Blood-Compatible Surfaces with Phosphorylcholine-Based Polymers

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Biological and Environmental Phenomena at the Interface

Blood compatible surfaces with phosphorylcholinebased polymers for cardiovascular medical devices Kazuhiko Ishihara Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b01565 • Publication Date (Web): 30 Jul 2018 Downloaded from http://pubs.acs.org on August 13, 2018

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Blood compatible surfaces with phosphorylcholine-based polymers for cardiovascular medical devices

Kazuhiko Ishihara

Department of Materials Engineering, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan

TEL: +81-3-5841-7124 Fax: +81-3-5841-8647 E-mail: [email protected]

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ABSTRACT: To obtain blood compatible materials, various hydrophilic polymers for surface modification have been examined. Among them, polymers with a representative phospholipid polar group, the phosphorylcholine (PC) group, are a successful example. These polymers were designed from inspiration of the cell membrane surface and provide protein adsorption resistance even following contact with plasma. This important property is based on the unique hydration state of water molecules surrounding hydrated polymer; in other words, water molecules weakly interact with the polymers and maintain their favorable cluster structure through hydrogen bonding. These polymers are not only hydrophilic, but also electrically neutral, important characteristics which make hydrogen bonding with water molecules less likely to occur and avoids hydrophobic interactions. Phosphorylcholine groups and other zwitterionic structures are significant as hydrophilic functional groups meeting these important requirements. In this review, blood compatibility of a polymer having a PC group is introduced in relation to its hydration structure, followed by a description of the applications of this polymer to cardiovascular medical devices.

Keywords: blood compatibility, phosphorylcholine group, zwitterionic polymers, protein adsorption, medical devices

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INTRODUCTION When blood encounters an artificial material, coagulation and thrombus formation immediately occur.1, 2 Thus, blood compatibility and antithrombogenicity are the most important properties required for blood-contacting medical devices.3-6 In particular, blood-contacting devices used in a living system for a long period of time, such as cardiovascular stents or implantable blood pumps, should have excellent blood compatibility. Although antithrombogenic treatments are available, the short-term application of blood-contacting devices used outside of a living system, such as blood purification devices and sensing devices, also require blood compatibility to reduce immune response and maintain device performance. To develop blood compatible materials, it is important for an understanding of blood-material interactions.7-9 Interactions occur reversibly and irreversibly between surfaces under biological circumstances and blood components, including ions, proteins, and cells. Further, interactions induce adsorption, denaturation, activation, and cell-cell interactions, all of which occur dynamically under variable conditions of exposure time. In addition, artificial materials quickly acquire an adsorption layer of protein whose protein composition of the outermost surface may vary with time in a complex manner. This phenomenon strongly depends on the chemical and physical properties of the material surface.10-12 Currently, the relationship between material surface properties and clinical performance of medical devices with the surface is not fully understood because the dynamics of protein-cell interactions on the surface under flow are extraordinary complex.

HYDROPHILIC POLYMERS FOR SURFACE MODIFICATION OF SUBSTRATES Considerable efforts have been made in eliminating protein adsorption on medical devices.8, 9, 13-15

Also, mechanism for protein adsorption on the solid surface have been examined from the

view point of physicochemistry.16-18 To prevent protein adsorption at the surface, hydrophilic polymers such as poly(2-hydroxyethyl methacrylate) (HEMA)) have been utilized.19-24 3


Indeed,

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HEMA-based polymers are hydrogels and are used as base materials for soft-contact lenses.19, 23 In addition, water-soluble polymers such as poly(ethylene oxide) (PEO) grafted on the substrate have been considered.25 Several approaches to PEO application have been examined and function well. These modifications provide proteins a characteristic similar to that of a high concentration PEO solution. PEO has a very unique solubility in that it not only dissolves in water, but also benzene. In an aqueous solution containing a high concentration of PEO, water molecules bind to PEO chains very tightly. As a result, at the high density PEO grafting surface, the water structure surrounding the PEO chains is strongly influenced by the PEO chain and can be altered. This change in water structure can induce conformational changes in proteins, resulting in a denatured protein that can cause problems in living organisms. In fact, some studies have claimed that protein adsorption resulting from a conformational change in the protein and platelet adhesion occur on PEO-modified surfaces.26-28 Another serious problem with PEO surfaces is degradation of the PEO chain by oxidation reaction in vivo. One study evaluated the effects of 3-mm diameter PEO-grafted segmented polyurethane (SPU) tubing on blood in vivo28, and found that the surface was covered with a thick protein adsorption layer about 100–200 nm thick 3 weeks after implantation, and the tubing was occluded by thrombus formation within 1 month. This phenomenon may be due to instability of the PEO grafting layer. Oxygen radicals formed by cells easily attack the ether bond in the PEO chain generating a peroxide linkage.29-32 This peroxide linkage can immediately decompose shortening the chain length and reducing the grafting density of PEO chains. Thus, PEO surfaces may be applied only in single-use blood-contacting devices for short treatment periods. As an alternative to surface modification with PEO, novel polymer systems have been considered and developed for long-term applications in medical devices. The most promising candidate polymer system is a phosphorylcholine (PC) group-bearing polymer (Fig. 1).33-37 Based on advanced research of this polymer system, further research on polymer systems possessing other similar structures has been pursued, with a focus on zwitterionic polymer 4


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systems. The surface properties and biological performance of which are introduced in the following section.

BIOLOGICALLY INERT SURFACES PREPARED BY POLYMERS WITH PC GROUPS The development of new blood compatible polymers was strongly inspired from the surface of the cell membrane. The extracellular surface of the lipid bilayer, which forms the matrix of the cell membrane, is mainly composed of the PC group of phosphatidylcholine and sphingomyelin. The PC group is a hydrophilic and an electrically neutral zwitterionic group that is inert in blood coagulation assays. In addition, phosphatidylcholine derivatives are applied as liposomal vehicles in pharmaceutical reagents to enhance reagent bioactivity. The liposomal formulation can be injected directly into the bloodstream. Chapman et al. observed that the introduction of phosphatidylcholine derivatives at the surface of the polymer and glass may possess antithrombogenicity.38 They evaluated the blood clotting process of poly(methyl methacrylate) (PMMA) bottles modified by coating with diparmitoylphosphatidylcholine (DPPC) or diparmitoylphosphatidylserine (DPPS), and found using a thromboelastometer that blood clotting was suppressed in the DPPC-treated bottle, while the non-treated PMMA bottle induced clot formation. The addition of DPPC liposomes in blood is not effective in reducing blood coagulation, and DPPS is also not effective in reducing clot formation. Based on these findings, they concluded that the PC groups on the surface effectively prevented surface-initiated clot formation. The same tendency, reduction of platelet adhesion and activation, was observed on the surface of cross-linked polydimethylsiloxane substrates or polyamide microcapsules treated with DPPC liposomes.39 Before biochemical research in the 1980s, developing new polymer materials in the 1970s in Japan required preparation of methacrylate monomers with phospholipid polar groups. Particularly, it was reported that polymethacrylate with PC groups may be used in biomedical polymeric materials.33, 36, 37 Based on the findings from these earlier studies, polymers with PC 5


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groups were good candidates in obtaining blood compatible polymeric materials; however, these attempts were not entirely successful because the purity, synthetic yield, and amount of compound were not satisfactory for use as a biomaterial at that time. Ishihara et al. took the challenge to synthesize a methacrylate monomer with a PC group, 2-methacryloyloxyethyl phosphorylcholine (MPC), using a convenient and efficient process. The synthesis of MPC was difficult; however, in 1987, they improved the synthesis process demonstrably obtaining a sufficient amount of MPC with excellent purity.40 Thus, it became possible to prepare various MPC polymers and their functionalities have been carefully evaluated.40-43 Currently, MPC and several MPC polymers are commercial available worldwide. Among MPC polymers, poly(MPC-co-n-butyl methacrylate (BMA)), with a MPC unit composition of 30 mol% and named PMB30, was the first such compound evaluated as a blood compatible polymer (Fig. 2).40,

