Skip to main content

Advertisement

Log in

Applications of microfluidics and microchip electrophoresis for potential clinical biomarker analysis

  • Review
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

This article reviews advances over the last five years in microfluidics and microchip-electrophoresis techniques for detection of clinical biomarkers. The variety of advantages of miniaturization compared with conventional benchtop methods for detecting biomarkers has resulted in increased interest in developing cheap, fast, and sensitive techniques. We discuss the development of applications of microfluidics and microchip electrophoresis for analysis of different clinical samples for pathogen identification, personalized medicine, and biomarker detection. We emphasize the advantages of microfluidic techniques over conventional methods, which make them attractive future diagnostic tools. We also discuss the versatility and adaptability of this technology for analysis of a variety of biomarkers, including lipids, small molecules, carbohydrates, nucleic acids, proteins, and cells. Finally, we conclude with a discussion of aspects that need to be improved to move this technology towards routine clinical and point-of-care applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Harrison DJ, Manz A, Fan Z, Lüdi H, Widmer HM (1992) Capillary electrophoresis and sample injection systems integrated on a planar glass chip. Anal Chem 64:1926–1932

    Article  CAS  Google Scholar 

  2. Gordon J, Michel G (2012) Discerning trends in multiplex immunoassay technology with potential for resource-limited settings. Clin Chem 58:690–698

    Article  CAS  Google Scholar 

  3. van der Meel R, Krawczyk-Durka M, van Solinge WW, Schiffelers RM (2014) Toward routine detection of extracellular vesicles in clinical samples. Int J Lab Hematol 36:244–253

    Article  Google Scholar 

  4. Nahavandi S, Baratchi S, Soffe R, Tang SY, Nahavandi S, Mitchell A, Khoshmanesh K (2014) Microfluidic platforms for biomarker analysis. Lab Chip 14:1496–1514

    Article  CAS  Google Scholar 

  5. Yang Z, Sweedler JV (2014) Application of capillary electrophoresis for the early diagnosis of cancer. Anal Bioanal Chem 406:4013–4031

    Article  CAS  Google Scholar 

  6. Oita I, Halewyck H, Thys B, Rombaut B, Vander Heyden Y, Mangelings D (2010) Microfluidics in macro-biomolecules analysis: macro inside in a nano world. Anal Bioanal Chem 398:239–264

    Article  CAS  Google Scholar 

  7. Zare RN, Kim S (2010) Microfluidic platforms for single-cell analysis. Annu Rev Biomed Eng 12:187–201

    Article  CAS  Google Scholar 

  8. Jokerst JC, Emory JM, Henry CS (2012) Advances in microfluidics for environmental analysis. Analyst 137:24–34

    Article  CAS  Google Scholar 

  9. Kenyon SM, Meighan MM, Hayes MA (2011) Recent developments in electrophoretic separations on microfluidic devices. Electrophoresis 32:482–493

    Article  CAS  Google Scholar 

  10. Mohammed MI, Desmulliez MPY (2011) Lab-on-a-chip based immunosensor principles and technologies for the detection of cardiac biomarkers: a review. Lab Chip 11:569–595

    Article  CAS  Google Scholar 

  11. Wisitsoraat A, Sritongkham P, Karuwan C, Phokharatkul D, Maturos T, Tuantranont A (2010) Fast cholesterol detection using flow injection microfluidic device with functionalized carbon nanotubes based electrochemical sensor. Biosens Bioelectron 26:1514–1520

    Article  CAS  Google Scholar 

  12. Ali MA, Srivastava S, Solanki PR, Agrawal VV, John R, Malhotra BD (2012) Nanostructured anatase-titanium dioxide based platform for application to microfluidics cholesterol biosensor. Appl Phys Lett 101:084105

    Article  Google Scholar 

  13. Labroo P, Cui Y (2014) Graphene nano-ink biosensor arrays on a microfluidic paper for multiplexed detection of metabolites. Anal Chim Acta 813:90–96

    Article  CAS  Google Scholar 

  14. Bai HY, Lin SL, Chung YT, Liu TY, Chan SA, Fuh MR (2011) Quantitative determination of 8-isoprostaglandin F(2α) in human urine using microfluidic chip-based nano-liquid chromatography with on-chip sample enrichment and tandem mass spectrometry. J Chromatogr A 1218:2085–2090

