Advanced manufacturing of nanoparticle formulations of drugs and biologics using microfluidics.

Numerous innovative nanoparticle formulations of drugs and biologics, named nano-formulations, have been developed in the last two decades. However, methods for their scaled-up production are still lagging, as the amount needed for large animal tests and clinical trials is typically orders of magnitude larger. This manufacturing challenge poses a critical barrier to successfully translating various nano-formulations. This review focuses on how microfluidics technology has become a powerful tool to overcome this challenge by synthesizing various nano-formulations with improved particle properties and product purity in large quantities. This microfluidic-based manufacturing is enabled by microfluidic mixing, which is capable of the precise and continuous control of the synthesis of nano-formulations. We further discuss the specific applications of hydrodynamic flow focusing, a staggered herringbone micromixer, a T-junction mixer, a micro-droplet generator, and a glass capillary on various types of nano-formulations of polymeric, lipid, inorganic, and nanocrystals. Various separation and purification microfluidic methods to enhance the product purity are reviewed, including acoustofluidics, hydrodynamics, and dielectrophoresis. We further discuss the challenges of microfluidics being used by broader research and industrial communities. We also provide future outlooks of its enormous potential as a decentralized approach for manufacturing nano-formulations.

Experimental and computational analysis of the injection-induced mechanical changes in the skin microenvironment during subcutaneous injection of biologics.

Subcutaneous (SQ) injection is an effective delivery route for various biologics, including proteins, antibodies, and vaccines. However, pain and discomfort induced during SQ injection pose a notable challenge for the broader and routine use of biologics. Understanding the underlying mechanism and quantification of injection-induced pain and discomfort (IPD) are urgently needed. A crucial knowledge gap is what changes in the skin tissue microenvironment are induced by the SQ injection, which may ultimately cause the IPD. In this study, thus, a hypothesis is postulated that the injection of biologics solution through the skin tissue microenvironment induces spatiotemporal mechanical changes. Specifically, the injection leads to tissue swelling and subsequent increases in the interstitial fluid pressure (IFP) and matrix stress around the injection site, which ultimately causes the IPD. To test this hypothesis, an engineered SQ injection model is developed capable of measuring tissue swelling during SQ injection. The injection model consists of a skin equivalent with quantum dot-labeled fibroblasts, which enables the measurement of injection-induced spatiotemporal deformation. The IFP and matrix stress are further estimated by computational analysis approximating the skin equivalent as a nonlinear poroelastic material. The result confirms significant injection-induced tissue swelling and increases in IFP and matrix stress. The extent of deformation is correlated to the injection rate. The results also suggest that the size of biologics particulates significantly affects the pattern and extent of the deformation. The results are further discussed to propose a quantitative understanding of the injection-induced changes in the skin microenvironment.

A timescale-guided microfluidic synthesis of tannic acid-FeIII network nanocapsules of hydrophobic drugs.

Many drugs are poorly water-soluble and suffer from low bioavailability. Metal-phenolic network (MPN), a hydrophilic thin layer such as tannic acid (TA)-FeIII network, has been recently used to encapsulate hydrophobic drugs to improve their bioavailability. However, it remains challenging to synthesize nanocapsules of a wide variety of hydrophobic drugs and to scale up the production in a continuous manner. Here, we present a microfluidic synthesis method to continuously produce TA-FeIII network nanocapsules of hydrophobic drugs. We hypothesize that nanocapsules can continuously be formed only when the microfluidic mixing timescale is shorter than the drug's nucleation timescale. The hypothesis was tested on three hydrophobic drugs - paclitaxel, curcumin, and vitamin D with varying solubility and nucleation timescale. The proposed mechanism was validated by successfully predicting the synthesis outcomes. The microfluidically-synthesized nanocapsules had well-controlled sizes of 100-200 nm, high drug loadings of 40-70%, and a throughput of up to 70 mg hr-1 per channel. The release kinetics, cellular uptake, and cytotoxicity were further evaluated. The effect of coating constituents on nanocapsule properties were characterized. Fe content of nanocapsules was reported. The stability of nanocapsules at different temperatures and pHs were also tested. The results suggest that the present method can provide a quantitative guideline to predictively design a continuous synthesis scheme for hydrophobic drug encapsulation via MPN nanocapsules with scaled-up capability.

Drop Encapsulated in Bubble: A New Encapsulation Structure.

A new fluid encapsulation structure, which is characterized by a bubble encapsulating a drop, is reported. It is stably generated from the breakup of a liquid column inside a bubble, which is achieved via the injection of Taylor flow into liquid. A model is constructed to explain the liquid column breakup mechanism. A dimensionless control guidance, which enables the possibility to create different-scale capsules, is provided. The encapsulation stability in external flows is verified, and a method to trigger the release of the encapsulated drop is provided, which supports potential applications with great advantages such as fluid transport.