Functionalized helical fibre bundles of carbon nanotubes as electrochemical sensors for long-term in vivo monitoring of multiple disease biomarkers

Abstract

Mechanical mismatches between implanted electronics and biological tissues can lead to inaccurate readings and long-term tissue damage. Here, we show that functionalized multi-walled carbon nanotubes twisted into helical fibre bundles that mimic the hierarchical structure of muscle can monitor multiple disease biomarkers in vivo. The flexible fibre bundles are injectable, have a low bending stiffness and display ultralow stress under compression. As proof-of-concept evidence of the sensing capabilities of these fibre bundles, we show that the fibre bundles enable the spatially resolved and real-time monitoring of H2O2 when implanted in tumours in mice, and that they can be integrated with a wireless transmission system on an adhesive skin patch to monitor calcium ions and glucose in the venous blood of cats for 28 d. The versatility of the helical fibre bundles as chemically functionalized electrochemical sensors makes them suitable for multiple sensing applications in biomedicine and healthcare.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Hierarchical helical structure and the implantation of CNT fibre.
Fig. 2: Mechanical match, biocompatibility and biointegration of the implanted CNT fibre.
Fig. 3: The structure and performance of the SSF library and the fabrication of MSFs.
Fig. 4: The structure and stability of the MSF.
Fig. 5: The use of MSFs for spatially resolved analysis.
Fig. 6: The use of MSFs for real-time and long-term multiplex monitoring in vivo.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets that were generated during this study are available from the corresponding authors on reasonable request.

References

  1. 1.

    Clausen, J. Man, machine and in between. Nature 457, 1080–1081 (2009).

  2. 2.

    Yoshida Kozai, T. D. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nat. Mater. 11, 1065–1073 (2012).

  3. 3.

    Canales, A. et al. Multifunctional fibers for simultaneous optical, electrical and chemical interrogation of neural circuits in vivo. Nat. Biotechnol. 33, 277–284 (2015).

  4. 4.

    Jun, J. J. et al. Fully integrated silicon probes for high-density recording of neural activity. Nature 551, 232–236 (2017).

  5. 5.

    Yun, S. H. & Kwok, S. J. J. Light in diagnosis, therapy and surgery. Nat. Biomed. Eng. 1, 0008 (2017).

  6. 6.

    Minev, I. R. et al. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).

  7. 7.

    An, D. et al. Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. Proc. Natl Acad. Sci. USA 115, E263–E272 (2018).

  8. 8.

    Vermesh, O. et al. An intravascular magnetic wire for the high-throughput retrieval of circulating tumour cells in vivo. Nat. Biomed. Eng. 2, 696–705 (2018).

  9. 9.

    Feiner, R. & Dvir, T. Tissue–electronics interfaces: from implantable devices to engineered tissues. Nat. Rev. Mater. 3, 17076 (2017).

  10. 10.

    Yu, X. et al. Needle-shaped ultrathin piezoelectric microsystem for guided tissue targeting via mechanical sensing. Nat. Biomed. Eng. 2, 165–172 (2018).

  11. 11.

    Lacour, S. P., Courtine, G. & Guck, J. Materials and technologies for soft implantable neuroprostheses. Nat. Rev. Mater. 1, 16063 (2016).

  12. 12.

    Chen, R., Canales, A. & Anikeeva, P. Neural recording and modulation technologies. Nat. Rev. Mater. 2, 16093 (2017).

  13. 13.

    Hong, G. & Lieber, C. M. Novel electrode technologies for neural recordings. Nat. Rev. Neurosci. 20, 330–345 (2019).

  14. 14.

    Yang, X. et al. Bioinspired neuron-like electronics. Nat. Mater. 18, 510–517 (2019).

  15. 15.

    Ling, S., Kaplan, D. L. & Buehler, M. J. Nanofibrils in nature and materials engineering. Nat. Rev. Mater. 3, 18016 (2018).

  16. 16.

    Buehler, M. J. Nature designs tough collagen: explaining the nanostructure of collagen fibrils. Proc. Natl Acad. Sci. USA 103, 12285–12290 (2006).

  17. 17.