41, 43-45

PMB30 was approved by the Food and Drug

Administration (FDA) in the United States under Master Access File LIPIDURE-CM5206. It is soluble in ethanol and the surface coating process can be performed by a simple dip-coating and drying procedure using the polymer solution. The thickness of the coating layer of PMB30 depends on the polymer concentration; at a concentration of 0.5 wt%, the thickness of the polymer layer on the substrate is approximately 50 nm.

SURFACE CHARACTERISTICS OF POLYMERS WITH PC GROUPS Surface wettability is an important parameter to take into account for biological applications. The contact angle that is formed between water and the substrate depends on mobility of the molecules on the surface. Thus, the dynamic contact angle loop of a polymer coated surface with PC group has a significant hysteresis caused by movement of the PC groups in the swelling process in response to environmental conditions.41, 46-48 In fact, immediately after the dip-coating process using an ethanol solution of PMB30, the hydrophobic BMA units located on the air contacting side of the coating layer on the substrate and contact angle by water is almost 80 6


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degrees. To reach an equilibrium state in aqueous medium, it takes several hours because the composition of the hydrophobic BMA unit is too high to provide stable attachment to the substrate. However, after equilibrium, the PC groups face the water-contact interface, and the water-contact angle is decreased dramatically to approximately 20 degrees, showing an extremely hydrophilic nature. By atomic force microscopic observation, it was revealed that the surface of a PMB30 coating is uniformly flat in an aqueous medium. Surface zeta-potential is another important parameter to determine protein adsorption. 49-53

The surface zeta-potentials of glass, poly(BMA), and poly(HEMA) are −60 mV, −40 mV,

and −16 mV, respectively. In contrast, coating with PMB30 results in a value of nearly zero (−0.4 mV).54 This difference is due to internal salt formation between trimethylammonium cations and phosphate anions in the PC group. In general, inorganic salts affect the electronic charge of the polymer even in the case of another zwitterionic polymer, poly(sulfobetaine methacrylate [SBMA]); however, for MPC polymers, no salt effects are observed.55-57 This finding is further evidence of the internal salt formation in the PC group and shielding of electrostatic interactions between the trimethylammonium cation and phosphate anion. When such internal salt formation occurs, the cation and anion are situated close to one another, with the three hydrophobic methyl groups bound to the nitrogen atom of the PC group located outside of the polymer chain. This arrangement provides a site that interacts favorably with water through hydrophobic hydration, inducing a more ordered water structure similar to that of free water in the bulk phase. The water molecules essentially make a clathrate around the trimethylammonium group of phosphatidylcholines.58, 59 This effect is considered to be due to the unique interfacial properties of PMB30 in an aqueous medium.60 Kitano et al. have performed significant and essential research regarding water structure in water-soluble polymer solutions and at water-contact interfaces of hydrophilic polymers. They evaluated water structure directly using Raman and infrared spectroscopies at the interface of MPC polymers, SBMA polymers, and a polymer containing a carboxybetaine 7


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methacrylate (CBMA) unit (Table 1).61-65 The N-value is defined as the number of hydrogen bonds between water molecules surrounding the polymer chains destroyed by hydration of the polymer. These polymers have N-values of almost zero or are slightly negative. In other words, these polymers show weak interactions with water molecules compared to those found of general polyelectrolyte and non-ionic hydrophilic polymers whose N-values are relatively large. From these observations, it is revealed that the PC group possesses a hydrophobic hydration layer that does not disturb the hydrogen bonding between the water molecules. Polymer brush structure using these polymers on the substrate shows other interesting properties as shown in Table 1.66 By comparison of the MPC polymer with other zwitterionic polymers, it takes much small effects to the water structure surrounding the polar group.

That is due to that the PC

group possesses a hydrophobic hydration layer that does not disturb the hydrogen bonding between the water molecules.

