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

项目摘要/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。在众多的 血管通路的类型，动静脉瘘(AVF)是首选，因为它具有更好的通畅率和更少的通畅率 比其他通道类型更复杂。然而，AVF的原发衰竭阻碍AVF成熟仍然是一种 这是一个常见的问题，增加了患者的发病率和死亡率。新生内膜增生症(NIH)已被 被确定为AVF失败的主要病理生理学罪魁祸首之一。因此，提高了AVF的成熟度， 减少NIH，优化成像以准确诊断和定位NIH损伤也是至关重要的 了解失败的机制，以便进行治疗干预。 基于我们的初步数据，我们建议开发新型的、可吸收的、具有不同种类的聚合物支架 物理化学性质，可以包裹在AVF周围以提供结构支撑，并且可以 装载多功能光声(PA)和计算机断层扫描(CT)活性纳米颗粒(TO (促进成像)和间充质干细胞(MSCs)(用于减轻炎症和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的动物模型的安全性和有效性。此外，我们还将评估 使用超声(US)和PA成像，结合正电子发射断层扫描(PET)成像 监测炎症和动静脉动静脉瘘成熟的技术。我们假设这一治疗策略曾经 局部持续给药将增加AVF中的浓度，而不会产生全身毒性， 以及提供结构支撑以增强向外重塑。我们将从三个具体的方面来检验这一假设 目的：1)开发一种含有纳米颗粒和间充质干细胞的可生物降解的聚合物支架以减轻炎症 2)评估用于监测的各种成像技术 动静脉动静脉瘘的成熟度和完整性，以及3)评估以下的生理、放射和病理变化 基因工程聚合物植入大鼠和猪医源性动静脉瘘周围的外膜组织 模特们。 提出的工作具有重要的意义和创新性，因为物理化学的逐步优化 聚合物支架的性能将改善AVF的结构，以及传递和保持 骨髓间充质干细胞，可提高终末期血液透析患者的动静脉瘘成熟率和通畅率。 这项工作的成功完成将有助于我们了解糖尿病的发病机制。 未成熟的血管紧张素转换因子，以及负载MSCs的聚合物支架是否能调节NIH。此外， US/PA和PET/CT联合成像的发展将不仅阐明炎症的作用，而且还将 AVF成熟/未成熟的其他目标，用于潜在的药物和/或设备开发。

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.