Immunomodulatory biomaterials for regenerative healing of burn wounds

在战斗中，我们军事人员的烧伤往往会给我们的退伍军人留下严重的皮肤疤痕， 痛性肌挛缩，伴有屏障或体温功能受损。可以预防或逆转的新疗法 纤维化是迫切需要的。胎儿伤口外，再生天然毛囊、汗腺和 脂肪组织，以前被认为是不可能的。最近的研究表明，原则上，非常大的皮肤 成年小鼠的伤口可以自发地再生新的毛囊和脂肪组织，而小伤口 或者，小鼠的大面积烧伤创面的结局与人类的临床创面相同：纤维性疤痕。我们最近 发现当我们的创新生物材料，微孔退火颗粒(MAP)水凝胶，激活一个 免疫反应，它可以诱导小鼠伤口毛囊再生，否则会愈合 伤痕累累。该提案结合了最先进的分子、生物信息学和生物工程技术，以：1) 提高我们对为什么小鼠烧伤创面导致纤维化，而大面积切除创面导致纤维化的理解 再生；以及2)使用免疫调节MAP水凝胶制剂来转化纤维化烧伤创面 微环境合二为一，有利于皮肤再生。 这一应用将检验我们的假设，通过设计免疫调节MAP水凝胶来特异性地 靶向促再生免疫反应和限制导致烧伤创面纤维化的途径，我们可以诱导 烧伤创面非常理想的再生反应。第一个目标是利用单细胞转录， 一种新的生物信息学方法来评估细胞间的通讯，以及功能突变的丧失来确定 烧伤创面纤维性愈合与大面积再生愈合相关的分子程序 切除伤口以单细胞分辨率显示。第二个目标是测试两个免疫调节图 在小的切除创面再生毛囊的配方可以将免疫细胞重新编程为成纤维细胞 烧伤创面微环境中的通讯网络激活再生。在第三个目标中，我们将 确认小鼠纤维化中的免疫和成纤维细胞信号网络在人烧伤创面中是活跃的 确定在再生伤口中激活的新的抗纤维化策略。 拟议的研究具有重要意义，因为它们将建立新的免疫细胞驱动机制 减少纤维化，为开发抗纤维化和/或促再生的治疗靶点提供机会 用于减少烧伤创面的疤痕。拟议的研究具有创新性，因为它们将建立新的 免疫调节生物材料的类型，并实现生物材料触发再生的新范式 对烧伤创面组织的反应。在未来，这项研究的成果将推动下一步的发展- 产生潜在临床应用的免疫调节创面生物材料。

During combat, burn injuries to our military personnel often leave our Veterans with severely scarred skin, painful contractures, with impaired barrier or temperature function. Novel therapies that can prevent or reverse fibrosis are desperately needed. Outside of fetal wounds, regeneration of native hair follicles, sweat glands, and adipose tissue, was previously thought impossible. Recent work has shown that, in principle, very large skin wounds in adult mice can spontaneously regenerate new hair follicles and adipose tissue, while small wounds or large burn wounds in mice end with the same fate as clinical wounds in humans: fibrotic scarring. We recently discovered that when our innovative biomaterial, Microporous Annealed Particle (MAP) hydrogel, activates an immune response, it can induce hair follicle regeneration in small murine wounds that would otherwise heal by scarring. This proposal combines state-of-the-art molecular, bioinformatic, and bioengineering techniques to: 1) improve our understanding of why burn wounds in mice result in fibrosis while large excisional wounds result in regeneration; and 2) use immunomodulatory MAP hydrogel formulations to transform the fibrotic burn wound microenvironment into one conducive of skin regeneration. This application will test our hypothesis that by engineering immunomodulatory MAP hydrogel to specifically target pro-regenerative immune responses and limit pathways contributing to burn wound fibrosis, we can induce a highly desirable regenerative response in burn wounds. The first aim will leverage single cell transcriptomics, a novel bioinformatics methodology to assess cell to cell communication, and loss of function mutants to define molecular programs responsible for fibrotic wound healing in burn wounds versus regenerative healing in large excisional wounds at single cell resolution. The second aim will test whether two immunomodulatory MAP formulations that regenerate hair follicles in small excisional wounds can reprogram immune cell to fibroblast communication networks in the burn wound microenvironment to activate regeneration. In the third aim, we will confirm that immune and fibroblast signaling networks in murine fibrosis are active in human burn wounds to identify novel anti-fibrotic strategies activated in regenerating wounds. The proposed studies are significant because they will establish new immune cell-driven mechanism for diminishing fibrosis and provide opportunities to develop anti-fibrotic and/or proregenerative targets for therapies for reducing scarring in burn wounds. The proposed studies are innovative because they will establish new types of immune-modulating biomaterials, and enable a new paradigm of biomaterial-triggered regenerative response for burn wounds tissues. In the future, the results of this study will drive the development of next- generation immune-modulating wound biomaterials for potential clinical use.