Continuous Flow Separation of Red Blood Cells and Platelets in a Y-Microfluidic Channel Device with Saw-Tooth Profile Electrodes via Low Voltage Dielectrophoresis.

Cell counting and sorting is a vital step in the purification process within the area of biomedical research. It has been widely reported and accepted that the use of hydrodynamic focusing in conjunction with the application of a dielectrophoretic (DEP) force allows efficient separation of biological entities such as platelets from red blood cell (RBC) samples due to their size difference. This paper presents computational results of a multiphysics simulation modelling study on evaluating continuous separation of RBCs and platelets in a microfluidic device design with saw-tooth profile electrodes via DEP. The theoretical cell particle trajectory, particle cell counting, and particle separation distance study results reported in this work were predicted using COMSOL v6.0 Multiphysics simulation software. To validate the numerical model used in this work for the reported device design, we first developed a simple y-channel microfluidic device with square "in fluid" electrodes similar to the design reported previously in other works. We then compared the obtained simulation results for the simple y-channel device with the square in fluid electrodes to the reported experimental work done on this simple design which resulted in 98% agreement. The design reported in this work is an improvement over existing designs in that it can perform rapid separation of RBCs (estimated 99% purification) and platelets in a total time of 6-7 s at a minimum voltage setting of 1 V and at a minimum frequency of 1 Hz. The threshold for efficient separation of cells ends at 1000 kHz for a 1 V setting. The saw-tooth electrode profile appears to be an improvement over existing designs in that the sharp corners reduced the required horizontal distance needed for separation to occur and contributed to a non-uniform DEP electric field. The results of this simulation study further suggest that this DEP separation technique may potentially be applied to improve the efficiency of separation processes of biological sample scenarios and simultaneously increase the accuracy of diagnostic processes via cell counting and sorting.

Computational Assessment of Magnetic Nanoparticle Targeting Efficiency in a Simplified Circle of Willis Arterial Model.

This paper presents the methodology and computational results of simulated medical drug targeting (MDT) via induced magnetism intended for administering intravenous patient-specific doses of therapeutic agents in a Circle of Willis (CoW) model. The multi-physics computational model used in this work is from our previous works. The computational model is used to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a magnetized region using the magnetic properties of magnetite (Fe3O4) and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil. A Eulerian-Lagrangian technique is implemented to resolve the hemodynamic flow and the motion of particles under the influence of a range of magnetic field strengths (Br = 2T, 4T, 6T, and 8T). Particle diameter sizes of 10 nm to 4 µm in diameter were assessed. Two dimensionless numbers are also investigated a priori in this study to characterize relative effects of Brownian motion (BM), magnetic force-induced particle motion, and convective blood flow on particle motion. Similar to our previous works, the computational simulations demonstrate that the greatest particle capture efficiency results for particle diameters within the micron range, specifically in regions where flow separation and vortices are at a minimum. Additionally, it was observed that the capture efficiency of particles decreases substantially with smaller particle diameters, especially in the superparamagnetic regime. The highest capture efficiency observed for superparamagnetic particles was 99% with an 8T magnetic field strength and 95% with a 2T magnetic field strength when analyzing 100 nm particles. For 10 nm particles and an 8T magnetic field strength, the particle capture efficiency was 48%, and for a 2T magnetic field strength the particle capture efficiency was 33%. Furthermore, it was found that larger magnetic field strengths, large particle diameter sizes (1 µm and above), and slower blood flow velocity increase the particle capture efficiency. The key finding in this work is that favorable capture efficiencies for superparamagnetic particles were observed in the CoW model for weak fields (Br < 4T) which demonstrates MDT as a possible viable treatment candidate for cardiovascular disease.

Design and Development of a Traveling Wave Ferro-Microfluidic Device and System Rig for Potential Magnetophoretic Cell Separation and Sorting in a Water-Based Ferrofluid.

The timely detection and diagnosis of diseases and accurate monitoring of specific genetic conditions require rapid and accurate separation, sorting, and direction of target cell types toward a sensor device surface. In that regard, cellular manipulation, separation, and sorting are progressively finding application potential within various bioassay applications such as medical disease diagnosis, pathogen detection, and medical testing. The aim of this paper is to present the design and development of a simple traveling wave ferro-microfluidic device and system rig purposed for the potential manipulation and magnetophoretic separation of cells in water-based ferrofluids. This paper details in full: (1) a method for tailoring cobalt ferrite nanoparticles for specific diameter size ranges (10-20 nm), (2) the development of a ferro-microfluidic device for potentially separating cells and magnetic nanoparticles, (3) the development of a water-based ferrofluid with magnetic nanoparticles and non-magnetic microparticles, and (4) the design and development of a system rig for producing the electric field within the ferro-microfluidic channel device for magnetizing and manipulating nonmagnetic particles in the ferro-microfluidic channel. The results reported in this work demonstrate a proof of concept for magnetophoretic manipulation and separation of magnetic and non-magnetic particles in a simple ferro-microfluidic device. This work is a design and proof-of-concept study. The design reported in this model is an improvement over existing magnetic excitation microfluidic system designs in that heat is efficiently removed from the circuit board to allow a range of input currents and frequencies to manipulate non-magnetic particles. Although this work did not analyze the separation of cells from magnetic particles, the results demonstrate that non-magnetic (surrogates for cellular materials) and magnetic entities can be separated and, in some cases, continuously pushed through the channel based on amperage, size, frequency, and electrode spacing. The results reported in this work establish that the developed ferro-microfluidic device may potentially be used as an effective platform for microparticle and cellular manipulation and sorting.

