On imparting radiopacity to a poly(urethane urea)

A poly(urethane urea) (PUU) synthesized from 2,4-toluene diisocyanate (TDI) and polyethylene glycol (PEG) with ethylenediamine (ED) as the chain extender was rendered radiopaque by attaching 3,4,5-triiodobenzoic acid (TIB) onto the polymer backbone. The radiopaque polyurethane obtained was characterized by infra red (IR) spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-radiography. By optimizing the reaction conditions, it was possible to carry out the modification without adversely affecting the properties of the starting polymer significantly. IR spectral evidence suggested that the hydrogen bonded structure of PUU remained undisrupted even after modification. However, the product exhibited altered thermal characteristics when compared to the parent polymer. Degradation characteristics as observed from the TGA remained unchanged, while one of the glass transitions got shifted to a lower temperature. The observed changes in thermal characteristics were explained on the basis of possible inter-phase mixing and the changes in the close packing of the polymer chains by the introduction of bulky iodine atoms.     

Telechelic Poly(methyl acrylate)s as Constituents for Multiblock Poly(urethane urea)s

New poly(urethane urea)s based on telechelic poly(methyl acrylate)s (PMAs) and different diisocyanates and diamines are prepared by a two‐step polyaddition process—formation of an isocyanate telechelic prepolymer followed by chain extension with a diamine to form the final poly(urethane urea)s. Hydroxyl‐telechelic or mixed amino‐hydroxyl‐telechelic PMAs are obtained by two different concepts: (i) according to the first concept methyl acrylate (MA) was polymerized by single electron transfer‐living radical polymerization (SET‐LRP) using 2‐hydroxyethyl 2‐bromoisobutyrate as initiator followed by nucleophilic substitution of the halogen end group with n‐butylamine, 2‐methylamino ethanol, or 3‐amino‐1‐propanol and (ii) according to the second concept after SET‐LRP under the same conditions the halogen end group is converted to an azide followed by a click reaction using sodium azide and propargyl alcohol in a one‐pot reaction. Applying the second concept, a hydroxyl‐functional PMA with a share of 83 mol% bifunctionality is obtained. This PMA‐diol is used in polyaddition reaction with different diisocyanates (isophorone diisocyanate (IPDI), 4,4′‐methylenebis(cyclohexyl isocyanate) (HMDI), and 4,4′‐methylenediphenyl diisocyanate (MDI)) resulting in an isocyanate‐telechelic prepolymer followed by chain extension with the corresponding diamines (isophorone diamine (IPDA), 4,4′‐methylenebis(cyclohexyl amine) (HMDA), and 4,4′‐methylenediphenyl diamine (MDA)). The polyurethane based on hydroxyl‐telechelic PMAs and IPDI/IPDA has a molecular weight of M_n = 44 500 g mol^?1 and a dispersity ? = 3.5, respectively; those based on HMDI/HMDA and MDI/MDA have M_n = 24 600 g mol^?1 and ? = 2.2 and M_n = 16 100 g mol^?1 and ? = 2.0, respectively.

     

Synthesis of segmented poly(ether urethane)s and poly(ether urethane urea)s incorporating various side-chain or backbone functionalities

A series of linear and branched functionalized high-molecular-weight segmented poly (ether urethane)s and poly(ether urethane urea)s were prepared by chain-extending isocyanate pre-polymers based on poly(tetramethylene oxide) with molecular weight 1000 and 4,4'-diphenylmethane diisocyanate. Different functional groups were incorporated within the polymer backbone or on side-chains by using several chain extenders during the synthesis: glycerol, 2,2-bis (hydroxymethyl) propionic acid, 1H, 1H,2H,3H,3H-perfluoroundecane-1,2-diol, 1H,1H,8H,8H-dodecanefluoro-1,8-octanediol, 1,3-diamino-2-hydroxypropane and 3,5-diaminobenzoic acid, using the method of gradual approach to stoichiometry. In some cases, pendant functional groups were used as reactive sites for the further attachment of side groups. Polymers were characterized using 1H-NMR and FT-IR spectroscopies and GPC in conjunction with chemical structural confirmation by a model compound comparison study of 4,4'-diphenylmethane diisocyanate or trifluoro-p-tolyl isocyanate reacted with 1,3-diamino-2-hydroxypropane and 1,4-butanediol.     

