Stiffness-Dependent Mechanotransductive Signaling in Silicone Implant-Associated Fibrotic Encapsulation

Abstract Fibrotic encapsulation remains a major limitation of silicone-based soft-tissue implants and contributes to capsular contracture. Although biochemical and immunological factors have been extensively investigated, the contribution of implant stiffness to the peri-implant foreign body response remains incompletely defined. Here, we evaluated whether silicone implant stiffness is associated with fibrotic remodeling and changes in mechanotransductive signaling. Polydimethylsiloxane (PDMS) substrates and implants with elastic moduli ranging from 60 to 2000 kPa were fabricated and examined using human dermal fibroblasts and a rat subcutaneous implantation model. Increasing stiffness was associated with enhanced β1 integrin expression, FAK phosphorylation, ROCK1 expression, actin cytoskeletal organization, nuclear YAP localization, and upregulation of profibrotic markers, including α-SMA, CTGF, COL1A1, and COL3A1. In vivo, stiffer implants showed greater capsule thickness, collagen deposition, inflammatory cell infiltration, MPO and TGF-β1 expression, and sustained stiffness-associated changes in mechanotransductive proteins at 4 and 12 weeks. In contrast, the most compliant silicone condition attenuated these fibrosis-associated responses. These findings support material stiffness as a modifiable design parameter for silicone-based implantable biomaterials and suggest that relative softening within a feasible silicone material range may help reduce peri-implant fibrotic encapsulation.