Synthesis of High-Molecular-Weight and Strength Polyisobutylene-Based Polyurethane and Its Use for the Development of a Synthetic Heart Valve.

Under optimized synthesis conditions, for the first time, polyisobutylene-based polyurethane (PIB-PU) is prepared with 70% PIB soft segment (i.e., a bioinert and calcification-resistant PU) with Mn > 100 000 Da, 32 MPa ultimate strength, and 630% elongation. The key parameters for this achievement are a) the precise stoichiometry of the polyurethane forming reaction, specifically the use of highly purified di-isocyanate (4,4'-methylene-bis (phenyl isocyanate), MDI), and b) the increased solid content of the synthesis solution to the limit beyond which increased viscosity prevents stirring. The shape of the stress-strain trace of PIB-PU indicates a two-step failure starting with a reversible elastic (Hookean) region up to ≈50% yield, followed by a slower linearly increasing high-modulus-deformation region suggesting the strengthening of PIB soft segments by entanglement/catenation, and the hard segments by progressively ordering urethane domains. This PIB-PU is a candidate for a fully synthetic bioprosthetic heart valve since preliminary studies show that PIB-PU has impressive fatigue life.

Correction: Design, development, testing at ISO standards and in vivo feasibility study of a novel polymeric heart valve prosthesis.

Correction for 'Design, development, testing at ISO standards and in vivo feasibility study of a novel polymeric heart valve prosthesis' by Joanna R. Stasiak et al., Biomater. Sci., 2020, DOI: .

Design, development, testing at ISO standards and in vivo feasibility study of a novel polymeric heart valve prosthesis.

Clinically available prosthetic heart valves are life-saving, but imperfect: mechanical valves requiring anticoagulation therapy, whilst bioprosthetic valves have limited durability. Polymer valves offer the prospect of good durability without the need for anticoagulation. We report the design and development of a polymeric heart valve, its bench-testing at ISO standards, and preliminary extra-vivo and in vivo short-term feasibility. Prototypes were manufactured by injection moulding of styrenic block copolymers to achieve anisotropic mechanical properties. Design was by finite element stress-strain modelling, which has been reported previously, combined with feedback from bench and surgery-based testing using various combinations of materials, valve geometry and processing conditions. Bench testing was according to ISO 5840:2015 standards using an in vitro cardiovascular hydrodynamic testing system and an accelerated fatigue tester. Bench comparisons were made with a best-in-class bio-prosthesis. Preliminary clinical feasibility evaluations included extra-vivo and short-term (1-24 hours) in vivo testing in a sheep model. The optimised final prototype met the requirements of ISO standards with hydrodynamic performance equivalent to the best-in-class bioprosthesis. Bench durability of greater than 1.2 billion cycles (30 years equivalent) was achieved (still ongoing). Extra-vivo sequential testing (n = 8) allowed refinement of external diameter, 3D shape, a low profile, flexibility, suturability, and testing of compatibility to magnetic resonance imaging and clinical sterilisation. In vivo short-term (1-24 hours) feasibility (n = 3) confirmed good suturability, no mechanical failure, no trans-valvular regurgitation, competitive trans-valvular gradients, and good biocompatibility at histopathology. We have developed and tested at ISO standards a novel prosthetic heart valve featuring competitive bench-based hydrodynamics and durability, well beyond the ISO requirements and comparable to a best-in-class bioprosthesis. In vivo short-term feasibility testing confirmed preliminary safety, functionality and biocompatibility, supporting progression to a long-term efficacy trial.

Correction: Maxwell-Stefan diffusion coefficient estimation for ternary systems: an ideal ternary alcohol system.

Correction for 'Maxwell-Stefan diffusion coefficient estimation for ternary systems: an ideal ternary alcohol system' by Tariq Allie-Ebrahim et al., Phys. Chem. Chem. Phys., 2017, 19, 16071-16077.

A predictive model for the diffusion of a highly non-ideal ternary system.

