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State-of-the-Art CMOS In Vitro Diagnostic Devices

  • Ka-Meng Lei
  • Pui-In Mak
  • Man-Kay Law
  • Rui Paulo Martins
Chapter

Abstract

CMOS technology enables low-cost and large-scale integration of transistors and physical sensing materials on tiny chips (e.g., <1 cm2), seamlessly combining the two key functions of biosensors: transducing and signal processing. Recent CMOS biosensors unified different transducing mechanisms (impedance, fluorescence, and nuclear spin), and readout electronics have demonstrated competitive sensitivity for in vitro diagnosis such as detection of DNA (down to 10 aM), protein (down to 10 fM), or bacteria/cell (single cell). Herein, we detail the recent advances of CMOS biosensors, centering on their key principles, requisites, and applications. They together may contribute to the advance of our healthcare system that should be decentralized by broadly utilizing point-of-care diagnostic tools.

Keywords

Biosensor Cell Chemical CMOS Deoxyribonucleic acid (DNA) In vitro diagnosis Lab-on-a-chip Point of care Protein 

References

  1. 1.
    J. Schmitz, Adding functionality to microchips by wafer post-processing. Nucl. Instrum. Methods Phys. Res., Sect. A 576(1), 142–149 (2007)MathSciNetCrossRefGoogle Scholar
  2. 2.
    C.G. Jakobson, U. Dinnar, M. Feinsod, Y. Nemirovsky, Ion-sensitive field-effect transistors in standard CMOS fabricated by post processing. IEEE Sensors J. 2(4), 279–287 (2002)CrossRefGoogle Scholar
  3. 3.
    A.H.D. Graham, S.M. Surguy, P. Langlois, C.R. Bowen, J. Taylor, J. Robbins, Modification of standard CMOS technology for cell-based biosensors. Biosens. Bioelectron. 31(1), 458–462 (2012)CrossRefGoogle Scholar
  4. 4.
    J.M. Rothberg, W. Hinz, T.M. Rearick, J. Schultz, W. Mileski, M. Davey, et al., An integrated semiconductor device enabling non-optical genome sequencing. Nature 475(7356), 348–352 (2011)CrossRefGoogle Scholar
  5. 5.
    A. Gao, N. Lu, Y. Wang, T. Li, Robust ultrasensitive tunneling-FET biosensor for point-of-care diagnostics. Sci Rep 6, 22554 (2016)CrossRefGoogle Scholar
  6. 6.
    J. Lee, J. Jang, B. Choi, J. Yoon, J.-Y. Kim, Y.-K. Choi, et al., A highly responsive silicon nanowire/amplifier MOSFET hybrid biosensor. Sci Rep 5, 12286 (2015)CrossRefGoogle Scholar
  7. 7.
    C. Stagni, C. Guiducci, L. Benini, B. Ricco, S. Carrara, B. Samori, et al., CMOS DNA sensor array with integrated A/D conversion based on label-free capacitance measurement. IEEE J. Solid State Circuits 41(12), 2956–2964 (2006)CrossRefGoogle Scholar
  8. 8.
    M. Barbaro, A. Bonfiglio, L. Raffo, A. Alessandrini, P. Facci, I. Barák, Fully electronic DNA hybridization detection by a standard CMOS biochip. Sens. Actuators B 118(1–2), 41–46 (2006)CrossRefGoogle Scholar
  9. 9.
    S.J. Han, H. Yu, B. Murmann, N. Pourmand, S.X. Wang, A high-density magnetoresistive biosensor array with drift-compensation mechanism, in IEEE International Solid-State Circuits Conference (ISSCC) Digest of Technical Papers, 2007, pp. 168–169Google Scholar
  10. 10.
    E. Anderson, J. Daniels, H. Yu, T. Lee, N. Pourmand, A label-free CMOS DNA microarray based on charge sensing, in Proceedings of International Instrumentation and Measurement Technology Conference, 2008, pp. 1631–1636Google Scholar
  11. 11.
