Integrated ultrasonic particle positioning and low excitation light fluorescence imaging

A compact hybrid system has been developed to position and detect fluorescent micro-particles by combining a Single Photon Avalanche Diode (SPAD) imager with an acoustic manipulator. The detector comprises a SPAD array, light-emitting diode (LED), lenses, and optical filters. The acoustic device is formed of multiple transducers surrounding an octagonal cavity. By stimulating pairs of transducers simultaneously, an acoustic landscape is created causing fluorescent micro-particles to agglomerate into lines. The fluorescent pattern is excited by a low power LED and detected by the SPAD imager. Our technique combines particle manipulation and visualization in a compact, low power, portable setup

Hybrid dual mode sensor for simultaneous detection of two serum metabolites

Metabolites are the ultimate readout of disease phenotype that plays a significant role in the study of human disease. Multiple metabolites sometimes serve as biomarkers for a single metabolic disease. Therefore, simultaneous detection and analysis of those metabolites facilitate early diagnostics of the disease. Conventional approaches to detect and quantify metabolites include mass spectrometry and nuclear magnetic resonance that require bulky and expensive equipment. Here, we present a disposable sensing platform that is based on complementary metal–oxide–semiconductor process. It contains two sensors: an ion sensitive field-effect transistor and photodiode that can work independently for detection of pH and color change produced during the metabolite-enzyme reaction. Serum glucose and cholesterol have been detected and quantified simultaneously with the new platform, which shows good sensitivity within the physiological range. Low cost and easy manipulation make our device a prime candidate for personal metabolome sensing diagnostics

Low Noise and High Photodetection Probability SPAD in 180 nm Standard CMOS Technology

A square shaped, low noise and high photo-response single photon avalanche diode suitable for circuit integration, implemented in a standard CMOS 180 nm high voltage technology, is presented. In this work, a p+ to shallow n-well junction was engineered with a very smooth electric field profile guard ring to attain a photo detection probability peak higher than 50% with a median dark count rate lower than 2 Hz/μm2 when operated at an excess bias of 4 V. The reported timing jitter full width at half maximum is below 300 ps for 640 nm laser pulses

Wide-Range Optical CMOS-Based Diagnostics

Colorimetric, chemiluminescence and refractive index based diagnostics are some of the most important sensing techniques in biomedical science and clinical medicine. Conventionally laboratories and medical clinics rely on bulky and dedicated equipment for each diagnostic technique independently. In this paper, we present CMOS sensor based solutions, comprising a single photon avalanche detector array and photodiode array. The CMOS platform offers low cost integration and wide range of light-based diagnostic techniques, leading to development of point-of-care devices

A 16 x 16 CMOS amperometric microelectrode array for simultaneous electrochemical measurements

There is a requirement for an electrochemical sensor technology capable of making multivariate measurements in environmental, healthcare, and manufacturing applications. Here, we present a new device that is highly parallelized with an excellent bandwidth. For the first time, electrochemical cross-talk for a chip-based sensor is defined and characterized. The new CMOS electrochemical sensor chip is capable of simultaneously taking multiple, independent electroanalytical measurements. The chip is structured as an electrochemical cell microarray, comprised of a microelectrode array connected to embedded self-contained potentiostats. Speed and sensitivity are essential in dynamic variable electrochemical systems. Owing to the parallel function of the system, rapid data collection is possible while maintaining an appropriately low-scan rate. By performing multiple, simultaneous cyclic voltammetry scans in each of the electrochemical cells on the chip surface, we are able to show (with a cell-to-cell pitch of 456 μm) that the signal cross-talk is only 12% between nearest neighbors in a ferrocene rich solution. The system opens up the possibility to use multiple independently controlled electrochemical sensors on a single chip for applications in DNA sensing, medical diagnostics, environmental sensing, the food industry, neuronal sensing, and drug discovery

Hybrid Amperometric and Potentiometric Sensing Based on a CMOS ISFET Array

Potentiometry and amperometry are some of the most important techniques for electroanalytical applications. Integrating these two techniques on a single chip using CMOS technology paves the way for more analysis and measurement of chemical solutions. In this paper, we describe the integration of electrode transducers (amperometry) on an ion imager based on an ISFET array (potentiometry). In particular, this integration enables the spatial representation of the potential distribution of active electrodes in a chemical solution under investigation

Design and implementation of miniaturised capsule for autofluorescence detection with possible application to the bowel disease

