Using a Mock Circulatory Loop as a Regulatory Science Tool to Simulate Different Heart Failure Conditions.

Mechanical circulatory support (MCS) device therapy is one of the primary treatment options for end-stage heart failure (HF), whereby a mechanical pump is integrated with the failing heart to maintain adequate tissue perfusion. The ISO 14708-5:2020 standard prescribes generic guidelines for nonclinical device evaluation and system performance testing of MCS devices using a mock circulatory loop (MCL). However, the utility of MCLs in premarket regulatory submissions of MCS devices is ambiguous, and the specific disease states that the device is intended to treat are not usually simulated. Hence, we aim to outline the potential of MCLs as a valuable regulatory science tool for characterizing MCS device systems by adequately representing target clinical-use HF conditions on the bench. Target pathophysiologic hemodynamics of HF conditions (i.e., cardiogenic shock (CS), left ventricular (LV) hypertrophy secondary to hypertension, and coronary artery disease), along with a healthy adult at rest and a healthy adult during exercise are provided as recommended test conditions. The conditions are characterized based on LV, aorta, and left atrium pressures using recommended cardiac hemodynamic indices such as systolic, diastolic, and mean arterial pressure, mean cardiac output (CO), cardiac cycle time, and systemic vascular resistance. This study is a first step toward standardizing MCLs to generate well-defined target HF conditions used to evaluate MCS devices.

Evaluation of Hemodynamics in a Prestressed and Compliant Tapered Femoral Artery Using an Optimization-Based Inverse Algorithm.

The important factors that affect the arterial wall compliance are the tissue properties of the arterial wall, the in vivo pulsatile pressure, and the prestressed condition of the artery. It is necessary to obtain the load-free geometry for determining the physiological level of prestress in the arterial wall. The previously developed optimization-based inverse algorithm was improved to obtain the load-free geometry and the wall prestress of an idealized tapered femoral artery of a dog under varying arterial wall properties. The compliance of the artery was also evaluated over a range of systemic pressures (72.5-140.7 mmHg), associated blood flows, and artery wall properties using the prestressed arterial geometry. The results showed that the computed load-free outer diameter at the inlet of the tapered artery was 6.7%, 9.0%, and 12% smaller than the corresponding in vivo diameter for the 25% softer, baseline, and 25% stiffer arterial wall properties, respectively. In contrast, the variations in the prestressed geometry and circumferential wall prestress were less than 2% for variable arterial wall properties. The computed compliance at the inlet of the prestressed artery for the baseline arterial wall property was 0.34%, 0.19%, and 0.13% diameter change/mmHg for time-averaged pressures of 72.5, 104.1, and 140.7 mmHg, respectively. However, the variation in compliance due to the change in arterial wall property was less than 6%. The load-free and prestressed geometries of the idealized tapered femoral artery were accurately (error within 1.2% of the in vivo geometry) computed under variable arterial wall properties using the modified inverse algorithm. Based on the blood-arterial wall interaction results, the arterial wall compliance was influenced significantly by the change in average pressure. In contrast, the change in arterial wall property did not influence the arterial wall compliance.

Uncertainty Analysis of the Core Body Temperature Under Thermal and Physical Stress Using a Three-Dimensional Whole Body Model.

Heat stress experienced by firefighters is a common consequence of extreme firefighting activity. In order to avoid the adverse health conditions due to uncompensable heat stress, the prediction and monitoring of the thermal response of firefighters is critical. Tissue properties, among other parameters, are known to vary between individuals and influence the prediction of thermal response. Further, measurement of tissue properties of each firefighter is not practical. Therefore, in this study, we developed a whole body computational model to evaluate the effect of variability (uncertainty) in tissue parameters on the thermal response of a firefighter during firefighting. Modifications were made to an existing human whole body computational model, developed in our lab, for conducting transient thermal analysis for a firefighting scenario. In conjunction with nominal (baseline) tissue parameters obtained from literature, and physiologic conditions from a firefighting drill, the Pennes bioheat and energy balance equations were solved to obtain the core body temperature of a firefighter. Subsequently, the uncertainty in core body temperature due to variability in the tissue parameters (input parameters), metabolic rate, specific heat, density, and thermal conductivity was computed using the sensitivity coefficient method. On comparing the individual effect of tissue parameters on the uncertainty in core body temperature, the metabolic rate had the highest contribution (within ±0.20°C) followed by specific heat (within ±0.10°C), density (within ±0.07°C), and finally thermal conductivity (within ±0.01 °C). A maximum overall uncertainty of ±0.23 °C in the core body temperature was observed due to the combined uncertainty in the tissue parameters. Thus, the model results can be used to effectively predict a realistic range of thermal response of the firefighters during firefighting or similar activities.

