The ongoing development of blood-contacting medical devices has undeniably facilitated extraordinary advances in the treatment of cardiovascular diseases. However, the susceptibility of many of these devices to blood clotting remains an enduring challenge that endangers patient safety and device longevity. Many devices, such as heart valve replacements, stents, cardiac catheters, or ventricular assist devices, are constructed from artificial materials that fit the mechanical criteria for their performance but often remain susceptible to clotting. Fundamentally, blood clots are initiated by the adsorption of various proteins to the material surface, which occurs spontaneously due to the foreign nature of these implants. This is an enduring concern for patients’ wellbeing, and is a challenge that must be addressed from a materials perspective. Given that the kinetics and thermodynamics of the interactions between the blood and the material surface dictate the material susceptibility to these undesirable responses, developing materials that could altogether avoid these interactions could improve patient health and advance the longevity and efficiency of a range of cardiovascular devices.

At the University of Sydney in Australia, our interdisciplinary team of researchers, including materials engineers, physicists, and medical scientists, have tackled this challenge by developing a protocol to transform the surface of medically useful polymers into superhydrophilic anti-adhesive interfaces with resistance to protein adsorption and blood clot formation. This was achieved by the strong attachment of zwitterionic moieties, which are unique molecules that contain equal amounts of positively- and negatively-charged groups. The resulting chemistry generates a remarkably strong affinity for water, resulting in a tightly associated layer of water surrounding the surface. Figure 1A demonstrates the affinity for water of a zwitterion-grafted polyurethane, with this high degree of water association effectively acting as a barrier against spontaneous protein adsorption. Effectively, this hydrated surface acts as a kind of “invisibility cloak”, hiding the underlying material from proteins and cells in the cardiovascular environment. Through various characterisation tools, we demonstrate that this changes the elemental composition and topography of the surface; Figure 1B demonstrates the unique wave-like topography generated by zwitterion grafting. This enables substantial increases in hydrophilicity, all while retaining the mechanical properties of the underlying substrate. Consequently, we fabricated materials that possessed resistance to protein adsorption, as demonstrated by reductions in the attachment of blood proteins such as albumin and fibrinogen, while also inducing lower amounts of clot formation, as demonstrated in Figure 1C.

We employed a unique plasma-mediated protocol to achieve zwitterionic surface modification. This involves the functionalisation of the polymer substrate with a powerful plasma system, termed plasma immersion ion implantation, wherein nitrogen ions are accelerated into the surface and generate surface-anchored reactive sites. These sites can then immobilise zwitterionic monomers, and due to the chemistries selected, also initiate polymerisation of zwitterionic chains. This approach was highly efficient and versatile, while avoiding the requirement for additional chemical reagents, such as initiators (which are typically used to induce polymerisation) or linker molecules (which are typically used as a bridge between the substrate and the modifying chemical). However, despite the success of the initial modification protocols, we quickly realised that the surface properties of the fabricated samples changed over time. Months after treatment, the surface of a zwitterion-modified polyurethane gradually transitioned from hydrophilic back to hydrophobic, thus slowly losing that effective invisibility cloak. As our objective was not only to develop blood-compatible materials, but to ensure that their use could extend the lifetime of blood-contacting devices, it was critical to investigate strategies to remedy these undesirable findings in order to ensure the real-world applicability of these material. Consequently, much of this study explored optimising various process parameters, from the plasma treatment to the zwitterion attachment mechanism to the storage conditions, with the objective of fabricating a material that was not just hydrophilic, but could also retain that hydrophilicity over time. Thus, we believe that this contribution not only proposes a promising strategy for creating blood compatible materials, but also approaches the challenge with real-world translation in mind, driving our necessity to explore the longevity of these modifications.

This publication represents the first stage in our development of a system for improving the biocompatibility of polymers for implantable medical devices. We anticipate that this technology will eventually facilitate the construction and clinical use of medical devices that are not limited by thrombotic events and other biological responses. Not only would this improve patient safety by avoiding the complications of clot formation, but it would also alleviate the requirements for clinical reinterventions to replace biologically degraded devices. Ultimately, we hope that the development of blood compatible materials using protocols such as the one developed in this contribution will continue to advance our ability to treat cardiovascular diseases.