Water Dynamics and Polymer Engineering: The Breakthrough Behind Advanced Antithrombogenic Artificial Kidneys

The Challenge of Thrombosis in Medical Devices

When blood interfaces with artificial materials in medical devices like dialysis filters, it triggers a complex cascade of protein adsorption, platelet adhesion, and inflammatory responses that ultimately leads to thrombosis. This biological response has represented one of the most significant challenges in the development of effective artificial kidneys. Traditional approaches to creating antithrombogenic surfaces have primarily focused on increasing polymer hydrophilicity, but these methods have shown limited success in clinical applications.

Beyond Conventional Hydrophilic Polymers

Early development efforts for polysulfone (PSf) membrane artificial kidneys centered on optimizing polyvinylpyrrolidone (PVP) attributes, including quantity and mobility within the membrane structure. However, researchers observed no significant improvement in antithrombogenic properties despite these modifications. The technical constraints were substantial: immobilization of antithrombogenic polymers could only be achieved with solvents that preserved the delicate nanoporous structure of hollow fiber membranes, while strict safety regulations limited elution potential. Compounding these challenges were cost constraints, with artificial kidneys needing to remain affordable at approximately 1,500 yen per unit.

The limitations of conventional approaches became increasingly apparent. Simply applying existing antithrombogenic polymers like PVP would not resolve the fundamental issues of thrombosis and inflammation. This realization prompted researchers to explore entirely new polymer design paradigms., as additional insights, according to market trends

The Water Mobility Hypothesis

The breakthrough came from examining the interaction between polymers and water at a molecular level. Previous research had established that the amount of water interacting with polymers influences their antithrombogenic properties. However, Toray Industries researchers developed this concept further by considering not just the water surrounding polymers, but also the water surrounding proteins.

Proteins in blood are surrounded by structured water molecules that contribute to their functional expression and structural stability. The research team hypothesized that when a protein approaches a polymer surface, the mismatch in water mobility between the protein’s hydration layer and the polymer’s hydration layer could cause dehydration and structural destabilization of the protein, leading to irreversible adhesion.

This hypothesis was confirmed through isothermal titration calorimetry (ITC) measurements using model aqueous solutions of PVP and albumin. The results demonstrated that interactions between PVP and proteins are driven by entropy changes, with protein adhesion initiated by dehydration processes., according to market analysis

Computational Chemistry Guides Polymer Design

Rather than following the conventional path of increasing hydrophilicity, the research team developed a novel molecular dynamics (MD) program to predict structures that control adsorbed water mobility. Their computational analysis revealed a crucial insight: the mobility of water adsorbed around proteins falls within a specific range of approximately 2.0-2.5 × 10⁹ s^-1.

By plotting the inverse relaxation time of adsorbed water (indicating mobility) against solvation energy (indicating hydrophilicity/hydrophobicity), researchers identified that polymers with higher hydrophobicity than PVP could potentially achieve water mobility matching that of proteins. This counterintuitive approach—increasing hydrophobicity to improve antithrombogenic properties—represented a significant departure from established thinking in biomaterial science., according to expert analysis

Hydrophobized PVP: Balancing Hydrophilicity and Hydrophobicity

The research led to the development of hydrophobized PVP, created through chemical modification of conventional PVP by introducing hydrophobic groups such as aliphatic or aromatic structures. The strategic placement of these hydrophobic groups created a polymer with balanced hydrophilic-hydrophobic properties.

Analysis through quasielastic neutron scattering (QENS) measurements and MD calculations revealed why hydrophobized PVP outperforms conventional PVP. In standard PVP, water mobility decreases around the hydrophilic vinylpyrrolidone groups, with relaxation motions occurring cooperatively in confined spaces. In hydrophobized PVP, the proximity of vinylpyrrolidone groups and hydrophobic groups moderately disrupts the hydrogen-bonded hydration structure, promoting exchange between adsorbed water and bulk water, thereby increasing overall water mobility.

Commercial Implementation and Clinical Benefits

The research culminated in the development of a technique to immobilize hydrophobized PVP on the inner surface of hollow fiber membranes with nanoscale precision—only a few nanometers thick—without altering the vital nanoporous structure. This innovation was commercialized as TORAYLIGHT™ NV in 2011, representing the world’s first practical application of a PSf membrane artificial kidney using an antithrombogenic polymer other than conventional PVP.

The clinical benefits have been substantial:

• Reduced Thrombosis and Inflammation: TORAYLIGHT™ NV demonstrates significantly lower platelet adhesion and reduced inflammation markers compared to conventional products
• Improved Clearance Performance: By suppressing protein adhesion, the membrane maintains higher removal performance during patient treatments
• Reduced Anticoagulant Use: Clinical studies report decreased requirements for anticoagulant medications
• Inflammatory Marker Reduction: Unlike conventional dialyzers that may increase IL-6 levels during treatment, TORAYLIGHT™ NV actually reduces this inflammatory protein

Expanding Applications and Future Potential

The success of TORAYLIGHT™ NV led to the development of HEMOFEEL™ SNV for acute renal failure in 2019. This product demonstrates remarkable durability, with usage time extended by more than 1.5 times compared to conventional alternatives. Survey data from 21 medical facilities revealed that in no cases did HEMOFEEL™ SNV have shorter usage times than conventional products, with approximately 18% of cases showing extended usage times—particularly valuable for patients prone to coagulation, including those with COVID-19.

The water mobility concept has proven to be based on clear fundamental principles, making it widely applicable beyond artificial kidneys. The computational design approach enables creation of polymers tailored to specific applications and materials, opening possibilities for improved medical devices across multiple therapeutic areas.

The research represents a paradigm shift in biomaterial design, demonstrating that understanding and engineering water-polymer interactions at the molecular level can yield significant improvements in medical device performance and patient outcomes. This approach has not only enhanced the quality of life for dialysis patients but also contributed to better medical economics through reduced medication requirements and improved treatment efficiency.

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