Bioengineered Composite for the Treatment of Peripheral Arterial Disease

用于治疗外周动脉疾病的生物工程复合材料

• 批准号: 10639077
• 负责人: Xiaowei Li
• 金额: $ 41.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639077
• 关键词: Address; Affect; Angiogenic Factor; Animal Model; Antioxidants; Arteries; Biochemical; Biocompatible Materials; Biological Assay; Biomedical Engineering; Blood capillaries; Blood flow; Cell Therapy; Cells; Characteristics; Clinical Trials; Defect; Development; Disease; Endothelial Cells; Environment; Excision; Fiber; Functional disorder; Goals; Growth Factor; Guanine Nucleotide Exchange Factors; Hindlimb; Histologic; Histology; Human; Hydrogels; Image; Immunohistochemistry; In Situ; In Vitro; Infection; Inflammation; Injectable; Intermittent Claudication; Intramuscular; Ischemia; Lasers; Leg; Ligation; Limb structure; Lipids; Local Therapy; Lower Extremity; Mechanics; Mediating; Modeling; Muscle; Muscle Contraction; Muscle Fibers; Myocardium; Myopathy; Natural regeneration; Oryctolagus cuniculus; Pathology; Patients; Performance; Perfusion; Peripheral arterial disease; Persons; Physiological; Porosity; Property; Rattus; Reactive Oxygen Species; Recovery; Recovery of Function; Reperfusion Therapy; Reporting; Repression; Running; Skeletal Muscle; Stromal Cell-Derived Factor 1; Swelling; System; Testing; Tissues; Trauma; Vascular Endothelial Growth Factors; Vascularization; Work; angiogenesis; biomaterial compatibility; blood perfusion; claudication; clinically relevant; controlled release; design; gene therapy; hemodynamics; improved; innovation; interfacial; mechanical properties; minimally invasive; nanofiber; novel; novel therapeutics; oxidation; oxidative damage; porcine model; prevent; recruit; resilience; skeletal; soft tissue; stem cells; therapy development; tool; treadmill

PROJECT SUMMARY Peripheral artery disease (PAD) affects 8-10 million people in the US. Clinical trials evaluating stem cell, growth factor, or gene therapy systems for the treatment of PAD have shown some promising results. Use of biomaterial matrices either to enhance therapies or as a standalone treatment are just beginning to be explored in small animal models of PAD, with promising findings indicating that a biomaterial strategy can enhance the efficacy of intramuscular cell therapies in treating the effects of leg ischemia. There are important requirements for optimal delivery, retention, and performance of a bioengineered composite in the mechanically, histologically, and biochemically dynamic intramuscular environment of the PAD leg. The material should: (a) undergo minimal swelling once inside the target tissue; (b) have proper mechanical properties with high resilience to tolerate repeated compressive strain during muscle contraction for its long-term intramuscular retention; (c) be porous enough to facilitate the exchange of trophic factors with the surrounding environment and to permit recruitment of host progenitor and endothelial cells; and (d) have antioxidative and angiogenic properties that can be beneficial to the management of the myopathy of PAD. The objective of the current proposal is to characterize and optimize a biomaterial-based treatment for PAD. We have recently developed an injectable, angiogenic, nanofiber-hydrogel composite with unique interfacial bonding between the hydrogel matrices and the fibers, and successfully applied the composite for the regeneration of soft tissue defects in a rabbit model. We have further modified the hydrogel to have antioxidant properties with minimal swelling and optimized mechanical characteristics to mimic skeletal muscle. Testing in a rat model of PAD, the hydrogel reduced lipid oxidation, enhanced local blood flow in the muscle, and improved running capacity of the treated rats. In addition, we have developed and validated a porcine model of hindlimb ischemia (iliofemoral artery ligation/excision), which recapitulates key aspects of the pathophysiology of human PAD/claudication and can be a platform for the development of therapies for PAD. We are now primed to develop and test our novel therapies for PAD in our porcine model. We have all of the tools in place to address the central hypothesis that a nanofiber-hydrogel composite with optimized mechanical, angiogenic, and antioxidative characteristics will improve hemodynamic, histologic, and physiological endpoints of the ischemic hindlimb in rat and porcine models of PAD. Successful completion of this project will deliver the first off-the-shelf synthetic composite matrix for the treatment of PAD patients. As providing local therapy for the ischemic leg is critical to prevent myopathy and to improve the performance of the affected lower limbs in PAD patients, this study will provide an important advancement over other currently available treatments for PAD. The composite developed in this project can also be readily applied to treat other disease entities, including skeletal and possibly heart muscle pathologies related to ischemia/reperfusion, trauma, infection, and inflammation.

项目摘要 外周动脉疾病（PAD）影响美国800 - 1000万人。评价干细胞生长的临床试验 用于治疗PAD的因子或基因治疗系统已经显示出一些有希望的结果。生物材料的使用 矩阵无论是加强治疗或作为一个独立的治疗刚刚开始探索，在小 PAD的动物模型，有希望的发现表明，生物材料策略可以提高 肌内细胞疗法治疗腿部缺血的影响。有重要的要求，最佳 生物工程复合材料在机械、组织学和 PAD腿的生化动态肌内环境。材料应：（a）经受最小的 （B）具有适当的机械性能，具有高弹性以耐受 在肌肉收缩过程中反复压缩应变，以便长期肌内保留;（c）多孔 足以促进营养因子与周围环境的交换并允许补充 和（d）具有抗氧化和血管生成特性， 有利于PAD肌病的治疗。 当前提案的目的是表征和优化PAD的生物材料治疗。我们 最近开发了一种具有独特界面结合的可注射的、血管生成的纳米纤维-水凝胶复合材料 之间的水凝胶基质和纤维，并成功地应用于再生的复合材料， 软组织缺损的兔模型。我们进一步修改了水凝胶，使其具有抗氧化性能， 最小的肿胀和优化的机械特性，以模拟骨骼肌。在大鼠模型中测试 水凝胶PAD减少了脂质氧化，增强了肌肉中的局部血液流动，并改善了跑步 处理大鼠的能力。此外，我们还建立了猪后肢缺血模型，并对其进行了验证 （髂股动脉结扎/切除），其概括了人类肿瘤的病理生理学的关键方面。 PAD/跛行，可以成为PAD治疗开发的平台。我们现在准备开发 并在猪模型中测试我们的PAD新疗法。 我们有所有的工具来解决中心假设，即纳米纤维-水凝胶复合材料与 优化的机械、血管生成和抗氧化特性将改善血液动力学， PAD大鼠和猪模型中缺血后肢的组织学和生理学终点。 该项目的成功完成将提供第一个现成的合成复合基质的治疗 PAD患者。因为为缺血性腿部提供局部治疗对于预防肌病和改善 PAD患者受累下肢的表现，这项研究将提供一个重要的进步 而不是其他目前可用的PAD治疗方法。在这个项目中开发的复合材料也可以很容易地 应用于治疗其他疾病实体，包括骨骼和可能的心肌病理学相关的 缺血/再灌注、创伤、感染和炎症。