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.

[1]  D. Blumenthal,et al.  Effects of pH, ionic strength, and temperature on activation by calmodulin an catalytic activity of myosin light chain kinase. , 1982, Biochemistry.

[2]  P. Bergveld The operation of an ISFET as an electronic device , 1981 .

[3]  C. Frost,et al.  A Metabolic Study of Huntington’s Disease , 2016, PloS one.

[4]  D. Mann,et al.  Novel Metabolite Biomarkers of Huntington's Disease As Detected by High-Resolution Mass Spectrometry. , 2016, Journal of proteome research.

[5]  D. Schomburg,et al.  GC–MS libraries for the rapid identification of metabolites in complex biological samples , 2005, FEBS letters.

[6]  H. Ha,et al.  Simultaneous determination of liquiritin, hesperidin, and glycyrrhizin by HPLC-photodiode array detection and the anti-inflammatory effect of Pyungwi-san , 2011, Archives of pharmacal research.

[7]  Cynthia K Larive,et al.  NMR spectroscopy for metabolomics and metabolic profiling. , 2015, Analytical chemistry.

[8]  Effect of subthreshold slope on the sensitivity of nanoribbon sensors. , 2016, Nanotechnology.

[9]  Vassilios S. Vassiliadis,et al.  Discovery of metabolite biomarkers: flux analysis and reaction-reaction network approach , 2013, BMC Systems Biology.

[10]  Michael P. Barrett,et al.  An Integrated Circuit for Chip-Based Analysis of Enzyme Kinetics and Metabolite Quantification , 2016, IEEE Transactions on Biomedical Circuits and Systems.

[11]  Wei Wang,et al.  Identifying Metabolite and Protein Biomarkers in Unstable Angina In-patients by Feature Selection Based Data Mining Method , 2011 .

[12]  R. Bligny,et al.  NMR and plant metabolism. , 2001, Current opinion in plant biology.

[13]  Israel Hanukoglu Steroidogenic enzymes: Structure, function, and role in regulation of steroid hormone biosynthesis , 1992, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  A. Fernie,et al.  Gas chromatography mass spectrometry–based metabolite profiling in plants , 2006, Nature Protocols.

[15]  E. Dorsey,et al.  Altered cholesterol and fatty acid metabolism in Huntington disease. , 2010, Journal of clinical lipidology.

[16]  N. Sims,et al.  Mitochondria, oxidative metabolism and cell death in stroke. , 2010, Biochimica et biophysica acta.

[17]  Hillel W. Cohen,et al.  Glucose-Cholesterol Interaction Magnifies Coronary Heart Disease Risk for Hypertensive Patients , 2004, Hypertension.

[18]  H. Risch,et al.  Plasma Metabolite Biomarkers for the Detection of Pancreatic Cancer , 2014, Journal of proteome research.

[19]  R. Crystal,et al.  Serum Metabolite Biomarkers Discriminate Healthy Smokers from COPD Smokers , 2015, PloS one.

[20]  R G Shulman,et al.  Spatially localized 1H NMR spectra of metabolites in the human brain. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Lehmann,et al.  Simultaneous measurement of cellular respiration and acidification with a single CMOS ISFET. , 2001, Biosensors & bioelectronics.

[22]  Mark A. Reed,et al.  Direct, rapid, and label-free detection of enzyme-substrate interactions in physiological buffers using CMOS-compatible nanoribbon sensors. , 2014, Nano letters.

[23]  Fengguo Xu,et al.  Discovery of Metabolite Biomarkers for Acute Ischemic Stroke Progression. , 2017, Journal of proteome research.

[24]  Rajbir Singh,et al.  Production, purification and characterization of cholesterol oxidase from a newly isolated Streptomyces sp. , 2013, World journal of microbiology & biotechnology.

[25]  N. Bardeesy,et al.  Pancreatic Cancer Metabolism: Breaking It Down to Build It Back Up. , 2015, Cancer discovery.

[26]  K. Alton,et al.  Application of mass spectrometry for metabolite identification. , 2006, Current drug metabolism.

[27]  Josep Samitier,et al.  ISFET-based biosensor to monitor sugar metabolism in bacteria , 2008 .

[28]  Kai Sun,et al.  Low-Cost Nanoribbon Sensors for Protein Analysis in Human Serum Using a Miniature Bead-Based Enzyme-Linked Immunosorbent Assay. , 2016, Analytical chemistry.

[29]  James H. Brown,et al.  Effects of Size and Temperature on Metabolic Rate , 2001, Science.

[30]  E. Vartiainen,et al.  Serum cholesterol distribution and coronary heart disease risk: observations and predictions among middle-aged population in eastern Finland. , 1998, Circulation.

[31]  Wenyun Lu,et al.  Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry. , 2006, Journal of chromatography. A.

[32]  Jun Feng Xiao,et al.  Metabolite identification and quantitation in LC-MS/MS-based metabolomics. , 2012, Trends in analytical chemistry : TRAC.

[33]  R. Wolfenden,et al.  The Temperature Dependence of Enzyme Rate Enhancements , 1999 .

[34]  G. Siuzdak,et al.  The Expanding Role of Mass Spectrometry in Metabolite Profiling and Characterization , 2005, Chembiochem : a European journal of chemical biology.

[35]  David R. S. Cumming,et al.  A Colorimetric CMOS-Based Platform for Rapid Total Serum Cholesterol Quantification , 2017, IEEE Sensors Journal.

[36]  K. Veselkov,et al.  A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments , 2016, Computational and structural biotechnology journal.