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.

  • Letter
  • Published:

Ultrasoft electronics to monitor dynamically pulsing cardiomyocytes

Abstract

In biointegrated electronics, the facile control of mechanical properties such as softness and stretchability in electronic devices is necessary to minimize the perturbation of motions inherent in biological systems1,2,3,4,5. For in vitro studies, multielectrode-embedded dishes6,7,8 and other rigid devices9,10,11,12 have been widely used. Soft or flexible electronics on plastic or elastomeric substrates13,14,15 offer promising new advantages such as decreasing physical stress16,17,18 and/or applying mechanical stimuli19,20. Recently, owing to the introduction of macroporous plastic substrates with nanofibre scaffolds21,22, three-dimensional electrophysiological mapping of cardiomyocytes has been demonstrated. However, quantitatively monitoring cells that exhibit significant dynamical motions via electric probes over a long period without affecting their natural motion remains a challenge. Here, we present ultrasoft electronics with nanomeshes that monitor the field potential of human induced pluripotent stem cell-derived cardiomyocytes on a hydrogel, while enabling them to move dynamically without interference. Owing to the extraordinary softness of the nanomeshes, nanomesh-attached cardiomyocytes exhibit contraction and relaxation motions comparable to that of cardiomyocytes without attached nanomeshes. Our multilayered nanomesh devices maintain reliable operations in a liquid environment, enabling the recording of field potentials of the cardiomyocytes over a period of 96 h without significant degradation of the nanomesh devices or damage of the cardiomyocytes.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: Nanomesh device to monitor dynamically pulsing cardiomyocytes differentiated from hiPSCs.
Fig. 2: Stretchability of the nanomesh devices.
Fig. 3: Movement observation of nanosubstrate-attached cardiomyocyte sheets.
Fig. 4: Electrophysiological monitoring of cardiomyocytes on a fibrin hydrogel using nanomesh sensors.

Similar content being viewed by others

Data availability

All data supporting the findings of this study are either included within the paper or available from the corresponding author upon request.

References

  1. Kim, D. et al. Epidermal electronics. Science 333, 838–843 (2011).

    Article  CAS  Google Scholar 

  2. Lipomi, D. J. et al. Skin-like pressure and strain sensors based on transparent elastic films of carbon nanotubes. Nat. Nanotechnol. 6, 788–792 (2011).

    Article  CAS  Google Scholar 

  3. Khodagholy, D. et al. In vivo recordings of brain activity using organic transistors. Nat. Commun. 4, 1575 (2013).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Jonsson, A. et al. Therapy using implanted organic bioelectronics. Sci. Adv. 1, e1500039 (2015).

    Article  Google Scholar 

  6. Clements, M. & Thomas, N. High-throughput multi-parameter profiling of electrophysiological drug effects in human embryonic stem cell derived cardiomyocytes using multi-electrode arrays. Toxicol. Sci. 140, 445–461 (2014).

    Article  CAS  Google Scholar 

  7. Asakura, K. et al. Improvement of acquisition and analysis methods in multi-electrode array experiments with iPS cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods 75, 17–26 (2015).

    Article  CAS  Google Scholar 

  8. Kitaguchi, T. et al. CSAHi study: detection of drug-induced ion channel/receptor responses, QT prolongation, and arrhythmia using multi-electrode arrays in combination with human induced pluripotent stem cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods 85, 73–81 (2017).

    Article  CAS  Google Scholar 

  9. Dunlop, J., Bowlby, M., Peri, R., Vasilyev, D. & Arias, R. High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology. Nat. Rev. Drug. Discov. 7, 358–368 (2008).

    Article  CAS  Google Scholar 

  10. Robinson, J. T. et al. Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits. Nat. Nanotech. 7, 180–184 (2012).

    Article  CAS  Google Scholar 

  11. Hai, A., Shappir, J. & Spira, M. E. In-cell recordings by extracellular microelectrodes. Nat. Methods 7, 200–202 (2010).

    Article  CAS  Google Scholar 

  12. Duan, X. et al. Intracellular recordings of action potentials by an extracellular nanoscale field-effect transistor. Nat. Nanotech. 7, 174–179 (2012).

    Article  CAS  Google Scholar 

  13. Graudejus, O., Yu, Z., Jones, J., Morrison, B. & Wagner, S. Characterization of an elastically stretchable microelectrode array and its application to neural field potential recordings. J. Electrochem. Soc. 156, 85–94 (2009).

    Article  Google Scholar 

  14. Inal, S. et al. Conducting polymer scaffolds for hosting and monitoring 3D cell culture. Adv. Biosyst. 1, 1700052 (2017).

    Article  Google Scholar 

  15. Kim, S. J. et al. Stretchable and transparent biointerface using cell-sheet–graphene hybrid for electrophysiology and therapy of skeletal muscle. Adv. Funct. Mater. 26, 3207–3217 (2016).

    Article  CAS  Google Scholar 

  16. Jacot, J. G., McCulloch, A. D. & Omens, J. H. Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys. J. 95, 3479–3487 (2008).

    Article  CAS  Google Scholar 

  17. Lacour, S. P. et al. Flexible and stretchable micro-electrodes for in vitro and in vivo neural interfaces. Med. Biol. Eng. Comput. 48, 945–954 (2010).

