Assessing the resistance to calcification of polyurethane membranes used in the manufacture of ventricles for a totally implantable artificial heart.

Ventricles made from segmented polyurethane membranes and used in the fabrication of a totally implantable artificial heart are known to undergo biomaterial-associated calcification. As there is no effective method currently available to prevent such biomaterials from calcifying, a practical solution is to use only materials with a relatively high resistance to calcification, to extend ventricular durability and ensure a longer functional life for the manufactured device. In the present study, an in vitro calcification protocol was used to determine the relative resistance to calcification of six different polyurethanes, namely, Carbothane PC3570A, Chronoflex AR, Corethane 80A, Corethane 55D, Tecoflex EG80A, and Tecothane TT1074A. The results demonstrated that all six polyurethanes did become calcified during the 60-day incubation period in the calcification solution. The degree of calcification was found to be associated with the surface chemistry of the particular polyurethane, with the Tecothane TT1074A exhibiting the highest level. The Corethane 80A and 55D polymers showed a relatively low propensity to calcify. These two membranes can, therefore, be considered as the most appropriate materials for the fabrication of ventricles for a totally implantable artificial heart. In addition, since the calcification occurred primarily at the surface of the membranes, without affecting the bulk microphase structure, the issue of modifying the surface chemistry to reduce the incidence of calcification is discussed.     

Analysis and evaluation of a biomedical polycarbonate urethane tested in an in vitro study and an ovine arthroplasty model. Part I: materials selection and evaluation

The polyurethane elastomer (PU) Corethane 80A (Corvita) is being considered as the acetabular bearing material in a novel total replacement hip joint. The biostability of Corethane 80A was investigated in vitro (this work) and in vivo (reported separately) in a fully functioning ovine total hip arthroplasty (THA) model, with the PU as the bearing layer in a prototype compliant layer acetabular cup. The in vitro studies assessed the resistance of Corethane 80A to the main degradation mechanisms observed in PUs: hydrolysis, environmental stress cracking (ESC), metal ion oxidation (MIO) and calcification. The performance of the polycarbonate PU Corethane 80A was assessed alongside three other commercially available biomedical PUs: polyether PUs Pellethane 2363-80A (DOW Chemical) and PHMO-PU (CSIRO, not supplied as a commercial material) as well as polycarbonate PU ChronoFlex AL-80A (CardioTech). Chemical and structural variables that affect the properties of the materials were analysed with particular attention to the nature of the material's hard and soft segments. PU degradation was probed using a range of analytical tools and physical-testing methods, including mechanical testing, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and environmental scanning microscopy (ESEM). Corethane 80A displayed the best overall resistance to hydrolysis, ESC, MIO and calcification, followed by ChronoFlex 80A and PHMO-PU. Pellethane 80A was the least stable. This study provides compelling evidence for the biostability and effectiveness of Corethane 80A and points to its suitability for use as a compliant bearing layer in hip arthroplasty, and possibly also other joints.     

Light stability and discoloration of segmented polyether urethanes

Three diamine-extended polyether urethanes were prepared and their photodegradation studied. We find that the structure of the urea, as well as the urethane linkage, is important in determining photodegradation and discoloration of the polymers. Both processes can be minimized by using aliphatic diisocyanates and aliphatic diamine chain-extenders that contain no activated hydrogen alpha to nitrogen. In particular, an N-aryl urethane and an N-benzyl urea polymer photodegrade at about the same rate, but the N-aryl urethane that can form an extended conjugated system discolors more rapidly. The mechanisms for photodegradation of aryl and alkyl urea groups involving initial N-C bond cleavage appear to be analogous to the accepted mechanisms for the corresponding urethanes. After initiation, degradation of the polyether poly(oxypropylene glycol) also contributes to loss in molecular weight. This work was sponsored by the National Heart, Lung and Blood Institute, National Institutes of Health, under contract No. H01-HV-3-2959. The authors wish to thank Bruce K. Fritzinger for synthesis of the polymers and fabrication of the polymer films.     

