Effects of molecular architecture of phospholipid polymers on surface modification of segmented polyurethanes

To modify the surface properties of segmented polyurethane (SPU), effects of the molecular architecture of the 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers on the performance of the SPU/MPC polymer membrane were investigated. We combined the random-type, block-type, and graft-type of the MPC polymers with a typical SPU, Tecoflex^® using double solution casting procedure. The graft-type MPC polymers composed of a poly(MPC) main chain and poly(2-ethylhexyl methacrylate (EHMA)) side chains were synthesized through the combination of two different living radical polymerization techniques to regulate the density and chain length of the side chains. The SPU membranes modified with the MPC polymers were characterized using X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. The results revealed that the MPC units were located on the SPU surface. Although the breaking strength of the SPU membranes modified with block-type poly(MPC-block-EHMA) and graft-type poly(MPC-graft-EHMA) was lower than that of SPU membranes modified with random-type poly(MPC-random-EHMA), their breaking strengths were adequate for manufacturing medical devices. On the other hand, better stability was observed in the MPC polymer layer on the SPU membrane after immersion in an aqueous medium, wherein the SPU membrane had been modified with the poly(MPC-graft-EHMA). This was because of the intermixing of the hydrophobic poly(EHMA) segments in the domain of the hard segments in the SPU membrane. After this modification, each SPU/MPC polymer membrane showed hydrophilic nature based on the MPC polymers and a dramatic suppression of protein adsorption. From these results, we concluded that the SPU membrane modified with the poly(MPC-graft-EHMA) was one of the promising polymeric biomaterials for making blood-contacting medical devices.     

The vascular prosthesis without pseudointima prepared by antithrombogenic phospholipid polymer

On the luminal surface of the common synthetic vascular prostheses, blood coagulation can occur and a thrombus membrane is formed when blood flow passes through it. The thrombus membrane should be organized according to the wound healing process and it becomes a pseudointima which could serve as a blood conduit. However, the small-diameter vascular prosthesis may be quickly occluded by the initial thrombus. Therefore, no clinically applicable small-diameter prostheses have been developed to date. 2-Methacrylovloxyethyl phosphoryleholine (MPC) polymers resemble the structure of an outer cell membrane similar to the fluid mosaic model and demonstrate excellent antithrombogenicity. The purpose of this study is to develop a clinically applicable small-diameter prosthesis based on the new concept of the MPC polymer. We prepared vascular prostheses (2mm ID) from polymer blend composed of segmented polyurethane and the MPC polymer. The prostheses were placed in rabbit carotid arteries. The luminal surface retrieved at eight weeks after implantation was clear without thrombus and pseudointima. We now realize that the vascular prosthesis having the MPC polymer can be applied as a small-diameter prosthesis because it functions without thrombus and pseudointima formation.     

Nano-scale surface modification of a segmented polyurethane with a phospholipid polymer

Nano-scale modification of a segmented polyurethane (SPU) with cross-linked 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer was performed to obtain a biocompatible elastomer. To control the domain size and the depth of the modified layer, various compositions of monomers, including MPC, 2-ethylhexyl methacrylate (EHMA), and glycerol 1,3-diglycerolate diacrylate, were examined. SPU film was immersed in the monomer solution and visible light irradiation was applied to initiate polymerization to the SPU film that was held by mica to condense MPC units at the surface. The surfaces of the obtained film were analyzed by X-ray photoelectron spectroscopy and water contact angle measurement. The surface density of MPC units changed with the monomer concentration, and the density was the highest when the ratio between MPC and EHMA was 7:3. In modified SPU films, 6- to 25-nm MPC unit-enriched domains were observed and the density of these domains gradually decreased with depth. The sizes of the domains depended on the MPC composition in the monomer solution. The mechanical properties of the modified films as evaluated by tensile strength measurement under wet conditions were not significantly different from those of SPU. With increase in the existence of MPC unit-enriched domains on the MEG film surface, platelet adhesion and activation were remarkably reduced compared to the SPU film. This nano-scale surface modification may be a useful technique for applying elastic polymer biomaterials.     