Diffusion plays a central part in many unit operations. The Maxwell-Stefan model is the dominant model for both gaseous and liquid diffusion. However, it was developed from the kinetic theory of gases, raising the question of whether it can be extended to non-ideal liquid systems. The dynamic fluctuation model is an alternative model based on the Cussler theory and predicts a smaller thermodynamic influence relative to the linear influence of the Maxwell-Stefan model due to dynamic concentration fluctuations. Since the dynamic fluctuation model, which uses the scaling factor α, had improved performance relative to the Maxwell-Stefan model for a wide range of binary systems, it is postulated that this improved performance should also be observed for a ternary system. In this work, the dynamic molecular fluctuation model was extended to a highly non-ideal ternary system, using the same scaling factor α, through matrix manipulation. Using self-diffusion data measured by NMR, mutual diffusion predictions of the developed model and the Maxwell-Stefan model were compared to experimental mutual diffusion data of the partially miscible system ethanol/toluene/n-decane. It is demonstrated that the dynamic fluctuation model gives improved predictions relative to the Maxwell-Stefan approach, consistent with previous observations on binary systems, showing that the reduced thermodynamic influence of the dynamic fluctuation model is an improvement. In addition, we show that the use of local mole fractions, to account for molecular association, in both the dynamic fluctuation and Maxwell-Stefan models, results in improved diffusion predictions for the ternary system. The results confirm that the dynamic fluctuation model improves predictions of mutual diffusion in liquid mixtures, suggesting a non-linear correction to the thermodynamic correction factor. The results also suggest that that the key assumptions in the Maxwell-Stefan model and its derivation, rooted in the kinetic theory of gases, are not entirely accurate for highly non-ideal liquid systems. The optimum α for the ternary system studied here is approximately 0.45, similarly to the optimum α of 0.40 to 0.80 for a range of binary systems previously studied, suggesting that the use of the α scaling factor, which is grounded in scaling laws theory, is of general validity.

Permeability and diffusivity of nitric oxide in human plasma and red cells.

A simple diffusion cell was made to measure the permeability and diffusivity of Nitric Oxide in human plasma and red cells. Nitric oxide was passed through the cell containing plasma or nitrited red cells enclosed by silicone membranes. Steady state permeability (αNODNO ) was calculated from the cell dimensions and from the NO bulk flow entering and leaving the cell. The diffusion coefficient (DNO) was calculated in three ways: (i) by dividing the steady state permeability by published values for solubility (αNO ) in water at 26 °C and 37 °C (ii) by a numerical method and (iii) by an analytical method. Mean steady state permeability (95% confidence intervals) were plasma (26 °C) 5.57 × 10-11 (2.35 × 10-11-1.32 × 10-10) and (37 °C) 5.48 × 10-11 (2.13 × 10-11-1.41 × 10-10) mol cm-1 s-1 atm-1 and red cells (26 °C) 6.74 × 10-12 (1.29 × 10-12-3.53 × 10-11) and (37 °C) 3.93 × 10-11 (1.39 × 10-11-1.11.10-10) mol cm-1 s-1 atm-1. Median Diffusion Coefficients (DNO) for plasma at 37 °C ranged from 3-3.36 × 10-5 cm2 s-1 and red cells 2.41-2.94 × 10-5 cm2 s-1 depending on the method used. These values may be used for modelling NO transport in vivo in the human lung and capillary. Parameters used for modelling in vivo should be measured at 37 °C.

Quantifying the Shift Toward Transcatheter Aortic Valve Replacement in Low-Risk Patients: A Meta-Analysis.

BACKGROUND: In recent years, use of transcatheter aortic valve replacement has expanded to include patients at intermediate- and low-risk cohorts. We sought to determine disease prevalence and treatment distribution including transcatheter aortic valve replacement eligibility in low-risk patients across 37 advanced economies. METHODS AND RESULTS: Four systematic searches were conducted across MEDLINE, EMBASE, and the Cochrane database for studies evaluating disease prevalence, severity, decision making, and survival in patients with aortic stenosis. Estimates of disease prevalence and treatment eligibility were calculated using stochastic simulation and population data for the 37 countries comprising the International Monetary Fund's advanced economies index. Fifty-six studies comprising 42 965 patients were included across 5 domains: prevalence, severity, symptom status, treatment modality, and outcome. The pooled prevalence in the general population aged 60 to 74 years and >75 years was 2.8% (95% confidence interval [CI], 1.4%-4.1%) and 13.1% (95% CI, 8.2%-17.9%), respectively-corresponding to an estimated 16.1 million (95% CI, 12.2-20.3) people in 37 advanced economies. Of these, an estimated 3.2 million (95% CI, 2.2-4.4) patients have severe aortic stenosis with 1.9 million (95% CI, 1.3-2.6) eligible for surgical aortic valve replacement. There are ≈485 230 (95% CI, 284 550-66 7350) high-risk/inoperable patients, 152 690 (95% CI, 73 410-263 000) intermediate-risk patients, and 378 890 (95% CI, 205 130-610 210) low-risk patients eligible for transcatheter aortic valve replacement. CONCLUSIONS: With a prevalence of 4.5%, an estimated 16.1 million people aged ≥60 years across 37 advanced economies have aortic stenosis. Of these, there are ≈1.9 million patients eligible for surgical aortic valve replacement and 1.0 million patients eligible for transcatheter aortic valve replacement.

