Search

In this study, we developed and demonstrated a millimeter-wave electric field imaging system using an electro-optic crystal and a highly sensitive polarization measurement technique using a polarization image sensor, which was fabricated using a 0.35-µm standard CMOS process. The polarization image sensor was equipped with differential amplifiers that amplified the difference between the 0° and 90° pixels. With the amplifier, the signal-to-noise ratio at low incident light levels was improved. Also, an optical modulator and a semiconductor optical amplifier were used to generate an optical local oscillator (LO) signal with a high modulation accuracy and sufficient optical intensity. By combining the amplified LO signal and a highly sensitive polarization imaging system, we successfully performed millimeter-wave electric field imaging with a spatial resolution of 30 × 60 µm at a rate of 1 FPS, corresponding to 2400 pixels/s. [ABSTRACT FROM AUTHOR]

The growth and development of embryophytes is deeply influenced by environmental stimuli, such as light, temperature, and soil nutrients. Understanding the mechanisms underlying the growth response of plants to environmental stimuli is crucial for agriculture. In this study, we examined the morphology of a flowering plant, Arabidopsis thaliana, using microfocus X‐ray computed tomography (µCT), which enables non‐destructive analysis of the external and internal structures of plants. Three‐dimensional (3D) images of the plant, which were reconstructed from X‐ray scanned data, clearly showed the shapes of its leaves, stems, and buds from any angle. At a higher magnification, the µCT also revealed the small hair‐like structures called trichomes on the Arabidopsis leaf epidermis. However, motion artifacts found in the 3D‐reconstructed images indicated that plant's growth rate was faster than scanning speed. Thus, scan parameters must be accordingly optimized. Additionally, CT‐based 3D printing can be used to design micro devices that can be further used to monitor plant growth. These results suggest that µCT is a useful technique for analyzing morphology of growing plants. [ABSTRACT FROM AUTHOR]

We propose and demonstrate a method for equivalent time sampling using image sensors to selectively detect only the target frequency. Shortening the exposure time of the image sensor and using equivalent time sampling allows for the detection of frequency components that are higher than the frame rate. However, the imaging system in our previous work was also sensitive to the frequency component at 1/4 of the frame rate. In this study, we control the phase relationship between the exposure time and observed signal by inserting an additional interval once every four frames to detect the target frequency selectively. With this technique, we conducted electric field imaging based on the electro-optic effect under high noise conditions in the low-frequency band to which the conventional method is sensitive. The results demonstrated that the proposed method improved the signal-to-noise ratio. [ABSTRACT FROM AUTHOR]

In this research, we combined our ultralight micro-imaging device for calcium imaging with microdialysis to simultaneously visualize neural activity in the dorsal raphe nucleus (DRN) and measure serotonin release in the central nucleus of the amygdala (CeA) and the anterior cingulate cortex (ACC). Using this platform, we observed brain activity following nociception induced by formalin injection in the mouse's hind paw. Our device showed that DRN fluorescence intensity increased after formalin injection, and the increase was highly correlated with the elevation in serotonin release in both the CeA and ACC. The increase in calcium fluorescence intensity occurred during the acute and inflammatory phases, which suggests the biphasic response of nociceptive pain. Furthermore, we found that the increase in fluorescence intensity was positively correlated with mouse licking behavior. Lastly, we compared the laterality of pain stimulation and found that DRN fluorescence activity was higher for contralateral stimulation. Microdialysis showed that CeA serotonin concentration increased only after contralateral stimulation, while ACC serotonin release responded bilaterally. In conclusion, our study not only revealed the inter-regional serotonergic connection among the DRN, the CeA, and the ACC, but also demonstrated that our device is feasible for multi-site implantation in conjunction with a microdialysis system, allowing the simultaneous multi-modal observation of different regions in the brain. [ABSTRACT FROM AUTHOR]

