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Pharmacokinetic modeling of 4,4'-methylenedianiline released from reused polyurethane dialyzer potting materials.

4, 4'-Methylenedianiline (MDA) is a hydrolysis degradation product that can be released from polyurethanes commonly used in medical device applications. MDA is mutagenic and carcinogenic in animals. In humans, it is hepatotoxic, a known contact and respiratory allergen, and a suspected carcinogen. A physiologically based pharmacokinetic (PBPK) model was developed to estimate the absorption, distribution, metabolism, and excretion of MDA in patients exposed to MDA leached from the potting materials of hemodialyzers. A worst-case reuse situation and a single use case were investigated. The PBPK model included five tissue compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues, and richly perfused tissues. Physiological and chemical parameters of a healthy individual used in the model were obtained from the literature. The model was calibrated using previously published kinetic studies of IV administered doses of (14) C-MDA to rats. The model was validated using independent data published for MDA-exposed workers. The PBPK results indicated that dialysis patients who are exposed to MDA released from dialyzers (new or reused) could accumulate low levels of MDA and metabolites (total MDA) over time.

Aniline Compounds↗

Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces.

Thin layers of gold were deposited on polyurethane film and chemisorbed with three peptides having an N-terminal cysteine: Cys-Pro-Arg, Cys-(L)Phe-Pro-Arg, and Cys-(D)Phe-Pro-Arg. The ability of these surfaces to act as thrombin scavengers was evaluated. The peptides are related to the known thrombin inhibitor Phe-Pro-Arg chloromethyl ketone and were shown to have significant thrombin inhibitory activity in solution. Attachment of the peptides to gold was confirmed by water contact angle and X-ray photoelectron spectroscopy measurements. Thrombin adsorption from a buffer and plasma was investigated, and chromogenic substrate assays were carried out for thrombin activity on the surfaces and in the supernatant following adsorption. The data suggest that the peptide-modified surfaces are able to adsorb thrombin with high affinity from a buffer and that thrombin is taken up selectively from plasma. The Cys-(D)Phe-Pro-Arg modified surfaces showed particularly high affinity for thrombin. It was also found that the activity of thrombin adsorbed on the peptide surfaces was inhibited, and inhibition was greatest on the Cys-(D)Phe-Pro-Arg surface. We concluded that the peptide surfaces may have potential as antithrombogenic materials via their ability to scavenge and inhibit thrombin generated as a result of blood-material contact.

Adsorption↗

Polyurethane membrane as an efficient immobilization carrier for high-density culture of rat hepatocytes in the fixed-bed reactor.

A fixed-bed bioreactor with a polyurethane membrane (PUM) as a cell-supporting material was developed for high-density culture of rat hepatocytes. The PUM has a heterogeneous porous structure of micropores (pore size <100 microm) and macropores (pore size >100 microm) with a porosity of 90%. One important feature of a PUM is that the macropores have finger-like structures and their diameters gradually decrease from the upper to the lower layer of the PUM. Most rat hepatocytes were readily immobilized in the micropores of PUM. Immobilized cell densities of 1-3 x 10(7) cells/cm(3) PUM were achieved within 5 min by natural downflow of cell suspension and their immobilization efficiencies were more than 99%. Using a syringe pump, a cell density of 5 x 10(7) cells/cm(3) PUM was achieved with more than 96% immobilization efficiency. Perfusion cultures using this reactor were performed for 7 days without cell leakage. The optimal cell density for albumin secretion was between 2 x 10(7) and 3 x 10(7) cells/cm(3) PUM. Albumin secretion in the perfusion culture was maintained for a relatively long period of time when compared to that in the monolayer culture. The rate of albumin secretion in the perfusion culture was about 50% of that in monolayer culture. Hepatocytes immobilized in PUM were slightly aggregated, but they maintained spherical form individually even after 7 days of cultivation. The above results show that PUM is a promising cell-supporting material for efficient immobilization of high cell density of hepatocytes.

Albumins↗

Highly efficient immobilization of glycosylated enzymes into polyurethane foams.

