Optically controlled nongenetic neuromodulation represents a promising approach for the fundamental study of neural circuits and the clinical treatment of neurological disorders. Among the existing material candidates that can transduce light energy into biologically relevant cues, silicon (Si) is particularly advantageous due to its highly tunable electrical and optical properties, ease of fabrication into multiple forms, ability to absorb a broad spectrum of light, and biocompatibility. This protocol describes a rational design principle for Si-based structures, general procedures for material synthesis and device fabrication, a universal method for evaluating material photoresponses, detailed illustrations of all instrumentation used, and demonstrations of optically controlled nongenetic modulation of cellular calcium dynamics, neuronal excitability, neurotransmitter release from mouse brain slices, and brain activity in the mouse brain in vivo using the aforementioned Si materials. The entire procedure takes ~4–8 d in the hands of an experienced graduate student, depending on the specific biological targets. We anticipate that our approach can also be adapted in the future to study other systems, such as cardiovascular tissues and microbial communities.

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Data availability

The authors declare that all data supporting the findings of this study are available within the original papers. Other supporting data are available upon reasonable request to the corresponding authors.

Additional information

Journal peer review information: Nature Protocols thanks Tal Dvir and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Key references using this protocol

Jiang, Y. et al. Nat. Mater. 15, 1023–1030 (2016): https://doi.org/10.1038/nmat4673

Parameswaran, R. et al. Nat. Nanotechnol. 13, 260–266 (2018): https://doi.org/10.1038/s41565-017-0041-7

Jiang, Y. et al. Nat. Biomed. Eng. 2, 508–521 (2018): https://doi.org/10.1038/s41551-018-0230-1


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This work was supported by the Air Force Office of Scientific Research (AFOSR FA9550-18-1-0503), the US Army Research Office (W911NF-18-1-0042), the US Office of Naval Research (N000141612530, N000141612958), the National Science Foundation (NSF MRSEC, DMR 1420709), the Searle Scholars Foundation, the National Institutes of Health (NIH NS101488, NS061963, GM030376, R21-EY023430, R21-EY027101), an MSTP Training Grant (T32GM007281), and the Paul and Daisy Soros Foundation. Atom-probe tomography was performed at the Northwestern University Center for Atom-Probe Tomography (NUCAPT), whose atom-probe tomography equipment was purchased and upgraded with funding from NSF-MRI (DMR-0420532) and ONR-DURIP (N00014-0400798, N00014-0610539, N00014-0910781) grants. NUCAPT is a Research Facility at the Materials Research Center of Northwestern University, supported by the National Science Foundation’s MRSEC program (grant DMR-1121262). Instrumentation at NUCAPT was further upgraded by the Initiative for Sustainability and Energy at Northwestern (ISEN). This work made use of the Japan Electron Optics Laboratory (JEOL) JEM-ARM200CF and JEOL JEM-3010 TEM in the Electron Microscopy Service of the Research Resources Center at the University of Illinois at Chicago (UIC). The acquisition of the UIC JEOL JEM-ARM200CF was supported by an MRI-R2 grant from the National Science Foundation (DMR-0959470).

Author information

Author notes

  1. These authors contributed equally: Yuanwen Jiang, Ramya Parameswaran, Xiaojian Li, João L. Carvalho-de-Souza.


  1. Department of Chemistry, The University of Chicago, Chicago, IL, USA

    • Yuanwen Jiang
    •  & Bozhi Tian
  2. The James Franck Institute, The University of Chicago, Chicago, IL, USA

    • Yuanwen Jiang
    • , Xiang Gao
    •  & Bozhi Tian
  3. The Graduate Program in Biophysical Sciences, The University of Chicago, Chicago, IL, USA

    • Ramya Parameswaran
  4. Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    • Xiaojian Li
    •  & Gordon M. G. Shepherd
  5. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA

    • João L. Carvalho-de-Souza
    •  & Francisco Bezanilla
  6. Insitute for Molecular Engineering, The University of Chicago, Chicago, IL, USA

    • Lingyuan Meng
  7. Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA

    • Francisco Bezanilla
    •  & Bozhi Tian
  8. Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

    • Francisco Bezanilla


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Y.J., R.P., X.L., J.L.C.-d.-S., F.B., G.M.G.S., and B.T. developed the protocol. Y.J., R.P., X.L., and J.L.C.-d.-S. performed the experiments. Y.J., R.P., X.L., and B.T. wrote the manuscript with input from J.L.C.-d.-S., X.G., L.M., F.B., and G.M.G.S.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Yuanwen Jiang or Bozhi Tian.

Supplementary information

  1. Reporting Summary

  2. Supplementary Data 1

    Mask design for the Si mesh structure

  3. Supplementary Data 2

    Mask design for the SU-8 pillar structure

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