    Hang, F. & Barber, A. H. Nano-mechanical properties of individual mineralized collagen fibrils from bone tissue. J. R. Soc. Interface 8, 500–505 (2011).

  18. 18.

    Depalle, B., Qin, Z., Shefelbine, S. J. & Buehler, M. J. Influence of cross-link structure, density and mechanical properties in the mesoscale deformation mechanisms of collagen fibrils. J. Mech. Behav. Biomed. Mater. 52, 1–13 (2015).

  19. 19.

    Dai, X., Hong, G., Gao, T. & Lieber, C. M. Mesh nanoelectronics: seamless integration of electronics with tissues. Acc. Chem. Res. 51, 309–318 (2018).

  20. 20.

    Darnell, M. & Mooney, D. J. Leveraging advances in biology to design biomaterials. Nat. Mater. 16, 1178–1184 (2017).

  21. 21.

    Baker, B. M. et al. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat. Mater. 14, 1262–1268 (2015).

  22. 22.

    Waldert, S. Invasive vs. non-invasive neuronal signals for brain–machine interfaces: will one prevail? Front. Neurosci. 10, 295 (2016).

  23. 23.

    Vitale, F. et al. Fluidic microactuation of flexible electrodes for neural recording. Nano Lett. 18, 326–335 (2018).

  24. 24.

    Liu, J. et al. Syringe-injectable electronics. Nat. Nanotechnol. 10, 629–636 (2015).

  25. 25.

    Close, R. I. Dynamic properties of mammalian skeletal muscles. Physiol. Rev. 52, 129–197 (1972).

  26. 26.

    Alonso, J. L. & Goldmann, W. H. Feeling the forces: atomic force microscopy in cell biology. Life Sci. 72, 2553–2560 (2003).

  27. 27.

    Liu, Y., Zhao, Y., Sun, B. & Chen, C. Understanding the toxicity of carbon nanotubes. Acc. Chem. Res. 46, 702–713 (2013).

  28. 28.

    Jhunjhunwala, S. et al. Neutrophil responses to sterile implant materials. PLoS ONE 10, e0137550 (2015).

  29. 29.

    Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008).

  30. 30.

    Yang, Z. et al. Recent advancement of nanostructured carbon for energy applications. Chem. Rev. 115, 5159–5223 (2015).

  31. 31.

    D’Amico, A. V., Chen, M.-H., Roehl, K. A. & Catalona, W. J. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N. Engl. J. Med. 351, 125–135 (2004).

  32. 32.

    Gao, W. et al. Fully integrated wearable sensor arrays for multiplexed in situ perspiration analysis. Nature 529, 509–514 (2016).

  33. 33.

    Zhu, S., Nih, L., Carmichael, S. T., Lu, Y. & Segura, T. Enzyme-responsive delivery of multiple proteins with spatiotemporal control. Adv. Mater. 27, 3620–3625 (2015).

  34. 34.

    Oxley, T. J. et al. Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity. Nat. Biotechnol. 34, 320–327 (2016).

  35. 35.

    Luo, Y., Liu, H., Rui, Q. & Tian, Y. Detection of extracellular H2O2 released from human liver cancer cells based on TiO2 nanoneedles with enhanced electron transfer of cytochrome c. Anal. Chem. 81, 3035–3041 (2009).

  36. 36.

    Rodenhizer, D. et al. A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients. Nat. Mater. 15, 227–234 (2016).

  37. 37.

    Chen, Q. et al. H2O2-responsive liposomal nanoprobe for photoacoustic inflammation imaging and tumor theranostics via in vivo chromogenic assay. Proc. Natl Acad. Sci. USA 114, 5343–5348 (2017).

  38. 38.

    Hong, G., Antaris, A. L. & Dai, H. Near-infrared fluorophores for biomedical imaging. Nat. Biomed. Eng. 1, 0010 (2017).

  39. 39.

    Lipani, L. et al. Non-invasive, transdermal, path-selective and specific glucose monitoring via a graphene-based platform. Nat. Nanotechnol. 13, 504–511 (2018).

  40. 40.

    Lee, H. et al. Wearable/disposable sweat-based glucose monitoring device with multistage transdermal drug delivery module. Sci. Adv. 3, e1601314 (2017).

