To date, blood compatibility testing of biomaterials and medical devices has not led to a consensus on what materials are non-thrombogenic nor has it advanced understanding of what and how variables and responses can be measured in vitro to begin to predict in vivo performance. While ISO 10993-4 identifies five categories of responses that should be considered (thrombosis, coagulation, platelets, leukocyte activation, and complement), the scientific and regulatory communities continue to focus on coagulation and platelets. The other ISO categories dealing with inflammation are typically dealt with early and separately as part of biomaterial development. This current approach all but guarantees missing interactions of coagulation and inflammation necessary to predict in vivo performance. Current testing methodologies also fail to evaluate the categorical responses under physiological limits of the key Virchow variables of blood flow, condition of the blood (e.g., coagulopathies), and the influence of the blood contacting surface. These uncertainties and the current cost of comprehensive testing stifle development of new materials or surface coatings. In fact, the FDA has repeatedly acknowledged these shortcomings and encouraged development of new test methods. Most recently, the FDA announced the Medical Device Development Tool program to address this matter. Therefore, Ension proposes development of a system (Ension Triad System or ETS) to provide effective positive and negative control ranges for each of the Virchow variables. ETS will enable designed experiments capable of generating quantitative analysis of variance and identify conditions for optimal performance in all five ISO categories. Preliminary Data: Ension has developed the Ension Bioactive Surface (EBS) that was inspired by the endothelial glycocalyx. We have published on critical interactions between the variables of blood condition (levels of anticoagulant) and bioactivity of the EBS (ATIII adsorption and FIIa deactivation) and we have demonstrated statistically significant categorical responses that identify known clinical mediators not revealed in current testing protocols. Specific Aims: This Phase I project proposes design and fabrication of the ETS system and assesses the feasibility of this tool for standardizing blood compatibility testing and enabling improved medical device development. In Specific Aim 1, we will fabricate a functional ETS prototype and optimize the EBS treatment on all of the ETS prototype's blood-contacting materials. Specific Aim 2 focuses on in vitro characterization of the ETS prototype to identify mechanical and chemical properties in human blood. Finally, in Specific Aim 3 we will utilize ETS systems with catheter test articles and vary the three Virchow variables to generate statistical correlations to both evaluate Phase I feasibility and provide a basis for extensive animal model testing planned for our Phase II effort. This Phase I effort will demonstrate a heretofore unattainable and reproducible rank ordering of blood compatible materials as well as identifying how category response vary within meaningful ranges of flow, blood condition, and surface properties.
Public Health Relevance Statement: Public Health Relevance: Current in vitro systems and methods to assess blood compatibility of biomaterials and medical products have been unable to achieve a comprehensive understanding of the blood-biomaterial interaction to predict in vivo performance. This Phase I proposes development of a standardized, cost effective, bench top blood circulation loop and accompanying testing protocols that can comprehensively address all five categories of blood compatibility and account for each Virchow variable in a single, highly controlled test. Terms:
