Ultrasmall silver sulfide nanoparticles (Ag 2 S-NP) have been identified as promising contrast agents for a number of modalities and in particular for dual-energy mammography. These Ag 2 S-NP have demonstrated marked advantages over clinically available agents with the ability to generate higher contrast with high biocompatibility. However, current synthesis methods are low-throughput and highly time-intensive, limiting the possibility of large animal studies or eventual clinical use of this potential imaging agent. We herein report the use of a scalable silicon microfluidic system (SSMS) for the large-scale synthesis of Ag 2 S-NP. Using SSMS chips with 1 channel, 10 parallelized channels, and 256 parallelized channels, we determined that the Ag 2 S-NP produced were of similar quality as measured by core size, concentration, UV-visible spectrometry, and in vitro contrast generation. Moreover, by combining parallelized chips with increasing reagent concentration, we were able to increase output by an overall factor of 3,400. We also found that in vivo imaging contrast generation was consistent across synthesis methods and confirmed renal clearance of the ultrasmall nanoparticles. Finally, we found best-in-class clearance of the Ag 2 S-NP occurred within 24 hours. These studies have identified a promising method for the large-scale production of Ag 2 S-NP, paving the way for eventual clinical translation.

The fabrication of microfluidic chips is becoming a mature field and channels can be reliably defined with micrometer‐scale precision in a variety of substrates. In addition to channel geometry, micrometer‐scale patterning of wettability in microfluidic channels is essential for many applications including multi‐phase flow stabilization and multiple emulsion generation. Unfortunately, current methods to pattern wettability in microfluidics suffer from low spatial resolution, inability for patterns to be arbitrarily defined, cumbersome procedures, and incompatibility with parallelized architectures for scaled‐up production of microfluidic generated materials. To address these issues, a method is developed to lithographically define micrometer‐scale resolution patterns of wettability on all channel surfaces (ceiling, floor, and walls) in silicon and glass microfluidic devices with complex 3D geometry. A process is reported to pattern silanes on microfluidic chips that uses photolithography and an optimized process that keeps silanized surfaces stable through the microfabrication process, including anodic bonding. The versatility of this approach is highlighted by patterning wettability of a silicon/glass device to generate both highly uniform water–in‐oil–in‐water and oil–in‐water–in‐oil double emulsions. The applicability of this process is demonstrated to the parallel generation of materials in a microfluidic chip with complex geometry, by fabricating and successfully validating parallelized double emulsion generators.

Microgels, 1–100 µm sized hydrogel particles, have emerged as versatile materials for constructing injectable tissue scaffolds, with superb control over various properties. Microfluidic synthesis of microgels offers significant advantages over conventional batch synthesis such as high uniformity and precise control over emulsion size. Despite these positive attributes, the gelation of microfluidic droplets is typically performed off‐chip, compromising the particle homogeneity, and confounding the ability to control their mechanical properties. To address this, a multistep microgel synthesis line is developed, comprising of a flow focusing droplet generator followed by a UV‐curing stage that delivers a precise UV dosage to each droplet, allowing precise control of the mechanical properties of hydrogel microparticles. Furthermore, parallel operation of 4080 identical synthesis lines on a single chip is demonstrates, generating precisely defined microgels at a throughput appropriate for commercial and clinical translation. The system is validated by generating poly(ethylene glycol) diacrylate microgel particles with a diameter down to 40 µm at a throughput above 1 kg h−1 (106 particles s−1), with a coefficient of variation of 3%. It is demonstrated that the stiffness of the microgels can be precisely controlled from 103 to 104 Pa by varying the UV dosage.

A major challenge to advance lipid nanoparticles (LNPs) for RNA therapeutics is the development of formulations that can be produced reliably across the various scales of drug development. Microfluidics can generate LNPs with precisely defined properties, but have been limited by challenges in scaling throughput. To address this challenge, we present a scalable, parallelized microfluidic device (PMD) that incorporates an array of 128 mixing channels that operate simultaneously. The PMD achieves a >100× production rate compared to single microfluidic channels, without sacrificing desirable LNP physical properties and potency typical of microfluidic-generated LNPs. In mice, we show superior delivery of LNPs encapsulating either Factor VII siRNA or luciferase-encoding mRNA generated using a PMD compared to conventional mixing, with a 4-fold increase in hepatic gene silencing and 5-fold increase in luciferase expression, respectively. These results suggest that this PMD can generate scalable and reproducible LNP formulations needed for emerging clinical applications, including RNA therapeutics and vaccines.

