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Wireless bioresorbable electronic system enables sustained nonpharmacological neuroregenerative therapy

Abstract

Peripheral nerve injuries represent a significant problem in public health, constituting 2–5% of all trauma cases1. For severe nerve injuries, even advanced forms of clinical intervention often lead to incomplete and unsatisfactory motor and/or sensory function2. Numerous studies report the potential of pharmacological approaches (for example, growth factors, immunosuppressants) to accelerate and enhance nerve regeneration in rodent models3,4,5,6,7,8,9,10. Unfortunately, few have had a positive impact in clinical practice. Direct intraoperative electrical stimulation of injured nerve tissue proximal to the site of repair has been demonstrated to enhance and accelerate functional recovery11,12, suggesting a novel nonpharmacological, bioelectric form of therapy that could complement existing surgical approaches. A significant limitation of this technique is that existing protocols are constrained to intraoperative use and limited therapeutic benefits13. Herein we introduce (i) a platform for wireless, programmable electrical peripheral nerve stimulation, built with a collection of circuit elements and substrates that are entirely bioresorbable and biocompatible, and (ii) the first reported demonstration of enhanced neuroregeneration and functional recovery in rodent models as a result of multiple episodes of electrical stimulation of injured nervous tissue.

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Fig. 1: Bioresorbable, wireless electrical stimulator as an electronic neuroregenerative medical device.
Fig. 2: Surgical implantation, operation, and acute demonstration of a bioresorbable, wireless electrical stimulator for the sciatic nerve in a rodent model.
Fig. 3: Accelerated regeneration of sciatic nerves injured by transection, treated with the use of biodegradable wireless stimulators.
Fig. 4: Effects of chronic electrical stimulation on functional nerve recovery.

Data availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

References

  1. Noble, J., Munro, C. A., Prasad, V. S. & Midha, R. Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J. Trauma 45, 116–122 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Kemp, S. W. P., Cederna, P. S. & Midha, R. Comparative outcome measures in peripheral regeneration studies. Exp. Neurol. 287, 348–357 (2017).

    Article  PubMed  Google Scholar 

  3. Sakiyama-Elbert, S. E. & Hubbell, J. A. Controlled release of nerve growth factor from a heparin-containing fibrin-based cell ingrowth matrix. J. Control Release 69, 149–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Sakiyama-Elbert, S. E. & Hubbell, J. A. Development of fibrin derivatives for controlled release of heparin-binding growth factors. J. Control Release 65, 389–402 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Taylor, S. J., McDonald, J. W. 3rd & Sakiyama-Elbert, S. E. Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury. J. Control Release 98, 281–294 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Maxwell, D. J., Hicks, B. C., Parsons, S. & Sakiyama-Elbert, S. E. Development of rationally designed affinity-based drug delivery systems. Acta Biomater. 1, 101–113 (2005).

    Article  PubMed  Google Scholar 

  7. Wood, M. D. et al. Fibrin matrices with affinity-based delivery systems and neurotrophic factors promote functional nerve regeneration. Biotechnol. Bioeng. 106, 970–979 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Konofaos, P. & Terzis, J. K. FK506 and nerve regeneration: past, present, and future. J. Reconstr. Microsurg. 29, 141–148 (2013).

    Article  PubMed  Google Scholar 

  9. Labroo, P. et al. Controlled delivery of FK506 to improve nerve regeneration. Shock 46, 154–159 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Labroo, P., Shea, J., Sant, H., Gale, B. & Agarwal, J. Effect of combining FK506 and neurotrophins on neurite branching and elongation. Muscle Nerve 55, 570–581 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Gordon, T. Electrical stimulation to enhance axon regeneration after peripheral nerve injuries in animal models and humans. Neurotherapeutics 13, 295–310 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Nix, W. A. & Hopf, H. C. Electrical stimulation of regenerating nerve and its effect on motor recovery. Brain Res. 272, 21–25 (1983).

    Article  CAS  PubMed  Google Scholar 

  13. Ray, W. Z., Mahan, M. A., Guo, D., Guo, D. & Kliot, M. An update on addressing important peripheral nerve problems: challenges and potential solutions. Acta Neurochir. (Wien) 159, 1765–1773 (2017).

    Article  Google Scholar 

  14. Cuoco, F. A. Jr & Durand, D. M. Measurement of external pressures generated by nerve cuff electrodes. IEEE Trans. Rehabil. Eng. 8, 35–41 (2000).

    Article  PubMed  Google Scholar 

  15. Leventhal, D. K., Cohen, M. & Durand, D. M. Chronic histological effects of the flat interface nerve electrode. J. Neural Eng. 3, 102–113 (2006).