Hybrid emission filters, comprising an interference filter and an absorption filter, exhibit high excitation light rejection performance and can act as lensless fluorescent devices. However, it has been challenging to produce them in large batches over a large area. In this study, we propose and demonstrate a method for transferring a Si substrate, on which the hybrid filter is deposited, onto an image sensor by attaching it to the sensor and removing the substrate via plasma etching. Through this method, we can transfer uniform filters onto fine micrometer-sized needle devices and millimeter-sized multisensor chips. Optical evaluation reveals that the hybrid filter emits light in the 500 to 560 nm range, close to the emission region of green fluorescent protein (GFP). Furthermore, by observing the fluorescence emission from the microbeads, a spatial resolution of 12.11 μm is calculated. In vitro experiments confirm that the fabricated device is able to discriminate GFP emission patterns from brain slices. [ABSTRACT FROM AUTHOR]

Dopamine (DA) is the most important neurotransmitter involved in motor control. Abnormalities in neurotransmitter levels may indicate brain disorders, such as Parkinson's disease and depression. Herein, electrochemical sensors containing metal oxide nanoparticles were fabricated for detecting DA. Specifically, iron oxide nanoparticles were applied onto a flexible polyimide substrate to obtain a flexible microelectrode and their DA detection performance was evaluated in vitro and in vivo. The electrochemical performance of the fabricated sensor was evaluated via fast-scan cyclic voltammetry conducted in a DA solution at concentrations between 0 and 50 nM. The peak current corresponding to the oxidation reaction of the Fe2O3-modified microelectrode for DA was observed at an applied potential of 0.49 V. The modified microelectrode exhibited a DA response with a high sensitivity of 34.14 nA/μm2 nM and a low limit of detection of 8.76 nM. In vivo experiments were performed using a freely moving mouse. Notably, 15 min after nicotine injection, the current increased considerably. The peak current corresponded to a 10 nM concentration in the calibration curve. The co-detection of DA and serotonin was also analyzed. The results showed that only the oxidation peak of DA appeared upon applying a triangular voltage waveform. Therefore, the proposed detector is capable of overcoming the drawbacks associated with conventional detectors and can be integrated with other implantable devices. [ABSTRACT FROM AUTHOR]

Fundus images contain extensive health information. However, patients hardly obtain their fundus images by themselves. Although glare-free infrared (IR) imaging enables easy acquisition of fundus images, it is monographic and challenging to process in real-time in response to high-speed and involuntary fixational eye movement and in vivo blurring. Therefore, we propose applying our IR color technology and providing clear fundus images by high-speed tracking of involuntary fixational eye movements and eliminating in vivo blurs by deconvolution. We tested whether the proposed camera system was applicable in medical practice and capable of medical examination. We verified the IR color fundus camera system could detect ophthalmological and lifestyle-related diseases. [ABSTRACT FROM AUTHOR]

In this article, We demonstrated an image sensor for detecting changes in polarization with high sensitivity. For this purpose, we constructed an optical system with a two-layer structure, comprising an external polarizer and polarizers on a pixel array. An external polarizer is used to enhance the polarization rotation while reducing the intensity to avoid pixel saturation of the image sensor. Using a two-layer structure, the two polarizers can be arranged under optimal conditions and the image sensor can achieve high polarization-change detection performance. We fabricated the polarization image sensor using a 0.35- $\mu \text{m}$ CMOS process and, by averaging 50 ${\times }\,\,50$ pixels and 96 frames, achieved a polarization rotation detection limit of 5.2 ${\times }\,\,10^{-4^{\circ}} $ at a wavelength of 625 nm. We also demonstrated the applicability of electric-field distribution imaging using an electrooptic crystal (ZnTe) for weak-polarization-change distribution measurements. [ABSTRACT FROM AUTHOR]

In this study, a dual-band hybrid filter that achieves high excitation light rejection performance in a lensless imaging system was fabricated and incorporated into an imaging device. The hybrid filter consisted of interference and absorption filters, and a fiber optic plate (FOP). The interference filters were attached to both sides of the FOP, which was placed on top of the absorption filter to suppress the decrease in spatial resolution. In addition, the lamination order was optimized to achieve a high fluorescence observation performance. The fabricated hybrid filter was mounted on an image sensor and had the ability to indicate the green and red fluorescence components. [ABSTRACT FROM AUTHOR]

