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，即如何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改进为可重复使用的人类胎盘测试系统(HPTS)提供更多建议，以提炼关于怀孕期间复合风险评估的指南的证据权重[1]。然而，从动物到人类，甚至从细胞/组织到整个生物体的推断，所有的毒性测试(体内、体外和硅胶中)都有局限性。鉴于关于动物使用的新的ICH S5修订版3指南，需要新的体外和硅胶方法来提高数据与其他分析方法的证据价值；并为制药行业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查能力以及展示模型的稳健性是关键。这一跨学科的博士项目通过开发、评估和标准化人类的“芯片胎盘”HPTS来解决紧迫的挑战，该HPTS已发展到受监管的水平，供制药行业使用，以获取测试化合物从母体到胎儿循环系统的可靠传输数据。该项目将吸引生物工程专业的学生，他们对开发合成的人类胎盘屏障和在学术和工业环境中模拟化合物的跨膜转移感兴趣。人类原代干细胞滋养层细胞[3]，形成真正的合体滋养层屏障[4]，将与人胎盘内皮细胞共培养，在相对的母体和胎儿循环系统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来自人类胎盘双灌流模型的体外数据、体内动物数据以及已知的怀孕期间已经开出的药物的人类胎儿与母体血浆比例进行比较。屏障的物理性质，包括扩散路径长度、孔隙率和胎儿侧(受体侧)流动将被建立数学模型，用于传递效果，并在开发的屏障系统中进行测试。应聘者将在所有地点灵活工作，以发展圣玛丽医院母婴健康研究中心(由Paul BrownBill和Peter Ruane博士监督)、曼彻斯特大学数学系(由Igor Chernyavsky博士监督)以及剑桥阿斯利康(由Nicola Powles-Glive和Rhiannon David博士监督)的临床药理学和安全科学团队的技能。

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).