Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> Provided are implantable, injectable and/ or surface mounted biomedical devices and related methods for interfacing with a target tissue. The devices have a substrate, one or more microfluidic channels embedded in or supported by the substrate and a fluid actuator in operational communication with one or more reservoirs and responsive to a wireless control signal. The components of the device are specially configured and packaged to be ultra-thin and mechanically compliant. In some embodiments, the devices are self-powered and fully implantable. The devices can be shaped to provide injection in a minimally invasive manner, thereby avoiding unnecessary tissue damage and providing a platform for long-term implantation for interfacing with biological tissue. <s> BIB001 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> Summary The emerging field of bioelectronic medicine seeks methods for deciphering and modulating electrophysiological activity in the body to attain therapeutic effects at target organs. Current approaches to interfacing with peripheral nerves and muscles rely heavily on wires, creating problems for chronic use, while emerging wireless approaches lack the size scalability necessary to interrogate small-diameter nerves. Furthermore, conventional electrode-based technologies lack the capability to record from nerves with high spatial resolution or to record independently from many discrete sites within a nerve bundle. Here, we demonstrate neural dust, a wireless and scalable ultrasonic backscatter system for powering and communicating with implanted bioelectronics. We show that ultrasound is effective at delivering power to mm-scale devices in tissue; likewise, passive, battery-less communication using backscatter enables high-fidelity transmission of electromyogram (EMG) and electroneurogram (ENG) signals from anesthetized rats. These results highlight the potential for an ultrasound-based neural interface system for advancing future bioelectronics-based therapies. Video Abstract <s> BIB002 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> A wireless electrical stimulation implant for peripheral nerves, achieving >10× improvement over state of the art in the depth/volume figure of merit, is presented. The fully integrated implant measures just 2 mm × 3 mm × 6.5 mm (39 mm ::: 3 ::: , 78 mg), and operates at a large depth of 10.5 cm in a tissue phantom. The implant is powered using ultrasound and includes a miniaturized piezoelectric receiver (piezo), an IC designed in 180 nm HV BCD process, an off-chip energy storage capacitor, and platinum stimulation electrodes. The package also includes an optional blue light-emitting diode for potential applications in optogenetic stimulation in the future. A system-level design strategy for complete operation of the implant during the charging transient of the storage capacitor, as well as a unique downlink command/data transfer protocol, is presented. The implant enables externally programmable current-controlled stimulation of peripheral nerves, with a wide range of stimulation parameters, both for electrical (22 to 5000 μA amplitude, ~14 to 470 μs pulse-width, 0 to 60 Hz repetition rate) and optical (up to 23 mW/mm ::: 2 ::: optical intensity) stimulation. Additionally, the implant achieves 15 V compliance voltage for chronic applications. Full integration of the implant components, end-to-end in vitro system characterizations, and results for the electrical stimulation of a sciatic nerve, demonstrate the feasibility and efficacy of the proposed stimulator for peripheral nerves. <s> BIB003 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> Capabilities for recording neural activity in behaving mammals have greatly expanded our understanding of brain function. Some of the most sophisticated approaches use light delivered by an implanted fiber-optic cable to optically excite genetically encoded calcium indicators and to record the resulting changes in fluorescence. Physical constraints induced by the cables and the bulk, size, and weight of the associated fixtures complicate studies on natural behaviors, including social interactions and movements in environments that include obstacles, housings, and other complex features. Here, we introduce a wireless, injectable fluorescence photometer that integrates a miniaturized light source and a photodetector on a flexible, needle-shaped polymer support, suitable for injection into the deep brain at sites of interest. The ultrathin geometry and compliant mechanics of these probes allow minimally invasive implantation and stable chronic operation. In vivo studies in freely moving animals demonstrate that this technology allows high-fidelity recording of calcium fluorescence in the deep brain, with measurement