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Thermoresponsive polymers incorporated with photo-absorbing agents have been widely utilized for controlled drug delivery using light as an external stimulus. However, previously developed thermoresponsive drug carriers have disadvantages such as low biocompatibility and implantation failure. In the present study, gold nanorods (GNRs)-encapsulated poly(N-vinyl caprolactam) (PVCL) (GNR-PVCL) microparticles were synthesized by the stop-flow lithography (SFL) method. The SFL method enabled the fabrication of near-infrared (NIR) light-responsive GNR-PVCL microparticles of uniform size, which can allow localized injection. Doxorubicin (DOX) was encapsulated into GNR-PVCL microparticles to achieve NIR light-responsive anticancer therapy. DOX-loaded GNR-PVCL (DOX-GNR-PVCL) microparticles exhibited NIR light-triggered drug release due to the photothermal effect of GNRs, which increases the local temperature above the volume phase transition temperature of GNR-PVCL microparticles. In addition, DOX-GNR-PVCL exhibited controlled DOX release in response to the periodic irradiation of NIR light. Moreover, we demonstrated the efficient intracellular release of DOX upon NIR light exposure, and thus, NIR light-responsive anticancer activity. This study demonstrates that DOX-GNR-PVCL microparticles have significant potential as implantable drug carriers enabling NIR light-triggered drug release.

Discontinuous dewetting (DD) is an attractive technique that enables the production of large liquid arrays in microwells and is applicable to the synthesis of anisotropic microparticles with complex morphologies. However, such loading of liquids into microwells presents a significant challenge, as the liquids used in this technique should exhibit low mold surface wettability. This study introduces DD in a degassed mold (DM), a simple yet powerful technique that achieves uniform loading of microparticle precursors into large microwell arrays within 1 min. Using this technique, hydrogel microparticles are produced by different polymerization mechanisms with various shapes and sizes, ranging from a few micrometers to hundreds of micrometers. Hydrophobic oil microparticles are produced by the simple plasma treatment of the DM, and agarose microparticles encapsulating bovine serum albumin (in a well-dispersed state) are produced by submerging the DM in fluorinated oil. To demonstrate additional functionality of microparticles using this technique, high concentrations of magnetic nanoparticles are loaded into microparticles for particle-based immunoassays performed in a microwell plate, and the immunoassay performance is comparable to that of ELISA.

Due to the growing interest in multiplex protein detection, encoded hydrogel microparticles have received attention as a possible path to high performance multiplex immunoassays through a combination of high multiplexing capability and enhanced binding kinetics. However, their practical operation in real complex samples is still limited because polyethylene glycol, which is the main component of hydrogel particles, suffers from oxidative damage and relatively high fouling properties in biochemical solutions. Here, we introduce poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-based encoded hydrogel microparticles to perform fouling-resistant multiplex immunoassays, where the anti-fouling characteristics are attributed to the zwitterionic PMPC. By applying a newly developed molding lithography technique, viscous PMPCs with low reactivity were successfully incorporated into the hydrogel network while maintaining uniformity and rigidity for use in multiplex immunoassays. Non-specific protein adsorption on the PMPC particles was reduced by about 37.5% compared to that of conventional PEG particles, which leads to better assay sensitivity. We also validate the multiplex capability of the PMPC particles by performing multiplex detection of two target proteins. Furthermore, we verify that the PMPC particles have a 70% enhancement in anti-fouling characteristics compared to PEG particles in human platelet-rich plasma, potentiating a practical immunoassay platform for clinical diagnosis.

The development of photo-triggered drug delivery system is promising for the temporal and spatial control of drug release. However, most of the progress in photothermal drug delivery has been focused on nanosized particles which can be removed from the injected sites by exocytosis. In this study, injectable and implantable near-infrared (NIR) light-responsive microparticles are fabricated using droplet-based microfluidics. The particles are composed of 1-tetradecanol, as a class of non-toxic phase change material, and IR780, as a NIR-absorbing photothermal agent. Doxorubicin, an anticancer drug, is encapsulated in the particles to obtain NIR light-responsive anticancer drug carriers. The photothermal response of IR780 to NIR irradiation facilitates the release of the encapsulated drug through the melting of 1-tetradecanol and demonstrates the NIR light-responsive drug release. This study shows that IR780-encapsulated 1-tetradecanol microparticles fabricated by droplet-based microfluidics have great potential as injectable and implantable drug carriers featuring NIR light-sensitive drug release.

