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, one of the first cells that infiltrate the fracture site, are indispensable for fracture healing as they promote osteoblastic differentiation and vascularization. Also, it is well recognized that mechanical conditions influence callus development and the type and extent of osteogenesis during fracture. But most work on the macrophage response, in the context of fracture healing, has focused on activation mediated by biochemical signals. The biophysical parameters of the fracture microenvironment, especially matrix mechanics and their influence on macrophage immunophenotypes, are largely overlooked. Our overall goal is to elucidate the influence of biophysical cues on macrophage function to develop an immunomodulatory platform reducing the burden of bone diseases in patients. Macrophages respond to changes in extracellular matrix mechanics through actin-cytoskeletal reorganization, nuclear deformation, and gene expression. We hypothesize that biophysical forces in the form of substrate mechanics elicit transcriptional control of macrophages via a transcriptional activator, MRTF-A, release (during actin polymerization) and redistribution of a cell signaling mediator, HDAC3 (chromatin compaction). The two independent aims for this project are: 1) Elucidate the actin cytoskeleton-mediated transcriptional control in macrophages in a murine fracture model, 2) Engineer immunomodulatory materials with suitable viscoelastic mechanics to guide the transcriptional machinery of macrophages to promote bone regeneration. Overall, our proposed research provides insights into the role of the innate immune response in fracture healing and develops next-generation immunomodulatory materials for therapeutic bone regeneration. Hence our research aligns well with the CPRI COBRE mission to facilitate translational chemical biology research to advance treatments and strategies to address significant health challenges.
