Evaluation of the novel total artificial heart Realheart in a pilot human fitting study.

Heart failure affects >26 million patients worldwide. Current cardiac devices save lives, but patients suffer complications. Hence, improved devices are needed. Realheart TAH is a novel total artificial heart which has shown promising results in acute pig studies. However, the device design needed to be evaluated in humans. Virtual implantations demonstrated the device fits in two of three patients, but that there was some interference with the left lung. Herein, we used an innovative 3D-printed model with swivelling device components to test the device in human cadavers. Our new method demonstrated how to optimize design to improve the surgical fit.

Virtual implantations to transition from porcine to bovine animal models for a total artificial heart.

Realheart total artificial heart (TAH) is a novel, pulsatile, four-chamber total artificial heart which had been successfully tested acutely in a porcine animal model. However, the bovine model is better suited for long-term testing and thus an evaluation of how the design would fit the bovine anatomy was required. Virtual implantation is a method that enables a computer simulated implantation based on anatomical 3D-models created from computer tomography images. This method is used clinically, but not yet adopted for animal studies. Herein, we evaluated its suitability in the redesign of the outer dimensions and vessel connections of Realheart TAH to transition from the porcine to the bovine animal model. Virtual implantations in combination with bovine cadaver studies enabled a series of successful acute bovine implantations. Virtual implantations are a useful tool to replace the use of animals in early device development and refine subsequent necessary in vivo experiments. The next steps are to carry out human virtual implantations and cadaver studies to ensure the design is optimized for all stages of testing as well as the final recipient.

Using 3D Physical Modeling to Plan Surgical Corrections of Complex Congenital Heart Defects.

Background Understanding the anatomy and physiology of congenital heart defects is crucial for planning interventions in these patients. Congenital heart procedures often involve complex three-dimensional (3D) reconstructions. Excellent imaging techniques are required to depict all anatomical details. We have used and evaluated fast 3D prototyping technology for reconstruction and planning of corrections of complex congenital heart defects. Materials and Methods 3D physical models were constructed from contrast-enhanced computed tomography (CT) datasets of patients with complex congenital heart defect. Two different commercially available printing technologies were used and their clinical application compared. Results Physical models of three different patients were used for preoperative surgical planning. All models showed good correspondence to patient anatomy. Both printing technologies gave excellent results. Conclusion Physical models could be easily constructed with the use of CT datasets. The printing process could be done efficiently, quite rapidly, and cost effectively. Surgical corrections could be planned based on these models.

Real-Time Visualization of Platelet Interaction With Micro Structured Surfaces.

Improving the hemocompatibility of artificial implants by micro structuring their surfaces has shown promising results, but the mechanisms which lead to this improvement are not yet understood. Therefore, we built a test setup for real-time visualization of platelet interaction with a plain and two micro structured surfaces. The micro structures, defined by the distance of the plain surface area between the structures, were chosen to be 3 and 30 µm, representing a positive and a negative effect on the hemocompatibility. The main part of the test setup was a flow chamber containing films of low density polyethylene (LDPE) with the differently structured surfaces. For different wall shear stresses, no considerable differences were observed in the platelet-surface interaction for all surface types. Whereas, major differences in flow behavior were observed when comparing the surfaces to each other. The platelets "rolled" along the smooth surface, being in constant contact with the surface material. Although the platelets "rolled" over the surface with small structures as well, they were only in contact with the tips of the structure and therefore had less surface contact with the foreign material. The increased distance and height of the structures of the last surface led to a trapping of platelets between the structures. This resulted in a longer contact time with the foreign material as well as a larger contact area, which both increase the risk of platelet activation, adhesion, and finally clotting. Our results showed the mechanisms which lead to these effects and thus revealed why micro structuring of surfaces impacts the hemocompatibility. Furthermore, we established a test setup which can be used for future investigations on the platelet-structure interactions.

Effects of Interaction Between Ventricular Assist Device Assistance and Autoregulated Mock Circulation Including Frank-Starling Mechanism and Baroreflex.

