Biomechanics and mechanobiology of human uterine fibroids

PROJECT SUMMARY/ ABSTRACT Uterine fibroids are the most prevalent noncancerous growths that form within the female body, present in 70 - 80% of women by age 50, and may result in severe pain, heavy menstrual bleeding, infertility, and preterm labor. Uterine fibroids are characterized by stiff, collagen-dense masses of tissue that exhibit a large degree of heterogeneity in terms of size, location, gross architecture, and composition, however, the mechanisms by which uterine fibroids initially form and grow are poorly understood. As such, current treatments are limited, relying primarily on surgical means of removal, which are associated with high recurrence rates. To address key knowledge gaps in the literature, this proposal will take a multifaceted, engineering-based approach to investigate uterine fibroid pathophysiology ex vivo and in vitro. I hypothesize that the altered mechanical microenvironment of uterine fibroids highlights underlying structural and compositional changes to the tissue, which in tum alters cell signaling pathways, namely mechanotransduction. In Aim 1, I seek to study the spatial variation in mechanical, structural, and compositional properties of small, medium, and large fibroids at the myometrium interface ex vivo to establish a categorization scheme for fibroids of all sizes. I expect uterine fibroids to exhibit increased stiffness and collagen content relative to patient-matched myometrium, regardless of fibroid size, demonstrating a significant degree of intra- and inter-fibroid variability with a sharp transition in material properties at the interface. This data will be foundational in the development of a novel endoscope for improved intrauterine detection and for drug delivery assessments. In Aim 2, I seek to elucidate the pathophysiology of uterine fibroids on the cellular level and quantitatively assess the role of mechanotransduction through targeted modulation in vitro. Specifically, I hypothesize that uterine smooth muscle cells (uSMCs) derived from fibroids will exhibit reduced responsiveness to different substrate stiffnesses and overexpression of focal adhesion kinase (FAK), a key mechanotransductive molecule, when compared to myometrial uSMCs. I further hypothesize that FAK inhibition of fibroid uSMCs will alter the cell behavior in such a way as to mimic the healthy myometrial phenotype. As such, this study will establish the validity of FAKi as a novel pharrnacologic treatment of uterine fibroids. In summary, given our team's strong expertise in soft tissue biomechanics, mechanobiology, materials science, ultrastructural imaging, and gynecologic health, the proposed study will generate foundational data in the characterization of uterine fibroid heterogeneity and the mechanisms by which fibroids develop and grow. Henceforth, I plan to leverage these findings in future work to develop clinically translatable diagnostic tools and treatment approaches for uterine fibroids.