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Micro-optics for microfluidic analytical applications
Abstract
This critical review summarizes the developments in the integration of micro-optical elements with microfluidic platforms for facilitating detection and automation of bio-analytical applications. Micro-optical elements, made by a variety of microfabrication techniques, advantageously contribute to the performance of an analytical system, especially when the latter has microfluidic features. Indeed the easy integration of optical control and detection modules with microfluidic technology helps to bridge the gap between the macroscopic world and chip-based analysis, paving the way for automated and high-throughput applications. In our review, we start the discussion with an introduction of microfluidic systems and micro-optical components, as well as aspects of their integration. We continue with a detailed description of different microfluidic and micro-optics technologies and their applications, with an emphasis on the realization of optical waveguides and microlenses. The review continues with specific sections highlighting the advantages of integrated micro-optical components in microfluidic systems for tackling a variety of analytical problems, like cytometry, nucleic acid and protein detection, cell biology, and chemical analysis applications.
... On the market, we can find flow cytometers based on three operating principles: impedance analysis, image-based and optical-based cytometry. Because of the limitations of both electrochemical and mechanical techniques, optical detection is mostly preferred for its robustness and sensitivity [16][17][18]. In this case, the fluid to be analyzed (and the particles it contains) is placed in a specific area of the instrument and illuminated by a focused laser beam. ...
... Fluorescence is proportional to the amount of fluorophore that enters or attaches externally to the particle, and it can be used to distinguish between different cell populations [20] and even to identify dead or membranedeficient cells [21]. However, although there are currently instruments capable of analyzing up to 14 parameters simultaneously [22], commercial flow cytometers present several disadvantages: (i) misalignment of the small focal point of the probing laser with respect to the flowing micrometric object during the run time (even with high-performance optics) and (ii) a lack of flexibility in rearranging the measurement chamber, which can affect the analysis [18]. Additionally, these laboratory instruments are expensive (the cost can be of the order of tens of thousands of dollars), complex to use, bulky, handle relatively large (mL) sample volumes and require trained operators for operating and maintenance [23]. ...
... In addition, huge amounts of plastic are known to enter the oceans every year, and as they decompose, even very small an innovative way to improve the performance of sensing applications. In many optomicrofluidic cytometer designs, micro-optic components (integrated waveguides, lenses and fiber optics) are used to precisely manage excitation light and collect both scattered and fluorescence signals in a controlled way [18]. There are many solutions in the literature for placing a high-performance detection system directly on an optofluidic chip. ...
Statistical analysis of the properties of single microparticles, such as cells, bacteria or plastic slivers, has attracted increasing interest in recent years. In this regard, field flow cytometry is considered the gold standard technique, but commercially available instruments are bulky, expensive, and not suitable for use in point-of-care (PoC) testing. Microfluidic flow cytometers, on the other hand, are small, cheap and can be used for on-site analyses. However, in order to detect small particles, they require complex geometries and the aid of external optical components. To overcome these limitations, here, we present an opto-fluidic flow cytometer with an integrated 3D in-plane spherical mirror for enhanced optical signal collection. As a result, the signal-to-noise ratio is increased by a factor of six, enabling the detection of particle sizes down to 1.5 µm. The proposed optofluidic detection scheme enables the simultaneous collection of particle fluorescence and scattering using a single optical fiber, which is crucial to easily distinguishing particle populations with different optical properties. The devices have been fully characterized using fluorescent polystyrene beads of different sizes. As a proof of concept for potential real-world applications, signals from fluorescent HEK cells and Escherichia coli bacteria were analyzed.
... Une large étude bibliographique résumant l'état de l'art dans le domaine de la miniaturisation de la détection par fluorescence a été menée. Sur la base de cette étude, un concept [46,47]. (b) Cross-section of the microfluidic-PCB fluorescence detector, built xiii using two PCBs. ...
... (c) Fluorescence detection system with back-side illumination scheme. Reproduced from Shin et al. (2015Shin et al. ( , 2017 [46,47] (1) -the optofluidic prototype, (2) the syringe pump used to stream the reagent solutions into the device, (3) 24 V DC source used to power the LEDs connected in series, (4) microcontroller board that accompanied the ULS 24 CMOS-image sensor running the dark noise management system. The USB is plugged to a PC where an interface is used to collect the data. ...
... Commercially-available LEDs and micro diode lasers have been widely implemented in microfluidic detection devices since their early development stage. Nowadays, OLEDs and dye lasers are very promising alternatives due to their capability to be monolithically integrated onto optofluidic structures [46]. Commonly, the waveguide is located perpendicularly on the light-emitter surface. ...
Formaldehyde (HCHO), a chemical compound used in the fabrication process of a broad range of household products, is present indoors as an airborne pollutant due to its high volatility caused by a low boiling point (T=-19℃). Miniaturization of analytical systems towards palm-held devices has the potential to provide not only more efficient, but also more sensitive tools for real-time monitoring of this hazardous air pollutant.This thesis presents the development of a microfluidic device for HCHO sensing based on the Hantzsch reaction detection method with an emphasis on the fluorescence detection component.An extensive literature survey summarizing the state-of-the art in the field of fluorescence sensing miniaturization has been performed. Based on this study, a modular fluorescence detection concept designed around a CMOS image sensor (CIS) has been proposed. Two three-layer fluidic cell configurations (configuration 1: quartz – SU-8 3050 – quartz, and configuration 2: silicon – SU-8 3050 – quartz) have been envisaged and tested in parallel for the same experimental conditions. The microfabrication procedures of the fluidic cells have been described in detail, including the off-the-shelf components integration and the experimental procedures.The CIS-based fluorescence detector proved the capability to detect an initial 10 µg/l HCHO concentration fully-derivatized into 3,5–diacetyl-1,4-dihydrolutidine (DDL) for both the quartz and silicon fluidic cells, both possessing a 3.5 µl interrogation volume. An apparent higher signal-to-noise ratio (SNR) has been observed for the silicon fluidic cell (〖SNR〗_silicon=6.1) when compared to the quartz fluidic cell (〖SNR〗_quartz=4.9). The signal intensity enhancement in the silicon fluidic cell was mainly due to silicon absorption coefficient at the excitation wavelength, a(λ_abs=420 nm)=5∙10^4 cm^(-1) which is approximately five times higher than the absorption coefficient at the fluorescence emission wavelength, a(λ_em=515 nm)=9.25∙10^3 cm^(-1).Computational fluid dynamics (CFD) simulations showed that HCHO is absorbed very fast into the liquid reagent due to its relatively high Henry’s law constant. Thus, the selection of the molecular trapping method (Taylor flow, annular flow, or membrane-based flow interaction) depends on the fluorescence detector reading performances. A preliminary concept based on a membrane-based interaction for continuous trapping of gaseous HCHO has been introduced by identifying the compatible materials, fabrication methodologies, and by analyzing the diffusion mechanism through the membrane.In the future, an improvement and simplification based on very sensitive fluorescence detectors with low limits-of-detection could thus be possible based on, e.g., Taylor flow or annular flow.
... Other methodologies, heavily relying on images, such as particle image velocimetry (PIV) [25,26], particle tracking velocimetry (PTV) [27,28], X-ray imaging [29], nuclear magnetic resonance imaging [30], infrared imaging [31], and optical Doppler tomographic velocity imaging [32] are all used to investigate and quantitatively characterize fluid flow inside microchannels. Together, optical tools and imaging methods are the fundamental components of current microfluidic systems. ...
... Multiple fields offer viable alternatives to conventional optical detection methodologies. Micro-optofluidics, a branch of microfluidics, focuses on the integration of optical and fluidic components into microscale systems with the ultimate goal of developing LOC devices that can manipulate both light and fluids at the microscale without the requirement of a bulky and costly equipment [29,[33][34][35][36]. Individual optical components, such as photodiodes, waveguides, lenses, and optical fibers, have been successfully integrated into microfluidic systems to investigate small volumes of fluids flowing inside microdevices [33,[37][38][39][40][41]. ...
This work proposes a multi-objective polydimethylsiloxane (PDMS) micro-optofluidic (MoF) device suitably designed and manufactured through a 3D-printed-based master–slave approach. It exploits optical detection techniques to characterize immiscible fluids or microparticles in suspension inside a compartment specifically designed at the core of the device referred to as the MoF chamber. In addition, we show our novel, fast, and cost-effective methodology, dual-slit particle signal velocimetry (DPSV), for fluids and microparticle velocity detection. Different from the standard state-of-the-art approaches, the methodology focuses on signal processing rather than image processing. This alternative has several advantages, including the ability to circumvent the requirement of complex and extensive setups and cost reduction. Additionally, its rapid processing speed allows for real-time sample manipulations in ongoing image-based analyses. For our specific design, optical signals have been detected from the micro-optics components placed in two slots designed ad hoc in the device. To show the devices’ multipurpose capabilities, the device has been tested with fluids of various colors and densities and the inclusion of synthetic microparticles. Additionally, several experiments have been conducted to prove the effectiveness of the DPSV approach in estimating microparticle velocities. A digital particle image velocimetry (DPIV)-based approach has been used as a baseline against which the outcomes of our methods have been evaluated. The combination of the suitability of the micro-optical components for integration, along with the MoF chamber device and the DPSV approach, demonstrates a proof of concept towards the challenge of real-time total-on-chip analysis.
... The optofluidic chip technology 41−46 provides a miniaturized platform for both optical measurement and fluid manipulation. It allows integrating micron-size optical elements such as microlenses 47 and enables the coupling of the chip to the light source and detectors via optical fibers (OF), thereby external optical elements can be eliminated from the setup, resolving the spatial constraints limiting the proximity of the illumination and BSC detection parts. The other important aspect of the optofluidic technology is the use of the flow focusing technique to create a narrow stream of the sample, which confines the transit of single particles to the focal spot of the incident beam for the scattering analysis and minimizes the concurrent detection of multiple particles. ...
... The optical measurement zone is composed of an illumination part and a detection part. In the illumination part, two cylindrical microlenses, using the so-called air gap technique (Figure 1b), 47 were implemented for collimating and focusing the incident light to the middle of the fluid channel, where particles transit. The scattered light of BSC, FSC, and SSC from single particles is collected in different trigonometrical angles of 135, 15, and −60°. ...
In this research, we designed and fabricated an optofluidic chip for the detection and differentiation of single particles via the combination of backscattered (BSC) and forward-scattered (FSC) or side-scattered (SSC) light intensity. The high sensitivity of BSC light to the refractive index of the particles enabled an effective approach for the differentiation of individual particles based on the type of material. By recording BSC as well as FSC and SSC light intensities from single particles, transiting through the illumination zone in a microfluidic channel, the size and type of material could be detected simultaneously. The analysis of model samples of polystyrene (PS), as a primary microplastic particle, and silica microspheres showed substantially higher BSC signal values of PS because of a larger refractive index compared to the silica. The scatter plots correlating contributions of BSC (FSC-BSC and SSC-BSC) allowed a clear differentiation of PS and silica particles. To demonstrate the great potential of this methodology, two "real-life" samples containing different types of particles were tested as application examples. Commercial toothpaste and peeling gel products, as primary sources of microplastics into effluents, were analyzed via the optofluidic chip and compared to results from scanning electron microscopy. The scattering analysis of the complex samples enabled the detection and simultaneous differentiation of particles such as microplastics according to their differences in the refractive index via distinctive areas of high and low BSC signal values. Hence, the contribution of BSC light measurements in multiangle scattering of single particles realized in an optofluidic chip opens the way for the discrimination of single particles in a liquid medium in manifold fields of application ranging from environmental monitoring to cosmetics.
... Its applications span across clinical chemistry [3], cell counting and sorting [4], and nucleic acid detection [5], offering significant advantages. Conventionally, microfluidic chips analyses have relied on the differential light refraction or transmission properties of the LUT [6], [7]. However, this optical method has its limitations. ...
