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We present a new method of measurement based on fluorescence lifetime imaging that reveals molecular-scale details of the mixing process in a continuous-flow turbulent microfluidic reactor. Our data provide a glimpse of the cascade to the minimal eddy size, followed by rapid diffusion involving the smallest eddies for final mixing.
We have developed a microfluidic assay for bacterial chemotaxis in which a gradient of chemoeffectors is established inside a microchannel via diffusion between parallel streams of liquid in laminar flow. The random motility and chemotactic responses to L-aspartate, L-serine, L-leucine, and Ni(2+) of WT and chemotactic-mutant strains of Escherichia coli were measured. Migration of the cells was quantified by counting the cells accumulating in each of 22 outlet ports. The sensitivity of the assay is attested to by the significant response of WT cells to 3.2 nM L-aspartate, a concentration three orders of magnitude lower than the detection limit in the standard capillary assay. The response to repellents was as robust and easily recorded as the attractant response. A surprising discovery was that L-leucine is sensed by Tar as an attractant at low concentrations and by Tsr as a repellent at higher concentrations. This assay offers superior performance and convenience relative to the existing assays to measure bacterial tactic responses, and it is flexible enough to be used in a wide range of different applications.
Miniaturized medical diagnostic and treatment devices are currently being developed. Microneedles and miniaturized microdialysis systems are particularly well suited to impact diabetes treatment for continuous glucose monitoring and feedback-controlled insulin delivery. Microneedles are an attractive advanced drug delivery system used to mechanically penetrate the skin and inject insulin intradermally where it is rapidly absorbed by the capillary bed into the bloodstream. The real advantage of microneedle-enhanced drug delivery lies in the fact that drug is actively injected into a patient so the dosage may be varied with time to allow complex drug delivery profiles. The delivery is independent of the drug composition and merely relies on the subsequent drug absorption into the bloodstream. A miniaturized microdialysis probe for continuous glucose sensing has also been designed. Microdialysis is based upon controlling the mass transfer rate of glucose diffusing across a semipermeable membrane into a dialysis fluid while excluding larger molecules such as proteins. Polymer microdialysis membranes are integrated with microfluidic systems. Because of the high surface area to fluid volume ratio of miniaturized fluid channels, faster recovery of glucose to increase glucose sensing frequency is expected. This work highlights recent advances made in the design and fabrication of microneedles to make them more biocompatible and more fracture resistant in order to effectively enter the biomedical market. In addition, the design of a miniaturized microdialysis system for increased glucose sampling frequency is presented. The sensing and infusion technologies may be combined into a miniaturized "artificial pancreas" for minimally invasive feedback-controlled insulin delivery.
We report on the experimental observation of a spatiotemporal resonance phenomenon, in which a temporal excitation locks with a spatial pattern in an open flow system. The observation is made in a microfluidic system. We obtain the expected regimes--mixing and resonant patterns--in qualitative agreement with the theory. As an application, we realized a dual system particle extraction-micromixer.
A phase-field method is applied to the modeling of flow and breakup of droplets in a T-shaped junction in the hydrodynamic regime where capillary and viscous stresses dominate over inertial forces, which is characteristic of microfluidic devices. The transport equations are solved numerically in the three-dimensional geometry, and the dependence of the droplet breakup on the flow rates, surface tension and viscosities of the two components is investigated in detail. The model reproduces quite accurately the phase diagram observed in experiments performed with immiscible fluids. The critical capillary number for droplet breakup depends on the viscosity contrast, with a trend which is analogous to that observed for individual isolated droplets in hyperbolic flow.
We present a model of microfluidic flow of several completely immiscible fluids and use it to simulate a whole flow focusing device chamber. Our efficient, practical model supports a large parameter space, spanned by surface wetting, surface tension, liquid-liquid wetting, viscosity ratio, and inlet velocity. It is based upon an N-component lattice Boltzmann method with interrupted coalescence [Dupin, Philos. Trans. R. Soc. London, Ser. A 362, 1885 (2004)], here adapted for calculations at low capillary and Reynolds numbers, with wetting and significantly reduced spurious flow. Results over 2 orders of magnitude in Reynolds number are presented.
