Integrated Circuit Design for Miniaturized, Trackable, Ultrasound Based Biomedical Implants

This thesis focuses on the design of an ultrasonography compatible implantable sensor platform, as a novel approach that implements a miniaturized, battery-less, real-time trackable parallel biosensing system. In addition to the frontend circuit, a sub-nW fully integrated pH sensor is designed in a way that can be easily integrated with the proposed sonography-compatible sensor platform. Combining the two integrated circuits together, the whole system will be able to map in vivo physiological information acquired from a distributed set of sensors on top of the ultrasound movie, leading to the idea envisioned as “augmented ultrasonography”. Implemented in a 0.18 μm technology, an ultrasound power and data frontend circuit is designed to enable medical sensing implants to operate in an ultrasonography compatible way. When placed within the field of view of an imaging transducer, the frontend circuit harvests the power through a piece of piezo crystal from a minimally modified brightness-mode (B-mode) ultrasound imaging process that is commonly adopted in modern medical practices. The implant can also establish bi-directional data communication channels with the imaging transducer, allowing data to be transmitted in a way synchronized to the frame rate of the B-mode film. The design of the circuit is made possible by a combination of ultra-low-power circuit techniques and novel frontend circuit topologies, as imaging ultrasound waves in the form of short pulses with extremely low duty cycle poses challenges that has not previously seen in other implantable sensor systems. The proposed prototype achieves a total area of 0.6mm² for the integrated circuit (IC), as well as 71mm theoretical maximum implantable depth (up to 40 mm is verified experimentally). These two together give opportunities for this design to become the next generation solution for deep-tissue bio-sensing implants. Realized using the same 0.18 μm technology, the fully integrated pH sensor is designed to deliver accurate pH readouts, at a reasonable speed of 1 sample per second, while consuming only 0.72 nW of power. Using an ion-sensitive field effect transistor (ISFET) and reference field effect transistor pair (REFET), the IC requires minimum additional post fabrication to deliver 10-bit resolution pH readouts at an end-to-end sensitivity of 65.8 LSB/pH. When working as a standalone device, this work advances the state-of-the-art of ISFET based pH sensor design. With an addition of 0.46 mm² of area, it is possible to integrate it with the ultrasound sonography compatible implant platform. This potential integration will further advance the vision of the augmented ultrasonography: real-time display of physiological information in a B-mode film, with the help from a distributed bio-sensor system for deep-tissue physiology monitoring

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

Design, Fabrication, and Validation of a Highly Miniaturized Wirelessly Powered Neural Implant

We have recently witnessed an explosion in the number of neurons that can be recorded and/or stimulated simultaneously during neurophysiological experiments. Experiments have progressed from recording or stimulation with a single electrode to Micro-Electrode Array (MEA) such as the Utah Array. These MEAs can be instrumented with current drivers, neural amplifiers, digitizers and wireless communication links. The broad interest in these MEAs suggests that there is a need for large scale neural recording and stimulation. The ultimate goal is to coordinate the recordings and stimulation of potentially thousands of neurons from many brain areas. Unfortunately, current state-of-the-art MEAs are limited by their scalability and long-term stability because of their physical size and rigid configuration. Furthermore, some applications prioritize a distributed neural interface over one that offers high resolution. Examples of biomedical applications that necessitate an interface with neurons from many sites in the brain include: i) understanding and treating neurological disorders that affect distributed locations throughout the CNS; ii) revolutionizing our understanding of the brain by studying the correlations between neural networks from different regions of the brain and the mechanisms of cognitive functions; and iii) covering larger area in the sensorimotor cortex of amputees to more accurately control robotic prosthetic limbs or better evoke a sense of touch. One solution to make large scale, fully specifiable, electrical stimulation and recording possible, is to disconnect the electrodes from the base, so that they can be arbitrarily placed, using a syringe, freely in the nervous system. To overcome the challenges of system miniaturization, we propose the “microbead”, an ultra-small neural stimulating implant, that is currently implemented in a 130nm CMOS technology with the following characteristics: 200 μm × 200 μm × 80 μm size; optimized wireless powering, all micro-electronics on single chip; and integrated electrodes and coil. The stimulating microbead is validated in a sciatic nerve by generating leg movements. A recording microbead is also investigated with following characteristics: wireless powering using steerable phased coil array, miniaturized front-end, and backscattering telemetry. These microbeads could eventually replace the rigid arrays that are currently the state-of-the-art in electrophysiology set-ups

