Article

Selective layer-free blood serum ionogram based on ion-specific interactions with a nanotransistor

Received:
Accepted:
Published online:

Abstract

Despite being ubiquitous in the fields of chemistry and biology, the ion-specific effects of electrolytes pose major challenges for researchers. A lack of understanding about ion-specific surface interactions has hampered the development and application of materials for (bio-)chemical sensor applications. Here, we show that scaling a silicon nanotransistor sensor down to ~25 nm provides a unique opportunity to understand and exploit ion-specific surface interactions, yielding a surface that is highly sensitive to cations and inert to pH. The unprecedented sensitivity of these devices to Na+ and divalent ions can be attributed to an overscreening effect via molecular dynamics. The surface potential of multi-ion solutions is well described by the sum of the electrochemical potentials of each cation, enabling selective measurements of a target ion concentration without requiring a selective organic layer. We use these features to construct a blood serum ionogram for Na+, K+, Ca2+ and Mg2+, in an important step towards the development of a versatile, durable and mobile chemical or blood diagnostic tool.

  • Subscribe to Nature Materials for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Huebsch, N. & Mooney, D. Inspiration and application in the evolution of biomaterials. Nature 462, 426–432 (2009).

  2. 2.

    Nel, A. E. et al. Underlying biophysicochemical interactions at the nano–bio interface. Nat. Mater. 8, 543–548 (2009).

  3. 3.

    Someya, T., Bao, Z. & Malliaras, G. G. The rise of plastic bioelectronics. Nature 540, 379–385 (2016).

  4. 4.

    Rembert, K. B. et al. Molecular mechanisms of ion-specific effects on proteins. J. Am. Chem. Soc. 134, 10039–10046 (2012).

  5. 5.

    Salis, A. & Ninham, B. W. Models and mechanisms of Hofmeister effects in electrolyte solutions, and colloid and protein systems revisited. Chem. Soc. Rev. 43, 7358–7377 (2014).

  6. 6.

    Hartkamp, R., Siboulet, B., Dufreche, J.-F. & Coasne, B. Ion-specific adsorption and electrosmosis in charged amorphous porous silica. Phys. Chem. Chem. Phys. 17, 24683–24695 (2015).

  7. 7.

    Tarasov, A. et al. Understanding the electrolyte background for biochemical sensing with ion-sensitive field-effect transistors. ACS Nano 6, 9291–9298 (2012).

  8. 8.

    Li, S. X., Guan, W., Weiner, B. & Reed, M. A. Direct observation of charge inversion in divalent nanofluidics devices. Nano Lett. 15, 5046–5051 (2015).

  9. 9.

    Kenzaki, H. et al. Cafemol: a coarse-grained biomolecular simulator for simulating proteins at work. J. Chem. Theor. Comput. 7, 1979–1989 (2011).

  10. 10.

    Snodin, B. E. K. et al. Introducing improved structural properties and salt dependence into a coarse-grained model of DNA. J. Chem. Phys. 142, 234901 (2015).

  11. 11.

    Shoorideh, K. & Chui, C.-O. On the origin of enhanced sensitivity in nanoscale FET-based biosensors. Proc. Natl. Acad. Sci. USA 111, 5111–5116 (2014).

  12. 12.

    Yates, D. E., Levine, S. & Healy, T. W. Site-binding model of the electrical double layer at the oxide/water interface. Faraday Trans. 70, 1807–1818 (1974).

  13. 13.

    Van Hal, R. E. G., Eijkel, J. C. T. & Bergveld, P. A. General model to describe the electrostatic potential at electrolyte oxide interfaces. Adv. Colloid Interface Sci. 69, 31–62 (1996).

  14. 14.

    Morag, J., Dishon, M. & Sivan, U. The governing role of surface hydration in ion specific adsorption to silica: an AFM-based account of the Hofmeister universality and its reversal. Langmuir 29, 6317–6322 (2012).

  15. 15.

    Hocine, S. et al. How ion condensation occurs at a charged surface: a molecular dynamics investigation of the Stern layer for water–silica interfaces. J. Phys. Chem. C. 120, 963–973 (2016).

  16. 16.

    Nostro, P. L. & Ninham, B. W. Hofmeister phenomena: an update on ion-specificity in biology. Chem. Rev. 112, 2286–2322 (2012).

  17. 17.

    Shchukarev, A., Rosenqvist, J. & Sjöberg, S. XPS study of the silica–water interface. J. Electron. Spectr. Rel. Phenom. 137, 171–176 (2004).

  18. 18.

    Criscenti, L.J., Cygan, R. T., Kooser, A.S. & Moffat, H.K. Water and halide adsorption to corrosion surfaces: molecular simulations of atmospheric interactions with aluminum oxyhydroxide and gold. Chem. Mater. 20, 4682–4693 (2008).

  19. 19.

    Larson, I. & Attard, P. Surface charge of silver iodide and several metal oxides. Are all surfaces Nernstian? J. Colloid Interface Sci. 227, 152–163 (2000).

