Development of a dual-responsive injectable GelMA/F127DA hydrogel for enhanced cartilage regeneration in osteoarthritis: Harnessing MMP-triggered and mechanical stress-induced release of therapeutic agents.

Abstract

Osteoarthritis (OA) presents a significant challenge in clinical settings due to the limited self-renewal capability of cartilage tissue. To address this, engineered biomaterials employing biomimetic strategies have been developed to modulate and enhance cell-microenvironment interactions, facilitating cartilage regeneration. Nonetheless, excessive mechanical stress on joint structures can induce inflammatory responses, thereby impeding the process of cartilage repair. In this study, we focus on the OA microenvironment, characterized by the overexpression of matrix metalloproteinases (MMPs), and the mechanical stimuli due to joint movement. We engineered a dual-responsive injectable hydrogel: a blend of MMP-responsive, thermo-sensitive GelMA and mechanically robust, reverse thermo-sensitive F127DA. This hydrogel was designed to deliver TGF-β and KGN in a controlled manner via simple temperature modulation. The hydrophilic properties of GelMA and the hydrophobic nature of F127DA allow for efficient intra-articular delivery of diverse drug types, optimizing their therapeutic effects. Photocrosslinking the hydrogel in situ effectively seals cartilage defects and prevents further degradation. The overexpressed MMP in the OA environment triggers the release of TGF-β, recruiting bone marrow-derived stem cells (BMSCs), while mechanical pressure from joint movements releases KGN, promoting chondrogenic differentiation and mitigating inflammation. In summary, our injectable hydrogel, responsive to both the OA microenvironment and mechanical stress, shows promise in enhancing cartilage regeneration in OA. This approach holds significant potential for advancing the field of OA cartilage tissue engineering.