ROS-responsive hydrogel loaded with capsaicin promotes tenogenic differentiation of tendon stem/progenitor cells and enhances tendon injury repair

TL;DR

A ROS-responsive hydrogel loaded with capsaicin helps repair tendon injuries by promoting tendon cell growth and reducing harmful inflammation.

Contribution

A novel ROS-responsive hydrogel loaded with capsaicin is developed to enhance tendon regeneration by modulating TSPC differentiation and inflammation.

Findings

CGT upregulates tenogenic markers and collagen synthesis while downregulating osteogenic markers in TSPCs.

In vivo, CGT promotes orderly collagen regeneration and reduces inflammation and heterotopic ossification in tendon defects.

CGT suppresses the PI3K-AKT-mTOR axis, reducing proinflammatory cytokine secretion.

Abstract

Tendon injury repair remains challenging in sports medicine and orthopedics, partly due to limited endogenous regenerative capacity and sustained low-grade inflammation, which disrupt tendon stem/progenitor cells (TSPCs) homeostasis, impairing tenogenesis and enhancing osteogenesis, leading to complications like heterotopic ossification. Here, we engineered a reactive oxygen species (ROS)-responsive hydrogel loaded with capsaicin (CGT) and explored its role in tendon regeneration. In vitro, under IL-1β-induced inflammatory conditions, CGT ameliorated TSPCs dysfunction by upregulating tenogenic markers (Scx, Tnmd, Mkx) and collagen synthesis, while downregulating osteogenic markers (OCN, Runx-2), reducing ALP activity, and inhibiting calcium nodule formation. Mechanistically, CGT may suppress the PI3K-AKT-mTOR axis, attenuating proinflammatory cytokine secretion (IL-6, TNF-α, IL-1β). In vivo, local injection of CGT alone or with exogenous TSPCs into SD rat Achilles tendon defects promoted orderly collagen regeneration, reduced inflammation, and inhibited heterotopic ossification at 8 weeks postoperatively, with favorable biosafety. Tissue immunostaining suggested CGT enhanced tenogenesis-related and suppressed osteogenesis-related gene expression. These findings preliminarily indicate that CGT may modulate TSPCs differentiation and inflammatory microenvironments via the PI3K-AKT-mTOR axis, supporting tendon regeneration. This study offers insights into functional biomaterial design, with CGT showing potential for tendon injury management.

Image 1

Figures