Electronic-Automated Micro-NMR Assay with DMF Device

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


We describe a micro-NMR relaxometer miniaturized into palm size and electronic-automated for multistep multi-sample chemical/biological diagnosis. The co-integration of microfluidic and microelectronic technologies enables association between droplet managements and micro-NMR assays inside a portable sub-Tesla magnet (1.2 kg, 0.46 Tesla). Targets captured by specific probe-decorated magnetic nanoparticles can be sequentially quantified by their spin-spin relaxation time via multiplexed micro-NMR screening. Distinct droplet samples are operated by a digital microfluidic device that electronically manages the electrowetting-on-dielectric effects over an electrode array. Each electrode (3.5 × 3.5 mm2) is scanned with capacitive sensing to locate distinct droplet samples in real time. A cross-domain-optimized Butterfly-coil-input semiconductor transceiver transduces between magnetic and electrical signals to/from a sub-10 μL droplet sample for high-sensitivity micro-NMR screening. We have implemented two prototypes. The first prototype was implemented with discrete electronics for verification of functionality, while the second prototype was designed with a CMOS TRX for better performance. Fabricated in 0.18-μm CMOS, the TRX occupies a die area of 2.1 mm2, consumes 6.6/23.7 mW of power in the TX/RX mode, and demonstrates the feasibility of electronic-automated biological (avidin) and chemical (CuSO4) assays achieving a detection limit on avidin of 0.2 pmol.


CMOS Digital microfluidic (DMF) Electronic automation Magnetic sensing Nuclear magnetic resonance (NMR) Radio frequency (RF) Receiver (RX) Transceiver (TRX) Transmitter (TX) 


