Microengineered Patient-derived Endometrium-on-a-Chip for the Evaluation of Endometrial Receptivity and Personalized Translational Medicine

Endometrial receptivity plays a pivotal role in determining the success of embryo implantation and supports early pregnancy development, playing a central role in species propagation. However, current methods for assessing endometrial receptivity lack robust evidence-based validation, and reliable technique for accurately evaluating this process in patients with infertility are lacking. In this study, we introduced a novel patient-derived vascularised endometrium-on-a-chip (EoC) model, comprising three distinct layers, namely the epithelium, stroma, and blood vessels. This EoC was cross-species validated using both mouse and human samples, successfully replicating the dynamic microenvironment and mimicking both temporal and spatial features of the endometrial tissue. Using our EoC, we developed a clinically relevant endometrial receptivity scoring system, ERS², based on the molecular expression profiles of crucial endometrial receptivity markers and the morphological analyses of endometrial angiogenesis. The ERS² enables the personalised analysis of endometrial health and the potential for embryo implantation, addressing the individual variations in endometrial biology that may not be captured by traditional diagnostic methods. By leveraging our EoC, the ERS² replicate the physiological characteristics of the endometrium and provided personalised, patient-specific analyses. While larger-scale validation is required before clinical implementation, this highlights its significant potential for identifying therapeutic candidates tailored to individual patient, advancing the prospects for personalised reproductive care. Furthermore, progressive improvements in the patient’s endometrial microenvironment were observed following platelet-rich-plasma treatments, and the optimal timing for embryo transfer was identified in patients with unexplained repeated implantation failure using the EoC-ERS². This highlights the practical utility of our model not only for assessing individual receptivity but also for evaluating the personalised efficiency of interventions aimed at improving implantation outcomes. This study represents the first use of a microengineered EoC model and its scoring system to assess endometrial receptivity and predict successful pregnancy outcomes, offering new insights into personalised infertility treatments and advancing the potential of targeted therapies in reproductive medicine. This study included endometrial RNA samples derived from two normal women and three women with recurrent implantation failure (RIF). In parallel, patient-derived stromal and epithelial cells were used to construct an EoC model, from which RNA was also extracted. For vascular compartment construction within the chip, human umbilical vein endothelial cells (HUVECs) were incorporated.