Biomaterial-Activated Macrophage-T Cell Crosstalk Promotes Myofibroblastic Differentiation of Mesenchymal Stem Cells

Biomaterials for orthopedic and dental implantation are designed to promote the timely resolution of inflammation and new bone formation while limiting the deposition of fibrotic tissue, which can cause implant failure. During the immune response to implantation, T cells at the peri-implant interface release cytokines that modulate innate immune cell response, mesenchymal stem cell (MSC) recruitment and proliferation, and new bone formation. However, T cells contribute to fibrosis in tissues such as the heart, lungs, liver, kidneys, and skin. This study aimed to determine how T cells contribute to peri-implant fibrosis using two biomaterials with differing inflammatory responses: pure titanium (Ti) and polyetheretherketone (PEEK). Following implantation of these materials in mice, we found greater recruitment of pro-inflammatory macrophages, CD4⁺ T cells, and CD8⁺ T cells in response to PEEK implants than to Ti implants. Likewise, macrophages cultured on PEEK surfaces demonstrated higher gene expression and protein secretion of pro-inflammatory factors (IL-6, IL-17A, TNF-α, and TGF-β1) than on Ti, an effect robustly enhanced when cells were cocultured with T cells. Finally, MSCs cultured with the conditioned media from macrophage-T cell co-cultures on PEEK had high expression of pro-fibrotic genes. Our findings demonstrate that biomaterial properties directly contribute to MSC differentiation toward myofibroblasts through the activation and crosstalk of macrophages and T cells, suggesting that these cells play a significant role in the fibrotic encapsulation of biomaterials.