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Hydrophilic materials display "bio-inert properties", meaning that they are less recognized as foreign substances by proteins and cells. Such materials are often water soluble; therefore, one general approach to enable the use of these materials in various applications deals with copolymerizing hydrophilic monomers with hydrophobic ones to facilitate such resulting copolymers water insoluble. However, reducing the hydrophilic monomer amount may reduce the bio-inert properties of the material. The decrease in bio-inert properties can be avoided when small amounts of fluorine are used in copolymers with hydrophilic monomers, as presented in this article. Even in small quantities (7.9 wt%), the fluorinated monomer, 1,1,1,3,3,3-hexafluoropropan-2-yl 2-fluoroacrylate (FAHFiP), contributed to the improved hydrophobicity of the polymers of the long side-chain poly(ethylene glycol) methyl ether methacrylate (mPEGMA) bearing nine ethylene glycol units turning them water insoluble. As evidenced by the AFM deformation image, a phase separation between the FAHFiP and mPEGMA domains was observed. The copolymer with the highest amount of the fluorinated monomer (66.2 wt%) displayed also high (82 %) FAHFiP amount at the polymer-water interface. In contrast, the hydrated sample with the lowest FAHFiP/highest mPEGMA amount was enriched of three times more hydrophilic domains at the polymer-water interface compared to that of the sample with the highest FAHFiP content. Thus, by adding a small FAHFiP amount to mPEGMA copolymers, water insoluble in the bulk too, could be turned highly hydrophilic at the water interface. The high content of intermediate water contributed to their excellent bio-inert properties. Platelet adhesion and fibrinogen adsorption on their surfaces were even more decreased as compared to those on poly(2-methoxyethyl acrylate), which is typically used in medical devices., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fluorine-containing polymers are used not only in industrial processes but also in medical applications, because they exhibit excellent heat, weather, and chemical resistance. As these polymers are not easily degraded in our body, it is difficult to use them in applications that require antithrombotic properties, such as artificial blood vessels. The material used for medical applications should not only be stable in vivo, but it should also be inert to biomolecules such as proteins or cells. In this review, this property is defined as "bio-inert," and previous studies in this field are summarized. Bio-inert materials are less recognized as foreign substances by proteins or cells in the living body, and they must be covered at interfaces designed with the concept of intermediate water (IW). On the basis of this concept, we present here the current understanding of bio-inertness and unusual blood compatibility found in fluoropolymers used in biomedical applications. IW is the water that interacts with materials with moderate strength and has been quantified by a variety of analytical methods and simulations. For example, by using differential scanning calorimetry (DSC) measurements, IW was defined as water frozen at around -40°C. To consider the role of the IW, quantification methods of the hydration state of polymers are also summarized. These investigations have been conducted independently because of the conflict between hydrophobic fluorine and bio-inert properties that require hydrophilicity. In recent years, not many materials have been developed that incorporate the good points of both aspects, and their properties have seldom been linked to the hydration state. This has been critically performed now. Furthermore, fluorine-containing polymers in medical use are reviewed. Finally, this review also describes the molecular design of the recently reported fluorine-containing bio-inert polymers for controlling their hydration state. STATEMENT OF SIGNIFICANCE: A material covered with a hydration layer known as intermediate water that interacts moderately with other objects is difficult to be recognized as a foreign substance and exhibits bio-inert properties. Fluoropolymers show high durability, but conflict with bio-inert characteristics requiring hydrophilicity as these research studies have been conducted independently. On the other hand, materials that combine the advantages of both hydrophobic and hydrophilic features have been developed recently. Here, we summarize the molecular architecture and analysis methods that control intermediate water and provide a guideline for designing novel fluorine-containing bio-inert materials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)