The last two decades have witnessed tremendous progress in the development of microfluidic chips that generate micrometer- and nanometer-scale materials. These chips allow precise control over composition, structure, and particle uniformity not achievable using conventional methods. These microfluidic-generated materials have demonstrated enormous potential for applications in medicine, agriculture, food processing, acoustic, and optical meta-materials, and more. However, because the basis of these chips' performance is their precise control of fluid flows at the micrometer scale, their operation is limited to the inherently low throughputs dictated by the physics of multiphasic flows in micro-channels. This limitation on throughput results in material production rates that are too low for most practical applications. In recent years, however, significant progress has been made to tackle this challenge by designing microchip architectures that incorporate multiple microfluidic devices onto single chips. These devices can be operated in parallel to increase throughput while retaining the benefits of microfluidic particle generation. In this review, we will highlight recent work in this area and share our perspective on the key unsolved challenges and opportunities in this field.

Because of the increasing concerns about the ecological damage and negative health effects that may be caused by petrochemical-based microbeads, many countries are banning their use in a wide range of consumer products. One particular class of particles that may never reach their full potential because of such a ban is Janus particles, which are particles with two opposite properties. Despite significant progress in the scalable synthesis of Janus particles, most studies rely on petrochemical-based materials and solvents to enable their synthesis. In this report, we present a single-emulsion polymerization method for scalable synthesis of amphiphilic Janus particles with materials derived from plants. Soybean oil-epoxidized acrylate (SBOEA) monomers are polymerized in single-emulsion droplets of SBOEA, ethyl cellulose (EC), butyl acetate, and initiators that can be generated by either bulk or microfluidic emulsification, leading to the formation of amphiphilic soybean oil polymer/EC (SBOP/EC) Janus particles. Interfacial anchoring of the in situ-formed SBOP particles at the interface of the emulsion droplet plays a key role in the formation of the SBOP/EC Janus particles. Large-scale preparation of uniform SBOP/EC Janus particles is also demonstrated using a glass-silicon microfluidic device. Finally, the SBOP/EC Janus particles show potential to stabilize oil-in-water emulsions that can stay stable under flowing conditions.

Recent advances in microfluidic technologies have enabled production of micro-scale compound bubbles that consist of gaseous cores surrounded by thin liquid shells, achieving control and uniformity not possible using conventional techniques. These compound bubbles have demonstrated enormous utility as functional materials for drug delivery, as ultra-lightweight structural materials, as engineered acoustic materials, and also as separating agents for extraction of metal ions from waste fluid streams. Despite these successful demonstrations, compound bubbles have largely remained at the laboratory-scale due to the slow production rates endemic to microfluidics (<10 mL h-1). Although parallelization approaches have enabled large-scale production of simple emulsions and bubbles, its application to the production of higher order dispersions such as compound bubbles has been limited because the optimal processing window for the production of uniform compound bubbles is relatively narrow and the required channel geometry is quite complex. In this report, we demonstrate the parallelization of multi-stage flow focusing droplet generators that produce compound ternary bubbles. We parallelize 400 multi-stage FFG devices, generating up to 3 L (∼1011 bubbles) of monodispersed (CV < 5%) compound bubbles in less than 1 hour. We show that it is critical to use multi-height channels and operate each individual generator in a flow regime that is minimally sensitive to variations in the flow rate to reliably produce uniform compound bubbles. To demonstrate the utility of our parallelized device, we take advantage of the buoyancy and the high mass transfer rate that comes from the thin shells of gas-in-oil-in-water compound bubbles to rapidly extract Nd ions from a model waste stream.

Correction for ‘Large-scale production of compound bubbles using parallelized microfluidics for efficient extraction of metal ions’ by Heon-Ho Jeong et al., Lab Chip, 2019, 19, 665-673.

