INTELLECTUAL MERIT: Polyurethane biomaterials dominate blood-contacting applications, but the fundamental basis for the hemocompatibility of these materials has yet to be understood. The goal of this proposal is to elucidate fundamental relationships between polyurethane microphase separated structures having characteristic dimensions similar to plasma proteins and biologic responses at the molecular scale by judicious application of materials imaging, characterization, and molecular analysis. In particular, the proposal seeks to relate polyurethane phase segregation at the hydrated polymer interface with the activity of adsorbed proteins to test the central hypothesis that: The chemical nature and nanoscale properties of phase separated biomaterials creates a distribution of unique interfacial environments that, in aggregate, influences conformation and activity of adsorbed blood-plasma proteins, in a manner that understandably correlates with phase distribution and chemistry. This hypothesis will be tested by investigating the role that molecular level surface properties play on the adsorption, structure and activity of plasma proteins in surface-induced thrombogenesis through completion of the following three tasks. (1) Characterize the interfacial environment of the separated microphases under physiologic buffer conditions for films of polyurethane copolymers by using atomic force microscope probes modified with self-assembled monolayers of controlled chemistry and with relevant plasma proteins. Determine the distribution of microdomains and the surface area occupied by both individual domains and hard segment/soft segment in aggregate for different polymer chemistries. (2) Quantify the adsorption of selected proteins to hard and soft polyurethane domains using atomic force microscopy under physiologic buffer conditions. (3) Determine changes in individual protein molecules by assessing the activity of adsorbed proteins using functional labeling of individual protein molecules and AFM bioadhesion measurements in order to establish structure/function relationships for each of the different polymer phases. Compare molecular measurements to traditional platelet adhesion measurements in order to address the role of microdomain properties on hemocompatibility.
BROADER IMPACTS: A persistent issue for materials intended for applications in contact with living tissue is compatibility between the tissue and the exogenous material. Materials intended for contact with blood must not provoke clotting if they are to be useful. This study addresses fundamental issues of blood protein-biomaterial interactions. While focusing on polyurethane materials, the generality of its approach promises to illuminate the broader field of protein-biomaterial compatibility. Integration of research and education is addressed here primarily in terms of research experience for students. Postdoctoral and summertime undergraduate students will be supported by the award. The PI has an excellent record of hosting high school students in his laboratory and plans to continue this practice.
Implanted medical devices lead to the formation of blood clots. These clots can lead to dehabilition or death. Our research program is intended to understand why these clots form, and why some materials used in medical devices are less likely to induce this clot formation than are other materials. The presence of materials can tilt the balance of clot formation and destruction normally seen in our blood to one of overactive clot formation. These clots eventually break off and travel through the bloodstream where they may induce a stroke.T Our research focused on looking at the small molecules in blood that serve as bridges for cells to stick to materials. These molecules, known as proteins, are present in an inactive form in blood. However, when these proteins encounter a material surface they are attracted to stick to it. As they stick to the material, they undergo changes in shape, and these changes in shape can make them take on different functions. One of the important functions they take on is to serve as a bridge for larger elements in blood called platelets. This process of shape change leading to activity change leading to platelet adhesion is critical in our normal circulation. However, when this occurs on a synthetic surface, we form too many clots with deleterious consequences. Our studies shed light onto why proteins undergo these shape changes, and more importantly, why some materials were more likely to induce these shape and function changes than were other materials. This provides insight into the process that can be utilized in development of new materials that will work better in the complex environment of blood.