    Article  PubMed  Google Scholar 

  16. Grill, W. M. & Mortimer, J. T. Neural and connective tissue response to long-term implantation of multiple contact nerve cuff electrodes. J. Biomed. Mater. Res. 50, 215–226 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Zierhofer, M. C. & Hochmair, E. S. Transcutaneous transmission of digital data and energy in a cochlear prosthesis system. Int. J. Artif. Organs 15, 379–382 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Winter, K. F., Hartmann, R. & Klinke, R. A stimulator with wireless power and signal transmission for implantation in animal experiments and other applications. J. Neurosci. Methods 79, 79–85 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Kang, S. K. et al. Bioresorbable silicon electronic sensors for the brain. Nature 530, 71–76 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Wodzicka, M. Studies on the thickness and chemical composition of the skin of sheep. N.Z. J. Agric. Res. 1, 582–591 (1958).

    Article  Google Scholar 

  21. Fornage, B. D. & Deshayes, J. L. Ultrasound of normal skin. J. Clin. Ultrasound 14, 619–622 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Hwang, S. W. et al. Dissolution chemistry and biocompatibility of single-crystalline silicon nanomembranes and associated materials for transient electronics. ACS Nano 8, 5843–5851 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Yin, L. et al. Dissolvable metals for transient electronics. Adv. Funct. Mater. 24, 645–658 (2014).

    Article  CAS  Google Scholar 

  24. Rojas-Molina, R., De León-Zapata, M. A., Saucedo-Pompa, S., Aguilar-Gonzalez, M. A. & Aguilar, C. N. Chemical and structural characterization of Candelilla (Euphorbia antisyphilitica Zucc.). J. Med. Plant Res. 7, 702–705 (2013).

    CAS  Google Scholar 

  25. Petersson, A. E. et al. Wax esters produced by solvent-free energy-efficient enzymatic synthesis and their applicability as wood coatings. Green Chem. 7, 837–843 (2005).

    Article  CAS  Google Scholar 

  26. Vieira, M. G. A., da Silva, M. A., dos Santos, L. O. & Beppu, M. M. Natural-based plasticizers and biopolymer films: a review. Eur. Polym J. 47, 254–263 (2011).

    Article  CAS  Google Scholar 

  27. Gamble, P., Stephen, M., MacEwan, M. & Ray, W. Z. Serial assessment of functional recovery following nerve injury using implantable thin-film wireless nerve stimulators. Muscle Nerve 54, 1114–1119 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Brushart, T. M. et al. Electrical stimulation promotes motoneuron regeneration without increasing its speed or conditioning the neuron. J. Neurosci. 22, 6631–6638 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Elzinga, K. et al. Brief electrical stimulation improves nerve regeneration after delayed repair in Sprague Dawley rats. Exp. Neurol. 269, 142–153 (2015).

    Article  PubMed  Google Scholar 

  30. Gordon, T., Amirjani, N., Edwards, D. C. & Chan, K. M. Brief post-surgical electrical stimulation accelerates axon regeneration and muscle reinnervation without affecting the functional measures in carpal tunnel syndrome patients. Exp. Neurol. 223, 192–202 (2010).

    Article  PubMed  Google Scholar 

  31. Gordon, T. & English, A. W. Strategies to promote peripheral nerve regeneration: electrical stimulation and/or exercise. Eur. J. Neurosci. 43, 336–350 (2016).

    Article  PubMed  Google Scholar 

  32. Gordon, T., Udina, E., Verge, V. M. K. & de Chaves, E. I. P. Brief electrical stimulation accelerates axon regeneration in the peripheral nervous system and promotes sensory axon regeneration in the central nervous system. Motor Control 13, 412–441 (2009).

    Article  PubMed  Google Scholar 

  33. Willand, M. P., Nguyen, M. A., Borschel, G. H. & Gordon, T. Electrical stimulation to promote peripheral nerve regeneration. Neurorehabil. Neural Repair 30, 490–496 (2016).

    Article  PubMed  Google Scholar 

  34. Christensen, M. B., Wark, H. A. C. & Hutchinson, D. T. A histological analysis of human median and ulnar nerves following implantation of Utah slanted electrode arrays. Biomaterials 77, 235–242 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Srinivasan, A. et al. Microchannel-based regenerative scaffold for chronic peripheral nerve interfacing in amputees. Biomaterials 41, 151–165 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Sasaki, R. et al. PLGA artificial nerve conduits with dental pulp cells promote facial nerve regeneration. J. Tissue Eng. Regen. Med. 5, 823–830 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Yang, Y. et al. Biocompatibility evaluation of silk fibroin with peripheral nerve tissues and cells in vitro. Biomaterials 28, 1643–1652 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Anderson, J. M. & Shive, M. S. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Deliv. Rev. 64, 72–82 (2012).

    Article  Google Scholar 

  39. Gu, X., Zheng, Y., Cheng, Y., Zhong, S. & Xi, T. In vitro corrosion and biocompatibility of binary magnesium alloys. Biomaterials 30, 484–498 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Lee, S. et al. Metal microparticle: polymer composites as printable, bio/ecoresorbable conductive inks. Mater. Today 21, 207–215 (2018).

    Article  CAS  Google Scholar 

  41. Lee, Y. RFID Coil Design. Report No. AN678 http://ww1.microchip.com/downloads/en/AppNotes/00678b.pdf (Microchip Technology Inc., 1998).

  42. Hingne, P. M. & Sluka, K. A. Differences in waveform characteristics have no effect on the anti-hyperalgesia produced by transcutaneous electrical nerve stimulation (TENS) in rats with joint inflammation. J. Pain 8, 251–255 (2007).

    Article  PubMed  Google Scholar 

  43. Barr, J. O., Nielsen, D. H. & Soderberg, G. L. Transcutaneous electrical nerve stimulation characteristics for altering pain perception. Phys. Ther. 66, 1515–1521 (1986).

    Article  CAS  PubMed  Google Scholar 

  44. Patel, N. B., Xie, Z., Young, S. H. & Poo, M. Response of nerve growth cone to focal electric currents. J. Neurosci. Res. 13, 245–256 (1985).

    Article  CAS  PubMed  Google Scholar 

  45. Winter, W. G., Schutt, R. C., Sisken, B. F. & Smith, S. D. Effects of low levels of direct current on peripheral nerve regeneration. Trans. Orthop. Res. Soc. 6, 304 (1981).

    Google Scholar 

  46. Hunter, D. A. et al. Binary imaging analysis for comprehensive quantitative histomorphometry of peripheral nerve. J. Neurosci. Methods 166, 116–124 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Mendez, J. & Keys, A. Density and composition of mammalian muscle. Metabolism 9, 184–188 (1960).

    CAS  Google Scholar 

  48. Gans, C. Fiber architecture and muscle function. Exerc. Sport Sci. Rev. 10, 160–207 (1982).

    Article  CAS  PubMed  Google Scholar 

  49. Kalliainen, L. K., Jejurikar, S. S., Liang, L. W., Urbanchek, M. G. & Kuzon, W. M. Jr A specific force deficit exists in skeletal muscle after partial denervation. Muscle Nerve 25, 31–38 (2002).

    Article  PubMed  Google Scholar 

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Acknowledgements

S.-K.K. is supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2018R1C1B5043901). H.M.L. is supported by a grant from NRF funded by the Korean government (MEST) (2011-0028612). Z.X. acknowledges support from the National Natural Science Foundation of China (grant no.11402134). Y.H. acknowledges support from National Science Foundation (grant nos. 1400169, 1534120, and 1635443). J.A.R. acknowledges support from DARPA and from the Center for Bio-Integrated Electronics at Northwestern University. We thank S. J. Robinson (Beckman Institute, University of Illinois at Urbana-Champaign) and K. Doty (Department of Comparative Biosciences Histology Service Laboratory, University of Illinois at Urbana-Champaign) for histology staining and images that greatly improved the manuscript.

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J. Koo, S.-K.K., S.M.W., Y.-Y.C., S.C., and J.A.R. designed and made the device. J. Koo, M.R.M., S.-K.K., S.B.K., S.M.L., J. Kim, R.Z., J.S., D.V.H., A.B., H.M.L., W.Z.R., and J.A.R. conceived the idea and performed the experiments and analysis. M.R.M., M.S., P.G., N.B., J. Khalifeh, Z.S.Z., K.B., M.P., Y.Y., and W.Z.R. performed the animal surgery, collected the nerve regeneration data, and analyzed the immunohistochemistry. Z.X., K.L., B.J., and Y.H. designed the antennas and ran the electromagnetic simulation. J. Koo, S.-K.K., M.R.M., Y.H., W.Z.R., and J.A.R. wrote the manuscript.

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Correspondence to Wilson Z. Ray or John A. Rogers.

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Supplementary Video 1

Twitch response by stimulating sciatic nerve with bioresorbable stimulator

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Koo, J., MacEwan, M.R., Kang, SK. et al. Wireless bioresorbable electronic system enables sustained nonpharmacological neuroregenerative therapy. Nat Med 24, 1830–1836 (2018). https://doi.org/10.1038/s41591-018-0196-2

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