Glycosylated enzymes, including aminoacylase from Aspergillus melleus, chloroperoxidase from Caldariomyces fumago, and phytase from Aspergillus ficuum, were covalently immobilized into polyurethane foams with very high enzyme loadings of up to 0.2 g protein per gram dry foam. The immobilization efficiency (retained activity) ranged from 100% at a low loading to 60% at high loadings. In contrast to many other immobilization methods no leaching of the enzyme from the support took place under the reaction conditions. In short, a universal method for the immobilization of enzymes from fungal sources was developed, affording a highly active, stable, and reusable biocatalyst.

6-Phytase↗

Type I atelocollagen grafting onto ozone-treated polyurethane films: cell attachment, proliferation, and collagen synthesis.

An approach is presented for the graft copolymerization of type I atelocollagen onto the surface of polyurethane (PU) films treated with ozone. Through inducing oxidization to modify PU surface by ozone, peroxide groups are easily generated on the surface. Those peroxides are broken by redox-polymerization, and provide active species which initiate graft polymerization by reacting with amines in the collagen molecules. The ozone oxidation time and voltage could readily control the amount of peroxide production. The surface density of generated peroxides on PU surface was determined by iodide method. The maximum concentration of peroxide was about 10.20 x 10(-8)mol/cm(2) when ozone oxidation was performed at 60 V for 30 min. After the reaction of PU by ozone oxidation, type I atelocollagen was graft-copolymerized onto the PU film. All the physical measurements on the collagen-grafted surface indicated that the PU surface was effectively covered with type I atelocollagen. The interaction of the collagen-grafted PU surface with fibroblasts could be greatly enhanced by the surface graft polymerization with type I atelocollagen. Attachment and proliferation of fibroblasts on the grafted type I atelocollagen were significantly enhanced, and it is assumed that the atelocollagen matrix supported the initial attachment and growth of cells. In the early stage of proliferation, collagen synthesis in fibroblasts was not activated and remained at a relatively low level due to the grafted type I atelocollagen, increasing only with fibroblast differentiation.

Animals↗

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.

Absorption↗

Plasma-based sterilization: effect on surface and bulk properties and hydrolytic stability of reprocessed polyurethane electrophysiology catheters.

Plasma-based sterilization is a promising alternative to ethylene oxide (EO) for reprocessing of electrophysiology catheters. To assess its safety in terms of material damage, modifications of surface and bulk properties as well as hydrolytic stability of sterilized catheters were evaluated. Polyurethane (PU) single-use electrophysiology catheters were subjected to one, five, and ten sterilization cycles by Sterrad-100S and Plazlyte, as well as by pure EO for comparison. Surface analysis techniques (ATR-FTIR, XPS, DCA) showed oxidation limited to the near-surface layer induced by both plasma-based sterilizers, whereas EO induced slight but deeper alkylation. Using bulk analysis techniques (RP-HPLC, SEC), oligomer alteration was observed after all three sterilization techniques, without modification of molecular weights. Hydrolytic stability of catheters was slightly changed by plasma-based sterilization, with a small increase in released oligomers. Finally, although Plazlyte and Sterrad are both plasma-based techniques, they induced different impacts on catheters, such as the degradation of an additive with Sterrad, and a clear difference in coloration with Plazlyte.

Catheterization↗

Biodegradation of polyether polyurethane inner insulation in bipolar pacemaker leads.

