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.

Understanding the role of the extracellular matrix (ECM) in vascular morphogenesis has been possible using natural ECMs as in vitro models to study the underlying molecular mechanisms. However, little is known about vascular morphogenesis in synthetic matrices where properties can be tuned toward both the basic understanding of tubulogenesis in modular environments and as a clinically relevant alternative to natural materials for regenerative medicine. We investigated synthetic, tunable hyaluronic acid (HA) hydrogels and determined both the adhesion and degradation parameters that enable human endothelial colony-forming cells ( IntroductionGenerating a functional vascular network can potentially improve treatment for vascular disease and successful organ transplantation. 1 Since their discovery, marrow-derived circulating endothelial progenitor cells (EPCs) have been demonstrated to participate in postnatal vasculogenesis. 2,3 Putative EPCs have been proposed as a potential therapeutic tool for treating vascular disease, either through infusion to the site of vascularization [4][5][6] or via ex vivo expansion to engineer vascularized tissue constructs. [7][8][9] Research has shown that endothelial colony-forming cells (ECFCs), a subtype of EPCs recently identified from circulating adult and human umbilical cord blood, express characteristics of putative EPCs. 10,11 These ECFCs are characterized by robust proliferative potential in forming secondary and tertiary colonies, as well as de novo blood vessel formation in vivo.The complex processes of vascular regeneration and repair require EPCs to break down the extracellular matrix (ECM), migrate, differentiate, and undergo tubulogenesis. In the last decade, our understanding of the role of the ECM in vascular morphogenesis has greatly expanded because of well-defined in vitro angiogenesis models. Such natural ECMs as matrigel, collagen, and fibrin gels have allowed us to study the molecular mechanisms that regulate endothelial cell (EC) tubulogenesis, 12,13 as well as to transplant vascular progenitor cells, such as human embryonic stem (hES) cell-derived ECs, 14 ECFCs, 15 EPCs, and mesenchymal stem cells (MSCs), 8,9,16 to generate vascular networks and in vivo. However, the inherent chemical and physical properties of these natural materials have limited their manipulability for engineering vascularized tissue constructs. Moreover, problems associated with complex purification processes, pathogen transfer, and immunogenicity have hampered their clinical usage. 17 Some have suggested synthetic biomaterials, xeno-free and more clinically relevant for regenerative medicine, as an alternative. 18 Unlike natural ECMs, we can engineer these synthetic biomaterials to provide instructive microenvironments capable of recapitulating complex stages of vascular morphogenesis. 17 Although several studies have attempted to generate vascular network assembly within such synthetic biomaterials in vitro, 19,20 no report to date demonstrates highly controlled vascular morphogenes...

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