Design and Validation of a 150 MHz HFFQCM Sensor for Bio-Sensing Applications

[EN] Acoustic wave resonators have become suitable devices for a broad range of sensing applications due to their sensitivity, low cost, and integration capability, which are all factors that meet the requirements for the resonators to be used as sensing elements for portable point of care (PoC) platforms. In this work, the design, characterization, and validation of a 150 MHz high fundamental frequency quartz crystal microbalance (HFF-QCM) sensor for bio-sensing applications are introduced. Finite element method (FEM) simulations of the proposed design are in good agreement with the electrical characterization of the manufactured resonators. The sensor is also validated for bio-sensing applications. For this purpose, a specific sensor cell was designed and manufactured that addresses the critical requirements associated with this type of sensor and application. Due to the small sensing area and the sensor's fragility, these requirements include a low-volume flow chamber in the nanoliter range, and a system approach that provides the appropriate pressure control for assuring liquid confinement while maintaining the integrity of the sensor with a good base line stability and easy sensor replacement. The sensor characteristics make it suitable for consideration as the elemental part of a sensor matrix in a multichannel platform for point of care applications.This work was funded by the European Commission Horizon 2020 Programme under Grant Agreement number ICT-28-2015/687785-LIQBIOPSENS (Reliable Liquid Biopsy technology for early detection of colorectal cancer).Fernández Díaz, R.; García Molla, P.; García, M.; García Narbón, JV.; Jiménez Jiménez, Y.; Arnau Vives, A. (2017). Design and Validation of a 150 MHz HFFQCM Sensor for Bio-Sensing Applications. Sensors. 17(9):1-13. https://doi.org/10.3390/s17092057S113179Soper, S. A., Brown, K., Ellington, A., Frazier, B., Garcia-Manero, G., Gau, V., … Wilson, D. (2006). Point-of-care biosensor systems for cancer diagnostics/prognostics. Biosensors and Bioelectronics, 21(10), 1932-1942. doi:10.1016/j.bios.2006.01.006Gubala, V., Harris, L. F., Ricco, A. J., Tan, M. X., & Williams, D. E. (2011). Point of Care Diagnostics: Status and Future. Analytical Chemistry, 84(2), 487-515. doi:10.1021/ac2030199Sauerbrey, G. (1959). Verwendung von Schwingquarzen zur W�gung d�nner Schichten und zur Mikrow�gung. Zeitschrift f�r Physik, 155(2), 206-222. doi:10.1007/bf01337937Tsortos, A., Papadakis, G., & Gizeli, E. (2008). Shear acoustic wave biosensor for detecting DNA intrinsic viscosity and conformation: A study with QCM-D. Biosensors and Bioelectronics, 24(4), 836-841. doi:10.1016/j.bios.2008.07.006Tuantranont, A., Wisitsora-at, A., Sritongkham, P., & Jaruwongrungsee, K. (2011). A review of monolithic multichannel quartz crystal microbalance: A review. 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Applied Physics Letters, 81(26), 5069-5071. doi:10.1063/1.1532750Ping Kao, Doerner, S., Schneider, T., Allara, D., Hauptmann, P., & Tadigadapa, S. (2009). A Micromachined Quartz Resonator Array for Biosensing Applications. Journal of Microelectromechanical Systems, 18(3), 522-530. doi:10.1109/jmems.2009.2015498Liang, J., Huang, J., Zhang, T., Zhang, J., Li, X., & Ueda, T. (2013). An Experimental Study on Fabricating an Inverted Mesa-Type Quartz Crystal Resonator Using a Cheap Wet Etching Process. Sensors, 13(9), 12140-12148. doi:10.3390/s130912140Zimmermann, B., Lucklum, R., Hauptmann, P., Rabe, J., & Büttgenbach, S. (2001). Electrical characterisation of high-frequency thickness-shear-mode resonators by impedance analysis. Sensors and Actuators B: Chemical, 76(1-3), 47-57. doi:10.1016/s0925-4005(01)00567-6Lubczyk, D., Siering, C., Lörgen, J., Shifrina, Z. B., Müllen, K., & Waldvogel, S. R. (2010). Simple and sensitive online detection of triacetone triperoxide explosive. Sensors and Actuators B: Chemical, 143(2), 561-566. doi:10.1016/j.snb.2009.09.061Brutschy, M., Schneider, M. W., Mastalerz, M., & Waldvogel, S. R. (2012). Porous Organic Cage Compounds as Highly Potent Affinity Materials for Sensing by Quartz Crystal Microbalances. Advanced Materials, 24(45), 6049-6052. doi:10.1002/adma.201202786Brutschy, M., Schneider, M. W., Mastalerz, M., & Waldvogel, S. R. (2013). Direct gravimetric sensing of GBL by a molecular recognition process in organic cage compounds. Chemical Communications, 49(75), 8398. doi:10.1039/c3cc43829eUttenthaler, E., Schräml, M., Mandel, J., & Drost, S. (2001). Ultrasensitive quartz crystal microbalance sensors for detection of M13-Phages in liquids. Biosensors and Bioelectronics, 16(9-12), 735-743. doi:10.1016/s0956-5663(01)00220-2March, C., García, J. V., Sánchez, Á., Arnau, A., Jiménez, Y., García, P., … Montoya, Á. (2015). High-frequency phase shift measurement greatly enhances the sensitivity of QCM immunosensors. Biosensors and Bioelectronics, 65, 1-8. doi:10.1016/j.bios.2014.10.001Sagmeister, B. P., Graz, I. M., Schwödiauer, R., Gruber, H., & Bauer, S. (2009). User-friendly, miniature biosensor flow cell for fragile high fundamental frequency quartz crystal resonators. Biosensors and Bioelectronics, 24(8), 2643-2648. doi:10.1016/j.bios.2009.01.023Abe, T., Hung, V., & Esashi, M. (2006). Inverted mesa-type quartz crystal resonators fabricated by deep-reactive ion etching. IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, 53(7), 1234-1236. doi:10.1109/tuffc.2006.1665070Rocha-Gaso, M.-I., March-Iborra, C., Montoya-Baides, Á., & Arnau-Vives, A. (2009). Surface Generated Acoustic Wave Biosensors for the Detection of Pathogens: A Review. Sensors, 9(7), 5740-5769. doi:10.3390/s90705740García, J. V., Rocha, M. I., March, C., García, P., Francis, L. A., Montoya, A., … Jimenez, Y. (2014). Love Mode Surface Acoustic Wave and High Fundamental Frequency Quartz Crystal Microbalance Immunosensors for the Detection of Carbaryl Pesticide. Procedia Engineering, 87, 759-762. doi:10.1016/j.proeng.2014.11.649Shockley, W., Curran, D. R., & Koneval, D. J. (1967). Trapped‐Energy Modes in Quartz Filter Crystals. The Journal of the Acoustical Society of America, 41(4B), 981-993. doi:10.1121/1.1910453Shen, F., Lu, P., O’Shea, S. J., & Lee, K. H. (2004). Frequency coupling and energy trapping in mesa-shaped multichannel quartz crystal microbalances. Sensors and Actuators A: Physical, 111(2-3), 180-187. doi:10.1016/j.sna.2003.10.017Beaver, W. D. (1968). Analysis of Elastically Coupled Piezoelectric Resonators. The Journal of the Acoustical Society of America, 43(5), 972-981. doi:10.1121/1.1910967Sheahan, D. F. (1970). An improved resonance equation for AT-cut quartz crystals. 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Development of a novel high resolution and high throughput biosensing technology based on a Monolithic High Fundamental Frequency Quartz Crystal Microbalance (MHFF-QCM). Validation in food control