This article presents a 24-GHz microfluidic sensor using frequency-locked loop (FLL) technology for detecting liquid concentrations. The sensor, based on FLL, features a microfluidic channel placed over an asymmetrical coplanar waveguide resonator (ACPWR) that functions as a sensing device. For testing purposes, we use ethanol-water mixtures and glucose-water solutions as the liquid under test (LUT). Due to the electric field distribution in media with varying dielectric constants, the phase of the signal undergoes different phase deviations. The FLL-based sensor is capable of detecting these phase deviations and, in response, produces a frequency-modulated signal. This signal is subsequently demodulated into a corresponding voltage with the aid of a frequency demodulator, realized through a phase detector. Consequently, the sensor demonstrates the capability to differentiate between tested liquids of varying concentrations and offers a linear response that correlates the output voltage with the liquid concentration. The proposed 24-GHz FLL microfluidic sensor offers advantages, such as cost effective, high sensitivity, and compact size. It has a great possibility to implement this sensor using the system-on-chip (SoC) technology. As it combined with Internet of Things (IoT) technologies, it may have a capability of real-time biomedical specimen sensing for daily life.
... Consequently, by choosing appropriate dye molecules in arrays or cascades, the L 2 waveguides may be used as integrated broadband optical sources (H. Yang & Gijs, 2018). The optofluidic microlenses can also be used for optical tuning, exploiting their ability to collect, direct and focus the light. ...
Background: The crucial requirement of pragmatic food safety methods remains paramount for both consumer health and food industry. The fusion of microfluidics with optics, known as optofluidics has been the leading focus of current scientific research owing to their exceptional properties. The integration of nanophotonic structures in optofluidics has unveiled promising opportunities in real-time sensing of food contaminants,
pathogens and assessment of nutritional value of food and food products.
Scope and approach: The review has outlined the potential of various nanophotonic structures with particular
focus on plasmonic nanomaterials and dielectric metasurfaces. We highlight the prospects of engineering sensitive and specific compact devices by leveraging the structural and optical dynamics of nanophotonic structures, and incorporating optoelectronics, microfluidics and data analysis tools on ultracompact chips. Moreover, the working principles of nanophotonic integrated optofluidics systems for food safety and quality monitoring, along with important advances have been discussed. We also discuss challenges in development of on-chip biosensors and provide an outlook for future possibilities of applying these biosensors to ensure food safety and integrity of
our food supply chain by bringing sensitive, real-time analysis that assists in early detection and prevention of potential hazards, leading to improved public health and economic growth.
Key findings and conclusion: This technology holds great promise to produce portable, high throughput devices. With novel architectures and intelligent algorithms, these flexible biosensors would enable multiplexing and accurate detection of small molecules with complex food matrices, significantly enhancing the feasibility to bring this technology to actual practice.
... Intensive research on separating single tumor cells by utilizing the physical properties of tumor cells, such as density 16,17 , size [18][19][20][21][22][23] , and deformability [24][25][26][27] , has achieved great success. With the introduction of external fields, tumor cells can also be separated from background cells based on differences in their dielectric properties [28][29][30] , magnetic susceptibility 31,32 , or refractive indices 33,34 . Initially, little attention was given to the separation of tumor cell clusters, but recent advances in the understanding of the biogenesis and dissemination of tumor cell clusters have repositioned the separation and identification of tumor cell clusters as critical tasks for preoperative cancer diagnosis 35,36 . ...
Tumor cell clusters are regarded as critical factors in cancer pathophysiology, and increasing evidence of their higher treatment resistance and metastasis compared to single tumor cells has been obtained. However, existing cell separation methods that are designed for single tumor cells cannot be used to simultaneously purify tumor cell clusters. To address this problem, we demonstrated a microfluidic approach for the high-throughput, continuous-flow ternary separation of single tumor cells, tumor cell clusters, and WBCs from clinical pleural or abdominal effusions by coupling slanted spiral channels and periodic contraction-expansion arrays. We first systematically explored the influence of particle size and flow rate on particle focusing. The separation performance indicated that 94.0% of WBCs were removed and more than 97% of MDA-MB-231 tumor cells were recovered at a high flow rate of 3500 µL/min. Moreover, more than 90% of tumor cell clusters were effectively preserved after separation. Finally, we successfully applied our device for the ternary separation of single tumor cells, tumor cell clusters, and WBCs from different malignant effusions collected from patients with metastatic cancer. Thus, our spiral-contraction-expansion device has potential as a sample pretreatment tool for the cytological diagnosis of malignant effusions.
... One approach to simplify and miniaturize the optical detection of droplets is to develop on-chip optofluidics by integrating micro-optical components such as lenses, waveguides and optical fibers within the chip design 29,32,[38][39][40] . In particular, microfluidic chipintegrated optical fibers have been demonstrated to function as effective waveguides for both the illumination of droplets by incident light and the collection of optical signals from droplets 33,35,36 . ...
Droplet microfluidics has emerged as a critical component of several high-throughput single-cell analysis techniques in biomedical research and diagnostics. Despite significant progress in the development of individual assays, multiparametric optical sensing of droplets and their encapsulated contents has been challenging. The current approaches, most commonly involving microscopy-based high-speed imaging of droplets, are technically complex and require expensive instrumentation, limiting their widespread adoption. To address these limitations, we developed the OptiDrop platform; this platform is a novel optofluidic setup that leverages the principles of flow cytometry. Our platform enables on-chip detection of the scatter and multiple fluorescence signals from the microfluidic droplets and their contents using optical fibers. The highly customizable on-chip optical fiber-based signal detection system enables simplified, miniaturized, low-cost, multiparametric sensing of optical signals with high sensitivity and single-cell resolution within each droplet. To demonstrate the ability of the OptiDrop platform, we conducted a differential expression analysis of the major histocompatibility complex (MHC) protein in response to IFN γ stimulation. Our results showed the platform’s ability to sensitively detect cell surface biomarkers using fluorescently labeled antibodies. Thus, the OptiDrop platform combines the versatility of flow cytometry with the power of droplet microfluidics to provide wide-ranging, scalable optical sensing solutions for research and diagnostics.
... The optical force acting on micro-/nanoparticles, usually divided into gradient force and scattering force, is induced through the exchange of momentum between irradiated particles and photons [39]. Especially, in POT, the optical force become more complex due to the local electromagnetic field enhancement. ...
The ability of plasmonic optical tweezers (POT) based on metal nanostructure to stably trap and dynamically manipulate nanoscale objects at low laser power has been widely used in nanotechnology and life sciences fields. In particular, the plasmonic nanocavity structure can improve the local field intensity and trap depth by confining electromagnetic fields to subwavelength volumes. In this paper, the optical force and potential well exerted on the nanoscale polystyrene (PS) particles (RNP≤50 nm) dependent on the geometric size of the nanocavity is theoretically investigated. It is revealed that the trapping performance can be flexibly adjusted by changing the structural parameters of the optical cavity unit (OCU), and it can provide a stable potential well for PS particles of RNP=14 nm when the cavity depth is 140 nm. In addition, the trapping properties of the hexagonal nanocavity array (HNCA) structures are also investigated and it is found that multiple trapping sites can be activated simultaneously in the laser irradiation area. This multi-site stable trapping platform composed of HCNA structures makes it possible to analyze multiple target particles contemporaneously.
... Currently, reported microfluidic technologies for cell manipulation and separation can be classified as either active or passive methods based on the sources of manipulating forces. In general, active methods apply external electrical [12][13][14], magnetic [15][16][17], acoustic [18,19], optical [20,21], and thermal force fields [22,23]. Active separation technologies offer the benefits of precise manipulation and real-time control by simply adjusting the external force fields. ...
Inertial microfluidics uses the intrinsic fluid inertia in confined channels to manipulate the particles and cells in a simple, high-throughput, and precise manner. Inertial focusing in a straight channel results in several equilibrium positions within the cross sections. Introducing channel curvature and adjusting the cross-sectional aspect ratio and shape can modify inertial focusing positions and can reduce the number of equilibrium positions. In this work, we introduce an innovative way to adjust the inertial focusing and reduce equilibrium positions by embedding asymmetrical obstacle microstructures. We demonstrated that asymmetrical concave obstacles could break the symmetry of original inertial focusing positions, resulting in unilateral focusing. In addition, we characterized the influence of obstacle size and 3 asymmetrical obstacle patterns on unilateral inertial focusing. Finally, we applied differential unilateral focusing on the separation of 10- and 15-μm particles and isolation of brain cancer cells (U87MG) from white blood cells (WBCs), respectively. The results indicated an excellent cancer cell recovery of 96.4% and WBC rejection ratio of 98.81%. After single processing, the purity of the cancer cells was dramatically enhanced from 1.01% to 90.13%, with an 89.24-fold enrichment. We believe that embedding asymmetric concave micro-obstacles is a new strategy to achieve unilateral inertial focusing and separation in curved channels.
... [155] Therefore, it is imperative to develop a miniaturized, functionally integrated, easy-to-use, and low-cost biochemical detection platform. [156,157] In this section, we start with a brief overview of microfluidic chips with integrated sensing capabilities and then review parts suitable for monitoring ROs from the applicative perspectives of detecting BRB function and RO development and metabolism based on chip sensors. ...
Retinal diseases are a rising concern as major causes of blindness in an aging society; therapeutic options are limited, and the precise pathogenesis of these diseases remains largely unknown. Intraocular drug delivery and nanomedicines offering targeted, sustained, and controllable delivery are the most challenging and popular topics in ocular drug development and toxicological evaluation. Retinal organoids (ROs) and organoid-on-a-chip (ROoC) are both emerging as promising in-vitro models to faithfully recapitulate human eyes for retinal research in the replacement of experimental animals and primary cells. In this study, we review the generation and application of ROs resembling the human retina in cell subtypes and laminated structures and introduce the emerging engineered ROoC as a technological opportunity to address critical issues. On-chip vascularization, perfusion, and close inter-tissue interactions recreate physiological environments in vitro, whilst integrating with biosensors facilitates real-time analysis and monitoring during organogenesis of the retina representing engineering efforts in ROoC models. We also emphasize that ROs and ROoCs hold the potential for applications in modeling intraocular drug delivery in vitro and developing next-generation retinal drug delivery strategies.
... Moreover, exosome purification and biomarkers detection relying on the lab-on-a-chip technique have been proven to be effective and efficient for future point-of-care diagnosis of PC recently. 22,78,110 The technique can be designed according to detection methods and can significantly accelerate the procedure and simplify the operation. The variability of manual operations may be avoided to generate reproducible results and better separation of samples. ...
... 1 The small size, low cost, and automation of microfluidic chips offer new capabilities for analytical devices. 2,3 To precisely manipulate the fluids inside microchannels, techniques such as electrowetting, 4 magnetics, 5 and optics 6 are widely incorporated in microfluidics. In recent years, there has been a considerable progress in the application of surface acoustic waves (SAWs) on miniatured devices for life science, which will be presented in detail and summarized in this review. ...
Over the past decade, surface acoustic wave (SAW) devices have been widely used in the field of biological detection, including as actuators for sample pretreatment processes and as biosensors for the qualitative or quantitative detection of various biological objectives, with favorable biocompatibility, contactless operation, and noninvasive features. In this review work, we choose types of SAWs as the thread to run through various implements. The theoretical basis is firstly explained to provide the physical principles governing the design and operation of SAW in the above fields. Also, the notable set-ups and key features in each category are summarized and discussed in detail, allowing rapid access to specific advancements for researchers in the field. Finally, the perspectives on the future trend in terms of opportunities and challenges of SAW-based detection devices are offered.
... The fundamental concepts on the continuum field approach to the treatment of matter had their origin well over some centuries ago in the works of Euler and later Cauchy, and yet the classical continuum mechanics is based on the idea that all material bodies possess continuous mass densities, and that the laws of motion and the axioms of constitution are valid for every part of the body regardless of its size [111,112]. From this conventional, undiscriminating viewpoint, continuous media are dense collections of point masses, i.e. concentrated infinitesimal masses devoid of internal structure [113][114][115][116]. ...
