Dynamic Regulation of Granular Hydrogels Through Guest-Host Interactions to Spatiotemporally Guide Cellular Migration

Cell migration plays a crucial role in the dynamic processes that guide tissue development, regeneration, and repair; yet, developing cell culture platforms that allow control over cell migration in 3D space and time remains a challenge. Here, a strategy is presented using chemically-responsive granular hydrogels to enable dynamic control over 3D cell migration. Dynamic microgels are fabricated via hyaluronic acid crosslinked via reversible guest-host interactions between adamantane (guest) and β-cyclodextrin (host), which swell in the presence of a cytocompatible competitive guest molecule (adamantane carboxylic acid, Ad-COOH) and de-swell when Ad-COOH is removed. When formed into granular hydrogels, the addition of Ad-COOH results in a dynamic porous material with reduced microgel stiffness and increased pore size. Ad-COOH addition also results in the reduction of mesenchymal stromal cell (MSC) migration from embedded aggregates (spheroids); however, MSC migration returns when Ad-COOH is removed. Furthermore, suspension bioprinting of jammed spheroids into dynamic granular hydrogels results in 4D printed constructs with patterned cellular regions (e.g., lines, zigzags, spirals) where cellular egress is controlled over time through the presence of Ad-COOH to create distinct spatiotemporal cellular patterns. This platform offers precise, on-demand modulation of cell migration, enabling new opportunities to fabricate dynamic, complex engineered tissues.