Bright-field and fluorescence chip-scale microscopy for biological imaging

Optical microscopy is an essential tool in biological science and one of the gold standards for medical examinations. Miniaturization of microscopes can be a crucial stepping stone towards realizing compact, cost-effective and portable platforms for biomedical research and healthcare. This thesis reports on implementations of bright-field and fluorescence chip-scale microscopes for a variety of biological imaging applications. The term “chip-scale microscopy” refers to lensless imaging techniques realized in the form of mass-producible semiconductor devices, which transforms the fundamental design of optical microscopes.

Our strategy for chip-scale microscopy involves utilization of low-cost Complementary metal Oxide Semiconductor (CMOS) image sensors, computational image processing and micro-fabricated structural components. First, the sub-pixel resolving optofluidic microscope (SROFM), will be presented, which combines microfluidics and pixel super-resolution image reconstruction to perform high-throughput imaging of fluidic samples, such as blood cells. We discuss design parameters and construction of the device, as well as the resulting images and the resolution of the device, which was 0.66 µm at the highest acuity. The potential applications of SROFM for clinical diagnosis of malaria in the resource-limited settings is discussed.

Next, the implementations of ePetri, a self-imaging Petri dish platform with microscopy resolution, are presented. Here, we simply place the sample of interest on the surface of the image sensor and capture the direct shadow images under the illumination. By taking advantage of the inherent motion of the microorganisms, we achieve high resolution (~1 µm) imaging and long term culture of motile microorganisms over ultra large field-of-view (5.7 mm × 4.4 mm) in a specialized ePetri platform. We apply the pixel super-resolution reconstruction to a set of low-resolution shadow images of the microorganisms as they move across the sensing area of an image sensor chip and render an improved resolution image. We perform longitudinal study of Euglena gracilis cultured in an ePetri platform and image based analysis on the motion and morphology of the cells. The ePetri device for imaging non-motile cells are also demonstrated, by using the sweeping illumination of a light emitting diode (LED) matrix for pixel super-resolution reconstruction of sub-pixel shifted shadow images. Using this prototype device, we demonstrate the detection of waterborne parasites for the effective diagnosis of enteric parasite infection in resource-limited settings.

Then, we demonstrate the adaptation of a smartphone’s camera to function as a compact lensless microscope, which uses ambient illumination as its light source and does not require the incorporation of a dedicated light source. The method is also based on the image reconstruction with sweeping illumination technique, where the sequence of images are captured while the user is manually tilting the device around any ambient light source, such as the sun or a lamp. Image acquisition and reconstruction is performed on the device using a custom-built android application, constructing a stand-alone imaging device for field applications. We discuss the construction of the device using a commercial smartphone and demonstrate the imaging capabilities of our system.

Finally, we report on the implementation of fluorescence chip-scale microscope, based on a silo-filter structure fabricated on the pixel array of a CMOS image sensor. The extruded pixel design with metal walls between neighboring pixels successfully guides fluorescence emission through the thick absorptive filter to the photodiode layer of a pixel. Our silo-filter CMOS image sensor prototype achieves 13-µm resolution for fluorescence imaging over a wide field-of-view (4.8 mm × 4.4 mm). Here, we demonstrate bright-field and fluorescence longitudinal imaging of living cells in a compact, low-cost configuration.

Sensing and Actuation from Biology to Electronics

We introduce an in vitro diagnostic magnetic biosensing platform for immunoassay and nucleic acid detection. The platform has key characteristics for a point-of-use (POU) diagnostic: portability, low-power consumption, low cost, and multiplexing capability. As a demonstration of capabilities, we use this platform for the room temperature, amplification-free detection of a 31 bp DNA oligomer and interferon-gamma (a protein relevant for tuberculosis diagnosis). Reliable assay measurements down to 100 pM for the DNA and 1 pM for the protein are demonstrated. We introduce a novel "magnetic freezing" technique for baseline measurement elimination and to enable spatial multiplexing. We have created a general protocol for adapting integrated circuit (IC) sensors to any of hundreds of commercially available immunoassay kits and custom designed DNA sequences.

