Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation


Both in vivo neuropharmacology and optogenetic stimulation can be used to decode neural circuitry, and can provide therapeutic strategies for brain disorders. However, current neuronal interfaces hinder long-term studies in awake and freely behaving animals, as they are limited in their ability to provide simultaneous and prolonged delivery of multiple drugs, are often bulky and lack multifunctionality, and employ custom control systems with insufficiently versatile selectivity for output mode, animal selection and target brain circuits. Here, we describe smartphone-controlled, minimally invasive, soft optofluidic probes with replaceable plug-like drug cartridges for chronic in vivo pharmacology and optogenetics with selective manipulation of brain circuits. We demonstrate the use of the probes for the control of the locomotor activity of mice for over four weeks via programmable wireless drug delivery and photostimulation. Owing to their ability to deliver both drugs and photopharmacology into the brain repeatedly over long time periods, the probes may contribute to uncovering the basis of neuropsychiatric diseases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Design and operation principles of soft optofluidic probe system with replaceable plug-n-play drug cartridges.
Fig. 2: Thermal, fluidic and mechanical characteristics of wireless plug-n-play optofluidic neural implants.
Fig. 3: Smartphone control of wireless plug-n-play optofluidic neural implants.
Fig. 4: Chronic, wireless drug delivery produces repeatable behavioural changes in mice.
Fig. 5: Wireless, selective control of drug delivery within a group of simultaneously behaving mice.
Fig. 6: Incorporation of wireless photostimulation and wireless pharmacology in awake, behaving mice.

Data availability

The authors declare that all data supporting the results in this study are available within the paper and its Supplementary Information.

Code availability

All BLE firmware is available in the Supplementary Information.


  1. Felix-Ortiz, A. C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013).

    Article  CAS  Google Scholar 

  2. Jennings, J. H. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013).

    Article  CAS  Google Scholar 

  3. Kramer, R. H., Mourot, A. & Adesnik, H. Optogenetic pharmacology for control of native neuronal signaling proteins. Nat. Neurosci. 16, 816–823 (2013).

    Article  Google Scholar 

  4. McCall, J. G. & Jeong, J.-W. Minimally invasive probes for programmed microfluidic delivery of molecules in vivo. Curr. Opin. Pharmacol. 36, 78–85 (2017).

    Article  CAS  Google Scholar 

  5. Sim, J. Y., Haney, M. P., Park, S. I., McCall, J. G. & Jeong, J.-W. Microfluidic neural probes: in vivo tools for advancing neuroscience. Lab. Chip 17, 1406–1435 (2017).

    Article  CAS  Google Scholar 

  6. Park, S. et al. One-step optogenetics with multifunctional flexible polymer fibers. Nat. Neurosci. 20, 612–619 (2017).

    Article  CAS  Google Scholar 

  7. Canales, A. et al. Multifunctional fibers for simultaneous optical, electrical and chemical interrogation of neural circuits in vivo. Nat. Biotechnol. 33, 277–284 (2015).

    Article  CAS  Google Scholar 

  8. Jeong, J.-W. et al. Wireless optofluidic systems for programmable in vivo pharmacology and optogenetics. Cell 162, 662–674 (2015).

    Article  CAS  Google Scholar 

  9. McCall, J. G. et al. Preparation and implementation of optofluidic neural probes for in vivo wireless pharmacology and optogenetics. Nat. Protoc. 12, 219–237 (2017).

    Article  CAS  Google Scholar 

  10. Hashimoto, M., Hata, A., Miyata, T. & Hirase, H. Programmable wireless light-emitting diode stimulator for chronic stimulation of optogenetic molecules in freely moving mice. Neurophotonics 1, 011002 (2014).

    Article  Google Scholar 

  11. Iwai, Y., Honda, S., Ozeki, H., Hashimoto, M. & Hirase, H. A simple head-mountable LED device for chronic stimulation of optogenetic molecules in freely moving mice. Neurosci. Res. 70, 124–127 (2011).

    Article  Google Scholar 

  12. Kim, T. et al. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 340, 211–216 (2013).

    Article  CAS  Google Scholar 

  13. McCall, J. G. et al. Fabrication and application of flexible, multimodal light-emitting devices for wireless optogenetics. Nat. Protoc. 8, 2413–2428 (2013).

    Article  CAS  Google Scholar 

  14. Noh, K. N. et al. Miniaturized, battery-free optofluidic systems with potential for wireless pharmacology and optogenetics. Small 14, 1702479 (2018).

