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Microchip based electrochemical-piezoelectric integrated multi-mode sensing system for continuous glucose monitoring

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... Biosensors, as the name implies, are devices that detect biomolecular recognition events through the use of a transducer, converting the physiochemical reaction phenomenon into a measurable electrical output [8,14]. They enable a real-time, label-free, simple and miniaturized platform for detecting a wide range of analytes from biomolecules, namely disease-causing biomarker antigens; proteins; pathogenic microorganisms; complex nucleic acid molecules; glucose monitoring; pH monitoring; and blood coagulation monitoring [15][16][17][18][19][20][21][22]. Two basic components are generally required for a biosensor, namely a bioreceptor layer that detects the biomolecules, and a transducer. ...
... Apart from being capable of detecting mass, the electroacoustic property of piezoelectric acoustic waves makes them sensitive to the dielectric properties, such as the conductivity and permittivity of the bioreceptor layer, or the medium in contact with it. This enables the acoustic biosensors to detect various complex biological samples, such as glucose, intracellular pH, and uric acid, in the human serum [15,18,52]. The enzymatic reaction between targets, such as glucose or uric acid, and the specific bioreceptor results in the changes in the pH and, hence, the conductivity of the medium in contact with the acoustic sensor. ...
... The frequency response of the FBAR sensor with each step of surface mass addition, is shown in Figure 21b. FBAR biosensors are also used for the study of protein-ligand interactions and the detection of proteins and biomolecules, such as thrombin, glucose, and pesticides, making them a promising candidate for LOC and POC devices, as well as for industrial applications [15,46,176,193]. The detection of thrombin was demonstrated using SMR FBAR with a 25° tilted c-axis AlN with SiO2/TaOx fully insulating alternating layers of non-λ/4 thickness as Bragg reflectors, using the aptamer as a bioreceptor [46]. ...
Article
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Lab-on-a-chip (LOC) technology has gained primary attention in the past decade, where label-free biosensors and microfluidic actuation platforms are integrated to realize such LOC devices. Among the multitude of technologies that enables the successful integration of these two features, the piezoelectric acoustic wave method is best suited for handling biological samples due to biocompatibility, label-free and non-invasive properties. In this review paper, we present a study on the use of acoustic waves generated by piezoelectric materials in the area of label-free biosensors and microfluidic actuation towards the realization of LOC and POC devices. The categorization of acoustic wave technology into the bulk acoustic wave and surface acoustic wave has been considered with the inclusion of biological sample sensing and manipulation applications. This paper presents an approach with a comprehensive study on the fundamental operating principles of acoustic waves in biosensing and microfluidic actuation, acoustic wave modes suitable for sensing and actuation, piezoelectric materials used for acoustic wave generation, fabrication methods, and challenges in the use of acoustic wave modes in biosensing. Recent developments in the past decade, in various sensing potentialities of acoustic waves in a myriad of applications, including sensing of proteins, disease biomarkers, DNA, pathogenic microorganisms, acoustofluidic manipulation, and the sorting of biological samples such as cells, have been given primary focus. An insight into the future perspectives of real-time, label-free, and portable LOC devices utilizing acoustic waves is also presented. The developments in the field of thin-film piezoelectric materials, with the possibility of integrating sensing and actuation on a single platform utilizing the reversible property of smart piezoelectric materials, provide a step forward in the realization of monolithic integrated LOC and POC devices. Finally, the present paper highlights the key benefits and challenges in terms of commercialization, in the field of acoustic wave-based biosensors and actuation platforms.
... A variety of sensing techniques (e.g., electrochemical, optical, piezoelectric) have been proposed for CGM [27][28][29][30][31][32][33][34][35], but most of the devices currently available on the market exploit the glucoseoxidase electrochemical principle [18,36]. In this family of devices, a minimally-invasive wire-based sensor, placed subcutaneously in the abdomen or in the arm, measures a current signal generated by [15]. ...
... A variety of sensing techniques (e.g., electrochemical, optical, piezoelectric) have been proposed for CGM [27][28][29][30][31][32][33][34][35], but most of the devices currently available on the market exploit the glucose-oxidase electrochemical principle [18,36]. In this family of devices, a minimally-invasive wire-based sensor, placed subcutaneously in the abdomen or in the arm, measures a current signal generated by the glucose-oxidase reaction, transmitting information on glucose concentration in the interstitial fluid. ...
Article
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Minimally invasive continuous glucose monitoring (CGM) sensors are wearable medical devices that provide real-time measurement of subcutaneous glucose concentration. This can be of great help in the daily management of diabetes. Most of the commercially available CGM devices have a wire-based sensor, usually placed in the subcutaneous tissue, which measures a “raw” current signal via a glucose-oxidase electrochemical reaction. This electrical signal needs to be translated in real-time to glucose concentration through a calibration process. For such a scope, the first commercialized CGM sensors implemented simple linear regression techniques to fit reference glucose concentration measurements periodically collected by fingerprick. On the one hand, these simple linear techniques required several calibrations per day, with the consequent patient’s discomfort. On the other, only a limited accuracy was achieved. This stimulated researchers to propose, over the last decade, more sophisticated algorithms to calibrate CGM sensors, resorting to suitable signal processing, modelling, and machine-learning techniques. This review paper will first contextualize and describe the calibration problem and its implementation in the first generation of CGM sensors, and then present the most recently-proposed calibration algorithms, with a perspective on how these new techniques can influence future CGM products in terms of accuracy improvement and calibration reduction.
... It also proves that portable electrochemical device has been fabricated for bioassays, which could be operated by unskillful person at minimal volume of samples [10]. Importantly, electrochemical biosensor based on glucose enzyme reactions has played a major role in the continuous monitoring of glucose levels in personal glucometers [11]. ...
... Figure 3 shows the piezoelectric-biosensing performance of self-powered implantable skin-like glucometer. The device is completely immersed in the aqueous solution of glucose, as shown in Fig. 3a [46]. Under an applied deformation, the device (being bended) can transfer the mechanical energy to piezoelectric voltage that carries the information of glucose concentration. ...
Article
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Implantable bioelectronics for analyzing physiological biomarkers has recently been recognized as a promising technique in medical treatment or diagnostics. In this study, we developed a self-powered implantable skin-like glucometer for real-time detection of blood glucose level in vivo. Based on the piezo-enzymatic-reaction coupling effect of GOx@ZnO nanowire, the device under an applied deformation can actively output piezoelectric signal containing the glucose-detecting information. No external electricity power source or battery is needed for this device, and the outputting piezoelectric voltage acts as both the biosensing signal and electricity power. A practical application of the skin-like glucometer implanted in mouse body for detecting blood glucose level has been simply demonstrated. These results provide a new technique path for diabetes prophylaxis and treatment. Electronic supplementary material The online version of this article (10.1007/s40820-017-0185-x) contains supplementary material, which is available to authorized users.
... Acoustic resonators are reported as one of the represented active actuators to heat the droplets [14], [15] due to the dissipation of the acoustic energy into the liquid. In a recent work, we have demonstrated the rapid heating and mixing in liquid droplets using a MEMS fabricated solid-mounted film bulk acoustic resonator (SMR) [13], [16] which has a clear advantage of CMOS compatibility, high effective electromechanical coupling, high solution stability, and is able to generating micro-vortices at device-liquid interface to enhance the droplet mixing [17]- [19]. ...
Article
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This work reported a wireless controlled micro-actuator system for rapid heating and mixing of multiple droplets using integrated arrays of micro-fabricated 2.5 GHz solid-mounted thin-film piezoelectric resonators (SMRs) and a millimeter-scale omnidirectional antenna. An equivalent circuit is proposed to analyze the mechanism of the heating, mixing of the SMR and the wireless communication system. The heating and mixing rate can be tuned by adjusting the input power as well as the transmission distance between the transmitting antenna and the receiving antennas. A heating rate up to 3.7 °C per second and ultra-fast mixing of the droplet was demonstrated with the wireless microsystem. In addition, two types of circuits, H-shaped and rake-shaped, were designed and fabricated for parallel operating actuator array and controlling the power distribution with the array. Both uniform and gradient heating of the multiple droplets are achieved, which can be potentially applied for developing high-throughput wireless micro-reactor system.
