Toward system-level integration of organoids for regenerative medicine

Abstract Regenerating complex human tissues requires proper cellular assembly and the recapitulation of coordinated functions across multiple biological levels. Organoids, as self-organized three-dimensional cellular structures, provide powerful models for rebuilding organ architecture and studying developmental processes. However, their regenerative potential remains limited by the lack of vascular, neural, and immune integration, which are essential for tissue development, homeostasis, and repair. Recent studies indicate that the progression from tissue-level organization to organ-level coordination and ultimately to system-level functionality depends on dynamic intercellular communication, feedback signaling, and niche interactions. The integration of biochemical, biomechanical, and bioelectrical cues enables multicellular systems to achieve synchronized growth, patterning, and functional adaptation. Complementary bioengineering strategies further guide these intrinsic processes by modulating spatial organization, microenvironmental signals, and intercellular connectivity. This review summarizes emerging methodologies and molecular mechanisms underlying system-level integration in organoids and discusses how these biological processes may bridge the gap between in vitro morphogenesis and in vivo functional regeneration.