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RF-microwave sensor development for cell and human in vitro and ex vivo monitoring
Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering. Microelectronics Research Unit, Faculty of Information Technology and Electrical Engineering, University of Oulu, Finland.ORCID iD: 0000-0001-7504-4727
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this research new RF/microwave-based sensor solutions were developed for the monitoring of biological cells and human beings to obtain a better understanding of their activity or state in a quick, cheap, easy and continuous way. The effect of different substances on cell behaviour can be monitored by measuring the electrical environment where changes are observed as cells react to a stimulus. The starting point of the study was a microchip with a capacitance measurement system integrated into the culturing chamber, enabling the monitoring of cell proliferation or death. The main challenge of the study was the correct interpretation of the received signals and the combination of “dry” electronics and “wet” biology, which is a difficult issue in terms of reliability and durability of the system. For this purpose, a low temperature co-fired ceramic package was developed which could withstand cell culture conditions and which did not interfere with the cell activity. A 1.1 MHz shift in resonance frequency of the system could clearly be measured, where the shift depended on the number of cells. Another topic of the research concentrated on a microwave sensor that can be utilized in the examination and analysis of fluid samples collected from the body which provide information about a person’s health status. A microwave sensor was developed, which was tested with liquid samples. Microfluidics were also integrated into the system which allowed the use of very small sample volumes and improved the usability of the device. The challenge of the work was to build the system so that the parts were integrated seamlessly without interfering with each other. The sensor concept was tested successfully using typical concentrations of NaCl found in human blood plasma i.e. 125 to 155 mmol/mol of water. The third topic of the thesis was aiming for a microwave sensor that enables real-time measurement of body fluid balance directly from the skin. The operation of the developed microwave sensor was based on a resonator whose resonance frequency reacted to the electrical properties of materials in its proximity, in this case the water content of the skin and its changes. The function of the sensor was tested with artificial skin, made in the laboratory, which corresponded to the properties of real skin. The observed changes in resonance frequency was +370 MHz and -220 MHz for dehydrated and hydrated skin compared to normal skin, thus providing a wide frequency range for detection of the status of the skin.

Abstract [fi]

