As an important application of functional biomaterials, neural probes have contributed substantially to studying the brain. Bioinspired and biomimetic strategies have begun to be applied to the development of neural probes, although these and previous generations of probes have had structural and mechanical dissimilarities from their neuron targets that lead to neuronal loss, neuroinflammatory responses and measurement instabilities. Here, we present a bioinspired design for neural probes—neuron-like electronics (NeuE)—where the key building blocks mimic the subcellular structural features and mechanical properties of neurons. Full three-dimensional mapping of implanted NeuE–brain interfaces highlights the structural indistinguishability and intimate interpenetration of NeuE and neurons. Time-dependent histology and electrophysiology studies further reveal a structurally and functionally stable interface with the neuronal and glial networks shortly following implantation, thus opening opportunities for next-generation brain–machine interfaces. Finally, the NeuE subcellular structural features are shown to facilitate migration of endogenous neural progenitor cells, thus holding promise as an electrically active platform for transplantation-free regenerative medicine.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The code used for data analysis is available from the corresponding author upon reasonable request.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ma, X. et al. Tuning crystallization pathways through sequence engineering of biomimetic polymers. Nat. Mater. 16, 767–774 (2017).
Fratzl, P., Kolednik, O., Fischer, F. D. & Dean, M. N. The mechanics of tessellations—bioinspired strategies for fracture resistance. Chem. Soc. Rev. 45, 252–267 (2016).
Green, J. J. & Elisseeff, J. H. Mimicking biological functionality with polymers for biomedical applications. Nature 540, 386–394 (2016).
Sadtler, K. et al. Design, clinical translation and immunological response of biomaterials in regenerative medicine. Nat. Rev. Mater. 1, 16040 (2016).
Chen, R., Canales, A. & Anikeeva, P. Neural recording and modulation technologies. Nat. Rev. Mater. 2, 16093 (2017).
Feiner, R. & Dvir, T. Tissue–electronics interfaces: from implantable devices to engineered tissues. Nat. Rev. Mater. 3, 17076 (2017).
Shoffstall, A. J. & Capadona, J. R. Bioinspired materials and systems for neural interfacing. Curr. Opin. Biomed. Eng. 6, 110–119 (2018).
Capadona, J. R., Shanmuganathan, K., Tyler, D. J., Rowan, S. J. & Weder, C. Stimuli-responsive polymer nanocomposites inspired by the sea cucumber dermis. Science 319, 1370–1374 (2008).
Smith, D. W. et al. Internal jugular vein compression mitigates traumatic axonal injury in a rat model by reducing the intracranial slosh effect. Neurosurgery 70, 740–746 (2012).
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).
Salatino, J. W., Ludwig, K. A., Kozai, T. D. Y. & Purcell, E. K. Glial responses to implanted electrodes in the brain. Nat. Biomed. Eng. 1, 862–877 (2017).
Kozai, T. D. Y. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nat. Mater. 11, 1065–1073 (2012).
Charkhkar, H. et al. Chronic intracortical neural recordings using microelectrode arrays coated with PEDOT–TFB. Acta Biomater. 32, 57–67 (2016).
Bedell, H. W. et al. Targeting CD14 on blood derived cells improves intracortical microelectrode performance. Biomaterials 163, 163–173 (2018).
Arati, S., Subramaniam, D. R. & Jit, M. Long-term changes in the material properties of brain tissue at the implant–tissue interface. J. Neural Eng. 10, 066001 (2013).
Liu, J. et al. Syringe-injectable electronics. Nat. Nanotechnol. 10, 629–636 (2015).
Fu, T.-M. et al. Stable long-term chronic brain mapping at the single-neuron level. Nat. Methods 13, 875–882 (2016).
Zhou, T. et al. Syringe-injectable mesh electronics integrate seamlessly with minimal chronic immune response in the brain. Proc. Natl Acad. Sci. USA 114, 5894–5899 (2017).
Canales, A. et al. Multifunctional fibers for simultaneous optical, electrical and chemical interrogation of neural circuits in vivo. Nat. Biotechnol. 33, 277–284 (2015).
Park, S. et al. One-step optogenetics with multifunctional flexible polymer fibers. Nat. Neurosci. 20, 612–619 (2017).
Minev, I. R. et al. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).
Luan, L. et al. Ultraflexible nanoelectronic probes form reliable, glial scar–free neural integration.Sci. Adv. 3, e1601966 (2017).
Garcia, J., Pena, J., McHugh, S. & Jerusalem, A. A model of the spatially dependent mechanical properties of the axon during its growth. Comput. Model. Eng. Sci. 87, 411–432 (2012).
Wang, S. S.-H. et al. Functional trade-offs in white matter axonal scaling. J. Neurosci. 28, 4047–4056 (2008).
Fu, T.-M., Hong, G., Viveros, R. D., Zhou, T. & Lieber, C. M. Highly scalable multichannel mesh electronics for stable chronic brain electrophysiology. Proc. Natl Acad. Sci. USA 114, E10046–E10055 (2017).
Jun, J. J. et al. Fully integrated silicon probes for high-density recording of neural activity. Nature 551, 232–236 (2017).
Hong, G. S. et al. Syringe injectable electronics: precise targeted delivery with quantitative input/output connectivity. Nano Lett. 15, 6979–6984 (2015).
Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000).
Zhuo, L. et al. Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev. Biol. 187, 36–42 (1997).
Chung, K. et al. Structural and molecular interrogation of intact biological systems. Nature 497, 332–337 (2013).
