NSF/FDA SIR: 3D Cell Culture Models as Regulatory Tools for Screening Macrophage Responses to Polymer Wear Debris.

非技术：该奖项由密歇根大学安娜堡分校材料研究部生物材料项目授予NSF/FDA驻校学者计划，旨在设计和测试3D水凝胶模型，用于研究人体医疗植入物磨损产生的免疫细胞和微观颗粒之间的相互作用。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是有效的，但由于关节植入物的表面破坏以及身体对这些植入物磨损产生的微观颗粒的炎症反应，它们的使用寿命有限。该项目将开发先进的方法来研究炎症细胞如何与磨损颗粒相互作用，目的是为预测和分类新型植入材料的生物反应提供更强大、更彻底的标准。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，这些环境可用于了解炎症的细胞机制。拟议的研究为学术、政府和工业研究实验室之间的合作研究提供了机会，有利于公共卫生和安全。技术方面：这项为期一年的驻学奖学金的目标是设计和测试3D组织工程模型，以评估巨噬细胞对植入设备聚合物磨损碎片的反应和炎症。使用此类植入物（II类特殊对照）可导致长期并发症，包括慢性炎症和骨溶解。正常使用产生的聚合物磨损碎片已被确定为决定设备寿命的主要因素，因此引入了新的耐磨聚合物来增加这些植入物的使用寿命。严格的标准和测试是保证患者安全所必需的，该项目将创建3D仿生组织模型来捕捉体外的生理反应。该3D模型有望概括细胞外微环境中全方位刺激下的炎症反应。因此，该项目的智力价值是基于提供先进的组织模型来测试材料特性对磨损颗粒生物活性的作用，弥合目前存在于简单的2D体外模型与动物模型或临床试验之间的差距。具体目标包括：1)开发具有最大灵敏度和选择性的3D工程组织模型，以表征细胞对聚合物磨损碎片的反应；2)应用工程模型研究选用聚合物产生的磨损碎片的理化性质与巨噬细胞反应的关系。具体来说，将聚醚醚酮和聚碳酸酯聚氨酯的磨损碎片与超高分子量聚乙烯进行比较，通过颗粒浓度、大小、形状、表面纹理、表面电荷和极性来确定巨噬细胞激活和炎症反应的标志物。这个项目更广泛的影响是它在发展对材料特性如何决定生物反应的基本理解方面的贡献。此外，这项研究有望满足FDA对更好的生物材料评估模型系统日益增长的需求。这样的系统解决了与植入成功有关的患者安全和有效性问题，并且与体内模型或回收的外植体相比，提供了一种负担更少、速度更快的材料测试方法，从而潜在地降低了新设备开发的成本。

Non-technical: This award under the NSF/FDA Scholar-in-Residence program by the Biomaterials program in the Division of Materials Research to University of Michigan Ann Arbor is to design and test a 3D hydrogel model for studying interactions between immune cells and microscopic particles produced by the wear and tear of medical implants in the body. The use of 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 of their surfaces breakdown, and body's inflammatory response to microscopic particles produced by the wear and tear of these implants. This project will develop advanced methods to study how inflammatory cells interact with wear particles, with the goal of informing the development of more robust and thorough standards for predicting and categorizing the biological response to new implant materials. The project team has extensive experience in fabricating 3D environments mimicking physiological conditions necessary that can be used to understand the cellular mechanisms of inflammation. The proposed studies present an opportunity for collaborative research among academic, government and industrial research labs benefitting public health and safety.Technical: The goal of this one-year Scholar-in-Residence award is to design and test 3D tissue engineered models in evaluating macrophage response and inflammation to polymeric wear debris characteristic of implant devices. Use of such implants (Class II special controls) can result in long-term complications including chronic inflammation and osteolysis. Polymeric wear debris generated by normal use has been identified as a primary factor determining device lifetime, and therefore new wear-resistant polymers have been introduced to increase the longevity of these implants. Rigorous standards and testing are necessary to preserve patient safety, and this project will create 3D biomimetic tissue models to capture physiological responses in vitro. This 3D model is expected to recapitulate the inflammatory response in the context of the full range of stimuli in the extracellular microenvironment. Therefore the intellectual merit of the project is based on providing an advanced tissue model for testing the role of material properties on wear particle bioactivity, bridging the current gap that exists between simple 2D in vitro models and animal models or clinical trials. The specific aims include: 1) develop a 3D engineered tissue model with maximum sensitivity and selectivity to characterize cell response to polymeric wear debris; and 2) apply engineered model to study the relationship between physiochemical properties of wear debris generated from selected polymers with macrophage response. Specifically, wear debris from polyether ether ketone and polycarbonate urethane will be compared against ultra-high molecular weight polyethylene for markers of macrophage activation and inflammatory response, as determined by particle concentration, size, shape, surface texture, surface charge, and polarity. The broader impact of this project is its contribution in developing the fundamental understanding of how material properties determine biological responses. In addition, this study is expected to meet the growing needs at FDA for better model systems in evaluating biomaterials. Such a system addresses patient safety and efficacy issues regarding implant success and potentially reduces costs of new device development by providing a less burdensome and more rapid method for material testing, compared to in vivo models or retrieved explants.