The degradation rate of collagen-based hydrogels regulates chondrogenic differentiation of bone marrow mesenchymal stem cells

Abstract Dynamic degradation of three-dimensional (3D) scaffolds is essential for cellular extracellular matrix (ECM) remodeling and neo-tissue formation. Collagen I (Col I)-based hydrogel scaffolds, which exhibit chondroinductive properties, have important applications in cartilage tissue engineering. However, Col I hydrogels are susceptible to rapid degradation, thereby limiting their application in tissue engineering. It remains unclear whether the degradation rate of Col I hydrogels influences their chondroinductive capacity. The present research aimed to investigate the effects of degradation rate of Col I hydrogels on the chondrogenic differentiation of mesenchymal stem cells (MSCs). In this work, methacrylated collagen (MC) with varying degrees of substitution (DS) was synthesized by reacting Col I with methacrylic anhydride (MA) and designated as MC10, MC30, MC50 and MC80, respectively. The corresponding collagen-based hydrogels with different degradation rates were fabricated following incubation and photo-crosslinking. Although MA modification did not significantly alter the characteristic conformation of collagen molecules, the density of the internal fiber network within the hydrogels formed by MCs increased with the increase of grafting degree. The degradation rate of MC hydrogels was inversely related to the extent of collagen methacrylation. A higher degree of modification resulted in a lower proliferation rate of MSCs encapsulated within the hydrogels. MSCs were encapsulated in these collagen-based hydrogels and underwent chondrogenesis under both in vitro and in vivo conditions. The degradation rate of collagen-based hydrogels was found to significantly influence both the contraction of hydrogel-MSC constructs and cell proliferation. Both MC10 and MC30 hydrogels, with suitably moderated degradation rates, more efficiently promoted chondrogenic differentiation of MSCs in both in vitro culture and in vivo ectopic implantation models. Furthermore, the degradation kinetics of MC30 hydrogels more closely matched the tempo of in vivo chondrogenesis, and accordingly, MC30 constructs demonstrated enhanced repair capacity in models of in situ cartilage regeneration. Therefore, the degradation rate of collagen-based hydrogels serves as a dynamic cue that influences chondrogenesis by modulating the tissue-inductive capacity of the scaffolds. Thus, precise regulation of scaffold degradation rate is essential for the rational design of cartilage tissue engineering scaffolds. Graphical abstract