Water Dynamics in Polymers: The Breakthrough Behind Advanced Antithrombogenic Artificial Kidneys

Introduction: The Challenge of Blood Compatibility in Medical Devices

When blood interacts with foreign materials, it triggers a complex cascade of events that can lead to thrombosis—a significant hurdle in developing medical devices like artificial kidneys. For decades, researchers attempted to solve this problem by increasing material hydrophilicity, assuming that more water-attracting surfaces would naturally resist blood clot formation. However, a groundbreaking approach focusing on water dynamics at the molecular level has revolutionized antithrombogenic polymer design, leading to commercially successful artificial kidneys that significantly improve patient outcomes., according to market analysis

The Limitations of Conventional Approaches

Initial development efforts for polysulfone (PSf) membrane artificial kidneys focused on optimizing polyvinylpyrrolidone (PVP) attributes, including quantity and mobility. Despite these attempts, no significant improvement in antithrombogenic properties was observed. The challenges were multifaceted: immobilization of antithrombogenic polymers required solvents that wouldn’t compromise the delicate nanoporous structure of hollow fiber membranes, strict safety regulations limited elution possibilities, and cost constraints (approximately 1,500 yen per unit) presented additional barriers. These limitations made it clear that simply applying existing antithrombogenic polymers like PVP wouldn’t suffice, necessitating exploration of entirely new polymer designs.

The Water-Protein Interaction Hypothesis

The traditional understanding of thrombosis initiation involves protein adhesion to material surfaces, followed by platelet adhesion and inflammation, ultimately leading to blood coagulation. Previous research had identified the amount of water interacting with polymers as a factor influencing antithrombogenic properties, while other studies highlighted the importance of polymer solvation in relation to protein adsorption. The breakthrough came when researchers expanded this concept to consider not just the amount of water on polymers, but also the water surrounding proteins—known as adsorbed water. This hydration layer contributes to protein functional expression and structural stabilization, and disturbances to this delicate balance could trigger irreversible adhesion.

The key insight was recognizing that when PVP and proteins come into contact, their differently mobile adsorbed water layers interact disruptively. The water adsorbed by proteins becomes disturbed upon contact with PVP, leading to dehydration and structural destabilization of the protein, progressing to irreversible adhesion. Isothermal titration calorimetry (ITC) measurements with PVP and protein (albumin) model solutions confirmed that their interaction is driven by entropy changes, with protein adhesion initiating through dehydration., according to expert analysis

A Revolutionary Design Concept: Matching Water Mobility

Instead of following the conventional path of increasing hydrophilicity, researchers adopted a novel design concept: creating polymers with water mobility matching that of protein-adsorbed water. The theory proposed that if both protein and polymer adsorbed water share equivalent mobility, their close contact would result merely in an exchange of hydration layers rather than dehydration and adhesion. This approach represented a paradigm shift from focusing solely on water quantity to prioritizing water behavior and dynamics at the molecular interface., according to industry reports

Computational Chemistry Guides Polymer Design

To implement this innovative concept, researchers developed proprietary molecular dynamics (MD) programs and employed computational chemistry to predict structures that control adsorbed water mobility. Their analysis revealed crucial relationships between water mobility (represented as the inverse of relaxation time of adsorbed water) and polymer characteristics (represented as solvation energy with water). Since the mobility of water around proteins was predicted to be approximately 2.0–2.5 × 10 s⁻¹, the focus shifted toward polymers with higher hydrophobicity than PVP to improve adsorbed water mobility.

This computational approach enabled precise balancing of hydrophilic and hydrophobic properties, moving beyond traditional hydrophilicity-maximization strategies. The results were striking: polymers discovered through this method demonstrated significantly suppressed platelet adhesion compared to PVP, with minimum platelet adhesion occurring precisely where protein and polymer water mobility were equivalent., according to technology insights

Hydrophobized PVP: The Optimal Solution

After considering factors including productivity, researchers selected hydrophobized PVP molecules achieved through chemical modification of PVP, introduction of copolymer components, or both approaches combined. By incorporating hydrophobic groups such as aliphatic or aromatic structures at specific sites, they created polymers with optimized water mobility characteristics., as earlier coverage, according to industry experts

The mechanism behind hydrophobized PVP’s improved performance involves dynamic restructuring of water organization. Quasielastic neutron scattering (QENS) measurements and MD calculations revealed that in standard PVP, water mobility around hydrophilic vinylpyrrolidone groups decreases, with relaxation motion occurring locally in confined spaces around pyrrolidone groups. In contrast, hydrophobized PVP demonstrates greater water mobility, with expanded relaxation regions. The proximity of vinylpyrrolidone groups and hydrophobic groups moderately disrupts the hydrogen-bonded, ordered hydration structure, promoting exchange between adsorbed water and bulk water, thereby enhancing mobility.

Commercial Implementation and Clinical Impact

The research culminated in TORAYLIGHT NV, commercialized in 2011 as the world’s first practical application of a PSf membrane artificial kidney using an antithrombogenic polymer other than conventional PVP. The technology immobilizes hydrophobized PVP on the membrane’s inner surface with a thickness of only a few nanometers without altering the nanoporous structure of hollow fiber membranes.

Clinical performance has demonstrated substantial improvements over conventional products. TORAYLIGHT NV shows superior suppression of adhesion, reducing both thrombosis and inflammation indicators. Compared to other commercially available options, it exhibits higher adhesion and inflammation suppression effects, with reported clinical benefits including:

• Reduced platelet adhesion in patients
• Lower inflammation levels during treatment
• Decreased anticoagulant usage while maintaining efficacy
• Enhanced removal performance by suppressing membrane pore clogging
• Improved inflammatory protein clearance, actually reducing IL-6 concentrations post-dialysis

Notably, while conventional products often show decreased removal performance over time and can induce inflammation during treatment (increasing IL-6 concentrations), TORAYLIGHT NV demonstrates consistent performance with genuine inflammatory marker reduction.

Expanding Applications and Future Directions

The success of TORAYLIGHT NV led to the 2019 launch of HEMOFEEL SNV for acute renal failure, which extends usable time per unit by more than 1.5 times. Surveys across 21 medical facilities revealed that in 0% of cases was usage time shorter than conventional products, while approximately 18% of cases showed longer usage times—remarkable consistency considering the varying conditions of acute patients. The product has proven particularly suitable for coagulation-prone patients, including those with COVID-19.

The water mobility concept has demonstrated wide applicability beyond artificial kidneys, with potential implications for various blood-contacting medical devices. The computational design approach now enables tailored polymer development for specific applications and materials, opening new possibilities for medical device innovation.

Conclusion: A Paradigm Shift in Biomaterial Design

The focus on water dynamics represents a fundamental shift in how we approach blood-compatible material design. By moving beyond superficial hydrophilicity to understand and engineer molecular-level water behavior, researchers have developed more effective, clinically superior artificial kidneys. This approach has not only improved patient outcomes through reduced thrombosis, inflammation, and better clearance performance but has also enhanced medical economics through reduced medication requirements. The water mobility principle establishes a clear foundation for future biomaterial innovation, promising continued advances in medical device technology and patient care.

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