Laser-Assisted Structuring of Graphene Films with Biocompatible Liquid Crystal Polymer for Skin/Brain-Interfaced Electrodes.

The work presented here introduces a facile strategy for the development of flexible and stretchable electrodes that harness the robust characteristics of carbon nanomaterials through laser processing techniques on a liquid crystal polymer (LCP) film. By utilizing LCP film as a biocompatible electronic substrate, control is demonstrated over the laser irradiation parameters to achieve efficient pattern generation and transfer printing processes, thereby yielding highly conductive laser-induced graphene (LIG) bioelectrodes. To enhance the resolution of the patterned LIG film, shadow masks are employed during laser scanning on the LCP film surface. This approach is compatible with surface-mounted device integration, enabling the circuit writing of LIG/LCP materials in a flexible format. Moreover, kirigami-inspired on-skin bioelectrodes are introduced that exhibit reasonable stretchability, enabling independent connections to healthcare hardware platforms for electrocardiogram (ECG) and electromyography (EMG) measurements. Additionally, a brain-interfaced LIG microelectrode array is proposed that combines mechanically compliant architectures with LCP encapsulation for stimulation and recording purposes, leveraging their advantageous structural features and superior electrochemical properties. This developed approach offers a cost-effective and scalable route for producing patterned arrays of laser-converted graphene as bioelectrodes. These bioelectrodes serve as ideal circuit-enabled flexible substrates with long-term reliability in the ionic environment of the human body.

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.

Simple and cost-effective microfabrication of flexible and stretchable electronics for wearable multi-functional electrophysiological monitoring.

The fabrication of flexible and stretchable electronics is a critical requirement for the successful application of wearable healthcare devices. Although such flexible electronics have been commonly fabricated by microelectromechanical system (MEMS) technologies, they require a specialised equipment for vacuum deposition, photolithography, and wet and dry etching. A photolithography-free simple patterning method using a desktop plotter cutter has been proposed; however, the metal formation and electrode opening still rely on the MEMS technology. To address this issue, we demonstrate a simple, rapid, cost-effective, and a complete microfabrication process for flexible and stretchable sensor platforms encompassing conductor formation and patterning to encapsulate and open sensing windows, which only require an economic plotter cutter and readily available supplies. Despite its simplicity, the proposed process could stably create microscale features of 200 µm wide conductor lines and 1 mm window openings, which are in the useful range for various wearable applications. The feasibility of the simple fabrication of multi-functional sensors for various physiological monitoring applications was successfully demonstrated in electrochemical (glucose), electrical (electrocardiogram), mechanical (strain), and thermal (body temperature) modalities.

Evaluation methods for long-term reliability of polymer-based implantable biomedical devices.

Long-term reliability of implantable biomedical devices is a critical issue for their practical usefulness and successful translation into clinical application. Reliability is particularly of great concern for recently demonstrated devices based on new materials typically relying on polymeric thin films and microfabrication process. While reliability testing protocol has been well-established for traditional metallic packages, common evaluation methods for polymer-based microdevices has yet to be agreed upon, even though various testing methods have been proposed. This article is aiming to summarize the evaluation methods on long-term reliability of emerging biomedical implants based on polymeric thin-films in terms of their theories and implementation with specific focus on difference from the traditional metallic packages.

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.

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.

Investigation of Surgical Techniques for Optimization of Long-Term Outcomes of LCP-Based Retinal Prosthesis Implantation.

PURPOSE: To investigate reproducible surgical techniques to optimize the long-term safety of liquid crystal polymer (LCP)-based retinal prosthesis implantation. METHODS: An LCP-based retinal prosthesis is fabricated monolithically on a single-body LCP substrate with all components, including the package and electrode array. We implanted the electrode array into the suprachoroidal space and anchored the package and transition part to the sclera in rabbits (n = 11). The safety profile was assessed upon the completion of the surgery and postoperatively. RESULTS: The surgical procedures for implantation of the entire system were easily performed in nine eyes (81.8%) without any intraoperative complications. In the other two eyes (18.2%), surgical complications related to electrode insertion, including optic nerve damage and retinal tear, arose. In 10 eyes (90.9%), the devices were well tolerated for at least 3 months. However, in most eyes (nine; 81.8%), two complications began to appear after 3 months, postoperatively, including conjunctival erosion or dehiscence over the package or transition part. The electrode arrays were maintained safely in the suprachoroidal space after surgery without any complications, regardless of the status of the extraocular components in all cases except two intraoperative complications. CONCLUSIONS: We established safe and reproducible surgical techniques for implantation of our LCP-based retinal prosthesis into the suprachoroidal space. Although issues related to surgical technique or device configuration were identified, further technical solutions would improve the long-term safety of device implantation. TRANSLATIONAL RELEVANCE: This study presents successful implantation of LCP-based retinal prosthesis. The technical solutions will permit an optimization of surgical techniques.

Novel four-sided neural probe fabricated by a thermal lamination process of polymer films.

