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:

A drug-mediated organic electrochemical transistor for robustly reusable biosensors

Nature Materials (2024)Cite this article

Subjects

Abstract

Reusable point-of-care biosensors offer a cost-effective solution for serial biomarker monitoring, addressing the critical demand for tumour treatments and recurrence diagnosis. However, their realization has been limited by the contradictory requirements of robust reusability and high sensing capability to multiple interactions among transducer surface, sensing probes and target analytes. Here we propose a drug-mediated organic electrochemical transistor as a robust, reusable epidermal growth factor receptor sensor with striking sensitivity and selectivity. By electrostatically adsorbing protonated gefitinib onto poly(3,4-ethylenedioxythiophene):polystyrene sulfonate and leveraging its strong binding to the epidermal growth factor receptor target, the device operates with a unique refresh-in-sensing mechanism. It not only yields an ultralow limit-of-detection concentration down to 5.74 fg ml−1 for epidermal growth factor receptor but, more importantly, also produces an unprecedented regeneration cycle exceeding 200. We further validate the potential of our devices for easy-to-use biomedical applications by creating an 8 × 12 diagnostic drug-mediated organic electrochemical transistor array with excellent uniformity to clinical blood samples.

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

Access options

Fig. 1: Schematic of the DM-OECT reusable sensor.
Fig. 2: Sensitive and specific EGFR detection.
Fig. 3: Reusability characterization of DM-OECTs.
Fig. 4: RIS mechanism of the DM-OECT.
Fig. 5: Reusable detection in clinical samples.

Similar content being viewed by others

Data availability

All data supporting the findings of this study are available in the article Source data and its Supplementary Information. Source data are provided with this paper. Other related raw data are available from the corresponding authors on reasonable request. The macromolecular structures of EGFR, AMPD2 and tubulin used in this study are available via the wwPDB database.

Code availability

The code that supports the theoretical plots within this paper is available from the corresponding authors upon reasonable request.

References

  1. Wan, J. C. M. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat. Rev. Cancer 17, 223–238 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Ignatiadis, M., Sledge, G. W. & Jeffrey, S. S. Liquid biopsy enters the clinic—implementation issues and future challenges. Nat. Rev. Clin. Oncol. 18, 297–312 (2021).

    Article  PubMed  Google Scholar 

  3. Pal, A., Shinde, R., Miralles, M. S., Workman, P. & de Bono, J. Applications of liquid biopsy in the pharmacological audit trail for anticancer drug development. Nat. Rev. Clin. Oncol. 18, 454–467 (2021).

    Article  PubMed  Google Scholar 

  4. Alix-Panabières, C. & Pantel, K. Clinical prospects of liquid biopsies. Nat. Biomed. Eng. 1, 0065 (2017).

    Article  Google Scholar 

  5. McNerney, R. & Daley, P. Towards a point-of-care test for active tuberculosis: obstacles and opportunities. Nat. Rev. Microbiol. 9, 204–213 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Land, K. J., Boeras, D. I., Chen, X. S., Ramsay, A. R. & Peeling, R. W. REASSURED diagnostics to inform disease control strategies, strengthen health systems and improve patient outcomes. Nat. Microbiol. 4, 46–54 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Najjar, D. et al. A lab-on-a-chip for the concurrent electrochemical detection of SARS-CoV-2 RNA and anti-SARS-CoV-2 antibodies in saliva and plasma. Nat. Biomed. Eng. 6, 968–978 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cohen, L. & Walt, D. R. Highly sensitive and multiplexed protein measurements. Chem. Rev. 119, 293–321 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Manoli, K. et al. Printable bioelectronics to investigate functional biological interfaces. Angew. Chem. Int. Ed. 54, 12562–12576 (2015).

    Article  CAS  Google Scholar 

  10. Aleman, J., Kilic, T., Mille, L. S., Shin, S. R. & Zhang, Y. S. Microfluidic integration of regeneratable electrochemical affinity-based biosensors for continual monitoring of organ-on-a-chip devices. Nat. Protoc. 16, 2564–2593 (2021).

