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.

项目总结 在美国，外周动脉疾病(PAD)影响着800-1000万人。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令人振奋的结果。生物材料的使用 用于加强治疗或作为独立治疗的矩阵才刚刚开始在小范围内进行探索 动物模型，有希望的发现表明，生物材料策略可以增强PAD的疗效 肌内细胞疗法在治疗小腿缺血中的作用有一些重要的要求是最优的 生物工程复合材料在机械、组织学和组织学中的传递、保持和性能 垫腿的生物化学动态肌肉内环境。材料应：(A)经过最低限度的 目标组织内一次肿胀；(B)具有适当的机械性能，具有较高的耐受性 肌肉收缩过程中的反复压缩应变，使其长期保持在肌肉内；(C)多孔 足以促进营养因子与周围环境的交换，并允许招募 以及(D)具有抗氧化和血管生成特性，可 有利于PAD肌病的治疗。 本提案的目的是描述和优化一种基于生物材料的PAD治疗方法。我们 最近开发了一种可注射的、血管生成的纳米纤维-水凝胶复合材料，具有独特的界面结合 在水凝胶基质和纤维之间，并成功地将该复合材料应用于再生 兔软组织缺损模型。我们对水凝胶进行了进一步的改性，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。在大鼠模型上进行试验 PAD，水凝胶减少了脂肪氧化，增强了肌肉的局部血液流动，改善了跑步 治疗组大鼠的容量。此外，我们还建立并验证了猪后肢缺血模型。 (髂股动脉结扎/切除)，它概括了人类病理生理学的关键方面 PAD/跛行，并可作为PAD治疗方法开发的平台。我们现在做好了开发的准备 并在我们的猪模型上测试我们对PAD的新疗法。 我们已经准备好了所有的工具来解决这个中心假设，即纳米纤维-水凝胶与 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患者的比例。由于对缺血小腿提供局部治疗是预防和改善肌病的关键 本研究将为PAD患者患肢功能的研究提供重要的进展 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，包括与以下相关的骨骼肌和可能的心肌病理 缺血/再灌流、创伤、感染和炎症。