This property is good corresponded to the Whiteside’s

hypothesis for observing protein adsorption resistance at interface. He says that surfaces that resist the adsorption of proteins, in the set incorporate groups that exhibit four molecular-level characteristics:67 (i) They are hydrophilic. (ii) They include hydrogen-bond acceptors. (iii) They do not include hydrogen-bond donors. (iv) Their overall electrical charge is neutral.68

Further

investigation regarding the water structure of these zwitterionic polymers including MPC polymer have been performed by sum frequency generation.69-71

These seem to provide useful

support for understanding the relationship the hydration state of these zwitterionic groups. This unique hydration is one of the important properties to obtain excellent protein adsorption resistance following cell adhesion.60 It has been demonstrated that the free water fraction in hydrated polymers determines the amount of protein adsorbed on the surface.54 Polymers that have been evaluated include non-ionic amphiphilic polymers, such as poly(HEMA), poly(acrylamide (AAm)-co-BMA), poly(N-vinylpyrrolidone (VPy)-co-BMA), and the anionic amphiphilic polymer poly(sodium 2-acrylamide-2-propane sulfonate (AMPS)-co-BMA), as well as PMB30 and another MPC 8


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polymer, poly(MPC-co-n-dodecyl methacrylate(DMA)). Evaluation of the temperature dependence of hydration of these polymers shows that PMB30 exhibits the opposite tendency compared to other polymers. Although the hydration degree of general amphiphilic polymers decreases with an increase in temperature in the range of 20 °C to 50 °C, the hydration degree of PMB30 increases. This characteristic is related to findings by Kitano who reported that water structure is strongly dependent on the chemical structure of the hydrophilic group.61,62 Generally speaking, the water content of a hydrated amphiphilic polymer possessing both hydrophilic and hydrophobic groups decreases with a rise in temperature.40 This effect can be explained by the thermal property of hydrophobic interactions based on water structure in the vicinity of the hydrophobic groups. The formation of a hydrophobic interaction is an endothermic process, and this interaction acts as a cross-link in amphiphilic polymer chains reducing the water content in the polymer. In contrast, water forms hydrogen bonds with the hydrophilic groups of the polymer, and this hydrophilic hydration increases with temperature. As a result, the polymer chain should expand entropically with temperature, causing an increase in the capacity for water absorption. In the case of PMB30, the latter phenomenon was considered a dominant factor in the hydrated state. Thus, hydration of PMB30 increases with an increase in temperature. Thermal analysis using differential scanning calorimetry (DSC) revealed much about differences in the water state in hydrated polymers.54 The DSC curve of hydrated poly(HEMA) has a main peak at approximately 0 °C (free water region), and a shoulder peak at around – 20 °C. Further, a broad peak in the temperature range between –20 °C and –40 °C (intermediate water region) was observed in DSC curves of poly(AAm-co-BMA) and poly(VPy-co-BMA). In contrast, PMB30 has a single peak near 0 °C. The exothermic peak at approximately 0 °C is assumed to be because of free water (bulk water), and that the free water fraction in the hydrated polymer membrane is calculated from the degree of equilibrium hydration. As shown in Table 2, hydrated MPC polymer has a large amount of free water.

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BIOLOGICAL REACTIONS AT THE POLYMER SURFACE Protein adsorption and conformational change.

The amount of adsorbed

proteins in blood, such as albumin and fibrinogen, depend on the free water fraction (Fig. 3).54, 72