... The shape of the device determines the profile of the AST. In this work, we take the best performance (quality factor, resonant frequency) as the priority principle of the device design; thus, a pentagonal UHF device with an area of 20 k μm 2 was used in this system 65,66 . Here, a 3D simulation model was applied to deeply analyze the interactions between lateral flow and the AST in 3D space. ...
Article
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At the single-cell level, cellular parameters, gene expression and cellular function are assayed on an individual but not population-average basis. Essential to observing and analyzing the heterogeneity and behavior of these cells/clusters is the ability to prepare and manipulate individuals. Here, we demonstrate a versatile microsystem, a stereo acoustic streaming tunnel, which is triggered by ultrahigh-frequency bulk acoustic waves and highly confined by a microchannel. We thoroughly analyze the generation and features of stereo acoustic streaming to develop a virtual tunnel for observation, pretreatment and analysis of cells for different single-cell applications. 3D reconstruction, dissociation of clusters, selective trapping/release, in situ analysis and pairing of single cells with barcode gel beads were demonstrated. To further verify the reliability and robustness of this technology in complex biosamples, the separation of circulating tumor cells from undiluted blood based on properties of both physics and immunity was achieved. With the rich selection of handling modes, the platform has the potential to be a full-process microsystem, from pretreatment to analysis, and used in numerous fields, such as in vitro diagnosis, high-throughput single-cell sequencing and drug development.
... The SMR is fabricated using a standard complementary metaloxide-semiconductor (CMOS) process, as presented in our previous paper. 22 This process is illustrated in Fig. 2 and can be described as follows. SMR devices are fabricated on 100-mm undoped Si wafers, beginning with the deposition of the Bragg reflector. ...
Article
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a r t i c l e i n f o Even as gigahertz (GHz) acoustic streaming has developed into a multi-functional platform technology for biochemical applications, including ultrafast microfluidic mixing, microparticle operations, and cellar or vesicle surgery , its theoretical principles have yet to be established. This is because few studies have been conducted on the use of such high frequency acoustics in microscale fluids. Another difficulty is the lack of velocimetry methods for microscale and nanoscale fluidic streaming. In this work, we focus on the basic aspects of GHz acoustic streaming, including its micro-vortex generation principles, theoretical model, and experimental characterization technologies. We present details of a weak-coupled finite simulation that represents our current understanding of the GHz-acoustic-streaming phenomenon. Both our simulation and experimental results show that the GHz-acoustic-induced interfacial body force plays a determinative role in vortex generation. We carefully studied changes in the formation of GHz acoustic streaming at different acoustic powers and flow rates. In particular, we developed a microfluidic-particle-image velocimetry method that enables the quantification of streaming at the microscale and even nanoscale. This work provides a full map of GHz acoustofluidics and highlights the way to further theoretical study of this topic.
... For enzyme-based microfluidic biosensors, the immobilization of enzymes is essential since the activity of electrode surfaces need to be maintained throughout the detection period. The enzymes are immobilized either on the surfaces of electrodes [16,17] or microchannels by techniques such as physical adsorption, sol-gel, and polymeric materials, covalent binding or cross-linking [11]. For example, by immobilizing the GOx on the surface of the PMMA channel, Ferreira et al. (2013) [18] developed a microfluidic reactor to achieve continuous glucose monitoring. ...
Article
Cellular metabolism involves complex sequences of controlled biochemical reactions and many chemical compounds or metabolites. The quantification of these metabolites will provide information on the dynamic cellular metabolism and the effect of environmental conditions. There have been extensive studies in this field since the last few decades, including the recent developments in microfluidic-based technologies. The article aims to provide a review on the current microfluidic detection techniques for quantifying the levels of main metabolites, including glucose, lactate, pyruvate, dissolved oxygen, pH and reactive oxygen species, with a focus on continuous and/or long-term detections. Most of the current developments are towards single metabolite detection and single-point or short-time detection techniques. There is increasing effort in the detection of multiple metabolites in microfluidics with integrated cell culturing. The future developments should address several major challenges such as cell culturing, long-term and sensitive detection of multiple metabolites in the dynamic cell environment.
... In recent years, various glucose-sensing mechanisms for non-invasive, or at least minimally invasive, CGM have been tested [18][19][20][21][22][23][24][25][26], in an attempt to match all fundamental requirements for an extended in vivo use, e.g., sensitivity, specificity, linearity within biological relevant range, biocompatibility, and lifetime [13]. Among all the proposed techniques, i.e., electrochemical, optical, and piezoelectric, the one that is today exploited by most of the commercialized CGM systems is the glucose-oxidase electrochemical principle [8]. ...
Article
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Worldwide, the number of people affected by diabetes is rapidly increasing due to aging populations and sedentary lifestyles, with the prospect of exceeding 500 million cases in 2030, resulting in one of the most challenging socio-health emergencies of the third millennium. Daily management of diabetes by patients relies on the capability of correctly measuring glucose concentration levels in the blood by using suitable sensors. In recent years, glucose monitoring has been revolutionized by the development of Continuous Glucose Monitoring (CGM) sensors, wearable non/minimally-invasive devices that measure glucose concentration by exploiting different physical principles, e.g., glucose-oxidase, fluorescence, or skin dielectric properties, and provide real-time measurements every 1-5 min. CGM opened new challenges in different disciplines, e.g., medicine, physics, electronics, chemistry, ergonomics, data/signal processing, and software development to mention but a few. This paper first makes an overview of wearable CGM sensor technologies, covering both commercial devices and research prototypes. Then, the role of CGM in the actual evolution of decision support systems for diabetes therapy is discussed. Finally, the paper presents new possible horizons for wearable CGM sensor applications and perspectives in terms of big data analytics for personalized and proactive medicine.
... Micro-sized water droplets have been widely used in multiple research fields, such as analytical chemistry [1], [2], precision engineering [3]- [7], biological sciences [8]- [12], etc. [13]- [17] In these droplet-based applications, for smoothing the edge of a substrate processed by wet etching [18], digitally studying pHsensitive enzymatic activities [19], [20] and precisely actuating intelligent structures made up of hydrogel and graphene [21]- [26], it is critical to produce ultramono-sized droplets with an exact pH value. However, currently, it is still a big challenge to achieve the goal explained above. ...
Preprint
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In this paper, a strategy to modify each micro-droplet’s volume and synchronously adjust its pH value as required based on the electrolysis reaction in silicone oil is demonstrated. A pair of platinum electrodes fixed onto the jaws of a vernier caliper was used to modify the micro-droplet’s volume and adjust its pH value by simply adjusting the distance between the two electrodes. To get a micro-droplet with desirable volume and pH values, three models, the relationship between the droplet’s volume and its diameter when the droplet was placed on a fluorinated ethylene propylene (FEP)–covered glass substrate, the relationship between the distance of the two electrodes and the size of the resulted micro-droplet, and the relationship between the pH value and the micro-droplet’s consuming rate, were built through the least square method. In our experiments, a droplet (5% sodium chloride solution, 1.4 uL, pH = 7) could consume 98.9% of its initial volume and form a new droplet with a volume of 0.016 µL and pH of 12.2. In addition, to validate that this method is also suitable in the acid and alkaline solutions, 0.001 mol/L NaOH and H2SO4 solutions were respectively operated using the same procedure. Both the volume and pH value could be controlled, which proved the potential application of our proposed method in analytical chemistry, precision engineering, etc.
... Owning to the development of microsystem and nanotechnology, acoustic devices based on piezoelectric materials have gained increasing attention in biochemical research field [41][42][43][44] which is due to their low cost, batch manufacturing, small volume and noninvasive to biomolecules [45][46][47]. Here, we demonstrated a novel and versatile controlled release approach using gigahertz ultrasound (hypersound) induced by a nano-electromechanical acoustic resonator composed of ultra-thin material layers (several tens to hundreds of nanometers thick). ...
Article
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Background Controllable and multiple DNA release is critical in modern gene-based therapies. Current approaches require complex assistant molecules for combined release. To overcome the restrictions on the materials and environment, a novel and versatile DNA release method using a nano-electromechanical (NEMS) hypersonic resonator of gigahertz (GHz) frequency is developed. Results The micro-vortexes excited by ultra-high frequency acoustic wave can generate tunable shear stress at solid–liquid interface, thereby disrupting molecular interactions in immobilized multilayered polyelectrolyte thin films and releasing embedded DNA strands in a controlled fashion. Both finite element model analysis and experiment results verify the feasibility of this method. The release rate and released amount are confirmed to be well tuned. Owing to the different forces generated at different depth of the films, release of two types of DNA molecules with different velocities is achieved, which further explores its application in combined gene therapy. Conclusions Our research confirmed that this novel platform based on a nano-electromechanical hypersonic resonator works well for controllable single and multi-DNA release. In addition, the unique features of this resonator such as miniaturization and batch manufacturing open its possibility to be developed into a high-throughput, implantable and site targeting DNA release and delivery system.
... The main contribution of the proposed study is to enhance the healthcare living facilities using IoMT for RHM of diabetic patients. Patients with diabetes need 24/7 monitoring [57,58] which can be achived by measuring the blood glucose (BG) level using wearable sensors [59][60][61][62]. ...
Article
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span>The latest advances and trends in information technology and communication have a vital role in healthcare industries. Theses advancements led to the Internet of Medical Things (IoMT) which provides a continuous, remote and real-time monitoring of patients. The IoMT architectures still face many challenges related to the bandwidth, communication protocols, big data and data volume, flexibility, reliability, data management, data acquisition, data processing and analytics availability, cost effectiveness, data security and privacy, and energy efficiency. The goal of this paper is to find feasible solutions to enhance the healthcare living facilities using remote health monitoring (RHM) and IoMT. In addition, the enhancement of the prevention, prognosis, diagnosis and treatment abilities using IoMT and RHM is also discussed. A case study of monitoring the vital signs of diabetic patients using real-time data processing and IoMT is also presented . </span
... In this work, UHF-AR works at resonant frequency of 1540 MHz with 1 um piezoelectric film. The fabrication process has been presented in detail in our previous published literatures [12,13]. The characterized width of the UHF-AR varies from nanometers to hundreds of micrometers, which is suitable to integrate with microfluidic systems. ...
Conference Paper
acoustofluidics. This paper reports a minimized bio-particles manipulation tool utilizing localized ultrahigh frequency acoustic resonators (UHF-AR). The resonator works at frequency of 1540 MHz, which is high enough to break through scale effect and trigger localized acoustofluidic streaming (in formation of 3-D vortices) within microfluidic systems. Especially, the vortices can be precisely tuned in principle, providing versatile manipulations of microparticles. In this paper, online trapping of particles with diameter from 50 nm to tens of micrometers has been demonstrated. Furthermore, single micro-scaled bioparticle can be well confined and locally rotated by the vortices. Compared with other acoustic tweezers, the UHF-AR acoustofluidic tool owns advantages of low power consumption, minimized size and IC-compatible fabrication, which enable it convenient to integrate with compliable lab-on-a-chip devices.
... Compared with typical transistors, the on-off ratio is greatly enhanced in acoustic transistors. The acoustic gra- phene transistor takes advantage of MEMS technology and graphene transistors, which is promising for development of integrated and multi-functional sensors and frequency comp- onents such as simultaneous detection of mass and electric charges and RF harvesters [31][32][33][34][35]. Our work demonstrates a paradigm of a hybrid MEMS and graphene device, taking a step forward in more-than-Moore technology. ...
Article
This paper introduces an on-chip acoustic graphene transistor based on lithium niobate thin film. The graphene transistor is embedded in a microelectromechanical systems (MEMS) acoustic wave device, and surface acoustic waves generated by the resonator induce a macroscopic current in the graphene due to the acousto-electric (AE) effect. The acoustic resonator and the graphene share the lithium niobate film, and a gate voltage is applied through the back side of the silicon substrate. The AE current induced by the Rayleigh and Sezawa modes was investigated, and the transistor outputs a larger current in the Rayleigh mode because of a larger coupling to velocity ratio. The output current increases linearly with the input radiofrequency power and can be effectively modulated by the gate voltage. The acoustic graphene transistor realized a five-fold enhancement in the output current at an optimum gate voltage, outperforming its counterpart with a DC input. The acoustic graphene transistor demonstrates a paradigm for more-than-Moore technology. By combining the benefits of MEMS and graphene circuits, it opens an avenue for various system-on-chip applications.
... Importantly, diabetes patients critically need 24/7 management [55]. Monitoring the blood glucose (BG) level using wearable sensors has a vital role in diabetes treatment revolution nowadays [56][57][58]. Table 2 shows wearable sensing technologies [59][60][61]. The proposed study aims to review wearable sensing technologies used to mangae and monitor T2D with PA. ...
Article
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Globally, the aging and the lifestyle lead to rabidly increment of the number of type two diabetes (T2D) patients. Critically, T2D considers as one of the most challenging healthcare issue. Importantly, physical activity (PA) plays a vital role of improving glycemic control T2D. However, daily monitoring of T2D using wearable devices/ sensors have a crucial role to monitor glucose levels in the blood. Nowadays, daily physical activity (PA) and exercises have been used to manage T2D. The main contribution of the proposed study is to review the literature about managing and monitoring T2D with daily PA through wearable devices and sensors. Finally, challenges and future trends are also highlighted. © 2021 Institute of Advanced Engineering and Science. All rights reserved.
... Training set data have been used also to estimate the error covariance matrix Σ e , used in (9). The error variance is assumed constant over time and its value is estimated from the distribution of the differences between SMBG measurements and the correspondent calibrated values (in mg/dL) given by the manufacturer. ...
Article
Objective: In most continuous glucose monitoring (CGM) devices used for diabetes management, the electrical signal measured by the sensor is transformed to glucose concentration by a calibration function whose parameters are estimated using self-monitoring of blood glucose (SMBG) samples. The calibration function is usually a linear model approximating the nonlinear relationship between electrical signal and glucose concentration in certain time intervals. Thus, CGM devices require frequent calibrations, usually twice a day. The aim here is to develop a new method able to reduce the frequency of calibrations. Methods: The algorithm is based on a multiple-day model of sensor time-variability with second-order statistical priors on its unknown parameters. In an online setting, these parameters are numerically determined by the Bayesian estimation exploiting SMBG sparsely collected by the patient. The method is assessed retrospectively on 108 CGM signals acquired for 7 days by the Dexcom G4 Platinum sensor, testing progressively less-calibration scenarios. Results: Despite the reduction of calibration frequency (on average from 2/day to 0.25/day), the method shows a statistically significant accuracy improvement compared to manufacturer calibration, e.g., mean absolute relative difference when compared to a laboratory reference decreases from 12.83% to 11.62% (p-value of 0.006). Conclusion: The methodology maintains (sometimes improves) CGM sensor accuracy compared to that of the original manufacturer, while reducing the frequency of calibrations. Significance: Reducing the need of calibrations facilitates the adoption of CGM technology both in terms of ease of use and cost, an obvious prerequisite for its use as replacement of traditional SMBG devices.
... The fabrication process of the Solid Mount Resonator (SMR) is according to a published procedure [24]. In brief, bragg reflectors of alternating AlN and SiO 2 layers are deposited on the silicon sub-strate, then 600 nm bottom molly electrode, 800 nm piezoelectric AlN layer and 300 nm top gold electrode was patterned on the bragg reflectors. ...
Article
On-chip integrating several functional components for developing integrated lab-on-a-chip microsystem remains as a challenge. In this work, by employing multiple microelectromechanical resonators both as actuators and sensors, on-chip heating, mixing and chemical reaction monitoring are successfully demonstrated. Mechanism studies using COMSOL simulations indicate that the local heating and mixing are induced by the acoustic wave attenuation during its transmission in liquid. On-line chemical reaction monitoring is realized by viscosity sensing using the same resonator through impedance analysis. Classic Diels-Alder reaction in a single droplet was performed to verify the feasibility of using such microsystem for mixing, heating and online reaction monitoring at microscale.
... The structure of SMR is presented in Fig. 1 (d)-(e), and the process is briefly described as follows: alternative thin films of silicon dioxide (SiO 2 ) and aluminum nitride (AlN) are deposited on the flat silicon substrate as the Bragg reflector (BR) layer using reaction sputtering system. And then the sandwiched structure of SMR is patterned following the process described in our previous published literatures 32,33 . As shown in Fig. 1 (d), the SMR device is Fig. 3 (a). ...
Article
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We present an acoustic microfluidic mixing approach via acousto-mechanically induced micro-vortices sustained by localized ultrahigh frequency (UHF) acoustic fields. A micro-fabricated solid-mounted thin-film piezoelectric resonator (SMR) with a frequency of 1.54 GHz has been integrated into microfluidic systems. Experimental and simulation results show that UHF-SMR triggers strong acoustic field gradients to produce efficient and highly localized acoustic streaming vortices, providing a powerful source for microfluidic mixing. Homogeneous mixing with 87% mixing efficiency at a Peclet number of 35520 within 1 ms has been achieved. The proposed strategy shows a great potential for microfluidic mixing and enhanced molecule transportation in minimized analytical systems.
... The GHz solid mounted thin film bulk acoustic resonator (SMR) was fabricated by standard CMOS compatible process [40]. Briefly, bragger reflector layers composed of three groups of aluminum nitride (AlN) and silicon dioxide (SiO 2 ) were deposited on undoped silicon wafer by plasma-enhanced chemical vapor deposition (PECVD) and reactive sputtering, respectively. ...
Article
Currently, researches on nanomaterials have been restricted by slow and multistep synthesis procedures. Herein, we demonstrate an ultrafast, one step method of purification and delivery of quantum dots into living cells, actuated by the acoustic streaming (AS) produced through a gigahertz resonator. Results demonstrate that the impurities in the carbon dots (CDs) can be extracted immediately aided by the acoustic forcing, with extra high purification efficiency of 93%. The system can also efficiently deliver the CDs into cells, showing excellent nucleus and mitochondria uptake under 3 min of acoustic streaming treatment, and making the organelles of cells to be recorded more easily and simultaneously. More importantly, the AS is found to further accelerate the bioreaction inside the cells, thus realizes the enhanced biosensing of Fe³⁺ in single living cells. This work develops a novel type of multifunctional method for effective purification, intracellular delivery and biosensing of nanomaterials, inspiring the biological/medical nanotechnology researches at subcellular level.
... Then, the sandwiched structure of the SMR is patterned following the process described in our previous published literatures. 32,33 As shown in Fig. 1(d), the SMR device is integrated into a Y-shape microfluidic chip by permanent bonding of the device with the polydimethylsiloxane (PDMS) channel and leaving the SMR in the center of the channel. The Y-shape PDMS microchannel is designed with the height of 40 lm and the width of 600 lm, which is prepared using standard soft lithography. ...
Article
We present an acoustic microfluidic mixing approach via acousto-mechanically induced microvortices sustained by localized ultrahigh frequency (UHF) acoustic fields. A micro-fabricated solid-mounted thin-film piezoelectric resonator (SMR) with a frequency of 1.54 GHz has been integrated into microfluidic systems. Experimental and simulation results show that UHF-SMR triggers strong acoustic field gradients to produce efficient and highly localized acoustic streaming vortices, providing a powerful source for microfluidic mixing. Homogeneous mixing with 87% mixing efficiency at a Peclet number of 35520 within 1 ms has been achieved. The proposed strategy shows a great potential for microfluidic mixing and enhanced molecule transportation in minimized analytical systems.
... The development of microfabrication technology has offered new opportunities for miniaturization of devices and integration of multifunctional sensors on a single chip. Zhao et al. introduced a novel CMOS-compatible microelectromechanical sensing system that integrates four pairs of electrochemical working electrodes and SMR on one chip (Zhao et al. 2016). This system enables detection of analytes with three sensing modes: electrochemistry, gravimetry, and viscometry. ...
Article
The hydrodynamic method mimics the in vivo environment of the mechanical effect on cell stimulation, which not only modulates cell physiology but also shows excellent intracellular delivery ability. Herein, a hydrodynamic intracellular delivery system based on the gigahertz acoustic streaming (AS) effect is proposed, which presents powerful targeted delivery capabilities with high efficiency and universality. Results indicate that the range of cells with AuNR introduction is related to that of AS, enabling a tunable delivery range due to the adjustability of the AS radius. Moreover, with the assistance of AS, the organelle localization delivery of AuNRs with different modifications is enhanced. AuNRs@RGD is inclined to accumulate in the nucleus, while AuNRs@BSA tend to enter the mitochondria and AuNRs@PEGnK tend to accumulate in the lysosome. Finally, the photothermal effect is proved based on the large quantities of AuNRs introduced via AS. The abundant introduction of AuNRs under the action of AS can achieve rapid cell heating with the irradiation of a 785 nm laser, which has great potential in shortening the treatment cycle of photothermal therapy (PTT). Thereby, an efficient hydrodynamic technology in AuNR introduction based on AS has been demonstrated. The outstanding location delivery and organelle targeting of this method provides a new idea for precise medical treatment.
Article
Nonspecific binding (NSB) is a general issue for surface based biosensors. Various approaches have been developed to prevent or remove the NSBs. However, these approaches either increased the background signals of the sensors or limited to specific transducers interface. In this work, we developed a hydrodynamic approach to selectively remove the NSBs using a microfabricated hypersonic resonator with 2.5 gigahertz (GHz) resonant frequency. The high frequency device facilitates to generate multiple controlled micro-vortices which then create cleaning forces at the solid-liquid interfaces. The competitive adhesive and cleaning forces have been investigated using the finite element method (FEM) simulation, identifying the feasibility of the vortices induced NSB removal. NSB proteins have been selectively removed experimentally both on the surface of the resonator and on other substrates which contact the vortices. Thus, the developed hydrodynamic approach is believed to be a simple and versatile tool for NSB removal and compatible to many sensor systems. The unique feature of the hypersonic resonator is that it can be used as a gravimetric sensor as well, thus a combined NSB removal and protein detection dual functional biosensor system is developed.
Chapter
This chapter reports on the state of the art of piezoelectric micro-/nano-mechanical devices in frequency control and sensing applications. Recent studies on bulk acoustic wave (BAW) devices are introduced, including investigation of high-coupling materials and filter and oscillator designs. A novel class of frequency devices based on Lamb waves is also reviewed. Micro- and nano-mechanical sensors for various sensing applications and integrated module are outlined.
Article
This review provides an overview of the current state‐of‐the‐art of the emerging field of flexible multifunctional sensors for wearable and robotic applications. In these application sectors, there is a demand for high sensitivity, accuracy, reproducibility, mechanical flexibility, and low cost. The ability to empower robots and future electronic skin (e‐skin) with high resolution, high sensitivity, and rapid response sensing capabilities is of interest to a broad range of applications including wearable healthcare devices, biomedical prosthesis, and human–machine interacting robots such as service robots for the elderly and electronic skin to provide a range of diagnostic and monitoring capabilities. A range of sensory mechanisms is examined including piezoelectric, pyroelectric, piezoresistive, and there is particular emphasis on hybrid sensors that provide multifunctional sensing capability. As an alternative to the physical sensors described above, optical sensors have the potential to be used as a robot or e‐skin; this includes sensory color changes using photonic crystals, liquid crystals, and mechanochromic effects. Potential future areas of research are discussed and the challenge for these exciting materials is to enhance their integration into wearables and robotic applications. Flexible multifunctional sensors can provide intelligent sensing for wearable and human–machine interacting robots. This review focuses on recent progress in the development and advancement of flexible and multifunctional sensors based on a range of sensory mechanisms and materials including piezoelectric, conductive, and optical materials. Potential future research directions and challenges are discussed.
Article
In this paper, multi-mode sensing for the detections of methotrexate (MTX), rutin (RT), quercetin (QCT) and temperature were achieved by a type of highly fluorescent CDs, benefiting from an excitation dependent emission combined with different quenching mechanisms. The highly luminescent CDs were prepared by a simple hydrothermal pyrolysis of citric acid and monoethanolamine at 180 °C for 4 h with a high quantum yield of 46.6%, exhibiting an excitation dependent emission. An approach to the detection of MTX was built by using the CDs as a sensor under excitation at 370 nm based on the synergistic action of inner filter effect (IFE) and photo induced electron transfer (PET). Although the absorption spectra of RT and QCT both centered at 350 nm are entirely overlapped, the maximum absorption of QCT can be moved from 350 to 430 nm since it forms a coordination complex with Cu²⁺ under acidic condition. Assisted by Cu²⁺, detections of individual RT and QCT were therefore achieved by the CDs via IFE under excitation at 350 and 430 nm, respectively. Moreover, a nanosensor for temperature sensing was also fabricated according to temperature caused aggregation of the CDs and aggregation induced quenching effect.
Article
Utilizing biosensors for multiplexed detection can greatly increase analysis throughput and thus, the amount of information obtained in a single assay. The microfluidic chip, a type of micro-total analysis system (µTAS), has provided a necessary platform for portable and high-throughput biosensors. Biosensors and microfluidic chips are powerful individually, and their super combination is very meaningful for analytical especially for biological applications. In this paper, every kind of microfluidic-chip-integrated electronic biosensors including some emerging technologies for simultaneous detection of multiple analytes are reviewed. Different ways to reduce or avoid cross-talking and more efforts to achieve lab on chip multisensors were also introduced to help readers form a general idea of current developments in different angles.
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We present a nanoscale acoustofluidic trap (AFT) which manipulates nanoparticles in a microfluidic system actuated by a gigahertz acoustic resonator. The AFT generates independent standing closed vortices with high-speed rotation. By carefully designing and optimizing the geometric confinements, the AFT is able to effectively capture and enrich sub-100 nm nanoparticles with low power consumption (0.25~5 μW/μm2) and rapid trapping (within 30 s), showing greatly enhanced particle operating ability towards its acoustic and optical counterparts. Using specifically functionalized nanoparticles (SFNPs) to selectively capture target molecules from the sample, the AFT produces a molecular concentration enhancement of ~200 times. We investigated the feasibility of the SFNPs-assisted AFT preconcentration method for biosensing applications, and successfully demonstrated its capability for serum prostate specific antigen (PSA) detection. The AFT is prepared with a fully CMOS-compatible process, and thus can be conveniently integrated on a single chip, with potential for “lab-on-a-chip” or point-of-care (POC) nanoparticle-based biosensing applications.
Article
High‐throughput screening, early diagnosis, prognosis, daily routine, and real‐time monitoring are the main factors in diabetes management. Novel nanodynamic sensory designs can support these processes by offering i) a great diversity of periodic glucose sensing assays, ii) multiple and large‐scale autosampling assessments of glucose levels, and iii) possible glucose analysis by using a small sample size. This work highlights the nano, biosensor design engineering rationales used to explore a wide range of glucose levels and transduce them into readable output signals for dead‐end and fast‐response analyses. Powerful nanoscale chemical sensor designs can be used as alternatives to traditional assessment and analytical methods in the laboratory and integrated into robotics, smartphones, or wearable devices. These innovations would offer the future steady progress required for biotechnological, analytical, and sensing applications with less time consumption and simple operation. A new generation of nano, bioglucose sensor designs featuring platforms with nanometric dimensions, geometries, surface functionality, and physical/chemical properties is also attractive as a candidate for developing diabetic sensing devices. Indeed, the developed fabrication of diabetic nanosensor devices with compact size miniaturization, autosampling analysis and collection, in situ controlling assays, and defined signaling read‐out detection is urgently needed to avoid a risk associated with diabetes. The nanoscale sensor is one of the most reliable cornerstones for nanofuture diabetes devices. The nano, biosensor glucose designs with readable output signals and rapid response analyses offer alternatives to traditional detection techniques. Integrating wearable sensor devices into robots and smartphones is a future of diabetic monitoring.
Article
Here, we present a high performance uncooled near-infrared (NIR) detector comprising of a giga hertz (GHz) solidly mounted resonator (SMR) and gold nanorods (GNRs) arrays. By coupling the localized surface plasmon resonances of GNRs, the resonator system exhibits optimized optical response to vis-NIR region. Both simulation and experiments demonstrate the hybrid GNRs-SMR exhibit significantly enhanced optical responsive sensitivity of NIR, the tunable aspect ratios (AR) of GNRs enable resonator respond sensitively to selected light. Specially, taking advantage of the acoustofluidic effect of SMR, the GNRs can be controllably and precisely modified on the microchip surface in an ultra-short time, which addresses one of the most fundamental challenges in the localized functionalization of micro/nano scale surface. The presented work opens new directions in development of novel miniaturized, tunable NIR detector.
Article
The development of rapid and efficient tools to modulate neurons is vital for the treatment of nervous system diseases. Here, a novel non-invasive neurite outgrowth modulation method based on a controllable acoustic streaming effect induced by an electromechanical gigahertz resonator microchip is reported. The results demonstrate that the gigahertz acoustic streaming can induce cell structure changes within a 10 min period of stimulation, which promotes a high proportion of neurite bearing cells and encourages longer neurite outgrowth. Specifically, the resonator stimulation not only promotes outgrowth of neurites, but also can be combined with chemical mediated methods to accelerate the direct entry of nerve growth factor (NGF) into cells, resulting in higher modulation efficacy. Owing to shear stress caused by the acoustic streaming effect, the resonator microchip mediates stress fiber formation and induces the neuron-like phenotype of PC12 cells. We suggest that this method may potentially be applied to precise single-cell modulation, as well as in the development of non-invasive and rapid disease treatment strategies.
Article
To improve the sensing performance of the traditional semiconductor sensor towards triethylamine (TEA), the poly(diallyldimethylammonium chloride) (PDDA) has been applied to functionalize the reduced graphene oxide (rGO), which has been further decorated by the polyaniline (PANI) nanocones via an in-situ polymerization method. The existence of PDDA during the synthetic process could efficiently prevent the restacking of rGO and promote the reduction of graphene oxide, which is beneficial for producing uniform PANI nanocones on the rGO sheets and improving the sensitivity to TEA. The sensor fabricated by the PDDA-rGO-PANI has exhibited excellent sensing performance to the TEA with superior sensitivity, stability and selectivity at room temperature. The sensor possesses a perfect linear coefficient of 0.999 from 2 to 100 ppm TEA and an extremely low limit-of-detection (LOD) of 74 ppb. In addition, the sensor has presented an outstanding anti-interference ability against humidity, other interfering gases (ammonia and common VOCs) and even mechanical bending. Finally, a self-powered sensing system containing a homemade triboelectric nanogenerator (TENG), a commercial flexible electrode, a button battery and the integrated circuit LTC3588 has been fabricated. The size of TENG is only 3.5×3.5 cm² while the sensing system after integrated on a PI membrane is just 2×4 cm², which makes the sensor a promising potential candidate of wearable sensing to TEA in daily life.
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The c-axis zinc oxide (ZnO) multi-layered films and ZnO-based solidly mounted resonators (SMR) based on high-resistivity silicon substrates have been fabricated by using the combination of sputtering and photolithography with the absence of oxygen and heating. Subsequent annealing procedure was performed to improve the quality of ZnO films and devices. The X-ray diffraction (XRD) measurements reveal that all ZnO films are well crystallized and highly textured, the grain size gradually increases from 18.2 to 20.5 nm with the increasing of annealing temperature (Tann). The X-ray photoelectron spectrometer (XPS) results indicate that the high concentration oxygen defects of as-deposited ZnO films can be reduced through increasing Tann. By comparing the measured electrical properties of the devices before and after various Tann annealing, it was found that the annealing treatment can be used to improve the resonance characteristics, the relative change in return loss (S11) increased from 0 to 0.72 dB and then decreased to 0.07 dB as Tann increases from room temperature to 700 °C. In addition, S11 relative change can also be enhanced from 0.29 to 0.67 by decreasing the effective working area of the devices from 100 × 160 μm² to 100 × 50 μm².
Article
Cell mechanical motion is a key physiological process that relies on the dynamics of actin filaments. Herein, a localized shear-force system based on gigahertz acoustic streaming (AS) is proposed, which can simultaneously realize intracellular delivery and cellular mechanical regulation. The results demonstrate that gold nanorods (AuNRs) can be delivered into the cytoplasm and even the nuclei of cancer and normal cells within a few minutes by AS stimulation. The delivery efficiency of AS stimulation is four times higher than that of endocytosis. Moreover, AS can effectively promote cytoskeleton assembly, regulate cell stiffness and change cell morphology. Since the inhibitory effect of AuNRs on cytoskeleton assembly, this AuNRs-AS system is able to inhibit or promote cell mechanical motion in a controlled manner by regulating the mechanical properties of cells. The bidirectional regulation of cell motion is further verified via scratch experiments, in which AuNRs-treated cells recover their motion ability through AS stimulation. In particular, the results of AuNRs-AS mechanical regulation on cell are related to the intrinsic properties of cell lines, revealing to more obvious effects on the cells with higher motor capacities. In summary, this acoustic technology has shown superiorities in controllable cell-motion manipulation, indicating its potential in building a multifunctional, integrated cytomechanics regulation platform.
Article
In this work, a novel enzymatic electrochemiluminescent (ECL) biosensor based on the sensitization from Au/TiO2 nano-composite was prepared for noninvasive glucose detection. The Au/TiO2 nano-composite was deposited on the surface of indium tin oxide glass by Nafion, which significantly enhanced the ECL of luminol after calcination, and a sensitive response toward hydrogen peroxide was obtained. Glucose oxidase was cross-linked with bovine serum albumin by glutaraldehyde and immobilized on electrode surface. It worked as the sensing matrix and catalyzed the oxidation of glucose to produce H2O2, thus an enhanced ECL emission was resulted. Under the optimized conditions, this biosensor showed good stability, selectivity, sensitivity and simplicity. It has a wide linear range for the detection of glucose from 7.0 μM to 100 μM with a detection limit of 0.22 μM. The sensor has been successfully applied to detect glucose in diluted human serums and saliva samples. Therefore, this sensor could be regarded as a simple, practical and disposable device in a noninvasive manner of routine glucose monitoring for diabetics.
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The purpose of this work was to measure viscosity of fluids at low microliter volumes by means of quartz crystal impedance analysis. To achieve this, a novel setup was designed that allowed for measurement of viscosity at volumes of 8 to 10 microL. The technique was based on the principle of electromechanical coupling of piezoelectric quartz crystals. The arrangement was simple with measurement times ranging from 2 to 3 minutes. The crystal setup assembly did not impose any unwanted initial stress on the unloaded quartz crystal. Quartz crystals of 5- and 10-MHz fundamental frequency were calibrated with glycerol-water mixtures of known density and viscosity prior to viscosity measurements. True frequency shifts, for the purpose of this work, were determined followed by viscosity measurement of aqueous solutions of sucrose, urea, PEG-400, glucose, and ethylene glycol at 25 degrees C +/- 0.5 degrees C. The measured viscosities were found to be reproducible and consistent with the values reported in the literature. Minor inconsistencies in the measured resistance and frequency shifts did not affect the results significantly, and were found to be experimental in origin rather than due to electrode surface roughness. Besides, as expected for a viscoelastic fluid, PEG 8000 solutions, the calculated viscosities were found to be less than the reported values due to frequency dependence of storage and loss modulus components of complex viscosity. From the results, it can be concluded that the present setup can provide accurate assessment of viscosity of Newtonian fluids and also shows potential for analyzing non-Newtonian fluids at low microliter volumes.
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A novel amperometric glucose biosensor based on the nine layers of multilayer films composed of multi-wall carbon nanotubes (MWCNTs), gold nanoparticles (GNp) and glucose oxidase (GOD) was developed for the specific detection of glucose. MWCNTs were chemically modified with the H(2)SO(4)-HNO(3) pretreatment to introduce carboxyl groups which were used to interact with the amino groups of poly(allylamine) (PAA) and cysteamine via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide cross-linking reaction, respectively. A cleaned Pt electrode was immersed in PAA, MWCNTs, cysteamine and GNp, respectively, followed by the adsorption of GOD, assembling the one layer of multilayer films on the surface of Pt electrode (GOD/GNp/MWCNTs/Pt electrode). Repeating the above process could assemble different layers of multilayer films on the Pt electrode. PBS washing was applied at the end of each assembly deposition for dissociating the weak adsorption. Film assembling and characterization were studied by transmission electron microscopy and quartz crystal microbalance, and properties of the resulting glucose biosensors were measured by electrochemical measurements. The marked electrocatalytic activity of Pt electrode based on multilayer films toward H(2)O(2) produced during GOD enzymatic reactions with glucose permitted effective low-potential amperometric measurement of glucose. Taking the sensitivity and selectivity into consideration, the applied potential of 0.35 V versus Ag/AgCl was chosen for the oxidation detection of H(2)O(2) in this work. Among the resulting glucose biosensors, the biosensor based on nine layers of multilayer films was best. It showed a wide linear range of 0.1-10mM glucose, with a remarkable sensitivity of 2.527 microA/mM, a detection limit of 6.7 microM estimated at a signal-to-noise ratio of 3 and fast response time (within 7s). Moreover, it exhibited good reproducibility, long-term stability and the negligible interferences of ascorbic acid, uric acid and acetaminophen. The study can provide a feasible approach on developing new kinds of oxidase-based amperometric biosensors, and can be used as an illustration for constructing various hybrid structures.
Article
This paper describes the development of ISFETs in an historical setting, but is not limited to that. Based on the development regarding the theory, the technology, the instrumentation and the experience with many specific applications, also future projects are defined, such as concerning cell acidification, REFET biasing and a complete new range of FET sensors based on local pressure induction by (bio)chemical interaction with immobilised charged molecules (hydrogels). Also the present patent and market position is discussed. It is concluded that in the past 30 years the ISFET research and development made continuous progress on a regular base, but the practical applications stayed behind, especially concerning the dynamic use of ISFETs in combination with an integrated pH actuator. The newly proposed research projects may be good for an other 30 years.
Article
In this study, we proposed and demonstrated a novel simultaneous analysis system of biosensing by combining semiconductor-based field effect transistor (FET) with quartz crystal microbalance with dissipation (QCM-D) monitoring system. Using the combined system, the changes of not only mass and viscoelasticity but also electrical charge for interaction of charged dextran molecules with substrate, recognition of glucose with low molecular weight and programmed cell death, apoptosis were simultaneously and quantitatively monitored in a label-free and real-time manner. The combined system will give more detailed information of bio-molecule/substrate interface for development of new bio-material.
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When multilayer films are built up with polycations and polyanions, their thickness can grow either linearly or exponentially with the number of deposited layer pairs, depending for example on the nature of the polyelectrolytes used. We investigate in the present work the construction of a film using a binary mixture of polyanions as polyanion solution. The two anionic components are chosen such that one of them causes the film to grow linearly while the other causes the film to grow exponentially. It is observed that a mixture of both components leads to a hybrid growth law, depending on its composition. At the beginning of the construction, the thickness of the film increases exponentially with the number of deposited bilayers. Once a given thickness is reached, one observes the crossover to a linear growth regime. This finding is discussed on the basis of the diffusion coefficients of the polyanions that are assumed to diffuse “in” and “out” of the film.
Article
Exponentially growing layer-by-layer (e-LBL) assembled films attracts a lot of attention mostly due to multiple practical applications in biology and medicine. However, e-LBL was observed only for a very limited number of polymers. This fact inevitably limits the area of research and functionalities that one can obtain for them. Also, it is fundamentally important to gain better understanding of the effect and importance of molecular flexibility for e-LBL films. Here we report that dispersions of rod-like nanocolloids such as single walled carbon nanotubes (SWNTs) and nanowires (NWs) can spontaneously “bore into” and stay in the e-LBL matrix. Molecular rigidity and surface charge appear to be the key parameters determining the possibility of such a process and its extent. SWNT forms a thick 2−25 μm penetration layer, while insufficient flexibility leads to hedgehog structures in the case of CdTe and Te NWs. Electrical properties of the films obtained display fundamental differences with SWNT composites made by standard methods. They were attributed to thermal activation of vibrational modes of film components disturbing nanotube-to-nanotube tunneling. The dynamic nature of the e-LBL film combined with unique SWNTs properties can lead to a new type of smart materials and can help a better understanding of methods of morphological control in nanocomposites.
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The application of portable, easy-to-use and highly sensitive lab-on-a-chip biosensing devices for real-time diagnosis could offer significant advantages over current analytical methods. Integrated optics-based biosensors have become the most suitable technology for lab-on-chip integration due to their ability for miniaturization, their extreme sensitivity, robustness, reliability, and their potential for multiplexing and mass production at low cost. This review provides an extended overview of the state-of-the-art in integrated photonic biosensors technology including interferometers, grating couplers, microring resonators, photonic crystals and other novel nanophotonic transducers. Particular emphasis has been placed on describing their real biosensing applications and wherever possible a comparison of the sensing performances between each type of device is included. The way towards achieving operative lab-on-a-chip platform incorporating the photonic biosensors is also reviewed. Concluding remarks regarding the future prospects and potential impact of this technology are also provided.
Article
Organic electrochemical transistors with glucose oxidase-modified Pt gate electrodes are successfully used as highly sensitive glucose sensors. The gate electrodes are modified with nanomaterials (multi-wall carbon nanotubes or Pt nanoparticles) for the first time, which results in a dramatic improvement in the sensitivity of the devices. The detection limit of the device modified with Pt nanoparticles on the gate electrode is about 5 nM, which is three orders of magnitude better than a device without the nanoparticles. The improvement of the device performance can be attributed to the excellent electrocatalytic properties of the nanomaterials and more effective immobilization of enzyme on the gate electrodes. Based on the same principle, many other types of enzyme sensors with high sensitivity and low cost are expected to be realized by modifying the gate electrodes of organic electrochemical transistors with specific enzymes and nanomaterials.
Article
We report investigations on the use of film bulk acoustic resonators for the label-free, multiplexed biosensing of DNA and proteins. The used acoustic resonators were operated in shear mode at about 800 MHz. From the measured changes of frequency and in dissipation, the mass and the viscoelasticity of biomolecular films formed at the top electrode of the device could be derived, respectively. A mass sensitivity of ∼2 kHz cm2/ng and a minimum detectable mass of ∼1 ng/cm2 were achieved. To demonstrate the highly sensitive detection of the time evolution of protein adsorption, the adsorption kinetics and recrystallisation of bacterial surface layer proteins on gold surfaces were investigated.
Article
Poly(diallyldimethylammonium chloride) (PDDA) was chosen to disperse single-walled carbon nanotubes (SWCNTs). The optimal conditions to prepare stable PDDA–SWCNTs aqueous dispersions were presented. Then, the positively charged PDDA–SWCNTs composite and negatively charged glucose oxidase (GOD) were employed to fabricate multilayer films on platinum (Pt) electrodes by layer-by-layer self-assembly technique. The consecutive growth of the multilayer films was confirmed by quartz crystal microbalance. Electrochemical measurements were used to study the properties of the proposed biosensor. Results demonstrated that SWCNTs were evenly dispersed within the PDDA films and efficiently improved the conductivity of the resulting films. Among the biosensors, the one based on seven layers of multilayer films got the best performance. It showed wide linear range of 0.05–12 mM, high sensitivity of 63.84 μA/(mM cm2), low detection limit of about 4 μM and small value of the apparent Michaelis–Menten constant, 8.46 mM. In addition, the biosensor also exhibited good suppression of interference and long-term operational stability. This protocol could be used to immobilize other enzymes to construct a range of biosensors.
Article
This paper describes the development of ISFETs in an historical setting, but is not limited to that. Based on the development regarding the theory, the technology, the instrumentation and the experience with many specific applications, also future projects are defined, such as concerning cell acidification, REFET biasing and a complete new range of FET sensors based on local pressure induction by (bio)chemical interaction with immobilised charged molecules (hydrogels). Also the present patent and market position is discussed. It is concluded that in the past 30 years the ISFET research and development made continuous progress on a regular base, but the practical applications stayed behind, especially concerning the dynamic use of ISFETs in combination with an integrated pH actuator. The newly proposed research projects may be good for an other 30 years.
Article
This paper presents a review of acoustic-wave based MEMS devices that offer a promising technology platform for the development of sensitive, portable, real-time biosensors. MEMS fabrication of acoustic wave based biosensors enables device miniaturization, power consumption reduction and integration with electronic circuits. For biological applications, the biosensors are integrated in a microfluidic system and the sensing area is coated with a biospecific layer. When a bioanalyte interacts with the sensing layer, mass and viscosity variations of the biospecific layer can be detected by monitoring changes in the acoustic wave properties such as velocity, attenuation, resonant frequency and delay time. Few types of acoustic wave devices could be integrated in microfluidic systems without significant degradation of the quality factor. The acoustic wave based MEMS devices reported in the literature as biosensors and presented in this review are film bulk acoustic wave resonators (FBAR), surface acoustic waves (SAW) resonators and SAW delay lines. Different approaches to the realization of FBARs, SAW resonators and SAW delay lines for various biochemical applications are presented. Methods of integration of the acoustic wave MEMS devices in the microfluidic systems and functionalization strategies will be also discussed.
Article
Piezoelectric microelectromechanical systems (MEMS) resonant sensors, known for their excellent mass resolution, have been studied for many applications, including DNA hybridization, protein-ligand interactions, and immunosensor development. They have also been explored for detecting antigens, organic gas, toxic ions, and explosives. Most piezoelectric MEMS resonant sensors are acoustic sensors (with specific coating layers) that enable selective and label-free detection of biological events in real time. These label-free technologies have recently garnered significant attention for their sensitive and quantitative multi-parameter analysis of biological systems. Since piezoelectric MEMS resonant sensors do more than transform analyte mass or thickness into an electrical signal (e.g., frequency and impedance), special attention must be paid to their potential beyond microweighing, such as measuring elastic and viscous properties, and several types of sensors currently under development operate at different resonant modes (i.e., thickness extensional mode, thickness shear mode, lateral extensional mode, flexural mode, etc.). In this review, we provide an overview of recent developments in micromachined resonant sensors and activities relating to biochemical interfaces for acoustic sensors.
Article
A novel set-up combining the quartz crystal microbalance with dissipation monitoring technique (QCM-D) and electrochemical impedance spectroscopy (EIS) under flow conditions was successfully used to follow supported lipid bilayer (SLB) formation on SiO(2). This study demonstrates the simultaneous detection, in real time, of both the electrical and the structural properties of the SLB. The combination of the two techniques provided novel insights regarding the mechanism of SLB formation: we found indications for an annealing process of the lipid alkyl chains after the mass corresponding to complete bilayer coverage had been deposited. Moreover, the interaction of the SLB with the pore-forming toxin, gramicidin D (grD) was studied for grD concentrations ranging from 0.05 to 40 mg L(-1). Membrane properties were altered depending on the toxin concentration. For low grD concentrations, the electrical properties of the SLB changed upon insertion of active ion channels. For higher concentrations, the QCM-D data showed dramatic changes in the viscoelastic properties of the membrane while the EIS spectra did not change. AFM confirmed significant structural changes of the membrane at higher grD concentrations. Thus, the application of combined QCM-D and EIS detection provides complementary information about the system under study. This information will be particularly important for the continued detailed investigation of interactions at model membrane surfaces.
Article
Piezoelectric sensors are acoustic sensors that enable the selective and label-free detection of biological events in real time. These sensors generate acoustic waves and utilize measurements of the variation of the wave propagation properties as a signal for probing events at the sensor surface. Quartz crystal microbalance (QCM) devices, the most widespread acoustic resonators, allow the study of viscoelastic properties of matter, the adsorption of molecules, or the motility of living cells. In a tutorial-like approach, this review addresses the physical principles associated with the QCM, as well as the origin and effects of major interfering phenomena. Special attention is paid to the possibilities offered by QCM that go beyond microweighing, and important recent examples are presented.
Article
Micro-total analysis systems (microTAS) integrate different analytical operations like sample preparation, separation and detection into a single microfabricated device. With the outstanding advantages of low cost, satisfactory analytical efficiency and flexibility in design, highly integrated and miniaturized devices from the concept of microTAS have gained widespread applications, especially in biochemical assays. Electrochemistry is shown to be quite compatible with microanalytical systems for biochemical assays, because of its attractive merits such as simplicity, rapidity, high sensitivity, reduced power consumption, and sample/reagent economy. This review presents recent developments in the integration of electrochemistry in microdevices for biochemical assays. Ingenious microelectrode design and fabrication methods, and versatility of electrochemical techniques are involved. Practical applications of such integrated microsystem in biochemical assays are focused on in situ analysis, point-of-care testing and portable devices. Electrochemical techniques are apparently suited to microsystems, since easy microfabrication of electrochemical elements and a high degree of integration with multi-analytical functions can be achieved at low cost. Such integrated microsystems will play an increasingly important role for analysis of small volume biochemical samples. Work is in progress toward new microdevice design and applications.
Article
Effective systems for rapid, sequence-specific nucleic acid detection at the point of care would be valuable for a wide variety of applications, including clinical diagnostics, food safety, forensics, and environmental monitoring. Electrochemical detection offers many advantages as a basis for such platforms, including portability and ready integration with electronics. Toward this end, we report the Integrated Microfluidic Electrochemical DNA (IMED) sensor, which combines three key biochemical functionalities--symmetric PCR, enzymatic single-stranded DNA generation, and sequence-specific electrochemical detection--in a disposable, monolithic chip. Using this platform, we demonstrate detection of genomic DNA from Salmonella enterica serovar Typhimurium LT2 with a limit of detection of <10 aM, which is approximately 2 orders of magnitude lower than that from previously reported electrochemical chip-based methods.
Article
Direct biosensors are devices operating by monitoring the amount of surface-bound analyte. In this work a new approach is presented where a label-free acoustic biosensor, based on a QCM-D device, and solution viscosity theory, are used to study DNA intrinsic viscosity. The latter is quantitatively related to the DNA conformation and specifically the molecule's shape and size, in a manner that is independent of the amount of bound DNA mass. It is shown that acoustic measurements can clearly distinguish between ds-DNA of same shape (straight rod) but various sizes (from 20 to 198bp (base pairs)) and same mass and size (90bp) but various shapes ("straight", "bent", "triangle"). These results are discussed in the broader context of "coil" and sphere-like molecules detected on surfaces. A mathematical formula is presented relating the length of straight, surface-protruding DNA to the acoustic ratio DeltaD/Deltaf. The development of real-time rapid techniques for the characterization of DNA intrinsic curvature as well as DNA conformational changes upon interaction with proteins is of significance to analytical biotechnology due to the large number of DNA sequences and potential DNA bending proteins involved in genome analysis and drug screening.
Article
The base pair stack within double helical DNA provides an effective medium for charge transport. The DNA pi-stack mediates oxidative DNA damage over long molecular distances in a reaction that is exquisitely sensitive to the sequence-dependent conformation and dynamics of DNA. A mixture of tunneling and hopping mechanisms have been proposed to account for this long-range chemistry, which is gated by dynamical variations within the stack. Electrochemical sensors have also been developed, based upon the sensitivity of DNA charge transport to base pair stacking, and these sensors provide a completely new approach to diagnosing single base mismatches in DNA and monitoring protein-DNA interactions electrically. DNA charge transport, furthermore, may play a role within the cell and, indeed, oxidative damage to DNA from a distance has been demonstrated in the cell nucleus. As a result, the biological consequences of and opportunities for DNA-mediated charge transport now require consideration.
Article
Resonance in soft films: The formation of multilayers of DNA-modified lipid vesicles (see graphic) was investigated with a quartz crystal microbalance and surface plasmon spectroscopy to investigate the assembly process, with specific attention placed on analyzing soft films approaching the sensing depth of these techniques.
Article
A multilayered glucose biosensor via sequential deposition of Prussian blue (PB) nanoclusters and enzyme-immobilized poly(toluidine blue) films was constructed on a bare Au electrode using electrochemical methods. The whole configuration of the present biosensor can be considered as an integration of several independent hydrogen peroxide sensing elements. In each sensing element, the poly(toluidine blue) film functioned as both the supporting matrix for the glucose oxidase immobilization and the inhibitor for the diffusion of interferences, such as ascorbic acid and uric acid. Meanwhile, the deposited Prussian blue nanocluster layers acts as a catalyst for the electrochemical reduction of hydrogen peroxide formed from enzymatic reaction. Performance of the whole multilayer configuration can be tailored by artificially arranging the sensing elements assembled on the electrode. Under optimal conditions, the biosensors exhibit a linear relationship in the range of 1 x 10(-4) to 1 x 10(-2) mol/L with the detection limit down to 10(-5) mol/L. A rapid response for glucose could be achieved in less than 3 s. For 1 mM glucose, 0.5 mM acetaminophen, 0.2 mM uric acid, and 0.1 mM ascorbic acid have no obvious interferences (<5%) for glucose detection at an optimized detection potential. The present multilayered glucose biosensor with a high selectivity and sensitivity is promising for practical applications.
Article
Since discovery and first use in the mid-1970s, evanescent wave fluorescence biosensors have developed into a diverse range of instruments, each designed to meet a particular detection need. In this review, we provide a brief synopsis of what evanescent wave fluorescence biosensors are, how they work, and how they are used. In addition, we have summarized the important patents that have impacted the evolution from laboratory curiosities to fully automated commercial products. Finally, we address the critical issues that evanescent wave fluorescence biosensors will face in the coming years.
Article
A bilayer of the polyelectrolytes poly(dimethyldiallylammonium chloride) (PDDA) and poly(sodium 4-styrenesulfonate) (PSS) was formed on a 3-mercapto-1-propanesulfonic-acid-modified Au electrode. Subsequently, multiwall carbon nanotubes (MWCNTs) wrapped by positively charged PDDA were assembled layer-by-layer with negatively charged glucose oxidase (GOx) onto the PSS-terminated bilayer. Electrochemical impedance spectroscopy and atomic force microscopy were adopted to monitor the regular growth of the PDDA-MWCNTs/GOx bilayers. Using GOx as a model enzyme, the assembled multilayer membranes showed some striking features such as the adsorbed form of GOx on individual MWCNT, uniformity, good stability, and electrocatalytic activity toward oxygen reduction. Based on the consumption of dissolved oxygen during the oxidation process of glucose catalyzed by the immobilized GOx, a sensitive amperometric biosensor was developed for the detection of glucose up to 5.0 mM with a detection limit of 58 microM. The sensitivity increased with increasing sensing layers up to five bilayers. Ascorbic acid and uric acid did not cause any interference due to the use of a low operating potential. The present method showed high reproducibility for the fabrication of carbon-nanotubes-based amperometric biosensors.
Article
The use of surface plasmon resonance (SPR) biosensors is increasingly popular in fundamental biological studies, health science research, drug discovery, clinical diagnosis, and environmental and agricultural monitoring. SPR allows for the qualitative and quantitative measurements of biomolecular interactions in real-time without requiring a labeling procedure. Today, the development of SPR is geared toward the design of compact, low-cost, and sensitive biosensors. Rapid advances in micro-fabrication technology have made available integratable opto-electronic components suitable for SPR. This review paper focuses on the progress made over the past 4 years toward this integration. Readers will find the descriptions of novel SPR optical approaches and materials. Nano-technology is also increasingly used in the design of biologically optimized and optically enhanced surfaces for SPR. Much of this work is leading to the integration of sensitive SPR to lab-on-a-chip platforms.
Article
Contents: 1. Introduction; 2 General Remarks; 3. Enzymatic Biosensors; 4. Immunosensors; 5. Biosensors Based on Ligand–Receptor Interactions; 6. Nucleic Acid Biosensors; 7. Whole Cell Biosensors; 8. Materials for Use in Optical Biosensors; 10. Refs.
Article
This paper describes a highly sensitive, film bulk acoustic resonator (FBAR) mass sensor (built on a micromachined silicon-nitride diaphragm with a piezoelectric thin film and Al electrodes) that can operate in vapor and liquid. The sensitivity of the device to mass change on its surface has been investigated by having various thicknesses of silicon-nitride support layer and also of Al layer. The sensor is measured to have a mass sensitivity of 726 cm $^2$ /g, which is about 50 times that of a typical quartz crystal microbalance (QCM). In vapor, the sensor (operating at around 1 GHz and having a relatively high quality (Q) factor of 200–300) shows a minimum detectable frequency shift of about 400 Hz, which corresponds to a mass change of $10^-9$ g/cm $^2$ on the sensor surface, comparable with that detectable by a QCM. In liquid, though the Q usually drops more than an order of magnitude, we obtain a Q of 40 at 2 GHz by using a second harmonic resonance of the resonator. And with the Q, a minimum 5 ppm resonant frequency shift can be detected, which corresponds to $10^- 8$ g/cm $^2$ change on the sensor surface. hfillhbox[1374]
  • C R Taitt
  • G P Anderson
  • F S Ligler
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