Computational modeling and fluorescence microscopy characterization of a two-phase magnetophoretic microsystem for continuous-flow blood detoxification.

Magnetic beads can be functionalized to capture and separate target pathogens from blood for extracorporeal detoxification. The beads can be magnetically separated from a blood stream and collected into a coflowing buffer solution using a two-phase liquid-liquid continuous-flow microfluidic device in the presence of an external field. However, device design and process optimization, i.e. high bead recovery with minimum blood loss or dilution remain a substantial technological challenge. We introduce a CFD-based Eulerian-Lagrangian computational model that enables the rational design and optimization of such systems. The model takes into account dominant magnetic and hydrodynamic forces on the beads as well as coupled bead-fluid interactions. Fluid flow (Navier-Stokes equations) and mass transfer (Fick's law) between the coflowing fluids are solved numerically, while the magnetic force on the beads is predicted using analytical methods. The model is demonstrated via application to a prototype device and used to predict key performance metrics; degree of bead separation, flow patterns, and mass transfer, i.e. blood diffusion to the buffer phase. The impact of different process variables and parameters - flow rates, bead and magnet dimensions and fluid viscosities - on both bead recovery and blood loss or dilution is quantified for the first time. The performance of the prototype device is characterized using fluorescence microscopy and the experimental results are found to match theoretical predictions within an absolute error of 15%. While the model is demonstrated here for analysis of a detoxification device, it can be readily adapted to a broad range of magnetically-enabled microfluidic applications, e.g. bioseparation, sorting and sensing.

[1]  Nicole Pamme,et al.  Magnetism and microfluidics. , 2006, Lab on a chip.

[2]  Michael D. Kaminski,et al.  In vitro studies of functionalized magnetic nanospheres for selective removal of a simulant biotoxin , 2005 .

[3]  Jun Jin,et al.  2, 2'-(Phenylazanediyl) diacetic acid modified Fe3O4@PEI for selective removal of cadmium ions from blood. , 2012, Nanoscale.

[4]  S. K. Vashist,et al.  Microfluidic solutions enabling continuous processing and monitoring of biological samples: A review. , 2016, Analytica chimica acta.

[5]  S. Bhattacharjya,et al.  Peptide-perylene diimide functionalized magnetic nano-platforms for fluorescence turn-on detection and clearance of bacterial lipopolysaccharides. , 2014, Chemical communications.

[6]  Sally A. Peyman,et al.  The importance of particle type selection and temperature control for on-chip free-flow magnetophoresis , 2009 .

[7]  T. A. Hatton,et al.  Bactericidal core-shell paramagnetic nanoparticles functionalized with poly(hexamethylene biguanide). , 2011, Langmuir : the ACS journal of surfaces and colloids.

[8]  Gabriel P López,et al.  Microfluidic cell sorting: a review of the advances in the separation of cells from debulking to rare cell isolation. , 2015, Lab on a chip.

[9]  Leidong Mao,et al.  Label-free ferrohydrodynamic cell separation of circulating tumor cells. , 2017, Lab on a chip.

[10]  Nicole Pamme,et al.  On-Chip Magnetic Particle-Based Immunoassays Using Multilaminar Flow for Clinical Diagnostics. , 2017, Methods in molecular biology.

[11]  E. Furlani,et al.  Analysis of the Dynamics of Magnetic Core–Shell Nanoparticles and Self-Assembly of Crystalline Superstructures in Gradient Fields , 2015 .

[12]  Robert N Grass,et al.  Blood purification using functionalized core/shell nanomagnets. , 2010, Small.

[13]  Edward P. Furlani,et al.  A Model for Predicting Field-Directed Particle Transport in the Magnetofection Process , 2012, Pharmaceutical Research.

[14]  K. J. Jeong,et al.  Synthetic ligand-coated magnetic nanoparticles for microfluidic bacterial separation from blood. , 2014, Nano letters.

[15]  Marcos Fallanza,et al.  Flow patterns and mass transfer performance of miscible liquid-liquid flows in various microchannels: Numerical and experimental studies , 2018, Chemical Engineering Journal.

[16]  Shashi K Murthy,et al.  Fundamentals and application of magnetic particles in cell isolation and enrichment: a review , 2015, Reports on progress in physics. Physical Society.

[17]  P. Carroad,et al.  Estimation of diffusion coefficients of proteins , 1980 .

[18]  D. Ingber,et al.  Micromagnetic-microfluidic blood cleansing device. , 2009, Lab on a chip.

[19]  T. A. Hatton,et al.  Binding of functionalized paramagnetic nanoparticles to bacterial lipopolysaccharides and DNA. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[20]  Leidong Mao,et al.  Label‐Free and Continuous‐Flow Ferrohydrodynamic Separation of HeLa Cells and Blood Cells in Biocompatible Ferrofluids , 2016, Advanced functional materials.

[21]  L. Mao,et al.  Biocompatible and label-free separation of cancer cells from cell culture lines from white blood cells in ferrofluids. , 2017, Lab on a chip.

