Tissue constructs: platforms for basic research and drug discovery

Abstract

The functions, form and mechanical properties of cells are inextricably linked to their extracellular environment. Cells from solid tissues change fundamentally when, isolated from this environment, they are cultured on rigid two-dimensional substrata. These changes limit the significance of mechanical measurements on cells in two-dimensional culture and motivate the development of constructs with cells embedded in three-dimensional matrices that mimic the natural tissue. While measurements of cell mechanics are difficult in natural tissues, they have proven effective in engineered tissue constructs, especially constructs that emphasize specific cell types and their functions, e.g. engineered heart tissues. Tissue constructs developed as models of disease also have been useful as platforms for drug discovery. Underlying the use of tissue constructs as platforms for basic research and drug discovery is integration of multiscale biomaterials measurement and computational modelling to dissect the distinguishable mechanical responses separately of cells and extracellular matrix from measurements on tissue constructs and to quantify the effects of drug treatment on these responses. These methods and their application are the main subjects of this review.

Keywords: Zahalak model; cell mechanics; drug discovery; homogenization; tissue constructs; tissue mechanics.

Figure 1.

Experimental systems available for probing tissue construct mechanics. (a) The Barocas–Tranquillo cell-seeded collagen microsphere assay, in which contractile force exerted by cells can be estimated from the time-varying diameter of the collagen microsphere. (b) Uniaxial stretch of rectangular tissue constructs, which leads to a spatially varying strain field. (c) Uniaxial stretch of ring-shaped tissue constructs, which provides a more uniform strain field along the tensile flanks of the tissue construct. (d) Van den Bergh devices, which estimate tissue construct contractile force from the displacements of the flexible cantilevers. (e) Palpation devices, which estimate tissue construct mechanics from the resistance to a centrally applied downward force. (Online version in colour.)

Figure 2.

(a) Simple uniaxial tests can be performed using the ring-shaped tissue constructs of figure 1c. (b) In response to a rapid, step-like stretch of a tissue construct followed by an isometric hold (inset), an initial rise in force is observed, followed by a relaxation. (c) In response to cyclic loading, substantial changes to hysteresis occur between the first and second loadings, but the tissue construct eventually approaches a steady state after repeated stretches (adapted from Wagenseil et al. [96]). (Online version in colour.)

Figure 3.

(a) In tissue constructs containing chick embryo cardiomyocytes and chick myofibroblasts, both the periodic and baseline force vary nonlinearly with strain with during a ramp loading and unloading. (b) The relationship between developed tension and tissue construct length approximates the Frank–Starling law that is characteristic of heart muscle (adapted from Asnes et al. [127]). (Online version in colour.)

Figure 4.

The cells in a tissue construct constrict and remodel the ECM over a 3 day incubation. Cell concentrations increase in all cases. The number of cells decreases or increases during incubation, so that the final cell concentration approaches the percolation threshold (adapted from Marquez et al. [140]). (Online version in colour.)

Figure 5.

Force versus strain for activated and CD-treated FPMs. The ECM contribution is approximated by the force versus strain curve of the CD-treated FPM. The difference between the two provides an estimate of the cell response (adapted from Wakatsuki et al. [45]). (Online version in colour.)

Figure 6.

The linearized Hill model for skeletal muscle combines parallel and series springs with a damped active element. (Online version in colour.)

Figure 7.

The modulus of ECM in a tissue construct increases with increasing cell concentration, and, contrary to cells cultured on two-dimensional substrata, the effective modulus of the cells decreases. The crossover occurs at a cell concentration near the percolation threshold for the cells. (Online version in colour.)