Developing Nonfouling Zwitterionic Coating for Biomedical Applications

Thesis (Ph.D.)--University of Washington, 2020During the past decades, the demand for biomaterials with good biocompatibility is increasing with the rapid development of advanced medical technologies, such as biosensors, implantable chips, hemodialysis and biopharmaceutical application. Currently, high biocompatibility can be achieved by hydrophilic polymers, such as poly(ethylene glycol) (PEG), polysaccharides, and zwitterionic polymers. These hydrophilic polymers can form a stable hydration layer through hydrogen bonding with water molecules in their aqueous environment and these hydration layers further prevent non-specific protein adsorption onto, and immune recognition of, the material surfaces. Among all hydrophilic materials, zwitterionic carboxybetaine (CB) distinguishes itself from the rest for its exceptional biocompatibility, superior hydration capability, low immunogenicity, and high stability as well as its potential for further functionalization. However, a reliable method to successfully introduce the biocompatible polymer onto the target surfaces still persists as a challenge. For example, “graft-from” methods, exemplified by surface-initiated atom transfer radical polymerization (SI-ATRP) can provide a dense layer but the harsh polymerization conditions and high cost impeded its large scale industrialization. On the other hand, “graft-to” methods are economic and realistic but their performance is highly surface-dependent and needs challenging optimization. There is a realistic demand to develop facile yet effective coating techniques. In this thesis, we aim to develop a universal coating technique that can have the advantages of “graft-to” and “graft-from” methods, is facile to use and generates a dense coating layer. This coating method can create an excellent biocompatible layer onto all surfaces thought a simple dip-coating process. To achieve this goal, we developed a series of (PCB)m-(DOPA)n (m=1,4 and n=1,2,4) conjugates with different combinations of polycarboxybetaine (PCB) and mussel-inspired binding groups (DOPA) groups to find out what is the optimal molecular structure for modifying surfaces. We found that the structure of the conjugates affects their coating performance: a star-shaped PCB chain structures combined with multiple DOPA groups can significantly increase the coating performance. In order to test the universal-protection ability of the molecules, we next applied this coating material on to respiratory devices to test the performance of a coating in an in vivo sheep and rabbit study. We demonstrated that through our universal coating technique, the PCB-DOPA coating can significantly improve the respiratory device lifespan from 4 hours to 35 hours and can reduce thrombosis in sheep studies. Expanding upon the well-known non-fouling ability of PCB coatings, we developed a new conjugate that can covalently immobilize bovine serum albumin antibody (anti-BSA) and fibrinogen antibody (anti-Fg) onto the PCB polymers. This coating was then applied onto a paper-based sensor surface via a “graft-to” immersion process to render the surface with both nonfouling and protein functionalizable properties. The coated paper sensor showed accelerated diffusion of analytes and improved sensitivity of glucose detection, particularly in real-world complex media such as human blood serum. Lastly, we propose a new method to detect the complement activation level in the blood exposed to biomaterials. This detection method can improve the current measuring techniques by achieving a more accurate measurement. By tailoring and molecule structure and chemistry, we have explored the strategies to improve the performance of non-fouling coating molecules. This new zwitterionic coating is developed to address major challenges associated with blood compatibility. These new molecules can not only greatly improve the life span and performance of medical devices, but also reduce the unfavorable immune response compare to current so-called “bio-inert” materials