As already explained, MPC polymers have an extremely high free water fraction. The

theoretical amounts of albumin and fibrinogen adsorbed on the surface in a monolayer state are 0.9 µg/cm2 and 1.7 µg/cm2, respectively. On the surface of PMB30, the determined amount of adsorbed proteins are less than these theoretical values, being approximately 0.1 µg/cm2 under this condition. The PC group effectively weakens protein adsorption force at the interface. Protein adsorption starts with a protein-trapping process by the network structure of water molecules at the surface.73,74 The longer a protein is in contact with the surface, the greater the chance of the protein interacting with the surface, undergoing a conformational change and inducing irreversible adsorption.73 The removal of water molecules induces direct contact between amino acid residues and the polymer surface. A repulsive solvation interaction, also known as a hydration interaction, arises whenever water molecules associate with surfaces containing hydrophilic groups, and its strength depends on the energy necessary to disrupt the ordered water structure and ultimately dehydrate the surface.75 Protein adsorbed on the surface loses bound water at the surface-contacting portion, causing a conformational change as the hydrophobic part of the protein is exposed and contacts the polymer surface directly. If the water state at the surface is similar to that in the bulk solution, the protein does not need to release bound water molecules even during contact with the surface. Conformational change of protein adsorbed on a polymer substrate is directly evaluated by circular dichroism spectrum measurement. PMB30 is coated on a quartz plate and immersed in protein solution.54 A negative ellipticity at 222 nm of albumin and fibrinogen, which is observed in phosphate-buffered saline, is maintained even following contact with a PMB30 surface. This determination means that the proteins have a native conformation at a PMB30 surface. In contrast, on a poly(HEMA) surface, a dramatic conformational change is observed after 60-min contact. 10


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Protein adsorption on PMB30 was determined from human plasma by radioimmunoassay and an immunogold labeling technique to understand the kind of protein localized to plasma contacting the surface. The results clearly showed that the amount of localized protein was small and there was no accumulation of any specific protein at the interface.45 Based on these findings, it was concluded that the PC group effectively reduces protein adsorption and conformational change, and that this effect may be due to unique hydration of the PC group at the polymer surface. Recent research has clearly found that the adsorption force of proteins at the well-defined MPC polymer and other zwitterionic polymer surfaces is very small compared to that observed on other hydrophilic polymers, and furthermore, there is very good correlation to the amount of protein adsorbed on the surface.76-78

Platelet adhesion and activation.

To understand blood compatibility, platelet adhesion

and activation should be considered. Platelets play a critical role in blood coagulation. After protein adsorption on the surface of a substrate, platelet adhesion follows through a ligand-receptor reaction. During this process, a conformational change of fibrinogen exposes peptide sequences that interact with and capture platelets. Platelet activation induces positive feedback resulting in a greater accumulation of platelets as well as fibrin deposition, resulting in thrombus generation. Therefore, these processes should be suppressed on blood-contacting surfaces. Coating polymer and metal substrates with PMB30 effectively suppresses adhesion and activation of platelets, which has been examined in vitro using both platelet-rich plasma and whole blood.37,

41, 44

Platelet activations can be determined by measuring the intracellular

concentration of calcium ions using a fluorescence probe.37, 79 Compared to that found on a glass substrate, platelet activation was significantly suppressed on a PMB30-coated substrate. A microfluidic device was used to evaluate platelet adhesion under dynamic flow.80-82 Flowing a platelet suspension through the microfluidic chip resulted in significant adhesion to the substrate 11


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following surface contact; however, coating the contact surface with PMB30 resulted in no platelet accumulation. Similarly, using a different evaluation system to test the PC group of MPC on a metal substrate, researchers found that the PC group effectively inhibits coagulation of blood components.81

Whole blood responses. In one study, whole blood responses under flow conditions are observed using a diaphragm-type blood pump made by segmented polyurethane (SPU) (Fig. 4)83. The PMB30 can be coated on the SPU easily by solution casting procedure.84

The inner

surface of the pump is coated with PMB30 and whole blood is circulated through the blood circuit. After 1-h circulation, the inner surface of the pump is examined with a scanning electron microscope (SEM). On a PMB30-coated surface, no blood cell adhesion or thrombus formation is observed, while severe platelet adhesion and fibrin deposition are found on the non-treated surface. This diaphragm-type blood pump is used in animal experiments to evaluate blood compatibility over a much longer period of time. The blood pump is attached to sheep by normal surgery as a ventricular assist device (VAD) attachment.85 Although severe thrombus formation is observed in the untreated pump after 4 days, no thrombus formation is observed 27 days post-implantation in the case of the pump with PMB30 coating.