    Article  CAS  PubMed  Google Scholar 

  11. Kim, J., Campbell, A. S., de Avila, B. E. & Wang, J. Wearable biosensors for healthcare monitoring. Nat. Biotechnol. 37, 389–406 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Naresh, V. & Lee, N. A review on biosensors and recent development of nanostructured materials-enabled biosensors. Sensors 21, 1109 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Goode, J. A., Rushworth, J. V. & Millner, P. A. Biosensor regeneration: a review of common techniques and outcomes. Langmuir 31, 6267–6276 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Sempionatto, J. R., Lasalde-Ramirez, J. A., Mahato, K., Wang, J. & Gao, W. Wearable chemical sensors for biomarker discovery in the omics era. Nat. Rev. Chem. 6, 899–915 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhang, Y. S. et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc. Natl Acad. Sci. USA 114, E2293–E2302 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bryan, T., Luo, X., Bueno, P. R. & Davis, J. J. An optimised electrochemical biosensor for the label-free detection of C-reactive protein in blood. Biosens. Bioelectron. 39, 94–98 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Huang, J. et al. Renal clearable polyfluorophore nanosensors for early diagnosis of cancer and allograft rejection. Nat. Mater. 21, 598–607 (2022).

    Article  CAS  PubMed  Google Scholar 

  18. Frutiger, A. et al. Nonspecific binding-fundamental concepts and consequences for biosensing applications. Chem. Rev. 121, 8095–8160 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Ali, M. A. et al. Sensing of COVID-19 antibodies in seconds via aerosol jet nanoprinted reduced-graphene-oxide-coated 3D electrodes. Adv. Mater. 33, e2006647 (2021).

    Article  PubMed  Google Scholar 

  20. Shen, H. et al. Molecular antenna tailored organic thin-film transistors for sensing application. Mater. Horiz. 5, 240–247 (2018).

    Article  CAS  Google Scholar 

  21. Kitao, Y. et al. The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action. Bioorg. Med. Chem. Lett. 80, 129110 (2023).

    Article  CAS  PubMed  Google Scholar 

  22. Sharafeldin, M. et al. Detecting cancer metastasis and accompanying protein biomarkers at single cell levels using a 3D-printed microfluidic immunoarray. Biosens. Bioelectron. 171, 112681 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Huse, M. & Kuriyan, J. The conformational plasticity of protein kinases. Cell 109, 275–282 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Xie, T., Saleh, T., Rossi, P. & Kalodimos, C. G. Conformational states dynamically populated by a kinase determine its function. Science 370, 189 (2020).

    Article  Google Scholar 

  25. Park, J., McDonald, J. J., Petter, R. C. & Houk, K. N. Molecular dynamics analysis of binding of kinase inhibitors to WT EGFR and the T790M mutant. J. Chem. Theory Comput. 12, 2066–2078 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Friedlein, J. T., McLeod, R. R. & Rivnay, J. Device physics of organic electrochemical transistors. Org. Electron. 63, 398–414 (2018).

    Article  CAS  Google Scholar 

  27. Romele, P., Ghittorelli, M., Kovács-Vajna, Z. M. & Torricelli, F. Ion buffering and interface charge enable high performance electronics with organic electrochemical transistors. Nat. Commun. 10, 3044 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Simon, P. & Gogotsi, Y. Materials for electrochemical capacitors. Nat. Mater. 7, 845–854 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Tybrandt, K., Zozoulenko, I. V. & Berggren, M. Chemical potential–electric double layer coupling in conjugated polymer–polyelectrolyte blends. Sci. Adv. 3, eaao3659 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Herbst, R. S., Fukuoka, M. & Baselga, J. Gefitinib—a novel targeted approach to treating cancer. Nat. Rev. Cancer 4, 956–965 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. da Cunha Santos, G., Shepherd, F. A. & Tsao, M. S. EGFR mutations and lung cancer. Annu. Rev. Pathol. 6, 49–69 (2011).

