Obstetrics and Gynaecology - Theses

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    Human amnion epithelial cells and bronchopulmonary dysplasia in preterm infants
    Baker, Elizabeth Kate ( 2021)
    Bronchopulmonary dysplasia (BPD) is a frequent and important morbidity for extremely preterm infants. The lung injury that gives rise to BPD occurs during the late canalicular and early saccular phases of lung maturation and is induced by various agents including hyperoxia, ventilation associated injury and infection. The result is arrest of alveolar development. Consequently, infants with BPD are more likely to have poorer respiratory health, not just in infancy, but through their lifetime. Sufferers of BPD are at greater risk of neurodevelopment challenges such as cerebral palsy and cognitive impairment. Treating, or better still, preventing this multifactorial disease is challenging. Cell therapy, with its capacity to modulate the inflammatory response, support angiogenesis and protect endogenous progenitor cells, is a unique and promising therapy for BPD. Human amnion epithelial cells (hAECs) are a type of cell therapy derived from the amniotic membrane of term placentae. The mechanisms of hAEC action and evidence of their therapeutic potential in BPD-like injury are evaluated here. Following this examination of the pre-clinical evidence, this thesis outlines the development and implementation of a phase 1 dose escalation study of hAECs in infants at significant risk of developing BPD. This work builds on an earlier, first in human study, of a modest dose of hAECs in infants with established severe BPD. The tolerability of larger doses of hAECs given to less mature infants in our study called ‘RENEWAL; Reducing Neonatal Lung Disease With Amnion Cells’ is reported. In an important and novel contribution to the field of neonatal cell therapy we have highlighted and resolved deficiencies in bedside cell therapy infusion protocols. Established infusion protocols were discovered to delivered less than 20% of the intended dose of hAECs during the early phases of the RENEWAL study. We solved this challenge with simple measures using equipment that was readily available in the neonatal unit. Finally, the strengths and limitations of the RENEWAL study are examined, and future directions for neonatal cell therapy are discussed. The RENEWAL study represents an important milestone in neonatal cell therapy. The RENEWAL study has detected and resolved important knowledge gaps. With its completion anticipated in the next 18 months, the RENEWAL study will add significantly to the body of evidence for the safety of cell therapy in extremely preterm infants. Importantly, the tolerable dose of hAECs in extremely preterm infants reported here provides a foundation on which to build the next series of cell therapy trials.