Credibility assessment of in silico clinical trials for medical devices.

In silico clinical trials (ISCTs) are an emerging method in modeling and simulation where medical interventions are evaluated using computational models of patients. ISCTs have the potential to provide cost-effective, time-efficient, and ethically favorable alternatives for evaluating the safety and effectiveness of medical devices. However, ensuring the credibility of ISCT results is a significant challenge.

A sharp interface Lagrangian-Eulerian method for flexible-body fluid-structure interaction.

This paper introduces a sharp-interface approach to simulating fluid-structure interaction (FSI) involving flexible bodies described by general nonlinear material models and across a broad range of mass density ratios. This new flexible-body immersed Lagrangian-Eulerian (ILE) scheme extends our prior work on integrating partitioned and immersed approaches to rigid-body FSI. Our numerical approach incorporates the geometrical and domain solution flexibility of the immersed boundary (IB) method with an accuracy comparable to body-fitted approaches that sharply resolve flows and stresses up to the fluid-structure interface.

Practical implications of the erroneous treatment of exposure time in the Eulerian hemolysis power law model.

Background: Eulerian and Lagrangian power-law formulations are both widely used for computational fluid dynamics (CFD) to predict flow-induced hemolysis in blood-contacting medical devices. Both are based on the same empirical power-law correlation between hemolysis and the shear stress and exposure time. In the Lagrangian approach, blood damage is predicted by tracking both the stress and exposure time along a finite number of pathlines in the domain.

Modeling flow in an anatomical cerebrovascular model with experimental validation.

Acute ischemic stroke (AIS) is a leading cause of mortality that occurs when an embolus becomes lodged in the cerebral vasculature and obstructs blood flow in the brain. The severity of AIS is determined by the location and how extensively emboli become lodged, which are dictated in large part by the cerebral flow and the dynamics of embolus migration which are difficult to measure in AIS patients. Computational fluid dynamics (CFD) can be used to predict the patient-specific hemodynamics and embolus migration and lodging in the cerebral vasculature to better understand the underlying mechanics of AIS.

Modeling Flow in an Anatomical Cerebrovascular Model with Experimental Validation.

Acute ischemic stroke (AIS) is a leading cause of mortality that occurs when an embolus becomes lodged in the cerebral vasculature and obstructs blood flow in the brain. The severity of AIS is determined by the location and how extensively emboli become lodged, which are dictated in large part by the cerebral flow and the dynamics of embolus migration which are difficult to measure in AIS patients. Computational fluid dynamics (CFD) can be used to predict the patient-specific hemodynamics and embolus migration and lodging in the cerebral vasculature to better understand the underlying mechanics of AIS.

Examining the universality of the hemolysis power law model from simulations of the FDA nozzle using calibrated model coefficients.

Computational fluid dynamics (CFD) is widely used to predict mechanical hemolysis in medical devices. The most popular hemolysis model is the stress-based power law model that is based on an empirical correlation between hemoglobin release from red blood cells (RBCs) and the magnitude of flow-induced stress and exposure time. Empirical coefficients are traditionally calibrated using data from experiments in simplified Couette-type blood-shearing devices with uniform-shear laminar flow and well-defined exposure times.

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.

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report.

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

Full-field microscale strain measurements of a nitinol medical device using digital image correlation.

Computational modeling and simulation are commonly used during the development of cardiovascular implants to predict peak strains and strain amplitudes and to estimate the associated durability and fatigue life of these devices. However, simulation validation has historically relied on comparison with surrogate quantities like force and displacement due to barriers to direct strain measurement-most notably, the small spatial scale of these devices. We demonstrate the use of microscale two-dimensional digital image correlation (2D-DIC) to directly characterize full-field surface strains on a nitinol medical device coupon under emulated physiological and hyperphysiological loading.

"Mucosal maps" of the canine nasal cavity: Micro-computed tomography and histology.

Nasal turbinals, delicate and complex bones of the nasal cavity that support respiratory or olfactory mucosa (OM), are now easily studied using high resolution micro-computed tomography (μ-CT). Standard μ-CT currently lacks the capacity to identify OM or other mucosa types without additional radio-opaque staining techniques. However, even unstained mucosa is more radio-opaque than air, and thus mucosal thickness can be discerned.

Fluid-Structure Interaction Models of Bioprosthetic Heart Valve Dynamics in an Experimental Pulse Duplicator.

Computer modeling and simulation is a powerful tool for assessing the performance of medical devices such as bioprosthetic heart valves (BHVs) that promises to accelerate device design and regulation. This study describes work to develop dynamic computer models of BHVs in the aortic test section of an experimental pulse-duplicator platform that is used in academia, industry, and regulatory agencies to assess BHV performance. These computational models are based on a hyperelastic finite element extension of the immersed boundary method for fluid-structure interaction (FSI).

An Immersed Interface Method for Discrete Surfaces.

Fluid-structure systems occur in a range of scientific and engineering applications. The immersed boundary (IB) method is a widely recognized and effective modeling paradigm for simulating fluid-structure interaction (FSI) in such systems, but a difficulty of the IB formulation of these problems is that the pressure and viscous stress are generally discontinuous at fluid-solid interfaces. The conventional IB method regularizes these discontinuities, which typically yields low-order accuracy at these interfaces.