Tutkimuksessa kehitettiin uusia RF-/mikroaaltoihin perustuvia anturiratkaisuja solujen ja ihmisen mittaukseen, jotta niiden toiminnasta tai tilasta saataisiin parempi kuva nopeasti, edullisesti, helposti ja jatkuvatoimisesti. Solujen toimintaa voidaan seurata mittaamalla niiden sähköistä ympäristöä missä havaitaan muutoksia, kun solut reagoivat erilaisiin aineisiin. Tutkimuksen lähtökohtana käytettiin soluanturiksi suunniteltua mikrosirua, jossa oli viljelyalustaan integroitu kapasitanssin mittausjärjestelmä, jonka avulla voitiin monitoroida solujen jakaantumista tai kuolemista. Tutkimuksen haasteena oli saatujen signaalien oikeanlainen tulkinta sekä ”kuivan” elektroniikan ja ”märän” biologian yhdistäminen järjestelmän luotettavuuden ja kestävyyden kannalta. Tähän tarkoitukseen työssä kehitettiin matalan lämpötilan yhteissintrattavaan keraamiin perustuva pakkaus, joka kestää soluviljelyn olosuhteita eikä häiritse solujen toimintaa. Testeissä voitiin havaita selvä 1.1 MHz muutos resonanssitaajuudessa, jonka suuruus riippui solujen lukumäärästä. Tutkimuksen toinen alue oli mikroaaltoanturi, jolla voidaan tutkia ja analysoida kehosta saatavia nestemäisiä näytteitä ja saada tietoa henkilön terveydentilasta. Työssä kehitettiin mikroaaltoanturi, jota testattiin nestemäisillä näytteillä. Nestenäytteiden käsittelemiseksi systeemiin integroitiin myös mikrofluidistiikka mikä mahdollistaa hyvin pienten näytemäärien käyttämisen ja parantaa laitteen. Työn haasteena oli järjestelmän rakentaminen siten, että osat integroituvat toisiinsa saumattomasti toisiaan häiritsemättä. Anturikonsepti testattiin onnistuneesti käyttämällä tyypillistä ihmisen veriplasmasta löytyvää NaCl-pitoisuutta vaihteluvälillä 125– 155 mmol/mol vedessä. Väitöstyön kolmas aihealue oli mikroaaltoanturin hyödyntäminen kehon nestetasapainon mittauksessa reaaliaikaisesti suoraan iholta. Kehitetyn mikroaaltoanturin toiminta perustui resonaattoriin, jonka resonanssitaajuus reagoi sen lähiympäristön sähköisiin ominaisuuksiin eli tässä tapauksessa ihon vesipitoisuuteen ja siinä tapahtuviin muutoksiin. Anturin toimintaa testattiin laboratoriossa valmistettujen keinoihojen avulla, jotka vastasivat ominaisuuksiltaan oikeata ihoa kuvastaen eri tilannetta kehon nestetasapainossa. Mitattu resonanssitaajuus muuttui +370 MHz ja -220 MHz kuivan ja kostean ihon välillä verrattuna normaaliin ihoon, tarjoten laajan taajuusalueen ihon tilanteen havainnointiin.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2021. , p. 60
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 2109
Keywords [en]
Cell culture monitoring, Lab-on-a-chip, Low temperature co-fired ceramic (LTCC), Microwave sensor, Interdigitated electrode (IDE), Complementary split ring resonator (CSRR), Dielectric properties, Health monitoring
Keywords [fi]
Soluviljelmä monitorointi, Lab-on-a-chip, Matalan lämpötilan yhteissintrautuva keraami (LTCC), Mikroaaltoanturi, Interdigitated electrode (IDE), Complementary split ring resonator (CSRR), Dielektriset ominaisuudet, Terveys monitorointi
Keywords [sv]
Övervakning av cellodling, Lab-on-a-chip, Låg temperatur keramik (LTCC), Mikrovågssensor, Interdigitated electrode (IDE), Complementary split ring resonator (CSRR), Dielektrisk mätning, Hälsoövervakning, Mikrovågssensor
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
URN: urn:nbn:se:liu:diva-178883ISBN: 9789179297398 (print)OAI: oai:DiVA.org:liu-178883DiVA, id: diva2:1590168
Public defence
2021-10-22, Online through Zoom (contact wendela.yonar@liu.se), video streamed in Planck, F Building, Campus Valla, Linköping and Lecture Hall L2, University of Oulu, Oulu, Finland, 10:00 (English)
Opponent
Supervisors
Available from: 2021-09-27 Created: 2021-09-01 Last updated: 2021-12-17Bibliographically approved
List of papers
1. Low temperature co-fired ceramic packaging of CMOS capacitive sensor chip towards cell viability monitoring
Open this publication in new window or tab >>Low temperature co-fired ceramic packaging of CMOS capacitive sensor chip towards cell viability monitoring
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2016 (English)In: Beilstein Journal of Nanotechnology, ISSN 2190-4286, Vol. 7, p. 1871-1877Article in journal (Refereed) Published
Abstract [en]

Cell viability monitoring is an important part of biosafety evaluation for the detection of toxic effects on cells caused by nanomaterials, preferably by label-free, noninvasive, fast, and cost effective methods. These requirements can be met by monitoring cell viability with a capacitance-sensing integrated circuit (IC) microchip. The capacitance provides a measurement of the surface attachment of adherent cells as an indication of their health status. However, the moist, warm, and corrosive biological environment requires reliable packaging of the sensor chip. In this work, a second generation of low temperature co-fired ceramic (LTCC) technology was combined with flip-chip bonding to provide a durable package compatible with cell culture. The LTCC-packaged sensor chip was integrated with a printed circuit board, data acquisition device, and measurement-controlling software. The packaged sensor chip functioned well in the presence of cell medium and cells, with output voltages depending on the medium above the capacitors. Moreover, the manufacturing of microfluidic channels in the LTCC package was demonstrated.

Place, publisher, year, edition, pages
BEILSTEIN-INSTITUT, 2016
Keywords
capacitance sensing; cell viability; lab-on-a-chip; low temperature co-fired ceramic (LTCC)
National Category
Materials Chemistry
Identifiers
urn:nbn:se:liu:diva-133386 (URN)10.3762/bjnano.7.179 (DOI)000388896500001 ()
Note

Funding Agencies|Academy of Finland [268944]; TEKES [1427/31/2010]

Available from: 2016-12-27 Created: 2016-12-22 Last updated: 2021-09-27
2. LTCC Packaged Ring Oscillator Based Sensor for Evaluation of Cell Proliferation
Open this publication in new window or tab >>LTCC Packaged Ring Oscillator Based Sensor for Evaluation of Cell Proliferation
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2018 (English)In: Sensors, E-ISSN 1424-8220, Vol. 18, no 10, article id 3346Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
capacitive sensing; cell proliferation assay; CMOS; lab-on-a-chip; low temperature co-fired ceramic; ring oscillator
National Category
Textile, Rubber and Polymeric Materials
Identifiers
urn:nbn:se:liu:diva-152824 (URN)10.3390/s18103346 (DOI)000448661500174 ()30301258 (PubMedID)
Note

Funding Agencies|Academy of Finland [268944]; TEKES [1427/31/2010]

Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2022-02-10
3. Microfluidic Microwave Sensor for Detecting Saline in Biological Range
Open this publication in new window or tab >>Microfluidic Microwave Sensor for Detecting Saline in Biological Range
2019 (English)In: Sensors, E-ISSN 1424-8220, Vol. 19, no 4Article in journal (Refereed) Published
Abstract [en]

A device for measuring biological small volume liquid samples in real time is appealing. One way to achieve this is by using a microwave sensor based on reflection measurement. A prototype sensor was manufactured from low cost printed circuit board (PCB) combined with a microfluidic channel made of polymethylsiloxane (PDMS). Such a sensor was simulated, manufactured, and tested including a vacuum powered sample delivery system with robust fluidic ports. The sensor had a broad frequency band from 150 kHz to 6 GHz with three resonance frequencies applied in sensing. As a proof of concept, the sensor was able to detect a NaCl content of 125 to 155 mmol in water, which is the typical concentration in healthy human blood plasma.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
Lab-on-a-chip, RF sensor, Microfluidic sensing, IDE
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:liu:diva-179587 (URN)10.3390/s19040819 (DOI)000460829200070 ()30781561 (PubMedID)2-s2.0-85061869070 (Scopus ID)
Available from: 2021-09-27 Created: 2021-09-27 Last updated: 2022-02-10Bibliographically approved
4. A Non-Invasive Method for Hydration Status Measurement With a Microwave Sensor Using Skin Phantoms
Open this publication in new window or tab >>A Non-Invasive Method for Hydration Status Measurement With a Microwave Sensor Using Skin Phantoms
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2020 (English)In: IEEE Sensors Journal, ISSN 1530-437X, E-ISSN 1558-1748, Vol. 20, no 2, p. 1095-1104Article in journal (Refereed) Published
Abstract [en]

Fluid balance is important for a healthy human being. In this paper, a method to measure hydration status was developed and tested towards non-invasive measurement from human skin. Measurement of hydration status was performed by a microwave sensor utilizing a complementary split ring resonator (CSRR). The sensor was modeled, manufactured and then characterized by measuring tailor made skin phantoms based on the realistic electrical properties of skin with different degrees of hydration status. Qualitative longer term (>24 h) evaluation of the sensor was also performed by measuring polyester tissue that was drying over the time. Hydration status, represented by dehydrated, normal and hydrated skin phantoms, based on polyurethane with carbon and ceramic additives, was measured successfully by monitoring the changes in resonance frequency around 5.52 GHz. All results were compared to the dielectric reference measurements done by a commercial laboratory instrument.

Place, publisher, year, edition, pages
Institute of Electrical and Electronics Engineers (IEEE), 2020
Keywords
Microwave sensors, Biomedical monitoring, Dielectric measurement, Skin phantoms, Health monitoring
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:liu:diva-179590 (URN)10.1109/JSEN.2019.2945817 (DOI)000522345700059 ()2-s2.0-85077812885 (Scopus ID)
Available from: 2021-09-27 Created: 2021-09-27 Last updated: 2021-10-07Bibliographically approved

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