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

子宫内膜异位症是一种慢性疾病，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，子宫内膜异位症影响了大约150万育龄女性。目前的治疗方法包括口服避孕药、孕激素和促性腺激素释放激素类似物，但这些只能起到缓解症状的作用。因此，迫切需要治疗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。在动物模型方面，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之前进行体内研究(FDA现代化法案2.0)，但传统的体外模型无法捕捉到月经周期驱动的子宫内膜组织变化的复杂性。因此，对先进而可靠的子宫内膜异位症模型的需求很大，可以通过微流控芯片器官技术提供这种模型。这种方法提供了一个受控的微环境，以标准化优化共培养子宫内膜细胞的条件，并更准确地再现自然子宫内膜组织的结构和功能以及疾病状态，这可能是药物筛选、制剂开发和毒理学研究的有力工具。这种方法可以提供一个高度可控的简化模型，该模型可以引入和标准化子宫内膜的结构和生理成分，以确保开发出更自然的模型。因此，本项目旨在开发包括子宫内膜间质细胞(ESCs)和人腹膜间皮细胞(HPMC)在内的人类子宫内膜异位症组织的微流控芯片上器官模型，以促进子宫内膜异位症产品的开发。一个有效的模型将代表体内的细胞微环境，并将模拟体内的药物输送条件。子宫内膜异位症的程度将通过监测胚胎干细胞向子宫内膜异位症细胞的自发迁移来评估。我们将根据疗效和效力来筛选候选药物，并将重点放在促进ESCs和HPMCs对治疗产生积极反应的递送制剂/装置上。因此，这项研究将导致开发一个通用和灵活的平台，用于高通量和高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选定候选药物的非侵入性局部给药系统(S)。预计筛选平台和开发的递送系统都可以成为未来在该领域和相关治疗领域筛选候选药物的平台的基础。

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.