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

Opportunities and challenges for biosensors and nanoscale analytical tools for pandemics: COVID-19

Biosensors and nanoscale analytical tools have shown a huge growth in literature in the past 20 years, with a large number of reports on the topic of ’ultra-sensitive’, ’costeffective’ and ’early-detection’ tools with a potential of ’mass-production’ cited on the web of science. Yet none of these tools are commercially available in the market or practically viable for mass production and use in pandemic diseases such as COVID-19. In this context, we review the technological challenges and opportunities of current bio/chemical sensors and analytical tools by critically analyzing the bottlenecks which have hindered the implementation of advanced sensing technologies in pandemic diseases. We also describe in brief COVID-19 by comparing it with other pandemic strains such as SARS and MERS for the identification of features that enable biosensing. Moreover, we discuss visualization and characterization tools that can potentially be used not only for sensing applications but also assist in speeding up the drug discovery and vaccine development process. Furthermore, we discuss the emerging monitoring mechanism, namely wastewater-based epidemiology, for early warning of the outbreak, focusing on sensors for rapid and on-site analysis of SARS-COV-2 in sewage. To conclude, we provide holistic insights into challenges associated with the quick translation of sensing technologies, policies, ethical issues, technology adoption, and an overall outlook of the role of the sensing technologies in pandemics

A Flexible, Highly Integrated, Low Power pH Readout

Medical devices are widely employed in everyday life as wearable and implantable technologies make more and more technological breakthroughs. Implantable biosensors can be implanted into the human body for monitoring of relevant physiological parameters, such as pH value, glucose, lactate, CO2 [carbon dioxide], etc. For these applications the implantable unit needs a whole functional set of blocks such as micro- or nano-sensors, sensor signal processing and data generation units, wireless data transmitters etc., which require a well-designed implantable unit.Microelectronics technology with biosensors has caused more and more interest from both academic and industrial areas. With the advancement of microelectronics and microfabrication, it makes possible to fabricate a complete solution on an integrated chip with miniaturized size and low power consumption.This work presents a monolithic pH measurement system with power conditioning system for supply power derived from harvested energy. The proposed system includes a low-power, high linearity pH readout circuits with wide pH values (0-14) and a power conditioning unit based on low drop-out (LDO) voltage regulator. The readout circuit provides square-wave output with frequency being highly linear corresponding to the input pH values. To overcome the process variations, a simple calibration method is employed in the design which makes the output frequency stay constant over process, supply voltage and temperature variations. The prototype circuit is designed and fabricated in a standard 0.13-μm [micro-meter] CMOS process and shows good linearity to cover the entire pH value range from 0-14 while the voltage regulator provides a stable supply voltage for the system

CMOS MULTI-MODAL INTEGRATED SYSTEMS FOR FUTURE BIOELECTRONICS AND BIOSENSORS

Cells are the basic structural biological units of all known living organisms. They are highly sophisticated system with thousands of molecules operating in hundreds of pathways to maintain their proper functions, phenotypes, and physiological behaviors. With this scale of complexity, cells often exhibit multi-physiological properties as their cellular fingerprints from external stimulations. In order to further advance the frontiers in bioscience and biotechnologies such as stem cell manufacturing, synthetic biology, and regenerative medicine, it is required to comprehend complex cell physiology of living cells. Therefore, a comprehensive set of technologies is needed to harvest quantitative biological data from given cell samples. Such demands have stimulated extensive research on new bioelectronics and biosensors to characterize their functional information by converting their biological activities to electrical signals. As a result, various bioelectronics and biosensors are reported and employed in many in vivo and in vitro applications. Since sensing electrodes of the devices are physically in touch with biological/chemical samples and record their signals, long-term biocompatibility and chemical/mechanical stability is of paramount importance in numerous biological applications. Furthermore, the devices should achieve high sensitivity/resolution/linearity, large field-of-view (FoV), multi-modal sensing, and real-time monitoring, while maintaining small feature size of devices to use small volume of biological/chemical samples and reduce cost. As a result, My Ph.D research aims to study interfacial electrochemical impedance spectroscopy (EIS) of electrodes with different combination of materials/sizes and to design novel multi-modal sensing/actuation array architectures with CMOS compatible in-house post-processing to address the design challenges of the bioelectronics and biosensors.Ph.D

COVID-9 Detection Strategies: Recent Advances and Future Prospects

COVID-19 pandemic has created a global medical and economic crisis. Having many unsuspecting asymptotically carriers interacting with others increases the risk of infecting healthy people which leads to problems such as overloaded clinics and hospitals. These conditions make tracing the asymptotic carriers of COVID-19 and detecting all infected individuals rapidly and accurately critical for the control and further prevention of this disease. Considering the long duration of vaccine development, their low efficiency for protection against some of the viral variants, and lack of any drugs for efficient COVID-19 treatment, diagnostic tests are essential for detecting the infection and limiting the viral spread. Therefore, how to efficiently screen for positive patients with coronavirus 2019 has become the primary task for epidemic prevention. Due to the critical roles of the diagnostic tools in fighting the coronavirus disease, a large number of techniques have rapidly. This work, as a comprehensive review, aims to cover not only the currently approved nucleic acid- and protein-based diagnostic technologies, but also the promising strategies for COVID-19 detection and also fighting future hazards. The goal is to bring together the most important advances from the broad discipline of biomedical engineering, enhancing their visibility through opinion and new articles, and providing overviews of the state-of-the-art in each field