    Article  CAS  Google Scholar 

  15. Takai M, Nagai M, Morimoto Y, Sasao K, Oki A, Nakanishi J, Inokuchi H, Chang CH, Kikuchi J, Ogawa H, Horiike Y (2013) Colorimetric microchip assay using our own whole blood collected by a painless needle for home medical care. Analyst 138:6469–6476

    Article  CAS  Google Scholar 

  16. Heller A, Feldman B (2008) Electrochemical glucose sensors and their applications in diabetes management. Chem Rev 108:2482–2505

    Article  CAS  Google Scholar 

  17. Cai L, Wang Y, Wu Y, Xu C, Zhong M, Lai H, Huang J (2014) Fabrication of a microfluidic paper-based analytical device by silanization of filter cellulose using a paper mask for glucose assay. Analyst 139:4593–4598

    Article  CAS  Google Scholar 

  18. Yu J, Ge L, Huang J, Wang S, Ge S (2011) Microfluidic paper-based chemiluminescence biosensor for simultaneous determination of glucose and uric acid. Lab Chip 11:1286–1291

    Article  CAS  Google Scholar 

  19. Lin YH, Wang SH, Wu MH, Pan TM, Lai CS, Luo JD, Chiou CC (2013) Integrating solid-state sensor and microfluidic devices for glucose, urea and creatinine detection based on enzyme-carrying alginate microbeads. Biosens Bioelectron 43:328–335

    Article  CAS  Google Scholar 

  20. Chen D, Mauk M, Qiu X, Liu C, Kim J, Ramprasad S, Ongagna S, Abrams WR, Malamud D, Corstjens PLAM, Bau HH (2010) An integrated, self-contained microfluidic cassette for isolation, amplification, and detection of nucleic acids. Biomed Microdevices 12:705–719

    Article  Google Scholar 

  21. Ferguson BS, Buchsbaum SF, Wu TT, Hsieh K, Xiao Y, Sun R, Soh HT (2011) Genetic analysis of H1N1 influenza virus from throat swab samples in a microfluidic system for point-of-care diagnostics. J Am Chem Soc 133:9129–9135

    Article  CAS  Google Scholar 

  22. Wang CH, Lien KY, Hung LY, Lei HY, Lee GB (2012) Integrated microfluidic system for the identification and multiple subtyping of influenza viruses by using a molecular diagnostic approach. Microfluid Nanofluid 13:113–123

    Article  CAS  Google Scholar 

  23. Danila DC, Fleisher M, Scher HI (2011) Circulating tumor cells as biomarkers in prostate cancer. Clin Cancer Res 17:3903–3912

    Article  CAS  Google Scholar 

  24. Thierry B, Kurkuri M, Shi JY, Lwin LEMP, Palms D (2010) Herceptin functionalized microfluidic polydimethylsiloxane devices for the capture of human epidermal growth factor receptor 2 positive circulating breast cancer cells. Biomicrofluidics 4:032205

    Article  Google Scholar 

  25. Issadore D, Chung J, Shao H, Liong M, Ghazani AA, Castro CM, Weissleder R, Lee H (2012) Ultrasensitive clinical enumeration of rare cells ex vivo using a micro-hall detector. Sci Transl Med 4:141ra92

    Article  Google Scholar 

  26. Berneis K, Jeanneret C, Muser J, Felix B, Miserez AR (2005) Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes. Metabolism 54:227–234

    Article  CAS  Google Scholar 

  27. Hopewell JC, Seedorf U, Farrall M, Parish S, Kyriakou T, Goel A, Hamsten A, Collins R, Watkins H, Clarke R, Consortium P (2014) Impact of lipoprotein(a) levels and apolipoprotein(a) isoform size on risk of coronary heart disease. J Intern Med 276:260–268

    Article  CAS  Google Scholar 

  28. DeFilippis AP, Blaha MJ, Martin SS, Reed RM, Jones SR, Nasir K, Blumenthal RS, Budoff MJ (2013) Nonalcoholic fatty liver disease and serum lipoproteins: the multi-ethnic study of atherosclerosis. Atherosclerosis 227:429–436

