LTCC packaging for Lab-on-a-chip application

LTCC -pakkaus Lab-on-a-chip -sovellukseen. Tiivistelmä. Tässä työssä suunniteltiin, valmistettiin ja testattiin uusi pakkaustekniikka ”Lab-on-a-chip” (LOC) -sovellukseen. Pakkaus tehtiin pii-mikrosirulle, jolla voidaan mitata solujen kiinnittymistä sirun pintaan solujen elinkelpoisuuden indikaattorina. Luotettavuustestaukset tehtiin daisy-chain -resistanssimittauksilla solunkasvatusolosuhteissa. Lisäksi työssä selvitettiin LTCC- ja ”Lab-on-a-chip” -teknologioiden perusteet teoreettiselta pohjalta. Mikrosirun pakkauksessa käytettiin joustavaa LTCC-teknologiaa. Sähköisiin kontakteihin ja niiden suojauksiin käytettiin sekä johtavia että eristäviä epoksi-liimoja. LOC-sovelluksiin on tärkeää kehittää uusia pakkausmenetelmiä jotta näiden laitteiden kaikki ominaisuudet saadaan toimimaan luotettavasti. Pakkaus testattiin samoissa olosuhteissa missä sitä tullaan käyttämään ja pakkaus kesti kaikki nämä haasteet. Lisäksi esitetty valmistusprosessi on sellainen, että sitä voidaan käyttää myös muihin ”Lab-on-a-chip” -sovelluksiin.Abstract. This work presents design, manufacturing and testing of new packaging method for Lab-on-a-chip (LOC) application. Packaging was made for silicon microchip which can measure cell adhesion on chips surface as indication of cell viability. Reliability testing was done with daisy-chain resistance measurement in real conditions. Moreover basic theory of LTCC and Lab-on-a-chip technology is presented. Resilient LTCC technology was used for packaging material and conductive/insulating epoxies were applied for electrical contacts and barriers against the environment. It is fundamentally important to develop new packaging methods for LOC applications, so all the properties can be utilized reliably. Packaging was tested under the cell growth conditions and the package showed to withstand all these challenges. Moreover the presented packaging method is possible to use also in other Lab-on-a-chip applications

RF-microwave sensor development for cell and human in vitro and ex vivo monitoring

Abstract 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.Tiivistelmä 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 käytettävyyttä. 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.Abstract I denna forskning utvecklades nya RF / mikrovågsbaserade sensorlösningar för övervakning av celler och människor för att få en bättre förståelse för deras aktivitet eller tillstånd snabbt, billigt, enkelt och kontinuerligt. Effekten av olika ämnen på beteendet hos celler kan övervakas genom att mäta deras elektriska miljö där förändringar observeras när celler reagerar på stimulanser. Utgångspunkten för studien var ett mikrochip med ett kapacitansmätsystem integrerat i odlingskammaren, vilket möjliggör övervakning av cellproliferation eller död. Utmaningen med studien var den korrekta tolkningen av de mottagna signalerna och kombinationen av ”torr” elektronik och ”våt” biologi, vilket är utmanande problemställningar som måste lösas för systemets tillförlitlighet och hållbarhet. För detta ändamål utvecklades en keramisk förpackning “tillverkad vid låg temperature” som tål cellodlingsförhållanden och inte stör cellaktiviteten. Ett tydligt skift på 1,1 MHz i systemets resonansfrekvens kunde mätas, där storlek på skiftet berodde på antalet celler. En annan del av forskningen i avhandlingen koncentrerade sig på mikrovågssensorn som kan användas vid undersökning och analys av vätskeprover, som kan samlas in från kroppen och ge information om en persons hälsotillstånd. En mikrovågssensor utvecklades som testades på flytande prover. Mikrofluidik integrerades i systemet för hanteringen av flytande prover, vilket möjliggör användning av mycket små provvolymer och förbättrar enhetens användbarhet. Utmaningen med arbetet var att bygga systemet med full integration av delarna och utan att dessa störde varandra. Sensorkonceptet testades framgångsrikt med användning av en typisk NaCl-koncentration som finns i human blodplasma, dvs. 125 till 155 mmol / mol vatten. Den tredje delen av avhandlingen syftade till en mikrovågssensor som möjliggör realtidsmätning av kroppsvätskebalansen direkt på huden. Funktionen för den utvecklade mikrovågssensorn baserades på en resonator, resonansfrekvensen beror på de elektriska egenskaperna hos material i dess närhet, i detta fall hudens vätskeinnehåll och dess förändringar. Sensorns funktion testades med konstgjord hud, som tillverkades i laboratoriet, med motsvarade egenskaper som hos riktig hud. Observerade förändringar i resonansfrekvensen var +370 MHz och -220 MHz för uttorkad och hydratiserad hud jämfört med normal hud, vilket ger ett brett frekvensområde för detektion av hudens statu

Microfluidic microwave sensor for detecting saline in biological range

Abstract 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

Stretchable sensors with tunability and single stimuli-responsiveness through resistivity switching under compressive stress

Abstract The fascinating human somatosensory system with its complex structure is composed of numerous sensory receptors possessing distinct responsiveness to stimuli. It is a continuous source of inspiration for tactile sensors that mimic its functions. However, to achieve single stimulus-responsiveness with mechanical decoupling is particularly challenging in the light of structural design and has not been fully addressed to date. Here we propose a novel structural design inspired by combining the characteristics of electronic skin (e-skin) and electronic textile (e-textile) into a hybrid interface to achieve a stretchable single stimuli-responsive tactile sensor. The stencil printable biocarbon composite/silver-plated nylon hybrid interface possesses an extraordinary resistance switching (ΔR/R0 up to ∼104) under compressive stress which is controllable by the composite film-thickness. It achieves a very high normal pressure sensitivity (up to 60.8 kPa–1) in a wide dynamic range (up to ∼50 kPa) in the piezoresistive operation mode and can effectively decouple stresses induced by stretching or bending. In addition, the device is capable of high accuracy strain sensing in its capacitive operation mode through dimensional change dominant response. Because of these intriguing features, it has potential for the next-generation Internet of Things devices and user-interactive systems capable of providing visual feedback and more advanced robotics or even prosthetics

Spinel-olivine microwave dielectric ceramics with low sintering temperature and high quality factor for 5 GHz wi-fi antennas

Abstract The patch antenna of spinel-olivine composite ceramic (Li2ZnGe3O8-Li2ZnGeO4) is designed, which can realize power ratio (59%) and S11 of -14 dB at 5.7 GHz. The low sintering temperature (< 960 °C), low relative permittivity (8.15) and good microwave dielectric properties (quality factor ~ 32,500 GHz, resonant frequency temperature coefficient ~ -74.8 ppm/ °C) were obtained for spinel-olivine composite ceramic. Li2ZnGe3O8-Li2ZnGeO4 composite microwave dielectric ceramics were synthesized at 900–980 °C using Li2CO3, ZnO and GeO2, which can co-fire with silver electrodes without chemical reaction. These exceptional characteristics enable high-speed signal transmission application of spinel-olivine composite ceramics (Li2ZnGe3O8-Li2ZnGeO4) in 5 GHz Wi-Fi antennas

Microwave sensing of brain water:a simulation and experimental study using human brain models

Abstract This paper introduces a microwave-based approach that aims to non-invasively measure water, particularly cerebrospinal fluid (CSF) dynamics, in the human brain. The microwave measurement technique is well-known in industrial applications. More recently microwave techniques have awakened interest also in biomedical applications. This is the first time it is suggested to be utilized in measurements of brain water, particularly of CSF. Two different head phantoms were built in order to validate the sensitivity of the technique to sense dynamic variations of CSF and water volume inside a human skull. These were comprised of multilayered head phantom, including a real human skull, mimicking the electromagnetic properties of a human head. In addition, the variation of the CSF is evaluated with electromagnetic simulations using a planar layer model and a hemispherical layer model. Moreover, propagation and power flow inside the head model is evaluated using 2D power flow presentations. Reflection sensor principle was selected due to its simplicity and ability to measure relatively thick samples. Importantly, reflection sensor requires only one-port measurement making it very feasible for in vivo brain monitoring. In addition, the measurement setup does not require attachment of the sensor to the head, thus the measurement can be realized also without touching the head. Our experimental study as well as simulation results demonstrated the possibility to non-invasively sense, by microwaves, small dynamic variations in CSF volume in the brain, in particularly in the subarachnoid space

Detection of brain hemorrhage in white matter using analysis of radio channel characteristics

Abstract This paper presents a simulation-based study on detection of stroke/brain hemorrhage even in the white matter using radio channel characteristics analysis. The idea is to utilize the fact that blood has different dielectric properties than brain’s white and grey matters and, thus, additional blood areas inside the brain change radio channel characteristics between the transmitter and receiver antennas located on the opposite sides of the head. The antennas should be strongly directive and designed to work attached to the body surface so that hemorrhages even in the white matter could be detected. The study is conducted using the electromagnetic simulation software CST and two different simulation models: a spherical tissue layer model and an anatomical voxel model. The antennas used in this study are bio-matched mini-horn antennas designed for implant communications at 1—4 GHz frequency range. Different sizes of the blood areas are evaluated. This initial study shows how even small sizes of hemorrhage can change radio channel even as the hemorrhage is located in the middle of the brain, in the white matter. The path loss difference is 0.5—10 dB between the hemorrhage and reference cases depending on the size and location of the hemorrhage. A practical solution of this hemorrhage detection technique could be a portable helmet type of structure having several small sized antennas around the internal part of the helmet. Such a helmet would be easy to use e.g. in ambulance, which would enable early detection of hemorrhage in its early phase and, hence, improve prospects of the cure significantly

Nanoparticle activated neutrophils-on-a-chip:a label-free capacitive sensor to monitor cells at work

Abstract Neutrophil granulocytes are the most abundant white blood cells in mammals and vital components of the immune system. They are involved in the early phase of inflammation and in generation of reactive oxygen species. These rapid cell-signaling communicative processes are performed in the time frame of minutes. In this work, the activity and the response of neutrophil granulocytes are monitored when triggered by cerium-oxide based nanoparticles, using capacitive sensors based on Lab-on-a-chip technology. The chip is designed to monitor activation processes of cells during nanoparticle exposure, which is for the first time recorded on-line as alteration of the capacitance. The complementary metal oxide semiconductor engineering chip design is combined with low temperature co-fired ceramic, LTCC, packaging technology. The method is label free and gently measures cells on top of an insulating surface in a weak electromagnetic field, as compared to commonly used four-point probes and impedance spectroscopy electric measurements where electrodes are in direct contact with the cells. In summary, this label free method is used to measure oxidative stress of neutrophil granulocytes in real time, minute by minute and visualize the difference in moderate and high cellular workload during exposure of external triggers. It clearly shows the capability of this method to detect cell response during exposure of external triggers. In this way, an informationally dense non-invasive method is obtained, to monitor cells at work

LTCC packaged ring oscillator based sensor for evaluation of cell proliferation

Abstract 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

Low temperature co-fired ceramic packaging of CMOS capacitive sensor chip towards cell viability monitoring

Abstract 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