Bacterial infection and biofilm formation resistance.

Bacterial infections can induce

severe problems for the proper function of medical devices implanted into a living system, and can even result in device failure. Although administration of antibiotics is carried out to treat the infection, biofilm formation and adherence to medical devices confounds effective treatment using antibiotics. Therefore, anti-bacterial adhesion, bacteria growth inhibition, and biofilm formation resistance are important characteristics for medical devices. Bacterial adhesion can be induced by proteins adsorbed on the surface. To improve resistance against bacterial adhesion and biofilm formation, coating surfaces with PMB30 have given excellent results.86-88 Stainless 12


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steel (SUS) substrates modified with PMB30 have been incubated in medium containing bacteria.86 On the untreated SUS surface, adherent bacteria as well as bacterial enveloping biofilms are observed, and the addition of antibiotics does not effectively decrease the number of bacteria on the surface. On the other hand, SUS surfaces modified with PMB coating have no biofilm formation and the number of adherent bacteria is significantly decreased. The addition of potent antibiotics further decreased the number of bacteria by 100 to 1000 times less. PMB30 coating combined with antibiotics may provide a method to simultaneously achieve a biocompatible device surface and prevent device-associated infection.

CARDIOVASCULAR APPLICATIONS Implantation of a VAD is associated with a number of complications, including infection, bleeding, and thromboembolism, and these biocompatibility concerns are the major reason why VADs are arguably underutilized for treating patients with heart failure.89,

90

In particular,

platelet adhesion and thrombus formation still occur on the surface of the titanium that the device is constructed from, resulting in thromboembolism or an increased risk of bleeding due to the necessary use of anticoagulants. For the latest VAD, EVAHEART® (Sun Medical Technology Research Co., Japan), titanium is mainly used as the base material. VADs provide circulatory support to those in end-stage heart failure via pulsatile or rotary actuation of blood. To improve blood compatibility of the titanium surface, PMB30 has been applied as a surface treatment using a solution casting procedure.91, 92 After a long-term movement test of the pump and in vivo animal tests, the first clinical implantation of EVAHEART® is successfully performed in a pilot study consisting of 18 patients in May 2005. After obtaining permission for production and covered by National Health Insurance since March 2011 in Japan, more than 160 patients have been supplied with EVAHEART® as of December 2017. A clinical trial of the device is underway in the United States (ClinicalTrials.gov Identifier: NCT01187368).

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It has been extensively shown that the modification of surfaces with MPC polymers is effective in improving blood compatibility by suppressing protein adsorption, platelet adhesion, and platelet activation at the blood-contacting surface. Therefore, MPC polymers have been recently applied to reduce thrombogenicity of blood contacting devices and cardiovascular devices, including stents, oxygenators, and small-diameter vascular prostheses, as summarized in Table 3.93-108

CONCLUDING REMARKS AND FUTURE PERSPECTIVE Polymers with a PC group are originally designed by inspiration from the structure and function of the cell membrane. Methacrylate with the PC group in the side chain, MPC, is produced at an industrial scale and is available worldwide. MPC polymers can be used for surface modification of substrates by simple procedures and provide an excellent biocompatible surface reducing surface protein adsorption.

In the initial period of the MPC polymer research, it is considered

that the adsorption of phospholipids and construct cell membrane-like structure on the MPC polymer surface might be a main factor to provide good blood compatibility.72

However, by

carrying out much detailed research with attention to the interface of water-contact surface, it is revealed that the water structure surrounding the PC group is unique, that is, its high free water fraction is much effect on generate protein adsorption resistance.54 During the last 20 years, many medical devices have utilized the MPC polymers.109, 110 The science of MPC polymers has also initiated significant interest in zwitterionic polymers, with attention recently being paid to the chemistry of carboxybetaine polymers 111-113 , sulfobetaine polymers114-117, and poly(choline phosphate).118-120