  20. 20.

    Knopfmacher, O. et al. Nernst limit in dual-gated Si-nanowire FET sensors. Nano Lett. 10, 2268–2274 (2010).

  21. 21.

    Shklovskii, B. I. Screening of a macroion by multivalent ions: correlation-induced inversion of charge. Phys. Rev. E 60, 5802–5811 (1999).

  22. 22.

    Grosberg, A. Yu., Nguyen, T. T. & Shklovskii, B. I. Colloquium: the physics of charge inversion in chemical and biological systems. Rev. Mod. Phys. 74, 329–345 (2002).

  23. 23.

    Martin-Molina, A., Rodriguez-Beas, C. & Faraudo, J. Charge reversal in anionic liposomes: experimental demonstration and molecular origin. Phys. Rev. Lett. 104, 168103 (2010).

  24. 24.

    Pinna, M.C., Salis, A., Monduzzi, M. & Ninham, B.W. Hofmeister series: the hydrolytic activity of aspergillus niger lipase depends on specific anion effects. J. Phys. Chem. B 109, 5406–5408 (2005).

  25. 25.

    Jung, W., Han, J. & Ahn, C. H. Point-of-care testing (POCT) diagnostic systems using microfluidic lab-on-chip technologies. Microelectron. Eng. 132, 46–57 (2015).

  26. 26.

    Bühlmann, P., Pretsch, E. & Bakker, E. Carrier-based ion-selective electrodes and bulk optodes. 2. Ionophores for potentiometric and optical sensors. Chem. Rev. 98, 1593–1688 (1998).

  27. 27.

    Cao, A. et al. Ionophore-containing siloprene membrane: direct comparison between conventional ion-selective electrodes and silicon nanowire-based field-effect transistors. Anal. Chem. 87, 1173–1179 (2015).

  28. 28.

    Wipf, M. et al. Selective sodium sensing with gold-coated silicon nanowire field-effect transistors in a differential setup. ACS Nano 7, 5978–5983 (2013).

  29. 29.

    Accasteli, E. et al. Multi-wire tri-gate silicon nanowires reaching milli-pH unit resolution in one micron square footprint. Biosensors 6, 9–15 (2016).

  30. 30.

    Stoop, R. L. et al. Competing surface reactions limiting the performance of ion-sensitive field-effect transistors. Sens. Actuat. B 220, 500–507 (2015).

  31. 31.

    Bergveld, P. Development of an ion-sensitive solid-state device for neurophysiological measurements. IEEE Trans. Biomed. Eng. 17, 70–71 (1970).

  32. 32.

    Cui, Y., Wei, Q., Park, H. & Lieber, C. M. Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species. Science 293, 1289–1292 (2001).

  33. 33.

    Stern, E. et al. Label-free immunodetection with CMOS-compatible semiconducting nanowires. Nature 445, 519–522 (2007).

  34. 34.

    Rothberg, J. M. et al. An integrated semiconductor device enabling non-optival genome sequencing. Nature 475, 348–352 (2011).

  35. 35.

    Tian, B. et al. Three-dimensional, flexible nanoscale field-effect transistors as localized bioprobes. Science 329, 830–834 (2010).

  36. 36.

    Li, J. et al. Sensitivity enhancement of Si nanowire field-effect transistor biosensors using single trap phenomena. Nano Lett. 14, 3504–3509 (2014).

  37. 37.

    Clement, N. et al. A silicon nanowire ion-sensitive field-effect transistor with elementary charge sensitivity. Appl. Phys. Lett. 98, 014104 (2011).

  38. 38.

    Takahashi, Y. et al. Fabrication technique for Si single-electron transistor operating at room temperature. Electron. Lett. 31, 136–137 (1995).

  39. 39.

    Uematsu, M. et al. Two-dimensional simulation of pattern-dependent oxidation of silicon nanostructures on silicon-on-insulator substrates. Solid-State Electron. 48, 1073–1078 (2004).

  40. 40.

    Han, X.-L. et al. Modelling and engineering of stress-based controlled oxidation effects for silicon nanostructure patterning. Nanotechnology 24, 495301 (2013).

  41. 41.

    Morag, J., Dishon, M. & Sivan, U. The governing role of surface hydration in ion specific adsorption to silica: an AFM-based account of the Hofmeister universality and its reversal. Langmuir 29, 6317–6322 (2012).

  42. 42.

    Ricci, M., Spijker, P. & Voitchovsky, K. Water-induced correlation between single ions imaged at the solid–liquid interface. Nat. Commun. 5, 4400 (2014).

  43. 43.

    Trasobares, J. et al Estimation of π–π electronic couplings from current measurements. Nano Lett. 17, 3215–3224 (2017).

  44. 44.

    Rigante, S. et al. Sensing with advanced computing technology: fin field-effect transistors with high-k gate stack on bulk silicon. ACS Nano 9, 4872–4991 (2015).

  45. 45.

    Schutt, J. et al. Compact nanowire sensors probe microdroplets. Nano Lett. 16, 4991–5000 (2016).

