Distinct Roles of Nanoparticle Incorporation and Polymer Degradation in Fibroblast Response to Device Design

Fibrotic encapsulation of implanted biomedical devices represents the highest cause of device failure across numerous fields, including orthopedics, breast implants and neural electrodes. While most research has focused on the immune system for driving the foreign body response and ultimate device success, fibroblasts are emerging as another key regulator of tissue response. Therefore, in the present study, we evaluated the activation of primary human dermal fibroblasts into myofibroblasts, a contractile cell that is a hallmark of fibrosis, in response to the design of porous scaffolds mimicking regenerative medicine implants. Over four weeks in culture, two factors were studied (1) nanoparticle incorporation into scaffolds for imaging functionality and (2) the scaffold’s polymer matrix, which dictates chemistry, mechanics and degradation. Incorporation of tantalum oxide (TaOx) nanoparticles, a radiopaque nanoparticle able to impart CT-visibility to radiolucent polymers, had a minimal effect on fibroblasts at ≤ 20 wt%, but significantly down-regulated expression of alpha smooth muscle actin (αSMA) (0.31 ± 0.1 fold change) compared to scaffolds without nanoparticles, likely driven by the increase in nanoscale surface roughness. Degradation rate of the polymer matrix altered myofibroblast activation, with a fast-degrading polymer, poly(lactide co-glycolide) (PLGA) 50:50, significantly up-regulating multiple myofibroblast markers, including αSMA (5.16 ± 2.5), vinculin, integrin β1, and integrin β5, compared to non-degrading polycaprolactone (PCL). The effect was due to the release of degradation products, namely lactic acid, which affects cellular metabolism. Together this highlights that scaffold design affects biological response immediately post-implantation in ways that impact the ultimate success or failure of biomedical devices.