Ex Utero Extracorporeal Support as a Model for Fetal Hypoxia and Brain Dysmaturity

McGovern, Patrick E.; Lawrence, Kendall M.; Baumgarten, Heron D.; Rossidis, Avery C.; Mejaddam, Ali Y.; Licht, Daniel J.; Grinspan, Judith B.; Schüpper, Alexander J.; Rychik, Jack; Didier, R; Vossough, Arastoo; Spray, Thomas L.; Peranteau, William H.; Davey, Mary‐Ann; Flake, Alan W.; Gaynor, J. William

doi:10.1016/j.athoracsur.2019.08.021

Cited by 14 publications

(18 citation statements)

References 27 publications

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“…Although they are often used interchangeably, AW and AP models differ in the extent to which they attempt to recreate fetal and utero-placental physiology. Cannula-related 71,98,103 Cardiac arrhythmia 98 Pericardial tamponade 98 Cardiac arrest 103 Equipment failure 81,87 Thrombo-embolism 86 Cannula-related 87 Equipment failure 135 Cannula-related 135 Umbilical spasm 135 Circuit clotting 135 Clinical translatability • Need for a planned EXIT procedure for cannulation on AW • Relative inaccessibility of the fetus complicating care and parental bonding…”

Section: Current Successful Ap and Aw Models: Design And Outcomesmentioning

confidence: 99%

“…AW models also provide a controlled environment to study the pathophysiology of abnormal conditions, for example, fetal hypoxia. 116,[121][122][123] The current animal models can evaluate potential therapeutic benefit of AW models for indications other than extreme prematurity. For example, fetal growth restriction caused by placental insufficiency may be reversed through delivery onto an AW model, ensuring adequate oxygen delivery and optimal nutrition, and early delivery on AW model may prove to be beneficial in the…”

Section: Aw Technology As Research Modelmentioning

confidence: 99%

“…In addition to its promising clinical potential, AW technology provides a novel research model to address fundamental questions regarding fetal physiology, such as the roles and contributions of the placenta and maternal hormones and growth factors to normal fetal development. AW models also provide a controlled environment to study the pathophysiology of abnormal conditions, for example, fetal hypoxia 116,121‐123 . The current animal models can evaluate potential therapeutic benefit of AW models for indications other than extreme prematurity.…”

Section: Aw Technology As Research Modelmentioning

confidence: 99%

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Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation

et al. 2020

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Extreme prematurity remains a major cause of neonatal mortality and severe long‐term morbidity. Current neonatal care is associated with significant morbidity due to iatrogenic injury and developmental immaturity of extreme premature infants. A more physiologic approach, replacing placental function and providing a womb‐like environment, is the foundational principle of artificial placenta (AP) and womb (AW) technology. The concept has been studied during the past 60 years with limited success. However, recent technological advancements and a greater emphasis on mimicking utero‐placental physiology have improved the success of experimental models, bringing the technology closer to clinical translation. Here, we review the rationale for and history of AP and AW technology, discuss the challenges that needed to be overcome, and compare recent successful models. We conclude by outlining some remaining challenges to be addressed on the path towards clinical translation and opportunities for future research.

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Section: Current Successful Ap and Aw Models: Design And Outcomesmentioning

confidence: 99%

Section: Aw Technology As Research Modelmentioning

confidence: 99%

Section: Aw Technology As Research Modelmentioning

confidence: 99%

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Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation

et al. 2020

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“…Mid-gestation fetuses were intubated through the umbilical cord vessels in a pumpless extracorporeal oxygenator and supported for 22 ± 2 days under hypoxic conditions in a fluid-filled environment, leading to an increase in white matter vessels, a decrease in neuronal density and damage to myelination ( Lawrence et al, 2019 ). Fetal lambs (111 ± 3 days) with oxygen delivery were limited by the umbilical circuit oxygenator maintained in the artificial womb for a mean of 22 ± 6 days, leading to altered cerebrovascular resistances and loss of brain mass ( McGovern et al, 2020 ). Pregnant ewes bred in time underwent aseptic surgery between 88 and 92 days gestational age to control the flow of blood to the brain through the common carotid and vertebral arteries and to disrupt maturation of arborization and activity in preterm fetal ovine subplate neurons ( McClendon et al, 2017 ).…”

Section: Prenatal Hypoxiamentioning

confidence: 99%

Effects of Prenatal Hypoxia on Nervous System Development and Related Diseases

et al. 2021

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The fetal origins of adult disease (FOAD) hypothesis, which was proposed by David Barker in the United Kingdom in the late 1980s, posited that adult chronic diseases originated from various adverse stimuli in early fetal development. FOAD is associated with a wide range of adult chronic diseases, including cardiovascular disease, cancer, type 2 diabetes and neurological disorders such as schizophrenia, depression, anxiety, and autism. Intrauterine hypoxia/prenatal hypoxia is one of the most common complications of obstetrics and could lead to alterations in brain structure and function; therefore, it is strongly associated with neurological disorders such as cognitive impairment and anxiety. However, how fetal hypoxia results in neurological disorders remains unclear. According to the existing literature, we have summarized the causes of prenatal hypoxia, the effects of prenatal hypoxia on brain development and behavioral phenotypes, and the possible molecular mechanisms.

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“…The EXTEND system is particularly well-suited to studying abnormal fetal development. It has proven to be a superb platform for studying the effects of chronic intrauterine hypoxia on mitochondria (86), myocardial development (87), and neurodevelopment (88)(89)(90).…”

Section: Organ Developmentmentioning

confidence: 99%

Development of an artificial placenta for support of premature infants: narrative review of the history, recent milestones, and future innovation

Fallon¹,

Mychaliska²

2021

Transl Pediatr

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Over 50 years ago, visionary researchers began work on an extracorporeal artificial placenta to support premature infants. Despite rudimentary technology and incomplete understanding of fetal physiology, these pioneering scientists laid the foundation for future work. The research was episodic, as medical advances improved outcomes of premature infants and extracorporeal life support (ECLS) was introduced for the treatment of term and near-term infants with respiratory or cardiac failure. Despite ongoing medical advances, extremely premature infants continue to suffer a disproportionate burden of mortality and morbidity due to organ immaturity and unintended iatrogenic consequences of medical treatment. With advancing technology and innovative approaches, there has been a resurgence of interest in developing an artificial placenta to further diminish the mortality and morbidity of prematurity. Two related but distinct platforms have emerged to support premature infants by recreating fetal physiology: a system based on arteriovenous (AV) ECLS and one based on veno-venous (VV) ECLS. The AV-ECLS approach utilizes only the umbilical vessels for cannulation. It requires immediate transition of the infant at the time of birth to a fluid-filled artificial womb to prevent umbilical vessel spasm and avoid gas ventilation. In contradistinction, the VV-ECLS approach utilizes the umbilical vein and the internal jugular vein. It would be applied after birth to infants failing maximal medical therapy or preemptively if risk stratified for high mortality and morbidity. Animal studies are promising, demonstrating prolonged support and ongoing organ development in both systems. The milestones for clinical translation are currently being evaluated.

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Ex Utero Extracorporeal Support as a Model for Fetal Hypoxia and Brain Dysmaturity

Cited by 14 publications

References 27 publications

Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation

Artificial placenta and womb technology: Past, current, and future challenges towards clinical translation

Effects of Prenatal Hypoxia on Nervous System Development and Related Diseases

Development of an artificial placenta for support of premature infants: narrative review of the history, recent milestones, and future innovation

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