Maxwell-Stefan diffusion coefficient estimation for ternary systems: an ideal ternary alcohol system.

The Maxwell-Stefan model is a popular diffusion model originally developed to model diffusion of gases, which can be considered thermodynamically ideal mixtures, although its application has been extended to model diffusion in non-ideal liquid mixtures as well. A drawback of the model is that it requires the Maxwell-Stefan diffusion coefficients, which are not based on measurable quantities but they have to be estimated. As a result, numerous estimation methods, such as the Darken model, have been proposed to estimate these diffusion coefficients. However, the Darken model was derived, and is only well defined, for binary systems. This model has been extended to ternary systems according to two proposed forms, one by R. Krishna and J. M. van Baten, Ind. Eng. Chem. Res., 2005, 44, 6939-6947 and the other by X. Liu, T. J. H. Vlugt and A. Bardow, Ind. Eng. Chem. Res., 2011, 50, 10350-10358. In this paper, the two forms have been analysed against the ideal ternary system of methanol/butan-1-ol/propan-1-ol and using experimental values of self-diffusion coefficients. In particular, using pulsed gradient stimulated echo nuclear magnetic resonance (PGSTE-NMR) we have measured the self-diffusion coefficients in various methanol/butan-1-ol/propan-1-ol mixtures. The experimental values of self-diffusion coefficients were then used as the input data required for the Darken model. The predictions of the two proposed multicomponent forms of this model were then compared to experimental values of mutual diffusion coefficients for the ideal alcohol ternary system. This experimental-based approach showed that the Liu's model gives better predictions compared to that of Krishna and van Baten, although it was only accurate to within 26%. Nonetheless, the multicomponent Darken model in conjunction with self-diffusion measurements from PGSTE-NMR represents an attractive method for a rapid estimation of mutual diffusion in multicomponent systems, especially when compared to exhaustive MD simulations.

Evaluation of an aortic valve prosthesis: Fluid-structure interaction or structural simulation?

Bio-inspired polymeric heart valves (PHVs) are excellent candidates to mimic the structural and the fluid dynamic features of the native valve. PHVs can be implanted as prosthetic alternative to currently clinically used mechanical and biological valves or as potential candidate for a minimally invasive treatment, like the transcatheter aortic valve implantation. Nevertheless, PHVs are not currently used for clinical applications due to their lack of reliability. In order to investigate the main features of this new class of prostheses, pulsatile tests in an in-house pulse duplicator were carried out and reproduced in silico with both structural Finite-Element (FE) and Fluid-Structure interaction (FSI) analyses. Valve kinematics and geometric orifice area (GOA) were evaluated to compare the in vitro and the in silico tests. Numerical results showed better similarity with experiments for the FSI than for the FE simulations. The maximum difference between experimental and FSI GOA at maximum opening time was only 5%, as compared to the 46.5% between experimental and structural FE GOA. The stress distribution on the valve leaflets clearly reflected the difference in valve kinematics. Higher stress values were found in the FSI simulations with respect to those obtained in the FE simulation. This study demonstrates that FSI simulations are more appropriate than FE simulations to describe the actual behaviour of PHVs as they can replicate the valve-fluid interaction while providing realistic fluid dynamic results.

Hemocompatibility of styrenic block copolymers for use in prosthetic heart valves.

Certain styrenic thermoplastic block copolymer elastomers can be processed to exhibit anisotropic mechanical properties which may be desirable for imitating biological tissues. The ex-vivo hemocompatibility of four triblock (hard-soft-hard) copolymers with polystyrene hard blocks and polyethylene, polypropylene, polyisoprene, polybutadiene or polyisobutylene soft blocks are tested using the modified Chandler loop method using fresh human blood and direct contact cell proliferation of fibroblasts upon the materials. The hemocompatibility and durability performance of a heparin coating is also evaluated. Measures of platelet and coagulation cascade activation indicate that the test materials are superior to polyester but inferior to expanded polytetrafluoroethylene and bovine pericardium reference materials. Against inflammatory measures the test materials are superior to polyester and bovine pericardium. The addition of a heparin coating results in reduced protein adsorption and ex-vivo hemocompatibility performance superior to all reference materials, in all measures. The tested styrenic thermoplastic block copolymers demonstrate adequate performance for blood contacting applications.