Tesis por compendio[ES] La sociedad actual demanda un mayor control en la seguridad y calidad de los alimentos que se consumen. Esta preocupación se ve reflejada en los diferentes planes estatales y europeos de investigación científica, los cuales, plantean la necesidad de innovar y desarrollar nuevas técnicas analíticas que cubran los requerimientos actuales. En el presente documento se aborda el problema de la presencia de residuos químicos en la miel. El origen de los mismos se debe, fundamentalmente, a los tramientos veterinarios con los que se tratan enfermedades y parásitos en las abejas, y a los tratamientos agrícolas con los que las abejas se ponen en contacto cuando recolectan el néctar en cultivos próximos a las colmenas. La Agencia Europea de Seguridad Alimentaria (EFSA) confirma esta realidad al notificar numerosas alertas sanitarias en la miel. En los últimos años, los métodos de análisis basados en inmunosensores piezoeléctricos se han posicionado como la base de una técnica de cribado muy prometedora, la cual puede ser empleada como técnica complementaria a las clásicas de cromatografía, gracias a su sencillez, rapidez y bajo coste. La tecnología de resonadores High-Fundamental Frequency Quartz Crystal Microbalance with Dissipation (HFF-QCMD) combina la detección directa en tiempo real, alta sensibilidad y selectividad con un fácil manejo y coste reducido en comparación con otras técnicas. Además, está tecnología permite aumentar el rendimiento del análisis mediante el diseño de arrays de resonadores en un mismo sustrato (Monolithic HFF-QCMD). En este documento se presenta el diseño de un array de 24 sensores HFF-QCMD, junto con un cartucho de micro-fluídica que traza diversos microcanales sobre los diferentes elementos sensores, a los que hace llegar la muestra de miel diluida a analizar. El cartucho actúa también como interfaz para realizar la conexión entre el array de resonadores y el instrumento de caracterización de los mismos. Para obtener el máximo partido del array diseñado, se desarrolla un método de medida robusto y fiable que permite elevar la tasa de adquisición de datos para facilitar la toma de registros eléctricos de un elevado número de resonadores de forma simultánea, e incluso en varios armónicos del modo fundamental de resonancia. La gran sensibilidad de la tecnología HFF-QCMD a los eventos bioquímicos a caracterizar se extiende también a otro tipo eventos externos, como son los cambios de temperatura o presión, lo que es necesario minimizar con el fin de reducir el impacto que estas perturbaciones no deseadas provocan en la estabilidad y fiabilidad de la medida. Con este fin, se desarrolla un algoritmo de procesado de señal basado en la Discrete Transform Wavelet (DTW). Finalmente, todos los desarrollos tecnológicos realizados se validan mediante la implementación de un inmunoensayo para la detección simultánea, en muestras de mieles reales, de residuos químicos de naturaleza química muy diferente, a saber, el fungicida tiabendazol y el antibiótico sulfatiazol.[CA] La societat actual demanda un major control en la seguretat i qualitat dels aliments que es consumeixen. Aquesta preocupació es veu reflectida en els diferents plans estatals i europeus d'investigació científica, els quals, plantegen la necessitat d'innovar i desenvolupar noves tècniques analítiques que cobrisquen els requeriments actuals. En el present document s'aborda el problema de la presència de residus químics en la mel. L'origen dels mateixos es deu, fonamentalment, als tractaments veterinaris amb els quals es tracten malalties i paràsits en les abelles, i als tractaments agrícoles amb els quals les abelles es posen en contacte quan recol·lecten el nèctar en cultius pròxims als ruscos. L'Agència Europea de Seguretat Alimentària (EFSA) confirma aquesta realitat notificant nombroses alertes sanitàries en la mel. En els últims anys, els mètodes d'anàlisis basades en immunosensors piezoelèctrics s'han posicionat com la base d'una tècnica de garbellat molt prometedora, la qual pot ser emprada com a tècnica complementària a les clàssiques de cromatografia, gràcies a la seua senzillesa, rapidesa i baix cost. La tecnologia de ressonadors High-Fundamental Frequency Quartz Crystal Microbalance with Dissipation (HFF-QCMD) combina la detecció directa en temps real, alta sensibilitat i selectivitat amb un fàcil maneig i cost reduït en comparació amb altres tècniques. A més, està tecnologia permet augmentar el rendiment del anàlisi mitjançant el disseny d'arrays de ressonadors en un mateix substrat (Monolithic HFF-QCMD). En aquest document es presenta el disseny d'un array de 24 sensors HFF-QCMD, juntament amb un cartutx de microfluídica que estableix diversos microcanals sobre els diferents elements sensors, als quals fa arribar la mostra de mel diluïda a analitzar. El cartutx actua també com a interfície per a realitzar la connexió entre l'array de ressonadors i l'instrument de caracterització d'aquests. Per a traure el màxim partit a l'array dissenyat, es desenvolupa un mètode de mesura robust i fiable que permet elevar la taxa d'adquisició de dades per a facilitar la presa de registres elèctrics d'un elevat nombre de ressonadors de manera simultània, i fins i tot en diversos harmònics del mode fonamental de ressonància. La gran sensibilitat de la tecnologia HFF-QCMD als esdeveniments bioquímics a caracteritzar s'estén també a un altre tipus esdeveniments externs, com són els canvis de temperatura o pressió, la qual cosa és necessari minimitzar amb la finalitat de reduir l'impacte que aquestes pertorbacions no desitjades provoquen en l'estabilitat i fiabilitat de la mesura. A aquest efecte, es desenvolupa un algorisme de processament de senyal basat en la Discrete Transform Wavelet (DTW). Finalment, tots els desenvolupaments tecnològics realitzats es validen mitjançant la implementació d'un immunoassaig per a la detecció simultània, en mostres de mel reals, de residus químics de naturalesa química molt diferent, a saber, el fungicida tiabendazol i l'antibiòtic sulfatiazol.