Micron-scale monolithically-integrated ultrasonic wireless sensing motes for physiological monitoring

There has been increasing interest in emerging implantable medical devices (IMDs) for continuous in vivo sensing of physiological signals, including temperature, PH, pressure, oxygen, and glucose, directly at the target locations. Many of these applications can benefit from wireless, miniaturized IMDs that eliminate the percutaneous power cords and facilitate the implantation procedures. This thesis describes such a device for real-time in vivo monitoring of physiological temperature, such as the monitoring of core body temperature and temperature evaluation during thermal-related therapeutic procedures. Featuring a custom temperature sensor chip with a micron-scale piezoelectric transducer fabricated on top of the chip, the monolithic device, in the form of a mote, measures only 380 μm × 300 μm × 570 μm and weighs only 0.3 mg. The device utilizes ultrasound for wireless powering and communication through the on-chip transducer and achieves aggressive miniaturization through “chip-as-system” integration. The proposed motes were successfully validated in both in vitro experiments with animal tissues and in vivo settings with a mouse model. Compared to the state-of-the-art and equivalent commercial devices, the motes performed comparably or better in a fully-wireless manner while presenting a more compact form factor. Such extreme miniaturization through monolithic integration enables multiple of these motes to be implanted/injected using minimally invasive surgeries with improved biocompatibility and reduced subject discomfort. This offers new approaches for localized in vivo monitoring of spatially-fine-grained temperature distributions and also provides a platform for sensing other types of physiological parameters

Advances in Bioengineering

The technological approach and the high level of innovation make bioengineering extremely dynamic and this forces researchers to continuous updating. It involves the publication of the results of the latest scientific research. This book covers a wide range of aspects and issues related to advances in bioengineering research with a particular focus on innovative technologies and applications. The book consists of 13 scientific contributions divided in four sections: Materials Science; Biosensors. Electronics and Telemetry; Light Therapy; Computing and Analysis Techniques

Integrated Microsystems for Wireless Sensing Applications

Personal health monitoring is being considered the future of a sustainable health care system. Biosensing platforms are a very important component of this system. Real-time and accurate sensing is essential for the success of personal health care model. Currently, there are many efforts going on to make these sensors practical and more useful for such measurements. Implantable sensors are considered the most widely applicable and most reliable sensors for such accurate health monitoring applications. However, macroscopic (cm scale) size has proved to be a limiting factor for successful use of these systems for long time and in large numbers. This work is focused to resolve the issues related with miniaturizing these devices to a microscopic (mm scale) size scale which can minimize many practical difficulties associated with their larger counterparts currently. To accomplish this goal of miniaturization while retaining or even improving on the necessary capabilities for such sensing platforms, an integrated approach is presented which focuses on system-level miniaturization using standard fabrication procedures. First, it is shown that a completely integrated and wireless system is the best solution to achieve desired miniaturization without sacrificing the functionality of the system. Hence, design and implementation of the different components comprising the complete system needs to be done according to the requirements of the overall integrated system. This leads to the need of on-chip functional sensors, integrated wireless power supply, integrated wireless communication and integrated control system for realization of such system. In this work, different options for implementation of each of these subsystems are compared and an optimal solution is presented for each subsystem. For such complex systems, it is imperative to use a standard fabrication process which can provide the required functionality for all subsystems at smallest possible size scale. Complementary Metal Oxide Semiconductor (CMOS) process is the most appropriate of the technologies in this regard and has enabled incredible miniaturization of the computing industry. It also provides options for designing different subsystems on the same platform in a monolithic process with very high yield. This choice then leads to actual designs of subsystems in the CMOS technology using different possible methods. Careful comparison of these subsystems provides insights into different design adjustments that are made until the desired functions are achieved at the desired size scale. Integration of all these compatible subsystems in the same platform is shown to provide the smallest possible sensing platform to date. The completely wireless system can measure a host of different important analyte and can transmit the data to an external device which can use it for appropriate purpose. Results on measurements in phosphate buffer solution, blood serum and whole blood along with wireless communication in real biological tissues are provided. Specific examples of glucose and DNA sensors are presented and the use for many other relevant applications is also proposed. Finally, insights into animal model studies and future directions of the research are discussed. </p