Early signs of intestinal cancer may be detected through variations in tissue autofluorescence (AF), however current endoscope-based AF systems are unable to inspect the small intestine. This thesis describes the design, fabrication, implantation, testing and packaging of a wireless pill capable of detecting the autofluorescence from cancerous cells, and able to reach parts of the gastrointestinal tract that are inaccessible to endoscopes. The pill exploits the fact that there is a significant difference in the intensity of autofluorescence emitted by normal and cancerous tissues when excited by a blue or ultra violet light source. The intensity differences are detected using very sensitive light detectors. The pill has been developed in two stages. The first stage starts with using an off-chip multi-pixel photon counter (MPPC) device as a light detector. In the second stage, the light detector is integrated into an application specific integrated circuit (ASIC). The pill comprises of an ASIC, optical filters, an information processing unit and a radio transmission unit, to transmit acquired data to an external base station. Two ASICs have been fabricated, the first stage of this work involved implementing an ASIC that contains two main blocks; the first block is capable of providing a variable DC voltage more than 72 V from a 3 V input to bias the MPPC device. The second main block is a front-end consisting of a high speed transimpedance amplifier (TIA) and voltage amplifiers to capture the very small current pulses produced by the MPPC. The second ASIC contains a high voltage charge pump up to (37.9 V) integrated with a single photon avalanche detector (SPAD). The charge pump is used to bias the SPAD above its breakdown voltage and therefore operate the device in Geiger mode. The SPAD was designed to operate in the visible region where its photon detection efficiency (PDE) peaks at 465 nm, which is near to human tissues autofluorescence peaking region (520±10 nm). The use of the ultra low light detector to detect the autofluorescence permits a lower excitation light intensity and therefore lower overall power consumption. The two ASICs were fabricated using a commercial triple-well high-voltage CMOS process. The complete device operates at 3V and draws an average of 7.1mA, enabling up to 23 hours of continuous operation from two 165mAh SR44 batteries

Monolithic Integration of a Plasmonic Sensor with CMOS Technology

Monolithic integration of nanophotonic sensors with CMOS detectors can transform the laboratory based nanophotonic sensors into practical devices with a range of applications in everyday life. In this work, by monolithically integrating an array of gold nanodiscs with the CMOS photodiode we have developed a compact and miniaturized nanophotonic sensor system having direct electrical read out. Doing so eliminates the need of expensive and bulky laboratory based optical spectrum analyzers used currently for measurements of nanophotonic sensor chips. The experimental optical sensitivity of the gold nanodiscs is measured to be 275 nm/RIU which translates to an electrical sensitivity of 5.4 V/RIU. This integration of nanophotonic sensors with the CMOS electronics has the potential to revolutionize personalized medical diagnostics similar to the way in which the CMOS technology has revolutionized the electronics industry

An integrated circuit for chip-based analysis of enzyme kinetics and metabolite quantification

We have created a novel chip-based diagnostic tools based upon quantification of metabolites using enzymes specific for their chemical conversion. Using this device we show for the first time that a solid-state circuit can be used to measure enzyme kinetics and calculate the Michaelis-Menten constant. Substrate concentration dependency of enzyme reaction rates is central to this aim. Ion-sensitive field effect transistors (ISFET) are excellent transducers for biosensing applications that are reliant upon enzyme assays, especially since they can be fabricated using mainstream microelectronics technology to ensure low unit cost, mass-manufacture, scaling to make many sensors and straightforward miniaturisation for use in point-of-care devices. Here, we describe an integrated ISFET array comprising 216 sensors. The device was fabricated with a complementary metal oxide semiconductor (CMOS) process. Unlike traditional CMOS ISFET sensors that use the Si3N4 passivation of the foundry for ion detection, the device reported here was processed with a layer of Ta2O5 that increased the detection sensitivity to 45 mV/pH unit at the sensor readout. The drift was reduced to 0.8 mV/hour with a linear pH response between pH 2 – 12. A high-speed instrumentation system capable of acquiring nearly 500 fps was developed to stream out the data. The device was then used to measure glucose concentration through the activity of hexokinase in the range of 0.05 mM – 231 mM, encompassing glucose’s physiological range in blood. Localised and temporal enzyme kinetics of hexokinase was studied in detail. These results present a roadmap towards a viable personal metabolome machine

A colorimetric CMOS-based platform for rapid total serum cholesterol quantification

Elevated cholesterol levels are associated with a greater risk of developing cardiovascular disease and other illnesses, making it a prime candidate for detection on a disposable biosensor for rapid point of care diagnostics. One of the methods to quantify cholesterol levels in human blood serum uses an optically mediated enzyme assay and a bench top spectrophotometer. The bulkiness and power hungry nature of the equipment limits its usage to laboratories. Here, we present a new disposable sensing platform that is based on a complementary metal oxide semiconductor process for total cholesterol quantification in pure blood serum. The platform that we implemented comprises readily mass-manufacturable components that exploit colorimetric changes of cholesterol oxidase and cholesterol esterase reactions. We have shown that our quantification results are comparable to that obtained by a bench top spectrophotometer. Using the implemented device, we have measured cholesterol concentration in human blood serum as low as 29 μM with a limit of detection at 13 μM, which is approximately 400 times lower than average physiological range, implying that our device also has the potential to be used for applications that require greater sensitivity