Published on 04 November 2020
This short review article is originally based on the research paper titled “One-Step Generation of Core–Gap–Shell Microcapsules for Stimuli-Responsive Biomolecular Sensing” authored by Hyejeong Kim,* Seong-Min Jo, Fanlong Meng, Yinzhou Guo, Héloïse Thérien-Aubin, Ramin Golestanian, Katharina Landfester, and Eberhard Bodenschatz.
The research paper was first published in the journal Advanced Functional Materials. The original research paper explores a microfluidic approach to synthesize stimuli-responsive microcapsules with temperature-responsive core-gap-shell structures for versatile design. The pressure-driven flow controller enabled the authors to achieve precise control over the generation of core gap-shell microcapsules for this study.
The elaborate design elements of stimuli-responsive microparticles embedding valuable biomolecules has immense potential in a range of engineering fields, for example – sensors, actuators, drug delivery, and catalysis. In this study, the results are reported on thermoresponsive core-gap-shell (TCGS) microcapsules made of PNIPAm (poly N-isopropylacrylamide), which encapsulate hydrophilic payloads in a simple and stable manner. These facts are realized by a one-step microfluidic approach using the phase separation of a supersaturated aqueous solution of NIPAm. A range of designs of microcapsules is created by individual control of the swelling or by incorporating pH-responsive co-monomers of the inner core and outer shell. The gap, i.e – the space between the inner core and outer shell, can be loaded with cargo-like nanoparticles. The outer shell can serve as a stimuli-responsive gateway for the transport of smaller molecules from the external solution. In this research paper it is demonstrated that the TCGS microcapsules are suitable as temperature controllable glucose sensors and have the potential to contribute to the design of controllable enzymatic reactions. The proposed platform provides a pathway for the development of a new-generation of micro-particles with possible use-cases in diverse engineering applications.
Bio-molecular sensing is a field of research that includes the development of procedures to measure bio-molecular markers in bodily tissues and fluids. With the help of Droplet-based microfluidics, it is relatively easy to generate micro-droplets with precise and adjustable configurations [1]. Recent developments in the field of microfluidics have made multiple-emulsion technology possible, which allows for the fabrication of microcapsules with a membrane (block copolymers, lipids etc.) and has applications for the bio-medical, food and cosmetics industries. [1a,b,d,2]. Microcapsules, also known as microcompartments, are potentially very important elements for the fabrication of proto-cells in the field of bottom-up-biology [3]. The ability of microcapsules to encapsulate cargo materials in a stable state makes them extremely versatile.
In recent studies, perfluoropolyether-based double emulsion drops [4], nanosensors encapsulating poly(ethyleneglycol) (PEG) microcapsules [5], PEG diacrylate-based microcapsules [6], and fluorocarbon oil-reinforced triple emulsion drops [7], have been able to carry out the encapsulation of a wide variety of cargoes within a single platform. In spite of these advances, it is definitely still considered a challenge to fabricate water cored capsules dispersed in an aqueous media that permits the encapsulation of hydrophilic biomolecules [1c,8]. Particularly, in order to produce stable & uniform multilayer droplets, the microchannel geometry, wettability as well as the flow rates in the individual multichannels need to be controlled to successfully fabricate uniform microcapsules with homogeneous geometry. This is the reason why a majority of studies focus on the production of a single-emulsion [9].
Stimuli-responsive microparticles are an excellent selection for the role of functional units in many engineering applications, such as sensors, actuators, drug delivery and catalysis.[8b] From the effect of various external stimuli, the microcapsule shells passively undergo mechanical deformation or chemical reactions. This enables the effective delivery of valuable and sensitive cargo in response to external field triggers.
