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Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces

Abstract

Implantable neural microelectrodes that can record extracellular biopotentials from small, targeted groups of neurons are critical for neuroscience research and emerging clinical applications including brain-controlled prosthetic devices. The crucial material-dependent problem is developing microelectrodes that record neural activity from the same neurons for years with high fidelity and reliability. Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad. The resulting implants are an order of magnitude smaller than traditional recording electrodes, and more mechanically compliant with brain tissue. They were found to elicit much reduced chronic reactive tissue responses and enabled single-neuron recording in acute and early chronic experiments in rats. This technology, taking advantage of new composites, makes possible highly selective and stealthy neural interface devices towards realizing long-lasting implants.

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Figure 1: Microthread electrodes.
Figure 2: In vitro electrical characterization of MTEs.
Figure 3: Physical characteristics of the MTEs.
Figure 4: In vivo single-unit recording capabilities.
Figure 5: Chronic in vivo recording capabilities of MTEs.
Figure 6: Histological comparison of tissue reaction to chronically implanted microthread and silicon probes.

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References

  1. Strumwasser, F. Long-term recording’ from single neurons in brain of unrestrained mammals. Science 127, 469–470 (1958).

    CAS  Google Scholar 

  2. Kipke, D. R. et al. Advanced neurotechnologies for chronic neural interfaces: New horizons and clinical opportunities. J. Neurosci. 28, 11830–11838 (2008).

    CAS  Google Scholar 

  3. Schmidt, E. M., Bak, M. J. & McIntosh, J. S. Long-term chronic recording from cortical neurons. Exp. Neurol. 52, 496–506 (1976).

    CAS  Google Scholar 

  4. Grill, W. M., Norman, S. E. & Bellamkonda, R. V. Implanted neural interfaces: Biochallenges and engineered solutions. Annu. Rev. Biomed. Eng. 11, 1–24 (2009).

    CAS  Google Scholar 

  5. Biran, R., Martin, D. C. & Tresco, P. A. Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays. Exp. Neurol. 195, 115–126 (2005).

    CAS  Google Scholar 

  6. Rousche, P. J. & Normann, R. A. Chronic recording capability of the Utah intracortical electrode array in cat sensory cortex. J. Neurosci. Methods 82, 1–15 (1998).

    CAS  Google Scholar 

  7. Ward, M. P., Rajdev, P., Ellison, C. & Irazoqui, P. P. Toward a comparison of microelectrodes for acute and chronic recordings. Brain Res. 1282, 183–200 (2009).

    CAS  Google Scholar 

  8. Purcell, E. K., Thompson, D. E., Ludwig, K. A. & Kipke, D. R. Flavopiridol reduces the impedance of neural prostheses in vivo without affecting recording quality. J. Neurosci. Methods 183, 149–157 (2009).

    CAS  Google Scholar 

  9. Kozai, T. D. Y., Vazquez, A. L., Weaver, C. L., Kim, S. G. & Cui, X. T. In vivo two photon microscopy reveals immediate microglial reaction to implantation of microelectrode through extension of processes. J. Neural Eng. 9, 066001 (2012).

    Google Scholar 

  10. Ludwig, K. A., Uram, J. D., Yang, J., Martin, D. C. & Kipke, D. R. Chronic neural recordings using silicon microelectrode arrays electrochemically deposited with a poly(3,4-ethylenedioxythiophene) (PEDOT) film. J. Neural Eng. 3, 59–70 (2006).

    Google Scholar 

  11. Szarowski, D. H. et al. Brain responses to micro-machined silicon devices. Brain Res. 983, 23–35 (2003).

    CAS  Google Scholar 

  12. Polikov, V. S., Tresco, P. A. & Reichert, W. M. Response of brain tissue to chronically implanted neural electrodes. J. Neurosci. Methods 148, 1–18 (2005).

