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The elusive structure of intermediate water and its biocompatibility

  • Despite its abundance, water is one of the most complex substances on Earth.
  • Trying to discern the exact arrangement and orientation of all individual water molecules in water or ice is a huge scientific challenge.
  • Dr Masaru Nakada of the Toray Research Center in Japan has been using a number of techniques, including x-ray and neutron scattering, to understand the structure of intermediate water.
  • His research is critical as it lays the foundation for making certain polymers biocompatible for use in artificial organs and membranes.

Biocompatibility is a huge challenge when designing materials for use in therapeutics and medical application. A suitable material must be non-toxic, inert, and stable, even within the relatively chemically harsh environment of the body. At the same time, the material needs to look ‘similar enough’ to human tissue so that various bioprotection mechanisms are not triggered, which can lead to tissue deposits on the implant.

Water is the most common molecule in the human body, and most environments in tissues or the blood are made up of water. When trying to design materials for implants, it is therefore crucial to understand how they react and interact with water. Many biological species in the blood, like proteins, will also be surrounded by water molecules which helps to protect and transport the protein species. The water acts as both a protective layer and a soluble medium for the biological systems.

The challenge for researchers designing new materials is to understand how materials interact with these water structures. This is no small task, as there are still many unsolved questions about the structure of liquid water and ices, in particular how the water molecules arrange themselves into networks joined together by a bonding force known as hydrogen bonding.

Dr Masaru Nakada of the Toray Research Center in Japan has been working with a range of analytical techniques to understand the role of intermediate water in hydration and, ultimately, the biocompatibility of certain polymer materials. By using techniques such as neutron scattering and x-ray diffraction, Nakada and his colleagues have been trying to map how the polymer molecules affect these extended water networks and understand how phenomena such as intermediate water layers relate to the biocompatibility of a material.

Intermediate water

When a material or a biological species is in a water environment, it is surrounded by ‘layers’ of water structure. Directly around the polymer is a layer of non-freezable water that has a tight, regular packing of water molecules. Surrounding the non-freezable layer is the intermediate layer, and then next to that is the free water. Free water is where the water molecules are free to move as they are in a solution, but the intermediate layer is somewhere between the two, with the motion of the molecules more restricted than the free layer but with a more disordered structure than the non-freezable layer.

Nakada and his colleagues have been trying to understand how phenomena such as intermediate water layers relate to the biocompatibility of a material.

Scientists have often used techniques like differential scanning calorimetry (DSC) to try and characterise the water layers around a polymer, but Nakada has shown that techniques like nuclear magnetic resonant (NMR) spectroscopy, x-ray scattering, and neutron scattering can paint a much more detailed picture of what happens at the water–polymer interface.

Biocompatible polymers

Polyvinyl pyrrolidone (PVP) is a polymer material that is one of the most widely used in medical devices and implants because it has many of the necessary material properties for use in the human body, such as excellent water solubility and non-toxicity. Nakada used PVP for all his studies to better understand the behaviour of the water layers at different temperatures.

Freezing is a very useful way of understanding the water structures as the local hydrogen bonding networks determine how readily water freezes and what shape and form the ice takes. With the x-ray and neutron scattering measurements, Nakada was able to monitor the freezing process in real time and identify the local density of molecules in the layer as well as how strong the relative interactions between the water molecules were.

Nakada was able to monitor the freezing process in real time and identify the local density of molecules in the layer as well as how strong the relative interactions between the water molecules were.

The x-ray and neutron scattering experiments were sufficiently sensitive that Nakada and the team could discriminate between the relative orientations of the hydrogen bonds between different water molecules. Nakada also studied how the structures of the ice networks evolved at different temperatures and how this affected the density of hydrogen bonding in certain regions near the biomolecule.


The Toray Research Center, where Nakada works, was established in June 1978 from the R&D division of Toray lndustries, Inc. The Center had a very important role in providing technical support for ‘cause analysis’ and ‘problem solving’ in many different fields of research. Recently, it won an award from the Society of Polymer Science, Japan, for the development of polymer coatings that prevent blood clot formations around artificial tissues, based on the work of Nakada.

Some of the key work in the Toray Research Center has been in the development of new analytical techniques and physical analyses, and Nakada has been finding out how these can be applied to challenging problems such as biocompatible polymer design.

Future work for Nakada and the team will be to examine how well PVP works as a ‘model’ system to understand and predict the behaviour of other polymer materials. Nakada’s results have also provided interesting information on how water molecules arrange themselves in the presence of surfaces and other interacting species like polymers as well as showing how these materials can affect the freezing process. The characterisation and role of intermediate water in preventing deposition on polymers is an important one and, in the future, material properties could be tuned to affect the behaviour of this layer of water specifically.

What inspired you to conduct this research?

I have studied the structure and dynamics of water since I was a student. After joining the Toray Research Center, I became interested in intermediate water when I learned that it contributes to the biocompatibility of medical materials.

What do you think will be the next breakthrough in understanding the biocompatibility of materials?

I think the ideal form of biomaterials is living organisms. So, understanding the structure and function of water and other components in the body could be the next breakthrough.

Do you think your research can be applied to other material types?

Yes, I believe that our approach can access to the information of interaction between water and materials in other materials.

What will be the next developments to study these kinds of problems?

I think the most important thing is to understand the interface between water and materials/bio-body from micro to macro.

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Further reading

Nakada, M, (2023) Low-temperature behaviors, cold crystallization, and glass transition in poly(vinylpyrrolidone) aqueous solution. The Journal of Physical Chemistry B, 127, 49, 10556–10563.

Nakada, M, Yamada, T, Ikeda, K, Otomo, T, (2021) Static and dynamic structure analysis of intermediate water on polyvinyl pyrrolidone using neutron scattering. JPS Conference Proceedings, 33, 011080.

Nakada, M, Ishida, H, Furushima, Y, (2020) Structural and dynamical characterisation of intermediate water interacting polyvinyl pyrrolidone. Materialia, 12, 100743.

Masaru Nakada

Masaru Nakada is Research Associate at the Toray Research Center, Inc. Nakada completed his PhD degree from Niigata University in 2011. His work focuses on the interaction between the bio-body and materials through water.

Contact Details

e: [email protected]


  • Professor Toshiya Otomo (KEK)
  • Dr Kazutaka Ikeda (CROSS)
  • Dr Takeshi Yamada (CROSS)
  • Dr Shigeo Kuwamoto (JASRI)
  • Yoshitomo Furushima (Toray Research Center, Inc.)
  • Hiroyuki Ishida (Toray Research Center, Inc.)
  • Koichi Ozaki (Toray Research Center, Inc.)

Cite this Article

Nakada, M, (2024) The elusive structure of intermediate water and its biocompatibility,
Research Features.

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