Conformable transistors for bioelectronics

The diversity of network disruptions that occur in patients with neuropsychiatric disorders creates a strong demand for personalized medicine. Such approaches often take the form of implantable bioelectronic devices that are capable of monitoring pathophysiological activity for identifying biomarkers to allow for local and responsive delivery of intervention. They are also required to transmit this data outside of the body for evaluation of the treatment’s efficacy. However, the ability to perform these demanding electronic functions in the complex physiological environment with minimum disruption to the biological tissue remains a big challenge. An optimal fully implantable bioelectronic device would require each component from the front-end to the data transmission to be conformable and biocompatible. For this reason, organic material-based conformable electronics are ideal candidates for components of bioelectronic circuits due to their inherent flexibility, and soft nature. In this work, first an organic mixed-conducting particulate composite material (MCP) able to form functional electronic components and non-invasively acquire high–spatiotemporal resolution electrophysiological signals by directly interfacing human skin is presented. Secondly, we introduce organic electrochemical internal ion-gated transistors (IGTs) as a high-density, high-amplification sensing component as well as a low leakage, high-speed processing unit. Finally, a novel wireless, battery-free strategy for electrophysiological signal acquisition, processing, and transmission that employs IGTs and an ionic communication circuit (IC) is introduced. We show that the wirelessly-powered IGTs are able to acquire and modulate neurophysiological data in-vivo and transmit them transdermally, eliminating the need for any hard Si-based electronics in the implant

Biomedical Engineering

Biomedical engineering is currently relatively wide scientific area which has been constantly bringing innovations with an objective to support and improve all areas of medicine such as therapy, diagnostics and rehabilitation. It holds a strong position also in natural and biological sciences. In the terms of application, biomedical engineering is present at almost all technical universities where some of them are targeted for the research and development in this area. The presented book brings chosen outputs and results of research and development tasks, often supported by important world or European framework programs or grant agencies. The knowledge and findings from the area of biomaterials, bioelectronics, bioinformatics, biomedical devices and tools or computer support in the processes of diagnostics and therapy are defined in a way that they bring both basic information to a reader and also specific outputs with a possible further use in research and development

Implantable Multi-panel Platform for Continuous Monitoring of Exogenous and Endogenous Metabolites for Applications in Personalized Medicine

Nowadays, scientific advances are leading to the discovery of newer, better, more targeted treatments that will improve the human health. However, despite the promising results and the major advantages in treatments offered to patients, these personalized medical treatments are limited to few cases. Translational medicine research with animals is needed to find innovative, safe and life-saving solutions for patients, especially in drug development. Although technological improvements may lead one day to the end of animal testing, today those strategies are not sufficient, due to the complexity of living organisms. The living conditions of these animals are of primary importance because high stress levels can affect the experimental results. In this respect, the monitoring of the animals in a small living space by means of a fully implantable device, can contribute to minimize the human intervention, increasing the comfort for the animals. The objective of this thesis is the design and characterization of a fully implantable biosensor array for the real-time detection of endogenous and exogenous metabolites, for the monitoring of small caged animals in drug development, and for future applications in personalized medicine. The fully implantable device consists of: a passive sensing platform consisting of an array of four independent electrochemical biosensors, together with a pH sensor and a temperature sensor for the optimization of the sensing performances in different physiological conditions; integrated circuits capable of performing multiple electrochemical measurements; a coil for remote powering of the integrated circuit and the short-range data transmission to an external device; a membrane packaging ensuring measurements with high signal-to-noise ratio, biocompatibility and selectivity against possible interfering molecules in biological fluids. ⢠In vitro monitoring of four anti-cancer drugs and an anti-inflammatory drug within the pharmacological ranges in undiluted human serum; ⢠Demonstration of the in vitro functionality of the complete system, showing that the external powering system correctly operate the device, and receive the data from the sensors; ⢠In vivo biocompatibility tests of the packaging, showing after 30 days a significant reduction of the inflammatory response in time, suggesting normal host recovery; ⢠In vivo continuous monitoring of an anti-inflammatory drug, demonstrating the proof of-concept of the system for future personalized medicine applications