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

基本信息

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
项目类别：
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

项目摘要

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常常使我们的退伍军人皮肤留下严重的疤痕，疼痛性挛缩，屏障或温度功能受损。可以预防或逆转的新疗法纤维化是迫切需要的。在胎儿伤口之外，原生毛囊、汗腺和脂肪组织，以前被认为是不可能的。最近的工作表明，原则上，非常大的皮肤成年小鼠的伤口可以自发再生新的毛囊和脂肪组织，而小伤口小鼠大面积烧伤伤口的结局与人类临床伤口相同：纤维化疤痕。我们最近发现当我们的创新生物材料微孔退火颗粒 (MAP) 水凝胶时，会激活免疫反应，它可以诱导小鼠小伤口的毛囊再生，否则这些伤口可以通过疤痕。该提案结合了最先进的分子、生物信息学和生物工程技术：1) 提高我们对为什么小鼠烧伤伤口会导致纤维化而大切除伤口会导致纤维化的理解再生; 2) 使用免疫调节 MAP 水凝胶制剂来转化纤维化烧伤创面形成有利于皮肤再生的微环境。该应用将测试我们的假设，即通过工程化免疫调节 MAP 水凝胶来特异性地针对促再生免疫反应并限制导致烧伤创面纤维化的途径，我们可以诱导烧伤伤口非常理想的再生反应。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间通讯，并定义功能丧失突变体负责烧伤伤口纤维化伤口愈合与大面积再生愈合的分子程序单细胞分辨率的切除伤口。第二个目标将测试两种免疫调节 MAP 是否在小切除伤口中再生毛囊的制剂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信网络激活再生。在第三个目标中，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活跃确定在再生伤口中激活的新型抗纤维化策略。拟议的研究意义重大，因为它们将建立新的免疫细胞驱动机制减少纤维化并为开发抗纤维化和/或再生治疗靶点提供机会用于减少烧伤伤口的疤痕。拟议的研究具有创新性，因为它们将建立新的类型的免疫调节生物材料，并启用生物材料触发再生的新范例对烧伤创面组织的反应。未来，这项研究成果将推动下一代的发展—— 产生用于潜在临床用途的免疫调节伤口生物材料。