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  • Author: Sylvia Pfensig x
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Abstract

In this study, varying amounts of NIPAAm and an ionic liquid (IL), namely 1-vinyl-3-isopropylimidazolium bromide ([ViPrIm]+[Br]), have been used to synthesize hybrid hydrogels by radical emulsion polymerization. Amounts of 70/30%, 50/50%, 30/70%, 15/85% and 5/95% (wt/wt) of PIL/pNIPAAm were used to produce hybrid hydrogels as well as the parental hydrogels. The adhesive strength was investigated and evaluated for mechanical characterization. Thermal properties of resulting hydrogels have been investigated using differential scanning calorimetry (DSC) in a default heating temperature range (heating rate 10 K min−1). The presence of poly ionic liquids (PIL) in the polymer matrix leads to a moved LCST (lower critical solution temperature) to a higher temperature range for certain hybrid hydrogels PIL/pNIPAAm. While pNIPAAm exhibits an LCST at 33.9 ± 0.3°C, PIL/pNIPAAm 5/95% and PIL/pNIPAAm 15/85% were found to have LCSTs at 37.6 ± 0.9°C and 52 ± 2°C, respectively. This could be used for controlled drug release that goes along with increasing body temperature in response to an implantation caused infection.

Abstract

For the treatment of severe symptomatic aortic valve stenosis, minimally invasive heart valve prostheses are increasingly used, especially for elderly patients. The current generation of devices is based on xenogenic leaflet material, involving limitations with regard to calcification and durability. Artificial polymeric leaflet-structures re-present a promising approach for improvement of valve performance. Within the current work, finite-element ana-lysis (FEA) design studies of polymeric leaflet structures were conducted. Design of an unpressurized and axially-symmetric trileaflet heart valve was developed based on nine parameters. Physiological pressurization in FEA was specified, based on in vitro hydrodynamic testing of a commercially available heart valve prosthesis. Hyper-elastic constitutive law for polymeric leaflet material was implemented based on experimental stress strain curves resulting from uniaxial tensile and planar shear testing. As a result of FEA, time dependent leaflet deformation of the leaflet structure was calculated. Obtained leaflet dynamics were comparable to in vitro performance of the analyzed prosthesis. As a major design parameter, the lunula angle has demonstrated crucial influence on the performance of the polymeric leaflet structures. FEA represented a useful tool for design of improved polymeric leaflet structures for minimally invasive implantable heart valve prostheses.

Abstract

The implantation of transcatheter aortic valve prostheses (TAVP) for therapy of aortic valve stenosis shows more and more clinically non-inferiority results compared to surgical valve replacement in intermediate and low risk patients. Commonly clinically used TAVP are manufactured from chemically fixed xenograft leaflet material, e.g. bovine or porcine pericardium. While the clinical use of TAVP currently extends, challenges concerning valve durability and leaflet calcification have to be addressed. In this regard, artificial leaflet materials represent a promising option for a next generation of TAVP. As a first step for the development of TAVP from polymeric nonwoven, the aim of this study was to determine the influence of leaflet geometry on hydrodynamic performance of TAVP prototypes. Based on a parametric model of the valve leaflets, we varied the curvature of the belly line forming the leaflet coaptation area from an initial, quite concave, leaflet geometry with a value of 0.5° to an almost straight geometry for the leaflets with a value 0.15°. Manufacturing of TAVP prototypes was conducted by means of electrospinning technique with a polycarbonate based silicone elastomer. Hydrodynamic characterization according to ISO 5840-3 standards was performed using a pulse duplicator system with a heart rate of 70 BPM, systolic duration of 35%, mean aortic pressure of 100 mmHg and a stroke volume of 96 ml. Cardiac output as well as mean transaortic pressure gradient, closing volume, leakage volume and regurgitation were measured to compare the different leaflet geometries. To summarize, the curvature of the leaflets’ belly has a crucial impact on TAVP hydrodynamics under physiological test conditions. In particular, the opening and closing behavior is strongly influenced by a steeper curvature leading to larger closing volumes and higher regurgitant fractions. Further studies are planned to identify an optimum with respect to leaflet material selection, leaflet geometry and hydrodynamic properties of TAVP.

