Immune Modulatory Nanofibers for Skeletal Muscle Reconstruction

用于骨骼肌重建的免疫调节纳米纤维

基本信息

批准号：
9565183
负责人：
Edward A. Botchwey
金额：
$ 39.45万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9565183
关键词：
Address Adoptive Transfer Aging Agonist Anti-Inflammatory Agents Anti-inflammatory Apoptotic Articular Range of Motion Behavior Biocompatible Materials Biological Assay Blood Blood Vessels Caliber Cell Communication Cell Maintenance Cell Proliferation Cells Clinical Defect Deposition Dorsal Skinfold Window Chamber Model Dose Elderly Endothelium Engineering Environmental Risk Factor Exhibits Fiber Fibrosis Flow Cytometry Functional disorder Genetic Models Growth Growth Factor Histologic Human Immune Immune response Immunologics Impaired wound healing Implant Infiltration Inflammation Inflammatory Inflammatory Infiltrate Injury Kinetics Lipids Measures Metabolic Metabolism Microvascular Dysfunction Modeling Mononuclear Morphology Mus Muscle Muscle Fibers Muscle satellite cell Muscular Atrophy Myeloid Cells Neuromuscular Junction Operative Surgical Procedures Outcome Pain Paper Pathologic Processes Patient-Focused Outcomes Phagocytes Pharmaceutical Preparations Pharmacology Polymers Population Pre-Clinical Model Prevention Proteins Publishing RANTES Recovery Recovery of Function Recruitment Activity Recurrence Research Resolution Rest Shoulder Pain Signal Transduction Skeletal Muscle Skeletal muscle injury Source Spatial Distribution Sphingosine-1-Phosphate Receptor Symptoms System TNF gene Therapeutic Time Tissues Trauma Vascularization Work Wound Healing angiogenesis base cost cytokine disability experimental study functional outcomes healing improved in vivo injured innovation liquid chromatography mass spectrometry macrophage monocyte mouse model muscle degeneration nanofiber nerve transection progenitor quadriceps muscle receptor reconstruction regenerative repaired response rotator cuff tear satellite cell scaffold small molecule sphingosine 1-phosphate stem tool

项目摘要

Abstract/Project Summary Severe skeletal muscle trauma resulting from ischemic damage, nerve transection injuries, or volumetric defects is an intractable problem. Dysfunction and disability owing to the latter are an increasingly significant clinical burden. To address this challenge, this proposal seeks to develop biomaterial delivery systems that regulate the micro-environmental factors that harness the pro-regenerative functions of recruited blood monocytes to enhance volumetric muscle healing outcomes. In a pre-clinical model of volumetric muscle loss, we have shown that delivery of immune modulatory small molecules targeted to bioactive lipid receptors increases wound repair macrophages within the injury niche and enhances repair mechanisms such as angiogenesis, matrix deposition, and muscle fiber regrowth. The overall hypothesis for the proposed research is that local pharmacological targeting of sphingosine 1-phosphate (S1P) receptors uniquely recruits Ly6Clo monocytes directly from blood to the injury niche where they serve as biased progenitors of wound healing macrophages within injured muscle. Our specific aims are as follows: Aim 1: To characterize inflammatory infiltrate into the murine spinotrapezius volumetric muscle loss model and immune cell interactions with muscle satellite cells; Aim 2: To assess the impact of local delivery of S1P receptor targeted small molecules from polymer scaffolds on myeloid cell accumulation and behavior after skeletal muscle injury; Aim 3: To evaluate functional outcomes within a critical-sized volumetric defect in the murine quadriceps in response to local delivery of S1P receptor targeted small molecules. As the sequelae of muscle injuries increases at a disproportionate rate with advancing age, the burden of muscle injury on an aging domestic population will be increasingly severe. Thud, mechanisms surrounding the healing of volumetric muscle defects must be elucidated in order to advance translational therapeutics.

摘要/项目摘要缺血性损伤、神经横断损伤或体积损伤导致的严重骨骼肌损伤缺陷是一个棘手的问题。后者造成的功能障碍和残疾日益严重临床负担。为了应对这一挑战，该提案旨在开发生物材料输送系统调节利用募集血液的促再生功能的微环境因素单核细胞可增强体积肌肉的愈合效果。在体积肌肉损失的临床前模型中，我们已经证明，针对生物活性脂质受体的免疫调节小分子的递送增加损伤生态位内的伤口修复巨噬细胞并增强修复机制，例如血管生成、基质沉积和肌纤维再生。拟议研究的总体假设 1-磷酸鞘氨醇 (S1P) 受体的局部药理学靶向独特地招募 Ly6Clo 单核细胞直接从血液到达损伤生态位，在那里它们充当伤口愈合的偏向祖细胞受伤肌肉内的巨噬细胞。我们的具体目标如下：目标 1：表征炎症渗透到小鼠斜方肌体积肌肉损失模型以及免疫细胞与肌肉的相互作用卫星细胞；目标 2：评估局部递送 S1P 受体靶向小分子的影响聚合物支架对骨骼肌损伤后骨髓细胞积累和行为的影响；目标 3：评估小鼠股四头肌临界尺寸体积缺损内的功能结果响应于局部递送S1P受体靶向小分子。随着肌肉损伤后遗症的增加随着年龄的增长，肌肉损伤的比例会不成比例地增加，国内人口老龄化带来的肌肉损伤负担将会增加越来越严重。砰的一声，围绕体积肌肉缺陷愈合的机制必须是阐明以推进转化疗法。