Nasal airflow in the pygmy slow loris () based on a combined histological, computed tomographic and computational fluid dynamics methodology.

'Macrosmatic' mammals have dedicated olfactory regions within their nasal cavity and segregated airstreams for olfaction and respiratory air-conditioning. Here, we examined the 3D distribution of olfactory surface area (SA) and nasal airflow patterns in the pygmy slow loris (), a primate with primitive nasal cavities, except for enlarged eyes that converge upon the posterodorsal nasal region. Using the head of an adult loris cadaver, we co-registered micro-computed tomography (CT) slices and histology sections to create a 3D reconstruction of the olfactory mucosa distribution.

Tests of the chromatographic theory of olfaction with highly soluble odors: a combined electro-olfactogram and computational fluid dynamics study in the mouse.

The idea that the vertebrate nasal cavity operates like a gas chromatograph to separate and discriminate odors, referred to herein as the 'chromatographic theory' (CT), has a long and interesting history. Though the last decade has seen renewed interest in the notion, its validity remains in question. Here we examine a necessary condition of the theory: a correlation between nasal odor deposition patterns based on mucus solubility and the distribution of olfactory sensory neuron odotypes.

Steady Flow in a Patient-Averaged Inferior Vena Cava-Part II: Computational Fluid Dynamics Verification and Validation.

Purpose: The embolus trapping performance of inferior vena cava (IVC) filters critically depends on how emboli flow through the IVC and, thereby, on the underlying hemodynamics. Most previous studies of IVC hemodynamics have used computational fluid dynamics (CFD), but few have validated their results by comparing with quantitative experimental measurements of the flow field and none have validated in an anatomical model of the IVC that includes the primary morphological features that influence the hemodynamics (iliac veins, infrarenal curvature, and non-circular vessel cross-section). In this study, we perform verification and validation of CFD simulations in a patient-averaged anatomical model of the IVC.

Steady Flow in a Patient-Averaged Inferior Vena Cava-Part I: Particle Image Velocimetry Measurements at Rest and Exercise Conditions.

Purpose: Although many previous computational fluid dynamics (CFD) studies have investigated the hemodynamics in the inferior vena cava (IVC), few studies have compared computational predictions to experimental data, and only qualitative comparisons have been made. Herein, we provide particle image velocimetry (PIV) measurements of flow in a patient-averaged IVC geometry under idealized conditions typical of those used in the preclinical evaluation of IVC filters.

Methods: Measurements are acquired under rest and exercise flow rate conditions in an optically transparent model fabricated using 3D printing.

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.

Predicting patient exposure to nickel released from cardiovascular devices using multi-scale modeling.

Unlabelled: Many cardiovascular device alloys contain nickel, which if released in sufficient quantities, can lead to adverse health effects. However, in-vivo nickel release from implanted devices and subsequent biodistribution of nickel ions to local tissues and systemic circulation are not well understood. To address this uncertainty, we have developed a multi-scale (material, tissue, and system) biokinetic model.

The Influence of Sniffing on Airflow and Odorant Deposition in the Canine Nasal Cavity.

Nasal airflow plays a critical role in olfaction by transporting odorant from the environment to the olfactory epithelium, where chemical detection occurs. Most studies of olfaction neglect the unsteadiness of sniffing and assume that nasal airflow and odorant transport are "quasi-steady," wherein reality most mammals "sniff." Here, we perform computational fluid dynamics simulations of airflow and odorant deposition in an anatomically accurate model of the coyote (Canis latrans) nasal cavity during quiet breathing, a notional quasi-steady sniff, and unsteady sniffing to: quantify the influence of unsteady sniffing, assess the validity of the quasi-steady assumption, and investigate the functional advantages of sniffing compared to breathing.

Tests of the sorption and olfactory "fovea" hypotheses in the mouse.

The spatial distribution of receptors within sensory epithelia (e.g., retina and skin) is often markedly nonuniform to gain efficiency in information capture and neural processing.

Computational predictions of the embolus-trapping performance of an IVC filter in patient-specific and idealized IVC geometries.

Embolus transport simulations are performed to investigate the dependence of inferior vena cava (IVC) filter embolus-trapping performance on IVC anatomy. Simulations are performed using a resolved two-way coupled computational fluid dynamics/six-degree-of-freedom approach. Three IVC geometries are studied: a straight-tube IVC, a patient-averaged IVC, and a patient-specific IVC reconstructed from medical imaging data.

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.

Biomimetic Sniffing Improves the Detection Performance of a 3D Printed Nose of a Dog and a Commercial Trace Vapor Detector.

Unlike current chemical trace detection technology, dogs actively sniff to acquire an odor sample. Flow visualization experiments with an anatomically-similar 3D printed dog's nose revealed the external aerodynamics during canine sniffing, where ventral-laterally expired air jets entrain odorant-laden air toward the nose, thereby extending the "aerodynamic reach" for inspiration of otherwise inaccessible odors. Chemical sampling and detection experiments quantified two modes of operation with the artificial nose-active sniffing and continuous inspiration-and demonstrated an increase in odorant detection by a factor of up to 18 for active sniffing.