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.

项目概要 外周动脉疾病 (PAD) 影响着美国 8-1000 万人。评估干细胞、生长的临床试验 用于治疗 PAD 的因子或基因治疗系统已显示出一些有希望的结果。生物材料的使用 用于增强治疗或作为独立治疗的基质刚刚开始进行小规模探索 PAD 动物模型，有希望的发现表明生物材料策略可以增强 PAD 的功效 肌内细胞疗法治疗腿部缺血的影响。对于优化有重要的要求 生物工程复合材料在机械、组织学和性能方面的传递、保留和性能 PAD 腿的生化动态肌内环境。该材料应： (a) 经过最少的 一旦进入目标组织就会肿胀； (b) 具有适当的机械性能和高耐受弹性 肌肉收缩时重复压缩应变，使其长期肌内保留； (c) 多孔 足以促进营养因子与周围环境的交换并允许补充 宿主祖细胞和内皮细胞； (d) 具有抗氧化和血管生成特性 有利于 PAD 肌病的治疗。 当前提案的目标是描述和优化基于生物材料的 PAD 治疗方法。我们 最近开发了一种可注射、血管生成、纳米纤维-水凝胶复合材料，具有独特的界面粘合 水凝胶基质和纤维之间，并成功地将复合材料应用于再生 兔子模型中的软组织缺陷。我们进一步修饰了水凝胶，使其具有抗氧化特性 最小的肿胀和优化的机械特性以模仿骨骼肌。在大鼠模型中进行测试 PAD，水凝胶减少脂质氧化，增强肌肉局部血流量，并改善跑步 治疗大鼠的能力。此外，我们还开发并验证了猪后肢缺血模型 （髂股动脉结扎/切除），概括了人类病理生理学的关键方面 PAD/跛行，可以成为开发 PAD 疗法的平台。我们现在准备开发 并在我们的猪模型中测试我们针对 PAD 的新疗法。 我们拥有所有工具来解决以下核心假设：纳米纤维-水凝胶复合材料 优化的机械、血管生成和抗氧化特性将改善血流动力学， 大鼠和猪 PAD 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用于治疗的现成合成复合基质 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肌病至关重要 对于 PAD 患者受影响下肢的表现，这项研究将提供重要的进展 优于目前可用的 PAD 治疗方法。该项目开发的复合材料也可以很容易地 用于治疗其他疾病实体，包括与以下疾病相关的骨骼疾病和可能的心肌疾病 缺血/再灌注、创伤、感染和炎症。