Microfluidic Research Research Articles

Fabrication of microfluidic paper-based analytical devices by filtration-assisted screen printing

Abstract In recent years, the paper-based microfluidics has been gaining attention because it is regarded as an inexpensive tool for detection and analysis in biomedical applications and clinical settings. This report, for the first time, describes a relatively simple and fast method, i.e. filtration-assisted screen printing (FASP) that can produce microfluidic paper-based analytical devices (μPAD) at ambient condition with time for constructing the channel wall of fluidic channel as less as 30 s. The channel walls are constructed by the polymer retained inside the filter paper at the designated locations through filtration. It is found that the flow behavior inside the channels was affected by the channel width while the influence of filtration time on the channel dimensions and porosity is minimal. Detection of glucose was demonstrated using the μPAD as fabricated. The proposed method provides a fast and reliable alternative to other state-of-the-art fabrication techniques, which can facilitate in extending the research and development in paper-based microfluidics.

Protein patterning using germanium as a sacrificial layer.

With the rise of microfluidic diagnostics, there is a need for more efficient methods of patterning surface-attached moieties, including proteins like antibodies, onto microchannel surfaces. This arises because almost all of the solvents and processes used for surface-attachment chemistries (or their payloads) are incompatible with sacrificial layers usually photoresist during microfabrication, rendering it difficult to easily pattern active chemistry onto a surface in manufacture scale. We present a simple method, based on thin film germanium dissolution, which is compatible with both modern nanolithographic techniques and surface chemistries. Simply, because germanium thin films dissolve readily, controllably and rapidly in water (but not organic solvents), these films can be used to mask and protect areas of the substrate during the attachment of surface chemistries. We demonstrate the process and results using microscale patterns. The resolution and alignment of this method depends on the photolithography tool used; nanoscale patterning is not difficult to achieve. In addition, we show that with non-conformal germanium deposition (e.g. e-beam evaporation), the conjugation of surface chemistry on vertical side walls can be manipulated by controlling the thickness of the deposited germanium layer, opening another dimension for microfluidic devices and cell manipulation research.

Thermo-optical Characterization of Photothermal Optical Phase Shift Detection in Extended-Nano Channels and UV Detection of Biomolecules.

The expansion of microfluidics research to nanofluidics requires absolutely sensitive and universal detection methods. Photothermal detection, which utilizes optical absorption and nonradiative relaxation, is promising for the sensitive detection of nonlabeled biomolecules in nanofluidic channels. We have previously developed a photothermal optical phase shift (POPS) detection method to detect nonfluorescent molecules sensitively, while a rapid decrease of the sensitivity in nanochannels and the introduction of an ultraviolet (UV) excitation system were issues to be addressed. In the present study, our primary aim is to characterize the POPS signal in terms of the thermo-optical properties and quantitatively evaluate the causes for the decrease in sensitivity. The UV excitation system is then introduced into the POPS detector to realize the sensitive detection of nonlabeled biomolecules. The UV-POPS detection system is designed and constructed from scratch based on a symmetric microscope. The results of simulations and experiments reveal that the sensitivity decreases due to a reduction of the detection volume, dissipation of the heat, and cancellation of the changes in the refractive indices. Finally, determination of the concentration of a nonlabeled protein (bovine serum albumin) is performed in a very thin 900 nm deep nanochannel. As a result, the limit of detection (LOD) is 2.3 μM (600 molecules in the 440 attoliter detection volume), which is as low as that previously obtained for our visible POPS detector. UV-POPS detection is thus expected be a powerful technique for the study of biomolecules, including DNAs and proteins confined in nanofluidic channels.

Refining particle positions using circular symmetry.

Particle and object tracking is gaining attention in industrial applications and is commonly applied in: colloidal, biophysical, ecological, and micro-fluidic research. Reliable tracking information is heavily dependent on the system under study and algorithms that correctly determine particle position between images. However, in a real environmental context with the presence of noise including particular or dissolved matter in water, and low and fluctuating light conditions, many algorithms fail to obtain reliable information. We propose a new algorithm, the Circular Symmetry algorithm (C-Sym), for detecting the position of a circular particle with high accuracy and precision in noisy conditions. The algorithm takes advantage of the spatial symmetry of the particle allowing for subpixel accuracy. We compare the proposed algorithm with four different methods using both synthetic and experimental datasets. The results show that C-Sym is the most accurate and precise algorithm when tracking micro-particles in all tested conditions and it has the potential for use in applications including tracking biota in their environment.

