Toward Implantation-Assisting Technologies: Lessons From In Vivo and Ex Vivo Models.

Background: Despite advances in assisted reproductive technology (ART), embryo implantation remains inefficient and represents a major barrier to successful pregnancy. Recurrent implantation failure persists even after transfer of high-quality embryos, reflecting an incomplete understanding of the molecular mechanisms governing implantation. Methods: This review synthesizes current knowledge from genetically modified mouse models and an ex vivo system using authentic uterine tissue. Implantation is organized as a hierarchical, multistep process comprising acquisition of uterine receptivity, embryo attachment, and trophoblast invasion. Main Findings: Uterine receptivity is acquired through the action of progesterone signaling. Embryo attachment requires FOXA2-mediated uterine gland maturation and activation of the LIF-STAT3 signaling axis. Subsequent invasion is driven by coordinated epithelial clearance, stromal differentiation, and embryonic activation. Disruption of these stage-specific mechanisms leads to implantation failure. To overcome experimental limitations inherent to in vivo models, an ex vivo uterine system has been developed that preserves native tissue architecture and enables direct manipulation of embryo-uterine interactions. Conclusion: Conceptualizing implantation as a hierarchical process reveals discrete regulatory checkpoints and identifies implantation as a biologically tractable target. Integration of mechanistic insights with ex vivo platforms supports the development of implantation-assisting technologies based on transient, trophectoderm-targeted interventions in next-generation reproductive medicine.