{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T09:26:16Z","timestamp":1777627576025,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T00:00:00Z","timestamp":1564704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sensors"],"abstract":"<jats:p>In this paper, we demonstrate the possibility of direct protein sensing beyond the Debye length limit using a molecular-charge-contact (MCC)-based ion-sensitive field-effect transistor (ISFET) sensor combined with a microfluidic device. Different from the MCC method previously reported, biotin-coated magnetic beads are set on the gate insulator of an ISFET using a button magnet before the injection of target molecules such as streptavidin. Then, the streptavidin\u2014a biotin interaction, used as a model of antigen\u2014antibody reaction is expected at the magnetic beads\/gate insulator nanogap interface, changing the pH at the solution\/dielectric interface owing to the weak acidity of streptavidin. In addition, the effect of the pH or ionic strength of the measurement solutions on the electrical signals of the MCC-based ISFET sensor is investigated. Furthermore, bound\/free (B\/F) molecule separation with a microfluidic device is very important to obtain an actual electrical signal based on the streptavidin\u2013biotin interaction. Platforms based on the MCC method are suitable for exploiting the advantages of ISFETs as pH sensors, that is, direct monitoring systems for antigen\u2013antibody reactions in the field of in vitro diagnostics.<\/jats:p>","DOI":"10.3390\/s19153393","type":"journal-article","created":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T11:58:16Z","timestamp":1564747096000},"page":"3393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Molecular-Charge-Contact-Based Ion-Sensitive Field-Effect Transistor Sensor in Microfluidic System for Protein Sensing"],"prefix":"10.3390","volume":"19","author":[{"given":"Haoyue","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1246-5000","authenticated-orcid":false,"given":"Toshiya","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1109\/TBME.1970.4502688","article-title":"Development of an Ion-Sensitive Solid-State Device for Neurophysiological Measurements","volume":"BME-17","author":"Bergveld","year":"1970","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1109\/TBME.1972.324137","article-title":"Development, Operation, and Application of the Tool for Electrophysiology","volume":"BME-19","author":"Bergveld","year":"1972","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1109\/TBME.1974.324338","article-title":"An Integrated Field-Effect Electrode for Biopotential Recording","volume":"BME-21","author":"Matsuo","year":"1974","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1109\/TBME.1978.326245","article-title":"Integrated Micro-Multi-Ion Sensor Using Field Effect of Semiconductor","volume":"BME-25","author":"Esashi","year":"1978","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"ref_5","unstructured":"Cheung, P.W. (1978). Technical Difficulties Remaining to the Application of ISFET Devices, Theory Design and Biomedical Applications of Solid State Chemical Sensors, CRC Press."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1002\/bbpc.192400182","article-title":"Zur Theorie der Elektrolytischen Doppelschicht","volume":"30","author":"Stern","year":"1924","journal-title":"Zeitschrift f\u00fcr Elektrochemie und Angewandte Physikalische Chemie"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0956-5663(90)80002-U","article-title":"A New Approach to ImmunoFET Operation","volume":"5","author":"Schasfoort","year":"1990","journal-title":"Biosens. Bioelectron."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0003-2670(00)80554-1","article-title":"Possibilities and Limitations of Direct Detection of Protein Charges by Means of an Immunological Field-Effect Transistor","volume":"238","author":"Schasfoort","year":"1990","journal-title":"Anal. Chim. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0956-5663(91)85009-L","article-title":"A Critical Evaluation of Direct Electrical Protein Detection Methods","volume":"6","author":"Bergveld","year":"1991","journal-title":"Biosens. Bioelectron."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1021\/jp963056h","article-title":"Direct Detection of the Hybridization of Synthetic Homo-Oligomer DNA Sequences by Field Effect","volume":"101","author":"Souteyrand","year":"1997","journal-title":"J. Phys. Chem. B"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0925-4005(00)00468-8","article-title":"A DNA Diagnostic Biosensor: Development, Characterisation and Performance","volume":"68","author":"Berney","year":"2000","journal-title":"Sens. Actuators B Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14142","DOI":"10.1073\/pnas.232276699","article-title":"Electronic Detection of DNA by Its Intrinsic Molecular Charge","volume":"99","author":"Fritz","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1039\/B204444G","article-title":"Recent Advances in Biologically Sensitive Field-Effect Transistors (BioFETs)","volume":"127","author":"Poghossian","year":"2002","journal-title":"Analyst"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/j.bios.2004.01.019","article-title":"Labelfree Fully Electronic Nucleic Acid Detection System Based on a Field-Effect Transistor Device","volume":"19","author":"Uslu","year":"2004","journal-title":"Biosens. Bioelectron."