Showing papers by "Takashi Tokuda published in 2006"

A CMOS image sensor with optical and potential dual imaging function for on-chip bioscientific applications

Abstract: An optical and potential dual imaging CMOS sensor for bioscientific applications was proposed and fabricated The CMOS image sensor has the capability to simultaneously capture optical and on-chip potential images The sensor is designed with target applications of on-chip DNA (or protein) microarray analysis and on-chip neural imaging A potential imaging function was implemented onto a CMOS image sensor with a simple pixel circuitry that is compatible with optical image sensor pixels The basic properties of the potential-sensing pixel were characterized By choosing an appropriate operating sequence and off-chip configuration, the sensor can be operated in either a wide-range potential imaging mode (>5 V) or a high-resolution potential imaging mode (16 mV) The sensor is applicable for most of the target applications and is capable of detecting a pH change in the solution placed on the surface Two-dimensional optical and potential dual imaging was successfully demonstrated, and the profile of a potential spot smaller than 50 μm was clearly observed

On-chip biofluorescence imaging inside a brain tissue phantom using a CMOS image sensor for in vivo brain imaging verification

Abstract: We have developed an on-chip biofluorescence imaging device by packaging a dedicated CMOS image sensor using a simple technique. By using on-chip imaging configuration, we have verified in vivo fluorescence imaging inside a specially developed brain tissue phantom that closely resembles the mammalian brain. In order to implement on-chip imaging, an excitation light filter is applied onto the chip. A transmittance of −44 dB is achieved by multiple coating of the filter. On-chip measurement of the AMC fluorophore shows that detection of concentration of 1 μM is possible. The phantom medium has mechanical rigidity and optical property similar to the mouse brain. Feasibility of imaging the released fluorophore inside the phantom sample is demonstrated. It is shown that light scattering in the phantom medium does not reduce the image resolution considerably, if the imaging depth is kept below 500 μm. The fully packaged chip, specially designed with this technique is about 350 μm thick and 2.7 mm wide. The image sensor pixel size of 7.5 μm × 7.5 μm is close to the size of a single neuron cell. Although the device is designed specially for in vivo imaging of the mouse hippocampus to study its neuronal activity, a wide range of applications are foreseen in the biomedical and pharmaceutical field.

Silicon LSI-based smart stimulators for retinal prosthesis

Abstract: In this article, the authors report on a retinal prosthesis smart stimulator that is biocompatible and fully compatible with a standard large-scale-integration (LSI) structure and that provides high-stimulation efficiency. Our stimulator is based on multimicrochip architecture. The stimulator has been specifically developed for retinal prostheses, but it could be applied to other neuroscience and clinical neuroengineering fields

The development of a multichannel electrode array for retinal prostheses

Abstract: The development of a multielectrode array is the key issue for retinal prostheses. We developed a 10 × 10 platinum electrode array that consists of an 8-µm polyimide layer sandwiched between 5-µm polymonochloro-para-xylylene (parylene-C) layers. Each electrode was formed as a 30-µm-high bump by Pt/Au double-layer electroplating. We estimated the charge delivery capability (CDC) of the electrode by measuring the CDCs of two-channel electrode arrays. The dimensions of each electrode of the two-channel array were the same as those of each electrode formed on the 10 × 10 array. The results suggest that for cathodic-first (CF) pulses, 80% of electrodes surpassed our development target of 318 µC/cm2, which corresponds to the charge density of pulses of 500 µs duration and 200 µA amplitude for a 200-µm-diameter planar electrode.

Pulse frequency modulation based CMOS image sensor for subretinal stimulation

Abstract: We have developed a CMOS image sensor based on pulse frequency modulation for subretinal implantation. The sensor chip forms part of the proposed intraocular retinal prosthesis system where data and power transmission are provided wirelessly from an extraocular unit. Image sensing and electrical stimulus are integrated onto the same chip. Image of sufficient resolution has been demonstrated using 16times16 pixels. Biphasic current stimulus pulses at above threshold levels of the human retina (500 muA) at varying frame rates (4 Hz to 8 kHz) have been achieved. The implant chip was fabricated using standard CMOS technology

A complementary metal-oxide-semiconductor image sensor for on-chip in vitro and in vivo imaging of the mouse hippocampus