Interfacial polymerization is an important method for producing organic and inorganic materials with expected micro-/nanoscale structure and properties. This work summarized and reviewed the interfacial polymerization method from the initial cases to recent reported cases by defining reported different cases related methods into the conventional and unconventional catalogues. In this review, the interfacial polymerization process has been firstly classified from different assistances, e.g. from physical, chemical, physic-chemical and others. The recently reported non-classical interfacial polymerization process has been also greatly focused on.
... In microfluidic configurations, it is important to obtain the effective refractive index in chemical and biological research [16]. In lab-on-a-chip system, microfluidics channels are the key elements for nanoparticle detections and manipulations and different biological applications [17,18]. Common optical materials for microfluidics are polydimethylsiloxane (PDMS), silica (SiO 2 ) or silicon (Si), thermoset polyester, etc. PDMS, SiO 2 and Si are often used due to their properties are well studied and they are relatively inexpensive [19][20][21]. ...
Reflection photonic jet (r-PJ) is a new type of photonic jet (PJ), formed in reflection mode, which has the potential to revolutionize mesoscale photonics in many applications, e.g. optical nanoparticle trapping, liquids and gas refractive index sensing, signal switching, etc. In this paper, we present a microfluidic channel based on a hollow micro-fiber structure with partially coated optically thick gold film to produce r-PJs for biofluid application. The proposed scheme is studied by the full-wave simulations using the finite element method. The key r-PJ parameters, such as the maximum field intensity, focus position and full width at half-maximum (FWHM)
are studied for different size of the microchannel and coated area. The proposed design allows a wide range of flexible control of the r-PJ parameters and can be easily integrated into microchannel systems.
... 13,14 Despite the aforementioned advantages of lab-on-a-chip devices assisted by ultrasonic waves, more attention deserves to be paid to diversity investigation in the field of patterned arrangement of manipulated specimens compared with the conventional high throughput of passive microfluidic methods (particle filtration, inertial movement, and hydraulic driving) [15][16][17] or the existing precision control of active manipulation techniques (mechanical, electric/dielectric, magnetic/diamagnetic, optical, and thermal effects). [18][19][20][21][22] Extensive research studies have also been carried out to achieve complex and diversified acoustofluidic distributions through the introduction of unconventional acoustic metamaterials, phononic crystals, acoustofluidic holography, etc. [23][24][25] However, most research studies in the regime of patterned arrangement using ultrasound field require sophisticated structural designs and complicated oscillation parameter modulations, restricting practical applications of these acoustofluidic manipulation platforms. ...
In this study, a novel strategy to generate sophisticated acoustic streaming vortices, which would be available for rotational manipulation of micro-/nano-scale objects, is proposed and simulated. All structural units in the microfluidic chamber are symmetric in design, and all radiation surfaces have the same settings of input frequency, oscillation amplitude, and initial phase. Different kinds of asymmetric acoustofluidic patterns can be generated in the originally static microfluidic chamber only because of the asymmetric arrangement of multiple radiation surfaces in space. The calculation results of kaleidoscopic acoustofluidic fields together with particle movement trajectories induced by cross structures with different radiation surface distributions further demonstrate the versatile particle manipulation capabilities of these functional microfluidic devices. In comparison to the existing oscillation modulation method, which requires multiple radiation surfaces with different initial phases, acoustofluidic devices with a same initial phase of all radiation surfaces can significantly reduce the required number of auxiliary signal generators and power amplifiers. The proposed generation method of acoustofluidic patterns is promising for microfluidic mixing without rotating machinery, driving operation of microrobots, and rotational manipulation of biological samples.
... Nowadays microfluidic platforms have become among the most prevalent technologies because of their tremendous applications, including biological and chemical analyses, fertility analyses, cell sorting, infectious disease diagnostics, DNA sequencing, ect [96]. Microfluidic platforms provide many attractive advantages, such as continuous sample processing to reduce target cell loss. ...
Circulating tumor cells (CTCs) are cells that shed from a primary tumor and travel through the bloodstream. Studying the functional and molecular characteristics of CTCs may provide in-depth knowledge regarding highly lethal tumor diseases. Researchers are working to design devices and develop analytical methods that can capture and detect CTCs in whole blood from cancer patients with improved sensitivity and specificity. Techniques using whole blood samples utilize physical prosperity, immunoaffinity or a combination of the above methods and positive and negative enrichment during separation. Further analysis of CTCs is helpful in cancer monitoring, efficacy evaluation and designing of targeted cancer treatment methods. Although many advances have been achieved in the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this burgeoning diagnostic approach. In this review, a brief summary of the biological characterization of CTCs is presented. We focus on the current existing CTC detection methods and the potential clinical implications and challenges of CTCs. We also put forward our own views regarding the future development direction of CTCs.
... One opportunity to try reducing costs and increase the substrate reproducibility is the recently explored scientific field called microfluidics. With this knowledge, it is possible to simulate and control different discrete systems at microscale for noble metal nanoparticle synthesis61 . different conditions, with and without surfactant, for the Au nanoparticle preparation. ...
In the present work, different microfluidic reactors were designed and fabricated for the microfluidic synthesis of Ag and Au nanoparticles, using a droplet generation system through segmented flow. First, the fabrication of PDMS/glass microfluidic devices was carried out using the soft lithography method which allow their obtainment in a reproducible way. However, the mixture of surface properties between the materials did not allow to control the reproducibility of the syntheses due to clogging problems through the channels and coalescence within the droplets, causing velocities disruptions on the fluids, and Ag growth deposits within the channels.Because of this, a tubular microfluidic reactor was fabricated. This, having the same surface property throughout the reactor, allowed the obtaining of Ag and Au nanoparticles with spherical morphologies and sizes of 7 and 15 nm, respectively. In addition, these nanoparticles presented an LSPR at 400 nm for Ag and 520 nm for Au, characteristics of these metals.On the other hand, Si/Pyrex microfluidic devices are conditioned and manufactured for later use as a SERS microfluidic substrate. These were functionalized through a silanization process with 3-mercaptopropyltrimethoxysilane to assemble the noble metal nanoparticles on the surface of their microchannels.Subsequently, Au nanoparticles were flowed through the microchannels of the microfluidic devices at 80 μL h-1 and then 4-aminothiophenol was flowed at 20 μL h-1 as a test molecule for its evaluation in the augmented Raman spectroscopy on surfaces, observing An analytical magnification factor of 17 on the characteristic signals of this molecule at 1590 and 1080 cm-1, concluding that the synthesis and microfluidic assembly of noble metal nanoparticles is an alternative for SERS analysis.
... Waveguides integrated with microfluidic channels often form the basis of microfluidic networks for optofluidic device design [11][12][13][14]. Integrated devices which combine both fluidic channels and optical waveguides on a planar platform have been demonstrated [15][16][17]. ...
We report an optofluidic hybrid silicon-polymer planar ring resonator with integrated microfluidic channels for efficient liquid delivery. The device features a planar architecture of intersecting liquid-core waveguides and microfluidic channels. A low-loss integration of microfluidic channels is accomplished by exploiting the interference pattern created by the self-imaging effect in the multimode interference-based coupler waveguides. Numerical simulations have been performed in order to minimize the propagation losses along the ring loop caused by the integration of microfluidic channels. The device has been fabricated and optically characterized by measuring the quality factor, obtaining a value of 4 × 103. This result is comparable with the quality factor of an optofluidic ring with the same optical layout but without integrated microfluidic channels, thus, confirming the suitability of the proposed approach for microfluidics integration in planar optofluidic design.
... It can be used to assess cell densities in case of autofluorescence activity, detect specific physiological activity by enhanced production of fluorescent metabolites, or measure fluorescence-labeled cells (Fig. 3B). To obtain morphological data of biological micro-objects, for example, to estimate early embryonic states of multicellular organisms in microfluidic environments or to assess the distribution and aggregation behavior of microorganisms as well as the shape and size of colonies in dependence on the concentration of applied noxious agents 49 inside microfluidic channels or compartments can be characterized by microscopic imaging, object-adapted numerical apertures can be applied in order to optimize depth of focus, required acquisition time and spatial resolution (Fig. 3C). Using micro and nanosensor beads can be used to read chemical information from micro fluid compartments by primary transduction of chemical signals into optical signals, for example, pH-or oxygen-sensitive microparticles-responding to variations in pH or content of dissolved oxygen by variation of fluorescence quantum yield; a parallel detection of two or three components can be realized by application of different wave length channels (Fig. 3D). ...
Microtoxicology is concerned with the toxic effects of small amounts of substances. In this progress report, we discuss the application of small amounts of noxious substances for toxicological investigation in...
This chapter focuses on a series of further sustainable and/or unconventional wet-chemical methods to prepare single metal, alloys, oxides, chalcogenides and other inorganic compounds in the form of nanoparticles (NPs) at low temperature (<200 °C). In particular, the aim of the chapter is to provide the reader with an overview of further methods not specifically addressed by other chapters of the book, such as hydrothermal, polyol-assisted, continuous-flow and sonochemical methods, as well as radiochemistry and laser ablation in liquid media. A theoretical background of each method, a description of the synthetic procedure and a discussion of the synthetic parameters involved, and their influence on the final features of the products, are given, with the pros and cons of the presented synthetic approaches also outlined. In addition, a description of the state-of-the-art of the compounds obtainable through each approach is presented.
From deciphering infection and disease mechanisms to identifying novel bio-markers and personalizing treatments, the characteristics of individual cells canprovide significant insights into a variety of biological processes and facilitatedecision-making in biomedical environments. Conventional single-cell analysismethods are limited in terms of cost, contamination risks, sample volumes,analysis times, throughput, sensitivity, and selectivity. Although microfluidicapproaches have been suggested as a low-cost, information-rich, and high-throughput alternative to conventional single-cell isolation and analysis methods,limitations such as necessary off-chip sample pre- and post-processing as well assystems designed for individual workflows have restricted their applications. Inthis review, a comprehensive overview of recent advances in integrated micro-fluidics for single-cell isolation and on-chip analysis in three prominentapplication domains are provided: investigation of somatic cells (particularlycancer and immune cells), stem cells, and microorganisms. Also, the use ofconventional cell separation methods (e.g., dielectrophoresis) in unconventionalor novel ways, which can advance the integration of multiple workflows inmicrofluidic systems, is discussed. Finally, a critical discussion related to currentlimitations of integrated microfluidic single-cell workflows and how they could beovercome is provided.
In a living system, the interactions between biomolecules can be said to be a key "cornerstone", that constitute the basic unit of activities supporting viability. Understanding biomolecular interactions can both help us understand life science more deeply, and provide theoretical and technical support for drug development, clinical diagnosis, food safety, and functional food development. Microfluidic systems and nanotechnology are widely applied in biomedical fields and have undergone great advances in recent years. This chapter briefly introduces microfluidic nano-detection systems for biomolecular interactions. First, this chapter explains and classifies different biomolecular interaction principles and introduces traditional biomolecular interaction analysis methods. Then, this chapter especially introduces the main units of the microfluidic nano-detection system. Subsequently, the common nanomaterials in the microfluidic detection system are described, and several typical microfluidic nano-detection systems are listed. The focus is on the application progress of microfluidic nano-detection systems in single cell detection, protein-protein interactions, and protein-other molecule interactions. Finally, the available commercial instruments for biomolecular interactions are summarized. Additionally, the development trends in microfluidic nano-detection system are discussed for biomolecular interaction analysis.
Microfluidic technologies have garnered significant attention due to their ability to rapidly process samples and precisely manipulate fluids in assays, making them an attractive alternative to conventional experimental methods. With the potential for revolutionary capabilities in the future, this concise review provides readers with insights into the fascinating world of microfluidics. It begins by introducing the subject's historical background, allowing readers to familiarize themselves with the basics. The review then delves into the fundamental principles, discussing the underlying phenomena at play. Additionally, it highlights the different aspects of microfluidic device design, classification, and fabrication. Furthermore, the paper explores various applications, the global market, recent advancements, and challenges in the field. Finally, the review presents a positive outlook on trends and draws lessons to support the future flourishing of microfluidic technologies.
