Heparin-functionalized polymer graft surface eluting MK2 inhibitory peptide to improve hemocompatibility and anti-neointimal activity

Abstract

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 (82.2% 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.

Therapeutic MK2 inhibition blocks pathological vascular smooth muscle cell phenotype switch

“…JCI Insight 2021;6(19):e142339 https://doi.org/10.1172/jci.insight.142339 of particular importance in the vascular graft treatment setting used herein, in which a single prophylactic treatment was given intraoperatively to provide a therapeutic benefit throughout the graft healing process. Increased cellular uptake and retention make MK2i-NPs the ideal treatment strategy over previously explored methods, such as a heparin-functionalized graft that elutes free MK2i peptide over time (58), which does not have the intracellular bioavailability benefits that come with PPAA complexation. A previous vascular graft study showed the greatest VSMC proliferation and inflammation in the first week after surgery, which waned thereafter (47), highlighting a critical window through which intraoperative vascular treatments must be retained as the vascular graft heals.…”

“…MK2i-NPs are a flexible and potent alternative to drug-eluting stents or balloons for delivery of compounds targeting IH. One important study described surface-based delivery of peptide from a synthetic polymer film that could potentially be developed as a vascular graft material ( 58 ). This biomaterial was functionalized with anionic heparin to which the cationic MK2i peptide was electrostatically adhered, allowing slow release of free MK2i peptide from the surface when applied in cultures.…”

Tissue Engineering for Mimics and Modulations of Immune Functions

“…First, heparin, a universal anticoagulant, was immobilized on graft surfaces to reinforce the antithrombotic properties. [ 30–41 ] Heparin interacted with antithrombin III and enhanced inhibition of blood coagulant factors including factor Xa and thrombin, thereby avoiding blood coagulation. [ 42 ] Heparin in multiple layers can be immobilized on ε ‐polycaprolactone (PCL) graft surfaces by combining EDC/NHS coupling and layer‐by‐layer assembly, preventing long‐term thrombus formation.…”

Nanostructure-Enabled and Macromolecule-Grafted Surfaces for Biomedical Applications

“…Graft stenosis and occlusion are a result of neointimal hyperplasia that is caused by smooth muscle cells (SMCs). Even though SMCs are necessary for the structure and the function of the neovessel, its abnormal proliferation can damage the vascular graft [ 102 , 103 ]. Transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF) have shown their ability to suppress the pathway of SMCs in neointimal hyperplasia [ 103 ].…”