Departments of Materials Science and Engineering, Biomedical Engineering, Chemistry, Neurological Surgery, Mechanical Engineering, Electrical Engineering and Computer Science, Simpson Querrey Institute & Feinberg Medical School, 2145 Sheridan Road, Evanston, IL 60208, United St
Keywords: neuroprosthetics, neurostimulation, microstimulation, floating stimulator, infrared tissue penetration, radiofrequency telemetry, ultrasound power transfer, energy harvesting
Emerging technologies enabled by interdisciplinary advances in materials science, optoelectronic devices, system engineering and mechanics design
of key considerations in technologies for neuroscience research. Examples of emerging tools. (b) Multifunctional fiber with electrical, optical and fluidic interfaces . (c) Silicon shank with electrical and optical interfaces . (d) Exploded-view images of a flexible probe with electrical, optical (emission and detection) thermal interfaces . (e) Soft probe with optical and fluidic interfaces 
of key considerations in technologies for neuroscience research. Examples of emerging tools. (b) Multifunctional fiber with electrical, optical and fluidic interfaces . (c) Silicon shank with electrical and optical interfaces . (d) Exploded-view images of a flexible probe with electrical, optical (emission and detection) thermal interfaces . (e) Soft probe with optical and fluidic interfaces .
Mechanical and Mechanical conformality Chemical Durability
Current Opinion in Neurobiology
bio-interface . Highly mobile, time-dynamic tissues intrinsic to many parts of the peripheral nervous system  give rise to difficulties in integration that are even more daunting than those associated with the brain. In all cases, minimizing size and weight is an essential engi- neering consideration .
Injectable, multifunctional platforms
Recent engineering developments greatly expand the scope of capabilities in neural interfaces. Platforms based on optical fibers as simple waveguides to transport light for optical stimulation  have evolved to multimodal probes for delivery of light, fluid and electrical current [20–23], sometimes with in situ recording and computing capabili- ties [24,25]. Other notable advances include syringe injectable electronics that unfold in target tissue to record electrical signals , ultra-thin organic transistor arrays for in situ myoelectric signal recording of optogenetically evoked spikes in muscles [27,28] and multifunctional electrodes for recordings in non-human primates  and wireless ultrasonic powered electrical devices for elec- tromyogram and electroneurogram measurements .
Successful animal behavioral experiments have been reported using multicore fibers shown in Figure 1b in which a core waveguide is surrounded by fluidic channels
and recording electrodes . Another example is in Figure 1c, where optical stimulation occurs via a light emitting diode (LED) monolithically integrated on a silicon platform that also supports electrodes for electrical recordings in the style of a conventional Michigan probe . Traditional wireless hardware has some utility in such cases, but major disadvantages follow from complex con- nections, undesirable mechanics, large sizes and weights [25,33], resulting in requirements for externally mounted head stages that can be cumbersome for small animal models. Monolithically integrated structures that combine diverse classes of materials in optimized mechanics layouts represent qualitatively differentiated types of technology. Here, entire optoelectronic systems with cellular-scale components can be configured as thin, flexible, injectable probes. Figure 1d shows such a miniaturized collection of devices, including a precision temperature sensor to mon- itor thermal load, microscale inorganic LEDs (m-ILEDs) to enable optical stimulation, a micro photodiode to allow for photometry and a micro electrode to perform electrical recording. The entire system has lateral dimensions of 300 mm and uses a thin (20 mm) polyimide support. The cross sectional size and bending stiffness are significantly smaller than those of optical fibers . Another example is in Figure 1e, where a collection of soft, microfluidic channels couple with m-ILEDs to allow combined
Current Opinion in Neurobiology 2018, 50:1–8
. Power and data telemetry
passive device, including the electromagnetic, optical, and acoustic methods,
A generic passive floating microstimulator implanted in the CNS. Stimulus energy is transferred to the device through acoustic, optic, or RF telemetry. Energy is converted to electric current and injected into the medium via the bipolar contacts to activate
microstimulation device, the BION
One of the commercial neurostimulation devices, the BION®, uses the Schottky diode for RF-to- DC conversion followed by an electrolytic capacitor,
single-channel microstimulator with RF telemetry
Pulsed Ultrasound (PUS) Power Telemetry
photodiodes based on nanoscale photo-ferroelectric thin films
Near-Infrared Power Telemetry
NIR power telemetry
optogenetic neural stimulation52 or measurement of chemical activity.
