Mechanical homeostasis in tissue equivalents: a review

Abstract

There is substantial evidence that growth and remodeling of load bearing soft biological tissues is to a large extent controlled by mechanical factors. Mechanical homeostasis, which describes the natural tendency of such tissues to establish, maintain, or restore a preferred mechanical state, is thought to be one mechanism by which such control is achieved across multiple scales. Yet, many questions remain regarding what promotes or prevents homeostasis. Tissue equivalents, such as collagen gels seeded with living cells, have become an important tool to address these open questions under well-defined, though limited, conditions. This article briefly reviews the current state of research in this area. It summarizes, categorizes, and compares experimental observations from the literature that focus on the development of tension in tissue equivalents. It focuses primarily on uniaxial and biaxial experimental studies, which are well-suited for quantifying interactions between mechanics and biology. The article concludes with a brief discussion of key questions for future research in this field.

Keywords: Growth and remodeling; Mechanical homeostasis; Mechanobiology; Mechanoregulation; Mechanosensation; Mechanotransduction; Tensional homeostasis.

Fig. 1

Cell-seeded collagen gels as tissue equivalents can provide information relevant to mechanical homeostasis of soft tissues. a Illustration of a patient with a local dilatation of the aorta (i.e., an aneurysm); due to ill-controlled mechanobiological processes; such aneurysms can continue to grow over years and often finally rupture, resulting in high mortality and morbidity; b in vivo studies often cannot provide the fine control needed to assess the cell-ECM interactions that are fundamental to promoting or preventing homeostasis, and thus understanding disease progression. c Cell-seeded collagen or fibrin gels have proven to be simple but powerful model systems to study soft tissue mechanobiology. d The much lower complexity of cell-seeded collagen gels compared to native ECM makes them useful for studying the fundamental cell-matrix interactions, often one cell type at a time

Fig. 2

Free-floating (a), uniaxially constrained (b), and biaxially constrained (c) fibroblast-seeded collagen gels (i.e., tissue equivalents) are observed to contract substantially over the first hours to days. Cells residing in the gel initially spread and attach to surrounding collagen fibers. Cellular contraction then compacts the surrounding matrix thus stressing the fibers. d Biaxial testing device reported in Eichinger et al. (2020). Sensors are installed along two axes to record the development of tension in a cruciform gel

Fig. 3

In uniaxially constrained tissue equivalents, the measured tensile force evolves in two characteristic phases: a steep increase (phase I) followed by a plateau (phase II). Here, we show experimental data from Eichinger et al. (2020). Each curve is an average of three identical experiments. a Dependence of the plateau value of tension on collagen concentration in the gel with a constant cell density of $0.5·{10}^6\text{cells/ml}$. Higher collagen concentrations lead to higher steady state values. b Influence of cell density for a collagen concentration of 1.5 mg/ml : Higher cell densities lead to both a steeper initial increase and a higher plateau value of the measured force. c If the tissue equivalent (collagen concentration 1.5 mg/ml , cell density $1.0·{10}^6$ cells/ml) is suddenly stretched or released after having reached the plateau state, force returns toward its value prior to this perturbation. The monotonically decreasing force qualitatively illustrates the expected evolution in case of cell lysis according to Marenzana et al. (2006); the fraction of the tensile force remaining in the gel has been called residual matrix tension (RMT)

Fig. 4

Schematic drawing of cell-matrix interactions in health and disease. Center: cell in normal conditions interacting via integrins with surrounding ECM, which in vivo typically exhibits some tension. Bottom row shows typical behavior of tissue equivalents developing a homeostatic nonzero plateau of tension over time. Right: In case of further increases in tension, i.e., overloading, healthy tissue seeks to restore the prior mechanical state due to a homeostatic feedback loop consisting of mechanosensation, mechanotransduction, and mechanoregulation. If this feedback loop is compromised, pathological signaling can lead to a fibrotic response (top right). In general, both the healthy and the fibrotic reaction may help to restore the preferred mechanical state (bottom right). Left: in case of decreases in tension, i.e., under-loading, e.g., due to injury, homeostatic feedback loops can lead to re-establishment of a homeostatic state. By contrast, pathological mechanosensitivity of tissues can lead to apoptosis (top row). The homeostatic feedback loop aims at restoring the homeostatic state, whereas apoptosis may lead to tissue failure (bottom row)