Functions and applications of extracellular matrix in cartilage tissue engineering

Successful regeneration of articular cartilage remains a major challenge in musculoskeletal healthcare. To address this challenge, it is essential to understand the function of cartilage extracellular matrix (ECM). Cartilage ECM is a hydrated biomolecular composite integrating collagen II/IX/XI fibrillar network and aggrecan−hyaluronan supramolecular aggregates. It endows cartilage with its distinctive biomechanical functions and provides chondrocytes with the specialized microenvironment to maintain cellular activities. In particular, within the ECM, chondrocytes are surrounded by the microniche known as the pericellular matrix (PCM). The PCM is a unique ~ 2–4-µm thick domain that has distinct composition and structure from the ECM bulk, and is directly responsible for mediating chondrocyte mechanotransduction. This chapter reviews recent advances in understanding the molecular activities that govern the assembly of ECM, mechanoregulatory role of PCM, as well as emerging applications of ECM and PCM in cartilage regeneration. Notably, recent progresses in the studies of regulatory ECM molecules, such as decorin and type III collagen, have provided new insights into the molecular assembly mechanisms of cartilage ECM. The PCM has been shown to have a pivotal role in disease initiation, and may serve as a target for disease intervention. Also, direct applications of cartilage ECM and PCM have shown promises in promoting stem cell chondrogenesis and biosynthesis in vitro. Further progresses that integrate the knowledge and skillset from tissue engineering, biomaterials, matrix biology, and biomechanics are expected to establish a unique path for improving cartilage regeneration and eventually, restoration of tissue function.