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

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

Noise characteristics with CMOS sensor array scaling

An important consideration when scaling semiconductor sensor devices is the effect it may have on noise performance. Overall signal to noise ratio can be improved both by increasing sensor size, or alternatively by averaging the signal from two or more smaller sensors. In the design of sensor systems it is not immediately clear which is the best strategy to pursue. In this paper, we present a detailed theoretical and experimental study based on three different sensor arrays that show that an array of small independent sensors is always less noisy than a large sensor of the same size

Capsule endoscopy compatible fluorescence imager demonstrated using bowel cancer tumours

We demonstrate a proof of concept highly miniaturised fluorescence imager and its application to detecting cancer in resected human colon cancer tissues. Fluorescence imaging modalities have already been successfully implemented in traditional endoscopy. However, the procedure still causes discomfort and requires sedation. Wireless fluorescence capsule endoscopy has the potential to improve diagnostic accuracy with less inconvenience for patients. In this paper we present a 5 mm x 6 mm x 5 mm optical block that is small enough to integrate into a capsule endoscope. The block integrates ultrathin filters for optical isolation and was successfully integrated with a sensitive CMOS SPAD array to detect green fluorescence from Flavin Adenine Dinucleotide (FAD), which is an endogenous fluorophore responsible for autofluorescence in human tissues, and fluorescence from the cancer selective molecular probe ProteoGREENTM-gGlu used to label colorectal cancer cells. In vitro studies were validated using a commercial ModulusTM Microplate reader. The potential use of the device in capsule endoscopy was further validated by imaging healthy and malignant resected human tissues from the colon to detect changes in autofluorescence signal that are crucial for cancer diagnosis

A 64x64 SPAD array for portable colorimetric sensing, fluorescence and X-ray imaging

We present the design and application of a 64x64 pixel SPAD array to portable colorimetric sensing, and fluorescence and x-ray imaging. The device was fabricated on an unmodified 180 nm CMOS process and is based on a square p+/n active junction SPAD geometry suitable for detecting green fluorescence emission. The stand-alone SPAD shows a photodetection probability greater than 60% at 5 V excess bias, with a dark count rate of less than 4 cps/µm2 and sub-ns timing jitter performance. It has a global shutter with an in-pixel 8-bit counter; four 5-bit decoders and two 64-to-1 multiplexer blocks allow the data to be read-out. The array of sensors was able to detect fluorescence from a fluorescein isothiocyanate (FITC) solution down to a concentration of 900 pM with a SNR of 9.8 dB. A colorimetric assay was performed on top of the sensor array with a limit of quantification of 3.1 µM. X-rays images, using energies ranging from 10 kVp to 100 kVp, of a lead grating mask were acquired without using a scintillation crystal

The Multicorder: A Handheld Multimodal Metabolomics-on-CMOS Sensing Platform

The use of CMOS platforms in medical point-of-care applications, by integrating all steps from sample to data output, has the potential to reduce the diagnostic cost and the time from days to seconds. Here we present the `Multicorder' technology, a handheld versatile multimodal platform for rapid metabolites quantification. The current platform is composed of a cartridge, a reader and a graphic user interface. The sensing core of the cartridge is the CMOS chip which integrates a 16×16 array of multi-sensor elements. Each element is composed of two optical and one chemical sensor. The platform is therefore capable of performing multi-mode measurements: namely colorimetric, chemiluminescence, pH sensing and surface plasmon resonance. In addition to the reader that is employed for addressing, data digitization and transmission, a tablet computer performs data collection, visualization, analysis and storage. In this paper, we demonstrate colorimetric, chemiluminescence and pH sensing on the same platform by on-chip quantification of different metabolites in their physiological range. The platform we have developed has the potential to lead the way to a new generation of commercial devices in the footsteps of the current commercial glucometers for quick multi-metabolite quantification for both acute and chronic medicines

