Objective: The detection of metabolites such as choline in blood are important in clinical care for patients with cancer and cardiovascular disease. Choline is only present in human blood at low concentrations hence accurate measurement in an affordable point-of-care format is extremely challenging. Although complementary metal-oxide semiconductor (CMOS) and microfluidics are individually mature technologies, their integration has presented challenges that we overcome in a novel, cost-effective, single-step process. Methods: To demonstrate the process, we present the microfluidic integration of a metabolomics-on-CMOS point-of-care platform with four capillary microfluidic channels on top of a CMOS optical sensor array. Results: The fabricated device was characterised to verify the required structural profile, mechanical strength, optical spectra, and fluid flow. As a proof of concept, we used the device for the in-vitro quantification of choline in human blood plasma with a limit of detection of 3.2 μM and a resolution of 1.6 μM. Significance: Integration of microfluidics on to CMOS technology has the potential to enable advanced sensing technologies with extremely low limit of detection that are well suited to multiple clinical metabolite measurements.

There is a global unmet need for rapid and cost-effective prognostic and diagnostic tools that can be used at the bedside or in the doctor’s office to reduce the impact of serious disease. Many cancers are diagnosed late, leading to costly treatment and reduced life expectancy. With prostate cancer, the absence of a reliable test has inhibited the adoption of screening programs. We report a microelectronic point-of-care metabolite biomarker measurement platform and use it for prostate cancer detection. The platform, using an array of photodetectors configured to operate with targeted, multiplexed, colorimetric assays confined in monolithically integrated passive microfluidic channels, completes a combined assay of 4 metabolites in a drop of human plasma in under 2 min. A preliminary clinical study using l-amino acids, glutamate, choline, and sarcosine was used to train a cross-validated random forest algorithm. The system demonstrated sensitivity to prostate cancer of 94% with a specificity of 70% and an area under the curve of 0.78. The technology can implement many similar assay panels and hence has the potential to revolutionize low-cost, rapid, point-of-care testing.

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 × 6 mm × 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.

Objective: Early stage diagnosis of sepsis without overburdening health services is essential to improving patient outcomes. Methods: A fast and simple-to-use platform that combines an integrated circuit with paper microfluidics for simultaneous detection of multiple-metabolites appropriate for diagnostics was presented. Paper based sensors are a primary candidate for widespread deployment of diagnostic or test devices. However, the majority of devices today use a simple paper strip to detect a single marker using the reflectance of light. However, for many diseases such as sepsis, one biomarker is not sufficient to make a unique diagnosis. In this work multiple measurements are made on patterned paper simultaneously. Using laser ablation to fabricate microfluidic channels on paper provides a flexible and direct approach for mass manufacture of disposable paper strips. A reusable photodiode array on a complementary metal oxide semiconductor chip is used as the transducer. Results: The system measures changes in optical absorbance in the paper to achieve a cost-effective and easily implemented system that is capable of multiple simultaneous assays. Potential sepsis metabolite biomarkers glucose and lactate have been studied and quantified with the platform, achieving sensitivity within the physiological range in human serum. Conclusion: We have detailed a disposable paper-based CMOS photodiode sensor platform for real-time simultaneous detection of metabolites for diseases such as sepsis. Significance: A combination of a low-cost paper strip with microfluidic channels and a sensitive CMOS photodiode sensor array makes our platform a robust portable and inexpensive biosensing device for multiple diagnostic tests in many different applications.

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. (C) 2019 The Authors. Published by Elsevier Ltd.

We present the design and application of a 64 x 64 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/mu m(2) and sub-ns timing jitter performance. It has a global shutter with an in-pixel 8-hit 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 an SNR of 9.8 dB. A colorimetric assay was performed on top of the sensor array with a limit of quantification of 3.1 mu m. X-rays images, using energies ranging from 10 kVp to 100 kVp, of a lead grating mask were acquired without using a scintillation crystal.

Precision metabolomics and quantification for cost-effective rapid diagnosis of disease are the key goals in personalized medicine and point-of-care testing. At present, 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 complementary metal-oxide-semiconductor 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 bio-assays performed on-chip for glucose, cholesterol, urea, and urate, each within their naturally occurring physiological range.