Computational Assessment of Unsteady Flow Effects on Magnetic Nanoparticle Targeting Efficiency in a Magnetic Stented Carotid Bifurcation Artery.

PURPOSE: Worldwide, cardiovascular disease is the leading cause of hospitalization and death. Recently, the use of magnetizable nanoparticles for medical drug delivery has received much attention for potential treatment of both cancer and cardiovascular disease. However, proper understanding of the interacting magnetic field forces and the hydrodynamics of blood flow is needed for effective implementation. This paper presents the computational results of simulated implant assisted medical drug targeting (IA-MDT) via induced magnetism intended for administering patient specific doses of therapeutic agents to specific sites in the cardiovascular system. The drug delivery scheme presented in this paper functions via placement of a faintly magnetizable stent at a diseased location in the carotid artery, followed by delivery of magnetically susceptible drug carriers guided by the local magnetic field. Using this method, the magnetic stent can apply high localized magnetic field gradients within the diseased artery, while only exposing the neighboring tissues, arteries, and organs to a modest magnetic field. The localized field gradients also produce the forces needed to attract and hold drug-containing magnetic nanoparticles at the implant site for delivering therapeutic agents to treat in-stent restenosis. METHODS: The multi-physics computational model used in this work is from our previous work and has been slightly modified for the case scenario presented in this paper. The computational model is used to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a magnetic stented region using the magnetic properties of magnetite (Fe3O4) and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil. The electromagnetic coil produces a uniform magnetic field in the computational arterial flow model domain, while both the particles and the implanted stent are paramagnetic. A Eulerian-Lagrangian technique is adopted to resolve the hemodynamic flow and the motion of particles under the influence of a range of magnetic field strengths (Br = 2T, 4T, 6T, and 8T). Particle diameter sizes of 10 nm-4 µm in diameter were evaluated. Two dimensionless numbers were evaluated in this work to characterize relative effects of Brownian motion (BM), magnetic force induced particle motion, and convective blood flow on particle motion. RESULTS: The computational simulations demonstrate that the greatest particle capture efficiency results for particle diameters within the micron range of 0.7-4 µm, specifically in regions where flow separation and vortices are at a minimum. Similar to our previous work (which did not involve the use of a magnetic stent), it was also observed that the capture efficiency of particles decreases substantially with particle diameter, especially in the superparamagnetic regime. Contrary to our previous work, using a magnetic stent tripled the capture efficiency of superparamagnetic particles. The highest capture efficiency observed for superparamagnetic particles was 78% with an 8 T magnetic field strength and 65% with a 2 T magnetic field strength when analyzing 100 nm particles. For 10 nm particles and an 8 T magnetic field strength, the particle capture efficiency was 55% and for a 2 T magnetic field strength the particle capture efficiency was observed to be 43%. Furthermore, it was found that larger magnetic field strengths, large particle diameter sizes (1 µm and above), and slower blood flow velocity improves the particle capture efficiency. The distribution of captured particles on the vessel wall along the axial and azimuthal directions is also discussed. Results for captured particles on the vessel wall along the axial flow direction showed that the particle density decreased along the axial direction, especially after the stented region. For the entrance section of the stented region, the captured particle density distribution along the axial direction is large, corresponding to the center-symmetrical distribution of the magnetic force in that section. CONCLUSION: The simulation results presented in this work have shown to yield favorable capture efficiencies for micron range particles and superparamagnetic particles using magnetized implants such as the stent discussed in this work. The results presented in this work justify further investigation of MDT as a treatment technique for cardiovascular disease.

Development of a Two-Way Coupled Eulerian-Lagrangian Computational Magnetic Nanoparticle Targeting Model for Pulsatile Flow in a Patient-Specific Diseased Left Carotid Bifurcation Artery.