Capacitive deionization (CDI) is an emerging desalination technique by utilizing the electrosorption of porous electrodes. Thus far, only linear concentration profiles in bulk electrolyte between the electrodes have been observed, during ion charging (ion depletion) or ion discharging (ion enrichment). This so-called linear ion concentration polarization (ICP) can be predicted by the simple convective-diffusion model. In this study, we demonstrate that capacitive charging can induce nonlinear concentration profiles in the electrolyte. To visualize nonlinear ICP dynamics, a miniaturized CDI platform is developed to observe in situ ion concentration profiles. Determined by the ion flux mismatching of electrosorption and bulk ion transport, we discovered four ICP regimes in CDI – steady, linear ICP, delayed-nonlinear ICP, and nonlinear ICP. We directly observed the signatures of nonlinear ICP: i) flat depletion zone with extremely low ion concentration, and ii) corresponding exponential current drop. Based on this observation, two scaling models are formulated to predict i) when the nonlinear ICP occurs, and ii) the propagation speed of the flat depletion zone. To the best of our knowledge, this is the first microscopic characterization of ICP in CDI systems, and it firmly establishes the existence of nonlinear ion transport dynamics in CDI's bulk electrolyte.

Recent interests in comprehensive protein surveys and protein biomarker studies have led to an increased demand for simultaneous measurement of multiple proteins in a single sample. Among various multiplex techniques, bead-based immunoassays, which use encoded particles attached with capture probes, have demonstrated distinct advantages of fluid-phase kinetics, high precision, and flexible target selection. In particular, encoded hydrogel particles composed of porous, hydrophilic, three-dimensional polymers have received positive attention because they enhance the binding kinetics of proteins, reduce protein denaturation, and increase the loading density of capture probes. Microfluidic techniques have been extensively used to fabricate the encoded hydrogel particles for multiplex immunoassays, enabling mass-production of highly monodisperse particles with complex morphologies in mild synthesis conditions. In this paper, we review microfluidic techniques available for the synthesis of encoded hydrogel particles and the important design parameters that determine the particles’ immunoassay performance. We also discuss currently reported multiplex immunoassay platforms that are based on encoded hydrogel particles.

Magnetic hydrogels have been commonly used in biomedical applications. As magnetite nanoparticles (MNPs) exhibit peroxidase enzyme-like activity, magnetic hydrogels have been actively used as signal transducers for biomedical assays. Droplet microfluidics, which uses photoinitiated polymerization, is a preferred method for the synthesis of magnetic hydrogels. However, light absorption by MNPs makes it difficult to obtain fully polymerized and homogeneous magnetic hydrogels through photoinitiated polymerization. Several methods have been reported to address this issue, but few studies have focused on investigating the light absorption properties of photoinitiators. In this study, we developed a simple method for the synthesis of poly(ethylene glycol) (PEG)-based uniform magnetic hydrogels that exploits the high ultraviolet absorption of a photoinitiator. Additionally, we investigated this effect on shape deformation and structural uniformity of the synthesized magnetic hydrogels. Two different photoinitiators, Darocur 1173 and lithium phenyl (2,4,6&ndash, trimethylbenzoyl) phosphinate (LAP), with significantly different UV absorption properties were evaluated based on the synthesis of magnetic hydrogels. The magnetic characteristics of the PEG-stabilized MNPs in hydrogels were investigated with a vibrating sample magnetometer. Finally, the colorimetric detection of hydrogen peroxide and glucose was conducted based on the enzyme-like property of MNPs and repeated several times to observe the catalytic activity of the magnetic hydrogels.

Despite a growing demand for more accessible diagnostic technologies, current methods struggle to simultaneously detect multiple analytes with acceptable sensitivity and portability. Colorimetric assays have been widely used due to their simplicity of signal readout, but the lack of multiplexibility has been a perpetual constraint. Meanwhile, particle-based assays offer multiplex detection by assigning an identity code to each analyte, but they often require lab-based equipment unsuitable for portable diagnostics. Here, by merging the two approaches, this paper reports a colorimetric multiplex immunoassay based on hydrogel microparticles that achieves the best of both worlds. The low-cost portable multiplex assay demonstrates sensitivities as high as and dynamic ranges greater than the lab-based enzyme-linked immunosorbent assay (ELISA). These critical advances are made possible by local precipitation and amplification of insoluble colour dyes inside the hydrogel networks. For the first time, enzymatic accumulation of colour dyes in hydrogel particles is reported and the kinetics of colour development is characterized in this work. By taking advantage of the colour signals in the visible spectrum, the hydrogel microparticles were imaged and analysed using low-cost portable devices. The colorimetric multiplex immunoassay was used to successfully detect three target biomarkers of preeclampsia and validated clinically using healthy and patient-derived plasma samples.

Flow lithography (FL), a versatile technique used to synthesize anisotropic multifunctional microparticles, has attracted substantial interest, given that the resulting particles with complex geometries and multilayered biochemical functionalities can be used in a wide variety of applications. However, after this process, there are double bonds remaining from the cross-linkable groups of monomers. The unreacted cross-linkable groups can affect the particles' biochemical properties. Here, we verify that the microparticles produced by FL contain a significant number of unreacted acrylate double bonds (UADBs), which could cause irreversible biochemical changes in the particle and pernicious effects to biological systems. We also confirm that the particles contain a considerable number of UADBs, regardless of the various synthetic (lithographic) conditions that can be used in a typical FL process. We present an effective way to eliminate a substantial amount of UADBs after synthesis by linking biochemically inert poly(ethylene glycol) based on click chemistry. We verify that eliminating UADBs by using this click chemistry approach can efficiently resolve problems, such as the occurrence of random reactions and the cytotoxicity of UADBs.