We present a new, robust three dimensional microfabrication method for highly parallel microfluidics, to improve the throughput of on-chip material synthesis by allowing parallel and simultaneous operation of many replicate devices on a single chip. Recently, parallelized microfluidic chips fabricated in Silicon and glass have been developed to increase the throughput of microfluidic materials synthesis to an industrially relevant scale. These parallelized microfluidic chips require large arrays (> 10,000) of Through Silicon Vias (TSVs) to deliver fluid from delivery channels to the parallelized devices. Ideally, these TSVs should have a small footprint to allow a high density of features to be packed into a single chip, have channels on both sides of the wafer, and at the same time minimize debris generation and wafer warping to enable permanent bonding of the device to glass. Because of these requirements and challenges, previous approaches cannot be easily applied to produce three dimensional microfluidic chips with a large array of TSVs. To address these issues, in this paper we report a fabrication strategy for the robust fabrication of three-dimensional Silicon microfluidic chips consisting of a dense array of TSVs, designed specifically for highly parallelized microfluidics. In particular, we have developed a two-layer TSV design that allows small diameter vias ( d < 20 µ m) without sacrificing the mechanical stability of the chip and a patterned SiO 2 etch-stop layer to replace the use of carrier wafers in Deep Reactive Ion Etching (DRIE). Our microfabrication strategy allows >50,000 ( d = 15 µ m) TSVs to be fabricated on a single 4” wafer, using only conventional semiconductor fabrication equipment, with 100% yield ( M = 16 chips) compared to 30% using previous approaches. We demonstrated the utility of these fabrication strategies by developing a chip that incorporates 20,160 flow focusing droplet generators onto a single 4” Silicon wafer, representing a 100% increase in the total number of droplet generators than previously reported. To demonstrate the utility of this chip for generating pharmaceutical microparticle formulations, we generated 5–9 µm polycaprolactone particles with a CV <5% at a rate as high as 60 g/hr (> 1 trillion particles / hour).

Soft lithography-based droplet microfluidics has enabled production of highly uniform and complex emulsions. Although there is a significant potential to use these emulsions as templates for functional materials syntheses, conventional elastomers that are used for microfluidic device preparation are significantly deformed and swollen by various organic solvents, limiting the types of materials that can be processed using conventional soft lithography-based droplet microfluidics. In this report, we demonstrate that both water-in-oil and oil-in water emulsion with organic solvents can be produced by using microfluidic devices that are prepared using cross-linked networks of perfluoropolyether (PFPE) and poly(ethylene glycol) diacrylate (PEGDA). We show that these PFPE-PEG networks are transparent and maintain excellent compatibility with various organic solvents. Importantly, the wettability of these devices can be systematically controlled by changing the ratio of the two macromonomers. By taking advantage of rapid prototyping and controlled surface wettability afforded by the PFPE-PEG network, we prepare three-dimensional monolithic elastomer devices for the parallel generation of oil-in-water and water-in-oil droplets. We also show that, using these devices, solid microparticles with high uniformity can be produced by using an organic solvent-based emulsion as a template. We believe the PFPE-PEG network will have broad impacts in the application of soft lithography-based elastomer microfluidic devices to a wide range of applications, including drug screening and solvent-based separation processes.

Microfluidic chips can generate emulsions, which can be used to synthesize polymer microparticles that have superior pharmacological performance compared to particles prepared by conventional techniques. However, low production rates of microfluidics remains a challenge to successfully translate laboratory discoveries to commercial manufacturing. We present a silicon and glass device that incorporates an array of 10,260 (285 × 36) microfluidic droplet generators that uses only a single set of inlets and outlets, increasing throughput by >10,000× compared to microfluidics with a single generator. Our design breaks the tradeoff between the number of generators and the maximum throughput of individual generators by incorporating high aspect ratio flow resistors. We test these design strategies by generating hexadecane microdroplets at >1 trillion droplets per h with a coefficient of variation CV <3%. To demonstrate the synthesis of biocompatible microparticles, we generated 8–16 µm polycaprolactone particles with a CV <5% at a rate of 277 g h −1 .

Nanosecond pulsed laser melting of ultrathin gold films immersed inside glycerol-water mixtures assemble into monomodal sized nanoparticles with small spacing. This is a result of the large vapor pressure gradient created at the metal-fluid interface.

Diafiltration is a membrane filtration technique that rapidly removes permeable molecules from a solution by controlling the tangential and orthogonal flows over a membrane and by replenishing the permeate with an equivalent amount of replacement buffer. However, its application to the purification of many key biomaterials and nanomaterials has been limited by the large dead volume (>10 mL) that is required to automate the process. To address this challenge, we have developed a diafiltration-on-a-chip device that can process low-volume samples (50 μL). The key innovation of this device is a magnetically-driven on-chip peristaltic pump that is able to continuously drive fluid flow at rates as high as 50 mL h-1 with minimal external instrumentation and a dead volume of <50 μL. To demonstrate the utility of this device, we purified microbeads from dye with >99% purity and >96% retention within two hours. We additionally showed that cells could be purified from microbeads with >97% purity and >97% retention in two hours. Because our approach requires minimal instrumentation, it is well suited for on-chip parallelization, which was demonstrated by incorporating four complete diafiltration systems onto a single credit card-sized chip.

