Recent advancements in microfluidics that integrate electrical sensors for whole blood analysis.

Whole blood analysis reveals crucial information about various physiological and pathological conditions, including cancer metastasis, infection, and immune status, among others. Despite this rich information, the complex composition of whole blood usually required multiple sample preparation steps to purify targeted analytes. Traditionally, whole blood preparation processes, including centrifugation, lysis, dilution, or staining, are usually manually operated by well-trained technicians using bench-top instruments. This preparation can require a large blood volume and cannot be directly integrated with detection systems. Recently, various studies have integrated microfluidics with electrical sensors for whole blood analysis, with a focus on cell-based analysis, such as cell type, number, morphology, phenotype, and secreted molecules. These miniaturized systems require less sample and shorter reaction times. Besides, the sample processing and analysis can be fully integrated and automated with minimal operations. We believe these systems can transfer the current whole blood analysis from hospitals or laboratories into clinics or home settings to enable real-time and continuous health condition monitoring in point-of-care settings.

[1]  V. Rotello,et al.  Fabrication and characterization of nanoelectrode arrays formed via block copolymer self-assembly , 2001 .

[2]  Kevin W. Plaxco,et al.  Microfluidic Chip-Based Detection and Intraspecies Strain Discrimination of Salmonella Serovars Derived from Whole Blood of Septic Mice , 2013, Applied and Environmental Microbiology.

[3]  H. Muncie,et al.  Alpha and beta thalassemia. , 2009, American family physician.

[4]  Eun-Cheol Lee,et al.  Highly selective, reusable electrochemical impedimetric DNA sensors based on carbon nanotube/polymer composite electrode without surface modification. , 2018, Biosensors & bioelectronics.

[5]  Sang Youl Yoon,et al.  Handheld mechanical cell lysis chip with ultra-sharp silicon nano-blade arrays for rapid intracellular protein extraction. , 2010, Lab on a chip.

[6]  Zhonghua Ni,et al.  Inertial microfluidic cube for automatic and fast extraction of white blood cells from whole blood. , 2019, Lab on a chip.

[7]  Z. G. Li,et al.  Single cell membrane poration by bubble-induced microjets in a microfluidic chip. , 2013, Lab on a Chip.

[8]  David J. Mooney,et al.  Label-free biomarker detection from whole blood , 2009, 2010 10th IEEE International Conference on Solid-State and Integrated Circuit Technology.

[9]  Jon N. Petzing,et al.  Understanding the contribution of operator measurement variability within Flow Cytometry data analysis for Quality Control of Cell and Gene Therapy manufacturing , 2020 .

[10]  Aaron R Wheeler,et al.  Electrochemistry, biosensors and microfluidics: a convergence of fields. , 2015, Chemical Society reviews.

[11]  Wei Zhang,et al.  Blood Coagulation Testing Smartphone Platform Using Quartz Crystal Microbalance Dissipation Method , 2018, Sensors.

[12]  T. Matsue,et al.  Spearhead Nanometric Field-Effect Transistor Sensors for Single-Cell Analysis. , 2016, ACS nano.

[13]  D. Weitz,et al.  Rapid additive-free bacteria lysis using traveling surface acoustic waves in microfluidic channels. , 2019, Lab on a chip.

[14]  J. Sturm,et al.  Automated leukocyte processing by microfluidic deterministic lateral displacement , 2016, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[15]  Yu-Ling Lin,et al.  Rapid and Safe Isolation of Human Peripheral Blood B and T Lymphocytes through Spiral Microfluidic Channels , 2019, Scientific Reports.

[16]  L. Yobas,et al.  Single-Cell Point Constrictions for Reagent-Free High-Throughput Mechanical Lysis and Intact Nuclei Isolation , 2019, Micromachines.

[17]  A. Pisano,et al.  Hierarchical Silicon Nanospikes Membrane for Rapid and High-Throughput Mechanical Cell Lysis , 2014, ACS applied materials & interfaces.

[18]  R. Bashir,et al.  Flow metering characterization within an electrical cell counting microfluidic device. , 2014, Lab on a chip.