Gold nanorods (GNRs) are of great interest in cancer therapy given their ability to ablate tumor cells using deep tissue-penetrating near-infrared light. GNRs coated with tumor-specific moieties have the potential to target tumor tissue to minimize damage to normal tissue. However, perfect targeting is difficult to achieve given that nanoparticles could be broadly dispersed inside the body. Moreover, interaction between targeting groups and biological molecules could lower targeting abilities, resulting in off-target accumulation which might produce nanotoxicity. Here we introduce GNR-encapsulated microcubes (GNR@MCs) that can be utilized as implantable photothermal agents. GNR@MCs are created by encapsulating GNRs in polymeric networks via stop flow lithography (SFL), a one-phase synthesis technique which allows for creation of surfactant-free, uniform particles, and injection of GNR@MCs into the body after a simple rinse step. GNRs are highly packed and firmly encapsulated inside MCs, and entrapped GNRs exhibit optical properties comparable to that of unbound GNRs and photothermal efficiency (58%) in line with that of nano-sized agents (51–95%). Photothermal ablation in murine models is achieved using GNR@MCs stably implanted into the tumor tissue, which suggests that GNR@MCs can be a safe and effective platform for cancer therapy.

Polydimethylsiloxane (PDMS) microfluidic devices, though they are commonly utilized in microfluidic applications, have several limitations, such as short-term modified surface condition, swelling in the presence of organic solvents, and deformation under high pressure or when built with low aspect ratios. To resolve the restrictions, Norland Optical Adhesive (NOA) has been introduced as an excellent alternative for PDMS. Here, we present a practical protocol for the fabrication of NOA microfluidic devices via a step-wise molding process. Through the indirect molding of NOA on wafers, the damage to the wafers can be significantly reduced. Furthermore, because we use positivepatterned wafers, which are commonly used to fabricate PDMS devices, no additional fabrication of the wafer is required. This simple strategy thus avoids damage to the wafers and simultaneously allows for the mass production of NOA devices without deformation. We also test the performance of NOA devices in oil-in-water droplet production and in a microfluidic process using organic solvents.

The effects of solvents such as water and ethanol on the rheological properties and crosslinking characteristics of poly(ethylene glycol) (PEG) hydrogels were examined. Real-time storage modulus data for pre-polymerized mixtures containing different solvents during the photo-polymerization process successfully explained the differences in the formation of crosslinked networks of the corresponding hydrogels. Various experimental methods for Fourier transform infrared spectroscopy (FT-IR), swelling ratio, Rhodamine-B (Rh-B) loading/release properties, and scratch/indentation depths on hydrogel surfaces, were employed to systematically compare macroscopic structural and mechanical properties of the crosslinked PEG hydrogels with different solvents (water and ethanol). The effects of the solvents on the hydrogel properties were satisfactorily consistent, and the results clearly indicated that water hindered the formation of the crosslinked network more severely than ethanol at the same weight ratio because of the presence of larger number of water molecules in pre-polymerized mixtures, which was a more favorable feature for water than ethanol in the initial crosslinking growth.

Replica molding techniques, which are used to synthesize microparticles inside anisotropic micromolds, have been developed to enable the mass production of hydrogel particles. However, these techniques are limited in their ability to synthesize only a narrow range of particle compositions and shapes because of the difficulty in loading precursors into the micromolds as well as the low particle homogeneity due to the uneven evaporation of the precursors. Herein, we describe a simple yet powerful technique, called degassed micromolding lithography, which can load precursors within 1 min regardless of the wettability. This technique is based on the gas-solubility of a degassed micromold that acts as a suction pump to completely fill the mold by drawing precursor liquids in. The semi-closed system within the micromold prevents the uneven evaporation of the precursor, which is essential for the production of homogeneous particles. Furthermore, controlled uniformity of the hydrogel microparticles (C.V. < 2%) can be achieved by engineering the design of the micromold array.

Encoded hydrogel microparticles mounting DNA probes are powerful tools for high-performance microRNA (miRNA) detection in terms of sensitivity, specificity, and multiplex detection capability. However, several particle rinsing steps in the assay procedure present challenges for rapid and efficient detection. To overcome this limitation, we encapsulated dense magnetic nanoparticles to reduce the rinsing steps and duration via magnetic separation. A large number of magnetic nanoparticles were encapsulated into hydrogel microparticles based on a discontinuous dewetting technique combined with degassed micromolding lithography. In addition, we attached DNA probes targeting three types of miRNAs related to preeclampsia to magnetically encoded hydrogel microparticles by post-synthesis conjugation and achieved sensitivity comparable to that of conventional nonmagnetic encoded hydrogel microparticles. To demonstrate the multiplex capability of magnetically encoded hydrogel microparticles while maintaining the advantages of the simplified rinsing process when addressing multiple samples, we conducted a triplex detection of preeclampsia-related miRNAs. In conclusion, the introduction of magnetically encoded hydrogel microparticles not only allowed efficient miRNA detection but also provided comparable sensitivity and multiplexed detectability to conventional nonmagnetic encoded hydrogel microparticles.