    B. Jang, P. Cao, A. Chevalier, A. Ellington, A. Hassibi, A CMOS fluorescent-based biosensor microarray, in IEEE International Solid-State Circuits Conference (ISSCC) Digest of Technical Papers, 2009, pp. 436–437Google Scholar
  12. 12.
    T.C.D. Huang, S. Sorgenfrei, P. Gong, R. Levicky, K.L. Shepard, A 0.18-μm CMOS array sensor for integrated time-resolved fluorescence detection. IEEE J. Solid State Circuits 44(5), 1644–1654 (2009)CrossRefGoogle Scholar
  13. 13.
    W. Hua, C. Yan, A. Hassibi, A. Scherer, A. Hajimiri, A frequency-shift CMOS magnetic biosensor array with single-bead sensitivity and no external magnet, in IEEE International Solid-State Circuits Conference (ISSCC) Digest of Technical Papers, 2009, pp. 438–439Google Scholar
  14. 14.
    P.M. Levine, P. Gong, R. Levicky, K.L. Shepard, Real-time, multiplexed electrochemical DNA detection using an active complementary metal-oxide-semiconductor biosensor array with integrated sensor electronics. Biosens. Bioelectron. 24(7), 1995–2001 (2009)CrossRefGoogle Scholar
  15. 15.
    A. Manickam, A. Chevalier, M. McDermott, A.D. Ellington, A. Hassibi, A CMOS electrochemical impedance spectroscopy (EIS) biosensor array. IEEE Trans. Biomed. Circuits Syst. 4(6), 379–390 (2010)CrossRefGoogle Scholar
  16. 16.
    H. Jafari, L. Soleymani, R. Genov, 16-channel CMOS impedance spectroscopy DNA analyzer with dual-slope multiplying ADCs. IEEE Trans. Biomed. Circuits Syst. 6(5), 468–478 (2012)CrossRefGoogle Scholar
  17. 17.
    K.H. Lee, S. Choi, J.O. Lee, J.B. Yoon, G.H. Cho, CMOS capacitive biosensor with enhanced sensitivity for label-free DNA detection, in IEEE International Solid-State Circuits Conference (ISSCC) Digest of Technical Papers, 2012, pp. 120–122Google Scholar
  18. 18.
    M. Barbaro, A. Caboni, D. Loi, S. Lai, A. Homsy, P.D. van der Wal, et al., Label-free, direct DNA detection by means of a standard CMOS electronic chip. Sens. Actuators B 171–172, 148–154 (2012)CrossRefGoogle Scholar
  19. 19.
    Y.J. Huang, C.W. Huang, T.H. Lin, C.T. Lin, L.G. Chen, P.Y. Hsiao, et al., A CMOS cantilever-based label-free DNA SoC with improved sensitivity for hepatitis B virus detection. IEEE Trans. Biomed. Circuits Syst. 7(6), 820–831 (2013)CrossRefGoogle Scholar
  20. 20.
    C. Toumazou, L.M. Shepherd, S.C. Reed, G.I. Chen, A. Patel, D.M. Garner, et al., Simultaneous DNA amplification and detection using a pH-sensing semiconductor system. Nat. Methods 10(7), 641–646 (2013)CrossRefGoogle Scholar
  21. 21.
    C.-W. Huang, Y.-J. Huang, P.-W. Yen, H.-H. Tsai, H.-H. Liao, Y.-Z. Juang, et al., A CMOS wireless biomolecular sensing system-on-chip based on polysilicon nanowire technology. Lab Chip 13(22), 4451–4459 (2013)CrossRefGoogle Scholar
  22. 22.
    A. Pai, A. Khachaturian, S. Chapman, A. Hu, H. Wang, A. Hajimiri, A handheld magnetic sensing platform for antigen and nucleic acid detection. Analyst 139(6), 1403–1411 (2014)CrossRefGoogle Scholar
  23. 23.
