Integrated in vitro and in silico microphysiological human placental barrier models for reproductive toxicology testing in the pharmaceutical industr

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The pharmaceutical industry has a pressing challenge of providing additional advice on the safety of prescription medicines in pregnancy and how ex vivo and in vitro human placental models might be advanced to reproducible human placental test systems (HPTSs), refining a weight of evidence to the guidance given around compound risk assessment during pregnancy [1]. However, all toxicity testing (in vivo, in vitro and in silico) have limitations when extrapolating from animals to the human, or even from cell/tissue to whole organism. Given new ICH S5 revision 3 guidelines on animal use, new in vitro and in silico approaches are needed to improve the evidential value of data alongside other assays; and to build a bigger picture for risk assessment of compounds passing through the testing pipeline in the pharmaceutical industry. Increasing screenability of test compounds within new test systems as well as to demonstrating the robustness of the models is key.This interdisciplinary PhD program addresses a pressing challenge via the development, evaluation and standardisation of a human "placenta on a chip" HPTS, advanced towards a regulated level for use by the pharmaceutical industry to acquire reliable transfer data of test compounds from the maternal to the fetal circulatory systems. The project will appeal to a bioengineering student interested in developing a synthetic human placental barrier and modelling [2] the transmembrane transfer of compounds in an academic and industrial environment. Human primary stem cell trophoblasts [3], forming a true syncytiotrophoblast barrier [4] will be co-cultured with human placental endothelial cells to form a differentiated and polarised placental barrier between opposing maternal and fetal circulatory-phase compartments. Barrier compound clearance studies will be compared to ex vivo data from the human placental dual perfusion model; in vivo animal data; and to known human fetal:maternal plasma ratios for drugs already prescribed in pregnancy. The physical properties of the barrier, including length of diffusional pathway, porosity and fetal-side (acceptor-side) flow will be mathematically modelled for transfer efficacy and tested in the developed barrier system. The candidate will be expected to work flexibly at all locations to develop skills within the Maternal & Fetal Health Research Centre at St Mary's Hospital (supervised by Drs Paul Brownbill and Peter Ruane) and the Department of Mathematics (supervised by Dr Igor Chernyavsky) at the University of Manchester; and the Clinical Pharmacology and Safety Sciences Team at AstraZeneca, Cambridge (supervised by Drs Nicola Powles-Glover and Rhiannon David).