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 with 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, fibroblasts produce an interfacial contracture (analog to capsular contraction around an implant), which tries and bends the construct; when seeded inside the material, they initiate a bulk contracture (analogue to a wound bed closure) that shrinks it from within. Secondly, we demonstrate that the interfacial and bulk contractures are also mechanically and biologically different processes. Thirdly, we show the potentially predictive value of this model, since it not only 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 appropriate therapies.