Modulating Thrombogenicity Through Nanoscale Surface Topography
Barbara S. Smith and Ketul C. Popat
School of Biomedical Engineering, Colorado State University, Fort Collins, CO 80523
The exposure of implants to blood introduces serious and ongoing concerns regarding poor blood-biomaterial interactions. To date, all blood-contacting devices have been shown to initiate immunological events in the form of inflammation, thrombosis, fibrosis and infection; potentially leading to complete implant failure. Titanium and titanium-based alloys are among the most widely used materials for implants such as cardiovascular stents, hard and soft tissue grafts, and intra-osseous transcutaneous implantable devices. Therefore, the ability to modulate thrombogenicity of titanium surfaces is critical for the long-term success of these blood-contacting devices. Material surfaces that provide biomimetic cues such as nanoscale architectures have been shown to elicit improved cellular interaction; thus providing a possible solution for enhancing blood-compatibility. Previous studies have shown titania nanotube arrays to elicit enhanced osseointegration, improved endothelialization, increased dermal matrix deposition and selective behavioral responses of stem cells. However, limited information exists about the thrombogenicity of the nanotube architecture. In this study, titania nanotube arrays, fabricated using an anodization process (diameter: approx. 100 nm, length: 1-1.5 µm), were analyzed after 2 h of contact with whole blood plasma. Platelet/leukocyte adhesion, activation, morphology and interaction, complement activation, contact activation, platelet release reaction, fibrinogen expression and material cytotoxicity were evaluated to determine the in vitro thrombogenicity of titania nanotube arrays. These results indicate a decrease in thrombogenic effects of titania nanotube arrays as compared to biomedical grade titanium after 2 hours of contact with whole blood plasma. The results presented here indicate a decrease in thrombogenic effects on titania nanotube arrays as compared to biomedical grade titanium after 2 hours of contact with whole blood plasma. Platelet/leukocyte adhesion, evaluated using fluorescence microscope images, indicate a significant decrease in cell numbers and coverage on titania nanotube arrays as compared to the control substrate. In addition, SEM images and enzyme immunoassays show limited surface-induced activation and morphology on both substrates, however identifying the leukocyte-induced activation of platelets present only on the control substrates. A significant increase in contact activation was further identified on titania nanotube arrays, likely resulting from their increased surface area. Enzyme immunoassays indicate slightly decreased levels of complement activation and a slightly increased degree of free fibrinogen expressed on titania nanotube arrays showing a decrease in surface induced fibrin clot formation. This work shows the improved blood-compatibility of titania nanotube arrays. This ability to modulate the thrombogenicity of titanium surfaces may prove beneficial towards the long-term success of these blood-contacting implantable devices. The thrombogenic response presented in this work may be optimized for specific in vivo applications by precisely tuning the nanotube dimensions by altering the anodization parameters.
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