Several bipolar coaxial pacemaker leads, composed of an outer silicone rubber insulation and an inner polyether polyurethane (PEU) insulation, which were explanted due to clinical evidence of electrical dysfunction, were analyzed in this study. Optical microscopy (OM) and scanning electron microscopy (SEM) were used to determine the cause of failure. Attenuated total reflectance-Fourier transform infrared microscopy (ATR-FTIR) was used to analyze the PEU insulation for chemical degradation. In all leads, the silicone rubber outer insulation showed no signs of physical damage. Physical damage to the inner PEU insulation was the source of electrical dysfunction. Cracks through the PEU compromised the insulation between the inner and outer conductor coils in the lead. It was observed with SEM that these cracks originated on the outer surface of the inner insulation and progressed inward. ATR-FTIR analysis showed that the PEU had chemically degraded via oxidation of the ether soft segment. Furthermore, it was revealed that chemical degradation was more advanced on the outer surface of the PEU. It was hypothesized that hydrogen peroxide permeated through the outer silicone insulation and decomposed into hydroxyl radicals that caused the chemical degradation of PEU. The metal in the outer conductor coil catalyzed the decomposition of the hydrogen peroxide. Chemical degradation of the PEU could also have been catalyzed by metal ions created from the corrosion of the metal in the outer conductor coil by hydrogen peroxide. Physical damage probably occurred in regions of the leads that were subjected to a higher hydrogen peroxide concentration from inflammatory cells and high degrees and rates of strain due to intercorporeal movement, including, but not limited to, cardiac movement. Chemical degradation and physical damage probably had a synergistic affect on failure of the insulation, in that as chemical degradation proceeded, the polymer surface became brittle and more susceptible to physical damage. As physical damage proceeded, cracks propagated into the unaffected bulk, exposing it to oxidants.

Biocompatible Materials↗

Cell adhesion peptide modification of gold-coated polyurethanes for vascular endothelial cell adhesion.

Gold-coated polyurethanes were chemisorbed with three cell-adhesion peptides having an N-terminal cysteine: cys-arg-gly-asp (CRGD), cys-arg-glu-asp-val (CREDV), and the cyclic peptide cys-cys-arg-arg-gly-asp-try-leu-cys (CCRRGDWLC). The peptides were selected based on their presumed preferential interactions with the cell-surface integrins on vascular endothelial cells. The ability of the surfaces to support the preferential adhesion of human vascular endothelial cells was studied by comparing in vitro adhesion results for these cells with those from mouse 3T3 fibroblasts. Surface modification with the peptides was confirmed by water-contact angles and XPS. Surface morphology was determined by AFM and SEM. In vitro cell-culture studies in conjunction with plasma-protein adsorption and immunoblotting were performed on the various modified surfaces. The data suggest that peptide-modified surfaces have significant potential for supporting cell adhesion. Little or no cell adhesion was noted on gold- or cysteine-modified control surfaces. Human vascular endothelial cells showed the greatest adhesion to the CCRRGDWLC-modified surfaces, and the 3T3 fibroblasts adhered best to the CREDV-modified surfaces. Protein adsorption studies suggest that the preferential adsorption of the cell-adhesive proteins fibronectin and vitronectin is not likely mediating the differences noted. It is concluded that the cell-adhesive peptide-modified gold-coated polymers have significant potential for further development both as model substrates for fundamental studies and for use in biomaterials applications.

3T3 Cells↗

Mutagenicity assessment of airborne particles from three polyurethane foam manufacturing facilities.

In conjunction with industrial hygiene surveys, mutagenicity studies were performed for the airborne contaminants in three polyurethane manufacturing plants. Airborne particles were collected on glass-fiber filters with Hi-Vol pumps from different locations in each plant. Gases were collected in multiple-sorbent cartridges. The collected airborne particles and sorbent cartridges were extracted with organic solvents. Each extract was tested for mutagenic activity using Salmonella typhimurium TA98 and TA100. The results showed that airborne particles from all three plants are mutagenic to TA98 with or without S9 activation. The mutagenicity with S9, however, was two to four times higher than that without S9. None of the samples of gases collected on sorbent cartridges showed mutagenic activity.

Air Pollutants, Occupational↗

Immunological evaluation of four arc welders exposed to fumes from ignited polyurethane (isocyanate) foam: antibodies and immune profiles.

