Biomedical Grade Polyurethane Research Articles

Interplay between thermal and magnetic properties of polymer nanocomposites with superparamagnetic Fe3O4 nanoparticles

Magnetic nanoparticles embedded in polymer matrices have excellent potential for multifunctional applications like magnetic remote heating, controlled drug delivery, hyperthermia, and thermally functionalized biomedical devices. A solvent-based processing method was developed to produce magnetic composites consisting of magnetite (Fe3O4) superparamagnetic nanoparticles embedded in a biomedical-grade polyurethane (ChronoFlex® C). The particles had a log-normal size distribution spanning from 4−16 nm, with a mean-size of 9.5 ± 2 nm. X-ray diffraction, transmission electron microscopy, and scanning electron microscopy with elemental mapping were used to assess the phase purity, surface morphology, particle size, and homogeneity of the resulting nanocomposite. The magnetic properties of composites with 7–13 wt% of Fe3O4 were studied between 5 and 300 K using vibrating sample magnetometry. Room temperature magnetic attraction was observed, with a saturation magnetization of up to 5 emu/g and a low coercive field (Hc < 50 Oe), where the non-zero coercive field was attributed to a small fraction of larger particles that are ferromagnetic at room temperature. Field-cooled and zero-field-cooled magnetometry data were fitted to a numerical model to determine the superparamagnetic mean blocking temperature (TB = 90 K) of the embedded magnetite particles, and an effective magnetic anisotropy of 6×105 erg/cm3. Using an AC magnetic field operating at 85 kHz, we demonstrate that remote heating of the base polyurethane material is greatly enhanced by compositing with Fe3O4 nanoparticles, leading to temperatures up to 45 °C within 18 min for composites submerged in water. This work demonstrates the fundamental principles of a custom-designed thermomagnetic polymer composite that could be used in applications, including medical and heat management.

Studies of combined NO-eluting/CD47-modified polyurethane surfaces for synergistic enhancement of biocompatibility

The blood compatibility of various intravascular (IV) devices (e.g., catheters, sensors, etc.) is compromised by activation of platelets that can cause thrombus formation and device failure. Such devices also carry a high risk of microbial infection. Recently, nitric oxide (NO) releasing polymers/devices have been proposed to reduce these clinical problems. CD47, a ubiquitously expressed transmembrane protein with proven anti-inflammation/anti-platelet properties when immobilized on polymeric surfaces, is a good candidate to complement NO release in both effectiveness and longevity. In this work, we successfully appended CD47 peptides (pepCD47) to the surface of biomedical grade polyurethane (PU) copolymers. SIRPα binding and THP-1 cell attachment experiments strongly suggested that the pepCD47 retains its biological properties when bound to PU films. In spite of the potentially high reactivity of NO toward various amino acid residues in CD47, the efficacy of surface-immobilized pepCD47 to prevent inflammatory cell attachment was not inhibited after being subjected to a high flux of NO for three days, demonstrating excellent compatibility of the two species. We further constructed a CD47 surface immobilized silicone tubing filled with NO releasing S-nitrosoglutathione/ascorbic acid (GSNO/AA) solution for synergistic biocompatibility evaluation. Via an ex vivo Chandler loop model, we demonstrate for the first time that NO release and CD47 modification could function synergistically at the blood/material interface and produce greatly enhanced anti-inflammatory/anti-platelet effects. This concept should be readily implementable to create a new generation of thromboresistant/antimicrobial implantable devices.

Surface Characterization, Antimicrobial Effectiveness, and Human Cell Response for a Biomedical Grade Polyurethane Blended with a Mixed Soft Block PTMO-Quat/PEG Copolyoxetane Polyurethane.

