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Control over vesicle size during nanoscale liposome synthesis is critical for defining the pharmaceutical properties of liposomal nanomedicines. Microfluidic technologies capable of size-tunable liposome generation have been widely explored, but scaling these microfluidic platforms for high production throughput without sacrificing size control has proven challenging. Here we describe a microfluidic-enabled process in which highly vortical flow is established around an axisymmetric stream of solvated lipids, simultaneously focusing the lipids while inducing rapid convective and diffusive mixing through application of the vortical flow field. By adjusting the individual buffer and lipid flow rates within the system, the microfluidic vortex focusing technique is capable of generating liposomes with precisely controlled size and low size variance, and may be operated up to the laminar flow limit for high throughput vesicle production. The reliable formation of liposomes as small as 27 nm and mass production rates over 20 g/h is demonstrated, offering a path toward production-scale liposome synthesis using a single continuous-flow vortex focusing device.

 

A method for in situ photografting during direct laser writing by two-photon polymerization is presented. The technique serves as a powerful approach to the formation of covalent bonds between 3D photoresist structures and thermoplastic surfaces. By leveraging the same laser for both pattern generation and localized surface reactions, crosslinking between the bulk photoresist and thermoplastic surface is achieved during polymerization. When applied to in-channel direct laser writing for microfluidic device fabrication, the process yields exceptionally strong adhesion and robust bond interfaces that can withstand pressure gradients as high as 7 MPa through proper channel design, photoinitiator selection, and processing conditions.

 

Rapid and efficient isolation of bacteria from complex biological matrices is necessary for effective pathogen identification in emerging single-cell diagnostics. Here, we demonstrate the isolation of intact and viable bacteria from whole blood through the selective lysis of blood cells during flow through a porous silica monolith. Efficient mechanical hemolysis is achieved while providing passage of intact and viable bacteria through the monoliths, allowing size-based isolation of bacteria to be performed following selective lysis. A process for synthesizing large quantities of discrete capillary-bound monolith elements and millimeter-scale monolith bricks is described, together with the seamless integration of individual monoliths into microfluidic chips. The impact of monolith morphology, geometry, and flow conditions on cell lysis is explored, and flow regimes are identified wherein robust selective blood cell lysis and intact bacteria passage are achieved for multiple gram-negative and gram-positive bacteria. The technique is shown to enable rapid sample preparation and bacteria analysis by single-cell Raman spectrometry. The selective lysis technique presents a unique sample preparation step supporting rapid and culture-free analysis of bacteria for the point of care.

 

A multifunctional microfluidic platform combining on-demand aqueous-phase droplet generation, multi-droplet storage, and controlled merging of droplets selected from a storage library in a single integrated microfluidic device is described. A unique aspect of the technology is a microfluidic trap design comprising a droplet trap chamber and lateral bypass channels integrated with a microvalve that supports the capture and merger of multiple droplets over a wide range of individual droplet sizes. A storage unit comprising an array of microfluidic traps operates in a first-in first-out manner, allowing droplets stored within the library to be analyzed before sequentially delivering selected droplets to a downstream merging zone, while shunting other droplets to waste. Performance of the microfluidic trap is investigated for variations in bypass/chamber hydrodynamic resistance ratio, micro-chamber geometry, trapped droplet volume, and overall flow rate. The integrated microfluidic platform is then utilized to demonstrate the operational steps necessary for cell-based assays requiring the isolation of defined cell populations with single cell resolution, including encapsulation of individual cells within an aqueous-phase droplet carrier, screening or incubation of the immobilized cell-encapsulated droplets, and generation of controlled combinations of individual cells through the sequential droplet merging process. Beyond its utility for cell analysis, the presented platform represents a versatile approach to robust droplet generation, storage, and merging for use in a wide range of droplet-based microfluidics applications. 

Hydrocyclones are a simple and powerful particle separation technology, widely used in macroscale industrial processes, with enormous potential for miniaturization. Although recent efforts to shrink hydrocyclones to the centimeter scale have shown great promise for passive and high‐throughput microparticle separations, further miniaturization is constrained by limited understanding of the impact of device size scale and design on separation performance, and challenges in realizing the complex internal structures of hydrocyclones at small size scales using conventional microfabrication techniques. Here, fundamental scaling issues for hydrocyclones with sub‐millimeter critical dimensions are investigated, and the first microscale hydrocyclones with critical feature size as small as 250 µm are demonstrated by taking advantages of 3D printing using stereolithography coupled with digital light processing. The resulting devices are shown to provide high separation efficiency for particles as small as 3.7 µm while operating at high flow rates up to 40 mL min⁻¹, with scaling analysis suggesting that sub‐micrometer particle separations can be achieved with further miniaturization, potentially making the technology suitable for the rapid isolation and concentration of both inorganic and biological nanoparticles.

 

The use of additive manufacturing to fabricate microfluidic devices capable of high throughout synthesis of nanoscale liposomes with tunable dimensions is demonstrated. Employing a high‐resolution 3D printing process based on stereolithography and digital light projection, microchannel geometries and printing parameters are optimized to enable reliable patterning of channel features with critical dimensions of 200 µm, supporting the production of lipid vesicles below 100 nm in diameter by microfluidic flow focusing. The additive manufacturing approach enables the fabrication of flow focusing microchannels with high aspect ratios, together with seamless fabrication of high‐pressure fluidic ports for world‐to‐chip interfacing, supporting large volumetric flow rates and high‐throughput nanoparticle synthesis, with demonstrated production rates for optimized liposomes as high as 4 mg min⁻¹from a single device.