An Artificial Placenta Protects Against Lung Injury and Promotes Continued Lung Development in Extremely Premature Lambs

Abstract

An artificial placenta (AP) utilizing extracorporeal life support (ECLS) could protect premature lungs from injury and promote continued development. Preterm lambs at estimated gestational age (EGA) 114–128 days (term = 145) were delivered by Caesarian section and managed in one of three groups: AP, mechanical ventilation (MV), or tissue control (TC). Artificial placenta lambs (114 days EGA, n = 3; 121 days, n = 5) underwent venovenous (VV)-ECLS with jugular drainage and umbilical vein reinfusion for 7 days, with a fluid-filled, occluded airway. Mechanical ventilation lambs (121 days, n = 5; 128 days, n = 5) underwent conventional MV until failure or maximum 48 hours. Tissue control lambs (114 days, n = 3; 121 days, n = 5; 128 days, n = 5) were sacrificed at delivery. At the conclusion of each experiment, lungs were procured and sectioned. Hematoxylin and eosin (H&E) slides were scored 0–4 in seven injury categories, which were summed for a total injury score. Slides were also immunostained for platelet-derived growth factor receptor (PDGFR)-α and α-actin; lung development was quantified by the area fraction of double-positive tips of secondary alveolar septa. Support duration of AP lambs was 163 ± 9 (mean ± SD) hours, 4 ± 3 for early MV lambs, and 40 ± 6 for late MV lambs. Total injury scores at 121 days were 1.7 ± 2.1 for AP vs. 5.5 ± 1.6 for MV (p = 0.02). Using immunofluorescence, double-positive tip area fraction at 121 days was 0.017 ± 0.011 in AP lungs compared with 0.003 ± 0.003 in MV lungs (p < 0.001) and 0.009 ± 0.005 in TC lungs. At 128 days, double-positive tip area fraction was 0.012 ± 0.007 in AP lungs compared with 0.004 ± 0.004 in MV lungs (p < 0.001) and 0.016 ± 0.009 in TC lungs. The AP is protective against lung injury and promotes lung development compared with mechanical ventilation in premature lambs.

Achieving sustained extrauterine life: Challenges of an artificial placenta in fetal pigs as a model of the preterm human fetus

“…Therefore, increasing the resistance leads to a reduction in circuit flow (Hornick et al, 2018). Additionally, at 106 days gestation MAP in the preterm piglet (37 ± 9 mm Hg) is lower than in larger preterm sheep (47 ± 5 mm Hg) previously supported on the AP (Coughlin et al, 2019), indicating that there may be insufficient arterial pressure to maintain normal UV flow in our experiment (Table 2). With declining circuit flow, it becomes increasingly difficult to achieve adequate oxygenation, often resulting in reduced fetal oxygen delivery, metabolic acidosis, and circulatory collapse (Carter, 1989; Omo‐Aghoja, 2014; Rudolph, 2009).…”

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

“…The group has reported the effect of their AP model on development and function of different organ systems (Table SS1). They demonstrated continued lung maturation during the 7 to 10 days on circuit and comparable lung function to GA‐matched controls upon ventilation 99,103 . It should be noted, however, that tracheal occlusion was applied by capping the amniotic fluid‐filled endotracheal tube, and corticosteroids were administered throughout the run to counteract inflammation and hypocortisolism observed in previous experiments.…”

“…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…”

Artificial lungs––Where are we going with the lung replacement therapy?

“…Research on artificial placenta technology led by Drs. Mychaliska and Bartlett at the University of Michigan established extracorporeal support in a lamb model of extreme prematurity 86,95,96 …”