Non-Equilibrium Hydrogel Demonstrates Cytocompatible and Seamless Heterotrophic Self-Growth

The growth of living organisms is achieved through the autonomous integration of external nutrients as building blocks under mild physiological conditions. Inspired by this biological property, researchers have developed self-growing materials based on the chemical polymerization of reactive monomers. However, the limited cytocompatibility of covalent bonding-driven self-growing materials hinders their biomedical applications. Herein, a non-equilibrium self-growing hydrogel driven is reported by cytocompatible ligand–ion coordination between calcium ion (Ca²⁺) and bisphosphonate-modified pectin (PT-BP). Multiform self-growth of the seed PT-BP-Ca²⁺ hydrogel occurs autonomously in a heterotrophic manner by seamlessly integrating supplied soluble PT-BP polymer as integral structures via the crosslinking mediated by Ca²⁺ diffusion. This self-growth enables diverse cytocompatible post-gelation modifications of hydrogels, including complex surface patterning and segmental growth-induced cold welding. Unlike the gap-interfered interfaces of self-healed hydrogels, the monolithic and continuous structures of self-growing PT-BP-Ca²⁺ hydrogels better support the migration and interactions of cells encapsulated in the seed hydrogel and newly grown regions. In vivo self-growth of cancer cell-seeded hydrogel in an animal model enhances macrophage infiltration, a key pathogenic feature during cancer progression. This work demonstrates a simple and cytocompatible strategy to fabricate bio-inspired heterotrophic self-growing materials for diverse biomedical applications.