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

Abstract

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.

Gold Nanoparticles for Monitoring of Mesenchymal Stem Cell–Loaded Bioresorbable Polymeric Wraps for Arteriovenous Fistulas

“…We found that PCL+MSC and PCL-Au+MSC AVFs demonstrated an improved wall-to- lumen ratio, a marker of vascular stenosis, compared with AVFs without MSCs in as early as 2 weeks after AVF creation. This is consistent with the results of a prior study, wherein the addition of MSCs to polymeric wrap reduced the AVF wall-to-lumen ratio when compared to polymeric wrap alone at 4 weeks after AVF creation (10). These results highlight the unique role of MSCs in improving AVF maturation.…”

“…We also found that all treatment groups demonstrated improved neointima-to-lumen ratios, a measure of NIH, versus control rats by 8 weeks after AVF creation. Our findings show that the reduction in the neointima-to-lumen ratio by PCL and PCL+MSC treatment versus control seen at 4 weeks after AVF creation in a previous study (10) can be maintained for up to 8 weeks. Moreover, the incorporation of AuNPs did not affect the ability of the wraps to reduce the AVF neointima-to-lumen ratio.…”

“…Prior studies have shown that a mesenchymal stem cell (MSC)–seeded polymeric wrap is capable of reducing neointimal hyperplasia (NIH) and enhancing arteriovenous fistula (AVF) maturation (10). However, the radiolucent nature of the polymeric wrap makes in vivo monitoring of its deployment and structural integrity difficult.…”

“…The resulting solutions were electrospun at 1.0 mL/h and 15 kV using a Spraybase electrospinning system (Avectas, Maynooth, Ireland). Synthesis and characterization of AuNP-infused polymeric wraps, MSC culture and attachment, AVF creation and perivascular wrap application, US, and histological analysis were conducted as described in a prior study (10).…”

“…In a recent study, the perivascular application of mesenchymal stem cell (MSC)–seeded polymeric scaffolds, in the form of wraps sutured around the AVF, was shown to reduce NIH and enhance AVF maturation (10). However, the polymeric wraps’ radiolucency makes in vivo monitoring challenging.…”