    Google Scholar 

  13. Clark, J. J. et al. Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals. Nature Methods 7, 126–129 (2010).

    CAS  Google Scholar 

  14. Van Horne, C. G., Bement, S., Hoffer, B. J. & Gerhardt, G. A. Multichannel semiconductor-based electrodes for in vivo electrochemical and electrophysiological studies in rat CNS. Neurosci. Lett. 120, 249–252 (1990).

    CAS  Google Scholar 

  15. Matsumura, M., Chen, D., Sawaguchi, T., Kubota, K. & Fetz, E. E. Synaptic interactions between primate precentral cortex neurons revealed by spike-triggered averaging of intracellular membrane potentials in vivo. J. Neurosci. 16, 7757–7767 (1996).

    CAS  Google Scholar 

  16. Neary, J. T., Kang, Y., Willoughby, K. A. & Ellis, E. F. Activation of extracellular signal-regulated kinase by stretch-induced injury in astrocytes involves extracellular ATP and P2 purinergic receptors. J. Neurosci. 23, 2348–2356 (2003).

    CAS  Google Scholar 

  17. Subbaroyan, J., Martin, D. C. & Kipke, D. R. A finite-element model of the mechanical effects of implantable microelectrodes in the cerebral cortex. J. Neural Eng. 2, 103–113 (2005).

    Google Scholar 

  18. Lee, H., Bellamkonda, R. V., Sun, W. & Levenston, M. E. Biomechanical analysis of silicon microelectrode-induced strain in the brain. J. Neural Eng. 2, 81–89 (2005).

    Google Scholar 

  19. LaPlaca, M. C., Cullen, D. K., McLoughlin, J. J. & Cargill, R. S. 2nd High rate shear strain of three-dimensional neural cell cultures: A new in vitro traumatic brain injury model. J. Biomech. 38, 1093–1105 (2005).

    Google Scholar 

  20. Gilletti, A. & Muthuswamy, J. Brain micromotion around implants in the rodent somatosensory cortex. J. Neural Eng. 3, 189–195 (2006).

    Google Scholar 

  21. Kim, D. H. et al. Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics. Nature Mater. 9, 511–517 (2010).

    CAS  Google Scholar 

  22. Takeuchi, S., Ziegler, D., Yoshida, Y., Mabuchi, K. & Suzuki, T. Parylene flexible neural probes integrated with microfluidic channels. Lab Chip 5, 519–523 (2005).

    CAS  Google Scholar 

  23. Rousche, P. J. et al. Flexible polyimide-based intracortical electrode arrays with bioactive capability. IEEE Trans. Biomed. Eng. 48, 361–371 (2001).

    CAS  Google Scholar 

  24. Seymour, J. P. & Kipke, D. R. Neural probe design for reduced tissue encapsulation in CNS. Biomaterials 28, 3594–3607 (2007).

    CAS  Google Scholar 

  25. Cui, X. T. & Zhou, D. D. Poly (3,4-ethylenedioxythiophene) for chronic neural stimulation. IEEE Trans. Neural Syst. Rehabil. Eng. 15, 502–508 (2007).

    Google Scholar 

  26. Azemi, E., Lagenaur, C. F. & Cui, X. T. The surface immobilization of the neural adhesion molecule L1 on neural probes and its effect on neuronal density and gliosis at the probe/tissue interface. Biomaterials 32, 681–692 (2011).

    CAS  Google Scholar 

  27. Lahann, J. Vapor-based polymer coatings for potential biomedical applications. Polym. Int. 55, 1361–1370 (2006).

    CAS  Google Scholar 

  28. Jiang, X. W., Chen, H. Y., Galvan, G., Yoshida, M. & Lahann, J. Vapor-based initiator coatings for atom transfer radical polymerization. Adv. Funct. Mater. 18, 27–35 (2008).

    CAS  Google Scholar 

  29. Katira, P. et al. Quantifying the performance of protein-resisting surfaces at ultra-low protein coverages using kinesin motor proteins as probes. Adv. Mater. 19, 3171 (2007).

