A 3D in vitro model for studying human implantation and implantation failure.

Abstract

A better understanding of human implantation is essential for improving assisted reproduction outcomes and addressing recurrent implantation failure (RIF). However, ethical constraints and limited access to human embryos make direct studies challenging. To overcome this, we developed a 3D in-chip implantation model using human blastoids or blastocysts co-cultured with a bioengineered human endometrial tissue, termed endometrioid. This system successfully recapitulates key events of human implantation and early post-implantation development. Importantly, when modeling implantation using samples derived from RIF patients, we observed significantly reduced blastoid implantation capability compared with endometrioids from fertile controls. Furthermore, a targeted screen of U.S. Food and Drug Administration (FDA)-approved compounds identified candidates that markedly enhanced implantation efficiency in RIF-derived endometrioids. Together, this 3D platform enables mechanistic investigation of human implantation and implantation failure and offers a scalable approach to evaluate therapeutic strategies for improving embryo-endometrium interaction in a clinical setting.