    Article  CAS  Google Scholar 

  29. Llanos AA, Makambi KH, Tucker CA, Wallington SF, Shields PG, Adams-Campbell LL (2012) Cholesterol, lipoproteins, and breast cancer risk in African American women. Ethn Dis 22:281–287

    Google Scholar 

  30. Williams PT, Zhao XQ, Marcovina SM, Otvos JD, Brown BG, Krauss RM (2014) Comparison of four methods of analysis of lipoprotein particle subfractions for their association with angiographic progression of coronary artery disease. Atherosclerosis 233:713–720

    Article  CAS  Google Scholar 

  31. Garber DW, Kulkarni KR, Anantharamaiah GM (2000) A sensitive and convenient method for lipoprotein profile analysis of individual mouse plasma samples. J Lipid Res 41:1020–1026

    CAS  Google Scholar 

  32. Otvos JD, Jeyarajah EJ, Bennett DW, Krauss RM (1992) Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement. Clin Chem 38:1632–1638

    CAS  Google Scholar 

  33. Ruecha N, Siangproh W, Chailapakul O (2011) A fast and highly sensitive detection of cholesterol using polymer microfluidic devices and amperometric system. Talanta 84:1323–1328

    Article  CAS  Google Scholar 

  34. Wang H, Wang D, Wang J, Wang H, Gu J, Han C, Jin Q, Xu B, He C, Cao L, Wang Y, Zhao J (2009) Application of poly(dimethylsiloxane)/glass microchip for fast electrophoretic separation of serum small, dense low-density lipoprotein. J Chromatogr A 1216:6343–6347

    Article  CAS  Google Scholar 

  35. Tyurin VA, Tyurina YY, Borisenko GG, Sokolova TV, Ritov VB, Quinn PJ, Rose M, Kochanek P, Graham SH, Kagan VE (2000) Oxidative stress following traumatic brain injury in rats: quantitation of biomarkers and detection of free radical intermediates. J Neurochem 75:2178–2189

    Article  CAS  Google Scholar 

  36. Cracowski JL, Ormezzano O (2004) Isoprostanes, emerging biomarkers and potential mediators in cardiovascular diseases. Eur Heart J 25:1675–1678

    Article  CAS  Google Scholar 

  37. Gibson LR II, Bohn PW (2013) Non-aqueous microchip electrophoresis for characterization of lipid biomarkers. Interface Focus 3:20120096

  38. Leymarie N, Griffin PJ, Jonscher K, Kolarich D, Orlando R, McComb M, Zaia J, Aguilan J, Alley WR, Altmann F, Ball LE, Basumallick L, Bazemore-Walker CR, Behnken H, Blank MA et al (2013) Interlaboratory study on differential analysis of protein glycosylation by mass spectrometry: the ABRF glycoprotein research multi-institutional study 2012. Mol Cell Proteomics 12:2935–2951

    Article  CAS  Google Scholar 

  39. Morelle W, Michalski JC (2007) Analysis of protein glycosylation by mass spectrometry. Nat Protoc 2:1585–1602

    Article  CAS  Google Scholar 

  40. Mitra I, Alley WR, Goetz JA, Vasseur JA, Novotny MV, Jacobson SC (2013) Comparative profiling of N-glycans isolated from serum samples of ovarian cancer patients and analyzed by microchip electrophoresis. J Proteome Res 12:4490–4496

    Article  CAS  Google Scholar 

  41. Zhuang Z, Starkey JA, Mechref Y, Novotny MV, Jacobson SC (2007) Electrophoretic analysis of N-glycans on microfluidic devices. Anal Chem 79:7170–7175

    Article  CAS  Google Scholar 

  42. Nagata H, Itoh T, Baba Y, Ishikawa M (2010) Highly sensitive detection of monosaccharides on microchip electrophoresis using pH discontinuous solution system. Anal Sci 26:731–736

    Article  CAS  Google Scholar 

  43. Sadee W, Dai Z (2005) Pharmacogenetics/genomics and personalized medicine. Hum Mol Genet 14:R207–R214

    Article  CAS  Google Scholar 

  44. Pirmohamed M (2006) Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol 62:509–511

    Article  Google Scholar 

  45. Poe BL, Haverstick DM, Landers JP (2012) Warfarin genotyping in a single PCR reaction for microchip electrophoresis. Clin Chem 58:725–731