Abstract: This paper describes the development of a complementary metal–oxide–semiconductor (CMOS) image sensor for in vitro and in vivo imaging of the hippocampus. The 176×144 pixel array image sensor is designed based on a modified three-transistor active pixel sensor circuit. Flexibility in readout for real-time imaging and wide dynamic range measurement is implemented using analog and digital output. A minimum light intensity detection level of 50 nW/cm2 has been measured using the image sensor. A novel packaging method is developed to enable both in vitro and in vivo imaging. In this method, a color filter is applied onto the image sensor that selectively blocks excitation light transmittance to below -44 dB. The packaged device thickness measuring 350 µm, limits tissue damage during invasive imaging. Using the device, static images of the mouse brain slice and real time imaging of the hippocampus of a mouse are successfully demonstrated for the first time.

An optical and potential dual-image CMOS sensor for on-chip neural and DNA imaging applications

Abstract: A CMOS image sensor which is capable to simultaneously sense an optical and an op-chip potential image was designed and fabricated. The sensor was designed with target applications to sense neural activities and DNA spots in on-chip configuration. We designed compatibly configured light sensing pixel and potential sensing pixel. The pixel size is 7.5 /spl mu/m. A QCIF (176 /spl times/ 144) dual image sensor was fabricated and characterized. The basic characteristics of the potential sensing pixel are discussed and dual imaging functions are demonstrated.

A new neural imaging approach using a CMOS imaging device.

Abstract: We have developed and demonstrated the use of a dedicated CMOS device for in vivo functional imaging of the mouse brain. In order to achieve this, a 176 × 144 pixel array image sensor is designed, fabricated and specially packaged using a novel process. By using on-chip fluorescence imaging configuration, we have successfully imaged deep inside the hippocampus of the mouse brain. Functional imaging is verified by using a fluorogenic substrate that detects the presence of serine protease in the brain. Introduction of kainic acid induces the expression of the serine protease. The protease reacts with the substrate which then fluorescence. By imaging and measuring the fluorescence signal, we have successfully measured the brain protease activity and accurately determined its reaction onset. This method represents a novel approach for neural imaging.

Toward 1000-ch electrode array based on distributed microchip architecture for retinal prosthesis

Abstract: A smart stimulator for retinal prosthesis that is biocompatible and fully compatible with a standard LSI structure was developed towards the goal of 1000-ch electrodes. Our stimulator is based on multi-microchip architecture and offers mechanical flexibility as a result of the distributed architecture used for the micro-sized LSI chips, which are small enough that the array can be bent. The device should allow tight fitting to the eyeball and thus effective stimulation of retinal cells. In addition, our stimulator can reduce the number of electrical connections required between electrodes; inter-chip communication circuits incorporated in the micro-sized LSI chip help to reduce electrical wiring between the micro-nodes. Toward a 1000-ch electrode, we have improved the smart distributed microchip-based stimulator.

A multi-chip-architecture based flexible stimulation device for retinal prosthesis with a flip-chip packaging technique.

Abstract: In the present work, we designed a multi-chip-architecture based flexible neural stimulation device for retinal prosthesis. Based on the multi-chip architecture, a novel CMOS stimulation device was successfully designed and characterized. A packaging technique for thin, flexible neural stimulation device was also proposed and demonstrated. Flip-chip bonding technology plays an essential role in the fabrication of the present thin and flexible neural stimulation device.

In vitro and in vivo on-chip biofluorescence imaging using a CMOS image sensor

Abstract: We have designed and fabricated a 176×144-pixels (QCIF) CMOS image sensor for on -chip bio-fluorescence imaging of the mouse brain. In our approach, a single CMOS image sensor chip without additional optics is used. This enables imaging at arbitrary depths into the brain; a clear advantage compared to existing optical microscopy methods. Packaging of the chip represents a challenge for in vivo imaging. We developed a novel packaging process whereby an excitation filter is applied onto the sensor. This eliminates the use of a filter cube found in conventional fluorescence microscopes. The fully packaged chip is about 350 µm thick. Using the device, we demonstrated in vitro on-chip fluorescence imaging of a 400 µm thick mouse brain slice detailing the hippocampus. The image obtained compares favorably to the image captured by conventional microscopes in terms of image resolution. In order to study imaging in vivo, we also developed a phantom media. In situ fluorophore measurement shows that detection through the turbid medium of up to 1 mm thickness is possible. We have successfully demonstrated imaging deep into the hippocampal region of the mouse brain where quantitative fluorometric meas urements was made. This work is expected to lead to a promising new tool for imaging the brain in vivo. Keywords: CMOS image sensor, bio-fluorescence, imaging, in vitro, in vivo, brain

