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.

A Reusable, Compliant, Small Volume Blood Reservoir for In Vitro Hemolysis Testing.

Bench-top in vitro hemolysis testing is a fundamental tool during the design and regulatory safety evaluation of blood-contacting medical devices. While multiple published experimental protocols exist, descriptions of the test loop reservoir remain ambiguous. A critical fixture within the circuit, there is no readily available blood reservoir that ensures thorough mixing and complete air evacuation: two major factors which can affect results. As part of the Food and Drug Administration (FDA) Critical Path Initiative, we developed a three-piece reservoir consisting of a 3D-printed base, a plastic clamp set, and a medical-grade blood bag. This simple, reusable, and cost-effective design was used successfully in the hemolysis assessment of FDA benchmark nozzles and prototype rotary blood pumps, and may be useful as an integral component to any in vitro blood circulation loop.

Multilaboratory study of flow-induced hemolysis using the FDA benchmark nozzle model.

Multilaboratory in vitro blood damage testing was performed on a simple nozzle model to determine how different flow parameters and blood properties affect device-induced hemolysis and to generate data for comparison with computational fluid dynamics-based predictions of blood damage as part of an FDA initiative for assessing medical device safety. Three independent laboratories evaluated hemolysis as a function of nozzle entrance geometry, flow rate, and blood properties. Bovine blood anticoagulated with acid citrate dextrose solution (2-80 h post-draw) was recirculated through nozzle-containing and paired nozzle-free control loops for 2 h. Controlled parameters included hematocrit (36 ± 1.5%), temperature (25 °C), blood volume, flow rate, and pressure. Three nozzle test conditions were evaluated (n = 26-36 trials each): (i) sudden contraction at the entrance with a blood flow rate of 5 L/min, (ii) gradual cone at the entrance with a 6-L/min blood flow rate, and (iii) sudden-contraction inlet at 6 L/min. The blood damage caused only by the nozzle model was calculated by subtracting the hemolysis generated by the paired control loop test. Despite high intralaboratory variability, significant differences among the three test conditions were observed, with the sharp nozzle entrance causing the most hemolysis. Modified index of hemolysis (MIHnozzle ) values were 0.292 ± 0.249, 0.021 ± 0.128, and 1.239 ± 0.667 for conditions i-iii, respectively. Porcine blood generated hemolysis results similar to those obtained with bovine blood. Although the interlaboratory hemolysis results are only applicable for the specific blood parameters and nozzle model used here, these empirical data may help to advance computational fluid dynamics models for predicting blood damage.

A dialyzer-based flow system for validating dynamic contrast enhanced MR image acquisition.

PURPOSE: Dynamic contrast enhanced magnetic resonance imaging (MRI) has proven to be quite sensitive for the characterization of masses and early response to therapy. However, it is fraught with a number of procedural challenges as well as a lack of standardization. In this article, we describe the use of a simple dialyzer-based flow system to evaluate reproducibility of dynamic contrast enhanced MRI under active flow conditions. METHODS: The MR signal during a bolus injection of Gd-DTPA was analyzed to test the precision and variability of contrast agent kinetics during a typical dynamic contrast enhanced MRI sequence. A simple model allows an estimation of the washout rate constant of Gd-DTPA through the polysulfone tubules of the dialyzer. RESULTS: The simple flow phantom described here provided reproducible measurements of the washout rate constants. The washout rate increased from 0.20 ± 0.005 min(-1) to 0.25 ± 0.008 min(-1) over 32 weeks. Measurements were also made at week 24 using dynamic computed tomography and found to be 0.27 ± 0.006 min(-1) . Overall, the computed tomography derived rate constants results were found be ∼12% higher than the corresponding MRI values. CONCLUSION: In this study, we show that a simple dialyzer-based flow phantom can be used for testing dynamic contrast enhanced MRI pulse sequences and also allows for short-term reproducibility testing of rate constants.

In vitro test methods for evaluating high molecular weight polyethylene oxide polymer induced hemolytic and thrombotic potential.

