Unlike bone, cartilage regeneration remains elusive

Abstract

Articular cartilage was predicted to be one of the first tissues to successfully be regenerated, but this proved incorrect. In contrast, bone (but also vasculature and cardiac tissues) has seen numerous successful reparative approaches, despite consisting of multiple cell and tissue types and, thus, possessing more complex design requirements. Here, we use bone-regeneration successes to highlight cartilage-regeneration challenges: such as selecting appropriate cell sources and scaffolds, creating biomechanically suitable tissues, and integrating to native tissue. We also discuss technologies that can address the hurdles of engineering a tissue possessing mechanical properties that are unmatched in human-made materials and functioning in environments unfavorable to neotissue growth.

Fig. 1

Differences in the physiologic environment and cellular make-up of bone and cartilage have profound effects on the potential to engineer these tissues. Through the presence of stem cells in marrow and in the periosteum, and access to abundant nutrients via vasculature, bone possesses inherent regenerative capability that can be harnessed in regenerative therapies. Cartilage's hypocellularity and lack of nutrient supply, coupled with the inability of bone marrow MSCs or resident chondroprogenitor cells to generate hyaline ECM, result in a tissue unable to mount a functional healing response. Thus, in contrast to bone's ability to heal, cartilage needs more robust exogenous approaches to achieve satisfactory regeneration.

Fig. 2

Various clinical strategies regenerate cartilage using chondrocytes or MSCs. Microfracture involves subchondral bone penetration to release bone marrow that forms a stem cell-rich clot. Augmented microfracture adds a scaffold to the microfracture technique to concentrate and aid in stem cell differentiation. Acellular scaffolds are also used in full-thickness defects. Autologous chondrocyte implantation involves harvest of the patient's chondrocytes; the cells are expanded in vitro, and then placed under a collagen membrane sutured over the defect site. Advancement of this technique involves seeding chondrocytes onto a scaffold and culturing in vitro prior to implantation. Scaffoldless engineered cartilage formed in vitro with chondrocytes is also used with two products currently undergoing clinical trials. In aforementioned strategies, MSCs can be used instead of chondrocytes; however, products based on these technologies are at earlier stages of development. Osteochondral grafts taken either from less-load bearing regions of the patient's own joint or cadaveric joints are implanted to fill focal defects. Intra-articular injections (e.g., hyaluronan) reduce the symptoms of cartilage degeneration, but the effects are only temporary. Total joint replacement is the final option when cartilage damage is so extensive that no other therapies can be effective.

Fig. 3

Scaffoldless tissue-engineering. The cell source chosen for cartilage generation, treated with appropriate culture conditions, must have the ability to produce matrix specific to articular cartilage and must not evoke an immune response. TGF-β family growth factors, physiologic mechanical stimulation, and matrix remodeling enzymes have shown a large degree of promise as stimuli.