Cellular processes are mechanisms carried out at the cellular level (within or among more than one cell interactions) that are aimed at guaranteeing the stability of the organism they comprise. The investigation of cellular processes is key to understanding cell fate, understanding pathogenic mechanisms, and developing new therapeutic technologies. Microfluidic platforms are thought to be the most powerful tools among all methodologies for investigating cellular processes because they can integrate almost all types of the existing intracellular and extracellular biomarker‐sensing methods and observation approaches for cell behavior, combined with precisely controlled cell culture, manipulation, stimulation, and analysis. Most importantly, microfluidic platforms can realize real‐time in situ detection of secreted proteins, exosomes, and other biomarkers produced during cell physiological processes (adhesion, differentiation, migration, apoptosis, and cell‐to‐cell communication), thereby providing the possibility to draw the whole picture for a cellular process. In addition, these can be used to study the process of cell or tissue response to changes in the microenvironment (drugs, physical signals, or types and quantities of surrounding cells). Owing to their advantages of high throughput, low sample consumption, and precise cell control, microfluidic platforms with real‐time in situ monitoring characteristics are widely being used in cell analysis (cellular heterogeneity analysis, cell sorting, and cellular marker detection), disease diagnosis, pharmaceutical research, and biological production. This review focuses on the basic concepts, recent progress, and application prospects of microfluidic platforms for real‐time in situ monitoring of biomarkers in cellular processes.
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Microfluidic devices are critical in lab-on-chip, drug delivery, flexible sensors, etc. However, a formidable challenge remains in fabricating microfluidic channels with complex shapes during design and verification. Herein, we present a facile approach for manufacturing polystyrene (PS) templates by in-suit combining microscale electrohydrodynamic (EHD) printing and mesoscale direct ink writing (DIW). The desired multiscale filament width from 20 μm to > 1 mm could be obtained through appropriate voltage and pressure with continuous printing. The further process parameters for adjusting line width including deposition speed, auxiliary heating for DIW/EHD printing mode were investigated detailly. And we prove the stability and feasibility for producing microfluidics via the method by AFM, EDS and filling test. Based on the solubility of PS in the organic solvent, we can readily reconfigure the existing template by erasing and printing part of the patterns for better remanufacturing. Finally, the LM-filling PDMS microfluidic is experimented to demonstrate the future potential and advantage of the printing technology for fabricating the flexible microfluidic device.Graphical Abstract
Optical microscopic imaging techniques are essential in biology and chemistry fields to observe and extract dynamic information of micro/nano-scale samples in microfluidic devices. However, the current microfluidic optical imaging schemes encounter dilemmas in simultaneously possessing high spatial and temporal resolutions. Recently, microsphere nanoscope has emerged as a competitive nano-imaging tool due to its merits like high spatial resolution, real-time imaging abilities, and cost-effectiveness, which make it a potential solution to address the aforementioned challenges. Here, a microsphere compound lens (MCL) integrated microfluidic imaging device is proposed for real-time super-resolution imaging. The MCL consists of two vertically stacked microspheres, which can resolve nano-objects with size beyond the optical diffraction limit and generate an image of the object with a magnification up to 10×. Exploiting the extraordinary nano-imaging and magnification ability of the MCL, optically transparent 100 nm polystyrene particles in flowing fluid can be discerned in real time by the microfluidic device under a 10× objective lens. Contrary to this, the single microsphere and the conventional optical microscope are incompetent in this case regardless of the magnification of objective lenses used, which demonstrates the superiority of the MCL imaging scheme. Besides, applications of the microfluidic device in nanoparticle tracing and live-cell monitoring are also experimentally demonstrated. The MCL integrated microfluidic imaging device can thus be a competent technique for diverse biology and chemistry applications.
An optofluidic sensor, which is composed of a fiber Fabry-Perot interferometer (FPI) and a microfluidic chip, is experimentally demonstrated to measure aerostatic pressure, local temperature, and fluidic flow rate in microfluidic chips. The aerostatic pressure sensitivity is as high as −2393.3 nm/Bar. By demodulating the aerostatic pressure and temperature with a sensitivity matrix, both the physical parameters can be predicted simultaneously. The noise-equivalent detection limit (NEDL) of aerostatic pressure is as low as 48.4 μBar. In addition, the experiment results show that the fluidic flow rate sensitivity is −1.8574 nm/(μl/min) and the NEDL of fluidic flow rate is 97.1 nl/min, respectively. The miniature optofluidic sensor based on the optical fiber Fabry-Perot interferometer provides a promising cost-effective sensing platform for monitoring multiple physical parameters in the microfluidic chips, which is of great significance for on-chip biochemical reactions.
The Covid-19 pandemic has led to greater recognition of the importance of the fast and timely detection of pathogens. Recent advances in point-of-care testing (POCT) technology have shown promising results for rapid diagnosis. Immunoassays are among the most extensive POCT assays, in which specific labels are used to indicate and amplify the immune signal. Nanoparticles (NPs) are above the rest because of their versatile properties. Much work has been devoted to NPs to find more efficient immunoassays. Herein, we comprehensively describe NP-based immunoassays with a focus on particle species and their specific applications. This review describes immunoassays along with key concepts surrounding their preparation and bioconjugation to show their defining role in immunosensors. The specific mechanisms, microfluidic immunoassays, electrochemical immunoassays (ELCAs), immunochromatographic assays (ICAs), enzyme-linked immunosorbent assays (ELISA), and microarrays are covered herein. For each mechanism, a working explanation of the appropriate background theory and formalism is articulated before examining the biosensing and related point-of-care (POC) utility. Given their maturity, some specific applications using different nanomaterials are discussed in more detail. Finally, we outline future challenges and perspectives to give a brief guideline for the development of appropriate platforms.
We present a unidirectional dielectric optical antenna, which can be chemically synthesized and controlled by magnetic fields. By applying magnetic fields, we successfully aligned an optical antenna on a prepatterned quantum dot nanospot with accuracy better than 40 nm. It confined the fluorescence emission into a 16-degree wide beam and enhanced the signal by 11.8 times. Moreover, the position of the antenna, and consequently the beam direction, can be controlled by simply adjusting the direction of the magnetic fields. Theoretical analyses show that this magnetic alignment technique is stable and accurate, providing a new strategy for building high-performance tunable nanophotonic devices.
The fast growing of infrared imaging system for non-contact thermography, night surveillance and night driving assistance demands highly integrated optical lenses with miniaturization feature for performance improvement. Herein, we fabricated refractive type of microlens arrays (MLAs) with high numerical aperture (NA) and high integration on commercial chalcogenide glass (As2Se3) by combining photoresist thermal reflow and soft mold imprinting process. PDMS-type concave MLAs (PDMS-MLAs) soft mold is prepared by transfer printing process on photoresist (PR) MLAs fabricated by standard UV exposure and thermal reflow. The microlens on PDMS-MLAs could be further transferred to the surface of As2Se3 glass through the hot imprinting technique, forming chalcogenide glass-based MLAs (ChG-MLAs). Morphology detection reveals that microlens in the MLAs has an average aperture and sag height of approximately 13.4 and 1.7 μm. Moreover, the optical performance investigation demonstrated that the ChG-MLAs with 700 × 700 array size (10.5 × 10.5 mm) showed good structure uniformity and focusing capability, and through the FDTD simulation, it further evidenced that focal lengths of 6.3–8.1 µm with high numerical aperture of 0.64–0.73 (wavelength range: 3–5 μm) was achieved.
Most multiplex nucleic acids detection methods require numerous reagents and high‐priced instruments. The emerging clustered regularly interspaced short palindromic repeats (CRISPR)/Cas has been regarded as a promising point‐of‐care (POC) strategy for nucleic acids detection. However, how to achieve CRISPR/Cas multiplex biosensing remains a challenge. Here, an affordable means termed CRISPR‐RDB (CRISPR‐based reverse dot blot) for multiplex target detection in parallel, which possesses the advantages of high sensitivity and specificity, cost‐effectiveness, instrument‐free, ease to use, and visualization is reported. CRISPR‐RDB integrates the trans‐cleavage activity of CRISPR‐Cas12a with a commercial RDB technique. It utilizes different Cas12a‐crRNA complexes to separately identify multiple targets in one sample and converts targeted information into colorimetric signals on a piece of accessible nylon membrane that attaches corresponding specific‐oligonucleotide probes. It has demonstrated that the versatility of CRISPR‐RDB by constructing a four‐channel system to simultaneously detect influenza A, influenza B, respiratory syncytial virus, and SARS‐CoV‐2. With a simple modification of crRNAs, the CRISPR‐RDB can be modified to detect human papillomavirus, saving two‐thirds of the time compared to a commercial PCR‐RDB kit. Further, a user‐friendly microchip system for convenient use, as well as a smartphone app for signal interpretation, is engineered. CRISPR‐RDB represents a desirable option for multiplexed biosensing and on‐site diagnosis.
Nanoscale plasmonic hotspots play a critical role in the enhancement of molecular Raman signals, enabling the sensitive and reliable trace analysis of biomedical molecules via surface-enhanced Raman spectroscopy (SERS). However, effective and label-free SERS diagnoses in practical fields remain challenging because of clinical samples' random adsorption and size mismatch with the nanoscale hotspots. Herein, we suggest a novel SERS strategy for interior hotspots templated with [email protected] core–shell nanostructures prepared via electrochemical one-pot Au deposition. The cytochrome c and lysates of SARS-CoV-2 (SLs) embedded in the interior hotspots were successfully functionalized to confine the electric fields and generate their optical fingerprint signals, respectively. Highly linear quantitative sensitivity was observed with the limit-of-detection value of 10⁻¹ PFU/mL. The feasibility of detecting the targets in a bodily fluidic environment was also confirmed using the proposed templates with SLs in human saliva and nasopharyngeal swabs. These interior hotspots templated with the target analytes are highly desirable for early and on-site SERS diagnoses of infectious diseases without any labeling processes.
Oral delivery is with high patient compliance but low bioavailability and controllability. The emerging microfluidics-derived microcarriers have sprung up to relieve the hurdles. Herein, a review on the recent progress in applying microfluidics-derived microcarriers for oral delivery is presented. First, we briefly introduce the microfluidic fabrication of microcarriers based on laminar flow and droplets. Then, we focus on the applications of microfluidics-derived microcarriers for oral delivery in stomach, small intestine, and colon. Last but not least, we discuss the challenges and outlooks of the microfluidics-derived microparticles for oral delivery in the end. This review is anticipated to help readers to follow up the research frontiers in this field, and guide the future development direction of microfluidics-derived microcarriers.
Lab-on-a-chip systems aim to integrate laboratory operations on a miniaturized device with broad application prospects in the field of point-of-care testing. However, bulky peripheral power resources, such as high-voltage supplies, function generators, and amplifiers, hamper the commercialization of the system. In this paper, a portable, self-powered microparticle manipulation platform based on triboelectrically driven dielectrophoresis (DEP) is reported. The rotary freestanding triboelectric nanogenerator (RF-TENG) and rectifier/filter circuit supply a high-voltage direct current signal to form a non-uniform electric field within the microchannel, realizing controllable actuation of the microparticles through DEP. The operating mechanism of this platform and the control performance of the moving particles were systematically studied and analyzed. Randomly distributed particles converged in a row after passing through the serpentine channel. And various particles were separated owing to the different DEP forces. Ultimately, the high-efficiency separation of live and dead yeast cells was achieved using this platform. RF-TENG as the power source for lab-on-a-chip exhibits better safety and portability than traditional high-voltage power sources. This study presents a promising solution for the commercialization of lab-on-a-chip. This article is protected by copyright. All rights reserved.