Abstract

While the current generation of devices for minimally invasive treatment of severe symptomatic aortic valve stenosis is based on xenogenic leaflet-material, artificial polymeric leaflet-structures represent a promising approach for future improvement of heart valve performance. For enhanced long-term success of polymeric leafletstructures, limitations regarding calcification and durability have to be addressed. The objective of the presented study was the development of a constitutive law representing the material properties of artificial polymeric leaflet-structures of transcatheter heart valve prostheses in numerical simulation to assess the in silico leaflet-performance. Mechanical characterization of cast films and nonwoven specimens of a polycarbonate based silicone elastomer were conducted by means of uniaxial tension and planar shear testing, respectively. For validation purposes, experimental data were compared with the results of finite-element analysis (FEA) using different hyperelastic models. Strain energy function for third-order ogden hyperelastic model achieved the best fit of the non-linear stress-strain behavior of the isotropic polymeric material with the experimental data. It was chosen for further FEA of valve leaflet-performance under physiological pressurization to analyze the suitability of various manufacturing processes for polymeric leafletstructures. Therefore a specific leaflet-design with a wall thickness of 400 μm was used. As a result of FEA, time dependent leaflet-deformation, leaflet coaptation surface area (CSA) and leaflet opening area (LOA) of cast and nonwoven leaflet-structures were calculated. While LOA was comparable for cast and nonwoven leaflet-structures, obtained leaflet-dynamics in a cardiac cycle under physiological pressurization demonstrated crucial influence of the manufacturing process. For nonwoven leafletstructures, an enhanced CSA could be demonstrated in comparison to cast structures. FEA using a validated hyperelastic constitutive law represents a useful tool for in silico performance evaluation of polymeric leaflet-structures under physiological loading and proves the suitability of the polymeric artificial leaflet-material for percutaneous heart valve prostheses.

Abstract

For the treatment of severe symptomatic aortic valve stenosis, minimally invasive heart valve prostheses have more recently become the lifesaving solution for elderly patients with high operational risk and thus, are often implanted in patients with challenging aortic root configuration. A correct prosthesis deployment and stent adaption to the target region is essential to ensure optimal leaflet performance and long-term prosthesis function. The objective of this study was the development of a suitable in silico setup for structural numerical simulation of a transcatheter aortic valve (TAV) in different cases of clinical relevance. A transcatheter valve prosthesis comprising an unpressurized trileaflet heart valve and an adapted stent configuration was designed. An aortic root (AR) model was developed, based on microcomputed tomography of a native healthy specimen. Using the finite-element analysis (FEA), various loading cases including prosthesis biomechanics with valve opening and closing under physiological pressure ratios throughout a cardiac cycle, prosthesis crimping as well as crimping and release into the developed AR model were simulated. Hyperelastic constitutive law for polymeric leaflet material and superelasticity of shape memory alloys for the self-expanding Nitinol stent structure were implemented into the FEA setup. Calculated performance of the valve including the stent structure demonstrated enhanced leaflet opening and closing as a result of stent deformation and redirected loading. Crimping and subsequent release into the AR model as well as the stent adaption to the target region after expansion proved the suitability of the TAV design for percutaneous application. FEA represented a useful tool for numerical simulation of an entire minimally invasive heart valve prosthesis in relevant clinical scenarios.

Abstract

In-stent thrombosis is a major complication of stent implantations. Unlike pathological occurrences as in-stent restenosis for instance, thrombosis represents an acute event associated with high mortality rates. Experiments show that low wall shear stress promotes undirected endothelial cell coverage of the vessel wall and therefore increases the risk of thrombus formation. Stent design represents a crucial factor influencing the surface areas of low wall shear stress and thus the incidence of acute in-stent thrombosis. In this study, we present an optimization method for stent designs with minimized thrombosis risk. A generic stent design was developed, based on five different stent design parameters. Optimization was conducted based on computational fluid dynamics analysis and the gradient-free Nelder-Mead approach. For each optimization step, a numerical fluid simulation was performed in a vessel with a reference vessel diameter of 2.70 mm with stent-overexpansion ratio of 1.0:1.1. For each numerical fluid simulation a physiological Reynolds number of 250, resulting in a mean velocity of 0.331 m/s at the inlet and a laminar flow as well as stiff vessel walls were assumed. The impact of different stent designs was analyzed based on the wall shear stress distribution. As a basis for the comparison of different stent designs, a dimensionless thrombosis risk number was calculated from the area of low wall shear stress and the overall stented area. The first two optimization steps already provide a decrease of thrombosis risk of approximately 83%. In conclusion, computational fluid dynamic analyses and optimization methods usind the Nelder-Mead approach represent a useful tool for the development of hemodynamically optimized stent designs with minimized thrombosis risk.

Abstract

Assessment of hydrodynamic performance of transcatheter aortic valve prostheses (TAVP) in vitro is es-sentially in the fields of development and approval of novel implants. For the prediction of clinical performance, in vitro testing of TAVP allows for benchmarking of different devic-es, likewise. In addition to the implant itself, also the testing environment has a crucial influence on leaflet dynamics and quantitative test results like effective orifice area (EOA) or aortic regurgitation.

