Improved Dermal Scaffolds for Skin Regeneration

描述(申请人提供)：皮肤替代物已经被开发出来，以促进深度皮肤伤口真皮的再生。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，以及容易从伤口部位剪切。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，通过加速进入皮肤替代品的血管生长，因为这是一个限速步骤，在伤口可以肯定地通过表皮移植闭合之前。趋化因子SDF-1是一种已知的趋化因子，它与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CXCR4受体结合。最近的证据表明，在较高浓度下，SDF-1也可以通过CXCR4击退炎症细胞。因此，SDF-1原则上可能具有双重功能：(A)调节局部炎症反应，(B)促进循环中的骨髓源性干细胞和内皮祖细胞的招募，这两者都可能有利于伤口的愈合。我们假设局部应用外源性SDF-1可以通过改变表达CXCR4的细胞(包括炎症细胞、内皮祖细胞和其他类型的干/祖细胞)的募集动态来促进皮肤伤口的愈合。在拟议的研究中，我们希望进一步确定SDF-1在伤口愈合中的作用，并阐明SDF-1的趋化和排斥作用对表达CXCR4的细胞在伤口部位募集动力学的影响。我们的具体目标是：(1)测试不同剂量和给药时间对炎症和创面愈合反应的动态影响；(2)研究SDF-1对循环中的骨髓来源细胞向支架材料和创面迁移的影响；(3)研究SDF-1对创面血管生成和白细胞-内皮相互作用的影响。拟议的研究将阐明SDF-1促进伤口愈合的潜力，并提供机制线索(即炎症减轻和/或干细胞募集)。由于SDF-1是一种稳定的多肽，具有良好的保质期，这些研究将引领下一代伤口敷料和皮肤替代品的发展，这些敷料和皮肤替代品可以帮助伤口更快地愈合，可以在更大、更具临床相关性的动物模型(如猪)以及人类中进行测试和优化。与公共卫生相关：缓慢愈合和无法愈合的伤口严重加重了美国医疗体系的负担。该项目的目标是开发皮肤伤口愈合支架，促进更快、更好的无疤痕愈合。这些研究将为下一代帮助伤口更快愈合的创面敷料和皮肤替代品开辟道路，这些材料可以在更大、更具临床相关性的动物模型(如猪)以及人类身上进行测试和优化。

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.