Sequential Release of Small Extracellular Vesicles from Bilayered Thiolated Alginate/Polyethylene Glycol Diacrylate Hydrogels for Scarless Wound Healing

Abstract

Excessive scar formation has adverse physiological and psychological effects on patients; therefore, a therapeutic strategy for rapid wound healing and reduced scar formation is urgently needed. Herein, bilayered thiolated alginate/PEG diacrylate (BSSPD) hydrogels were fabricated for sequential release of small extracellular vesicles (sEVs), which acted in different wound healing phases, to achieve rapid and scarless wound healing. The sEVs secreted by bone marrow derived mesenchymal stem cells (B-sEVs) were released from the lower layer of the hydrogels to promote angiogenesis and collagen deposition by accelerating fibroblast and endothelial cell proliferation and migration during the early inflammation and proliferation phases, while sEVs secreted by miR-29b-3p-enriched bone marrow derived mesenchymal stem cells were released from the upper layer of the hydrogels and suppressed excessive capillary proliferation and collagen deposition during the late proliferation and maturation phases. In a full-thickness skin defect model of rats and rabbit ears, the wound repair rate, angiogenesis, and collagen deposition were evaluated at different time points after treatment with BSSPD loaded with B-sEVs. Interestingly, during the end of the maturation phase in the in vivo model, tissues in the groups treated with BSSPD loaded with sEVs for sequential release (SR-sEVs@BSSPD) exhibited a more uniform vascular structure distribution, more regular collagen arrangement, and lower volume of hyperplastic scar tissue than tissues in the other groups. Hence, SR-sEVs@BSSPD based on skin repair phases was successfully designed and has considerable potential as a cell-free therapy for scarless wound healing.

Treatment of Wound Healing with Sequential Therapy to Accelerate Recovery and Inhibit Scar Hyperplasia: A Case Report

“…However, in the late stage of wound healing, 11 excessive deposition of collagen and extracellular matrix (ECM) originated from extremely alive fibroblasts results in improper scar formation, impairing the original tissue’s functional recovery. 12 , 13 In our case, we employ various treatments to target different wound healing stages to attain the best therapeutic outcome.…”

Rational Design and Preparation of Functional Hydrogels for Skin Wound Healing

“…TGF-β inhibitor was released from the microcapsules by pulse during the late wound healing, resulting in the acceleration of skin wound healing and the inhibition of collagen deposition in wounds and thereby reducing scar formation during wound healing. In addition to TGF-β inhibitors, Shen et al (2021) designed and prepared a double-layer sodium alginate/polyethylene glycol diacrylate hydrogel for the continuous release of extracellular vesicles at different wound healing stages to achieve a rapid wound healing. In the late stage of wound healing, the small extracellular vesicles secreted by miR-29b-3p-enriched bone marrow-derived mesenchymal stem cells were released from the upper layer of the hydrogel, inhibiting the excessive capillary proliferation and collagen deposition.…”

Engineering Polysaccharides for Tissue Repair and Regeneration

“…As wounds dressing, alginate scaffolds can absorb wound exudates, provide moist environment for wounds and reduce bacterial infection, thereby promoting rapid epithelialization and granulation tissue formation. [ 61 ]…”