A wireless closed-loop system for optogenetic peripheral neuromodulation
Open accessAbstract
The fast-growing field of bioelectronic medicine aims to develop engineered systems that can relieve clinical conditions by stimulating the peripheral nervous system1–5. This type of technology relies largely on electrical stimulation to provide neuromodulation of organ function or pain. One example is sacral nerve stimulation to treat overactive bladder, urinary incontinence and interstitial cystitis (also known as bladder pain syndrome)4,6,7. Conventional, continuous stimulation protocols, however, can cause discomfort and pain, particularly when treating symptoms that can be intermittent (for example, sudden urinary urgency)8. Direct physical coupling of electrodes to the nerve can lead to injury and inflammation9–11. Furthermore, typical therapeutic stimulators target large nerve bundles that innervate multiple structures, resulting in a lack of organ specificity. Here we introduce a miniaturized bio-optoelectronic implant that avoids these limitations by using (1) an optical stimulation interface that exploits microscale inorganic light-emitting diodes to activate opsins; (2) a soft, high-precision biophysical sensor system that allows continuous measurements of organ function; and (3) a control module and data analytics approach that enables coordinated, closed-loop operation of the system to eliminate pathological behaviours as they occur in real-time. In the example reported here, a soft strain gauge yields real-time information on bladder function in a rat model. Data algorithms identify pathological behaviour, and automated, closed-loop optogenetic neuromodulation of bladder sensory afferents normalizes bladder function. This all-optical scheme for neuromodulation offers chronic stability and the potential to stimulate specific cell types. A closed-loop implantable bioelectronic device that can modulate peripheral neuronal activity is used to improve bladder function in a rat model of cystitis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Wireless power transfer techniques can shrink the form factor and reduce invasiveness of implantable medical devices.
“While many remain battery-powered, wireless power transfer techniques can further reduce the form factor and invasiveness of these devices4–10.”
From Synchronized Biventricular Heart Pacing in a Closed-chest Porcine Model based on Wirelessly Powered Leadless Pacemakers (2020) · cites this paper as [10]
The device description reports a miniaturized implant with wireless power transfer, and Methods > Wireless communication describes a battery-free version. The device description also says its design avoids direct nerve interfaces and bladder incisions. Neither passage establishes that wireless power transfer itself reduces implant size or invasiveness relative to battery-powered devices. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation
Lin, J. Y., Knutsen, P. M., Muller, A., Kleinfeld, D., & Tsien, R. Y. (2013) · Nature Neuroscience · doi:10.1038/nn.3502 · Cited by 837 · see citing works
Highly Sensitive Skin‐Mountable Strain Gauges Based Entirely on Elastomers
Lu, N., Lu, C., Yang, S., & Rogers, J. A. (2012) · Advanced Functional Materials · doi:10.1002/adfm.201200498 · Cited by 824 · see citing works
Self-citationCameron, T. (2004) · Journal of Neurosurgery Spine · doi:10.3171/spi.2004.100.3.0254 · Cited by 800 · see citing works
Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics
Park, S. I., Brenner, D. S., Shin, G., Morgan, C. D., Copits, B. A., Chung, H. U., Pullen, M. Y., Noh, K. N., Davidson, S., Oh, S. J., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3415 · Cited by 794 · see citing works
