Immunometabolic cues recompose and reprogram the microenvironment around biomaterials

Circulating monocytes infiltrate and coordinate immune responses in various inflamed tissues, such as those surrounding implanted biomaterials, affecting therapeutic, diagnostic, tissue engineering and regenerative applications. Here, we show that immunometabolic cues in the biomaterial microenvironment govern CCR2- and CX3CR1-dependent trafficking of immune cells, including neutrophils and monocytes; ultimately, this affects the composition and activation states of macrophage and dendritic cell populations. Furthermore, immunometabolic cues around implants orchestrate the relative composition of proinflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+CX3CR1+ immune cell populations. Consequently, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment in part by myeloid cells around amorphous polylactide implants. In addition to, Arginase 1-expressing myeloid cells, T helper 2 cells and γδ+ T-cells producing IL-4 significantly contribute to shaping the metabolically reprogramed, pro-regenerative microenvironment around crystalline polylactide biomaterials. Taken together, we find that local metabolic states regulate inflammatory processes in the biomaterial microenvironment, with implications for translational medicine. ### Competing Interest Statement C.V.M and C.H.C are inventors on a pending patent application filed by Michigan State University on metabolic reprogramming to biodegradable polymers.