A mock heart circulation loop (MHCL) is a hydraulic model simulating the human circulatory system. It allows in vitro investigations of the interaction between cardiac assist devices and the human circulatory system. In this study, a preload sensitive MHCL, the MHCLAUTO , was developed to investigate the interaction between the left ventricle and left ventricular assist devices (LVADs). The Frank-Starling mechanism was modeled by regulating the stroke volume (SV) based on the measured mean diastolic left atrial pressure (MLAPdiast ). The baroreflex autoregulation mechanism was implemented to maintain a constant mean aortic pressure (MAP) by varying ventricular contractility (Emax ), heart rate (HR), afterload/systemic vascular resistance (SVR) and unstressed venous volume (UVV). The DP3 blood pump (Medos Medizintechnik GmbH) was used to simulate the LVAD. Characteristic parameters were measured in pathological conditions both with and without LVAD to assess the hemodynamic effect of LVAD on the MHCLAUTO . The results obtained from the MHCLAUTO show a high correlation to literature data. The study demonstrates the possibility of using the MHCLAUTO as a research tool to better understand the physiological interactions between cardiac implants and human circulation.

Impact of left atrial appendage occlusion device position on potential determinants of device-related thrombus: a patient-specific in silico study.

BACKGROUND: Device-related thrombus (DRT) after left atrial appendage occlusion (LAAO) is potentially linked to adverse events. Although clinical reports suggest an effect of the device type and position on the DRT risk, in-depth studies of its mechanistic basis are needed. This in silico study aimed to assess the impact of the position of non-pacifier (Watchman) and pacifier (Amulet) LAAO devices on surrogate markers of DRT risk. METHODS: The LAAO devices were modeled with precise geometry and virtually implanted in different positions into a patient-specific left atrium. Using computational fluid dynamics, the following values were quantified: residual blood, wall shear stress (WSS) and endothelial cell activation potential (ECAP). RESULTS: In comparison to an ostium-fitted device position, deep implantation led to more residual blood, lower average WSS and higher ECAP surrounding the device, especially on the device's atrial surface and the surrounding tissue, suggesting increased risk for potential thrombus. For the non-pacifier device, an off-axis device orientation resulted in even more residual blood, higher ECAP and similar average WSS as compared to an ostium-fitted device position. Overall, the pacifier device showed less residual blood, higher average WSS and lower ECAP, compared to the non-pacifier device. CONCLUSIONS: In this in silico study, both LAAO device type and implant position showed an impact on potential markers of DRT in terms of blood stasis, platelet adhesion and endothelial dysfunction. Our results present a mechanistic basis for clinically observed risk factors of DRT and the proposed in silico model may aid in the optimization of device development and procedural aspects.

Possible Contexts of Use for In Silico Trials Methodologies: A Consensus-Based Review.

The term "In Silico Trial" indicates the use of computer modelling and simulation to evaluate the safety and efficacy of a medical product, whether a drug, a medical device, a diagnostic product or an advanced therapy medicinal product. Predictive models are positioned as new methodologies for the development and the regulatory evaluation of medical products. New methodologies are qualified by regulators such as FDA and EMA through formal processes, where a first step is the definition of the Context of Use (CoU), which is a concise description of how the new methodology is intended to be used in the development and regulatory assessment process. As In Silico Trials are a disruptively innovative class of new methodologies, it is important to have a list of possible CoUs highlighting potential applications for the development of the relative regulatory science. This review paper presents the result of a consensus process that took place in the InSilicoWorld Community of Practice, an online forum for experts in in silico medicine. The experts involved identified 46 descriptions of possible CoUs which were organised into a candidate taxonomy of nine CoU categories. Examples of 31 CoUs were identified in the available literature; the remaining 15 should, for now, be considered speculative.

Estimation of left ventricular stroke work based on a large cohort of healthy children.