Safe and cost-effective rapid-prototyping of multilayer PMMA microfluidic devices

The rapid translation of research from bench to bedside, as well as the generation of commercial impact, has never been more important for both academic and industrial researchers. It is therefore unsurprising that more and more microfluidic groups are investigating research using a wide range of thermoplastics which can be readily translated to large-scale manufacturing, if the technology is taken to commercialisation. While structuring, via additive or subtractive manufacturing, is becoming relatively easy through the use of commercial-grade devices, reliable and fast assembly remains a challenge. In this article, we propose an innocuous and cost-effective, under 2-min technique which enables the bonding of multiple poly(methyl methacrylate) layers. This bonding technique relies on the application of small amounts (10 µl/cm2) of ethanol, low temperatures (70 °C) and relatively low pressures (~1.6 MPa). Our characterisation analysis shows that using a bonding time of 2 min is enough to produce a strong bond able to withstand pressures always above 6.2 MPa (with mean of 8 MPa, highest reported in the literature), with minimal channel deformation (<5%). This technique, which we demonstrate on assembly comprising up to 19 layers, presents an exciting improvement in the field of rapid prototyping of microfluidic devices, enabling extremely fast design cycles in microfluidic research with a material compatible with mass manufacturing, thus allowing a smoother transition from the laboratory to the market. Beyond the research community, this robust prototyping technique has the potential to impact on the deliverability of other scientific endeavours including educational projects and will directly fuel the fluidic maker movement.

Investigation of Tumor Cell Behaviors on a Vascular Microenvironment-Mimicking Microfluidic Chip.

The extravasation of tumor cells is a key event in tumor metastasis. However, the mechanism underlying tumor cell extravasation remains unknown, mainly hindered by obstacles from the lack of complexity of biological tissues in conventional cell culture, and the costliness and ethical issues of in vivo experiments. Thus, a cheap, time and labor saving, and most of all, vascular microenvironment-mimicking research model is desirable. Herein, we report a microfluidic chip-based tumor extravasation research model which is capable of simultaneously simulating both mechanical and biochemical microenvironments of human vascular systems and analyzing their synergistic effects on the tumor extravasation. Under different mechanical conditions of the vascular system, the tumor cells (HeLa cells) had the highest viability and adhesion activity in the microenvironment of the capillary. The integrity of endothelial cells (ECs) monolayer was destroyed by tumor necrosis factor-α (TNF-α) in a hemodynamic background, which facilitated the tumor cell adhesion, this situation was recovered by the administration of platinum nanoparticles (Pt-NPs). This model bridges the gap between cell culture and animal experiments and is a promising platform for studying tumor behaviors in the vascular system.

Dynamic manipulation of particles via transformative optofluidic waveguides.

Optofluidics is one of the most remarkable areas in the field of microfluidic research. Particle manipulation with optofluidic platforms has become central to optical chromatography, biotechnology, and μ-total analysis systems. Optical manipulation of particles depends on their sizes and refractive indices (n), which occasionally leads to undesirable separation consequences when their optical mobilities are identical. Here, we demonstrate rapid and dynamic particle manipulation according to n, regardless of size. Integrated liquid-core/solid-cladding (LS) and liquid-core/liquid-cladding (L2) waveguides were fabricated and their characteristics were experimentally and theoretically determined. The high and low n particles showed the opposite behaviors by controlling the contrast of their n values to those of the working fluids. The LS waveguide was found to successfully manipulate particles according to n, and the L2 waveguide was found to provide additional system stability and flexibility, compared to the LS system.

Two-photon excitation in chip electrophoresis enabling label-free fluorescence detection in non-UV transparent full-body polymer chips.