[19]  Ehsan Samiei,et al.  A review of sorting, separation and isolation of cells and microbeads for biomedical applications: microfluidic approaches. , 2018, The Analyst.

[20]  Xin Huang,et al.  Microcantilever biosensors for chemicals and bioorganisms. , 2011, The Analyst.

[21]  X. D. Hoa,et al.  Towards integrated and sensitive surface plasmon resonance biosensors: a review of recent progress. , 2007, Biosensors & bioelectronics.

[22]  H. Amini,et al.  Label-free cell separation and sorting in microfluidic systems , 2010, Analytical and bioanalytical chemistry.

[23]  Barry Merriman,et al.  Progress in Ion Torrent semiconductor chip based sequencing , 2012, Electrophoresis.

[24]  A. Erdem,et al.  Impedimetric detection of pathogenic bacteria with bacteriophages using gold nanorod deposited graphite electrodes , 2016 .

[25]  Yen-Wen Lu,et al.  Enhancement of microfluidic particle separation using cross-flow filters with hydrodynamic focusing. , 2016, Biomicrofluidics.

[26]  Yue Cui,et al.  Graphene nano-ink biosensor arrays on a microfluidic paper for multiplexed detection of metabolites. , 2014, Analytica chimica acta.

[27]  Juan Xu,et al.  Spiral microchannel with ordered micro-obstacles for continuous and highly-efficient particle separation. , 2017, Lab on a chip.

[28]  A. Undar,et al.  A microfluidic device for continuous, real time blood plasma separation. , 2006, Lab on a chip.

[29]  Andrew G. Dempster,et al.  Parasite detection and identification for automated thin blood film malaria diagnosis , 2010, Comput. Vis. Image Underst..

[30]  Aram J. Chung,et al.  Continuous inertial microparticle and blood cell separation in straight channels with local microstructures. , 2016, Lab on a chip.

[31]  Magnus Willander,et al.  Highly efficient potentiometric glucose biosensor based on functionalized InN quantum dots , 2012 .

[32]  S. Tripathi,et al.  Microdevice for plasma separation from whole human blood using bio-physical and geometrical effects , 2016, Scientific Reports.

[33]  Qihui Fan,et al.  Localized Single-Cell Lysis and Manipulation Using Optothermally-Induced Bubbles , 2017, Micromachines.

[34]  Fernando Benito-Lopez,et al.  Review on microfluidic paper-based analytical devices towards commercialisation. , 2018, Analytica chimica acta.

[35]  Whoi-Yul Kim,et al.  Continuous Separation of Circulating Tumor Cells from Whole Blood Using a Slanted Weir Microfluidic Device , 2019, Cancers.

[36]  Wei-En Hsu,et al.  Review-field-effect transistor biosensing: Devices and clinical applications , 2018 .

[37]  Maksim Zalkovskij,et al.  Separation of cancer cells from white blood cells by pinched flow fractionation. , 2015, Lab on a chip.

[38]  D. Pappas,et al.  Isolation of proliferating cells from whole blood using Human Transferrin Receptor in a two-stage separation system. , 2019, Talanta.

[39]  Utkan Demirci,et al.  Photonic crystals: emerging biosensors and their promise for point-of-care applications. , 2017, Chemical Society reviews.

[40]  G. Lim,et al.  Electrical force-based continuous cell lysis and sample separation techniques for development of integrated microfluidic cell analysis system: A review , 2018, Microelectronic Engineering.

[41]  Dino Di Carlo,et al.  Reagentless mechanical cell lysis by nanoscale barbs in microchannels for sample preparation. , 2003, Lab on a chip.

[42]  Yu Sun,et al.  High-throughput biophysical measurement of human red blood cells. , 2012, Lab on a chip.

[43]  Hakan Urey,et al.  Coagulation measurement from whole blood using vibrating optical fiber in a disposable cartridge , 2017, Journal of biomedical optics.

[44]  Rashid Bashir,et al.  Microfluidic CD4+ and CD8+ T Lymphocyte Counters for Point-of-Care HIV Diagnostics Using Whole Blood , 2013, Science Translational Medicine.

