Reconciling Granular Hydrogel Microstructure and Mechanics via a Temporary Thermo-Responsive and Cell-Invadable...

Granular hydrogels are biomaterials composed of densely packed microparticles forming microporous structures. Their architecture can be controlled by tuning microparticle size, shape, and packing density. However, the mechanical properties of granular hydrogels mainly depend on interparticle interactions, whereby increasing the separation distance between microparticles to improve void volume weakens overall mechanical properties and induces unjamming, severely limiting their design and applicability. This study develops Thermo-Responsive Granular Hydrogels (TRGHs) with adjustable interparticle spacing and preserved mechanical integrity through incorporating a temporary thermo-responsive and cell-invadable interstitial matrix. It is shown that the interstitial space can be increased by more than 150% and the storage modulus can be increased by 4 orders of magnitude from 5 to 8900 Pa and maintained at this level by first processing at 5°C and then increasing the temperature to 37°C. Crucially, TRGHs show improved extrudability and structural integrity after 3D printing, support enhanced in vitro cell migration from embedded spheroids, and permit uninhibited in vivo cell and vessel invasion after subcutaneous injection. By addressing the trade-off between interparticle space and mechanical properties, these advanced biomaterials broaden the design possibilities for granular hydrogels in biofabrication, in vitro disease modeling, and tissue repair.