Considering the Blood Compatibility materiaks for Medical Devices (Part 2 of 3)

Part 2 | What is Intermediate Water? – A New Concept of Biocompatibility Developed from PMEA Research

The reason why PMEAs and biomolecules can coexist peacefully with blood—the answer lies in the "state of the water."

Professor Ken Tanaka began independently studying DSC measurement after encountering a certain paper in 1998, and pioneered a new perspective by classifying water in materials into three types: "free water," "nonfreeze water," and "intermediate water." The presence of "intermediate water" is common to highly biocompatible materials, from synthetic polymers such as PMEA, MPC polymers, and PEG, to DNA, RNA, and hyaluronic acid.

This discovery has moved blood compatibility evaluation beyond phenomenological analysis and elevated it to a measurable concept as a design indicator. This is the second installment, offering engineers involved in the surface design of medical devices a new perspective on materials and biological interfaces.

Kiyan: I read in Professor Ishihara's paper that "water is important," and that's how I started learning DSC on my own.

Professor Tanaka: At first, it didn't go well at all (laughs). DSC is not my area of expertise, so I didn't know the measurement conditions. PMEA is viscous, so even just sealing it neatly in an aluminum pan was a struggle. Sampling was also a continuous process of trial and error. But as I kept at it, I gradually got the hang of it, and when I measured hydrated PMEA, I started to get peaks that were exactly like those of hydrated PEG, appearing repeatedly. "Cold crystallization"—the behavior of crystallizing at low temperatures—appeared with good reproducibility.

Kiyan: So you compared that peak with other materials as well?

Professor Tanaka:PMEA, PHEMA, MPC polymer, PEG We compared them. As a result, Highly biocompatible materials commonly exhibit this peak.. on the other hand,PHEMAThen it hardly ever appeared. That was the deciding factor.

The water content of PHEMA is much higher. However, the expected peak did not appear. It became clear that "high water content" and "high biocompatibility" are not the same thing.

Kiyan: So, the textbook explanation that "higher hydrophilicity is better" is overturned here as well.

Professor Tanaka: That's right. It's not the quantity of water content that's important, but the "state" of the water.

Kiyan: What did you discover when you broadened the scope of your analysis?

Professor Tanaka: We expanded our scope beyond synthetic polymers to include biomolecules (high-molecular-weight molecules). These include nucleic acids such as DNA and RNA, polysaccharides such as heparin and hyaluronic acid, and proteins such as albumin. In other words, we observed similar characteristics in molecules that make up living organisms.

Whether biomolecules or synthetic polymers, materials with high biocompatibility share the same behavior of water—and that's when the hypothesis arose: "Is there some universal law at play?"

Kiyan: Around what point did that hypothesis turn into a conviction?

Professor Tanaka: "It was like a feeling that it might be 70 or 80 percent gradually built up. But it was hard to get to 100 percent. Furthermore, when we gathered data at the cellular and protein levels and took correlation coefficients with the intermediate water content, it came out particularly clearly in blood cells. At that point, it turned into a conviction that there were no exceptions."

Kiyan: What changes when intermediate water is present?

Professor Tanaka: I believe that intermediate water plays a role in "reducing unnecessary interactions."

• Suppresses unwanted protein adsorption and denaturation.

• Suppresses unwanted platelet adhesion

• Suppresses unwanted bacterial adhesion and inflammatory responses.

On the other hand, essential molecular recognition—such as specific receptor binding—can occur under appropriate conditions. The idea is that intermediate water plays a crucial role in maintaining this delicate balance.

Kiyan: From the perspective of living organisms, the ideal surface is not one that "sticks to anything and everything," but rather one that "can recognize only what is necessary." Intermediate water acts as a regulator in that process.

Professor Tanaka: That's exactly right. From a materials design perspective, "how to form intermediate water" will become a new design indicator for improving biocompatibility. It's a quantitative indicator that can be measured with DSC.

Kiyan: Currently, surface design is becoming important in many fields, not only for blood contact devices, but also for sensors, drug delivery systems, and microfluidic devices.

Professor Tanaka: The concept of intermediate water provides a perspective not only on "which material to use," but also on "how to design the interface between the material and the living organism." Differences that cannot be explained by water content or contact angle alone can be explained by the amount of intermediate water. This is a "new way of thinking about biocompatible materials."

The blood compatibility of PMEA can now be explained by the concept of intermediate water. However, connecting product development with basic research is not easy.

In the third installment, we will delve into how publishing research papers became a bridge to the medical field, my encounter with Professor Teiji Tsuruta, and the perspectives required of researchers in the age of AI and the value of industry-academia collaboration.