Endothelial retention and phenotype on carbonized cardiovascular implant surfaces

Abstract

Heart valve disease is an increasing clinical burden for which there is no effective treatment outside of prosthetic replacement. Over the last 20 years, clinicians have increasingly preferred the use of biological prosthetics to mechanical valves despite their superior durability because of the lifelong anticoagulation therapy that is required. Mechanical valve surface engineering has largely focused on being as non-thrombogenic as possible, but despite decades of iteration has had insufficient impact on the anticoagulation burden. In this study, we systematically evaluate the potential for endothelialization of the pyrolytic carbon surface used in mechanical valves. We compared adsorbed adhesion ligand type (collagen I, fibronectin, laminin, and purified adhesion domain fragments GFOGER and FN7-10) and concentration on endothelial adhesion rates and adhesion strength on Medtronic-Hall prosthetic valve surfaces. Regardless of ligand type or concentration, endothelial adhesion strengthening was insufficient for their intended ultra-high shear stress environment. We then hypothesized that microfabricated trenches would reduce shear stress to tolerable levels while maintaining endothelial access to the flow stream, thereby promoting a confluent and anticoagulant endothelial monolayer. Computational fluid dynamics simulations predicted an empirical relationship of channel width, depth, and spacing that would maintain interior surface shear stress within tolerable levels. Endothelial cells seeded to confluence in these channels retained a confluent monolayer when exposed to 600 dynes/cm2 shear stress for 48 hours regardless of applied adhesive ligand. Furthermore, sheared EC expressed a mature anti-coagulant profile, including endothelial nitric oxide synthase (eNOS), VE-cadherin, and significantly downregulated plasminogen activator inhibitor-1 (PAI-1). As a final test, channeled pyrolytic carbon surfaces with confluent EC reduced human platelet adhesion 1000-fold over pyrolytic carbon alone. These results advance a promising biohybrid approach to enable active moderation of local coagulative response in mechanical heart valves, which could significantly extend the utility of this important treatment for heart valve disease.

Tailoring biomaterial surface properties to modulate host-implant interactions: implication in cardiovascular and bone therapy

“…In a recent study, Frendl et al emphasized that endothelial adhesion is not alone sufficient to withstand ultra-high shear stress environment regardless of the adhesive nature, type and concentration of the ligand used on pyrolitic carbon surfaces. This problem was overcome by producing microfabricated trenches on the pyrolitic carbon surfaces that allowed a sensible reduction on the value of shear stress detected by cells, that retained their confluent monolayer when exposed to 600 dyn/cm 2 95 . This approach represents an important advance in the design of biomimetic surfaces that can retain the monolayer of endothelial cells intact when exposed to higher shear stress (Fig 2).…”

“…c) Fluorescent image showing the retention of endothelial cells at 600 dynes/cm 2 after 48 h in culture, d & e) Fluorescent images highlighting the absence of plasminogen activator inhibitor (PAI-1), an activator of fibronolysis in collagen I and fibronectin coated channels respectively under sheared and static conditions. Reprinted with permission from ref 95. Copyright 2014 Elsevier.…”

Current progress in tissue engineering of heart valves: multiscale problems, multiscale solutions

“…29 However, long term survival (>10 years years) range from 60-70%. 28,30 Amongst the newer technologies being explored in mechanical prosthetics are smoother hinge designs to limit blood aggregation and strategies to enable endothelial attachment and survival 31,32 , but it remains to be seen whether the anticoagulation burden can be reduced sufficiently for more widespread indication.…”

Effects of different components of the extracellular matrix on endothelialization

“…Therefore, different strategies are applied to accelerate the endothelialization of biomaterials. Biomimetic surface modifications are regarded as promising approach to stimulate cellular adherence and proliferation at the interface of implant materials [2,4,8,11,13,24,26,28,31]. It was shown that e.g.…”