Four arc welders having a flu-like illness with multiple health complaints following an exposure to high concentrations of isocyanate fumes from ignited polyurethane foam underwent immunological tests as follows: ELISA antibody assays, activated lymphocyte profiles, and lymphocyte blastogenesis. ELISA procedures revealed the presence of antibodies to hexamethylene diisocyanate (HDI) and formaldehyde (F) conjugated to human serum albumin (HDI-SA and F-SA). The results from the activated lymphocyte profiles showed deviations from the norm as follows: three welders had elevated helper/suppressor (H/S) ratios; all four had elevated percentages of Tal positive cells; two had decreases in B cells; and one had low total white cell and lymphocyte counts. In contrast, the percentage and absolute numbers of ILS receptor cells were normal in the four subjects. T cell blastogenesis to PHA, Con A and PWM resulted in the following: T-cells from one subject responded normally; in another, a high response (212% of controls) to PHA occurred with normal mitogenesis to Con A and PWM. In the remaining two welders, the T cells responded abnormally low (50 to 75% of controls) to the three mitogens. In conclusion, the existence of IgG antibodies to HDI-SA and F-SA, the altered activated immune profiles, the elevated Tal cells, and the abnormal blastogenesis are interpreted as being linked with the episode of HDI and F exposure and the subsequent flu-like illness of the four welders.

Adult↗

Metabolism of triethylamine in polyurethane foam manufacturing workers.

In 20 workers studied before, during, and after exposure to triethylamine (TEA) in a polyurethane-foam producing plant the amount of TEA and its metabolite triethylamine-N-oxide (TEAO) excreted in urine corresponded to an average of 80% of the inhaled amount. An average of 27% was TEAO, but with a pronounced interindividual variation. Older subjects excreted more than younger ones; less than 0.3% was excreted as diethylamine. The data indicate half-lives for TEA and TEAO excretion in urine of about 3 hr. The postshift level of TEA in urine and plasma are good indicators of the time-weighted average air level during the preceding work day, and might thus be used for biological monitoring. An air level of 10 mg/m3 (proposed occupational standard) corresponds to a urinary excretion of 65 mmol TEA/mol creatinine and a plasma level of 1.9 mumol/liter (biological exposure indices).

Adolescent↗

High-activity enzyme-polyurethane coatings.

The synthesis of water-borne polyurethane coatings in the presence of diisopropylfluorophosphatase (DFPase, E.C. 3.8.2.1) enabled the irreversible attachment of the enzyme to the polymeric matrix. The distribution of immobilized DFPase as well as activity retention are homogeneous within the coating. The resulting enzyme-containing coating (ECC) film hydrolyzes diisopropylfluorophosphate (DFP) in buffered media at high rates, retaining approximately 39% intrinsic activity. Decreasing ECC hydrophilicity, via the use of a less hydrophilic polyisocyanate during polymerization, significantly enhanced the intrinsic activity of the ECC. DFPase-ECC has biphasic deactivation kinetics, where the initial rapid deactivation of DFPase-ECC leads to the formation of a hyperstable and active form of enzyme.

Coated Materials, Biocompatible↗

Potential of silver nanoparticle-coated polyurethane foam as an antibacterial water filter.

Silver nanoparticles can be coated on common polyurethane (PU) foams by overnight exposure of the foams to nanoparticle solutions. Repeated washing and air-drying yields uniformly coated PU foam, which can be used as a drinking water filter where bacterial contamination of the surface water is a health risk. Nanoparticles are stable on the foam and are not washed away by water. Morphology of the foam was retained after coating. The nanoparticle binding is due to its interaction with the nitrogen atom of the PU. Online tests were conducted with a prototypical water filter. At a flow rate of 0.5 L/min, in which contact time was of the order of a second, the output count of Escherichia coli was nil when the input water had a bacterial load of 10(5) colony-forming units (CFU) per mL. Combined with the low cost and effectiveness in its applications, the technology may have large implications to developing countries.

Anti-Bacterial Agents↗

Experimental experience with a temporary intraluminal heparin-bonded polyurethane arterial shunt.

After vascular injury, intraluminal arterial shunting may be employed if definitive surgery must be delayed. This paper describes use of a heparin-bonded polyurethane shunt to restore distal circulation after ligation of the femoral artery in sheep. In studies to determine tissue viability for 12 h after insertion into the femoral artery, five of seven shunts remained patent. In another series of experiments to study tissue viability after limb ischaemia, the femoral artery was ligated and a tight Esmarch bandage applied to the limb for 6 h before shunt insertion. The shunt remained patent for 12 h in five of six cases. Nearly all shunt failures occurred shortly after placement and were attributable to intimal damage arising from difficulties during insertion.

