Hyaluronan is a naturally occurring organic polymer that is also a major component of the extracellular matrix of the oocyte-cumulus complex. During the natural fertilization process human oocytes are surrounded by hyaluronan, which is acting as a ‘‘physiologic selector’’ of spermatozoa.²

Only fully mature spermatozoa can bind to hyaluronan, as hyaluronan receptors appear on the plasma membrane during late spermiogenesis after the maturation-related plasma membrane remodeling.⁴ This is accompanied by the loss of the residual body via cytoplasmic extrusion, DNA repackaging from histones to protamines and zona pellucida-binding site formation.⁴ It was demonstrated that the ability of spermatozoa to bind to hyaluronan is correlated with sperm maturity, increased chromatin integrity, decreased chances of aneuploidy, lower sperm DNA fragmentation and better sperm DNA packaging⁶.

Indeed, immature spermatozoa that fail to undergo membrane remodeling have no receptors to hyaluronan and the zona-pellucida. They also demonstrate presence of residual cytoplasm, persistent histones, increased risk of chromosomal aneuploidies and DNA fragmentation.^5,6 Immature spermatozoa are unable to bind to hyaluronan and the zona pellucida and therefore would be excluded from the natural fertilization process.

During standard ICSI, all natural selection mechanisms are bypassed, and spermatozoa are selected based on their morphology and motility only.

Selection of spermatozoa, capable to bind to hyaluronan for ICSI mimics the natural sperm selection process and is therefore often called “physiologic ICSI.” It was demonstrated, that sperm selection with hyaluronic acid improves live birth outcomes among older couples and is connected to sperm DNA quality, potentially affecting all treatment outcomes⁷.