Development and characterisation of organ-on-a-chip model of the endometrium for disease modelling and drug discovery

用于疾病建模和药物发现的子宫内膜器官芯片模型的开发和表征

• 批准号: 2840156
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2840156
• 关键词: Development; characterisation; organ; chip; model

Endometriosis is a chronic condition, defined as the growth of endometrial tissue outside the uterine cavity. As the second most common gynaecological disease in the UK, endometriosis affects around 1.5 million women in reproductive age. Current therapies include combined oral contraceptive pill, progestins and GnRH-analogues, but these only provide symptomatic relief. New treatments for endometriosis are therefore urgently needed, but the field lacks a reliable preclinical model of disease to enable drug development. In terms of animal models, the menstrual cycle in rabbits and rodents is not representative of the human one, and the only animals capable of developing spontaneous endometriosis are macaques and baboons. While FDA no longer requires in vivo studies before human trials (FDA Modernization Act 2.0), traditional in vitro models fail to capture the complexity of the menstrual cycle-driven changes in the endometrial tissue.There is therefore a large need for advanced and reliable models of endometriosis, which can be provided by microfluidic organ-on-chip technologies. This approach offers a controlled microenvironment to standardise the conditions for an optimised co-culture of endometrial cells and to reproduce more accurately the architecture and functions of native endometrial tissues and diseases states, which can be a powerful tool for drug screening, formulation development and toxicology studies. Such an approach can provide a highly controllable reductionist model, that can introduce and standardise the structural and physiological components of the endometrium in a way to ensure the development of a more native model. This project therefore aims to develop a microfluidic organ-on-chip model of the human endometriotic tissue, including endometrial Stromal Cells (ESCs) and human peritoneal mesothelial cells (HPMCs), to facilitate endometriosis product development. A valid model will be representative of the in vivo cellular microenvironment and will mimic in vivo drug delivery conditions. The extent of the endometriosis will be assessed by monitoring the spontaneous migration of ESCs towards HPMCs. We will screen drug candidates in terms of efficacy and potency, and will focus on the delivery formulations/devices that facilitate a positive response of the ESCs and HPMCs to the therapy. Hence, this research will lead to the development of a versatile and flexible platform for high-throughput and cost-effective screening of endometriosis drug candidates culminating in the design and characterisation of a non-invasive topical system for administration of the selected drug candidate(s). It is expected that both the screening platform and the developed delivery system could form the basis of a platform for future drug candidate screening in this and allied therapy areas.

子宫内膜异位症是一种慢性病，定义为子宫腔外子宫内膜组织的生长。作为英国第二常见的妇科疾病，子宫内膜异位症在生殖时代影响约150万妇女。当前的疗法包括口服避孕药，孕激素和GNRH-Analogues，但这些仅提供症状缓解。因此，迫切需要针对子宫内膜异位症的新疗法，但是该领域缺乏可靠的疾病临床前模型来实现药物发育。就动物模型而言，兔子和啮齿动物的月经周期不是人类的代表，而唯一能够发育自发子宫内膜异位症的动物是猕猴和狒狒。尽管FDA在人体试验之前不再需要体内研究（FDA Modernation Act 2.0），但传统的体外模型无法捕获子宫内膜组织中月经周期驱动的变化的复杂性。因此，对基质的高级和可靠模型的需求很大，可以由微型纤维纤维纤维纤维构成有机体构成技术提供。这种方法提供了一种受控的微环境，以标准化性子宫内膜细胞共培养的条件，并更准确地重现天然子宫内膜组织和疾病状态的结构和功能，这可能是用于药物筛查，配方，配方开发和毒理学研究的强大工具。这种方法可以提供高度可控的还原主义模型，该模型可以以确保开发更本地模型的方式引入和标准化子宫内膜的结构和生理组成部分。因此，该项目旨在开发人子宫内膜组织组织的微流体器官芯片模型，包括子宫内膜基质细胞（ESC）和人腹膜间皮细胞（HPMC），以促进子宫内膜异位的产物发育。有效的模型将代表体内细胞微环境，并模仿体内药物递送条件。子宫内膜异位症的程度将通过监测ESC向HPMC的自发迁移来评估。我们将在疗效和效力方面筛选候选药物，并将重点放在促进ESC和HPMC对治疗的积极反应的交付配方/设备上。因此，这项研究将导致开发一个多功能，灵活的平台，用于高通量和具有成本效益的子宫内膜异位症候选药物的筛查，最终在设计和表征非侵入性局部系统以施用所选药物的非侵入性局部系统。预计筛选平台和开发的交付系统都可以构成在此和联盟治疗领域进行未来候选药物筛查的基础。