    Article  PubMed  Google Scholar 

  32. Dinish, U. S. et al. Highly sensitive SERS detection of cancer proteins in low sample volume using hollow core photonic crystal fiber. Biosens. Bioelectron. 33, 293–298 (2012).

    Article  Google Scholar 

  33. Kumar, R. R., Meenakshi, A. & Sivakumar, N. Enzyme immunoassay of human epidermal growth factor receptor (hEGFR). Hum. Antibodies 10, 143–147 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Chen, J.-C., Sadhasivam, S. & Lin, F.-H. Label free gravimetric detection of epidermal growth factor receptor by antibody immobilization on quartz crystal microbalance. Process Biochem. 46, 543–550 (2011).

    Article  CAS  Google Scholar 

  35. Wegner, K. D. et al. Nanobodies and nanocrystals: highly sensitive quantum dot-based homogeneous FRET immunoassay for serum-based EGFR detection. Small 10, 734–740 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Wang, Y. et al. Low sample volume origami-paper-based graphene-modified aptasensors for label-free electrochemical detection of cancer biomarker-EGFR. Microsyst. Nanoeng. 6, 32 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Li, R. et al. Electrochemical biosensor for epidermal growth factor receptor detection with peptide ligand. Electrochim. Acta 109, 233–237 (2013).

    Article  CAS  Google Scholar 

  38. Vasudev, A., Kaushik, A. & Bhansali, S. Electrochemical immunosensor for label free epidermal growth factor receptor (EGFR) detection. Biosens. Bioelectron. 39, 300–305 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Elshafey, R., Tavares, A. C., Siaj, M. & Zourob, M. Electrochemical impedance immunosensor based on gold nanoparticles–protein G for the detection of cancer marker epidermal growth factor receptor in human plasma and brain tissue. Biosens. Bioelectron. 50, 143–149 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Altintas, Z., Kallempudi, S. S. & Gurbuz, Y. Gold nanoparticle modified capacitive sensor platform for multiple marker detection. Talanta 118, 270–276 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Shen, Y. C. et al. IGZO thin film transistor biosensors functionalized with ZnO nanorods and antibodies. Biosens. Bioelectron. 54, 306–310 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, Z. et al. A flexible and regenerative aptameric graphene–Nafion biosensor for cytokine storm biomarker monitoring in undiluted biofluids toward wearable applications. Adv. Funct. Mater. 31, 2005958 (2020).

    Article  Google Scholar 

  43. Ferguson, B. S. et al. Integrated microfluidic electrochemical DNA sensor. Anal. Chem. 81, 6503–6508 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Bronder, T. S., Poghossian, A., Jessing, M. P., Keusgen, M. & Schoning, M. J. Surface regeneration and reusability of label-free DNA biosensors based on weak polyelectrolyte-modified capacitive field-effect structures. Biosens. Bioelectron. 126, 510–517 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Wang, S. et al. An automated microfluidic system for single-stranded DNA preparation and magnetic bead-based microarray analysis. Biomicrofluidics 9, 024102 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pursey, J. P., Chen, Y., Stulz, E., Park, M. K. & Kongsuphol, P. Microfluidic electrochemical multiplex detection of bladder cancer DNA markers. Sens. Actuators B 251, 34–39 (2017).

    Article  CAS  Google Scholar 

  47. Xu, S. et al. Real-time reliable determination of binding kinetics of DNA hybridization using a multi-channel graphene biosensor. Nat. Commun. 8, 14902 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fenoy, G. E., Marmisolle, W. A., Azzaroni, O. & Knoll, W. Acetylcholine biosensor based on the electrochemical functionalization of graphene field-effect transistors. Biosens. Bioelectron. 148, 111796 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Zhang, X. et al. Photoinduced regeneration of an aptamer-based electrochemical sensor for sensitively detecting adenosine triphosphate. Anal. Chem. 90, 4968–4971 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Liu, N. et al. Regenerative field effect transistor biosensor for in vivo monitoring of dopamine in fish brains. Biosens. Bioelectron. 188, 113340 (2021).