An optical and potential dual-image CMOS sensor for bioscientific applications

Abstract: We have fabricated a CMOS image sensor which can simultaneously capture optical and on-chip potential images. The target applications of the sensor are; 1) on-chip DNA (and other biomolecular) sensing and 2) on-chip neural cell imaging. The sensor was fabricated using a 0.35μm 2-poly, 4-metals standard CMOS process. The sensor has a pixel array that consists of alternatively aligned optical sensing pixels (88×144) and potential sensing pixels (88×144). The total size of the array is QCIF (176×144). The size of the pixel is 7.5μm×7.5μm. The potential sensing pixel has a sensing electrode which capacitively couples with the measurement target on the sensor. It can be operated either in a wide-range (over 5V) mode or in a high-sensitivity (1.6mV/LSB) mode. Two-dimensional optical and potential imaging function was also demonstrated. Probes with gel tips were placed on the sensor surface and potential was applied. A potential spot with diameter smaller than 50μm was successfully observed in the dual imaging operation.

An Optical/Potential/Voltammetric Multifunctional CMOS Image Sensor for On-chip Biomolecular/Neural Sensing Applications

Abstract: We have developed an on-chip image sensor with target applications of on-chip biomolecular and neural imaging. The sensor pixel can sense not only intensity of incident light, but also on-chip electric potential. The light shield structure on the pixel circuit was used as a sensing electrode. Once the passivation layer on the sensing electrode was removed, one can perform on-chip voltammetric measurement, which will be a powerful solution for on-chip biosensing applications. To realise the on-chip voltammetric measurement, we used a column reset line as a current path. Basic characteristics of the sensor was characterized in either optical / potential image sensor operation or optical / voltammetric image sensor operation.

Optimization of Electrical Stimulus Pulse Parameter for Low-Power Operation of Retinal Prosthetic Device

Abstract: In this paper, we describe the investigation of an electrical stimulus pulse parameter for use in a low-power retinal prosthesis. To obtain efficient stimulus pulse parameters, in vitro electrical stimulus experiments with a detached frog retina were performed using a fabricated pulse-frequency modulation (PFM) image sensor as a retinal prosthesis. The evaluated electrical stimulus pulse parameters were pulse duration, pulse amplitude, and the number of pulses. From the experiments, the firing rate of the retinal ganglion cells (retinal ganglion cells; RGCs) was observed to depend on the injection charge in single-pulse stimulation and the injection charge of the first pulse in pulse-train stimulation. In addition, pulse-train stimulation was found to have a RGC firing rate lower than that of single-pulse stimulation at the same injection charge. From power consumption measurements and an in vitro experiment, it was verified that the stimulus pulse of a short-pulse duration is suitable for use in a low-power retinal prosthesis.

A pulse-frequency-modulation vision chip using a capacitive feedback reset with an in-pixel 1-bit image processor

Abstract: We report a low-voltage digital vision chip based on a pulse-frequency-modulation (PFM) photosensor using capacitive feedback reset and pulse-domain digital image processing to explore its feasibility of low power consumption and high dynamic range even at a low power-supply voltage. An example of the applications of the vision chip is retinal prosthesis, in which supplied power is limited. The pixel is composed of a PFM photosensor with a dynamic pulse memory, pulse gates, and a 1-bit digital image processor. The binary value stored at the dynamic pulse memory is read to the 1-bit digital image processor. The image processor executes spatial filtering by mutual operations between the pulses from the pixel and those from the four neighboring pixels. The weights in image processing are controlled by pulse gates. We fabricated a test chip in a standard 0.35-μm CMOS technology. Pixel size and pixel counts were 100 μm sq. and 32 x 32, respectively. In the experiments, four neighboring pixels were considered in image processing. The test chip successfully operated at low power supply voltage around 1.25 V. The frame rate was 26 kfps. Low-pass filtering, edge enhancement, and edge detection have been demonstrated. Relationships between power supply voltages and characteristics of the vision chip are investigated.

Prototyping and Evaluation of a 32*32-pixel Pulse-frequency-modulation Vision Chip with Capacitive Feedback Reset

Abstract: We fabricated a low-voltage 32×32-pixel pulse-frequency-modulation vision chip with an image processing function executed in a pulse domain in a standard 0.35-μm CMOS technology. We showed the characteristics and feasibility of our vision chip architecture.

