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

制药业面临着一项紧迫的挑战，即就怀孕期间处方药的安全性以及如何将体外和体外人类胎盘模型推进到可重复的人类胎盘试验系统（hpss）提供额外的建议，完善孕期复合风险评估指导的证据份量。然而，所有的毒性测试（体内、体外和计算机）在从动物推断到人类，甚至从细胞/组织推断到整个生物体时都有局限性。鉴于新的ICH S5修订3动物使用指南，需要新的体外和计算机方法来提高数据和其他分析的证据价值；并为制药工业中通过测试管道的化合物的风险评估建立一个更大的图景。提高测试化合物在新测试系统中的筛选能力以及证明模型的稳健性是关键。这个跨学科的博士项目通过开发、评估和标准化人类“胎盘芯片”HPTS来解决一个紧迫的挑战，该HPTS已达到制药行业使用的规范水平，以获取测试化合物从母体到胎儿循环系统的可靠转移数据。该项目将吸引对开发合成人类胎盘屏障和在学术和工业环境中模拟化合物跨膜转移感兴趣的生物工程专业学生。人原代干细胞滋养层细胞[3]将与人胎盘内皮细胞共同培养，形成一个真正的合胞滋养层屏障[4]，在相反的母体和胎儿循环期室之间形成分化和极化的胎盘屏障。屏障化合物清除研究将与人类胎盘双灌注模型的离体数据进行比较；体内动物数据；以及已知的人类胎儿：孕妇血浆比率已经在怀孕期间开处方的药物。屏障的物理性质，包括扩散路径的长度、孔隙度和胎儿侧（受体侧）流动，将被数学建模用于传递效率，并在开发的屏障系统中进行测试。应聘者将在圣玛丽医院的母婴健康研究中心（由Paul Brownbill博士和Peter Ruane博士监督）和曼彻斯特大学数学系（由Igor Chernyavsky博士监督）灵活地在所有地点工作，以发展技能；剑桥阿斯利康的临床药理学和安全科学小组（由Nicola Powles-Glover博士和Rhiannon David博士监督）。

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).