Yang, B. et al. Single-cell phenotyping within transparent intact tissue through whole-body clearing. Cell 158, 945–958 (2014).
Saxena, T. & Bellamkonda, R. V. A sensor web for neurons. Nat. Mater. 14, 1190–1191 (2015).
Igarashi, K. M., Lu, L., Colgin, L. L., Moser, M.-B. & Moser, E. I. Coordination of entorhinal–hippocampal ensemble activity during associative learning. Nature 510, 143–147 (2014).
Jackson, A. & Fetz, E. E. Compact movable microwire array for long-term chronic unit recording in cerebral cortex of primates. J. Neurophysiol. 98, 3109–3118 (2007).
Dickey, A. S., Suminski, A., Amit, Y. & Hatsopoulos, N. G. Single-unit stability using chronically implanted multielectrode arrays. J. Neurophysiol. 102, 1331–1339 (2009).
Quiroga, R. Q., Nadasdy, Z. & Ben-Shaul, Y. Unsupervised spike detection and sorting with wavelets and superparamagnetic clustering. Neural Comput. 16, 1661–1687 (2004).
Schmitzer-Torbert, N., Jackson, J., Henze, D., Harris, K. & Redish, A. D. Quantitative measures of cluster quality for use in extracellular recordings. Neuroscience 131, 1–11 (2005).
Schmitzer-Torbert, N. & Redish, A. D. Neuronal activity in the rodent dorsal striatum in sequential navigation: separation of spatial and reward responses on the multiple T task. J. Neurophysiol. 91, 2259–2272 (2004).
Spratley, J. P. F., Ward, M. C. L. & Hall, P. S. Bending characteristics of SU-8. IET Micro Nano Lett. 2, 20–23 (2007).
Jog, M. S. et al. Tetrode technology: advances in implantable hardware, neuroimaging, and data analysis techniques. J. Neurosci. Methods 117, 141–152 (2002).
Buzsáki, G. et al. Tools for probing local circuits: high-density silicon probes combined with optogenetics. Neuron 86, 92–105 (2015).
Weiler, S. et al. High-yield in vitro recordings from neurons functionally characterized in vivo. Nat. Protoc. 13, 1275–1293 (2018).
Cossell, L. et al. Functional organization of excitatory synaptic strength in primary visual cortex. Nature 518, 399–403 (2015).
Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).
Gonçalves, J. T., Schafer, S. T. & Gage, F. H. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167, 897–914 (2016).
Ming, G.-l & Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28, 223–250 (2005).
Reza, M. et al. In vivo migration of endogenous brain progenitor cells guided by an injectable peptide amphiphile biomaterial. J. Tissue Eng. Regen. Med. 12, e2123–e2133 (2018).
James, C. B. et al. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates. J. Neural Eng. 10, 066014 (2013).
Rozenberg, B. Kinetics, thermodynamics and mechanism of reactions of epoxy oligomers with amines. Adv. Polym. Sci. 75, 113–165 (1986).
Schuhmann, T. G., Yao, J., Hong, G., Fu, T.-M. & Lieber, C. M. Syringe-injectable electronics with a plug-and-play input/output interface. Nano Lett. 17, 5836–5842 (2017).
Schuhmann, T. G. et al. Syringe-injectable mesh electronics for stable chronic rodent electrophysiology. J. Vis. Exp. 137, e58003 (2018).
Murray, E. et al. Simple, scalable proteomic imaging for high-dimensional profiling of intact systems. Cell 163, 1500–1514 (2015).
The authors thank D. Richardson and S. Terclavers for help with image acquisition, data handling and critical discussion, and J. Huang for assistance with recording instrumentation. This work is supported by the National Institute on Drug Abuse of the National Institutes of Health (1R21DA043985-01), a NIH Director’s Pioneer Award (1DP1EB025835-01) and the Air Force Office of Scientific Research (FA9550-14-1-0136) (to C.M.L.), the Simmons Awards (to X.Y.) and an American Heart Association Postdoctoral Fellowship (16POST27250219) and NIH Pathway to Independence Award (1K99AG056636-02) (to G.H.). This work was performed in part at the Harvard Center for Biological Imaging (HCBI) and Harvard University Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI) supported by the National Science Foundation.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Notes, Supplementary Figures 1–21, Supplementary Tables 1–3, Supplementary Video Legends 1–3, Supplementary References
Full 3D NeuE/neuron interface—360°-rotation video of the full 3D NeuE/neuron interface shown in Fig. 1d. Green and red colours represent neurons and NeuE, respectively.
Structurally indistinguishable NeuE/neuron interface—video showing depth-coding structures corresponding to Fig. 1f(II), highlighting structural indistinguishability between neuron neurites and NeuE neurite-like interconnects.
Junction between neuron neurites and NeuE neurite-like interconnect—video showing channel-coding and depth-coding structures corresponding to Fig. 1f(III),(IV), highlighting closely contacted junction between neuron neurites and NeuE neurite-like interconnect.
About this article
Cite this article
Yang, X., Zhou, T., Zwang, T.J. et al. Bioinspired neuron-like electronics. Nat. Mater. 18, 510–517 (2019). https://doi.org/10.1038/s41563-019-0292-9
Recent advances in three-dimensional microelectrode array technologies for in vitro and in vivo cardiac and neuronal interfaces
Biosensors and Bioelectronics (2021)
Chemical Society Reviews (2020)
Nature Communications (2020)
Science Advances (2020)
Supramolecular Peptide Hydrogel-Based Soft Neural Interface Augments Brain Signals through a Three-Dimensional Electrical Network
ACS Nano (2020)