  41. 41.

    Tarlani, A. et al. New ZnO nanostructures as non-enzymatic glucose biosensors. Biosens. Bioelectron. 67, 601–607 (2015).

  42. 42.

    Tang, Z., Fu, Y. & Ma, Z. Bovine serum albumin as an effective sensitivity enhancer for peptide-based amperometric biosensor for ultrasensitive detection of prostate specific antigen. Biosens. Bioelectron. 94, 394–399 (2017).

  43. 43.

    Chen, P. et al. Hierarchically arranged helical fibre actuators driven by solvents and vapours. Nat. Nanotechnol. 10, 1077–1083 (2015).

  44. 44.

    He, X. Q. et al. Buckling analysis of multi-walled carbon nanotubes: a continuum model accounting for van der Waals interaction. J. Mech. Phys. Solids 53, 303–326 (2005).

  45. 45.

    Ru, C. Q. Effect of van der Waals forces on axial buckling of a double-walled carbon nanotube. J. Appl. Phys. 87, 7227–7231 (2000).

  46. 46.

    Natsuki, T. et al. Stability analysis of double-walled carbon nanotubes as AFM probes based on a continuum model. Carbon 49, 2532–2537 (2011).

  47. 47.

    Timesli, A. et al. Prediction of the critical buckling load of multi-walled carbon nanotubes under axial compression. C. R. Mec. 345, 158–168 (2017).

  48. 48.

    Khosravian, N. & Rafii-Tabar, H. Computational modelling of a non-viscous fluid flow in a multi-walled carbon nanotube modelled as a Timoshenko beam. Nanotechnology 19, 275703 (2008).

  49. 49.

    Sun, H. et al. Energy harvesting and storage in 1D devices. Nat. Rev. Mater. 2, 17023 (2017).

  50. 50.

    Tang, T. et al. Adhesion between single-walled carbon nanotubes. J. Appl. Phys. 97, 074304 (2005).

  51. 51.

    Huang, S. Q. et al. Pattern instability of a soft elastic thin film under van der Waals forces. Mech. Mater. 38, 88–99 (2006).

  52. 52.

    Israelachvili, J. N. Intermolecular and Surface Forces (Academic, 2011).

Download references

Acknowledgements

We thank A. L. Chun of Science Storylab for her suggestions and critique; F. Han from Fudan University for help with the wireless-transmitting system. This work was supported by MOST (grant number 2016YFA0203302), NSFC (grant numbers 21634003, 51573027, 51673043, 21604012, 21805044, 21875042, 11602058 and 11872150), STCSM (grant numbers 16JC1400702, 17QA1400400, 18QA1400700, 18QA1400800 and 19QA1400500), SHMEC (grant number 2017-01-07-00-07-E00062), SEDF (grant number 16CG01) and Yanchang Petroleum Group and China Postdoctoral Science Foundation (grant numbers 2017M610223 and 2018T110334). This work was also supported by Shanghai Municipal Science and Technology Major Project (2018SHZDZX01) and ZJLab (to H.Y.).

Author information

Affiliations

Authors

Contributions

X.S., F.X., H.Y. and H.P. conceived and designed the research project. L.W., Z.W. and S.X. performed the experiments. F.L. and Y.Y. performed numerical simulations. L.W., S.X. and Z.W. analysed the data. All of the authors discussed the data and wrote the paper.

Corresponding authors

Correspondence to Xuemei Sun or Fan Xu or Hongbo Yu or Huisheng Peng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

41551_2019_462_MOESM3_ESM.mp4

Wireless monitoring system integrated with MSFs on a living cat for the real-time transmission of data.

Supplementary Information

Supplementary methods, figures, tables, references and caption for Supplementary Video 1.

Reporting Summary

Supplementary Video 1

Wireless monitoring system integrated with MSFs on a living cat for the real-time transmission of data.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Xie, S., Wang, Z. et al. Functionalized helical fibre bundles of carbon nanotubes as electrochemical sensors for long-term in vivo monitoring of multiple disease biomarkers. Nat Biomed Eng 4, 159–171 (2020). https://doi.org/10.1038/s41551-019-0462-8

Download citation

Further reading