The fast-growing field of bioelectronic medicine aims to develop engineered systems that can relieve clinical conditions by stimulating the peripheral nervous system1,2,3,4,5. 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 inflammation9,10,11. 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.
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The data that support the findings of this study are either provided in the source data or are available from the corresponding authors upon reasonable request. iOS code is available at https://github.com/noh21/bladder_cloc.
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We acknowledge the generosity of the donor families, as well as Mid-America Transplant for making the studies of human sensory neurons possible. J. Lemen provided instrumental help during human DRG surgical extractions. We thank J. Sinn-Hanlon for the illustrations, L. Strong for technical assistance with the CT imaging, S. Vogt for technical support and C. Morgan for early input on the project. This work was funded by an NIH Director’s Transformative Research Award TR01 NS081707 (R.W.G. and J.A.R.), an NIH SPARC Award via the NIBIB of the NIH U18 EB021793 (R.W.G. and J.A.R.), R01 NS42595 (R.W.G.), NRSA F32 DK115122 (A.D.M.), the McDonnell Center for Cellular and Molecular Neurobiology Postdoctoral Fellowship (A.D.M.), K01 DK115634 (V.K.S.), the Urology Care Foundation Research Scholars Program and Kailash Kedia Research Scholar Endowment (V.K.S.), NSF Grant 1635443 (Y.H.), the Ryan Fellowship and the Northwestern University International Institute for Nanotechnology (Y.X.), T32 DA007261 (L.A.M.), T32 DK108742 (K.W.M.), T32 GM 108539 (B.A.C.), Washington University BioSURF Fellowship (P.S.) DK082315 (H.H.L.) and K08 DK094964 (H.H.L.).
Nature thanks T. Chai, C. Moritz, E. Roche and S. Zderic for their contribution to the peer review of this work.