Modulation of Macrophages Differentiation by Nanoscale-Engineered Geometric and Chemical Features

Macrophage differentiation into M1 (inflammatory) and M2 (healing) phenotypes plays a vital role in determining the fate of biomaterials. The biophysical properties of the extracellular matrix are known to affect macrophage behavior. Mimicking these special biophysical properties of the extracellular matrix has led to increasing interest in biomaterial constructs with tailor-engineered surface nanotopographical and chemical properties. However, a significant gap of knowledge exists in the role played by the combinational effect of surface nanotopography and chemistry. To address this gap, we have fabricated nanoporous surfaces of controlled pore size (30, 65, and 200 nm) and lateral spacing with uniform outermost surface chemistry tailored with amines (NH₂), carboxyl (COOH-) and hydrocarbon (CH₃-) functionalities. We show that the combinatory effects of surface properties can direct the differentiation of macrophages to the pro-healing M2 phenotype. This is most evident on the surface featuring nanopores of 200 nm and -COOH functionality. Overall, the concentration of pro-inflammatory cytokines significantly decreases, while the concentration of anti-inflammatory cytokines increases many folds on nanotopographically, and chemically, modified surfaces compared to their planar counterparts. Our data provide pioneering knowledge that could provide pathways to tuning inflammatory and foreign body responses and instruct the design of tailor-engineered biomaterial implants to enable better clinical outcomes.