Semi-interpenetrating polymer networks composed of biocompatible phospholipid polymer and segmented polyurethane

2-Methacryloyloxyethyl phosphorylcholine (MPC) polymers, which have excellent biocompatibility, have been receiving increasing attention in biomedical and bioengineering fields; however, the mechanical strength of the hydrated MPC polymers is not sufficient for use in these fields as a bulk material. Therefore, we hypothesized that a novel material might be realized by reinforcing the MPC polymer network with segmented polyurethane (SPU). Semi-interpenetrating polymer networks (IPNs) composed of crosslinked MPC polymer and SPU were prepared. The mechanical properties of the IPN membrane were significantly improved compared with those of the MPC polymer membrane. Three-dimensional polymer networks of the MPC polymer in the IPNs were observed after solvent extraction of SPU. An X-ray photoelectron spectrum analysis revealed that the MPC units were exposed on the IPN surface. When the IPN was alternately soaked in water and ethanol, the swelling ratio was found to be completely reversible and no disintegration of the network structure was observed. The permeation coefficient of 1, 4-di(2-hydroxyethoxy)benzene through the IPN membrane was 1.11 x 10(-7) cm(-2)s(-1). The amount of adsorbed protein and the number of adherent platelets on the IPN membrane were effectively reduced compared with those on SPU. We concluded that IPNs composed of the MPC polymer and SPU are a new bulk biomaterial, which possesses both blood compatibility and good mechanical properties.     

Improvement of blood compatibility on cellulose hemodialysis membrane: IV. Phospholipid polymer bonded to the membrane surface

To improve the surface blood compatibility on a cellulose hemodialysis membrane, 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers with a phospholipid polar group were immobilized on the surface through covalent bonding. The MPC polymers had a carboxylic group, which can react with hydroxyl groups on the cellulose membrane, and were synthesized by conventional radical polymerization. The reaction between the MPC polymers and the cellulose membrane was carried out in a heterogeneous system using a condensation reagent. Surface analysis of the modified membrane by X-ray photoelectron spectroscopy revealed the immobilization of the MPC polymer on the surface. The mechanical strength and permeability for a solute of the membrane did not change even after the modification. The modified cellulose membrane was blood-compatible, as determined by the prevention of adhesion, deformation, and aggregation of platelets after contact with platelet-rich plasma. Based on these results, it is concluded that the MPC polymers may be a useful material for improving the blood compatibility of cellulose hemodialysis membranes.     

Segmented polyurethane modified by photopolymerization and cross-linking with 2-methacryloyloxyethyl phosphorylcholine polymer for blood-contacting surfaces of ventricular assist devices

To improve the biocompatibility of pulsatile ventricular assist devices (VADs), the blood-contacting surface of the segmented polyurethane (SPU) diaphragm employed in an electromechanical VAD was modified by introducing 2-methacryloyloxyethyl phosphorylcholine (MPC) units into its surface and forming an interpenetrating polymer network (IPN) structure, which contained independently cross-linked MPC polymer and SPU. The SPU diaphragm modified with an IPN structure was then assembled into a target test pump and underwent continuous pump operation at 37°C for 2 weeks in a simulated systemic circulation using a mock circulatory loop. The surface characteristics of the pump diaphragm after 2 weeks of pump operation were then analyzed with an X-ray photoelectron spectroscope (XPS) and gold-colloid-labeled immunoassay. The XPS surface analysis of the IPN-modified SPU indicated the firm anchoring of MPC units even after 2 weeks of pump operation (the phosphor : carbon ratio was reduced by only 0.09%). The IPN-modified diaphragm prevented protein adsorption as well as cell adhesion in comparison to the unmodified SPU surface. This result thus validated that (1) the IPN structure could firmly secure MPC units to the SPU surface even in a high-mechanical-stress and high-shear environment, (2) the antithrombogenic power of MPC units remained unchanged after 2 weeks of continuous exposure to a high-shear environment, and (3) the IPN modified SPU cross-linked with MPC could be a powerful antithrombogenic surface for blood pumps used for chronic circulatory support of cardiac patients.     

