Female reproductive tract-on-a-chip for selecting sperm with ultra-low DNA fragmentation index

High levels of sperm DNA fragmentation index (DFI) represent a critical factor in male infertility, with detrimental effects on embryonic development and offspring well-being. However, selecting sperm with low DFI remains a tremendous challenge. Here, we present an organ-level selection strategy capable of isolating spermatozoa with ultra-low DFI, achieving a remarkable reduction to 0.13% compared to 34.57% observed in raw semen. We design and fabricate a female reproductive tract (FRT)-on-a-chip (FRToC) device that mimics the entire physiological microenvironment for in vivo sperm selection, with clinical validation performed using samples from patients. The FRToC selects sperm with ultra-low DFI (mean: 0.71%) from patients with high DFI (mean: 41.93%), while also ensuring superior sperm motility and acrosome integrity. Additionally, trace sperm proteomic and single-cell copy number variants (CNV) analyses revealed that sperm sorted by FRToC exhibited an increased capacity to mitigate oxidative stress, thus resulting in more intact chromosomes. Our organ-scale selection method underscores the potential of the FRToC to select high-quality spermatozoa, offering a promising improvement for assisted reproductive technology (ART).