One of the most commonly employed detection methods in microfluidic research is fluorescence detection, due to its ease of integration and excellent sensitivity. Many analytes though do not show luminescence when excited in the visible light spectrum, require suitable dyes. Deep-ultraviolet (UV) excitation (<300 nm) allows label-free detection of a broader range of analytes but also mandates the use of expensive fused silica glass, which is transparent to UV light. Herein, we report the first application of label-free deep UV fluorescence detection in non-UV transparent full-body polymer microfluidic devices. This was achieved by means of two-photon excitation in the visible range (λex = 532 nm). Issues associated with the low optical transmittance of plastics in the UV range were successfully circumvented in this way. The technique was investigated by application to microchip electrophoresis of small aromatic compounds. Various polymers, such as poly(methyl methacrylate), cyclic olefin polymer, and copolymer as well as poly(dimethylsiloxane) were investigated and compared with respect to achievable LOD and ruggedness against photodamage. To demonstrate the applicability of the technique, the method was also applied to the determination of serotonin and tryptamine in fruit samples.

Time-resolved velocity measurements in a magnetic micromixer

Mixing efficiency is lower in passive micromixers due to viscous forces and substantial research effort is focused on designing high performance micromixers. Active micromixers make use of external forces to enhance mixing efficiency. Among these, magnetic forces are popular because they are non-contact and therefore the micromixer design can be kept simple. Laser-based diagnostic tools have great potential in providing multi-parameter information in microfluidics research on mixing. MicroPIV experiments are performed to investigate the transient flow field in a magnetic micromixer undergoing labyrinthine instability. Velocity and interface front information is extracted from a sequence of time-resolved particle images. The use of image pre-processing functions proves to be essential in two-phase flow microfluidics: Velocity measurements are obtained using an adaptive cross-correlation algorithm, where particle image contrast was enhanced using local contrast normalization and difference of Gaussian filters. Interface location is estimated using Prewitt edge detection filter together with a combination of standard image processing functions. A detailed uncertainty analysis is provided. Time resolved information on velocity and interface location provides a new understanding of the mixing processes in microscale and opens new possibilities for validation for computational and theoretical studies.

How can chemometrics improve microfluidic research?

Chemometrics has the potential to embolden microfluidics to become that enabling technology for so long sought after. In this Feature article, we describe a historical perspective on microfluidics and its current challenges, a perspective on chemometric methods including response surface methodology (RSM), and how a combination of artificial neural network with experimental design (ANN-ED) have demonstrated promise in addressing basic microfluidic problems.

The Study of Temperature Rise in a 90-Degree Sharp Bend Microchannel Flow Under Constant Wall Temperature Condition

AbstractThis study presents the fluid temperature measurement at a 90-degree sharp bend inside a microchannel using molecule-based temperature sensor technique. This technique provides both detailed and global information for temperature investigation in microfluidic research. Rhodamine B was selected as the molecule-based temperature probe in the experiment to provide non-invasive and straightforward measurements. To resolve the luminescence deviation in the microscale temperature measurements introduced by the corner structure, in-situ calibration method and pixel-by-pixel correction were applied during the data reduction. The temperature measurement was performed in a 200μm wide, 67μm deep and 2cm long PDMS microchannel with a 90-degree sharp bend at the center. The temperature profile was measured at a Reynolds number of 27.66 using Rhodamine B in DI water while the bottom of channel was heated at 50°C. As revealed by the molecule-based temperature sensor, the temperature variation along the central line increased 2°C while passing the corner. Additionally, the lateral temperature distributions upstream of the corner show the temperature increase near the outer side of microchannel and decreased near the inner side. The velocity profiles around the 90-degree sharp bend were acquired to analyze the flow after corner. Secondary flow structure after the corner was observed in the velocity profiles along the depth of the microchannel. This study analyzes the thermal flow fields in the microchannel with a 90-degree sharp bend and reveals that regardless of the low Reynolds number, the flow mixing after the corner resulted in the increase of temperature downstream of the bend.