[45]  J. Petriz,et al.  Flow cytometry counting of CD34+ cells in whole blood , 2000, Nature Medicine.

[46]  Marco Buscaglia,et al.  Emerging applications of label-free optical biosensors , 2017 .

[47]  S. Shevkoplyas,et al.  Integrated separation of blood plasma from whole blood for microfluidic paper-based analytical devices. , 2012, Lab on a chip.

[48]  Yi Zhao,et al.  Rheological analysis of non-Newtonian blood flow using a microfluidic device☆ , 2011 .

[49]  Yoichiroh Hosokawa,et al.  Focusing of sub-micrometer particles in microfluidic devices. , 2019, Lab on a chip.

[50]  M. Suciu,et al.  Impedimetric aptasensor for the label-free and selective detection of Interleukin-6 for colorectal cancer screening. , 2019, Biosensors & bioelectronics.

[51]  Dongqing Li,et al.  A novel microfluidic resistive pulse sensor with multiple voltage input channels and a side sensing gate for particle and cell detection. , 2019, Analytica chimica acta.

[52]  E. Khaled,et al.  Calixarene/carbon nanotubes based screen printed sensors for potentiometric determination of gentamicin sulphate in pharmaceutical preparations and spiked surface water samples , 2017 .

[53]  J. Cooper,et al.  Nanofabrication of electrode arrays by electron-beam and nanoimprint lithographies. , 2006, Lab on a chip.

[54]  Lauro T Kubota,et al.  Sensing approaches on paper-based devices: a review , 2013, Analytical and Bioanalytical Chemistry.

[55]  Xiangchun Xuan,et al.  Continuous Microfluidic Particle Separation via Elasto-Inertial Pinched Flow Fractionation. , 2015, Analytical chemistry.

[56]  R. Hájek,et al.  Current applications of multiparameter flow cytometry in plasma cell disorders , 2017, Blood Cancer Journal.

[57]  M. Vidrevich,et al.  Potentiometry for the determination of oxidant activity , 2016 .

[58]  Da-Han Kuan,et al.  A Microfluidic Device for Simultaneous Extraction of Plasma, Red Blood Cells, and On-Chip White Blood Cell Trapping , 2018, Scientific Reports.

[59]  Separation of spermatozoa from erythrocytes using their tumbling mechanism in a pinch flow fractionation device , 2019, Microsystems & nanoengineering.

[60]  Yen-Hung Lin,et al.  A microfluidic device integrating dual CMOS polysilicon nanowire sensors for on-chip whole blood processing and simultaneous detection of multiple analytes. , 2016, Lab on a chip.

[61]  Dino Di Carlo,et al.  Microfluidic sample preparation for diagnostic cytopathology. , 2013, Lab on a chip.

[62]  S. Gawad,et al.  Impedance spectroscopy flow cytometry: On‐chip label‐free cell differentiation , 2005, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[63]  M. Berggren,et al.  EGOFET Peptide Aptasensor for Label‐Free Detection of Inflammatory Cytokines in Complex Fluids , 2018 .

[64]  Luke P. Lee,et al.  Self-powered integrated microfluidic point-of-care low-cost enabling (SIMPLE) chip , 2017, Science Advances.

[65]  Saulius Juodkazis,et al.  Nanotopography as a trigger for the microscale, autogenous and passive lysis of erythrocytes. , 2014, Journal of materials chemistry. B.

[66]  Laura M Lechuga,et al.  Microcantilever-based platforms as biosensing tools. , 2010, The Analyst.

[67]  S. Jahns,et al.  Handheld imaging photonic crystal biosensor for multiplexed, label-free protein detection. , 2015, Biomedical optics express.

[68]  S. Manalis,et al.  Weighing of biomolecules, single cells and single nanoparticles in fluid , 2007, Nature.

[69]  A. Babataheri,et al.  Mechanical Criterion for the Rupture of a Cell Membrane under Compression. , 2016, Biophysical journal.

[70]  Aman Russom,et al.  Acoustic micro-vortexing of fluids, particles and cells in disposable microfluidic chips , 2016, Biomedical microdevices.