We also introduce a method for immunotherapy treatment of malignant gliomas. We utilize leukocytes internalized with immunostimulatory nanoparticle-oligonucleotide conjugates to localize and retain immune cells near the tumor site. As a proof-of-principle, we develop a novel cell imaging and incubation chamber for in vitro magnetic motility experiments. We use the apparatus to demonstrate the controlled movement of magnetically loaded THP-1 leukocytes.

Finally, we introduce an IC transmitter and power ampli er (PA) that utilizes electronic digital infrastructure, sensors, and actuators to self-heal and adapt to process, dynamic, and environmental variation. Traditional IC design has achieved incredible degrees of reliability by ensuring that billions of transistors on a single IC die are all simultaneously functional. Reliability becomes increasingly difficult as the size of a transistor shrinks. Self-healing can mitigate these variations.

A high temperature SOI CMOS NO2 sensor

For more than 20 years researchers have been interested in developing micro-gas sensors based on silicon technology. Most of the reported devices are based on micro-hotplates, however they use materials that are not CMOS compatible, and therefore are not suitable for large volume manufacturing. Furthermore, they do not allow the circuitry to be integrated on to the chip. CMOS compatible devices have been previously reported. However, these use polysilicon as the heater material, which has long term stability problems at high temperatures. Here we present low power, low cost SOI CMOS NO2 sensors, based on high stability single crystal silicon P+ micro-heaters platforms, capable of measuring gas concentrations down to 0.1 ppm. We have integrated a thin tungsten molybdenum oxide layer as a sensing material with a foundry-standard SOI CMOS micro-hotplate and tested this to NO2. We believe these devices have the potential for use as robust, very low power consumption, low cost gas sensors. © 2011 American Institute of Physics.

Zinc oxide nanowire based hydrogen sensor on SOI CMOS platform

Here we report on the successful low-temperature growth of zinc oxide nanowires (ZnONWs) on silicon-on-insulator (SOI) CMOS micro-hotplates and their response, at different operating temperatures, to hydrogen in air. The SOI micro-hotplates were fabricated in a commercial CMOS foundry followed by a deep reactive ion etch (DRIE) in a MEMS foundry to form ultra-low power membranes. The micro-hotplates comprise p+ silicon micro-heaters and interdigitated metal electrodes (measuring the change in resistance of the gas sensitive nanomaterial). The ZnONWs were grown as a post-CMOS process onto the hotplates using a CMOS friendly hydrothermal method. The ZnONWs showed a good response to 500 to 5000 ppm of hydrogen in air. We believe that the integration of ZnONWs with a MEMS platform results in a low power, low cost, hydrogen sensor that would be suitable for handheld battery-operated gas sensors. © 2011 Published by Elsevier Ltd.

Performance and power dissipation comparisons between 28 Gb/s NRZ, PAM, CAP and optical OFDM systems for data communication applications

Theoretical investigations have been carried out to analyze and compare the link power budget and power dissipation of non-return-to-zero (NRZ), pulse amplitude modulation-4 (PAM-4), carrierless amplitude and phase modulation-16 (CAP-16) and 16-quadrature amplitude modulation-orthogonal frequency division multiplexing (16-QAM-OFDM) systems for data center interconnect scenarios. It is shown that for multimode fiber (MMF) links, NRZ modulation schemes with electronic equalization offer the best link power budget margins with the least power dissipation for short transmission distances up to 200 m; while OOFDM is the only scheme which can support a distance of 300 m albeit with power dissipation as high as 4 times that of NRZ. For short single mode fiber (SMF) links, all the modulation schemes offer similar link power budget margins for fiber lengths up to 15 km, but NRZ and PAM-4 are preferable due to their system simplicity and low power consumption. For lengths of up to 30 km, CAP-16 and OOFDM are required although the schemes consume 2 and 4 times as much power respectively compared to that of NRZ. OOFDM alone allows link operation up to 35 km distances. © 1983-2012 IEEE.

