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Go with the flow: advances and trends in magnetic flow cytometry

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Abstract

The growing need for biological information at the single cell level has driven the development of improved cytometry technologies. Flow cytometry is a particularly powerful method that has evolved over the past few decades. Flow cytometers have become essential instruments in biomedical research and routine clinical tests for disease diagnosis, prognosis, and treatment monitoring. However, the increasing number of cellular parameters unveiled by genomic, proteomic, and metabolomic data platforms demands an augmented multiplexability. Also, the need for identification and quantification of relevant biomarkers at low levels requires outstanding analytical sensitivity and reliability. In addition, growing awareness of the advantages associated with miniaturization of analytical devices is pushing forward the progress in integrated and compact, microfluidic-based devices at the point-of-care. In this context, novel types of flow cytometers are emerging during the search to tackle these challenges. Notwithstanding the relevance of other promising alternatives to standard optical flow cytometry (e.g., mass cytometry, various optical and electrical microcytometers), this report focuses on a recent microcytometric technology based on magnetic sensors and magnetic particles integrated into microfluidic structures for dynamic bioanalysis of fluid samples—magnetic flow cytometry. Its concept, main developments, targeted applications, as well as the challenges and trends behind this technology are presented and discussed.

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Abbreviations

ADC:

Analog to digital converter

AMR :

Anisotropic magnetoresistance

FM :

Ferromagnetic

GMI :

Giant magneto impedance

GMR :

Giant magnetoresistance

M :

Metallic

MACS :

Magnetically assisted cell sorting

MFC :

Magnetic flow cytometry

MNPs :

Magnetic nanoparticles

MR :

Magnetoresistance

MRI :

Magnetic resonance imaging

MTJ :

Magnetic tunnel junctions

PHE :

Planar Hall effect

PMTs :

Photomultiplier tubes

PoC :

Point-of-care

S :

Sensitivity

SERF :

Spin-exchange relaxation-free

SNR :

Signal-to-noise ratio

SV :

Spin valve

TMR :

Tunneling magnetoresistance

TOF :

Time-of-flight

References

  1. Moldavan A. Photo-electric technique for the counting of microscopical cells. Science. 1934;80:188–9.

    Article  CAS  PubMed  Google Scholar 

  2. Hejazian M, Li W, Nguyen N-T. Lab on a chip for continuous-flow magnetic cell separation. Lab Chip. 2015;15:959–70. https://doi.org/10.1039/C4LC01422G.

    Article  CAS  PubMed  Google Scholar 

  3. Plouffe BD, Murthy SK, Lewis LH. Fundamentals and application of magnetic particles in cell isolation and enrichment. Rep Prog Phys. 2015;78:16601. https://doi.org/10.1088/0034-4885/78/1/016601.

    Article  CAS  Google Scholar 

  4. Loureiro J, Fermon C, Pannetier-Lecoeur M, Arrias G, Ferreira R, Cardoso S, et al. Magnetoresistive detection of magnetic beads flowing at high speed in microfluidic channels. IEEE Trans Magn. 2009;45:4873–6. https://doi.org/10.1109/TMAG.2009.2026287.

    Article  Google Scholar 

  5. Chícharo A, Martins M, Barnsley LC, Taouallah A, Fernandes J, Silva BFB, et al. Enhanced magnetic microcytometer with 3D flow focusing for cell enumeration. Lab Chip. 2018;18:2593–603. https://doi.org/10.1039/C8LC00486B.

    Article  PubMed  Google Scholar 

  6. Tasadduq B, Lam W, Alexeev A, Sarioglu AF, Sulchek T. Enhancing size based size separation through vertical focus microfluidics using secondary flow in a ridged microchannel. Sci Rep. 2017;7:17375. https://doi.org/10.1038/s41598-017-17388-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhao Y, Li Q, Hu X. Universally applicable three-dimensional hydrodynamic focusing in a single-layer channel for single cell analysis. Anal Methods. 2018;10:3489–97. https://doi.org/10.1039/C8AY01017J.

    Article  CAS  Google Scholar 

  8. Bougas L, Langenegger LD, Mora CA, Zeltner M, Stark WJ, Wickenbrock A, et al. Nondestructive in-line sub-picomolar detection of magnetic nanoparticles in flowing complex fluids. Sci Rep. 2018;8:3491. https://doi.org/10.1038/s41598-018-21802-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fodil K, Denoual M, Dolabdjian C, Treizebre A, Senez V. In-flow detection of ultra-small magnetic particles by an integrated giant magnetic impedance sensor. Appl Phys Lett. 2016;108:173701. https://doi.org/10.1063/1.4948286.