Left ventricular stroke work is an important prognostic marker to analyze cardiac function. Standard values for children are, however, missing. For clinicians, standards can help to improve the treatment decision of heart failures. For engineers, they can help to optimize medical devices. In this study, we estimated the left ventricular stroke work for children based on modeled pressure-volume loops. A lumped parameter model was fitted to clinical data of 340 healthy children. Reference curves for standard values were created over age, weight, and height. Left ventricular volume was measured with 3D echocardiography, while maximal ventricular pressure was approximated with a regression model from the literature. For validation of this method, we used 18 measurements acquired by a conductance catheter in 11 patients. The method demonstrated a low absolute mean difference of 0.033 J (SD: 0.031 J) for stroke work between measurement and estimation, while the percentage error was 21.66 %. According to the resulting reference curves, left ventricular stroke work of newborns has a median of 0.06 J and increases to 1.15 J at the age of 18 years. Stroke work increases over weight and height in a similar trend. The percentile curves depict the distribution. We demonstrate how reference curves can be used for quantification of differences and comparison in patients.

Virtual Fitting and Hemodynamic Simulation of the EVAHEART 2 Left Ventricular Assist Device and Double-Cuff Tipless Inflow Cannula.

Inflow malposition during surgery, postoperative pump migration, inflow obstruction, and right ventricular compression are major contributors to low flow and adverse events in patients with ventricular assist devices (VADs). These position abnormalities can lead to adverse events including ischemic stroke. To address these problems, we conducted a virtual anatomical fitting study and hemodynamic simulation on iterative cannula designs, resulting in the EVAHEART 2 with the novel double-cuff tipless (DCT) inflow cannula and smaller pump design. Anatomical fitting was based on computed tomography scans of six patients with heart failure, and a fluid-structure-integration (FSI) model of the left ventricle with a lumped parameter model of the entire cardiovascular system during VAD support was created. Using this model, the hemodynamics of three inflow cannula insertion lengths for two patient-specific ventricles were calculated for both full and partial VAD support. The DCT cannula with the smaller pump housing proved resistant to obstruction even when the pump housing was adjusted. The complete system also had a smaller pump pocket size than the other designs and avoided position abnormalities that commonly lead to adverse events. Compared with conventional cadaver studies, virtual fitting and numerical simulations are more beneficial and economical for iteratively designing medical devices.

Crucial Aspects for Using Computational Fluid Dynamics as a Predictive Evaluation Tool for Blood Pumps.

The suitability of computational fluid dynamics (CFD) as a regulatory tool for safety assessment of medical devices is still limited: A lack of standardized validation and evaluation methods impairs the quantitative comparability and reliability of simulation studies, particularly regarding the assessment of hemocompatibility. This study investigated important aspects of validation and verification for three common turbulence modeling approaches (laminar, k-ω shear stress transport [SST] and stress-blended eddy simulation [SBES]) and three different mesh refinements. Simulation results for pressure head, characteristic velocity, and shear stress for the benchmark blood pump model of the Food and Drug Administration critical path initiative were compared with its published experimental results. For the highest mesh resolution, all three models predicted the hydraulic pump characteristics with a relative deviation averaged over six operating conditions below 6.1%. In addition, the SBES model showed an accurate agreement of the characteristic velocity field in the pump's diffusor region (relative error <2.9%), while the laminar and SST model calculated significantly elevated and deviating velocity amplitudes (>43.6%). The ability to quantify shear stress is fundamental for the prediction of blood damage. In this respect, this study demonstrated that: 1) a close agreement and validation of both pressure head and characteristic velocity was feasible and 2) the shear stress quantification demanded higher near-wall mesh resolutions, although such high resolutions were not required for the validation of only pressure heads or velocity. Hence, a mesh verification analysis for shear stresses may prove significant for the development of credible CFD blood damage predictions in the future.

Computational Fluid Dynamics Assessment Associated with Transcatheter Heart Valve Prostheses: A Position Paper of the ISO Working Group.

The governing international standard for the development of prosthetic heart valves is International Organization for Standardization (ISO) 5840. This standard requires the assessment of the thrombus potential of transcatheter heart valve substitutes using an integrated thrombus evaluation. Besides experimental flow field assessment and ex vivo flow testing, computational fluid dynamics is a critical component of this integrated approach. This position paper is intended to provide and discuss best practices for the setup of a computational model, numerical solving, post-processing, data evaluation and reporting, as it relates to transcatheter heart valve substitutes. This paper is not intended to be a review of current computational technology; instead, it represents the position of the ISO working group consisting of experts from academia and industry with regards to considerations for computational fluid dynamic assessment of transcatheter heart valve substitutes.

Fluid-structure interaction of a pulsatile flow with an aortic valve model: A combined experimental and numerical study.

The complex fluid-structure interaction problem associated with the flow of blood through a heart valve with flexible leaflets is investigated both experimentally and numerically. In the experimental test rig, a pulse duplicator generates a pulsatile flow through a biomimetic rigid aortic root where a model of aortic valve with polymer flexible leaflets is implanted. High-speed recordings of the leaflets motion and particle image velocimetry measurements were performed together to investigate the valve kinematics and the dynamics of the flow. Large eddy simulations of the same configuration, based on a variant of the immersed boundary method, are also presented. A massively parallel unstructured finite-volume flow solver is coupled with a finite-element solid mechanics solver to predict the fluid-structure interaction between the unsteady flow and the valve. Detailed analysis of the dynamics of opening and closure of the valve are conducted, showing a good quantitative agreement between the experiment and the simulation regarding the global behavior, in spite of some differences regarding the individual dynamics of the valve leaflets. A multicycle analysis (over more than 20 cycles) enables to characterize the generation of turbulence downstream of the valve, showing similar flow features between the experiment and the simulation. The flow transitions to turbulence after peak systole, when the flow starts to decelerate. Fluctuations are observed in the wake of the valve, with maximum amplitude observed at the commissure side of the aorta. Overall, a very promising experiment-vs-simulation comparison is shown, demonstrating the potential of the numerical method.

Development of an In Vitro PIV Setup for Preliminary Investigation of the Effects of Aortic Compliance on Flow Patterns and Hemodynamics.

The aorta with its compliance plays a major role in hemodynamics as it saves a portion of ejected blood during systole which is then released in diastole. The aortic compliance decreases with increasing age, which is related to several cardiovascular imparities and diseases. Changes in flow patterns and pressure curves, due to varying aortic compliance, are difficult to investigate in vivo. As a result, the aim of the present work was to develop an in vitro setup enabling standardized investigations on the effect of compliance changes on flow patterns and pressure curves. Therefore an experimental setup with an anatomically correct silicone phantom of the aortic arch was developed, suitable for optical flow measurements under pulsatile inflow conditions. The setup was developed for precise adjustments of different compliances and optical flow measurements. Particle image velocimetry measurements were carried out downstream of the aortic valve in the center plane perpendicular to the valve with compliance adjusted between 0.62 × 10-3 to 1.82 × 10-3 mmHg-1. Preliminary results of the in vitro investigations showed that decreases in compliance results in significant increases in pressure changes with respect to time (dp/dt) and altered pressure curves in the aortic arch. In terms of flow, an increased aortic stiffness lead to higher mean velocities and decreased vortex development in the aortic sinuses. As in vivo validation and translation remains difficult, the results have to be considered as preliminary in vitro insights into the mechanisms of (age-related) compliance changes.

Fluid Dynamics in Rotary Piston Blood Pumps.

Mechanical circulatory support can maintain a sufficient blood circulation if the native heart is failing. The first implantable devices were displacement pumps with membranes. They were able to provide a sufficient blood flow, yet, were limited because of size and low durability. Rotary pumps have resolved these technical drawbacks, enabled a growing number of mechanical circulatory support therapy and a safer application. However, clinical complications like gastrointestinal bleeding, aortic insufficiency, thromboembolic complications, and impaired renal function are observed with their application. This is traced back to their working principle with attenuated or non-pulsatile flow and high shear stress. Rotary piston pumps potentially merge the benefits of available pump types and seem to avoid their complications. However, a profound assessment and their development requires the knowledge of the flow characteristics. This study aimed at their investigation. A functional model was manufactured and investigated with particle image velocimetry. Furthermore, a fluid-structure interaction computational simulation was established to extend the laboratory capabilities. The numerical results precisely converged with the laboratory measurements. Thus, the in silico model enabled the investigation of relevant areas like gap flows that were hardly feasible with laboratory means. Moreover, an economic method for the investigation of design variations was established.

