Expansion of Chondrocytes for Cartilage Tissue Engineering: A Review of Chondrocyte Dedifferentiation and Redifferentiation as a Function of Growth in Expansion Culture

Culture-expansion is a common step in the use of autologous chondrocytes for cartilage tissue engineering. Chondrocytes dedifferentiate in monolayer expansion culture, and conditions that are sufficient to induce redifferentiation change as a function of cumulative growth. The objective of this review was to characterize the relationship between expansion and redifferentiation, from which requirements to induce redifferentiation were identified for selected approaches to cartilage tissue engineering. While chondrocytes dedifferentiate rapidly in expansion culture, transferring the cells to a three-dimensional scaffold is sufficient to induce redifferentiation for up to ~6 population doublings (PDs). Redifferentiation is possible beyond 6 PDs, although exposure to chondrogenic cytokines is needed. These data indicate that dedifferentiation with expansion for treating focal defects (~6 PDs) can be reversed with transfer to a scaffold, while joint resurfacing (~10 PDs) is anticipated to require exposure to chondrogenic cytokines. During expansion, growth factor supplementation can accelerate proliferation and improve redifferentiation. However, redifferentiation may require chondrogenic cytokines, and should be considered for approaches that involve expansion beyond the limit for spontaneous redifferentiation.