photodiode power telemetry
MEMS-GaAs is an attractive material for the fabrication of various electronic and micro-electromechanical (MEMS) devices. However, GaAs can release toxic materials such as As and AsOx that cause cell death. It was shown that GaAs surfaces can be coated with various biocompatible materials to prevent the release of toxic substances.64 A potential coating material is Parylene C (poly-paraxylylene), which has been widely used as a structural material for bioMEMS systems, and as a coating material in electronic circuits and implantable electrodes.65 Parylene C has several desirable properties, such as biocompatibility, chemical inertness, high flexibility, and reliable hermetic sealing of the electronic implantable systems.66 For this application the coating material over the active area must be transparent to allow the passage of photons. Parylene C has an 80% transmittance at NIR wavelengths.65 Xu Chao et al. showed that the transmittance can be improved to above 90% by depositing porous silica on Parylene C films.67
transcutaneous NIR power telemetry
FLOATING LIGHT-ACTIVATED MICROELECTRICAL (FLAME) STIMULATOR
single-channel passive floating micro-stimulation device
powered by a beam of NIR light. A microdevice that can collect the optical energy inside the tissue and then convert it into electrical current can provide neural stimulation5
direct optical stimulation technique.
The simplest electro- optical device with maximum efficiency is a silicon photodiode with a large intrinsic layer to collect all the charge carriers, i.e., a P-I-N photodiode.
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Electrical model of the FLAME stimulators, 60 which includes multiple photodiodes in series to increase the output voltage compliance, the interface with the tissue at the contacts, and the tissue impedance (B). The drawing on top shows the arrangement of the photodiode active area and the contacts on the wafer (A). Some decrease of output current occurs during the pulse due to the current that flows through the intrinsic diodes as the device voltage is increasing with charging of contact capacitors. Contact capacitors are discharged passively through the parallel resistor (R) during the off phase of the pulse cycle. A small stray capacitor (Cstr) is placed between the device terminals during fabrication.
optical micro-electrical stimulator
sufficient number of photons can be transmitted to a microstimulator implanted
The challenge is to have an optimized device design that can collect a sufficient number of photons to produce the specified current while keeping the device size small enough for the targeted implant site. Optimization of FLAME stimulators using computer simulations has been reported elsewhere.60 Here we will discuss some critical design issues, such as NIR penetration into tissue, heating effect, and the choice of fabrication materials.
NIR wavelengths have long been recognized for their ease of penetration into living tissue compared to visible light.6
NIR laser beam is to be applied only as short pulses with a very low duty cycle
Monte Carlo simulations become useful to compute the trajectory of a photon in a medium with known absorption, scattering, and anisotropy coefficients. One can calculate the probabilistic distribution of light density in the medium by simulating the trajectory of a large number of photons
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Simulated NIR photon density (W/cm3) inside the human gray (A) and white (B) matters due to a 0.2 cm radius NIR beam and the resulting temperature elevations in the tissue (C for gray and D for white). The NIR light beam is aimed from the top to the center of the cylindrical volume with a radius of 0.5 cm. Because of cylindrical symmetry, plots are made only for one half of the vertical cross sectional area. Note that maximum temperature is observed not at the surface but at 1.2 mm and 0.7 mm below the surface, respectively. Absorption and scattering coefficients for human gray and white matters were adopted from Refs. 85 and 86 and thermal conductivity of gray (0.57) and white (0.5 Wm−1ºC−1) matters from Ref. 87
All photons captured inside the tissue are absorbed eventually and converted to heat
The temperature elevation profile due to photon absorption can be computed with a finite element software for this inhomogeneous yet radially symmetrical geometry
NIR Penetration Depth
Materials for FLAME Stimulators
Gallium arsenide (GaAs) is a direct band-gap material that has a high absorption coefficient in the visible spectrum (~400–700 nm) as well as extending up to 900 nm in the NIR range.63
semiconductor photodiodes, electron-hole pairs are produced everywhere photons are absorbed.