Microlens arrays (MLAs) are key micro-optical components that possess a high degree of parallelism and ease of integration. However, rapid and low-cost fabrication of MLAs with flexible focusing remains a challenge. Herein, liquid MLAs with dynamic tunability are presented using non-contact acoustic relocation of inhomogeneous fluids. By designing ring-shaped acoustic pressure node (PN) arrays, the denser fluid of miscible liquids is relocated to PNs, and liquid MLAs with ideal morphology are obtained. The experimental results demonstrate that the liquid MLAs possess a powerful reconfigurability with long-term stability and sharp imaging that can conveniently switch between the on and off state and can dynamically magnify by simply adjusting the acoustic amplitude. Moreover, the high biocompatibility inherited from liquids accompanied by the acoustic treatment allows cells to be within working distance of the MLAs without immersion, as would be required for a solid lens. This innovative liquid MLA is inexpensive to manufacture and possesses continuous focus, fast response, and satisfactory bioaffinity, and thus offers promising potential for microfluidic adaptive imaging and biomedical sensing, especially for live cell imaging.
Colorimetric detection has been widely used in sweat colorimetric analysis due to its advantages of convenient detection and easy implementation. However, its relatively low detection accuracy limits its application. It is therefore necessary to develop new methods to extract quantitative data from the colorimetric biosensor. In this work, a plug type paper-based analytical device (μPad) sensor was fabricated and put into a Polydimethylsiloxane (PDMS) microfluidic chamber prepared through 3D-Printing. Photoelectric sensor with a light-emitting diode (LED) light source was utilized for acquiring the colour change information (including R, G, B, Lux, colour temperature value) before and after the colorimetric sensing. Wireless Bluetooth transmission module was used for data acquisition. The obtained multi-parameter data was fitted through machine learning algorithm using Python to establish the relationship between the multi-parameter and the concentration of analyte. Discoloration experiments of glucose, lactic acid and pH were used to verify the feasibility of the sensor and data analysis method. Analysis of human sweat in a running volunteer has proved its potential as a wearable device and provided a new insight for data analysis of colorimetric method of wearable colorimetric biosensors.
Curved artificial compound eyes (ACEs) attract enormous research interest owing to their potential applications in medical devices, surveillance imaging, target tracking, and so on. However, fog, dust, or other liquids are likely to condense on the device surface under a humid, low‐temperature environment or outdoors, thus affecting the optical performance. In this work, a multi‐functional ACE (MF‐ACE) is fabricated by a combination of i) femtosecond laser wet etching, ii) soft lithography, and iii) polydimethylsiloxane (PDMS) swelling methods. The fabricated device is close‐packed with over 3000 microlenses (≈108 µm diameter and ≈15 µm height) on a spherical macrolens (6.56 cm diameter and 0.87 cm height). The trapped silicone oil in the cross‐linked PDMS endows the as‐fabricated ACE with excellent water repellence and anti‐fogging, anti‐fouling, and self‐cleaning abilities. In addition, the ACE shows high optical performance and the ommatidia have a spatial resolution of 50.8 lp mm⁻¹. The imaging and focusing experiments demonstrate its high optical properties and uniformity. It is anticipated that this research may provide useful guidelines for the fabrication of anti‐fogging and anti‐fouling optical devices, and such device enables potential applications in autonomous vehicles, medical, or vision systems under harsh environmental conditions.
Three different approaches for the analytical detection of fluids by means of rectangular glass micro-capillaries working in the near infrared wavelength region are presented. At first, a non-specific refractometric measurement for the detection of glucose concentration in solutions is reported, exploiting the micro-capillaries as optical resonators: by monitoring the spectral shift of the ratio between the transmitted and reflected optical spectra (T/R) from the capillary, it is possible to extract the wavelength positions of the cavity resonances (maxima of T/R) for fluids with different refractive index. When the refractive index of the sample fluid filling the channel increases, a shift towards longer wavelengths is observed. Then, a spectral phase shift interferometric technique for the detection of the wavelength position of the resonances is proposed. When the capillary is inserted in an interferometric setup, it is possible to distinguish fluids by knowing the dependence of the wavelength positions of the steep jumps in the cosine signal on the refractive index of the filling fluid. Finally, the potentiality of micro-capillaries is investigated for specific sensing, exploiting absorption spectroscopy. All the proposed optical readout approaches are remote, contactless and non-invasive. In addition, the glass-micro-capillaries are very suitable for analytical detection of fluids: they are low-cost devices, available in several formats. Thanks to their micrometric size, they can be incorporated in micro-fluidic circuits. Borosilicate glass is a bio-compatible material, allowing the use of the micro-fluidic platforms in a wide range of applications for label-free optical sensing.
Acoustic-based microfluidics has been widely used in recent years for fundamental research due to its simple device design, biocompatibility, and contactless operation. In this article, the basic theory, typical devices, and technical applications of acoustic microfluidics technology are summarized. First, the theory of acoustic microfluidics is introduced from the classification of acoustic waves, acoustic radiation force, and streaming flow. Then, various applications of acoustic microfluidics including sorting, mixing, atomization, trapping, patterning, and acoustothermal heating are reviewed. Finally, the development trends of acoustic microfluidics in the future were summarized and looked forward to.
The detection and separation of biological samples are of great significance for achieving accurate diagnoses and state assessments. Currently, the detection and separation of cells mostly adopt labeling methods, which will undoubtedly affect the original physiological state and functions of cells. Therefore, in this study, a label-free cell detection method based on microfluidic chips is proposed. By measuring the scattering of cells to identify cells and then using optical tweezers to separate the target cells, the whole process without any labeling and physical contact could realize automatic cell identification and separation. Different concentrations of 15 µm polystyrene microspheres and yeast mixed solution are used as samples for detection and separation. The detection accuracy is over 90%, and the separation accuracy is over 73%.
Microfluidics has enabled a new era of cellular and molecular assays due to the small length scales, parallelization, and the modularity of various analysis and actuation functions. Droplet microfluidics, in particular, has been instrumental in providing new tools for biology with its ability to quickly and reproducibly generate drops that act as individual reactors. A notable beneficiary of this technology has been single-cell RNA sequencing, which has revealed new heterogeneities and interactions for the fundamental unit of life. However, viruses far surpass the diversity of cellular life, affect the dynamics of all ecosystems, and are a chronic source of global health crises. Despite their impact on the world, high-throughput and high-resolution viral profiling has been difficult, with conventional methods being limited to population-level averaging, large sample volumes, and few cultivable hosts. Consequently, most viruses have not been identified and studied. Droplet microfluidics holds the potential to address many of these limitations and offers new levels of sensitivity and throughput for virology. This Feature highlights recent efforts that have applied droplet microfluidics to the detection and study of viruses, including for diagnostics, virus-host interactions, and cell-independent virus assays. In combination with traditional virology methods, droplet microfluidics should prove a potent tool toward achieving a better understanding of the most abundant biological species on Earth.
Inertial microfluidics functions solely based on the fluid dynamics at relatively high flow speed. Thus, channel geometry is the critical design parameter that contributes to the performance of the device. Four basic channel geometries (i.e., straight, expansion-contraction, spiral and serpentine) have been proposed and extensively studied. To further enhance the performance, innovative channel design through combining two or more geometries is promising. This work explores embedding periodic concave and convex obstacle microstructures in sinusoidal channels and investigates their influence on particle inertial focusing and separation. The concave obstacles could significantly enhance the Dean flow and tune the flow range for particle inertial focusing and separation. Based on this finding, we propose a cascaded device by connecting two sinusoidal channels consecutively for rare cell separation. The concave obstacles are embedded in the second channel to adapt its operational flow rates and enable the functional operation of both channels. Polystyrene beads and breast cancer cells (T47D) spiking in the blood were respectively processed by the proposed device. The results indicate an outstanding separation performance, with 3 to 4 orders of magnitude enhancement in purity for samples with a primary cancer cells ratio of 0.01% and 0.001%, respectively. Embedding microstructures as obstacles brings more flexibility to the design of inertial microfluidic devices, offering a feasible new way to combine two or more serial processing units for high-performance separation.
Silica fibers are nowadays cornerstones in several technological implementations from long‐distance communication, to sensing applications in many scenarios. To further enlarge the functionalities, the compactness, and the performances of fiber‐based devices, one needs to reliably integrate small‐footprint components such as sensors, light sources, and detectors onto single optical fiber substrates. Here, a novel proof of concept is presented to deterministically integrate optoelectronic chips onto the facet of an optical fiber, further implementing the electrical contacting between the chip and fiber itself. The CMOS‐compatible procedure is based on a suitable combination of metal deposition, laser machining, and micromanipulation, directly applied onto the fiber tip. The proposed method is validated by transferring, aligning, and bonding a quantum‐well based laser on the core of a multimode optical fiber. The successful monolithic device integration on fiber shows simultaneously electrical contacting between the laser and the ferrule, and 20% light in‐coupling in the fiber. These results pave new ways to develop the next generation of optoelectronic systems on fiber. The technological approach will set a new relevant milestone along the lab‐on‐fiber roadmap, opening new avenues for a novel class of integrated optoelectronic fiber platforms, featuring unrivaled miniaturization, compactness, and performances levels, designed for specific applications.
Vortex-aided particle separation is a powerful method to efficiently isolate circulating tumor cells from blood, since it allows high throughput and continuous sample separation, with no need for time-consuming sample preprocessing. With this approach, only the larger particles from a heterogeneous sample will be stably trapped in reservoirs that expand from a straight microfluidic channel, allowing for efficient particle sorting along with simultaneous concentration. A possible limitation is related to the loss of particles from vortex traps due to particle–particle interactions that limit the final cellularity of the enriched solution. It is fundamental to minimize this issue considering that a scant number of target cells are diluted in highly cellular blood. In this work, we present a device for size-based particle separation, which exploits the well-consolidated vortex-aided sorting, but new reservoir layouts are presented and investigated in order to increase the trapping efficiency of the chip. Through simulations and experimental validations, we have been able to optimize the device design to increase the maximum number of particles that can be stably trapped in each reservoir and therefore the total efficiency of the chip.
Optical super-resolution imaging is a desirable technique in many fields, including medical and material sciences and nanophotonics. We demonstrated feasibility of optical microscopy, with resolution improvement by a factor of 2-3, by using microsphere-embedded coverslips composed of barium titanate glass microspheres (refractive index n~1.9-2.1) fixed in a transparent layer of polydimethylsiloxane. Imaging was performed by a conventional microscope and a fluorescent microscope with the microsphere-embedded layer placed in a contact position with various biological specimens and semiconductor nanostructures. We investigated a biomedical application of microsphere-assisted imaging technique by immunostaining of kidney sections where cellular distribution of a motor protein Myo1c and a podocyte specific protein ZO-1 was analyzed. A significant visual enhancement in the distribution pattern of the proteins was noted in the stained glomeruli by using microsphere-assisted imaging technique. Our results suggest that microsphere-assisted imaging technique is a promising candidate for applications in medical and cancer research, as well as in microfluidics and nanophotonics.
Whispering gallery mode biosensors have been widely exploited over the past decade to study molecular interactions by virtue of their high sensitivity and applicability in real-time kinetic analysis without the requirement to label. There have been immense research efforts made for advancing the instrumentation as well as the design of detection assays, with the common goal of progressing towards real-world sensing applications. We therefore review a set of recent developments made in this field and discuss the requirements that whispering gallery mode label-free sensors need to fulfill for making a real world impact outside of the laboratory. These requirements are directly related to the challenges that these sensors face, and the methods proposed to overcome them are discussed. Moving forward, we provide the future prospects and the potential impact of this technology.
Nanoscale correlation of structural information acquisition with specific-molecule identification provides new insight for studying rare subcellular events. To achieve this correlation, scanning electron microscopy has been combined with super-resolution fluorescent microscopy, despite its destructivity when acquiring biological structure information. Here we propose time-efficient non-invasive microsphere-based scanning superlens microscopy that enables the large-area observation of live-cell morphology or sub-membrane structures with sub-diffraction-limited resolution and is demonstrated by observing biological and non-biological objects. This microscopy operates in both non-invasive and contact modes with B200 times the acquisition efficiency of atomic force microscopy, which is achieved by replacing the point of an atomic force microscope tip with an imaging area of microspheres and stitching the areas recorded during scanning, enabling sub-diffraction-limited resolution. Our method marks a possible path to non-invasive cell imaging and simultaneous tracking of specific molecules with nanoscale resolution, facilitating the study of subcellular events over a total cell period.
