NSF/FDA SIR: Impact of Mechanotransduction in Polymer Microparticle-Induced Macrophage Inflammation and Osteolysis

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

NSF/FDA SIR: Impact of Mechanotransduction in Polymer Microparticle-Induced Macrophage Inflammation and Osteolysis PI: Jan P. Stegemann, University of Michigan Non-technical: This award under the NSF/FDA Scholar-in-Residence program is for a collaborative project to study how wear particles from medical devices may interact with the body. The use of total joint implants has been expanding to younger and more active patient populations. Though effective in restoring joint motion and enabling patient independence, joint implants have a finite lifespan because their surfaces can wear over time. The microscopic wear particles produced can trigger the body's inflammatory response, which can lead to health complications. This project will develop advanced methods to study how polymer wear particles from medical implants can interact with macrophage cells in the joint capsule, and in particular how these interaction are influenced by fluid pressure. It is a follow-on to a project under the same program to design and test a 3D hydrogel model for studying interactions between immune cells and microscopic wear debris generated by medical implants. The project team has extensive experience fabricating 3D environments mimicking physiological conditions necessary that can be used to understand the cellular mechanisms of inflammation. The work presents an opportunity for collaborative research between academic and government research labs benefitting public health and safety. Technical: The goal of this one year Scholar-in-Residence program is to investigate the role of the local mechanical environment characteristic of joint synovium in determining the degree of inflammation mounted by resident macrophages to polymeric wear debris. It will apply a simple 3D cell culture model of macrophage inflammation, representing the biological and histological components of the joint space, combined with a pressure system control hydrostatic pressure, mimicking the mechanical environment. The role of mechanotransduction on macrophage activation and the resulting inflammatory response to wear particles will be evaluated in vitro using a pressure-controlled culture environment that mimics the spatial configuration of the physical cell-wear particle interaction, as well as the changes in the hydrodynamic environment caused by inflammation or implant micromotion. The outcome biomarkers of interest will be those that exhibit a release pattern dependent on the local concentrations and physiochemical properties of wear particles as well as the surrounding mechanical environment. A combination of 3D in vitro mechanobiological and physiochemical tests will be applied to evaluate the biocompatibility of polymeric wear debris, focusing on how phagocytic cell response alters implant fixation or promotes osteolysis. More robust and predictive studies at the cellular level are necessary to limit the potential risk to patients benefitting from the next generation of medical devices. The broader impact of the proposed project includes its contribution to our collective understanding of macrophage mechanobiology and it also provides a model system for screening new potential biomaterials under normal or pathologically-relevant mechanical conditions. Outcomes of this study may be applied to predict how mechanical demands caused by physiological location or pre-existing pathology could impact the lifespan of a total joint device. Such a system is important for the FDA's mission as it addresses potential patient safety and efficacy issues that are related to implant success, and potentially reduces the costs of new device development by providing a relatively less burdensome and more rapid method for materials testing.