Antithrombogenic polymer alloy composed of 2-methacryloyloxyethyl phosphorylcholine polymer and segmented polyurethane

To evaluate the antithrombogenicity of a new polymeric biomaterial in vivo, a polymer alloy tube composed of poly[2-methacryloyloxyethyl phosphorylcholine(MPC)-co-2-ethylhexyl methacrylate](PMEH) polymer and a segmented polyurethane (SPU) was prepared by a solvent evaporation method on a Teflon rod from a homogeneous solution containing both the PMHE and SPU. The composition of the PMEH vs the SPU was 10 wt%. The inner and outer surfaces of the polymer alloy tubing were characterized by X-ray electron spectroscopic (XPS) measurements. The MPC units were located on the inner surface of the polymer alloy tubing rather than the outer surface. After immersion in aqueous media, a higher concentration of the MPC units was observed on both surfaces. Selective staining of the MPC units with osmium tetraoxide was carried out to observe the morphology of the PMEH domain on the surface of the polymer alloy. There were large-sized PMEH domains on the inner surface of the tubing but small-sized domains were found on the outer surface. This result was in good agreement with the XPS results. Blood compatibility of the polymer alloy was evaluated by observation of fibrinogen adsorption and platelet adhesion from human plasma. A lot of fibrinogen was adsorbed and many platelets adhered to the inner surface of the original SPU tubing. On the other hand, the PHEH/SPU polymer alloy tubing suppressed these adsorptions and adhesions. When the PMEH/SPU polymer alloy tubing was implanted into a rabbit's artery, thrombus could not be observed even after a 7-day implantation but the original SPU tubing was almost totally occluded only after a 90-min implantation due to serious thrombus deposition on the surface. These results clearly indicated that the PMEH in the SPU matrix acted as an antithrombus reagent by suppression of protein adsorption and platelet adhesion and activation. Particularly, the MPC units played a significant role in this function.     

Physical properties and blood compatibility of surface-modified segmented polyurethane by semi-interpenetrating polymer networks with a phospholipid polymer

Segmented polyurethanes, (SPU)s, are widely used in the biomedical fields because of their excellent mechanical property. However, when blood is in contact with the SPU, non-specific biofouling on the SPU occurs which reduces its mechanical property. To obtain novel blood compatible elastomers, the surface of the SPU was modified with 2-methacryloyloxyethyl phosphorylcholine (MPC) by forming a semi-interpenetrating polymer network (semi-IPN). The SPU film modified by MPC polymer with the semi-IPN (MS-IPN film) was prepared by visible light irradiation of the SPU film in which the monomers were diffused. X-ray photoelectron spectroscopy confirmed that the MPC units were exposed on the MS-IPN film surface. The mechanical properties of the MS-IPN film characterized by tensile testing were similar to those of the SPU film. Platelet adhesion on MS-IPN films was also investigated before and after stress loading to determine the effects of the surface modification on the blood compatibility. Many platelets did adhere on the SPU film before and after stress loading. On the other hand, the MS-IPN film prevented platelet adhesion even after repeated stress loading.     

Synthesis, characterization and platelet adhesion of segmented polyurethanes grafted phospholipid analogous vinyl monomer on surface.

New segmented polyurethanes (SPUs) grafted phospholipid analogous vinyl monomer, 2-(methacryloyloxy)ethyl phosphorylcholine (MPC) on surface were synthesized. The soft segment of these polyurethanes was hydroxylated poly(isoprene) diol and the hard segments were 4,4'-methylenediphenyl diisocyanate (MDI) and 1,4-butanediol (BD). SPUs were hydroxylated by potassium peroxodisulfate and MPC was grafted on the surface of hydroxylated SPUs using di-ammonium cerium (IV) nitrate (ceric ammonium nitrate, CAN) as a radical initiator. The bulk characterization of synthesized SPUs was investigated by infrared spectroscopy (IR) and gel-permeation chromatography (GPC). The existence of phospholipid analogous groups on the surface of these SPUs was revealed by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS) and contact angle measurements. The surfaces of MPC-grafted SPUs showed decreased water contact angles compared to non-grafted SPU and the presence of phosphorylcholine groups. The blood compatibilities of the new polymers were evaluated by platelet rich plasma (PRP) contact studies and viewed by scanning electron microscopy (SEM) using BioSpan and non-grafted polyurethane as references. We found that fewer platelets adhered to the MPC-grafted surfaces and that they showed less shape variation than the references. These results suggest that these grafted polymers may have the possibility of the usage for biomaterials.     