An understanding of the contact line dynamics of viscoelastic liquids is essential for the successful application of liquid processing methods in many industries. In this article, the contact line motion of a λ-DNA solution is considered both experimentally and theoretically to understand the contact line motion of polymeric solutions. Experimentally, by using fluorescently tagged λ-DNAs in glycerin, the depletion of λ-DNA near the contact line is observed. The depletion length increases with time in a range near 10 µm. DNA fragments in glycerin did not show such a depletion region. The geometric exclusion of λ-DNA from the region cannot be the proper reason for the depletion because λ-DNA is in the stretched state. It is suggested that the depletion region might be developed by the migration of polymers from the solid wall to the bulk due to the elasticity of polymers. In the theoretical study, the Stokes flow near the contact line region is solved analytically for a drop-spreading problem to obtain the inhomogeneous flow field. Then, the motions of DNAs are considered in the flow using the FENE-P dumbbell model at the dilute limit. Two independent mechanisms of migration of the dumbbells were considered: migration due to wall-bead hydrodynamic interactions and the migration of stretched dumbbells in the inhomogeneous flow. It was found that the migration of stretched dumbbells in the inhomogeneous flow appears to be the dominant reason for the presence of the depletion region. The effects of the severe extension of dumbbells on migration are also discussed for both mechanisms.

This work describes a simple aqueous-phase synthesis of single-crystal ZnO nanobolts with sizes of 250 nm by reacting Zn(NO 3 ) 2 with octylamine. The synthesized ZnO nanobolts exhibit a hierarchical structure consisting of two well-defined hexagonal nanorods of different sizes. In a study of the growth behavior of the ZnO nanobolts, we observed that aggregates of around 600 nm in size became single-crystal ZnO nanobolts with sizes of 250 nm. We also investigated the influence of reaction temperature and Zn(NO 3 ) 2 concentration on the synthesis, demonstrating that these experimental factors were critical in terms of the size, morphology, and aggregation of ZnO nanobolts.

We report the precise decoding of a shape-modulated hydrogel barcode particle using a micropore fluidic device. Using an electrical simulation, we deduced the optimal pore geometry that yields the maximal sensing signal. We fabricated hydrogel particles with different dimensions and prepared the micropore device along with a fluidic cell and a patch clamp. Accordingly, we experimentally determined the most appropriate shape of the hydrogel barcode particle that allows efficient differentiation between a 0 code and a 1 code. Thus, we successfully decoded 4-bit hydrogel barcode particles with high speed and high accuracy.

Flow lithography (FL) is a microfluidic technique distinguished for its ability to produce hydrogel microparticles of various geometrical and chemical designs. While FL is typically performed in room temperature, this paper reports a new technique called low temperature flow lithography that uses low synthesis temperature to increase the degree of polymerization of microparticles without compromising other aspects of flow lithography. We suggest that decreased oxygen diffusivity in low temperature is responsible for the increase in polymerization. Microparticles that exhibit a higher degree of polymerization display a more developed polymer network, ultimately resulting in a more defined morphology, higher incorporation of materials of interest, and improved functional performance. This work demonstrates the increase in the degree of polymerization by examining the temperature effect on both the physical and chemical structures of particles. We show applications of this technique in synthesizing thin microparticles and enhancing microparticle-based detection of microRNA. Low temperature FL offers a simple and easy method of improving the degree of polymerization, which can be implemented in a wide range of FL applications.

Various thermo-responsive polymers have been developed for controlled drug delivery upon the local application of external heat. The development of thermo-responsive polymers with high biocompatibility and tunable thermo-sensitivity is crucial for safe and efficient therapeutic application. In this study, thermo-responsive drug carriers featuring tunable thermo-sensitivities were synthesized using biocompatible poly(N-vinyl caprolactam) (PVCL) and stop-flow lithography. The PVCL-based particles showed selective drug release depending on temperature, illustrating their feasibility for on-demand controlled drug delivery. The volume phase transition temperature (VPTT) of the PVCL-based particles can be adjusted to vary from room temperature to body temperature by controlling their monomer compositions. In addition, modulated drug release was achieved by constructing multicompartments of different thermo-sensitivities within the PVCL particles. To accomplish thermo-responsive anticancer therapy, doxorubicin (DOX) was encapsulated into the PVCL particles as an anticancer drug. The DOX-loaded PVCL particles exhibited both thermo-responsive drug release and anticancer activity. This study demonstrates that thermo-responsive PVCL particles are highly promising carriers for safe and targeted anticancer therapy.