Here, pressure-driven flow controlled microfluidics was employed to achieve the below mentioned objectives:
The pregel solution – N-rich and N-poor phase solutions are prepared by dissolving 1g of NIPAm in 1ml of distilled water. Next, for the microfluidic generation of double emulsions, the two solutions were injected into the PDMS device using a pressure-driven flow controller – the Elveflow OB1. Given below are images of the experimental setup for this study:
With the help of the thermodynamic properties of the supersaturated NIPAm solution, TCGS microcapsules can be produced from Wn-poor/Wn-rich/O double emulsions produced from a polydimethylsiloxane (PDMS) microfluidic device. At a temperature upwards of 25 °C, the super-saturated NIPAm solution gets separated into two immiscible phases – the first phase, Wn-rich, is NIPAm-rich (N-rich) and hydrophobic and the second phase, Wn-poor, is N-poor and hydrophilic. This is showcased in Figure 2A. These two Wn-poor & Wn-rich pregel solutions were used in the microfluidic channel as inner fluid and middle fluid, respectively (Figure 2B). Wn-poor/Wn-rich/O double emulsions were successfully generated without any chemical treatment of the channel surface.
Once the double emulsions of microparticles were produced, polymerization and cross-linking of these microdroplets took place using UV radiation (Figure 2C).
The microfluidic platform used in this study to produce TCGS microcapsules using a phase separated NIPAm solution, increases the production yield of stable microcapsule templates by reducing the order of emulsions. The benefits of this platform become evident when the number of target layers of microcapsules increases. This approach successfully avoids coalescence which henceforth increases the yield of stable microcapsules.
The TCGS structure is flexible and allows various functional designs by varying chemical compositions in the separated inner phase and middle phase of double emulsions templates.
In order to explore the effect of crosslinker concentration on water adsorption behavior, microparticles are fabricated with different amounts of crosslinker composition from single emulsion template (Figure 3A).
When both the pre-gel solutions have the same concentration of crosslinker, the N-rich particles have much larger swelling ratio when compared to N-poor particles (Figure 4A). This different tendency of water absorption ability is due to different NIPAm/H2O mole ratio for the N-rich solution is approximately 0.77, whereas that of the N-poor solution is around 0.04 at 25°C.
With the same amount of crosslinker, the larger quantity of NIPAm in the N-rich solution is found to result in fewer crosslinking points per unit volume. This thereby provides a higher swelling ratio. The different compositions of N-poor inner fluid and N-rich outer fluid were combined, resulting in the formation of TCGS microcapsules with different water absorption properties (Figure 4B).
Most aqueous-dispersed materials were inadequate to be encapsulated within the PNIPAm capsule by emulsion methods because the precursor monomer solution of PNIPAm has a similar polarity to the encapsulated materials.
As encapsulation cannot be performed, the materials are loaded by diffusion or absorption after the formation of the PNIPAm capsules. The successful encapsulation of these nanoparticles inside the polymer network was captured using a confocal microscope (Figure 5). It is also observed that even though the volume of microcapsules changed suddenly, with a gradual change in temperature, the encapsulated nanoparticles remained inside (Figure 5B).
In addition to those interesting findings, a practical application was developed where the TCGS microcapsule platform was used as a thermo controlled glucose sensor. For a detailed insight into this section of the study, please refer to the original research paper on Hyejeong Kim et al.
In this work, a one-step synthesis of stimuli-responsive microcapsules with temperature-responsive core-gap-shell structures for versatile design was introduced. Microfluidics approach was chosen to perform this work because it is a straight-forward and low risk technique. The core-gap-shell structure could be obtained with the help of a double emulsion template, which in turn reduced the risk of instability in high-order emulsions. In addition, this new generation approach might allow larger scale microcapsules production due to the removal of the surface treatment step in the preparation procedure.
Although, it is important to control the microchannel geometry, wettability, and as importantly, flow rates. The microcapsule design variability was tuned by individually controlling the water adsorption of the inner core and outer shells.
In addition, based on free-radical polymerization with pH-responsive itaconic acid, the inner core and outer shell of the microcapsules could be specifically designed with stimuli-responsive materials.
These exciting results were achieved with the help of precise pressure-driven flow controlled microfluidics.
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