Exosome-Loaded GelMA Hydrogel as a Cell-Free Therapeutic Strategy for Hypertrophic Scar Inhibition

Hui Wang,1,2 Xijuan Gao,2 Yanxia Zhao,2 Shudong Sun,2 Yuxiu Liu,1 Kun Wang2 1School of Nursing, Shandong Second Medical University, Weifang, People’s Republic of China; 2Department of Burns and Wound Repair, Weifang People’s Hospital, Shandong Second Medical University, Weifang, People’s Republic of ChinaCorrespondence: Yuxiu Liu, School of Nursing, Shandong Second Medical University, Weifang, People’s Republic of China, Email [email protected] Kun Wang, Department of Burns and Wound Repair, Weifang People’s Hospital, Shandong Second Medical University, Weifang, People’s Republic of China, Email [email protected]: Hypertrophic scar (HS) is a fibrotic proliferative disorder that arises from an abnormal wound healing process. It is a significant clinical challenge, primarily characterized by the excessive accumulation of extracellular matrix (ECM) and abnormal angiogenesis. This study introduces a novel injectable hydrogel system that integrates sustained-release Exosomes for targeted hypertrophic scar modulation. Exosomes (Exos) from adipose-derived stem cells (ASCs) are emerging as promising treatment for hypertrophic scar inhibition. But when treated independently, it must be applied regularly multiple times to maintain its optimal concentration. Gelatin Methacryloyl (GelMA) hydrogel is an ideal biomaterial candidate for engineering skin tissues because of its similarity to ECM, and importantly GelMA hydrogel can maintain drug concentrations via the encapsulation and sustained release of it, which enhances the potential of clinical applications.Methods: The Exosome-Loaded GelMA Hydrogel (Exos-GelMA) hydrogel was fabricated and characterized for its pore size and biocompatibility. A rabbit ear HS model was established. Three skin defects on each ear were treated with GelMA hydrogel, Exos-GelMA hydrogel, or left untreated as a blank group. The effects of HS inhibition were assessed through Hematoxylin and Eosin (HE) staining, Masson’s trichrome staining, and immunohistochemical staining of Collagen I (COL I), Collagen III (COL III), α-smooth muscle actin (α-SMA), as well as immunofluorescence staining of vascular endothelial growth factor (VEGF).Results: The Exos-GelMA hydrogel demonstrated an appropriate pore size distribution, excellent biocompatibility, and enhanced fibroblast proliferation in vitro. In the rabbit ear HS model, the Exos-GelMA hydrogel significantly inhibited excessive collagen fiber deposition and the overexpression of the angiogenic factor VEGF. Quantitative analysis of immunohistochemical and immunofluorescence staining showed comparing to blank group the Exos-GelMA hydrogel significantly reduced COL I deposition by 43%, COL III deposition by 15%, α-SMA expression by 31%, and VEGF expression by 35% at 28 day.Conclusion: In summary, the Exos-GelMA composite hydrogel exhibits significant potential for the prevention and treatment of HS. This study supports the feasibility of Exos-GelMA as a cell-free therapeutic approach for the management of HS.Keywords: hypertrophic scar, ADSC-exosomes, GelMA hydrogel, collagen, angiogenesis, cell-free therapy