Conformable hyaluronic acid hydrogel delivers adipose-derived stem cells and promotes regeneration of burn injury

Abstract

Injury to the skin from severe burns can cause debilitating physical and psychosocial distress to the patients. Upon healing, deep dermal burns often result in devastating hypertrophic scar formation. For many decades, stem cell-based therapies have shown significant potential in improving wound healing. However, current cell delivery methods are often insufficient to maintain cell viability in a harmful burn wound environment to promote skin regeneration. In this study, we developed an enhanced approach to deliver adipose-derived stem cells (ASCs) for the treatment of burn wounds, using an in-situ-formed hydrogel system comprised of a hyperbranched poly(ethylene glycol) diacrylate (HB-PEGDA) polymer, a commercially available thiol-functionalized hyaluronic acid (HA-SH) and a short RGD peptide. Stable hydrogels with tunable swelling and mechanical properties form within five minutes under physiological conditions via the Michael-type addition reaction. Combining with RGD peptide, as a cell adhesion motif, significantly alters the cellular morphology, enhances cell proliferation, and increases the paracrine activity of angiogenesis and tissue remodeling growth factors and cytokines. Bioluminescence imaging of luciferase⁺ ASCs indicated that the hydrogel protected the implanted cells from the harmful wound environment in burns. Hydrogel-ASC treatment significantly enhanced neovascularization, accelerated wound closure and reduced the scar formation. Our findings suggest that PEG-HA-RGD-based hydrogel provides an effective niche capable of augmenting the regenerative potential of ASCs and promoting burn wound healing. STATEMENT OF SIGNIFICANCE: Burn injury is one of the most devastating injures, and patients suffer from many complications and post-burn scar formation despite modern therapies. Here, we designed a conformable hydrogel-based stem cell delivery platform that allows rapid in-situ gelation upon contact with wounds. Adipose-derived stem cells were encapsulated into a PEG-HA-RGD hydrogels. Introducing of RGD motif significantly improved the cellular morphology, proliferation, and secretion of angiogenesis and remodeling cytokines. A deep second-degree burn murine model was utilized to evaluate in-vivo cell retention and therapeutic effect of the hydrogel-ASC-based therapy on burn wound healing. Our hydrogel remarkably improved ASCs viability in burn wounds and the hydrogel-ASC treatment enhanced the neovascularization, promoted wound closure, and reduced scar formation.

Keywords: Adipose-derived stem cell; Burn; Hyaluronic acid; Injectable hydrogel; Wound healing.