Biodegradable Radiopaque Polymeric Scaffolds Loaded with Mesenchymal Stem Cells for Image-Guided Arteriovenous Fistula Maturation and Long-Term Patency

装载有间充质干细胞的可生物降解的不透射线聚合物支架，用于图像引导动静脉瘘的成熟和长期通畅

• 批准号: 10606532
• 负责人: Marites Pasuelo Melancon
• 金额: $ 41.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606532
• 关键词: Address; Adventitious Tissue; Adverse reactions; Animal Model; Anti-Inflammatory Agents; Arteriovenous fistula; Blood Vessels; CCL2 gene; Catheters; Cells; Chronic Kidney Failure; Clinical Trials; Data; Development; Device or Instrument Development; Devices; Diameter; Dilatation - action; Electrospinning; End stage renal failure; Endothelium; Engineering; Environment; Failure; Family suidae; Goals; Hemodialysis; Histology; Homeostasis; Human; Hyperplasia; Hypoxia; Iatrogenesis; Image; Imaging Techniques; In Vitro; Inflammation; Inflammatory; Legal patent; Lesion; Measures; Mechanics; Mediator; Medical Device; Medical Imaging; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Modeling; Monitor; Morbidity - disease rate; Natural regeneration; Operative Surgical Procedures; Oxygen; Pathogenesis; Pathologic; Patients; Physiological; Polymers; Positron-Emission Tomography; Property; Public Health; Radiology Specialty; Rattus; Recommendation; Research; Role; Safety; Solvents; Source; Stenosis; Stress; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Thick; Thrombosis; Time; Tissues; Toxic effect; Ultrasonography; United States; Uremia; Veins; Venous; Viscosity; Visualization; Work; X-Ray Computed Tomography; accurate diagnosis; arteriovenous graft; biodegradable polymer; cytokine; design; drug development; hemodynamics; image guided; imaging capabilities; imaging modality; implantation; improved; in vivo; innovation; migration; mortality; nanoparticle; non-invasive imaging; non-invasive monitor; novel; novel therapeutic intervention; optoacoustic tomography; photoacoustic imaging; porcine model; prevent; repaired; response; scaffold; shear stress; stem cell delivery; systemic toxicity; treatment strategy; ultrasound; vascular injury

PROJECT SUMMARY/ABSTRACT Complications associated with vascular access for hemodialysis represent one of the most important sources of morbidity among patients with end-stage renal disease (ESRD) in the United States today. Among the various types of vascular access, arteriovenous fistula (AVF) is preferred because it has better patency rates and fewer complications than other access types. However, AVF primary failure impeding AVF maturation remains a common problem and adding to patients’ morbidity and mortality. Neointimal hyperplasia (NIH) has been identified as one of the main pathophysiologic culprits underlying AVF failure. Thus, improving AVF maturation, reducing NIH, and optimizing imaging for accurate diagnosis and localization of NIH lesions are critical, as well as understanding the mechanism of failure, so that therapeutic interventions can be executed. Based on our preliminary data, we propose to develop novel, resorbable polymeric scaffolds with varying physico-chemical properties that can be wrapped around the AVF to offer structural support and that can be loaded with multifunctional, photoacoustic (PA)- and computed tomography (CT)-active nanoparticles (to facilitate imaging) and mesenchymal stem cells (MSCs) (to mitigate inflammation and NIH). We will then test their safety and efficacy in vitro and in vivo using a uremic rat and pig animal models. In addition, we will assess the use of ultrasound (US) and PA imaging, in combination with positron emission tomography (PET) imaging techniques for monitoring inflammation and AVF maturation. We hypothesize that this therapeutic strategy once delivered locally and in a sustained manner, will increase the concentration in the AVF without systemic toxicity, as well as provide structural support to enhance outward remodeling. We will test this hypothesis in three specific aims: 1) develop a biodegradable polymeric scaffold containing nanoparticles and MSCs to mitigate inflammation and subsequent pathologic NIH during AVF maturation, 2) assess various imaging techniques for monitoring AVF maturation and integrity, and 3) assess physiologic, radiologic, and pathologic changes following implantation of the engineered polymer in the peri-adventitial tissue surrounding iatrogenic AVFs in rat and pig models. The proposed work is significant and innovative because the step-by-step optimization of the physico-chemical properties of the polymeric scaffold will improve the structure of the AVF, as well as delivery and retention of MSCs, which would yield improved rates of AVF maturation and patency among ESRD patients on hemodialysis. The successful completion of the proposed work will help us understand the mechanism of the pathogenesis of non-maturing AVFs and whether polymeric scaffolds loaded with MSCs can modulate NIH. Furthermore, the development of combined US/PA and PET/CT imaging will elucidate the role of not only inflammation but also other targets in AVF maturation/non-maturation for potential drug and/or device development.

项目总结/摘要 与血液透析血管通路相关的并发症是最重要的并发症来源之一， 目前，美国终末期肾病（ESRD）患者的发病率。的各种 血管通路类型，动静脉瘘（AVF）是首选，因为它具有更好的通畅率和更少的 比其他接入类型更复杂。然而，阻碍AVF成熟的AVF原发性衰竭仍然是一个潜在的问题。 常见问题，增加患者的发病率和死亡率。新生内膜增生（NIH）已被 被认为是AVF失败的主要病理生理学原因之一。因此，改善AVF成熟， 减少NIH和优化成像以准确诊断和定位NIH病变也至关重要 就像理解失败的机制一样，这样就可以进行治疗干预。 基于我们的初步数据，我们建议开发新的，可吸收的聚合物支架， 物理化学性质，可以包裹在AVF周围，提供结构支撑， 装载有多功能的光声（PA）和计算机断层扫描（CT）活性纳米颗粒（以 促进成像）和间充质干细胞（MSC）（以减轻炎症和NIH）。然后我们将测试 它们在体外和体内使用尿毒症大鼠和猪动物模型的安全性和有效性。此外，我们将评估 使用超声（US）和PA成像，结合正电子发射断层扫描（PET）成像 监测炎症和AVF成熟的技术。我们假设这种治疗策略一旦 以局部和持续的方式输送，将增加AVF中的浓度，而不会产生全身毒性， 并提供结构支撑以增强外部重塑。我们将在三个具体的实验中验证这一假设。 目的：1）开发一种含有纳米颗粒和MSC的可生物降解的聚合物支架，以减轻炎症 以及AVF成熟期间随后的病理性NIH，2）评估用于监测的各种成像技术 AVF成熟和完整性，以及3）评估以下生理、放射学和病理学变化 将工程聚合物植入大鼠和猪医源性AVF周围的外膜周围组织中 模型 本文的工作是有意义的和创新的，因为逐步优化的物理化学 聚合物支架的性质将改善AVF的结构，以及AVF的递送和保留。 骨髓间充质干细胞，这将提高血液透析ESRD患者AVF成熟率和通畅率。 该工作的成功完成将有助于我们更好地了解 未成熟的AVF以及装载有MSC的聚合物支架是否可以调节NIH。而且 联合US/PA和PET/CT成像的发展不仅将阐明炎症的作用， AVF成熟/不成熟中的其他目标，用于潜在的药物和/或器械开发。