Microbubble-Infused Hydrogel Scaffolds With Tunable Porosity for Regenerative-Medicine Applications.

Abstract

Tissue-engineering scaffolds require interconnected porous networks to support cell infiltration, nutrient diffusion, and waste removal. Conventional methods to introduce porosity-such as particulate leaching, gas foaming, and freeze-drying-can leave cytotoxic residues. We propose a scalable, cytocompatible approach to tune hydrogel porosity using lipid-shelled gas microbubbles as a transient porogen. In this study, we demonstrate that lipid-shelled microbubbles can be incorporated into alginate, poly(ethylene glycol) diacrylate (PEGDA), or gelatin methacrylate (GelMA) precursors, and subsequently expanded post-gelation with mild heat or vacuum to yield controlled porosity. In alginate fibers, the vacuum expansion of embedded microbubbles increased the swelling capacity by approximately 74% relative to nonporous control, without reducing compressive strength. Porous PEGDA hydrogels showed faster degradation (approximately 40% reduction in degradation time) and a lower compressive modulus compared to the dense PEGDA control, reflecting a tunable trade-off between porosity and stiffness. Unlike traditional porogen-based or 3D-printing techniques, this microbubble method requires no toxic additives or specialized equipment and is compatible with both ionic (alginate) and photo-crosslinked (PEGDA, GelMA) systems. We further demonstrate integration of this approach with a microfluidic fiber production platform. We validate that porosity modulation via microbubbles does not adversely affect the viability of mesenchymal stem cells on GelMA hydrogels. Overall, this work establishes a broadly applicable and easily scaled strategy in which porosity can be tuned post-gelation with simple triggers (heat or vacuum), enabling application-specific control of nutrient transport, degradation, and mechanics across multiple biomaterials.