Fibronectin Mimetics and Synergistic Ultrasound Therapy for Wound Healing in Aging

慢性伤口已成为一种“无声的流行病”，影响着全世界2000万人，其中包括5-7人 百万美国人。无法愈合的伤口会给患者带来疼痛和不适，并伴有健康并发症。 从严重感染到截肢到死亡。仅在美国，治疗的医疗费用 据估计，每年慢性创伤的费用为250亿美元，其中大部分费用针对的是年龄超过50岁的成年人。 65岁。细胞与细胞外基质(ECM)形式的纤维连接蛋白(FN)的特异性相互作用 控制伤口修复所必需的广泛功能。细胞外基质FN纤维也可用作机械感觉 组织中的元素，促进内皮细胞骨架重组和血管扩张。因此，恢复 不可愈合创面中ECM FN的功能和结构特性作为一种 有效的治疗方法，刺激和促进老年人的组织修复。交付ECM FN 直接传递给慢性伤口细胞的信号，我们开发了一系列可溶性FN片段，这些片段被设计成模拟 FN的ECM形式。这些重组的“FN基质模拟物”将细胞和组织的功能刺激到类似的或 比ECM FN幅度更大。此外，局部应用FN基质模拟物治疗全层创面。 幼年糖尿病小鼠加速伤口闭合，促进肉芽组织沉积，组织重塑， 以及血运重建。这个项目的目标有三个：(I)推进我们的临床前FN矩阵模拟 用于治疗与衰老有关的慢性伤口；(Ii)利用从这些研究中获得的信息 确定随年龄增长而失调的细胞外基质重塑的机制，以及(Iii)确定协同作用 FN基质模拟物与辅助伤口机械疗法，特别是治疗性超声波的作用。如果 成功后，我们基于FN的ECM疗法将有助于满足对新的创新方法的迫切需求 治疗衰老中的溃疡伤口，并将提供关于衰老中细胞外基质缺陷的新信息，这将 告知设计新的治疗方法。 好了！

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. !