Microfluidics in male reproduction: is ex vivo culture of primate testis tissue a future strategy for ART or toxicology research?

Abstract

The significant rise in male infertility disorders over the years has led to extensive research efforts to recapitulate the process of male gametogenesis in vitro and to identify essential mechanisms involved in spermatogenesis, notably for clinical applications. A promising technology to bridge this research gap is organ-on-chip (OoC) technology, which has gradually transformed the research landscape in ART and offers new opportunities to develop advanced in vitro culture systems. With exquisite control on a cell or tissue microenvironment, customized organ-specific structures can be fabricated in in vitro OoC platforms, which can also simulate the effect of in vivo vascularization. Dynamic cultures using microfluidic devices enable us to create stimulatory effect and non-stimulatory culture conditions. Noteworthy is that recent studies demonstrated the potential of continuous perfusion in OoC systems using ex vivo mouse testis tissues. Here we review the existing literature and potential applications of such OoC systems for male reproduction in combination with novel bio-engineering and analytical tools. We first introduce OoC technology and highlight the opportunities offered in reproductive biology in general. In the subsequent section, we discuss the complex structural and functional organization of the testis and the role of the vasculature-associated testicular niche and fluid dynamics in modulating testis function. Next, we review significant technological breakthroughs in achieving in vitro spermatogenesis in various species and discuss the evidence from microfluidics-based testes culture studies in mouse. Lastly, we discuss a roadmap for the potential applications of the proposed testis-on-chip culture system in the field of primate male infertility, ART and reproductive toxicology.

European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology

“…We recommend against testicular tissue cryopreservation and against spermatogonial stem cell retrieval in children with KS. So far, these procedures are not justified as there is no method of in vitro spermatogenesis, but this may change in future 59 …”

“…So far, these procedures are not justified as there is no method of in vitro spermatogenesis, but this may change in future. 59 We place a moderate value on the recommendation regarding determination of LH and FSH during the first three months after birth because treatment of hypogonadism in this period of life is currently not recommended. We place a high value to the recommendation against testosterone supplementation during early childhood in all patients with KS, as it has currently no justification.…”

Understanding and Assisting Reproduction in Wildlife Species Using Microfluidics

“…Producing germ cells from ex vivo gonadal tissues is considered to be the best approach for wildlife reproduction. In this context, microfluidic technology offers better controlled environment for the culture, maintenance, and maturation of these ex vivo tissues [17], as well as a unique opportunity to screen and optimize culture conditions through device parallelization. This microfluidic approach has been pioneered on mouse prepubertal testicular tissues viably cultured for up to 6 months, achieving full gametogenesis.…”

“…Microfluidic platforms are also likely to play an important role in the ex vivo culture of gonadal tissues, first by generating new fundamental knowledge about gametogenesis and then in producing gametes in vitro (while using minimal amounts of these precious samples) [17]. Indeed, difficulties in gamete recovery from wildlife species undermine the development and use of in vitro technologies.…”

Recent Microfluidic Innovations for Sperm Sorting

“…Some examples of these methods include surface charge selection, hyaluronic acid binding, sperm apoptosis assay, sperm birefringence, intra-cytoplasmic morphologically selected sperm injection (IMSI), motile sperm organelle morphology examination, DNA/chromatin integrity, hypo-osmotic swelling test (HOST), Raman spectroscopy [20,35], and zona-binding sperm selection [25]. This is because the use of microfluidic devices for sperm processing in the past decade has created new opportunities for the field [36].…”