Cilostazol-loaded acellular vascular graft for suppressing intimal hyperplasia

Local vascular injury caused by vascular transplantation and endarterectomy causes intimal hyperplasia accompanied by matrix degradation by the matrix metalloproteinase (MMP) and proliferation of acute smooth muscle cells (SMCs) during the wound healing. In small vessels, excessive intimal thickening easily induces graft occlusion, and regulation of these local events is critical for graft patency. Although cilostazol (CLZ) has been investigated in clinical trials as a stenosis-suppressing medicine, strategies targeting the suppression of anastomotic stenosis are insufficient. In this study, we developed CLZ-loaded acellular grafts that respond to MMP using a reprecipitation process. CLZ weighing 112 μg was loaded into an acellular graft (CLZ-Graft) weighing 10 mg via reprecipitation. The loaded CLZ was gradually released via matrix degradation but did not leak without degradation. The SMC phenotype changed to a contracted type and proliferation was suppressed when the SMCs were cultured with the CLZ-Graft lysate. The lysate did not inhibit endothelial cell migration or vasculogenesis. In a rat carotid artery ablation model, the graft diameter decreased to 48 % under control conditions. When the CLZ-Graft was placed around the injured carotid artery in rats, acute stenosis was suppressed to only 31 % and 18 % at two and four weeks, respectively. These results indicated that intimal hyperplasia was effectively suppressed by the local release of CLZ from CLZ-Graft in response to MMP. These findings demonstrate that drug-releasing from the decellularized tissue that responds to MMP is an effective strategy for inhibiting vascular stenosis.