This study proposes an alternating current (AC)‐driven retinal prosthesis device using an implantable CMOS‐LSI chip that can control multiple electrodes. The proposed device uses AC power with the electrical grounds of the main and stimulation units separated to reduce the possibility of current leakage and to improve safety. The stimulation unit implanted in the eye cannot include large capacitor chips for ground separation. To solve this problem, large capacitor chips are mounted on the implantable control unit that supplies power, not on the stimulating device, and a cooperative mode of operation is devised. In this way, it is realised that a circuit configuration that achieves both miniaturisation and improved power supply efficiency. This study verifies the functionality of the proposed circuit. The results suggest that power supply and stimulation operations are possible through coupling capacitors. In addition, this stimulation operation can be performed continuously. [ABSTRACT FROM AUTHOR]

Long-term operational stability and high-efficiency neuron stimulation are key to the development of retinal prostheses. In this research, a retinal device with a chemically inert and flexible substrate is introduced, which satisfies these requirements. We have developed a honeycomb-type retinal device that has a high-performance electrode for suprachoroidal transretinal stimulation. The device structure, in which conjunctional bioceramic substrates are embedded with large numbers of stimulating electrodes, provides high-resolution electrical stimulation. The custom CMOS microchip precisely controls the stimulation delivery of the electrodes to initiate artificial vision, offering a partial remedy for retinal ophthalmic diseases. The CMOS chip design was optimized to drastically reduce the number of input wirings. A high-performance stimulating electrode based on iridium oxide was fabricated using a unique solution process called chemical bath deposition (CBD). The honeycomb-type retinal device, equipped with CBD-derived iridium oxide electrodes, was used to evaluate the electrodes' and device's performances in vitro. [ABSTRACT FROM AUTHOR]

To develop a visual prosthesis, it is necessary to understand the changes in the electrochemical properties of stimulating electrodes implanted in the body. To evaluate these properties, we examined three types of equivalent circuit models that represented the electrode interface 23 weeks after the stimulation began. The results indicated that the Randles circuit model with Warburg impedance exhibited the difference in the electrochemical properties of the active and inactive electrodes, which might have been caused by the desorption of adsorbed protein from the electrode surface owing to the stimulation current. This model can be used to characterize the changes in the properties of porous stimulating electrodes. [ABSTRACT FROM AUTHOR]

In this study, we propose a complementary-metal-oxide-semiconductor (CMOS) image sensor with a self-resetting system demonstrating a high signal-to-noise ratio (SNR) to detect small intrinsic signals such as a hemodynamic reaction or neural activity in a mouse brain. The photodiode structure was modified from N-well/P-sub to P+/N-well/P-sub to increase the photodiode capacitance to reduce the number of self-resets required to decrease the unstable stage. Moreover, our new relay board was used for the first time. As a result, an effective SNR of over 70 dB was achieved within the same pixel size and fill factor. The unstable state was drastically reduced. Thus, we will be able to detect neural activity. With its compact size, this device has significant potential to become an intrinsic signal detector in freely moving animals. We also demonstrated in vivo imaging with image processing by removing additional noise from the self-reset operation. [ABSTRACT FROM AUTHOR]

In this paper, we report a method of fabricating an implantable image sensor equipped a bandpass hybrid filter for highly sensitive fluorescence observation. A hybrid filter that combines an interference filter and an absorption filter enables a high excitation light removal performance in an implantable image sensor that does not use a lens. In this study, a thin hybrid filter was successfully mounted on the image sensor using the transfer method by using a laser lift‐off technique. The transferred filter has no crack. It was demonstrated that the prototype device exhibited high excitation light removal performance and was able to acquire a fluorescent image with high contrast. [ABSTRACT FROM AUTHOR]

Fluorescence imaging devices have been indispensable in elucidating the workings of the brain in living animals, including unrestrained, active ones. Various devices are available, each with their own strengths and weaknesses in terms of many factors. We have developed CMOS-based needle-type imaging devices that are small and lightweight enough to be doubly implanted in freely moving mice. The design also allowed angled implantations to avoid critical areas. We demonstrated the utility of the devices by using them on GCaMP6 mice in a formalin test experiment. Simultaneous implantations to the capsular-lateral central amygdala (CeLC) and dorsal raphe nucleus (DRN) were proven to be safe and did not hinder the execution of the study. Analysis of the collected calcium signaling data, supported by behavior data, showed increased activity in both regions as a result of pain stimulation. Thus, we have successfully demonstrated the various advantages of the device in its application in the pain experiment. [ABSTRACT FROM AUTHOR]