Surface modification of poly(ether urethane urea) with modified dehydroepiandrosterone for improved in vivo biostability

In this study, a fatty acid urethane derivative of dehydroepiandrosterone (DHEA) was synthesized and evaluated as a polyurethane additive to increase long-term biostability. The modification was hypothesized to reduce the water solubility of the DHEA and physically anchor the additive in the polyurethane during implantation. Polyurethane film weight loss in water as a function of time was studied to determine the polymer retention of the modified DHEA. The polyurethane film with unmodified DHEA had significant weight loss in the first day (10%) that was previously correlated to rapid leaching of the additive. The polyurethane film with modified DHEA had significantly less weight loss at all time points indicating improved polymer retention. The effect of the modified DHEA additive on the biostability of a poly(ether urethane urea) was examined after 5 weeks of subcutaneous implantation in Sprague-Dawley rats. Optical micrographs and infrared analysis of the specimens indicated that the modified DHEA bloomed to the surface of the film forming a crystalline surface layer approximately 10-15 microns thick. After explantation, this surface layer was intact without measurable differences in surface chemistry as monitored by attenuated total reflectance-Fourier transform infrared spectroscopy. There was no evidence of degradation of the polyurethane underneath the modified DHEA surface layer as compared with the polyurethane control. We have concluded that the modified DHEA self-assembled into a protective surface coating that inhibited degradation of the polyurethane. The roughness of the modified DHEA surface layer prevented adherent cell analysis to determine if the additive retained the ability to down-regulate macrophage activity. Subsequent studies will investigate the ability of surface-modifying additives to modulate cellular respiratory bursts in addition to the formation of an impermeable barrier. This bimodal approach to improving biostability holds great promise in the field of polyurethane biomaterials.     

Surface and bulk characteristics of a polyether urethane for artificial hearts.

A segmented polyether urethane was used as the blood contacting surface in a series of 10 heart assist devices implanted in calves for periods up to 35 weeks. At termination, each was examined to correlate blood compatibility and device performance with surface properties, chemical purity, physical stability and affinity for lipid absorption.     

Biodegradable poly(ester urethane)urea elastomers with variable amino content for subsequent functionalization with phosphorylcholine

While surface modification is well suited for imparting biomaterials with specific functionality for favorable cell interactions, the modification of degradable polymers would be expected to provide only temporary benefit. Bulk modification by incorporating pendant reactive groups for subsequent functionalization of biodegradable polymers would provide a more enduring approach. Towards this end, a series of biodegradable poly(ester urethane)urea elastomers with variable amino content (PEUU–NH₂ polymers) were developed. Carboxylated phosphorycholine was synthesized and conjugated to the PEUU–NH₂ polymers for subsequent bulk functionalization to generate PEUU–PC polymers. Synthesis was verified by proton nuclear magnetic resonance, X-ray photoelectron spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy. The impact of amine incorporation and phosphorylcholine conjugation was shown on mechanical, thermal and degradation properties. Water absorption increased with increasing amine content, and further with PC conjugation. In wet conditions, tensile strength and initial modulus generally decreased with increasing hydrophilicity, but remained in the range of 5–30 MPa and 10–20 MPa, respectively. PC conjugation was associated with significantly reduced platelet adhesion in blood contact testing and the inhibition of rat vascular smooth muscle cell proliferation. These biodegradable PEUU–PC elastomers offer attractive properties for applications as non-thrombogenic, biodegradable coatings and for blood-contacting scaffold applications. Further, the PEUU–NH₂ base polymers offer the potential to have multiple types of biofunctional groups conjugated onto the backbone to address a variety of design objectives.     

