Liquid Crystal Polymer-Based Miniaturized Fully Implantable Deep Brain Stimulator.

A significant challenge in improving the deep brain stimulation (DBS) system is the miniaturization of the device, aiming to integrate both the stimulator and the electrode into a compact unit with a wireless charging capability to reduce invasiveness. We present a miniaturized, fully implantable, and battery-free DBS system designed for rats, using a liquid crystal polymer (LCP), a biocompatible and long-term reliable material. The system integrates the simulator circuit, the receiver coil, and a 20 mm long depth-type microelectrode array in a dome-shaped LCP package that is 13 mm in diameter and 5 mm in height. Wireless powering and control via an inductive link enable device miniaturization, allowing for full implantation and, thus, the free behavior of untethered animals. The eight-channel stimulation electrode array was microfabricated on an LCP substrate to form a multilayered system substrate, which was monolithically encapsulated by a domed LCP lid using a specialized spot-welding process. The device functionality was validated via an in vivo animal experiment using a neuropathic pain model in rats. This experiment demonstrated an increase in the mechanical withdrawal threshold of the rats with microelectrical stimulation delivered using the fully implanted device, highlighting the effectiveness of the system.

Computational analysis of multichannel magnetothermal neural stimulation using magnetic resonator array.

Heating nanoparticles with a magnetic field could facilitate selective remote control of neural activity in deep tissue. However, current magnetothermal stimulation approaches are limited to single-channel stimulation. Here, we investigated various designs for multichannel magnetothermal stimulation based on an array of resonant coils that are driven by a single loop coil. Using a tuning capacitor that allows resonant coils to resonate at the operating frequency, each coil's ON and OFF resonance can be controlled, enabling us to select stimulation channels. We found that smaller inner diameters of resonant coils produce more localized magnetic fields while larger coils produce magnetic fields over a longer distance. The constructed multichannel resonant coil arrays can provide a high enough magnetic field intensity to raise the temperature of nanoparticles by 8 °C when we apply 35.2 W into the loop coil that is spaced 1 mm from the target neurons. This multichannel stimulation using a simple resonant circuit approach would be useful for clinical applications of magnetothermal neural stimulation.

The effect of topic familiarity and volatility of auditory scene on selective auditory attention.

Selective auditory attention has been shown to modulate the cortical representation of speech. This effect has been well documented in acoustically more challenging environments. However, the influence of top-down factors, in particular topic familiarity, on this process remains unclear, despite evidence that semantic information can promote speech-in-noise perception. Apart from individual features forming a static listening condition, dynamic and irregular changes of auditory scenes-volatile listening environments-have been less studied. To address these gaps, we explored the influence of topic familiarity and volatile listening on the selective auditory attention process during dichotic listening using electroencephalography. When stories with unfamiliar topics were presented, participants' comprehension was severely degraded. However, their cortical activity selectively tracked the speech of the target story well. This implies that topic familiarity hardly influences the speech tracking neural index, possibly when the bottom-up information is sufficient. However, when the listening environment was volatile and the listeners had to re-engage in new speech whenever auditory scenes altered, the neural correlates of the attended speech were degraded. In particular, the cortical response to the attended speech and the spatial asymmetry of the response to the left and right attention were significantly attenuated around 100-200 ms after the speech onset. These findings suggest that volatile listening environments could adversely affect the modulation effect of selective attention, possibly by hampering proper attention due to increased perceptual load.

Development of a miniaturized, reconnectable, and implantable multichannel connector.

