Fibroblasts play a critical role in normal wound healing, but this process can be unintentionally activated upon implantation of medical devices. This activation can result in fibrotic encapsulation and lead to device failure. Within fibrotic tissue, fibroblasts undergo myofibroblastic differentiation, initiated by TGF� signaling. This differentiation is culminating in the expression of a-smooth muscle actin (aSMA) and increased production of extracellular matrix (ECM) components, such as collagen I and III. Our previously published results demonstrate that topographic cues down regulate both TGF� signaling and myofibroblastic differentiation in fibroblasts. Yet, it is currently unclear the mechanism through which topography regulates myofibroblastic differentiation and fibrosis.We have fabricated a series of films with micro-sized fibers by laminating medical grade polypropylene through a microporous polycarbonate membrane. The fiber length and diameter can be reliably controlled allowing tunable topography. As fiber length increases, the characteristic elongated morphology of cultured fibroblasts decreases dramatically. Intercellular tension is also decreased, as marked by a decrease in phosphorylated myosin light chain. Moreover, as fiber length increases, fibroblastic gene expression for components of the TGF� pathway, including TGF�1, Smad3 and TGF� receptor II (T�RII) decreases. This reduction suggests that fibroblasts become insensitive to TGF� as fiber length increases. As expected, the reduction in TGF� signaling results in a decrease in aSMA, Cola2, and Col3a1 gene expression. In an in vivo wounding model, microfiber films implanted in the subcutaneous layer of wild type mice dramatically reduce deposition of collagen around the films compared to flat controls. This result suggests that modifying the surface of a material to include microfibers could reduce fibrotic encapsulation of implanted medical devices. The mechanisms elucidated by further studies could also reveal novel therapeutic targets for fibrotic diseases such as keloids and hypertrophic scars.

Microfibrous films reduce fibrotic encapsulation through the TGF� pathway

248th National Meeting (2014)

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