The fundus camera is a system that enables retinal observations for the diagnosis of eye diseases. A near-infrared (NIR) multispectral fundus imaging system can capture color images using NIR light instead of visible light, thus avoiding irritation of the eyes and allowing for easier observations of the fundus. In this study, we developed an NIR fundus camera with a patterned metal mask for retinal patterned illumination. The pattern illuminated fundus images from the experiment prove the feasibility of retinal scattering detection using retinal patterned illumination. The layout of the patterned mask was optimized to prevent the interaction of scattered light and the multi-layer film structures of a patterned interference filter were proposed. The simulated transmission spectra showed that the transmittance of the linear stripe pattern, visual target, and fundus illumination are sufficiently high for the retinal patterned illumination. [ABSTRACT FROM AUTHOR]

In this study, we developed a miniaturized InGaN blue μLED-based excitation source intended for an implantable lens-less brain imaging system. To enhance its implantability, the μLED was thinned further through the laser lift-off process. A filtering component comprising a short-pass interference filter and a low-NA fiber optic plate (FOP), was loaded onto the μLED. The addition of an interference filter reduced normal incident green-end band emissions from the μLED by two orders of magnitude. The application of FOP enables the resolution of the angle-dependent problem of the interference filter. Further, a fluorescent imaging experiment was carried out on the proposed excitation source. The proposed device produced bright fluorescence images that are sufficient for implantable in vivo application. The thickness of the proposed excitation device was 180 μm, making it suitable for implantable brain fluorescent imaging applications. [ABSTRACT FROM AUTHOR]

Wireless epidermal wearable devices attract interests and expectations as a tool for personalized, low-cost health monitoring technology. The concept of the wireless attachable personal health monitoring devices has been more widely considered by combining them with biosensors. To bring the most advantage out of the structure of the epidermal attachable device, a battery-free approach was introduced to reduce the volume and extend the lifetime of the device. In this work, an energy harvesting technology and noninvasive sensor were applied with the attachable battery-free devices as a wireless power system and painless measuring system. A glucose sensor was used as an example to develop the wireless wearable device for diabetes-monitoring. The device consists of two functional parts: an optical power transfer and an electrochemical sensing part. The operation starts when the optical power transfer part accumulates power from series-connected photovoltaic cells and intermittently supplies the power to the electrochemical sensing part. In the electrochemical sensing part, an amperometric method was used for controlling the oxidation voltage and measuring a faraday current from the noninvasive sensor and current as brightness and duration of light pulses from a light-emitting diode (LED). The experiment results show that the device works as expected for a variety of glucose concentrations. [ABSTRACT FROM AUTHOR]

We demonstrate a highly sensitive lensless fluorescence imaging device with a wide field-of-view by using a hybrid bandpass filter composed of interference filters, an absorption filter, and a fiber optic plate. The hybrid filter shows high excitation light rejection characteristics even in a lensless setup. In this study, we fabricated a hybrid bandpass filter and improved fluorescence observation performance for a target with auto-fluorescence. The filter was combined with a large image sensor with an imaging area of 67 mm2. As a demonstration, a brain slice from a green fluorescent protein transgenic mouse was observed and fluorescent cell bodies were detected with the lensless imaging device. [ABSTRACT FROM AUTHOR]

