Ex vivo dual perfusion of an isolated human placenta cotyledon: Towards protocol standardization and improved inter-centre comparability

Schneider, H.; Albrecht, Christiane; Ahmed, Mahmoud S.; Broekhuizen, Michelle; Aengenheister, Leonie; Buerki-Thurnherr, Tina; Danser, A.H. Jan; Gil, Sophie; Hansson, Stefan R.; Greupink, Rick; Lewis, Rohan M.; Markert, Udo R.; Mathiesen, Line; Powles-Glover, Nicola; Wadsack, Christian; Brownbill, Paul

doi:10.1016/j.placenta.2022.05.003

Cited by 11 publications

(7 citation statements)

References 53 publications

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“…In addition, the wide range of cotyledon weights and surface areas could affect tissue binding, but wide variation in perfusion parameters is a common obstacle of the model. 44 Nevertheless, a systemic review of placental perfusion experiments demonstrated that the fetal-to-maternal drug concentration ratios matched well between placental perfusion studies and samples taken at the time of delivery from maternal and cord blood. The pH-and protein binding-corrected ex vivo-to-in vivo ratios correlated well, with R 2 = 85.…”

Section: Study Strengths and Limitationsmentioning

confidence: 87%

“…Nonetheless in a subanalysis, after removing the case from 34.5 days and those with background diseases, the CBD distribution results did not change considerably. In addition, the wide range of cotyledon weights and surface areas could affect tissue binding, but wide variation in perfusion parameters is a common obstacle of the model 44 . Nevertheless, a systemic review of placental perfusion experiments demonstrated that the fetal‐to‐maternal drug concentration ratios matched well between placental perfusion studies and samples taken at the time of delivery from maternal and cord blood.…”

Section: Discussionmentioning

confidence: 99%

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Placental disposition of cannabidiol: An ex vivo perfusion study

Berman,

Erenburg,

Beloosesky

et al. 2023

Epilepsia

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ObjectiveIn the absence of safety data in humans, the use of cannabidiol (CBD) is not recommended during pregnancy. Yet >50% of pregnancies in women with epilepsy are unintended, making fetal exposure to CBD possible. As a small‐molecule, highly lipid‐soluble drug, CBD is likely to distribute into the placenta and cross it. To estimate the placental distribution profile of CBD and its potential short‐term placental effects, we conducted an ex vivo perfusion study in human placentas.MethodsPlacentas were obtained from healthy women undergoing cesarean deliveries. Selected cotyledons were cannulated and perfused for 180 min with a CBD‐containing medium (250 ng/mL, 0.796 μmol/L; representative of a low therapeutic concentration; n=8). CBD concentrations were determined at 180 min in the medium and placental tissues using LC‐MS/MS analysis. A customized gene panel array was used to analyze the expression of selected genes in the perfused placental cotyledons as well as in placentas perfused with 1000 ng/mL CBD (3.18 μmol/L; high therapeutic concentration; n=8) and in those exposed to the vehicle.ResultsCBD sequestered in the placental tissue, exhibiting significant variability across samples (median 5,342 ng/g tissue; range 1,066‐9,351 ng/g tissue). CBD concentrations in the fetal compartment were one‐fifth of those measured in the maternal compartment (median 59 ng/mL; range 48‐72 ng/mL, vs. 280 ng/mL, range 159‐388 ng/mL, respectively; p<0.01). Placental gene expression was not significantly altered by CBD.SignificanceThe placenta acts as a depot compartment for CBD, slowing‐down its distribution to the fetus. This phenomenon might yield flatter but prolonged fetal CBD levels in vivo. The attenuated transplacental CBD transfer does not imply that its use by pregnant women is safe for the fetus. Only pregnancy registries and neurocognitive assessments would establish the risk of being antenatally exposed to CBD.

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Section: Study Strengths and Limitationsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Placental disposition of cannabidiol: An ex vivo perfusion study

Berman,

Erenburg,

Beloosesky

et al. 2023

Epilepsia

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“…Given the variety of ways ex vivo human cotyledon perfusions are conducted, a combined effort of European groups is currently underway to harmonize protocols. This includes recommendations on the use of quality criteria for successful perfusions ( Schneider, 2022 ). While such criteria and corresponding cut-off values are not harmonized yet, most groups include loss of fluid from the fetal circulation, and maternal-to-fetal transfer of the small molecule antipyrine ( van Hove, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model

Eliesen,

Fransen,

van Hove

et al. 2024

Current Research in Toxicology

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“…The placenta can be obtained immediately after delivery and installed in the perfusion system within an ischemia time of less than 30 min. Routinely, it can be maintained completely functional for 6 h, which can be assessed by numerous parameters [ 26 ]. The method was invented and established in the late 1960s [ 27 ].…”

Section: Human-relevant Nams For Developmental Toxicity Testingmentioning

confidence: 99%

Human-Based New Approach Methodologies in Developmental Toxicity Testing: A Step Ahead from the State of the Art with a Feto–Placental Organ-on-Chip Platform

Luconi

Sogorb

Markert

et al. 2022

IJERPH

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Developmental toxicity testing urgently requires the implementation of human-relevant new approach methodologies (NAMs) that better recapitulate the peculiar nature of human physiology during pregnancy, especially the placenta and the maternal/fetal interface, which represent a key stage for human lifelong health. Fit-for-purpose NAMs for the placental–fetal interface are desirable to improve the biological knowledge of environmental exposure at the molecular level and to reduce the high cost, time and ethical impact of animal studies. This article reviews the state of the art on the available in vitro (placental, fetal and amniotic cell-based systems) and in silico NAMs of human relevance for developmental toxicity testing purposes; in addition, we considered available Adverse Outcome Pathways related to developmental toxicity. The OECD TG 414 for the identification and assessment of deleterious effects of prenatal exposure to chemicals on developing organisms will be discussed to delineate the regulatory context and to better debate what is missing and needed in the context of the Developmental Origins of Health and Disease hypothesis to significantly improve this sector. Starting from this analysis, the development of a novel human feto–placental organ-on-chip platform will be introduced as an innovative future alternative tool for developmental toxicity testing, considering possible implementation and validation strategies to overcome the limitation of the current animal studies and NAMs available in regulatory toxicology and in the biomedical field.

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Ex vivo dual perfusion of an isolated human placenta cotyledon: Towards protocol standardization and improved inter-centre comparability

Cited by 11 publications

References 53 publications

Placental disposition of cannabidiol: An ex vivo perfusion study

Placental disposition of cannabidiol: An ex vivo perfusion study

Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model

Human-Based New Approach Methodologies in Developmental Toxicity Testing: A Step Ahead from the State of the Art with a Feto–Placental Organ-on-Chip Platform

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