To combat opioid abuse, the U.S. Food and Drug Administration (FDA) released a comprehensive action plan to address opioid addiction, abuse, and overdose that included increasing the prevalence of abuse-deterrent formulations (ADFs) in opioid tablets. Polyethylene oxide (PEO) has been widely used as an excipient to deter abuse via nasal insufflation. However, changes in abuse patterns have led to unexpected shifts in abuse from the nasal route to intravenous injection. Case reports identify adverse effects similar to thrombotic thrombocytopenic purpura (TTP) syndrome following the intravenous (IV) abuse of opioids containing PEO excipient. Increased risk of IV opioid ADF abuse compared to clinical benefit of the drug led to the removal of one opioid product from the market in 2017. Because many generic drugs containing PEO are still in development, there is interest in assessing safety consistent with generic drug regulation and unintended uses. Currently, there are no guidelines or in vitro assessment tools to characterize the safety of PEO excipients taken via intravenous injection. To create a more robust excipient safety evaluation tool and to study the mechanistic basis of HMW PEO-induced TMA, a dynamic in vitro test system involving blood flow through a needle model has been developed.

Next generation microfluidics: fulfilling the promise of lab-on-a-chip technologies.

Microfluidic lab-on-a-chip technologies enable the analysis and manipulation of small fluid volumes and particles at small scales and the control of fluid flow and transport processes at the microscale, leading to the development of new methods to address a broad range of scientific and medical challenges. Microfluidic and lab-on-a-chip technologies have made a noteworthy impact in basic, preclinical, and clinical research, especially in hematology and vascular biology due to the inherent ability of microfluidics to mimic physiologic flow conditions in blood vessels and capillaries. With the potential to significantly impact translational research and clinical diagnostics, technical issues and incentive mismatches have stymied microfluidics from fulfilling this promise. We describe how accessibility, usability, and manufacturability of microfluidic technologies should be improved and how a shift in mindset and incentives within the field is also needed to address these issues. In this report, we discuss the state of the microfluidic field regarding current limitations and propose future directions and new approaches for the field to advance microfluidic technologies closer to translation and clinical use. While our report focuses on using blood as the prototypical biofluid sample, the proposed ideas and research directions can be extrapolated to other areas of hematology, oncology, biology, and medicine.

A Systematic Analysis of Recent Technology Trends of Microfluidic Medical Devices in the United States.

In recent years, the U.S. Food and Drug Administration (FDA) has seen an increase in microfluidic medical device submissions, likely stemming from recent advancements in microfluidic technologies. This recent trend has only been enhanced during the COVID-19 pandemic, as microfluidic-based test kits have been used for diagnosis. To better understand the implications of this emerging technology, device submissions to the FDA from 2015 to 2021 containing microfluidic technologies have been systematically reviewed to identify trends in microfluidic medical applications, performance tests, standards used, fabrication techniques, materials, and flow systems. More than 80% of devices with microfluidic platforms were found to be diagnostic in nature, with lateral flow systems accounting for about 35% of all identified microfluidic devices. A targeted analysis of over 40,000 adverse event reports linked to microfluidic technologies revealed that flow, operation, and data output related failures are the most common failure modes for these device types. Lastly, this paper highlights key considerations for developing new protocols for various microfluidic applications that use certain analytes (e.g., blood, urine, nasal-pharyngeal swab), materials, flow, and detection mechanisms. We anticipate that these considerations would help facilitate innovation in microfluidic-based medical devices.

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.

Results of the Interlaboratory Computational Fluid Dynamics Study of the FDA Benchmark Blood Pump.

