Marc Horner

Transport in a Grooved Perfusion Flat-Bed Bioreactor for Cell Therapy Applications

This study considers the transport of oxygen (a growth‐associated solute) and lactate (a metabolic byproduct) in a flat‐bed perfusion chamber modified to retain cells through the addition of grooves, perpendicular to the direction of flow, at the chamber bottom. The chamber has been successfully applied to hematopoietic cell culture and may be useful for other basic and applied biomedical applications. The objective of this study is to characterize the culture environment in terms of solute transport under various operational conditions. This will allow one to improve the design and operating strategy of the perfusion system for maximizing cell numbers. The system is numerically simulated using the finite element package FIDAP. The reaction kinetics describing oxygen uptake by cells are simplified to zero order to give an upper bound for the oxygen consumption. A flat‐bed chamber without grooves is considered here as a benchmark. We show that the growth environment is not oxygen limited (local oxygen concentration above 10 μM) for a variety of flow rates and culture conditions (qO2 = 0.1 μmol/(106 cells h) ). With a medium flow rate of 2.5 mL/min through the reactor, the model predicts that the 29‐cm2 reactor can support at least 33.4 × 106 total cells when the inlet medium is in equilibrium with high (20%) oxygen concentration. The culture becomes oxygen limited however for the same flow rate for low (5%) oxygen concentration and can only support 7.2 × 106 total cells. Comparison of grooved vs nongrooved chambers reveals that the presence of grooves only affects solute transport on a local scale. This result is attributed to the small size (200 μm) of the cavities relative to the chamber dimensions. The comparison also yields an empirical relation that allows for rapid estimation of oxygen and lactate concentrations in the grooves using only the numerical simulation of the simpler nongrooved chamber. Finally, our investigation shows that, while decreasing the spacing between cavities decreases the total number of cells the reactor can support, the efficiency of the reactor is increased by 25% (on an area basis) without growth restriction.

Progress in the CFD Modeling of Flow Instabilities in Anatomical Total Cavopulmonary Connections

Intrinsic flow instability has recently been reported in the blood flow pathways of the surgically created total-cavopulmonary connection. Besides its contribution to the hydrodynamic power loss and hepatic blood mixing, this flow unsteadiness causes enormous challenges in its computational fluid dynamics (CFD) modeling. This paper investigates the applicability of hybrid unstructured meshing and solver options of a commercially available CFD package (FLUENT, ANSYS Inc., NH) to model such complex flows. Two patient-specific anatomies with radically different transient flow dynamics are studied both numerically and experimentally (via unsteady particle image velocimetry and flow visualization). A new unstructured hybrid mesh layout consisting of an internal core of hexahedral elements surrounded by transition layers of tetrahedral elements is employed to mesh the flow domain. The numerical simulations are carried out using the parallelized second-order accurate upwind scheme of FLUENT. The numerical validation is conducted in two stages: first, by comparing the overall flow structures and velocity magnitudes of the numerical and experimental flow fields, and then by comparing the spectral content at different points in the connection. The numerical approach showed good quantitative agreement with experiment, and total simulation time was well within a clinically relevant time-scale of our surgical planning application. It also further establishes the ability to conduct accurate numerical simulations using hybrid unstructured meshes, a format that is attractive if one ever wants to pursue automated flow analysis in a large number of complex (patient-specific) geometries.

Transport enhancement mechanisms in open cavities

By experiments and supporting computations we investigate two methods of transport enhancement in two-dimensional open cellular flows with inertia. First, we introduce a spatial dependence in the velocity eld by periodic modulation of the shape of the wall driving the flow; this perturbs the steady-state streamlines in the direction perpendicular to the main flow. Second, we introduce a time dependence through transient acceleration{deceleration of a flat wall driving the flow; surprisingly, even though the streamline portrait changes very little during the transient, there is still signicant transport enhancement. The range of Reynolds and Reynolds{Strouhal numbers studied is 7:76 Re6 46:5 and 0:526 ReSr6 12:55 in the spatially dependent mode and 126 Re6 93 and 0:266 ReSr6 5:02 in the time-dependent mode. The transport is described theoretically via lobe dynamics. For both modications, a curve with one maximum characterizes the various transport enhancement measures when plotted as a function of the forcing frequency. A qualitative analysis suggests that the exchange rst increases linearly with the forcing frequency and then decreases as 1=Sr for large frequencies.

