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 and are 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 and attempts have been made 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 function only at the blood-material interface where bioactivity is targeted. The strategy of this research 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 significantly high levels of nitric oxide and (2) allow systematic modification while maintaining the structural properties that make them suitable for clinical applications. Therefore, the principal premise of this project investigator is to utilize the inherent structural features o MOF materials to develop physiologically-relevant NO catalysts. As a part of this exploratory grant, the new MOFs will be prepared, blended into device coatings and rigorously tested for their long-term function and mechanical properties, and finally evaluated for safety via toxicity studies and characterized by an array of in vitro bioassays. The outcomes of the studies performed will be used to translate the most promising composite formulations to future in vivo models.
The current paradigm of creating materials for non-thrombogenic medical devices focuses on disrupting key biological processes which ultimately results in complications and more difficulty in managing patient care, especially with critically ill patient populations. The release of nitric oxide (NO) at the device interface has been shown to prevent clotting without the deleterious side effects of systemic anticoagulants. The problem with current NO materials, as replacement therapies, are that the useful therapeutic action is limited to acute applications. This project involves developing novel heterogeneous catalysts that can extend the therapeutic levels of NO for longer periods. The new catalysts will be applied as medical device coatings and their performance evaluated in preclinical models. The work will result in a new approach for developing NO- releasing biomaterials with longer device lifetimes that are able to be manufactured with common techniques, thus making their translation to a product easier. As such, the project will have far reaching outcomes in both in the design of new materials but also in their application to clinically relevant devices. As a result, patient care will increase and helth care expenditures will decrease.
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