Vascular endothelium glycocalyx-mimetic surfaces designed for blood contacting devices

Abstract

Each year millions of blood-contacting devices are used in clinical scenarios, with contact durations designed to range anywhere from hours to years. Current blood-contacting devices can perform their intended purposes well but require the assistance of systemic drugs to inhibit failure via unfavorable interactions between the material's surface and the surrounding biology. The drugs used to inhibit failure of these devices are associated with side effects that can cause increased morbidity of patients because of their systemic administration. Thus, there is a need to design materials that can inhibit thrombus, inflammation, and infection locally at the surface of a device for the device's lifetime. In this work bio-inspired surfaces were engineered to reduce unfavorable blood-material reactions. The success of the designed surfaces was tested by evaluating their cell-material interactions, whole blood interactions, enzymatic stability, and mechanical durability. The inspiration behind these surfaces is the vascular endothelial glycocalyx, which is the luminal side of blood vessels and inhibits blood coagulation during hemostasis. The vascular endothelial glycocalyx is a meshwork of glycosaminoglycans (GAGs), proteoglycans (PGs), and glycoproteins which are predominantly negatively charged that acts as mediator between the blood and the underlying tissue. The surfaces proposed in this work are made to mimic the glycocalyx in its topography and chemistry by adsorbing polyelectrolyte multilayers (PEMs) onto a substrate, and subsequently adsorbing PG mimics on top of the PEMs. There are two different PG mimics used for this project which are: polyelectrolyte complex nanoparticles (PCNs) and proteoglycan mimetic graft copolymers (GC); both of which will present either heparin (HEP) or chondroitin sulfate (CS). Some of the surfaces will also be made to release nitric oxide (NO) from the surfaces through a modified version of chitosan (CHIT). Additionally, further modifications were made to the PEM surfaces to make them more mechanically durable by 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N-hydroxysuccinimide (NHS) crosslinking of the CHIT and hyaluronan (HA) layers, and the addition of an initial polydopamine (PDA) layer. In the first chapter of this work outlines the current approaches to blood-contacting materials and their limitations, along with the biological components and processes that they will need to interact. The second chapter evaluates PCN and PEM surfaces that do and do not release NO via their cell-material interactions with key cell types in the processes of thrombosis, inflammation, and infection. Chapter three examines the interactions between two different PG-mimics (PC or GCs) and enzymes when suspended in solution or adsorbed onto PEM surfaces. The fourth chapter includes an evaluation of the mechanical durability of PEM and mechanically improved PEM surfaces, and whole blood evaluations of PG, GC, and modified and unmodified PEM surfaces. Taken together, this work produces multiple bioinspired surfaces that have varying degrees of success in their blood compatibility and longevity.