We set up an analytical framework that allows one to describe and compute streaming effects and electro-osmosis on an equal footing. This framework relies on the thin double layer approximation commonly used for description of electroosmotic flows, but rarely used for streaming problems. Using this framework we quantitatively assess the induction of bulk streaming current patterns by topographic or charge heterogeneities on surfaces. This too also permits analytical computation of all linear electrokinetic effects in complex microfluidic geometries, and we discuss a few immediate applications.
Experiments performed on droplets breaking up in microfluidic junctions of various angles are described. A critical length is found that controls the breakup process. This quantity depends on the flow geometry only; it is independent of the flow conditions and the fluid characteristics. A theory assuming small capillary numbers describes well the conditions that govern the breakup process.
We study the dynamics of two microfluidic droplets emitters placed in parallel. We observe complex dynamical behavior, including synchronization, quasiperiodicity, and chaos. This dynamics has a considerable impact on the properties of the resulting emulsions: chaotic and quasi-periodic regimes give rise to polydispersed emulsions with poorly controllable characteristics, whereas synchronized regimes generate well-controlled monodispersed emulsions. We derive a dynamical model that reproduces the trends observed in the experiment.
The Letter reports an experimental study of microfluidic droplets produced in T junctions and subjected to a local periodic forcing. Synchronized and quasiperiodic regimes--organized into Arnold tongues and devil staircases--are reported for the first time for a system dedicated to drop emission. The nature of the dynamical regime controls the droplet characteristics. These phenomena are mostly controlled by the characteristics of the forcing and the flow conditions.
We show how holographic optical trapping can be used for the multipoint measurement of fluid flow in microscopic geometries. An array of microprobes can be simultaneously trapped and used to map out the fluid flow in a microfluidic device. The optical traps are alternately turned on and off such that the probe particles are displaced by the flow of the surrounding fluid and then retrapped. The particles' displacements are monitored by digital video microscopy and directly converted into velocity field values. This technique enables the measurement of a two-dimensional flow field at points arbitrarily distributed in a three-dimensional volume. The validity of the technique is demonstrated for the case of the flow around a spinning sphere and the flow at the outlet of a microchannel.
We have designed, built, and tested microfluidic systems capable of transporting individual, preimplantation mouse embryos (100-microm to 150-microm diameter) through a network of channels. Typical channels are 160 to 200 microm deep, 250 to 400 microm wide at the top, and narrower at the bottom (0 to 250 microm wide) due to the fabrication process. In these channels, a pressure gradient of 1 Pa/mm causes the medium to flow on the order of 10(-10) m3/s (100 nl/s), with an average speed of 1 to 2 mm/s. Under these flow conditions the embryos roll along the bottoms of the channels, traveling at 1/2 the speed of the fluid. By manipulating the pressure at the wells connected to the ends of the channels, the embryos can be transported to (and retained at) specific locations including culture compartments and retrieval wells.
Here we demonstrate the microfabrication of deep (> 25 microns) polymeric microstructures created by replica-molding polydimethylsiloxane (PDMS) from microfabricated Si substrates. The use of PDMS structures in microfluidics and biological applications is discussed. We investigated the feasibility of two methods for the microfabrication of the Si molds: deep plasma etch of silicon-on-insulator (SOI) wafers and photolithographic patterning of a spin-coated photoplastic layer. Although the SOI wafers can be patterned at higher resolution, we found that the inexpensive photoplastic yields similar replication fidelity. The latter is mostly limited by the mechanical stability of the replicated PDMS structures. As an example, we demonstrate the selective delivery of different cell suspensions to specific locations of a tissue culture substrate resulting in micropatterns of attached cells.