Abstract Propranolol, a β-adrenergic receptor blocker, is one of the most commonly used prophylactic drugs for migraines. Cortical spreading depression (CSD) is the propagation wave of neuronal excitation along with cerebral blood flow (CBF) changes over the cerebral cortex and has been implicated in the pathological process of migraine auras and its pain response. However, the effect of propranolol on CSD-related CBF changes and behavioral responses remains poorly understood. In this study, we measured CSD-related CBF responses using a micro-device with a green light emitting diode (LED) and micro-complementary-metal-oxide-semiconductor (CMOS) image sensor and evaluated pain-related reduced locomotor activity in mice. An injection of KCl into the visual cortex led to CSD-related CBF changes; however, propranolol prevented the increase in CBF as well as delayed the propagation velocity in KCl-induced CSD. Furthermore, an injection of KCl reduced locomotor activity and induced freezing behavior in awake and freely moving mice, which were prevented by propranolol treatment. These results suggest that the modulation of CSD-related CBF responses by the blockade of β-adrenergic receptor contributes to its prophylactic effects on migraines. Highlights • We measured cerebral blood flow changes using a novel CMOS imaging device. • Propranolol improves CBF responses in KCl-induced CSD. • Propranolol prevents the reduced locomotion in KCl-induced CSD in freely moving mice. [ABSTRACT FROM AUTHOR]

In digital enzyme-linked immunosorbent assay, which is used for biomarker detection and diagnosis, the concentration of target biomarkers is estimated by counting the number of fluorescence chambers in the microchamber array. We propose a compact system for counting fluorescent chambers. Our system consists of three components: a micro-reaction chamber array, an absorption filter for attenuating excitation light, and a photodetector. The absorption filter has a micro-light-pipe array (m-LPA) structure. A stacked photodiode CMOS image sensor (CIS), which can discriminate color, is applied as a photodetector. This paper describes the fabrication process enabling thin m-LPA chips. The unique low-noise characteristics of the stacked photodiode CIS that attains high sensitivity by adopting the 4T-APS configuration are explained. Furthermore, a detection method using the photobleaching phenomenon is proposed for high-sensitivity fluorescence detection. This method suggests that fluorescence by a single molecular enzyme can be detected within 30 min of the start of the fluorescence reaction. [ABSTRACT FROM AUTHOR]

In this work, we present a simple complementary metal-oxide semiconductor (CMOS)-controlled photovoltaic power-transfer platform that is suitable for very small (less than or equal to 1–2 mm) electronic devices such as implantable health-care devices or distributed nodes for the Internet of Things. We designed a 1.25 mm × 1.25 mm CMOS power receiver chip that contains integrated photovoltaic cells. We characterized the CMOS-integrated power receiver and successfully demonstrated blue light-emitting diode (LED) operation powered by infrared light. Then, we integrated the CMOS chip and a few off-chip components into a 1-mm3 implantable optogenetic stimulator, and demonstrated the operation of the device. [ABSTRACT FROM AUTHOR]

In this review, we present an implantable microimaging device to observe brain activities of small experimental animals such as mice and rats. Three categories of such devices are described: an optical fiber system, a head-mountable fluorescent microscope, and an ultrasmall image sensor that can be directly implanted into the brain. Among them, we focus on the third one, because this is a powerful tool to explore brain activities in deep brain region in a freely moving mouse. The device structure and performance are shown with some examples of deep brain images of mice. [ABSTRACT FROM AUTHOR]

In this paper, we propose and demonstrate an implantable CMOS image sensor with self-resetting pixels. The self-resetting function is implemented using a four-transistor Schmitt trigger inverter. The pixel has no counter for the number of self-resets, because the application does not require radiometric (linear) response. The pixel is fabricated using the 0.35- \mu \textm 2-poly 4-metal standard CMOS technology, which results in the pixel size of 15~\mu \text m \times 15 ~\mu \textm and a fill factor of 31%. The effective peak signal-to-noise ratio is >59 dB. An image sensor prototype comprising a $60\times 134$ pixel array is designed, and an implantable device is fabricated. As an example imaging experiment, we demonstrate blood-flow imaging of a rat-brain surface using the sensor. Intensity-change images are successfully obtained from the self-resetting pixel outputs with the image processing. [ABSTRACT FROM AUTHOR]