Silicon detectors are also appropriate for the visible and NIR spectral range (<1000 nm). The optical absorption coefficient of silicon, however, is one to two orders of magnitude lower than that of the direct band-band transition semiconductors such as GaAs at the NIR wavelengths.
OPTIMIZATION OF A GENERIC FLOATING MICROSTIMULATOR A. Heating Effect
The physical principle behind the energy transfer from the external electronics (not necessarily extracorporeal, but just outside the CNS) to the implanted microstimulator determines the energy loss across the tissue, as well as the transducer type to be used for collection of energy.
monopolar and bipolar electrode
activation function (AF) as a measure. The peak values of AF reache farther to the right in case of the monopolar electrode.
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Comparison of activation function generated by bipolar (left plot) and monopolar (right plot) electrodes for a 10-μm myelinated axon placed vertically on the page. AF is calculated as the second derivative of the extracellular voltage along the axon.69 The vertical positioning of the axon and its three central nodes are shown on the right for Y = 0, X = 250 μm. The X,Y coordinates in the AF plots indicate the position of the central node as the fiber is moved around. The activation function changes as indicated by the color (red positive, blue negative) as a function of vertical and horizontal displacements of the axon with respect to the electrodes. Contact locations are indicated with black blocks on the left of each plot. Center-to-center separation between the anode and cathode is 400 μm for the bipolar electrodes. The monopolar cathodic electrode is located at X = 0, Y = −200 μm. The side lobes of the activation function on each side of the electrodes occur where the off-center nodes of Ranvier line up with the contact locations
Selection of Contact Material
Once the stimulus energy is collected by the implanted device, it needs to be transferred to the targeted neural tissue in an efficient way. Low efficiency in either energy collection or energy transfer would require an increase in the device size itself regardless of the physical principle used for wireless power transfer
Charge injection capacity (CIC
Charge injection capacity (CIC) of the contact material as well as the contacts’ shape, size, and location play a major role in efficient transfer of stimulus pulse to the surrounding neural tissue. Injection of high currents through microscale contacts imposes challenges for the electrode-electrolyte interface. Whether the current is injected through faradaic or capacitive mechanisms, the voltage across the interface is limited by the water window. Several materials have been investigated for their high CIC.
The iridium oxide (IrOx) contacts obtained either by activation of iridium or a sputtering process can achieve very large CIC values as measured under biphasic pulsing.70 (The CIC of an IrOx electrode might be somewhat less with chronic implants in live tissue.71) The very high CIC values reported for the IrOx electrodes are achieved by anodically biasing the electrode, which necessitates a built-in active circuitry on the device. Therefore, other materials that can provide comparable CIC values at the open-circuit voltage of the interface may be a better choice for a passive floating microstimulator. If the mechanism for charge injection is faradaic, then these chemical reactions should be reversed by passing an opposite current through the electrode interface during the off phase of the cycle. This may also require incorporation of active electronics on board to ensure a charge-balanced waveform. On the other hand, when the capacitive mechanism is employed, the interface capacitances can discharge during the off times through a simple resistance placed in parallel with the electrode contacts. The maximum value of this resistance can easily be calculated based on the value of the interface capacitance and the duty cycle of the stimulator. Some electrode materials that primarily use the capacitive mechanism are tantalum pentoxide (Ta2Ox5), titanium nitride (TiN),72 and polymers like poly-3,4- ethylenedioxythiophene (PEDOT).73 Tissue reaction to these materials and their long-term stability inside the hostile body environment as well as their mechanical durability are currently under investigation. 74,75
DESIGN OF AN IMPLANTATION TOOL
Implantation of a floating microstimulator demands a tool to hold the device during insertion, taking the place of the electrode substrate onto which the contacts are permanently attached in the case of traditional shank electrodes. With floating stimulators, however, the implantation tool is removed after insertion and the stab wound caused by the insertion tool will be repaired to a large extent by the immune system.3 An additional advantage is that the surgeon can select the exact positions of the stimulators without being limited by the fixed interelectrode distances or needing to find a cortical or spinal area that will conform to the shape of the electrode substrate as in the case of multielectrode arrays. The implantation tool should have current-delivering capabilities on its own in order to verify the implant location before deploying the microstimulator. Such a tool should be designed according to the physical dimensions of the microstimulator to minimize the tissue damage during insertion. A microfabricated silicon-based electrode carrier or a small-caliber stainless steel needle may function as an implantation tool.
