FAK modulates immune response and fibroblast activation in biomaterial-induced fibrosis.

Fibrotic capsule formation remains a major barrier in the clinical performance of biomedical implants. Here, we demonstrate that synthetic hydrogels mimicking the mechanical properties of fibrotic tissue trigger stromal cell activation and immune remodeling via focal adhesion kinase (FAK)-mediated mechanotransduction. Using a mechanically tunable poly(ethylene glycol) hydrogel platform and subcutaneous implantation in mice, we show that pharmacological inhibition of FAK activity significantly reduces α-smooth muscle actin (α-SMA)-positive myofibroblast activation, collagen I deposition, and fibrotic capsule thickness in a hydrogel stiffness-dependent manner. Flow cytometry and cytokine profiling revealed that FAK inhibition alters the fibrotic niche by reducing CD163-positive M2c macrophages and significantly downregulating pro-fibrotic cytokines including IL-6, and VEGF, while transiently increasing regulatory T cells and elevating IL-10 levels. Importantly, these changes occurred without parallel increases in canonical pro-inflammatory cytokines, indicating selective modulation rather than global immune suppression or activation. These findings position FAK as a central hub translating mechanical cues into coordinated stromal and immune responses. Targeting FAK mechanotransduction may provide a therapeutic strategy to mitigate foreign body responses and improve implant integration across regenerative applications.