Ethanol-free Cross-Linking of Alginate Nanofibers Enables Controlled Release into a Simulated Gastrointestinal Tract Model.

The use of alginate nanofibers in certain biomedical applications, including targeted delivery to the gut, is limited because an ethanol-free, biocompatible cross-linking method has not been demonstrated. Here, we developed water-stable, alginate-based nanofibers by systematically exploring post-electrospinning cross-linking approaches that used calcium ions dissolved in (1) a glycerol/water cosolvent system and (2) acidic, neutral, or basic aqueous solutions. Scanning electron microscopy proved that the fibers cross-linked in a glycerol cosolvent or pH-optimized solutions had maintained the same morphology as the ethanol-based literature control. Notably, cross-linked fibers were generally smaller in diameter than the as-spun fibers due to both chemical interactions and mass loss during cross-linking, which was supported by mass measurements, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. During stability tests wherein the cross-linked fibers were exposed to three aqueous solutions, the cross-linked fibers were stable in water and acid buffer yet swelled in phosphate buffer saline, making them useful scaffolds for pH-controlled release applications. Proof-of-concept release experiments were conducted using a simulated gastrointestinal tract model. As desired, the cargo remained encapsulated within the cross-linked nanofibers when exposed to an acidic solution that modeled the stomach. Upon exposure to a solution that mimicked the intestines, the cargo was released. We suggest that these cross-linked, alginate-based nanofiber mats hold the potential to be broadly used in biomedical and environmental applications.