Encoded hydrogel particles have attracted attention in diagnostics as these particles can be used for high-performance multiplexed assays. Here, we present encoded tetragonal hydrogel microparticles for multiplexed detection of miRNAs that are strongly related to Alzheimer's disease (AD). The particles are comprised of vertically distinct code and probe regions, and incorporated with quantum dots (QDs) in the code regions. By virtue of the particle geometry, the particles can be synthesized at a high production rate in vertically stacked micro-flows using hydrodynamic focusing lithography. To detect multiple AD-miRNAs, various code labels to identify the loaded probes are designed by changing wavelengths of QDs, increasing the number of code layers and adjusting the thickness of code layers. The probe regions are incorporated with complementary sequences of target miRNAs, and optimized for accurate and timely detection of AD-miRNAs. For proof of concept, we demonstrate the multiplexed capability of the particles by performing a 3-plexed assay of AD-miRNAs.

Semiconducting WS2 nanohybrids with different sizes of silver nanoparticles are designed via amine-assisted in situ reduction and growth of Ag(+) ions. These nanohybrids exhibit characteristic photocatalytic activity for the reduction of 4-nitrophenol as a function of their structure.

Transition metals, such as iron (Fe)- or cobalt (Co)-based nanomaterials, are promising electrocatalysts for oxygen reduction reactions (ORR) in fuel cells due to their high theoretical activity and low cost. However, a major challenge to using these metals in place of precious metal catalysts for ORR is their low efficiency and poor stability, thus new concepts and strategies should be needed to address this issue. Here, we report a hybrid aciniform nanostructures of Fe nanofragments embedded in thin nitrogen (N)-doped graphene (Fe@N-G) layers via a heat treatment of graphene oxide-wrapped iron oxide (Fe2O3) microparticles with melamine. The heat treatment leads to transformation of Fe2O3 microparticles to nanosized zero-valent Fe fragments and formation of core-shell structures of Fe nanofragments and N-doped graphene layers. Thin N-doped graphene layers massively promote electron transfer from the encapsulated metals to the graphene surface, which efficiently optimizes the electronic structure of the graphene surface and thereby triggers ORR activity at the graphene surface. With the synergistic effect arising from the N-doped graphene and Fe nanoparticles with porous aciniform nanostructures, the Fe@N-G hybrid catalyst exhibits high catalytic activity, which was evidenced by high E1/2 of 0.82 V, onset potential of 0.93 V, and limiting current density of 4.8 mA cm−2 indicating 4-electron ORR, and even exceeds the catalytic stability of the commercial Pt catalyst.

Stop Flow Lithography (SFL) is a microfluidic-based particle synthesis method for creating anisotropic multifunctional particles with applications that range from MEMS to biomedical engineering. Polydimethylsiloxane (PDMS) has been typically used to construct SFL devices as the material enables rapid prototyping of channels with complex geometries, optical transparency, and oxygen permeability. However, PDMS is not compatible with most organic solvents which limit the current range of materials that can be synthesized with SFL. Here, we demonstrate that a fluorinated elastomer, called perfluoropolyether (PFPE), can be an alternative oxygen permeable elastomer for SFL microfluidic flow channels. We fabricate PFPE microfluidic devices with soft lithography and synthesize anisotropic multifunctional particles in the devices via the SFL process – this is the first demonstration of SFL with oxygen lubrication layers in a non-PDMS channel. We benchmark the SFL performance of the PFPE devices by comparing them to PDMS devices. We synthesized particles in both PFPE and PDMS devices under the same SFL conditions and found the difference of particle dimensions was less than a micron. PFPE devices can greatly expand the range of precursor materials that can be processed in SFL because the fluorinated devices are chemically resistant to most organic solvents, an inaccessible class of reagents in PDMS-based devices due to swelling., Kwanjeong Educational Foundation (Korea), Singapore-MIT Alliance for Research and Technology (SMART), National Science Foundation (U.S.) (Grants CMMI-1120724 and DMR- 1006147)

Flow Lithography (FL) is the technique used for the synthesis of hydrogel microparticles with various complex shapes and distinct chemical compositions by combining microfluidics with photolithography. Although polydimethylsiloxane (PDMS) has been used most widely as almost the sole material for FL, PDMS microfluidic chips have limitations: (1) undesired shrinkage due to the thermal expansion of masters used for replica molding and (2) interfacial delamination between two thermally cured PDMS layers. Here, we propose the utilization of ultraviolet (UV)-curable PDMS (X-34-4184) for FL as an excellent alternative material of the conventional PDMS. Our proposed utilization of the UV-curable PDMS offers three key advantages, observed in our study: (1) UV-curable PDMS exhibited almost the same oxygen permeability as the conventional PDMS. (2) The almost complete absence of shrinkage facilitated the fabrication of more precise reverse duplication of microstructures. (3) UV-cured PDMS microfluidic chips were capable of much stronger interfacial bonding so that the burst pressure increased to ∼0.9 MPa. Owing to these benefits, we demonstrated a substantial improvement of productivity in synthesizing polyethylene glycol diacrylate microparticles via stop flow lithography, by applying a flow time (40 ms) an order of magnitude shorter. Our results suggest that UV-cured PDMS chips can be used as a general platform for various types of flow lithography and also be employed readily in other applications where very precise replication of structures on micro- or sub-micrometer scales and/or strong interfacial bonding are desirable.

