Abstract
Cells within living soft biological tissues seem to promote the maintenance of a mechanical state within a defined range near a so-called set-point. This mechanobiological process is often referred to as mechanical homeostasis. During this process, cells interact with the fibers of the surrounding extracellular matrix (ECM). It remains poorly understood, however, what individual cells actually regulate during these interactions, and how these micromechanical regulations are translated to the tissue-level to lead to what we observe as biomaterial properties. Herein, we examine this question by a combination of experiments, theoretical analysis, and computational modeling. We demonstrate that on short time scales (hours) - during which deposition and degradation of ECM fibers can largely be neglected - cells appear to not regulate the stress / strain in the ECM or their own shape, but rather only the contractile forces that they exert on the surrounding ECM. Statement of significanceCells in soft biological tissues sense and regulate the mechanical state of the extracellular matrix to ensure structural integrity and functionality. This so-called mechanical homeostasis plays an important role in the natural history of various diseases such as aneurysms in the cardiovascular system or cancer. Yet, it remains poorly understood to date which target quantity cells regulate on the mircroscale and how it translates to the macroscale. In this paper, we combine experiments, computer simulations, and theoretical analysis to compare different hypotheses about this target quantity. This allows us to identify a likely candidate for it at least on short time scales and in the simplified environment of tissue equivalents.
Highlights
While many engineering materials remain stress-free, or in their respective production-induced stress state, in the absence of external loading, living soft tissues generally seek to establish a preferred mechanical state that is not stress-free
A major shortcoming of previous studies about how tissue equivalents restore a preferred level of tension after an external perturbation (e.g., [8,32]) is the short period of less than an hour over which restoration of tension was monitored
No new steady state of tension was re-established, leaving unanswered the question, within which tolerance the prior tension is restored after perturbations. This made it difficult to understand which mechanical target quantity is preserved by mechanical homeostasis
Summary
While many engineering materials remain stress-free, or in their respective production-induced stress state, in the absence of external loading, living soft tissues generally seek to establish a preferred mechanical state that is not stress-free. Tissue equivalents are simple model systems of living soft tissues that consist often of collagen fibers seeded with living cells When fixed at their boundaries in an initially stressfree configuration, tissue equivalents exhibit a characteristic behavior observed in numerous independent studies [8,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. This level of tension is maintained for a prolonged period (phase II) If this steady state is perturbed (e.g., by stretching or releasing the tissue equivalent slightly), cells seem to regulate their activity such that the tension in the gel is restored toward the value prior to the perturbation [8,32,33]. Whether this value is recovered within a range consistent with homeostasis, noting that “homeo” means similar to in contrast with “homo” which means the same as [46]
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