A Magnetically Responsive Biomaterial System for Flexibly Regulating the Duration between Pro- and Anti-Inflammatory Cytokine Deliveries

While inflammation can be problematic, it is nonetheless necessary for proper tissue regeneration. However, it remains unclear how the magnitude and duration of the inflammatory response impacts regenerative outcome. This is partially due to the difficulty in temporally regulating macrophage phenotype at wound sites. Here, a magnetically responsive biomaterial system potentially capable of temporally regulating macrophage phenotypes through sequential, on-demand cytokine deliveries is presented. This material system is designed to (i) rapidly recruit proinflammatory macrophages (M1) through initial cytokine deliveries and (ii) subsequently transition macrophages toward anti-inflammatory phenotypes (M2s) through delayed, magnetically triggered cytokine release. Here, the ability of this system to initially deliver proinflammatory cytokines (i.e., monocyte chemoattractant protein-1 and interferon gamma), recruit, and harbor an expanding macrophage population, and delay deliveries of anti-inflammatory cytokines (i.e., IL-4 and IL-10) until the application of magnetic fields from simple hand-held magnets is demonstrated. Critically, the timing and rate of these delayed deliveries can be remotely/magnetically controlled. This biomaterial system can provide a powerful tool in (i) understanding the relationship between inflammation and regenerative outcome, (ii) developing optimized cytokine delivery strategies, and (iii) clinically implementing those optimized delivery strategies with the on-demand versatility needed to alter the course of therapies in real time.