A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle

Xiao, Shuo; Coppeta, Jonathan; Rogers, Hunter B.; Isenberg, Brett C.; Zhu, Jie; Olalekan, Susan; McKinnon, Kelly E.; Dokic, Danijela; Rashedi, Alexandra S.; Haisenleder, Daniel J.; Malpani, Saurabh S.; Arnold-Murray, Chanel A.; Chen, Kuan-Wei; Jiang, Mingyang; Bai, Lu; Nguyen, Cathy; Zhang, Jiyang; Laronda, Monica M.; Hope, Thomas J.; Maniar, Kruti P.; Pavone, Mary Ellen; Avram, Michael J.; Sefton, Elizabeth C.; Getsios, Spiro; Burdette, Joanna E.; Kim, Julie; Borenstein, Jeffrey T.; Woodruff, Teresa K.

doi:10.1038/ncomms14584

Cited by 389 publications

(331 citation statements)

References 44 publications

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“…We have recently demonstrated similar but amplified responses of our recellularized endometrial scaffolds to a 28-day cycle driven by ovarian follicles in a microfluidic system [62]. Improvement of the 3D recellularized endometrial cultures would entail adding other cell types, including epithelial, endothelial and immune cells, to create a more complete endometrium.…”

Section: Discussionmentioning

confidence: 97%

Development of a novel human recellularized endometrium that responds to a 28-day hormone treatment†

Olalekan

Burdette

Getsios

et al. 2017

Biology of Reproduction

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Three-dimensional (3D) in vitro models have been established to study the physiology and pathophysiology of the endometrium. With emerging evidence that the native extracellular matrix (ECM) provides appropriate cues and growth factors essential for tissue homeostasis, we describe, a novel 3D endometrium in vitro model developed from decellularized human endometrial tissue repopulated with primary endometrial cells. Analysis of the decellularized endometrium using mass spectrometry revealed an enrichment of cell adhesion molecules, cytoskeletal proteins, and ECM proteins such as collagen IV and laminin. Primary endometrial cells within the recellularized scaffolds proliferated and remained viable for an extended period of time in vitro. In order to evaluate the hormonal response of cells within the scaffolds, the recellularized scaffolds were treated with a modified 28-day hormone regimen to mimic the human menstrual cycle. At the end of 28 days, the cells within the endometrial scaffold expressed both estrogen and progesterone receptors. In addition, decidualization markers, IGFBP-1 and prolactin, were secreted upon addition of dibutyryl cyclic AMP indicative of a decidualization response. This 3D model of the endometrium provides a new experimental tool to study endometrial biology and drug testing. Summary SentencePrimary endometrial cells within a recellularized scaffold respond to a 28-day menstrual cycle.

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Section: Discussionmentioning

confidence: 97%

Development of a novel human recellularized endometrium that responds to a 28-day hormone treatment†

Olalekan

Burdette

Getsios

et al. 2017

Biology of Reproduction

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“…Liver, ovary, ectocervix, uterus and fallopian tube modules are linked by microfluidic channels (left). Ovarian hormone secretion over 28 days in culture with oestradiol and progesterone mimics the human menstrual cycle 30 . Image adapted under a Creative Commons 4.0 license from Xiao et al 30 .…”

Section: Figurementioning

confidence: 99%

“…Another integrated system modeling the female reproductive tract was recently published 30 , and could be a powerful tool in drug development pipelines that historically focus heavily on toxicity and safety screening in male-derived cells and organisms. The system, dubbed “EVATAR”, consists of organ modules for the ovary, fallopian tube, uterus, cervix and liver in a single MPS platform, and could simulate a 28-day menstrual cycle hormone profile (Figure 3).…”

Section: Tissue Chips As Tools For Drug Developmentmentioning

confidence: 99%

“…Together with the flexibility with complexity and design, there is a growing interest in MPS development, and support from governmental funding agencies 13, 14 and private industry has led to a wide, and ever-expanding, range of organ tissues being modeled. These include liver 15, 16 , skin 17 , heart 18–20 , vasculature 21, 22 , brain 23, 24 , blood-brain barrier 25, 26 , bone 27 , the female reproductive system 28–30 , gut 31 , muscle 32 , kidney 33, 34 , pancreas 35, 36 , and cornea 37 , amongst others (see Bhatia and Ingber 38 ).…”

