Sebastian Kaule

Correlating Coating Characteristics with the Performance of Drug-Coated Balloons – A Comparative In Vitro Investigation of Own Established Hydrogel- and Ionic Liquid-Based Coating Matrices

Drug-coated balloons (DCB), which have emerged as a therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficacy and safety within a number of clinical studies. In vitro studies elucidating the correlation between coating additive and DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this regard, we examined three different DCB-systems, which were developed in former studies based on the ionic liquid cetylpyridinium salicylate, the body-own hydrogel hyaluronic acid and the pharmaceutically well-established hydrogel polyvinylpyrrolidone, considering coating morphology, coating thickness, drug-loss, drug-transfer to the vessel wall, residual drug-concentration on the balloon surface and entire drug-load during simulated use in an in vitro vessel model. Moreover, we investigated particle release of the different DCB during simulated use and determined the influence of the three coatings on the mechanical behavior of the balloon catheter. We could show that coating characteristics can be indeed correlated with the performance of DCB. For instance, paclitaxel incorporation in the matrix can reduce the drug wash-off and benefit a high drug transfer. Additionally, a thin coating with a smooth surface and high but delayed solubility can reduce drug wash-off and decrease particle burden. As a result, we suggest that it is very important to characterize DCB in terms of mentioned properties in vitro in addition to their clinical efficacy in order to better understand their function and provide more data for the clinicians to improve the tool of DCB in coronary angioplasty.

Novel paclitaxel-coated angioplasty balloon catheter based on cetylpyridinium salicylate: Preparation, characterization and simulated use in an in vitro vessel model

Drug-coated balloons (DCB), which have emerged as therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficiency and safety within a number of clinical studies. In vitro studies elucidating the correlation of coating method and composition with DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this context, we evaluated the applicability of a pipetting, dip-coating, and spray-coating process for the establishment of DCB based on paclitaxel (PTX) and the ionic liquid cetylpyridinium salicylate (Cetpyrsal) as novel innovative additive in three different compositions. Among tested methods and compositions, the pipetting process with 50 wt.% PTX resulted in most promising coatings as drug load was less controllable by the other processes and higher PTX contents led to considerable drug crystallization, as visualized by electron microscopy, accelerating PTX loss during short-term elution. Applying these conditions, homogeneous coatings could be applied on balloon catheter, whose simulated use in an in vitro vessel model revealed percental drug losses of 36 and 28% during transit and percental drug transfers of 12 and 40% under expansion for coatings applied in expanded and folded balloon condition, respectively. In comparison to literature values, these results support the high potential of Cetpyrsal as novel DCB matrix regarding low drug loss and efficient drug transfer.

Development and In Vitro Characterization of Hyaluronic Acid-Based Coatings for Implant-Associated Local Drug Delivery Systems

The development of drug-eluting coatings based on hyaluronic acid (HA) is especially promising for implant-associated local drug delivery (LDD) systems, whose implantation provokes high insertion forces, as, for instance, cochlear implants or drug-coated balloons (DCB). The lubricious character of HA can then reduce the coefficient of friction and serve as drug reservoir simultaneously. In this context, we investigated several plasma- and wet-chemical methods for the deposition of HA-based coatings with LDD function on polyamide 12 as a model implant surface, conventionally used for DCB. In contrast to aminosilane, epoxy silane surface layers allowed the covalent attachment of a smooth and uniform HA base layer, which provided good adherence of further HA layers deposited by manual dip coating at a subsequent processing stage. The applied HA-crosslinking procedure during dip coating influences the transfer and release of paclitaxel, which could be reproducibly incorporated via infiltration. While crosslinking with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride provided HA coatings on DCB, which allowed for an efficient paclitaxel transfer upon expansion in a vessel model, crosslinking with glutardialdehyde resulted in a slower drug release being more appropriate for implants with longer residence time in the body. The developed HA coating is hence well suited for spontaneous and sustained LDD.

