Ki Wan Bong

Microfluidic Synthesis of pH-Sensitive Multicompartmental Microparticles for Multimodulated Drug Release.

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.

Fabrication of NOA microfluidic devices based on sequential replica molding

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.

Effects of solvents on rheological and crosslinking properties of photo-polymerized poly(ethylene glycol) hydrogels

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.

Flow lithography in ultraviolet-curable polydimethylsiloxane microfluidic chips

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.

Fabrication of dual stimuli-responsive multicompartmental drug carriers for tumor-selective drug release

There has been increasing attention to the development of multi-stimuli-responsive drug carriers for precisely controlled drug release at target disease areas. In this study, pH- and redox-responsive hybrid drug carriers were fabricated by using both ketal-based acid-cleavable precursors and disulfide-based reducible precursors via stop-flow lithography. pH- and redox-sensitive drug release of the dual stimuli-responsive hybrid particles was confirmed, demonstrating their feasibility for selective and efficient drug release into tumor tissues in acidic and highly reductive environments. It was also found that the drug release rate of the particles was fine-tuned by modulating monomer compositions in the precursor. Importantly, the dual stimuli-responsive hybrid particles exhibited synergistic, controlled drug release in complex stimuli (both pH and redox stimuli) environments. To achieve tumor-selective combination chemotherapy, multicompartmental drug carriers consist of an acid-degradable compartment and a reducible compartment, which can separately encapsulate individual model drugs in each of the compartments. The multicompartmental particles exhibited independent drug release upon exposure to the corresponding stimulus. The dual stimuli-responsive, multicompartmental particles are effective drug carriers for tumor-selective release of a drug cocktail, leading to synergistic combination chemotherapy.

Microfluidic fabrication of biocompatible poly(N-vinylcaprolactam)-based microcarriers for modulated thermo-responsive drug release

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.

Low temperature flow lithography

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.