{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T17:14:12Z","timestamp":1776446052930,"version":"3.51.2"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,7]],"date-time":"2018-10-07T00:00:00Z","timestamp":1538870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["268944"],"award-info":[{"award-number":["268944"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003406","name":"Tekes","doi-asserted-by":"publisher","award":["1427\/31\/2010"],"award-info":[{"award-number":["1427\/31\/2010"]}],"id":[{"id":"10.13039\/501100003406","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sensors"],"abstract":"<jats:p>A complementary metal-oxide-semiconductor (CMOS) chip biosensor was developed for cell viability monitoring based on an array of capacitance sensors utilizing a ring oscillator. The chip was packaged in a low temperature co-fired ceramic (LTCC) module with a flip chip bonding technique. A microcontroller operates the chip, while the whole measurement system was controlled by PC. The developed biosensor was applied for measurement of the proliferation stage of adherent cells where the sensor response depends on the ratio between healthy, viable and multiplying cells, which adhere onto the chip surface, and necrotic or apoptotic cells, which detach from the chip surface. This change in cellular adhesion caused a change in the effective permittivity in the vicinity of the sensor element, which was sensed as a change in oscillation frequency of the ring oscillator. The sensor was tested with human lung epithelial cells (BEAS-2B) during cell addition, proliferation and migration, and finally detachment induced by trypsin protease treatment. The difference in sensor response with and without cells was measured as a frequency shift in the scale of 1.1 MHz from the base frequency of 57.2 MHz. Moreover, the number of cells in the sensor vicinity was directly proportional to the frequency shift.<\/jats:p>","DOI":"10.3390\/s18103346","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T10:44:53Z","timestamp":1538995493000},"page":"3346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["LTCC Packaged Ring Oscillator Based Sensor for Evaluation of Cell Proliferation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-4727","authenticated-orcid":false,"given":"Joni","family":"Kilpij\u00e4rvi","sequence":"first","affiliation":[{"name":"Microelectronics Research Unit, University of Oulu, P.O. Box 4500, FI-90014 Oulu, Finland."}]},{"given":"Niina","family":"Halonen","sequence":"additional","affiliation":[{"name":"Microelectronics Research Unit, University of Oulu, P.O. Box 4500, FI-90014 Oulu, Finland."}]},{"given":"Maciej","family":"Sobocinski","sequence":"additional","affiliation":[{"name":"Microelectronics Research Unit, University of Oulu, P.O. Box 4500, FI-90014 Oulu, Finland."}]},{"given":"Antti","family":"Hassinen","sequence":"additional","affiliation":[{"name":"Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014 Oulu, Finland"}]},{"given":"Bathiya","family":"Senevirathna","sequence":"additional","affiliation":[{"name":"Department of Electrical &amp; Computer Engineering and the Institute for Systems Research, University of Maryland, College Park, MD 20742, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0314-4291","authenticated-orcid":false,"given":"Kajsa","family":"Uvdal","sequence":"additional","affiliation":[{"name":"Division of Molecular Surface Physics and Nanoscience, Department of Physics, Chemistry and Biology, Link\u00f6ping University, SE-58183 Link\u00f6ping, Sweden"}]},{"given":"Pamela","family":"Abshire","sequence":"additional","affiliation":[{"name":"Department of Electrical &amp; Computer Engineering and the Institute for Systems Research, University of Maryland, College Park, MD 20742, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3921-2265","authenticated-orcid":false,"given":"Elisabeth","family":"Smela","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering and the Institute for Systems Research, University of Maryland, College Park, MD 20742, USA"}]},{"given":"Sakari","family":"Kellokumpu","sequence":"additional","affiliation":[{"name":"Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014 Oulu, Finland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7876-8242","authenticated-orcid":false,"given":"Jari","family":"Juuti","sequence":"additional","affiliation":[{"name":"Microelectronics Research Unit, University of Oulu, P.O. Box 4500, FI-90014 Oulu, Finland."