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 16x16 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.

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/μm 2 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.

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.

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 $\mu \text{m}$ ) 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.

The authors have developed a wireless fluorescence imaging capsule endoscope, potentially capable of detecting early signs of disease in the human intestine which can be missed by white-light imaging (WLI) capsule endoscopy (Figure 1). Intestinal fluorescence imaging exploits variations in tissue autofluorescence between healthy and diseased areas in response to illumination, or application of fluorescent labels which preferentially bind to diseased sites. To validate the capsule’s capability to image fluorescently-labelled tissue, a small area of a sample of ex vivo porcine small intestine was sonicated with 6 nm CdZnMg fluorescent quantum dots, and the labelled area clearly differentiated from surrounding tissue by the fluorescence imaging capsule.

The measurement of nanophotonic sensors currently requires the use of external measuring equipment for their read-out such as an optical spectrum analyzer, spectrophotometer, or detectors. This requirement of external laboratory-based measuring equipment creates a “chip-in-a-lab” dilemma and hinders the use of nanophotonic sensors in practical applications. Making nanophotonic sensors usable in everyday life requires miniaturization of not only the sensor chip itself but also the equipment used for its measurement. In this paper, we have removed the need of external measuring equipment by monolithically integrating 1-D grating structures with a complementary metal-oxide-semiconductor (CMOS) integrated circuit having an array of photodiodes. By doing so, we get a direct electrical read-out of the refractive index changes induced when applying different analytes to grating structures. The gratings are made of CMOS compatible silicon nitride. Employing a nanophotonic sensor made of CMOS compatible material allows fabrication of the integrated sensor chip in a commercial CMOS foundry, enabling mass production for commercialization with low cost. Our results present a significant step toward transforming present laboratory-based nanophotonic sensors into practical portable devices to enable applications away from the analytical laboratory. We anticipate the work will have a major impact on technology for personalized medicine, environmental, and industrial sensing.

Scalable immunoassay multiplexing offers a route to creating rapid point-of-care (POC) diagnostics. We present a method for multiplexing immunoassays on the surface of a complementary metal oxide semiconductor (CMOS) sensor array integrated circuit (IC) without the use of physical separators such as wells or channels. Major advantages of using a CMOS sensor array include low mass-manufacturing costs, the possibility to multiplex multiple assays on a single IC, and improved signal when averaging multiple sensors, along with providing a platform where wash steps can be incorporated to maximize selectivity and sensitivity compared to paper based lateral flow immunoassay. The device was able to differentiate between samples containing either, neither, or both rabbit anti-mouse (RAM) antibodies and/or anti-HIV gp120 antibodies in serum using a gold-nanoparticle promoted silver enhancement immunoassay. HIV antibody concentrations down to 100 μg/mL were readily detected, which is three times lower than those typically found in infected humans (300–500 μg/mL), and the limit of detection was 10 μg/mL.

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.

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.

Video capsule endoscopy (VCE) is now a clinically accepted diagnostic modality in which miniaturized technology, an on-board power supply and wireless telemetry stand as technological foundations for other capsule endoscopy (CE) devices. However, VCE does not provide therapeutic functionality, and research towards therapeutic CE (TCE) has been limited. In this paper, a route towards viable TCE is proposed, based on multiple CE devices including important acoustic sensing and drug delivery components. In this approach, an initial multimodal diagnostic device with high-frequency quantitative microultrasound that complements video imaging allows surface and subsurface visualization and computer-assisted diagnosis. Using focused ultrasound (US) to mark sites of pathology with exogenous fluorescent agents permits follow-up with another device to provide therapy. This is based on an US-mediated targeted drug delivery system with fluorescence imaging guidance. An additional device may then be utilized for treatment verification and monitoring, exploiting the minimally invasive nature of CE. While such a theranostic patient pathway for gastrointestinal treatment is presently incomplete, the description in this paper of previous research and work under way to realize further components for the proposed pathway suggests it is feasible and provides a framework around which to structure further work.