A portable metabolomics-on-CMOS platform for point-of-care testing

Metabolomics is the study of the metabolites, small molecules produced during the metabolism. Metabolite levels mirror the health status of an individual and therefore have enormous potential in medical point-of-care (POC) applications. POC platforms are miniaturised and portable systems integrating all steps from sample collection to result of a medical test. POC devices offer the possibility to reduce the diagnostic costs, shorten the testing time, and, ultimately, save lives for several applications. The glucose meter, arguably the most successful example of metabolomics POC platform, has already demonstrated the dramatic impact that such platforms can have on the society. Nevertheless, other relevant metabolomic tests are still relegated to centralised laboratories and bulky equipment. In this work, a metabolomics POC platform for multi-metabolite quantification was developed. The platform aims to untap metabolomics for the general population. As case studies, the platform was designed and evaluated for prostate cancer and ischemic stroke. For prostate cancer, new affordable diagnostic tools to be used in conjunction with the current clinical standard have are needed to reduce the medical costs due to overdiagnosis and increase the survival rate. Thus, a novel potential metabolic test based on L-type amino acids (LAA) profile, glutamate, choline, and sarcosine blood concentrations was developed. For ischemic stroke, where the portable and rapid test can make a difference between life and death, lactate and creatinine blood levels were chosen as potential biomarkers. All the target metabolites were quantified using an optical method (colorimetry). The platform is composed of three units: the cartridge, the reader, and the graphical user interface (GUI). The cartridge is the core of the platform. It integrates a CMOS 16x16 array of photodiodes, capillary microfluidics, and biological receptors onto the same ceramic package. To measure multiple metabolites, a novel method involving a combination of replica moulding and injection moulding was developed for the monolithic integration of microfluidics onto integrated chips. The reader is composed of a custom PCB and a microcontroller board. It is used for addressing, data digitisation and data transfer to the GUI. The GUI - a software running on a portable electronic device - is used for interfacing the system, visualise, acquire, process, and store the data. The analysis of the microfluidic structures showed successful integration. The selection of the specific chemistry for detecting the analytes of interest was demonstrated to be suitable for the performance of the sensors. Quick and reliably capillary flow of human plasma, serum and blood was demonstrated. On-chip quantification of the target metabolites was demonstrated in diluted human serum and human plasma. Calibration curves, kinetics parameter and other relevant metrics were determined. For all the metabolites, the limits of detection were lower than the physiological range, demonstrating the capability of the platform to be used in the target applications. Multi-metabolite testing capability was also demonstrated using commercially and clinically sourced human plasma. For multiplexed assays, reagents were preloaded in the microfluidic channel and lyophilised. Lyophilisation also improved the shelf-life of the reagents. Alternative configurations, involving the use of paper microfluidics, integration of passive blood filter and use of whole blood, were investigated. The chracterisation of the platform culminated with a clinical evaluation for both the target applications. The same platform with minimal modification of the cartridge was able to provide clinically relevant information for both the distinct applications, highlighting the versatility of the platform for POC determination of metabolic biomarkers. For prostate cancer, the platform was used for the quantification of the potential metabolic biomarker in 10 healthy samples and 16 patients affected by prostate cancer. LAA, glutamate and choline average concentrations were elevated in the cancer group with respect to the control group and were therefore regarded as metabolic biomarkers in this population. Metabolomic profiles were used to train a classifier algorithm, which improved the performance of the current clinical blood test, for this population. For ischemic stroke, lactate determination was performed in clinically sourced samples. Clinical evaluation for ischemic stroke was performed using 10 samples from people diagnosed with ischemic stroke. Results showed that the developed platform provided comparable results with an NHS-based gold standard method in this population. This comparison demonstrated the potential of the platform for its on-the-spot use. The developed platform has the potential to lead the way to a new generation of low-cost and rapid POC devices for the early and improved diagnosis of deadly diseases

A cybersecure P300-based brain-to-computer interface against noise-based and fake P300 cyberattacks

In a progressively interconnected world where the internet of things (IoT), ubiquitous computing, and artificial intelligence are leading to groundbreaking technology, cybersecurity remains an underdeveloped aspect. This is particularly alarming for brain-to-computer interfaces (BCIs), where hackers can threaten the user’s physical and psychological safety. In fact, standard algorithms currently employed in BCI systems are inadequate to deal with cyberattacks. In this paper, we propose a solution to improve the cybersecurity of BCI systems. As a case study, we focus on P300-based BCI systems using support vector machine (SVM) algorithms and EEG data. First, we verified that SVM algorithms are incapable of identifying hacking by simulating a set of cyberattacks using fake P300 signals and noise-based attacks. This was achieved by comparing the performance of several models when validated using real and hacked P300 datasets. Then, we implemented our solution to improve the cybersecurity of the system. The proposed solution is based on an EEG channel mixing approach to identify anomalies in the transmission channel due to hacking. Our study demonstrates that the proposed architecture can successfully identify 99.996% of simulated cyberattacks, implementing a dedicated counteraction that preserves most of BCI functions

Disposable paper-on-CMOS platform for real-time simultaneous detection of metabolites

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

Factor VIII companion diagnostic for haemophilia

Haemophilia is predominantly an inherited disorder that impairs the body’s ability to make blood clots, a process needed to stop bleeding. The condition of this disease is complex to manage, but many patients do so through home therapy and often only see their core multidisciplinary healthcare team annually. There is an increasing need for patients to be able to monitor their condition efficiently at home while staying connected with their healthcare team. As a consequence, a low-cost handheld self-monitoring solution for clotting factor is required. Here we have demonstrated a suitable one-step Factor VIII companion diagnostic sensing approach based on a chromogenic assay for haemophilia A. The results show comparable performance to the gold standard method. Our approach is able to deliver accurate cost-effective results in under 5 min from undiluted human plasma. It has the potential to be able to reduce the human and monetary costs of over- or under-medication for haemophiliacs

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

Micromolar metabolite measurement in an electronically multiplexed format

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. Integration of microfluidics on to complementary metal-oxide semiconductor (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. Although CMOS and microfluidics are individually mature technologies, their integration has presented challenges that we overcome in a novel, cost-effective, single-step process. 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. 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 M and a resolution of 1.6 M

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