BACKGROUND: Ideally, neural probes should have channels with a three-dimensional (3-D) configuration to record the activities of 3-D neural circuits. Many types of 3-D neural probes have been developed; however, most of them were designed as an array of multiple shanks with electrodes located along one side of the shanks. NEW METHOD: We developed a novel liquid crystal polymer (LCP)-based neural probe with four-sided electrodes. This probe has electrodes on four sides of the shank, i.e., the front, back and two sidewalls. To generate the proposed configuration of the electrodes, we used a thermal lamination process involving LCP films and laser micromachining. RESULTS: The proposed novel four-sided neural probe, was used to successfully perform in vivo multichannel neural recording in the mouse primary somatosensory cortex. COMPARISON WITH EXISTING METHOD: The multichannel neural recording showed that the proposed four-sided neural probe can record spiking activities from a more diverse neuronal population than single-sided probes. This was confirmed by a pairwise Pearson correlation coefficient (Pearson's r) analysis and a cross-correlation analysis. CONCLUSION: The developed four-sided neural probe can be used to record various signals from a complex neural network.

Long-term evaluation of a liquid crystal polymer (LCP)-based retinal prosthesis.

OBJECTIVE: The aim of this study is to evaluate the long-term reliability of a recently presented liquid crystal polymer (LCP) -based retinal prosthesis in vitro as well as in vivo. Because an all-polymer implant introduces another intrinsic leak type due to gas permeation, for which the traditional helium leak test for metallic packages was not designed to quantify, a new method to investigate its durability is required. APPROACH: We designed and carried out a series of reliability tests specifically for all-polymer implants by quantitatively investigating moisture ingress through various pathways of the polymer surface, and the polymer-polymer and polymer-metal adhesions. Moisture permeation through the bulk material was estimated by analytic calculation, while water ingress through the adhesively sealed LCP-LCP and LCP-metal interfaces was investigated using the separate parts of an electrode array and a package in an accelerated aging condition. In vivo tests were done in rabbits to examine the long-term biocompatibility and implantation stability by fundus observation and optical coherence tomography (OCT) imaging. MAIN RESULTS: The analytic calculation estimated good barrier properties of the LCP. Samples of the LCP-based electrode array failed after 114 days in 87 °C saline as a result of water penetration through the LCP-metal interface. An eye-conformable LCP package survived for 87 days in an accelerated condition at 87 °C. The in vivo results confirmed that no adverse effects were observed around the retina 2.5 years after the implantation of the device. SIGNIFICANCE: These long-term evaluation results show the potential for the chronic use of LCP-based biomedical implants to provide an alternative to traditional metallic packages.

A miniaturized, eye-conformable, and long-term reliable retinal prosthesis using monolithic fabrication of liquid crystal polymer (LCP).

A novel retinal prosthetic device was developed using biocompatible liquid crystal polymer (LCP) to address the problems associated with conventional metal- and polymer-based devices: the hermetic metal package is bulky, heavy, and labor-intensive, whereas a thin, flexible, and MEMS-compatible polymer-based system is not durable enough for chronic implantation. Exploiting the advantageous properties of LCP such as a low moisture absorption rate, thermobonding, and thermoforming, we fabricate a small, light-weight, long-term reliable retinal prosthesis that can be conformally attached on the eye-surface. A LCP fabrication process using monolithic integration and conformal deformation was established enabling miniaturization and a batch manufacturing process as well as eliminating the need for feed-through technology. The functionality of the fabricated device was tested through wireless operation in saline solution. Its efficacy and implantation stability were verified through in vivo animal tests by measuring the cortical potential and monitoring implanted dummy devices for more than a year, respectively.

A wireless power transmission system for implantable devices in freely moving rodents.

Reliable wireless power delivery for implantable devices in animals is highly desired for safe and effective experimental use. Batteries require frequent replacement; wired connections are inconvenient and unsafe, and short-distance inductive coupling requires the attachment of an exterior transmitter to the animal's body. In this article, we propose a solution by which animals with implantable devices can move freely without attachments. Power is transmitted using coils attached to the animal's cage and is received by a receiver coil implanted in the animal. For a three-dimensionally uniform delivery of power, we designed a columnar dual-transmitter coil configuration. A resonator-based inductive link was adopted for efficient long-range power delivery, and we used a novel biocompatible liquid crystal polymer substrate as the implantable receiver device. Using this wireless power delivery system, we obtain an average power transfer efficiency of 15.2% (minimum efficiency of 10% and a standard deviation of 2.6) within a cage of 15×20×15 cm3.

A polymer-based multichannel cochlear electrode array.

