Microinjection molded disposable microfluidic lab-on-a-chip for efficient detection of agglutination

Previous diagnosing methods based on agglutination have a limitation in view of emergency and point-of-care diagnoses due to the requirement of large scale equipments and much agglutination time. In this paper, we propose a low cost microfluidic lab-on-a-chip for more efficient detection of agglutination. In the present lab-on-a-chip, two inlet microwells, flow guiding microchannels, chaotic micromixer and reaction microwell are fully integrated. Mold inserts for the lab-on-a-chip were manufactured by UV photolithography and nickel electroplating process. The complete lab-on-a-chip was realized by the microinjection molding of cyclic olefin copolymer and the subsequent thermal bonding. The improved serpentine laminating micromixer, developed by our group, integrated in the lab-on-a-chip showed the high-level of chaotic mixing, thereby enabling us to get a reliable mixing of sample and reagent. The performance of the fabricated lab-on-a-chip was demonstrated by agglutination experiments with simulated bloods of 10 μl and simulated sera of 10 μl. The results of agglutination inside the reaction microwell were clearly read by means of the level of light transmission. The present microfluidic lab-on-a-chip could be widely applied to various clinical diagnostics based on agglutination tests.     

Development and characterisation of integrated microfluidics on waveguide-based photonic platforms fabricated from hybrid materials

This article reports on a detailed investigation of sol–gel processed hybrid organic–inorganic materials for use in lab-on-a-chip (LoC) applications. A particular focus on this research was the implementation of integrated microfluidic circuitry in waveguide-based photonic sensing platforms. This objective is not possible using other fabrication technologies that are typically used for microfluidic platforms. Significant results on the surface characterisation of hybrid sol–gel processed materials have been obtained which highlight the ability to tune the hydrophilicity of the materials by careful adjustment of material constituents and processing conditions. A proof-of-principle microfluidic platform was designed and a fabrication process was established which addressed requirements for refractive index tuning (essential for waveguiding), bonding of a transparent cover layer to the device, optimized sol–gel deposition process, and a photolithography process to form the microchannels. Characterisation of fluid flow in the resulting microchannels revealed volumetric flow rates between 0.012 and 0.018 μl/min which is characteristic of capillary-driven fluid flow. As proof of the integration of optical and microfluidic functionality, a microchannel was fabricated crossing an optical waveguide which demonstrated that the presence of optical waveguides does not significantly disrupt capillary-driven fluid flow. These results represent the first comprehensive evaluation of photocurable hybrid sol–gel materials for use in waveguide-based photonic platforms for lab-on-a-chip applications.     

Anti-scattering X-ray grid

 Various optical or x-ray applications require reduction of scattered radiation on the imaging detector to produce sharper images. The scattered radiation is reduced when the radiation impacting on the detector is from a chosen small solid angle. This requires a mask in front of the detector with small holes and high aspect ratio. We are applying the SLIGA process to perform a proof-of-principle demonstration with the capability of making a large and high area anti-scattering grid. The approach is by assembling and stacking small pieces of grid. To maintain high throughput of the desired radiation, the wall of the grid has to be thin. We designed and fabricated four grid patterns all with 20 μm thick walls and 80 μm×80 μm holes. The individual pieces were 210 μm high and made of nickel. The pieces were assembled and stacked to make a 5 mm×5 mm grid 2.1 mm high. Much larger grids can be made by the SLIGA process, which was chosen because of its capability to fabricate high aspect ratio devices with precision. Received: 25 August 1997/Accepted: 24 October 1997     

Fabrication of microgratings on PMMA plate and curved surface by using copper mesh as X-ray lithography mask

We demonstrate experimentally the X-ray lithography technique to fabricate microgratings on a PMMA plate and on curved surfaces such as PMMA cylinder lens surfaces with X-ray lithography by copper mesh as mask. Some gratings with 12.7 μm pitches on the plate and on PMMA curved surface with large area (10 mm × 10 mm) by vertically moving or rotating the resist stage exposure are realized.     