NEUROPROSTHETIC APPLICATIONS FOR FLOATING MICROSTIMULATORS
A mechanically floating microscale stimulator with no tethering wire attachments can solve the problems associated with movement of the electrodes in situ
neural prosthetic applications for floating microstimulator
individual microstimulators can be made smaller than a single shank of a multielectrode array, the volume of tissue replaced by each electrode is reduced. Also, because the microstimulators are discrete without any surface superstructure to connect them, there is no compression of the superficial neural tissue observed with multielectrode arrays. On the other hand, implantation of individual microstimulators may become prohibitively difficult with the increasing number of stimulation channels.
Intraspinal microstimulation can reportedly generate functionally useful motor activity with only a few channels of wired implants.76,77 Chronically implantable microelectrode arrays for intraspinal stimulation currently do not have sufficient longevity to withstand high mobility of the spinal cord inside the vertebral column. Therefore, spinal cord applications would perhaps be the ones to benefit first from the availability of floating microstimulators. The drawing of Fig. 6 illustrates the concept of using an optical stimulator for intraspinal microstimulation. The idea can easily be extrapolated to acoustic and RF microstimulators. Potential applications include activation of intraspinal networks for coordinated movements of legs, as in locomotion,78,79 upper extremities,80 respiratory networks,81 the bladder,7,82 sexual function,83 or the colon and anal sphincter.84
Microstimulation of the lumbosacral spinal cord using an optical, floating microstimulator is envisioned as shown. The internal unit will activate multiple microstimulators at different wavelengths through optical fibers.
Another class of applications is to use the floating microstimulators for activation of cutaneous mechanoreceptors as a substitute for the lost sense of touch. A few of these devices can be implanted into the healthy skin, for instance around the upper arm, provided that they are small enough and each device can be activated selectively. This “smart tattoo” can then be used to substitute for the sense of touch in the hand that is impaired as a result of spinal cord injury. A similar approach can be visualized for the blind to provide them with an additional sensory modality on an area of the skin that is not normally used for probing the environment.
implantable electrodes that can last a lifetime in the CNS and be minimally traumatic to the surrounding neural tissue
Wireless multielectrode arrays with built-in integrated microcircuits
Many applications dealing with stimulation of the sensory areas of the cerebral cortex, such as visual and auditory prosthesis, require a large number of stimulation channels for their functionality.
clinical implementation of cortical neuroprosthetics.
neural prosthetic applications
submillimeter-size single-channel floating wireless stimulators
Wireless power coupling of passive microscale stimulating devices using infrared, RF, or acoustic methods has a potential to significantly improve the longevity and reduce the tissue trauma for mobile neural substrates such as the spinal cord.
Optical wireless power transfer
central nervous system
lead zirconate titanate
floating light-activated micro-electrical
charge injection capacity
UIUC. UIC 1Biomedical Engineering Department,
ILLINOIS Institute of Technology,
2Neural Engineering Program, UNIVERSITY ILLINOIS UNIVERSITY CHICAGO. NW UNIVERSITY MEDICINE
UIUC Medical Research Institutes,
*Address all correspondence to Mesut Sahin, PhD, Biomedical Engineering Department, New Jersey Institute of Technology, Newark, NJ 07102
Mesut Sahin, PhD, Biomedical Engineering Department, New Jersey Institute of Technology, Newark, NJ 07102; ude.tijn@nihas