PURPOSE: The aim of the present work is to present the development of a computational two-way coupled (fluid and particle coupled) magnetic nanoparticle targeting model to investigate the efficacy of magnetic drug targeting (MDT) in a patient-specific diseased left carotid bifurcation artery. MDT of therapeutic agents using multifunctional carrier particles has the potential to provide effective treatment of both cancer and cardiovascular disease by enabling a variety of localized treatment and diagnostic modalities while minimizing side effects. METHODS: A computational model is developed to analyze pulsatile blood flow, particle motion, and particle capture efficiency in a diseased left carotid bifurcation artery using the magnetic properties of magnetite (Fe3O4) and equations describing the magnetic forces acting on particles produced by an external cylindrical electromagnetic coil. A Eulerian-Lagrangian technique is adopted to resolve the hemodynamic flow and the motion of particles under the influence of a magnetic field (Br= 2T). Particle diameter sizes of 20 nm-4 µm in diameter were considered. RESULTS: The computational simulations demonstrate that the greatest particle capture efficiency results for particle diameters within the micron range, specifically 4 µm in regions where flow separation and vortices are at a minimum. It was also determined that the capture efficiency of particles decreases substantially with particle diameter, especially in the superparamagnetic regime. Particles larger than 2 µm were targeted and captured at the desired location by the external magnetic field, and the largest capture efficiency observed was approximately 98%. CONCLUSION: The simulation results presented in the present work have shown to yield favorable capture efficiencies for micron range particles and a potential for enhancing capture efficiency of superparamagnetic particles in smaller arteries and/or using magnetized implants such as cardiovascular stents. The present work presents results for justifying further investigation of MDT as a treatment technique for cardiovascular disease.

Development of an Experimental and Digital Cardiovascular Arterial Model for Transient Hemodynamic and Postural Change Studies: "A Preliminary Framework Analysis".

The ultimate goal of the present work is to aid in the development of tools to assist in the treatment of cardiovascular disease. Gaining an understanding of hemodynamic parameters for medical implants allow clinicians to have some patient-specific proposals for intervention planning. In the present work an experimental and digital computational fluid dynamics (CFD) arterial model consisting of a number of major arteries (aorta, carotid bifurcation, cranial, femoral, jejunal, and subclavian arteries) were fabricated to study: (1) the effects of local hemodynamics (flow parameters) on global hemodynamics (2) the effects of transition from bedrest to upright position (postural change) on hemodynamics, and (3) diffusion of dye (medical drug diffusion simulation) in the arterial system via experimental and numerical techniques. The experimental and digital arterial models used in the present study are the first 3-D systems reported in literature to incorporate the major arterial vessels that deliver blood from the heart to the cranial and femoral arteries. These models are also the first reported in literature to be used for flow parameter assessment via medical drug delivery and orthostatic postural change studies. The present work addresses the design of the experimental and digital arterial model in addition to the design of measuring tools used to measure hemodynamic parameters. The experimental and digital arterial model analyzed in the present study was developed from patient specific computed tomography angiography (CTA) scans and simplified geometric data. Segments such as the aorta (ascending and descending) and carotid bifurcation arteries of the experimental and digital arterial model was created from online available patient-specific CTA scan data provided by Charite' Clinical and Research Hospital. The cranial and coronary arteries were simplified arterial geometries developed from dimensional specification data used in previous work. For the patient specific geometries, a MATLAB code was written to upload the CTA scans of each artery, calculate the centroids, and produce surface splines at each discrete cross section along the lumen centerline to create the patient specific arterial geometries. The MATLAB code worked in conjunction with computer aided software (CAD) Solidworks to produce solid models of the patient specific geometries and united them with the simplified geometries to produce the full arterial model (CAD model). The CAD model was also used as a blueprint to fabricate the experimental model which was used for flow visualization via particle imaging velocimetry (PIV) and postural change studies. A custom pulse duplicator (pulsatile pump) was also designed and developed for the present work. The pulse duplicator is capable of producing patient-specific volumetric waveforms for inlet flow to the experimental arterial model. A simple fluid structure interaction (FSI) study was also conducted via optical techniques to establish the magnitude of vessel diameter change due to the pulsatile flow. A medical drug delivery (dye dispersion and tracing) case was simulated via a dye being dispersed into the pulsatile flow stream to measure the transit time of the dye front. Pressure waveforms for diseased cases (hypertension & stenotic cases) were also obtained from the experimental arterial model during postural changes from bedrest (0°) to upright position (90°). The postural changes were simulated via attaching the experimental model to a tile table the can transition from 0° to 90°. The PIV results obtained from the experimental model provided parametric data such as velocity and wall shear stress data. The medical drug delivery simulations (experimental and numerical) studies produce time dependent data which is useful for predicting flow trajectory and transit time of medical drug dispersion. In the case of postural change studies, pressure waveforms were obtained from the common carotid artery and the femoral sections to yield pressure difference data useful for orthostatic hypotension analysis. Flow parametric data such as vorticity (flow reversal), wall shear stress, normal stress, and medical drug transit data was also obtained from the digital arterial model CFD simulations. Although the present work is preliminary work, the experimental and digital models proves to be useful in providing flow parametric data of interest such as: (1) normal stress which is useful for predicting the magnitude of forces which could promote arterial rupture or dislodging of medical implants, (2) wall shear stress which is useful for analyzing the magnitude of drug transport at the arterial wall, (3) vorticity which is useful for predicting the magnitude of flow reversal, and (4) arterial compliance in the case of the experimental model which could be useful in the efforts of developing FSI numerical simulations that incorporates compliance which realistically models the flow in the arterial system.