fig. 5

Cell morphology and collagen alignment of the knee meniscus and TMJ disc. (a) A representation of the wedge-shape of the meniscus is depicted with the innermost region showing rounded, chondrocyte-like cells transitioning to spindle-shaped, fibroblast-like cells toward the outermost region. Figure reused with permission from Springer Nature: Cellular and Molecular Bioengineering [59]. (b) Scanning electron micrographs showing (1) the circumferential collagen alignment, (2) a close-up view depicting individual collagen fibers, (3) a cross section of a collagen bundle, and (4) the random collagen orientation on the outer surfaces of the meniscus. Figure reused with permission from SAGE Publications: Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine [61]. (c) Ratio between fibroblasts and chondrocyte-like cells, and overall cellularity in the TMJ disc are reported, showing the posterior and anterior bands have a higher proportion of fibroblasts when compared to the intermediate zone. Figure reused with permission from Elsevier: Journal of Oral and Maxillofacial Surgery [47]. (d) Scanning electron micrographs of various regions of the TMJ disc showing primarily anteroposterior alignment in the intermediate zone, while the anterior and posterior bands show circumferential alignment. Scale bars are 10 μm except for the lateral region where the scale bar represents 200 μm. Figure reused with permission from Elsevier: Matrix Biology [56].