Hemocompatibility of micropatterned biomaterial surfaces is dependent on topographical feature size

Abstract

Small-diameter synthetic vascular grafts that have improved hemocompatibility and patency remain an unmet clinical need due to thrombosis. A surface modification that has potential to attenuate these failure mechanisms while promoting an endothelial layer is the micropatterning of luminal surfaces. Anisotropic features have been shown to downregulate smooth muscle cell proliferation, direct endothelial migration, and attenuate platelet adhesion and activation. However, the effect of micropatterning feature size and orientation relative to whole blood flow has yet to be investigated within a systematic study. In this work, hemocompatibility of micropattern grating sizes of 2, 5, and 10 µm were investigated. The thrombogenicity of the micropattern surface modifications were characterized by quantifying FXIIa activity, fibrin formation, and static platelet adhesion in vitro. Additionally, dynamic platelet attachment and end-point fibrin formation were quantified using an established, flowing whole blood ex vivo non-human primate shunt model without antiplatelet or anticoagulant therapies. We observed a higher trend in platelet attachment and significantly increased fibrin formation for larger features. We then investigated the orientation of 2 µm gratings relative to whole blood flow and found no significant differences between the various orientations for platelet attachment, rate of linear platelet attachment, or end-point fibrin formation. MicroCT analysis of micropatterned grafts was utilized to quantify luminal patency. This work is a significant step in the development of novel synthetic biomaterials with improved understanding of hemocompatibility for use in cardiovascular applications.

Thrombogenicity of biodegradable metals

“…Preclinical work with monoclonal antibodies to FXII and FXI demonstrated a reduction in platelet attachment and thrombosis on nitinol stents under venous and arterial flow conditions [ 35 ]. In this work, the in vitro generation of FXIIa and initiation time of fibrin generation in human plasma were quantified, with in vitro results correlating to the ex vivo work, as was seen with previous biomaterial experiments [ 34 , 35 ]. The generation of FXIIa and reduction in the initiation of fibrin clotting time suggests that the activation of the contact pathway was initiated by all metals except Mg.…”

“…This work characterized the thrombogenicity of pure, biodegradable metals (Fe, Zn, Mg, Mo) and alloys common in clinical cardiovascular devices (NiTi, SS, CoCr), using methods previously validated with other biomaterials [ 34 , 35 ]. These tests included in vitro quantification of FXIIa and the time to initial fibrin formation, representing the activation of the contact and common pathways of coagulation, respectively.…”

“…In vitro testing was performed, based on previous work [ 34 , 35 ], with protocol modifications for the metal wires, described in detail below.…”

Targeting the Contact Pathway of Coagulation for the Prevention and Management of Medical Device-Associated Thrombosis

“…22 23 Substantial efforts have been made to improve the biocompatibility of blood-contacting medical devices, 24 25 26 ranging from methods to control the wettability, 27 28 surface charge, 29 or physical properties. 30 Yet, ultimately, medical devices accumulate plasma proteins and blood cells as part of protein fouling, 31 32 leading to thrombin generation, 15 fibrin formation, 33 blood cell entrapment, and activation. 18 34 This process can result in either catastrophic device failure and systemic thromboembolic or inflammatory events.…”