Roll manufacturing of flexible microfluidic devices in thin PMMA and COC foils by embossing and lamination

Microfluidics on foil is gaining momentum due to a number of advantages of employing thin films combined with the capability of cost-effective high-volume manufacturing of devices. In this work, ultra-thin, flexible Y-microreactors with microchannels of 100 μm width and 30 μm depth were fabricated in thermoplastic polymer foils. The fluidic pattern was hot roll embossed in 125 μm thick poly-methyl-methacrylate (PMMA) and 130 μm thick cyclic-olefin-copolymer (COC) films using a dry-etched microstructured silicon wafer as a flat embossing tool in a laminator. The sealing of the channels was performed with two different techniques, one based on lamination of SU8 dry film resist (DFR) and the other one based on spin-coated poly-dimethylsiloxane (PDMS). Testing of the interconnected microreactor was carried out using two dye colorant solutions to demonstrate mixing.     

Seed bubbles trigger boiling heat transfer in silicon microchannels

The smooth channel surface of microsystems delays boiling incipience in heated microchannels. In this paper, we use seed bubbles to trigger boiling heat transfer and control thermal non-equilibrium of liquid and vapor phases in parallel microchannels. The test section consisted of a top glass cover and a silicon substrate. Microheater array was integrated at the top glass cover surface and driven by a pulse voltage signal to generate seed bubbles in time sequence. Each microheater corresponds to a specific microchannel and is located in the microchannel upstream. Five triangular microchannels with a hydraulic diameter of 100 μm and a length of 12.0 mm were etched in the silicon substrate. A thin platinum film was deposited at the back surface of silicon chip with an effective heating area of 4,500 × 1,366 μm, acting as the main heater for the heat transfer system. Acetone liquid was used. With the data range reported here, boiling incipience was not initiated if wall superheats are smaller than 15°C without seed bubbles assisted. Injection seed bubbles triggers boiling incipience and controls thermal non-equilibrium between liquid and vapor phases successfully. Four modes of flow and heat transfer are identified. Modes 1, 2, and 4 are the stable ones without apparent oscillations of pressure drops and heating surface temperatures, and mode 3 displays flow instabilities with apparent amplitudes and long periods of these parameters. The four modes are divided based on the four types of flow patterns observed in microchannels. Seed bubble frequency is a key factor to influence the heat transfer. The higher the seed bubble frequency, the more decreased non-equilibrium between two phases and heating surface temperatures are. The seed bubble frequency can reach a saturation value, at which heat transfer enhancement attains the maximum degree, inferring that a complete thermal equilibrium of two phases is approached. The saturation frequency is about a couple of thousand Hertz in this study.     

Interfacing microfluidics to LDI-MS by automatic robotic spotting

We developed a method of interfacing microfluidics with mass spectrometry (MS) using a robotic spotting system to automate the contact spotting process. We demonstrate that direct and automated spotting of analyte from multichannel microfluidic chips to a custom microstructured MALDI target plate was a simple, robust, and high-throughput method for interfacing parallel microchannels using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Using thermoplastic cyclic olefin copolymer (COC) polymer microfluidic chips containing eight parallel 100 μm × 46 μm microchannels connected to a single input port, spotting volume repeatability and MALDI-MS signal uniformity are evaluated for a panel of sample peptides. The COC microfluidic chips were fabricated by hot embossing and solvent bonding techniques followed by chip dicing to create open ends for MS interfacing. Using the automatic robotic spotting approach, microfluidic chip-based reversed-phase liquid chromatography (RPLC) separations were interfaced with electrochemically etched nanofilament silicon (nSi) target substrate, demonstrating the potential of this approach toward chip-based microfluidic separation coupled with matrix-free laser desorption/ionization mass spectrometry.     