Objective. Connectors for implantable neural prosthetic systems provide several advantages such as simplification of surgery, safe replacement of implanted devices, and modular design of the implant systems. With the rapid advancement of technologies for neural implants, miniaturized multichannel implantable connectors are also required. In this study, we propose a reconnectable and area-efficient multichannel implantable connector.Approach. A female-to-female adapter was fabricated using the thermal-press bonding of micropatterned liquid crystal polymer films. A bump inside the adapter enabled a reliable electrical connection by increasing the contact pressure between the contact pads of the adapter and the inserted cable. After connection, the adapter is enclosed in a metal case sealed with silicone elastomer packing. With different sizes of the packings, leakage current tests were performed under accelerated conditions to determine the optimal design for long-term reliability. Repeated connection tests were performed to verify the durability and reconnectability of the fabricated connector. The connector was implanted in rats, and the leakage currents were monitored to evaluate the stability of the connectorin vivo. Main results. The fabricated four- and eight-channel implantable connectors, assembled with the metal cases, had a diameter and length of 6 and 17 mm, respectively. Further, the contact resistances of the four- and eight-channel connectors were 53.2 and 75.2 mΩ, respectively. The electrical contact remained stable during repeated connection tests (50 times). The fabricated connectors with packings having 125%, 137%, and 150% volume ratios to the internal space of the metal case failed after 14, 88, and 14 d, respectively, in a 75 °C saline environment. In animal tests with rats, the connector maintained low leakage current levels for up to 92 d.Significance. An implantable and reconnectable multichannel connector was developed and evaluated. The feasibility of the proposed connector was evaluated in terms of electrical and mechanical characteristics as well as sealing performance. The proposed connector is expected to have potential applications in implantable neural prosthetic systems.

A Fully Implantable Miniaturized Liquid Crystal Polymer (LCP)-Based Spinal Cord Stimulator for Pain Control.

Spinal cord stimulation is a therapy to treat the severe neuropathic pain by suppressing the pain signal via electrical stimulation of the spinal cord. The conventional metal packaged and battery-operated implantable pulse generator (IPG) produces electrical pulses to stimulate the spinal cord. Despite its stable operation after implantation, the implantation site is limited due to its bulky size and heavy weight. Wireless communications including wireless power charging is also restricted, which is mainly attributed to the electromagnetic shielding of the metal package. To overcome these limitations, here, we developed a fully implantable miniaturized spinal cord stimulator based on a biocompatible liquid crystal polymer (LCP). The fabrication of electrode arrays in the LCP substrate and monolithically encapsulating the circuitries using LCP packaging reduces the weight (0.4 g) and the size (the width, length, and thickness are 25.3, 9.3, and 1.9 mm, respectively). An inductive link was utilized to wirelessly transfer the power and the data to implanted circuitries to generate the stimulus pulse. Prior to implantation of the device, operation of the pulse generator was evaluated, and characteristics of stimulation electrode such as an electrochemical impedance spectroscopy (EIS) were measured. The LCP-based spinal cord stimulator was implanted into the spared nerve injury rat model. The degree of pain suppression upon spinal cord stimulation was assessed via the Von Frey test where the mechanical stimulation threshold was evaluated by monitoring the paw withdrawal responses. With no spinal cord stimulation, the mechanical stimulation threshold was observed as 1.47 ± 0.623 g, whereas the stimulation threshold was increased to 12.7 ± 4.00 g after spinal cord stimulation, confirming the efficacy of pain suppression via electrical stimulation of the spinal cord. This LCP-based spinal cord stimulator opens new avenues for the development of a miniaturized but still effective spinal cord stimulator.

Development and Characterization of a Biomimetic Totally Implantable Artificial Basilar Membrane System.

Cochlear implants (CIs) have become the standard treatment for severe-to-profound sensorineural hearing loss. Conventional CIs have some challenges, such as the use of extracorporeal devices, and high power consumption for frequency analysis. To overcome these, artificial basilar membranes (ABMs) made of piezoelectric materials have been studied. This study aimed to verify the conceptual idea of a totally implantable ABM system. A prototype of the totally implantable system composed of the ABM developed in previous research, an electronic module (EM) for the amplification of electrical output from the ABM, and electrode was developed. We investigated the feasibility of the ABM system and obtained meaningful auditory brainstem responses of deafened guinea pigs by implanting the electrode of the ABM system. Also, an optimal method of coupling the ABM system to the human ossicle for transducing sound waves into electrical signals using the middle ear vibration was studied and the electrical signal output according to the sound stimuli was measured successfully. Although the overall power output from the ABM system is still less than the conventional CIs and further improvements to the ABM system are needed, we found a possibility of the developed ABM system as a totally implantable CIs in the future.