  46. 46.

    Wang, C. et al. A label-free and portable graphene FET aptasensor for children blood lead detection. Sci. Rep. 6, 21711 (2016).

  47. 47.

    Knopmacher, O. et al. Silicon-based ion-sensitive field-effect transistor shows negligible dependence on salt concentration at constant pH. Chem. Phys. Chem. 13, 1157–1160 (2012).

  48. 48.

    Parizi, K. B., Xu, X., Pal, A., Hu, X. & Wong, H. S. P. ISFET pH sensitivity: counter-ions play a key role. Sci. Rep. 7, 41305 (2017).

  49. 49.

    Aleveque, O. et al. Electroactive self-assembled monolayers: Laviron’s interaction model extended to non-random distribution of redox centers. Electrochem. Commun. 12, 1462–1466 (2010).

  50. 50.

    Yamahata, G., Giblin, S. P., Kataoka, M., Karasawa, T. & Fujiwara, A. Gigahertz single-electron pumping in silicon with an accuracy better than 9.2 parts in 107. Appl. Phys. Lett. 109, 013101 (2016).

  51. 51.

    Chida, K., Desai, S., Nishiguchi, K. & Fujiwara, A. Power generation by Maxwell’s demon. Nat. Commun. 8, 15310 (2017).

  52. 52.

    Clement, N., Nishiguchi, K., Fujiwara, A. & Vuillaume, D. One-by-one trap activation in silicon nanowire transistors. Nat. Commun. 1, 92 (2010).

  53. 53.

    Tarasov, A. et al. Understanding the electrolyte background for biochemical sensing with ion-sensitive field-effect transistors. ACS Nano 6, 9291–9298 (2012).

  54. 54.

    Sivakumarasamy, R. et al A simple and inexpensive technique for PDMS/silicon chip alignment with sub-μm alignment. Anal. Methods 6, 97–101 (2014).

  55. 55.

    Hartkamp, R., Siboulet, B., Dufreche, J.-F. & Coasne, B. Ion-specific adsorption and electrosmosis in charged amorphous porous silica. Phys. Chem. Chem. Phys. 17, 24683–24695 (2015).

Download references

Acknowledgements

The authors thank M. Clément at ‘Clinique Vétérinaire du Clair Matin’ for performing the ionogram for [Mg2+], S. Frickey for discussions on the use of ionograms in the medical environment, Y. Coffinier for providing FBS and for discussions, and P. Joseph for advice on microfluidic chips. The authors also thank B. Coasne for assistance regarding MD and for discussions, and A. Shuchukarev, F. Alibart, A. Charrier, P. Temple-Boyer, A.M. Gué, C. Bergaud, L. Nicu, A. Bancaud, G. Larrieu, D. Vuillaume, D. Guérin, S. Lenfant and I. Mahboob for their feedback on the manuscript. This study was funded by Singlemol and BQR projects from the Nord-Pas de Calais Council, Lille University and NTT.

Author information

Author notes

  1. These authors contributed equally: R. Sivakumarasamy, R. Hartkamp.

Affiliations

  1. Institute of Electronics, Microelectronics, and Nanotechnology, CNRS, University of Lille, Villeneuve d’Ascq, France

    • R. Sivakumarasamy
    •  & N. Clément
  2. Process and Energy Department, Delft University of Technology, Delft, the Netherlands

    • R. Hartkamp
  3. Institut de Chimie Separative de Marcoule ICSM, ICSM, CEA, CNRS, ENSCM, Montpellier University, Marcoule, Bagnols-sur-Ceze, France

    • B. Siboulet
    •  & J.-F. Dufrêche
  4. NTT Basic Research Laboratories, NTT Corporation, Atsugi-shi, Japan

    • K. Nishiguchi
    • , A. Fujiwara
    •  & N. Clément

Authors

  1. Search for R. Sivakumarasamy in:

  2. Search for R. Hartkamp in:

  3. Search for B. Siboulet in:

  4. Search for J.-F. Dufrêche in:

  5. Search for K. Nishiguchi in:

  6. Search for A. Fujiwara in:

  7. Search for N. Clément in:

Contributions

R.S. fabricated the lab-on-a-chip, prepared solutions, performed electrical measurements and analysed the data. R.H., B.S. and J.-F.D. performed MD simulations. R.H. addressed overscreening and mixed electrolyte issues by MD and provided careful feedback on the manuscript. J.-F.D. derived equations (6) and (7) and wrote the related program. K.N. fabricated the silicon nanotransistors. A.F. continuously gave input on the study process and the manuscript. All authors discussed the results. N.C supervised the study, analysed the data, proposed the models for large slopes and additive effects, and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to N. Clément.

Supplementary information

  1. Supplementary Information

    Supplementary Note 1, Supplementary Figures 1–8, Supplementary Tables 1–3, Supplementary References 1–8

  2. Life Sciences Reporting Summary

Video

  1. Supplementary Video 1

    Supplementary Video 1