Spermidine reduces peri-implant inflammation and fibrosis to nurture osseointegration

Medical implants of exogenous materials often induce foreign body response (FBR) in hosts, which is characterized by inflammation and fibrosis. Herein, composite scaffolds with interpenetrating hard and soft phases were fabricated, consisting of titanium alloy and a biomatrix mimicking extracellular matrix. Spermidine-functionalized biomatrix (CST@GOA) not only inhibits inflammatory response and osteoclastogenesis of macrophages, but also fosters migration and osteogenesis of MC3T3-E1 cells. Interestingly, CST@GOA can mitigate acute inflammation and fibrosis, characteristics of FBR, against silicone implanted in rats. Moreover, bone repair experiments in rabbits show that CST@GOA-interpenetrated porous titanium alloy scaffolds attenuate FBR against metal implants and promote osseointegration. Meanwhile, diethylenetriamine, a polyamine resembling spermidine in chemistry, has been used in place of spermidine to enable 'operando' comparison in both cell and animal experiments. Proteomic analysis of rabbit bone tissues reveals that spermidine modulates PI3K-Akt pathway by upregulating PTEN, which may play a pivotal role in coordinating downstream signaling of inflammation, autophagy and bone homeostasis. Together, it is demonstrated that spermidine can endow either synthetic polymers or metal implants with anti-FBR activity by regulating host response and nurture peri-implant niche to improve osseointegration of metal implants. Hence, spermidine affords a natural and elegant strategy to alleviate FBR against medical implants.