Effect of Source Animal Age upon Macrophage Response to Extracellular Matrix Biomaterials

Extracellular matrix biomaterials have been shown to promote constructive remodeling in many preclinical and clinical applications. This response has been associated with the promotion of a timely switch from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages. A previous study has shown that this beneficial response is lost when these biomaterials are derived from aged animals. This study examined the impact of small intestine submucosa (SIS) derived from 12, 26 and 52 week old pigs on the phenotype and function of bone marrow macrophages derived either from 2 or 18 month old mice. Results showed that 52 week old SIS promoted less iNOS in 2 month macrophages and Fizz1 expression in 2 and 18 month compared to 12 week SIS. Pro-inflammatory cytokine exposure to 52 week SIS-treated macrophages resulted in higher iNOS in 18 month macrophages and reduced MHC-II expression in 2 month macrophages, as well as reduced nitric oxide production in comparison to 12 week SIS. These results indicate that ECM derived from aged animals promotes an altered macrophage phenotype compared to young controls. This suggests that sourcing of ECM from young donors is important to preserve constructive remodeling outcomes of ECM biomaterials. Alteration of macrophage phenotype by aged ECM also raises the hypothesis that alterations in aged ECM may play a role in immune dysfunction in aged individuals.