David C. Ng

Real time in vivo imaging and measurement of serine protease activity in the mouse hippocampus using a dedicated complementary metal-oxide semiconductor imaging device.

The aim of the present study is to demonstrate the application of complementary metal-oxide semiconductor (CMOS) imaging technology for studying the mouse brain. By using a dedicated CMOS image sensor, we have successfully imaged and measured brain serine protease activity in vivo, in real-time, and for an extended period of time. We have developed a biofluorescence imaging device by packaging the CMOS image sensor which enabled on-chip imaging configuration. In this configuration, no optics are required whereby an excitation filter is applied onto the sensor to replace the filter cube block found in conventional fluorescence microscopes. The fully packaged device measures 350 microm thick x 2.7 mm wide, consists of an array of 176 x 144 pixels, and is small enough for measurement inside a single hemisphere of the mouse brain, while still providing sufficient imaging resolution. In the experiment, intraperitoneally injected kainic acid induced upregulation of serine protease activity in the brain. These events were captured in real time by imaging and measuring the fluorescence from a fluorogenic substrate that detected this activity. The entire device, which weighs less than 1% of the body weight of the mouse, holds promise for studying freely moving animals.

Integrated In Vivo Neural Imaging and Interface CMOS Devices: Design, Packaging, and Implementation

We have developed two CMOS devices to demonstrate the use of CMOS technology for neural imaging and interfacing with the aim of studying the functions of the brain at the molecular level. In this work, we discuss the design, packaging, and implementation of a compact, single device imaging system for imaging inside the mouse brain. We show that the device is capable of imaging and measuring fluorophore concentrations down to 1 mum . The packaged device was tested for in vivo fluorescence imaging by imaging the activity of serine protease in the mouse hippocampus. The result shows imaging of neural activity with spatial resolution close to the pixel size of 7.5 mum and less than 300 ms temporal resolution. A second device was developed to image neuronal network activity and to provide a means for electrical interfacing with neurons. Characterization tests show that the device has comparable performance to current tools used in electrophysiological experiments of the brain. This work paves the way for simultaneous imaging and electrophysiological experiments using a single compact and minimally invasive device in the future.

Pulse-domain digital image processing for vision chips employing low-voltage operation in deep-submicrometer technologies

A new architecture for pixel-level parallel image processing in the pulse domain for CMOS vision chips has been developed. Image processing such as edge enhancement, edge detection, and blurring are realized based on suppression and promotion of digital pulses; the pixel value is represented by the frequency of digital pulses by use of a pulse-frequency modulation (PFM) photosensor or that with an in-pixel 1-bit analog-to-digital converter. The proposed architecture is suitable for low-voltage operation in deep-submicrometer technologies because the image processing is implemented by 1-bit fully digital circuits with a small number of logic gates. The principles of the image processing are addressed. We have fabricated a 16 /spl times/ 16-pixel prototype vision chip. The relationship between illumination and the output pulse frequency is characterized. Step responses of the prototype vision chip for fundamental image processing operations show good agreement with those expected by correlation-based spatial filtering. A simple image binarization method specific to our architecture is also presented. The histograms of the intervals of the output pulses after image processing show multiple peaks, which indicates that averaging of the intervals is required for longer periods to achieve higher image-processing quality. To improve the linearity of pulse frequency dependence on illumination, usage of random clocks is discussed.

Pulse frequency modulation based CMOS image sensor for subretinal stimulation

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

Wireless power delivery for retinal prostheses

Delivering power to an implanted device located deep inside the body is not trivial. This problem is made more challenging if the implanted device is in constant motion. This paper describes two methods of transferring power wirelessly by means of magnetic induction coupling. In the first method, a pair of transmit and receive coils is used for power transfer over a large distance (compared to their diameter). In the second method, an intermediate pair of coils is inserted in between transmit and receive coils. Comparison between the power transfer efficiency with and without the intermediate coils shows power transfer efficiency to be 11.5 % and 8.8 %, respectively. The latter method is especially suitable for powering implanted devices in the eye due to immunity to movements of the eye and ease of surgery. Using this method, we have demonstrated wireless power delivery into an animal eye.

A study of bending effect on pulse-frequency-modulation-based photosensor for retinal prosthesis

In this work, we study the effect of bending on the pulse-frequency-modulation (PFM)-based photosensor. Based on the results of our study of strain on metal oxide semiconductor field-effect transistor (MOSFET) devices, we explain the behavior of the photosensor under compressive and tensile bending. We found that the maximum frequency variation to bending is about +4% when extrapolated to the curvature of the human eye. From this study we hope to minimize or eliminate the effect of bending on LSI circuits. Although this study specifically deals with the PFM photosensor circuit, any other LSI circuit subjected to strain can be treated similarly.

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

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.

Closed-loop inductive link for wireless powering of a high density electrode array retinal prosthesis

A retinal prosthesis intended for rehabilitation of vision impaired patients will require continuous power supply in order to achieve real-time moving images. In this work, we explore the use of inductive coils fabricated using flexible circuit technologies for inductive powering of the implanted prosthetic device. We found that manufacturing technologies dictate the optimum operating frequency of the coil. For a minimum track width and spacing of 4 mils, the optimum frequency was found to be 2.9 MHz. We also looked at the distribution of electric and magnetic fields generated by the inductive coils in and surrounding the eye. These simulation results show that there are electric field concentrations around the conductive coils. Apart from the coils, we need to design an efficient circuit to drive the transmit coil and recover the transmitted power. In order to maintain optimal operation of the link, a closed-loop load modulation feedback operation is proposed. Adaptive control using back-telemetry of the induced voltage on the secondary side can close the power supply loop and result in optimum power transfer by boosting the supply voltage on the primary side when load is high and reducing this voltage when load is small.

A super low power MICS band receiver front-end down converter on 65 nm CMOS

This paper presents a super low power MICS band receiver front-end down converter on 65 nm CMOS for implantable biomedical devices. This down converter, including a LNA and a quadrature mixer, only consumes 500 µA DC current under 1 V supply. With a small LO swing of 300 mV, it provides a voltage conversion gain of 35 dB and a noise figure of 7.4 dB, while a −20 dBm IIP3 is obtained. In order to achieve super low power, current-reuse structure is adopted and all transistors are operated in deep sub-threshold region. Circuits level issues and techniques are also discussed.

Development of a Fully Integrated Complementary Metal–Oxide–Semiconductor Image Sensor-Based Device for Real-Time In vivo Fluorescence Imaging inside the Mouse Hippocampus

In our previous work, we demonstrated the potential of a complementary metal–oxide–semiconductor (CMOS) imaging device for use in imaging of the mouse brain. We showed that the device is capable of detecting fluorescence signal inside the mouse brain and successfully imaged real-time protease activity inside the hippocampus. In this work, we have improved the imaging device by integrating an excitation light source in the form of an ultraviolet light-emitting diode chip and an injection needle onto the sensor chip. This results in a compact single device imaging system for minimal invasive imaging inside the mouse brain. Also experimental repeatability is improved which enabled us to successful perform calibration of fluorophore concentration using the device. Fluorescence imaging experiments inside the brain phantom as well as in the mouse brain show that the device is capable of real time fluorescence detection. Using the device, we found that diffusion rate of chemical injected into the brain is smaller than 10 pmol/min. This work is expected to lead to the successful use of a CMOS imaging device for the study of the functions of the brain.