Ταυτοποίηση και μελέτη της έκφρασης νέων εναλλακτικών μεταγράφων του ανθρώπινου γονιδίου της κυκλινοεξαρτώμενης κινάσης 4 (CDK4) σε καρκινικά κύτταρα με χρήση μεθοδολογιών μαζικής παράλληλης αλληλούχησης

Το γονίδιο CDK4 είναι μέλος της οικογένειας των κυκλινοεξαρτώμενων κινασών, η οποία έχει εξαιρετικά σημαντικό ρόλο στα μονοπάτια σηματοδότησης του κυττάρου, τη ρύθμιση της μεταγραφής και την κυτταρική διαίρεση. Η ελαττωματική δράση του συμπλόκου που δημιουργεί η κινάση με την κυκλίνη D1, ενδέχεται να οδηγεί σε ενίσχυση του κυτταρικού πολλαπλασιασμού και επομένως να εμπλέκεται στην καρκινογένεση. Παρά το γεγονός ότι ο βιολογικός ρόλος του γονιδίου CDK4 έχει μελετηθεί σε μεγάλο βαθμό, ο μηχανισμός που αφορά την ωρίμανση των πρόδρομων mRNA μορίων, τόσο σε φυσιολογικές όσο και παθολογικές καταστάσεις, δεν έχει διερευνηθεί. Επομένως, η ταυτοποίηση πιθανών νέων εναλλακτικών μεταγράφων του γονιδίου CDK4, ειδικά εκείνων που κωδικοποιούν για πρωτεινες, θα μπορούσε να οδηγήσει στο χαρακτηρισμό νέων διαγνωστικών ή/και προγνωστικών βιοδεικτών ή νέων θεραπευτικών στόχων. Στην παρούσα διπλωματική εργασία, σχεδιάστηκε και εφαρμόστηκε μια στοχευμένη μέθοδος αλληλούχησης με τη χρήση της τεχνολογίας του νανοπόρου, με την οποία επιτεύχθηκε εξαιρετικά υψηλό βάθος ανάγνωσης και εκτεταμένη διερεύνηση νέων πιθανών CDK4 mRNA μορίων. Εξαιτίας του αυξημένου ποσοστού λαθών που συμβαίνουν κατά την αλληλούχηση μέσω νανοπόρων, η πειραματική επιβεβαίωση των αποτελεσμάτων πραγματοποιήθηκε με αντίδραση αλληλούχησης νέας γενιάς και πιο συγκεκριμένα με χρήση της τεχνολογίας αλληλούχησης μέσω ημιαγωγού. Η παρούσα διπλωματική εργασία αποσαφηνίζει για πρώτη φορά το περίπλοκο μεταγραφικό προφίλ του ανθρώπινου γονιδίου CDK4, αποκαλύπτωντας την παρουσία άγνωστων εναλλακτικών μεταγράφων που προέρχονται από νέα γεγονότα εναλλακτικής συρραφής. Παράλληλα, η μελέτη της μεταφραστικής ικανότητας των νέων μεταγράφων οδήγησε στο συμπέρασμα πως η πλειοψηφία των νέων μορίων mRNAs διαθέτουν ανοιχτό πλαίσιο ανάγνωσης και συνεπώς προβλέπεται να κωδικοποιούν νέες πρωτεϊνικές ισομορφές. Επιπλέον, πραγματοποιήθηκε μελέτη του προφίλ έκφρασης των νέων CDK4 μεταγράφων σε ανθρώπινες καρκινικές κυτταρικές σειρές με τη χρήση ποσοτικής PCR σε πραγματικό χρόνο. Το ευρύ φάσμα των εναλλακτικών μεταγράφων του γονιδίου CDK4 (CDK4 v.2 – v.42) αποτελεί το πρώτο βήμα για την συναρμολόγηση των κομματίων που θα αποκαλύψουν την εμπλοκή της κινάσης στην κυτταρική ομοιόσταση και την παθοφυσιολογία.CDK4 is a member of the cyclin-dependent kinases, a family of protein kinases with outstanding roles in signalling pathways, transcription regulation and cell division. Defective or overactivated CDK4/cyclin D1 pathway leads to enhanced cellular proliferation, thus being implicated in human cancers. Although the biological role of CDK4 has been extensively studied, its pre-mRNA processing mechanism under normal or pathological conditions is neglected. Thus, the identification of novel CDK4 mRNA transcripts, especially protein-coding ones, could lead to the identification of new diagnostic and/or prognostic biomarkers or new therapeutic targets. In the present study, instead of using the “gold-standard” direct RNA sequencing application, a targeted nanopore sequencing approach was designed and employed, which offered a tremendously higher sequencing depth and enabled the thorough investigation of new putative CDK4 mRNAs. Due to the notable error rates of nanopore sequencing, validation of the results was carried out with next-generation sequencing based on the semi-conductor technology. The present study elucidates for the first time the complex transcriptional landscape of the human CDK4 gene, highlighting the existence of previously unknown CDK4 transcripts with new alternative splicing events and protein-coding capacities. The relative expression levels of each novel CDK4 transcript in human malignancies were elucidated with custom qPCR-based assays. The presented wide spectrum of CDK4 transcripts (CDK4 v.2 – v.42) is only the first step to distinguish and assemble the missing pieces regarding the exact functions and implications of this fundamental kinase in cellular homeostasis and pathophysiology