Preparation and properties of biomedical segmented polyurethanes based on poly(ether ester) and uniform-size diurethane diisocyanates

This study describes the preparation and properties of a novel aliphatic cost-effective segmented polyurethanes (SPUs) based on poly(ether ester) (poly-(ε-caprolactone-co-l-lactide)-poly(ethylene glycol)-poly-(ε-caprolactone-co-l-lactide), PECLA) and uniform-size diurethane diisocyanates (HDI-BDO-HDI). PECLA was synthesized via bulk ring-opening polymerization with poly(ethylene glycol) (PEG) as an initiator and ε-caprolactone, l-lactide as monomers. By chain extension of PECLA diol with HDI-BDO-HDI, three SPUs with different hydrophilic segments content and hard segments content were obtained. The chemical structures of the chain extender, PECLA and SPUs were confirmed by ¹H NMR, ¹³C NMR, FT-IR, HR-TOF-MS and GPC. The influences of PEG content and uniform-size hard segments on in vitro degradability and mechanical properties of SPU films were researched. Similar thermostability observed in TGA curves of SPU films indicated that the hard segments and PEG content had little influence on the thermostability. The formation of microsphase-separated morphologies, which were demonstrated by the results of DSC and XRD, and physical-linking (H-bonds) network structures led to better mechanical properties of SPU films (ultimate stress: 23.1–17.9 MPa; elongation at break: 840–1130%). The results of water absorption and water contact angle showed that the bulk and surface hydrophilicity were closely related with the hydrophilic PEG content in SPU backbone. And the water absorption being less than 10 wt% indicated that the SPU films had low swelling property. In vitro hydrolytic degradation studies showed that the time of the SPU films becoming fragments was 34–19 days and the degradation rate increased with the increasing content of hydrophilic segments in SPUs, indicating that the degradation rate of SPU films could be controlled by adjusting PEG content. Cytotoxicity test of film extracts were conducted using L929 cells, and the relative growth rate exceeded 90% after incubation for 24, 48 and 72 h, showing excellent cytocompatibility. The acceptable mechanical properties, controllable biodegradability and excellent cytocompatibility of the polyurethanes can make them good candidates for further biomedical applications.     

Antithrombogenic polymer alloy composed of 2-methacryloyloxyethyl phosphorylcholine polymer and segmented polyurethane

To evaluate the antithrombogenicity of a new polymeric biomaterial in vivo, a polymer alloy tube composed of poly[2-methacryloyloxyethyl phosphorylcholine(MPC)-co-2-ethylhexyl methacrylate](PMEH) polymer and a segmented polyurethane (SPU) was prepared by a solvent evaporation method on a Teflon rod from a homogeneous solution containing both the PMHE and SPU. The composition of the PMEH vs the SPU was 10 wt%. The inner and outer surfaces of the polymer alloy tubing were characterized by X-ray electron spectroscopic (XPS) measurements. The MPC units were located on the inner surface of the polymer alloy tubing rather than the outer surface. After immersion in aqueous media, a higher concentration of the MPC units was observed on both surfaces. Selective staining of the MPC units with osmium tetraoxide was carried out to observe the morphology of the PMEH domain on the surface of the polymer alloy. There were large-sized PMEH domains on the inner surface of the tubing but small-sized domains were found on the outer surface. This result was in good agreement with the XPS results. Blood compatibility of the polymer alloy was evaluated by observation of fibrinogen adsorption and platelet adhesion from human plasma. A lot of fibrinogen was adsorbed and many platelets adhered to the inner surface of the original SPU tubing. On the other hand, the PHEH/SPU polymer alloy tubing suppressed these adsorptions and adhesions. When the PMEH/SPU polymer alloy tubing was implanted into a rabbit's artery, thrombus could not be observed even after a 7-day implantation but the original SPU tubing was almost totally occluded only after a 90-min implantation due to serious thrombus deposition on the surface. These results clearly indicated that the PMEH in the SPU matrix acted as an antithrombus reagent by suppression of protein adsorption and platelet adhesion and activation. Particularly, the MPC units played a significant role in this function.     