Diagnostic uncertainties during assessment of serial coronary stenoses: an in vitro study.

Currently, the diagnosis of coronary stenosis is primarily based on the well-established functional diagnostic parameter, fractional flow reserve (FFR: ratio of pressures distal and proximal to a stenosis). The threshold of FFR has a "gray" zone of 0.75-0.80, below which further clinical intervention is recommended. An alternate diagnostic parameter, pressure drop coefficient (CDP: ratio of trans-stenotic pressure drop to the proximal dynamic pressure), developed based on fundamental fluid dynamics principles, has been suggested by our group. Additional serial stenosis, present downstream in a single vessel, reduces the hyperemic flow, Q˜h, and pressure drop, Δp˜, across an upstream stenosis. Such hemodynamic variations may alter the values of FFR and CDP of the upstream stenosis. Thus, in the presence of serial stenoses, there is a need to evaluate the possibility of misinterpretation of FFR and test the efficacy of CDP of individual stenoses. In-vitro experiments simulating physiologic conditions, along with human data, were used to evaluate nine combinations of serial stenoses. Different cases of upstream stenosis (mild: 64% area stenosis (AS) or 40% diameter stenosis (DS); intermediate: 80% AS or 55% DS; and severe: 90% AS or 68% DS) were tested under varying degrees of downstream stenosis (mild, intermediate, and severe). The pressure drop-flow rate characteristics of the serial stenoses combinations were evaluated for determining the effect of the downstream stenosis on the upstream stenosis. In general, Q˜h and Δp˜ across the upstream stenosis decreased when the downstream stenosis severity was increased. The FFR of the upstream mild, intermediate, and severe stenosis increased by a maximum of 3%, 13%, and 19%, respectively, when the downstream stenosis severity increased from mild to severe. The FFR of a stand-alone intermediate stenosis under a clinical setting is reported to be ∼0.72. In the presence of a downstream stenosis, the FFR values of the upstream intermediate stenosis were either within (0.77 for 80%-64% AS and 0.79 for 80%-80% AS) or above (0.88 for 80%-90% AS) the "gray" zone (0.75-0.80). This artificial increase in the FFR value within or above the "gray" zone for an upstream intermediate stenosis when in series with a clinically relevant downstream stenosis could lead to misinterpretation of functional stenosis severity. In contrast, a distinct range of CDP values was observed for each case of upstream stenosis (mild: 8-10; intermediate: 47-54; and severe: 130-155). The nonoverlapping range of CDP could better delineate the effect of the downstream stenosis from the upstream stenosis and allow for the accurate diagnosis of the functional severity of the upstream stenosis.

A review of biotransport education in the 21st century: lessons learned from experts.

The field of bioengineering is relatively new and complex including multiple disciplines encompassing areas in science and engineering. Efforts including the National Science Foundation (NSF) sponsored Integrative Graduate Education and Research Traineeship (IGERT) and VaNTH Engineering Research Center in Bioengineering Educational Technologies have been made to establish and disseminate knowledge and proven methods for teaching bioengineering concepts. Further, the summer bioengineering conference (SBC), sponsored by the American Society of Mechanical Engineers' (ASME) Bioengineering Division, was established to provide a meeting place for engineering educators and students having common interests in biological systems. Of the many subdisciplines of bioengineering, biotransport is a key subject that has wide applicability to many issues in engineering, biology, medicine, pharmacology, and environmental science, among others. The absence of standard content, guidelines, and texts needed for teaching biotransport courses to students motivated the Biotransport committee of ASME's Bioengineering Division to establish a biotransport education initiative. Biotransport education workshop sessions were conducted during the SBC 2011, 2012, and 2013 as part of this initiative. The workshop sessions included presentations from experienced faculty covering a spectrum of information from general descriptions of undergraduate biotransport courses to very detailed outlines of graduate courses to successful teaching techniques. A list of texts and references available for teaching biotransport courses at undergraduate and graduate levels has been collated and documented based on the workshop presentations. Further, based on individual teaching experiences and methodologies shared by the presenters, it was noted that active learning techniques, including cooperative and collaborative learning, can be useful for teaching undergraduate courses while problem based learning (PBL) can be a beneficial method for graduate courses. The outcomes of the education initiative will help produce students who are knowledgeable in the subject of biotransport, facile in applying biotransport concepts for solving problems in various application areas, and comfortable with their own abilities as life-long learners.