An integrated flow-cell for full sample stream control

In this study, we present a novel three-dimensional hydrodynamic sheath flow chip that allows full control of a sample stream. The chip offers the possibility to steer each of the four side sheath flows individually. The design of the flow-cell exhibits high flexibility in creating different sample stream profiles (width and height) and allows navigation of the sample stream to every desired position inside the microchannel (vertical and horizontal). This can be used to bring the sample stream to a sensing area for analysis, or to an area of actuation (e.g. for cell sorting). In addition, we studied the creation of very small sample stream diameters. In microchannels (typically 25 × 40 μm2), we created sample stream diameters that were five to ten times smaller than the channel dimensions, and the smallest measured sample stream width was 1.5 μm. Typical flow rates are 0.5 μl/min for the sample flow and around 100 μl/min for the cumulated sheath flows. The planar microfabricated chip, consisting of a silicon–glass sandwich with an intermediate SU-8 layer, is much smaller (6 × 9 mm2) than the previously presented sheath flow devices, which makes it also cost-effective. We present the chip design, fluidic simulation results and experiments, where the size, shape and position of the sample stream have been established by laser scanning confocal microscopy and dye intensity analysis.     

A micro roller embossing process for structuring large-area substrates of laminated ceramic green tapes

This paper presents a micro roller embossing process for patterning large-area substrates of laminated green ceramic tapes. The aim of this research is to develop a large-area microstructure formation technique for green ceramic substrates using a thermal roller laminator, which is compatible with screen printing apparatus. A thin film nickel mold was developed via photolithographic patterning and nickel electroplating on a 75-μm-thick nickel film. The mold had an effective panel size of 150 mm × 150 mm with the height of plated protrusive patterns being about 38 μm. Formation of micro patterns was successfully demonstrated over the whole panel area on laminated green ceramic tapes using roller embossing. Micro patterns for inductors, heaters as well as interconnection with 50 μm line-width were embossed on green ceramic substrates. By means of tuning process parameters including roller temperature, applied pressure and feeding speed, we have demonstrated that micro roller embossing is a promising method for patterning large-area green ceramic substrates.     

Microfluidic inverse phase ELISA via manipulation of magnetic beads

We report a new technique for conducting immuno-diagnostics on a microfluidic platform. Rather than handling fluid reagents against a stationary solid phase, the platform manipulates analyte-coated magnetic beads through stationary plugs of fluid reagents to detect an antigenic analyte. These isolated but accessible plugs are pre-encapsulated in a microchannel by capillary force. We call this platform microfluidic inverse phase enzyme-linked immunosorbent assay (μIPELISA). μIPELISA has distinctive advantages in the family of microfluidic immunoassay. In particular, it avoids pumping and valving fluid reagents during assaying, thus leading to a lab-on-a-chip format that is free of instrumentation for fluid actuation and control. We use μIPELISA to detect digoxigenin-labeled DNA segments amplified from E. coli O157:H7 by polymerase chain reaction (PCR), and compare its detection capability with that of microplate ELISA. For 0.259 ng μl⁻¹ of digoxigenin-labeled amplicon, μIPELISA is as responsive as the microplate ELISA. Also, we simultaneously conduct μIPELISA in two parallel microchannels.     

Quasi-3D microstructure fabrication technique utilizing hard X-ray lithography of synchrotron radiation

 Quasi-three-dimensional (3D) microstructure fabrication technique utilizing hard X-ray lithography (HXL) has been developed. In this technique, as the intensity distribution of the X-rays is controlled by a newly developed bending mirror, the exposure residual depth of polymethyl methacrylate (PMMA) resist is controlled over the exposed area. The maximum difference of depths was approximately 50 μm over the large area more than 60 mm (horizontal) × 5 mm (vertical). We also investigated the effects of controlling the beam intensity distribution for exposure changing X-ray mask absorber shapes and angle on the obtained quasi-3D resist pattern shapes. As the results, Quasi-3D PMMA patterns with inclined shape sidewall and graded depths were successfully fabricated. We believe this technique greatly expands applications of LIGA process. Received: 10 August 2001/Accepted: 24 September 2001 This paper was presented at the Fourth International Workshop on High Aspect Ratio Microstructure Technology HARMST 2001 in June 2001.     

