The contracture-in-a-well. An in vitro model distinguishes bulk and interfacial processes of irreversible (fibrotic) cell-mediated contraction

Tissue contractures are processes of cell-mediated contraction, irreversible in nature and typically associated to fibrotic phenomena. Contractures can be reproduced in vitro; here, we have used a medium-throughput model based on fibroblast-seeded fibrin (the ‘contracture well’). Firstly, we show how profoundly these processes depend on the location of the contractile cells: when on top of the material, they produce an interfacial contracture (analog to capsular contraction around an implant), which tends to bend the construct; when seeded in the matrix, they initiate a bulk contracture (analogue to a wound bed closure) that shrinks it from within. Secondly, we demonstrate that the geometrically different interfacial and bulk contractures are also mechanically and biologically different processes. Thirdly, we show the potentially predictive value of this model, since not only it recapitulates the effect of pro-fibrotic factors (TGF-β1 for dermal (myo)fibroblasts), but can also indicate the fibrotic potential of a given cell population (here, dystrophic myoblasts more fibrotic than healthy or genetically corrected ones), which may have important implications in the identification of an appropriate therapies.