Low-cost experimentation for the study of droplet microfluidics.

The continued growth of microfluidics into industry settings in areas such as point-of-care diagnostics and targeted therapeutics necessitates a workforce trained in microfluidic technologies and experimental methods. Laboratory courses for students at the university and high school levels will require cost-effective in-class demonstrations that instruct in chip design, fabrication, and experimentation at the microscale. We present a hand-operated pressure pumping system to form monodisperse picoliter to nanoliter droplet streams at low cost, and a series of exercises aimed at instructing in the specific art of droplet formation. Using this setup, the student is able to generate and observe the modes of droplet formation in flow-focusing devices, and the effect of device dimensions on the characteristics of formed droplets. Lastly, at ultra-low cost we demonstrate large plug formation in a T-junction using coffee stirrers as a master mold substitute. Our method reduces the cost of experimentation to enable intuitive instruction in droplet formation, with additional implications for creating droplets in the field or at point-of-care.

Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications.

Ultrasound imaging often calls for the injection of contrast agents, micron-sized bubbles which echo strongly in blood and help distinguish vascularized tissue. Such microbubbles are also being augmented for targeted drug delivery and gene therapy, by the addition of surface receptors and therapeutic payloads. Unfortunately, conventional production methods yield a polydisperse population, whose nonuniform resonance and drug-loading are less than ideal. An alternative technique, microfluidic flow-focusing, is able to produce highly monodisperse microbubbles with stabilizing lipid membranes and drug-carrying oil layers. However, the published 1 kHz production rate for these uniform drug bubbles is very low compared to conventional methods, and must be improved before clinical use can be practical. In this study, flow-focusing production of oil-layered lipid microbubbles was tested up to 300 kHz, with coalescence suppressed by high lipid concentrations or inclusion of Pluronic F68 surfactant in the lipid solution. The transition between geometry-controlled and dripping production regimes was analysed, and production scaling was found to be continuous, with a power trend of exponent ~5/12 similar to literature. Unlike prior studies with this trend, however, scaling curves here were found to be pressure-dependent, particularly at lower pressure-flow equilibria (e.g. <15 psi). Adjustments in oil flow rate were observed to have a similar effect, akin to a pressure change of 1-3 psi. This analysis and characterization of high-speed dual-layer bubble generation will enable more-predictive production control, at rates practical for in vivo or clinical use.

Parallel generation of uniform fine droplets at hundreds of kilohertz in a flow-focusing module.

Droplet-based microfluidic systems enable a variety of biomedical applications from point-of-care diagnostics with third world implications, to targeted therapeutics alongside medical ultrasound, to molecular screening and genetic testing. Though these systems maintain the key advantage of precise control of the size and composition of the droplet as compared to conventional methods of production, the low rates at which droplets are produced limits translation beyond the laboratory setting. As well, previous attempts to scale up shear-based microfluidic systems focused on increasing the volumetric throughput and formed large droplets, negating many practical applications of emulsions such as site-specific therapeutics. We present the operation of a parallel module with eight flow-focusing orifices in the dripping regime of droplet formation for the generation of uniform fine droplets at rates in the hundreds of kilohertz. Elevating the capillary number to access dripping, generation of monodisperse droplets of liquid perfluoropentane in the parallel module exceeded 3.69 × 10(5) droplets per second, or 1.33 × 10(9) droplets per hour, at a mean diameter of 9.8 µm. Our microfluidic method offers a novel means to amass uniform fine droplets in practical amounts, for instance, to satisfy clinical needs, with the potential for modification to form massive amounts of more complex droplets.

Scaled-Up Production of Monodisperse, Dual Layer Microbubbles Using Multi-Array Microfluidic Module for Medical Imaging and Drug Delivery.

The production of uniform-sized and multilayer microbubbles enables promising medical applications that combine ultrasound contrast and targeted delivery of therapeutics, with improvements in the consistency of acoustic response and drug loading relative to non-uniform populations of microbubbles. Microfluidics has shown utility in the generation of such small multi-phase systems, however low production rates from individual devices limit the potential for clinical translation. We present scaled-up production of monodisperse dual-layered microbubbles in a novel multi-array microfluidic module containing four or eight hydrodynamic flow-focusing orifices. Production reached 1.34 × 10(5) Hz in the 8-channel configuration, and microbubble diameters in the high-speed regime (> 5 × 10(4) Hz) ranged between 18.6-22.3 µm with a mean pooled polydispersity index under 9 percent. Results demonstrate that microfluidic scale-up for high-output production of multilayer bubbles is possible while maintaining consistency in size production, suggesting that this method may be appropriate for future clinical applications.

Microfluidic generation of acoustically active nanodroplets.

A microfluidic approach for the generation of perfluorocarbon nanodroplets as the primary emulsion with diameters as small as 300-400 nm is described. The system uses a pressure-controlled delivery of all reagents and increased viscosity in the continuous phase to drive the device into an advanced tip-streaming regime, which results in generation of droplets in the sub-micrometer range. Such nanodroplets may be appropriate for emerging biomedical applications.

Precision manufacture of phase-change perfluorocarbon droplets using microfluidics.

Liquid perfluorocarbon droplets have been of interest in the medical acoustics community for use as acoustically activated particles for tissue occlusion, imaging and therapeutics. To date, methods to produce liquid perfluorocarbon droplets typically result in a polydisperse size distribution. Because the threshold of acoustic activation is a function of diameter, there would be benefit from a monodisperse population to preserve uniformity in acoustic activation parameters. Through use of a microfluidic device with flow-focusing technology, the production of droplets of perfluoropentane with a uniform size distribution is demonstrated. Stability studies indicate that these droplets are stable in storage for at least two weeks. Acoustic studies illustrate the thresholds of vaporization as a function of droplet diameter, and a logarithmic relationship is observed between acoustic pressure and vaporization threshold within the size ranges studied. Droplets of uniform size have very little variability in acoustic vaporization threshold. Results indicate that microfluidic technology can enable greater manufacturing control of phase-change perfluorocarbons for acoustic droplet vaporization applications.

High-speed, clinical-scale microfluidic generation of stable phase-change droplets for gas embolotherapy.

In this study we report on a microfluidic device and droplet formation regime capable of generating clinical-scale quantities of droplet emulsions suitable in size and functionality for in vivo therapeutics. By increasing the capillary number-based on the flow rate of the continuous outer phase-in our flow-focusing device, we examine three modes of droplet breakup: geometry-controlled, dripping, and jetting. Operation of our device in the dripping regime results in the generation of highly monodisperse liquid perfluoropentane droplets in the appropriate 3-6 µm range at rates exceeding 10(5) droplets per second. Based on experimental results relating droplet diameter and the ratio of the continuous and dispersed phase flow rates, we derive a power series equation, valid in the dripping regime, to predict droplet size, D(d) approximately equal 27(Q(C)/Q(D))(-5/12). The volatile droplets in this study are stable for weeks at room temperature yet undergo rapid liquid-to-gas phase transition, and volume expansion, above a uniform thermal activation threshold. The opportunity exists to potentiate locoregional cancer therapies such as thermal ablation and percutaneous ethanol injection using thermal or acoustic vaporization of these monodisperse phase-change droplets to intentionally occlude the vessels of a cancer.