Stimuli-responsive carriers releasing multiple drugs have been researched for synergistic combinatorial cancer treatment with reduced side-effects. However, previously used drug carriers have limitations in encapsulating multiple drug components in a single carrier and releasing each drug independently. In this work, pH-sensitive, multimodulated, anisotropic drug carrier particles are synthesized using an acid-cleavable polymer and stop-flow lithography. The particles exhibit a faster drug release rate at the acidic pH of tumors than at physiological pH, demonstrating their potential for tumor-selective drug release. The drug release rate of the particles can be adjusted by controlling the monomer composition. To accomplish multimodulated drug release, multicompartmental particles are synthesized. The drug release profile of each compartment is programmed by tailoring the monomer composition. These pH-sensitive, multicompartmental particles are promising drug carriers enabling tumor-selective and multimodulated release of multiple drugs for synergistic combination cancer therapy.

We report on modeling and experimental studies of the synthesis of opaque microparticles made via stop-flow lithography. Opaque magnetic beads and UV-absorbing dyes incorporated into hydrogel microparticles during synthesis changed the height and the degree of cross-linking of the polymer matrices formed. The effect of the concentration of these opaque materials on the particle height was determined experimentally and agreed well with model predictions based on the photopolymerization process over a wide range of UV absorbance. We also created particles with two independent anisotropies, magnetic and geometric, by applying magnetic fields during particle synthesis. Our work provides a platform for rational design of lithographic patterned opaque particles and also a new class of structured magnetic microparticles.

Molds having physical dimensions different from those on a template, can be obtained from a single template in a predictable way by stretching an elastomeric mold. Stretching results in a reduction of the pitch for line and space patterns. The duty ratio that is the ratio of line width to pitch can also be reduced independently of the change in the pitch. For two dimensional patterns, the feature shape and size can be altered. The ability to produce any number of different molds from one template should provide an easy route to optimize the feature size and shape in optics inexpensively.

Magnetic polymer particles have been used in a wide variety of applications ranging from targeting and separation to diagnostics and imaging. Current synthesis methods have limited these particles to spherical or deformations of spherical morphologies. In this paper, we report the use of stop flow lithography to produce magnetic hydrogel microparticles with a graphical code region, a probe region, and a magnetic tail region. These anisotropic multifunctional magnetic polymer particles are an enhanced version of previously synthesized "barcoded" particles (Science, 2007, 315, 1393-1396) developed for the sensitive and rapid multiplexed sensing of nucleic acids. The newly added magnetic region has acquired dipole moments in the presence of weak homogeneous magnetic fields, allowing the particles to align along the applied field direction. The novel magnetic properties have led to practical applications in the efficient orientation and separation of the barcoded microparticles during biological assays without disrupting detection capabilities.

Anisotropic multifunctional particles hold great promise for drug delivery, imaging, and construction of building blocks for dynamic mesostructures such as self-assembled tissues and 3-D electrical circuits. Of particular interest, multifunctional particles with unique barcodes have been suggested as diagnosis tools for rapid screening of biomolecules. For these applications, particle design is at least as important as size and requires a fabrication technique with precise control over shape and chemical patchiness. Methods currently used to generate multifunctional particles include microcutting, co-jetting, core–shell systems, photo resist-based lithography, and the PRINT method (particle replication in non-wetting templates). The morphology of particles prepared by co-jetting, microcutting, and core–shell systems has been limited to spheres and cylinders. Although multilayer lithography overcomes this limitation, the use of photoresist materials renders this approach suboptimal for many applications. While the PRINT method has its strength in producing small sub-mm particles, to date multiphasic particles beyond a 1-D stripe have not been synthesized. Furthermore, during multifunctional particle synthesis, the technique needs multiple steps and does not provide flexibility as particle shapes are restricted to the pre-defined stamping molds. Previously, we have shown that flow lithography (FL) can be used to generate multifunctional particles—we exploited several microfluidic characteristics such as co-flow of liquid monomers, rapid fluidic exchange, and simple controllability. In FL, we can use a combination of adjacent flowing photocurable monomers with lithographic masks to simultaneously define the shape and chemical pattern of particles. Recently, we also developed lock release lithography (LRL) to extend chemical patterning to multiple dimensions. However, these FL-based approaches for generating particles with patterned chemistries require precise alignment of masks at flow interfaces and concomitant modest particle throughput. Currently, FL cannot be used to synthesize multifunctional particles with chemical anisotropy in the channel height direction (z direction in this article, c.f. Figure 1A). Here, we introduce a new method called hydrodynamic focusing lithography (HFL) that harnesses flow focusing to create stacked flows in two-layered channels for particle synthesis. Contrary to our prior methods to create multilayered particles, here the fluid interface can be perpendicular to the UV light propagation direction and precise mask alignment at the interface is no longer needed. This change in geometry also allows us to polymerize 2-D arrays, compared to 1-D in the prior method, which can increase throughput substantially. In HFL, multiple monomer streams can be simultaneously stacked in both the z and y direction leading to more complex particles than before. Finally, we demonFigure 1. Hydrodynamic focusing lithography (HFL) for high-throughput synthesis of Janus microparticles. A) Microfluidic device used in HFL. P1 and P2 represent the inlet pressures of top and bottom channel respectively. All inlet dimensions are 40 40 mm. Particles are synthesized after layered flows are widened up to 1 mm in a 40 mm tall region of the channel. B) A side view of flow focusing and particle polymerization. C) A fluorescent image of 50 mm triangular particles with green (200 nm, green fluorescent beads) and red (rhodamine A) layers. H1 and H2 are the heights of top (red) and bottom (green) layer in a particle. D) Comparison of measured H2/H1 versus estimated flow ratio Q2/Q1 (see Supporting Information). The dashed line is the prediction from a hydrodynamic model (Eq. (12) in Supporting Information). E) Uniformity of Janus particles synthesized at a, b, c, d, and e spots across a 1 mm width channel. The intervals between spots are 100 mm. Scale bars are 50 mm (C,E) and 20 mm (D).

