Immunomodulatory Therapy for Bone Regeneration

炎症在骨形成、骨吸收和骨折愈合过程中起着至关重要的作用。骨折愈合的过程在生物学上与急性炎症和先天免疫的过程纠缠在一起。适当的炎症信号序列和剂量对骨愈合至关重要。巨噬细胞是最早渗透到骨折部位的细胞之一，由于其促进成骨细胞分化和血管化，对骨折愈合是必不可少的。此外，众所周知，机械条件会影响骨折时骨痂的发育以及成骨的类型和程度。但是，在骨折愈合的背景下，大多数关于巨噬细胞反应的研究都集中在生化信号介导的激活上。断裂微环境的生物物理参数，特别是基质力学及其对巨噬细胞免疫表型的影响在很大程度上被忽视。我们的总体目标是阐明生物物理线索对巨噬细胞功能的影响，以开发一种减轻骨病患者负担的免疫调节平台。

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.