NSF/FDA SIR: Three-Dimensional In Vitro Modeling of Interactions Between Orthopedic Wear Particles, Biofilm, and Macrophages

非技术摘要：NSF/FDA驻校学者计划下的这一奖项是为了研究医疗器械的磨损颗粒如何与体内细菌相互作用，以及这如何导致医疗植入物松动的合作项目。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。虽然在恢复关节运动和使患者独立性方面有效，但关节植入物的表面会随着时间的推移而磨损，产生微观磨损碎屑。该项目研究这些颗粒如何与体内的细菌相互作用，以及磨损颗粒和细菌如何影响炎症细胞的功能。它是同一计划下先前项目的后续项目，旨在设计和测试先进的组织模型，以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safety.Technical摘要：这一年的驻校学者计划的目标是了解磨损颗粒，生物膜和免疫细胞如何协同作用，以促进全关节置换术器械的无菌性松动。重要的是，它采用先进的基于生物材料的3D组织模型，模拟生理环境。具体而言，该项目的智力价值集中在使用这些模型来模拟生物膜附着的磨损颗粒和巨噬细胞之间直接接触的体内情况，从而改变炎症反应和骨质溶解。该项目得益于Stegemann实验室（美国）的专业知识。Michigan）在制造生理相关的体外组织结构方面，与FDA OSEL实验室在磨损颗粒、生物膜和巨噬细胞之间相互作用的物理化学测试和评价方面的技术和经验合作。该项目的第一个目标是根据其物理化学特性，评价植入物材料中磨损颗粒的细菌粘附和生物膜形成倾向。对代表性材料（聚乙烯、PEEK、PMMA、Co-Cr、CP-Ti）的磨屑进行了全面表征，其理化性质与支持金黄色葡萄球菌（一种通常与骨科感染相关的细菌）产生的生物膜的能力相关。第二个目标是使用含或不含同种异体骨碎片的3D体外组织模型，在磨损颗粒与生物膜相互作用的背景下定量磨损颗粒的炎症和溶骨性反应。将磨损颗粒（+/-生物膜）和巨噬细胞纳入3D工程组织模型，并评估材料的生物反应。该项目通过开发FDA监管产品中使用的材料的临床前模型，对FDA的监管优先事项产生了更广泛的影响，这些模型可用于检测，识别和量化生物相互作用。需要更好地了解磨损颗粒和生物膜之间的相互作用，以及它们对医疗器械引起的严重慢性炎症潜在发展的综合影响。基于生物材料的先进工具使FDA能够更好地评估医疗器械中使用的新兴材料的适用性，减少监管负担，加快其进入市场的步伐。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

Non-technical Abstract:This award under the NSF/FDA Scholar-in-Residence program is for a collaborative project to study how wear particles from medical devices interact with bacteria in the body, and how this may lead to loosening of medical implants. 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, the surface of joint implants can wear over time, producing microscopic wear debris. This project studies how these particles interact with bacteria in the body, and furthermore how both wear particles and bacteria affect the function of inflammatory cells. It is a follow-on to previous projects under the same program to design and test advanced models of tissue 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 Abstract: The goal of this one year Scholar-in-Residence program is to understand how wear particles, biofilm, and immune cells act in concert to contribute to aseptic loosening of total joint arthroplasty devices. Importantly, it applies advanced, biomaterial-based 3D tissue models that mimic the physiological environment. Specifically, the intellectual merit of this project focuses on using such models to simulate the in vivo scenario of direct contact between biofilm attached-wear particles and macrophages contributing to altered inflammatory response and osteolysis. The project benefits from the expertise of the Stegemann lab (U. Michigan) in fabricating physiologically-relevant in vitro tissue constructs, in collaboration with the technology and experience at the OSEL labs at FDA in physicochemical testing and evaluation of the interaction between wear particles, biofilm, and macrophages. The first objective of the project is to evaluate the propensity of wear particles from implant materials for bacterial adhesion and biofilm formation based on their physicochemical characteristics. Wear debris from representative materials (Polyethylene, PEEK, PMMA, Co-Cr, CP-Ti) are comprehensively characterized and their physicochemical properties are correlated with the ability to support biofilms produced by Staphylococcus aureus, a bacterium commonly associated with orthopedic infections. The second objective is to quantitate the inflammatory and osteolytic response of wear particles in the context of their interactions with biofilm, using 3D in vitro tissue models with or without bone allograft fragments. Wear particles (+/- biofilm) and macrophages are incorporated into 3D engineered tissue models and the biological responses of the materials are assessed. This project has broader impact on the regulatory priorities of the FDA by developing preclinical models of materials used in FDA-regulated products, which can be used to detect, identify, and quantify biological interactions. There is a need for a better understanding of the interplay between wear particles and biofilm, and their combined effects on the potential development of serious chronic inflammation caused by medical devices. Advanced biomaterials-based tools enable FDA to better evaluate the suitability of newly-emerging materials used in medical devices, decreasing the regulatory burden, and accelerating their path to the market.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.