The Space Within: How Architected Voids Promote Tissue Formation

Physiological void spaces exist at every scale of the human body, from organs to molecules, facilitating transport, signal propagation, and localized biochemical activity. Constriction of these spaces (e.g., arterial occlusion, fibrosis) highlights their importance, making their mimicry essential in tissue engineering (TE). This review examines four key strategies for introducing porosity into hydrogels across multiple length scales: templating, microgels, phase separation, and 3D printing. The first three methods enable the engineering of physiological environments at the nano- to micro-scale, mimicking tissue- and extracellular matrix (ECM)-level spaces. Templating involves embedding and removal of gas, liquid, or solid phases, leaving behind pores. Microgel annealing generates inherent interstitial voids. Liquid-liquid phase separation (LLPS) creates biphasic networks reminiscent of native ECM. The fourth approach, extrusion- and light-based 3D printing techniques, enables the fabrication of larger-scale spaces, such as luminal structures (e.g., vasculature, airways, and ducts). Combining these methods enables the creation of hierarchical architectures from the nano- to centimeter scale. The review also highlights Filamented Light (FLight) technology, which creates internal microstructural voids relevant to anisotropic tissues. This review offers insights into current methods and their convergence for generating biomimetic void spaces to meet the physiological demands of cells, tissues, and organs.