Various techniques for image color reproducibility under low-light conditions have been proposed, such as high sensitivity, a combination of visible (VIS) and infrared (IR) light, and coloring monochromatic images. However, when the illuminance falls below a certain level, color images cannot be obtained without prior color information. Previously, the exclusive use of IR without VIS illumination was proposed to achieve a pseudocolor image (basic IR color). It improved visibility compared with conventional monochrome images. However, there are cases, depending on the objects, when basic IR light cannot reproduce the correct color. An image processing method for enhancing color reproducibility is proposed, particularly for objects that are not suitable for the basic IR color (enhanced IR color). Moreover, we developed an algorithm to combine the advantages of both VIS and IR colors by utilizing signals of six wavelengths: three wavelengths each of VIS and IR. The proposed method includes an automatic transition between the optimal combination of VIS and IR colors when the illumination level changes, thus providing images with superior color reproducibility under various illumination levels compared with basic IR color. [ABSTRACT FROM AUTHOR]

Significance: Intrinsic optical signals (IOS) generated in the cortical tissue as a result of various interacting metabolic processes are used extensively to elucidate the underlying mechanisms that govern neurovascular coupling. However, current IOS measurements still often rely on bulky, tabletop imaging systems, and there remains a dearth of studies in freely moving subjects. Lightweight, miniature head-mounted imaging devices provide unique opportunities for investigating cortical dynamics in small animals under a variety of naturalistic behavioral settings. Aim: The aim of this work was to monitor IOS in the somatosensory cortex of wild-type mice by developing a lightweight, biocompatible imaging device that readily lends itself to animal experiments in freely moving conditions. Approach: Herein we describe a method for realizing long-term IOS imaging in mice using a 0.54-g, compact, CMOS-based, head-mounted imager. The two-part module, consisting of a tethered sensor plate and a base plate, allows facile assembly prior to imaging sessions and disassembly when the sensor is not in use. LEDs integrated into the device were chosen to illuminate the cortical mantle at two different wavelengths in the visible regime (λcenter: 535 and 625 nm) for monitoring volume- and oxygenation state-dependent changes in the IOS, respectively. To test whether the system can detect robust cortical responses, we recorded sensory-evoked IOS from mechanical stimulation of the hindlimbs (HL) of anesthetized mice in both acute and long-term implantation conditions. Results: Cortical IOS recordings in the primary somatosensory cortex hindlimb receptive field (S1HL) of anesthetized mice under green and red LED illumination revealed robust, multiphasic profiles that were time-locked to the mechanical stimulation of the contralateral plantar hindpaw. Similar intrinsic signal profiles observed in S1HL at 40 days postimplantation demonstrated the viability of the approach for long-term imaging. Immunohistochemical analysis showed that the brain tissue did not exhibit appreciable immune response due to the device implantation and operation. A proof-of-principle imaging session in a freely behaving mouse showed minimal locomotor impediment for the animal and also enabled estimation of blood flow speed. Conclusions: We demonstrate the utility of a miniature cortical imaging device for monitoring IOS and related hemodynamic processes in both anesthetized and freely moving mice, cueing potential for applications to some neuroscientific studies of sensation and naturalistic behavior. [ABSTRACT FROM AUTHOR]

Dopamine (DA) is the key regulator of reward behavior. The DA neurons in the ventral tegmental area (VTA) and their projection areas, which include the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala, play a primary role in the process of reward-driven behavior induced by the drugs of addiction, including nicotine and alcohol. In our previous study, we developed a novel platform consisting of micro-LED array devices to stimulate a large area of the brain of rats and monkeys with photo-stimulation and a microdialysis probe to estimate the DA release in the PFC. Our results suggested that the platform was able to detect the increased level of dopamine in the PFC in response to the photo-stimulation of both the PFC and VTA. In this study, we used this platform to photo-stimulate the VTA neurons in both ChrimsonR-expressing (non-specific) wild and dopamine transporter (DAT)-Cre (dopamine specific) mice, and measured the dopamine release in the nucleus accumbens shell (NAcShell). We measured the DA release in the NAcShell in response to optogenetic stimulation of the VTA neurons and investigated the effect of GABAergic neurons on dopaminergic neurons by histochemical studies. Comparing the photo-stimulation frequency of 2 Hz with that of 20 Hz, the change in DA concentration at the NAcShell was greater at 20 Hz in both cases. When ChrimsonR was expressed specifically for DA, the release of DA at the NAcShell increased in response to photo-stimulation of the VTA. In contrast, when ChrimsonR was expressed non-specifically, the amount of DA released was almost unchanged upon photo-stimulation. However, for nonspecifically expressed ChrimsonR, intraperitoneal injection of bicuculline, a competitive antagonist at the GABA-binding site of the GABAA receptor, also significantly increased the release of DA at the NAcShell in response to photo-stimulation of the VTA. The results of immunochemical staining confirm that GABAergic neurons in the VTA suppress DA activation, and also indicate that alterations in GABAergic neurons may have serious downstream effects on DA activity, NAcShell release, and neural adaptation of the VTA. This study also confirms that optogenetics technology is crucial to study the relationship between the mesolimbic dopaminergic and GABAergic neurons in a neural-specific manner. [ABSTRACT FROM AUTHOR]