Atomic force microscopy visualization of poly(urethane urea) microphase rearrangements under aqueous environment

Polyurethane biomaterials are a critically important class of polymers used in a variety of medical devices. It has been suggested that the good blood compatibility of polyurethanes arises from nanoscale chemical heterogeneities at the surface as a consequence of the microphase separated morphology. In this study, we used tapping mode atomic force microscopy with phase imaging under aqueous conditions to visualize the distribution of the surface microphases for a series of poly(urethane urea) block co-polymers with varying hard segment content. The surfaces were prehydrated for 24 h under a flow of 1 mM phosphate buffer. Topographic images showed the formation of nanometer-sized raised features on the surface, having lateral dimensions of 50-70 nm and heights of 10-15 nm. Phase images, reflecting the local distribution of the mechanical properties under aqueous conditions, were quite different from those obtained in ambient conditions, consistent with water-induced structural reorientation. Images suggest that there is little soft phase material at the polymer surface in the presence of water, while images acquired after dehydration of the samples show that the surface layer remains rich in hard domains, indicating that the films do not return to their original states over the time period studied.     

Atomic force microscopy visualization of poly(urethane urea) microphase rearrangements under aqueous environment

Polyurethane biomaterials are a critically important class of polymers used in a variety of medical devices. It has been suggested that the good blood compatibility of polyurethanes arises from nanoscale chemical heterogeneities at the surface as a consequence of the microphase separated morphology. In this study, we used tapping mode atomic force microscopy with phase imaging under aqueous conditions to visualize the distribution of the surface microphases for a series of poly(urethane urea) block co-polymers with varying hard segment content. The surfaces were prehydrated for 24 h under a flow of 1 mM phosphate buffer. Topographic images showed the formation of nanometer-sized raised features on the surface, having lateral dimensions of 50–70 nm and heights of 10–15 nm. Phase images, reflecting the local distribution of the mechanical properties under aqueous conditions, were quite different from those obtained in ambient conditions, consistent with water-induced structural reorientation. Images suggest that there is little soft phase material at the polymer surface in the presence of water, while images acquired after dehydration of the samples show that the surface layer remains rich in hard domains, indicating that the films do not return to their original states over the time period studied.     

Influence of plasticised poly(vinyl chloride) on platelet adhesion and platelet aggregates

The most widely used plasticiser for poly(vinyl chloride) (PVC) is di-(2-ethyl-hexyl) phthalate (DEHP), which is extracted in contact with blood. One approach to reducing plasticiser extraction is to incorporate the higher molecular weight plasticisers trioctyl trimellitate (TOTM) and polymeric adipate (PA). This investigation has compared the influence of these plasticisers with that of DEHP on platelet adhesion and platelet aggregate formation. PVC tubing was tested in the absence of anticoagulants and in the presence of heparin. Our results demonstrate the influence of plasticisers on platelet response and support the view that evaluation of such plasticisers should be extended from an examination of toxicological properties to a comprehensive blood compatibility assessment.     

Development of a novel glucose polymer solution (icodextrin) for adhesion prevention: pre-clinical studies

Intra-abdominal adhesion formation causes significant post-operative morbidity. Controlled studies using animal models have been carried out to assess the tolerability and preventive efficacy of icodextrin solution (a biodegradable, biocompatible, glucose polymer). Reduction of adhesion formation was first evaluated in a rabbit double uterine horn model, applying 10-75 ml of 7.5 and 20%, or 50 ml of 2.5-20% icodextrin solution post-operatively. Significant increases in adhesion free sites (P < 0.005) were observed with volumes > or =25 ml, and at concentrations > or =4%. Efficacy of 50 ml 4 and 20% icodextrin was then evaluated both during and after surgery, demonstrating significant reductions in adhesion formation (P < 0. 002). In one study, intra- plus post-operative use of 4% icodextrin produced the greatest reduction of non-surgical site adhesions; in others, the post-operative effect was predominant. Post-surgical administration of 50 ml 4% icodextrin in a rabbit sidewall model also resulted in more adhesion-free animals, and a significant reduction (P < 0.001) in areas of adhesion formation and reformation. In a rat infection potentiation model, 4% icodextrin produced no difference in mortality, abscess formation or overall abscess score. These data suggest that 4% icodextrin offers a well-tolerated and effective means of reducing post-surgical adhesion formation.     