Influence of gold thin-film interlayers on anodic bonding of copper microstructures produced by LIGA

 Neither pure copper nor solid gold can be anodically bonded to glass. It is only the gold coating on the copper which allows a joint to be built up as a result of the copper ions diffusing into the gold layer, but not many of them being able to migrate into the glass. To encapsulate microstructures produced by the LIGA technique, anodic bonding of gold-coated copper to Corning 0211-type glass was studied. For demonstration purposes, a glass platelet made of Corning 0211 was anodically bonded to a LIGA linear actuator consisting of electroplated copper coated with 1 μm of gold. A better understanding about the decisive parameters in anodic bonding was obtained by varying the bonding temperature and the thickness of the gold layer. Glass can be bonded on to the entire surface of gold layers 0.5–1 μm thick at temperatures as low as 300 °C; however, when the systems cool to room temperature, stress-induced cracks arise in the glass. On the other hand, thicker gold layers of 2.5 to 10 μm thickness require higher bonding temperatures for the same period of heating, but prevent the occurrence of such cracks because of their higher ductility. Received: 11 December 1997/Accepted: 11 March 1998     

Uncooled matrix IR detector based on optoacoustic cells and optoelectronic reading system

The matrix structure 200 × 200 of optoacoustic cells (OAC) for uncooled IR imager with optoelectronic reading system is fabricated and investigated at the first time. Cells 100 μm in diameter shaped on ZnSe window and filled by xenon. Photosensitive layer consisted of SiO₂ film with adsorption range 8–14 μm. Flexible membrane 0.1 μm of thick consisted of SiO₂ and Al films. Radiation temperature sensitivity and noise equivalent power with optics f/1 were 0.15 K/Hz^1/2 and 10 nW/Hz^1/2, respectively, and the thermal response time was below 30 ms. The article is published in the original.     

Fabrication of RF MEMS variable capacitors by deep X-ray lithography and electroplating

Radio frequency micro electro-mechanical systems (RF MEMS) vertical cantilever variable capacitors fabricated using deep X-ray lithography and electroplating are presented. Polymethylmethacrylate (PMMA) layers of 100 μm and 150 μm have been patterned and electroplated with 70 μm and 100 μm thick nickel. A 3 μm thick titanium layer was used as plating base as well as etch time-controlled sacrificial layer for the release of the cantilever beam. The parallel plate layout includes narrow gaps and cantilever beams with an aspect ratio in nickel of up to 60 for 1 mm long features. Auxiliary structures support the beams and gaps during the processing. Room temperature electroplating significantly reduces the risk of deformations compared to the standard process temperature of 52°C. The capacitors operate in the 1–5 GHz range, and demonstrate good RF performance, with quality factors on the order of 170 at 1 GHz for a 1 pF capacitance.     

Novel positive-tone thick photoresist for high aspect ratio microsystem technology

 A methacrylate copolymer combining chemically amplified concept and casting technique was developed as a novel thick photoresist for the UV-LIGA process. Photoresist layers up to 500 μm in thickness can be fabricated easily. Microstructures fabricated by the novel thick photoresist were demonstrated. At present, the ring-shape microstructures with 150 μm tall and 15 μm wide have been realized and the calculated aspect ratio is 10. Received: 10 August 2001/Accepted: 24 September 2001     

Fabrication of metallic micromolds by laser and electro-discharge micromachining

A method of creating metallic micromolds with features that have high-aspect ratios is described in this paper. The proposed manufacturing process utilizes laser micromachining to cut the negative two-dimensional profiles of the desired microfeatures and fluidic network patterns on a 100 μm thick brass sheet. The positive relief of the cut pattern is then created by using electro-discharge micromachining (micro-EDM) die-sinking the metallic mask onto a brass substrate. The final substrate with the desired relief pattern becomes the molding tool used for either elastomer casting or thermoplastic hot embossing. To validate the proposed fabrication methodology and evaluate the quality of surface finishes, a brass mold master of a T-channel micromixer (50 μm width, 25 μm height) is developed and multiple replicated devices are cast on this mold using poly-di-methyl-siloxane (PDMS). The surface finish of both the original micromold master and final molded channels on PDMS are measured using an optical profiler and found to have a roughness of approximately 400 nm Ra. The ability of the proposed fabrication technique to create high-aspect ratio features is illustrated by manufacturing a Y-channel micromixer with an aspect ratio of 4. Experimental results are discussed and suggestions for improvement are presented.     

