Hydrogel encapsulation of a tissue repair protein to treat chronic wounds

项目总结 伤口护理是对公共卫生的一大挑战，由于日益增加的负担，负担正在迅速增长 医疗费用、人口老龄化以及糖尿病和糖尿病等疾病发病率的急剧上升 导致伤口愈合不良的肥胖。虽然多种因素可能会导致并发症 与伤口愈合有关，受损的组织修复是无法愈合的潜在原因 伤口。研究小组最近的一系列研究发现了一种新的TRIM家族蛋白，名为 MG53作为细胞膜修复机的重要组成部分。在这里，我们提供证据，证明 MG53是伤口愈合重要组成部分，局部应用重组人(Rh)MG53 蛋白质具有促进慢性伤口愈合的潜力。MG53能够使膜成核 角质形成细胞中的修复机制，从而保护表皮损伤。MG53出现在 细胞外液可以促进成纤维细胞在划痕伤后的迁移，从而有助于 有效的伤口闭合再上皮化。此外，我们发现了一个新的发现，循环MG53与 伤口闭合的慢性和重塑阶段上皮干细胞的接触。而当 上皮干细胞不表达内源性MG53蛋白，它们可以从循环中摄取MG53 对皮肤损伤的反应。重组人MG53的治疗效果将取决于配方和 交付MG53的方法。MG53直接给药到伤口处，间接给药 血管内注射是可能的方法，但由于MG53在体内的半衰期较短，因此疗效较低。 血液循环。重要的是，我们开发了一种适当的配方，以持续地将rhMG53输送到 以提高治疗效果。这个项目的目标是测试MG53的假设 通过增强细胞膜修复和上皮干细胞功能，促进慢性伤口的愈合；以及 重组人MG53水凝胶制剂是一种有效的皮肤创面愈合方法。三个具体目标 建议：a)阐明MG53的S在伤口愈合中的作用机制(目标1)；b)发展 以水凝胶为基础的重组人MG53治疗皮肤创伤(目标2)；以及c)进行概念验证研究 用于慢性创面愈合的rhMG53/水凝胶(目标3)。应推进这些研究的落实工作 我们对MG53在伤口愈合中的生物学知识的了解，并为MG53的翻译应用奠定了基础 重组人粒细胞集落刺激因子53治疗老年慢性创面

PROJECT SUMMARY Wound care is a major challenge to the public health, and the burden is rapidly growing due to increasing health care costs, an aging population and a sharp rise in the incidence of disease such as diabetes and obesity that contribute to poor wound healing. While multiple factors may contribute to complications associated with wound healing, compromised tissue repair represents an underlying cause for non-healing wounds. A recent series of studies by the investigator’s team identified a novel TRIM family protein named MG53 as an essential component of the cell membrane repair machinery. Here we provide evidence that MG53 is a vital component of wound healing and that topical application of recombinant human (rh)MG53 protein has potential to promote healing of chronic wounds. MG53 is capable of nucleating the membrane repair machinery in keratinocytes, therefore protecting injuries to the epidermis. MG53 present in the extracellular solution can facilitate migration of fibroblasts in response to scratch wounding, thus contributing to efficient reepithelization of wound closure. Moreover, we made a novel finding that links circulating MG53 to the engagement of epithelial stem cells during the chronic and remodeling phase of wound closure. While epithelial stem cells do not express endogenous MG53 protein, they can take up MG53 from circulation in response to dermal injury. Therapeutic efficacy of rhMG53 will depend on the formulation as well as the approaches of delivering MG53. Direct administration of MG53 to the wound site and indirect delivery by intravascular injection are possible approaches, but will have low efficacy due to the short half-life of MG53 in blood circulation. It is important that we develop a proper formulation for sustained delivery of rhMG53 to the wound site in order to enhance therapeutic efficacy. The goal of this project is to test the hypothesis that MG53 facilitates healing of chronic wounds by enhancing cell membrane repair and epithelial stem cell function, and hydrogel formulation of rhMG53 represents an effective means for dermal wound healing. Three specific aims are proposed: a) elucidate the mechanisms that underlie MG53’s function in wound healing (Aim 1); b) develop hydrogel-based delivery of rhMG53 to treat dermal wound (Aim 2); and c) conduct proof-of-concept study on rhMG53/hydrogel for chronic wound healing application (Aim 3). Fulfillment of these studies should advance our knowledge on the biology of MG53 in wound healing and lay the foundation for translational application of rhMG53 in treating chronic wounds in the elderly population.