Analysis and evaluation of a biomedical polycarbonate urethane tested in an in vitro study and an ovine arthroplasty model. Part II: in vivo investigation

The polyurethane (PU) elastomer Corethane 80A (Corvita) is being considered as the acetabular bearing material in a novel total replacement hip joint. Its biostability was investigated in vitro (Analysis and evaluation of a biomedical polycarbonate urethane tested in an in vitro study and an ovine arthroplasty model. Part I: material selection and evaluation, Biomaterials, in press) together with three other commercially available biomedical PUs: Pellethane 2363-80A (DOW Chemical), a polyhexamethylene oxide based PU, PHMO-PU (CSIRO, not supplied as a commercial product) and ChronoFlex AL-80A (CardioTech). From the in vitro studies, Corethane 80A displayed the best overall resistance to hydrolysis, ESC, MIO and calcification, followed by ChronoFlex 80A and PHMO-PU, with Pellethane 80A being the least stable. Building on the in vitro investigation, the follow-up in vivo study (reported here) assessed Corethane 80A as the bearing layer in a prototype compliant layer acetabular cup, in a fully functioning ovine total hip arthoplasty (THA) model. PU degradation in the retrieved cups was analysed using a range of analytical and physical-testing methods including mechanical testing, differential scanning calorimetry, Fourier transform infrared spectroscopy and environmental scanning electron microscopy. The Corethane 80A functioned well in the THA model, with the bearing surfaces of the retrieved hip cups showing no significant evidence of biodegradation or wear damage after 3 years in vivo. The findings in this study provide compelling evidence for the biostability and effectiveness of acetabular cups incorporating a Corethane 80A compliant bearing layer.     

Current status of extracorporeal ventricular assist devices in Japan

Extracorporeal VADs are less expensive, their prices reimbursable by the health insurance being about one-sixth of those of implantable VADs in Japan. However, a disadvantage is that, in Japan, their use is restricted to hospitals, necessitating prolonged hospitalization, reducing the patients’ quality of life. According to the Japanese registry for Mechanically Assisted Circulatory Support, the survival rate does not differ significantly between patients with extracorporeal and implantable VADs. As in Europe and North America, extracorporeal VADs in Japan are commonly used as Bridge to Decision or Bridge to Recovery. Extracorporeal VADs are switched to implantable VADs as a Bridge-to-Bridge strategy after stabilization or when cardiac function recovery fails. They are also used as right ventricular assist devices (RVADs) in patients with right heart failure. A special characteristic of extracorporeal VADs in Japan is their frequent use as a Bridge to Candidacy. In Japan, indications for implantable VADs are restricted to patients registered for heart transplantation. Therefore, in patients who cannot be registered for transplantation because of transient renal dysfunction, etc., due to heart failure, extracorporeal VADs are used first, and then replaced by implantable VADs after transplant registry is done. Here, we describe the current status of extracorporeal VADs in Japan, focusing on the environmental backgrounds, along with a review of the relevant literature.     

Effect of soft-segment chemistry on polyurethane biostability during in vitro fatigue loading

The effect of soft-segment chemistry on biostability of polyurethane elastomers was studied with a diaphragm-type film specimen under conditions of static and dynamic loading. During testing, the films were exposed to an H(2)O(2)/CoCl(2) solution, which simulated the oxidative component of the in vivo environment. Films treated for up to 24 days were evaluated by IR spectroscopy and by optical and scanning electron microscopy. Biostability of a poly(ether urethane) (PEU), which is known to undergo oxidative degradation, was compared with biostability of a poly(carbonate urethane) (PCU), which is thought to be more resistant to oxidation than PEU. Materials similar to PEU and PCU, in which the polyether or polycarbonate soft segment was partially replaced with poly(dimethylsiloxane) (PDMS), were also tested with the expectation that PDMS would improve soft-segment biostability. Oxidative degradation of the polyether soft segment of PEU was manifest chemically as chain scission and cross-linking and physically as surface pitting. Biaxial fatigue accelerated chemical degradation of PEU and eventually caused brittle stress cracking. In comparison, the polycarbonate soft segment was more stable to oxidation; there was minimal chemical or physical degradation of PCU, even in biaxial fatigue. Partial substitution of the polyether soft segment with PDMS enhanced oxidative stability of PEU. Although both strategies for modifying soft-segment chemistry improved the resistance to oxidative degradation, the outstanding mechanical properties of PEU were compromised to some extent.     

