Improving sperm selection strategies for assisted reproduction through closing the knowledge gap in sperm maturation mechanics.

Background: Male factors contribute to ∼50% of all infertility cases globally and are a major contributor to escalating use of ART. In most instances, sub-fertile men retain the ability to produce spermatozoa, albeit with reduced quality and function. By necessity, an important feature of ART is the use of technologies that bypass the natural selection barriers that prevent poor-quality spermatozoa from participating in fertilization. This means that ART carries a significant risk of facilitating fertilization with poor-quality gametes harbouring undetected DNA damage and/or altered epigenomes. Such a scenario may account for the epidemiological links between the use of 'high intervention' technologies [e.g. ICSI] and an increased risk of adverse offspring outcomes. Such data highlight a pressing need for improved sperm selection tools that better mimic natural selection barriers, to ensure only the highest-quality spermatozoa are used for ART.

Objective And Rationale: Current sperm selection techniques for ART and the processes underpinning sperm maturation have often been considered independently and therefore reviewed separately. Here we outline the requirement for connecting research paradigms towards advancing clinical outcomes. This review highlights the importance of combining our advancing knowledge of sperm maturation biology with the pursuit of rational sperm selection strategies for the clinic; specifically, this narrative review summarizes the current clinical technologies used for sperm selection with a focus on their physiological relevance and limitations. We have given consideration to the events associated with sperm maturation and the importance of zona pellucida (ZP) binding as inspiration to inform the development of the next generation of sperm selection strategies. The connections and information presented should provide utility and interest for both clinicians and reproductive biologists alike.

Search Methods: The PubMed database was queried using the keywords: sperm selection/function/DNA quality/epigenome, ART, ICSI, male infertility, capacitation, zona pellucida, sperm-zona pellucida binding, DNA damage, and biofabrication. These keywords were combined with other relevant phrases. Literature was restricted to peer-reviewed articles in English (published between 1972 and 2024) with references within these articles also searched.

Outcomes: During natural conception, high-quality sperm are 'selected', maximizing the chances of fertilization with healthy gametes carrying intact genomic/epigenetic cargo. This sub-population of spermatozoa possess the capacity to interact with the female reproductive tract and complete the suite of functional maturation processes required for successful fertilization and initiation of embryonic development. However, ART 'high intervention' strategies bypass these selective barriers leading to an increased risk of inadvertently transferring genomic defects to the offspring with potential downstream consequences for offspring health. This review contextualizes why current sperm selection technologies have provided only minor improvement to live birth rates following ART. We posit that capitalizing on sperm-ZP binding (the penultimate step of successful fertilization) with novel ZP mimetic technologies provides an attractive, but understudied, tool for clinical selection of fertilization-competent spermatozoa for ART improvement.

Limitations Reasons For Caution: The risk of bias in the interpretation of findings for a narrative review cannot be completely eliminated. Literature was limited to the language the authors speak: English.

Wider Implications: ART has provided transformative advancement for infertile couples, however, gaps in our fundamental understanding of how the best gametes are 'selected' during natural conception, which when unaccounted for during clinical conception, present a risk of continued reliance on ART and health consequences for the next generation. The purpose of this article was to contextualize our current knowledge across both sperm maturation events and current selection strategies for these cells in the clinic. We outline the potential for improved clinical outcomes through the advancement of our understanding in gamete biology in concert with the development of novel methods for artificial gamete selection.

Study Funding/competing Interests: No external funding, but financial support was received from the School of Environmental and Life Sciences, University of Newcastle, Australia. R.J.A. is a scientific advisor to Memphasys Ltd, a biotechnology company with interests in reproductive health and responsible for developing the Felix™ electrophoretic sperm isolation device. R.J.A. receives salary and grant from, and has stock in, Memphasys Ltd. The other authors declare no conflicts of interest.