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疾病，定义为子宫内膜组织在子宫腔外生长。作为英国第二常见的妇科疾病，子宫内膜异位症影响着大约 150 万育龄妇女。目前的治疗方法包括复方口服避孕药、孕激素和 GnRH 类似物，但这些只能缓解症状。因此，迫切需要子宫内膜异位症的新疗法，但该领域缺乏可靠的临床前疾病模型来支持药物开发。就动物模型而言，兔子和啮齿动物的月经周期不能代表人类的月经周期，唯一能够发生自发性子宫内膜异位症的动物是猕猴和狒狒。虽然 FDA 不再要求在人体试验前进行体内研究（FDA 现代化法案 2.0），但传统的体外模型无法捕捉月经周期驱动的子宫内膜组织变化的复杂性。因此，非常需要先进且可靠的子宫内膜异位症模型，这些模型可以通过微流控芯片器官技术提供。这种方法提供了一个受控的微环境，以标准化子宫内膜细胞优化共培养的条件，并更准确地再现天然子宫内膜组织的结构和功能以及疾病状态，这可以成为药物筛选、制剂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模型，可以引入并标准化子宫内膜的结构和生理成分，以确保开发更天然的模型。因此，该项目旨在开发人类子宫内膜异位组织的微流控芯片器官模型，包括子宫内膜基质细胞（ESC）和人类腹膜间皮细胞（HPMC），以促进子宫内膜异位症产品的开发。有效的模型将代表体内细胞微环境并模拟体内药物递送条件。通过监测 ESC 向 HPMC 的自发迁移来评估子宫内膜异位症的程度。我们将根据功效和效力筛选候选药物，并将重点关注促进 ESC 和 HPMC 对治疗产生积极反应的递送配方/设备。因此，这项研究将导致开发一个多功能且灵活的平台，用于高通量和具有成本效益的子宫内膜异位症候选药物筛选，最终设计和表征用于管理所选候选药物的非侵入性局部系统。预计筛选平台和开发的递送系统都可以构成该领域和相关治疗领域未来候选药物筛选平台的基础。