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

Dielectrophoresis based discrimination of human embryonic stem cells from differentiating derivatives

Assessment of the dielectrophoresis(DEP) cross-over frequency (f xo), cell diameter, and derivative membranecapacitance (C m) values for a group of undifferentiated human embryonic stem cell (hESC) lines (H1, H9, RCM1, RH1), and for a transgenic subclone of H1 (T8) revealed that hESC lines could not be discriminated on their mean f xo and C m values, the latter of which ranged from 14 to 20 mF/m2. Differentiation of H1 and H9 to a mesenchymal stem cell-like phenotype resulted in similar significant increases in mean C m values to 41–49 mF/m2 in both lines (p < 0.0001). BMP4-induced differentiation of RCM1 to a trophoblast cell-like phenotype also resulted in a distinct and significant increase in mean C m value to 28 mF/m2 (p < 0.0001). The progressive transition to a higher membranecapacitance was also evident after each passage of cell culture as H9 cells transitioned to a mesenchymal stem cell-like state induced by growth on a substrate of hyaluronan. These findings confirm the existence of distinctive parameters between undifferentiated and differentiating cells on which future application of dielectrophoresis in the context of hESC manufacturing can be based

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

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

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

Dielectrophoretic study of human embryonic stem cells and their differentiated progeny

This thesis describes for the first time, how the membrane capacitance of pluripotent human embryonic stem cells (H1, H9, RCM1) increases with their differentiation (H1-MSC, H9-MSC, RCM1-trophoblast) based on the literature review. The method used to determine membrane capacitance was dielectrophoresis (DEP), which is an electrokinetic technique capable of characterising and sorting cells without the need for antibody-based cell surface markers, magnetic beads, or other chemical tags. This finding has potential biomedical importance because human embryonic stem cell (hESCs) isolated from early blastocyst-stage embryos and differentiated progeny have been identified to be of possible use in drug screening and regenerative cell based therapeutic treatment. Current cell sorting methods require membrane surface markers that limit their applicability in stem cell therapeutics, a limitation that is either removed or reduced if DEP-based sorting was used. The work described in this thesis consists of the design, fabrication and testing of DEP based microfluidic devices for characterization and separation of human embryonic stem cells. The cells studied were human undifferentiated hESC lines (H1, H9, RCM1, RH1, and T8) and their differentiated progeny (H1-MSC, H9-MSC, RCM1-trophoblast, hES-MP). The cell membrane capacitance (Cm) of the cells was determined by measuring a parameter known as the DEP cross-over frequency (fxo), where the electrical polarisability of a cell equals that of its suspending electrolyte and so experiences no DEP force. The studies of hESC lines cultured from different sources indicate, on the basis of their similar Cm values, that they have similar membrane morphologies. The change in calculated Cm value upon differentiation of these hESCs indicates that changes occur in their membrane morphology, texturing and possibly of their membrane thickness. Subsequent enrichment of these hESCs from human dermal fibroblasts (hDFs) has been achieved based on fxo measurements. The results presented in this thesis confirm the existence, previously indicated in the literature, of distinctive parameters for undifferentiated and differentiating cells on which future application of DEP in hESC manufacturing can be based