Totally implantable enzymatic biofuel cell and brain stimulator operating in bird through wireless communication.

Animals digest food to fuel brain neurometabolism via cellular respiration. This study demonstrates the combination of a biofuel cell (BFC) and an animal brain stimulator (ABS) implanted in a pigeon. Glucose oxidation and oxygen reduction in an enzymatic BFC supplied electrical power to the ABS. Power from the BFC reached 0.12 mW in vitro and 0.08 mW in vivo using only the natural glucose and oxygen in the pigeon's body. A power management integrated circuit is used to harvest energy from the in vivo BFC at a rate of 28.4 mJ over 10 min, which is sufficient for intermittent neurostimulation.

One-Pot Four-Component Coupling Approach to Polyheterocycles: 6H-Furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine.

A novel polyheterocyclic chemical space, 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine, was generated by a one-pot four-component coupling reaction where multiple bonds (three C-C, one C-O, and one C-N) were formed through a domino sequence. Two heterocyclic rings (furan and diazepine) were sequentially constructed from the monocyclic pyrrole derivative under environment-friendly reaction conditions to furnish the tricyclic fused scaffold.

Investigation of stereotactic surgery for avian brain stimulation by a fully implanted wireless system.

OBJECTIVE: The authors' goal was to study avian motor brain mapping via wireless stimulation to induce certain behaviors. In this paper, the authors propose an electrode design that is suitable for avian brain stimulation as well as a stereotactic implant procedure for the proposed electrode. METHODS: An appropriate breed for avian brain study was chosen. A fully implantable remote-controlled electrical stimulation system was inserted to minimize discomfort. A suitable electrode design and stereotactic surgery method based on the electrode design were investigated. RESULTS: Using a wireless stimulation system, flapping and rotation behaviors were induced by stimulating the ventral part of the nucleus intercollicularis and formatio reticularis medialis mesencephali both on the ground and during flight. CONCLUSIONS: The authors were able to implant the entire brain stimulation system inside the avian body without any surgical complications. Postoperative observations suggested that the bird did not find the implant uncomfortable.

Retinal Prosthetic Approaches to Enhance Visual Perception for Blind Patients.

Retinal prostheses are implantable devices that aim to restore the vision of blind patients suffering from retinal degeneration, mainly by artificially stimulating the remaining retinal neurons. Some retinal prostheses have successfully reached the stage of clinical trials; however, these devices can only restore vision partially and remain insufficient to enable patients to conduct everyday life independently. The visual acuity of the artificial vision is limited by various factors from both engineering and physiological perspectives. To overcome those issues and further enhance the visual resolution of retinal prostheses, a variety of retinal prosthetic approaches have been proposed, based on optimization of the geometries of electrode arrays and stimulation pulse parameters. Other retinal stimulation modalities such as optics, ultrasound, and magnetics have also been utilized to address the limitations in conventional electrical stimulation. Although none of these approaches have been clinically proven to fully restore the function of a degenerated retina, the extensive efforts made in this field have demonstrated a series of encouraging findings for the next generation of retinal prostheses, and these could potentially enhance the visual acuity of retinal prostheses. In this article, a comprehensive and up-to-date overview of retinal prosthetic strategies is provided, with a specific focus on a quantitative assessment of visual acuity results from various retinal stimulation technologies. The aim is to highlight future directions toward high-resolution retinal prostheses.

A preliminary implementation of an active intraocular prosthesis as a new image acquisition device for a cortical visual prosthesis.