A novel microfluidic chip with integrated Teflon AF1600 surface liquid core optical waveguide (LCW) modified with nano gold was proposed and fabricated in this article. Physical deposite method was used to integrate Teflon AF1600 LCW into microchannel. After that, the inner surface of Teflon AF1600 LCW was chemically modified at temperature of 40 °C, subsequent nano gold were in situ immobilied on the silanized inner surface of Teflon AF LCW precoated with a thin layer of poly(diallyldimethylammonium chloride) within microchannel by a chemical self-assembly method. Under the optimized conditions, the prepared microfluidic SERS chip exhibited high sensitivity for R6G with detection limit of 10−11 mol/L and SERS enhancement factor (EF) of 2.7 × 108. Compared to single nano gold SERS enhancement substrate within a microfluidic chip, the SERS detection sensitivity for R6G was improved 4 orders of magnitude. Apart from high SERS enhancement effect, the as-prepared integrated microstructure had extremely good SERS detection reproducibility and duration stability. Furthermore, it was successfully used to detect the bovine serum albumin (BSA), and exhibited excellent SERS response. The research showed great prospects and technical support for design and fabrication of integrated SERS microfluidic chip and sensitive detection of trace biochemical samples.
The application of optical biosensors, specifically those that use optical fibers and planar waveguides, has escalated throughout the years in many fields, including environmental analysis, food safety and clinical diagnosis. Fluorescence is, without doubt, the most popular transducer signal used in these devices because of its higher selectivity and sensitivity, but most of all due to its wide versatility. This paper focuses on the working principles and configurations of fluorescence-based fiber optic and planar waveguide biosensors and will review biological recognition elements, sensing schemes, as well as some major and recent applications, published in the last ten years. The main goal is to provide the reader a general overview of a field that requires the joint collaboration of researchers of many different areas, including chemistry, physics, biology, engineering, and material science.
Dielectric microspheres with appropriate refractive index can image objects with super-resolution, i.e. with a precision well beyond the classical diffraction limit. A microsphere is also known to generate, upon illumination, a photonic nanojet, which is a scattered beam of light with a high-intensity main lobe and very narrow waist. Here we report a systematic study of the imaging of water-immersed nanostructures by barium titanate glass microspheres of different size. A numerical study of the light propagation through a microsphere points out the light focusing capability of microspheres of different size and the waist of their photonic nanojet. The former correlates to the magnification factor of the virtual images obtained from linear test nanostructures, the biggest magnification being obtained with microspheres of ~ 6-7 µm in size. Analyzing the light intensity distribution of microscopy images allows determining analytically the point spread function of the optical system and thereby quantifies its resolution. We find that the super-resolution imaging of a microsphere is dependent on the waist of its photonic nanojet, the best resolution being obtained with a 6 μm Ø microsphere, which generates the nanojet with the minimum waist. This comparison allows elucidating the super-resolution imaging mechanism.
The efficient selection and isolation of individual cells of interest from a mixed population is desired in many biomedical and clinical applications. Here we show the concept of using photoswitchable semiconducting polymer dots (Pdots) as an optical ' painting' tool, which enables the selection of certain adherent cells based on their fluorescence, and their spatial and morphological features, under a microscope. We first develop a Pdot that can switch between the bright (ON) and dark (OFF) states reversibly with a 150-fold contrast ratio on irradiation with ultraviolet or red light. With a focused 633-nm laser beam that acts as a ' paintbrush' and the photoswitchable Pdots as the ' paint', we select and ' paint' individual Pdot-labelled adherent cells by turning on their fluorescence, then proceed to sort and recover the optically marked cells (with 90% recovery and near 100% purity), followed by genetic analysis.
In this paper, we introduce a liquid core antiresonant reflecting optical waveguide (ARROW) as a novel optofluidic device that can be used to create innovative and highly functional microsensors. Liquid core ARROWs, with their dual ability to guide the light and the fluids in the same microchannel, have shown great potential as an optofluidic tool for quantitative spectroscopic analysis. ARROWs feature a planar architecture and, hence, are particularly attractive for chip scale integrated system. Step by step, several improvements have been made in recent years towards the implementation of these waveguides in a complete on-chip system for highly-sensitive detection down to the single molecule level. We review applications of liquid ARROWs for fluids sensing and discuss recent results and trends in the developments and applications of liquid ARROW in biomedical and biochemical research. The results outlined show that the strong light matter interaction occurring in the optofluidic channel of an ARROW and the versatility offered by the fabrication methods makes these waveguides a very promising building block for optofluidic sensor development.
This paper reports a new design of optofluidic tunable lens using a laser-induced thermal gradient. It makes use of two straight chromium strips at the bottom of the microfluidic chamber to absorb the continuous pump laser to heat up the moving benzyl alcohol solution, creating a 2D refractive index gradient in the entrance part between the two hot strips. This design can be regarded as a cascade of a series of refractive lenses, and is distinctively different from the reported liquid lenses that mimic the refractive lens design and the 1D gradient index lens design. CFD simulation shows that a stable thermal lens can be built up within 200 ms. Experiments were conducted to demonstrate the continuous tuning of focal length from initially infinite to the minimum 1.3 mm, as well as the off-axis focusing by offsetting the pump laser spot. Data analyses show the empirical dependences of the focal length on the pump laser intensity and the flow velocity. Compared with previous studies, this tunable lens design enjoys many merits, such as fast tuning speed, aberration-free focusing, remote control, and enabling the use of homogeneous fluids for easy integration with other optofluidic systems.
The massive outbreak of highly lethal Ebola hemorrhagic fever in West Africa illustrates the urgent need for diagnostic instruments that can identify and quantify infections rapidly, accurately, and with low complexity. Here, we report on-chip sample preparation, amplification-free detection and quantification of Ebola virus on clinical samples using hybrid optofluidic integration. Sample preparation and target preconcentration are implemented on a PDMS-based microfluidic chip (automaton), followed by single nucleic acid fluorescence detection in liquid-core optical waveguides on a silicon chip in under ten minutes. We demonstrate excellent specificity, a limit of detection of 0.2 pfu/mL and a dynamic range of thirteen orders of magnitude, far outperforming other amplification-free methods. This chip-scale approach and reduced complexity compared to gold standard RT-PCR methods is ideal for portable instruments that can provide immediate diagnosis and continued monitoring of infectious diseases at the point-of-care.
There is a rapidly growing demand to use silicon and silicon nitride (Si 3 N 4) integrated photonics for sensing applications , ranging from refractive index to spectroscopic sensing. By making use of advanced CMOS technology, complex miniaturized circuits can be easily realized on a large scale and at a low cost covering visible to mid-IR wavelengths. In this paper we present our recent work on the development of silicon and Si 3 N 4-based photonic integrated circuits for various spectroscopic sensing applications. We report our findings on waveguide-based absorption, and Raman and surface enhanced Raman spectroscopy. Finally we report on-chip spectrometers and on-chip broadband light sources covering very near-IR to mid-IR wavelengths to realize fully integrated spectroscopic systems on a chip.
We present an all-polymer photonic sensing platform based on whispering-gallery mode microgoblet lasers integrated into a microfluidic chip. The chip is entirely made from polymers, enabling the use of the devices as low-cost disposables. The microgoblet cavities feature quality factors exceeding 10(5) and are fabricated from poly(methyl methacrylate) (PMMA) using spin-coating, mask-based optical lithography, wet chemical etching, and thermal reflow. In contrast to silica-based microtoroid resonators, this approach replaces technically demanding vacuum-based dry etching and serial laser-based reflow techniques by solution-based processing and parallel thermal reflow. This enables scaling to large-area substrates, and hence significantly reduces device costs. Moreover, the resonators can be fabricated on arbitrary substrate materials, e.g., on transparent and flexible polymer foils. Doping the microgoblets with the organic dye pyrromethene 597 transforms the passive resonators into lasers. Devices have lasing thresholds below 0.6 nJ per pulse and can be efficiently pumped via free-space optics using a compact and low-cost green laser diode. We demonstrate that arrays of microgoblet lasers can be readily integrated into a state-of-the-art microfluidic chip replicated via injection moulding. In a proof-of-principle experiment, we show the viability of the lab-on-a-chip via refractometric sensing, demonstrating a bulk refractive index sensitivity (BRIS) of 10.56 nm per refractive index unit.
We report a 3D microfluidic pulsed laser-triggered fluorescence-activated cell sorter capable of sorting at a throughput of 23 000 cells per s with 90% purity in high-purity mode and at a throughput of 45 000 cells per s with 45% purity in enrichment mode in one stage and in a single channel. This performance is realized by exciting laser-induced cavitation bubbles in a 3D PDMS microfluidic channel to generate high-speed liquid jets that deflect detected fluorescent cells and particles focused by 3D sheath flows. The ultrafast switching mechanism (20 μs complete on–off cycle), small liquid jet perturbation volume, and three-dimensional sheath flow focusing for accurate timing control of fast (1.5 m s−1) passing cells and particles are three critical factors enabling high-purity sorting at high-throughput in this sorter.
Sizing individual nanoparticles and dispersions of nanoparticles provides invaluable information in applications such as nanomaterial synthesis, air and water quality monitoring, virology, and medical diagnostics. Several conventional nanoparticle sizing approaches exist; however, there remains a lack of high-throughput approaches that are suitable for low-resource and field settings, i.e., methods that are cost-effective, portable, and can measure widely varying particle sizes and concentrations. Here we fill this gap using an unconventional approach that combines holographic on-chip microscopy with vapor-condensed nanolens self-assembly inside a cost-effective hand-held device. By using this approach and capturing time-resolved in situ images of the particles, we optimize the nanolens formation process, resulting in significant signal enhancement for the label-free detection and sizing of individual deeply subwavelength particles (smaller than λ/10) over a 30 mm(2) sample field-of-view, with an accuracy of ±11 nm. These time-resolved measurements are significantly more reliable than a single measurement at a given time, which was previously used only for nanoparticle detection without sizing. We experimentally demonstrate the sizing of individual nanoparticles as well as viruses, monodisperse samples, and complex polydisperse mixtures, where the sample concentrations can span ∼5 orders-of-magnitude and particle sizes can range from 40 nm to millimeter-scale. We believe that this high-throughput and label-free nanoparticle sizing platform, together with its cost-effective and hand-held interface, will make highly advanced nanoscopic measurements readily accessible to researchers in developing countries and even to citizen-scientists, and might especially be valuable for environmental and biomedical applications as well as for higher education and training programs.
We detect by optical microscopy Au and fluorescent nanoparticles (NPs) during their motion in water-based medium, using an array of dielectric microspheres that are patterned in a microwell array template. The microspheres act as lenses focusing the light originating from a microscope objective into so-called photonic nanojets that expose the medium within a microfluidic channel. When a NP is randomly transported through a nanojet, its back-scattered light (for a bare Au NP) or its fluorescent emission is instantaneously detected by video microscopy. Au NPs down to 50 nm in size, as well as fluorescent NPs down to 20 nm in size, are observed by using a low magnification/low numerical aperture microscope objective in bright-field or fluorescence mode, respectively. Compared to the NPs present outside of the photonic nanojets, the light scattering or fluorescence intensity of the NPs in the nanojets is typically enhanced by up to a factor ~40. The experimental intensity is found to be proportional to the area occupied by the NP in the nanojet. The technique is also used for immunodetection of biomolecules immobilized on Au NPs in buffer and, in future, it may develop into a versatile tool to detect nanometric objects of environmental or biological importance, such as NPs, viruses or other biological agents.