    Article  Google Scholar 

  15. Park, S. I. et al. Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Nat. Biotechnol. 33, 1280–1286 (2015).

    Article  CAS  Google Scholar 

  16. Shin, G. et al. Flexible near-field wireless optoelectronics as subdermal implants for broad applications in optogenetics. Neuron 93, 509–521 (2017).

    Article  CAS  Google Scholar 

  17. Montgomery, K. L. et al. Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice. Nat. Methods 12, 969–974 (2015).

    Article  CAS  Google Scholar 

  18. Alam, M., Chen, X. & Fernandez, E. A low-cost multichannel wireless neural stimulation system for freely roaming animals. J. Neural Eng. 10, 066010 (2013).

    Article  Google Scholar 

  19. Ativanichayaphong, T., He, J. W., Hagains, C. E., Peng, Y. B. & Chiao, J.-C. A combined wireless neural stimulating and recording system for study of pain processing. J. Neurosci. Methods 170, 25–34 (2008).

    Article  Google Scholar 

  20. Chang, C.-W. & Chiou, J.-C. A wireless and batteryless microsystem with implantable grid electrode/3-dimensional probe array for ECoG and extracellular neural recording in rats. Sensors 13, 4624–4639 (2013).

    Article  Google Scholar 

  21. Park, S. I. et al. Ultraminiaturized photovoltaic and radio frequency powered optoelectronic systems for wireless optogenetics. J. Neural Eng. 12, 056002 (2015).

    Article  Google Scholar 

  22. Pinnell, R. C., Dempster, J. & Pratt, J. Miniature wireless recording and stimulation system for rodent behavioural testing. J. Neural Eng. 12, 066015 (2015).

    Article  CAS  Google Scholar 

  23. Wentz, C. T. et al. A wirelessly powered and controlled device for optical neural control of freely-behaving animals. J. Neural Eng. 8, 046021 (2011).

    Article  Google Scholar 

  24. Yeh, A. J. et al. Wirelessly powering miniature implants for optogenetic stimulation. Appl. Phys. Lett. 103, 163701 (2013).

    Article  Google Scholar 

  25. Massey, L. K. Permeability Properties of Plastics and Elastomers:A Guide to Packaging and Barrier Materials 2nd edn (William Andrew, 2003).

  26. Frank, R., Bronzi, W., Castignani, G. & Engel, T. Bluetooth low energy: an alternative technology for VANET applications. in 2014 11th Annual Conference on Wireless On-demand Network Systems and Services (WONS) 104–107 (IEEE, 2014).

  27. Getting Started with SimbleeCOM v1.0 (RF Digital Corp, 2015).

  28. Jenck, F., Bozarth, M. & Wise, R. A. Contraversive circling induced by ventral tegmental microinjections of moderate doses of morphine and [D-Pen2, D-Pen5]enkephalin. Brain Res. 450, 382–386 (1988).

    Article  CAS  Google Scholar 

  29. Devine, D. P. & Wise, R. A. Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats. J. Neurosci. 14, 1978–1984 (1994).

    Article  CAS  Google Scholar 

  30. Namburi, P., Al-Hasani, R., Calhoon, G. G., Bruchas, M. R. & Tye, K. M. Architectural representation of valence in the limbic system. Neuropsychopharmacology 41, 1697–1715 (2016).

    Article  Google Scholar 

  31. Jennings, J. H., Rizzi, G., Stamatakis, A. M., Ung, R. L. & Stuber, G. D. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517–1521 (2013).

    Article  CAS  Google Scholar 

  32. Al-Hasani, R. et al. Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron 87, 1063–1077 (2015).

    Article  CAS  Google Scholar 

  33. McCall, J. G. et al. CRH Engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron 87, 605–620 (2015).

    Article  CAS  Google Scholar 

  34. Dagdeviren, C. et al. Miniaturized neural system for chronic, local intracerebral drug delivery. Sci. Transl. Med. 10, eaan2742 (2018).

    Article  Google Scholar 

  35. Spieth, S., Schumacher, A., Kallenbach, C., Messner, S. & Zengerle, R. The neuromedicator—a micropump integrated with silicon microprobes for drug delivery in neural research. J. Micromech. Microeng. 22, 065020 (2012).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Qiu, Y. & Park, K. Environment-sensitive hydrogels for drug delivery. Adv. Drug Deliv. Rev. 53, 321–339 (2001).

