Each year billions of health care dollars are spent on medical devices that fail in clinical practice. These device failures occur over various timescales of the devices due to multiple factors including thrombosis, inflammation, infection, and tissue overgrowth on the surface of the implanted device as well as mechanical device failures. Over the last 50 years, much has been learned about these device failures resulting in attempts to prevent failures using (1) alternative systemic drug therapies, (2) surface modifications on the device, or (3) a combination of both approaches. Despite efforts to improve the efficacy of blood-contacting and implantable medical devices, the incompatibility of these materials within human blood and tissue still causes serious complications in patients. Thus, systemic or regional drug therapies such as heparin remain necessary. As a result, strategies that can leverage the biological properties of naturally occurring bioagents such as nitric oxide (NO) have clear implications for a wide variety of medical devices. These materials offer localized control of platelets at the blood-material interface where bioactivity is targeted. The research strategy detailed here in focuses on developing materials that can produce NO from endogenous sources for extended periods of time and will overcome the fundamental limitations of current NO materials. Using metal organic frameworks (MOFs) as NO catalysts, device coatings will now be able to (1) produce NO for longer time period than ever achieved to date and (2) allow systematic modification while maintaining the structural properties that make them suitable for clinical applications. The principal premise of this project proposal is to utilize the inherent structural features of MOF materials to develop physiologically-relevant NO catalysts for use in catheter coatings. As a part of this grant, MOFs will be prepared, blended into catheter coatings and rigorously tested for their long- term function and mechanical properties, evaluated for safety via toxicity studies and characterized by an array of in vitro bioassays. Final catheter prototypes will be tested in a rabbit model for their anti-thrombotic properties at time points beyond the capabilities of current technologies.
The current paradigm of creating materials for non-thrombogenic medical devices focuses on understanding and disrupting the biochemical interactions that occur due to biological processes at blood-material interfaces. These challenges are a fundamental concern, as they lead to major complications in patient care and morbidity in the critically ill patient population. The release of nitric oxide (NO) at the device interface has been shown to prevent clotting without the deleterious side effects of systemic anticoagulants, yet the use of current NO materials is limited to acute applications due finite loading capacities of the materials. This project involves using novel heterogeneous catalysts that can extend the therapeutic levels of NO for longer periods without introduction of undesirable properties. The new catalysts will be applied as intravenous catheter coatings and their performance evaluated in both preclinical models for blood compatibility, toxicity and in vivo performance. The work will result in a new approach for developing more effective blood contacting catheters with longer device lifetimes that are able to be manufactured with common techniques, thus making their translation to a product easier. As such, the research will result in significant advances in the design of new materials and provide the system necessary for application as clinically relevant devices. As a result, patient care will increase while enabling a substantial decrease in healthcare expenditures.