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/cbic.200400253","article-title":"Potentiometric Detection of Single Nucleotide Polymorphism Using Genetic Field Effect Transistor","volume":"6","author":"Sakata","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1002\/anie.200503154","article-title":"DNA Sequencing Based on Intrinsic Molecular Charges","volume":"45","author":"Sakata","year":"2006","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.bios.2006.05.031","article-title":"Direct Transduction of Primer Extension into Electrical Signal Using Genetic Field Effect Transistor","volume":"22","author":"Sakata","year":"2007","journal-title":"Biosens. Bioelectron."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2834","DOI":"10.1016\/j.bios.2006.11.019","article-title":"Label-Free Detection of Single Nucleotide Polymorphisms Utilizing the Differential Transfer Function of Field-Effect Transistors","volume":"22","author":"Ingebrandt","year":"2007","journal-title":"Biosens. Bioelectron."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s00249-014-0948-y","article-title":"Molecular Charge Contact Biosensing Based on the Interaction of Biologically Modified Magnetic Beads with an Ion-Sensitive Field Effect Transistor","volume":"43","author":"Miyazawa","year":"2014","journal-title":"Eur. Biophys. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10130","DOI":"10.1039\/C8NR02950D","article-title":"Elucidation of interfacial pH behaviour at cell\/substrate nanogap for in situ monitoring of cellular respiration","volume":"10","author":"Satake","year":"2018","journal-title":"Nanoscale"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12731","DOI":"10.1021\/acs.analchem.8b03070","article-title":"Live Monitoring of Microenvironmental pH Based on Extracellular Acidosis around Cancer Cells with Cell-Coupled Gate Ion-Sensitive Field-Effect Transistor","volume":"90","author":"Sakata","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_22","first-page":"185","article-title":"Zur Theorie der Elektrolyte","volume":"24","author":"Debye","year":"1923","journal-title":"Physikalische Zeitschrift"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature05498","article-title":"Label-Free Immunodetection with CMOS-Compatible Semiconducting Nanowires","volume":"445","author":"Stern","year":"2007","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1021\/nl071792z","article-title":"Importance of the Debye Screening Length on Nanowire Field Effect Transistor Sensors","volume":"7","author":"Stern","year":"2007","journal-title":"Nano Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/0371-1951(47)80005-0","article-title":"Die berechnung der nachweisempfindlichkeit","volume":"3","author":"Kaiser","year":"1947","journal-title":"Spectrochim. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/0003-2697(80)90610-7","article-title":"Ion Selective Electrode Estimation of Avidin and Biotin Using a Lysozyme Label","volume":"103","author":"Gebauer","year":"1980","journal-title":"Anal. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/0003-2697(85)90068-5","article-title":"A Fluorometric Assay for the Biotin-Avidin Interaction Based on Displacement of the Fluorescent Probe 2-Anilinonaphthalene-6-sulfonic Acid","volume":"151","author":"Mock","year":"1985","journal-title":"Anal. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1021\/ac00160a006","article-title":"Determination of Avidin and Biotin by Fluorescence Polarization","volume":"60","author":"Schray","year":"1988","journal-title":"Anal. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"64520","DOI":"10.1039\/C5RA05549K","article-title":"A Quartz Crystal Microbalance as a Tool for Biomolecular Interaction Studies","volume":"5","author":"Wu","year":"2015","journal-title":"RSC Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.bios.2016.07.054","article-title":"A Simple and Efficient Design to Improve the Detection of Biotin-Streptavidin Interaction with Plasmonic Nanobiosensors","volume":"86","author":"Focsan","year":"2016","journal-title":"Biosens. Bioelectron."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12918","DOI":"10.1021\/acs.analchem.7b03688","article-title":"Nonoptical Detection of Allergic Response with a Cell-Coupled Gate Field-Effect Transistor","volume":"89","author":"Yang","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Saito, A., and Sakata, T. (2019). Sperm-Cultured Gate Ion-Sensitive Field-Effect Transistor for Nonoptical and Live Monitoring of Sperm Capacitation. Sensors, 19.","DOI":"10.3390\/s19081784"}],"container-title":["Sensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8220\/19\/15\/3393\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:12:41Z","timestamp":1760188361000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8220\/19\/15\/3393"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,2]]},"references-count":32,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["s19153393"],"URL":"https:\/\/doi.org\/10.3390\/s19153393","relation":{},"ISSN":["1424-8220"],"issn-type":[{"value":"1424-8220","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,2]]}}}