An active intraocular prosthesis is herein proposed as a new image acquisition device for a cortical visual prosthesis. A conventional intraocular prosthesis is a passive device that helps blind patients underwent eye enucleation to maintain the shape of an eyeball. In contrast, an active intraocular prosthesis, which works as an implantable wireless camera, can capture real-time images and transmit them to a cortical visual prosthesis to restore partial vision of the patients. This active device has distinct advantages in that it can garner a variety of image information while focusing on objects in accordance with natural eye movements, compared with a glasses-mounted camera and implanted micro-photodiodes in typical artificial vision systems. Coated with an epoxy and sealed by an elastomer for biocompatibility as well as durability, the active intraocular prosthesis was fabricated in a spherical form miniaturized enough to be inserted into the eye. Its operation was evaluated by wireless image acquisition displaying a processed gray-scale image. Furthermore, signal-to-noise ratio measurements were conducted to find a reliable communication range of the fabricated prosthesis, while it was covered by an 8-mm-thick biological medium that mimicked in vivo environments. In conclusion, the feasibility of the active intraocular prosthesis to cooperate with a cortical visual prosthesis is discussed.

Palatal implant system can provide effective treatment for obstructive sleep apnea by recovering retropalatal patency.

OBJECTIVE: Obstructive sleep apnea (OSA) is a disorder with a high prevalence rate that may induce serious complications. Recent progress in the area of hypoglossal nerve stimulation has played a role as an alternative to conventional therapies though, some patients having retropalatal collapse still have not benefitted. Therefore, here we propose a new type of upper-airway stimulation, referred to as the palatal implant system, which recovers the upper-airway patency by electrically stimulating the soft palate. APPROACH: The system consists of two major parts: an implant that stimulates the soft palate through electrodes and an intra-oral device that delivers power and data simultaneously to the implant via an inductive link. Evaluations of the system are conducted in bench-top, in vitro, and in vivo tests to evaluate its feasibility as an OSA treatment, and the potential development of the system is addressed in the discussion section. MAIN RESULTS: In the bench-top test, the power efficiency was 12.4% at d = 5 mm and the system could operate up to 8 mm distance in a bio-medium. Data transmission was also successful at distances ranging 2 to 8 mm within an error margin of 10%. The measured CSCc and the impedance magnitude of the electrode were 62.25 mC cm-2 and 390 Ω, respectively, proving a feasibility of the electrode as a stimluator interface. The system was applied to a rabbit and contraction of the soft palate muscle was recorded via a C-arm fluoroscopy. SIGNIFICANCE: As a proof of concept, we suggest and demonstrate the palatal implant system as a new therapy for those undergoing treatment for OSA.

Implantable electrical stimulation bioreactor with liquid crystal polymer-based electrodes for enhanced bone regeneration at mandibular large defects in rabbit.

The osseous regeneration of large bone defects is still a major clinical challenge in maxillofacial and orthopedic surgery. Previous studies demonstrated that biphasic electrical stimulation (ES) stimulates bone formation; however, polyimide electrode should be removed after regeneration. This study presents an implantable electrical stimulation bioreactor with electrodes based on liquid crystal polymer (LCP), which can be permanently implanted due to excellent biocompatibility to bone tissue. The bioreactor was implanted into a critical-sized bone defect and subjected to ES for one week, where bone regeneration was evaluated four weeks after surgery using micro-CT. The effect of ES via the bioreactor was compared with a sham control group and a positive control group that received recombinant human bone morphogenetic protein (rhBMP)-2 (20 µg). New bone volume per tissue volume (BV/TV) in the ES and rhBMP-2 groups increased to 132% (p < 0.05) and 174% (p < 0.01), respectively, compared to that in the sham control group. In the histological evaluation, there was no inflammation within the bone defects and adjacent to LCP in all the groups. This study showed that the ES bioreactor with LCP electrodes could enhance bone regeneration at large bone defects, where LCP can act as a mechanically resistant outer box without inflammation. Graphical abstract To enhance bone regeneration, a bioreactor comprising collagen sponge and liquid crystal polymer-based electrode was implanted in the bone defect. Within the defect, electrical current pulses having biphasic waveform were applied from the implanted bioreactor.