Biodegradable poly(ester urethane) urea scaffolds for tissue engineering: Interaction with osteoblast-like MG-63 cells

Porous three-dimensional scaffolds with potential for application as cancellous bone graft substitutes were prepared from aliphatic segmented poly(ester urethane) urea using the phase-inverse technique. Proton nuclear magnetic resonance, size-exclusion chromatography, electron spectroscopy for chemical analysis, secondary ion mass spectrometry, infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry, computed tomography and mechanical tests were carried out, to characterize the scaffolds’ physicochemical properties. Human osteosarcoma MG-63 cells were seeded into the scaffolds for 1, 2, 3 and 4 weeks to evaluate their potential to support attachment, growth and proliferation of osteogenic cells. The scaffold–cell interaction was assessed by analysis of DNA content, total protein amount, alkaline phosphatase activity and WST-1 assay. The scaffolds supported cell attachment, growth and proliferation over the whole culture period of 4 weeks (DNA, total protein amount). There was, however, a reduction in the WST-1 assay values at 4 weeks, which might suggest a reduction in the rate of cell proliferation at this time.     

Evaluation of soft tissue response to a poly(urethane urea).

Variations in the performance of vascular prostheses constructed of polyurethanes, and some evidence which suggested that these variations could be due not to the properties of the polymer itself, but to differences in the cellular response to the various microstructures of porous polyurethanes require investigation. Experiments were performed to evaluate quantitatively the extent of the cell behaviour adjacent to a series of polyurethane samples. It was shown that, with Biomer, a polyurethane urea, the profile of cell behaviour as a function of distance from the implant surface and of time following implantation, the response of cells in general and macrophages in particular, varied considerably with different internal microstructure. This supports the suggestion that the cellular response to different structures and susceptibility to degradation are related.     

Platelet adhesion onto polyetherurethane urea derivatives: effect of cytoskeleton proteins of the platelet

Adhesion and activation of platelets upon adhesion onto synthetic polymers were investigated with reference to participation of the cytoskeleton proteins. Platelets were treated with cytoskeleton breakers, and then the adhesion of platelets onto polyetherurethane urea derivatives and serotonin release from adhered platelets were investigated. In the adhesion onto glass, platelets were strongly stimulated and accompanied rearrangement of the cytoskeleton system, and also serotonin release involved the action of the cytoskeleton system. On the other hand, platelets were not strongly stimulated upon adhering onto polyetherurethane urea derivatives. The platelet adhesion onto cationic polymers exceptionally accompanied the rearrangement of the cytoskeleton system. The participation of the cytoskeleton in platelet adhesion onto polyetherurethane urea derivatives was influenced by the presence of plasma proteins. It was found that protein layers deposited on the material surface play an important role in platelet adhesion.     

Characterization of surface microphase structures of poly(urethane urea) biomaterials by nanoscale indentation with AFM

Atomic force microscopy utilizing both tapping mode and force mode imaging is used to visualize the separated microphases in poly(urethane urea) films under ambient and aqueous conditions. The topography of the PUU surface changed upon hydration with the formation of nanometer-sized features on the surface. The surface becomes enriched in hard domains with hydration time and this enrichment is irreversible after dehydration. Force mode measurements were used to quantify mechanical properties as both indentation and modulus measurements. Analysis of the modulus during indentation reveals the three-dimensional nature of the structures, with the surface being covered by a 2-20-nm-thick soft segment overlayer under ambient conditions, while hydration leads to the loss of this overlayer. The force measurements also reveal the presence of regions having modulus values between those of the hard and soft phases and located spatially near the interface between the hard and soft domains. However, such regions with intermediate modulus were only rarely seen following hydration. Calculation of the Young's modulus from the compression data shows that hydration increases the modulus of the PUU surface by both enrichment of the amount of hard domain present and increasing the modulus of the individual hard and soft phases themselves. Direct visualization of the distribution of these different domains on the surface by nanoscale measurements provides an important path to characterizing the relationships between the surface properties of these materials and subsequent performance in biomedical applications.     