Self-citationMattis, J., Tye, K. M., Ferenczi, E. A., Ramakrishnan, C., O'Shea, D. J., Prakash, R., Gunaydin, L. A., Hyun, M., Fenno, L. E., Gradinaru, V., et al. (2012) · Nature Methods · doi:10.1038/nmeth.1808 · Cited by 780 · see citing works
Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice
Montgomery, K. L., Yeh, A. J., Ho, J. S., Tsao, V., Mohan Iyer, S., Grosenick, L., Ferenczi, E. A., Tanabe, Y., Deisseroth, K., Delp, S. L., et al. (2015) · Nature Methods · doi:10.1038/nmeth.3536 · Cited by 565 · see citing works
A jump-start for electroceuticals
Famm, K., Litt, B., Tracey, K. J., Boyden, E. S., & Slaoui, M. (2013) · Nature · doi:10.1038/496159a · Cited by 554 · see citing works
Chronic vagus nerve stimulation: A new and promising therapeutic approach for chronic heart failure
De Ferrari, G. M., Crijns, H. J. G. M., Borggrefe, M., Milasinovic, G., Smid, J., Zabel, M., Gavazzi, A., Sanzo, A., Dennert, R., Kuschyk, J., et al. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehq391 · Cited by 523 · see citing works
SIEGEL, S. W., CATANZARO, F., Dijkema, H. E., et al. (2000) · Urology · doi:10.1016/s0090-4295(00)00597-5 · Cited by 412 · see citing works
Double nerve intraneural interface implant on a human amputee for robotic hand control
Rossini, P. M., Micera, S., Benvenuto, A., Carpaneto, J., Cavallo, G., Citi, L., Cipriani, C., Denaro, L., Denaro, V., Di Pino, G., et al. (2010) · Clinical Neurophysiology · doi:10.1016/j.clinph.2010.01.001 · Cited by 396 · see citing works
Bioelectronic medicines: a research roadmap
Birmingham, K., Gradinaru, V., Anikeeva, P., Grill, W. M., Pikov, V., McLaughlin, B., Pasricha, P., Weber, D., Ludwig, K., & Famm, K. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4351 · Cited by 322 · see citing works
Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice
Iyer, S. M., Montgomery, K. L., Towne, C. L., Lee, S. Y., Ramakrishnan, C., Deisseroth, K. A., & Delp, S. L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2834 · Cited by 219 · see citing works
Rodent models for urodynamic investigation
Andersson, K., Soler, R., & Füllhase, C. (2011) · Neurourology and Urodynamics · doi:10.1002/nau.21108 · Cited by 203 · see citing works
Temperature dependence of thermal conductivity of biological tissues
Bhattacharya, A., & Mahajan, R. L. (2003) · Physiological Measurement · doi:10.1088/0967-3334/24/3/312 · Cited by 175 · see citing works
Optogenetic Control of Targeted Peripheral Axons in Freely Moving Animals
Towne, C., Montgomery, K. L., Iyer, S. M., Deisseroth, K., & Delp, S. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072691 · Cited by 156 · see citing works
Long–Term Effectiveness of Sacral Nerve Stimulation for Refractory Urge Incontinence
Janknegt, R. A., Janknegt, R. A., HASSOUNA, M. M., et al. (2001) · European Urology · doi:10.1159/000052420 · Cited by 141 · see citing works
Valtcheva, M. V., Copits, B. A., Davidson, S., Sheahan, T. D., Pullen, M. Y., McCall, J. G., Dikranian, K. T., & Gereau, R. W. (2016) · Nature Protocols · doi:10.1038/nprot.2016.111 · Cited by 131 · see citing works
Self-citationRen, Y.-T., Qi, H., Chen, Q., & Ruan, L.-M. (2016) · International Journal of Heat and Mass Transfer · doi:10.1016/j.ijheatmasstransfer.2016.10.067 · Cited by 129 · see citing works
Fully implantable, battery-free wireless optoelectronic devices for spinal optogenetics
Samineni, V. K., Yoon, J., Crawford, K. E., Jeong, Y. R., McKenzie, K. C., Shin, G., Xie, Z., Sundaram, S. S., Li, Y., Yang, M. Y., et al. (2017) · Pain · doi:10.1097/j.pain.0000000000000968 · Cited by 119 · see citing works
Self-citationCentral Amygdala Metabotropic Glutamate Receptor 5 in the Modulation of Visceral Pain
Crock, L. W., Kolber, B. J., Morgan, C. D., Sadler, K. E., Vogt, S. K., Bruchas, M. R., & Gereau, R. W. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1473-12.2012 · Cited by 108 · see citing works
Self-citationOptogenetic and chemogenetic strategies for sustained inhibition of pain
