Granular aerogel scaffolds with engineered pore microarchitecture for rapid cell infiltration, tissue integration, and vascularization.

Porous biomaterials that integrate tunable biophysical and biochemical cues have been extensively studied for guiding cell behavior and harnessing the body's intrinsic regenerative potential. Aerogels, characterized by their ultralight structure, high porosity, and large surface area, have emerged as promising porous scaffolds for tissue engineering; however, their limited pore tunability may hinder efficient cell infiltration and functional tissue integration. To address this persistent limitation, we develop a new class of porous biomaterials called granular aerogel scaffolds (GAS), assembled from size-tunable gelatin methacryloyl (GelMA) microparticles, enabling the precise control of pore geometry and interconnected micron-scale void networks within the aerogels. GelMA hydrogel microparticles are jammed and photocrosslinked to yield granular hydrogel scaffolds (GHS), followed by supercritical carbon dioxide drying, yielding GAS with tunable pore microarchitecture and preserved structural integrity. Importantly, rehydrated GAS have comparable mechanical, rheological, and pore characteristics to GHS. In vitro analyses and in vivo subcutaneous implantation show that GAS are non-toxic and support progressively greater cell infiltration as the size of their microparticle building blocks increases. Further in vivo analyses using a hindlimb micropuncture surgery model show an increase in scaffold vascularization and vessel maturation with an increase in microparticle size. This work establishes a platform for engineering aerogels with precisely tuned cell-scale interconnected pores, enabling rapid cell infiltration, tissue integration, and vascularization. GAS may serve as versatile, shelf-ready biomaterials for tissue engineering and regenerative medicine.