Thermal property and processability of elastomeric polymer alloy composed of segmented polyurethane and phospholipid polymer

To develop a thermoplastic elastomer with high blood compatibility, a 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer was blended with the segmented polyurethane (SPU) for preparing the polymer alloy. A tensile strength measurement was carried out to evaluate its mechanical strength. The mechanical strength of the SPU/MPC polymer alloy is the same as that of the original SPU and sufficient for use in medical applications. The thermal properties of the polymer alloy were evaluated by differential scanning calorimetry (DSC). The DSC curves indicated that the MPC polymer blended into the SPU did not affect the hard segment domain of the SPU. The SPU/MPC polymer alloy can be processed by heat treatment at 150 degrees C. Even after heat treatment, the SPU/MPC polymer alloy showed good mechanical properties, and MPC units were observed on the surface. Protein adsorption from human plasma was observed to evaluate the blood compatibility of the polymer alloy. The SPU/MPC polymer alloy suppressed protein adsorption on the surface before and after the heat treatment. Based on these results, it is concluded that the SPU/MPC polymer alloy has an excellent potential for application in various medical devices.     

Grafting of acrylonitrile to poly(styrene-co-acrylonitrile) by transformation with a titanium catalyst

Poly(styrene-co-acrylonitrile)-graft-polyacrylonitrile graft copolymers were prepared using a mixed (free-radical Vanionic) mechanism technique. For this purpose, poly(styrene-co-acrylo-nitrile) random copolymers which contain different amounts of acrylonitrile segments were regarded as saturated high-molecular-weight nitrile compounds and were allowed to react with tetrakis(dimethyl amino)titanium. By this treatment pendant nitrile groups were transformed to organometallic active sites. These active groups lead to the polymerization of acrylonitrile via an anionic insertion process. Polyacrylonitrile grafts were grown on the poly(styrene-co-acrylonitrile) backbone.     

Protein-Resistant Materials via Surface-Initiated Atom Transfer Radical Polymerization of 2-Methacryloyloxyethyl Phosphorylcholine

Poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC)) was grafted from various polymeric substrates to prepare protein-resistant materials. The poly(MPC) chain length was adjusted via the ratio of monomer to sacrificial initiator in solution. The surfaces were characterized by water contact angle and X-ray photoelectron spectroscopy (XPS). The protein-resistant properties of the poly(MPC)-grafted surfaces were evaluated by single adsorption experiments with fibrinogen and lysozyme. It was shown that the simple three-step grafting method could be applied to modify various biomaterial surfaces including polyurethane and silicones. The adsorption of fibrinogen and lysozyme to the modified surfaces was greatly reduced compared to the unmodified surfaces, and adsorption decreased with increasing poly(MPC) chain length. On polyurethane film grafted with poly(MPC) of chain length 100, the reduction in adsorption was approx. 96% for lysozyme and approx. 99% for fibrinogen.     

Effect of soft segment chemistry on the biostability of segmented polyurethanes. II. In vitro hydrolytic degradation and lipid sorption.

A series of segmented polyurethanes (SPUs) with various polyol soft segments was prepared and their hydrolytic degradation and degradation due to lipid sorption was investigated. The hydrolytic degradation of the SPUs was investigated in a papain solution, where it was shown that the SPU based on poly(ethyleneoxide) (PEO) soft segment was susceptible to hydrolytic degradation. X-ray photoelectron spectroscopic (XPS) data suggest dissociation of the urethane linkage by enzymatic degradation. Degradation by lipid sorption was observed for the SPU based on a poly(dimethylsiloxane) (PDMS) soft segment. This is ascribed to the high solubility of lipid in the PDMS segment of the SPU.     

