Physiomimetic Models of Adenomyosis

Abstract

Adenomyosis remains an enigmatic disease in the clinical and research communities. The high prevalence, diversity of morphological and symptomatic presentations, array of potential etiological explanations, and variable response to existing interventions suggest that different subgroups of patients with distinguishable mechanistic drivers of disease may exist. These factors, combined with the weak links to genetic predisposition, make the entire spectrum of the human condition challenging to model in animals. Here, after an overview of current approaches, a vision for applying physiomimetic modeling to adenomyosis is presented. Physiomimetics combines a system's biology analysis of patient populations to generate hypotheses about mechanistic bases for stratification with in vitro patient avatars to test these hypotheses. A substantial foundation for three-dimensional (3D) tissue engineering of adenomyosis lesions exists in several disparate areas: epithelial organoid technology; synthetic biomaterials matrices for epithelial–stromal coculture; smooth muscle 3D tissue engineering; and microvascular tissue engineering. These approaches can potentially be combined with microfluidic platform technologies to model the lesion microenvironment and can potentially be coupled to other microorgan systems to examine systemic effects. In vitro patient-derived models are constructed to answer specific questions leading to target identification and validation in a manner that informs preclinical research and ultimately clinical trial design.

Organoid co-culture model of the cycling human endometrium in a fully-defined synthetic extracellular matrix reveals epithelial-stromal crosstalk

“…To physiologically model the endometrium, we focused on the soft (3 wt%) hydrogels to generate the co-cultures, however, these stiffness-mediated phenotypes may provide insight into cell- ECM interactions in endometriotic diseases. 91 We conclude that the dual-peptide 3wt%-MIX formulations is a novel approach to generate a synthetic matrix that is suitable for the culture of both the epithelial and stromal cells either as mono- or co-cultures. To test the efficacy of the synthetic matrix, we validated that expansion of scEEOs from original primary tissue is feasible in the synthetic ECM without the need to first expand in Matrigel (Fig S14).…”

Pre-clinical models to study abnormal uterine bleeding (AUB)

“…The prospects for applying such physiomimetic modelling to adenomyosis has been extensively reviewed by Gnecco et al in 2020. 64 …”

“…The prospects for applying such physiomimetic modelling to adenomyosis has been extensively reviewed by Gnecco et al in 2020. 64 Co-culturing of endometrial cells can be a useful model to study cell-cell interactions in vitro, which could be perturbed in patients suffering with AUB. However, like other models, co-cultures can have key limitations that must be considered.…”

Adenomyosis and fertility: does adenomyosis impact fertility and does treatment improve outcomes

“…Although the cause of adenomyosis is debated, the presence of adenomyosis is associated with predictable molecular changes in the endometrium and surrounding myometrium leading to abnormal function [24][25][26]. Dysmenorrhea is thought to be a result of myometrial hypercontractility, while abnormal uterine bleeding is thought to be related to neoangiogenesis, abnormal uterine contractility and high microvessel density [25].…”