    Article  Google Scholar 

  18. Sasaki, M. et al. Highly conductive stretchable and biocompatible electrode–hydrogel hybrids for advanced tissue engineering. Adv. Healthc. Mater. 3, 1919–1927 (2014).

    Article  CAS  Google Scholar 

  19. Simmons, C. S., Petzold, B. C. & Pruitt, B. L. Microsystems for biomimetic stimulation of cardiac cells. Lab Chip 12, 3235–3248 (2012).

    Article  CAS  Google Scholar 

  20. Khoshfetrat Pakazad, S., Savov, A., Van De Stolpe, A. & Dekker, R. A novel stretchable micro-electrode array (SMEA) design for directional stretching of cells. J. Micromech. Microeng. 24, 034003 (2014).

    Article  Google Scholar 

  21. Dai, X., Zhou, W., Gao, T., Liu, J. & Lieber, C. M. Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues. Nat. Nanotech. 11, 776–782 (2016).

    Article  CAS  Google Scholar 

  22. Feiner, R. et al. Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function. Nat. Mater. 15, 679–685 (2016).

    Article  CAS  Google Scholar 

  23. Sasaki, D. et al. Contractile force measurement of human induced pluripotent stem cell-derived cardiac cell sheet-tissue. PLoS One 13, e0198026 (2018).

    Article  Google Scholar 

  24. Shaikh, F. M. et al. Fibrin: a natural biodegradable scaffold in vascular tissue engineering. Cells Tissues Organs 188, 333–346 (2008).

    Article  CAS  Google Scholar 

  25. Park, J. et al. Electromechanical cardioplasty using a wrapped elasto-conductive epicardial mesh. Sci. Transl. Med. 8, 344ra86 (2016).

    Article  Google Scholar 

  26. Lin, S. et al. Stretchable hydrogel electronics and devices. Adv. Mater. 28, 4497–4505 (2016).

    Article  CAS  Google Scholar 

  27. Jang, K. I. et al. Soft network composite materials with deterministic and bio-inspired designs. Nat. Commun. 6, 6566 (2015).

    Article  CAS  Google Scholar 

  28. Haraguchi, Y. et al. Fabrication of functional three-dimensional tissues by stacking cell sheets in vitro. Nat. Protoc. 7, 850–858 (2012).

    Article  CAS  Google Scholar 

  29. Miyamoto, A. et al. Inflammation-free, gas-permeable, lightweight, stretchable on-skin electronics with nanomeshes. Nat. Nanotech. 12, 907–913 (2017).

    Article  CAS  Google Scholar 

  30. Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511–523 (2014).

    Article  CAS  Google Scholar 

  31. Ribeiro, M. C. et al. Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro—correlation between contraction force and electrophysiology. Biomaterials 51, 138–150 (2015).

    Article  CAS  Google Scholar 

  32. Seta, H., Matsuura, K., Sekine, H., Yamazaki, K. & Shimizu, T. Tubular cardiac tissues derived from human induced pluripotent stem cells generate pulse pressure in vivo. Sci. Rep. 7, 45499 (2017).

    Article  CAS  Google Scholar 

  33. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by JSPS KAKENHI (grant number 17H06149). The authors thank S. Lee, W. Lee and D. Ordinario for technical support and discussions.

Author information

Authors and Affiliations

Authors

Contributions

S.L., D.K. and M.M. fabricated the nanomesh devices. D.S., K.M. and T. Shimuzu fabricated the hiPSC-derived cardiomyocytes. S.L., D.K., H.L., S.P., K.F., T.Y., M.S. and T. Someya contributed the electric and mechanical characterizations and analyses of nanomesh devices. S.L. and D.S. contributed to the strain analyses and the field potential measurements of the hiPSC-derived cardiomyocytes. S.L. and T. Someya wrote the manuscript, and T. Someya supervised this project.

Corresponding author

Correspondence to Takao Someya.

Ethics declarations

Competing interests

There is a potential competing interest: T. Shimizu is a shareholder and a member of the scientific advisory board of CellSeed Inc. Tokyo Women’s Medical University receives a research fund from CellSeed Inc. All other authors have 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

Supplementary Information

Supplementary Text, Supplementary References 1–7, Supplementary Figures 1–18, Supplementary Video Captions 1–6

Supplementary Video 1

Phase-contrast microscopy movie of polyurethane-only nanosubstrate attached cardiomyocytes

Supplementary Video 2

Phase-contrast microscopy movie of cardiomyocytes without attaching nanosubstrate

Supplementary Video 3

Microscopy video of polyurethane-only nanosubstrate attached cardiomyocytes without phase-contrast filter

Supplementary Video 4

Phase-contrast microscopy movie of polyurethane/100-nm-thick parylene nanosubstrate attached cardiomyocytes

Supplementary Video 5

Phase-contrast microscopy video of polyurethane/400-nm-thick parylene nanosubstrate attached cardiomyocytes

Supplementary Video 6

Microscopy video of nanomesh device attached cardiomyocytes with and without phase-contrast filter

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, S., Sasaki, D., Kim, D. et al. Ultrasoft electronics to monitor dynamically pulsing cardiomyocytes. Nature Nanotech 14, 156–160 (2019). https://doi.org/10.1038/s41565-018-0331-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41565-018-0331-8

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