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

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.