Hydrogels have been widely used for therapeutic delivery applications due to their tunability and biocompatibility, although delivery of small molecules is difficult due to high burst release and rapid diffusion from the device. Nanosilicate clays (nanoclays) have shown the adsorption potential of small molecules, offering a lever to prolong the release kinetics of hydrogel delivery devices. However, further characterization of small molecule–nanoclay interactions and their effect on molecule release is needed to allow for the custom design of tunable nanocomposite hydrogel delivery devices. Here, we have characterized the adsorption of small molecules onto three nanoclays, Laponite, montmorillonite, and halloysite, and monitored their release in various conditions. The layered structures of Laponite and montmorillonite led to cationic exchange of the small molecules into the interlayer space, whereas the small molecules were adsorbed onto the surface of the tubular halloysite. The addition of nanoclays to polyethylene glycol (PEG) hydrogels significantly slowed the release of small molecules, especially from Laponite (500-fold decrease) and montmorillonite (∼3000-fold decrease) composite gels. Cationic small molecules were shown to be released significantly slower from nanocomposite hydrogels than anionic ones. The incubation time of small molecules with nanoclays prior to hydrogel encapsulation also played a key role in determining their release rate, with montmorillonite showing near-immediate adsorption while halloysite exhibited a higher dependence on incubation time due to slower adsorption kinetics. Release buffer salt concentration and pH were shown to affect release kinetics due to modulation of nanoclay–small molecule interactions. These results show the potential for formation of a highly tunable nanocomposite hydrogel delivery device for a greatly prolonged release of small molecules compared to traditional hydrogels.

Introduction: Hydrogel microspheres are an attractive option for drug delivery applications due to their ease of injection and potential for tunable controlled delivery. However, their utility is limited due to high initial burst release and rapid overall release, which is especially pronounced for small molecules or small size microspheres. We and others have shown that the addition of two-dimensional nanosilicate (NS) particles to hydrogels can significantly prolong release kinetics from hydrogels while minimizing burst release.Materials and Methods: Here we explored whether NS could modulate release kinetics of small molecules from small size injectable microspheres. Polyethylene glycol (PEG)-based hydrogel microspheres were fabricated via polymer/salt aqueous two-phase separation (ATPS), which is facile, high yield, and scalable, without the need for organic solvents or oils.Results and Discussion: Importantly, NS and acridine orange (AO), a model cationic small molecule, were shown to phase separate into the PEG-rich phase, allowing for successful encapsulation within hydrogel microspheres. The fabricated microspheres were stable, similar in size to red blood cells, and easily injectable. The effect of various fabrication parameters, including the addition of NS and AO, on microsphere size and polydispersity were explored. Release of AO was significantly slowed from PEG-NS microspheres compared to PEG-only microspheres and correlated with NS concentration. Two additional small molecules, the chemotherapeutic doxorubicin (positive charge), and the model small molecule Brilliant Blue FCF (negative charge), were shown to exhibit prolonged release, underscoring the broad utility of the system. The dependence of release kinetics on encapsulated NS concentration allows for tunable and prolonged release of small molecules from an injectable hydrogel delivery device.

The objective of this study was to fabricate and characterize monodisperse polyethylene glycol (PEG)‐based barium sulfate hydrogel microspheres for applications in prostatic hyperplasia and prostate cancer treatments. Currently, catheter embolization procedures used in prostatic hyperplasia treatments employ non‐opaque microspheres with a tracer dye, which can result in off‐target embolization. The goal of this study was to fabricate monodisperse, radiopaque microspheres that can be easily tracked via microcomputed tomography (microCT) during embolization procedures. The hydrogel microspheres were fabricated using 4‐arm PEG‐Acrylate macromer and PEG‐dithiol crosslinker solutions in a custom‐designed microfluidic chip that allowed for on‐chip mixing and gelation of a timed‐gelation system, greatly improving bead fabrication throughput and reproducibility. Microspheres were loaded with 1 μm barium sulfate particles and bovine serum albumin to aid in barium suspension. Microspheres were imaged both before and after washing with buffer using an inverted microscope to measure microsphere diameter and degradation. Settling of barium sulfate solutions was measured qualitatively in microcentrifuge tubes. Monodisperse, barium sulfate loaded‐hydrogel microspheres were produced, the size of which could be controlled by modulating the inlet flow rates of the dispersed and continuous phases. Furthermore, the results show that the opacity of the barium sulfate microspheres increased with increased barium sulfate concentration. In conclusion, the results indicate that this study successfully fabricated monodisperse and opaque barium sulfate PEG‐based hydrogel microspheres. Future experiments will evaluate the radiopacity under microCT, swelling and degradation properties, and injectability of the hydrogel microspheres to help further confirm the application of these microspheres in catheter embolization procedures.

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