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