Automating microfluidic part verification

Microfluidic devices promise to significantly advance the field of medicine by providing diagnostic tools that may be administered at the point-of-care (POC). Currently, a major barrier to entry for POC microfluidic diagnostic technologies is part qualification where specific features of a microfluidic technology must be qualified during the manufacturing process to ensure the device performs properly, e.g., Tantra and van Heeren (Lab Chip 13:2199, 2013). Additionally, microfluidic device research is moving toward therapeutic applications where quality control requirements may be more stringent. In this paper, we use soft embossing—a replication technology—to manufacture high aspect ratio thermoplastic deterministic lateral displacement (DLD) parts, where DLD is a size-based microfluidic particle separation technology based on shift post arrays. Morphological data are collected using optical profilometry, and key metrics are automatically extracted using a novel image analysis algorithm. This algorithm allows us to rapidly quantify the average post height, post shape, array pitch and surface roughness in order to compare a lot of 12 devices to the original design and the deep reactive ion etched silicon master mold. During the run of 12 devices, the post height was 63.0 ± 5.1 μm (mean ± 6σ), the pitch was 35.6 ± 0.31 μm, the post eccentricity was 0.503 ± 0.197, the post circularity was 1.195 ± 0.084 and the root-mean-square surface roughness was 4.19 ± 3.39 μm. Importantly, this automated part qualification technique reduced data analysis time by 75- to 100-fold while allowing for additional qualification metrics and significantly reducing the need for manual measurement. Overall, this paper indicates that it is possible to improve the quality and efficiency of microfluidic part qualification using optical profilometry coupled with a novel image analysis algorithm.

Lab-on-a-chip technology: impacting non-invasive prenatal diagnostics (NIPD) through miniaturisation

This paper aims to provide a concise review of non-invasive prenatal diagnostics (NIPD) to the lab-on-a-chip and microfluidics community. Having a market of over one billion dollars to explore and a plethora of applications, NIPD requires greater attention from microfluidics researchers. In this review, a complete overview of conventional diagnostic procedures including invasive as well as non-invasive (fetal cells and cell-free fetal DNA) types are discussed. Special focus is given to reviewing the recent and past microfluidic approaches to NIPD, as well as various commercial entities in NIPD. This review concludes with future challenges and ethical considerations of the field.

Cavity optomechanics on a microfluidic resonator with water and viscous liquids

Currently, optical or mechanical resonances are commonly used in microfluidic research. However, optomechanical oscillations by light pressure were not shown with liquids. This is because replacing the surrounding air with water inherently increases the acoustical impedance and hence, the associated acoustical radiation losses. Here, we bridge between microfluidics and optomechanics by fabricating a hollow-bubble resonator with liquid inside and optically exciting vibrations with 100 MHz rates using only mW optical-input power. This constitutes the first time that any microfluidic system is optomechanically actuated. We further prove the feasibility of microfluidic optomechanics on liquids by demonstrating vibrations on organic fluids with viscous dissipation higher than blood viscosity while measuring density changes in the liquid via the vibration frequency shift. Our device will enable using cavity optomechanics for studying non-solid phases of matter, while light is easily coupled from the outer dry side of the capillary and fluid is provided using a standard syringe pump. Scientists in the USA have successfully used optomechanics to probe a microfluidic system. Kyu Hyun Kim and co-workers at the University of Michigan and the University of Illinois at Urbana-Champaign fabricated a bulbous hollow-glass capillary and filled it with sugar-water solution. They then used a tapered optical fibre to couple light evanescently in the perimeter of the capillary and thus excite optical whispering gallery modes. This optical mode excites a vibrational mode of the liquid-filled glass structure via the centrifugal radiation pressure that light applies while circumferentially circulating, which in turn modulated the light at a particular frequency. The frequency of the induced vibrations varied with the sugar concentration of the liquid, thus indicating the potential of the structure to function as a sensor. The researchers found that input optical powers as small as 1 mW were sufficient to induce vibrations.

Advances in ion beam micromachining for complex 3D microfluidics

In this paper, the authors present microfluidic mixers containing complex curvilinear and several tens of microns deep three-dimensional (3D) geometries used to decrease mixing lengths in passive microfluidic systems. In order to create these 3D geometries, the authors use ion beam micromachining (IBμM) and address redeposition and exposure strategy effects that follow this type of fabrication. Results of this work clearly demonstrate that fabrication of 3D microfluidic mixers using IBμM is achievable for real practical applications. In order to scale up to the tens of microns width and depth, and hundreds of microns in length fabrication, high current is required. This raises unique challenges of redeposition handling. This was achieved by realizing that redeposited silicon can be removed with an extended buffered oxide etch. In addition, data management and writing strategies not encountered in electron beam lithography have to be considered when designing the solid to be milled. Both designs, straight 3D and serpentine 3D mixers, were significantly faster mixers than the standard focusing mixer with no 3D texturing. This demonstrates that adding programmed depth variations to existing microfluidic devices can open new opportunities in microfluidic research and IBμM.