    Article  CAS  PubMed  Google Scholar 

  51. Chen, Y., Yang, Y. & Tu, Y. An electrochemical impedimetric immunosensor for ultrasensitive determination of ketamine hydrochloride. Sens. Actuators B Chem. 183, 150–156 (2013).

    Article  CAS  Google Scholar 

  52. Xu, M., Luo, X. & Davis, J. J. The label free picomolar detection of insulin in blood serum. Biosens. Bioelectron. 39, 21–25 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Liu, Y. L. et al. Mechanical distension induces serotonin release from intestine as revealed by stretchable electrochemical sensing. Angew. Chem. Int. Ed. 59, 4075–4081 (2020).

    Article  CAS  Google Scholar 

  54. Yoo, H. et al. Magnetically-refreshable receptor platform structures for reusable nano-biosensor chips. Nanotechnology 27, 045502 (2016).

    Article  PubMed  Google Scholar 

  55. Ariffin, E. Y. et al. An ultrasensitive hollow-silica-based biosensor for pathogenic Escherichia coli DNA detection. Anal. Bioanal. Chem. 410, 2363–2375 (2018).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge financial support from the National Natural Science Foundation (22125504, 61971396 and 22021002), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0520200), the K. C. Wong Education Foundation (GJTD-2020-02), Key Research Program of Frontier Sciences CAS (ZDBS-LYSLH034), the Beijing Municipal Natural Science Foundation (Z220025) and Fundamental Research Funds for the Central Universities.

Author information

Authors and Affiliations

  1. School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing, China

    Ziling Jiang, Lanyi Xiang, Junfang Yang, Danfeng Zhi, Qian Peng, Fengjiao Zhang & Chong-an Di

  2. Beijing National Laboratory for Molecular Sciences, CAS Kay Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China

    Ziling Jiang, Dekai Ye, Zihan He, Xiaojuan Dai, Yingqiao Ma, Ye Zou, Shu Wang & Chong-an Di

  3. Zhangjiang Laboratory, Shanghai, China

    Dekai Ye

  4. Department of Oncology, Chinese PLA General Hospital, Beijing, China

    Qi Xiong

  5. Department of Orthopedics, Chinese PLA General Hospital, Beijing, China

    Jia Li

  6. National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Beijing, China

    Jia Li

Authors
  1. Ziling Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dekai Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lanyi Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zihan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaojuan Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junfang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qi Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yingqiao Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Danfeng Zhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ye Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qian Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fengjiao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Chong-an Di
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.Z. and C.-a.D. conceived and led the study. Z.J., D.Y. and F.Z. performed the experiments. Z.J., D.Y., L.X., F.Z. and C.-a.D. conducted the data analyses and mechanism discussion. J.Y. and Q.P. carried out the molecular dynamics simulation. X.D. and Y.Z. performed the XPS and UPS detection. Z.H., Y.M. and S.W. helped with the concept modification. Q.X. and J.L. provided the clinical blood samples and clinical testing. All the authors contributed to paper organization and preparation. Z.J., D.Y. and L.X. contributed equally to the work.

Corresponding authors

Correspondence to Jia Li, Fengjiao Zhang or Chong-an Di.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Materials thanks Dirk Mayer, Y. Shrike Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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 Notes 1–6, Figs. 1–44, Tables 1–9, caption for Video 1 and References.

Reporting Summary

Supplementary Video 1

A POC toolbox based on DM-OECT for blood detection.

Source data

Source Data Fig. 2

Source data for Fig. 2a–e. Source Data Fig. 3 Source data for Fig. 3a–g. Source Data Fig. 4 Source data for Fig. 4b–e. Source Data Fig. 5 Source data for Fig. 5b–e,g.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, Z., Ye, D., Xiang, L. et al. A drug-mediated organic electrochemical transistor for robustly reusable biosensors. Nat. Mater. (2024). https://doi.org/10.1038/s41563-024-01970-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41563-024-01970-5

This article is cited by

Search

Advanced 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