characteristics that match or exceed those associated with fiber photometry systems. The resulting capabilities in optical recordings of neuronal dynamics in untethered, freely moving animals have potential for widespread applications in neuroscience research. <s> BIB004 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> This paper presents a 0.13- $\mu \text{m}$ CMOS system-on-chip (SoC) for simultaneous multichannel optogenetics and multichannel neural recording in freely moving laboratory animals. This fully integrated system provides 10 multimodal recording channels with analog-to-digital conversion and a four- channel LED driver circuit for optogenetic stimulation. The bio-amplifier design includes a programmable bandwidth (BW) (0.5 Hz–7 kHz) to collect either the action potentials (APs) and/or the local field potentials (LFPs) and has a noise efficiency factor (NEF) of 2.30 for an input-referred noise of 3.2 $\mu V_{\text {rms}}$ within a BW of 10–7 kHz. The low-power delta–sigma ( $\Delta \Sigma $ ) MASH 1-1-1 analog-to-digital converter (ADC) is designed to work at low oversampling ratios (OSRs) (≤50) and has an effective number of bits (ENOB) of 9.75 bits at an OSR of 25 (BW of 10 kHz). The utilization of a $\Delta \Sigma $ ADC is the key to address the flexibility needed to address different noise versus power consumption tradeoff of various experimental settings. It leverages a new technique that reduces its size by subtracting the output of each $\Delta \Sigma $ branch in the digital domain, instead of in the analog domain as done conventionally. The ADC is followed by an on-chip fourth-order cascaded integrator-comb (CIC4) decimation filter (DF). A whole recording channel, including the bio-amplifier, the $\Delta \Sigma $ MASH 1-1-1, and the DF consumes 11.2 $\mu \text{W}$ . Optical stimulation is performed with an LED driver using a regulated cascode current source with feedback that can accommodate a wide range of LED parameters and battery voltages. The SoC is validated in vivo within a wireless experimental platform in both the ventral posteromedial nucleus (VPM) and cerebral motor cortex brain regions of a virally mediated Channelrhodopsin-2 (ChR2) rat. <s> BIB005 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> A 0.8 mm$^3$ wireless, ultrasonically powered, free-floating neural recording implant is presented. The device is comprised only of a 0.25 mm$^2$ recording IC and a single piezoceramic resonator that is used for both power harvesting and data transmission. Uplink data transmission is performed by analog amplitude modulation of the ultrasound echo. Using a 1.78 MHz main carrier, >35 kbps/mote equivalent uplink data rate is achieved. A technique to linearize the echo amplitude modulation is introduced, resulting in 2.5x, resulting in the highest measured depth/volume ratio by $\sim$3x. Orthogonal subcarrier modulation enables simultaneous operation of multiple implants, using a single-element ultrasound external transducer. Dual-mote simultaneous power up and data transmission is demonstrated at a rate of 7 kS/s at the depth of 50 mm. <s> BIB006 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> This paper proposes a novel system for ultrasonically-power optogenetic microstimulator. In this system, a novel powering approach for the comparators is proposed that improves the power conversion efficiency of the rectifier. This is done by lowering the Rail-to-Rail supply voltage of the comparators and consequently their propagation delay. This technique enhances the power conversion efficiency of the active rectifiers in two ways: a. decreasing the propagation delay of the comparators; and b. enabling reuse of consumed power by the comparators and drivers of power transistors. The proposed system including the active rectifier, a novel double-pass regulator, a current reference, and a burst detection circuit is simulated in TSMC 0.18-μm CMOS technology and occupies an area of 0.09 mm2. The proposed active rectifier connected to a load of 3 kΩ, generates an output voltage of up to 3 V out of an input AC signal with the amplitude of 3.2V and the frequency range of 1–14 MHz. In the same frequency range and with the same load, it exhibits a voltage conversion ratio of 92.25–93.75% and power conversion efficiency of up to 95%. The double-pass regulator is proposed for seeking both power efficiency and over-voltage protection in this specific design. <s> BIB007 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> A major obstacle during the design of brain–computer interfaces is the unavailability of a neural implantable device that is µ-scale in size and is wireless, self-powered, and long-lasting. The current state-of-the-art implantable devices suffer from various limitations. Electromagnetic-based wireless devices are big in size