Modulating the Inflammatory Response of Macrophages on Biomaterial Surfaces
The foreign body response is an inflammatory response to implanted materials and poses significant challenges for biomaterials-based medical applications, often leading to the degradation or fibrous encapsulation of an implanted device. The host response is largely dictated by the proteins that adsorb to the biomaterial surface, including damage-associated molecular patterns (DAMPs) that are released by cells upon necrosis or when under considerable amounts of stress. The immune response to implanted materials is carried out primarily by macrophages, which recognize DAMPs and other surface-adsorbed proteins with toll-like receptors (TLRs), initiating an inflammatory response. Macrophages play key roles in inflammatory and wound healing responses due to their ability to transition from a pro-inflammatory M1-like phenotype to a pro-resolution M2-like phenotype. This thesis explores the use of a model of biomaterial-induced macrophage inflammatory response, and the ability of two molecules to modulate this response. A human macrophage-like cell line was treated with T6167923, a MyD88 signal transduction inhibitor. MyD88 is a critical component in the TLR pathway, which plays a significant role in inflammation and has been implicated in biomaterial-induced macrophage activation. Unfortunately, the inhibitor consistently precipitated in cell culture media, at all concentrations and with all dilution methods attempted. The presence of the particles may have encouraged pro-inflammatory activation of the cells via phagocytosis. However, some conditions did result in reduced activation with inhibitor treatment, suggesting further work with this molecule is warranted. The second investigated molecule was Maresin 1 (MaR1), an endogenous pro-resolving mediator that contributes to the active transition from the inflammatory phase of wound healing towards resolution. The effect of MaR1 on macrophage activation was studied in two macrophage-like cell lines and primary macrophages, and produced conflicting results. However, the inconsistency was attributed to the sensitivity of MaR1 to degradation. This could not only produce some confounding results, but also raised significant technical challenges in handling MaR1. Nonetheless, fresh, undegraded MaR1 did reduce pro-inflammatory cytokine expression in TLR2-activated dTHP1-XBlue macrophages. Although both molecules posed significant technical challenges, their effects should be investigated further. Drug delivery systems should be explored to overcome these challenges and allow for direct delivery to cells.