Multimodal integrated sensor platform for rapid biomarker detection

Precision metabolomics and quantification for cost-effective, rapid diagnosis of disease are key goals in personalized medicine and point-of-care testing. Presently, patients are subjected to multiple test procedures requiring large laboratory equipment. Microelectronics has already made modern computing and communications possible by integration of complex functions within a single chip. As More than Moore technology increases in importance, integrated circuits for densely patterned sensor chips have grown in significance. Here, we present a versatile single CMOS chip forming a platform to address personalized needs through on-chip multimodal optical and electrochemical detection that will reduce the number of tests that patients must take. The chip integrates interleaved sensing subsystems for quadruple-mode colorimetric, chemiluminescent, surface plasmon resonance and hydrogen ion measurements. These subsystems include a photodiode array and a single photon avalanche diode array, with some elements functionalized to introduce a surface plasmon resonance mode. The chip also includes an array of ion sensitive field effect transistors. The sensor arrays are distributed uniformly over an active area on the chip surface in a scalable and modular design. Bio-functionalization of the physical sensors yields a highly selective simultaneous multiple-assay platform in a disposable format. We demonstrate its versatile capabilities through quantified bioassays performed on-chip for glucose, cholesterol, urea and urate, each within their naturally occurring physiological range

Ultralow-light-level color image reconstruction using high-efficiency plasmonic metasurface mosaic filters

As single-photon imaging becomes progressively more commonplace in sensing applications such as low-light-level imaging, three-dimensional profiling, and fluorescence imaging, there exist a number of fields where multispectral information can also be exploited, e.g., in environmental monitoring and target identification. We have fabricated a high-transmittance mosaic filter array, where each optical filter was composed of a plasmonic metasurface fabricated in a single lithographic step. This plasmonic metasurface design utilized an array of elliptical and circular nanoholes, which produced enhanced optical coupling between multiple plasmonic interactions. The resulting metasurfaces produced narrow bandpass filters for blue, green, and red light with peak transmission efficiencies of 79%, 75%, and 68%, respectively. After the three metasurface filter designs were arranged in a 64×64 format random mosaic pattern, this mosaic filter was directly integrated onto a CMOS single-photon avalanche diode detector array. Color images were then reconstructed at light levels as low as approximately 5 photons per pixel, on average, via the simultaneous acquisition of low-photon multispectral data using both three-color active laser illumination and a broadband white-light illumination source

An integrated portable system for single chip simultaneous measurement of multiple disease associated metabolites

Metabolites, the small molecules that underpin life, can act as indicators of the physiological state of the body when their abundance varies, offering routes to diagnosis of many diseases. The ability to assay for multiple metabolites simultaneously will underpin a new generation of precision diagnostic tools. Here, we report the development of a handheld device based on complementary metal oxide semiconductor (CMOS) technology with multiple isolated micro-well reaction zones and integrated optical sensing allowing simultaneous enzyme-based assays of multiple metabolites (choline, xanthine, sarcosine and cholesterol) associated with multiple diseases. These metabolites were measured in clinically relevant concentration range with minimum concentrations measured: 25 μM for choline, 100 μM for xanthine, 1.25 μM for sarcosine and 50 μM for cholesterol. Linking the device to an Android-based user interface allows for quantification of metabolites in serum and urine within 2 min of applying samples to the device. The quantitative performance of the device was validated by comparison to accredited tests for cholesterol and glucose

A cross-sectional study evaluating hospitalization rates for chronic limb-threatening ischemia during the COVID-19 outbreak in Campania, Italy

The expansion of coronavirus disease 2019 (COVID-19) prompted measures of disease containment by the Italian government with a national lockdown on March 9, 2020. The purpose of this study is to evaluate the rate of hospitalization and mode of in-hospital treatment of patients with chronic limb-threatening ischemia (CLTI) before and during lockdown in the Campania region of Italy. The study population includes all patients with CLTI hospitalized in Campania over a 10-week period: 5 weeks before and 5 weeks during lockdown (n = 453). Patients were treated medically and/or underwent urgent revascularization and/or major amputation of the lower extremities. Mean age was 69.2 +/- 10.6 years and 27.6% of the patients were women. During hospitalization, 21.9% of patients were treated medically, 78.1% underwent revascularization, and 17.4% required amputations. In the weeks during the lockdown, a reduced rate of hospitalization for CLTI was observed compared with the weeks before lockdown (25 vs 74/100,000 inhabitants/year; incidence rate ratio: 0.34, 95% CI 0.32-0.37). This effect persisted to the end of the study period. An increased amputation rate in the weeks during lockdown was observed (29.3% vs 13.4%; p < 0.001). This study reports a reduced rate of CLTI-related hospitalization and an increased in-hospital amputation rate during lockdown in Campania. Ensuring appropriate treatment for patients with CLTI should be prioritized, even during disease containment measures due to the COVID-19 pandemic or other similar conditions