Guoming Sun

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

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.

Functional neovascularization of biodegradable dextran hydrogels with multiple angiogenic growth factors

Slow vascularization of functional blood limits the transplantation of tissue constructs and the recovery of ischemic and wounded tissues. Despite the widespread investigation of polysaccharide-based hydrogel scaffolds for their therapeutic applications, blood vessel ingrowth into these hydrogel scaffolds remains a challenge. We hypothesized that modifying the properties of biodegradable hydrogel scaffolds with immobilization of multiple angiogenic growth factors (GFs) would induce a rapid proliferation of functional vasculature into the scaffolds. To this end, we remodeled the hydrogel structure by decreasing crosslinking density via reduced degree of substitution of crosslinking groups, which resulted in improved hydrogel properties including reduced rigidity, increased swelling, increased vascular endothelial GF (VEGF) release capability, and facilitated rapid hydrogel disintegration and tissue ingrowth. Immobilizing VEGF in the scaffolds promoted tissue ingrowth and expedited biodegradation. Furthermore, a synergistic effect of multiple angiogenic GFs was established; the coimmobilization of VEGF+ angiopoietin-1, and VEGF+ insulin-like GF+ stromal cell-derived factor-1 induced more and larger blood vessels than any individual GF, while the combination of all GFs dramatically increased the size and number of newly formed functional vessels. Altogether, our data demonstrate that rapid, efficient, and functional neovascularization can be achieved by precisely manipulating hydrogel scaffold properties and immobilizing defined angiogenic GFs.

Functional groups affect physical and biological properties of dextran-based hydrogels

Modification of dextran backbone allows the development of a hydrogel with specific characteristics. To enhance their functionality for tissue-engineered scaffolds, a series of dextran-based macromers was synthesized by incorporating various functional groups, including allyl isocyanate (Dex-AI), ethylamine (Dex-AE), chloroacetic acid (Dex-AC), or maleic-anhydride (Dex-AM) into dextrans. The dextran-based biodegradable hybrid hydrogels are developed by integrating polyethylene glycol diacrylate (PEGDA). To explore the effect of different derivatives on hydrogel properties, three different ratios of Dex/PEGDA are examined: low (20/80), medium (40/60), and high (60/40). Differences in physical and biological properties of the hydrogels are found, including swelling, degradation rate, mechanics, crosslinking density, biocompatibility (in vitro and in vivo), and vascular endothelial growth factor release. The results also indicate that the incorporation of amine groups into dextran gives rise to hydrogels with better biocompatible and release properties. We, therefore, conclude that the incorporation of different functional groups affects the fundamental properties of a dextran-based hydrogel network, and that amine groups are preferred to generate hydrogels for biomedical use.

Vascular regeneration: engineering the stem cell microenvironment

Vascular diseases are a major threat to human health nowadays. While current treatments can cure some vascular diseases, their beneficial effects are only temporary; vascular regeneration holds the promise of permanent, effective treatments for many vascular diseases. Stem cells and endothelial progenitor cells can differentiate into vascular lineages and therefore have the potential to repair vascular systems. However, engineering appropriate microenvironments that will allow cell maturation and delivery remains the major challenge to the successful implementation of this treatment. This review introduces the cells that are being studied for vascular differentiation and regeneration; we then consider recent approaches to engineering microenvironments, including proper signaling cues and biodegradable scaffolds that will guide the development of these cells into vessels suitable for cell-based vascular therapy.

Development of a Biodegradable, Temperature-sensitive Dextran-based Polymer as a Cell-detaching Substrate

A biodegradable, temperature-sensitive dextran-allyl isocyanate-ethylamine (TSDAIE) as a nonenzymatic cell detachment polymeric substrate for human endothelial progenitor cells (EPCs) is developed and examined. The lower critical solution temperature of TSDAIE is determined; its phase transition occurrs at 18 to 22 °C. For EPC culture, cell culture flasks are coated with TSDAIE and type I collagen. The TSDAIE coating enables EPC detachment when the culture is cooled to 4 °C. The concentration of TSDAIE affects EPC attachment, which is thereby used to optimize the concentration of TSDAIE for coating. At the determined optimal concentration, TSDAIE is found to be compatible for use in EPC culture as revealed by cell attachment, spreading, proliferation, and phenotype. Overall, biodegradable TSDAIE shows promise for applications that culture and expand EPCs including vascular regenerative medicine and tissue engineering.

The Integrated Role of Biomaterials and Stem Cells in Vascular Regeneration

A healthy vascular system is essential for maintaining normal blood supply and circulation in the body, while ischemia can lead to limb amputation or even death. Vascular regeneration engineering holds the promise of permanent, effective treatments for many vascular diseases. However, many challenges also remain to bring the therapy to the clinic, as the formation of blood vessels is a complicated process. One major challenge facing vascular engineering is developing the ability to maintain large masses of viable and functional cells during in vitro culture and following their transfer from in vitro conditions into the patient. This chapter introduces the cells being studied for vascular differentiation and regeneration and introduces the biomaterials being investigated for vascular engineering, including their sources, properties, and different scaffold types. We then discuss recent approaches to engineering microenvironments, including proper signaling cues and biodegradable scaffolds that will guide the development of these cells into vessels suitable for cell-based vascular therapy. These functional biomaterials may be used as environments to stimulate the generation of blood vessels, to deliver cells to angiogenic areas of the vasculature, or to promote differentiation from progenitor cells into mature vascular cells.

Engineering Pro‐Regenerative Hydrogels for Scarless Wound Healing

Skin and skin appendages protect the body from harmful environment and prevent internal organs from dehydration. Superficial epidermal wounds usually heal without scarring, however, deep dermal wound healing commonly ends up with nonfunctioning scar formation with substantial loss of skin appendage. Wound healing is one of the most complex dynamic biological processes, during which a cascade of biomolecules combine with stem cell influx and matrix synthesis and synergistically contribute to wound healing at all levels. Although many approaches have been investigated to restore complete skin, the clinically effective therapy is still unavailable and the regeneration of perfect skin still remains a significant challenge. The complete mechanism behind scarless skin regeneration still requires further investigation. Fortunately, recent advancement in regenerative medicine empowers us more than ever to restore tissue in a regenerative manner. Many studies have elucidated and reviewed the contribution of stem cells and growth factors to scarless wound healing. This article focuses on recent advances in scarless wound healing, especially strategies to engineer pro-regenerative scaffolds to restore damaged skin in a regenerative manner.