Classification et indications des dispositifs d’assistance cardiaque mécanique

Mechanical cardiac support represents a large spectrum of devices, differing by the duration of assistance, the support or replacement of the heart, the mono or bi ventricular assistance, the paracorporal or implantable positioning, the pulsed or continuous flow, the pneumatic or electric power source. We can distinguish: 1) the ECMO/ECLS systems (extracorporeal membrane oxygenation–extracorporeal life support) systems of peripheral extracorporeal circulation, accessible at patient bedside, that benefited from technological developments allowing longer assistance and therefore more indications; 2) the ventricular assist devices (VADs) that comprise pneumatic ventricles (mono- or biventricular, extra- or paracorporal), implantable left-VAD (pulsed-flow electromechanical ventricles and continuous-flow axial pumps), total artificial hearts (partially or totally implantable) and percutaneous left-VAD (available in the catheterization laboratory, still in the development stage). Partial or total mechanical cardiac support, although used in routine for 20 years, remains a technology seldom used outside the operating room. This slow diffusion is due to the small number of indications (end-stage heart failure and different heart failures considered as reversible), but also to its extreme complexity and to the alternative offered by heart transplantation. However, this situation is changing with the decreasing availability of organs and with the improvements of devices.     

Blood-compatible biomaterials by surface coating with a novel antithrombin-heparin covalent complex.

Covalent antithrombin-heparin complex (ATH) was covalently grafted to a polycarbonate urethane (Corethane) endoluminal graft (a kind gift of Corvita Corporation) after being activated using 0.3% m/m NaOCl in 0.15 M phosphate pH 6.0. ATH graft density (1.98 x 10(-7) mol/m2) was 6 times the maximum amount of unfractionated heparin (UFH) that could be bound to polycarbonate urethane surfaces. Surface-bound ATH could be stored in sterile 0.15 M NaCl at 4 degrees C for at least 2 months with good antithrombotic activity before being implanted into rabbits. Analysis of ATH-coated tubing showed that it contained significant direct thrombin inhibitory activity. In vivo testing in a rabbit model was compared to non-activated non-coated surfaces, activated-non-coated surfaces, hirudin-coated surfaces and antithrombin (AT)-coated surfaces. The weight of the clot generated in the ATH-coated graft tubing was significantly less than the weight of the clot generated within the hirudin-coated graft (p = 0.03 with a 1-tailed Student's t test). The anticoagulant nature of ATH grafts in vivo was shown to be due to bound ATH because boththe AT-coated surfaces and non-coated but activated surfaces showed similar thromboresistant efficacy to that of untreated material (ANOVA; p < 0.05). Apart from the direct antithrombin activity that contributed to much of the prolonged patency in vivo, surface-bound ATH likely catalyzed AT inhibition of thrombin, as evidenced by a significant number of 125I-AT binding sites (> or = 1.5 x 10(-8) mol/m2). Thus, ATH appears to be a good candidate for coating cardiovascular devices, such as endoluminal grafts, with high levels of substitution and significant long-term blood-compatibility.     

Synthesis and thermal stability of oligourethanes based on the cycloaliphatic diisocyanate trans,trans-4,4′-methylenebis(cyclohexylisocyanate)

The synthesis of molecularly uniform and isomerically pure oligourethanes is described. The compounds are models for the hard segments in polyurethane elastomers based on the aliphatic trans,trans-4,4′-methylenebis(cyclohexylisocyanate) (ttHMDI)/butanediol system. The thermostability of the urethanes was determined by differential scanning calorimetry (DSC), gel permeation chromatography (GPC) and temperature-dependent FT-IR spectroscopy. The aliphatic urethane group was found to be more stable than urethanes based on the corresponding aromatic 4,4′-methylenebis(phenylisocyanate) (MDI). The stability also depends on the physical properties and morphology of the oligourethane. The ttHMDI urethane group does not decompose up to the individual melting point of the oligomer, whereas in aromatic MDI diisocyanate systems decomposition occurs already significantly below the melting; the MDI-specific transurethanization is not observed in the ttHMDI-based urethanes.     

Enzyme-induced biodegradation of polycarbonate polyurethanes: dependence on hard-segment concentration

Polycarbonate-based polyurethanes with varying hard segment contents were synthesized. The physical and chemical structures were characterized by using gel permeation chromatography, differential scanning calorimetry, water uptake testing, Fourier transform infrared, and attenuated total reflectance--Fourier transform infrared. The polymers were incubated with cholesterol esterase in a phosphate buffer solution at 37 degrees C over 10 weeks. A higher resistance to hydrolytic degradation was observed in polycarbonate-based urethanes with higher hard segment content. The analysis of the material structures revealed that the degradation of polycarbonate-based urethanes was preferentially initiated at non-hydrogen-bonded carbonates and urethanes. Although the crystallinity of the polycarbonate soft segment may contribute to reducing the hydrolytic degradation catalyzed by cholesterol esterase, it was found to be relatively minor in comparison to the importance of hydrogen bonding between the carbonate and urethane groups. These observations suggest that the biostability of polyurethanes and specifically polycarbonate-based polyurethanes can be improved by manipulating the degree of hydrogen bonding within the materials.     

Mechanical circulatory support devices for bridge to heart transplantation, bridge to recovery, or destination therapy

Both the ventricular assist device (VAD) and the total artificial heart (TAH) have been effective in supporting circulation of end-stage cardiac patients and in bridging to heart transplantation. However, because of a shortage of donor hearts and age limitations, destination therapy with the completely implantable VAD has also been started. The totally implantable TAH in the United States is in the final stage of development and will go into preclinical trials in 2004. In Japan, heart transplantation has been re-instituted since last year, but because of shortages of donor hearts the waiting time prior to transplantation is fairly long. To date, six heart transplantations have been carried out, of which four have been bridged transplantations, using extracorporeal or implantable VADs. With the extracorporeal VADs, patients cannot be discharge home, which increases the hospital expenses. With the implantable VADs such as Novacor and HeartMate imported from the USA, patients can be discharged home, but major threats with these devices are thromboembolic, complications and infection. These devices are also fairly large, being designed for 80-kg patients, and are thus difficult to implant in patients of 50 to 60 kg, including women. Because of these limitations, there is a strong clinical demand for a compact, high-performance, implantable, permanent-use VAD. This paper addresses the current status of the artificial heart research and development program at the Tokyo Medical and Dental University, which was started in May 1999.     

Microstructure and Properties of Poly(amide urethane)s: Comparison of the Reactivity of α‐Hydroxy‐ω‐O‐phenyl Urethanes and α‐Hydroxy‐ω‐O‐hydroxyethyl Urethanes

Summary: Poly(amide urethane)s were prepared from ε‐caprolactam, amino alcohols, and diphenyl carbonate or ethylene carbonate in three steps. Polycondensation was performed either with α‐hydroxy‐ω‐O‐phenyl urethanes or with α‐hydroxy‐ω‐O‐hydroxyethyl urethanes; it was found that the reactivity at 90 °C of the first is much higher than that of the latter. For nearly equal reactivity, the temperature for the polycondensation of α‐hydroxy‐ω‐O‐hydroxyethyl urethanes had to be increased from 90 °C to 150 °C. The microstructure of the resulting poly(amide urethane)s differs by the content of urea groups in the polymer chains, which is 5% for poly(amide urethane)s prepared from α‐hydroxy‐ω‐O‐phenyl urethanes and 15% for poly(amide urethane)s prepared from α‐hydroxy‐ω‐O‐hydroxyethyl urethanes. As a consequence, the thermal properties of the poly(amide urethane)s differ slightly.

Synthesis of poly(amide urethane)s.     

Use of charged membranes to control interference by body chemicals in a glucose biosensor

The prerequisite for the continuous in vivo monitoring of glucose concentration is the development of an implantable glucose sensor with long-term stability. A new enzyme electrode concept featuring fluid-state glucose oxidase modified carbon powder along with a cross-linked glucose oxidase enzyme layer has been developed. The glucose sensor incorporating this enzyme electrode has been tested in vitro at 37°C. It has a lifetime of three months after which it can be recharged with fresh enzyme. The next step in the characterization of this sensor is its in vitro behaviour in the presence of interfering substances commonly encountered in human blood. Here we report such a study of the sensor. The glucose diffusion membranes used were polycarbonate membranes. We used standard polycarbonate membranes (membranes treated with polyvinylpyrrolidone or PVP), PVP-free polycarbonate membranes, and standard polycarbonate membranes coated with positively and negatively charged hydrogel layers. The sensors showed a response to glucose concentrations <300 mg dL⁻¹, both in pure phosphate buffer and in the presence of interferences. The influence of ascorbic acid, bilirubin, creatinine, L-cystine, glycine, uric acid and urea on the amperometric signal of the sensor was investigated. The polycarbonate membrane coated with the negatively charged hydrogel layer provided good protection for the enzyme electrode, especially in the presence of ascorbic acid and uric acid.     

