Morphing electronics enable neuromodulation in growing tissue

Abstract

Bioelectronics for modulating the nervous system have shown promise in treating neurological diseases1,2,3. However, their fixed dimensions cannot accommodate rapid tissue growth4,5 and may impair development6. For infants, children and adolescents, once implanted devices are outgrown, additional surgeries are often needed for device replacement, leading to repeated interventions and complications6,7,8. Here, we address this limitation with morphing electronics, which adapt to in vivo nerve tissue growth with minimal mechanical constraint. We design and fabricate multilayered morphing electronics, consisting of viscoplastic electrodes and a strain sensor that eliminate the stress at the interface between the electronics and growing tissue. The ability of morphing electronics to self-heal during implantation surgery allows a reconfigurable and seamless neural interface. During the fastest growth period in rats, morphing electronics caused minimal damage to the rat nerve, which grows 2.4-fold in diameter, and allowed chronic electrical stimulation and monitoring for 2 months without disruption of functional behavior. Morphing electronics offers a path toward growth-adaptive pediatric electronic medicine.

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Fig. 1: MorphE using viscoplastic electronic materials.
Fig. 2: Self-bonding MorphE for soft and conformable neural interfaces.
Fig. 3: MorphE accommodates developmental growth for chronically stable neuromodulation, nerve growth monitoring and conduction velocity testing.
Fig. 4: Behavior study and biocompatibility of MorphE on growing nerves.

Data availability

All data are available in the article or Supplementary Information.

Change history

  • 27 April 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. 1.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Johnson, R. L. & Wilson, C. G. A review of vagus nerve stimulation as a therapeutic intervention. J. Inflamm. Res. 11, 203–213 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Borzage, M., Blüml, S. & Seri, I. Equations to describe brain size across the continuum of human lifespan. Brain Struct. Funct. 219, 141–150 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Meier, J. M. et al. Assessment of age-related changes in abdominal organ structure and function with computed tomography and positron emission tomography. Semin. Nucl. Med. 37, 154–172 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Samuels-Reid, J. H. & Cope, J. U. Medical devices and adolescents: points to consider. JAMA Pediatr. 170, 1035–1036 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Samdani, A. F. et al. Anterior vertebral body tethering for immature adolescent idiopathic scoliosis: one-year results on the first 32 patients. Eur. Spine J. 24, 1533–1539 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Aalbers, M. W., Rijkers, K., Klinkenberg, S., Majoie, M. & Cornips, E. M. J. Vagus nerve stimulation lead removal or replacement: surgical technique, institutional experience, and literature overview. Acta Neurochir. 157, 1917–1924 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Lee, W. et al. Nonthrombogenic, stretchable, active multielectrode array for electroanatomical mapping. Sci. Adv. 4, eaau2426 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Xu, L. et al. 3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium. Nat. Commun. 5, 3329 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Liu, Y. et al. Soft and elastic hydrogel-based microelectronics for localized low-voltage neuromodulation. Nat. Biomed. Eng. 3, 58–68 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Aaberg, K. M. et al. Short-term seizure outcomes in childhood epilepsy. Pediatrics 141, e20174016 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Peña, C., Bowsher, K. & Samuels-Reid, J. FDA-approved neurologic devices intended for use in infants, children, and adolescents. Neurology 63, 1163–1167 (2004).

    PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Wang, Y. et al. A highly stretchable, transparent, and conductive polymer. Sci. Adv. 3, e1602076 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Savagatrup, S., Printz, A. D., O’Connor, T. F., Zaretski, A. V. & Lipomi, D. J. Molecularly stretchable electronics. Chem. Mater. 26, 3028–3041 (2014).

    CAS  Article  Google Scholar 

  17. 17.

    Kang, J. et al. Tough and water-insensitive self-healing elastomer for robust electronic skin. Adv. Mater. 30, e1706846 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  18. 18.

    Khalifa, A. et al. The microbead: a 0.009 mm3 implantable wireless neural stimulator. IEEE Trans. Biomed. Circuits Syst. 13, 971–985 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    O’Brien, J. P. et al. A model of chronic nerve compression in the rat. Ann. Plast. Surg. 19, 430–435 (1987).

    PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Restaino, S. M., Abliz, E., Wachrathit, K., Krauthamer, V. & Shah, S. B. Biomechanical and functional variation in rat sciatic nerve following cuff electrode implantation. J. Neuroeng. Rehabil. 11, 73 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Rivnay, J., Wang, H., Fenno, L., Deisseroth, K. & Malliaras, G. G. Next-generation probes, particles, and proteins for neural interfacing. Sci. Adv. 3, e1601649 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Wilks, S. Poly(3,4-ethylene dioxythiophene) (PEDOT) as a micro-neural interface material for electrostimulation. Front. Neuroen. 2, 7 (2009).

    CAS  Article  Google Scholar 

  23. 23.

    Cragg, B. G. & Thomas, P. K. The relationships between conduction velocity and the diameter and internodal length of peripheral nerve fibres. J. Physiol. 136, 606–614 (1957).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    de Medinaceli, L., Freed, W. J. & Wyatt, R. J. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp. Neurol. 77, 634–643 (1982).

