Toward Integrated Molecular Diagnostic System ($i$ MDx): Principles and Applications

Integrated molecular diagnostic systems (iMDx), which are automated, sensitive, specific, user-friendly, robust, rapid, easy-to-use, and portable, can revolutionize future medicine. This review will first focus on the components of sample extraction, preservation, and filtration necessary for all point-of-care devices to include for practical use. Subsequently, we will look for low-powered and precise methods for both sample amplification and signal transduction, going in-depth to the details behind their principles. The final field of total device integration and its application to the clinical field will also be addressed to discuss the practicality for future patient care. We envision that microfluidic systems hold the potential to breakthrough the number of problems brought into the field of medical diagnosis today.

[1]  Rashid Bashir,et al.  Rapid thermal lysis of cells using silicon-diamond microcantilever heaters. , 2010, Lab on a chip.

[2]  Bingcheng Lin,et al.  Rapid prototyping of paper‐based microfluidics with wax for low‐cost, portable bioassay , 2009, Electrophoresis.

[3]  P. Pouteau,et al.  Passive microfluidic devices for plasma extraction from whole human blood , 2008 .

[4]  W. Wang,et al.  Lyophilization and development of solid protein pharmaceuticals. , 2000, International journal of pharmaceutics.

[5]  Gengfeng Zheng,et al.  Fabrication of silicon nanowire devices for ultrasensitive, label-free, real-time detection of biological and chemical species , 2006, Nature Protocols.

[6]  Wei Shen,et al.  Fabrication of paper-based microfluidic sensors by printing. , 2010, Colloids and surfaces. B, Biointerfaces.

[7]  Bryan Lincoln,et al.  Integrated microfluidic tmRNA purification and real-time NASBA device for molecular diagnostics. , 2008, Lab on a chip.

[8]  Joseph Wang,et al.  Point-of-care biosensor systems for cancer diagnostics/prognostics. , 2006, Biosensors & bioelectronics.

[9]  Luke P. Lee,et al.  Rapid detection of Aβ aggregation and inhibition by dual functions of gold nanoplasmic particles: catalytic activator and optical reporter. , 2013, ACS nano.

[10]  Gijs W K van Dedem,et al.  Quantitative analysis in nanoliter wells by prefilling of wells using electrospray deposition followed by sample introduction with a coverslip method. , 2005, Analytical chemistry.

[11]  Kevin W Plaxco,et al.  Rapid, sensitive, and quantitative detection of pathogenic DNA at the point of care through microfluidic electrochemical quantitative loop-mediated isothermal amplification. , 2012, Angewandte Chemie.

[12]  Hanyoup Kim,et al.  Nanodroplet real-time PCR system with laser assisted heating. , 2009, Optics express.

[13]  Ye Ai,et al.  Separation of Escherichia coli Bacteria from Peripheral Blood Mononuclear Cells Using Standing Surface Acoustic Waves , 2013, Analytical chemistry.

[14]  Brian T. Cunningham,et al.  Photonic crystal optical biosensor incorporating structured low-index porous dielectric , 2005 .

[15]  Kelvin H. Lee,et al.  On-chip coupling of electrochemical pumps and an SU-8 tip for electrospray ionization mass spectrometry , 2008, Biomedical microdevices.

[16]  Dandan Han,et al.  An overview of liposome lyophilization and its future potential. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

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

[18]  L. Gervais,et al.  Toward one-step point-of-care immunodiagnostics using capillary-driven microfluidics and PDMS substrates. , 2009, Lab on a chip.

[19]  Harold G. Craighead,et al.  Virus detection using nanoelectromechanical devices , 2004 .

[20]  G. Whitesides,et al.  Understanding wax printing: a simple micropatterning process for paper-based microfluidics. , 2009, Analytical chemistry.

[21]  P. Craw,et al.  Isothermal nucleic acid amplification technologies for point-of-care diagnostics: a critical review. , 2012, Lab on a chip.

[22]  Luke P. Lee,et al.  Digital LAMP in a sample self-digitization (SD) chip. , 2012, Lab on a chip.