Fluid dynamic characterization of a polymeric heart valve prototype (Poli-Valve) tested under continuous and pulsatile flow conditions.

PURPOSE: Only mechanical and biological heart valve prostheses are currently commercially available. The former show longer durability but require anticoagulant therapy; the latter display better fluid dynamic behavior but do not have adequate durability. New Polymeric Heart Valves (PHVs) could potentially combine the hemodynamic properties of biological valves with the durability of mechanical valves. This work presents a hydrodynamic evaluation of 2 groups of newly developed supra-annular, trileaflet prosthetic heart valves made from styrenic block copolymers (SBC): Poli-Valves. METHODS: 2 types of Poli-Valves made of SBC and differing in polystyrene fraction content were tested under continuous and pulsatile flow conditions as prescribed by ISO 5840 Standard. A pulse duplicator designed ad hoc allowed the valve prototypes to be tested at different flow rates and frequencies. Pressure and flow were recorded; pressure drops, effective orifice area (EOA), and regurgitant volume were computed to assess the behavior of the valve. RESULTS: Both types of Poli-Valves met the minimum requirements in terms of regurgitation and EOA as specified by the ISO 5840 Standard. Results were compared with 5 mechanical heart valves (MHVs) and 5 tissue heart valves (THVs), currently available on the market. CONCLUSIONS: Based on these results, PHVs based on styrenic block copolymers, as are Poli-Valves, can be considered a promising alternative for heart valve replacement in the near future.

A Newly Developed Tri-Leaflet Polymeric Heart Valve Prosthesis.

The potential of polymeric heart valves (PHV) prostheses is to combine the hemodynamic performances of biological valves with the durability of mechanical valves. The aim of this work is to design and develop a new tri-leaflet prosthetic heart valve (HV) made from styrenic block copolymers. A computational finite element model was implemented to optimize the thickness of the leaflets, to improve PHV mechanical and hydrodynamic performances. Based on the model outcomes, 8 prototypes of the designed valve were produced and tested in vitro under continuous and pulsatile flow conditions, as prescribed by ISO 5840 Standard. A specially designed pulse duplicator allowed testing the PHVs at different flow rates and frequency conditions. All the PHVs met the requirements specified in ISO 5840 Standard in terms of both regurgitation and effective orifice area (EOA), demonstrating their potential as HV prostheses.

A bio-inspired microstructure induced by slow injection moulding of cylindrical block copolymers.

It is well known that block copolymers with cylindrical morphology show alignment with shear, resulting in anisotropic mechanical properties. Here we show that well-ordered bi-directional orientation can be achieved in such materials by slow injection moulding. This results in a microstructure, and anisotropic mechanical properties, similar to many natural tissues, making this method attractive for engineering prosthetic fibrous tissues. An application of particular interest to us is prosthetic polymeric heart valve leaflets, mimicking the shape, microstructure and hence performance of the native valve. Anisotropic layers have been observed for cylinder-forming block copolymers centrally injected into thin circular discs. The skin layers exhibit orientation parallel to the flow direction, whilst the core layer shows perpendicularly oriented domains; the balance of skin to core layers can be controlled by processing parameters such as temperature and injection rate. Heart valve leaflets with a similar layered structure have been prepared by injection moulding. Numerical modelling demonstrates that such complex orientation can be explained and predicted by the balance of shear and extensional flow.

Mechanical strength of sutured block copolymers films for load bearing medical applications.

The mechanical behavior of three styrenic thermoplastic block copolymer elastomers with applied surgical sutures was studied by uniaxial tensile testing. The materials exhibited oriented cylindrical microstructure. Distinct macroscopic deformation mechanisms have been observed upon stretching of samples with vertical and horizontal orientation. Deformation progressed along the axis of the suture in samples with parallel orientation (P), while it in case of normal orientation (N) the whole sample responded to the applied force. Also the analysis of the stress-strain curves showed a significant difference between samples P and N. Greater stress at break was observed for samples P, while samples N showed the capability to tolerate higher strain. The influence of morphology on the tear-out shape has been also observed. The thread made a vertical tear out in samples P while for samples N ripping off the bottom was observed.

Zebra mussel filtration and its potential uses in industrial water treatment.