OBJECTIVE: Compared with conventional cochlear electrode arrays, which are hand assembled and wire-based, polymer-based implants have several advantages. They are very precise, and their fabrication is inexpensive because of the use of thin-film processes. In the present study, a cochlear electrode array based on a high-performance liquid crystal polymer material is devised. Furthermore, the device is encapsulated in silicone elastomer. METHODS: The fabrication steps introduced here include thin-film processes with liquid crystal polymer (LCP) films and customized self-aligning molding processes for the electrode array. To assess the feasibility of the proposed electrode array, the charge storage capacitance and impedance were measured using a potentiostat. Vertical and horizontal deflection forces were measured using a customized fixture and a force sensor. Insertion and extraction forces were also measured using a transparent human cochlear plastic model, and five cases involving human temporal insertion trials were undertaken to assess the level of safety during the insertion process. RESULTS: The charge storage capacity and impedance at 1 kHz were 33.26 mC/cm and 1.02 kΩ, respectively. Likewise, the vertical force and horizontal force of the electrode array were 3.15 g and 1.07 g. The insertion force into a transparent plastic cochlear model with displacement of 8 mm from a round window was 8.2 mN, and the maximum extraction force was 110.4 mN. Two cases of human temporal bone insertion showed no observable trauma, whereas 3 cases showed a rupture of the basilar membrane. CONCLUSION: An LCP-based intracochlear electrode array was fabricated, and its electrical and mechanical properties were found to be suitable for clinical use.

Columnar transmitter based wireless power delivery system for implantable device in freely moving animals.

A wireless power delivery system is developed to deliver electrical power to the neuroprosthetic devices that are implanted into animals freely moving inside the cage. The wireless powering cage is designed for long-term animal experiments without cumbersome wires for power supply or the replacement of batteries. In the present study, we propose a novel wireless power transmission system using resonator-based inductive links to increase power efficiency and to minimize the efficiency variations. A columnar transmitter coil is proposed to provide lateral uniformity of power efficiency. Using this columnar transmitter coil, only 7.2% efficiency fluctuation occurs from the maximum transmission efficiency of 25.9%. A flexible polymer-based planar type receiver coil is fabricated and assembled with a neural stimulator and an electrode. Using the designed columnar transmitter coil, the implantable device successfully operates while it moves freely inside the cage.

Advancements in fabrication process of microelectrode array for a retinal prosthesis using Liquid Crystal Polymer (LCP).

Liquid Crystal Polymer (LCP) has been considered as an alternative biomaterial for implantable biomedical devices primarily for its low moisture absorption rate compared with conventional polymers such as polyimide, parylene and silicone elastomers. A novel retinal prosthetic device based on monolithic encapsulation of LCP is being developed in which entire neural stimulation circuitries are integrated into a thin and eye-conformable structure. Micromachining techniques for fabrication of a LCP retinal electrode array have been previously reported. In this research, however, for being used as a part of the LCP-based retinal implant, we developed advanced fabrication process of LCP retinal electrode through new approaches such as electroplating and laser-machining in order to achieve higher mechanical robustness, long-term reliability and flexibility. Thickened metal tracks could contribute to higher mechanical strength as well as higher long-term reliability when combined with laser-ablation process by allowing high-pressure lamination. Laser-thinning technique could improve the flexibility of LCP electrode.

In vitro biocompatibility of various polymer-based microelectrode arrays for retinal prosthesis.

PURPOSE: The purpose of our study is to evaluate the biocompatibility of various polymers used as microelectrode arrays (MEAs) in retinal prostheses through in vitro cytotoxicity testing following a standardized METHODS: Three types of polymer-based MEAs were examined: silicone-based platinum, polyimide-based gold and liquid crystal polymer (LCP)-based gold MEAs. The silicone/platinum MEAs were fabricated by a Nd:YAG laser, polyimide/gold MEAs by a semiconductor manufacturing technique, and LCP/gold MEAs by laser micromachining and thermal-bonding process. All experimental procedures followed the International Organization for Standardization (ISO) 10993-5. To obtain the extracts of specimens, 4 g of each type of MEA were eluted by culture media, MEM, for 24 hours. Then, several diluents of extracts, including the original extracts, were applied to a cultured-cell monolayer, L929 fibroblasts. The morphologic changes of cells were analyzed by microscope after 24 and 48 hours of incubation. The quantitative evaluations of cell viability were performed by MTT assay after 24 hours of incubation. RESULTS: The microscopic evaluations revealed that extracts from polymer-based MEAs did not induce morphologic changes or reduction of cells compared with control irrespective of concentrations of extracts. The MTT assay showed high viability values of approximately 80 to 130% regardless of diluted ratio of extracts from polymer-based MEAs. None of the polymers demonstrated a significant reduction of cell viability when compared with control. CONCLUSIONS: All types of polymer-based MEAs, including silicone/platinum, polyimide/gold, and LCP/gold MEAs, meet the criteria of biocompatibility guided by international standards, ISO 10993-5.

Eye-surface conformable telemetric structure for polymer-based retinal prosthesis.

In this research, inductive telemetric structure for retinal prosthesis was developed based on Liquid Crystal Polymers. For power and data transmission into the polymer-based retinal implant which is conformable to eye surface, the designed coil was thermo-formed into convex shape. The geometric parameters of the coil were optimized using finite element method (FEM) simulations for maximizing coupling coefficient and quality factor. The electrical properties of fabricated coils were characterized and their power and data transmission performance was tested. The properties of deformed structure were compared to those of the planar structure. In vivo experiment were also conducted to confirm the functionality of telemetry system in implanted conditions as well as to estimate the influence of biological media upon link properties.