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

NSF/FDA SIR：机械转导在聚合物微粒诱导的巨噬细胞炎症和骨溶解中的影响PI：Jan P.Stegemann，密歇根大学非技术：NSF/FDA学者驻留计划下的这个奖项是为了一个合作项目，研究医疗设备中的磨损颗粒如何与人体相互作用。全关节植入物的使用已经扩展到更年轻和更活跃的患者群体。虽然关节植入物在恢复关节运动和使患者独立方面有效，但其寿命有限，因为它们的表面会随着时间的推移而磨损。产生的微小磨损颗粒会触发人体的炎症反应，从而导致健康并发症。该项目将开发先进的方法来研究医疗植入物中的聚合物磨损颗粒如何与关节囊中的巨噬细胞相互作用，特别是这些相互作用如何受到流体压力的影响。这是同一计划下的一个项目的后续项目，该项目旨在设计和测试3D水凝胶模型，以研究免疫细胞和医疗植入物产生的微观磨损颗粒之间的相互作用。该项目团队在构建模拟生理条件的3D环境方面拥有丰富的经验，这些条件可以用来理解炎症的细胞机制。这项工作为学术和政府研究实验室之间的合作研究提供了机会，有利于公众的健康和安全。技术：这项为期一年的学者驻留计划的目标是调查关节滑膜局部机械环境特征在确定常驻巨噬细胞对聚合物磨损碎屑的炎症程度中的作用。它将应用一个简单的巨噬细胞炎症的3D细胞培养模型，代表关节间隙的生物和组织成分，结合控制静液压力的压力系统，模拟机械环境。在体外，将使用压力控制的培养环境来模拟物理细胞-磨损颗粒相互作用的空间构型，以及炎症或种植体微运动引起的流体动力学环境的变化，来评估机械转导在巨噬细胞激活和由此产生的对磨损颗粒的炎症反应中的作用。最终的生物标志物将是那些表现出依赖于磨损颗粒的局部浓度和物理化学性质以及周围机械环境的释放模式的生物标志物。将采用3D体外机械生物学和物理化学测试相结合的方法来评估聚合物磨损碎片的生物相容性，重点是吞噬细胞反应如何改变种植固定或促进骨溶解。有必要在细胞水平上进行更有力和更具预测性的研究，以限制受益于下一代医疗设备的患者的潜在风险。拟议项目的更广泛影响包括它对我们对巨噬细胞机械生物学的集体理解的贡献，它还为在正常或病理相关的机械条件下筛选新的潜在生物材料提供了一个模型系统。这项研究的结果可能被应用于预测生理位置或先前存在的病理所引起的机械需求如何影响整个关节装置的寿命。这样的系统对FDA的使命非常重要，因为它解决了与植入成功相关的潜在患者安全和疗效问题，并通过提供一种相对较轻和更快速的材料测试方法，潜在地降低了新设备开发的成本。

NSF/FDA SIR: Impact of Mechanotransduction in PolymerMicroparticle-Induced Macrophage Inflammation and OsteolysisPI: Jan P. Stegemann, University of MichiganNon-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.