In vitro evaluation of paclitaxel coatings for delivery via drug-coated balloons

Lately, drug-coated balloons have been introduced in interventional cardiology as an approach to treat occluded blood vessel. They were developed for the rapid transfer of antiproliferative drugs during the angioplasty procedure in stenosed vessels with the intent to reduce the risk of restenosis. In this study five different paclitaxel (PTX) balloon coatings were tested in vitro in order to examine how solvents and additives influence coating stability and drug transfer rates. PTX-coated balloons were advanced through a guiding catheter and a simulated coronary artery pathway under perfusion and were then inflated in a hydrogel acceptor compartment. The fractions transferred to the gel, remaining on the balloon and the PTX lost in the simulated coronary pathway were then analysed. The results obtained suggest that the solvent used for the coating process strongly influences the surface structure and the stability of the coating. Ethanol/water and acetone based PTX coatings showed the lowest drug transfer rates to the simulated vessel wall (both <1%) due to their high drug losses during the prior passage through the coronary artery model (more than 95%). Balloons coated with PTX from ethyl acetate-solutions showed smaller drug loss (83%±9%), but most of the remaining PTX was not transferred (mean balloon residue approximately 15%). Beside the solvent, the use of additives seemed to have a great impact on transfer properties. The balloon pre-treatment with a crosslinked polyvinylpyrrolidone (PVP) film was able to increase the PTX transfer rate from less than 1% (without PVP) to approximately 6%. The best results in this study were obtained for balloon coatings with commercially available SeQuent© Please balloons containing the contrast agent iopromide. For this formulation drug transfer rates of approximately 17% were determined. Fluorescence microscopic imaging could visualize the particulate transfer of labelled PTX from the balloon surface during dilatation. The findings of this study underline the importance of drug adhesion and coating stability for the efficiency of PTX transfer.

Usage of different vessel models in a flow-through cell: in vitro study of a novel coated balloon catheter

Drug-coated balloon catheters are a novel clinical treatment alternative for coronary and peripheral artery diseases. Calcium alginate, poly(vinylethylimidazolium bromide) and polyacrylamide hydrogels were used as vessel models in this in vitro study. In comparison to a simple silicone tube their properties can be easily modified simulating different types of tissue. Local drug delivery after balloon dilation in the first crucial minute was determined in a vessel-simulating flow-through cell by a simulated blood stream. Balloon catheters were coated with paclitaxel using the ionic liquid cetylpyridinium salicylate as a novel carrier. Drug transfer from coated balloon catheters to different simulated vessel walls was evaluated and compared to a silicone tube. The highest paclitaxel delivery upon dilation was achieved with calcium alginate as the vessel model (60%) compared to polyacrylamide with 20% drug transfer. The silicone tube showed the least amount of wash-off (<1%) by a simulated blood stream after one minute from the vessel wall. The vessel-simulating flow-through cell was combined with a model coronary artery pathway to estimate drug loss during simulated use in an in vitro model. Calcium alginate and polyacrylamide hydrogels were used as tissue models for the simulated anatomic implantation process. In both cases, similar transfer rates for paclitaxel upon dilation were detected.

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.

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.

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.

Fluid-structure interaction of heart valve dynamics in comparison to finite-element analysis

Abstract An established therapy for aortic valve stenosis and insufficiency is the transcatheter aortic valve replacement. By means of numerical simulation the valve dynamics can be investigated to improve the valve prostheses performance. This study examines the influence of the hemodynamic properties on the valve dynamics utilizing fluidstructure interaction (FSI) compared with results of finiteelement analysis (FEA). FEA and FSI were conducted using a previously published aortic valve model combined with a new developed model of the aortic root. Boundary conditions for a physiological pressurization were based on measurements of ventricular and aortic pressure from in vitro hydrodynamic studies of a commercially available heart valve prosthesis using a pulse duplicator system. A linear elastic behavior was assumed for leaflet material properties and blood was specified as a homogeneous, Newtonian incompressible fluid. The type of fluid domain discretization can be described with an arbitrary Lagrangian-Eulerian formulation. Comparison of significant points of time and the leaflet opening area were used to investigate the valve opening behavior of both analyses. Numerical results show that total valve opening modelled by FEA is faster compared to FSI by a factor of 5. In conclusion the inertia of the fluid, which surrounds the valve leaflets, has an important influence on leaflet deformation. Therefore, fluid dynamics should not be neglected in numerical analysis of heart valve prostheses.

Development of a microstent system for minimally invasive glaucoma surgery

Abstract Glaucoma is the leading cause of irreversible blindness worldwide. An increased intraocular pressure (IOP) is known as major risk factor. Currently, drainage devices that are implanted by means of minimally invasive glaucoma surgery (MIGS) represent a promising approach for IOP low-ering. Commercially available devices for MIGS suffer from unregulated drainage involving ocular hypotony. Further-more, long term drainage capability of current devices is limited by fibrotic encapsulation processes. Therefore, our group focusses on the development of a valved drug-eluting microstent for MIGS. Within the current work, we developed two alternative injector devices for minimally invasive mi-crostent implantation. Both injector devices were based on a cannula in which the microstent is loaded and a mandrel inside the cannula. Injector device A is designed to push the microstent out of the cannula and injector device B is de-signed to withdraw the cannula above the microstent. Manu-facturing of injector devices was conducted using rapid prototyping. Simplified polymeric microstents were manu-factured from polycarbonate based silicone elastomer. Simulated use was performed in a silicone eye model. The presented injector devices were suitable for minimally in-vasive ab interno microstent implantation into suprachoroidal space. Ongoing miniaturization of the microstent system will allow the use of a 22 G cannula in future ex vivo experiments.