Pro‐Regenerative Hydrogel Restores Scarless Skin during Cutaneous Wound Healing

Abstract

The transformation of fibrotic healing process to regenerative one has great potential to fully restore wounded skin. The M2 macrophage phenotype promotes constructive tissue remodeling and instructs tissue repair in a regenerative manner. It is hypothesized that hydrogels that can establish robustness of endogenous cells to regulate M2 phenotype will promote constructive dermal remodeling. Toward this end, a series of dextran‐based bioabsorbable hydrogels are developed and self‐crosslinkable dextran‐isocyanatoethyl methacrylate‐ethylamine (DexIEME) is identified as the potential scaffold. The initial screening study revealed that DexIEME has superior biocompatibility in varying concentrations. Although DexIEME brings about low proinflammatory responses, it promotes M2 macrophage phenotype. Then the optimized hydrogel formulation is tested for acute skin injuries using both murine and porcine models. Preliminary data demonstrated that the innovative DexIEME hydrogel promotes complete skin regeneration with hair regrowth on pre‐existing scars, while untreated scars remain intact. Preclinical studies further demonstrated that the DexIEME hydrogel regenerated perfect skin during deep porcine wound healing. Overall, the approach to investigate immune‐modulated hydrogels yields pro‐regenerative DexIEME hydrogel, which may lead to greater clinical success in treating deep dermal injury and attenuating scar formation.

ADM Scaffolds Generate a Pro-regenerative Microenvironment During Full-Thickness Cutaneous Wound Healing Through M2 Macrophage Polarization via Lamtor1

“…Our experimental results showed that the ADM scaffolds promoted adipose tissue formation in the newly reconstituted skin (Figure 7D ). A similar phenomenon has been observed in hydrogel-treated acute skin injuries, in which the hydrogel promotes adipose tissue formation (Sun and Sun, 2017 ). Additionally, M2 polarization in ADM scaffold-treated wounds compared with that in saline-treated wounds greatly reduced the acceleration of fibrous encapsulation to approach normal collagen tissue (Figures 7B,E ).…”

Current and Future Perspectives on Skin Tissue Engineering: Key Features of Biomedical Research, Translational Assessment, and Clinical Application

“…The group found that this material induced polarization to an M2‐like phenotype as characterized by both surface marker expression and cytokine production. Similarly, Sun described the use of a dextran‐isocyanatoethylmethacrylate‐ethylamine (DexIEME) hydrogel to stimulate skin regeneration in both porcine and mouse models . This dextran‐based, bioabsorbale hydrogel was also shown to promote healing at pre‐existing scar sites and promote the formation of hair follicles.…”

Skin Tissue Substitutes and Biomaterial Risk Assessment and Testing

“…The use of immunomodulatory biomaterials in an implant localizes immunosuppression to the wound site by removing the need for immunosuppressive drugs while having the potential to further reduce poor cosmetic outcomes. Common strategies in immunomodulation for skin regeneration include macrophage polarization (Sun, 2017 ; Castellano et al, 2018 ), the use of glycosaminoglycans (GAGs) (Bhowmick et al, 2017 ; Pezeshki-Modaress et al, 2017 ), and the use of decellularized matrices (Kuna et al, 2017 ).…”

“…Their sensitivity to stimuli and ubiquity in immune processes makes them a prime target for strategic immunomodulation, with polarization to the M2 type being the goal. For example, dextran-isocyanatoethyl methacrylate-ethylamine (DexIEME) used as a hydrogel scaffold for cutaneous wound healing was shown to be effective in treating both pre-existing scars in mice and deep wounds in porcine animal models by promoting M2 macrophage polarization (Sun, 2017 ). DexIEME first led to differentiation of monocytes into macrophages followed by further polarization of differentiated macrophages to the M2 phenotype in vitro .…”