Bone Regeneration Suing Engineered Materials

A bioinspired strategy to elicit transcriptional control of macrophages for bone regeneration Inflammation plays a vital role during bone formation, resorption, and fracture healing. The process of fracture healing is biologically entangled with that of acute inflammation and innate immunity. A proper sequence and dose of inflammatory signals are critical for proper bone healing. Macrophages are one of the first cells that infiltrate the fracture site and are indispensable for fracture healing. Macrophages are shown to promote osteoblastic differentiation and vascularization. It is well recognized that mechanical conditions influence callus development and the type and extend of osteogenesis during fracture. But the majority of the work on macrophage response, in the context of fracture healing, has focused on activation mediated by biochemical signals. The physical parameters of the fracture microenvironment, especially matrix mechanics and their influence on macrophage immunophenotypes, are largely overlooked. Macrophages respond to the changes in extracellular matrix mechanics through actin- cytoskeletal reorganization, nuclear deformation, and gene expression. We hypothesized that the physical forces in the form of substrate mechanics can elicit transcriptional control of macrophages via MRFT-A release (from G-actin) and HDAC3 redistribution. The two independent goals for this project are 1) To test the hypothesis and elucidate the actin cytoskeleton-mediated transcriptional control in macrophages during fracture in a murine model; 2) To engineer immunomodulatory materials with suitable viscoelastic mechanics to guide the transcriptional machinery of macrophages towards therapeutic bone regeneration. The proposed research not only provides insights into the role of the innate immune response in fracture healing but also develops next-generation immunomodulatory materials for enhanced bone regeneration.