because of their large antenna, which must be larger than one-tenth of the wavelength of the operational frequency. Ultrasound-based wireless devices, in addition to their low data rate, have massive loss in the skull and need an intermediate electromagnetic transceiver under the skull. Furthermore, almost all state-of-the-art wireless devices use micro-electrodes for neuronal recording, which are not reliable in long-term monitoring applications because of the direct contact between the tissue and metal electrodes. In this paper, we propose a novel, wireless, and ultra-compact implantable device termed NanoNeuroRFID. At the core of this device, there is a magnetoelectric (ME) antenna array. ME antennas are smart and ultra-miniaturized (<200 μm diameter) and can perform multiple tasks. First, can harvest electromagnetic energy to power the NanoNeuroRFID system. Their limit of the detection for RF magnetic fields is 40 pT; second, they can sense quasi-static neuronal magnetic fields as small as 200 pT without direct contact to the tissue, allowing a long lifetime and reliable neural recording; and third, they can communicate with an external transceiver, and their operational frequency could be 10 to 100 s of MHz, where tissue loss is small. <s> BIB008 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> We present a platform technology encompassing a family of innovations that together aim to tackle key challenges with existing implantable brain machine interfaces. The ENGINI (Empowering Next Generation Implantable Neural Interfaces) platform utilizes a 3-tier network (external processor, cranial transponder, intracortical probes) to inductively couple power to, and communicate data from, a distributed array of freely-floating mm-scale probes. Novel features integrated into each probe include: (1) an array of niobium microwires for observing local field potentials (LFPs) along the cortical column; (2) ultra-low power instrumentation for signal acquisition and data reduction; (3) an autonomous, self-calibrating wireless transceiver for receiving power and transmitting data; and (4) a hermetically-sealed micropackage suitable for chronic use. We are additionally engineering a surgical tool, to facilitate manual and robot-assisted insertion, within a streamlined neurosurgical workflow. Ongoing work is focused on system integration and preclinical testing. <s> BIB009 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> This paper presents the concept and some preliminary results of a millimeter-scale wireless addressable optoelectronic implant (WAOI), a network of which can be distributed over the brain for large-scale optogenetics. The WAOI contains a wireless receiver (base), which establishes wireless power transfer and data communication with an external unit, connected to an optoelectronic shank, which integrates liquid crystal-based silicon photonic on CMOS electronics for switchable optical emission. The liquid crystal-switched waveguide can provide light switching of a single light source (e.g. laser diode), which is integrated on the base, along the shank, thus minimizing heat generation within brain parenchyma. To reduce interconnect wiring between the base and the shank, a power-line communication technique is presented for data transfer from the base to the shank. Simplified prototypes of the base and shank ASICs were designed and developed in 0.35-μm 2P4M CMOS process. The simulation results of these ASICs for addressing of 16 stimulation pixels on the shank are presented. Moreover, a macroscale example of liquid crystal-switched waveguide was fabricated and measured to demonstrate basic liquid crystal switch operation. <s> BIB010 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> F. Ultrasound Based Wireless System <s> 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. <s> BIB011
Among others, Maharbiz et al. studied the ultrasound based wireless neural implants as evidenced through their Neural Dust BIB002 and Stim Dust  . In one of the most recent studies BIB006 , they developed a 0.8 mm 3 ultrasonically powered miniaturized wireless neural implant. The size of the recording IC is 0.25 mm 2 only and for both power and data transmission a single piezoceramic resonator was used, as pictured in Fig. 8(e) . This small device with wireless power capability can minimize tissue damage, scar formation, and neuroinflammatory response. The device can operate at a depth of 5 cm, allowing neural recording from the deep brain regions and most peripheral nerves. The implants achieved simultaneous power and data delivery with an inexpensive unfocused single-element transducer placed externally. This allows for maximized working depth and optimum frequency thereby improving the spatiotemporal resolution in a distributed recording environment. Another