[23]  Peter Kauffman,et al.  Microfluidics without pumps: reinventing the T-sensor and H-filter in paper networks. , 2010, Lab on a chip.

[24]  Tony Jun Huang,et al.  Microfluidic diagnostics for the developing world. , 2012, Lab on a chip.

[25]  E. Sollier,et al.  Fast and continuous plasma extraction from whole human blood based on expanding cell-free layer devices , 2010, Biomedical microdevices.

[26]  Luke P. Lee,et al.  Nanowell surface enhanced Raman scattering arrays fabricated by soft-lithography for label-free biomolecular detections in integrated microfluidics , 2005 .

[27]  S. S. Sibbett,et al.  Multiplex lateral-flow test strips fabricated by two-dimensional shaping. , 2009, ACS applied materials & interfaces.

[28]  Paul Yager,et al.  Cell lysis and protein extraction in a microfluidic device with detection by a fluorogenic enzyme assay. , 2002, Analytical chemistry.

[29]  R. Jäggi,et al.  Microfluidic depletion of red blood cells from whole blood in high-aspect-ratio microchannels , 2006 .

[30]  S. Head,et al.  Assessing a novel room-temperature RNA storage medium for compatibility in microarray gene expression analysis. , 2009, BioTechniques.

[31]  Anne Kopf-Sill,et al.  Novel isothermal, linear nucleic acid amplification systems for highly multiplexed applications. , 2005, Clinical chemistry.

[32]  S. Quake,et al.  Microfluidic Large-Scale Integration , 2002, Science.

[33]  R. Tompkins,et al.  Equilibrium separation and filtration of particles using differential inertial focusing. , 2008, Analytical chemistry.

[34]  Mehmet Toner,et al.  Single-cell chemical lysis in picoliter-scale closed volumes using a microfabricated device. , 2004, Analytical chemistry.

[35]  Luke P. Lee,et al.  Correction: A Handheld Point-of-Care Genomic Diagnostic System , 2013, PLoS ONE.

[36]  D. Citterio,et al.  Inkjet-printed microfluidic multianalyte chemical sensing paper. , 2008, Analytical chemistry.

[37]  Lukas Novak,et al.  Rapid detection of viral RNA by a pocket-size real-time PCR system. , 2010, Lab on a chip.

[38]  Mehmet Toner,et al.  Continuous flow microfluidic device for rapid erythrocyte lysis. , 2004, Analytical chemistry.

[39]  Á. Holguín,et al.  Performance of OraQuick Advance Rapid HIV-1/2 Antibody Test for detection of antibodies in oral fluid and serum/plasma in HIV-1+ subjects carrying different HIV-1 subtypes and recombinant variants. , 2009, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[40]  Chang Lu,et al.  A microfluidic flow-through device for high throughput electrical lysis of bacterial cells based on continuous dc voltage. , 2006, Biosensors & bioelectronics.

[41]  S. Au,et al.  Nanoliter dispensing method by degassed poly(dimethylsiloxane) microchannels and its application in protein crystallization. , 2007, Analytical chemistry.

[42]  D. McNevin,et al.  Human tissue preservation for disaster victim identification (DVI) in tropical climates. , 2012, Forensic science international. Genetics.

[43]  Eun Kyu Lee,et al.  Loop Mediated Isothermal Amplification of DNA , 2008 .

[44]  A Manz,et al.  Chemical amplification: continuous-flow PCR on a chip. , 1998, Science.

[45]  G. Whitesides,et al.  Patterned paper as a platform for inexpensive, low-volume, portable bioassays. , 2007, Angewandte Chemie.

[46]  H. Ji,et al.  Silicon-based microfilters for whole blood cell separation , 2008, Biomedical microdevices.

[47]  Thomas Otto,et al.  Highly-integrated lab-on-chip system for point-of-care multiparameter analysis. , 2012, Lab on a chip.

[48]  Peter Westh,et al.  Trehalose accumulation in the tardigrade Adorybiotus coronifer during anhydrobiosis , 1991 .

[49]  D. Leckband,et al.  Development and characterization of an ELISA assay in PDMS microfluidic channels , 2001 .