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2817-3574","authenticated-orcid":false,"given":"Anita","family":"Lloyd Spetz","sequence":"additional","affiliation":[{"name":"Division of Sensor and Actuator Systems, Department of Physics, Chemistry and Biology, Link\u00f6ping University, SE-58183 Link\u00f6ping, Sweden"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/nrd3799","article-title":"Revisiting lab-on-a-chip technology for drug discovery","volume":"11","author":"Giselbrecht","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1039\/C6LC01002D","article-title":"CMOS biosensors for in vitro diagnosis\u2014Transducing mechanisms and applications","volume":"16","author":"Lei","year":"2016","journal-title":"Lab Chip"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1109\/TCSI.2009.2015202","article-title":"A fully differential rail-to-rail CMOS capacitance sensor with floating-gate trimming for mismatch compensation","volume":"56","author":"Prakash","year":"2009","journal-title":"IEEE Trans. Circuits Syst. I"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1109\/TBCAS.2014.2336596","article-title":"A new fully differential CMOS capacitance to digital converter for lab-on-chip applications","volume":"9","author":"Nabovati","year":"2015","journal-title":"IEEE Trans. Biomed. Circuits Syst."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.bios.2007.12.015","article-title":"Tracking cancer cell proliferation on a CMOS capacitance sensor chip","volume":"23","author":"Prakash","year":"2008","journal-title":"Biosens. Bioelectron."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1109\/TBCAS.2015.2416372","article-title":"A 16 \u00d7 16 CMOS Capacitive Biosensor Array Towards Detection of Single Bacterial Cell","volume":"10","author":"Couniot","year":"2016","journal-title":"IEEE Trans. Biomed. Circuits Syst."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1021\/bp025733x","article-title":"On-line monitoring of cell growth and cytotoxicity using electric cell-substrate impedance sensing (ECIS)","volume":"19","author":"Xiao","year":"2003","journal-title":"Biotechnol. Prog."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1109\/JSSC.2015.2500362","article-title":"Oscillator-Based Reactance Sensors with Injection Locking for High-Throughput Flow Cytometry Using Microwave Dielectric Spectroscopy","volume":"51","author":"Chien","year":"2016","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_9","first-page":"159","article-title":"A capacitance-to-frequency converter with on-chip passivated microelectrodes for bacteria detection in saline buffers up to 575 MHz","volume":"62","author":"Couniot","year":"2015","journal-title":"IEEE Trans. Circuits Syst. II Express Briefs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1039\/C8LC00299A","article-title":"A high-throughput flow cytometry-on-a-CMOS platform for single-cell dielectric spectroscopy at microwave frequencies","volume":"18","author":"Chien","year":"2018","journal-title":"Lab Chip"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1109\/JSSC.2016.2605001","article-title":"CMOS Biosensor IC Focusing on Dielectric Relaxations of Biological Water with 120 and 60 GHz Oscillator Arrays","volume":"51","author":"Mitsunaka","year":"2016","journal-title":"IEEE J. Solid-State Circuits"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4465","DOI":"10.1039\/c2lc40392g","article-title":"A magnetic cell-based sensor","volume":"12","author":"Wang","year":"2012","journal-title":"Lab Chip"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1039\/C8LC00156A","article-title":"Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening","volume":"18","author":"Park","year":"2018","journal-title":"Lab Chip"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.sna.2014.10.005","article-title":"Integrated multifunctional cell-based biosensor system for monitoring extracellular acidification and cellular growth","volume":"220","author":"Su","year":"2014","journal-title":"Sens. Actuators A Phys."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1039\/c4lc00135d","article-title":"Packaging commercial CMOS chips for lab on a chip integration","volume":"14","author":"Abshire","year":"2014","journal-title":"Lab Chip"},{"key":"ref_16","first-page":"677","article-title":"Sensors and packages based on LTCC and thick-film technology for severe conditions","volume":"34","author":"Jacq","year":"2009","journal-title":"Sadhana Acad. Proc. Eng. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s10404-012-1087-3","article-title":"Prospects of low temperature co-fired ceramic (LTCC) based microfluidic systems for point-of-care biosensing and environmental sensing","volume":"14","author":"Vasudev","year":"2013","journal-title":"Microfluid. Nanofluid."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12001","DOI":"10.1088\/1757-899X\/104\/1\/012001","article-title":"LTCC based bioreactors for cell cultivation","volume":"104","author":"Bartsch","year":"2016","journal-title":"IOP Conf. Ser. Mater. Sci. Eng."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1007\/s00216-009-2651-x","article-title":"Monitoring of cell cultures with LTCC microelectrode array","volume":"393","author":"Ciosek","year":"2009","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_20","unstructured":"Imanaka, Y. (2005). Multilayered Low Temperature Cofired Ceramics (LTCC) Technology, Springer Science & Business Media."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nchem.961","article-title":"Single cells and intracellular processes studied by a plasmonic-based electrochemical impedance microscopy","volume":"3","author":"Wang","year":"2011","journal-title":"Nat. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1039\/B922830F","article-title":"Modular integration of electronics and microfluidic systems using flexible printed circuit boards","volume":"10","author":"Wu","year":"2010","journal-title":"Lab Chip"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1039\/c2lc21037a","article-title":"Single-cell recording and stimulation with a 16k micro-nail electrode array integrated on a 0.18 \u03bcm CMOS chip","volume":"12","author":"Huys","year":"2012","journal-title":"Lab Chip"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.proeng.2015.08.769","article-title":"Low temperature co-fired ceramic package for lab-on-CMOS applied in cell viability monitoring","volume":"120","author":"Halonen","year":"2015","journal-title":"Proc. Eng."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.3762\/bjnano.7.179","article-title":"Low temperature co-fired ceramic packaging of CMOS capacitive sensor chip towards cell viability monitoring","volume":"7","author":"Halonen","year":"2016","journal-title":"Beilstein J. Nanotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Naviasky, E., Datta-Chaudhuri, T., and Abshire, P. (2014, January 1\u20135). High resolution capacitance sensor array for real-time monitoring of cell viability. Proceedings of the IEEE International Symposium on Circuits and Systems (ISCAS), Melbourne VIC, Australia.","DOI":"10.1109\/ISCAS.2014.6865215"},{"key":"ref_27","unstructured":"Bathiya, S., Castro, A., Dandin, M., Smela, E., and Abshire, P. (2016, January 22\u201325). Lab-on-CMOS capacitance sensor array for real-time cell viability measurements with I2C readout. Proceedings of the IEEE International Symposium on Circuits and Systems (ISCAS), Montreal, QC, Canada."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Senevirathna, B., Lu, S., and Abshire, P. (2017, January 8\u201331). Characterization of a High Dynamic Range Lab-on-CMOS Capacitance Sensor Array. Proceedings of the IEEE International Symposium on Circuits and Systems (ISCAS), Baltimore, MD, USA.","DOI":"10.1109\/ISCAS.2017.8050735"},{"key":"ref_29","unstructured":"(2018, March 01). OriginLab\u2014The Percentile Filter Method. Available online: https:\/\/www.originlab.com\/doc\/Origin-Help\/Smooth-Algorithm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1128\/IAI.73.4.1907-1916.2005","article-title":"Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells","volume":"73","author":"Fink","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1023\/A:1009686704506","article-title":"Nature of the Silicon-Animal Cell Interface","volume":"7","author":"Bayliss","year":"2000","journal-title":"J. Porous Mater."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1007\/s10856-008-3384-7","article-title":"Surface modifications of silicon nitride for cellular biosensor applications","volume":"19","author":"Gustavsson","year":"2008","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1109\/JPROC.2010.2066532","article-title":"Growing cells atop microelectronic chips: Interfacing electrogenic cells in vitro with CMOS-based microelectrode arrays","volume":"99","author":"Hierlemann","year":"2011","journal-title":"Proc. IEEE"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Medina Benavente, J.J., Mogami, H., Sakurai, T., and Sawada, K. (2014). Evaluation of silicon nitride as a substrate for culture of PC12 cells: An interfacial model for functional studies in neurons. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090189"},{"key":"ref_35","first-page":"8","article-title":"Poly-L-Lysine Cell Attachment Protocol","volume":"3","author":"Sitterley","year":"2008","journal-title":"BioFiles"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sliz, R., Suzuki, Y., Nathan, A., Myllyl\u00e4, R., and Jabbour, G.E. (2012). Organic solvent wetting properties of UV and plasma treated ZnO nanorods: Printed electronics approach. Oraganic Photovolataics XIII, SPIE.","DOI":"10.1117\/12.929631"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bembnowicz, P., Nowakowska, D., and Golonka, L.J. (2009, January 13\u201317). Integrated LTCC chamber with optical ports and thermal control elements. Proceedings of the 32nd International Spring Seminar on Electronics Technology, Brno, Czech Republic.","DOI":"10.1109\/ISSE.2009.5207070"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.jeurceramsoc.2009.08.025","article-title":"Integration of transparent glass window with LTCC technology for \u03bcTAS application","volume":"30","author":"Bembnowicz","year":"2010","journal-title":"J. Eur. Ceram. Soc."}],"container-title":["Sensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8220\/18\/10\/3346\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:24:16Z","timestamp":1760196256000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8220\/18\/10\/3346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,7]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["s18103346"],"URL":"https:\/\/doi.org\/10.3390\/s18103346","relation":{},"ISSN":["1424-8220"],"issn-type":[{"value":"1424-8220","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,7]]}}}