Atomistic Simulation of the Shape‐Memory Effect in Dry and Water Swollen Poly[(rac‐lactide)‐co‐glycolide] and Copolyester Urethanes Thereof

An atomistic molecular dynamics simulation approach is applied to model the influence of urethane linker units as well as the addition of water molecules on the simulated shape‐memory properties of poly[(rac‐lactide)‐co‐glycolide] (PLGA) and PLGA‐based copolyester urethanes comprising different urethane linkers. The shape‐memory performance of these amorphous packing models is explored in a simulated heating–deformation–cooling–heating procedure. Depending on the type of incorporated urethane linker, the mechanical properties of the dry copolyester urethanes are found to be significantly improved compared with PLGA, which can be attributed to the number of intermolecular hydrogen bonds between the urethane units. Good shape‐memory properties are observed for all the modeled systems. In the dry state, the shape fixation is found to be improved by implementation of urethane units. After swelling of the copolymer models with water, which results in a reduction of their glass transition temperatures, the relaxation kinetics during unloading and shape recovery are found to be substantially accelerated.

     

Biocompatibility of six elastomers in vitro

The biocompatibility of two silicone rubbers, Silastic and Dow Corning Elastomer, and of a polyether and a polyester urethane, a polyether polyester copolymer, and polypropylene oxide was assessed in vitro. These elastomers were selected for assessment as a possible alloplastic tympanic membrane. For these studies use was made of rat middle ear mucosa explants and serially cultured epithelium. The quantitative results were based on epithelial growth curves, the morphological picture was based on the findings in epithelium, and the aging of a biomaterial was simulated. Epithelium morphology was investigated by scanning and transmission electron microscopy and x-ray microanalysis. Quantitative results showed that on Dow Corning Elastomer and polypropylene oxide, cell proliferation was significantly lower compared to normal growth curves. The morphological findings were negative for polypropylene oxide, and did not discriminate between the other biomaterials under study. The simulation results indicated better biocompatibility for the polyurethanes and the polyether polyester copolymer compared with that of polypropylene oxide and both silicone rubbers. Under the simulation conditions, cells exposed to Silastic showed silicon-containing inclusions. These in vitro results suggest that the biocompatibility of the polyurethanes and the polyether polyester copolymer is better than that of both silicone rubbers and polypropylene oxide.     

聚碳酸酯型聚氨酯的体外降解研究

本研究聚碳酸酯型聚氨酯(PCU),在预氧化处理后(5%H2O2/0.05M CoCl2溶液),再用酶(番木瓜蛋白酶,20U/ml的溶液)水解处理后的表面形态及分子结构变化,同时与聚醚聚氨酯(PEU)和氟碳化合物封端的聚碳酸酯型聚氨酯(PCUF)材料作对比。通过扫描电镜(SEM),光电子能谱(XPS)和分子量(GPC)表征材料表面降解情况和分子结构变化。结果证实了材料的抗氧化性能直接影响材料的整体降解情况,结果显示PCU抗氧化性能优良,所以它的整体抗降解能力比抗氧化能力较低的PEU强,而且在PCU中引入氟碳化合物,其抗降解能力会更强。     

Conversion from long-term AB-5000 to EVAHEART using a combined left thoracotomy and sternotomy approach

Because of the extreme donor shortage in Japan, waiting times for heart transplantation exceed 2 years. Since 1980s in Japan, device availability has also been an issue, with only a few paracorporeal ventricular assist devices (VADs) available as a bridge to transplantation or recovery. However, two implantable VADs became commercially available in 2011. Given these constraints in our healthcare system, we report a relatively rare case of bridge-to-bridge use of an implanted EVAHEART after having used a paracorporeal AB-5000 support for an extended period of time. We successfully employed a combined left thoracotomy and median sternotomy approach as a conversion technique.     