Therefore, within the current study we developed simpli-fied physiological and pathophysiological vessel models of the aortic root as a tool for in vitro hydrodynamic testing of TAVP in idealized and worst case conditions. We used 3D printing and silicone cast molding for manufacturing of aortic root models with variable degree of stenosis. Design of aortic roots with normal, mild and severe stenosis was developed according to Reul et al. For manufacturing of tripartite cast-ing molds, a 3D printer was used. Both outer mold parts and the mold core were manufactured from polylactide filament and water soluble polyvinylalcohol filament, respectively. In vitro hydrodynamic performance testing of an exemplary commercially available TAVP implanted in different aortic root models was conducted according to DIN EN ISO 5840-3:2013, using a pulse duplicator system. Manufactured aortic root models were highly transparent, dimensionally stable and therefore suitable for hydrodynamic testing of TAVP. Both, EOA and regurgitant fraction in-creased with increasing degree of stenosis from 1.6 ± 0.1 cm2 to 1.8 ± 0.1 cm2 and 8.6 ± 6.5% to 20.2 ± 4.2% (n = 30 cy-cles), respectively.

We successfully developed a testing environment ena-bling sophisticated evaluation of hydrodynamic performance of TAVR in pathophysiological worst case conditions.

Abstract

Xenogenic leaflet material, bovine and porcine pericardium, is widely used for the fabrication of surgically implanted and transcatheter heart valve prostheses. As a biological material, long term durability of pericardium is limited due to calcification, degeneration and homogeneity. Therefore, polymeric materials represent a promising approach for a next generation of artificial heart valve leaflets with improved durability. Within the current study we analyzed the mechanical performance of polymeric structures based on elastomeric materials. Polymeric cast films were prepared and nonwovens were manufactured in an electrospinning process. Analysis of cyclic stress-strain behavior was performed, using a universal testing machine. The uniaxial cyclic tensile experiments of the elastomeric samples yielded a non-linear elastic response due to viscoelastic behavior with hysteresis. Equilibrium of stress-strain curves was found after a specific number of cycles, for cast films and nonwovens, respectively. In conclusion, preconditioning was found obligatory for the evaluation of the mechanical performance of polymeric materials for the use as artificial leaflet material for heart valve prostheses.

Abstract

Mitral regurgitation (MR) occurs with a prevalence of approximately 10 % in patients aged 75 years or older and therefore is one of the most frequent indications for heart valve surgery. During the last decade surgical mitral valve repair (MVR) procedures emerged as the gold standard for the treatment of clinically relevant MR. However, for surgically inoperable or high-risk patients transcatheter-based MVR devices present a valuable treatment option. Within the current study, we developed an experimental setup to investigate the hydrodynamic performance of transcatheterbased MVR devices in vitro. The bicuspid mitral valve (MV) model employed in the experimental setup features a D-shaped MV annulus with d1 = 26.30 mm, d2= 30.05 mm and chordae tendineae with a length of l1= 25 mm attached to two papillary muscle structures. Pressure gradient - volumetric flow rate (Δp-Q) relations were investigated for steady state backward flow with transvalvular pressure gradients ranging from 0.75 mmHg ≤ Δp ≤ 103.13 mmHg. Deionized water at 37 °C with a dynamic viscosity of 1.002 mPa∙s and a density of 998 kg/m3 was used. A test-chamber consisting of a press-fit MV holder and cylindrical in- and outflow tracts were developed. Different designs for the exchangeable press-fit MV holder were manufactured using additive manufacturing technologies providing an optimal fitting for variable MV sizes and pathologies. In- and outflow tracts featuring a diameter of d = 50 mm and a height of h = 60 mm were made from transparent polymethylmethacrylate to allow for easy optical access during measurements. The experimentally investigated Δp-Q relation yields a quadratic correlation for the open MV and a linear correlation for the closed MV. A transvalvular closing pressure of (4.94 ± 0.04) mmHg was measured for the MV model.

Abstract

Glaucoma represents the leading cause of irreversible blindness worldwide. Therapeutic approaches are based on the lowering of intraocular pressure (IOP). Micro-invasive glaucoma surgery (MIGS) offers perspectives for implant based IOP-reduction with reduced complication rates compared to conventional surgical approaches. Nevertheless, available devices suffer from complications like hypotony and fibrotic encapsulation. The current work focuses on the development of a minimally invasive implantable drugeluting microstent for the drainage of aqueous humour into suprachoroidal or subconjunctival space. Technical feasibility of a micro-scale resorbable nonwoven for the prevention of hypotony and of a drug-eluting coating for the prevention of fibrosis is assessed. Microstent base bodies with a length of 10 mm and an inner/outer diameter of 0.20 mm / 0.35 mm were manufactured. For the prevention of hypotony, resorbable nonwovens with an adequate flow resistance of 1.543 mmHg/μl min-1 were manufactured in the inflow area of microstents. A drug-eluting coating in the outflow area of microstents was developed based on the model drug fluorescein diacetate. Micro-invasive ab interno implantation of a microstent prototype into suprachoroidal space of a porcine eye post mortem was successfully performed, using an injector device. Future studies will focus on the development of an antifibrotic drug-eluting coating and further in vitro, ex vivo and in vivo testing of the devices.