    CAS  Google Scholar 

  30. Jan, E. et al. Layered carbon nanotube-polyelectrolyte electrodes outperform traditional neural interface materials. Nano Lett. 9, 4012–4018 (2009).

    CAS  Google Scholar 

  31. Harris, J. P. et al. Mechanically adaptive intracortical implants improve the proximity of neuronal cell bodies. J. Neural Eng. 8, 066011 (2011).

    CAS  Google Scholar 

  32. Bjornsson, C. S. et al. Effects of insertion conditions on tissue strain and vascular damage during neuroprosthetic device insertion. J. Neural Eng. 3, 196–207 (2006).

    CAS  Google Scholar 

  33. Ivens, S. et al. TGF- β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130, 535–547 (2007).

    Google Scholar 

  34. Nadal, A., Fuentes, E., Pastor, J. & McNaughton, P. A. Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Proc. Natl Acad. Sci. USA 92, 1426–1430 (1995).

    CAS  Google Scholar 

  35. Kozai, T. D. Y. et al. Reduction of neurovascular damage resulting from microelectrode insertion into the cerebral cortex using in vivo two-photon mapping. J. Neural Eng. 7, 046011 (2010).

    CAS  Google Scholar 

  36. Unterberg, A. W., Stover, J., Kress, B. & Kiening, K. L. Edema and brain trauma. Neuroscience 129, 1021–1029 (2004).

    CAS  Google Scholar 

  37. Barzo, P., Marmarou, A., Fatouros, P., Hayasaki, K. & Corwin, F. Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging. J. Neurosurg. 87, 900–907 (1997).

    CAS  Google Scholar 

  38. Dixon, C. E., Clifton, G. L., Lighthall, J. W., Yaghmai, A. A. & Hayes, R. L. A controlled cortical impact model of traumatic brain injury in the rat. J. Neurosci. Methods 39, 253–262 (1991).

    CAS  Google Scholar 

  39. Nishimura, N., Schaffer, C. B., Friedman, B., Lyden, P. D. & Kleinfeld, D. Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc. Natl Acad. Sci. USA 104, 365–370 (2007).

    CAS  Google Scholar 

  40. Najafi, K. & Suzuki, K. Measurement of fracture stress, Young’s modulus, and intrinsic stress of heavily boron-doped silicon microstructures. Thin Solid Films 181, 251–258 (1989).

    CAS  Google Scholar 

  41. Hosseini, N. H. et al. Comparative study on the insertion behavior of cerebral microprobes. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2007, 4711–4714 (2007).

    Google Scholar 

  42. Seymour, J. P., Langhals, N. B., Anderson, D. J. & Kipke, D. R. Novel multi-sided, microelectrode arrays for implantable neural applications. Biom. Microdevices 13, 441–451 (2011).

    Google Scholar 

  43. Williams, J. C., Rennaker, R. L. & Kipke, D. R. Long-term neural recording characteristics of wire microelectrode arrays implanted in cerebral cortex. Brain. Res. Brain Res. Protoc. 4, 303–313 (1999).

    CAS  Google Scholar 

  44. Luo, X., Weaver, C. L., Zhou, D. D., Greenberg, R. & Cui, X. T. Highly stable carbon nanotube doped poly(3,4-ethylenedioxythiophene) for chronic neural stimulation. Biomaterials 32, 5551–5557 (2011).

    CAS  Google Scholar 

  45. Shim, B. S. et al. Integration of conductivity transparency, and mechanical strength into highly homogeneous layer-by-layer composites of single-walled carbon nanotubes for optoelectronics. Chem. Mater. 19, 5467–5474 (2007).

    CAS  Google Scholar 

  46. Keefer, E. W., Botterman, B. R., Romero, M. I., Rossi, A. F. & Gross, G. W. Carbon nanotube coating improves neuronal recordings. Nature Nanotech. 3, 434–439 (2008).