Flexible and extensible retinal prosthesis based on multi-chip architecture

Abstract: We present a multi-chip electric stimulator for a retinal prosthesis. The stimulator consists of small silicon devices (unit chips) molded in a thin film. It has an advantage over the conventional devices in physical flexibility and extendibility. The smart unit chip (600 μm square, in this work) is an integrated circuit (IC) that includes digital serial interface circuits, analog switch circuits and on-chip stimulus electrodes. In contrast to conventional stimulators, the present stimulator can be driven with only four wires. The multi-chip configuration enables to make the stimulator flexible and durable to bending stress. The device can be bended to place the stimulation electrodes in good contact with retinal tissue. In this paper, we present the design of the stimulator device with 0.35-μm complementary metal-oxide semiconductor (CMOS) technology. We also report a thin, flexible packaging technique for the stimulator and preliminary experimental results of a sputtered iridium oxide (IrO x ) film that can be used for chronic stimulation.

Electrical stimulus experiments of the frog retina using a pulse frequency modulation image sensor for retinal prosthesis

Abstract: We have designed and fabricated a 16 × 16 pixel pulse frequency modulation (PFM) image sensor for retinal prosthesis. This sensor is a prototype for demonstrating application in in vitro electrophysiological experiments. Each pixel has a bonding pad on which a stimulus electrode is formed by a Pt/Au stacked biocompatible bump electrode. We have evaluated the PFM image sensor for retinal prosthesis by in vitro electrophysiological experiments using the detached frog retina, and confirmed that it can electrically stimulate the retinal cells effectively.

On-Chip In vivo Functional Imaging of the Mouse Brain Using a CMOS Image Sensor

Abstract: We have developed a new method for in vivo functional imaging of the mouse brain using a dedicated CMOS image sensor chip The image sensor has 176times144-pixels with pixel size of 75times75 mum 2 A novel packaging process is developed to enable on-chip fluorescence imaging The sensor chip is attached to a flexible polyimide substrate and sealed in epoxy A thin-film resist is spin-coated directly onto the image sensor chip for excitation light filtering By applying multiple coating, a transmittance below -44 dB is achieved Also, the device has a selectivity of more than 80% for the fluorescence emission of 7-amino-4-methylcoumarin (AMC) The entire packaged device is about 350 mum thick, hence minimizing injury during invasive imaging inside the brain In vivo functional imaging is performed by using a synthetic fluorogenic substrate which detects the presence of two serine proteases species in the brain The introduction of kainic acid induces the expression of these protease species, which then reacts with the substrate to release the AMC fluorophore Imaging of the AMC fluorescence allows the serine protease activity to be measured in real-time We have successfully measured the protease activity and accurately determined its reaction onset

Development of a CMOS Imaging Device for Functional Imaging Inside the Mouse Brain

Abstract: We propose the use of a CMOS image sensor for in vivo functional imaging of the mouse brain. A dedicated image sensor with 176 times 144 pixels array is designed, fabricated, and packaged to enable on-chip fluorescence imaging. Using this configuration, we have successfully performed imaging inside the intact mouse brain. Furthermore, we have demonstrated functional imaging inside the mouse brain. This is done in conjunction with a fluorogenic substrate, which detects the presence of serine protease inside the brain. By imaging the fluorescence signal upon injection of a stimulant, we have successfully measured the brain protease activity and accurately determined its reaction onset, which is close to 1 hr 28 min after injection of the stimulant. This method represents a new approach for neural imaging using an inexpensive CMOS imaging device

SiGe/Si "Micro-Origami" Epitaxial MEMS Device on SOI Substrate

Abstract: In the last decade, fabrication technology of microelectromechanical system (MEMS) was greatly developed and various devices have been demonstrated. Epitaxial MEMS structure is one of the variations of MEMS structure. The epitaxial MEMS has some advantages such as atomically flat surfaces and possibility of direct implementation of circuitry on the MEMS structure. In this work, we fabricated an epitaxial MEMS structure based on strain-induced bending of a SiGe/Si released layer. The present MEMS strucuture was named as "micro-origami". We released a SiGe/Si heteroepitaxial layer and a micromirror device was fabricated. The fabrication process and characteristics of the micro-origami device is described