Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: 0D ISFETs show negligible sensitivity to pH near neutral pH.
Fig. 2: Signatures of ion-specific effects.
Fig. 3: Additive contribution of multiple species on ψ0.
Fig. 4: Selective-layer-free blood ionogram.
Fig. 5: Subnanolitre sensing and high integration.

Similar content being viewed by others

References

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    Google Scholar 

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

    CAS  Google Scholar 

  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).

    Google Scholar 

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

    Google Scholar 

  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).

    Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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

    Google Scholar 

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

    CAS  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  Google Scholar 

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

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to N. Clément.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Supplementary information

Supplementary Information

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

Life Sciences Reporting Summary

Video

Supplementary Video 1

Supplementary Video 1

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sivakumarasamy, R., Hartkamp, R., Siboulet, B. et al. Selective layer-free blood serum ionogram based on ion-specific interactions with a nanotransistor. Nature Mater 17, 464–470 (2018). https://doi.org/10.1038/s41563-017-0016-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41563-017-0016-y

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing