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Solid-State Microfluidics with Integrated Thin-Film Acoustic Sensors
Abstract
For point-of-care applications, integrating sensors into a microfluidic chip is a nontrivial task, since conventional detection modules are bulky and microfluidic chips are small in size, and their fabrication processes are not compatible. In this work, a solid-state microfluidic chip with on-chip acoustic sensors using standard thin-film technologies is introduced. The integrated chip is essentially a stack of thin films on silicon substrate, featuring compact size, electrical input (fluid control) and electrical output (sensor read-out). These features all contribute to portability. In addition, by virtue of processing discrete micro-droplets, the chip provides a solution to the performance degradation bottleneck of acoustic sensors in liquid-phase sensing. Label-free immunoassays in serum are carried out and the viability of the chip is further demonstrated by result comparison with commercial ELISA in prostate-specific antigen sensing experiments. The solid-state chip is believed to fit specific applications in personalized diagnostics and other relevant clinical settings where instrument portability matters.
... Rapid advancements in microfabrication technology have led to the proposal of various micromechanical piezoelectric resonators, such as thin film bulk acoustic resonators (FBARs) [1,2], surface acoustic wave resonators (SAWRs) [3,4], and flexural mode resonators (FMRs) [5][6][7]. These resonators feature manufacturing processes that are compatible with mainstream integrated circuit technology. ...
Piezoelectric material-based devices have garnered considerable attention from scientists and engineers due to their unique physical characteristics, resulting in numerous intriguing and practical applications. Among these, flexural-mode piezoelectric resonators (FMPRs) are progressively gaining prominence due to their compact, precise, and efficient performance in diverse applications. FMPRs, resonators that utilize one- or two-dimensional piezoelectric materials as their resonant structure, vibrate in a flexural mode. The resonant properties of the resonator directly influence its performance, making in-depth research into the resonant characteristics of FMPRs practically significant for optimizing their design and enhancing their performance. With the swift advancement of micro-nano electronic technology, the application range of FMPRs continues to broaden. These resonators, representing a domain of piezoelectric material application in micro-nanoelectromechanical systems, have found extensive use in the field of physical sensing and are starting to be used in micropower systems and biomedicine. This paper reviews the structure, working principle, resonance characteristics, applications, and future prospects of FMPRs.
... The commonly used acoustic waves for microfluidics include Rayleigh wave, [133][134][135] Lamb wave, 136 and bulk acoustic waves, as also including film bulk acoustic resonator (FBAR). 137,138 The mechanism of acoustic streaming is mainly due to acoustic velocity mismatch between the liquid and piezoelectric substrate, which changes the wave mode to a leaky mode and dissipating acoustic energy into the liquid medium to produce an acoustic streaming force to actuate the liquid droplet. 139 With proper surface texture/treatments and under enough applied power, the flowing liquid in a channel or a liquid droplet on the SAW propagating paths can experience streaming, vibration, pumping, jetting, and even nebulization. ...
Flexible and wearable acoustic wave technology has recently attracted tremendous attention due to their wide-range applications in wearable electronics, sensing, acoustofluidics, and lab-on-a-chip, attributed to its advantages such as low power consumption, small size, easy fabrication, and passive/wireless capabilities. Great effort has recently been made in technology development, fabrication, and characterization of rationally designed structures for next-generation acoustic wave based flexible electronics. Herein, advances in fundamental principles, design, fabrication, and applications of flexible and wearable acoustic wave devices are reviewed. Challenges in material selections (including both flexible substrate and piezoelectric film) and structural designs for high-performance flexible and wearable acoustic wave devices are discussed. Recent advances in fabrication strategies, wave mode theory, working mechanisms, bending behavior, and performance/evaluation are reviewed. Key applications in wearable and flexible sensors and acoustofluidics, as well as lab-on-a-chip systems, are discussed. Finally, major challenges and future perspectives in this field are highlighted.
... However, current exosome isolation technologies have low yields and can damage exosomes, resulting in a loss of biomarkers 18 . Furthermore, conventional ultracentrifugation and affinity capture take a long time (several hours to several days), which limits their use in point-of-care settings [19][20][21][22] . As a result, with most current exosome isolation technologies, it is not suitable to use exosomes as point-of-care biomarkers for TBI screening and diagnosis. ...
Traumatic brain injury (TBI) is a global cause of morbidity and mortality. Initial management and risk stratification of patients with TBI is made difficult by the relative insensitivity of screening radiographic studies as well as by the absence of a widely available, noninvasive diagnostic biomarker. In particular, a blood-based biomarker assay could provide a quick and minimally invasive process to stratify risk and guide early management strategies in patients with mild TBI (mTBI). Analysis of circulating exosomes allows the potential for rapid and specific identification of tissue injury. By applying acoustofluidic exosome separation—which uses a combination of microfluidics and acoustics to separate bioparticles based on differences in size and acoustic properties—we successfully isolated exosomes from plasma samples obtained from mice after TBI. Acoustofluidic isolation eliminated interference from other blood components, making it possible to detect exosomal biomarkers for TBI via flow cytometry. Flow cytometry analysis indicated that exosomal biomarkers for TBI increase in the first 24 h following head trauma, indicating the potential of using circulating exosomes for the rapid diagnosis of TBI. Elevated levels of TBI biomarkers were only detected in the samples separated via acoustofluidics; no changes were observed in the analysis of the raw plasma sample. This finding demonstrated the necessity of sample purification prior to exosomal biomarker analysis. Since acoustofluidic exosome separation can easily be integrated with downstream analysis methods, it shows great potential for improving early diagnosis and treatment decisions associated with TBI.
... More fabrication details can be found in our previous work. 25 ...
Heavy metal pollution in water environments poses a great threat to public health and to the ecological environment due to its high toxicity and non-degradability. However, many existing detection methods require laboratory-based bulky instruments and time-consuming manual operations. Although some on-site systems exist, they are difficult to deploy on a large scale owing to their large size and high cost. Here, we report a sensing node featuring low power consumption and low cost, achieved by integrating microsensor, microfluidic, and electronic modules into a compact size for automatic and scalable heavy metal pollution monitoring. Digital microfluidic and electrochemical sensing modules are integrated on a chip, thereby combining the procedures of sample pretreatment, electrochemical sensing, and waste removal for automatic and continuous monitoring. The feasibility of the platform is demonstrated by Pb2+ detection in tap water. With a 3500 mA·h battery, the compact sensing node could work for several years in principle. There is scope for further improvements to the system in terms of wider functionality and reductions in size, power consumption, and cost. The sensing node presented here is a strong candidate for distributed monitoring of water quality as an Internet-of-Things application.
... Although QCMs have high Q, large power handling capability and excellent temperature stability for certain cut angles, miniaturization of quartz resonators is still very challenging, which makes it difficult to integrate the quartz resonators monolithically with integrated circuits (IC) [4]. With the rapid development of micro-fabrication techniques, resonant sensors based on various micromachined piezoelectric resonators, such as thin film bulk acoustic wave resonators (FBARs) [5][6][7], laterally vibrating resonators (LVRs) [8][9][10][11] and flexural-mode beam resonators [12][13][14], have been proposed with fabrication processes compatible with mainstream IC technologies. For FBARs and flexural-mode beam resonators, the sensitivity per unit area and resonant frequency are both dependent on the thickness of resonant structures, which makes it hard to decouple these two important design parameters [15]. ...
Over the last two decades, piezoelectric resonant sensors based on micro-electromechanical systems (MEMS) technologies have been extensively studied as such sensors offer several unique benefits, such as small form factor, high sensitivity, low noise performance and fabrication compatibility with mainstream integrated circuit technologies. One key challenge for piezoelectric MEMS resonant sensors is enhancing their quality factors (Qs) to improve the resolution of these resonant sensors. Apart from sensing applications, large values of Qs are also demanded when using piezoelectric MEMS resonators to build high-frequency oscillators and radio frequency (RF) filters due to the fact that high-Q MEMS resonators favor lowering close-to-carrier phase noise in oscillators and sharpening roll-off characteristics in RF filters. Pursuant to boosting Q, it is essential to elucidate the dominant dissipation mechanisms that set the Q of the resonator. Based upon these insights on dissipation, Q-enhancement strategies can then be designed to target and suppress the identified dominant losses. This paper provides a comprehensive review of the substantial progress that has been made during the last two decades for dissipation analysis methods and Q-enhancement strategies of piezoelectric MEMS laterally vibrating resonators.
The concept of digital microfluidics (DMF) enables highly flexible and precise droplet manipulation at a picoliter scale, making DMF a promising approach to realize integrated, miniaturized "lab-on-a-chip" (LOC) systems for research and clinical purposes. Owing to its simplicity and effectiveness, electrowetting-on-dielectric (EWOD) is one of the most commonly studied and applied effects to implement DMF. However, complex biomedical assays usually require more sophisticated sample handling and detection capabilities than basic EWOD manipulation. Alternatively, combined systems integrating EWOD actuators and other fluidic handling techniques are essential for bringing DMF into practical use. In this paper, we briefly review the main approaches for the integration/combination of EWOD with other microfluidic manipulation methods or additional external fields for specified biomedical applications. The form of integration ranges from independently operating sub-systems to fully coupled hybrid actuators. The corresponding biomedical applications of these works are also summarized to illustrate the significance of these innovative combination attempts.
A wedge transducer is developed using poly-phenylene-sulfide (PPS) as an exciter of high-intensity surface acoustic wave (SAW) to remove droplets adhering to automobiles’ front shield glass. Since the front shield glass has a glass/rubber/glass triple-layered configuration, SAW is needed to be employed to confine the vibration energy within the first glass layer and avoid the energy absorption in the rubber layer. PPS is chosen among popular engineering polymers for the vibrating body because its attenuation at ultrasonic frequency is lower than other polymer materials. To assess the feasibility of our proposal, we designed and fabricated a PPS wedge transducer, and investigated the vibration characteristics and the capability to remove droplets. The transducer, which incorporated a lead-zirconate-titanate (PZT) plate and a PPS wedge, had the total volume of
mm
3
. At the voltage of 24.8 V, a SAW having the wavelength of 2 mm and the vibration velocity of 14.5 mm/s was excited on the glass plate, and the droplets were removed with the SAW.
Major scientific discoveries in the last two decades have been enabled by the development of high-throughput sequencing and mass spectrometry (MS) technologies. Omics analysis, at the genome, transcriptome, proteome, or metabolome levels has paved the way for the elucidation of many molecular mechanisms that underlie disease, biomarker and drug-target discovery, and diagnostics and precision medicine applications. With the realization that the biological interpretation of results generated from biological tissues or cell-derived samples is highly impacted by cell heterogeneity in an apparently homogeneous cell population, many efforts have been redirected toward the omics characterization of single cells. As miniaturized devices represent ideal platforms for the analysis of small sample amounts, omics analysis has found a flourishing ground in the microfluidics instrumentation development arena. This review aims at capturing the latest protein and proteome analysis technologies that have been developed and implemented on microfluidic platforms, with focus on developments that have been documented in the past two years, and emphasis placed on challenging aspects that relate to sensitivity and handling sample complexity, as well as on applications that target the solving of demanding biological and biomedical problems.
Biosensors are analytical devices or systems used to detect a specific target by converting and amplifying a biomolecular recognition event to a dateable semi-quantitative or quantitative signal. Biosensors are powerful analytical tools for the detection of biological or chemical molecules.1 In general, a biosensor consists of biological recognition and signal output elements. There are some definitions insist that the recognition element be physically adjacent to the signal output element. We appreciate this definition, but here we provide a board definition of the biosensor or biosensing system that incorporates any method coupling these two key elements, and ultimately achieving “sample-in-answer-out”.
In this paper, a 2.6 GHz air-gap type thin film piezoelectric MEMS resonator was fabricated on a flexible polyethylene terephthalate film. A fabrication process combining transfer printing and hot-embossing was adopted to form a free-standing structure. The flexible radio frequency MEMS resonator possesses a quality factor of 946 and an effective coupling coefficient of 5.10%, and retains its high performance at a substrate bending radius of 1 cm. The achieved performance is comparable to that of conventional resonators on rigid silicon wafers. Our demonstration provides a viable approach to realizing universal MEMS devices on flexible polymer substrates, which is of great significance for building future fully integrated and multi-functional wireless flexible electronic systems.
We report on Lamb wave resonators (LWRs) on a flexible substrate made of polyethylene terephthalate (PET) by transferring method. LWRs with three different topologies were fabricated on the same silicon wafer and then were transferred simultaneously to a flexible substrate with air cavities using a polydimethylsiloxane (PDMS) stamp. The resonators were aligned accurately with the air cavities on the PET, and presented equivalent performance to those on the silicon wafer. The flexible resonator implementing thickness field excitation exhibited a quality factor of 1294 and a coupling coefficient of 2.2%. The flexible two-port resonator presented a low insertion loss of 3.8 dB. The resonator demonstrated excellent mechanical stability under a series of deformations. These results pave the way for flexible electronic filters and oscillators in future wearable electronic systems.
Nanostructured microelectrodes (NMEs) are three-dimensional electrodes that have superb sensitivity for electroanalysis. Here we report the integration of NMEs with the versatile fluid-handling system digital microfluidics (DMF), for eventual application to distributed diagnostics outside of the laboratory. In the new methods reported here, indium tin oxide DMF top plates were modified to include Au NMEs as well as counter and pseudoreference electrodes. The new system was observed to outperform planar sensing electrodes of the type that are typically integrated with DMF. A rubella virus (RV) IgG immunoassay was developed to evaluate the diagnostic potential for the new system, relying on magnetic microparticles coated with RV particles and analysis by differential pulse voltammetry. The limit of detection of the assay (0.07 IU mL(-1)) was >100× below the World Health Organization defined cut-off for rubella immunity. The sensitivity of the integrated device and its small size suggest future utility for distributed diagnostics.
Although digital microfluidics has shown great potential in a wide range of applications, a lab-on-a-chip with integrated digital droplet actuators and powerful biochemical sensors is still lacking. To address the demand, a fully integrated chip with electrowetting-on-dielectric (EWOD) and a film bulk acoustic resonator (FBAR) sensor is introduced, where an EWOD actuator manipulates digital droplets and the FBAR sensor detects the presence of substances in the droplets, respectively. The piezoelectric layer of the FBAR sensor and the dielectric layer of the EWOD share the same aluminum nitride (AlN) thin film, which is a key factor to achieve the full integration of the two completely different devices. The liquid droplets are reliably managed by the EWOD actuator to sit on or move off the FBAR sensor precisely. Sessile drop experiments and limit of detection (LOD) experiments are carried out to characterize the EWOD actuator and the FBAR sensor, respectively. Taking advantage of the digital droplet operation, a ‘dry sensing mode’ of the FBAR sensor in the lab-on-a-chip microsystem is proposed, which has a much higher signal to noise ratio than the conventional ‘wet sensing mode’. Hg2+ droplets with various concentrations are transported and sensed to demonstrate the capability of the integrated system. The EWOD–FBAR chip is expected to play an important role in many complex lab-on-a-chip applications.
Topical Review
This work makes an overview of the progress made during the last decade with regard to a novel class of piezoelectric microwave devices employing acoustic Lamb waves in micromachined thin film membranes. This class of devices is referred to as either thin film Lamb wave resonators or piezoelectric contour-mode resonators both employing thin film aluminum nitride membranes. These devices are of interest for applications in both frequency control and sensing. High quality factor Lamb wave resonators exhibiting low noise, low loss and thermally stable performance are demonstrated and their application in high resolution gravimetric and pressure sensors further discussed. A specific emphasis is put on the ability of these devices to operate in contact with liquids. Future research directions are further outlined.
The throughput is an important parameter for label-free biosensors. Acoustic resonators like the quartz crystal microbalance have a low throughput because the number of sensors which can be used at the same time is limited. Here we present an array of 64 CMOS-integrated film bulk acoustic resonators. We compare the performance with surface plasmon resonance and the quartz crystal microbalance and demonstrate the performance of the sensor for multiplexed detection of DNA.
This article presents a multichannel droplet-based surface plasmon resonance platform. The platform comprises a digital electrowetting-on-dielectric (EWOD) microfluidic device coupled to surface plasmon resonance imaging (SPRi). SPRi is now a well-established detection technique that enables in-situ monitoring of multiple reactions occurring at the surface of the chip without the use of labels. Currently, the limiting factor in the application of SPRi for high-throughput applications is the flow-cell technology which relies on sequential sample processing within the continuous fluid flow. An original solution compared to the continuous flow-cell technology is proposed to increase the capability of existing SPRi technology. A parallel SPRi detection of different samples on the surface is achieved using the array-based digital microfluidic device.
Point of care testing is playing an increasingly important role in improving the clinical outcome in health care management. The salient features of a point of care device are rapid results, integrated sample preparation and processing, small sample volumes, portability, multifunctionality and low cost. In this paper, we demonstrate some of these salient features utilizing an electrowetting-based Digital Microfluidic platform. We demonstrate the performance of magnetic bead-based immunoassays (cardiac troponin I) on a digital microfluidic cartridge in less than 8 minutes using whole blood samples. Using the same microfluidic cartridge, a 40-cycle real-time polymerase chain reaction was performed within 12 minutes by shuttling a droplet between two thermal zones. We further demonstrate, on the same cartridge, the capability to perform sample preparation for bacterial infectious disease pathogen, methicillin-resistant Staphylococcus aureus and for human genomic DNA using magnetic beads. In addition to rapid results and integrated sample preparation, electrowetting-based digital microfluidic instruments are highly portable because fluid pumping is performed electronically. All the digital microfluidic chips presented here were fabricated on printed circuit boards utilizing mass production techniques that keep the cost of the chip low. Due to the modularity and scalability afforded by digital microfluidics, multifunctional testing capability, such as combinations within and between immunoassays, DNA amplification, and enzymatic assays, can be brought to the point of care at a relatively low cost because a single chip can be configured in software for different assays required along the path of care.
The developing world does not have access to many of the best medical diagnostic technologies; they were designed for air-conditioned laboratories, refrigerated storage of chemicals, a constant supply of calibrators and reagents, stable electrical power, highly trained personnel and rapid transportation of samples. Microfluidic systems allow miniaturization and integration of complex functions, which could move sophisticated diagnostic tools out of the developed-world laboratory. These systems must be inexpensive, but also accurate, reliable, rugged and well suited to the medical and social contexts of the developing world.
Nanomechanical resonators enable the measurement of mass with extraordinary sensitivity. Previously, samples as light as 7 zeptograms (1 zg = 10(-21) g) have been weighed in vacuum, and proton-level resolution seems to be within reach. Resolving small mass changes requires the resonator to be light and to ring at a very pure tone-that is, with a high quality factor. In solution, viscosity severely degrades both of these characteristics, thus preventing many applications in nanotechnology and the life sciences where fluid is required. Although the resonant structure can be designed to minimize viscous loss, resolution is still substantially degraded when compared to measurements made in air or vacuum. An entirely different approach eliminates viscous damping by placing the solution inside a hollow resonator that is surrounded by vacuum. Here we demonstrate that suspended microchannel resonators can weigh single nanoparticles, single bacterial cells and sub-monolayers of adsorbed proteins in water with sub-femtogram resolution (1 Hz bandwidth). Central to these results is our observation that viscous loss due to the fluid is negligible compared to the intrinsic damping of our silicon crystal resonator. The combination of the low resonator mass (100 ng) and high quality factor (15,000) enables an improvement in mass resolution of six orders of magnitude over a high-end commercial quartz crystal microbalance. This gives access to intriguing applications, such as mass-based flow cytometry, the direct detection of pathogens, or the non-optical sizing and mass density measurement of colloidal particles.
The advent of digital microfluidic lab-on-a-chip (LoC) technology offers a platform for developing diagnostic applications with the advantages of portability, increased automation, low-power consumption, compatibility with mass manufacturing, and high throughput. However, most digital microfluidic platforms incorporate limited optical capabilities (e.g., optical transmission) for integrated sensing, because more complex optical functions are difficult to integrate into the digital microfluidic platform. This follows since the sensor must be compatible with the hydrophobic surfaces on which electrowetting liquid transport occurs. With the emergence of heterogeneous photonic component integration technologies such as those described herein, the opportunity for integrating advanced photonic components has expanded considerably. Many diagnostic applications could benefit from the integration of more advanced miniaturized optical sensing technologies, such as index of refraction sensors (surface plasmon resonance sensors, microresonator sensors, etc.). The advent of these heterogeneous integration technologies, that enable the integration of thin-film semiconductor devices onto arbitrary host substrates, enables more complex optical functions, and in particular, planar optical systems, to be integrated into microfluidic systems. This paper presents an integrated optical sensor based upon the heterogeneous integration of an InGaAs-based thin-film photodetector with a digital microfluidic system. This demonstration of the heterogeneous integration and operation of an active optical thin-film device with a digital microfluidic system is the first step toward the heterogeneous integration of entire planar optical sensing systems on this platform.
Reports the completion of four fundamental fluidic operations considered essential to build digital microfluidic circuits, which can be used for lab-on-a-chip or micro total analysis system (μTAS): 1) creating, 2) transporting, 3) cutting, and 4) merging liquid droplets, all by electrowetting, i.e., controlling the wetting property of the surface through electric potential. The surface used in this report is, more specifically, an electrode covered with dielectrics, hence, called electrowetting-on-dielectric (EWOD). All the fluidic movement is confined between two plates, which we call parallel-plate channel, rather than through closed channels or on open surfaces. While transporting and merging droplets are easily verified, we discover that there exists a design criterion for a given set of materials beyond which the droplet simply cannot be cut by EWOD mechanism. The condition for successful cutting is theoretically analyzed by examining the channel gap, the droplet size and the degree of contact angle change by electrowetting on dielectric (EWOD). A series of experiments is run and verifies the criterion.
Recently, piezoelectric thin films including zinc oxide (ZnO) and aluminium nitride (AlN) have found a broad range of lab-on-chip applications such as biosensing, particle/cell concentrating, sorting/patterning, pumping, mixing, nebulisation and jetting. Integrated acoustic wave sensing/microfluidic devices have been fabricated by depositing these piezoelectric films onto a number of substrates such as silicon, ceramics, diamond, quartz, glass, and more recently also polymer, metallic foils and bendable glass/silicon for making flexible devices. Such thin film acoustic wave devices have great potential for implementing integrated, disposable, or bendable/flexible lab-on-a-chip devices into various sensing and actuating applications. This paper discusses the recent development in engineering high performance piezoelectric thin films, and highlights the critical issues such as film deposition, MEMS processing techniques, control of deposition/processing parameters, film texture, doping, dispersion effects, film stress, multilayer design, electrode materials/designs and substrate selections. Finally, advances in using thin film devices for lab-on-chip applications are summarised and future development trends are identified.
We present a multi sensor chip comprising an array of whispering-gallery mode (WGM) micro-goblet lasers integrated into a digital microfluidic (DMF) system. In contrast to earlier demonstrations, the lasers are fabricated from dye-doped poly-methyl methacrylate (PMMA) at low-cost using spin-coating, mask-based optical lithography, wet chemical etching, and thermal reflow techniques. Pumping and read-out of the devices is accomplished via simple free-space optics, thereby allowing to address large-scale sensor arrays. We demonstrate the viability of the system by bulk refractive index-sensing and by measuring the specific binding of streptavidin to a biotinylated sensor surface. This is the first time that optical cavities are used for label-free detection of biomolecules in a DMF system. The approach can be extended to a versatile detector platform that targets a wide range of clinically relevant biomolecules.
We developed a wireless and passive piezoelectric resonant sensor for contimuous volatile organic compound detection. An equivalent circuit is proposed to model the sensing system, and Lamb wave resonators are adopted to demonstrate the wireless interrogation achieved by near-field inductive coupling. The wireless sensing system is employed to monitor the ethanol vapor concentration, and the sensitivity of the wireless sensor barely degrades compared to that of the wired one. Further, we simultaneously and wirelessly tracked several resonance frequencies of a monolithic sensor array, which demonstrates its potential for high-throughput and real-time point-of-care test. Published by AIP Publishing.
Following the development of microfluidic systems, there has been a high tendency towards developing lab-on-a-chip devices for biochemical applications. A great deal of effort has been devoted to improve and advance these devices with the goal of performing complete sets of biochemical assays on the device and possibly developing portable platforms for point of care applications. Among the different microfluidic systems used for such a purpose, digital microfluidics (DMF) shows high flexibility and capability of performing multiplex and parallel biochemical operations, and hence, has been considered as a suitable candidate for lab-on-a-chip applications. In this review, we discuss the most recent advances in the DMF platforms, and evaluate the feasibility of developing multifunctional packages for performing complete sets of processes of biochemical assays, particularly for point-of-care applications. The progress in the development of DMF systems is reviewed from eight different aspects, including device fabrication, basic fluidic operations, automation, manipulation of biological samples, advanced operations, detection, biological applications, and finally, packaging and portability of the DMF devices. Success in developing the lab-on-a-chip DMF devices will be concluded based on the advances achieved in each of these aspects.
Electrochemistry, biosensors and microfluidics are popular research topics that have attracted widespread attention from chemists, biologists, physicists, and engineers. Here, we introduce the basic concepts and recent histories of electrochemistry, biosensors, and microfluidics, and describe how they are combining to form new application-areas, including so-called "point-of-care" systems in which measurements traditionally performed in a laboratory are moved into the field. We propose that this review can serve both as a useful starting-point for researchers who are new to these topics, as well as being a compendium of the current state-of-the art for experts in these evolving areas.
Microfluidics, a technology characterized by the engineered manipulation of fluids at the submillimetre scale, has shown considerable promise for improving diagnostics and biology research. Certain properties of microfluidic technologies, such as rapid sample processing and the precise control of fluids in an assay, have made them attractive candidates to replace traditional experimental approaches. Here we analyse the progress made by lab-on-a-chip microtechnologies in recent years, and discuss the clinical and research areas in which they have made the greatest impact. We also suggest directions that biologists, engineers and clinicians can take to help this technology live up to its potential.
Unlike the quartz crystal microbalance, which has been used extensively for the analysis of biochemical interactions, only few measurements with biochemical adsorbent have been done with film bulk acoustic resonators (FBAR). In this paper, the FBAR behaviour on exposure to a lipid vesicle solution and the formation of a polyelectrolyte multilayer structure is investigated and compared with the results obtained with the quartz crystal microbalance. Differences in the resonator response were found between the two techniques and depending on the resonators resonance frequency ranging from the MHz to the GHz regime. As an explanation, we suggest that the penetration depth and the influence on viscoelastic properties, which are both known to be frequency dependent, cause the variations in the results. As a consequence, the higher operating resonance frequencies of the FBAR increase the sensitivity to changes in the viscoelasticity of the adsorbent and also decrease the sensing length of the device.
Wird eine Fremdschicht auf eine zu Dickenscherungsschwingungen angeregte Schwingquarzplatte aufgebracht, so ndert sich die Eigenfrequenz der Platte infolge Vergrerung der schwingenden Masse. Da die Frequenznderung eines Schwingquarzes sehr genau vermessen werden kann, ergibt sich daraus eine sehr empfindliche Methode zur Wgung dnner Schichten.Massenbelegung der Fremdschicht und Frequenznderung sind einander proportional. Die Proportionalittskonstante lt sich aus der Eigenfrequenz des Schwingquarzes berechnen, so da eine empirische Eichung bei der Schichtwgung mit Schwingquarzen entfllt.Die Genauigkeit des Schichtwgeverfahrens ist in erster Linie durch die Temperaturabhngigkeit der Quarzeigenfrequenz begrenzt und betrgt bei 1 C zugelassener Temperaturschwankung etwa 4 10–9 g cm–2. Das entspricht einer mittleren Dicke von 0,4 bei der Dichte =1 g cm–3.Das Verfahren wurde auch zur direkten Wgung einer Masse ausgenutzt (Mikrowgung). Dabei lie sich eine Genauigkeit von 10–10g erreichen.
Thin-film bulk acoustic resonators (FBAR) are an effective platform for sensitive biological and chemical detection, where their high operating frequencies make them many times more sensitive than a quartz crystal microbalance. Here, we present a monolithic, solidly mounted FBAR oscillator array on CMOS for mass-sensing applications. Through monolithic integration with CMOS drive circuitry, we aim to overcome the spatial and parasitic load limitations of externally coupled resonators to build dense sensor arrays without specialized fabrication techniques. The sensors in this work are constructed in a 6 à 4 array atop a 0.18 ¿m CMOS active substrate, and mass sensitivity comparable to off-chip FBAR sensors is demonstrated.
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.
The application of microresonators in fluids is predominantly constrained by the strong damping caused by the viscid drag and the additional inertia of the liquid in the interfacial layer. In this paper we propose the new concept of partial wetting that exploits another property of liquids, its surface energy, to adapt physically the interface of the microresonator to the liquid by the formation of a meniscus. First experiments performed with technically simple batch-fabricated prototypes validate the potential of partial wetting as a vital route to improve the quality factor of microresonators in viscid fluids to values up to 600 exceeding those of conventional microresonators by almost two orders of magnitude.
A large part of the excitement behind microfluidics is in its potential for producing practical devices, but surprisingly few lab-on-a-chip based technologies have been successfully introduced into the market. Here, we review current work in commercializing microfluidic technologies, with a focus on point-of-care diagnostics applications. We will also identify challenges to commercialization, including lessons drawn from our experience in Claros Diagnostics. Moving forward, we discuss the need to strike a balance between achieving real-world impact with integrated devices versus design of novel single microfluidic components.
A new platform for lab-on-a-chip system is suggested that utilizes a biosensor array embedded in a digital microfluidic device. With field effect transistor (FET)-based biosensors embedded in the middle of droplet-driving electrodes, the proposed digital microfluidic device can electrically detect avian influenza antibody (anti-AI) in real time by tracing the drain current of the FET-based biosensor without a labeling process. Digitized transport of a target droplet enclosing anti-AI from an inlet to the embedded sensor is enabled by the actuation of electrowetting-on-dielectrics (EWOD). A reduction of the drain current is observed when the target droplet is merged with a pre-existing droplet on the embedded sensor. This reduction of the drain current is attributed to the specific binding of the antigen and the antibody of the AI. The proposed hybrid device consisting of the FET-based sensor and an EWOD device, built on a coplanar substrate by monolithic integration, is fully compatible with current fabrication technology for control and read-out circuitry. Such a completely electrical manner of inducing the transport of bio-molecules, the detection of bio-molecules, the recording of signals, signal processing, and the data transmission process does not require a pump, a fluidic channel, or a bulky transducer. Thus, the proposed platform can contribute to the construction of an all-in-one chip.
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.
We present a long (204 mm), curved (curvature of 0.04 mm(-1)), and closed droplet pathway in "droplet-on-a-wristband" (DOW) with the designed digital microfluidic modular interfaces for electric signal and droplet connections based on the study of electrowetting-on-dielectric (EWOD) in inclined and curved devices. Instead of using sealed and leakage-proof pipes to transmit liquid and pumping pressure, the demonstrated modular interface for electrowetting-driven digital microfluidics provides simply electric and fluidic connections between two adjacent parallel-plate modules which are easy-to-attach/detach, showing the advantages of using droplets for microfluidic connections between modules. With the previously reported digital-to-channel interfaces (Abdelgawad et al., Lab Chip, 2009, 9, 1046-1051), the chip-to-chip interface presented here would be further applied to continuous microfluidics. Droplet pumping across a single top plate gap and through a modular interface with two gaps between overlapping plates are investigated. To ensure the droplet transportation in the DOW, we actuate droplets against gravity in an inclined or curved device fabricated on flexible PET substrates prepared by a special razor blade cutter and low temperature processes. Pumping a 2.5 μl droplet at a speed above 105 mm s(-1) is achieved by sequentially switching the entire 136 driving electrodes (1.5 mm × 1.5 mm) along the four flexible modules of the DOW fabricated by 4-inch wafer facilities.
The advances in genomics and proteomics have unveiled an exhaustive catalogue of biomarkers that can potentially be used as diagnostic and prognostic indicators of genetic and infectious diseases. Current thrust in biosensor development is towards rapid, real-time, label-free and highly sensitive detection of the indicative biomarkers. While surface plasmon resonance imaging (SPRi) biosensors could potentially be the best suited candidate for biomarker-based diagnosis, important milestones need to be reached. Commercially available SPRi instrumentation is currently limited by the flow-cell technology to serial-sample processing and has limited sensitivity for the detection of markers present at low concentration. In this paper, we have implemented an approach to enhance sample handling and increase the sensitivity of the SPRi detection technique. We have developed a digital microfluidic platform with an integrated nanostructured biosensor interface that allows for rapid, ultra-low volume, sensitive, and automated on-chip SPRi detection of DNA hybridization reactions. Through the exploitation of electromagnetic properties of nanofabricated periodic gold nanoposts, SPRi signal was increased by 200% with the estimated limit of detection of 500 pM (90 attomoles). Using the versatile fluidic manipulation provided by the digital microfluidics, rapid and parallel target identification was achieved on multiple array elements within 1 min using 180 nL sample volume. By delivering multiple target analytes in individually addressable low volume droplets, without external pumps and fluidic interconnects, the overall assay time, cost and complexity was reduced. The proposed platform allows extreme versatility in the manipulation of precious low volume samples which makes this technology very suitable for diagnostic applications.
The ambition of lab-on-a-chip (LOC) systems to achieve chip-level integration of a complete analytical process capable of performing a complex set of biomedical protocols is hindered by the absence of standard fluidic components able to be assembled. As a result, most microfluidic platforms built to date are highly specialized and designed to fulfill the requirements of a single particular application within a limited set of operations. Electrowetting-on-dielectric (EWOD) digital microfluidic technology has been recently introduced as a new methodology in the quest for LOC systems. Herein, unit volume droplets are manipulated along electrode arrays, allowing a microfluidic function to be reduced to a set of basic operations. The highly reprogrammable architecture of these systems can satisfy the needs of a diverse set of biochemical assays and ensure reconfigurability, flexibility and portability between different categories of applications and requirements. While important progress was made over past years in the fabrication, miniaturization and function programming of the basic EWOD fluidic operations, the success of this technology will in great part depend on the ability of researchers to couple or integrate digital microfluidics to detection approaches that can make the system competitive for LOC applications. The detection techniques should be able to circumvent the limitations of hydrophobic surfaces and exploit the advantages of the array format, high droplet transport speeds and rapid mixing schemes. This review provides an in-depth look at recent developments for the coupling and integration of detection techniques with digital microfluidic platforms for bio-chemical applications.
Voltage pulses that cause changes in fluid shape or movement can be used to drive optical components and miniaturized assays.
We describe devices in which optics and fluidics are used synergistically to synthesize novel functionalities. Fluidic replacement or modification leads to reconfigurable optical systems, whereas the implementation of optics through the microfluidic toolkit gives highly compact and integrated devices. We categorize optofluidics according to three broad categories of interactions: fluid-solid interfaces, purely fluidic interfaces and colloidal suspensions. We describe examples of optofluidic devices in each category.
To realize multiplexed sample preparation on a digital microfluidic chip for high-throughput Matrix Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-MS), several fluidic functions need to be integrated. These include the generation of multiple droplets from a reservoir and parallel in-line sample purification. In this paper, we develop two critical new functions in handling protein solutions and standard proteomic reagents with electrowetting-on-dielectric (EWOD) actuation, leading to an integrated chip for multiplexed sample preparation for MALDI-MS. The first is a voltage sequence designed to generate a series of droplets from each of the three reservoirs--proteomic sample, rinsing fluid, and MALDI reagents. It is the first time that proteomic reagents have been dispensed using EWOD in an air (as opposed to oil) environment. The second is a box-in-box electrode pattern developed to allow droplet passing over dried sample spots, making the process of in-line sample purification robust for parallel processing. As a result, parallel processing of multiple sample droplets is demonstrated on the integrated EWOD-MALDI-MS chip, an important step towards high-throughput MALDI-MS. The MS results, collected directly from the integrated devices, are of good quality, suggesting that the tedious process of sample preparation can be automated on-chip for MALDI-MS applications as well as other high-throughput proteomics applications.
A full-field view laser ultrasonic imaging method has been developed that measures acoustic motion at a surface without scanning. Images are recorded at normal video frame rates by using dynamic holography with photorefractive interferometric detection. By extending the approach to ultra high frequencies, an acoustic microscope has been developed that is capable of operation at gigahertz frequency and micron length scales. Both acoustic amplitude and phase are recorded, allowing full calibration and determination of phases to within a single arbitrary constant. Results are presented of measurements at frequencies of 800-900 MHz, illustrating a multitude of normal mode behavior in electrically driven thin film acoustic resonators. Coupled with microwave electrical impedance measurements, this imaging mode provides an exceptionally fast method for evaluation of electric-to-acoustic coupling of these devices and their performance. Images of 256 /spl times/ 240 pixels are recorded at 18 fps rates synchronized to obtain both in-phase and quadrature detection of the acoustic motion. Simple averaging provides sensitivity to the subnanometer level at each pixel calibrated over the image using interferometry. Identification of specific acoustic modes and their relationship to electrical impedance characteristics show the advantages and overall high speed of the technique.