A temperature sensor from a self-assembled carbon nanotube microbridge

Recent studies show that carbon nanotubes (CNTs) can be used as temperature sensors, and offer great opportunities towards extreme miniaturization, high sensitivity, low power consumption, and rapid response. Previous CNT based temperature sensors are fabricated by either dielectrophoresis or piece-wise alignment of read-out electronics around randomly dispersed CNTs. We introduce a new deterministic and parallel microsensor fabrication method based on the self-assembly of CNTs into three-dimensional microbridges. We fabricated prototype microbridge sensors on patterned electrodes, and found their sensitivity to be better than -0.1 %/K at temperatures between 300K and 420K. This performance is comparable to previously published CNT based temperature sensors. Importantly, however, our research shows how unique sensor architectures can be made by self-assembly, which can be achieved using batch processing rather than piecewise assembly. ©2010 IEEE.

Thermo-optical characterization of fluorescent rhodamine B based temperature-sensitive nanosensors using a CMOS MEMS micro-hotplate

A custom designed microelectromechanical systems (MEMS) micro-hotplate, capable of operating at high temperatures (up to 700 C), was used to thermo-optically characterize fluorescent temperature-sensitive nanosensors. The nanosensors, 550 nm in diameter, are composed of temperature-sensitive rhodamine B (RhB) fluorophore which was conjugated to an inert silica sol-gel matrix. Temperature-sensitive nanosensors were dispersed and dried across the surface of the MEMS micro-hotplate, which was mounted in the slide holder of a fluorescence confocal microscope. Through electrical control of the MEMS micro-hotplate, temperature induced changes in fluorescence intensity of the nanosensors was measured over a wide temperature range. The fluorescence response of all nanosensors dispersed across the surface of the MEMS device was found to decrease in an exponential manner by 94%, when the temperature was increased from 25 C to 145 C. The fluorescence response of all dispersed nanosensors across the whole surface of the MEMS device and individual nanosensors, using line profile analysis, were not statistically different (p < 0.05). The MEMS device used for this study could prove to be a reliable, low cost, low power and high temperature micro-hotplate for the thermo-optical characterisation of sub-micron sized particles. The temperature-sensitive nanosensors could find potential application in the measurement of temperature in biological and micro-electrical systems. The Authors. © 2013 Published by Elsevier B.V. All rights reserved.

A silicon-on-insulator-based thermo-optic waveguide switch with low insertion loss and fast response

A silicon-on-insulator-based thermo-optic waveguide switch integrated with spot size converters is designed and fabricated by inductively coupled plasma reactive ion etching. The device shows good characteristics, including low, insertion loss of 8 +/- 1 dB for wavelength 1530-1580 nm and fast response times of 4.6 As for rising edge and 1.9 mu s for failing edge. The extinction ratios of the two channels are 19.1 and 18 dB, respectively.

A 5.6-mW Power Dissipation CMOS Frequency Synthesizer for L1/L2 Dual-Band GPS Application

This paper presents a wide tuning range CMOS frequency synthesizer for dual-band GPS receiver, which has been fabricated in a standard 0.18-um RF CMOS process. With a high Q on-chip inductor, the wide-band VCO shows a tuning range from 2 to 3.6GHz to cover 2.45GHz and 3.14GHz in case of process corner or temperature variation, with a current consumption varying accordingly from 0.8mA to 0.4mA, from a 1.8V supply voltage. The measurement results show that the whole frequency synthesizer costs a very low power consumption of 5.6mW working at L I band with in-band phase noise less than -82dBc/Hz and out-of-band phase noise about -112 dBc/Hz at 1MHz offset from a 3.142GHz carrier.

