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 battery-free, soft implantable nerve cuff system provides wireless delivery of light and drugs to modulate nerve activity.

Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene (Agtr2) expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism. We show that selective antagonism of AT2R attenuates neuropathic but not inflammatory mechanical and cold pain hypersensitivity behaviors in mice. Agtr2-expressing macrophages (MΦs) constitute the predominant immune cells that infiltrate the site of nerve injury. Interestingly, neuropathic mechanical and cold pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs and AT2R-null hematopoietic cell transplantation. Our study identifies AT2R on peripheral MΦs as a critical trigger for pain sensitization at the site of nerve injury, and therefore proposes a translatable peripheral mechanism underlying chronic neuropathic pain. Significance Neuropathic pain is a widespread problem that is undermanaged by currently available analgesic drugs. An antagonist of the type II angiotensin II receptor (AT2R) reduces pain behaviors related to neuropathy, suggesting that angiotensin receptor signaling is involved in this pain. We find that AT2R expression is detected not in sensory neurons themselves, but in macrophages that infiltrate the site of nerve injury. Inducible depletion of peripheral macrophages attenuates mechanical and cold pain hypersensitivity related to neuropathy, as does transplantation of AT2R-null bone marrow into an otherwise WT recipient. Our observations provide powerful evidence that neuropathic pain is dependent upon angiotensin signaling, macrophages, and the AT2R-mediated downstream signaling therein.

Significance: Soft, multichannel antennas enable wireless, battery-free operation of fully implantable optoelectronic systems designed for use in studies of brain function. These systems support independent, remote control of multiple light-emitting diodes that inject into targeted regions of the deep brain, where they separately stimulate activity in genetically and spatially discrete neural circuits, via the use of the techniques of optogenetics. These capabilities represent significant advancements over alternative technology approaches for this important branch of neuroscience research. In vivo studies using optimized systems demonstrate wireless control of two different brain regions and distinct activation of subpopulations of neurons using separately activated light sources associated with these subdermal devices.