Design of a right ventricular mock circulation loop as a test bench for right ventricular assist devices.

Right heart failure (RHF), e.g. due to pulmonary hypertension (PH), is a serious health issue with growing occurrence and high mortality rate. Limited efficacy of medication in advanced stages of the disease constitutes the need for mechanical circulatory support of the right ventricle (RV). An essential contribution to the process of developing right ventricular assist devices (RVADs) is the in vitro test bench, which simulates the hemodynamic behavior of the native circulatory system. To model healthy and diseased arterial-pulmonary hemodynamics in adults (mild and severe PH and RHF), a right heart mock circulation loop (MCL) was developed. Incorporating an anatomically shaped silicone RV and a silicone atrium, it not only enables investigations of hemodynamic values but also suction events or the handling of minimal invasive RVADs in an anatomical test environment. Ventricular pressure-volume loops of all simulated conditions as well as pressure and volume waveforms were recorded and compared to literature data. In an exemplary test, an RVAD was connected to the apex to further test the feasibility of studying such devices with the developed MCL. In conclusion, the hemodynamic behavior of the native system was well reproduced by the developed MCL, which is a useful basis for future RVAD tests.

A numerical framework to investigate hemodynamics during endovascular mechanical recanalization in acute stroke.

Ischemic stroke, caused by embolism of cerebral vessels, inflicts high morbidity and mortality. Endovascular aspiration of the blood clot is an interventional technique for the recanalization of the occluded arteries. However, the hemodynamics in the Circle of Willis (CoW) are not completely understood, which results in medical misjudgment and complications during surgeries. In this study we establish a multiscale description of cerebral hemodynamics during aspiration thrombectomy. First, the CoW is modeled as a 1D pipe network on the basis of computed tomography angiography (CTA) scans. Afterwards, a vascular occlusion is placed in the middle cerebral artery and the relevant section of the CoW is transferred to a 3D computational fluid dynamic (CFD) domain. A suction catheter in different positions is included in the CFD simulations. The boundary conditions of the 3D domain are taken from the 1D domain to ensure system coupling. A Eulerian-Eulerian multiphase simulation describes the process of thrombus aspiration. The physiological blood flow in the 1D and 3D domains is validated with literature data. Further on, it is proved that domain reduction and pressure coupling at the boundaries are an appropriate method to reduce computational costs. Future work will apply the developed framework to various clinical questions.

Investigation of hemodynamics during cardiopulmonary bypass: A multiscale multiphysics fluid-structure-interaction study.

Neurological complications often occur during cardiopulmonary bypass (CPB). Hypoperfusion of brain tissue due to diminished cerebral autoregulation (CA) and thromboembolism from atherosclerotic plaque reduce the cerebral oxygen supply and increase the risk of perioperative stroke. To improve the outcome of cardiac surgeries, patient-specific computational fluid dynamic (CFD) models can be used to investigate the blood flow during CPB. In this study, we establish a computational model of CPB which includes cerebral autoregulation and movement of aortic walls on the basis of in vivo measurements. First, the Baroreflex mechanism, which plays a leading role in CA, is represented with a 0-D control circuit and coupled to the 3-D domain with differential equations as boundary conditions. Additionally a two-way coupled fluid-structure interaction (FSI) model with CA is set up. The wall shear stress (WSS) distribution is computed for the whole FSI domain and a comparison to rigid wall CFD is made. Constant flow and pulsatile flow CPB is considered. Rigid wall CFD delivers higher wall shear stress values than FSI simulations, especially during pulsatile perfusion. The flow rates through the supraaortic vessels are almost not affected, if considered as percentages of total cannula output. The developed multiphysic multiscale framework allows deeper insights into the underlying mechanisms during CPB on a patient-specific basis.

