Improved Dermal Scaffolds for Skin Regeneration

描述（由申请人提供）：已开发皮肤替代品以促进深层皮肤伤口的真皮再生。这些产品的主要局限性包括它们对感染的敏感性、血管生长时间长以及易于从伤口部位剪切。我们的长期目标是改进这些技术，以促进更快、更好的“无疤痕”愈合，更具体地说，是通过加快血管生长到皮肤替代品中，因为这是在伤口可以通过表皮移植物完全闭合之前的限速步骤。趋化因子SDF-1是一种已知的趋化剂，其结合在许多血源性免疫细胞以及几种类型的祖细胞和干细胞上表达的受体CXCR 4。最近的证据表明，在更高的浓度下，SDF-1也可以通过CXCR 4排斥炎症细胞。因此，SDF- 1原则上可以执行双重功能：（a）调节局部炎症反应，和（B）促进循环骨髓源性干细胞和内皮祖细胞的募集，这两者都可以有益于伤口愈合。我们假设局部应用外源性SDF-1可以通过改变CXCR 4表达细胞（包括炎性细胞、内皮祖细胞和其他类型的干/祖细胞）的募集动态来改善皮肤伤口愈合。在拟议的研究中，我们希望进一步表征SDF-1对伤口愈合的影响，以及阐明SDF-1的趋化作用与驱避作用对伤口部位表达CXCR 4的细胞募集动力学的影响。我们的具体目标是：（1）测试SDF-1给药的不同剂量和时间表对炎症和伤口愈合反应动力学的影响，（2）表征SDF-1对循环骨髓来源的细胞迁移到支架材料和伤口部位的影响，和（3）表征SDF-1对伤口部位血管生成和白细胞-内皮相互作用的影响。拟议的研究将阐明SDF-1改善伤口愈合的潜力，并提供机制线索（即炎症减轻和/或干细胞募集）。由于SDF-1是一种具有良好保质期的稳定肽，这些研究将引领下一代伤口敷料和皮肤替代品的发展，帮助伤口更快地愈合，这可以在更大和更临床相关的动物模型（例如猪）以及人类中进行测试和优化。公共卫生相关性：缓慢和不愈合的伤口严重负担美国医疗保健系统。该项目的目标是开发皮肤伤口愈合支架，促进更快，更好的“疤痕”愈合。这些研究将引领下一代伤口敷料和皮肤替代品的发展，帮助伤口更快地愈合，这可以在更大和更临床相关的动物模型（例如猪）以及人类中进行测试和优化。

DESCRIPTION (provided by applicant): Skin substitutes have been developed to promote regeneration of the dermis in deep skin wounds. The main limitations of these products include their susceptibility to infection, lengthy time for blood vessel growth, and being prone to shearing from the wound site. Our long-term goals are to improve these technologies to promote faster and better "scarless" healing, more specifically by expediting blood vessel growth into the skin substitute, as this is a rate-limiting step before the wound can be definitely closed by an epidermal graft. The chemokine SDF-1 is a known chemotactic agent that binds the receptor CXCR4 expressed on many blood-borne immune cells as well as several types of progenitor and stem cells. Recent evidence suggests that, at higher concentrations, SDF-1 can also repel inflammatory cells via CXCR4. Thus, SDF- 1 may in principle perform dual functions: (a) modulate the local inflammatory response, and (b) promote the recruitment of circulating bone marrow-derived stem cells and endothelial progenitors, both of which may be beneficial to wound healing. We hypothesize that local application of exogenous SDF-1 can improve skin wound healing by altering the dynamics of recruitment of CXCR4-expressing cells, including inflammatory cells, endothelial progenitors, and other types of stem/progenitor cells. In the proposed studies, we wish to further characterize the effects of SDF-1 on wound healing, as well as elucidate the impact of chemotactic vs. repellent effects of SDF-1 on the dynamics of recruitment of cells expressing CXCR4 in the wound site. Our specific aims are: (1) To test different doses and schedules of administration of SDF-1 on the dynamics of the inflammatory and wound healing responses, (2) to characterize the effects of SDF-1 on the migration of circulating bone marrow-derived cells into the scaffold material and wound site, and (3) to characterize the effects of SDF-1 on angiogenesis and leukocyte-endothelium interactions in the wound site. The proposed studies will elucidate the potential of SDF-1 to improve wound healing, and provide mechanistic cues (i.e. inflammation reduction and/or stem cell recruitment). Since SDF-1 is a stable peptide with good shelf-life, these studies will lead the way to the next generation of wound dressings and skin substitutes that help wounds heal faster, which could be tested and optimized in a larger and more clinically relevant animal model (e.g. pig), as well as humans. PUBLIC HEALTH RELEVANCE: Slow- and non-healing wounds severely burden the US healthcare system. The goal of this project is to develop skin wound healing scaffolds that promote faster and better "scar"-less healing. These studies will lead the way to the next generation of wound dressings and skin substitutes that help wounds heal faster, which could be tested and optimized in a larger and more clinically relevant animal model (e.g. pig), as well as in humans.