    H.M. Jafari, K. Abdelhalim, L. Soleymani, E.H. Sargent, S.O. Kelley, R. Genov, Nanostructured CMOS wireless ultra-wideband label-free PCR-free DNA analysis SoC. IEEE J. Solid State Circuits 49(5), 1223–1241 (2014)CrossRefGoogle Scholar
  24. 24.
    H. Norian, R.M. Field, I. Kymissis, K.L. Shepard, An integrated CMOS quantitative-polymerase-chain-reaction lab-on-chip for point-of-care diagnostics. Lab Chip 14(20), 4076–4084 (2014)CrossRefGoogle Scholar
  25. 25.
    C.H. Chen, R.Z. Hwang, L.S. Huang, S.M. Lin, H.C. Chen, Y.C. Yang, et al., A wireless bio-MEMS sensor for C-reactive protein detection based on nanomechanics. IEEE Trans. Biomed. Eng. 56(2), 462–470 (2009)CrossRefGoogle Scholar
  26. 26.
    N. Sun, Y. Liu, H. Lee, R. Weissleder, D. Ham, CMOS RF biosensor utilizing nuclear magnetic resonance. IEEE J. Solid State Circuits 44(5), 1629–1643 (2009)CrossRefGoogle Scholar
  27. 27.
    O. Tigli, L. Bivona, P. Berg, M.E. Zaghloul, Fabrication and characterization of a surface-acoustic-wave biosensor in CMOS technology for cancer biomarker detection. IEEE Trans. Biomed. Circuits Syst. 4(1), 62–73 (2010)CrossRefGoogle Scholar
  28. 28.
    N. Sun, T.J. Yoon, H. Lee, W. Andress, R. Weissleder, D. Ham, Palm NMR and 1-chip NMR. IEEE J. Solid State Circuits 46(1), 342–352 (2011)CrossRefGoogle Scholar
  29. 29.
    S. Gambini, K. Skucha, P.P. Liu, J. Kim, R. Krigel, A 10 kPixel CMOS hall sensor array with baseline suppression and parallel readout for immunoassays. IEEE J. Solid State Circuits 48(1), 302–317 (2013)CrossRefGoogle Scholar
  30. 30.
    D.A. Hall, R.S. Gaster, K.A.A. Makinwa, S.X. Wang, B. Murmann, A 256 pixel magnetoresistive biosensor microarray in 0.18μm CMOS. IEEE J. Solid State Circuits 48(5), 1290–1301 (2013)CrossRefGoogle Scholar
  31. 31.
    L. Sandeau, C. Vuillaume, S. Contie, E. Grinenval, F. Belloni, H. Rigneault, et al., Large area CMOS bio-pixel array for compact high sensitive multiplex biosensing. Lab Chip 15(3), 877–881 (2015)CrossRefGoogle Scholar
  32. 32.
    C. Sapsanis, S. Sivashankar, H. Omran, U. Buttner, K.N. Salama, Capacitive immunosensor for C-reactive protein quantification, in Proceedings of the ICEE International Midwest Symposium on Circuits and Systems, 2015, pp. 1–4Google Scholar
  33. 33.
    L.Y. Hong, S. McManus, H. Yang, K. Sengupta, A fully integrated CMOS fluorescence biosensor with on-chip nanophotonic filter, in Proceedings of Symposium on VLSI Circuits, 2015, pp. C206–C207Google Scholar
  34. 34.
    P.H. Kuo, J.C. Kuo, H.T. Hsueh, J.Y. Hsieh, Y.C. Huang, T. Wang, et al., A smart CMOS assay SoC for rapid blood screening test of risk prediction. IEEE Trans. Biomed. Circuits Syst. 9(6), 790–800 (2015)Google Scholar
  35. 35.
    H. Klapproth, S. Bednar, J. Baader, M. Lehmann, I. Freund, T. Brandstetter, et al., Development of a multi-analyte CMOS sensor for point-of-care testing. Sens. Bio-Sens. Res. 5, 117–122 (2015)CrossRefGoogle Scholar
  36. 36.
