Conference Agenda

Mechanical homeostasis is a ubiquitous biological and physiological process whereby particular quantities are regulated to remain, within a tolerance, near preferred values called set points. Under normal conditions in adulthood, load bearing soft tissues exhibit homeostatic responses to modest perturbations in mechanical loading. By contrast, compromised or lost homeostasis is often a contributor to pathogenesis and disease progression. In this presentation, we will study mechanical homeostasis and its loss within the context of both continuum models and coupled models that integrate tissue-level biomechanics and cell signaling models. We will identify conditions that drive homeostasis and focus on inflammatory mechanisms that compromise homeostasis. Whereas the general framework will apply to most soft tissues, we will use aortic growth and remodeling as an archetype to illustrate both the methods and novel predictions. For further reading, please see [1-4]. [1]. Humphrey JD, Dufrense E, Schwartz MA (2014) Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15: 802-812. [2]. Humphrey JD, Schwartz MA (2021) Vascular mechanobiology: homeostasis, adaptation, and disease. Annu Rev Biomed Engr 23:1-27. [3]. Latorre M, Spronck B, Humphrey JD (2021) Complementary roles of mechanotransduction and inflammation in vascular homeostasis. Proceed R Soc A 477:20200622. [4]. Irons L, Latorre M, Humphrey JD (2021) From transcript to tissue: multiscale modeling from cell signaling to matrix remodeling. Annl Biomed Engr 49:1701-1715.

Cell organisation controls critical physiological functions in a range of organs, but this organisation has never been thought to be influenced by tissue shape. We show that the overall shape of the tissue strongly affects the alignment of fibroblasts. For rectangular-shaped tissues, cells align preferentially with the long axis, with the degree of alignment increasing with both the tissue aspect ratio and cell density. Remarkably, this alignment occurs without corresponding realignment of the collagen. Moreover, there is no spatial gradient in cell distribution, consistent with the fact that self-similarly increasing tissue size did not affect cell alignment; all of this suggests a very long-range mechanism by which cells detect the overall tissue shape. We demonstrate that these counterintuitive observations can be rationalized by recognizing that, unlike a collection of non-living particles that collectively attain an equilibrium state, the internal metabolic processes within living cells drive them to maintain a homeostatic state individually. This individual constraint, combined with the overall constraint of the tissue, drives a long-range mechanism of tissue shape detection.

We introduce an innovative model of the human corneal stroma, regarded as a fluid-saturated continuum, with to objective to describe important swelling and thinning phenomena observed in pathological conditions. In contrast with well-settled approaches that model the stroma as a quasi-incompressible hyperelastic medium, possibly including anisotropy and heterogeneity, here we focus on the actual nature of the tissue, where the content of water reaches about 78% in weight. Although purely mechanics models have been shown to be very good at predicting physiological behaviors, they have not been able to reproduce the evolution of pathologies related to the imbalance of water content in the stroma. We regard the tissue as a fully saturated mixture of a solid phase and a fluid phase, preserving the possibility to characterize both phases in terms of multiple components. This study represents a first step towards the development of a multiphysics model capable of explaining corneal swelling and ectasia. The work is done in collaboration with Alessandro Giammarini (Polimi).