Section: Introductionmentioning

confidence: 99%

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Tissue chips – innovative tools for drug development and disease modeling

2017

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The high rate of failure during drug development is well-known, however recent advances in tissue engineering and microfabrication have contributed to the development of microphysiological systems (MPS), or ‘organs-on-chips’ that recapitulate the function of human organs. These ‘tissue chips’ could be utilized for drug screening and safety testing to potentially transform the early stages of the drug development process. They can also be used to model disease states, providing new tools for the understanding of disease mechanisms and pathologies, and assessing effectiveness of new therapies. In the future, they could be used to test new treatments and therapeutics in populations - via clinical trials-on-chips - and individuals, paving the way for precision medicine. Here we will discuss the wide-ranging and promising future of tissue chips, as well as challenges facing their development.

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“…MPS approaches to the study of female reproductive biology, reviewed by Young et al, 21 have utilized a multiorgan platform recently announced by Draper Laboratory. 49,50 Cyr et al 51 discuss the application of microfluidic microformulators for replicating hormonal circadian rhythms in individual or coupled organ MPS studies. The introduction of low-cost, multiport microformulators should simplify the customization and temporal control of TC perfusion media and accommodate the secretions of organs missing from an MPS homunculus.…”

Section: Fitting Into the "Grand Scheme"mentioning

confidence: 99%

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

Watson

Hunziker

Wikswo

2017

Exp Biol Med (Maywood)

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Impact statementMicrophysiological systems (MPS), which include engineered organoids and both individual and coupled organs-on-chips and tissue chips, are a rapidly growing topic of research that addresses the known limitations of conventional cellular monoculture on flat plastic -a wellperfected set of techniques that produces reliable, statistically significant results that may not adequately represent human biology and disease. As reviewed in this article and the others in this thematic issue, MPS research has made notable progress in the past three years in both cell sourcing and characterization. As the field matures, currently identified challenges are being addressed, and new ones are being recognized. Building upon investments by the Defense Advanced Research Projects Agency, National Institutes of Health, Food and Drug Administration, Defense Threat Reduction Agency, and Environmental Protection Agency of more than $200 million since 2012 and sizable corporate spending, academic and commercial players in the MPS community are demonstrating their ability to meet the translational challenges required to apply MPS technologies to accelerate drug development and advance toxicology. AbstractMicrophysiological systems (MPS), which include engineered organoids (EOs), single organ/tissue chips (TCs), and multiple organs interconnected to create miniature in vitro models of human physiological systems, are rapidly becoming effective tools for drug development and the mechanistic understanding of tissue physiology and pathophysiology. The second MPS thematic issue of Experimental Biology and Medicine comprises 15 articles by scientists and engineers from the National Institutes of Health, the IQ Consortium, the Food and Drug Administration, and Environmental Protection Agency, an MPS company, and academia. Topics include the progress, challenges, and future of organs-on-chips, dissemination of TCs into Pharma, children's health protection, liver zonation, liver chips and their coupling to interconnected systems, gastrointestinal MPS, maturation of immature cardiomyocytes in a heart-on-a-chip, coculture of multiple cell types in a human skin construct, use of synthetic hydrogels to create EOs that form neural tissue models, the blood-brain barrier-on-a-chip, MPS models of coupled female reproductive organs, coupling MPS devices to create a body-on-a-chip, and the use of a microformulator to recapitulate endocrine circadian rhythms. While MPS hardware has been relatively stable since the last MPS thematic issue, there have been significant advances in cell sourcing, with increased reliance on human-induced pluripotent stem cells, and in characterization of the genetic and functional cell state in MPS bioreactors. There is growing appreciation of the need to minimize perfusate-to-cell-volume ratios and respect physiological scaling of coupled TCs. Questions asked by drug developers are followed by an analysis of the potential value, costs, and needs of Pharma. Of highest value and lowest switching costs may be the d...

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A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle

Cited by 389 publications

References 44 publications

Development of a novel human recellularized endometrium that responds to a 28-day hormone treatment†

Development of a novel human recellularized endometrium that responds to a 28-day hormone treatment†

Tissue chips – innovative tools for drug development and disease modeling

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

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