Dextran hydrogel scaffolds enhance angiogenic responses and promote complete skin regeneration during burn wound healing

Abstract

Neovascularization is a critical determinant of wound-healing outcomes for deep burn injuries. We hypothesize that dextran-based hydrogels can serve as instructive scaffolds to promote neovascularization and skin regeneration in third-degree burn wounds. Dextran hydrogels are soft and pliable, offering opportunities to improve the management of burn wound treatment. We first developed a procedure to treat burn wounds on mice with dextran hydrogels. In this procedure, we followed clinical practice of wound excision to remove full-thickness burned skin, and then covered the wound with the dextran hydrogel and a dressing layer. Our procedure allows the hydrogel to remain intact and securely in place during the entire healing period, thus offering opportunities to simplify the management of burn wound treatment. A 3-week comparative study indicated that dextran hydrogel promoted dermal regeneration with complete skin appendages. The hydrogel scaffold facilitated early inflammatory cell infiltration that led to its rapid degradation, promoting the infiltration of angiogenic cells into the healing wounds. Endothelial cells homed into the hydrogel scaffolds to enable neovascularization by day 7, resulting in an increased blood flow significantly greater than treated and untreated controls. By day 21, burn wounds treated with hydrogel developed a mature epithelial structure with hair follicles and sebaceous glands. After 5 weeks of treatment, the hydrogel scaffolds promoted new hair growth and epidermal morphology and thickness similar to normal mouse skin. Collectively, our evidence shows that customized dextran-based hydrogel alone, with no additional growth factors, cytokines, or cells, promoted remarkable neovascularization and skin regeneration and may lead to novel treatments for dermal wounds.

Pro‐Regenerative Hydrogel Restores Scarless Skin during Cutaneous Wound Healing

“…The burn injury was performed as previously reported. [36] Briefly, mice were first anesthetized, then the dorsum was shaved and cleaned with alcohol. A 1.2 cm diameter third degree burn was then generated.…”

“…Our previous work indicated that amine group could also increase the biocompatibility. [40] It is worthy to note that our prior study demonstrated that a dextran-based (Dex-AE/PEGDA,80/20) hydrogel could promote full dermal regeneration with skin appendages on a murine third degree burn injury, [36] but the skin regeneration was incomplete during preclinical studies. [37] In this formula, polyethylene glycol (PEG) was not biodegradable and could also have potentially caused immobilization due to its hydrophilicity, which repels cell infiltration.…”

“…[35][36][37] To examine its regenerative capacity, we assessed DexIEME hydrogels for two desirable applications, including treating pre-existing scars from previous wounds and acute cutaneous wounds (Figure 4). The pre-existing scars or acute wounds may take place from various impairments, including both surgical and traumatic wounds (e.g., incision, burn, and puncture).…”

“…Moreover, treating scarred skins has caused tremendous economic burden. [4] Distinct from the prior model, [36] we first explored its potential in regenerating new skin on pre-existing scarred skin with a murine model ( Figure 5). The scar was first created by a third degree burn ( Figure 5Ai).…”

“…Those biomaterials that have great biocompatibility and can guide macrophages into M2 phenotype are greatly desirable for skin regeneration. Our prior study demonstrated that dextran-allyl isocyanate-ethylamine (Dex-AE) and polyethylene glycol-diacrylate (PEGDA) hydrogel promoted dermal regeneration on a third degree burn injury in mice, [36] but it was unable to regenerate complete skin during preclinical tests. [37] Given the pro-regenerative potential of immune modulating scaffolds for wound healing, we set forth to develop dextran-based bioabsorbable hydrogels that can modu late immune responses by promoting M2 macrophage phenotype, and further attenuating scar formation during cutaneous wound healing.…”