Restoring tendon microenvironment in tendinopathy: Macrophage modulation and tendon regeneration with injectable tendon hydrogel and tendon-derived stem cells exosomes

Tendinopathy is a common musculoskeletal disorder in which a significant number of patients do not attain effective therapeutic outcomes. The extent of the inflammatory response and the dynamics of collagen synthesis metabolism are critical factors that influence the intrinsic self-repair capacity of tendons. However, the poor microenvironment within the tendon significantly impedes the self-repair process in tendinopathy. In this study, an injectable tendon-derived decellularized extracellular matrix (tdECM) hydrogel was utilized to treat tendinopathy. This hydrogel provides a more cytocompatible microenvironment while retaining certain bioactive factors of native tendon extracellular matrix (ECM), compared to collagen hydrogel. Notably, it was discovered for the first time that the tdECM hydrogel promotes M2 macrophage polarization, thereby exerting an antiinflammatory effect in vivo. Furthermore, utilizing tdECM as a carrier for the sustained release of tendonderived stem cells exosomes (TDSCs-Exos), our findings from both in vitro and in vivo studies indicate that the tdECM hydrogel, in conjunction with exosomes, demonstrated a pronounced synergistic enhancement in modulating inflammation, promoting M2 macrophage polarization, and facilitating tendon regeneration and repair efficacy. These results suggest its potential as a promising therapeutic strategy for tendon disorders.