Microinterfaces in bicontinuous hydrogels guide rapid 3D cell migration

Abstract

Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or may instead utilize existing ECM microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3D migration, few have recapitulated these natural migration paths. Here, we developed a biopolymer-based (i.e., gelatin and hyaluronic acid) bicontinuous hydrogel system formed through controlled solution immiscibility whose continuous subdomains and high micro-interfacial surface area enabled rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior was mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which was shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a new design that leverages important local interfaces to guide rapid cell migration.

Injectable MSC Spheroid and Microgel Granular Composites for Engineering Tissue

“…[27,30,33] Additionally, granular hydro-gels have been extensively used as in vitro platforms to investigate biological processes (e.g., angiogenesis, cellular outgrowth, cell condensation) with the incorporation of individual spheroids or cellular suspensions within the pores. [34][35][36][37] Here, we combine the positive attributes of spheroids and granular hydrogels to engineer tissues through the formation of granular composites (Figure 1a). Specifically, spheroids are mixed with microgels to form granular composites that i) are injectable for delivery to molds or defects, ii) introduce cell-cell contacts and spheroid fusion that are conducive to tissue formation, and iii) undergo interparticle crosslinking via light to immediately stabilize constructs.…”