Synthesis and thermotropic liquid-crystalline properties of polyurethane-polystyrene graft copolymers

New polyurethane-graft-polystyrenes (4) of well-defined structures and compositions were synthesized by macromonomer technique and the structure-liquid-crystalline (LC) property relationship is discussed. The expected graft copolymers with polystyrene grafts were prepared by melt polycondensation of a mixture of a dihydroxy derivative of biphenyl as a mesogenic moiety (1) and a dihydroxy-terminated styrene macromonomer (2) with diphenyl N,N′-hexamethylenedi-carbamate (3) . Of the resulting polymers mesogenic unit-rich graft copolymers retain the LC mesophases in spite of introduction of the polystyrene segments onto the polyurethane backbones and possess microphase-separated structures. Polystyrene-rich copolymers reveal no well-defined LC mesophases and analogous thermal properties to the polystyrene segments.     

Synthesis of poly(vinyl alcohol)-graft-poly(tetrahydrofuran)

The reaction of a living poly(tetrahydrofuran) (poly(THF)), prepared with methyl trifluoromethanesulfonate as an initiator, with 3-sodiopropoxydimethylvinylsilane was carried out to produce a uniform poly(THF) macromonomer with a vinylsilane end-group. Poly(vinyl acetate)-graft-poly(THF) of controlled graft segment length was then synthesized through radical copolymerization of this poly(THF) macromonomer with vinyl acetate. The subsequent saponification with NaOH in methanol provided poly(vinyl alcohol)-graft-poly(THF).     

Selective Grafting of Block Copolymers, 3a. Multigraft Copolymers

Double‐grafted copolymers, poly(hydrogenated isoprene)‐block‐{polystyrene‐graft‐[poly(4‐methylstyrene)‐graft‐polystyrene]} and poly(hydrogenated isoprene)‐block‐{polystyrene‐graft‐[poly(4‐methylstyrene)‐graft‐poly(tert‐butyl methacrylate)]}, were prepared using a procedure consisting of two steps. The starting block copolymer, poly(hydrogenated isoprene)‐block‐polystyrene, was metallated using a sec‐butyllithium/N,N,N ´,N ´‐tetramethylethylenediamine complex. The multi‐metallated intermediate produced served as a multifunctional initiator for the anionic polymerization of 4‐methylstyrene, giving rise to the corresponding graft copolymer. The similar grafting‐from procedure was again applied to the synthesized graft copolymer. Using phenylpotassium superbase as the metallating agent and styrene or tert‐butyl methacrylate as the monomers to be grafted, enabled the corresponding double‐grafted copolymers to be prepared.     

A nonthrombogenic gas-permeable membrane composed of a phospholipid polymer skin film adhered to a polyethylene porous membrane

Polymer membranes are widely used in biomedical applications such as hemodialysis, membrane oxygenator, etc. When the membranes come in contact with blood or body fluids, protein adsorption and cell adhesion occur rapidly. Nonspecific protein adsorption and cell adhesion on the membranes induce not only various bio-rejections but also a decrease in their performance. We hypothesized that a blood compatible gas-permeable membrane could be prepared from polyethylene (PE) porous membranes modified with phospholipid polymers. In this study, poly[(2-methacryloyloxyethyl phosphorylcholine) (MPC)-co-dodecyl methacrylate] (PMD) skin film adhered to a PE porous membrane (PMD/PE porous membrane) was prepared. Elution of PMD was not detected meaning that the PMD film did not detach from the PE porous membrane even after soaking in water for more than 6 months. The permeation coefficient of oxygen gas through the PE membrane with the adhered PMD containing more than 0.20 mole fraction of the MPC unit, was the same as that of the original PE porous membrane. The PMD surface effectively reduced biofouling. We concluded that the PMD/PE porous membrane is useful as a novel membrane oxygenator due to its excellent gas-permeability and blood compatibility.