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质溶解中的影响PI：Jan P. Stegemann，University of Pennsylvania非技术：NSF/FDA驻校学者计划下的该奖项是为了研究医疗器械中的磨损颗粒如何与身体相互作用的合作项目。全关节植入物的使用已经扩展到更年轻和更活跃的患者人群。虽然有效地恢复关节运动和使患者独立，关节植入物具有有限的寿命，因为它们的表面可以随着时间的推移磨损。产生的微观磨损颗粒会引发身体的炎症反应，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。这是同一项目下的一个项目的后续项目，该项目设计和测试了一个3D水凝胶模型，用于研究免疫细胞与医疗植入物产生的微观磨损碎片之间的相互作用。该项目团队在制造模拟生理条件的3D环境方面拥有丰富的经验，可用于了解炎症的细胞机制。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一个机会，使公众健康和安全受益。技术：这项为期一年的驻校学者计划的目标是调查关节滑膜局部机械环境特征在确定由常驻巨噬细胞安装到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学和组织学成分，结合压力系统控制静水压力，模拟机械环境。将使用模拟物理细胞-磨损颗粒相互作用的空间构型以及由炎症或植入物微动引起的流体动力学环境变化的压力控制培养环境，在体外评价机械转导对巨噬细胞活化的作用以及对磨损颗粒产生的炎症反应。关注的生物标志物是那些表现出依赖于磨损颗粒的局部浓度和理化性质以及周围机械环境的释放模式的生物标志物。将应用3D体外机械生物学和生理化学试验的组合来评价聚合物磨屑的生物相容性，重点关注吞噬细胞反应如何改变植入物固定或促进骨质溶解。有必要在细胞水平进行更稳健和预测性的研究，以限制受益于下一代医疗器械的患者的潜在风险。拟议项目的更广泛影响包括其对我们对巨噬细胞机械生物学的集体理解的贡献，它还提供了一个模型系统，用于在正常或病理相关的机械条件下筛选新的潜在生物材料。本研究的结果可用于预测生理位置或既存病变引起的机械需求如何影响全关节器械的寿命。这种系统对于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性和有效性问题，并通过提供相对较轻的负担和更快速的材料测试方法来降低新器械开发的成本。

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.