[EN] Currently, society demands greater control over the safety and quality of the food consumed. This concern is reflected in the different states and European plans for scientific research, which establish the necessity to innovate and develop new analytical techniques that meet current requirements. This document addresses the problem of the presence of chemical residues in honey. Its origin is fundamentally due to the veterinary treatments against diseases and parasites in bees, and also to the agricultural treatments with which the bees come into contact when they collect the nectar in crops close to the hives. The European Food Safety Agency (EFSA) confirms this reality by notifying numerous health alerts in honey. In recent years, analysis methods based on piezoelectric immunosensors have been positioned as the basis of a very promising screening technique, which can be used as a complementary technique to the classic chromatography, thanks to its simplicity, speed and low cost. High-Fundamental Frequency Quartz Crystal Microbalance with Dissipation (HFF-QCMD) resonator technology combines direct real-time detection, high sensitivity and selectivity with easy handling and low cost compared to other techniques. In addition, this technology allows increasing the performance of the analysis through the design of resonator arrays on the same substrate (Monolithic HFF-QCMD). This document presents the design of an array of 24 HFF-QCMD sensors, together with a microfluidic cartridge that establish various microchannels on the different sensor elements, to provide them the diluted honey sample to be analyzed. The cartridge also acts as an interface to make the connection between the array of resonators and the characterization instrument. To get the most out of the designed array, a robust and reliable measurement method has been developed that allows increasing the data acquisition rate to facilitate electrical parameters readout from a high number of resonators simultaneously, and even in several harmonics of the fundamental resonance mode. The great sensitivity of the HFF-QCMD technology to the biochemical events to be characterized also is extended to other types of external events, such as changes in temperature or pressure, which must be minimized in order to reduce the impact that these unwanted disturbances cause in the stability and reliability of the measurement. To this end, a signal processing algorithm based on the Discrete Transform Wavelet (DTW) is developed. Finally, all the technological developments carried out are validated through the implementation of an immunoassay for the simultaneous detection, in real honey samples, of chemical residues of very different chemical nature, namely, the fungicide thiabendazole and the antibiotic sulfathiazole.The authors would also like to thank Jorge Martínez from the Laboratory of High Frequency Circuits (LCAF) of the Universitat Politècnica de València (UPV) for assistance with profilometry, and Manuel Planes, José Luis Moya, Mercedes Tabernero, Alicia Nuez and Joaquin Fayos from the Electron Microscopy Services of the UPV for helping with the AFM, and SEM measurements. M.Calero is the recipient of the doctoral fellowship BES-2017-080246 from the Spanish Ministry of Economy, Industry and Competitiveness (Madrid, Spain). This research was funded by Spanish Ministry of Economy and Competitiveness with FEDER funds (AGL 2016-77702-R) and European Commission Horizon 2020 Programme (Grant Agreement number H2020-FETOPEN-2016-2017/737212-CATCH-U-DNA - Capturing non-Amplified Tumor Circulating DNA with Ultrasound Hydrodynamics) for which the authors are grateful. Román Fernández is with the Center for Research and Innovation in Bioengineering (Ci2B), Universitat Politècnica de València, València, Spain and with Advanced Wave Sensors S.L., Paterna, València, Spain. (e-mail: [email protected]); Yolanda Jiménez, Antonio Arnau and María Calero are with the Center for Research and Innovation in Bioengineering (Ci2B), Universitat Politècnica de València, València, Spain; Ilya Reiviakine is with Advanced Wave Sensors S.L., Paterna, Valencia, Spain and with the Department of Bioengineering, University of Washington, Seattle, WA, 98150 USA; María Isabel Rocha-Gaso and José Vicente García are with Advanced Wave Sensors S.L., Paterna, València, Spain.Calero Alcarria, MDS. (2022). Development of a novel high resolution and high throughput biosensing technology based on a Monolithic High Fundamental Frequency Quartz Crystal Microbalance (MHFF-QCM). Validation in food control [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182652TESISCompendi

OSTEMER polymer as a rapid packaging of electronics and microfluidic system on PCB

[EN] A new heterogeneous integration method is presented that allows the integration of a microfluidic platform and a multi-channel quartz crystal microbalance array on a printed circuit board (PCB) using a dry adhesive bonding method. In this work, the microfluidic platform is a replica molded using a UV-curable OSTEMER 322 Crystal Clear polymer. The OSTEMER acts both as a final package for the cartridge and as a functional material for hosting molded microfluidic channels, the input reservoirs and the waste reservoir. The method is demonstrated by the integration of an array of 24 of a 150 MHz high fundamental frequency quartz crystal microbalance (HFF-QCM) to the OSTEMER microfluidic packaging. The resulting bond interface is shown to be completely homogeneous and void free, and the package is tested to a differential pressure of up to 4 bars. The leak test of the cartridge is performed by pressurizing a microfluidic channel with an aqueous solution using an external peristaltic pump for more than 4 h. The cartridge performance is evaluated by the electrical characterization. Q-factor values of 9507 and of 650are achieved in air and DI water, respectively. Results show that this simple integration method of the HFF-QCM is a promising way to integrate microfluidics into the more complex heterogeneous system.This work was funded by the European Commission Horizon 2020 Programme under the Grant Agreement number ICT-28-2015/687785-LIQBIOPSENS (Reliable Liquid Biopsy technology for early detection of colorectal cancer).El Fissi, L.; Fernández Díaz, R.; García Molla, P.; Calero-Alcarria, MDS.; García Narbón, JV.; Jiménez Jiménez, Y.; Arnau Vives, A.... (2019). OSTEMER polymer as a rapid packaging of electronics and microfluidic system on PCB. Sensors and Actuators A Physical. 285:511-518. https://doi.org/10.1016/j.sna.2018.11.050S51151828

A fast method for monitoring the shifts in resonance frequency and dissipation of the QCM sensors of a Monolithic array in biosensing applications

© 2021 IEEE. Personal use of this material is permitted. Permissíon from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertisíng or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.[EN] Improvement of data acquisition rate remains as an important challenge in applications with Quartz Crystal Microbalance (QCM) technology where high throughput is required. To address this challenge, we developed a fast method capable of measuring the response of a large number of sensors and/or overtones, with a high time resolution. Our method, which can be implemented in a low-cost readout electronic circuit, is based on the estimation of fr (frequency shift) and D (dissipation shift) from measurements of the sensor response obtained at a single driving frequency. By replacing slow fitting procedures with a direct calculation, the time resolution is only limited by the physical characteristics of the sensor (resonance frequency and quality factor), but not by the method itself. Capabilities of the method are demonstrated by monitoring multiple overtones with a single 5 MHz sensor and a Monolithic QCM array comprising 24 50MHz-sensors. Accuracy of the method is validated and compared with the state-of-the-art, as well as with a reference method based on impedance analysis.This work was supported in part by the Ministerio de Economía, Industria y Competitividad de España-Agencia Estatal de Investigación with Fondo Europeo de Desarrollo Regional (FEDER) Funds under Grant AGL2016-77702-R and in part by the European Commission Horizon 2020 Programme (Capturing non-amplified tumor circulating DNA with ultrasound hydrodynamics) under Agreement H2020-FETOPEN-2016-2017/737212-CATCH-UDNA. The work of María Calero was supported by the Spanish Ministry of Economy, Industry and Competitiveness, Madrid, Spain, under Grant BES-2017-080246.Fernández Díaz, R.; Calero-Alcarria, MDS.; García Narbón, JV.; Reiviakine, I.; Arnau Vives, A.; Jiménez Jiménez, Y. (2021). A fast method for monitoring the shifts in resonance frequency and dissipation of the QCM sensors of a Monolithic array in biosensing applications. IEEE Sensors Journal. 21(5):6643-6651. https://doi.org/10.1109/JSEN.2020.3042653S6643665121

High Fundamental Frequency (HFF) Monolithic Resonator Arrays for Biosensing Applications: Design, Simulations, Experimental, Characterization

© 2020 IEEE. Personal use of this material is permitted. Permissíon from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertisíng or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.[EN] Miniaturized, high-throughput, cost-effective sensing devices are needed to advance lab-on-a-chip technologies for healthcare, security, environmental monitoring, food safety, and research applications. Quartz crystal microbalance with dissipation (QCMD) is a promising technology for the design of such sensing devices, but its applications have been limited, until now, by low throughput and significant costs. In this work, we present the design and characterization of 24-element monolithic QCMD arrays for high-throughput and low-volume sensing applications in liquid. Physical properties such as geometry and roughness, and electrical properties such as resonance frequency, quality factor, spurious mode suppression, and interactions between array elements (crosstalk), are investigated in detail. In particular, we show that the scattering parameter, S 21 , commonly measured experimentally to investigate crosstalk, contains contributions from the parasitic grounding effects associated with the acquisition circuitry. Finite element method simulations do not take grounding effects into account explicitly. However, these effects can be effectively modelled with appropriate equivalent circuit models, providing clear physical interpretation of the different contributions. We show that our array design avoids unwanted interactions between elements and discuss in detail aspects of measuring these interactions that are often-overlooked.The authors would also like to thank Jorge Martínez from the Laboratory of High Frequency Circuits (LCAF) of the Universitat Politècnica de València (UPV) for assistance with profilometry, and Manuel Planes, José Luis Moya, Mercedes Tabernero, Alicia Nuez, and Joaquin Fayos from the Electron Microscopy Services of the UPV for helping with the AFM, and SEM measurements. M. Calero is the recipient of the doctoral fellowship BES-2017-080246 from the Spanish Ministry of Economy, Industry and Competitiveness, Madrid, Spain.Fernández Díaz, R.; Calero-Alcarria, MDS.; Reviakine, I.; García, JV.; Rocha-Gaso, MI.; Arnau Vives, A.; Jiménez Jiménez, Y. (2021). High Fundamental Frequency (HFF) Monolithic Resonator Arrays for Biosensing Applications: Design, Simulations, Experimental, Characterization. IEEE Sensors Journal. 21(1):284-295. https://doi.org/10.1109/JSEN.2020.3015011S28429521

Probing multivalent particle–surface interactions using a quartz crystal resonator

The rise in market-approved cellular therapies demands for advancements in process analytical technology (PAT) capable of fulfilling the requirements of this new industry. Unlike conventional biopharmaceuticals, cell-based therapies (CBT) are complex “live” products, with a high degree of inherent biological variability. This exacerbates the need for in-process monitoring and control of critical product attributes, in order to guarantee safety, efficacious and continuous supply of this CBT. There are therefore mutual industrial and regulatory motivations for high throughput, non-invasive and non-destructive sensors, amenable to integration in an enclosed automated cell culture system. While a plethora of analytical methods is available for direct characterization of cellular parameters, only a few satisfy the requirements for online quality monitoring of industrial-scale bioprocesses. [Continues.

A Multichannel Microfluidic Sensing Cartridge for Bioanalytical Applications of Monolithic Quartz Crystal Microbalance

[EN] Integrating acoustic wave sensors into lab-on-a-chip (LoC) devices is a well-known challenge. We address this challenge by designing a microfluidic device housing a monolithic array of 24 high-fundamental frequency quartz crystal microbalance with dissipation (HFF-QCMD) sensors. The device features six 6-µL channels of four sensors each for low-volume parallel measurements, a sealing mechanism that provides appropriate pressure control while assuring liquid confinement and maintaining good stability, and provides a mechanical, electrical, and thermal interface with the characterization electronics. We validate the device by measuring the response of the HFF-QCMD sensors to the air-to-liquid transition, for which the robust Kanazawa¿Gordon¿Mason theory exists, and then by studying the adsorption of model bioanalytes (neutravidin and biotinylated albumin). With these experiments, we show how the effects of the protein¿surface interactions propagate within adsorbed protein multilayers, offering essentially new insight into the design of affinity-based bioanalytical sensorsThis work was supported in part by Ministerio de Economía, Industria y Competitividad de España Agencia Estatal de Investigación with FEDER (Fondo Europeo de Desarrollo Regional) funds under Project AGL2016-77702-R and in part by the European Commission Horizon 2020 Programme, Capturing non-Amplified Tumor Circulating DA with Ultrasound Hidrodynamics, under Grant H2020-FETOPEN-2016-2017/737212-CATCH-U-DNA. M. Calero is the recipient of the doctoral fellowship BES-2017-080246 from the Ministerio de Economía, Industria y Competitividad de España.Calero-Alcarria, MDS.; Fernández Díaz, R.; Garcia Molla, P.; García Narbón, JV.; García, M.; Gamero-Sandemetrio, E.; Reviakine, I.... (2020). 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