work, STARDUST project envisions the implementation of an implant, which is going to be used primarily for optogenetics, and later as a recording device with a drug-delivery system. The first version of this optogenetic device (i.e., dust) to be used only for optogenetics has been fabricated and tested, which includes a PZT cube of 560 × 560 × 490 µm 3 , a µ-LED of 280 × 180 × 100 µm 3 and an active rectifier with the size of 300 × 300 µm 2 BIB007 . The vision of this project is to develop a Dust with the same dimensions for other applications including recording and drug-delivery leading a full system in micro-scale dimension for freely moving animals for Parkinson's disease treatment. Ultrasound based wireless systems enables low signal attenuation in biological tissue, minimized geometry, and can be used safely with human. However, complicated circuitry and complexity in addressing the ultrasound frequency remain the two main bottlenecks. In addition, ultrasound-based wireless systems have low data rate (e.g., Kb/s), has a signal is greatly attenuated by the skull and needs an intermediate transceiver based on electromagnetic coupling beneath the skull. So far, some of the most common forms of wireless power system for implantable neural devices are discussed and summarized in Table II . Apart from these, there are emerging technologies which combines multiple stimulation options and optofluidic channel BIB003 , BIB001 , uses innovative approach to achieve an ultra-miniaturized implant BIB008 , introduces scalable and distributed wireless neural platform BIB009 , BIB010 , wireless optoelectronic photometer for dynamic mapping of the brain BIB004 , simultaneous multichannel optogenetics stimulation and multichannel electrical recording system BIB005 . Fig. 9 shows the comparison among different power transfer schemes with respect to the power transfer range to achieve the power requirement for the neural implants. In terms of device miniaturization and signal propagation, ultrasound allows better wireless solution than the solar and electromagnetic based technologies. To add more, the ultrasound energy has low propagation loss in biological tissues. In accordance with to FDA (Food and Drug Administration), the ultrasound exposure to the human tissue is limited to 720 mW/cm 2 , whilst RF is 10 mW/cm 2 . Manufacturing complexity is the main obstacle of ultrasound technology. On the other hand, with increasing frequency, the antenna size can be miniaturized thus application of electromagnetic approaches more appealing for device miniaturization. As it is expected that the next-generation implants will require less power, lower size and form factor, the resonant coupling based on midfield and far-field based wireless power transfer would be beneficial. In addition to power transfer, simultaneous data transmission is another crucial parameter to remotely control and monitor the activities. Among all power transfer systems, only the ultrasound and near-field methods have the capability to enable simultaneous power and data transfer. As a result, the near-field inductive-coupling scheme still can meet the power requirements by the most commonly used implantable devices. In conclusion, implantable neural device design must consider specific types of power transfer schemes depending on the application for superior performance. In one of the most recent studies, a fully implantable wireless closed loop optogenetics system has been introduces that can monitor and control bladder function through a smart device BIB011 . The schematic of this closed loop system is given in Fig. 10 . The authors use a soft elastomeric material (PDMS), which shows negligible inflammatory response after 7 days of implantation. The implant/smart device user interface was developed though a software using XCode to log the recording data and to provide systematic stimulations. Such system can be easily adapted to address several application scenarios beyond the bladder control. Furthermore, the sensing module could be modified to associate different biophysical (e.g., temperature, pressure) and/or biochemical (e.g., metabolites, proteins) sensors, as well as can be integrated with numerous actuators (e.g., pharmacological) to allow the appropriate modulation, all utilizing control given by the wireless module through developing Fig. 10 . Schematic of a futuristic fully wireless implantable neural system that can be interfaced through a smart device for versatile neural modulation control. a proper user interface. These wireless closed loop technologies may act as a platform to realize the futuristic vision by integrating the wireless optogenetics system into smart healthcare using mobile and electronic technology for better diagnosis of the brain diseases, improved treatment, and enhanced quality of lives.