The zebra mussel (Dreissena polymorpha) is a notorious freshwater biofouling pest, and populations of the species can alter aquatic environments through their substantial filtration capabilities. Despite the ecological importance of zebra mussel filtration, many predictions of their large-scale effects on ecosystems rely on extrapolations from filtration rates obtained in static laboratory experiments, not accounting for natural mussel densities, boundary layer effects, flow rates or elevated algal concentrations. This study used large-scale industrial flume trials to investigate the influence of these factors on zebra mussel filtration and proposes some novel industrial applications of these findings. The flume trials revealed some of the highest zebra mussel clearance rates found to date, up to 574+/-20mlh(-1)g(-1) of wet tissue mass. Under low algal concentrations, chlorophyll a removal by zebra mussels was not proportional to mussel density, indicating that field rates of zebra mussel grazing may be much lower than previous studies have predicted. Increasing ambient velocities up to 100mls(-1) ( approximately 4cms(-1)) led to increased clearance rates by zebra mussels, possibly due to the replenishment of locally depleted resources, but higher velocities of 300mls(-1) (12cms(-1)) did not lead to further significant increases in clearance rate. When additional algal cultures were dosed into the flumes, chlorophyll a removal increased approximately logarithmically with zebra mussel density and there were no differences in the clearance of three different species of alga: Ankyra judayi, Pandorina morum and Cyclotella meneghinia. Some novel industrial uses of these zebra mussel filtration studies are proposed, such as: (1) helping to inform models that predict the large-scale grazing effects of the mussels, (2) allowing estimates of zebra mussel densities in industrial pipelines, and (3) constructing large-scale biofilters for use in water clarification.

Electron transfer of plurimodified DNA SAMs.

An STM-based current-voltage (I/V) investigation of deoxyribonucleic acid (DNA) 18 base pair (bp) oligonucleotide monolayers on gold is presented. Three bases of each of the immobilized and complementary strands were modified with either iodine or phenylethylene moieties. The oligonucleotides were immobilized on template stripped gold (tsg) surfaces and characterized by atomic force microscopy (AFM) and scanning tunneling microscopy (STM). AFM imaging showed that monolayers of the expected height were formed. A comparative study of normal, halogenated, and phenyl-modified DNA was made with the STM in tunneling spectroscopy (TS) mode. I/V spectroscopic measurements in the range +/-250 mV on both single- and double-stranded (ds) DNA monolayers (modified and unmodified) showed that for negative substrate bias (U(sub)) electron transfer is more efficient through a phenyl-modified monolayer than through normal or halogenated DNA. This effect was particularly clear below a threshold bias of -100 mV. For positive U(sub), unmodified ds DNA was found to conduct slightly better than the modified strands. This is presumably caused by greater order in the unmodified versus modified DNA monolayers. Modifications on the immobilized (thiolated) strand seem to improve electron transport through the DNA monolayer more than modifications on the complementary (not surface-bound) strand.

Microencapsulated BioBullets for the control of biofouling zebra mussels.

The widespread invasion of freshwaters by the zebra mussel, Dreissena polymorpha, during the last 2 decades has made it one of the world's most economically and ecologically important pests. Since arriving in the North American Great Lakes in the 1980s, zebra mussels have become a major biofouler, blocking the raw water cooling systems of power stations and water treatment works and costing U.S. dollars 1-5 billion per year. Despite the development of numerous control methods, chlorination remains the only widespread and licensed technique. Zebra mussels are able to sense chlorine and othertoxins in their surrounding environment and respond by closing their valves, thus enabling them to avoid toxic effects for up to 3 weeks. Furthermore, prolonged dosing of chlorine in raw water produces ecotoxic trihalomethanes (THMs) by reaction with organic material in the water. We have developed a novel, environmentally safe, and effective method for controlling the zebra mussel: the BioBullet. Our method uses the encapsulation of an active ingredient (KCI) in microscopic particles of edible material. The mussels' natural filtering ability then removes and concentrates the particles from the water, without stimulating the valve-closing response. By using the mussels' filtering behavior to concentrate BioBullets the absolute quantity of active ingredient added to the water can be reduced substantially. Our approach allows us to engineer the particles to break up and dissolve completely within a few hours, thus eliminating the risk of polluting the wider ecosystem. We demonstrate that the effectiveness of a toxin in the control of biofouling filter-feeders can be enhanced greatly by using our technique. This paves the way for a new approach to the control of some of the world's most important economic pests.