Cell-adhesive particles are of significant interest in biotechnology, the bioengineering of complex tissues, and biomedical research. Their applications range from platforms to increase the efficiency of anchorage-dependent cell culture to building blocks to loading cells in heterogeneous structures to clonal-population growth monitoring to cell sorting. Although useful, currently available cell-adhesive particles can accommodate only homogeneous cell culture. Here, we report the design of anisotropic hydrogel microparticles with tunable cell-adhesive regions as first step toward micropatterned cell cultures on particles. We employed stop flow lithography (SFL), the coupling reaction between amine and N-hydroxysuccinimide (NHS) and streptavidin–biotin chemistry to adjust the localization of conjugated collagen and poly-L-lysine on the surface of microscale particles. Using the new particles, we demonstrate the attachment and formation of tight junctions between brain endothelial cells. We also demonstrate the geometric patterning of breast cancer cells on particles with heterogeneous collagen coatings. This new approach avoids the exposure of cells to potentially toxic photoinitiators and ultraviolet light and decouples in time the microparticle synthesis and the cell culture steps to take advantage of the most recent advances in cell patterning available for traditional culture substrates.

Controlled manipulation of particles from very large volumes of fluid at high throughput is critical for many biomedical, environmental and industrial applications. One promising approach is to use microfluidic technologies that rely on fluid inertia or elasticity to drive lateral migration of particles to stable equilibrium positions in a microchannel. Here, we report on a hydrodynamic approach that enables deterministic focusing of beads, mammalian cells and anisotropic hydrogel particles in a microchannel at extremely high flow rates. We show that on addition of micromolar concentrations of hyaluronic acid, the resulting fluid viscoelasticity can be used to control the focal position of particles at Reynolds numbers up to Re≈10,000 with corresponding flow rates and particle velocities up to 50 ml min[superscript −1] and 130 m s[superscript −1]. This study explores a previously unattained regime of inertio-elastic fluid flow and demonstrates bioparticle focusing at flow rates that are the highest yet achieved., National Institute for Biomedical Imaging and Bioengineering (U.S.) (P41 BioMicroElectroMechanical Systems Resource Center), National Institute for Biomedical Imaging and Bioengineering (U.S.) (P41 EB002503), National Science Foundation (U.S.). Graduate Research Fellowship, United States. Army Research Office (Institute for Collaborative Biotechnologies Grant W911NF-09-0001)

Flow lithography has become a powerful particle synthesis technique. Currently, flow lithography relies on the use of polydimethylsiloxane microchannels, because the process requires local inhibition of polymerization, near channel interfaces, via oxygen permeation. The dependence on polydimethylsiloxane devices greatly limits the range of precursor materials that can be processed in flow lithography. Here we present oxygen-free flow lithography via inert fluid-lubrication layers for the synthesis of new classes of complex microparticles. We use an initiated chemical vapour deposition nano-adhesive bonding technique to create non-polydimethylsiloxane-based devices. We successfully synthesize microparticles with a sub-second residence time and demonstrate on-the-fly alteration of particle height. This technique greatly expands the synthesis capabilities of flow lithography, enabling particle synthesis, using water-insoluble monomers, organic solvents, and hydrophobic functional entities such as quantum dots and single-walled carbon nanotubes. As one demonstrative application, we created near-infrared barcoded particles for real-time, label-free detection of target analytes. Flow lithography is used to synthesize microparticles but relies on polydimethylsiloxane microchannels for oxygen to permeate and inhibit polymerization near channel interfaces. Now, non-polydimethylsiloxane devices have been developed, which allow oxygen-free lithography, increasing the capabilities of flow lithography.

