Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits <s> BIB001 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> In this letter, we developed an integrated neural probe prototype for optogenetic stimulation by microscale light-emitting diode (μLED) and simultaneous recording of neural activities with microelectrodes on a single-polyimide platform. Optogenetics stimulates in vivo neural circuits with high-cellular specificity achieved by genetic targeting and precise temporal resolution by interaction of light-gated ion channels with optical beam. In our newly developed optrode probe, during optogenetic stimulation of neurons, continuous sensing of neuronal activities in vicinity of the activation site can provide feedback to stimulation or examine local responses in signal pathways. In the device, focusing the light from the μLED was achieved with an integrated photo-polymerized lens. The efficacy of the optrode for cortical stimulation and recording was tested on mice visual cortex neurons expressing channelrhodopsin-2. Stimulation intensity and frequency-dependent spiking activities of visual cortex were recorded. Our device has shown advantages over fiber-coupled laser-based optrode in terms of closed-loop integration, single-implant compactness and lower electrical power requirements, which would be clinically applicable for future prosthetic applications in personalized medicine. <s> BIB002 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> We report a scalable method to monolithically integrate microscopic light emitting diodes (μLEDs) and recording sites onto silicon neural probes for optogenetic applications in neuroscience. Each μLED and recording site has dimensions similar to a pyramidal neuron soma, providing confined emission and electrophysiological recording of action potentials and local field activity. We fabricated and implanted the four-shank probes, each integrated with 12 μLEDs and 32 recording sites, into the CA1 pyramidal layer of anesthetized and freely moving mice. Spikes were robustly induced by 60 nW light power, and fast population oscillations were induced at the microwatt range. To demonstrate the spatiotemporal precision of parallel stimulation and recording, we achieved independent control of distinct cells ∼ 50 μm apart and of differential somato-dendritic compartments of single neurons. The scalability and spatiotemporal resolution of this monolithic optogenetic tool provides versatility and precision for cellular-level circuit analysis in deep structures of intact, freely moving animals. <s> BIB003 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> Brain function depends on simultaneous electrical, chemical and mechanical signaling at the cellular level. This multiplicity has confounded efforts to simultaneously measure or modulate these diverse signals in vivo. Here we present fiber probes that allow for simultaneous optical stimulation, neural recording and drug delivery in behaving mice with high resolution. These fibers are fabricated from polymers by means of a thermal drawing process that allows for the integration of multiple materials and interrogation modalities into neural probes. Mechanical, electrical, optical and microfluidic measurements revealed high flexibility and functionality of the probes under bending deformation. Long-term in vivo recordings, optogenetic stimulation, drug perturbation and analysis of tissue response confirmed that our probes can form stable brain-machine interfaces for at least 2 months. We expect that our multifunctional fibers will permit more detailed manipulation and analysis of neural circuits deep in the brain of behaving animals than achievable before. <s> BIB004 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> Optogenetic studies of the peripheral nervous system and spinal cord are enabled by soft, wirelessly powered biocompatible devices. <s> BIB005 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> Small, lightweight LED implants and a radio-frequency transducer as a power source enable wireless optogenetic stimulation in the brain, spinal cord and peripheral nervous system of behaving mice. <s> BIB006 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> Controlling neural circuits is a powerful approach to uncover a causal link between neural activity and behaviour. Optogenetics has been widely adopted by the neuroscience community as it offers cell-type-specific perturbation with millisecond precision. However, these studies require light delivery in complex patterns with cellular-scale resolution, while covering a large volume of tissue at depth in vivo. Here we describe a novel high-density silicon-based microscale light-emitting diode (μLED) array, consisting of up to ninety-six 25 μm-diameter μLEDs emitting at a wavelength of 450 nm with a peak irradiance of 400 mW/mm(2). A width of 100 μm, tapering to a 1 μm point, and a 40 μm thickness help minimise tissue damage during insertion. Thermal properties permit a set of optogenetic operating regimes, with ~0.5 °C average temperature increase. We demonstrate depth-dependent activation of mouse neocortical neurons in vivo, offering an inexpensive novel tool for the precise manipulation of neural activity. <s> BIB007 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> We report on a compact optrode, i.e. a MEMS-based, invasive, bidirectional neural interface allowing to control neural activity using light while neural signals are recorded nearby. The optrode consists of a silicon (Si) base carrying two pairs of bare laser diodes (LDs) emitting at 650 nm and of two 8 mm-long, 250 µm-wide and down to 50 µm-thick shanks extending from the base. Each LD is efficiently coupled to one of four 15 or 20 µm-wide and 13 µm-high SU-8 waveguides (WGs) running in pairs along the shanks. In addition, each shank comprises four 20 µm-diameter platinum electrodes for neural recording near the WG end facets. After encapsulation of the LDs with a Si cover chip blocking stray light and protecting the LDs from the harsh environment to which the probe is destined, the compact base measures only 4 × 4 × 0.43 mm3. The time averaged radiant emittance at the WG end facet is 96.9 mW mm−2 for an LD current of 35 mA at a duty cycle of 5%. The absolute electrode impedance at 1 kHz is 1.54 ± 0.06 MΩ. Using infrared thermography, the temperature increase of the probe during LD operation was