# Early Radial Extracorporeal Shockwave Stimulation on Proximal Tibial Circular Osteotomy Site Enhanced Heterotopic Skin Wound Healing via Small Extracellular Vesicles

## TL;DR

Using shockwave therapy on a tibial bone site improved wound healing in rats through small vesicles that promote healing processes.

## Contribution

This study introduces radial extracorporeal shockwave therapy as a novel method to enhance wound healing via extracellular vesicles.

## Key findings

- Radial extracorporeal shockwave therapy at the tibial osteotomy site accelerated wound healing in rats.
- Small extracellular vesicles released via ATP/P2X7R/p38MAPK pathway modulated macrophage polarization to aid healing.
- Thrombospondin 1 in extracellular vesicles enhanced healing by promoting M2 macrophage polarization.

## Abstract

Wound healing represents a complex biological process necessitating innovative therapeutic approaches, particularly for chronic wounds such as diabetic foot ulcers (DFUs). Inspired by the regenerative effects of tibial bone transport for DFUs, we explored whether radial extracorporeal shockwave therapy (rESWT) at the tibial annular osteotomy site (TOE) could enhance wound healing in rats. We found that TOE accelerated dorsal foot wound healing via small extracellular vesicles (sEV). This sEVs showed strong regenerative effects and modulated macrophage polarizations in vitro and in vivo. Single‐cell sequencing revealed mesenchymal stem cells as the likely sEV source, with rESWT triggering sEV release through ATP/P2X7R/p38MAPK pathway. Proteomic analysis identified five differentially expressed proteins in sEVs, with Thrombospondin 1 (Thbs1)‐enhanced sEVs enhancing wound healing by promoting IL4‐induced M2 macrophage polarization. This innovative approach represents a promising alternative strategy for wound management, with potential for future DFU treatment.

A schematic diagram of the mechanism where small extracellular vesicles mediate the enhancement of heterotopic wound healing by radial extracorporeal shockwave stimulation at a proximal tibial osteotomy site.