Dual dynamic cross-linked self-healing chitosan-based hydrogels for microenvironmental reconstruction maintaining mitochondrial homeostasis to ameliorate tendinopathy progression.

Tendinopathy is a disease of the musculoskeletal system resulting from excessive or abnormal mechanical loading of tendons. Reconstruction of disorganized fibers remains a preceding issue and challenge in sports medicine. Therefore, developing novel delivery systems to promote regeneration after tendinopathy is imminently desired. A dual-dynamic crosslinked framework was constructed here through ligand bonds created between the amino or carboxyl groups in gelatin and Fe3+, as well as hydrogen-binding between gelatin and curcumin-grafted carboxymethyl chitosan (CMCS). Scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS) analyses indicated that the iron was uniformly distributed in the porosity structure. G-CM@Cur/Fe system combines excellent adhesion, sustained drug release, and anti-inflammatory properties, enabling responsive degradation in the injury area of tendons for the on-demand release of curcumin. Stained slices indicated the 2-week intervention reduced the Bonar score in tendinopathy by approximately 61.7 %. The G-CM@Cur/Fe exhibits reduced inflammation and ordered collagen fibers alignment. In this study, a multifunctional hydrogel was designed to sustain curcumin release and support mitochondrial homeostasis and immune microenvironment remodeling, providing a potential therapeutic approach for tendinopathy.