Optogenetics allows rapid, temporally specific control of neuronal activity via targeted expression and activation of light-sensitive proteins. Implementation typically requires remote light sources and fiber-optic delivery schemes that impose significant physical constraints on natural behaviors. In this report we bypass these limitations using novel technologies that combine thin, mechanically soft neural interfaces with fully implantable, stretchable wireless radio power and control systems. The resulting devices achieve optogenetic modulation of the spinal cord and peripheral nervous system. This is demonstrated with two form factors; stretchable film appliques that interface directly with peripheral nerves, and flexible filaments that insert into the narrow confines of the spinal epidural space. These soft, thin devices are minimally invasive, and histological tests suggest they can be used in chronic studies. We demonstrate the power of this technology by modulating peripheral and spinal pain circuitry, providing evidence for the potential widespread use of these devices in research and future clinical applications of optogenetics outside the brain.

Summary Paragraph The fast-growing field of bioelectronic medicine aims to develop engineered systems that relieve clinical conditions through stimulation of the peripheral nervous system (PNS) 1 – 5 . Technologies of this type rely 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/bladder pain syndrome 4 , 6 , 7 . Conventional, continuous stimulation protocols, however, cause discomfort and pain, particularly when treating symptoms that can be intermittent in nature (e.g. sudden urinary urgency) 8 . Direct physical coupling of electrodes to the nerve can lead to injury and inflammation 9 – 11 . Furthermore, typical therapeutic stimulators target large nerve bundles that innervate multiple structures, resulting in a lack of organ specificity. This paper introduces a miniaturized bio-optoelectronic implant that avoids these limitations, via the use of (1) an optical stimulation interface that exploits microscale inorganic light emitting diodes (μ-ILEDs) to activate opsins, (2) a soft, precision biophysical sensor system that allows continuous measurements of organ function, and (3) a control module and data analytics approach that allows coordinated, closed-loop operation of the system to eliminate pathological behaviors as they occur in real-time. In an example reported here, a soft strain gauge yields real-time information on bladder function. Data analytics algorithms identify pathological behavior, and automated, closed-loop optogenetic neuromodulation of bladder sensory afferents normalize bladder function in the context of acute cystitis. This all-optical scheme for neuromodulation offers chronic stability and the potential for cell-type-specific stimulation.

Combination of optogenetics and pharmacology represents a unique approach to dissect neural circuitry with high specificity and versatility. However, conventional tools available to perform these experiments, such as optical fibers and metal cannula, are limited due to their tethered operation and lack of biomechanical compatibility. To address these issues, a miniaturized, battery-free, soft optofluidic system that can provide wireless drug delivery and optical stimulation for spatiotemporal control of the targeted neural circuit in freely behaving animals is reported. The device integrates microscale inorganic light-emitting diodes and microfluidic drug delivery systems with a tiny stretchable multichannel radiofrequency antenna, which not only eliminates the need for bulky batteries but also offers fully wireless, independent control of light and fluid delivery. This design enables a miniature (125 mm ), lightweight (220 mg), soft, and flexible platform, thus facilitating seamless implantation and operation in the body without causing disturbance of naturalistic behavior. The proof-of-principle experiments and analytical studies validate the feasibility and reliability of the fully implantable optofluidic systems for use in freely moving animals, demonstrating its potential for wireless in vivo pharmacology and optogenetics.

Optogenetic methods to modulate cells and signaling pathways via targeted expression and activation of light-sensitive proteins have greatly accelerated the process of mapping complex neural circuits and defining their roles in physiological and pathological contexts. Recently demonstrated technologies based on injectable, microscale inorganic light-emitting diodes (μ-ILEDs) with wireless control and power delivery strategies offer important functionality in such experiments, by eliminating the external tethers associated with traditional fiber optic approaches. Existing wireless μ-ILED embodiments allow, however, illumination only at a single targeted region of the brain with a single optical wavelength and over spatial ranges of operation that are constrained by the radio frequency power transmission hardware. Here we report stretchable, multiresonance antennas and battery-free schemes for multichannel wireless operation of independently addressable, multicolor μ-ILEDs with fully implantable, miniaturized platforms. This advance, as demonstrated through in vitro and in vivo studies using thin, mechanically soft systems that separately control as many as three different μ-ILEDs, relies on specially designed stretchable antennas in which parallel capacitive coupling circuits yield several independent, well-separated operating frequencies, as verified through experimental and modeling results. When used in combination with active motion-tracking antenna arrays, these devices enable multichannel optogenetic research on complex behavioral responses in groups of animals over large areas at low levels of radio frequency power (<1 W). Studies of the regions of the brain that are involved in sleep arousal (locus coeruleus) and preference/aversion (nucleus accumbens) demonstrate the unique capabilities of these technologies.wireless optogenetics | stretchable electronics | wireless power transmission | deep brain stimulation | antenna O ptogenetics exploits a toolbox of light-sensitive proteins for optical manipulation of neural networks as a powerful means for the study of circuit-level mechanisms that underlie psychiatric diseases (1-4). Canonical optogenetic experiments in the brain require cranial insertion of an optical fiber to illuminate a region of interest (5, 6). Although this approach permits simple behavior modeling, constraints in animal motion and alterations in natural behaviors due to fiber tethering and external fixation complicate use in chronic longitudinal models and in experiments that assess complex responses. Many of these limitations can be bypassed with optoelectronic technologies and wireless receivers, as recently demonstrated in optogenetic stimulation of the brain, the peripheral nerves, and the spinal cord (4, 7-13). Systems that offer soft, compliant mechanical properties and thin, fully implantable designs are particularly advantageous (7). These systems, however, have still not been optimized to fully take advantage of the power of combining mouse genetics/optogentics with long-term beha...

Wireless control and power harvesting systems that operate injectable, cellular-scale optoelectronic components provide important demonstrated capabilities in neuromodulatory techniques such as optogenetics. Here we report a radio frequency (RF) control/harvesting device that offers dramatically reduced size, decreased weight and improved efficiency compared to previously reported technologies. Combined use of this platform with ultrathin, multijunction, high efficiency solar cells allows for hundred-fold reduction of transmitted RF power, which greatly enhances the wireless coverage. Optogenetics studies with social groups of mice demonstrate the utility of these systems, and suggest their potential for widespread use in neuroscience.