  1. 1.
    J.D. Trumbull, I.K. Glasgow, D.J. Beebe, R.L. Magin, Integrating microfabricated fluidic systems and NMR spectroscopy. IEEE Trans. Biomed. Eng. 47(1), 3–7 (2000)CrossRefGoogle Scholar
  2. 2.
    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
  3. 3.
    C. Massin, F. Vincent, A. Homsy, K. Ehrmann, G. Boero, P.A. Besse, et al., Planar microcoil-based microfluidic NMR probes. J. Magn. Reson. 164(2), 242–255 (2003)CrossRefGoogle Scholar
  4. 4.
    I. Barbulovic-Nad, H. Yang, P.S. Park, A.R. Wheeler, Digital microfluidics for cell-based assays. Lab Chip 8(4), 519–526 (2008)CrossRefGoogle Scholar
  5. 5.
    J. Gao, X.M. Liu, T.L. Chen, P.I. Mak, Y.G. Du, M.I. Vai, et al., An intelligent digital microfluidic system with fuzzy-enhanced feedback for multi-droplet manipulation. Lab Chip 13(3), 443–451 (2013)CrossRefGoogle Scholar
  6. 6.
    F. Lapierre, M. Harnois, Y. Coffinier, R. Boukherroub, V. Thomy, Split and flow: reconfigurable capillary connection for digital microfluidic devices. Lab Chip 14(18), 3589–3593 (2014)CrossRefGoogle Scholar
  7. 7.
    M.G. Pollack, A.D. Shenderov, R.B. Fair, Electrowetting-based actuation of droplets for integrated microfluidics. Lab Chip 2(2), 96–101 (2002)CrossRefGoogle Scholar
  8. 8.
    M.H. Shamsi, K. Choi, A.H.C. Ng, A.R. Wheeler, A digital microfluidic electrochemical immunoassay. Lab Chip 14(3), 547–554 (2014)CrossRefGoogle Scholar
  9. 9.
    V. Srinivasan, V.K. Pamula, R.B. Fair, An integrated digital microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids. Lab Chip 4(4), 310–315 (2004)CrossRefGoogle Scholar
  10. 10.
    A.R. Wheeler, Chemistry—putting electrowetting to work. Science 322(5901), 539–540 (2008)CrossRefGoogle Scholar
  11. 11.
    I. Barbulovic-Nad, S.H. Au, A.R. Wheeler, A microfluidic platform for complete mammalian cell culture. Lab Chip 10(12), 1536–1542 (2010)CrossRefGoogle Scholar
  12. 12.
    G.J. Shah, A.T. Ohta, E.P.Y. Chiou, M.C. Wu, C.-J. Kim, EWOD-driven droplet microfluidic device integrated with optoelectronic tweezers as an automated platform for cellular isolation and analysis. Lab Chip 9(12), 1732–1739 (2009)CrossRefGoogle Scholar
  13. 13.
    R. Sista, Z. Hua, P. Thwar, A. Sudarsan, V. Srinivasan, A. Eckhardt, et al., Development of a digital microfluidic platform for point of care testing. Lab Chip 8(12), 2091–2104 (2008)CrossRefGoogle Scholar
  14. 14.
    Y.-H. Chang, G.-B. Lee, F.-C. Huang, Y.-Y. Chen, J.-L. Lin, Integrated polymerase chain reaction chips utilizing digital microfluidics. Biomed. Microdevices 8(3), 215–225 (2006)CrossRefGoogle Scholar
  15. 15.
    Z. Hua, J.L. Rouse, A.E. Eckhardt, V. Srinivasan, V.K. Pamula, W.A. Schell, et al., Multiplexed real-time polymerase chain reaction on a digital microfluidic platform. Anal. Chem. 82(6), 2310–2316 (2010)CrossRefGoogle Scholar
  16. 16.
    D. Witters, K. Knez, F. Ceyssens, R. Puers, J. Lammertyn, Digital microfluidics-enabled single-molecule detection by printing and sealing single magnetic beads in femtoliter droplets. Lab Chip 13(11), 2047–2054 (2013)CrossRefGoogle Scholar
  17. 17.
    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
  18. 18.
    J. Kim, B. Hammer, R. Harjani, A 5–300MHz CMOS transceiver for multi-nuclear NMR spectroscopy, in Proceeding IEEE Custom Integrated Circuits Conference (CICC), 2012, pp. 1–4Google Scholar
  19. 19.
    J. Anders, P. SanGiorgio, G. Boero, A fully integrated IQ-receiver for NMR microscopy. J. Magn. Reson. 209(1), 1–7 (2011)CrossRefGoogle Scholar
  20. 20.
    D.I. Hoult, R.E. Richards, The signal-to-noise ratio of the nuclear magnetic resonance experiment. J. Magn. Reson. 24(1), 71–85 (1976)Google Scholar
  21. 21.
    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
  22. 22.
    P. Andreani, K. Kozmin, P. Sandrup, M. Nilsson, T. Mattsson, A TX VCO for WCDMA/EDGE in 90 nm RF CMOS. IEEE J. Solid State Circuits 46(7), 1618–1626 (2011)CrossRefGoogle Scholar