We demonstrate microscopic fluidic control and memory elements through the use of an aqueous viscoelastic polymer solution as a working fluid. By exploiting the fluid's non-Newtonian rheological properties, we were able to demonstrate both a flux stabilizer and a bistable flip-flop memory. These circuit elements are analogous to their solid-state electronic counterparts and could be used as components of control systems for integrated microfluidic devices. Such miniaturized fluidic circuits are insensitive to electromagnetic interference and may also find medical applications for implanted drug-delivery devices.
Microfluidic networks (microFNs) were used to pattern biomolecules with high resolution on a variety of substrates (gold, glass, or polystyrene). Elastomeric microFNs localized chemical reactions between the biomolecules and the surface, requiring only microliters of reagent to cover square millimeter-sized areas. The networks were designed to ensure stability and filling of the microFN and allowed a homogeneous distribution and robust attachment of material to the substrate along the conduits in the microFN. Immunoglobulins patterned on substrates by means of microFNs remained strictly confined to areas enclosed by the network with submicron resolution and were viable for subsequent use in assays. The approach is simple and general enough to suggest a practical way to incorporate biological material on technological substrates.
The single- and multiple-dose pharmacokinetics of and tolerability to a new microfluidized suspension of atovaquone were studied in human immunodeficiency virus-seropositive patients with CD4 counts of < or = 200 cells per mm3 in order to define a dosing regimen for the treatment of Pneumocystis carinii pneumonia. This was an open study with groups of six patients each. In the first part of the study, six subjects received escalating single doses of 500, 1,000, and 1,500 mg after an overnight fast at weekly intervals. In the second part of the study, groups of six subjects were dosed for 14 days according to three regimens: 1,000 mg twice daily fasting, twice daily with a high-fat meal, or once daily with a high-fat meal. Plasma atovaquone levels were assayed by high-performance liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental methods, and statistical comparison of parameters for single doses was performed by analysis of variance. Plasma drug concentrations increased with single doses from 500 to 1,000 mg but were no higher with a dose of 1,500 mg. Thus, 1,000 mg was selected for multiple administration. A regimen of 1,000 mg twice daily with food resulted in a 93% increase in the average trough steady-state concentration compared with 1,000 mg once daily with food. Food increased the bioavailability of atovaquone 1.4-fold over that in the fasting state. All patients who received 1,000 mg twice daily with food achieved target steady-state concentrations in plasma of 15 to 25 micrograms/ml. Multiple-dose regimens were generally well tolerated, but the higher levels in plasma achieved by 1,000 mg twice daily with food were associated with an increased incidence of rash. In conclusion, target plasma atovaquone concentrations for the treatment of P. carinii pneumonia can be achieved in most patients with 1,000 mg twice daily in a fasting state and in all patients with 1,000 mg twice daily administered with food, but at higher concentrations in plasma, there may be an increased risk of rash.
A novel type of liquid microlens, bounded by a microfabricated, distensible membrane and activated by a microfluidic liquid-handling system, is presented. By use of an elastomer membrane fabricated by spin coating onto a dry-etched silicon substrate, the liquid-filled cavity acts as a lens whereby applied pressure changes the membrane distension and thus the focal length. Both plano-convex and plano-concave lenses, individual elements as well as arrays, were fabricated and tested. The lens surface roughness was seen to be approximately 9 nm rms, and the focal length could be tuned from 1 to 18 mm. This lens represents a robust, self-contained tunable optical structure suitable for use in, for example, a medical environment.
The recently developed whole-column-imaging detection technique for capillary electrophoresis (CE) and capillary isoelectric focusing (CIEF), a commercial whole-column-imaged CIEF instrument and its standard operation protocol are introduced. Furthermore, new developments and applications of whole-column-imaging detection in protein-protein interaction study, in protein separation using microfluidic devices and CIEF methods without carrier ampholytes, as well as in 2D separation techniques are reviewed. Miniaturization of whole-column-imaging CIEF and axially illuminated fluorescence whole-column-imaging CIEF are also discussed.