We propose a PDMS-based photonic system for the accurate measurement of protein concentration with minute amounts of sample. As opposed to the state of the art, in the multiple path photonic lab on a chip (MPHIL), analyte concentration or molar absorptivity is obtained with a single injection step, by performing simultaneous parallel optical measurements varying the optical path length. Also, as opposed to the standard calibration protocol, MPHIL approach does not require a series of measurements at different concentrations. MPHIL has three main advantages: firstly the possibility of dynamically select the path length, always working in the absorbance vs concentration linear range for each target analyte. Secondly, a dramatic reduction of the total volume of sample required to obtain statistically reliable results. Thirdly, since only one injection is required, the measurement time is minimized, reducing both contamination and signal drifts. These characteristics are clearly advantageous when compared to commercial micro-spectrophotometers. The MPHIL concept was validated by testing three commercial proteins, Lysozyme (HEWL), Glucose Isomerase (D-xylose-ketol-isomerase, GI) and Aspergillus sp. Lipase L (BLL), as well as two proteins expressed and purified for this study, B. cereus formamidase (FASE) and dihydropyrimidinase from S. meliloti CECT41 (DHP). The use of the MPHIL is also proposed for any spectrophotometric measurement in the UV-VIS range, as well as for its integration as a concentration measurement platform in more advanced photonic lab on a chip systems.
A novel in situ microspectroscopic monitoring system was developed, coupling a microspectrophotometer with a microscope and optical elements, for real time monitoring of chemical reaction progress within a microfluidic reactor by absorbance measurements. The formation process and rapid changes in size and shape of silver nanoprisms were successfully detected and reveal that these changes take place in a very short section of the microreactor.
Fabrication and performance of a functional photonic-microfluidic flow cytometer is demonstrated. The devices are fabricated on a Pyrex substrate by photolithographically patterning the microchannels and optics in a SU-8 layer that is sealed via a poly(dimethylsiloxane) (PDMS) layer through a unique chemical bonding method. The resulting devices eliminate the free-space excitation optics through integration of microlenses onto the chip to mimic conventional cytometry excitation. Devices with beam waists of 6 mu m and 12 mu m in fluorescent detection and counting tests using 2.5 and 6 mu m beads-show CVs of 9%-13% and 23% for the two devices, respectively. These results are within the expectations for a conventional cytometer (5%-15%) and demonstrate the ability to integrate the photonic components for excitation onto the chip and the ability to maintain the level of reliable detection.
The field of microfluidics has yet to develop practical devices that provide real clinical value. One of the main reasons for this is the difficulty in realizing low-cost, sensitive, reproducible, and portable analyte detection microfluidic systems. Previous research has addressed two main approaches for the detection technologies in lab-on-a-chip devices: (a) study of the compatibility of conventional instrumentation with microfluidic structures, and (b) integration of innovative sensors contained within the microfluidic system. Despite the recent advances in electrochemical and mechanical based sensors, their drawbacks pose important challenges to their application in disposable microfluidic devices. Instead, optical detection remains an attractive solution for lab-on-a-chip devices, because of the ubiquity of the optical methods in the laboratory. Besides, robust and cost-effective devices for use in the field can be realized by integrating proper optical detection technologies on chips. This review examines the recent developments in detection technologies applied to microfluidic biosensors, especially addressing several optical methods, including fluorescence, chemiluminescence, absorbance and surface plasmon resonance.
Channel waveguide-based evanescent-field optical sensors are developed to make a fully integrated chip biosensor. The optical system senses fluorescent analytes immobilized within a micrometric sized bioreactor well realized within an optical waveguide. The main novelty of this work is related to the fact that, within the bioreactor well, the excitation of the fluorescent signal is achieved by means of the evanescent field propagating through a silicon oxynitride waveguide. The immobilization of the emitting molecules is realized by functionalization of the waveguide surface by a wet chemical method. These photonic biosensors are successfully applied to detect low surface concentration (10−11 mol cm−2) of a green emitting organic dye.
This approach could permit the selective detection of a wide range of chemical and biological species in complex matrices and can be exploited to set-up array-based screening devices. In this regard, the preferential excitation of the dye molecules in the close vicinity of the exposed waveguide core is also analysed.
We experimentally demonstrate the use of high contrast, CMOS-compatible integrated photonic waveguides for Raman spectroscopy. We also derive the dependence of collected Raman power with the waveguide parameters and experimentally verify the derived relations. Isopropyl alcohol (IPA) is evanescently excited and detected using single-mode silicon-nitride strip waveguides. We analyze the measured signal strength of pure IPA corresponding to an 819 cm − 1 Raman peak due to in-phase C-C-O stretch vibration for several waveguide lengths and deduce a pump power to Raman signal conversion efficiency on the waveguide to be at least 10 − 11 per cm .
Cost-effective, high-performance diagnostic instruments are vital to providing the society with accessible, affordable, and high-quality healthcare. Here we present an integrated, “microfluidic drifting” based flow cytometry chip as a potential inexpensive, fast, and reliable diagnostic tool. It is capable of analyzing human blood for cell counting and diagnosis of diseases. Our device achieves a throughput of ~3754 events/s. Calibration with Flow-Check calibration beads indicated good congruency with a commercially available benchtop flow cytometer. Moreover, subjection to a stringent 8-peak rainbow calibration particle test demonstrated its ability to perform high-resolution immunological studies with separation resolution of 4.28 between the two dimmest fluorescent populations. Counting accuracy at different polystyrene bead concentrations showed strong correlation (r = 0.9991) with hemocytometer results. Finally, reliable quantification of CD4+ cells in healthy human blood via staining with monoclonal antibodies was demonstrated. These results demonstrate the potential of our microfluidic flow cytometry chip as an inexpensive yet high-performance point-of-care device for mobile medicine.
We demonstrate a series of advantages of microsphere-assisted imaging over confocal and solid immersion lens microscopies including intrinsic flexibility, better resolution, higher magnification, and longer working distances. We discerned minimal feature sizes of ̃50-60 nm in nanoplasmonic arrays at the illumination wavelength λ = 405 nm. It is demonstrated that liquid-immersed, high-index (n ̃ 1.9-2.1) spheres provide a superior image quality compared to that obtained by spheres with the same index contrast in an air environment. We estimate that using transparent microspheres at deep UV wavelengths of ̃200 nm might make possible imaging of various nanostructures with extraordinary high ̃30 nm resolution.
A hybrid silicon-poly(dimethysiloxane) (PDMS) optofluidic platform for lab-on-a-chip applications is proposed. A liquid-core waveguide with a self-aligned solid-core waveguide and a microfluidic device are integrated with a multilayer approach, resulting in a three-dimensional device assembly. The optofluidic layer was fabricated with a hybrid silicon-polymer technology, whereas the microfluidic layer was fabricated with a soft lithography technique. The combination of different materials and fabrication processes allows a modular approach, enabling both the benefits from the high optical quality achievable with silicon technology and the low cost of polymer processing. The proposed chip has been tested for fluorescence measurements on Cy5 water solutions, demonstrating the possibility to obtain a limit of detection of 2.5 nM.
Cellular analysis plays important roles in various biological applications, such as cell biology, drug development, and disease diagnosis. Conventional cellular analysis usually measures the average response from a whole cell group. However, bulk measurements may cause misleading interpretations due to cell heterogeneity. Another problem is that current cellular analysis may not be able to differentiate various subsets of cell populations, each exhibiting a different behavior than the others. Single-cell analysis techniques are developed to analyze cellular properties, conditions, or functional responses in a large cell population at the individual cell level. Integrating optics with microfluidic platforms provides a well-controlled microenvironment to precisely control single cell conditions and perform non-invasive high-throughput analysis. This paper reviews recent developments in optofluidic technologies for various optics-based single-cell analyses, which involve single cell manipulation, treatment, and property detection. Finally, we provide our views on the future development of integrated optics with microfluidics for single-cell analysis and discuss potential challenges and opportunities of this emerging research field in biological applications.
Because of the small sizes of most viruses (typically 5–150 nm), standard optical microscopes, which have an optical diffraction limit of 200 nm, are not generally suitable for their direct observation. Electron microscopes usually require specimens to be placed under vacuum conditions, thus making them unsuitable for imaging live biological specimens in liquid environments. Indirect optical imaging of viruses has been made possible by the use of fluorescence optical microscopy that relies on the stimulated emission of light from the fluorescing specimens when they are excited with light of a specific wavelength, a process known as labeling or self-fluorescent emissions from certain organic materials. In this paper, we describe direct white-light optical imaging of 75-nm adenoviruses by submerged microsphere optical nanoscopy (SMON) without the use of fluorescent labeling or staining. The mechanism involved in the imaging is presented. Theoretical calculations of the imaging planes and the magnification factors have been verified by experimental results, with good agreement between theory and experiment.
Elastomeric stamps and molds provide a great opportunity to eliminate some of the disadvantages of photolithograpy, which is currently the leading technology for fabricating small structures. In the case of "soft lithography" there is no need for complex laboratory facilities and high-energy radiation. Therefore, this process is simple, inexpensive, and accessible even to molecular chemists. The current state of development in this promising area of research is presented here.
A high surface to bulk fluorescence ratio is very useful in bio-imaging, sensing, sequencing and physical chemistry characterization. We used the evanescent field of a photonic waveguide for highly localized excitation and collection of molecular fluorescence. As both near-field excitation and collection are strongly distance dependent, we were able to increase the surface to bulk fluorescence ratio significantly. We have also experimentally investigated the combined excitation and collection efficiency as a function of the position of the molecule in the near-field. Finally, We formulated and experimentally verified a general condition for the waveguide-molecule interaction length for maximum optical efficiency of the device.
A microfluidic cytometer with integrated on-chip optical systems was designed for red blood cell (RBC) and platelet (PLT) counting. The design, fabrication, and characterization of the microfluidic cytometer with on-chip optical signal detection were described. With process using only a single mask, the device that integrates optical fibers and on-chip microlens with microfluidic channels on a polydimethylsiloxane layer by standard soft photolithography. This compact structure increased the sensitivity of the device and eliminated time-consuming free-space optical alignments. The microfluidic cytometer was used to count red blood cells and platelets. Forward scatter and extinction were collected simultaneously for each cell. Experimental results indicated that the microfluidic cytometer exhibited comparable performance with a conventional cytometer and demonstrated superior capacity to detect on-chip optical signals in a highly compact, simple, truly portable, and low-cost format that is well suitable for point-of-care clinical diagnostics.
In this paper, a compact refractive index (RI) sensor based on the resonant interaction between surface plasmon polaritons (SPP) mode and polymer waveguide mode is demonstrated. The hybrid plasmonic waveguide consists of ultraviolet (UV) sensitive SU-8 polymer and thin gold film on a silica layer. The SPP mode field is theoretically confirmed to be sensitive to the RI of analyte on the metal film surface. UV light bleaching method is adopted to fabricate the channel waveguide, which is covered by a 35 nm-thick gold layer. Microfluidic channel is used to flow organic solutions with RI of 1.52 to 1.60 through the sensing area. The experimental result indicates that the device has a sensitivity of 1023 dB/RIU, corresponding to a resolution of 1 × 10⁻⁶ refractive index units (RIU) at 1550 nm. The advantages of inherent feature and simple fabrication promise its potential for a portable, compact, and easily-produced refractometer.
In the last two decades, microfluidic technologies have shown the great potential in developing portable and point-of care testing blood cell analysis devices. It is challenging to integrate all free-space detecting components in a single microfluidic platform. In this paper, a microfluidic cytometer with integrated on-chip optical components was demonstrated. To facilitate on-chip detection, the device integrated optical fibers and on-chip microlens with microfluidic channels on one polydimethylsiloxane layer by standard soft photolithography. This compact design increased the sensitivity of the device and also eliminated time-consuming free-space optical alignments. Polystyrene particles, together with red blood cells and platelets, were measured in the microfluidic cytometer by small angle forward scatter. Experimental results indicated that the performance of the microfluidic device was comparable to a conventional cytometer. And it was also demonstrated its ability to detect on-chip optical signals in a highly compact, simple, truly portable and low cost format which was perfect suitable for point-of-care testing clinical hematology diagnostics.
