Covalently conjugated transforming growth factor-β1 in modular chitosan hydrogels for the effective treatment of articular cartilage defects

Abstract

Approaches to control precisely growth factor presentation to a tissue defect in a sustained fashion are of increasing interest for a number of complex tissue engineering applications. Although transforming growth factor beta-1 (TGF-β1) plays a key role in promoting chondrogenesis, the therapeutic use of TGF-β1 is limited by its inherent protein instability, requiring high amounts of the protein that can cause adverse side effects with inefficient cartilage formation. In this work, we have developed strategies to stabilize TGF-β1 signaling in the injectable, visible blue light inducible chitosan (MeGC) hydrogel system for specific use in cartilage regeneration. We successfully modulated delivery of TGF-β1 with reduced burst release in a complex biological environment of serum and cells by covalently conjugating the protein to MeGC hydrogels with preserving type II collagen, one of the major cartilaginous extracellular matrix (ECM) components. The hydrogel system supported cellular condensation and deposition of cartilaginous ECM by encapsulating adipose derived stem cells in vitro. We confirmed further the ability of these TGF-β1 functionalized hydrogel systems to promote cartilage regeneration in challenging healing environments such as in a rat partial-thickness chondral defect model which present a limited source of subchondral bone marrow elements. These results suggest a new injectable delivery modality of therapeutic agents to improve clinical cartilage repair.