Stefan Siewert

In vitro performance investigation of bioresorbable scaffolds – Standard tests for vascular stents and beyond

BACKGROUND/PURPOSE Biodegradable polymers are the main materials for coronary scaffolds. Magnesium has been investigated as a potential alternative and was successfully tested in human clinical trials. However, it is still challenging to achieve mechanical parameters comparative to permanent bare metal (BMS) and drug-eluting stents (DES). As such, in vitro tests are required to assess mechanical parameters correlated to the safety and efficacy of the device. METHODS/MATERIALS In vitro bench tests evaluate scaffold profiles, length, deliverability, expansion behavior including acute elastic and time-dependent recoil, bending stiffness and radial strength. The Absorb GT1 (Abbott Vascular, Temecula, CA), DESolve (Elixir Medical Corporation, Sunnyvale, CA) and the Magmaris (BIOTRONIK AG, Bülach, Switzerland) that was previously tested in the BIOSOLVE II study, were tested. RESULTS Crimped profiles were 1.38±0.01mm (Absorb GT1), 1.39±0.01mm (DESolve) and 1.44±0.00mm (Magmaris) enabling 6F compatibility. Trackability was measured depending on stiffness and force transmission (pushability). Acute elastic recoil was measured at free expansion and within a mock vessel, respectively, yielding results of 5.86±0.76 and 5.22±0.38% (Absorb), 7.85±3.45 and 9.42±0.21% (DESolve) and 5.57±0.72 and 4.94±0.31% (Magmaris). Time-dependent recoil (after 1h) was observed for the Absorb and DESolve scaffolds but not for the Magmaris. The self-correcting wall apposition behavior of the DESolve did not prevent time-dependent recoil under vessel loading. CONCLUSIONS The results of the suggested test methods allow assessment of technical feasibility based on objective mechanical data and highlight the main differences between polymeric and metallic bioresorbable scaffolds.

Numerical simulation of pulsatile flow through a coronary nozzle model based on FDA’s benchmark geometry

Abstract Computational fluid dynamics (CFD) is a powerful tool to extent knowledge of biomechanical processes in cardiovascular implants. To provide a standardized method the U.S. Food and Drug Administration (FDA) initialized a CFD round robin study. One of the developed benchmark standard models is a generic nozzle geometry, consisting of a cylindrical throat with a conical collector and sudden expansion on either side. Several fluid mechanical data obtained from international institutes by means of CFD and particle image velocimetry (PIV) measurements under different flow regimes (Re = 500, 2000, 3500, 5000 and 6500) are freely available. This database includes only steady state simulations. In this study we performed pulsatile CFD simulations to consider the physiological environment of the coronary vessels. Furthermore, the nozzle geometry was scaled down to coronary dimension (Dinlet = 12 mm to 3 mm) while retaining the average Reynolds number Re = 500 constant. The pulsatile character is described by a Womersley number of Wo = 2.065. Our CFD code was previously validated by using FDA’s data for steady state inflow conditions. It could be shown that time averaged wall shear stress and shear stress values agree well with steady state results. We conclude that steady state simulations are valid for hemodynamic analyses if only time averaged values are needed. This could save computational costs of future hemodynamic investigations. In addition, this study expands FDA’s benchmark case by pulsatile inlet condition for further code validation. This could be necessary for the development of new numerical methods as well as for validation of CFD codes used in the approval process of medical devices.

Development of a Test Facility for Microfluidic Characterization of Glaucoma Drainage Devices

Microfluidic characterization plays an outstanding role in the development of glaucoma drainage devices. Here, we describe the optimization of an existing test facility with regard to measurement of small volumetric flow rates in the range of 1 μl/min to 40 μl/min in a minimized testing time. The existing test facility is extended by a flow sensor and validated by microfluidic characterization of glass capillaries. Finally, two micro-mechanical valve prototypes are successfully analysed with regard to opening and closing pressure.

Hemodynamic influence of design parameters of novel venous valve prostheses

Abstract Venous ulcers of the lower limbs are one clinical manifestation of chronic venous insufficiency. Currently, there is no venous valve prosthesis available. This study presents novel venous valve prostheses made of threedimensional electrospun fibrous nonwoven leaflets. The aim of this study was to prove the feasibility of the manufacturing process as well as to investigate design features of the venous valve prostheses from a hemodynamic point of view. An adapted pulse duplicator system (ViVitrolabs, Victoria, BC, CA) was used for characterization of the hydrodynamic performance. For eight different venous valve prototypes flow rate, effective orifice area and regurgitation fraction was investigated in vitro. In particular, tricusp valve designs showed an up to 40% higher effective orifice area as well as 15% higher maximum flowrate compared to bicusp valve designs. However, the regurgitation fraction of the bicusp valve designs is up to 86% lower compared to tricusp valve. Additionally, the hemodynamic performance of the tricuspid valves showed a high sensitivity regarding the leaflet length. Bicuspid valves are less sensitive to changes of design parameters, more sufficient and therefore highly reliable.

