Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Andriy I. Batchinsky, M.D.

Co-Major Professor

Jay B. Dean, Ph.D.

Committee Member

Mack H. Wu, M.D.

Committee Member

Jerome W. Breslin, Ph.D.

Committee Member

Byeong J. Cha, Ph.D.

Keywords

biomaterials, coagulation, extracorporeal life support, extracorporeal membrane oxygenation, metal organic framework, perfluorocarbons

Abstract

Extracorporeal life support (ECLS) is a class of technologies used to support or replace the function of failing organs. During ECLS, blood is withdrawn from systemic circulation and circulated through an artificial organ or “treatment membrane” that performs the function of the failing organ, prior to return to systemic circulation. While ECLS provides life-saving therapy to wide patient populations from pre-term infants to combat-wounded soldiers, this therapy is limited due to secondary thrombotic and bleeding complications that result from: 1) exposure of blood to the foreign surfaces in the device circuit and 2) administration of anticoagulant drugs to prevent clot formation in the circuit.

In this study, we assessed a biomaterial solution to the challenge of hemostasis during ECLS by modifying surfaces in the circuit to improve compatibility with blood. This approach would provide local coagulation management at the blood-biomaterial interface, obviating the use of systemic anticoagulant drugs that cause secondary bleeding. We investigated a non-adhesive, liquid-infused coating called tethered liquid perfluorocarbon (TLP) that prevents plasma protein adsorption. We also investigated a metal-organic framework that catalyzes nitric oxide release from endogenous donors, localizing the platelet inhibitory effects of nitric oxide to the biomaterial surface as occurs in the endothelium. Our objective was to determine if these coatings were a robust biomaterials solution for ECLS without administration of anticoagulant drugs. We developed a three-step approach to assess the efficacy and safety of biomaterials for ECLS. First, materials were first evaluated in vitro in healthy donor blood using thromboelastography and platelet aggregometry. Second, we proceeded with evaluation of TLP applied to complete ECLS circuits in vivo using a swine model for 6 hours of circulation. We assessed thrombus formation by scanning electron microscopy, coagulation function using clinical tests, gas exchange performance of the membrane using pre- and post-membrane blood gases and assessed safety using vital signs and histology. Finally we evaluated TLP in a 72-hour intensive care unit study without supplemental anticoagulation utilizing similar methods as described in our 6 hour model, with additional analysis of mechanical ventilation settings, systemic cytokine expression, hematology and protein adhesion. We hypothesized that TLP would enable 72 hours of heparin-free ECLS by inhibiting protein adsorption, preventing thrombotic circuit occlusion and preserving native blood parameters; all without impeding membrane performance or causing systemic complications.

Both TLP and the nitric oxide catalyst reduced the time and rate of thrombus initiation as well as clot strength ex vivo. The nitric oxide catalyst also reduced platelet aggregation. In our 6 hour evaluation, TLP applied to ECLS circuits reduced thrombus formation compared to control, heparin-coated circuits and did not affect gas transfer across the membrane lung or cause untoward effects. In our 72 hour evaluation, TLP failed to prevent thrombotic circuit occlusion, and additionally altered the performance of the membrane lung requiring greater support from the mechanical ventilator compared to control animals that received heparin-coated ECLS circuits with systemic anticoagulation therapy. We concluded that TLP is currently not an efficacious solution to permit ECLS for 72 hours without anticoagulant drugs. Future studies are needed that utilize the three-step assessment method we have developed here to evaluate multi-functional biomaterials with combined ability to prevent protein adsorption and inhibit platelet activation, such as occurs in the endothelium.

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