Bioresorbable Mesenchymal Stem Cell–Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation in a Rat Model of Chronic Kidney Disease

In the setting of chronic kidney disease (CKD), the periadventitial injection of mesenchymal stem cells (MSCs) has shown significant potential in improving arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). However, the rapid clearance of MSCs remains a challenge. Hence, we fabricated an electrospun perivascular scaffold from polycaprolactone (PCL) to support MSC attachment and allow gradual MSC elution at the outflow vein, the AVF site most prone to NIH. We performed 5/6th nephrectomy to induce CKD in Sprague-Dawley rats, followed by direct AVF formation and perivascular scaffold application. We then compared the following groups of CKD rats: no perivascular scaffold (i.e., control), PCL scaffold, and PCL+MSC scaffold. On ultrasonography, the PCL and PCL+MSC groups showed significantly reduced wall thickness and wall-to-lumen ratio and increased luminal diameter and flow rate. Of note, PCL+MSC group showed greater improvement in luminal diameter and flow rate compared to PCL alone. Moreover, 18F-fluorodeoxyglucose positron emission tomography showed that only PCL+MSC resulted in a significant reduction in uptake. On histology, the PCL and PCL+MSC groups showed significantly reduced neointima-to-lumen and neointima-to- media ratios and reduced neointimal CD45, α-SMA, and vimentin fluorescence staining compared to control. Although the two scaffold treatments did not differ significantly in histology, in vivo imaging suggested that addition of MSCs promoted greater luminal expansion and blood flow and reduced the inflammatory process underlying NIH. Our results demonstrate the utility of a mechanical support loaded with MSCs at the outflow vein immediately after AVF formation to support maturation by minimizing NIH. TRANSLATIONAL STATEMENT Current strategies to improve rates of arteriovenous fistula (AVF) maturation by minimizing neointimal hyperplasia (NIH) remain insufficient. Here, we pioneered a bioresorbable electrospun polymeric scaffold to deliver mesenchymal stem cells (MSCs) to the outflow vein, the site most prone to NIH in AVFs. This approach increased luminal diameter and flow rate and decreased inflammation and neointimal thickening, as seen on ultrasonography, 18F-FDG-PET, and histology. This study provides a foundation for the development and clinical use of MSC-seeded perivascular scaffolds that could improve AVF patency outcomes, reduce salvage interventions, and eventually reduce morbidity and mortality associated with vascular access failure.