Thermally induced time dependence of mechanical properties in biomedical grade polyurethanes.

The time dependence of the mechanical properties of segmented urethanes as well as urethane-urea systems were monitored after the materials had been given a short thermal treatment followed by rapid cooling. Both linear and crosslinked materials were studied but the major focus was on many of the common biomedical grade urethanes. As had been noted in earlier studies on nonmedical segmented urethanes from this laboratory, many of the biomedical grade materials also showed time-dependent changes in mechanical properties that can be directly related to time-dependent changes in the degree of domain structure (microphase separation) that may occur in these segmented copolymers. Interestingly, those systems possessing significant amounts of urea linkage show little or no significant time-dependent changes in structure or properties following thermal treatment. The effect of chemical cross-linking can also influence the domain formation process and its thermal stability. The ramifications of these time dependent effects may have bearing on the biomaterial applications of segmented urethane polymers.     

Permeability of PEUU membranes: their modification towards blood compatibility

An attempt was made to develop haemodialysis membranes using polyether urethane urea synthesised in our laboratory. It was observed that the processing parameters such as precipitation medium, precipitation temperature etc. can influence the porosity of the membrane and subsequently the permeability property. It was also noted that the permeability of the dried membrane was negligible even though it was kept in distilled water overnight before use. The effect of pH on permeability through the membrane was studied by dialysis experiment using mixtures of various components such as urea, creatinine, uric acid, inulin, albumin, NaCl and KCl at various pH. Standard cellulose acetate (CA) membrane was used for comparison. Membranes were also prepared using biomer solution by precipitating in distilled water at room temperature and the monomer, 2-hydroxy ethyl methacrylate (HEMA) was grafted onto it by glow discharge technique. It was found that the permeability was increased by HEMA grafting with some loss of tensile strength and strain. A comparative study of fibrinogen adsorption during dialysis and adsorption by direct exposure of samples to a mixture containing urea, uric acid, creatinine, dextran, fibrinogen and electrolytes like sodium and potassium ions was also done with 125I labelled fibrinogen. Platelet adhesion studies indicated that the number of adhered platelets was less on the HEMA grafted samples which may enhance blood compatibility. Finally, the membranes were subjected to different sterilization processes possible under wet conditions such as glutaraldehyde treatment and autoclaving. The contact angle, permeability, mechanical property and platelet adhesion studies indicated that the sterilization method can affect the performance of the membrane.     

Structural characterization, mechanical properties, and in vitro cytocompatibility evaluation of fibrous polycarbonate urethane membranes for biomedical applications

This paper reports the electrospinning of a series of oxidatively stable polycarbonate urethanes (PCU) [carbothane (ECT), bionate (EBN), and chronoflex (ECF)] using N,N-dimethyl formamide and tetrahydrofuran as the mixed solvent. The nonwoven membranes were characterized for their structure, performance, and compatibility with cells. Scanning electron microscope was utilized to study the structural morphology and fiber diameter. Microcomputed tomography (micro-CT) was used to characterize the 3D architecture, pore size distribution, and percentage porosity. All the membranes displayed a porous architecture with average fiber diameter in the range of 1.5-2 μm. Static mechanical tests on the membranes revealed that the tensile strength was greater than 7 MPa and the dynamic mechanical tests showed that the average storage modulus (E(i) ) is 2 MPa at 37°C. PCU membranes were subjected to accelerated in vitro degradation for 90 days in 20% hydrogen peroxide/0.1M cobalt chloride solution. Mechanical characterization of the membranes postdegradation confirmed a 64% reduction in tensile strength for EBN at the end of 90 days where as ECF and ECT did not show any significant mechanical property deterioration in the oxidative medium. Cytotoxicity of the membranes was evaluated using L929 fibroblast cells and the results indicated that all the PCU membranes were cytocompatible and showed good adherence to L929 cells. Accordingly, these results highlight the potential of these fibrous PCU membranes for biomedical applications but further in vivo correlation studies are required for better understanding of the biodegradation and biological efficacy. ? 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A:3042-3050, 2012.