A key challenge in the development of a microflow cytometry platform is the integration of the optical components with the fluidics as this requires compatible micro-optical and microfluidic technologies. In this work a microflow cytometry platform is presented comprising monolithically integrated waveguides and deep microfluidics in a rugged silica chip. Integrated waveguides are used to deliver excitation light to an etched microfluidic channel and also collect transmitted light. The fluidics are designed to employ inertial focussing, a particle positioning technique, to reduce signal variation by bringing the flowing particles onto the same plane as the excitation light beam. A fabrication process is described which exploits microelectronics mass production techniques including: sputtering, ICP etching and PECVD. Example devices were fabricated and the effectiveness of inertial focussing of 5.6 μm fluorescent beads was studied showing lateral and vertical confinement of flowing beads within the microfluidic channel. The fluorescence signals from flowing calibration beads were quantified demonstrating a CV of 26%. Finally the potential of this type of device for measuring the variation in optical transmission from input to output waveguide as beads flowed through the beam was evaluated.
High-resolution optical microscopy has traditionally relied on high-magnification and high-numerical aperture objective lenses. In contrast, lensless microscopy can provide high-resolution images without the use of any focusing lenses, offering the advantages of a large field of view, high resolution, cost-effectiveness, portability, and depth-resolved three-dimensional (3D) imaging. Here we review various approaches to lensless imaging, as well as its applications in biosensing, diagnostics, and cytometry. These approaches include shadow imaging, fluorescence, holography, superresolution 3D imaging, iterative phase recovery, and color imaging. These approaches share a reliance on computational techniques, which are typically necessary to reconstruct meaningful images from the raw data captured by digital image sensors. When these approaches are combined with physical innovations in sample preparation and fabrication, lensless imaging can be used to image and sense cells, viruses, nanoparticles, and biomolecules. We conclude by discussing several ways in which lensless imaging and sensing might develop in the near future.
The analysis of disease-specific biomarker panels holds promise for the early detection of a range of diseases, including cancer. Blood-based biomarkers, in particular, are attractive targets for minimally-invasive disease diagnosis. Specifically, a panel of organ-specific biomarkers could find utility as a general disease surveillance tool enabling earlier detection or prognostic monitoring. Using arrays of chip-integrated silicon photonic sensors, we describe the simultaneous detection of eight cancer biomarkers in serum in a relatively rapid (1 hour) and fully automated antibody-based sandwich assay. Biomarkers were chosen for their applicability to a range of organ-specific cancers, including disease of the pancreas, liver, ovary, breast, lung, colorectum, and prostate. Importantly, we demonstrate that selected patient samples reveal biomarker "fingerprints" that may be useful for a personalized cancer diagnosis. More generally, we show that the silicon photonic technology is capable of measuring multiplexed panels of protein biomarkers that may have broad utility in clinical diagnostics.
The miniaturization and integration of analytical assays into micro-chips has given rise to the Lab-on-a-Chip (LoC) concept. In particular, the replacement of silicon/glass technology by low-cost polymeric materials has resulted in the development of extremely sophisticated (microfluidic) networks for analyte detection and manipulation. However, the opportunities offered by direct integration of transducers into the microfluidic platforms for in situ quantitative analysis have not been equally developed. In this work we examine the advantages of the integration of optical spectroscopy in LoC, defining the so-called Photonic Lab-on-a-Chip (PhLoC). We revisit the main principles underlying this technology as well as practical aspects concerning design and fabrication in order to approach this low-cost, but highly effective paradigm to a non-expert audience. Finally we demonstrate its potential through several examples of applications with different approaches to common analytical problems.
Optofluidic behavior has been studied over a decade for the transmission of light through fluidic channels by virtue of versatile fabrication schemes such as (soft-) lithography techniques. One of the crucial factors in the consideration of device design involves the use of a fluidic core filled into the solid channels to effectively control the planar direction of light guiding based on total internal reflection (TIR). However, there are still few studies investigating the optical performance of light transmission associated with an optofluidic design for bifurcation and out-of-plane transmission of light beams. This paper reports a droplet filling method that can significantly improve the controllability over the formation of liquid flow and solid convex lenses utilizing the polydimethylsiloxane (PDMS) layers fabricated by soft-lithography technique. Analytical and experimental and results indicate that the curvatures of hemispherical profiles for the refractive microlenses formed were simply varied by different droplet volumes (single droplet of 1-10 pl) placed on the cavity-structured surfaces, thus providing the capability of control over volumes in design. In this way, the individual LGs fabricated from the micromolding and inkjet printing could be applied in many applications, in particular the future lab-on-a-chip (LOC) microsystem and micrototal analysis system (μTAS).
Whispering-gallery-mode microresonators enable materials for single-molecule label-free detection and imaging because of their high sensitivity to their micro-environment. However, fabrication and materials challenges prevent scalability and limit functionality. All-glass on-chip microresonators significantly reduce these difficulties. Construction of all-glass toroidal microresonators with high quality factor and low mode volume is reported and these are used as platforms for label-free single-particle imaging.
Electrochemical methods were combined with redox-active surfactants to actively control the motions and positions of aqueous
and organic liquids on millimeter and smaller scales. Surfactant species generated at one electrode and consumed at another
were used to manipulate the magnitude and direction of spatial gradients in surface tension and guide droplets of organic
liquids through simple fluidic networks. Solid microparticles could be transported across unconfined surfaces. Electrochemical
control of the position of surface-active species within aqueous films of liquid supported on homogeneous surfaces was used
to direct these films into periodic arrays of droplets with deterministic shapes and sizes.
We describe the integration of an actively controlled programmable microfluidic sample processor with on-chip optical fluorescence detection to create a single, hybrid sensor system. An array of lifting gate microvalves (automaton) is fabricated with soft lithography, which is reconfigurably joined to a liquid-core, anti-resonant reflecting optical waveguide (ARROW) silicon chip fabricated with conventional microfabrication. In the automaton, various sample handling steps such as mixing, transporting, splitting, isolating, and storing are achieved rapidly and precisely to detect viral nucleic acid targets, while the optofluidic chip provides single particle detection sensitivity using integrated optics. Specifically, an assay for detection of viral nucleic acid targets is implemented. Labeled target nucleic acids are first captured and isolated on magnetic microbeads in the automaton, followed by optical detection of single beads on the ARROW chip. The combination of automated microfluidic sample preparation and highly sensitive optical detection opens possibilities for portable instruments for point-of-use analysis of minute, low concentration biological samples.
This paper describes the realization of highly sensitive surface-enhanced Raman spectroscopy (SERS) via an integrated three-dimensional liquid-core/liquid-cladding waveguide. The cladding flow enclosed the core flow in both the horizontal and vertical directions within a single-layered microfluidic channel, and the laser beam was guided through the core stream. Deionized water was used to suspend SERS-active silver nanocolloids to form the core fluid, and 2,2,2-trifluoroethanol was used as the cladding fluid. Dipicolinic acid, commonly used as a biomarker for the detection of Bacillus anthracis, was employed as the target analyte. The sensitivity of the SERS signal was enhanced through this design because the signals backscattered from the analytes accumulated along the core stream and increased the SERS detection volume. The SERS data was evaluated in terms of the analyte concentration in the core fluid, the irradiated laser power, and the cross-sectional area of the core stream. The present data were compared with a conventional SERS detection approach in order to quantify the enhancement factor. The detection limit of concentration, 50 nM at an acquisition time of 6 s, was a factor of 35 smaller than that of conventional methods.
This article reviews recent advances and developments in the field of wearable sensors with emphasis on a subclass of these devices that are able to perform highly‐sensitive electrochemical analysis. Recent insights into novel fabrication methodologies and electrochemical techniques have resulted in the demonstration of chemical sensors able to augment conventional physical measurements (i.e. heart rate, EEG, ECG, etc.), thereby providing added dimensions of rich, analytical information to the wearer in a timely manner. Wearable electrochemical sensors have been integrated onto both textile materials and directly on the epidermis for various monitoring applications owing to their unique ability to process chemical analytes in a non‐invasive and non‐obtrusive fashion. In this manner, multi‐analyte detection can easily be performed, in real time, in order to ascertain the overall physiological health of the wearer or to identify potential offenders in their environment. Of profound importance is the development of an understanding of the impact of mechanical strain on textile‐ and epidermal (tattoo)‐based sensors and their failure mechanisms as well as the compatibility of the substrate employed in the fabrication process. We conclude this review with a retrospective outlook of the field and identify potential implications of this new sensing paradigm in the healthcare, fitness, security, and environmental monitoring domains. With continued innovation and detailed attention to core challenges, it is expected that wearable electrochemical sensors will play a pivotal role in the emergent body sensor networks arena.
Nano-structured optical components, such as nanolenses, direct light at subwavelength scales to enable, among others, high-resolution lithography, miniaturization of photonic circuits, and nanoscopic imaging of biostructures. A major challenge in fabricating nanolenses is the appropriate positioning of the lens with respect to the sample while simultaneously ensuring it adopts the optimal size and shape for the intended use. One application of particular interest is the enhancement of contrast and signal-to-noise ratio (SNR) in the imaging of nanoscale objects, especially over wide fields-of-view (FOVs), which typically come with limited resolution and sensitivity for imaging nano-objects. Here we present a self-assembly method for fabricating time- and temperature-tunable nanolenses based on the condensation of a polymeric liquid around a nanoparticle, which we apply to the high-throughput on-chip detection of spheroids smaller than 40 nm, rod-shaped particles with diameter smaller than 20 nm, and bio-functionalized nanoparticles, all across an ultra-large FOV of > 20 mm^2. Previous nanoparticle imaging efforts across similar FOVs have detected spheroids no smaller than 100 nm, and therefore our results demonstrate the detection of particles >15 fold smaller in volume, which in free space have >240 times weaker Rayleigh scattering compared to the particle sizes detected in earlier wide-field imaging work. This entire platform, with its tunable nanolens condensation and wide-field imaging functions, is also miniaturized into a cost-effective and portable device, which might be especially important for field use, mobile sensing, and diagnostics applications, including e.g., the measurement of viral load in bodily fluids.
We describe a sheath-less micro-cytometer that measures four different parameters, namely fluorescence, large angle side scatter and dual frequency electrical impedance (electrical volume and opacity). The cytometer was benchmarked using both size and fluorescent bead standards and demonstrates excellent size accuracy (CVs ≤ 2.1%), sensitivity and dynamic range (3.5 orders of magnitude) at sample flow rates of 80 μL per minute. The cytometer was evaluated by analysing human blood, and a four part differential leukocyte assay for accurate CD4+ T-cell enumeration was demonstrated. The integration of impedance, fluorescence and side scatter into a single miniature cytometer platform provides the core information content of a classical cytometer in a highly compact, simple, portable and low cost format.
Flow systems have been successfully utilized for a wide variety of applications in chemical research and development, including the miniaturization of (bio)analytical methods and synthetic (bio)organic chemistry. Currently, we are witnessing the growing use of microfluidic technologies for the discovery of new chemical entities. As a consequence, chemical biology and molecular medicine research are being reshaped by this technique. In this Minireview we portray the state-of-the-art, including the most recent advances in the application of microchip reactors as well as the micro- and mesoscale coil reactor-assisted synthesis of bioactive small molecules, and forecast the potential future use of this promising technology.
The microsphere optical nanoscopy (MONS) technique recently demonstrated
the capability to break the optical diffraction limit with a microsphere
size of 2-9 μm fused silica. We report that larger polystyrene
microspheres of 30, 50 and 100 μm diameters can overcome the
diffraction limit in optical imaging. The sub-diffraction features of a
Blu-ray Disc and gold nano-patterned quartz were experimentally observed
in air by coupling the microspheres with a standard optical microscope
in the reflected light illumination mode. About six to eight times
magnification was achieved using the MONS. The mechanism of the MONS was
theoretically explained by considering the transformation of near-field
evanescent waves into far-field propagating waves. The super-resolution
imaging was demonstrated by experiments and theoretical simulations.