    CAS  Google Scholar 

  47. Luo, X., Matranga, C., Tan, S., Alba, N. & Cui, X. T. Carbon nanotube nanoreservior for controlled release of anti-inflammatory dexamethasone. Biomaterials 32, 6316–6323 (2011).

    CAS  Google Scholar 

  48. Cui, X. et al. Surface modification of neural recording electrodes with conducting polymer/biomolecule blends. J. Biomed. Mater. Res. 56, 261–272 (2001).

    CAS  Google Scholar 

  49. Kozai, T. D. Y. & Kipke, D. R. Insertion shuttle with carboxyl terminated self-assembled monolayer coatings for implanting flexible polymer neural probes in the brain. J. Neurosci. Methods 184, 199–205 (2009).

    CAS  Google Scholar 

  50. Gilgunn, P. J. et al. An ultra-compliant, scalable neural probe with molded biodissolvable delivery vehicle. in Micro Electro Mechanical Systems (MEMS), 2012 IEEE 25th Int. Conf. on 56–59 (IEEE, 2012).

    Google Scholar 

  51. Kotov, N. A. et al. Nanomaterials for neural interfaces. Adv. Mater. 21, 1–35 (2009).

    Google Scholar 

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Acknowledgements

This work was financially supported by a National Institutes of Health Challenge Grant in Health and Science Research from the National Institute of Neurological Disorders and Stroke (1RC1NS068396-0110) and the Center for Neural Communication Technology, a P41 Resource Center funded by the National Institute of Biomedical Imaging and Bioengineering (P41 EB002030). A. Agarwal and F. S. Midani assisted in chronic probe assembly/packaging, chronic surgery and chronic electrophysiological recordings. A. L. Ryan and S. Saha conducted ATRP. H-Y. Chen carried out Raman spectroscopy. Multiphoton imaging of chronically implanted tissue was conducted by Wadsworth Center Advanced Light Microscopy & Image Analysis Core. L. Hains cut the tissue and conducted preliminary immunohistochemistry. Confocal images were collected on the Zeiss LSM510 at the University of Michigan Microscopy and Image Analysis Laboratory. N.A.K. and D.R.K. acknowledge partial financial support of this work from a DARPA STTR grant (W31P4Q-08-C-0426).

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T.D.Y.K., N.B.L., J.L., N.A.K. and D.R.K. planned the project. Carbon fibres were provided by H.Z. MTEs were assembled by T.D.Y.K. and P.R.P. CVD parameters were designed by X.D., and CVD was carried out by X.D. and T.D.Y.K. PEGMA coatings and biofouling testing were carried out by X.D. Raman spectroscopy data were analysed by X.D. PEDOT deposition parameters were designed by N.B.L. and T.D.Y.K. and carried out by P.R.P. and T.D.Y.K. P.R.P. and T.D.Y.K. also conducted in vitro characterization of the devices. SEM imaging and energy-dispersive X-ray analysis was carried out by H.Z. In vivo recordings were carried out by N.B.L. and T.D.Y.K. Chronic in vivo experiments were planned, carried out and analysed by T.D.Y.K. Data analysis was carried out by N.B.L. and T.D.Y.K. K.L.S. led and carried out the two-photon immunohistochemistry and imaging for the chronic implant. Cryo-immunohistochemistry was planned by P.R.P. and T.D.Y.K. and conducted by T.D.Y.K. T.D.Y.K. and D.R.K. wrote the manuscript. All authors discussed the results.

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Correspondence to Takashi D. Yoshida Kozai, Nicholas A. Kotov or Daryl R. Kipke.

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Competing interests

D.R. Kipke has a significant financial and leadership interest in NeuroNexus Technologies, a company specializing in neural interface devices. At the time of this study, N.B. Langhals was a consultant for NeuroNexus Technologies.

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Kozai, T., Langhals, N., Patel, P. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nature Mater 11, 1065–1073 (2012). https://doi.org/10.1038/nmat3468

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