A handheld neural stimulation controller for avian navigation guided by remote control.

BACKGROUND: Animal learning based on brain stimulation is an application in a brain-computer interface. Especially for birds, such a stimulation system should be sufficiently light without interfering with movements of wings. OBJECTIVE: We proposed a fully-implantable system for wirelessly navigating a pigeon. In this paper, we report a handheld neural stimulation controller for this avian navigation guided by remote control. METHODS: The handheld controller employs ZigBee to control pigeon's behaviors through brain stimulation. ZigBee can manipulate brain stimulation remotely while powered by batteries. Additionally, simple switches enable users to customize parameters of stimuli like a gamepad. These handheld and user-friendly interfaces make it easy to use the controller while a pigeon flies in open areas. RESULTS: An electrode was inserted into a nucleus (formatio reticularis medialis mesencephalic) of a pigeon and connected to a stimulator fully-implanted in the pigeon's back. Receiving signals sent from the controller, the stimulator supplied biphasic pulses with a duration of 0.080 ms and an amplitude of 0.400 mA to the nucleus. When the nucleus was stimulated, a 180-degree turning-left behavior of the pigeon was consistently observed. CONCLUSIONS: The feasibility of remote avian navigation using the controller was successfully verified.

Nitramine-Group-Containing Energetic Prepolymer: Synthesis, and Its Properties as a Binder for Propellant.

A composite solid propellant which generates high propulsive force in a short time is typically composed of an oxidizer, a metal fuel powder and a binder. Among these, the binder is an important component. The binder maintains the mechanical properties of propellant grains and endures several thermal and mechanical stresses in the engine. Several studies have been reported for the development of energetic propellant binders for increasing the propellant's propulsive force. While several materials have been studied for the synthesis of energetic prepolymers, a nitramine-group-containing prepolymer is a suitable candidate because these types of prepolymers are less toxic and more cost-effective when compared to the traditional glycidyl azide polymers (GAP) and triazole-based prepolymers. Considering the lack of studies for the binder using a nitramine-group-containing prepolymers, we synthesized a nitramine-group-containing monomer and polymerized a nitramine-group-containing prepolymer. The prepolymer was then used for the preparation of the binder and its thermal and mechanical properties, as well as the effect of the plasticizer, were studied. The binder that was prepared using the prepolymer containing a nitramine-group showed very high elongation, tensile strength. Nitrate-ester (NE)-type plasticizer could reduce the glassy transition temperature (Tg)of the binder successfully. Also, high-energy is released due to the decomposition of the nitramine-group at around 245 °C, thus exhibiting the efficiency of the nitramine-group-containing prepolymer as an excellent energetic binder material.

Emerging Encapsulation Technologies for Long-Term Reliability of Microfabricated Implantable Devices.

The development of reliable long-term encapsulation technologies for implantable biomedical devices is of paramount importance for the safe and stable operation of implants in the body over a period of several decades. Conventional technologies based on titanium or ceramic packaging, however, are not suitable for encapsulating microfabricated devices due to their limited scalability, incompatibility with microfabrication processes, and difficulties with miniaturization. A variety of emerging materials have been proposed for encapsulation of microfabricated implants, including thin-film inorganic coatings of Al2O3, HfO2, SiO2, SiC, and diamond, as well as organic polymers of polyimide, parylene, liquid crystal polymer, silicone elastomer, SU-8, and cyclic olefin copolymer. While none of these materials have yet been proven to be as hermetic as conventional metal packages nor widely used in regulatory approved devices for chronic implantation, a number of studies have demonstrated promising outcomes on their long-term encapsulation performance through a multitude of fabrication and testing methodologies. The present review article aims to provide a comprehensive, up-to-date overview of the long-term encapsulation performance of these emerging materials with a specific focus on publications that have quantitatively estimated the lifetime of encapsulation technologies in aqueous environments.

Recent Progress on Non-Conventional Microfabricated Probes for the Chronic Recording of Cortical Neural Activity.

