Engineering a GelMA Hydrogel-Based Biomimetic Endometrium-on-a-Chip for Studying Embryo Implantation

Abstract Recurrent implantation failure is a critical bottleneck that limits the clinical success rates of assisted reproductive technologies. Existing in vitro implantation models often struggle to balance the conflicting needs of "fluid supply" and "embryo protection": static models lack necessary hydrodynamic stimulation, whereas traditional microfluidic perfusion frequently causes blastocyst damage due to excessive shear stress. Furthermore, most existing scaffold materials fail to mimic the critical dynamic mechanical remodeling of the endometrium during the implantation window. To overcome these limitations, this study constructed a biomimetic endometrium-on-a-chip based on methacryloyl gelatin (GelMA) hydrogels and micropillar arrays, aiming to reconstruct an implantation mechanical microenvironment that closely mimics in vivo conditions. In terms of engineering design, we optimized the micropillar array structure via COMSOL Multiphysics simulation to achieve spatial decoupling of shear stress. This design created a "mechanical sanctuary" for the embryo with shear stress lower than 0.3 dyn/cm2, effectively preventing fluid shear-induced damage while ensuring dynamic nutrient exchange. Regarding the material strategy, this study revealed the concentration-dependent degradation kinetics of GelMA hydrogels. Leveraging their "fast-then-slow" degradation behavior, we recapitulated the mechanical transition of the endometrium, aligning our matrix's softening profile with the physiological shift toward the receptive state characteristic of the implantation window. Biological experiments demonstrated that the GelMA-based hydrogel significantly enhanced the adhesion and zona hatching rates of mouse blastocysts compared to traditional static cultures. Furthermore, by integrating this biomimetic scaffold into a dynamically perfused microfluidic platform, we successfully established a robust in vitro model of mouse embryo implantation.