Significance: Gene expression analysis is an important fundamental area of biomedical research. However, live gene expression imaging has proven challenging due to constraints in conventional optical devices and fluorescent reporters. Aim: Our aim is to develop smaller, more cost-effective, and versatile imaging capabilities compared with conventional devices. Bioluminescence reporter-based gene expression analysis was targeted due to its advantages over fluorescence-based imaging. Approach: We created a small compact imaging system using micro-CMOS image sensors (μCIS). The μCIS model had an improved pixel design and a patterned absorption filter array to detect the low light intensity of bioluminescence. Results: The device demonstrated lower dark current, lower temporal noise, and higher sensitivity compared with previous designs. The filter array enabled us to subtract dark current drift and attain a clearer light signal. These improvements allowed us to measure bioluminescence reporter-based gene expression in living mammalian cells. Conclusion: Using our μCIS system for bioluminescence imaging in the future, the device can be implanted in vivo for simultaneous gene expression imaging, behavioral analysis, and optogenetic modulation. [ABSTRACT FROM AUTHOR]

An observation technique for animal brain activity under freely moving conditions is important to understand brain functions because brain activity under an anesthetized condition is different from that under a nonanesthetized condition. We have developed an ultrasmall CMOS imaging device for brain activity observation under freely moving conditions. This device is composed of a CMOS image sensor chip and nine LEDs for illumination. It weighs only 0.02 g and its small size enables experiments to be performed without restricting animal movement. This feature is advantageous for brain imaging, particularly in freely moving situations. In this study, we have demonstrated blood-flow imaging using the device for the stable observation of brain activity over a long period. The blood flow can be observed without staining the brain during optical imaging. We have successfully estimated the blood-flow velocity under freely moving conditions. [ABSTRACT FROM AUTHOR]

A readout device for a dual-functional neural observation system is presented. The authors separately developed the reading operation of an implantable CMOS image sensor and a setup for fast-scan cyclic voltammetry and implemented them together in a microcontroller-based device. The developed imaging readout device with a size of [Formula: see text] can reach the highest reading rate of 160 fps with a 120×268 pixel image sensor. The voltammetry function was verified through an experiment using commercial carbon fiber electrodes in phosphate-buffered saline. When the imaging is sequentially operated with 400 V/s-scan rate voltammetry from -0.4 to 1.3 V, the system can operate at up to 60 fps. With this system, calcium imaging and dopamine recording in a freely behaving mouse can be achieved together in a simpler manner. This study aims to be the basis for the development of an implantable multi-functional sensor.

Optical and electronic neural interface devices based on CMOS technology are presented. Concept, design strategy, and fabrication of the CMOS-based optoelectronic neural interface devices are described. The devices are based on a technology of implantable CMOS image sensor. To realize addressable local optical stimulation, blue light-emitting diode array chip was integrated on the implantable CMOS image sensors. Functional demonstrations of the devices are also presented. Optical stimulation capability was demonstrated in both in vitro and in vivo experiments. Further perspective including wireless device architecture is also presented.

A chronic brain blood-flow imaging device was developed for cerebrovascular disease treatment. This device comprises a small complementary metal-oxide semiconductor image sensor and a chronic fiber-optic plate window on a mouse head. A long-term cerebral blood-flow imaging technique was established in a freely moving mouse. Brain surface images were visible for one month using the chronic FOP window. This device obtained brain surface images and blood-flow velocity. The blood-flow changes were measured in behavioral experiments using this device. The chronic brain blood-flow imaging device may contribute to determining the cause of cerebrovascular disease and the development of cerebrovascular disease treatment., Competing Interests: The authors declare that there are no conflicts of interest related to this article.