[50]  Joo H. Kang,et al.  Microfluidic biomechanical device for compressive cell stimulation and lysis , 2007 .

[51]  Roland Zengerle,et al.  Microstructuring of polymer films for sensitive genotyping by real-time PCR on a centrifugal microfluidic platform. , 2010, Lab on a chip.

[52]  Harold G. Craighead,et al.  Multiplexed Microcolumn-Based Process for Efficient Selection of RNA Aptamers , 2013, Analytical chemistry.

[53]  Zhihong Nie,et al.  Programmable diagnostic devices made from paper and tape. , 2010, Lab on a chip.

[54]  David Erickson,et al.  A method for nanofluidic device prototyping using elastomeric collapse , 2009, Proceedings of the National Academy of Sciences.

[55]  Dino Di Carlo,et al.  On-chip cell lysis by local hydroxide generation. , 2005, Lab on a chip.

[56]  Brian E. McIntosh,et al.  Development of an Efficient Targeted Cell-SELEX Procedure for DNA Aptamer Reagents , 2013, PloS one.

[57]  T. Crowley,et al.  Isolation of plasma from whole blood using planar microfilters for lab-on-a-chip applications. , 2005, Lab on a chip.

[58]  H. Lang,et al.  Multiple label-free biodetection and quantitative DNA-binding assays on a nanomechanical cantilever array , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Yongqiang Cheng,et al.  Ultrasensitive detection of microRNAs by exponential isothermal amplification. , 2010, Angewandte Chemie.

[60]  J. L. Delaney,et al.  Electrogenerated chemiluminescence detection in paper-based microfluidic sensors. , 2011, Analytical chemistry.

[61]  Guo-Li Shen,et al.  Fluorescence aptameric sensor for strand displacement amplification detection of cocaine. , 2010, Analytical chemistry.

[62]  Y. K. Cheung,et al.  1 Supplementary Information for : Microfluidics-based diagnostics of infectious diseases in the developing world , 2011 .

[63]  H. Stone,et al.  Geometrical focusing of cells in a microfluidic device: an approach to separate blood plasma. , 2006, Biorheology.

[64]  P. Hünenberger,et al.  Trehalose–protein interaction in aqueous solution , 2004, Proteins.

[65]  Rashid Bashir,et al.  BioMEMS: state-of-the-art in detection, opportunities and prospects. , 2004, Advanced drug delivery reviews.

[66]  Charles M. Lieber,et al.  Direct ultrasensitive electrical detection of DNA and DNA sequence variations using nanowire nanosensors , 2004 .

[67]  Hai-Qing Gong,et al.  Microfluidic devices harboring unsealed reactors for real-time isothermal helicase-dependent amplification , 2009, Microfluidics and nanofluidics.

[68]  G. Domingo,et al.  Post-extraction stabilization of HIV viral RNA for quantitative molecular tests. , 2012, Journal of virological methods.

[69]  A. Pardi,et al.  A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[70]  Peter J. Asiello,et al.  Miniaturized isothermal nucleic acid amplification, a review. , 2011, Lab on a chip.

[71]  J. Kang,et al.  Novel electrical detection of label-free disease marker proteins using piezoresistive self-sensing micro-cantilevers. , 2005, Biosensors & bioelectronics.

[72]  Seung Soo Oh,et al.  Quantitative selection of DNA aptamers through microfluidic selection and high-throughput sequencing , 2010, Proceedings of the National Academy of Sciences.

[73]  Jaephil Do,et al.  An integrated disposable device for DNA extraction and helicase dependent amplification , 2010, Biomedical microdevices.

[74]  Molly M Stevens,et al.  Plasmonic ELISA for the ultrasensitive detection of disease biomarkers with the naked eye. , 2012, Nature nanotechnology.

[75]  Zhengping Li,et al.  One-step ultrasensitive detection of microRNAs with loop-mediated isothermal amplification (LAMP). , 2011, Chemical communications.

[76]  Paul Yager,et al.  Controlled microfluidic reconstitution of functional protein from an anhydrous storage depot. , 2004, Lab on a chip.

[77]  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.

[78]  A. D. Mello,et al.  Focus DNA amplification: does ‘small’ really mean ‘efficient’? , 2001 .

[79]  Michael G. Roper,et al.  A fully integrated microfluidic genetic analysis system with sample-in–answer-out capability , 2006, Proceedings of the National Academy of Sciences.

[80]  Suhyeon Kim,et al.  Microchip-based one step DNA extraction and real-time PCR in one chamber for rapid pathogen identification. , 2006, Lab on a chip.

[81]  George M. Whitesides,et al.  Paper-based electroanalytical devices for accessible diagnostic testing , 2013 .

[82]  Luke P. Lee,et al.  Integrated microfluidic cell culture and lysis on a chip. , 2007, Lab on a chip.

[83]  Xu Li,et al.  A perspective on paper-based microfluidics: Current status and future trends. , 2012, Biomicrofluidics.

[84]  Ji Yoon Kang,et al.  A polymer lab-on-a-chip for reverse transcription (RT)-PCR based point-of-care clinical diagnostics. , 2008, Lab on a chip.

[85]  Jennifer L. Osborn,et al.  Enabling a microfluidic immunoassay for the developing world by integration of on-card dry reagent storage. , 2008, Lab on a chip.

[86]  Brian N. Johnson,et al.  An integrated nanoliter DNA analysis device. , 1998, Science.

[87]  George M Whitesides,et al.  Rapid fabrication of pressure-driven open-channel microfluidic devices in omniphobic R(F) paper. , 2013, Lab on a chip.

[88]  R. Tompkins,et al.  Continuous inertial focusing, ordering, and separation of particles in microchannels , 2007, Proceedings of the National Academy of Sciences.

[89]  Q. Park,et al.  Performance Evaluation of the OraQuick Hepatitis C Virus Rapid Antibody Test , 2013, Annals of laboratory medicine.

[90]  Bruce Budowle,et al.  Assessing a novel room temperature DNA storage medium for forensic biological samples. , 2012, Forensic science international. Genetics.

[91]  R. Zengerle,et al.  Centrifugal extraction of plasma from whole blood on a rotating disk. , 2006, Lab on a chip.

[92]  G. Whitesides,et al.  Three-dimensional microfluidic devices fabricated in layered paper and tape , 2008, Proceedings of the National Academy of Sciences.

[93]  J. Szostak,et al.  In vitro selection of RNA molecules that bind specific ligands , 1990, Nature.

[94]  Daniel Citterio,et al.  Inkjet-printed paperfluidic immuno-chemical sensing device , 2010, Analytical and bioanalytical chemistry.

[95]  H. Craighead,et al.  Microfluidic encapsulated nanoelectromechanical resonators , 2007 .

[96]  U. Pastorino,et al.  Quantification of Free Circulating DNA As a Diagnostic Marker in Lung Cancer , 2003 .

[97]  Daniel Irimia,et al.  Ultrasensitive detection of low-abundance surface-marker protein using isothermal rolling circle amplification in a microfluidic nanoliter platform. , 2011, Small.

[98]  Jeong-Woo Choi,et al.  Electrochemical cell lysis device for DNA extraction. , 2010, Lab on a chip.

[99]  Robert J. O'Connell,et al.  Performance of the OraQuick Rapid Antibody Test for Diagnosis of Human Immunodeficiency Virus Type 1 Infection in Patients with Various Levels of Exposure to Highly Active Antiretroviral Therapy , 2003, Journal of Clinical Microbiology.

[100]  A. Cass,et al.  Nucleic acid aptamers: ideal reagents for point-of-care diagnostics? , 2011, Faraday discussions.

[101]  M. McClain,et al.  Microfluidic devices for the high-throughput chemical analysis of cells. , 2003, Analytical chemistry.

[102]  Daniel T Chiu,et al.  Disposable microfluidic devices: fabrication, function, and application. , 2005, BioTechniques.

[103]  Roland Zengerle,et al.  Microfluidic lab-on-a-foil for nucleic acid analysis based on isothermal recombinase polymerase amplification (RPA). , 2010, Lab on a chip.

[104]  Yoshihide Hayashizaki,et al.  Rapid SNP diagnostics using asymmetric isothermal amplification and a new mismatch-suppression technology , 2007, Nature Methods.

