Immunomodulatory biomaterials for regenerative healing of burn wounds

用于烧伤创面再生愈合的免疫调节生物材料

• 批准号: 10480614
• 负责人: PHILIP SCUMPIA
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480614
• 关键词: Ablation; Acceleration; Adipose tissue; Adult; Biocompatible Materials; Bioinformatics; Biology; Biomedical Engineering; Burn injury; Cell Communication; Cells; Characteristics; Cicatrix; Clinical; Communication; Contracture; Cosmetics; Data; Data Set; Deposition; Dermis; Development; Engineering; Equilibrium; Excision; Extracellular Matrix; Fibroblasts; Fibrosis; Formulation; Functional disorder; Future; Genetic; Grant; Hair; Hair follicle structure; Histology; Human; Hydrogels; Immune; Immune response; Immune signaling; Immunology; Impairment; Inflammation; Inflammatory; Knowledge; Ligands; Macrophage; Mammals; Methodology; Microscopy; Military Personnel; Modality; Modeling; Molecular; Molecular Profiling; Mus; Natural regeneration; Neomycin resistance gene; Pain; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Population; Porosity; Postoperative Period; Receptor Activation; Receptor Signaling; Regenerative capacity; Regenerative response; Resolution; Role; SHH gene; Science; Sebaceous Glands; Series; Signal Pathway; Signal Transduction; Skin; Speed; Structure; Sweat Glands; T-Lymphocyte; Techniques; Temperature; Testing; Tissues; Transgenic Organisms; Translating; Veterans; Work; Wound models; acute wound; adaptive immune response; beta catenin; bioscaffold; burn therapy; burn wound; combat; experimental study; fetal; hair regeneration; healing; immunoregulation; improved; innovation; loss of function; microbiome; mouse model; mutant; next generation; novel; novel therapeutics; overexpression; particle; prevent; programs; receptor; regeneration function; regenerative; single-cell RNA sequencing; skin barrier; skin regeneration; skin wound; targeted treatment; therapy outcome; tissue regeneration; transcriptomics; translational model; wound; wound care; wound closure; wound healing; wound treatment

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.

在战斗中，我们的军事人员烧伤经常给我们的退伍军人留下严重的皮肤疤痕， 疼痛性挛缩，屏障或温度功能受损。可以预防或逆转 纤维化是迫切需要的。在胎儿伤口外，天然毛囊、汗腺和 脂肪组织，这在以前被认为是不可能的。最近的研究表明，原则上， 成年小鼠的伤口可以自发地再生新的毛囊和脂肪组织，而小的伤口， 或小鼠的大面积烧伤伤口与人类临床伤口的结局相同：纤维化瘢痕。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，它可以诱导毛囊再生的小老鼠伤口，否则将愈合， 疤痕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： 提高我们对小鼠烧伤伤口导致纤维化而大切除伤口导致纤维化原因的理解， 再生;和2）使用免疫调节MAP水凝胶制剂来转化纤维化烧伤伤口 微环境转化为一个有利于皮肤再生。 该应用将测试我们的假设，即通过工程化免疫调节MAP水凝胶， 针对促再生免疫应答和限制导致烧伤伤口纤维化途径，我们可以诱导 在烧伤伤口中高度期望的再生反应。第一个目标将利用单细胞转录组学， 一种新的生物信息学方法来评估细胞与细胞的通讯，以及功能突变体的丧失， 烧伤创面纤维化愈合与再生愈合的分子程序 单细胞分辨率的切除伤口。第二个目的将测试两种免疫调节MAP是否 在小的切除伤口中再生毛囊的配方可以将免疫细胞重新编程为成纤维细胞 通信网络在烧伤创面微环境中激活再生。第三个目标，我们将 证实小鼠纤维化中的免疫和成纤维细胞信号网络在人类烧伤伤口中是活跃的， 鉴定在再生伤口中激活的新的抗纤维化策略。 这些研究具有重要意义，因为它们将建立新的免疫细胞驱动机制， 减少纤维化，并提供开发用于治疗的抗纤维化和/或促再生靶点的机会 用于减少烧伤伤口的疤痕。拟议的研究是创新的，因为它们将建立新的 类型的免疫调节生物材料，并使生物材料触发再生的新范例， 对烧伤创面组织的反应。在未来，这项研究的结果将推动下一个发展- 产生用于潜在临床用途的免疫调节伤口生物材料。