It can clearly expect the lower

protein adsorption on these zwitterionic polymers from the viewpoints of water structure of the carboxybetaine polymers, sulfobetaine polymers. 121 The water structures have been examined by Kitano’s group firstly using IR spectrophotometory63-65, followed by sum frequency generation vibrational spectroscopy69-71, 122-124 and dynamic molecular simulations.125,126 14


As

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explained briefly, at the water-contacting surface, these polymers have a hydration layer based on the electrostatic interactions between charged groups and water molecules. This layer induces the ordering of water molecules surrounding the polymers and forms bulk-water like structure by hydrogen bonding. Although the hydration layer influences the water structure by ions in the aqueous medium, protein molecules attached at the interface do not influence the hydration structure.122,123

These findings are important to explain low protein adsorption

phenomena on these zwitterionic polymers. Biological responses, such as platelet adhesion and bacteria adhesion, following the protein adsorption process on these polymers, are also suppressed, when they are examined in vitro and ex vivo.111,112,115,116,127-129

In order for these

polymers to be used as materials for preparing the medical devices, it is necessary to exhibit not only biological performance of the polymers but also their safety and stability for sterilization130, 131

, long-term storage, and clinical use. The number of articles concerning these polymers

increases year by year, and it is expected that biomedical devices incorporating them will soon be developed in a similar manner to that found with MPC polymers.

ACKNOWLEDGEMENTS The author thanks Dr. Kyoko Fukazawa and Dr. Yuuki Inoue at The University of Tokyo for their kind supports in the preparation of the manuscript.

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Figure Captions

Figure 1. Molecular design of MPC, its polymers, and the chemical structure of other zwitterionic methacrylate monomers.

Figure 2. Chemical structure and fundamental properties of PMB30, a representative MPC polymer approved by the FDA.

Figure 3. Relationship between free water fraction in the polymer layer and amount of protein adsorbed on the surface. Open circle: albumin adsorption; closed square: fibrinogen adsorption.54

Figure 4. Blood compatibility under flow conditions using a blood pump and circuit. Images on the left show the complete experiment set up and those on the right are SEM images of the surface after 1-h blood circulation.83

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Figure 1. Molecular design of MPC, its polymers, and the chemical structure of other zwitterionic methacrylate monomers. 254x190mm (72 x 72 DPI)


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Figure 2. Chemical structure and fundamental properties of PMB30, a representative MPC polymer approved by the FDA. 254x190mm (72 x 72 DPI)


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Figure 3. Relationship between free water fraction in the polymer layer and amount of protein adsorbed on the surface. Open circle: albumin adsorption; closed square: fibrinogen adsorption.54 254x190mm (72 x 72 DPI)


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Figure 4. Blood compatibility under flow conditions using a blood pump and circuit. Images on the left show the complete experiment set up and those on the right are SEM images of the surface after 1-h blood circulation.83 254x190mm (72 x 72 DPI)


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Table 1. Interfacial properties of polymers bearing PC group, sulfobetaine group and carboxybetaine group. Poly(HEMA)

Poly(MPC)

Poly(MPC-co-BMA)

Poly(SBMA )

Poly(SBMA-co-BMA)

Poly(CBMA )

Poly(CBMA-co-BMA)

Mole fraction of polar group

1.00

1.00

0.30

1.00

0.34

1.00

0.45

Air contact angle in water

150.4 ± 2.1a)

170 ± 0.8b)

152.2 ± 1.9 a)

155 ± 1.9 b)

150.2 a)

148 ± 1.8 a)

150.4 b)

(polymer brush) Interfacial energy of polymer brush

(polymer brush)

(polymer brush)

-

74.5

-

73.1

-

70.8

-

N valuec)

-

-0.7

-0.4

1.2

3.4d)

-0.27

0.02

Amount of protein adsorbed on the

50 – 100

Blood-Compatible Surfaces with Phosphorylcholine-Based Polymers

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