[22]  E. Furlani Permanent Magnet and Electromechanical Devices: Materials, Analysis, and Applications , 2001 .

[23]  C. Fernandes,et al.  Magnetic solid-phase extraction based on mesoporous silica-coated magnetic nanoparticles for analysis of oral antidiabetic drugs in human plasma. , 2014, Materials science & engineering. C, Materials for biological applications.

[24]  Stephen C Jacobson,et al.  Diffusion coefficient measurements in microfluidic devices. , 2002, Talanta.

[25]  W. Stark,et al.  Nanomagnet-based removal of lead and digoxin from living rats. , 2013, Nanoscale.

[26]  Young Ki Hahn,et al.  Label-free cell separation using a tunable magnetophoretic repulsion force. , 2012, Analytical chemistry.

[27]  G. Fonnum,et al.  Characterisation of Dynabeads® by magnetization measurements and Mössbauer spectroscopy , 2005 .

[28]  Henrik Bruus,et al.  Acoustofluidics 10: scaling laws in acoustophoresis. , 2012, Lab on a chip.

[29]  Shashi K Murthy,et al.  Computational design optimization for microfluidic magnetophoresis. , 2011, Biomicrofluidics.

[30]  Edward P. Furlani,et al.  Analytical model for the magnetic field and force in a magnetophoretic microsystem , 2006 .

[31]  Edward P. Furlani,et al.  Magnetic Bead Separation from Flowing Blood in a Two-Phase Continuous-Flow Magnetophoretic Microdevice: Theoretical Analysis through Computational Fluid Dynamics Simulation , 2017 .

[32]  W. Stark,et al.  Quantitative Recovery of Magnetic Nanoparticles from Flowing Blood: Trace Analysis and the Role of Magnetization , 2013 .

[33]  R. A. Grant,et al.  Numbering-up Y–Y microfluidic chips for higher-throughput solvent extraction of platinum(IV) chloride , 2016 .

[34]  Peter Fischer,et al.  Microfluidic Technique for the Simultaneous Quantification of Emulsion Instabilities and Lipid Digestion Kinetics. , 2017, Analytical chemistry.

[35]  I. Swiecicka,et al.  Growth arrest and rapid capture of select pathogens following magnetic nanoparticle treatment. , 2015, Colloids and surfaces. B, Biointerfaces.

[36]  E P Furlani,et al.  Analytical model of magnetic nanoparticle transport and capture in the microvasculature. , 2006, Physical review. E, Statistical, nonlinear, and soft matter physics.

[37]  Haitao Chen,et al.  2D modeling and preliminary in vitro investigation of a prototype high gradient magnetic separator for biomedical applications. , 2008, Medical engineering & physics.

[38]  S. Balachandar,et al.  On the added mass force at finite Reynolds and acceleration numbers , 2007 .

[39]  Yan Hu,et al.  β-Cyclodextrin conjugated magnetic nanoparticles for diazepam removal from blood. , 2011, Chemical communications.

[40]  Edward P. Furlani,et al.  Analysis of separators for magnetic beads recovery: From large systems to multifunctional microdevices , 2017 .

[41]  Donald E Ingber,et al.  An extracorporeal blood-cleansing device for sepsis therapy , 2014, Nature Medicine.

[42]  John A Kellum,et al.  Clinical review: Blood purification for sepsis , 2011, Critical care.

[43]  W. Stark,et al.  Magnetic separation-based blood purification: a promising new approach for the removal of disease-causing compounds? , 2015, Journal of Nanobiotechnology.

[44]  Edward P. Furlani,et al.  Magnetic Biotransport: Analysis and Applications , 2010, Materials.

[45]  Ralf Pörtner,et al.  Cell and Tissue Reaction Engineering , 2008 .

[46]  Nicole Pamme,et al.  On-chip processing of particles and cells via multilaminar flow streams , 2013, Analytical and Bioanalytical Chemistry.

[47]  Michael D. Kaminski,et al.  Detoxification of blood using injectable magnetic nanospheres: A conceptual technology description , 2005 .

[48]  E. P. Furlani,et al.  Analysis of particle transport in a magnetophoretic microsystem , 2006 .

[49]  E. P. Furlani,et al.  Magnetophoretic separation of blood cells at the microscale , 2006, physics/0612005.

[50]  J. Karimi-Sabet,et al.  Pressure-driven liquid-liquid separation in Y-shaped microfluidic junctions , 2017 .

[51]  E P Furlani,et al.  A model for predicting magnetic particle capture in a microfluidic bioseparator , 2007, Biomedical microdevices.

[52]  E. Furlani,et al.  Magnetofection Mediated Transient NANOG Overexpression Enhances Proliferation and Myogenic Differentiation of Human Hair Follicle Derived Mesenchymal Stem Cells. , 2015, Bioconjugate chemistry.

[53]  Bing Xu,et al.  A biocompatible method of decorporation: bisphosphonate-modified magnetite nanoparticles to remove uranyl ions from blood. , 2006, Journal of the American Chemical Society.