[71]  Hywel Morgan,et al.  Label-free enrichment of primary human skeletal progenitor cells using deterministic lateral displacement. , 2019, Lab on a chip.

[72]  M. Roukes,et al.  Comparative advantages of mechanical biosensors. , 2011, Nature nanotechnology.

[73]  Sung Yang,et al.  A microfluidic device for continuous white blood cell separation and lysis from whole blood. , 2010, Artificial organs.

[74]  J. Spivak,et al.  Polycythemia vera: myths, mechanisms, and management. , 2002, Blood.

[75]  A. F. Sarioglu,et al.  Hybrid negative enrichment of circulating tumor cells from whole blood in a 3D-printed monolithic device. , 2019, Lab on a chip.

[76]  I. Sarangadharan,et al.  Single Drop Whole Blood Diagnostics: Portable Biomedical Sensor for Cardiac Troponin I Detection. , 2018, Analytical chemistry.

[77]  Sung Yang,et al.  On-chip Extraction of Intracellular Molecules in White Blood Cells from Whole Blood , 2015, Scientific Reports.

[78]  M. Yamada,et al.  Pinched flow fractionation: continuous size separation of particles utilizing a laminar flow profile in a pinched microchannel. , 2004, Analytical chemistry.

[79]  Paul I. Okagbare,et al.  Highly efficient circulating tumor cell isolation from whole blood and label-free enumeration using polymer-based microfluidics with an integrated conductivity sensor. , 2008, Journal of the American Chemical Society.

[80]  K. Morton,et al.  Anisotropic permeability in deterministic lateral displacement arrays. , 2016, Lab on a chip.

[81]  Wenchan Zhang,et al.  A sensitive impedimetric DNA biosensor for the determination of the HIV gene based on electrochemically reduced graphene oxide , 2015 .

[82]  Yang Yang,et al.  Aptamer–field-effect transistors overcome Debye length limitations for small-molecule sensing , 2018, Science.

[83]  P. Nath,et al.  Label-free biodetection using a smartphone. , 2013, Lab on a chip.

[84]  H. Karnes,et al.  Microfluidic immunoaffinity separations for bioanalysis. , 2008, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[85]  Yuze Sun,et al.  Sensitive optical biosensors for unlabeled targets: a review. , 2008, Analytica chimica acta.

[86]  Volumetric measurement of human red blood cells by MOSFET‐based microfluidic gate , 2015, Electrophoresis.

[87]  Hakan Urey,et al.  Microcantilever based disposable viscosity sensor for serum and blood plasma measurements. , 2013, Methods.

[88]  P. Shankar,et al.  A review of fiber-optic biosensors , 2007 .

[89]  A Radial Pillar Device (RAPID) for continuous and high-throughput separation of multi-sized particles , 2018, Biomedical microdevices.

[90]  Gwo-Bin Lee,et al.  Continuous nucleus extraction by optically-induced cell lysis on a batch-type microfluidic platform. , 2016, Lab on a chip.

[91]  Aman Russom,et al.  Inertial microfluidics combined with selective cell lysis for high throughput separation of nucleated cells from whole blood , 2017 .

[92]  Mehmet Toner,et al.  A robust electrical microcytometer with 3-dimensional hydrofocusing. , 2009, Lab on a chip.

[93]  J. Min,et al.  Electrochemical immunosensor for highly sensitive and quantitative detection of tumor necrosis factor-α in human serum. , 2018, Bioelectrochemistry.

[94]  P. Sajeesh,et al.  Particle separation and sorting in microfluidic devices: a review , 2014 .

[95]  N. Klein,et al.  Chemically Functionalised Graphene FET Biosensor for the Label-free Sensing of Exosomes , 2019, Scientific Reports.

[96]  L. Goodnough,et al.  Anemia of chronic disease. , 2005, The New England journal of medicine.

[97]  Yu Sun,et al.  Electrical measurement of red blood cell deformability on a microfluidic device. , 2013, Lab on a chip.

[98]  Kin Fong Lei,et al.  Real-Time Electrical Impedimetric Monitoring of Blood Coagulation Process under Temperature and Hematocrit Variations Conducted in a Microfluidic Chip , 2013, PloS one.