Low threshold current density, low resistance oxide-confined VCSEL fabricated by a dielectric-free approach

We present the fabrication process and experimental results of 850-nm oxide-confined vertical cavity surface emitting lasers (VCSELs) fabricated by using dielectric-free approach. The threshold current of 0.4 mA, which corresponds to the threshold current density of 0.5 kA/cm(2), differential resistance of 76 Omega, and maximum output power of more than 5 mW are achieved for the dielectric-free VCSEL with a square oxide aperture size of 9 mu m at room temperature (RT). L-I-V characteristics of the dielectric-free VCSEL are compared with those of conventional VCSEL with the similar aperture size, which indicates the way to realize low-cost, low-power consumption VCSELs with extremely simple process. Preliminary study of the temperature-dependent L-I characteristics and modulation response of the dielectric-free VCSEL are also presented.

A Novel Power Supply Solution of a Passive RFID Transponder

This paper presents a power supply solution for fully integrated passive radio-frequency identification(RFID) transponder IC,which has been implemented in 0.35μm CMOS technology with embedded EEPROM from Chartered Semiconductor.The proposed AC/DC and DC/DC charge pumps can generate stable output for RFID applications with quite low power dissipation and extremely high pumping efficiency.An analytical model of the voltage multiplier,comparison with other charge pumps,simulation results,and chip testing results are presented.

基于MSP430 单片机和DS18B20 的多分支多通道温度测量系统远程监控软件

This paper present that the system can acquire the remote temperature measurement data of 40 monitoring points,through the RS-232 serial port and the Intranet.System s hardware is consist of TI s MSP430F149 mixed-signal processor and UA7000A network module.Using digital temperature sensor DS18B20,the structure is simple and easy to expand,the sensors directly send out the temperature data.MSP430F149 has the advantage of ultra-low-power and high degree of integration.Using msp430F149,the multi-branch multi-p...中文文摘：文章论述了通过RS-232串口和Intranet网络,来实现对远端的40个温度测量点的监控。系统硬件由TI公司的MSP430F149混合信号处理器和UA7000A网络模块构成。传感器采用数字式温度传感器DS18B20,它将直接得到温度的数字量,结构简单,易于扩展。MSP430F149处理器具有超低功耗和高度集成等优点,利用它构建的多分支多通道温度测量系统功能强大,结构简单,可靠性高,抗干扰能力强。系统客户端软件采用Microsoft Visual C++6.0设计。本监控系统能够很好地完成对4个分支共40个温度测量点的远程实时监控。

基于DSP的动态传感器网络实验平台的设计和开发

介绍了一种基于DSP2812的动态传感器网络实验平台的设计与开发.该实验平台的设计由配备各种低成本、低功耗的传感器和无线通信模块的可移动的传感器节点组成.在介绍动态传感器网络实验平台的各个组成部分之后,对系统进行了的基本实验测试,并给出了测试结果.*

Development of a highly-miniaturised wireless ISE/pH sensor

The goal of this work is to fabricate robust, highly-miniaturised, wireless sensor modules that incorporates ion-selective electrodes (ISEs). pH is one of the main parameters in assessment of the quality of our environment (water, soil) and these ISE/pH sensors will be deployed in a miniaturised, programmable modular system. The simplicity of ISEs (low costs and low power requirements) allow for the preparation of sensors that are all very similar in construction but can at the same time be easily made for variety of different environmentally important ions (i.e. heavy metals). This is important because of the increasing focus on the impact of the quality of the environment on society, both locally, and globally. The work described will contribute to a widely distributed sensor network for monitoring the quality of our environment, focused mainly on soil and water quality.

Practical wireless sensor networks power consumption metrics for building energy management applications

The power consumption of wireless sensor networks (WSN) module is an important practical concern in building energy management (BEM) system deployments. A set of metrics are created to assess the power profiles of WSN in real world condition. The aim of this work is to understand and eventually eliminate the uncertainties in WSN power consumption during long term deployments and the compatibility with existing and emerging energy harvesting technologies. This paper investigates the key metrics in data processing, wireless data transmission, data sensing and duty cycle parameter to understand the system power profile from a practical deployment prospective. Based on the proposed analysis, the impacts of individual metric on power consumption in a typical BEM application are presented and the subsequent low power solutions are investigated.