Anastomosis, Surgical↗

Polyurethane foam chips combined with liquid chromatography in the determination of unmetabolized polycyclic aromatic hydrocarbons excreted in human urine.

A method suitable for the determination of unmetabolized polycyclic aromatic hydrocarbons (PAHs) excreted at trace levels (ng/L) in human urine for the monitoring of exposure of the general population to PAH contamination was developed. PAHs were determined, after enrichment by solid-phase extraction on polyurethane foam (PUF) chips, by HPLC with fluorescence detection. Different parameters affecting analyte extraction to the PUF, including urine salting-out and organic additives, and optimization of conditions for clean-up and desorption have been investigated. Optimized conditions were 40 mL acidified urine sample, added with magnesium sulfate, tetrahydrofuran and a 2 cm3 PUF chip, and extracted by shaking at 30 rpm for 1 h at ambient temperature. Desorption was performed, after a clean-up step with diluted sodium hydroxide, using a small amount of diethyl ether. The recovery of PAH congeners from spiked urines was >90% in the 2-100 ng/L range; the detection limit was 0.1-0.5 ng/L, depending on the considered PAH congener; day-to-day precision, at 50 ng/L native PAH content, was CV = 10-20%. The proposed technique provides a simple, economical and effective procedure for the determination of trace amounts of unmetabolized PAHs excreted in human urine spot samples.

Calibration↗

Growth and metastasis of human tumors in nude mice following tumor-cell inoculation into a vascularized polyurethane sponge matrix.

Growth and metastasis of human tumor cells in immunodeficient nude mice were improved when tumor cells were inoculated within a vascularized artificial polyurethane sponge matrix. The sponges had been implanted 7-10 days earlier and were vascularized at the time of cell injection. All cell lines tested, including colon carcinoma-derived lines from primary tumors (HT29, PT3 and PT4) or from liver metastasis (LM3), and a metastatic variant from a melanoma (MeWo-Met) grew in a high percentage (78-94%) of the inoculated sponge grafts. When growth in sponge grafts is compared with growth at a subcutaneous site, the sponge matrix appears to increase tumorigenicity, at least for some cell lines. Regular formation of metastases was observed when cells had been injected into sponges. Most metastases were found in a second sponge graft implanted at a contralateral site, but some were also found at other s.c. sites. In vivo depletion of NK cells by pre-treatment with cyclophosphamide could not further enhance the formation of metastasis. Tumor cells from fresh surgical specimens could be propagated in sponge matrix grafts and subsequently established as cell lines in tissue culture.

Animals↗

Phosphonated polyurethanes that resist calcification.

Cardiovascular implant mineralization involving bioprosthetic materials, such as glutaraldehyde cross linked porcine aortic valves or synthetic materials such as polyurethanes, is an important problem that frequently leads to clinical failure of bioprosthetic heart valves, and complicates long-term experimental artificial heart device implants. Novel, proprietary, calcification resistant polyetherurethanes (PEU) as an alternative to bioprosthetic materials were the subject of these investigations. A series of PEU was derivatized through a proprietary reaction mechanism to achieve covalent binding of 100 to 500 nM/mg of bisphosphonate (2-hydroxyethane bisphosphonic acid, HEBP). The stability of HEBP (physically dispersed or covalently bound) verified by studying the release kinetics in physiological buffer (pH 7.4) at 37 degrees C, demonstrated the covalent binding reaction to be stable, efficient, and permanent. Surface (FTIR-ATR, ESCA, SEM/EDX) and bulk (solubility, GPC) properties demonstrated that the covalent binding of HEBP occurs in the soft segment of the PEU, reduces surface degradation, and does not affect the original material properties of the PEU (prior to derivatization). In vitro calcium diffusion of the derivatized PEU showed a decrease in calcium permeation as the concentration of HEBP covalent binding was increased. In vivo properties of underivatized and derivatized PEU (containing 100 nM of covalently bound HEBP) were studied with rat subdermal implants for 60 days. Explants demonstrated calcification resistance due to the covalently bound HEBP without any side effects. It is concluded that a PEU containing HEBP might serve as a calcification resistant candidate material for the fabrication of a heart valve prosthesis and other implantable devices.

Animals↗