Computational fluid dynamics (CFD) is widely used to simulate blood-contacting medical devices. To be relied upon to inform high-risk decision making, however, model credibility should be demonstrated through validation. To provide robust data sets for validation, researchers at the FDA and collaborators developed two benchmark medical device flow models: a nozzle and a centrifugal blood pump. Experimental measurements of the flow fields and hemolysis were acquired using each model. Concurrently, separate open interlaboratory CFD studies were performed in which participants from around the world, who were blinded to the measurements, submitted CFD predictions of each benchmark model. In this study, we report the results of the interlaboratory CFD study of the FDA benchmark blood pump. We analyze the results of 24 CFD submissions using a wide range of different flow solvers, methods, and modeling parameters. To assess the accuracy of the CFD predictions, we compare the results with experimental measurements of three quantities of interest (pressure head, velocity field, and hemolysis) at different pump operating conditions. We also investigate the influence of different CFD methods and modeling choices used by the participants. Our analyses reveal that, while a number of CFD submissions accurately predicted the pump performance for individual cases, no single participant was able to accurately predict all quantities of interest across all conditions. Several participants accurately predicted the pressure head at all conditions and the velocity field in all but one or two cases. Only one of the eight participants who submitted hemolysis results accurately predicted absolute plasma free hemoglobin levels at a majority of the conditions, though most participants were successful at predicting relative hemolysis levels between conditions. Overall, this study highlights the need to validate CFD modeling of rotary blood pumps across the entire range of operating conditions and for all quantities of interest, as some operating conditions and regions (e.g., the pump diffuser) are more challenging to accurately predict than others. All quantities of interest should be validated because, as shown here, it is possible to accurately predict hemolysis despite having relatively inaccurate predictions of the flow field.

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.

Overcoming technological barriers in microfluidics: Leakage testing.

The miniaturization of laboratory procedures for Lab-on-Chip (LoC) devices and translation to various platforms such as single cell analysis or Organ-on-Chip (OoC) systems are revolutionizing the life sciences and biomedical fields. As a result, microfluidics is becoming a viable technology for improving the quality and sensitivity of critical processes. Yet, standard test methods have not yet been established to validate basic manufacturing steps, performance, and safety of microfluidic devices. The successful development and widespread use of microfluidic technologies are greatly dependent on the community's success in establishing widely supported test protocols. A key area that requires consensus guidelines is leakage testing. There are unique challenges in preventing and detecting leaks in microfluidic systems because of their small dimensions, high surface-area to volume ratios, low flow rates, limited volumes, and relatively high-pressure differentials over short distances. Also, microfluidic devices often employ heterogenous components, including unique connectors and fluid-contacting materials, which potentially make them more susceptible to mechanical integrity failures. The differences between microfluidic systems and traditional macroscale technologies can exacerbate the impact of a leak on the performance and safety on the microscale. To support the microfluidics community efforts in product development and commercialization, it is critical to identify common aspects of leakage in microfluidic devices and standardize the corresponding safety and performance metrics. There is a need for quantitative metrics to provide quality assurance during or after the manufacturing process. It is also necessary to implement application-specific test methods to effectively characterize leakage in microfluidic systems. In this review, different methods for assessing microfluidics leaks, the benefits of using different test media and materials, and the utility of leakage testing throughout the product life cycle are discussed. Current leakage testing protocols and standard test methods that can be leveraged for characterizing leaks in microfluidic devices and potential classification strategies are also discussed. We hope that this review article will stimulate more discussions around the development of gas and liquid leakage test standards in academia and industry to facilitate device commercialization in the emerging field of microfluidics.

Accelerating innovation and commercialization through standardization of microfluidic-based medical devices.

Worldwide, the microfluidics industry has grown steadily over the last 5 years, with the market for microfluidic medical devices experiencing a compound growth rate of 22%. The number of submissions of microfluidic-based devices to regulatory agencies such as the U.S. Food & Drug Administration (FDA) has also steadily increased, creating a strong demand for the development of consistent and accessible tools for evaluating microfluidics-based devices. The microfluidics community has been slow, or even reluctant, to adopt standards and guidelines, which are needed for harmonization and for assisting academia, researchers, designers, and industry across all stages of product development. Appropriate assessments of device performance also remain a bottleneck for microfluidic devices. Standards reside at the core of mature supply chains generating economies of scale and forging a consistent pathway to match stakeholder expectations, thus creating a foundation for successful commercialization. This article provides a unique perspective on the need for the development of standards specific to the emerging biomedical field of microfluidics. Our aim is to facilitate innovation by encouraging the microfluidics community to work together to help bridge knowledge gaps and improve efficiency in getting high-quality microfluidic medical devices to market faster. We start by acknowledging the progress that has been made in various areas over the past decade. We then describe the existing gaps in the standardization of flow control, interconnections, component integration, manufacturing, assembly, packaging, reliability, performance of microfluidic elements and safety testing of microfluidic devices throughout the entire product life cycle.