Application of Multiphase Computational Fluid Dynamics to Analyze Monocyte Adhesion

Study of the mechanisms of monocyte adhesion initiating atheroslerotic lesions has engaged investigators for decades. Single-phase computational fluid dynamics (CFD) analyses fail to account for particulate migration. Consequently, inconsistencies arise when correlating adhesion with wall shear stress (WSS). The purpose of this paper is to present, to our knowledge, the first computational analysis of in vitro U937 monocyte-like human cell adhesion data using a coupled multiphase CFD-population balance adhesion model. The CFD model incorporates multiphase non-Newtonian hemodynamic models to compute the spatial distributions of freely flowing monocytes and WSSs in control volumes adjacent to the wall. Measurements of monocyte adhesion onto an E-selectin-coated flow model that included an idealized stenosis and an abrupt expansion were available from the literature. In this study, we develop a new monolayer population balance adhesion model, based on the widely accepted mechanism of ligand–receptor binding, coupled to the CFD results. The monolayer population balance model accounts for the interactions of freely flowing, rolling, and adhering monocytes with surfaces via first-order reactions, transport of rolling cells in the monolayer, and the concept of a WSS detachment threshold, clearly evident in the adhesion experiments. The new paradigm of coupling the multiphase hemodynamic CFD model with the proposed adhesion model is illustrated by determining and interpreting the model parameters for experimental datasets having Reynolds numbers of 100 and 140. The coupled multiphase CFD adhesion model is able to simultaneously predict the spatial variations in freely flowing monocytes, their adherent number density, and carrier fluid WSSs adjacent to ligand-coated flow cell surfaces.

Quantification of speed-up and accuracy of multi-CPU computational flow dynamics simulations of hemodynamics in a posterior communicating artery aneurysm of complex geometry.

Background Towards the translation of computational fluid dynamics (CFD) techniques into the clinical workflow, performance increases achieved with parallel multi-central processing unit (CPU) pulsatile CFD simulations in a patient-derived model of a bilobed posterior communicating artery aneurysm were evaluated while simultaneously monitoring changes in the accuracy of the solution. Methods Simulations were performed using 2, 4, 6, 8, 10 and 12 processors. In addition, a baseline simulation was obtained with a dual-core dual CPU computer of similar computational power to clinical imaging workstations. Parallel performance indices including computation speed-up, efficiency (speed-up divided by number of processors), computational cost (computation time × number of processors) and accuracy (velocity at four distinct locations: proximal and distal to the aneurysm, in the aneurysm ostium and aneurysm dome) were determined from the simulations and compared. Results Total computation time decreased from 9 h 10 min (baseline) to 2 h 34 min (10 CPU). Speed-up relative to baseline increased from 1.35 (2 CPU) to 3.57 (maximum at 10 CPU) while efficiency decreased from 0.65 to 0.35 with increasing cost (33.013 to 92.535). Relative velocity component deviations were less than 0.0073% and larger for 12 CPU than for 2 CPU (0.004±0.002%, not statistically significant, p=0.07). Conclusions Without compromising accuracy, parallel multi-CPU simulation reduces computing time for the simulation of hemodynamics in a model of a cerebral aneurysm by up to a factor of 3.57 (10 CPUs) to 2 h 34 min compared with a workstation with computational power similar to clinical imaging workstations.