Iyer, S. M., Vesuna, S. S., Ramakrishnan, C., Huynh, K., Young, S., Berndt, A., Lee, S. Y., Gorini, C., Deisseroth, K. A., & Delp, S. L. (2016) · Scientific Reports · doi:10.1038/srep30570 · Cited by 106 · see citing works
Interfaces with the Peripheral Nerve for the Control of Neuroprostheses
del Valle, J., & Navarro, X. (2013) · International Review of Neurobiology · doi:10.1016/b978-0-12-420045-6.00002-x · Cited by 105 · see citing works
Beaudry, H., Daou, I., Ase, A. R., Ribeiro‐da‐Silva, A., & Séguéla, P. (2017) · Pain · doi:10.1097/j.pain.0000000000001016 · Cited by 84 · see citing works
Animal Models in Overactive Bladder Research
Parsons, B. A., & Drake, M. J. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-16499-6_2 · Cited by 76 · see citing works
Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain
Samineni, V. K., Mickle, A. D., Yoon, J., Grajales‐Reyes, J. G., Pullen, M. Y., Crawford, K. E., Noh, K. N., Gereau, G. B., Vogt, S. K., Lai, H. H., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-16129-3 · Cited by 64 · see citing works
Self-citationFast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats
Boada, D., Martin, T. J., Peters, C. M., Hayashida, K., Harris, M. H., Houle, T. T., Boyden, E. S., Eisenach, J. C., & Ririe, D. G. (2014) · Pain · doi:10.1016/j.pain.2014.09.030 · Cited by 59 · see citing works
Yoshida, K., Farina, D., Akay, M., & Jensen, W. (2010) · Proceedings of the IEEE · doi:10.1109/jproc.2009.2038613 · Cited by 53 · see citing works
Lai, H. H., Gereau, R. W., Luo, Y., O’Donnell, M. A., Rudick, C. N., Pontari, M. A., Mullins, C., & Klumpp, D. J. (2015) · Urology · doi:10.1016/j.urology.2015.03.007 · Cited by 52 · see citing works
Self-citationImpact of Bioelectronic Medicine on the Neural Regulation of Pelvic Visceral Function
de Groat, W. C., & Tai, C. (2015) · Bioelectronic Medicine · doi:10.15424/bioelectronmed.2015.00003 · Cited by 51 · see citing works
Li, B., Yang, X., Qian, F., et al. (2015) · Brain Research · doi:10.1016/j.brainres.2015.03.008 · Cited by 45 · see citing works
Korkmaz, I., & Rogg, B. (2006) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2006.02.014 · Cited by 44 · see citing works
The Use of Cystometry in Small Rodents: A Study of Bladder Chemosensation
Uvin, P., Everaerts, W., Pinto, S., et al. (2012) · Journal of Visualized Experiments · doi:10.3791/3869 · Cited by 42 · see citing works
Liu, J., Zhu, L. K., & Xu, L. X. (2000) · Journal of Biomechanical Engineering · doi:10.1115/1.1288208 · Cited by 42 · see citing works
Low-cost carbon thick-film strain sensors for implantable applications
Gutierrez, C. A., & Meng, E. F. (2010) · Journal of Micromechanics and Microengineering · doi:10.1088/0960-1317/20/9/095028 · Cited by 34 · see citing works
Noninvasive optical inhibition with a red-shifted microbial rhodopsin
Chuong, A. S., Miri, M. L., Busskamp, V., Matthews, G. A. C., Acker, L. C., Sørensen, A. T., Young, A., Klapoetke, N. C., Henninger, M. A., Kodandaramaiah, S. B., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3752 · Cited by 33 · see citing works
Zerboni, L., Che, X., Reichelt, M., et al. (2012) · Journal of Virology · doi:10.1128/jvi.01375-12 · Cited by 28 · see citing works
DeBerry, J. J., Samineni, V. K., Copits, B. A., Sullivan, C. J., Vogt, S. K., Albers, K. M., Davis, B. M., & Gereau, R. W. (2018) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2018.00005 · Cited by 27 · see citing works
Self-citationKavvadias, T., Huebner, M., Brucker, S. Y., et al. (2017) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-017-4303-2 · Cited by 18 · see citing works
Biomechanics of the Human Urinary Bladder
Miftahof, R. N., & Nam, H. G. (2013) · Springer eBooks · doi:10.1007/978-3-642-36146-3 · Cited by 15 · see citing works
Does it matter, the shape of the bladder?