Optimization of planar interdigitated microelectrode array for biofluid transport by AC electrothermal effect

Point-of-care (POC) diagnostics is one of the most important applications for microfluidic research. However, the development of microfluidic POC devices needs to overcome great obstacles to reach market. One challenge is to find a chip-scale pumping strategy that is of low cost, small size, and light weight. Because of their simple implementation, electrokinetic techniques have been extensively investigated as a promising candidate for realizing disposable pumps, with the majority of research effort focusing on direct current and alternating current (AC) electroosmosis. As POC applications often need to handle conductive biofluids with medium to high salt content, AC electrothermal (ACET) effect has been investigated recently for pumping of biofluids, albeit with less than desirable pumping performance. In order to achieve effective on-chip ACET micropumps, this paper presents one of the first efforts in optimizing ACET micropump design utilizing planar interdigitated electrodes. The effects of electrode dimensions on pumping rate were numerically studied using COMSOL Multiphysics and MATLAB, and an optimal ratio of electrode geometry was found for various pumping scenarios. The optimal geometry ratio was tested to be valid over a wide range of electrode characteristic lengths, AC signals, and fluid ionic strengths. Experimental validation of the simulation results was also conducted, and higher flow velocities over prior reports were consistently demonstrated by optimized electrode arrays.

Microfluidics in radiopharmaceutical chemistry

The increased demand for molecular imaging tracers useful in assessing and monitoring diseases has stimulated research towards more efficient and flexible radiosynthetic routes, including newer technologies. The traditional vessel-based approach suffers from limitations concerning flexibility, reagent mass needed, hardware requirements, large number of connections and valves, repetitive cleaning procedures and overall big footprint to be shielded from radiation. For these reasons, several research groups have started to investigate the application of the fast growing field of microfluidic chemistry to radiosynthetic procedures. After the first report in 2004, many scientific papers have been published and demonstrated the potential for increased process yields, reduced reagent use, improved flexibility and general ease of setup. This review will address definitions occurring in microfluidics as well as analyze the different approaches under two macro-categories: microvessel and microchannel. In this perspective, several works will be collected, involving the use of positron emitting species ((11)C, (18)F, (64)Cu) and the fewer examples of gamma emitting radionuclides ((99m)Tc, (125/131)I). New directions in microfluidic research applied to PET radiochemistry, future developments and challenges are also discussed.

Editorial: Moving on in biomicrofluidics.

Editorial: Moving on in biomicrofluidics.

Microfluidic fabrication of monodisperse microcapsules for glucose-response at physiological temperature

Hydrogel-based hollow microcapsules with good monodispersity and repeated glucose-response under physiological temperature and glucose concentration conditions have been fabricated by a simple emulsion-template approach. Double emulsions from microfluidic devices are used as templates to synthesize the monodisperse glucose-responsive microcapsules. In the poly(N-isopropylacrylamide-co-3-aminophenylboronic acid-co-acrylic acid) (P(NIPAM-co-AAPBA-co-AAc)) hydrogel shell of the microcapsules, the thermo-responsive PNIPAM network and the glucose-responsive AAPBA moiety are respectively used for actuation and glucose response, and the AAc moiety is used for adjusting the volume phase transition temperature of the shell. Glucose-responsive microcapsules prepared with 2.4 mol% AAc exhibit reversible and repeated swelling/shrinking response to glucose concentration changes within the physiological blood glucose concentration range (0.4–4.5 g L−1) at 37 °C. Rhodamine B and fluorescein-isothiocyanate-labeled insulin are used as model molecules and model drugs to demonstrate the potential application of the microcapsules for glucose-responsive controlled release. The microcapsules provide a promising and feasible model for developing glucose-responsive sensors and self-regulated delivery systems for diabetes and cancer therapy. Moreover, the microfluidic fabrication approach and research results presented here provide valuable guidance for the design and fabrication of monodisperse glucose-responsive microcapsules.

Preface to Special Topic: Microfluidics in Cancer Research

Preface to Special Topic: Microfluidics in Cancer Research