Microphysiological modeling of the reproductive tract: A fertile endeavor

Abstract

Preclinical toxicity testing in animal models is a cornerstone of the drug development process, yet it is often unable to predict adverse effects and tolerability issues in human subjects. Species-specific responses to investigational drugs has led researchers to utilize human tissues and cells to better estimate human toxicity. Unfortunately, human cell-derived models are imperfect because toxicity is assessed in isolation, removed from the normal physiologic microenvironment. Microphysiological modeling, often referred to as ‘organ-on-a-chip’ or ‘human-on-a-chip’ places human tissue into a microfluidic system that mimics the complexity of human in vivo physiology, thereby allowing for toxicity testing on several cell types, tissues, and organs within a more biologically relevant environment. Here we describe important concepts when developing a repro-on-a-chip model. The development of female and male reproductive microfluidic systems is critical to sex-based in vitro toxicity and drug testing. This review addresses the biological and physiological aspects of the male and female reproductive systems in vivo and what should be considered when designing a microphysiological human-on-a-chip model. Additionally, interactions between the reproductive tract and other systems are explored, focusing on the impact of factors and hormones produced by the reproductive tract and disease pathophysiology.

Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: Translating lessons from murine models

“…As noted above (section 3.3), these in vitro studies revealed that this toxicant acts to disrupt the anti-inflammatory action of progesterone, leading to an increase in endometrial cell sensitivity to inflammatory stimuli [17]. Nevertheless, mechanistic interpretation of these results remains limited as a consequence of a non-physiological experimental setting [144–146]. Multi-cell culture assays, including organ cultures, co-cultures and tissue recombinants, clearly demonstrate the significant role of cell-cell communication in normal endometrial physiology [16, 147, 148].…”

The relevance and potential roles of microphysiological systems in biology and medicine

“…39 Next is a perspective on the scientific, practical, and governmental regulatory expectations for such efforts. 40 The body of the issue comprises fourteen articles describing constructs that can serve as in vitro models for bone and cartilage, 41 brain, 42 gastrointestinal tract, 43;44 lung, 45 liver, 46;47 microvasculature, 48 reproductive tract, 49 skeletal muscle, 50 and skin, 51 as well as the interconnection of organs-on-chips to support physiologically based pharmacokinetics 52 and anticancer drug screening. 53 These research areas will eventually benefit from microscale technologies that regulate stem cell differentiation.…”

Programming microphysiological systems for children’s health protection

“…The recapitulation of the 28-day menstrual cycle and pregnant-like hormone control has been achieved through integrating multiple tissues into an MPS microfluidic culture system called EVATAR TM . 22 A microfluidic organ-on-chip model of the uterine endometrium (EndoChip) has been engineered to reassemble the endometrium (immune, vascular, stromal and epithelial components) to individually compartmentalize each cell type with control over endocrine and biomechanical stimuli (e.g. shear stresses).…”

“…Microphysiological modeling of hormonal balance has been presented in concept for the male reproductive tract. 22 Although there are no MPS data yet available on this challenge in a human MPS model, a three-dimensional co-culture model of rat testis development has shown promise for incorporating local metabolic capability and pharmacokinetics for phthalate male reproductive toxicants. 24 When anchored to developmental regulation of the testicular transcriptome the changes will capture critical processes in puberty such as the peak in steroidogenesis and increase in meiosis and spermatogenesis-related pathways during the first wave of spermatogenesis.…”