The directed assembly of shape anisotropic magnetic particles into targeted macrostructures requires judicious particle design. We present a framework to understand the self-assembly of magnetic non-Brownian H-shaped particles and the formation of branched networks under an applied magnetic field. A finite element integration (FEI) method is developed to identify the preferred particle orientation (relative to the applied field) at different values of the geometric parameters defining H shapes, and used to construct a phase diagram to generalize the results. Theoretical predictions are validated by comparing with experiments performed using magnetic hydrogels synthesized using stop-flow lithography (SFL). We demonstrate the ability of H-shaped particles to form chains parallel to the field that can thicken in a direction orthogonal to the field, and in some cases with branching. The assembly of a suspension containing H-shaped particles, or rods, or a combination of both, is reported.

Vapor deposited functional polymer thin films can undergo rapid covalent functionalization. Patterning of two functional layers displaying orthogonal reactivity enables sorting of aqueous mixtures of dyes and nanoparticles, such as quantum dots, onto selective areas of nanopatterned surfaces.

We present a method called “Lock Release Lithography (LRL)” that utilizes a combination of channel topography, mask design, and pressure-induced channel deformation to form and release particles in a cycled fashion. This technique provides a means for the high-throughput production of particles with complex 3D morphologies and composite particles with spatially configurable chemistries. In this work, we demonstrate a diverse set of functional particles including those displaying heterogeneous swelling characteristics and containing functional entities such as nucleic acids, proteins and beads.

A novel high-strength nano-adhesive is demonstrated for fabricating nano- and microfluidic devices. While the traditional plasma sealing methods are specific for sealing glass to poly(dimethylsiloxane) (PDMS), the new method is compatible with a wide variety of polymeric and inorganic materials, including flexible substrates. Additionally, the traditional method requires that sealing occur within minutes after the plasma treatment. In contrast, the individual parts treated with the nano-adhesive could be aged for at least three months prior to joining with no measurable deterioration of post-cure adhesive strength. The nano-adhesive is comprised of a complementary pair of polymeric nanolayers. An epoxy-containing polymer, poly(glycidyl methacrylate) (PGMA) was grown via initiated chemical vapor deposition (iCVD) on the substrate containing the channels. A plasma polymerized polyallylamine (PAAm) layer was grown on the opposing flat surface. Both CVD monomers are commercially available. The PGMA nano-adhesive layer displayed conformal coverage over the channels and was firmly tethered to the substrate. Contacting the complementary PGMA and PAAm surfaces, followed by curing at 70 degrees C, resulted in nano- and micro-channel structures. The formation of the covalent tethers between the complementary surfaces produces no gaseous by-products which would need to outgas. The nano-adhesive layers did not flow significantly as a result of curing, allowing the cross-sectional profile of the channel to be maintained. This enabled fabrication of channels with widths as small as 200 nm. Seals able to withstand > 50 psia were fabricated employing many types of substrates, including silicon wafer, glass, quartz, PDMS, polystyrene petri dishes, poly(ethylene terephthalate) (PET), polycarbonate (PC), and poly(tetrafluoro ethylene) (PTFE).

A method is presented for patterning the pentacene active layer of organic thin film transistor. The method involves forming a metal pattern on a gate dielectric surface by transfer patterning, depositing pentacene over the whole surface, and then lifting off a bilayer of pentacene on the metal with a flat elastomeric mold. Compared with the method of direct pentacene transfer reported earlier [S. Y. Park, T. Kwon, and H. H. Lee, Adv. Mater. (Weinheim, Ger.) 18, 1861 (2006)], this alternative allows one to choose a surface for larger pentacene grain size and eliminates a high off-current associated with the direct transfer method. The rigid nature of a rigiflex mold allows the pentacene pattern size to be defined in submicrometer range and the flexible nature of rigiflex and elastomeric molds permits large area application.

Large-scale microparticle arrays (LSMAs) are key for material science and bioengineering applications. However, previous approaches suffer from trade-offs between scalability, precision, specificity and versatility. Here, we present a porous microwell-based approach to create large-scale microparticle arrays with complex motifs. Microparticles are guided to and pushed into microwells by fluid flow through small open pores at the bottom of the porous well arrays. A scaling theory allows for the rational design of LSMAs to sort and array particles on the basis of their size, shape, or modulus. Sequential particle assembly allows for proximal and nested particle arrangements, as well as particle recollection and pattern transfer. We demonstrate the capabilities of the approach by means of three applications: high-throughput single-cell arrays; microenvironment fabrication for neutrophil chemotaxis; and complex, covert tags by the transfer of an upconversion nanocrystal-laden LSMA.