"Out-of-the-box" Granular Gel Bath Based on Cationic Polyvinyl Alcohol Microgels for Embedded Extrusion Printing.

Embedded extrusion printing provides a versatile platform for fabricating complex hydrogel-based biological structures with living cells. However, the time-consuming process and rigorous storage conditions of current support baths hinder their commercial application. This work reports a novel "out-of-the-box" granular support bath based on chemically crosslinked cationic polyvinyl alcohol (PVA) microgels, which is ready to use by simply dispersing the lyophilized bath in water. Notably, with ionic modification, PVA microgels yield reduced particle size, uniform distribution, and appropriate rheological properties, contributing to high-resolution printing. Following by the lyophilization and re-dispersion process, ion-modified PVA baths recover to its original state, with unchanged particle size, rheological properties, and printing resolution, demonstrating its stability and recoverability. Lyophilization facilitates the long-term storage and delivery of granular gel baths, and enables the application of "out-of-the-box" support materials, which will greatly simplify experimental procedures, avoid labor-intensive and time-consuming operations, thus accelerating the broad commercial development of embedded bioprinting.

Drug Incorporation into Polymer Filament Using Simple Soaking Method for Tablet Preparation Using Fused Deposition Modeling.

The use of three-dimensional (3D) printing technology is expanding in various fields. The application of 3D printing is expected to increase in the pharmaceutical industry after 3D-printed tablets were approved by the U.S. Food and Drug Administration (FDA). Fused deposition modeling (FDM), a type of 3D printing, has been extensively studied for the manufacturing of tablets. A drug-loaded polymer filament, the ink of FDM 3D printers, can be prepared using the hot melt extrusion method or a simple drug-soaking method. In the present study, we investigate the influence of the experimental conditions on the loading of curcumin (model drug with fluorescence) into a polyvinylalcohol polymer filament using the soaking method. We show that organic solvent type (isopropanol, methanol, acetone, and ethanol), temperature (25 and 80°C), and drug concentration (2-333 mg/mL) greatly affect drug loading. Around 5% curcumin can be incorporated into the polyvinylalcohol filament using the soaking method. The drug dissolution from 3D-printed tablets depends on the drug content in the polymer filament. The incorporation of a higher amount of curcumin, which has poor water solubility, greatly delays drug dissolution. These results provide useful information on the preparation of 3D-printed tablets using a drug-loaded polymer filament obtained with the soaking method.

Comparative analysis of the residues of granular support bath materials on printed structures in embedded extrusion printing.

Embedded extrusion printing facilitates the fabrication of complex biological structures using soft hydrogels that are challenging to construct using conventional manufacturing methods. While this targeting strategy is appealing, the residues of support materials on the printed objects have been overlooked. Here, we quantitatively compare the bath residues on fibrin gel fibers printed in granular gel baths that are conjugated with fluorescent probes for visualization, including physically crosslinked gellan gum (GG) and gelatin (GEL) baths and chemically crosslinked polyvinyl alcohol baths. Notably, all support materials can be detected on a microscopic scale, even on structures without any visible residues. Quantitative results indicate that baths with smaller size or lower shear viscosity show more and deeper diffusion into the extruded inks, and the removal efficiency of support materials depends mainly on the dissolving property of the granular gel baths. The residual amount of chemically cross-linked support materials on fibrin gel fibers is 28-70µg mm-2, which is tens of times higher than physically cross-linked GG (7.5µg mm-2) and GEL (0.3µg mm-2) baths. Meanwhile, cross-sectional images suggest that most gel particles are distributed around the fiber surface, but a small amount is in the fiber center. Such bath residues or the blank pores created by the removal of gel particles induce changes in product surface morphology, physicochemical and mechanical properties, impeding cell adhesion. This study will draw attention to the effects of residual support materials on printed structures and encourage the development of new strategies to diminish these residues or to take advantage of the residual support baths to improve product performances.

Application of 3D printing technology for generating hollow-type suppository shells.

The application of 3D printing technology for generating tablets is attracting the attention of the pharmaceutical industry following approval of a 3D printed tablet (Spritam) by the US Food and Drug Administration. Here we focused on hollow-type suppository formulations typically prepared as suppository shells by pharmacists in hospitals. We used a fused deposition modeling-type 3D printer and polyvinyl alcohol filament as a water soluble material to print suppository shells with various thicknesses and different inner structures by changing the printing conditions for the 3D designed objects. The hardness of the suppository shell was dependent on the thickness and designed inner structure. An active pharmaceutical ingredient ionic liquid, a novel type of liquid drug formulation, was loaded in the suppository shells. The drug dissolution profile of the suppository formulations differed depending on the type of suppository shell. Composite suppository formulations (two drugs in separate compartments in the suppository shell) were prepared as a model tailored medicine for pediatric patients. Our findings suggest that 3D printing technology is applicable to the preparation of hollow-type suppository formulations and may be compatible with on-site hospital production.

3D printing of unique water-soluble polymer-based suppository shell for controlled drug release.

3D printing technology holds promise for application to personalized pharmaceuticals. Mold fabrication is a common technique in industrial 3D printing to produce objects with complex structures and could be used in new applications in pharmaceutical production. The aim of the current study is the fabrication of unique suppository shell molds composed of a water-soluble polymer (polyvinylalcohol) using a fused deposition modeling-type 3D printer so that hospital pharmacists can prepare tailored suppository formulations containing progesterone (a model drug for vaginal suppository formulations) in future clinical settings. Suppository formulations with holes in the shells were prepared. The drug release profiles related well to the positions of the holes (upper, middle, lower), the number of holes (0-2 holes), and the diameters of the holes (0-5 mm) in the suppositories. Matryoshka-type suppository formulations composed of 3D-printed multilayered shells were then prepared. The drug release profiles showed pulsed release, and the volumes of the inner/outer spaces in the suppository shells (1/1, 1/3) and the drug concentration (3/1, 1/1) were reflected in the observed drug release profiles. Our study indicates that a 3D printer can produce not only unique and complex suppository formulations, but also provides flexibility and expands possible applications for the development of tailored medicine.

Defined drug release from 3D-printed composite tablets consisting of drug-loaded polyvinylalcohol and a water-soluble or water-insoluble polymer filler.

3D-printed tablets are a promising new approach for personalized medicine. In this study, we fabricated composite tablets consisting of two components, a drug and a filler, by using a fused deposition modeling-type 3D printer. Polyvinylalcohol (PVA) polymer containing calcein (a model drug) was used as the drug component and PVA or polylactic acid (PLA) polymer without drug was used as the water-soluble or water-insoluble filler, respectively. Various kinds of drug-PVA/PVA and drug-PVA/PLA composite tablets were designed, and the 3D-printed tablets exhibited good formability. The surface area of the exposed drug component is highly correlated with the initial drug release rate. Composite tablets with an exposed top and a bottom covered with a PLA layer were fabricated. These tablets showed zero-order drug release by maintaining the surface area of the exposed drug component during drug dissolution. In contrast, the drug release profile varied for tablets whose exposed surface area changed. Composite tablets with different drug release lag times were prepared by changing the thickness of the PVA filler coating the drug component. These results which used PVA and PLA filler will provide useful information for preparing the tablets with multi-components and tailor-made tablets with defined drug release profiles using 3D printers.