# 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.

## Key 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.

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