  23. 23.
    T. Mattsson, Method of and inductor layout for reduced VCO coupling, US Patent US 7,151,430, 19 Dec 2006Google Scholar
  24. 24.
    M. Nagata, H. Masuoka, S.I. Fukase, M. Kikuta, M. Morita, N. Itoh, 5.8 GHz RF transceiver LSI including on-chip matching circuits, in 2006 Bipolar/BiCMOS Circuits and Tech. Meeting, 2006, pp. 263–266Google Scholar
  25. 25.
    F. Mugele, J.C. Baret, Electrowetting: from basics to applications. J. Phys. Condens. Matter 17(28), R705–R774 (2005)CrossRefGoogle Scholar
  26. 26.
    F. Fiorillo, C. Beatrice, Energy losses in soft magnets from DC to radiofrequencies: theory and experiment. J. Supercond. Nov. Magn. 24(1–2), 559–566 (2011)CrossRefGoogle Scholar
  27. 27.
    W.K. Peng, L. Chen, J. Han, Development of miniaturized, portable magnetic resonance relaxometry system for point-of-care medical diagnosis. Rev. Sci. Instrum. 83(9), 095115 (2012)CrossRefGoogle Scholar
  28. 28.
    J.M. Pope, N. Repin, A simple approach to T2 imaging in MRI. Magn. Reson. Imaging 6(6), 641–646 (1988)CrossRefGoogle Scholar
  29. 29.
    B. Blumich, J. Perlo, F. Casanova, Mobile single-sided NMR. Prog. Nucl. Magn. Reson. Spectrosc. 52(4), 197–269 (2008)CrossRefGoogle Scholar
  30. 30.
    T.T. Zhang, P.I. Mak, M.I. Vai, P.U. Mak, M.K. Law, S.H. Pun, et al., 15-nW biopotential LPFs in 0.35-μm CMOS using subthreshold-source-follower biquads with and without gain compensation. IEEE Trans. Biomed. Circuits Syst. 7(5), 690–702 (2013)CrossRefGoogle Scholar
  31. 31.
    S. D’Amico, M. Conta, A. Baschirotto, A 4.1-mW 10-MHz fourth-order source-follower-based continuous-time filter with 79-dB DR. IEEE J. Solid State Circuits 41(12), 2713–2719 (2006)CrossRefGoogle Scholar
  32. 32.
    J. Watzlaw, S. Gloggler, B. Blumich, W. Mokwa, U. Schnakenberg, Stacked planar micro coils for single-sided NMR applications. J. Magn. Reson. 230(1), 176–185 (2013)CrossRefGoogle Scholar
  33. 33.
    J. Gong, C.J. Kim, All-electronic droplet generation on-chip with real-time feedback control for EWOD digital microfluidics. Lab Chip 8(6), 898–906 (2008)CrossRefGoogle Scholar
  34. 34.
    V. Gubala, L.F. Harris, A.J. Ricco, M.X. Tan, D.E. Williams, Point of care diagnostics: status and future. Anal. Chem. 84(2), 487–515 (2012)CrossRefGoogle Scholar
  35. 35.
    P.Y. Keng, S.P. Chen, H.J. Ding, S. Sadeghi, G.J. Shah, A. Dooraghi, et al., Micro-chemical synthesis of molecular probes on an electronic microfluidic device. Proc. Nat. Acad. Sci. (PNAS) 109(3), 690–695 (2012)CrossRefGoogle Scholar
  36. 36.
    K.-M. Lei, P.-I. Mak, M.-K. Law, R.P. Martins, NMR–DMF: a modular nuclear magnetic resonance–digital microfluidics system for biological assays. Analyst 139(23), 6204–6213 (2014)CrossRefGoogle Scholar
  37. 37.
    K.-M. Lei, P.-I. Mak, M.-K. Law, R.P. Martins, A thermal-insensitive all-electronic modular μNMR relaxometer with a 2D digital microfluidic chip for sample management, in Proceeding 19th International Conference on Miniaturized System Chemistry and Life Sciences (MicroTAS), 2015, pp. 302–304Google Scholar
  38. 38.
    K.-M. Lei, P.-I. Mak, M.-K. Law, R.P. Martins, A μNMR CMOS transceiver using a Butterfly-coil input for integration with a digital microfluidic device inside a portable magnet, in Proceeding IEEE Asian Solid-State Circuits Conference (A-SSCC), 2015, pp. 1–4Google Scholar
  39. 39.
    K.-M. Lei, P.-I. Mak, M.-K. Law, R.P. Martins, A palm-size μNMR relaxometer using a digital microfluidic device and a semiconductor transceiver for chemical/biological diagnosis. Analyst 140(15), 5129–5137 (2015)CrossRefGoogle Scholar
  40. 40.
    K.-M. Lei, P.-I. Mak, M.-K. Law, R.P. Martins, A μNMR CMOS transceiver using a Butterfly-coil input for integration with a digital microfluidic device inside a portable magnet. IEEE J. Solid State Circuits 51(10), 2274–2286 (2016)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

Personalised recommendations