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: 10464154
• 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/10464154
• 关键词: Address; Adventitious Tissue; Adverse reactions; Animal Model; Anti-Inflammatory Agents; Arteriovenous fistula; Blood Vessels; CCL2 gene; Caliber; Catheters; Cells; Chronic Kidney Failure; Clinical Trials; Data; Development; Device or Instrument Development; Devices; Dilatation - action; Electrospinning; Emission-Computed Tomography; 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; Lead; Lesion; Measures; Mechanics; Mediator of activation protein; 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; Veins; Venous; Viscosity; Visualization; Work; X-Ray Computed Tomography; accurate diagnosis; arteriovenous graft; base; biodegradable polymer; cytokine; design; drug development; hemodynamics; image guided; 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.

项目概要/摘要 与血液透析血管通路相关的并发症是最重要的来源之一。 当今美国终末期肾病 (ESRD) 患者的发病率。 血管通路类型中，动静脉内瘘（AVF）是首选，因为它具有更好的通畅率和更少的 然而，AVF 原发性失败仍然是阻碍 AVF 成熟的一个因素。 新内膜增生（NIH）已成为常见问题并增加患者的发病率和死亡率。 被认为是 AVF 失败的主要病理生理学罪魁祸首之一，因此，改善 AVF 成熟， 减少 NIH 并优化成像以准确诊断和定位 NIH 病变也至关重要 了解失败的机制，以便可以执行治疗干预措施。 根据我们的初步数据，我们建议开发具有不同性能的新型可吸收聚合物支架 物理化学特性可以包裹在 AVF 周围以提供结构支撑，并且可以 装载有多功能、光声 (PA) 和计算机断层扫描 (CT) 活性纳米粒子（ 促进成像）和间充质干细胞（MSC）（以减轻炎症和 NIH）。 此外，我们将使用尿毒症大鼠和猪动物模型评估其体外和体内的安全性和有效性。 使用超声波 (US) 和 PA 成像，并结合正电子发射断层扫描 (PET) 成像 我们曾经追求过这种治疗策略。 以持续的方式局部递送，将增加 AVF 中的浓度，而不会产生全身毒性， 以及为加强外部重塑提供结构支持，我们将在三个具体方面检验这一假设。 目标：1）开发含有纳米颗粒和间充质干细胞的可生物降解聚合物支架，以减轻炎症 以及随后 AVF 成熟期间的病理性 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 模型。 所提出的工作具有重要意义和创新性，因为物理化学的逐步优化 聚合物支架的特性将改善 AVF 的结构，以及药物的输送和保留 MSCs，这将提高血液透析 ESRD 患者 AVF 的成熟率和通畅率。 该工作的成功完成将有助于我们了解该疾病的发病机制。 未成熟的 AVF 以及装载 MSC 的聚合物支架是否可以调节 NIH。 US/PA 和 PET/CT 联合成像的发展将不仅阐明炎症的作用，而且阐明 AVF 成熟/未成熟的其他目标，用于潜在的药物和/或设备开发。