    Article  CAS  Google Scholar 

  46. Madsen BE, Villesen P, Wiuf C (2008) Short tandem repeats in human exons: a target for disease mutations. BMC Genomics 9:410

    Article  Google Scholar 

  47. Le Roux D, Root BE, Hickey JA, Scott ON, Tsuei A, Li J, Saul DJ, Chassagne L, Landers JP, de Mazancourt P (2014) An integrated sample-in-answer-out microfluidic chip for rapid human identification by STR analysis. Lab Chip 14:4415–4425

    Article  Google Scholar 

  48. Jin S, Anderson GJ, Kennedy RT (2013) Western blotting using microchip electrophoresis interfaced to a protein capture membrane. Anal Chem 85:6073–6079

    Article  CAS  Google Scholar 

  49. Wang D, Bodovitz S (2010) Single cell analysis: the new frontier in 'omics'. Trends Biotechnol 28:281–290

    Article  CAS  Google Scholar 

  50. Hughes AJ, Spelke DP, Xu Z, Kang CC, Schaffer DV, Herr AE (2014) Single-cell western blotting. Nat Methods 11:749–755

    Article  CAS  Google Scholar 

  51. Kang CC, Lin JMG, Xu Z, Kumar S, Herr AE (2014) Single-cell western blotting after whole-cell imaging to assess cancer chemotherapeutic response. Anal Chem 86:10429–10436

    Article  CAS  Google Scholar 

  52. Murphy MP, LeVine H 3rd (2010) Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis 19:311–323

    Google Scholar 

  53. Mohamadi MR, Svobodova Z, Verpillot R, Esselmann H, Wiltfang J, Otto M, Taverna M, Bilkova Z, Viovy JL (2010) Microchip electrophoresis profiling of Aβ peptides in the cerebrospinal fluid of patients with Alzheimer's disease. Anal Chem 82:7611–7617

    Article  CAS  Google Scholar 

  54. Huang G, Ouyang J, Delanghe JR, Baeyens WRG, Dai Z (2004) Chemiluminescent image detection of haptoglobin phenotyping after polyacrylamide gel electrophoresis. Anal Chem 76:2997–3004

    Article  CAS  Google Scholar 

  55. Maes M, Delanghe J, Bocchio Chiavetto L, Bignotti S, Tura GB, Pioli R, Zanardini R, Altamura CA (2001) Haptoglobin polymorphism and schizophrenia: genetic variation on chromosome 16. Psychiatry Res 104:1–9

    Article  CAS  Google Scholar 

  56. Hochberg I, Roguin A, Nikolsky E, Chanderashekhar PV, Cohen S, Levy AP (2002) Haptoglobin phenotype and coronary artery collaterals in diabetic patients. Atherosclerosis 161:441–446

    Article  CAS  Google Scholar 

  57. Huang B, Huang C, Liu P, Wang F, Na N, Ouyang J (2011) Fast haptoglobin phenotyping based on microchip electrophoresis. Talanta 85:333–338

    Article  CAS  Google Scholar 

  58. Whiteaker JR, Zhao L, Anderson L, Paulovich AG (2010) An automated and multiplexed method for high throughput peptide immunoaffinity enrichment and multiple reaction monitoring mass spectrometry-based quantification of protein biomarkers. Mol Cell Proteomics 9:184–196

    Article  CAS  Google Scholar 

  59. Kalish H, Phillips TM (2012) Assessment of chemokine profiles in human skin biopsies by an immunoaffinity capillary electrophoresis chip. Methods 56:198–203

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funding for this work was provided by the National Institutes of Health under grant R01 EB006124.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Adam T. Woolley.

Additional information

Published in the topical collection Capillary Electrophoresis of Biomolecules with guest editor Lisa Holland.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pagaduan, J.V., Sahore, V. & Woolley, A.T. Applications of microfluidics and microchip electrophoresis for potential clinical biomarker analysis. Anal Bioanal Chem 407, 6911–6922 (2015). https://doi.org/10.1007/s00216-015-8622-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-015-8622-5

Keywords

Navigation