Jacob Brubert

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.

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.

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 Computational Tool for the Microstructure Optimization of a Polymeric Heart Valve Prosthesis

Styrene-based block copolymers are promising materials for the development of a polymeric heart valve prosthesis (PHV), and the mechanical properties of these polymers can be tuned via the manufacturing process, orienting the cylindrical domains to achieve material anisotropy. The aim of this work is the development of a computational tool for the optimization of the material microstructure in a new PHV intended for aortic valve replacement to enhance the mechanical performance of the device. An iterative procedure was implemented to orient the cylinders along the maximum principal stress direction of the leaflet. A numerical model of the leaflet was developed, and the polymer mechanical behavior was described by a hyperelastic anisotropic constitutive law. A custom routine was implemented to align the cylinders with the maximum principal stress direction in the leaflet for each iteration. The study was focused on valve closure, since during this phase the fibrous structure of the leaflets must bear the greatest load. The optimal microstructure obtained by our procedure is characterized by mainly circumferential orientation of the cylinders within the valve leaflet. An increase in the radial strain and a decrease in the circumferential strain due to the microstructure optimization were observed. Also, a decrease in the maximum value of the strain energy density was found in the case of optimized orientation; since the strain energy density is a widely used criterion to predict elastomers lifetime, this result suggests a possible increase of the device durability if the polymer microstructure is optimized. The present method represents a valuable tool for the design of a new anisotropic PHV, allowing the investigation of different designs, materials, and loading conditions.

Structural changes of block copolymers with bi-modal orientation under fast cyclical stretching as observed by synchrotron SAXS

Here we examine a block copolymer with cylindrical morphology having a bio-inspired microstructure of anisotropic orthogonally oriented layers and report changes of the microstructure under uniaxial strain.

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.

Quantifying the Shift Toward Transcatheter Aortic Valve Replacement in Low-Risk Patients

British Heart Foundation Translational Award TG/15/4/31891 (Drs De Sciscio, Brubert, and Moggridge) and British Heart Foundation Special Project Grant SP/15/5/31548 (Drs Serrani, Stasiak, and Moggridge).

A NOVEL TEST BENCH TO SIMULATE THE INTERACTION OF VAD WITH THE FAILING SUPERIOR CAVO-PULMONARY CONNECTION

Abstracts from the XLIII Congress of the European Society for Artificial Organs, 14-17 September 2016, Warsaw, Poland.

Material Selection and Performance Index for Polymeric Prosthetic Heart Valve Design

The number of patients requiring replacement heart valves due to valvular heart disease is forecast to rise from 290,000 in 2003 to 850,000 in 2050. Currently, treatment of these patients is dominated by either surgically implanted mechanical or bioprosthetic valves. Unfortunately, none of these solutions are optimal, they simply replace native valvular disease with “prosthetic valvular disease”—mechanical valves require lifelong anticoagulation, and bioprostheses have a limited durability of approximately 15 yr. As such, since the 1950s, researchers have sought solutions which may overcome these drawbacks. Flexible leaflet polymeric prosthetic heart valves (PHVs) have been proposed as a potential solution—able to provide good longterm durability and function without the need for anticoagulation, however, no valve has been clinically successful, and in the past 40 years of development no valve has reached clinical trials [1]. As such, the process by which we design polymeric valves should be seriously considered. The design of polymeric valves may be split into a structural valve design and material selection problem. The use of material selection indices to aid the quantitative design of engineering components was formalized by Ashby et al. [2], and in this report, we propose the use of a novel material performance index (PI) to evaluate potential polymer materials for PHVs. We identify the leaflets as the critical component for the valves, and this report is focused on material selection for leaflets. We limit our search of the material “kingdom” to elastomeric materials whose mechanical properties are similar to the biological tissues. This allows us to produce quasi-physiological flow. We proceed by producing a shortlist of materials based upon hemocompatibility (minimum of inflammation and thrombogenicity) and biostability (resistance to oxidation and hydrolysis). A number of elastomers and coatings fulfill these criteria. In the realm of PHV, a number of “biocompatible” and “biostable” polymers have been proposed: polyhedral oligomeric silsesquioxane polycarbonate urethane, polystyrene (PS)-block-polyisobutyleneb-PS (and cross linked), Elasteon, cellulose, PS-b-polyethylenepropylene-b-PS, and polyethylene-hydraluron. Within a group such as this we seek to determine the most suitable polymer to fulfill the PHV role. Durability and calcification are the two failure routes which have plagued all flexible leaflet polymeric valves tested in vitro or in vivo. Durability is a function of material and valve design. Although various leaflet forms and dimensions can result in reduced leaflet stresses, the first order determinant of the stresses induced in a leaflet when loaded during diastole is a function of the leaflet’s thickness; thicker leaflets have lower stresses. Concurrently, we must be mindful of the hemodynamics of the valve. In general, the reduction in leaflet thickness leads to a lower mean pressure gradient [3]. Given these conflicting criteria regarding leaflet thickness, we must seek a compromise, leading to the use of a material PI [2]. We must define a relationship for hemodynamics and durability using leaflet thickness and appropriate material parameters. For a trileaflet valve to successfully function the curvature of each leaflet must be reversed, in theory, TPGmax / Et where TPGmax is the maximum transvalvular pressure gradient, E is the Young’s Modulus (or flexural modulus), and t is the leaflet thickness. Using this relation for hydrodynamics, Haworth [4] used tear strength as the parameter for prediction of lifetime. The use of tear strength failed in part because it describes failure at a stress state several magnitudes greater than those found in physiological scenarios. Parfeev et al. [5] improved upon this by comparing polymers based upon wear limits after 10 cycles at 22 Hz. We performed frequency sweep dynamic mechanical analysis of candidate polymers showing that they undergo a transition at 15–20 Hz, making testing at such a high frequency unacceptable for predicting low frequency behavior. Since the 1980s, fatigue testing and prediction of rubber component failure has received significant research in other fields. In particular, the use of crack growth models to predict long term behavior has been successfully employed in the cyclic straining of various rubber components [6]. We now propose a novel material PI based on cyclic fatigue theory, for the improved design of polymeric PHVs.

Prevalence, Treatment Eligibility and Postoperative Survival for Europeans with Aortic Stenosis

Aortic Stenosis (AS) is the most frequent valvular pathology in the developed world. Whilst much is known about its pathogenesis and treatment, a paucity of data exists on the prevalence and number of patients eligible for valve replacement.