    Article  CAS  Google Scholar 

  38. Jang, K.-I. et al. Soft network composite materials with deterministic and bio-inspired designs. Nat. Commun. 6, 6566 (2015).

    Article  CAS  Google Scholar 

  39. Liu, Y. et al. Epidermal mechano-acoustic sensing electronics for cardiovascular diagnostics and human-machine interfaces. Sci. Adv. 2, e1601185 (2016).

    Article  Google Scholar 

  40. Banghart, M. R. & Sabatini, B. L. Photoactivatable neuropeptides for spatiotemporally precise delivery of opioids in neural tissue. Neuron 73, 249–259 (2012).

    Article  CAS  Google Scholar 

  41. Tochitsky, I. et al. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron 81, 800–813 (2014).

    Article  CAS  Google Scholar 

  42. Banala, S. et al. Photoactivatable drugs for nicotinic optopharmacology. Nat. Methods 15, 347–350 (2018).

    Article  CAS  Google Scholar 

  43. Mehrabian, A. & Abousleiman, Y. General solutions to poroviscoelastic model of hydrocephalic human brain tissue. J. Theor. Biol. 291, 105–118 (2011).

    Article  Google Scholar 

  44. Liu, Q., Wang, Z., Lou, Y. & Suo, Z. Elastic leak of a seal. Extrem. Mech. Lett. 1, 54–61 (2014).

    Article  Google Scholar 

  45. Bruchas, M. R., Land, B. B., Lemos, J. C. & Chavkin, C. CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS ONE 4, e8528 (2009).

    Article  Google Scholar 

  46. Siuda, E. R. et al. Spatiotemporal control of opioid signaling and behavior. Neuron 86, 923–935 (2015).

    Article  CAS  Google Scholar 

Download references


This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (grant nos. NRF-2018R1C1B6001706 and NRF-2018025230, J.-W.J.). This work was also supported by Mallinckrodt Professorship (M.R.B.), NIH (grant no. R01DA037152), NIDA Diversity Supplement (grant no. R01DA033396-S1, M.R.B. and A.G.), and grant no. NIDA F32DA043999 (D.C.C). Support was also provided by the Hope Center Viral Vectors Core. We thank J.-W. Yu (KAIST) for providing equipment to conduct BLE wireless transmission tests.

Author information

Authors and Affiliations



R.Q., A.G., M.R.B. and J.-W.J. conceptualized the project and designed the experiments with methodology. R.Q., J.A. and A.A. fabricated and prepared the devices for behavioural tests. R.Q., A.G. and D.C.C. performed the in vivo behavioural, tracing and imaging experiments. R.Q., A.G., Z.Z., J.X., J.Y.S., C.Y.K., S.-H.B., B.C.L., K.I.J., J.X., M.R.B. and J.-W.J. performed the investigation, analysed the data and wrote up the modelling results. R.Q., Y.X., A.A. and F.L., designed the firmware and software. R.Q., A.G., D.C.C, M.R.B. and J.-W.J. wrote the paper. M.R.B. and J.-W.J. acquired funding and supervised the project. M.R.B. and J.-W.J. are co-senior authors.

Corresponding authors

Correspondence to Michael R. Bruchas or Jae-Woong Jeong.

Ethics declarations

Competing interests

M.R.B. is a co-founder and scientific advisor for Neurolux, Inc., a neurotechnology company that offers neuroscience tools. The device described in this study is not currently sold or manufactured by this company.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary methods, figures, tables and video captions.

Reporting Summary

Supplementary Video 1

Highly precise and wirelessly reprogrammable temporal control for the sequenced delivery of two distinct fluids, with a 1 s delay in between.

Supplementary Video 2

Wireless operation of the plug-n-play optofluidic device.

Supplementary Video 3

Spatiotemporal heat analysis during fluid actuation using the IR camera.

Supplementary Video 4

Smartphone App Graphical User Interface for the wireless, selective and programmable control of multimodal plug-n-play optofluidic devices.

Supplementary Video 5

Demonstration of a dependent closed-loop concept through the SimbleeCOM Protocol, using model mice.

Supplementary Video 6

Wireless chronic drug delivery in a freely moving mouse.

Supplementary Video 7

Wireless selective control triggering of intra-VTA DAMGO release in a group of four mice during a 60-min open-field test.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qazi, R., Gomez, A.M., Castro, D.C. et al. Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation. Nat Biomed Eng 3, 655–669 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing