액정폴리머를 기반의 소형, 안구밀착형, 장기안정적인 인공망막장치

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 8. 김성준.A novel retinal prosthetic device was developed using 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, thermo-bonding and thermo-forming, a small, light-weight, long-term reliable retinal prosthesis was fabricated 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 fabricated 16-channels LCP-based retinal implant had 14 mm-diameter with the maximum thickness of 1.4 mm and weight of 0.4 g and could be operated wirelessly up to 16 mm of distance in the air. The long-term reliability of the all-LCP retinal device was evaluated in vitro as well as in vivo. Because an all-polymer implant introduces intrinsic gas permeation for which the traditional helium leak test for metallic packages was not designed to quantify, a new set of reliability tests were designed and carried out specifically for all-polymer implants. Moisture ingress through various pathways were classified into polymer surface, polymer-polymer and polymer-metal adhesions each of which were quantitatively investigated by analytic calculation, in vitro aging test of electrode part and package part, respectively. The functionality and long-term implantation stability of the device was verified through in vivo animal experiments by measuring the cortical potential and monitoring implanted dummy devices for more than a year, respectively. Samples of the LCP electrodes array failed after 114 days in 87°C salin as a result of water penetration through the LCP-metal interface. An eye-confirmable LCP package survived more than 35 days in an accelerated condition at 87°C. The in vivo results confirmed that no adverse effects around the retina were observed after implantation of the device for more than a year.ABSTRACT i Contents iv List of Figures xi List of Tables xxi Chapter 1 : Introduction 1 1.1. Neuroprosthetic devices 1 1.2. Retinal prosthesis 2 1.2.1. Concept 2 1.2.2. Three approaches 3 1.2.3. Camera vs. Photodiode 4 1.3. Conventional devices 5 1.4. Liquid Crystal Polymer (LCP) 7 1.4.1. Low moisture absorption and permeability 9 1.4.2. Thermoplastic property 9 1.4.3. Compatibility with MEMS technologies 10 1.4.4. RF characteristics 10 1.5. LCP-based retinal prosthesis 11 1.6. Long-term reliability 12 1.7. Dissertation outline 14 Chapter 2: Methods 16 2.1. System Overview 16 2.2. Microfabrication on LCP 18 2.2.1. Limitations of the previous microfabrication technique on LCP 19 2.2.2. Improved LCP-based microfabrication 22 2.2.2.1. Electroplated micro-patterning 23 2.2.2.2. Laser-thinning for higher flexibility 24 2.2.2.3. Laser-ablation for site opening 25 2.3. All-LCP Monolithic Fabrication 26 2.3.1. Multilayered integration 29 2.3.1.1. Electrical components 29 2.3.1.2. Thermal lamination 32 2.3.1.3. Layer configuration 34 2.3.2. Thermal deformation 35 2.3.2.1. Deformation process 35 2.3.2.2. Wavy lines for stretchability 36 2.3.2.3. Electrical properties of the deformed coil 40 2.3.3. Circuit Assembly 40 2.3.3.1. Stimulation ASIC 40 2.3.3.2. Surrounding circuitries 41 2.3.4. Packaging 43 2.3.5. Laser Machining 44 2.4. Device characterization 44 2.4.1. Transmitter Circuit and Wireless Operation 45 2.4.1.1. Transmitter circuit 45 2.4.1.2. Transmitter coil 46 2.4.1.3. Wireless operation test 46 2.4.2. Electrochemical measurements 48 2.5. Long-term reliability tests in vitro 49 2.5.1. Failure mechanisms of an all-LCP device 49 2.5.2. Analytic calculation 51 2.5.3. Long-term reliability tests in accelerated environment 55 2.5.3.1. Long-term reliability of electrode array 55 2.5.3.2. Long-term reliability of package 57 2.5.3.3. Long-term reliability of complete device 58 2.5.4. Long-term electrochemical stability 59 2.6. Acute and Chronic Evaluation in vivo 60 2.6.1. Surgical implantation 60 2.6.2. Acute functionality test 62 2.6.3. Long-term implantation stability 63 Chapter 3: Results 64 3.1. Microfabrication on LCP 64 3.1.1. Electroplated micro-patterning 64 3.1.2. Laser-ablation for site opening 67 3.1.3. Laser-thinning for higher flexibility 69 3.2. All-LCP Monolithic fabrication 71 3.2.1. Multilayered integration 71 3.2.2. Thermal deformation 73 3.2.2.1. Deformation results 73 3.2.2.2. Wavy lines for stretchability 74 3.2.2.3. Effect on the electrical properties 74 3.2.3. Circuit assembly 76 3.2.4. Packaging 77 3.2.5. Laser machining 79 3.3. Device Characterization 80 3.3.1. General specifications 81 3.3.2. Transmitter circuit and coil 83 3.3.3. Wireless operation 83 3.3.4. Electrochemical measurements 84 3.4. Long-term reliability tests in vitro 86 3.4.1. Analytic calculation 87 3.4.2. Long-term reliability tests in accelerated condition 90 3.4.2.1. Long-term reliability of electrode arrays 90 3.4.2.2. Long-term reliability of package 92 3.4.2.3. Long-term reliability of complete device 93 3.4.3. Long-term Electrochemical stability 93 3.5. Acute and chronic evaluation in vivo 95 3.5.1. Surgical implantation 95 3.5.2. Acute functionality test 96 3.5.3. Long-term implantation stability 97 Chapter 4: Discussion 100 4.1. Comparison with conventional devices 100 4.2. Potential applications 102 4.3. Opportunities for further improvements 102 4.4. Long-term reliability 104 Chapter 5: Conclusion 108 Reference 110 국문초록 118 감사의 글 121Docto

인공시각장치 개발을 위한 동물모델 평가와 수술기법 연구

학위논문 (박사)-- 서울대학교 대학원 : 공과대학 협동과정 바이오엔지니어링전공, 2019. 2. 서종모.본 연구진은 액정폴리머 기반의 일체형 인공망막장치를 개발하였는데, 이는 세라믹 또는 금속으로 만들어진 기존의 신경보철장치에 비해 얇고 가볍다는 장점이 있다. 그러나 인공망막장치 체내 삽입술은 고난위도의 수술기법을 요구하므로, 장기간 체내 안전성을 확보하기 위한 수술기법을 확립하기 위해서는 아직 많은 노력이 필요하다. 본 논문에서는 동물실험을 통해 액정폴리머 기반의 인공망막장치의 장기간 안전성을 최적화하기 위한 수술기법을 개발하고자 하였다. 예비연구에서 프로토타입 인공망막장치를 2마리의 토끼에 삽입하였다. 전극은 맥락막상강으로 삽입하고 시스템 패키지는 두개골 위에 장착하였다. 전극과 패키지 사이의 연결부는 안와 주변의 조직을 박리한 뒤 측두근 아래로 통과시켰다. 삽입술은 합병증 없이 성공적으로 시행되었다. 수술 후 시행한 안저검사, 빛간섭단층촬영과 X-선 촬영에서도 안내출혈, 망막박리, 절개부 벌어짐, 장치 이탈 등의 합병증은 관찰되지 않았다. 다음으로 액정폴리머 기반의 인공망막장치의 형태를 개선하여 안구에 완전히 이식할 수 있도록 수정하고, 11마리의 토끼에서 삽입술을 시행하였다. 전극은 맥락막상강으로 삽입하고, 패키지는 공막에 고정하였으며, 전극과 패키지 사이의 이행부는 공막에 고정하였다. 삽입술은 9마리(81.8%)에서 합병증 없이 성공적으로 이루어졌다. 그러나 2마리(18.2%)에서는 전극삽입 중 시신경 손상 및 망막 열공의 합병증이 발생하였다. 술 후 적어도 3개월동안은 10마리(90.9%)에서 인공망막장치가 체내에서 안정적으로 유지되었다. 그러나 3개월 후 9마리(81.8%)에서 패키지 또는 이행부를 덮은 결막의 미란 또는 벌어짐이 확인되었다. 그러나 이와 관계없이 맥락막상강에 삽입된 전극은 술 후에도 부작용 없이 안정적으로 유지되었다. 본 연구를 통해 수술기법 또는 장치의 형태와 관련된 몇몇 문제를 확인하였고, 추후 기술적인 개선책으로 인공망막장치 체내 삽입술의 장기간 안전성을 향상시킬 수 있을 것으로 기대한다. 또한 궁극적으로 사람에서 안전하게 인공망막장치를 삽입할 수 있는 수술기법 개발의 디딤돌이 될 것으로 기대한다. 사람과 동물모델을 기반으로 많은 연구들이 이루어져왔지만, 망막변성질환의 병태생리는 아직 명확히 밝혀지지 않았다. 생체내 망막의 구조적 변화에 대한 연구는 망막변성질환의 발병 및 진행을 이해하는데 중요하다. 근래에 빛간섭단층촬영은 망막 구조에 대한 생체연구에서 가장 유용한 검사법이지만, 아직 망막변성질환에서 비정상적인 빛간섭단층촬영 소견에 부합하는 해부학적 소견에 대해서는 명확히 알려지지 않았다. 본 논문에서는 유리체강내 요오드산나트륨을 주입한 토끼 망막변성모델에서 망막전위도 검사결과로 뒷받침되는 빛간섭단층촬영에서의 병적 변화에 부합하는 해부학적 소견을 분석하고자 하였다. 20마리의 토끼를 5마리씩 4군으로 나누어, 각 토끼의 단안에 요오드산나트륨을 군별로 0.1, 0.2, 0.4, 또는 0.8mg을 유리체강내 주입하였다. 투여 전 및 투여 후 28일 동안 각 토끼는 안저검사, 빛간섭단층촬영, 망막전위도 및 조직학적 검사를 시행하였다. 요오드산나트륨 0.2mg 군에서는 빛간섭단층촬영상 외경계막 소실 및 경도의 불분명한 타원체구역의 소견이 일시적으로 관찰되었으나, 조직학적 검사에서는 명확한 변화는 확인되지 않았다. 망막전위도 검사상 초기의 일시적인 a-파와 b-파의 감소는 투여 후 28일경에는 완전히 회복되었다. 0.4mg 군에서는 투여 후 1일째부터 빛간섭단층촬영상 외경계막 및 타원체구역이 소실되었지만, 초기 조직학적 검사에서는 빛수용세포의 핵, 내절 및 외절의 층판 구조는 비교적 유지되고 경도의 외절 및 내절의 구조적 손상만 관찰되었다. 이후에는 빛간섭단층촬영 및 조직학적 검사상 외망막층의 손상은 진행되어, 투여 후 28일경에는 빛수용세포는 완전히 소실되었다. 망막전위도 검사에서는 경과관찰 기간 동안 심한 a-파 및 b-파의 진폭의 감소가 지속되었다. 결론적으로 본 논문에서 빛간섭단층촬영은 조직학적 검사상 명확한 해부학적 변화가 나타나기 이전에 빛수용세포의 초미세구조의 변화를 초기에 확인할 수 있었다. 또한 빛간섭단층촬영상 외경계막 및 타원체구역의 손상 정도로 빛수용세포가 손상된 정도를 예측할 수 있었다.Our group has developed and manufactured a seamless liquid crystal polymer (LCP)-based monolithic retinal prosthesis. This device is thin and light which is superior to other prosthetic devices made of ceramic or metal. However, the establishment of reliable and reproducible surgical procedures ensuring the long-term safety of the prosthesis remains a challenge. In the first section of this dissertation, the reproducible surgical techniques were developed to optimize the long-term safety of implantation surgery of our LCP-based retinal prosthesis by in vivo experiments. In the pilot study, 2 eyes of 2 New Zealand white rabbits were operated to implant the prototype LCP-based prosthetic device. The electrode array was inserted into the suprachoroidal space and the system package was anchored on the skull. The interconnection cable was passed through the tunnel under the temporalis muscle. The implantation surgery was successfully performed without any complications. No postoperative complications were detected including intraocular hemorrhage, retinal detachment, wound dehiscence and displacement of the device under fundus examination, optical coherence tomography (OCT) images and x-ray. Next, our group has modified the device to implant the device in the eyeball as a whole. Eleven rabbits were operated for the implantation of totally implantable prosthetic device. The electrode array was inserted into the suprachoroid space and the package was fixed onto the sclera under the conjunctiva. The transition part between the electrode array and package were anchored onto the sclera. 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 (nine81.8%), 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. Although issues related to surgical technique or device configuration were identified, further technical solution would improve the long-term safety of device implantation. Finally, these experiments would provide a stepping stone to achieve the safe and reproducible surgical techniques for human in the future. Despite many studies in human and animal models, the pathophysiology of retinal degenerative diseases is not still clear. In vivo evaluation of the structural changes of retina is important for understanding the development and progression in retinal degenerative diseases. Currently, OCT is the most useful tool for in vivo evaluation of the retinal architecture. However, information is still lacking on the anatomic correspondences with abnormal OCT features in eyes with retinal degenerative diseases. In the second section of this dissertation, the anatomic correlates with pathologic OCT features were investigated supported by electroretinography (ERG) findings in experimental retinal degeneration model induced by intravitreal sodium iodate (NaIO3) administration. Twenty rabbits were underwent unilateral intravitreal injections of four different NaIO3 doses: 0.1, 0.2, 0.4 or 0.8mg (n=5 for each dose). Comprehensive ophthalmic examinations were performed including fundus examination, OCT, ERG and histologic analyses from baseline to 28 days after NaIO3 administration. In the 0.2-mg group, there were transient changes of outer retinal layers on OCT, including an indistinguishable external limiting membrane (ELM) and slightly obscure ellipsoid zone (EZ) without significant changes in the histologic sections. In addition, there was transient reduction of a- and b-wave amplitudes followed by complete restoration at day 28. In the 0.4-mg group, the EZ and ELM became completely indistinguishable as early as day 1, whereas the histologic analysis showed only slightly disorganized photoreceptor inner and outer segments (IS and OS) with relatively preserved overall laminations of photoreceptor cell nuclei, IS and OS. Damage to outer retinal layers progressed in both the OCT and histologic analyses, leading to complete loss of photoreceptors by day 28. Extreme reduction of the a- and b-wave amplitudes persisted throughout the study. In conclusion, OCT can reflect early ultrastructural changes of photoreceptors manifesting as disrupted EZ and ELM prior to overt morphologic changes in histologic sections. In addition, the degree of changes in the EZ and ELM on OCT might predict the severity of impairment of photoreceptors.Abstract……………………………………………………………………………. i Contents…………………………………………………………………………….v List of Tables………………………………………………………………………..x List of Figures………………………………………………………………………x 1. Chapter 1: Introduction………………………………………………………...1 1.1. Retinal prosthesis…………………………………………………………1 1.1.1. Concept of retinal prosthesis………………………………………….…..1 1.1.2. Basic components of retinal prosthesis…………………………………...2 1.1.3. Liquid crystal polymer-based retinal prosthesis…………………………..3 1.1.4. Current approaches for surgical implantation of electrode array…………3 1.1.5. Development of reproducible and safe surgical techniques for LCP-based retinal prosthesis…………………………………………………………...5 1.2. Experimental retinal degeneration……………………………………….8 1.2.1. Sodium iodate……………………………………………………………..8 1.2.2. Assessment tools for retinal structural changes in retinal degeneration….8 1.3. Dissertation outlines……………………………………………………11 1.3.1. Establishment of optimized surgical procedures for implantation of LCP-based retinal prosthesis…………………………………………………...11 1.3.2. Anatomic correspondence with pathologic OCT features in experimental retinal degeneration……………………………………………………….11 2. Chapter 2: Methods…………………………………………………………...12 2.1. LCP-based retinal prosthesis…………………………………………….12 2.1.1. Pilot study………………………………………………………………..12 2.1.1.1. Prototype LCP-based prosthetic device………………………..12 2.1.1.2. Surgical techniques for implantation of prototype prosthetic device……………………………………………………………………..13 2.1.1.3. Assessments of biocompatibility and safety after surgery……..15 2.1.2. Totally implantable LCP-based retinal prosthesis……………………….17 2.1.2.1. Totally implantable LCP-based retinal prosthesis……………..17 2.1.2.2. Surgical procedures for implantation of prosthetic device…….18 2.1.2.3. Assessment of safety during and after surgery………………...21 2.2. Experimental retinal degeneration……………………………………...21 2.2.1. Preparation of animals and NaIO3 solution……………………………...21 2.2.2. Assessments of structural and functional changes of retina……………..22 2.2.2.1. Fundus photography and optical coherence tomography……...22 2.2.2.2. Electroretinography……………………………………………23 2.2.2.3. Histology……………………………………………………….23 2.2.3. Statistical analysis……………………………………………………….24 3. Chapter 3: Results…………………………………………………………….25 3.1. LCP-based retinal prosthesis…………………………………………...25 3.1.1. Pilot study………………………………………………………………..25 3.1.2. Totally implantable LCP-based retinal prosthesis……………………….28 3.1.2.1. Implantation surgery…………………………………………...28 3.1.2.2. Postoperative assessments……………………………………..31 3.2. Experimental retinal degeneration……………………………………….36 3.2.1. Comparative analysis of morphological changes of retina……………...36 3.2.1.1. Low-dose NaIO3 group (0.1 and 0.2mg)………………………36 3.2.1.2. Intermediate-dose NaIO3 group (0.4mg)………………………39 3.2.1.3. High-dose NaIO3 group (0.8mg)………………………………42 3.2.2. Functional changes of retina……………………………………………..44 3.2.2.1. Low-dose NaIO3 group (0.1 and 0.2mg)………………………44 3.2.2.2. Intermediate-dose NaIO3 group (0.4mg)………………………44 3.2.2.3. High-dose NaIO3 group (0.8mg)………………………………45 4. Chapter 4: Discussion…………………………………………………………47 4.1. Surgical techniques to optimize the long-term outcomes of LCP-based retinal prosthesis………………………………………………………………47 4.1.1. Pilot study………………………………………………………………..47 4.1.2. Totally implantable LCP-based retinal prosthesis……………………….47 4.2. Anatomic correlations with retinal changes seen on OCT in NaIO3-induced retinal degeneration………………………………………………….52 5. Chapter 5: Conclusion………………………………………………………...57 References…………………………………………………………………………58 Abstract in Korean………………………………………………………………...62Docto

광 다이오드 기반 인공 망막 시스템을 위한 저전력 설계 및 LCP 패키징에 대한 연구

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2017. 2. 김성준.The retinal prosthesis is an implantable electronic device that delivers electrical stimuli containing visual information to the retina for the visual restoration of the blinds. The currently available retinal prostheses have several problems in the number of pixels. They are limited in the number of pixels, which restricts the amount of visual information they can deliver. Many research groups are trying to improve their device in this aspect. In order to achieve a significant number of pixels, retinal prosthesis needs large stimulus power dissipation. A typical device consumes more than 20 mW of power to drive 1000 channels. Some of this power can lead to temperature rise which is a safety issue. As the power dissipation scales up with the increase in the number of channels, it is desired to minimize the power per channel as much as possible. Another problem is the absence of a suitable packaging material for the long-term reliable optical window. Due to the curved and narrow implant space available for this kind of device, as well as the transparency required for the incoming wavelengths of lights, it is quite difficult to choose a material that satisfies all requirements of long-term hermetic packaging with optically transparent window. Sapphire glass with titanium metal package are too bulky and rigid, and flexible transparent polymers such as polyimide and parylene-C have high moisture absorption for the implant. This dissertation proposes strategies and methods to solve the problems mentioned above. Two stimulation strategies are proposed. One strategy is to confine the stimulus level with a threshold that cell is activated. Thus we coin it as thresholding strategy.' The other strategy is to reduce the number of stimulation channels by using only outlines of images (outline extraction strategy). Prototype ICs were designed and fabricated for the verification of the effects of these strategies. The simulation and the measurement agree to show that retinal implant with the thresholding and outline extraction strategies consumes below one-third of the stimulus power of the conventional photodiode-based devices. Area-efficient designs of the voltage-controlled current source are also adopted to increase the number of channels. The unit pixel area of the fabricated prototype IC was 0.0072 mm2, expanding up to 1200-channels in the macular area. Liquid crystal polymer (LCP) is proposed as the long-term implantable packaging material with an optical window. It is an inert, biocompatible, and flexible polymer material that has a moisture absorption rate similar to Pyrex glass. We showed that an LCP film with a thickness less than 10 μm allows transmission of the lights in the visible wavelengths by more than 10 %, as the rate increases with thinner films. Thus a thinning process was developed. O2 DRIE was shown effective in reducing the roughness of the film, and the corresponding light scattering. The spatial resolution of LCP with 8.28 μm thickness showed a minimum distinguishable pitch of 90 μm, allowing a 1200 channel integration within a macular area.Chapter 1: Introduction 1 1.1. Retinal Prosthesis – State of the Arts 2 1.1.1. Retinal Prosthesis with External Camera 3 1.1.2. Retinal Prosthesis with Internal Photodiode Array 5 1.2. Photodiode-based Retinal Prosthesis 8 1.2.1. Problems 8 1.2.2. Possible Solutions 12 Chapter 2: Methods 17 2.1. Thresholding 17 2.1.1. Concept 17 2.1.2. Circuit Descriptions 19 2.2. Outline Extraction 28 2.2.1. Concept 28 2.2.2. Circuit Descriptions 30 2.3. Average Stimulus Power Estimation 40 2.3.1. Stimulus Patterns Generation of Conventional and Proposed Strategies 40 2.3.2. Minimum Distinguishable Channels to Recognize 41 2.4. Virtual Channel 43 2.4.1. Concept 43 2.4.2. Circuit Descriptions 44 2.5. Polymer Packaging 51 2.5.1. LCP as a Long-term Reliable Packaging Material 51 2.5.2. Test Methods 53 Chapter 3: Results 58 3.1. Thresholding 58 3.1.1. Fabricated IC 58 3.1.2. Test Setup 60 3.1.3. Test Results 61 3.2. Outline Extraction 65 3.2.1. Simulation Results 65 3.2.2. Fabricated IC 67 3.2.3. Test Setup 68 3.2.4. Test Results 72 3.3. Average Stimulus Power Estimation 76 3.4. Virtual Channels 79 3.4.1. Fabricated IC 79 3.4.2. Test Setup 80 3.4.3. Test Results 81 3.4.4. Two-dimensional Virtual Channel Generator– Test setup and Its Result 84 3.5. Polymer Packaging 87 3.5.1. Light Transmittance according to LCP Thickness 87 3.5.2. Thickness Control of LCP 89 3.5.3. Spatial Resolution of LCP 89 Chapter 4: Discussion 92 4.1. Average Stimulus Power 92 4.2. Visual Acuity 95 4.3. Hermeticity of the Thinned LCP Film 97 Chapter 5: Conclusion and Future Directions 99 References 103 Appendix – Generated Stimulus Patterns of Various the Number of Channels 112 국 문 초 록 139Docto

액정폴리머기반의 신경 전극의 제작과 성과: 사면 전극과 옵트로드

학위논문 (박사)-- 서울대학교 대학원 공과대학 전기·컴퓨터공학부, 2017. 8. 김성준.A novel liquid-crystal polymer (LCP)-based neural probe with four-sided electrode sites is developed. Ideally, neural probes should have channels with a three-dimensional (3-D) configuration to record 3-D neural circuits. Many types of three-dimensional neural probes have been developedhowever, most of them were formulated as an array of multiple shanks with electrode sites located along one side of the shanks. The proposed LCP-based neural probe has electrode sites on four sides of the shank, i.e., the front, back and two side walls. To generate the suggested configuration of the electrode sites, a thermal lamination process involving LCP films and laser micromachining are used. Using the proposed novel four-sided neural probe, in vivo multichannel neural recording is successfully performed in the mouse primary somatosensory cortex. The multichannel neural recording shows that the proposed four-sided neural probe can record spiking activities from a diverse neuronal population compared to neural probes with single-sided electrodes. This is confirmed by a pair-wise Pearson correlation coefficient (Pearson's r) analysis and a cross- correlation analysis. This study also presents the development of LCP-based depth-type stimulation electrodes with a high charge storage capacity using electrodeposited iridium oxide film (EIROF). On the electrode sites, iridium oxide is electrodeposited to increase the charge storage capacity for facilitating neural stimulation. After electrodeposition using different numbers of rectangular voltage pulses and triangular waveforms, the iridium oxide electrodes are characterized in terms of charge storage capacity and electrochemical impedance. And the surfaces of EIROFs are examined using atomic force microscopy (AFM) and scanning electron microscopy (SEM). In addition, the elementary composition of the EIROF surfaces is quantitatively determined using X-ray photoelectron spectroscopy (XPS). The in vivo neural experiments verified the feasibility of the proposed LCP-based depth-type stimulation electrode. Additionally, LCP-based optrode is suggested for optical stimulation and electrical recording. The suggested neural probes have four contacts at the tip of the electrode shank. After thermally laminating the LCP films, the four tip electrodes are made by cut-exposing the thickness of the electroplated metals. The four tip electrodes have enough contact areas and electrochemical impedance to ensure good quality of neural signal recordings. After the laser cutting process, an optic fiber is integrated to the neural probes. To demonstrate optical stimulation and electrical recording capability of the fabricated LCP-based optrode, in vivo experiments are done. Spontaneous activity and light-evoked activity are successfully recorded from the cortex and the deep brain area.Chapter 1 Introduction 1 1.1 Neural Probes 2 1.1.1 Recording Probes 2 1.1.2 Stimulation Electrodes 3 1.1.3 Optrodes 6 1.2 Proposed Neural Probes 7 1.2.1 Recording Probes 7 1.2.2 Depth-type Stimulation Electrode 8 1.2.3 Optrode 8 1.3 Dissertation Outlines 9 Chapter 2 Materials and Methods 11 2.1 Liquid Crystal Polymer (LCP) 12 2.2 Electrode Configuration 13 2.2.1 Recording Probes 13 2.2.1.1 Four-sided Neural Probe 13 2.2.1.2 Single-sided Neural Probe 15 2.2.1.3 Tetrode 15 2.2.2 Depth-type Stimulation Electrode 16 2.2.3 Optrode 17 2.3 Fabrication Processes 18 2.4 Electrochemical characterization 26 2.5 Electrodeposited Iridium Oxide Film (EIROF) 27 2.5.1 Electrodeposition of Iridium Oxide Film 27 2.5.2 Electrochemical Measurements 29 2.5.3 Surface Morphology and Mechanical Stability 30 2.6 In vivo Experiments 31 2.6.1 In vivo Neural Signal Recording Experiments 31 2.6.2 In vivo Electrical Stimulation Experiments 32 2.6.3 In vivo Optical Stimulation and Electrical Recording Experiment 35 Chapter 3 Results 38 3.1 Neural Probes 39 3.1.1 Recording Probes 39 3.1.1.1 Four-sided Neural Probe 39 3.1.1.2 Single-sided Neural Probe 39 3.1.1.3 Tetrode 41 3.1.2 Depth-type Stimulation Electrode 41 3.1.3 Optrode 42 3.2 Electrochemical Characterization 43 3.3 Electrodeposited Iridium Oxide Film 45 3.3.1 Electrochemical Measurements - 45 3.3.2 Surface Morphology and Mechanical Stability 51 3.4 In vivo Experiments 57 3.4.1 In vivo Neural Signal Recording Experiments 57 3.4.2 In vivo Electrical Stimulation Experiments 62 3.4.3 In vivo Optical Stimulation and Electrical Recording Experiment 64 Chapter 4 Discussion 72 4.1 LCP-based Recording Probes 73 4.2 LCP-based Depth-type Stimulation Electrode 82 4.3 LCP-based Optrode 86 Chapter 5 Conclusion 88 References 92 Abstract in Korean 103Docto

완전 이식형 시각 보철 시스템을 위한 연구

학위논문(박사)--서울대학교 대학원 :공과대학 전기·정보공학부,2020. 2. 김성준.A visual prosthetic system typically consists of a neural stimulator, which is a surgically implantable device for electrical stimulation intended to restore the partial vision of blind patients, and peripheral external devices including an image sensor, a controller, and a processor. Although several visual prosthetic systems, such as retinal prostheses or retinal implants, have already been commercialized, there are still many issues on them (e.g., substrate materials for implantable units, electrode configurations, the use of external hardware, power supply and data transmission methods, design and fabrication approaches, etc.) to be dealt with for an improved visual prosthetic system. In this dissertation, a totally implantable visual prosthetic system is suggested with four motivations, which are thought to be important, as in the following: 1) simple fabrication of implantable parts, such as micro-sized electrodes and a case, for a neural stimulator based on polymer without semiconductor techniques, 2) multi-polar stimulation for virtual channel generation to overcome a limited number of physical electrodes in a confined space, 3) a new image acquisition strategy using an implantable camera, and 4) power supply as well as data transmission to a neural stimulator without hindering patients various activities. First, polymer materials have been widely used to develop various implantable devices for visual prosthetic systems because of their outstanding advantages including flexibility and applicability to microfabrication, compared with metal, silicon, or ceramic. Most polymer-based implantable devices have been fabricated by the semiconductor technology based on metal deposition and photolithography. This technology provides high accuracy and precision for metal patterning on a polymer substrate. However, the technology is also complicated and time-consuming as it requires masks for photolithography and vacuum for metal deposition as well as huge fabrication facilities. This is the reason why biocompatible cyclic olefin polymer (COP) with low water absorption (<0.01 %) and high light transmission (92 %) was chosen as a new substrate material of an implantable device in this study. Based on COP, simple fabrication process of an implantable device was developed without masks, vacuum, and huge fabrication facilities. COP is characterized by strong adhesion to gold and high ultraviolet (UV) transparency as well. Because of such adhesion and UV transparency, a gold thin film can be thermally laminated on a COP substrate with no adhesion layer and micromachined by a UV laser without damaging the substrate. Using the developed COP-based process, a depth-type microprobe was fabricated first, and its electrochemical and mechanical properties as well as functionality were evaluated by impedance measurements, buckling tests, and in vivo neural signal recording, respectively. Furthermore, the long-term reliability of COP encapsulation formed by the developed process was estimated through leakage current measurements during accelerated aging in saline solution, to show the feasibility of the encapsulation using COP as well. Second, even if stimulation electrodes become sufficiently small, it is demanding to arrange them for precise stimulation on individual neurons due to electrical crosstalk, which is the spatial superposition of electric fields generated by simultaneous stimuli. Hence, an adequate spacing between adjacent electrodes is required, and this causes a limited number of physical electrodes in a confined space such as in the brain or in the retina. To overcome this limitation, many researchers have proposed stimulation strategies using virtual channels, which are intermediate areas with large magnitudes of electric fields between physical electrodes. Such virtual channels can be created by multi-polar stimulation that can combine stimuli output from two or more electrodes at the same time. To produce more delicate stimulation patterns using virtual channels herein, penta-polar stimulation with a grid-shaped arrangement of electrodes was leveraged specially to generate them in two dimensions. This penta-polar stimulation was realized using a custom-designed integrated circuit with five different current sources and surface-type electrodes fabricated by the developed COP-based process. The effectiveness of the penta-polar stimulation was firstly evaluated by focusing electric fields in comparison to mono-polar stimulation. In addition, the distribution of electric fields changed by the penta-polar stimulation, which indicated virtual channel generation, was estimated in accordance with an amplitude ratio between stimuli of the two adjacent electrodes and a distance from them, through both finite element analysis and in vitro evaluation. Third, an implantable camera is herein proposed as a new image acquisition approach capturing real-time images while implanted in the eye, to construct a totally implantable visual prosthetic system. This implantable camera has distinct advantages in that it can provide blind patients with benefits to perform several ordinary activities, such as sleep, shower, or running, while focusing on objects in accordance with natural eye movements. These advantages are impossible to be achieved using a wearing unit such as a glasses-mounted camera used in a conventional partially implantable visual prosthetic system. Moreover, the implantable camera also has a merit of garnering a variety of image information using the complete structure of a camera, compared with a micro-photodiode array of a retinal implant. To fulfill these advantageous features, after having been coated with a biocompatible epoxy to prevent moisture penetration and sealed using a medical-grade silicone elastomer to gain biocompatibility as well as flexibility, the implantable camera was fabricated enough to be inserted into the eye. Its operation was assessed by wireless image acquisition that displayed a processed black and white image. In addition, to estimate reliable wireless communication ranges of the implantable camera in the body, signal-to-noise ratio measurements were conducted while it was covered by an 8-mm-thick biological medium that mimicked an in vivo environment. Lastly, external hardware attached on the body has been generally used in conventional visual prosthetic systems to stably deliver power and data to implanted units and to acquire image signals outside the body. However, there are common problems caused by this external hardware, including functional failure due to external damages, unavailability during sleep, in the shower, or while running or swimming, and cosmetic issues. Especially, an external coil for power and data transmission in a conventional visual prosthetic system is connected to a controller and processor through a wire, which makes the coil more vulnerable to the problems. To solve this issue, a totally implantable neural stimulation system controlled by a handheld remote controller is presented. This handheld remote controller can control a totally implantable stimulator powered by a rechargeable battery through low-power but relatively long-range ZigBee wireless communication. Moreover, two more functions can be performed by the handheld controller for expanded applications; one is percutaneous stimulation, and the other is inductive charging of the rechargeable battery. Additionally, simple switches on the handheld controller enable users to modulate parameters of stimuli like a gamepad. These handheld and user-friendly interfaces can make it easy to use the controller under various circumstances. The functionality of the controller was evaluated in vivo, through percutaneous stimulation and remote control especially for avian navigation, as well as in vitro. Results of both in vivo experiments were compared in order to verify the feasibility of remote control of neural stimulation using the controller. In conclusion, several discussions on results of this study, including the COP-based simple fabrication process, the penta-polar stimulation, the implantable camera, and the multi-functional handheld remote controller, are addressed. Based on these findings and discussions, how the researches in this thesis can be applied to the realization of a totally implantable visual prosthetic system is elucidated at the end of this dissertation.시각 보철 시스템은 일반적으로 실명 환자들의 부분 시력을 전기 자극으로 회복시키기 위하여 수술적으로 이식될 수 있는 장치인 신경 자극기와 이미지 센서 또는 컨트롤러, 프로세서를 포함하는 외부의 주변 장치들로 구성된다. 망막 보철 장치 또는 망막 임플란트와 같이 몇몇 시각 보철 시스템은 이미 상용화 되었지만, 여전히 더 나은 시각 보철 시스템을 위하여 다뤄져야 할 많은 이슈들 (예를 들어, 이식형 장치의 기판 물질, 전극의 배열, 외부 하드웨어의 사용, 전력 공급 및 데이터 전송 방법, 설계 및 제작 방식 등)이 있다. 본 학위논문은 완전 이식형 시각 보철 시스템을 제안하며, 이를 위하여 다음과 같이 중요하다고 생각되는 총 네 가지의 이슈들과 관련된 연구 내용을 다룬다. 1) 폴리머를 기반으로 한 신경 자극기의 미세 전극 및 패키지와 같은 이식 가능한 부분을 반도체 기술 없이 간단하게 제작하는 방법과 2) 제한된 공간에서 전극 개수의 물리적인 한계를 극복하기 위하여 가상 채널을 형성하는 다극성 자극 방식, 3) 이식형 카메라를 사용하는 새로운 이미지 획득 전략, 4) 환자의 다양한 활동을 방해하지 않으면서 신경 자극기에 전력을 공급하고 데이터를 전송하는 방법. 첫째로, 금속이나 실리콘, 세라믹에 비하여 폴리머는 유연성 및 미세 제작에의 적용 가능성을 포함하는 두드러진 이점들이 있기 때문에 시각 보철 시스템을 구성하는 다양한 이식 가능한 부분들에 널리 이용되었다. 대부분의 폴리머 기반 이식형 장치들은 금속 증착과 사진 식각을 기반으로 하는 반도체 공정으로 제작되었다. 이 공정은 폴리머 기판 위에 금속을 패터닝 하는 데에 있어서 높은 정확성과 정밀도를 제공한다. 하지만 그 공정은 또한, 사진 식각에 쓰이는 마스크와 금속 증착을 위한 진공뿐만 아니라 아주 큰 공정 설비를 요구하기 때문에 시간 소모가 심하고 복잡하다. 이는 본 연구에서 낮은 수분 흡수 (<0.01 %)와 높은 빛 투과 (92 %)를 특징으로 하는 생체적합한 고리형 올레핀 폴리머 (cyclic olefin polymer, COP)가 이식형 장치를 위한 새로운 기판 물질로써 선택된 이유이다. COP를 기반으로 하여, 마스크와 진공, 큰 공정 설비가 필요 없이 이식 가능한 장치를 간단하게 제작하는 공정이 개발되었다. COP는 금과의 강한 접합과 자외선에 대한 높은 투명성을 또 다른 특징으로 한다. 이와 같은 접합 특성과 자외선 투명성 덕분에, 금박은 COP 기판에 별도의 접합층 없이 열로 접합될 수 있을 뿐만 아니라 그 기판에 손상을 주지 않으면서 자외선 레이저를 통하여 미세하게 가공될 수 있다. 개발된 COP 기반의 공정을 처음으로 사용하여 침습형 미세 프로브가 제작되었고, 그 전기화학적, 기계적 특성과 기능성이 각각 임피던스 측정과 버클링 테스트, 생체 내 신경신호 기록으로 평가되었다. 그리고 COP를 사용한 밀봉의 가능성도 알아보기 위하여, 개발된 공정을 사용하여 형성된 COP 밀봉의 장기 안정성이 생리식염수에서의 가속 노화 중 누설 전류 측정을 통하여 추정되었다. 둘째로, 자극 전극의 크기가 충분히 작아진다고 하더라도, 동시에 출력되는 자극에 의해 형성되는 전기장의 중첩인 크로스 토크 때문에 개개의 신경세포를 정밀하게 자극하기 위하여 전극을 배열하는 것은 아주 어렵다. 따라서 인접한 전극 사이에 적당한 간격이 필요하게 되고, 이는 특히 뇌 또는 망막과 같은 제한된 공간에서 전극 개수의 물리적인 한계를 야기한다. 이 한계를 극복하기 위하여, 많은 연구자들은 실제 전극 사이에서 큰 전기장 세기를 갖는 중간 영역을 나타내는 가상 채널을 이용한 자극 전략을 제안하였다. 이러한 가상 채널은 둘 이상의 전극에서 동시에 출력되는 자극 파형을 합칠 수 있는 다극성 자극에 의하여 형성이 가능하다. 본 연구에서는 가상 채널을 이용하여 더 정교한 자극 패턴을 만들기 위하여, 특히 2차원에서의 가상 채널을 생성하고자 격자형 배열의 전극과 함께 5극성 자극이 사용되었다. 이 5극성 자극은 다섯 개의 서로 다른 전류원을 갖도록 맞춤 설계된 집적회로와 개발된 COP 기반 공정으로 제작된 평면형 전극을 사용하여 구현되었다. 먼저, 5극성 자극의 효과를 확인하고자 이 자극으로 전기장을 한 곳에 더 집중된 형태로 만들 수 있음이 단극성 자극과의 비교를 통하여 검증되었다. 그리고 유한 요소 분석과 생체 외 평가 둘 모두를 통하여, 5극성 자극으로 인한 가상 채널 형성을 뜻하는 전기장 분포가 인접한 두 전극에서 나오는 자극의 진폭비와 그 전극으로부터 떨어진 거리에 따라 변화됨이 추정되었다. 셋째로, 본 연구에서는 눈에 이식된 채로 실시간 이미지를 얻음으로써 완전 이식형 시각 보철 시스템을 구성하는 이식형 카메라를 새로운 이미지 획득 방식으로써 제안한다. 이 이식형 카메라는 실명 환자들이 자연스러운 눈의 움직임을 따라서 물체를 볼 수 있으며 잠이나 샤워, 달리기와 같은 일상적인 활동들을 방해 받지 않고 수행할 수 있도록 돕는다는 점에서 독특한 장점을 갖는다. 기존의 부분 이식형 시각 보철 시스템에서 쓰이는 안경 부착형 카메라와 같은 착용 장비로는 이러한 장점들을 얻을 수 없다. 게다가, 이식형 카메라는 망막 임플란트의 미세 포토다이오드 어레이와 달리 완전한 카메라 구조를 이용하여 다양한 이미지 정보를 획득할 수 있다는 장점을 갖는다. 이러한 이점들을 달성하기 위하여, 그 이식형 카메라는 수분 침투를 막고자 생체적합한 에폭시로 코팅되었고 생체적합성과 유연성을 얻기 위하여 의료용 실리콘 엘라스토머로 밀봉된 후에 눈에 충분히 삽입될 수 있는 형태 및 크기로 제작되었다. 이 장치의 동작은 흑백으로 처리된 이미지를 표시하는 무선 이미지 획득으로 시험되었다. 그리고 몸 안에서 이식형 카메라 갖는 안정적인 통신 거리를 측정하기 위하여, 장치가 생체 내 환경을 모사하기 위한 8 mm 두께의 생체 물질로 덮인 상태에서 그 장치의 신호 대 잡음비가 측정되었다. 마지막으로, 기존의 시각 보철 시스템에서 몸에 부착된 형태의 외부 하드웨어는 이식된 장치에 전력과 데이터를 안정적으로 전달하고 이미지 신호를 수집하기 위하여 일반적으로 사용되었다. 그럼에도 불구하고, 이러한 하드웨어는 외부로부터의 손상으로 인한 기능적인 결함과 수면 및 샤워, 달리기, 수영 활동 중 이용 불가능성, 외형적인 이슈 등을 포함하는 공통적인 문제들을 야기한다. 전력 및 데이터 전송을 위한 외부 코일은 시각 보철 시스템에서 컨트롤러와 프로세서에 유선으로 연결되고, 이러한 연결은 그 코일이 앞서 언급된 문제들에 특히 취약하게 만든다. 이러한 이슈를 해결하고자, 휴대용 무선 컨트롤러로 제어되는 완전 이식형 신경 자극 시스템이 제안된다. 이 휴대용 무선 컨트롤러는 저전력이지만 비교적 장거리 통신이 가능한 직비 (ZigBee) 무선 통신을 통하여 재충전 가능한 배터리로 동작하는 완전 이식형 자극기를 제어할 수 있다. 이 외에도, 이 휴대용 컨트롤러를 사용하면 폭넓은 응용을 위한 두 가지 기능을 추가로 수행할 수 있다. 하나는 유선 경피 자극이며, 다른 하나는 재충전 가능한 배터리의 유도 충전 기능이다. 또한, 이 휴대용 컨트롤러의 간단한 스위치를 사용하면 사용자는 게임패드와 같이 자극 파라미터를 쉽게 조절할 수 있다. 이러한 휴대 가능하고 사용자 친화적인 인터페이스를 통해 다양한 상황에서 그 컨트롤러를 쉽게 사용할 수 있다. 그 컨트롤러의 기능은 생체 외 평가뿐만 아니라 조류의 움직임 제어를 위한 유선 경피 자극 및 원격 제어를 통해 생체 내에서도 평가되었다. 또한, 그 컨트롤러를 사용한 원격 신경 자극 제어의 수행 가능성을 검증하기 위하여 두 생체 내 실험의 결과가 서로 비교되었다. 결론적으로, COP 기반의 간단한 제작 공정과 5극성 자극, 이식형 카메라, 휴대용 다기능 무선 컨트롤러를 포함하는 연구 결과에 대한 여러 논의가 이루어진다. 그리고 이러한 결과와 고찰에 기초하여, 본 학위논문의 연구가 완전 이식형 시각 보철 시스템의 구현에 어떻게 적용될 수 있는 지가 이 논문의 끝에서 상세히 설명된다.Abstract ------------------------------------------------------------------ i Contents ---------------------------------------------------------------- vi List of Figures ---------------------------------------------------------- xi List of Tables ----------------------------------------------------------- xx List of Abbreviations ------------------------------------------------ xxii Chapter 1. Introduction --------------------------------------------- 1 1.1. Visual Prosthetic System --------------------------------------- 2 1.1.1. Current Issues ------------------------------------------------- 2 1.1.1.1. Substrate Materials ---------------------------------------- 3 1.1.1.2. Electrode Configurations --------------------------------- 5 1.1.1.3. External Hardware ----------------------------------------- 6 1.1.1.4. Other Issues ------------------------------------------------- 7 1.2. Suggested Visual Prosthetic System ------------------------ 8 1.3. Four Motivations ---------------------------------------------- 10 1.4. Proposed Approaches ---------------------------------------- 11 1.4.1. Cyclic Olefin Polymer (COP) ------------------------------ 11 1.4.2. Penta-Polar Stimulation ----------------------------------- 13 1.4.3. Implantable Camera --------------------------------------- 16 1.4.4. Handheld Remote Controller ---------------------------- 18 1.5. Objectives of this Dissertation ------------------------------ 20 Chapter 2. Materials and Methods ----------------------------- 23 2.1. COP-Based Fabrication and Encapsulation -------------- 24 2.1.1. Overview ----------------------------------------------------- 24 2.1.2. Simple Fabrication Process ------------------------------- 24 2.1.3. Depth-Type Microprobe ---------------------------------- 26 2.1.3.1. Design ----------------------------------------------------- 26 2.1.3.2. Characterization ----------------------------------------- 27 2.1.3.3. In Vivo Neural Signal Recording ---------------------- 30 2.1.4. COP Encapsulation ---------------------------------------- 31 2.1.4.1. In Vitro Reliability Test ---------------------------------- 33 2.2. Penta-Polar Stimulation ------------------------------------- 34 2.2.1. Overview ---------------------------------------------------- 34 2.2.2. Design and Fabrication ----------------------------------- 35 2.2.2.1. Integrated Circuit (IC) Design ------------------------- 35 2.2.2.2. Surface-Type Electrode Fabrication ------------------ 38 2.2.3. Evaluations -------------------------------------------------- 39 2.2.3.1. Focused Electric Field Measurement ---------------- 42 2.2.3.2. Steered Electric Field Measurement ----------------- 42 2.3. Implantable Camera ----------------------------------------- 43 2.3.1. Overview ---------------------------------------------------- 43 2.3.2. Design and Fabrication ----------------------------------- 43 2.3.2.1. Circuit Design -------------------------------------------- 43 2.3.2.2. Wireless Communication Program ------------------ 46 2.3.2.3. Epoxy Coating and Elastomer Sealing -------------- 47 2.3.3. Evaluations ------------------------------------------------- 50 2.3.3.1. Wireless Image Acquisition --------------------------- 50 2.3.3.2. Signal-to-Noise Ratio (SNR) Measurement -------- 52 2.4. Multi-Functional Handheld Remote Controller --------- 53 2.4.1. Overview ---------------------------------------------------- 53 2.4.2. Design and Fabrication ----------------------------------- 53 2.4.2.1. Hardware Description ---------------------------------- 53 2.4.2.2. Software Description ----------------------------------- 57 2.4.3. Evaluations -------------------------------------------------- 57 2.4.3.1. In Vitro Evaluation -------------------------------------- 57 2.4.3.2. In Vivo Evaluation --------------------------------------- 59 Chapter 3. Results ------------------------------------------------- 61 3.1. COP-Based Fabrication and Encapsulation ------------- 62 3.1.1. Fabricated Depth-Type Microprobe ------------------- 62 3.1.1.1. Electrochemical Impedance -------------------------- 63 3.1.1.2. Mechanical Characteristics --------------------------- 64 3.1.1.3. In Vivo Neural Signal Recording --------------------- 66 3.1.2. COP Encapsulation --------------------------------------- 68 3.1.2.1. In Vitro Reliability Test --------------------------------- 68 3.2. Penta-Polar Stimulation ------------------------------------ 70 3.2.1. Fabricated IC and Surface-Type Electrodes ---------- 70 3.2.2. Evaluations ------------------------------------------------- 73 3.2.2.1. Focused Electric Field Measurement --------------- 73 3.2.2.2. Steered Electric Field Measurement ---------------- 75 3.3. Implantable Camera ---------------------------------------- 76 3.3.1. Fabricated Implantable Camera ----------------------- 76 3.3.2. Evaluations ------------------------------------------------ 77 3.3.2.1. Wireless Image Acquisition -------------------------- 77 3.3.2.2. SNR Measurement ------------------------------------ 78 3.4. Multi-Functional Handheld Remote Controller ------- 80 3.4.1. Fabricated Remote Controller ------------------------- 80 3.4.2. Evaluations ------------------------------------------------ 81 3.4.2.1. In Vitro Evaluation ------------------------------------ 81 3.4.2.2. In Vivo Evaluation ------------------------------------- 83 Chapter 4. Discussions ------------------------------------------ 86 4.1. COP-Based Fabrication and Encapsulation ------------ 87 4.1.1. Fabrication Process and Fabricated Devices -------- 87 4.1.2. Encapsulation and Optical Transparency ------------ 89 4.2. Penta-Polar Stimulation------------------------------------ 99 4.2.1. Designed IC and Electrode Configurations --------- 99 4.2.2. Virtual Channels in Two Dimensions ---------------- 101 4.3. Implantable Camera -------------------------------------- 102 4.3.1. Enhanced Reliability by Epoxy Coating ------------- 106 4.4. Multi-Functional Handheld Remote Controller ------ 107 4.4.1. Brief Discussions of the Two Extra Functions ------ 108 4.5. Totally Implantable Visual Prosthetic System --------- 113 Chapter 5. Conclusion ------------------------------------------ 117 References -------------------------------------------------------- 121 Supplements ------------------------------------------------------ 133 국문 초록 ----------------------------------------------------------- 143Docto

소형동물의 뇌신경 자극을 위한 완전 이식형 신경자극기

학위논문(박사)--서울대학교 대학원 :공과대학 전기·정보공학부,2020. 2. 김성준.In this study, a fully implantable neural stimulator that is designed to stimulate the brain in the small animal is described. Electrical stimulation of the small animal is applicable to pre-clinical study, and behavior study for neuroscience research, etc. Especially, behavior study of the freely moving animal is useful to observe the modulation of sensory and motor functions by the stimulation. It involves conditioning animal's movement response through directional neural stimulation on the region of interest. The main technique that enables such applications is the development of an implantable neural stimulator. Implantable neural stimulator is used to modulate the behavior of the animal, while it ensures the free movement of the animals. Therefore, stable operation in vivo and device size are important issues in the design of implantable neural stimulators. Conventional neural stimulators for brain stimulation of small animal are comprised of electrodes implanted in the brain and a pulse generation circuit mounted on the back of the animal. The electrical stimulation generated from the circuit is conveyed to the target region by the electrodes wire-connected with the circuit. The devices are powered by a large battery, and controlled by a microcontroller unit. While it represents a simple approach, it is subject to various potential risks including short operation time, infection at the wound, mechanical failure of the device, and animals being hindered to move naturally, etc. A neural stimulator that is miniaturized, fully implantable, low-powered, and capable of wireless communication is required. In this dissertation, a fully implantable stimulator with remote controllability, compact size, and minimal power consumption is suggested for freely moving animal application. The stimulator consists of modular units of surface-type and depth-type arrays for accessing target brain area, package for accommodating the stimulating electronics all of which are assembled after independent fabrication and implantation using customized flat cables and connectors. The electronics in the package contains ZigBee telemetry for low-power wireless communication, inductive link for recharging lithium battery, and an ASIC that generates biphasic pulse for neural stimulation. A dual-mode power-saving scheme with a duty cycling was applied to minimize the power consumption. All modules were packaged using liquid crystal polymer (LCP) to avoid any chemical reaction after implantation. To evaluate the fabricated stimulator, wireless operation test was conducted. Signal-to-Noise Ratio (SNR) of the ZigBee telemetry were measured, and its communication range and data streaming capacity were tested. The amount of power delivered during the charging session depending on the coil distance was measured. After the evaluation of the device functionality, the stimulator was implanted into rats to train the animals to turn to the left (or right) following a directional cue applied to the barrel cortex. Functionality of the device was also demonstrated in a three-dimensional maze structure, by guiding the rats to navigate better in the maze. Finally, several aspects of the fabricated device were discussed further.본 연구에서는 소형 동물의 두뇌를 자극하기 위한 완전 이식형 신경자극기가 개발되었다. 소형 동물의 전기자극은 전임상 연구, 신경과학 연구를 위한 행동연구 등에 활용된다. 특히, 자유롭게 움직이는 동물을 대상으로 한 행동 연구는 자극에 의한 감각 및 운동 기능의 조절을 관찰하는 데 유용하게 활용된다. 행동 연구는 두뇌의 특정 관심 영역을 직접적으로 자극하여 동물의 행동반응을 조건화하는 방식으로 수행된다. 이러한 적용을 가능케 하는 핵심기술은 이식형 신경자극기의 개발이다. 이식형 신경자극기는 동물의 움직임을 방해하지 않으면서도 그 행동을 조절하기 위해 사용된다. 따라서 동물 내에서의 안정적인 동작과 장치의 크기가 이식형 신경자극기를 설계함에 있어 중요한 문제이다. 기존의 신경자극기는 두뇌에 이식되는 전극 부분과, 동물의 등 부분에 위치한 회로부분으로 구성된다. 회로에서 생산된 전기자극은 회로와 전선으로 연결된 전극을 통해 목표 지점으로 전달된다. 장치는 배터리에 의해 구동되며, 내장된 마이크로 컨트롤러에 의해 제어된다. 이는 쉽고 간단한 접근방식이지만, 짧은 동작시간, 이식부위의 감염이나 장치의 기계적 결함, 그리고 동물의 자연스러운 움직임 방해 등 여러 문제점을 야기할 수 있다. 이러한 문제의 개선을 위해 무선통신이 가능하고, 저전력, 소형화된 완전 이식형 신경자극기의 설계가 필요하다. 본 연구에서는 자유롭게 움직이는 동물에 적용하기 위하여 원격 제어가 가능하며, 크기가 작고, 소모전력이 최소화된 완전이식형 자극기를 제시한다. 설계된 신경자극기는 목표로 하는 두뇌 영역에 접근할 수 있는 표면형 전극과 탐침형 전극, 그리고 자극 펄스 생성 회로를 포함하는 패키지 등의 모듈들로 구성되며, 각각의 모듈은 독립적으로 제작되어 동물에 이식된 뒤 케이블과 커넥터로 연결된다. 패키지 내부의 회로는 저전력 무선통신을 위한 지그비 트랜시버, 리튬 배터리의 재충전을 위한 인덕티브 링크, 그리고 신경자극을 위한 이상성 자극파형을 생성하는 ASIC으로 구성된다. 전력 절감을 위해 두 개의 모드를 통해 사용률을 조절하는 방식이 장치에 적용된다. 모든 모듈들은 이식 후의 생물학적, 화학적 안정성을 위해 액정 폴리머로 패키징되었다. 제작된 신경자극기를 평가하기 위해 무선 동작 테스트가 수행되었다. 지그비 통신의 신호 대 잡음비가 측정되었으며, 해당 통신의 동작거리 및 데이터 스트리밍 성능이 검사되었고, 장치의 충전이 수행될 때 코일간의 거리에 따라 전송되는 전력의 크기가 측정되었다. 장치의 평가 이후, 신경자극기는 쥐에 이식되었으며, 해당 동물은 이식된 장치를 이용해 방향 신호에 따라 좌우로 이동하도록 훈련되었다. 또한, 3차원 미로 구조에서 쥐의 이동방향을 유도하는 실험을 통하여 장치의 기능성을 추가적으로 검증하였다. 마지막으로, 제작된 장치의 특징이 여러 측면에서 심층적으로 논의되었다.Chapter 1 : Introduction 1 1.1. Neural Interface 2 1.1.1. Concept 2 1.1.2. Major Approaches 3 1.2. Neural Stimulator for Animal Brain Stimulation 5 1.2.1. Concept 5 1.2.2. Neural Stimulator for Freely Moving Small Animal 7 1.3. Suggested Approaches 8 1.3.1. Wireless Communication 8 1.3.2. Power Management 9 1.3.2.1. Wireless Power Transmission 10 1.3.2.2. Energy Harvesting 11 1.3.3. Full implantation 14 1.3.3.1. Polymer Packaging 14 1.3.3.2. Modular Configuration 16 1.4. Objectives of This Dissertation 16 Chapter 2 : Methods 18 2.1. Overview 19 2.1.1. Circuit Description 20 2.1.1.1. Pulse Generator ASIC 21 2.1.1.2. ZigBee Transceiver 23 2.1.1.3. Inductive Link 24 2.1.1.4. Energy Harvester 25 2.1.1.5. Surrounding Circuitries 26 2.1.2. Software Description 27 2.2. Antenna Design 29 2.2.1. RF Antenna 30 2.2.1.1. Design of Monopole Antenna 31 2.2.1.2. FEM Simulation 31 2.2.2. Inductive Link 36 2.2.2.1. Design of Coil Antenna 36 2.2.2.2. FEM Simulation 38 2.3. Device Fabrication 41 2.3.1. Circuit Assembly 41 2.3.2. Packaging 42 2.3.3. Electrode, Feedthrough, Cable, and Connector 43 2.4. Evaluations 45 2.4.1. Wireless Operation Test 46 2.4.1.1. Signal-to-Noise Ratio (SNR) Measurement 46 2.4.1.2. Communication Range Test 47 2.4.1.3. Device Operation Monitoring Test 48 2.4.2. Wireless Power Transmission 49 2.4.3. Electrochemical Measurements In Vitro 50 2.4.4. Animal Testing In Vivo 52 Chapter 3 : Results 57 3.1. Fabricated System 58 3.2. Wireless Operation Test 59 3.2.1. Signal-to-Noise Ratio Measurement 59 3.2.2. Communication Range Test 61 3.2.3. Device Operation Monitoring Test 62 3.3. Wireless Power Transmission 64 3.4. Electrochemical Measurements In Vitro 65 3.5. Animal Testing In Vivo 67 Chapter 4 : Discussion 73 4.1. Comparison with Conventional Devices 74 4.2. Safety of Device Operation 76 4.2.1. Safe Electrical Stimulation 76 4.2.2. Safe Wireless Power Transmission 80 4.3. Potential Applications 84 4.4. Opportunities for Further Improvements 86 4.4.1. Weight and Size 86 4.4.2. Long-Term Reliability 93 Chapter 5 : Conclusion 96 Reference 98 Appendix - Liquid Crystal Polymer (LCP) -Based Spinal Cord Stimulator 107 국문 초록 138 감사의 글 140Docto

금나노입자의 국소표면플라즈몬공명을 이용한 향상된 신경자극 시스템

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2016. 8. 김성준.Modulating neural activity is essential to clinical treatment of neurological disorder and to the study of neural function. In particular, there has been growing interest in the development of a contact-free and high spatial selective infrared neural stimulation (INS) technique for use in clinics as well as research area. Despite a potential of INS for modulating neural activities, INS suffers from limited light confinement and tissue damage due to bulk heating. This dissertation provides fundamental information on the development of enhanced INS that could circumvent the limitations of conventional INS. The first part of this dissertation demonstrates for the first time that localized surface plasmon resonance of gold nanorods (GNRs) could induce neural depolarization with safe manner by lowering the stimulation threshold. To perform optical stimulation of neural tissue with GNRs, controllable fiber-coupled laser diode system, GNRs complex and neural cells are prepared. Pulsed near-infrared (NIR) light to efficiently absorbed to GNRs rather than bulk tissue and converted into localized heat which finally triggers neural activation. In the second part of this dissertation, surface-modified GNRs are used to bind to neuronal membrane to achieve washout resistance and to locally heat the neuronal membrane for which neural activation is responsible. INS using cell-targeted GNRs are employed in other types of cells, which is discussed in third part of this dissertation. Transient intracellular calcium waves are evoked in the astrocyte cells revealing GNRs-mediated INS stimulation can be applied in variety of cells. In the last part of this dissertation, the mechanism underlying GNRs-mediated INS is discussed. Illumination of NIR light to the GNRs at their resonant wavelength leads to local electromagnetic field enhancement and the generation localized heat. Local heat diffuses to the nearby plasma membrane which result transient temperature elevation. Transient temperature increase lead to capacitance change and/or opening of the temperature sensitive ion-channel (e.g. transient receptor potential vanilloid 1 (TRPV1) channel) which both trigger the neural depolarization. A neuron model is developed to theoretically and mathematically demonstrate on the mechanism underlying GNRs-mediated INS. These experimental and theoretical findings are expected to open up new possibilities for applications to non-invasive investigations of diverse excitable tissues and treatments of neurological disorders.Chapter 1: Introduction 1 1.1. Background 1 1.1.1. Neuroprosthetic devices 1 1.1.2. Neural stimulation techniques 2 1.1.3. Infrared neural stimulation (INS) 3 1.1.4. Localized surface plasmon resonance (LSPR) 6 1.2. Objectives 8 1.2.1. GNRs-mediated NIR neural stimulation system 8 1.2.2. Theoretical elucidation on the origin of GNRs-mediated INS 9 Chapter 2: Materials and Methods 11 2.1. Experimental overview 11 2.2. Laser system 13 2.2.1. Design 13 2.2.2. Hardware 14 2.2.3. Software 17 2.2.4. Calibration 18 2.3. GNRs complex 20 2.3.1. Characteristics of GNRs 20 2.3.2. Photothermal effect of GNRs 21 2.3.3. Orientation of GNRs 24 2.4. Neural cells 29 2.5. Experimental protocols 30 2.5.1. Safe INS 30 2.5.2. Effective INS 32 2.5.3. Wide applicable INS 41 2.6. Numerical modeling 45 2.6.1. Overview 46 2.6.2. Background theory 47 2.6.3. Laser induced heat modeling 56 2.6.4. Neuronal membrane modeling 60 2.6.5. Capacitance change and conductance change induced action potential 69 Chapter 3: Results 73 3.1. GNRs-mediated safe INS 73 3.1.1. In vivo rat sciatic nerve 73 3.2. Cell-targeted GNRs-mediated effective INS 78 3.2.1. In vitro cultured rat hippocampal neuron 78 3.2.2. In vivo rat motor cortex 84 3.3. Cell-targeted GNRs-mediated wide applicable INS 90 3.3.1. In vitro cultured astrocyte 90 3.4. Numerical analysis 97 3.4.1. Numerical analysis using capacitance change considered H-H model 97 3.4.2. Numerical analysis using TRPV1 channel considered H-H model 98 3.4.3. Numerical analysis using capacitance change and TRPV1 channel considered H-H model 102 Chapter 4: Discussion 104 4.1. Comparison with previous results 104 4.2. Safety of gold nanoparticle mediated infrared neural stimulation 107 4.3. Link between experimental and simulation results 109 4.4. TRPV1 channel and membrane capacitance 112 4.5. Possible mechanisms of GNRs-mediated INS 113 4.6. Potential applications 114 4.7. Opportunities for further improvements 115 Chapter 5: Conclusion 118 Reference 120 국문 초록 129Docto