Damaser, M. S., & Lehman, S. L. (1993) · Neurourology and Urodynamics · doi:10.1002/nau.1930120312 · Cited by 9 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [34]Bhattacharya A & Mahajan RL in BiOS 2001 The International Symposium on Biomedical Optics. 10 (SPIE).
Cited by
Sorted by citations
Wireless and battery-free technologies for neuroengineering
Won, S. M., Cai, L., Gutruf, P., & Rogers, J. A. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00683-3 · Cited by 360 · see citing works
Self-citationCardiogenic control of affective behavioural state
Hsueh, B., Chen, R., Jo, Y., Tang, D., Raffiee, M., Kim, Y. S., Inoue, M., Randles, S., Ramakrishnan, C., Patel, S., et al. (2023) · Nature · doi:10.1038/s41586-023-05748-8 · Cited by 335 · see citing works
Self-citationFunctions of interoception: From energy regulation to experience of the self
Quigley, K. S., Kanoski, S., Grill, W. M., Barrett, L. F., & Tsakiris, M. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.09.008 · Cited by 286 · see citing works
Recent advances in neurotechnologies with broad potential for neuroscience research
Vázquez-Guardado, A., Yang, Y., Bandodkar, A. J., & Rogers, J. A. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-00739-8 · Cited by 202 · see citing works
Self-citationPowering implantable and ingestible electronics
Yang, S., Sencadas, V., You, S. S., Jia, N. Z., Srinivasan, S. S., Huang, H., Ahmed, A. E., Liang, J. Y., & Traverso, G. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202009289 · Cited by 183 · see citing works
Miniature battery-free bioelectronics
Nair, V., Dalrymple, A. N., Yu, Z., Balakrishnan, G., Bettinger, C. J., Weber, D. J., Yang, K., & Robinson, J. T. (2023) · Science · doi:10.1126/science.abn4732 · Cited by 128 · see citing works
Wireless closed-loop optogenetics across the entire dorsoventral spinal cord in mice
Kathe, C., Michoud, F., Schönle, P., Rowald, A., Brun, N., Ravier, J., Furfaro, I., Paggi, V., Kim, K., Soloukey, S., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-021-01019-x · Cited by 119 · see citing works
Conformable hybrid systems for implantable bioelectronic interfaces
Fallegger, F., Schiavone, G., & Lacour, S. P. (2020) · Advanced Materials · doi:10.1002/adma.201903904 · Cited by 113 · see citing works
Anpilov, S., Shemesh, Y., Eren, N., Harony-Nicolas, H., Benjamin, A., Dine, J., Oliveira, V. E. M., Forkosh, O., Karamihalev, S., Hüttl, R.-E., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.05.028 · Cited by 89 · see citing works
Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation
Kim, D., Yokota, T., Suzuki, T., Lee, S., Woo, T., Yukita, W., Koizumi, M., Tachibana, Y., Yawo, H., Onodera, H., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007395117 · Cited by 81 · see citing works
Self-citationCompliant peripheral nerve interfaces.
Paggi, V., Akouissi, O., Micera, S., & Lacour, S. P. (2021) · Journal of Neural Engineering · doi:10.1088/1741-2552/abcdbe · Cited by 60 · see citing works
“Alternatively to temperature monitoring, heat generation in PNIs can be directly limited by mounting micro-LEDs on heat dissipating substrates such as stainless steel [188].”
BackgroundA shape-memory and spiral light-emitting device for precise multisite stimulation of nerve bundles
Zheng, H., Zhang, Z., Jiang, S., Yan, B., Shi, X., Xie, Y., Huang, X., Yu, Z., Liu, H., Weng, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10418-3 · Cited by 58 · see citing works
Self-citationSong, H., Kim, M., Kim, E., Lee, J., Jeong, I., Lim, K., Ryu, S. Y., Oh, M., Kim, Y., & Park, J. (2024) · BMEMat · doi:10.1002/bmm2.12048 · Cited by 61 · see citing works
Lyu, H., John, M., Burkland, D., Greet, B., Post, A., Babakhani, A., & Razavi, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-59017-z · Cited by 51 · see citing works
Li, C., Cauwe, M., Yang, Y., Schaubroeck, D., Mader, L., & Op de Beeck, M. (2019) · Coatings · doi:10.3390/coatings9090579 · Cited by 46 · see citing works
Recent advances in recording and modulation technologies for next-generation neural interfaces.