Assessment of Flow through Microchannels for Inertia-Based Sorting: Steps toward Microfluidic Medical Devices.

The development of new standardized test methods would allow for the consistent evaluation of microfluidic medical devices and enable high-quality products to reach the market faster. A comprehensive flow characterization study was conducted to identify regulatory knowledge gaps using a generic inertia-based spiral channel model for particle sorting and facilitate standards development in the microfluidics community. Testing was performed using 2-20 µm rigid particles to represent blood elements and flow rates of 200-5000 µL/min to assess the effects of flow-related factors on overall system performance. Two channel designs were studied to determine the variability associated with using the same microchannel multiple times (coefficient of variation (CV) of 27% for Design 1 and 18% for Design 2, respectively). The impact of commonly occurring failure modes on device performance was also investigated by simulating progressive and complete channel outlet blockages. The pressure increased by 10-250% of the normal channel pressure depending on the extent of the blockage. Lastly, two common data analysis approaches were compared-imaging and particle counting. Both approaches were similar in terms of their sensitivity and consistency. Continued research is needed to develop standardized test methods for microfluidic systems, which will improve medical device performance testing and drive innovation in the biomedical field.

Technical considerations for medical device manufacturers when designing gastrostomy tubes (G-tubes) using the new ISO 80369-3 connector.

BACKGROUND: Gastrostomy tubes (G-tubes) are typically used when people cannot eat food by mouth. The connector section that allows G-tubes to connect to other devices, such as feeding sets or syringes, has been modified on some of the devices to reduce misconnections in hospital settings. The narrow internal diameter of the new connector, standardized under ISO 80369-3, has caused some users to express concern about a reduced flow rate. Previous studies performed on commercial devices determined that it was not conclusive how much the ISO 80369-3 connector contributed towards the reduced flow rate, because when manufacturers designed these new connector-based devices, they often changed other geometric variables (such as distal tube diameter, or length) at the same time. Thus, it became difficult isolating the effect of the connector from other geometric variables. METHOD: The key objective of this study was to investigate how different design variables impacted the flow rate through the G-tubes. 3D-printed devices were used to assess the geometric parameters in a systematic manner. Commercial diets and Newtonian analog fluids with matched viscosities were used for testing. RESULTS: The flow path length of the "transition section" encompassing the standardized ISO 80369-3 connector in the new devices was found to cause reduced flow. Additionally, results showed that a shortened (≤ 10 mm) transition section, along with a 10% increase in the distal inner diameter of large bore devices (e.g., 24 Fr), can restore flow rates to levels consistent with the previous devices prior to the connector standardization. CONCLUSIONS: The strategy for restoring flow rates to previous levels may help alleviate concerns raised by multiple stakeholders such as health care professionals, patients, caregivers and device manufacturers. In addition, the approach proposed here can be used as a tool for designing future G-tube devices.

Impact of design parameters on bileaflet mechanical heart valve flow dynamics.