In vitro degradation and in vivo biocompatibility study of a new linear poly(urethane urea)

Segmented poly(urethane urea)s (PUUs) with hard segments derived only from methyl 2,6-diisocyantohexanoate (LDI) without the use of a chain extender have previously been described. These materials, which contain hard segments with multiple urea linkages, show exceptionally high strain capability (1600-4700%). In the study reported here, the rate and effect of hydrolysis of these materials were determined for gamma-sterilized and nonsterilized samples. Materials investigated contained PCL, PTMC, P(TMC-co-CL), P(CL-co-DLLA), or P(TMC-co-DLLA) as soft segments and, as well as their mechanical properties, changes in mass, inherent viscosity (I.V.), and thermal properties were studied over 20 weeks. Results showed that the degradation rate was dependant on the soft segment structure, with a higher rate of degradation for the polyester-dominating PUUs exhibiting a substantial loss in I.V. A tendency of reduction of tensile strength and strain hardening was seen for all samples. Also, loss in elongation at break was detected, for PUU-P(CL-DLLA) it went from 1600% to 830% in 10 weeks. Gamma radiation caused an initial loss in I.V. and induced more rapid hydrolysis compared with nonsterilized samples, except for PUU-PTMC. A cytotoxicity test using human fibroblasts demonstrated that the material supports cell viability. In addition, an in vivo biocompatibility study showed a typical foreign body reaction after 1 and 6 weeks.     

Thermoplastic Poly(urethane urea)s From Novel,Bio‐based Amorphous Polyester Diols

In this study, two novel, bio‐based, amorphous polyester diols, namely poly(1,2‐dimethylethylene adipate) (PDMEA) and poly(1,2‐dimethylethylene succinate) (PDMES) are used to prepare thermoplastic poly(urethane urea)s (TPUUs). Interestingly, the TPUUs based on PDMEA show similar thermal and mechanical properties as their counterparts based on poly(1,2‐propylene glycol). By decreasing the hard segment length, the flow temperature (T_fl) of the TPUUs decreases. The T_fl values of the 3U series are around 170 °C, which is below their degradation temperatures. The methyl groups adjacent to the ester groups in PDMEA and PDMES may hinder the hydrolysis of the polyester soft segments in the TPUUs.     

Amidine surface modification of poly(acrylonitrile-co-vinyl chloride) reduces platelet adhesion

The surface nitrile groups of solvent-cast polyacrylonitrile-co-vinyl chloride (PAN-VC) films were converted into amidine groups through a two-step process analogous to Pinner's method of 1877. The amidine groups were hypothesized to reduce platelet adhesion and activation through the inhibition of the classical complement pathway, as was noted for benzamidine and pentamidine in earlier studies. A slightly higher nitrogen content was detected on the amidine-surface modified (ASM) samples by X-ray photoelectron spectroscopy relative to the solvent-treated and unmodified controls. Reaction with pentafluoroaldehyde resulted in increased fluorine and decreased nitrogen contents (relative), consistent with the formation of a Schiff base with the primary nitrogen of the amidine on ASM PAN-VC surface. The corresponding yield was 17.2% based on nitrile groups and 9.6% based on all repeating units of the base polymer. Despite this low degree of amidine modification, platelet adhesion was approximately 40% lower on the amidine-modified film compared to the solvent-treated and unmodified controls. The scanning electron micrographs also showed less activation in the adherent platelets. A small reduction in C1s binding was also noted on the amidine-modified surface. Taken together, these results support the notion that amidine modification may be a useful approach to improve the nonthrombogenicity of a biomaterial. However, much effort is required to improve the degree of surface modification and to provide unequivocal evidence linking amidines to the improved thrombogenicity.     

