Fibronectin Mimetics and Synergistic Ultrasound Therapy for Wound Healing in Aging

纤连蛋白模拟物和协同超声治疗促进衰老伤口愈合

基本信息

批准号：
10417157
负责人：
DIANE DALECKI
金额：
$ 33.88万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417157
关键词：
Adjuvant Adult Affect Age Aging American Binding Binding Sites Biological Cell Adhesion Cell Proliferation Cells Cessation of life Chronic Clinical Treatment Clinical effectiveness Collagen Complex Cytoskeletal Modeling Deposition Dermal Diabetes Mellitus Diabetic mouse Direct Costs Effectiveness Elderly Elements Endothelium Engineering Epidemic Event Extracellular Matrix Female Fibronectins Formulation Gender Glycoproteins Goals Granulation Tissue Health Health Care Costs Healthcare Heart Diseases Heparin Binding Impaired healing Impairment Incidence Individual Infection Kidney Malignant Neoplasms Malnutrition Mechanics Molecular Conformation Mus Obesity Pain Pathway interactions Patients Peptides Persons Play Population Process Property Proteins Protomer Recombinants Role Series Signal Transduction Site Skin Skin wound healing Specific qualifier value Structure Therapeutic Thick Tissues Topical application Ulcer Ultrasonic Therapy Varicose Ulcer Vasodilation Venous Wound healing therapy aged analog base care burden chronic ulcer chronic wound comorbidity decubitus ulcer design diabetic ulcer healing human old age (65+)innovation insight limb amputation male mechanical force middle age migration mimetics non-healing wounds pre-clinical response skin ulcer skin wound therapeutic effectiveness therapeutically effective tissue repair ultrasound wound wound bed wound closure wound healing wound response

项目摘要

Chronic wounds have become a `silent epidemic', affecting 20 million people worldwide, including 5-7 million Americans. Non-healing wounds cause pain and discomfort for the patient, with health complications ranging from serious infections to limb amputations to death. In the U.S. alone, health care costs for treating chronic wounds are estimated to be $25 billion annually, with the majority of those costs directed at adults over the age of 65. Specific interactions between cells and the extracellular matrix (ECM) form of fibronectin (FN) control a broad range of functions essential to wound repair. ECM FN fibrils also serve as mechanosensory elements in tissue, facilitating endothelial cytoskeletal reorganization and vasodilation. As such, restoring the functional and structural properties of ECM FN within non-healing wounds holds immense promise as an effective therapeutic approach to stimulate and facilitate tissue repair in older adults. To deliver ECM FN signals directly to cells in chronic wounds, we developed a series of soluble FN fragments engineered to mimic the ECM form of FN. These recombinant “FN matrix mimetics” stimulate cell and tissue functions to a similar or greater extent than ECM FN. Moreover, topical application of FN matrix mimetics to full-thickness wounds in young diabetic mice accelerates wound closure and promotes granulation tissue deposition, tissue remodeling, and revascularization. The goals of this project are three-fold: (i) to advance our pre-clinical FN matrix mimetics to the treatment of chronic wounds associated with aging, (ii) to use information obtained from these studies to identify mechanisms of ECM remodeling that become dysregulated with age, and (iii) to identify synergistic actions of FN matrix mimetics with adjuvant wound mechanotherapies, specifically therapeutic ultrasound. If successful, our ECM FN-based therapies will help to fill a critical need for new and innovative approaches to treat ulcerative wounds in aging, and will provide new information regarding ECM deficiencies in aging that will inform the design of new treatment approaches. !

慢性伤口已成为一种“沉默的流行病”，影响了全球2000万人，其中包括5-7 百万美国人。不愈合的收益会给患者带来疼痛和不适，患有健康并发症从严重的感染到肢体截肢到死亡。仅在美国，医疗保健费用慢性胜利估计每年为250亿美元，其中大多数费用针对成年人 65岁的年龄。细胞与细胞外基质（ECM）形式之间的特异性相互作用（FN）控制伤口修复必不可少的广泛功能。 ECM FN纤维也充当机理组织中的元素，支持内皮细胞骨架的重组和血管舒张。因此，恢复 ECM FN在非污染伤口内的功能和结构特性具有巨大的希望有效的治疗方法刺激和促进老年人的组织修复。提供ECM FN 直接向慢性伤口细胞的信号，我们开发了一系列设计用于模仿的固体FN片段 Fn的ECM形式。这些重组“ FN基质模拟物”刺激细胞和组织的功能比ECM FN更大。此外，局部应用FN矩阵Mimetics在全厚性伤口中的局部应用年轻的糖尿病小鼠会加速伤口闭合并促进组织沉积，组织重塑，和血运重建。该项目的目标是三个方面：（i）推进我们的临床前FN矩阵Mimetics 处理与衰老相关的慢性逻辑逻辑的处理，（ii）使用从这些研究获得的信息识别ECM重塑的机制，这些机制因年龄的失调而失调，并且（iii）识别协同作用 FN基质模拟物具有可调节的伤口机械疗法的作用，特别是治疗性超声。如果成功的基于ECM FN的疗法将有助于满足新的创新方法的关键需求治疗衰老中的溃疡性伤口，并将提供有关衰老中ECM缺陷的新信息告知新治疗方法的设计。呢