Infection is a serious medical complication associated with health care environments. Despite advances, the 5-10% incidence of infections for hospital patients is well documented. Sources of pathogenic organisms include medical devices such as catheters and endotracheal tubes. Offering guidance for curbing the spread of such infections, a model antimicrobial coating is described herein that kills bacteria on contact but is compatible with human cells. To achieve these characteristics, a novel blend of a conventional biomedical grade polyurethane (Tecoflex) with mixed soft block polyurethane is described. The functional polyurethane (UP-C12-50-T) has a copolyoxetane soft block P-C12-50 with quaternary ammonium (C12) and PEG-like side chains and a conventional poly(tetramethylene oxide) (PTMO, T) soft block. DSC and DMA data point to limited miscibility of UP-C12-50-T with Tecoflex. The blend of Tecoflex with 10 wt % UP-C12-50-T designated UP-C12-50-T-10 radically changed surface properties. Evidence for surface concentration of the P-C12-50 soft block was obtained by atomic force microscopy (AFM), dynamic contact angles (DCAs), zeta potentials (ζ), and X-ray photoelectron spectroscopy (XPS). The antimicrobial effectiveness of the blend coatings was established by the ASTM E2149 "shake flask" test for challenges of E. coli and a methicillin resistant strain of S. epidermidis. Cytocompatibility was demonstrated with an in vitro test designed for direct contact (ISO 10993-5). Growth of human mesenchymal stem cells (MSCs) beside and under UP-C12-50-T-10 indicated remarkable biocompatibility for a composition that is also strongly antimicrobial. Overall, the results point to a model coating with a level of P-C12-50 that combines high antimicrobial effectiveness and low toxicity to human cells.

Plasma-Generated Poly(allyl alcohol) Antifouling Coatings for Cellular Attachment.

Conformal poly(allyl alcohol) (PAA) coatings were grown on a biomedical grade polyurethane scaffold using pulsed plasma polymerization of the allyl alcohol monomer. The creation of a continuous wave polymer primer layer increases the interfacial adhesion and stability of a subsequent pulsed plasma deposited PAA film. The resulting PAA coatings are strongly hydrophilic and stable following 7 days incubation in biological media. Films prepared through this energy-efficient, two-step process promote human dermal fibroblast cell culture, while resisting E. coli biofilm formation.

Design Considerations for Silica-Particle-Doped Nitric-Oxide-Releasing Polyurethane Glucose Biosensor Membranes.

Nitric oxide (NO)-releasing polymers have proven useful for improving the biocompatibility of in vivo glucose biosensors. Unfortunately, leaching of the NO donor from the polymer matrix remains a critical design flaw of NO-releasing membranes. Herein, a toolbox of NO-releasing silica nanoparticles (SNPs) was utilized to systematically evaluate SNP leaching from a diverse selection of biomedical-grade polyurethane sensor membranes. Glucose sensor analytical performance and NO-release kinetics from the sensor membranes were also evaluated as a function of particle and polyurethane (PU) chemistries. Particles modified with N-diazeniumdiolate NO donors were prone to leaching from PU membranes due to the zwitterionic nature of the NO donor modification. Leaching was minimized (<5% of the entrapped silica over 1 month) in low water uptake PUs. However, SNP modification with neutral S-nitrosothiol (RSNO) NO donors lead to biphasic leaching behavior. Particles with low alkanethiol content (<3.0 wt % sulfur) leached excessively from a hydrogel PU formulation (HP-93A-100 PU), while particles with greater degrees of thiol modification did not leach from any of the PUs tested. A functional glucose sensor was developed using an optimized HP-93A-100 PU membrane doped with RSNO-modified SNPs as the outer, glucose diffusion-limiting layer. The realized sensor design responded linearly to physiological concentrations of glucose (minimum 1-21 mM) over 2 weeks incubation in PBS and released NO at >0.8 pmol cm-2 s-1 for up to 6 days with no detectable (<0.6%) particle leaching.

Acylase-containing polyurethane coatings with anti-biofilm activity.