[105]  T. Vo‐Dinh,et al.  Biosensors and biochips: advances in biological and medical diagnostics , 2000, Fresenius' journal of analytical chemistry.

[106]  Paul Yager,et al.  Controlled release of dry reagents in porous media for tunable temporal and spatial distribution upon rehydration. , 2012, Lab on a chip.

[107]  Kristen L. Helton,et al.  Microfluidic Overview of Global Health Issues Microfluidic Diagnostic Technologies for Global Public Health , 2006 .

[108]  Luke P. Lee,et al.  Stand-alone self-powered integrated microfluidic blood analysis system (SIMBAS). , 2011, Lab on a chip.

[109]  Douglas D. Taylor,et al.  Exosomal microRNA: a diagnostic marker for lung cancer. , 2008, Clinical lung cancer.

[110]  C. Culbertson,et al.  Paper-based microfluidic devices for analysis of clinically relevant analytes present in urine and saliva , 2010, Analytical and bioanalytical chemistry.

[111]  K. Jensen,et al.  A microfluidic electroporation device for cell lysis. , 2005, Lab on a chip.

[112]  P Belgrader,et al.  Lysing bacterial spores by sonication through a flexible interface in a microfluidic system. , 2001, Analytical chemistry.

[113]  Johannes D. Seelig,et al.  Label-free protein assay based on a nanomechanical cantilever array , 2002 .

[114]  Charles M Lieber,et al.  Label-free detection of small-molecule-protein interactions by using nanowire nanosensors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[115]  J Andrew,et al.  DNA amplification: does 'small' really mean 'efficient'? , 2001 .

[116]  A Mukherjee,et al.  Nucleic acid aptamers: clinical applications and promising new horizons. , 2011, Current medicinal chemistry.

[117]  Markus A. Grohme,et al.  Anhydrobiosis in tardigrades--the last decade. , 2011, Journal of insect physiology.

[118]  Yi Xiao,et al.  Probing the Limits of Aptamer Affinity with a Microfluidic SELEX Platform , 2011, PloS one.

[119]  Jayna J. Shah,et al.  Microwave-induced adjustable nonlinear temperature gradients in microfluidic devices , 2010 .

[120]  Chang Lu,et al.  A microfluidic device for physical trapping and electrical lysis of bacterial cells , 2008 .

[121]  Laser-treated Parchment Paper: An Inexpensive Microfluidic Platform , 2011 .

[122]  T. Granade,et al.  Performance of the OraQuick and Hema-Strip rapid HIV antibody detection assays by non-laboratorians. , 2004, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[123]  Luke P. Lee,et al.  Rapid Detection of Protein Aggregation and Inhibition by Dual Functions of Gold Nanoplasmonic Particles: Catalytic Activator and Optical Reporter , 2013 .

[124]  Jens Ducrée,et al.  Integrated microfluidic array plate (iMAP) for cellular and molecular analysis. , 2011, Lab on a chip.

[125]  P. Gill,et al.  Nucleic Acid Isothermal Amplification Technologies—A Review , 2008, Nucleosides, nucleotides & nucleic acids.

[126]  Yi Xiao,et al.  Detection of proteins in serum by micromagnetic aptamer PCR (MAP) technology. , 2010, Angewandte Chemie.

[127]  Robert Pelton,et al.  Streaming potential sensing in paper-based microfluidic channels , 2010 .

[128]  R S Foote,et al.  Microchip device for cell lysis, multiplex PCR amplification, and electrophoretic sizing. , 1998, Analytical chemistry.

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

[130]  Young-Ho Cho,et al.  A continuous electrical cell lysis device using a low dc voltage for a cell transport and rupture , 2007 .

[131]  Dong-Ki Lee,et al.  Selection and elution of aptamers using nanoporous sol-gel arrays with integrated microheaters. , 2009, Lab on a chip.

[132]  Emanuel Carrilho,et al.  Paper-based ELISA. , 2010, Angewandte Chemie.

[133]  J. Carpenter,et al.  Modes of stabilization of a protein by organic solutes during desiccation , 1988 .