A parallelized microfluidic device is used to generate highly monodisperse gas bubbles at a production rate of ∼1 L h−1.

Digital droplet assays — in which biological samples are compartmentalized into millions of femtoliter volume droplets and interrogated individually — have generated enormous enthusiasm for their ability to robustly detect nucleic acids and proteins with single molecule sensitivity. A key challenge in the field however has been the cumbersome instrumentation necessary to generate, process, and detect millions of individual droplets. We have demonstrated the miniaturization of droplet diagnostics into a portable platform that can process millions of droplets per second by combining the parallelization of thousands of microfluidic droplet generators onto a single chip and a strategy to rapidly detect droplets using time-domain encoded cell phone imaging. Building on our work in this area, we show that multiple fluorescent dyes can be detected in each individual droplet by encoding the excitation light from multiple LEDs with unique maximum length sequences that are decoded using cloud-based computation. By developing a strategy to carry out multiplexed digital droplet assays in a portable platform at a rate (106 droplets / sec), 1000x faster than conventional approaches on a cell phone based device, we have demonstrated a key step towards translating the sensitivity of digital assays from research laboratories to portable molecular diagnostics.

The ability to easily manufacture nanostructures with a desirable attribute, such as well-defined size and shape, especially from any given initial shapes or sizes of the material, will be helpful towards accelerating the use of nanomaterials in various applications. In this work we report the transformation of discontinuous irregular nanostructures (DIN) of silver metal by rapid heating under a bulk fluid layer. Ag films were changed into DIN by dewetting in air and subsequently heated by nanosecond laser pulses under water. Our findings show that the DIN first ripens into elongated structures and then breaks up into nanoparticles. From the dependence of this behavior on laser fluence we found that under water irradiation reduced the rate of ripening and also decreased the characteristic break-up length scale of the elongated structures. This latter result was qualitatively interpreted as arising from a Rayleigh-Plateau instability modified to yield significantly smaller length scales than the classical process due to pressure gradients arising from the rapid evaporation of water during laser melting. These results demonstrate that it is possible to fabricate a dense collection of monomodally sized Ag nanoparticles with significantly enhanced plasmonic quality starting from the irregular shaped materials. This can be beneficial towards transforming discontinuous Ag films into nanostructures with useful plasmonic properties, that are relevant for biosensing applications.

Droplet-based microfluidics has led to transformational new approaches in diverse areas including materials synthesis and high-throughput biological assays. However, the translation of droplet microfluidics technology into commercial applications requires scale-up of droplet generation from the laboratory (<10 mL h(-1)) to the industrial (>1 L h(-1)) scale. To address this challenge, we develop a three-dimensional monolithic elastomer device (3D MED) for mass production of monodisperse emulsion droplets. Using double-sided imprinting, 3D microchannels are formed in a single elastomer piece that has 1000 parallel flow focusing generators (k-FFGs). Compared to previous work that parallelizes droplet generation, the 3D MED eliminates the needs for alignment and bonding of multiple pieces and thus makes it possible to achieve the high flow rates and pressure necessary for the kilo-scale generation of droplets. Using this approach, we demonstrate mass production of water-in-oil (W/O) emulsion droplets at production rates as high as 1.5 L h(-1) (>30 billion 45 μm diameter droplets per hour), with a coefficient of variation of droplet diameter of only 6.6%. Because of the simplicity, robustness, and manufacturability of our 3D MED architecture, it is well suited to bridge the gap between the continuously growing library of promising microfluidic technologies to generate microparticles that have been demonstrated in laboratory settings and their successful application in industry.

Techniques that can characterize the early stages of thin film deposition from liquid phase processes can aid greatly in our understanding of mechanistic aspects of chemical bath deposition (CBD). Here we have used localized surface plasmon resonance (LSPR) spectroscopy to monitor the in situ kinetics of early stage growth of cadmium sulfide (CdS) thin films on Ag nanoparticle on quartz substrates. Real-time shift during CdS deposition showed that the LSPR wavelength red-shifted rapidly due to random deposition of CdS on the substrate but saturated at longer times. LSPR modeling showed that these features could be interpreted as an initial deposition of CdS islands followed by preferential deposition onto itself. The CdS also showed significantly enhanced Raman signals up to 170 times due to surface-enhanced Raman scattering (SERS) from the CdS/Ag NP regions. The ex situ SERS effect supported the LSPR shift, suggesting that these techniques could be used to understand nucleation and growth phenomena from the liquid phase.