Microfabrication technology for cortical interfaces has advanced rapidly over the past few decades for electrophysiological studies and neuroprosthetic devices offering the precise recording and stimulation of neural activity in the cortex. While various cortical microelectrode arrays have been extensively and successfully demonstrated in animal and clinical studies, there remains room for further improvement of the probe structure, materials, and fabrication technology, particularly for high-fidelity recording in chronic implantation. A variety of non-conventional probes featuring unique characteristics in their designs, materials and fabrication methods have been proposed to address the limitations of the conventional standard shank-type ("Utah-" or "Michigan-" type) devices. Such non-conventional probes include multi-sided arrays to avoid shielding and increase recording volumes, mesh- or thread-like arrays for minimized glial scarring and immune response, tube-type or cylindrical probes for three-dimensional (3D) recording and multi-modality, folded arrays for high conformability and 3D recording, self-softening or self-deployable probes for minimized tissue damage and extensions of the recording sites beyond gliosis, nanostructured probes to reduce the immune response, and cone-shaped electrodes for promoting tissue ingrowth and long-term recording stability. Herein, the recent progress with reference to the many different types of non-conventional arrays is reviewed while highlighting the challenges to be addressed and the microfabrication techniques necessary to implement such features.

CNT bundle-based thin intracochlear electrode array.

OBJECTIVE: It is known that the insertion of the intracochlear electrode is critical procedure because the damage around cochlear structures can deteriorate hearing restoration. To reduce the trauma during the electrode insertion surgery, we developed a thin and flexible intracochlear electrode array constructed with carbon nanotube (CNT) bundles. METHODS: Each CNT bundle was used for an individual electrode channel after coated with parylene C for insulation. By encapsulating eight CNT bundles with silicone elastomer, an 8-channel intracochlear electrode array was fabricated. The mechanical and electrochemical characteristics were assessed to evaluate the flexibility and feasibility of the electrode as a stimulation electrode. The functionality of the electrode was confirmed by electrically evoked auditory brainstem responses (eABR) recorded from a rat. RESULTS: The proposed electrode has a thickness of 135 µm at the apex and 395 µm at the base. It was demonstrated that the CNT bundle-based electrodes require 6-fold the lower insertion force than metal wire-based electrodes. The electrode impedance and the cathodic charge storage capacitance (CSCc) were 2.70 kΩ âˆ -20.4° at 1 kHz and - 708 mC/cm2, respectively. The eABR waves III and V were observed when stimulation current is greater than 50 µA. CONCLUSION: A thin and flexible CNT bundle-based intracochlear electrode array was successfully developed. The feasibility of the proposed electrode was shown in terms of mechanical and electrochemical characteristics. A proposed CNT bundle-based intracochlear electrode may reduce the risk of trauma during electrode insertion surgery.

A Feasibility Study on Optically Transparent Encapsulation for Implantable Neural Prostheses.

Optically transparent encapsulation is presented with results from long-term reliability and light transmission tests. This technology is required in certain implantable neural prostheses that demand the transmission of optical signals through an encapsulating material, such as in retinal implants or in optogenetic applications. In this study, biocompatible film-type cyclic olefin polymers (COPs) with low moisture absorption (<; 0.01 %) and high light transmission (92 %) are utilized as encapsulating materials based on thermal lamination. The reliability of COP encapsulation is characterized through accelerated soak tests in a 75 °C saline solution to measure the leakage currents from encapsulated inter-digitated electrodes. These tests had been done for 211 days with the estimated lifetime of 8.05 years at 37 °C. In addition, the optical properties of a thermally laminated COP film sample in relation to its thickness are evaluated by an experimental setup which uses projected line patterns on an image sensor. The light transmittance of COP film samples thinner than 376 µm exceeded 91.69 %, and the minimum distinguishable line pitch was 47.6 µm at a thickness of 26 µm. These results validate the feasibility of optically transparent encapsulation using COPs and may contribute to its use in future implantable neural prostheses.