Fluid-Structure Interaction Model of a Percutaneous Aortic Valve: Comparison with an In Vitro Test and Feasibility Study in a Patient-Specific Case.

Transcatheter aortic valve replacement (TAVR) represents an established recent technology in a high risk patient base. To better understand TAVR performance, a fluid-structure interaction (FSI) model of a self-expandable transcatheter aortic valve was proposed. After an in vitro durability experiment was done to test the valve, the FSI model was built to reproduce the experimental test. Lastly, the FSI model was used to simulate the virtual implant and performance in a patient-specific case. Results showed that the leaflet opening area during the cycle was similar to that of the in vitro test and the difference of the maximum leaflet opening between the two methodologies was of 0.42%. Furthermore, the FSI simulation quantified the pressure and velocity fields. The computed strain amplitudes in the stent frame showed that this distribution in the patient-specific case is highly affected by the aortic root anatomy, suggesting that the in vitro tests that follow standards might not be representative of the real behavior of the percutaneous valve. The patient-specific case also compared in vivo literature data on fast opening and closing characteristics of the aortic valve during systolic ejection. FSI simulations represent useful tools in determining design errors or optimization potentials before the fabrication of aortic valve prototypes and the performance of tests.

Hemodynamic analysis of outflow grafting positions of a ventricular assist device using closed-loop multiscale CFD simulations: Preliminary results.

Subclavian arteries are a possible alternate location for left ventricular assist device (LVAD) outflow grafts due to easier surgical access and application in high risk patients. As vascular blood flow mechanics strongly influence the clinical outcome, insights into the hemodynamics during LVAD support can be used to evaluate different grafting locations. In this study, the feasibility of left and right subclavian artery (SA) grafting was investigated for the HeartWare HVAD with a numerical multiscale model. A 3-D CFD model of the aortic arch was coupled to a lumped parameter model of the cardiovascular system under LVAD support. Grafts in the left and right SA were placed at three different anastomoses angles (90°, 60° and 30°). Additionally, standard grafting of the ascending and descending aorta was modelled. Full support LVAD (5l/min) and partial support LVAD (3l/min) in co-pulsation and counter-pulsation mode were analysed. The grafting positions were investigated regarding coronary and cerebral perfusion. Furthermore, the influence of the anastomosis angle on wall shear stress (WSS) was evaluated. Grafting of left or right subclavian arteries has similar hemodynamic performance in comparison to standard cannula positions. Angularity change of the graft anastomosis from 90° to 30° slightly increases the coronary and cerebral blood flow by 6-9% while significantly reduces the WSS by 35%. Cannulation of the SA is a feasible anastomosis location for the HVAD in the investigated vessel geometry.

A curious interplay in the films of N-heterocyclic carbene Pt(II) complexes upon deposition of alkali metals.

The recently synthesized series of Pt(II) complexes containing cyclometallating (phenylpyridine or benzoquinoline) and N-heterocyclic carbene ligands possess intriguing structures, topologies, and light emitting properties. Here, we report curious physicochemical interactions between in situ PVD-grown films of a typical representative of the aforementioned Pt(II) complex compounds and Li, Na, K and Cs atoms. Based on a combination of detailed core-level photoelectron spectroscopy and quantum-chemical calculations at the density functional theory level, we found that the deposition of alkali atoms onto the molecular film leads to unusual redistribution of electron density: essential modification of nitrogen sites, reduction of the coordination Pt(II) centre to Pt(0) and decrease of electron density on the bromine atoms. A possible explanation for this is formation of a supramolecular system "Pt complex-alkali metal ion"; the latter is supported by restoration of the system to the initial state upon subsequent oxygen treatment. The discovered properties highlight a considerable potential of the Pt(II) complexes for a variety of biomedical, sensing, chemical, and electronic applications.