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

Abstract

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.

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