The leading cause of synthetic graft failure includes thrombotic occlusion and intimal hyperplasia at the site of vascular anastomosis. Herein, we report a co-immobilization strategy of heparin and potent anti-neointimal drug (Mitogen Activated Protein Kinase II inhibitory peptide; MK2i) by using a tyrosinase-catalyzed oxidative reaction for preventing thrombotic occlusion and neointimal formation of synthetic vascular grafts. The binding of heparin–tyramine polymer (HT) onto the polycarprolactone (PCL) surface enhanced blood compatibility with significantly reduced protein absorption (64.7% decrease) and platelet adhesion (85.6% decrease) compared to bare PCL surface. When loading MK2i, 1) the HT depot surface gained high MK2i-loading efficiency through charge-charge interaction, and 2) this depot platform enabled long-term, controlled release over 4 weeks (92–272 μg/mL of MK2i). The released MK2i showed significant inhibitory effects on VSMC migration through down-regulated phosphorylation of target proteins (HSP27 and CREB) associated with intimal hyperplasia. In addition, it was found that the released MK2i infiltrated into the tissue with a cumulative manner in ex vivo human saphenous vein (HSV) model. This present study demonstrates that enzymatically HT-coated surface modification is an effective strategy to induce long-term MK2i release as well as hemocompatibility, thereby improving anti-neointimal activity of synthetic vascular grafts.
Bibliographical noteFunding Information:
This research was funded and supported by AHA GRANT 25890018 , NSF CBET BME 1056046 , NSF DMR BMAT 1506717 , and NIH EB 019509 . This study was also financially supported by the Faculty Research Assistance Program of Yonsei University College of Medicine for 2016 (6-2016-0031) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science , ICT & Future Planning ( 2016M3A9E9941743 , 2015M3A9E2028578 , and 2015M3A9E2028643 ). Frozen sectioning was performed by Vanderbilt Translational Pathology Shared Resource. Fluorescent whole slide imaging of HSV segments was conducted by Digital Histology Shared Resource at Vanderbilt University Medical Center.
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science