CANNULATION STRATEGY FOR AORTIC ARCH RECONSTRUCTION USING DEEP HYPOTHERMIC CIRCULATORY ARREST

BACKGROUND Aortic arch reconstruction in neonates is commonly performed using deep hypothermic circulatory arrest. However, concerns have arisen regarding potential adverse neurologic outcomes from this complex procedure, raising questions about the best arterial cannulation approach for cerebral perfusion and effective systemic hypothermia. In this study, we use computational fluid dynamics to investigate the effect of different cannulation strategies in neonates. METHODS We used a realistic template of a hypoplastic neonatal aorta as the base geometry to investigate four cannulation options: (1) right innominate artery, (2) innominate root, (3) patent ductus arteriosus (PDA), or (4) innominate root and PDA. Performance was evaluated according to the numerically predicted cerebral and systemic flow distributions compared with physiologic perfusion under neonatal conditions. RESULTS The four cannulation strategies were associated with different local hemodynamics; however, this did not translate into any significant effect on the measured flow distributions. The largest difference only represented 0.8% of the cardiac output and was measured in the innominate artery, which received 23.2% of the cardiac output in option 3 vs 24% in option 4. Pulmonary artery snaring benefited all systemic vessels uniformly. CONCLUSIONS Because of the very high vascular resistances in neonates, downstream vascular resistances dictated flow distribution to the different vascular beds rather than the cannulation strategy, allowing the surgical team to choose their method of preference. However, patients with aortic coarctation warrant further investigation and will most likely benefit from a 2-cannulae approach (option 4).

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.

Statistical Shape Modeling of Femurs Using Morphing and Principal Component Analysis

In this paper, we describe a method for automatically building a statistical shape model by applying a morphing method and a principal component analysis (PCA) to a large database of femurs. One of the major challenges in building a shape model from a training data set of 3D objects is the determination of the correspondence between different shapes. In our work, we solve this problem by using a morphing method. The morphing method consists of deforming the same template mesh over a large database of femur geometries, which results in isotopological meshes and one to one correspondences; i.e., the resulting meshes have the same number of nodes, the same number of elements, and the same connectivity in all morphed meshes. By applying the morphing-based registration followed by PCA to a large database of femurs, we demonstrate that the method can be used to derive a low dimensional representation of the main variabilities of the femur geometry.

Credibility, Replicability, and Reproducibility in Simulation for Biomedicine and Clinical Applications in Neuroscience

Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical disciplines. In this manuscript, we introduce some basic concepts that will be important in the development of credible clinical neuroscience models: reproducibility and replicability; verification and validation; model configuration; and procedures and processes for credible mechanistic multiscale modeling. We also discuss how garnering strong community involvement can promote model credibility. Finally, in addition to direct usage with patients, we note the potential for simulation usage in the area of Simulation-Based Medical Education, an area which to date has been primarily reliant on physical models (mannequins) and scenario-based simulations rather than on numerical simulations.

A uniform-shear rate microfluidic bioreactor for real-time study of proplatelet formation and rapidly-released platelets

Platelet transfusions, with profound clinical importance in blood clotting and wound healing, are entirely derived from human volunteer donors. Hospitals rely on a steady supply of donations, but these methods are limited by a 5‐day shelf life, the potential risk of contamination, and differences in donor/recipient histocompatibility. These challenges invite the opportunity to generate platelets ex vivo. Although much progress has been made in generating large numbers of culture‐derived megakaryocytes (Mks, the precursor cells to platelets), stimulating a high percentage of Mks to undergo platelet release remains a major challenge. Recent studies have demonstrated the utility of shear forces to enhance platelet release from cultured Mks. In this study, we performed a computational fluid dynamics (CFD) analysis of several published platelet microbioreactor systems, and used the results to develop a new 7‐µm slit bioreactor—with well‐defined flow patterns and uniform shear profiles. This uniform‐shear‐rate bioreactor (USRB‐7µm) permits real‐time visualization of the proplatelet (proPLT) formation process and the rapid‐release of individual platelet‐like‐particles (PLPs), which has been observed in vivo, but not previously reported for platelet bioreactors. We showed that modulating shear forces and flow patterns had an immediate and significant impact on PLP generation. Surprisingly, using a single flow instead of dual flows led to an unexpected six‐fold increase in PLP production. By identifying particularly effective operating conditions within a physiologically relevant environment, this USRB‐7µm will be a useful tool for the study and analysis of proPLT/PLP formation that will further understanding of how to increase ex vivo platelet release.