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Kohane, D. S. et al. A re-examination of tetrodotoxin for prolonged duration local anesthesia. Anesthesiology 89, 119–131 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Nitz, A. J., Dobner, J. J. & Matulionis, D. H. Structural assessment of rat sciatic nerve following tourniquet compression and vascular manipulation. Anat. Rec. 225, 67–76 (1989).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Dyck, P. J., Lais, A. C., Giannini, C. & Engelstad, J. K. Structural alterations of nerve during cuff compression. Proc. Natl Acad. Sci. USA 87, 9828–9832 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Beel, J. A., Groswald, D. E. & Luttges, M. W. Alterations in the mechanical properties of peripheral nerve following crush injury. J. Biomech. 17, 185–193 (1984).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Rydevik, B., McLean, W. G., Sjöstrand, J. & Lundborg, G. Blockage of axonal transport induced by acute, graded compression of the rabbit vagus nerve. J. Neurol. Neurosurg. Psychiatry 43, 690–698 (1980).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Bora, F. W., Richardson, S. & Black, J. The biomechanical responses to tension in a peripheral nerve. J. Hand Surg. Am. 5, 21–25 (1980).

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Nam, S., Lee, J., Brownfield, D. G. & Chaudhuri, O. Viscoplasticity enables mechanical remodeling of matrix by cells. Biophys. J. 111, 2296–2308 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    George, P. M. et al. Fabrication and biocompatibility of polypyrrole implants suitable for neural prosthetics. Biomaterials 26, 3511–3519 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    George, P. M. et al. Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery. Biomaterials 142, 31–40 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    George, P. M. et al. Three-dimensional conductive constructs for nerve regeneration. J. Biomed. Mater. Res. A 91, 519–527 (2009).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  35. 35.

    Thalhammer, J. G., Vladimirova, M., Bershadsky, B. & Strichartz, G. R. Neurologic evaluation of the rat during sciatic nerve block with lidocaine. Anesthesiology 82, 1013–1025 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Masters, D. B. et al. Prolonged regional nerve blockade by controlled release of local anesthetic from a biodegradable polymer matrix. Anesthesiology 79, 340–346 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Oh, S. S., Hayes, J. M., Sims-Robinson, C., Sullivan, K. A. & Feldman, E. L. The effects of anesthesia on measures of nerve conduction velocity in male C57Bl6/J mice. Neurosci. Lett. 483, 127–131 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Zotova, E. G. & Arezzo, J. C. Noninvasive evaluation of nerve conduction in small diameter fibers in the rat. Physiol. J. 2013, 1–11 (2013).

    Article  Google Scholar 

  39. 39.

    Mokarram, N. et al. Immunoengineering nerve repair. Proc. Natl Acad. Sci. USA 26, E5077–E5084 (2017).

    Google Scholar 

  40. 40.

    Hort-Legrand, C., Noah, L., Mériguet, E. & Mésangeau, D. Motor and sensory nerve conduction velocities in Yucatan minipigs. Lab. Anim. 40, 53–57 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Amanatullah, D. F. et al. Local estrogen axis in the human bone microenvironment regulates estrogenreceptor-positive breast cancer cells. Breast Cancer Res. 19, 121 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Goldner, J. A modification of the Masson trichrome technique for routine laboratory purposes. Am. J. Pathol. 14, 237–243 (1938).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank P. Chu for her assistance in this work. We thank K. Xu for assistance with statistical analysis. We thank Agfa for providing PEDOT:PSS Orgacon ICP 1050. Part of this work was performed at the Stanford Nano Shared Facilities, supported by the National Science Foundation under award ECCS-1542152. Y.L. is supported by National Science Scholarship (A*STAR, Singapore). This research was supported in part by the Stanford Bio-X seed funding (Z.B.), Stanford University Dean’s Postdoctoral Fellowship (S.S.), National Institutes of Health (NIH) F32HD098808 (S.S.), and NIH K08NS089976 (P.G.) and the Alliance for Regenerative Rehabilitation Research and Training supported by NIH P2C HD086843 (P.G.).

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Y.L., J.L., S.S., P.G. and Z.B. designed the project and experiments. Y.L., J.L., J.K., S.C., Y.T., W.X., Y.Z. and V.M. developed the materials and performed device fabrication and characterization. Y.L., S.S. and J.L. performed animal experiments. S.S. and K.M. performed animal behavior tests and tissue processing. Y.L., J.L., S.S., J.B.-H.T., P.G. and Z.B. wrote the manuscript. All authors reviewed and commented on the manuscript.

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Correspondence to Paul M. George or Zhenan Bao.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–24.

Reporting Summary

Supplementary Video 1

Robust interface between MorphE and sciatic nerve 4 weeks after implantation. MorphE maintains a stable enclosure during pulling with a tweezer.

Supplementary Video 2

Gait comparison between rat implanted with MorphE and cuff electrodes for 4 weeks. The devices are implanted in the left leg only.

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Liu, Y., Li, J., Song, S. et al. Morphing electronics enable neuromodulation in growing tissue. Nat Biotechnol (2020). https://doi.org/10.1038/s41587-020-0495-2

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