determined to be about 1 K under neuroscientifically relevant operating conditions. <s> BIB008 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> Microfluidic neural probes hold immense potential as in vivo tools for dissecting neural circuit function in complex nervous systems. Miniaturization, integration, and automation of drug delivery tools open up new opportunities for minimally invasive implants. These developments provide unprecedented spatiotemporal resolution in fluid delivery as well as multifunctional interrogation of neural activity using combined electrical and optical modalities. Capitalizing on these unique features, microfluidic technology will greatly advance in vivo pharmacology, electrophysiology, optogenetics, and optopharmacology. In this review, we discuss recent advances in microfluidic neural probe systems. In particular, we will highlight the materials and manufacturing processes of microfluidic probes, device configurations, peripheral devices for fluid handling and packaging, and wireless technologies that can be integrated for the control of these microfluidic probe systems. This article summarizes various microfluidic implants and discusses grand challenges and future directions for further developments. <s> BIB009 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> This paper presents a solar energy harvesting power management using the high-efficiency switched-capacitor DC-DC converter for biomedical implant applications. By employing an on-chip start-up circuit with parallel connected Photovoltaic (PV) cells, a small efficiency improvement can be obtained when compared with the traditional stacked photodiode methodology to boost the harvested voltage while preserving a single-chip solution. The PV cells have been optimised in the PC1D software and the optimal parameters modelled in the Cadence environment. A cross-coupled circuit with level shifter loop is also proposed to improve the overall step up voltage output and hybrid converter increases the start-up speed by 23.5%. The proposed system is implemented in a standard $0.18-{\mu}\mathrm{m}$ CMOS technology. Simulation results show that the 4-phase start-up and cross-coupled with level-shifter can achieve a maximum efficiency of 60%. <s> BIB010 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <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> BIB011 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <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> BIB012 </s> Biointegrated and Wirelessly Powered Implantable Brain Devices: A Review <s> IV. FULLY IMPLANTABLE WIRELESS NEURAL DEVICE <s> Biomedical implant devices are fast becoming a growing part of the healthcare industry. Providing power to these devices in such a confined area is a critical challenge. Consequently, resonancebased wireless power delivery provides a harmless yet effective way for powering these implantable biomedical devices. This technique relies on transferring power via the inductive coupling technique. In this regard, optimizing the quality factor and matched resonant frequency is required to achieve high efficiency. However, the efficiency depends on the space available for the coil and the separation distance between the two coils. In our case, the minimum separation distance between the two coils needs to be at least 2 cm. Therefore, we demonstrate the design, simulation and experimental procedure of an optimized wireless power delivery system for bio-implantable applications with various considerations for size limitations. Our design delivers 68 mW output power to a 50-Ω load with an efficiency of 67% in vitro test and 74.8% in the FEM simulation. <s> BIB013
Traditional methods for optogenetics depend on stiff and battery-powered systems to transfer power to the brain from outside power supplies BIB001 . Such method harms the normal tissue environment due to the micro-motion introduced by these systems. For optogenetics, recent researches have focused on reducing mechanical stress and damage of tissue by minimizing implant size by applying SU-8 waveguides coupled with small laser diode and integrated silicon devices based on microscale inorganic light-emitting diodes (µ-LEDs) BIB007 BIB008 BIB003 BIB011 . Nonetheless, their rigid mechanisms still misaligned with the soft tissue of the brain BIB009 , which institutes substantial tissue trauma and swelling as time goes by, as described before. Other approaches to address this issue made use of biocompatible flexible polymers BIB004 , BIB002 , which also rely on wired or tethered systems with external sources and cause excessive mechanical pressure and continuous annoyance in freely moving rodents by obstructing their normal behaviour. In recent years, thanks to the wireless power engineering, significant advancements have been achieved by integrating wireless methodologies to enable chronic in vivo implantable neural device in freely moving animals. Ultrasonic or induction based power supplies for signal and/or power communication BIB005 , BIB012 BIB006 BIB010 BIB013 are some of the most commonly used techniques for wireless interface. Integrating these wireless implantable devices with multichannel and/or optofluidic channel, while challenging, may enable simultaneous neural recording and stimulation or drug delivery. These elusive combinational wireless technologies will enable to study long-term progression and recognize future therapeutic interventions for psychiatric and neurological conditions such as schizophrenia or Parkinson's disease. Although relatively new, there is a recent surge in developing wireless implantable neural system and the potential benefits of wireless devices are tremendous. In the following subsection, progress in wireless system for both conventional electrical stimulation and optogenetics will be discussed. A subset of wireless solutions for development of an implantable neural device will be explored, as illustrated in Fig. 8 . These wireless technologies mainly include ultrasound, electromagnetic, and solar. The thought for choosing the suitable wireless innovation incorporates propagation characteristics, implant size, and power adequacy. In view of this, we give a correlation in Fig. 9 between the diverse wireless power transfer schemes. Fig. 9 . Comparison among different wireless power transfer scheme in terms of stimulation intensity and power transfer distance.