    Article  CAS  Google Scholar 

  10. Lin G, Karnaushenko DD, Bermúdez GSC, Schmidt OG, Makarov D. Magnetic suspension array technology: controlled synthesis and screening in microfluidic networks. Small. 2016;12:4553–62. https://doi.org/10.1002/smll.201601166.

    Article  CAS  PubMed  Google Scholar 

  11. Lin G, Makarov D, Medina-Sanchez M, Guix M, Baraban L, Cuniberti G, et al. Magnetofluidic platform for multidimensional magnetic and optical barcoding of droplets. Lab Chip. 2015;15:216–24. https://doi.org/10.1039/c4lc01160k.

    Article  PubMed  Google Scholar 

  12. Kim KW, Reddy V, Torati SR, Hu XH, Sandhu A, Kim CG. On-chip magnetometer for characterization of superparamagnetic nanoparticles. Lab Chip. 2015;15:696–703. https://doi.org/10.1039/C4LC01076K.

    Article  CAS  PubMed  Google Scholar 

  13. Lin G, Makarov D, Melzer M, Si W, Yan C, Schmidt OG. A highly flexible and compact magnetoresistive analytic device. Lab Chip. 2014;14:4050–8. https://doi.org/10.1039/c4lc00751d.

    Article  CAS  PubMed  Google Scholar 

  14. Fodil K, Denoual M, Dolabdjian C, Harnois M, Senez V. Dynamic sensing of magnetic nanoparticles in microchannel using GMI technology. IEEE Trans Magn. 2013;49:93–6. https://doi.org/10.1109/TMAG.2012.2218797.

    Article  CAS  Google Scholar 

  15. Lin G, Baraban L, Han L, Karnaushenko D, Makarov D, Cuniberti G, et al. Magnetoresistive emulsion analyzer. Sci Rep. 2013;3:2548.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Melzer M, Karnaushenko D, Makarov D, Baraban L, Calvimontes A, Mönch I, et al. Elastic magnetic sensor with isotropic sensitivity for in-flow detection of magnetic objects. RSC Adv. 2012;2:2284–8. https://doi.org/10.1039/C2RA01062C.

    Article  CAS  Google Scholar 

  17. Pekas N, Porter MD, Tondra M, Popple A, Jander A. Giant magnetoresistance monitoring of magnetic picodroplets in an integrated microfluidic system. Appl Phys Lett. 2004;85:4783–5. https://doi.org/10.1063/1.1825059.

    Article  CAS  Google Scholar 

  18. Reisbeck M, Richter L, Helou MJ, Arlinghaus S, Anton B, van Dommelen I, et al. Hybrid integration of scalable mechanical and magnetophoretic focusing for magnetic flow cytometry. Biosens Bioelectron. 2018;109:98–108. https://doi.org/10.1016/j.bios.2018.02.046.

    Article  CAS  PubMed  Google Scholar 

  19. Chícharo A, Barnsley L, Martins M, Cardoso S, Dieguez L, Espiña B, et al. Custom magnet design for a multi-channel magnetic microcytometer. IEEE Trans Magn. 2018;54:1–5. https://doi.org/10.1109/TMAG.2018.2835369.

    Article  Google Scholar 

  20. García-Arribas A, Martínez F, Fernández E, Ozaeta I, Kurlyandskaya GV, Svalov AV, et al. GMI detection of magnetic-particle concentration in continuous flow. Sensors Actuators A Phys. 2011;172:103–8. https://doi.org/10.1016/j.sna.2011.02.050.

    Article  CAS  Google Scholar 

  21. Mönch I, Makarov D, Koseva R, Baraban L, Karnaushenko D, Kaiser C, et al. Rolled-up magnetic sensor: nanomembrane architecture for in-flow detection of magnetic objects. ACS Nano. 2011;5:7436–42. https://doi.org/10.1021/nn202351j.

    Article  CAS  PubMed  Google Scholar 

  22. Aledealat K, Mihajlović G, Chen K, Field M, Sullivan GJ, Xiong P, et al. Dynamic micro-Hall detection of superparamagnetic beads in a microfluidic channel. J Magn Magn Mater. 2010;322:L69–72. https://doi.org/10.1016/j.jmmm.2010.08.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Loureiro J, Ferreira R, Cardoso S, Freitas PP, Germano J, Fermon C, et al. Toward a magnetoresistive chip cytometer: integrated detection of magnetic beads flowing at cm/s velocities in microfluidic channels. Appl Phys Lett. 2009;95:34104. https://doi.org/10.1063/1.3182791.