Hong, J.-W., Yoon, C., Jo, K., Won, J. H., & Park, S. (2021) · iScience · doi:10.1016/j.isci.2021.103550 · Cited by 25 · see citing works
Self-citationActive Neural Interface Circuits and Systems for Selective Control of Peripheral Nerves: A Review
Habibollahi, M., Jiang, D., Lancashire, H. T., & Demosthenous, A. (2024) · IEEE Transactions on Biomedical Circuits and Systems · doi:10.1109/tbcas.2024.3430038 · Cited by 11 · see citing works
Design Considerations for Implantable Neural Circuits and Systems
Hsu, W.-Y., Hsieh, P.-H., & Chen, H. (2023) · Handbook of Neuroengineering · doi:10.1007/978-981-16-5540-1_19 · Cited by 1 · see citing works
- Authors
- Mickle, A. D., Won, S. M., Noh, K. N., Yoon, J., Meacham, K. W., Xue, Y., McIlvried, L. A., Copits, B. A., Samineni, V. K., Crawford, K. E., Kim, D. H., Srivastava, P., Kim, B. H., Min, S., Shiuan, Y., Yun, Y., Payne, M. A., Zhang, J., Jang, H., Li, Y., Lai, H. H., Huang, Y., Park, S.-I., Gereau, R. W., & Rogers, J. A.
- Affiliations
- Washington University in St. Louis (US)
- University of Illinois Urbana-Champaign (US)
- Northwestern University (US)
- University of Central Florida (US)
- Beihang University (CN)
- Texas A&M University (US)
- Corresponding author
- Gereau, Robert W.
- Rogers, John A.
- ORCID
- Mickle, Aaron D.
- Won, Sang Min
- Yoon, Jangyeol
- Meacham, Kathleen W.
- Xue, Yeguang
- McIlvried, Lisa A.
- Copits, Bryan A.
- Samineni, Vijay K.
- Crawford, Kaitlyn E.
- Kim, Do Hoon
- Kim, Bong Hoon
- Min, Seunghwan
- Yun, Yeojeong
- Payne, Maria A.
- Zhang, Jianpeng
- Jang, Hokyung
- Li, Yuhang
- Lai, H. Henry
- Huang, Yonggang
- Park, Sung-Il
- Gereau, Robert W.
- Rogers, John A.
- Venue
- Nature
- Published
- 2019-01-02
- Volume
- 565
- Issue
- 7739
- Pages
- 361-365
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6336505
- OpenAlex
- W2906572232
- Cited by
- 514
- References
- 40
- Citations by year
- 2026: 39 · 2025: 57 · 2024: 70 · 2023: 78 · 2022: 70 · 2021: 92 · 2020: 63 · 2019: 42 · 2018: 1
- FWCI
- 22.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Drug Abuse (T32DA007261)
- National Institute of General Medical Sciences (T32GM108539)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK115634, T32DK108742, F32DK115122, K08DK094964, U01DK082315)
- National Institute of Neurological Disorders and Stroke (R01NS081707, R01NS042595)
- National Institute of Biomedical Imaging and Bioengineering (U18EB021793)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neural Engineering
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
- Health Sciences › Medicine › Urology › Urinary Bladder and Prostate Research
- Keywords
- optogenetics, peripheral neuromodulation, closed-loop neuromodulation, bioelectronic medicine, sacral neuromodulation, interstitial cystitis, inorganic light-emitting diodes, opsin, strain gauges
- MeSH terms
- Algorithms, Animals, Urinary Bladder, Cells, Cultured, Electronics, Female, Ganglia, Spinal, Humans, Neurons, Spinal Nerve Roots, Rats, Sprague-Dawley, Rats, Wireless Technology, Optogenetics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