    Y. Zheng, N. Shang, P.S. Haddad, M. Sawan, A microsystem for magnetic immunoassay based on planar microcoil array. IEEE Trans. Biomed. Circuits Syst. 10(2), 477–486 (2016)CrossRefGoogle Scholar
  37. 37.
    S.B. Prakash, P. Abshire, On-chip capacitance sensing for cell monitoring applications. IEEE Sensors J. 7(3–4), 440–447 (2007)CrossRefGoogle Scholar
  38. 38.
    S.B. Prakash, P. Abshire, Tracking cancer cell proliferation on a CMOS capacitance sensor chip. Biosens. Bioelectron. 23(10), 1449–1457 (2008)CrossRefGoogle Scholar
  39. 39.
    E.P. Dupont, E. Labonne, Y. Maruyama, C. Vandevyver, U. Lehmann, M.A.M. Gijs, et al., Fluorescent magnetic bead and cell differentiation/counting using a CMOS SPAD matrix. Sens. Actuators B 174, 609–615 (2012)CrossRefGoogle Scholar
  40. 40.
    Y. Chen, C.C. Wong, T.S. Pui, R. Nadipalli, R. Weerasekera, J. Chandran, et al., CMOS high density electrical impedance biosensor array for tumor cell detection. Sens. Actuators B 173, 903–907 (2012)CrossRefGoogle Scholar
  41. 41.
    K.H. Lee, J. Nam, S. Choi, H. Lim, S. Shin, G.H. Cho, A CMOS impedance cytometer for 3D flowing single-cell real-time analysis with ΔΣ error correction, in IEEE International Solid-State Circuits Conference (ISSCC) Digest of Technical Papers, 2012, pp. 304–306Google Scholar
  42. 42.
    H. Wang, A. Mahdavi, D.A. Tirrell, A. Hajimiri, A magnetic cell-based sensor. Lab Chip 12(21), 4465–4471 (2012)CrossRefGoogle Scholar
  43. 43.
    T. Saeki, M. Hosokawa, T. Lim, M. Harada, T. Matsunaga, T. Tanaka, Digital cell counting device integrated with a single-cell array. PLoS One 9(2), e89011 (2014)CrossRefGoogle Scholar
  44. 44.
    P. Murali, I. Izyumin, D. Cohen, J.C. Chien, A.M. Niknejad, B. Boser, A CMOS micro-flow cytometer for magnetic label detection and classification, in IEEE International Solid-State Circuits Conference (ISSCC) Digest of Technical Papers, 2014, pp. 422–423Google Scholar
  45. 45.
    M. Roy, G. Jin, D. Seo, M.-H. Nam, S. Seo, A simple and low-cost device performing blood cell counting based on lens-free shadow imaging technique. Sens. Actuators B 201, 321–328 (2014)CrossRefGoogle Scholar
  46. 46.
    K. Niitsu, S. Ota, K. Gamo, H. Kondo, M. Hori, K. Nakazato, Development of microelectrode arrays using electroless plating for CMOS-based direct counting of bacterial and HeLa cells. IEEE Trans. Biomed. Circuits Syst. 9(5), 607–619 (2015)CrossRefGoogle Scholar
  47. 47.
    C. Laborde, C. Pittino, H.A. Verhoeven, S.G. Lemay, L. Selmi, M.A. Jongsma, et al., Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays. Nat. Nanotechnol. 10(9), 791–795 (2015)CrossRefGoogle Scholar
  48. 48.
    T. Chi, J.S. Park, J.C. Butts, T.A. Hookway, A. Su, C. Zhu, et al., A multi-modality CMOS sensor array for cell-based assay and drug screening. IEEE Trans. Biomed. Circuits Syst. 9(6), 801–814 (2015)CrossRefGoogle Scholar
  49. 49.
    K.T. Chang, Y.J. Chang, C.L. Chen, Y.N. Wang, Multichannel lens-free CMOS sensors for real-time monitoring of cell growth. Electrophoresis 36(3), 413–419 (2015)CrossRefGoogle Scholar
  50. 50.
    J.C. Love, L.A. Estroff, J.K. Kriebel, R.G. Nuzzo, G.M. Whitesides, Self-assembled monolayers of thiolates on metals as a form of nanotechnology. Chem. Rev. 105(4), 1103–1169 (2005)CrossRefGoogle Scholar
  51. 51.
    A. Manickam, C.A. Johnson, S. Kavusi, A. Hassibi, Interface design for CMOS-integrated electrochemical impedance spectroscopy (EIS) biosensors. Sensors 12(11), 14467 (2012)CrossRefGoogle Scholar
  52. 52.
    C. Berggren, P. Stalhandske, J. Brundell, G. Johansson, A feasibility study of a capacitive biosensor for direct detection of DNA hybridization. Electroanalysis 11(3), 156–160 (1999)CrossRefGoogle Scholar
  53. 53.
    J. Enderlein, T. Ruckstuhl, S. Seeger, Highly efficient optical detection of surface-generated fluorescence. Appl. Opt. 38(4), 724–732 (1999)CrossRefGoogle Scholar
  54. 54.
    M. Alvarez, L.M. Lechuga, Microcantilever-based platforms as biosensing tools. Analyst 135(5), 827–836 (2010)CrossRefGoogle Scholar
  55. 55.
    H. Wohltjen, R. Dessy, Surface acoustic wave probe for chemical analysis. I. Introduction and instrument description. Anal. Chem. 51(9), 1458–1464 (1979)CrossRefGoogle Scholar
  56. 56.
    C. Min, H.L. Shao, M. Liong, T.J. Yoon, R. Weissleder, H. Lee, Mechanism of magnetic relaxation switching sensing. ACS Nano 6(8), 6821–6828 (2012)CrossRefGoogle Scholar
  57. 57.
    L. Josephson, J.M. Perez, R. Weissleder, Magnetic nanosensors for the detection of oligonucleotide sequences. Angew. Chem. 113(17), 3304–3306 (2001)CrossRefGoogle Scholar
  58. 58.
    J.M. Perez, L. Josephson, T. O’Loughlin, D. Hogemann, R. Weissleder, Magnetic relaxation switches capable of sensing molecular interactions. Nat. Biotechnol. 20(8), 816–820 (2002)CrossRefGoogle Scholar
  59. 59.
    H. Lee, E. Sun, D. Ham, R. Weissleder, Chip-NMR biosensor for detection and molecular analysis of cells. Nat. Med. 14(8), 869–874 (2008)CrossRefGoogle Scholar
  60. 60.
    I. Koh, R. Hong, R. Weissleder, L. Josephson, Sensitive NMR sensors detect antibodies to influenza. Angew. Chem. 47(22), 4119–4121 (2008)CrossRefGoogle Scholar
  61. 61.
    D. Issadore, C. Min, M. Liong, J. Chung, R. Weissleder, H. Lee, Miniature magnetic resonance system for point-of-care diagnostics. Lab Chip 11(13), 2282–2287 (2011)CrossRefGoogle Scholar
  62. 62.
    M. Liong, A.N. Hoang, J. Chung, N. Gural, C.B. Ford, C. Min, et al., Magnetic barcode assay for genetic detection of pathogens. Nat. Commun. 4(1752), 1–9 (2013)Google Scholar
  63. 63.
    C.M. Castro, A.A. Ghazani, J. Chung, H.L. Shao, D. Issadore, T.J. Yoon, et al., Miniaturized nuclear magnetic resonance platform for detection and profiling of circulating tumor cells. Lab Chip 14(1), 14–23 (2014)CrossRefGoogle Scholar
  64. 64.
    E. Engvall, P. Perlmann, Enzyme-linked immunosorbent assay (ELISA) quantitative assay of immunoglobulin G. Immunochemistry 8(9), 871–874 (1971)CrossRefGoogle Scholar
  65. 65.
    R.W. Peeling, H. Artsob, J.L. Pelegrino, P. Buchy, M.J. Cardosa, S. Devi, et al., Evaluation of diagnostic tests: dengue. Nat. Rev. Microbiol. 8, S30–S37 (2010)CrossRefGoogle Scholar
  66. 66.
    N. Scholler, M. Crawford, A. Sato, C.W. Drescher, K.C. O’Briant, N. Kiviat, et al., Bead-based ELISA for validation of ovarian cancer early detection markers. Clin. Cancer Res. 12(7), 2117–2124 (2006)CrossRefGoogle Scholar
  67. 67.
    S. Velumani, H.-T. Ho, F. He, S. Musthaq, M. Prabakaran, J. Kwang, A novel peptide ELISA for universal detection of antibodies to human H5N1 influenza viruses. PLoS One 6(6), e20737 (2011)CrossRefGoogle Scholar
  68. 68.
    C. Kandoth, M.D. McLellan, F. Vandin, K. Ye, B. Niu, C. Lu, et al., Mutational landscape and significance across 12 major cancer types. Nature 502(7471), 333–339 (2013)CrossRefGoogle Scholar
  69. 69.
    E.A. Ottesen, J.W. Hong, S.R. Quake, J.R. Leadbetter, Microfluidic digital PCR enables multigene analysis of individual environmental bacteria. Science 314(5804), 1464–1467 (2006)CrossRefGoogle Scholar
  70. 70.
    M. Schena, D. Shalon, R.W. Davis, P.O. Brown, Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270(5235), 467–470 (1995)CrossRefGoogle Scholar
  71. 71.
    H. Shafiee, S. Wang, F. Inci, M. Toy, T.J. Henrich, D.R. Kuritzkes, et al., Emerging technologies for point-of-care management of HIV infection. Annu. Rev. Med. 66(1), 387–405 (2015)CrossRefGoogle Scholar
  72. 72.
    J.L. Arlett, E.B. Myers, M.L. Roukes, Comparative advantages of mechanical biosensors. Nat. Nanotechnol. 6(4), 203–215 (2011)CrossRefGoogle Scholar
  73. 73.
    T. Bryan, X. Luo, P.R. Bueno, J.J. Davis, An optimised electrochemical biosensor for the label-free detection of C-reactive protein in blood. Biosens. Bioelectron. 39(1), 94–98 (2013)CrossRefGoogle Scholar
  74. 74.
    J.T. Kirk, N.D. Brault, T. Baehr-Jones, M. Hochberg, S. Jiang, D.M. Ratner, Zwitterionic polymer-modified silicon microring resonators for label-free biosensing in undiluted humanplasma. Biosens. Bioelectron. 42, 100–105 (2013)CrossRefGoogle Scholar
  75. 75.
    K.R. Thulborn, J.C. Waterton, P.M. Matthews, G.K. Radda, Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim. Biophys. Acta 714(2), 265–270 (1982)CrossRefGoogle Scholar
  76. 76.
    E. Ghafar-Zadeh, M. Sawan, A hybrid microfluidic/CMOS capacitive sensor dedicated to lab-on-chip applications. IEEE Trans. Biomed. Circuits Syst. 1, 270–277 (2007)CrossRefGoogle Scholar
  77. 77.
    W.K. Peng, T.F. Kong, C.S. Ng, L. Chen, Y. Huang, A.A.S. Bhagat, et al., Micromagnetic resonance relaxometry for rapid label-free malaria diagnosis. Nat. Med. 20(9), 1069–1073 (2014)CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Ka-Meng Lei
    • 1
  • Pui-In Mak
    • 2
  • Man-Kay Law
    • 1
  • Rui Paulo Martins
    • 2
    • 3
  1. 1.State-Key Laboratory of Analog and Mixed-Signal VLSIUniversity of MacauMacauChina
  2. 2.State-Key Laboratory of Analog and Mixed-Signal VLSI and FST-ECEUniversity of MacauMacauChina
  3. 3.Instituto Superior Técnico Universidade de LisboaLisbonPortugal

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