BACKGROUND AND AIM OF THE STUDY: One significant problem encountered during surgery to implant mechanical heart valve prostheses is the propensity for thrombus formation near the valve leaflet and housing. This may be caused by the high shear stresses present in the leakage jet flows through small gaps between leaflets and the valve housing during the valve closure phase. METHODS: A two-dimensional (2D) study was undertaken to demonstrate that design changes in bileaflet mechanical valves result in notable changes in the flow-induced stresses and prediction of platelet activation. A Cartesian grid technique was used for the 2D simulation of blood flow through two models of bileaflet mechanical valves, and their flow patterns, closure characteristics and platelet activation potential were compared. A local mesh refinement algorithm allowed efficient and fast flow computations with mesh adaptation based on the gradients of the flow field in the gap between the leaflet and housing at the instant of valve closure. Leaflet motion was calculated dynamically, based on the fluid forces acting on it. Platelets were modeled and tracked as point particles by a Lagrangian particle tracking method which incorporated the hemodynamic forces on the particles. RESULTS: A comparison of results showed that the velocity, wall shear stress and simulated platelet activation parameter were lower in the valve model, with a smaller angle of leaflet traverse between the fully open to the fully closed position. The parameters were also affected to a lesser extent by local changes in the leaflet and housing geometry. CONCLUSION: Computational simulations can be used to examine local design changes to help minimize the fluid-induced stresses that may play a key role in thrombus initiation with the implanted mechanical valves.

A CFD-based Kriging surrogate modeling approach for predicting device-specific hemolysis power law coefficients in blood-contacting medical devices.

Most stress-based hemolysis models used in computational fluid dynamics (CFD) are based on an empirical power law correlation between hemolysis generation and the flow-induced stress and exposure time. Empirical model coefficients are typically determined by fitting global hemolysis measurements in simplified blood shearing devices under uniform shear conditions and with well-defined exposure times. CFD simulations using these idealized global empirical coefficients are then performed to predict hemolysis in a medical device with complex hemodynamics. The applicability, however, of this traditional approach of using idealized coefficients for a real device with varying exposure times and non-uniform shear is currently unknown. In this study, we propose a new approach for determining device- and species-specific hemolysis power law coefficients (C, a, and b). The approach consists of calculating multiple hemolysis solutions using different sets of coefficients to map the hemolysis response field in three-dimensional (C, a, b) parameter space. The resultant response field is then compared with experimental data in the same device to determine the coefficients that when incorporated into the locally defined power law model yield correct global hemolysis predictions. We first develop the generalized approach by deriving analytical solutions for simple uniform and non-uniform shear flows (planar Couette flow and circular Poiseuille flow, respectively) that allow us to continuously map the hemolysis solution in (C, a, b) parameter space. We then extend our approach to more practical cases relevant to blood-contacting medical devices by replacing the requirement for an analytical solution in our generalized approach with CFD and Kriging surrogate modeling. Finally, we apply our verified CFD-based Kriging surrogate modeling approach to predict the device- and species-specific power law coefficients for developing laminar flow in a small capillary tube. We show that the resultant coefficients are much different than traditional idealized coefficients obtained from simplified uniform shear experiments and that using such idealized coefficients yields a highly inaccurate prediction of hemolysis that is in error by more than 2000% compared to experiments. Our approach and surrogate modeling framework may be applied to more complex medical devices and readily extended to determine empirical coefficients for other continuum-based models of hemolysis and other forms of flow-induced blood damage (e.g., platelet activation and thrombosis).

Inter-Laboratory Characterization of the Velocity Field in the FDA Blood Pump Model Using Particle Image Velocimetry (PIV).

PURPOSE: A credible computational fluid dynamics (CFD) model can play a meaningful role in evaluating the safety and performance of medical devices. A key step towards establishing model credibility is to first validate CFD models with benchmark experimental datasets to minimize model-form errors before applying the credibility assessment process to more complex medical devices. However, validation studies to establish benchmark datasets can be cost prohibitive and difficult to perform. The goal of this initiative sponsored by the U.S. Food and Drug Administration is to generate validation data for a simplified centrifugal pump that mimics blood flow characteristics commonly observed in ventricular assist devices. METHODS: The centrifugal blood pump model was made from clear acrylic and included an impeller, with four equally spaced, straight blades, supported by mechanical bearings. Particle Image Velocimetry (PIV) measurements were performed at several locations throughout the pump by three independent laboratories. A standard protocol was developed for the experiments to ensure that the flow conditions were comparable and to minimize systematic errors during PIV image acquisition and processing. Velocity fields were extracted at the pump entrance, blade passage area, back gap region, and at the outlet diffuser regions. A Newtonian blood analog fluid composed of sodium iodide, glycerin, and water was used as the working fluid. Velocity measurements were made for six different pump flow conditions, with the blood-equivalent flow rate ranging between 2.5 and 7 L/min for pump speeds of 2500 and 3500 rpm. RESULTS: Mean intra- and inter-laboratory variabilities in velocity were ~ 10% at the majority of the measurement locations inside the pump. However, the inter-laboratory variability increased to more than ~ 30% in the exit diffuser region. The variability between the three laboratories for the peak velocity magnitude in the diffuser region ranged from 5 to 25%. The bulk velocity field near the impeller changed proportionally with the rotational speed but was relatively unaffected by the pump flow rate. In contrast, flow in the exit diffuser region was sensitive to both the flow rate and the rotational speed. Specifically, at 3500 rpm, the exit jet tilted toward the inner wall of the diffuser at a flow rate of 2.5 L/min, but the jet tilted towards the outer wall when the flow rate was 7 L/min. CONCLUSIONS: Inter-laboratory experimental mean velocity data (and the corresponding variance) were obtained for the FDA pump model and are available for download at https://nciphub.org/wiki/FDA_CFD . Experimental datasets from the inter-laboratory characterization of benchmark flow models, including the blood pump model presented herein and our previous nozzle model, can be used for validating future CFD studies and to collaboratively develop guidelines on best practices for verification, validation, uncertainty quantification, and credibility assessment of CFD simulations in the evaluation of medical devices (e.g. ASME V&V 40 standards working group).

Use of patient simulators to characterize the repeatability and reproducibility of automated oscillometric blood pressure monitors.

OBJECTIVES: Automated oscillometric blood pressure (BP) monitors can be critical health assessment tools if they are accurate and can provide repeatable and reproducible readings. Commercial patient simulators are capable of screening for poorly performing oscillometric BP monitors. A valid screening bench test method to identify unreliable and underperforming BP monitors could advance surveillance of these devices and support regulatory decision making. METHODS: Two simulators were used to characterize a total of 19 legally marketed upper arm, wrist, hospital-grade, and public-use BP monitors. These oscillometric BP monitors were tested for repeatability and reproducibility across different simulated patient populations. The metrics for evaluating these devices were the difference between the simulated pressure and the BP monitor output, and the variability from repeated measurements. RESULTS: All but one of the BP monitors tested provided repeatable readings (<3 mmHg). The mean error between the simulated pressure and the BP monitor output was largest for the wrist devices, whereas hospital-grade BP monitors most closely estimated the target BP waveforms. In general, device error and measurement variability increased at elevated BPs. CONCLUSION: Patient simulators are more suitable for repeatability analysis as opposed to assessing device accuracy. Despite their limitations, patient simulators can be used as effective tools to screen and improve the quality of BP monitors.

FDA Benchmark Medical Device Flow Models for CFD Validation.

Computational fluid dynamics (CFD) is increasingly being used to develop blood-contacting medical devices. However, the lack of standardized methods for validating CFD simulations and blood damage predictions limits its use in the safety evaluation of devices. Through a U.S. Food and Drug Administration (FDA) initiative, two benchmark models of typical device flow geometries (nozzle and centrifugal blood pump) were tested in multiple laboratories to provide experimental velocities, pressures, and hemolysis data to support CFD validation. In addition, computational simulations were performed by more than 20 independent groups to assess current CFD techniques. The primary goal of this article is to summarize the FDA initiative and to report recent findings from the benchmark blood pump model study. Discrepancies between CFD predicted velocities and those measured using particle image velocimetry most often occurred in regions of flow separation (e.g., downstream of the nozzle throat, and in the pump exit diffuser). For the six pump test conditions, 57% of the CFD predictions of pressure head were within one standard deviation of the mean measured values. Notably, only 37% of all CFD submissions contained hemolysis predictions. This project aided in the development of an FDA Guidance Document on factors to consider when reporting computational studies in medical device regulatory submissions. There is an accompanying podcast available for this article. Please visit the journal's Web site (www.asaiojournal.com) to listen.