Biological tissues hinge on blood perfusion and mechanical toughness to function. Injectable hydrogels that possess both high permeability and toughness have profound impacts on regenerative medicine but remain a long‐standing challenge. To address this issue, injectable, pore‐forming double‐network hydrogels are fabricated by orchestrating stepwise gelation and phase separation processes. The interconnected pores of the resulting hydrogels enable direct medium perfusion through organ‐sized matrices. The hydrogels are amenable to cell encapsulation and delivery while promoting cell proliferation and spreading. They are also pore insensitive, tough, and fatigue resistant. When tested in biomimetic perfusion bioreactors, the hydrogels maintain physical integrity under prolonged, high‐frequency biomechanical stimulations (>6000 000 cycles at 120 Hz). The excellent biomechanical performance suggests the great potential of the new injectable hydrogel technology for repairing mechanically dynamic tissues, such as vocal folds, and other applications, such as tissue engineering, biofabrication, organs‐on‐chips, drug delivery, and disease modeling.

Scars composed of fibrous connective tissues are natural consequences of injury upon incisional wound healing in soft tissues.  Hydrogels that feature a sustained presentation of immunomodulatory cytokines are known to modulate wound healing. However, existing immunomodulatory hydrogels lack interconnected micropores to promote cell ingrowth. Other limitations include invasive delivery procedures and harsh synthesis conditions that are incompatible with drug molecules. Here, hybrid nanocomposite microgels containing interleukin‐10 (IL‐10) are reported to modulate tissue macrophage phenotype during wound healing. The intercalation of laponite nanoparticles in the polymer network yields microgels with tissue‐mimetic elasticity (Young's modulus in the range of 2–6 kPa) and allows the sustained release of IL‐10 to promote the differentiation of macrophages toward proregenerative phenotypes. The porous interstitial spaces between microgels promote fibroblast proliferation and fast trafficking (an average speed of ≈14.4 µm h−1). The incorporation of hyaluronic acid further enhances macrophage infiltration. The coculture of macrophages and fibroblasts treated with transforming growth factor‐beta 1 resulted in a twofold reduction in collagen‐I production for microgels releasing IL‐10 compared to the IL‐10 free group. The new microgels show potential toward regenerative healing by harnessing the antifibrotic behavior of host macrophages.