A Balance Between Inter- and Intra- Microgel Mechanics Governs Stem Cell Viability in Injectable Dynamic Granular Hydrogels.

Injectable hydrogels are increasingly explored for the delivery of cells to tissue. These materials exhibit both liquid-like properties, protecting cells from mechanical stress during injection, and solid-like properties, providing a stable 3D engraftment niche. Many strategies for modulating injectable hydrogels tune liquid- and solid-like material properties simultaneously, such that formulation changes designed to improve injectability can reduce stability at the delivery site. The ability to independently tune liquid- and solid-like properties would greatly facilitate formulation development. Here we demonstrate such a strategy in which cells are ensconced in the pores between microscopic granular hyaluronic acid (HA) hydrogels (microgels), where we tune elasticity with static covalent intra-microgel crosslinks and flowability with mechanosensitive adamantane-cyclodextrin (AC) inter-microgel crosslinks. Using the same AC-free microgels as a 3D printing support bath, we preserve the location of each cell as it exits the needle, allowing us to identify the mechanism driving mechanical trauma-induced cell death. We vary microgel AC concentration to find the threshold from microgel yielding- to AC interaction- dominated injectability and exploit this threshold to fabricate a microgel with better injection-protecting performance. Our delivery strategy, and the balance between intra- and inter-microgel properties it reveals, may facilitate the development of new cell injection formulations. This article is protected by copyright. All rights reserved.