Due to the prevalence of biofilm-related infections, which are mediated by bacterial quorum sensing, there is a critical need for materials and coatings that resist biofilm formation. We have developed novel anti-biofilm coatings that disrupt quorum sensing in surface-associated bacteria via the immobilization of acylase in polyurethane films. Specifically, acylase from Aspergillus melleus was covalently immobilized in biomedical grade polyurethane coatings via multipoint covalent immobilization. Coatings containing acylase were enzymatically active and catalyzed the hydrolysis of the quorum sensing (QS) molecules N-butyryl-L-homoserine lactone (C4-LHL), N-hexanoyl-L-homoserine lactone (C6-LHL), and N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-LHL). In biofilm inhibition assays, immobilization of acylase led to an approximately 60% reduction in biofilm formation by Pseudomonas aeruginosa ATCC 10145 and PAO1. Inhibition of biofilm formation was consistent with a reduction in the secretion of pyocyanin, indicating the disruption of quorum sensing as the mechanism of the coating activity. Scanning electron microscopy further showed that acylase-containing coatings contained far fewer bacterial cells than control coatings that lacked acylase. Moreover, acylase-containing coatings retained 90% activity when stored dry at 37°C for 7 days and were more stable than the free enzyme in physiological conditions, including artificial urine. Ultimately, such coatings hold considerable promise for the clinical management of catheter-related infections as well as the prevention of infections in orthopedic applications (i.e., on hip and knee prostheses) and on contact lenses. Biotechnol. Bioeng. 2016;113: 2535-2543. © 2016 Wiley Periodicals, Inc.

Lipoprotein interactions with a polyurethane and a polyethylene oxide-modified polyurethane at the plasma-material interface.

Lipoproteins [high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoprotein (VLDL)] are present in blood in relatively high concentrations, and, given their importance in cardiovascular disease, the interactions of these species with blood contacting biomaterials and their possible role in thrombogenesis is of interest. In the present communication, quantitative data on the adsorption of apolipoprotein AI, apolipoprotein AII (the main protein components of HDL), and apolipoprotein B (the main protein component of LDL and VLDL), as well as the lipoproteins themselves from plasma to a biomedical grade polyurethane (PU) with and without a copolymer additive that contains polyethylene oxide (PEO) segments, were investigated. Adsorption from some binary solutions was also studied. Significant quantities of the apolipoproteins were found to adsorb from plasma to the PU, while adsorption to the PEO material was more than 90% lower, demonstrating strong protein resistance of the latter material. In contrast, significant quantities of the lipoproteins were found to adsorb to the PEO as well as to the PU material. From these and previously published results, it is concluded that the protein layer formed on the PU surface from plasma (and by extension from blood) contains apolipoproteins and lipoproteins in addition to other plasma proteins; the layer formed on the PEO surface, however, appears to contain minimal quantities of plasma proteins (including free apolipoproteins) but significant quantities of lipoproteins.

Interactions of Apolipoproteins AI, AII, B and HDL, LDL, VLDL with Polyurethane and Polyurethane-PEO Surfaces.

The lipoproteins (HDL, LDL, VLDL) are important components of blood present in high concentration. Surprisingly, their role in blood-biomaterial interactions has been largely ignored. In previous work apolipoprotein AI (the main protein component of HDL) was identified as a major constituent of protein layers adsorbed from plasma to biomaterials having a wide range of surface properties, and quantitative data on the adsorption of apo AI to a biomedical grade polyurethane were reported. In the present communication quantitative data on the adsorption of apo AI, apo AII and apoB (the latter being a constituent of LDL and VLDL), as well as the lipoprotein particles themselves (HDL, LDL, VLDL), to a biomedical segmented polyurethane (PU) with and without an additive containing poly(ethylene oxide) (material referred to as PEO) are reported. Using radiolabeled apo AI, apo AII, and apoB, adsorption levels on PU from buffer at a protein concentration of 50 μg/mL were found to be 0.34, 0.40, and 0.14 μg/cm(2) (12, 23, and 0.25 nmol/cm(2)) respectively. Adsorption to the PEO surface was <0.02 μg/cm(2) for all three apolipoproteins demonstrating the strong protein resistance of this material. In contrast to the apolipoproteins, significant amounts of the lipoproteins were found to adsorb to the PEO as well as to the PU surface. X-ray photoelectron spectra, following exposure of the surfaces to the lipoproteins, showed a strong phosphorus signal, confirming that adsorption had occurred. It therefore appears that a PEO-containing surface that is resistant to apolipoproteins may be less resistant to the corresponding lipoproteins.

A Tunable, Stable, and Bioactive MOF Catalyst for Generating a Localized Therapeutic from Endogenous Sources

The versatile chemical and physical properties of metal organic frameworks (MOFs) have made them unique platforms for the design of biomimetic catalysts, but with only limited success to date due to instability of the MOFs employed in physiological environments. Herein, the use of Cu(II)1,3,5‐Benzene‐tris‐triazole (CuBTTri) is demonstrated for the catalytic generation of the bioactive agent nitric oxide (NO) from endogenous sources, S‐nitrosothiols (RSNOs). CuBTTri exhibits structural integrity in aqueous environments, including phosphate buffered saline (76 h, pH 7.4, 37 °C), cell media used for in vitro testing (76 h, pH 7.4, 37 °C), and fresh citrated whole blood (30 min, pH 7.4, 37 °C). The application of CuBTTri for use in polymeric medical devices is explored through the formation of a composite CuBTTri‐poly by blending CuBTTri into biomedical grade polyurethane matrices. Once prepared, the CuBTTri‐poly material retains the catalytic function towards the generation of NO with tunable release kinetics proportional to the total content of CuBTTri embedded into the polymeric material with a surface flux corresponding to the therapeutic range of 1–100 nm cm−2 min−1, which is maintained even following exposure to blood.

Surface Modification of Biomedical Grade Polyurethane to Enable the Ordered Co-immobilization of Two Proteins

Surface modifications of polyurethane (PU)-based implantable materials have the potential to enhance or improve hemo- or cellular-biocompatibility. In general, surface modification methods of PU have included surface treatments, physio-adsorption of desired biomolecules, and the covalent immobilization of reactive or therapeutic biomolecules. When multi-protein immobilizations are desired to mimic the enzymatic reactions found on cells and tissues, it is often necessary to design and develop surface modification strategies that will allow the co-immobilization of proteins. In this study, a surface modification strategy is presented that enables the sequential additional of proteins to a bi-dentate moiety grafted onto the PU surface. The modifications were confirmed via IR and XPS signatures. While the strategy presented is applicable to a wide variety of biomolecules, bovine serum albumin (BSA) and human immunoglobulin (hIgG) were selected as model proteins. A total immobilized protein density of 0.298 ± 0.037 μg/cm2 was obtained, with nearly equal amounts of protein on each arm of the bi-dentate moiety. Proteins immobilizations were also visualized with immunofluorescent staining. Finally, the method proposed in this study was used to demonstrate a significant increase (P < 0.05) in the catalytic conversion of protein C (PC) to activated PC (APC) using sequentially immobilized thrombomodulin (TM) and endothelial PC receptor (EPCR) as compared to the two proteins immobilized onto a surface in random order.

Polyurethane with tethered copper(II)–cyclen complex: Preparation, characterization and catalytic generation of nitric oxide from S-nitrosothiols

The preparation and characterization of a commercial biomedical-grade polyurethane (Tecophilic ®, SP-93A-100) material possessing covalently linked copper(II)–cyclen moieties as a nitric oxide (NO) generating polymer are described. Chemiluminescence NO measurements demonstrate that the prepared polymer can decompose endogenous S-nitrosothiols (RSNOs) such as S-nitrosoglutathione and S-nitrosocysteine to NO in the presence of thiol reducing agents (RSHs; e.g., glutathione and cysteine) at physiological pH. Since such RSNO and RSH species already exist in blood, the proposed polymer is capable of spontaneously generating NO when in contact with fresh blood. This is demonstrated by utilizing the polymer as an outer coating at the distal end of an amperometric NO sensor to create a device that generates response toward the RSNO species in the blood. This polymer possesses the combined benefits of a commercial biomedical-grade polyurethane with the ability to generate biologically active NO when in contact with blood, and thus may serve as a useful coating to improve the hemocompatibility of various medical devices.

An XPS study of pulsed plasma polymerised allyl alcohol film growth on polyurethane

The growth of highly functionalised poly allyl alcohol films by pulsed plasma polymerisation of CH 2 CHCH 2OH on biomedical grade polyurethane has been followed by X-ray photoelectron spectroscopy (XPS) and contact angle measurements. Film thickness is observed to increase approximately linearly with plasma modification time, suggesting a layer-by-layer growth mode of poly allyl alcohol. Water contact angle measurements reveal the change in the surface free energy of wetting decreases linearly with plasma modification up to the monolayer point after which a constant limiting value of −24 mJ m −2 was attained. Films prepared at 20 W plasma power with a duty cycle of 10 μs:500 μs exhibit a high degree of hydroxyl ( OH) retention with minimal fragmentation of the monomer observed. Increasing the plasma power up to 125 W is found to improve OH retention at the expense of ether formation generating films close to the monomer stoichiometry. Duty cycle plays an important role in controlling both film composition and thickness, with longer off times increasing OH retention, while longer on times enhance allyl alcohol film growth.

In vitro thrombogenicity investigation of new water-dispersible polyurethane anionomers bearing carboxylate groups

New segmented polyurethane (PU) anionomers based on hydroxytelechelic polybutadiene were synthesized via an aqueous dispersion process. Incorporation of carboxylic groups was achieved using thioacids of different length. Surface properties were investigated by mean of water absorption analysis and static contact-angle measurements using water, diiodomethane, formamide and ethylene glycol. Blood compatibility of the PUs was evaluated by in vitro adhesion assays using 111In-radiolabeled platelet-rich plasma and [125I]fibrinogen. Morphology of the adhered platelets was examined by scanning electron microscopy (SEM). Results were compared to two biomedicalgrade PUs, namely Pellethane® and Tecoflex®. Insertion of carboxylic groups increased surface hydrophilicity and limited water uptake (<8% for an ion content of 5% by weight). Surface energy of all synthesized PUs was between 40 and 45 mJ/m2. Platelet adhesion and fibrinogen adsorption on the PU anionomer surfaces were affected as a function to the increase of graft length; thiopropionic was the most haemocompatible, followed by thiosuccinic and then thioglycolic acid. SEM analyses of all ionic PU samples exhibited low platelet adhesion to surfaces with no morphological modification. In conclusion, increased hydrophily, dynamic mobility and charge repulsion are synergistic key factors for enhanced haemocompatibility.

Characteristics of crosslinked blends of Pellethene ® and multiblock polyurethanes containing phospholipid

A series of segmented multiblock polyurethanes (MPUs) were synthesized by polyaddition reaction using hexamethylene diisocyanate (HDI)/poly(ethylene oxide) (PEO, as a hydrophilic component)/ poly(tetramethylene oxide) (PTMO)/ poly(butadiene diol)(PBD)/1,4-butanediol(BD)/{2-[bis(2-hydroxyethyl) methyl ammonio]ethyl stearyl phosphate}[BESP, as a phospholipids component: 0–42 mol% (0–9 wt%)]. To improve the blood compatibility of biomedical grade polyurethane (Pellethene ®), the Pellethene ® was blended with MPUs and then crosslinked using dicumyl peroxide as a crosslinking agent. Effects of BESP content [0–42 mol% (0–9 wt%)] in MPUs on the properties of MPUs and blend (Pellethene ®/MPUs) films were investigated. The X-ray photoelectron spectra indicated that the BESP moieties were located at the surface of the crosslinked blend (Pellethene ®/MPUs) films. As the BESP content in MPUs increased, the water contact angle on the surfaces of corsslinked blend film was decreased but the water absorption and mechanical properties were markedly increased. By the test of platelet adhesion on the surfaces of corsslinked blend film, it was found that the platelet adhesion on the surface was significantly decreased from 70% to 6% by increasing BESP content from 0 to 42 mol% (0–9 wt%) in MPUs. These results suggest that crosslinked blend films may have more potential as a new material for biomedical applications, which are directly in contact with blood.

