Rational Design of Dynamic Antifouling Material Topographies for Safer Medical Devices

非技术总结：截至2017年2月，FDA已收到359份关于乳房植入物相关间变性大细胞淋巴瘤（BIA-ALCL）的医疗器械报告（mdr），包括9例死亡。在231份报告中，有关于种植体表面的信息，203份报告为纹理种植体，28份报告为光滑种植体。据推测，BIA-ALCL可能是由细菌定植和乳房植入物上生物膜（附着细胞的多细胞结构）的形成引起的。然而，目前尚不清楚为什么有纹理的植入物与ALCL有特定的联系。也不知道如何提高这些植入物的安全性。这一挑战主要是由于对表面形貌如何影响微生物粘附和生物膜形成的基本理解方面的知识差距，以及缺乏防污形貌设计的指导原则。雪城大学和FDA的团队将合作应对这一挑战，并通过互补研究获得关键的新知识。具体来说，该团队将合作研究细菌在附着过程中对表面形貌的反应，以及如何设计新的表面来防止细菌附着。该项目的结果将为FDA提供新的知识和有价值的信息，了解哪些类型的表面更容易被定植，这将有助于FDA对新型抗生物膜地形的监管。除了研究之外，该团队还将利用该项目促进学生培训，特别是来自代表性不足群体的个人；并教育下一代工程师成为解决具有挑战性的技术和社会问题的领导者，以改善人类的健康和福祉。技术概述：细菌通过鞭毛、毛和其他因素（如粘连素）附着在植入的医疗器械上。微生物的附着导致随后形成生物膜，这是一种表面附着的多细胞结构，由附着细胞分泌的细胞外基质组成。生物膜感染很难治疗，因为生物膜细胞对抗菌剂和消毒剂的耐受性极高（与浮游细胞相比，耐受性高达1000倍）。由于基质材料的表面化学、硬度、疏水性、粗糙度、地形和电荷等特性会影响细菌的粘附，因此可以通过调整这些特性来抑制生物膜的形成。然而，以往通过改变表面形貌来控制生物膜的研究大多是经验性的，缺乏对细菌如何通过感知和响应表面形貌来决定浮游生物生长和生物膜形成的机制理解。此外，迄今为止设计的防污地形大部分是静态的，不能移动。即使少量细菌细胞附着，它们也可以繁殖并逐渐克服大多数抗生物膜的地形。为了更有效地控制生物污染，设计能够根据环境变化改变表面形貌的新型动态材料是很重要的。一种动态物质既可以阻止最初的细菌粘附，又可以破坏已建立的生物膜，导致定植菌分散成浮游生物形式，在那里它们可以被宿主免疫系统和抗生素治疗根除。该团队假设，可以合理设计特定的微米级表面形貌，以抑制细菌生物膜的形成，同时促进哺乳动物细胞的粘附。还假设，在需要时，通过按需触发，可以通过这种表面地形的动态变化来去除已建立的生物膜。研究小组将以大肠杆菌、铜绿假单胞菌和金黄色葡萄球菌为模型物种，通过研究细菌对不同表面地形的反应来验证这些假设。该奖项反映了美国国家科学基金会的法定使命，并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，被认为值得支持。

Non-technical Summary: As of February 2017, the FDA had received 359 medical device reports (MDRs) of breast implant associated anaplastic large cell lymphoma (BIA-ALCL), including nine deaths. Among the 231 reports that had information about the implant surface, 203 were reported to be textured implants and 28 were reported to be smooth implants. It has been hypothesized that BIA-ALCL may be caused by bacterial colonization and formation of biofilms (multicellular structures of attached cells) on breast implants. However, it is not clear why textured implants have a specific association with ALCL. It is also not known how to improve the safety of these implants. This challenge is largely due to the knowledge gap in the fundamental understanding of how surface topography affects microbial adhesion and biofilm formation, as well as the lack of guiding principles for the design of antifouling topographies. The teams at Syracuse University and FDA will collaborate to address this challenge and gain critical new knowledge through complementary studies. Specifically, the team will collaborate to investigate how bacteria respond to surface topography during attachment and how to engineer new surfaces to prevent bacterial attachment. The results of this project will provide new knowledge and valuable information to FDA about what types of surfaces are more likely to be colonized, which will be useful for FDA's regulation of novel anti-biofilm topographies. In addition to research, the team will also leverage this project to promote student training, especially the individuals from underrepresented groups; and educate the next generation of engineers to be leaders solving challenging technical and societal problems to improve human health and well being.Technical Summary: Bacteria attach to implanted medical devices using flagella, pili, and other factors such as adhesins. The attachment of microbes leads to the subsequent formation of a biofilm, which is a surface-attached multicellular structure comprised of an extracellular matrix secreted by the attached cells. Biofilm infections are difficult to treat because of extremely high tolerance of biofilm cells to antimicrobials and disinfectants (up to 1000 times higher compared to their planktonic counterparts). Since properties of the substratum material such as surface chemistry, stiffness, hydrophobicity, roughness, topography, and charge affect bacterial adhesion, biofilm formation may be inhibited by tailoring these properties. However, previous research on biofilm control by altering surface topography is largely empirical and lacks a mechanistic understanding of how bacteria make a decision between planktonic growth and biofilm formation by sensing and responding to surface topography. In addition, the engineered antifouling topographies to date are largely static and cannot move. Even if a small number of bacteria cells attach, they can multiply and gradually overcome most anti-biofilm topographies. To more effectively control biofouling, it is important to engineer new dynamic materials that can change surface topography upon an environmental cue. A dynamic material can both prevent initial bacterial adhesion and disrupt established biofilms, causing the colonizers to disperse into planktonic form where they can be eradicated by the host immune system and antibiotic treatment. The team hypothesizes that specific micron-scale surface topographies can be rationally designed to inhibit bacterial biofilm formation while promoting the adhesion of mammalian cells. It is also hypothesized that established biofilms can be removed by dynamic changes in such surface topographies via on-demand triggering when needed. The team will test these hypotheses by studying how bacteria respond to different surface topographies using Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus as model species.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.