    Article  CAS  Google Scholar 

  24. Shen W, Liu X, Mazumdar D, Xiao G. In situ detection of single micron-sized magnetic beads using magnetic tunnel junction sensors. Appl Phys Lett. 2005;86:253901. https://doi.org/10.1063/1.1952582.

    Article  CAS  Google Scholar 

  25. Ferreira HA, Graham DL, Parracho P, Soares V, Freitas PP. Flow velocity measurement in microchannels using magnetoresistive chips. IEEE Trans Magn. 2004;40:2652–4. https://doi.org/10.1109/TMAG.2004.830403.

    Article  CAS  Google Scholar 

  26. Murali P, Niknejad AM, Boser BE. CMOS microflow cytometer for magnetic label detection and classification. IEEE J Solid-State Circuits. 2017;52:543–55. https://doi.org/10.1109/JSSC.2016.2621036.

    Article  Google Scholar 

  27. Reisbeck M, Helou MJ, Richter L, Kappes B, Friedrich O, Hayden O. Magnetic fingerprints of rolling cells for quantitative flow cytometry in whole blood. Sci Rep. 2016;6:32838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee C-P, Lai M-F, Huang H-T, Lin C-W, Wei Z-H. Wheatstone bridge giant-magnetoresistance based cell counter. Biosens Bioelectron. 2014;57:48–53. https://doi.org/10.1016/j.bios.2014.01.028.

    Article  CAS  PubMed  Google Scholar 

  29. Vila A, Martins VC, Chícharo A, Rodriguez-Abreu C, Fernandes AC, Cardoso FA, et al. Customized design of magnetic beads for dynamic magnetoresistive cytometry. IEEE Trans Magn. 2014;50:1–4. https://doi.org/10.1109/TMAG.2014.2324411.

    Article  Google Scholar 

  30. Boser BE, Murali P. Flow cytometer-on-a-chip. In: 2014 IEEE Biomedical Circuits and Systems Conference (BioCAS) Proceedings. Lausanne; 2014. p. 480–483. https://doi.org/10.1109/BioCAS.2014.6981767.

  31. Issadore D, Chung J, Shao H, Liong M, Ghazani AA, Castro CM, et al. Ultrasensitive clinical enumeration of rare cells ex vivo using a μ-Hall detector. Sci Transl Med. 2012;4:141ra92. https://doi.org/10.1126/scitranslmed.3003747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Loureiro J, Andrade PZ, Cardoso S, da Silva CL, Cabral JM, Freitas PP. Magnetoresistive chip cytometer. Lab Chip. 2011;11:2255–61. https://doi.org/10.1039/c0lc00324g.

    Article  CAS  PubMed  Google Scholar 

  33. Duarte C, Costa T, Carneiro C, Soares R, Jitariu A, Cardoso S, et al. Semi-quantitative method for Streptococci magnetic detection in raw milk. Biosensors. 2016;6:19. https://doi.org/10.3390/bios6020019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fernandes AC, Duarte CM, Cardoso FA, Bexiga R, Cardoso S, Freitas PP. Lab-on-Chip cytometry based on magnetoresistive sensors for bacteria detection in milk. Sensors (Basel). 2014;14:15496–524. https://doi.org/10.3390/s140815496.

    Article  CAS  PubMed Central  Google Scholar 

  35. Issadore D, Chung HJ, Chung J, Budin G, Weissleder R, Lee H. muHall chip for sensitive detection of bacteria. Adv Healthc Mater. 2013;2:1224–8. https://doi.org/10.1002/adhm.201200380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McGuire T, Potter R. Anisotropic magnetoresistance in ferromagnetic 3d alloys. IEEE Trans Magn. 1975;11:1018–38. https://doi.org/10.1109/TMAG.1975.1058782.

    Article  Google Scholar 

  37. van de Veerdonk RJM, Beliën PJL, Schep KM, Kools JCS, de Nooijer MC, Gijs MAM, et al. 1/f noise in anisotropic and giant magnetoresistive elements. J Appl Phys. 1997;82:6152–64. https://doi.org/10.1063/1.366533.

    Article  Google Scholar 

  38. Nguyen Van Dau F, Schuhl A, Childress JR, Sussiau M. Magnetic sensors for nanotesla detection using planar Hall effect. Sensors Actuators A Phys. 1996;53:256–60. https://doi.org/10.1016/0924-4247(96)01152-1.

    Article  CAS  Google Scholar 

  39. Ejsing L, Hansen MF, Menon AK, Ferreira HA, Graham DL, Freitas PP. Planar Hall effect sensor for magnetic micro- and nanobead detection. Appl Phys Lett. 2004;84:4729–31. https://doi.org/10.1063/1.1759380.

    Article  CAS  Google Scholar 

  40. Damsgaard C, Cardoso S, Freitas P, Hansen M. Exchange-biased planar Hall effect sensor optimized for biosensor applications. J Appl Phys. 2008;103(7):07A302–07A302-3.

    Article  CAS  Google Scholar 

  41. Freitas P, Ferreira H, Graham D, Clarke L, Amaral M, Martins V, et al. Magnetoresistive biochips E. In: Johnson M, editor. Magnetoelectronics. Amsterdam: Elsevier.

  42. Baibich MN, Broto JM, Fert A, Van Dau FN, Petroff F, Etienne P, et al. Giant magnetoresistance of (001)Fe/(001)Cr magnetic superlattices. Phys Rev Lett. 1988;61:2472–5. https://doi.org/10.1103/PhysRevLett.61.2472.

    Article  CAS  PubMed  Google Scholar 

  43. Binasch G, Grünberg P, Saurenbach F, Zinn W. Enhanced magnetoresistance in layered magnetic structures with antiferromagnetic interlayer exchange. Phys Rev B. 1989;39:4828–30. https://doi.org/10.1103/PhysRevB.39.4828.

    Article  CAS  Google Scholar 

  44. Dieny B, Speriosu VS, Parkin SSP, Gurney BA, Wilhoit DR, Mauri D. Giant magnetoresistive in soft ferromagnetic multilayers. Phys Rev B. 1991;43:1297–300. https://doi.org/10.1103/PhysRevB.43.1297.

    Article  CAS  Google Scholar 

  45. Heim DE, Fontana RE, Tsang C, Speriosu VS, Gurney BA, Williams ML. Design and operation of spin valve sensors. IEEE Trans Magn. 1994;30:316–21. https://doi.org/10.1109/20.312279.

    Article  CAS  Google Scholar 

  46. Freitas PP, Ferreira R, Cardoso S, Cardoso F. Magnetoresistive sensors. J Phys Condens Matter. 2007;19:165221. https://doi.org/10.1088/0953-8984/19/16/165221.

    Article  CAS  Google Scholar 

  47. Hayakawa J, Ikeda S, Lee YM, Matsukura F, Ohno H. Effect of high annealing temperature on giant tunnel magnetoresistance ratio of CoFeB/MgO/CoFeB magnetic tunnel junctions. Appl Phys Lett. 2006;89:232510. https://doi.org/10.1063/1.2402904.

    Article  CAS  Google Scholar 

  48. Graham DL, Ferreira HA, Freitas PP. Magnetoresistive-based biosensors and biochips. Trends Biotechnol. 2004;22:455–62. https://doi.org/10.1016/j.tibtech.2004.06.006.

    Article  CAS  PubMed  Google Scholar 

  49. Krieg E, Weissman H, Shirman E, Shimoni E, Rybtchinski B. A recyclable supramolecular membrane for size-selective separation of nanoparticles. Nature Nanotechnol. 2011;6:141–6. https://doi.org/10.1038/nnano.2010.274.

    Article  CAS  Google Scholar 

  50. Robertson JD, Rizzello L, Avi M, Gaitzsch J. Purification of nanoparticles by size and shape. Sci Rep. 2016;6:27494. https://doi.org/10.1038/srep27494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Helou M, Reisbeck M, Tedde SF, Richter L, Bär L, Bosch JJ, et al. Time-of-flight magnetic flow cytometry in whole blood with integrated sample preparation. Lab Chip. 2013;13:1035–8. https://doi.org/10.1039/c3lc41310a.

    Article  CAS  PubMed  Google Scholar 

  52. Martins SSA, Martins VC, Cardoso FA, Freitas PP, Fonseca LP. Waterborne pathogen detection using a magnetoresistive immuno-chip BT. In: Tiquia-Arashiro SM, editor. Molecular biological technologies for ocean sensing. Totowa: Humana; 2012. p. 263–88.

    Chapter  Google Scholar 

  53. He J, Huang M, Wang D, Zhang Z, Li G. Magnetic separation techniques in sample preparation for biological analysis: a review. J Pharm Biomed Anal. 2014;101:84–101. https://doi.org/10.1016/j.jpba.2014.04.017.

    Article  CAS  PubMed  Google Scholar 

  54. Ripka P, Janosek M. Advances in magnetic field sensors. IEEE Sens J. 2010;10:1108–16. https://doi.org/10.1109/JSEN.2010.2043429.

    Article  Google Scholar 

  55. Hoffman RA, Wood JCS. Characterization of flow cytometer instrument sensitivity. Curr Protoc Cytom. 2007;40:1.20.1–1.20.18. https://doi.org/10.1002/0471142956.cy0120s40.

    Article  Google Scholar 

  56. Jiang Z, Llandro J, Mitrelias T, Bland JAC. An integrated microfluidic cell for detection, manipulation, and sorting of single micron-sized magnetic beads. J Appl Phys. 2006;99:08S105. https://doi.org/10.1063/1.2176238.

    Article  CAS  Google Scholar 

  57. Piyasena ME, Graves SW. The intersection of flow cytometry with microfluidics and microfabrication. Lab Chip. 2014;14:1044–59. https://doi.org/10.1039/C3LC51152A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Frankowski M, Theisen J, Kummrow A, Simon P, Ragusch H, Bock N, et al. Microflow cytometers with integrated hydrodynamic focusing. Sensors (Basel). 2013;13(4):4674–93.

    Article  Google Scholar 

  59. Wolff A, Perch-Nielsen IR, Larsen UD, Friis P, Goranovic G, Poulsen CR, et al. Integrating advanced functionality in a microfabricated high-throughput fluorescent-activated cell sorter. Lab Chip. 2003;3:22–7. https://doi.org/10.1039/b209333b.

    Article  CAS  PubMed  Google Scholar 

  60. Liu C, Stakenborg T, Peeters S, Lagae L. Cell manipulation with magnetic particles toward microfluidic cytometry. J Appl Phys. 2009;105:102014. https://doi.org/10.1063/1.3116091.

    Article  CAS  Google Scholar 

  61. Huang C, Zhou X, Ying D, Hall DA. A GMR-based magnetic flow cytometer using matched filtering. In: 2017 IEEE Sensors. Glasgow, 2017. p. 1–3. https://doi.org/10.1109/ICSENS.2017.8233892.

  62. Sun X, Feng Z, Zhi S, Lei C, Zhang D, Zhou Y. An integrated microfluidic system using a micro-fluxgate and micro spiral coil for magnetic microbeads trapping and detecting. Sci Rep. 2017;7:12967. https://doi.org/10.1038/s41598-017-13389-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cardoso FA, Costa T, Germano J, Cardoso S, Borme J, Gaspar J, et al. Integration of magnetoresistive biochips on a CMOS circuit. IEEE Trans Magn. 2012;48:3784–7. https://doi.org/10.1109/TMAG.2012.2198449.

    Article  CAS  Google Scholar 

  64. Costa T, Cardoso FA, Germano J, Freitas PP, Piedade MS. A CMOS front-end with integrated magnetoresistive sensors for biomolecular recognition detection applications. IEEE Trans Biomed Circuits Syst. 2017;11:988–1000. https://doi.org/10.1109/TBCAS.2017.2743685.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work has received funding from European Structural & Investment Funds through the COMPETE Program and from National Funds through FCT – Fundação para a Ciência e a Tecnologia under the grants SAICTPAC/0019/2015, MUSIC-PESSOA 2017-38027RF and MagScopy4IHC- LISBOA-01-0145-FEDER-031200. The authors acknowledge funding from the European Union through the project MAGNAMED- H2020-MSCA-RISE-2016 grant n. 734801. The authors R. Soares, D. M. Caetano and P. H. Fonseca, acknowledge their PhD grants, PD/BD/128205 /2016, PD/BD/128208/2016, PD/BD/135272/2017, respectively, funded through the Advanced Integrated Microsystems (AIM) doctoral program.

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Published in the topical collection Nanoparticles for Bioanalysis with guest editors María Carmen Blanco-López and Montserrat Rivas.

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Soares, R., Martins, V.C., Macedo, R. et al. Go with the flow: advances and trends in magnetic flow cytometry. Anal Bioanal Chem 411, 1839–1862 (2019). https://doi.org/10.1007/s00216-019-01593-9

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