In digital enzyme-linked immunosorbent assay, which is used for biomarker detection and diagnosis, the concentration of target biomarkers is estimated by counting the number of fluorescence chambers in the microchamber array. We propose a compact system for counting fluorescent chambers. Our system consists of three components: a micro-reaction chamber array, an absorption filter for attenuating excitation light, and a photodetector. The absorption filter has a micro-light-pipe array (m-LPA) structure. A stacked photodiode CMOS image sensor (CIS), which can discriminate color, is applied as a photodetector. This paper describes the fabrication process enabling thin m-LPA chips. The unique low-noise characteristics of the stacked photodiode CIS that attains high sensitivity by adopting the 4T-APS configuration are explained. Furthermore, a detection method using the photobleaching phenomenon is proposed for high-sensitivity fluorescence detection. This method suggests that fluorescence by a single molecular enzyme can be detected within 30 min of the start of the fluorescence reaction.

We report a lens-free fluorescence imaging device using a composite filter composed of an interference filter and an absorption filter, each applied to one side of a fiber optic plate (FOP). The transmission of angled excitation light through the interference filter is absorbed by the absorption filter. The auto-fluorescence of the absorption filter is reduced by the reflection from the interference filter of normally incident excitation light. As a result, high-performance rejection of excitation light is achieved in a lens-free device. The FOP provides a flat, hard imaging device surface that does not degrade the spatial resolution. We demonstrate excitation rejection of approximately 10 8 :1 at a wavelength of 450 nm in a fabricated lens-free device. The resolution of fluorescence imaging is approximately 12 µ m. Time-lapse imaging of cells containing green fluorescent protein was performed in a 5- µ m thin-film chamber. The small dimensions of the device allow observation of cell culturing in a CO 2 incubator. We also demonstrate that the proposed lens-free filter is compatible with super-resolution bright-field imaging techniques. These features open a way to develop a high-performance, dual-mode, lens-free imaging device that is expected to be a powerful tool for many applications, such as imaging of labeled cells and point-of-care assay., Competing Interests: The authors declare that there are no conflicts of interest related to this article.

To better understand the brain function based on neural activity, a minimally invasive analysis technology in a freely moving animal is necessary. Such technology would provide new knowledge in neuroscience and contribute to regenerative medical techniques and prosthetics care. An application that combines optogenetics for voluntarily stimulating nerves, imaging to visualize neural activity, and a wearable micro-instrument for implantation into the brain could meet the abovementioned demand. To this end, a micro-device that can be applied to the brain less invasively and a system for controlling the device has been newly developed in this study. Since the novel implantable device has dual LEDs and a CMOS image sensor, photostimulation and fluorescence imaging can be performed simultaneously. The device enables bidirectional communication with the brain by means of light. In the present study, the device was evaluated in an in vitro experiment using a new on-chip 3D neuroculture with an extracellular matrix gel and an in vivo experiment involving regenerative medical transplantation and gene delivery to the brain by using both photosensitive channel and fluorescent Ca(2+) indicator. The device succeeded in activating cells locally by selective photostimulation, and the physiological Ca(2+) dynamics of neural cells were visualized simultaneously by fluorescence imaging.

The application of the fluorescence imaging method to living animals, together with the use of genetically engineered animals and synthesized photo-responsive compounds, is a powerful method for investigating brain functions. Here, we report a fluorescence imaging method for the brain surface and deep brain tissue that uses compact and mass-producible semiconductor imaging devices based on complementary metal-oxide semiconductor (CMOS) technology. An image sensor chip was designed to be inserted into brain tissue, and its size was 1500 × 450 μm. Sample illumination is also a key issue for intravital fluorescence imaging. Hence, for the uniform illumination of the imaging area, we propose a new method involving the epi-illumination of living biological tissues, and we performed investigations using optical simulations and experimental evaluation.