Joonsoo Jeong

Monolithic Encapsulation of Implantable Neuroprosthetic Devices Using Liquid Crystal Polymers

Flexible polymers have gained much attention in the development of low cost, magnetic resonance compatible, and nonfragile implantable medical devices. However, efficacy of the conventional polymer encapsulations containing hybrid interfaces is limited due to their relatively high moisture absorption and unstable interfacial adhesion in aqueous environments. As an alternative, we report on a monolithic encapsulation platform for neuroprosthetic devices using liquid crystal polymers (LCPs), which have a very low degree of moisture absorption (<;0.04%) and a fusion bondable interface. This platform offers monolithic encapsulation by fusion bonding of the hemispherical LCP package lids and LCP-based microelectrode arrays. The package lids were fabricated by thermoforming of the LCP films to provide the desired shape and size for encasing the electronic components and wireless telemetry coils. Fusion-bonded LCP encapsulations were evaluated using electrical leakage current measurements during in vitro soak tests. The measurements were done in both 37°C and 75°C phosphate-buffered saline (PBS) solution and showed that LCP encapsulation was superior and more reliable in PBS than polyimide and parylene-C encapsulations. In addition, LCP-based monolithic encapsulation provided reliable electrical insulation for more than 300 days in both 37°C and 75°C PBS solution.

Modeling of brain D2 receptor occupancy-plasma concentration relationships with a novel antipsychotic, YKP1358, using serial PET scans in healthy volunteers

YKP1358 is a novel serotonin (5‐HT2A) and dopamine (D2) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D2 receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D2 receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose‐escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [11C]raclopride. The D2 receptor occupancy of striatum was measured pre‐dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D2 receptor occupancy by YKP1358 increased to 53–83% at 2 h, and then decreased afterwards, ranging from 40–64% at 5 h to 20–51% at 10 h. The YKP1358 dose‐plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D2 receptor occupancy that was well predicted by a sigmoid Emax model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D2 receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D2 receptor occupancy.

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 METHOD 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.

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.

Changes of 2-deoxyglucose uptake in the rat auditory pathway after bilateral ablation of the cochlea

It has been reported that the area of decreased glucose metabolism in the FDG-PET of prelingually deaf children correlates significantly with speech performance after cochlear implantation. In this study, we undertook to confirm changes of glucose metabolism in the cerebral cortex using an animal model with age-matching groups to completely exclude the influence of age differences between the deaf and normal-hearing groups. The cochlea was ablated bilaterally at a postnatal 10-14 days in the deaf groups; 3-4 deaf and normal rats were included at each time point at 1, 2, 4 and 8 weeks and 7 months after ablation. After injecting 2-deoxyglucose intraperitoneally, digitalized autoradiographic images were obtained, and analyzed by using two different methods; 3-dimensional voxel-wise statistical analysis and conventional 2-dimensional densitometry. The hypometabolic area analyzed using 3-dimensional analysis and the differences of optical density between normal and deaf as determined by densitometry were widest and most prominent between 4 and 8 weeks after ablation. Differences were not significant before 2 weeks or after 7 months after ablation. This result shows that the hypometabolic area becomes prominent after a critical period and it decreases as the duration of deafness increases. We believe that cross-modal plasticity may be the mechanism of changes in glucose metabolism and that this result reinforced the usefulness of evaluating hypometabolic area using FDG-PET in deaf children.

Loss of asymmetry in D2 receptors of putamen in unaffected family members at increased genetic risk for schizophrenia

Objective:  Dopamine dysregulation has been implicated in the pathophysiology of schizophrenia. The present study was performed to examine whether unaffected relatives at high genetic risk of schizophrenia have dopamine dysregulation in comparison with healthy controls.

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.

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.

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/cm2 and 1.02 k&OHgr;, 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.

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.