Validation of a Multiscale Computational Model Using a Mock Circulatory Loop to Simulate Cardiogenic Shock.

The objectives of this study are to characterize the hemodynamics of cardiogenic shock (CS) through a computational model validated using a mock circulatory loop (MCL) and to perform sensitivity analysis and uncertainty propagation studies after the American Society of Mechanical Engineers (ASME) Validation and Verification (V&V) guidelines. The uncertainties in cardiac cycle time ( ), total resistance ( ), and total volume ( ) were quantified in the MCL and propagated in the computational model. Both models were used to quantify the pressure in the left atrium, aorta (Ao), and left ventricle (LV), along with the flow through the aortic valve, reaching a good agreement. The results suggest that 1) is the main source of uncertainty in the variables under study, 2) showed its greatest impact on the uncertainty of Ao hemodynamics, and 3) mostly affected the uncertainty of LV pressure and Ao flow at the late-systolic phase. Comparison of uncertainty levels in the computational and experimental results was used to infer the presence of additional contributing factors that were not captured and propagated during a first analysis. Future work will expand upon this study to analyze the impact of mechanical circulatory support devices, such as ventricular assist devices, under CS conditions.

Mock circulatory loop generated database for dynamic characterization of pressure-based cardiac output monitoring systems.

Pulse contour cardiac output monitoring systems allow real-time and continuous estimation of hemodynamic variables such as cardiac output (CO) and stroke volume variation (SVV) by analysis of arterial blood pressure waveforms. However, evaluating the performance of CO monitoring systems to measure the small variations in these variables sometimes used to guide fluid therapy is a challenge due to limitations in clinical reference methods. We developed a non-clinical database as a tool for assessing the dynamic attributes of pressure-based CO monitoring systems, including CO response time and CO and SVV resolutions. We developed a mock circulation loop (MCL) that can simulate rapid changes in different parameters, such as CO and SVV. The MCL was configured to simulate three different states (normovolemic, cardiogenic shock, and hyperdynamic) representing a range of flow and pressure conditions. For each state, we simulated stepwise changes in the MCL flow and collected datasets for characterizing pressure-based CO systems. Nine datasets were generated that contain hours of peripheral pressure, central flow and pressure waveforms. The MCL-generated database is provided open access as a tool for evaluating dynamic characteristics of pressure-based CO algorithms and systems in detecting variations in CO and SVV indices. In an example application of the database, a CO response time of 10 s, CO and SVV resolutions with lower and upper limits of (-9.1%, 8.4%) and (-5.0%, 3.8%), respectively, were determined for a pressure-based CO benchtop system. This tool will support a more comprehensive assessment of pressure-based CO monitoring systems and algorithms.

Simulating Radial Pressure Waveforms with a Mock Circulatory Flow Loop to Characterize Hemodynamic Monitoring Systems.

PURPOSE: Mock circulatory loops (MCLs) can reproducibly generate physiologically relevant pressures and flows for cardiovascular device testing. These systems have been extensively used to characterize the performance of therapeutic cardiac devices, but historically MCLs have had limited use for assessing patient monitoring systems. Here, we adapted an MCL to include peripheral components and evaluated its utility for qualitative and quantitative benchtop testing of hemodynamic monitoring devices. METHODS: An MCL was designed to simulate three physiological hemodynamic states: normovolemia, cardiogenic shock, and hyperdynamic circulation. The system was assessed for stability in pressure and flow values over time, repeatability, waveform morphology, and systemic-peripheral pressure relationships. RESULTS: For each condition, cardiac output was controlled to the nearest 0.2 L/min, and flow rate and mean arterial pressure remained stable and repeatable over a 60-s period (n = 5, standard deviation of ± 0.1 L/min and ± 0.84 mmHg, respectively). Transfer function analyses showed that the systemic-peripheral relationships could be adequately manipulated. The results from this MCL were comparable to those from other published MCLs and computational simulations. However, resolving current limitations of the system would further improve its utility. Three pulse contour analysis algorithms were applied to the pressure and flow data from the MCL to demonstrate the potential role of MCLs in characterizing hemodynamic monitoring systems. CONCLUSION: Overall, the development of robust analysis methods in conjunction with modified MCLs can expand device testing applications to hemodynamic monitoring systems. Properly validated MCLs can create a stable and reproducible environment for testing patient monitoring systems over their entire operating ranges prior to clinical use.

Evaluation of pulmonary artery stenosis in congenital heart disease patients using functional diagnostic parameters: An in vitro study.

Congenital pulmonary artery (PA) stenosis is often associated with abnormal PA hemodynamics including increased pressure drop (Δp) and reduced asymmetric flow (Q), which may result in right ventricular dysfunction. We propose functional diagnostic parameters, pressure drop coefficient (CDP), energy loss (Eloss), and normalized energy loss (E¯loss) to characterize pulmonary hemodynamics, and evaluate their efficacy in delineating stenosis severity using in vitro experiments. Subject-specific test sections including the main PA (MPA) bifurcating into left and right PAs (LPA, RPA) with a discrete LPA stenosis were manufactured from cross-sectional imaging and 3D printing. Three clinically-relevant stenosis severities, 90% area stenosis (AS), 80% AS, and 70% AS, were evaluated at different cardiac outputs (COs). A benchtop flow loop simulating pulmonary hemodynamics was used to measure Q and Δp within the test sections. The experimental Δp-Q characteristics along with clinical data were used to obtain pathophysiologic conditions and compute the diagnostic parameters. The pathophysiologic QLPA decreased as the stenosis severity increased at a fixed CO. CDPLPA, Eloss,LPA (absolute), and E¯loss,LPA (absolute) increased with an increase in LPA stenosis severity at a fixed CO. Importantly, CDPLPA and E¯loss,LPA had reduced variability with CO, and distinct values for each LPA stenosis severity. Under variable CO, a) CDPLPA values were 14.5-21.0 (70% AS), 60.7- 2.2 (80% AS), ≥ 261.6 (90% AS), and b) E¯loss,LPA values (in mJ per QLPA) were -501.9 to -1023.8 (70% AS), -1247.6 to -1773.0 (80% AS), -1934.5 (90% AS). Hence, CDPLPA and E¯loss,LPA are expected to assess the true functional severity of PA stenosis.

Use of the FDA nozzle model to illustrate validation techniques in computational fluid dynamics (CFD) simulations.

A "credible" computational fluid dynamics (CFD) model has the potential to provide a meaningful evaluation of safety in medical devices. One major challenge in establishing "model credibility" is to determine the required degree of similarity between the model and experimental results for the model to be considered sufficiently validated. This study proposes a "threshold-based" validation approach that provides a well-defined acceptance criteria, which is a function of how close the simulation and experimental results are to the safety threshold, for establishing the model validity. The validation criteria developed following the threshold approach is not only a function of Comparison Error, E (which is the difference between experiments and simulations) but also takes in to account the risk to patient safety because of E. The method is applicable for scenarios in which a safety threshold can be clearly defined (e.g., the viscous shear-stress threshold for hemolysis in blood contacting devices). The applicability of the new validation approach was tested on the FDA nozzle geometry. The context of use (COU) was to evaluate if the instantaneous viscous shear stress in the nozzle geometry at Reynolds numbers (Re) of 3500 and 6500 was below the commonly accepted threshold for hemolysis. The CFD results ("S") of velocity and viscous shear stress were compared with inter-laboratory experimental measurements ("D"). The uncertainties in the CFD and experimental results due to input parameter uncertainties were quantified following the ASME V&V 20 standard. The CFD models for both Re = 3500 and 6500 could not be sufficiently validated by performing a direct comparison between CFD and experimental results using the Student's t-test. However, following the threshold-based approach, a Student's t-test comparing |S-D| and |Threshold-S| showed that relative to the threshold, the CFD and experimental datasets for Re = 3500 were statistically similar and the model could be considered sufficiently validated for the COU. However, for Re = 6500, at certain locations where the shear stress is close the hemolysis threshold, the CFD model could not be considered sufficiently validated for the COU. Our analysis showed that the model could be sufficiently validated either by reducing the uncertainties in experiments, simulations, and the threshold or by increasing the sample size for the experiments and simulations. The threshold approach can be applied to all types of computational models and provides an objective way of determining model credibility and for evaluating medical devices.