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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，我们的军事人员的烧伤通常会给我们的退伍军人留下严重的皮肤疤痕，