Fabrication of hydroxyapatite/chitosan composite hydrogels loaded with exosomes derived from miR-126-3p overexpressed synovial mesenchymal stem cells for diabetic chronic wound healing.

The exploration of an effective diabetic chronic wound healing process still remains a great challenge. Herein, we used gene overexpression technology to obtain synovial mesenchymal stem cells (SMSCs) and the miR-126-3p highly expressed SMSCs (SMSCs-126). The exosomes derived from miR-126-3p overexpressed SMSCs (SMSCs-126-Exos) with a particle size of 85 nm were encapsulated in hydroxyapatite/chitosan (HAP-CS) composite hydrogels (HAP-CS-SMSCs-126-Exos) as wound dressings. The SMSCs-126-Exos, CS and low-crystallinity HAP nanorods with a length of 200 nm and a diameter of 50 nm are uniformly dispersed within the whole composite hydrogel. The HAP-CS-SMSCs-126-Exos possess the controlled release property of SMSCs-126-Exos for at least 6 days. The released SMSCs-126-Exos nanoparticles stimulate the proliferation and migration of human dermal fibroblasts and human dermal microvascular endothelial cells (HMEC-1). At the same time, the migration and capillary-network formation of HMEC-1 are promoted through the activation of MAPK/ERK and PI3K/AKT. In vivo tests demonstrate that the HAP-CS-SMSCs-126-Exos successfully promote wound surface re-epithelialization, accelerate angiogenesis, and expedite collagen maturity due to the presence of HAP, CS and SMSCs-126-Exos. Therefore, the HAP-CS-SMSCs-126-Exos possess great potential application for diabetic chronic wound healing, and especially provide the possibility of using exosomes derived from modified cells as a new approach to bring wonderful functionality and controllability in future chronic wound therapy.