Standardized technique of water permeability measurement for biomedical applications

Abstract Standardized methods and measures are ubiquitous in biomedical engineering and a key factor for the successful development and certification of novel biomaterials, implants or other medical devices. Hence, the development of standardized measurement techniques, which can be applied to nearly every material and device is of crucial importance. Within the current work, we introduce a method to evaluate the water permeability according to ISO/FDIS 7198. The setup was designed to determine the volumetric flow through a test sample for a given hydraulic pressure. One key feature is the effortless replacement of the chamber containing the test sample. The measurement technique can thus be applied to a variety of materials and medical devices. To demonstrate the functionality of the setup we fabricated nanofiber membranes using the process of electrospinning. Nonwovens with comparable thickness and varying morphology were analyzed with regard to water permeability. In particular the different fiber diameters as well as the modified inter-fiber distances result in large deviations of the water permeability. Furthermore, there are hints for a rearrangement of the nanofibers due to the applied hydraulic pressure. The developed measurement technique provides a powerful tool for the standardized quantification of the water permeability and can be applied to a variety of biomaterials and medical devices.

Optimization of stent designs regarding the thrombosis risk using computational fluid dynamics

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.

Experimental and numerical investigations of fluid flow in bioreactors for optimized in vitro stem cell loading in xenografts

Abstract In tissue engineering and regenerative medicine mesenchymal stem cells (MSC) are widely used to replace and restore the function of dysfunctional or missing tissue. Recent studies have shown significant enhancements of the in vivo healing process following dentofacial bone augmentation procedures employing stem cell-loaded xenografts. We conducted experimental and numerical investigations in perfusion flow bioreactor-xenograft-systems to identify flow conditions as well as bioreactor design features that allow for homogeneous MSC-distribution in Geistlich Bio- Oss Block xenografts. Pressure gradient - velocity characteristics and flow distributions were investigated experimentally and numerically for two bioreactor designs at steady-state flow conditions with Reynolds numbers (Re) ranging from 0.01 ≤ Re ≤ 0.32. Distilled water at 20°C with a dynamic viscosity of 1.002 mPa∙s and a density of 998 kg/m3 was used. The geometry of the xenograft utilized in three-dimensional computational fluid dynamics (CFD) simulation was obtained by means of micro-computed tomography (μCT) at an isotropic spatial resolution of 9.5 μm. The permeability values calculated from the experimental data are in good accordance with the numerical results. The investigations showed that the increase of the inflow- and outflow-area diameter, as well as the decrease of the volumetric flow rate, result in a decreasing heterogeneity of the flow distribution within the xenograft. The calculated wall shear stress rates in the three-dimensional (3D) scaffold range from 1∙10-12Pa ≤ τ ≤ 0.2 Pa. Experimentally validated CFD simulations introduced in this study provide an applicable tool to assess optimal flow conditions for homogeneous MSC distribution in bioreactor-xenograft-systems.

Development of a drug-eluting microstent for micro-invasive glaucoma surgery

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.

Numerical simulation of a transcatheter aortic heart valve under application-related loading

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.

Hydrophilic silicone elastomer with excellent cell adhesion capability - A promising material for ophthalmic micro-implants

Abstract For minimising tissue reactions of implants hydrophilic silicone elastomers feature a high potential to be utilised as material for micro-implants in ophthalmologic pathology. To estimate the biocompatibility we quantified cell viability of human primary fibroblasts from scleral (hSF) and choroideal (hCF) origin in direct contact test and evaluated cell adhesion and cell morphology with Phalloidin- TRITC stained hSF and EA.hy926. Mechanical properties were analysed by means of uniaxial tensile testing. Direct contact testing revealed a good biocompatibility from 65 to 70% relative cell viability for hCF and moderate viabilities (46 to 63%) for hSF. EA.hy926 and also hSF exhibited typical cell morphology on the silicones. Improvement of cell adhesion was observed with increasing amount of hydrophilic component. Mechanical testing shows a minor decrease in elongation at break from 236% to 155% with increasing amount of hydrophilic component. These findings indicate that the investigated silicones may ensure a reliable integration of implants into the ocular tissues.