Effect of microstructure of poly(propylene-oxide)-segmented polyamides on platelet adhesion

The relationship between microstructure and platelet adhesivity of six types of poly(propylene oxide) (PPO)-segmented polyamides based on the polyamide segments nylon 210, 310, 410, 510, 610, and 710 were investigated. These multiblock PPO-segmented copolymers were prepared by interfacial polycondensation. Physical characterization of these copolymers was by means of thermal analysis, transmission electron microscope, wide-angle X-ray diffraction (WAXD), and small-angle X-ray scattering (SAXS). The WAXD and SAXS measurements showed that the copolymers had microstructures containing crystalline and amorphous phases and that these microstructures, represented by means of crystallite thickness and long period, varied with incorporation of PPO segments. Blood compatibility of these copolymers was evaluated by estimating the amount of adhering platelets on the copolymer surfaces. The amount of adhering platelets was minimum for the surfaces of the copolymers having a crystallite thickness of 6.0-6.5 nm and a long period of 12-13 nm. This result suggests that the particular size and distribution of the crystalline and amorphous phases in the copolymer could be determining factors for suppressing platelet adhesion on the copolymer surface, and that the control of these factors could lead to ideal antithrombogenic polymers.     

Synthesis, characterization and platelet adhesion studies of novel ion-containing aliphatic polyurethanes

Two novel ion-containing aliphatic polyurethanes based on 4,4'-methylene dicyclohexyl diisocyanate (H12MDI), polytetramethyl oxide (PTMO) were synthesized using either sulfonated or carboxylated chain extender. The nonionic polyurethane chain extended with 1,4-butanediol, which is denoted as H-M-BD, was synthesized. Pellethane, a biomedical-grade polyurethane, was also studied for comparison. The polymer's bulk, surface, and platelet-contacting properties were studied using Fourier transform infrared spectrophotometry, differential scanning calorimetry, water absorption analysis, electron spectroscopy for chemical analysis, static contact angle analysis, and in vitro platelet adhesion experiments. The effects of ion incorporation on the morphology, surface properties and blood compatibility are discussed. Unlike MDI-based Pellethane, all H12MDI-based polyurethanes are not composed of crystalline hard segment domain but are amorphous. The ionic polyurethanes exhibit a smaller fraction of hydrogen-bonded carbonyl groups, poorer phase separation, smaller fraction of PTMO residing at the surface, and smaller contact angle; however, significant higher water absorption value than H-M-BD and Pellethane. The in vitro platelet adhesion experiments indicated that ion incorporation, especially for carboxylate, significantly reduced the number and the degree of activation of the adherent platelets.     

Enzymatic degradation of poly(ether urethane) and poly(carbonate urethane) by cholesterol esterase

This study examined the effect of cholesterol esterase (CE) on the degradation of commercial poly(ether urethane) (PEU) and poly(carbonate urethane) (PCU). Unstrained PEU and PCU films were incubated in 400 U/mL CE solution or a buffer control for 36 days. The study used a concentration of cholesterol esterase that was considerably higher than the estimated physiological level in order to accelerate degradation. However, characterization of treated polyurethane films with SEM, attenuated total reflectance Fourier transform infrared (ATR-FTIR) and GPC analysis revealed only a small loss in surface soft segment content. Comparison with implanted PEU and PCU films led to the conclusion that any effect of enzymatic hydrolysis was confined to the immediate surface, and the magnitude of the effect was too small to contribute significantly to in vivo degradation. The study confirmed that oxidation, rather than enzymatic hydrolysis, is the primary mechanism responsible for the observed biodegradation of PEU and PCU. The oxidative H(2)O(2)/CoCl(2) treatment continues to accurately predict the long-term biostability of polyurethanes.