Fabrication of functional materials using microfluidics: Materials at microscale have many advantages in biological and biomedical applications, due to their unique size compatibility with cells. My research focuses on using glass capillary microfluidic devices to fabricate various functional materials for bio-applications. By precisely manipulating the fluids using microfluidic technology, I can produce various types of droplets, including single-emulsion droplets and double-emulsion droplets, with controllable size and structures. For example, I prepare poly(ethylene glycol) based microhydrogels using an oil-in-water single emulsion method. These biocompatible microhydrogels can either incorporate hydrophobic drugs with high quantity and homogeneity for drug delivery application, or carry hydrophilic DNA for droplet barcoding for single cell sequencing application. Another example is microcapsules fabricated using a water-in-oil-in-water double emulsion method to encapsulate various valuable biomaterials, such as enzymes and antibodies, for controlled release.

Subtitle 1: Universal approach to fabricate microhydrogels containing hydrophobic or hydrophilic components

Due to their unique physicochemical properties, microhydrogels have been widely used for drug delivery. However, as a drug delivery system, microhydrogels have limitation in loading hydrophobic drugs with high quantity and homogeneity in hydrogel matrices. Here we prepare microhydrogels using a glass capillary microfluidic device, as shown in Fig. 1. Hydrophobic drugs with hydrogel precursors such as poly(ethylene glycol) diacrylate (PEGDA) are dissolved in dichloromethane (DCM) used as oil phase, and 10% poly(vinyl alcohol) solution as continuous phase. After forming oil-in-water single emulsion drops followed by UV exposure to polymerize hydrogel precursors, we wash as-prepared particles with water to remove DCM to get PEG based microhydrogel particles with uniformly distributed hydrophobic drugs with high quantity. In addition, we also demonstrate, the microhydrogel system can be used to carry DNA barcode for single cell sequencing. To achieve this, we prepare microhydrogels using PEGDA mixed with acrylic acid. After removing DCM, we use EDC/NHS to activate carboxyl groups in microhydrogels. Then amino functionalized DNA are added to the microhydrogel suspension to link DNA to the microhydrogel network. With this strategy, we can prepare microhydrogel with very high loading efficiency of DNA, which is very suitable for barcoding applications.

Figure 1. Schematic illustration of fabricating microhydrogels using a microfluidic process.

Subtitle 2: Microcapsules for encapsulation and controlled release

Microcapsules are spherical cores surrounded by a solid shell. This hollow core-shell structure offers significant advantages for encapsulation: a very high encapsulation efficiency (over 99%) can be achieved with very minimum encapsulants. The solid shell can act as a barrier to isolate encapsulated sensitive cargo from environment and keep them under optimized condition in the core, so that the sensitive cargo can be protected for long-term storage and processing. More importantly, with microfluidic technology, we can design and precisely control the microcapsule size and shell composition as well as structure to obtain effective controlled release properties. One example of my research in this direction was designing inhomogeneous microcapsules to encapsulate concentrated antibodies for osmotic pressure triggered release.

Concentrated antibodies can be hardly used for subcutaneous injection due to high viscosity. Previous results indicate that after being encapsulated, the viscosity of antibodies will greatly decrease. In this project, we are developing a novel encapsulation system to encapsulate highly viscous antibodies for triggered release in human body environment. Viscous antibodies dissolved in buffer solution are used as inner phase. PEG divinyl ether and multifunctional thiol as a cross-linker in DCM used are used as middle phase. We fabricate microcapsules using water-in-oil-in-water double emulsion drops using a glass capillary microfluidic device followed by UV exposure to polymerize shell materials, as shown in Fig. 2. By tuning the flow rates of inner phase and middle phase, we can obtain microcapsules with inhomogeneous shell thickness. Very interestingly, we demonstrate that these microcapsules are very sensitive to osmotic pressure change, due to mechanical instability of shell raised from inhomogeneous shell thickness. We also find after optimizing experimental conditions, we can achieve over 90% rupture fraction upon osmotic pressure change, which is suitable for encapsulating and releasing of antibodies.

Figure 2. (a) Schematic illustration of producing inhomogeneous microcapsules using a microfluidic process; (b) Images showing droplet formation and microcapsules; (c) Images showing a microcapsule at different stages of osmotic pressure triggered release.

Contact: Weixia Zhang wxzhang@seas.harvard.edu