Reliability study of hermetic wafer level MEMS packaging with through-wafer interconnect

In this paper, we developed a hermetic wafer level packaging for MEMS devices. Au–Sn eutectic bonding technology in a relatively low temperature is used to achieve hermetic sealing, and the vertical through-hole via filled with electroplated copper for the electrical connection is also used. The MEMS package has the size of 1 mm × 1 mm × 700 μm, and a square loop Au–Sn metallization of 70 μm in width for hermetic sealing. The robustness of the package is confirmed by several tests such as shear strength test, reliability tests, and hermeticity test. The reliability issues of Au–Sn bonding technology, and copper through-wafer interconnection are discussed, and design considerations to improve the reliability are also presented. By applying O₂ plasma ashing and fabrication process optimization, we can achieve the void-free structure within the bonding interface. The mechanical effects of copper through-vias are also investigated numerically and experimentally. Several factors which could induce via hole cracking failure are investigated such as thermal expansion mismatch, via etch profile, copper diffusion phenomenon, and cleaning process. Alternative electroplating process is suggested for preventing Cu diffusion and increasing the adhesion performance of the electroplating process.     

Transient flow of microcapsules through convergent–divergent microchannels

The study deals with a microfluidic method to investigate the transient behavior of microcapsules in flow. The technique consists of investigating ovalbumin microcapsules passing through a convergent–divergent microchannel made of PolyDiMethylSiloxane. We work with three types of square microchannel with, respectively, cross section values of h × h = 30 × 30, 50 × 50 and 70 × 70 μm. The microchannels length is L = 3h. We analyze the kinetics of deformation of the microcapsules in the microchannels for velocity ranging from 2 to 5 cm/s and for microcapsule size ratio d/h ranging from 0.9 to 2.5. The relaxation process at the pore outlet is modeled using an exponential relaxation law. We show that that the relaxation time at the divergent outlet depends on the microcapsule size ratio d/h. Thanks to the analytical expression of the relaxation, we extract a shear modulus of the membrane equal to 0.04 N/m. This value is consistent with the value of 0.07 N/m that we found using the steady state analysis performed in cylindrical glass capillaries. Thus, it is interesting to notice that the microcapsule behavior based on a simple analytical model can be successfully described despite the complex flow situation consisting of deformable microcapsule in confined square microchannels.     

Micromachining of passive planar micromixer on poly (methyl methacrylate) substrate with excimer laser ablation

Excimer laser ablation technique was introduced into this work to fabricate a passive planar micromixer on the PMMA substrate. T-junction shaped and width-changed S-shaped microchannels were both designed in this micromixer to enhance mixing effect. The mixing experiment of distilled water and Rhodamine B with injection flow rate of 500 and 1,500 μm/s validates the mixing effectivity of this micromixer, and indicates the feasibility of excimer laser ablation in the microfabrication of μ-TAS device.     

Rubber-assisted micro forming of polymer thin films

Polymer thin films patterned with microstructures at a characteristic size greater than the film thickness are difficult to fabricate using the standard hot embossing technology. This study investigated a rubber-assisted embossing process for structuring polymer thin films. The main advantages of a rubber support, instead of a hard counter-tool, include simplification of the embossing tool, protection of the embossing master, buildup of uniform embossing pressure, and ease of demolding. The testing pattern for rubber-assisted embossing was a microgroove pattern with a characteristic size of 100 μm on a 25-μm thick polystyrene film. Results showed that the uniformity and replicability of the embossed pattern were significantly affected by the embossing temperature, the rubber hardness, and the embossing pressure. With an embossing temperature about 20°C above the glass transition temperature and appropriate rubber hardness and embossing force, uniform microgroove patterns were successfully replicated.