Hemocompatibilty of new ionic polyurethanes: influence of carboxylic group insertion modes

New segmented polyurethane (PU) anionomers based on hydroxytelechelic polybutadiene (HTPB) were synthesized via two environment-friendly chemical routes. The effects of carboxylic content and ion incorporation mode on the surface properties were investigated by mean of water absorption analysis and static contact angle measurements using water, diiodomethane, formamide and ethylene glycol. Blood compatibility of the PUs was evaluated by in vitro adhesion assay using 111In-radiolabeled platelet rich plasma and 125I-fibrinogen. The morphology of platelet adhesion was also observed by scanning electron microscopy (SEM). Results were compared with a biomedical-grade PU, Pellethane ®. Insertion of the carboxylic groups on the soft segments (S- α series), using thioglycolic acid (TGA), increases surface hydrophilicity, limits water uptake (5%, for an ion content of 3.6 wt%), and reduces platelet adhesion and fibrinogen adsorption on the PUs’ surfaces. In contrast, the classical insertion onto the hard segment (H- α series), using dimethylolpropionate (DMPA) as chain extender, leads to high water uptake (18%, for an ion content of 3.6 wt%) and promotes platelet and fibrinogen adhesion. SEM analyses of the non-ionic PUs exhibited surfaces with adhered platelets which underwent morphological modification. Similarly, the H- α ionic PUs show adherent and activated platelets. On the contrary, no platelet morphology changes were observed on the S- α ionic surfaces. In conclusion, insertion of carboxyl groups on the soft segments of PUs reduces their thrombogenicity.

Polyurethane coatings release bioactive antibodies to reduce bacterial adhesion

This study describes the formulation of a biomedical grade polyurethane hydrogel coating containing solid dispersed bioactive antibodies cast from an organic solvent onto a model polymer biomaterial substrate. A prepolymer dispersion in anhydrous isopropanol containing a uniformly distributed slurry of 22 μm sieved commercial lyophilized polyclonal pooled human immunoglobulin G (IgG) solids was coated onto polymer substrates by simple immersion. Maximum antibody release was approximately 50 μg/cm2 from a 15% w/w IgG polymer coating. In vitro antimicrobial studies utilized Escherichia coli to compare performance of bare uncoated tubing, hydrogel-coated tubing with added aqueous phase antibodies, and antibody-dispersed hydrogel-coated tubing. Bacterial adhesion was reduced significantly (p<0.05) in the presence of antibodies with the greatest reduction seen with the antibody releasing coating. The presence of antibody also significantly enhanced the killing of the bacteria in an in vitro opsonophagocytic assay using freshly isolated blood neutrophils over 2 h indicating that antibody bioactivity is maintained. This controlled release polyurethane hydrogel coating imparts infection resistance by exploiting the low adhesive properties of the biomedical grade hydrogel and the intrinsic bioactive role of the antibodies to reduce bacterial adhesion and promote clearance via natural immune mechanisms.

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 (H 12MDI), 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 H 12MDI-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.

In vivo biocompatibility of an aliphatic crosslinked polyurethane in rabbit

A cage implantation technique has been adopted in a rabbit animal model to investigate the biocompatibility of an aliphatic crosslinked polyurethane based on hexamethylene diisocyanate (HDI). In this study, four cages are represented; the cage containing the candidate polyurethane material, biomedical grade polyurethane (Tecoflex), the commercial grade polyvinylchloride (PVC), and an empty cage which were implanted subcutaneously in rabbits. Exudates were aspirated from these cages at 4, 7, 14, and 21 days postimplantation. Exudates were analyzed for variations in proteins, cell counts, and extracellular enzymes. Results with the four types of cage implants showed that the candidate polyurethane caused an inflammatory response comparable to that caused by medical-grade Tecoflex and the empty cage control.

Development of an Aliphatic Biomedical-Grade Polyurethane Elastomer

Development of an Aliphatic Biomedical-Grade Polyurethane Elastomer