Rational Design of Dynamic Antifouling Material Topographies for Safer Medical Devices

非技术摘要：截至2017年2月，FDA已收到359例隆胸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份有关于植入物表面信息的报告中，203份报告是纹理植入物，28份报告是光滑植入物。据推测，BIA-ALCL可能是由于细菌在乳房植入物上的定植和生物膜(附着细胞的多细胞结构)的形成所致。然而，目前还不清楚为什么纹理植入物与ALCL有特定的联系。如何提高这些植入物的安全性也是未知的。这一挑战在很大程度上是由于对表面地形如何影响微生物附着和生物膜形成的基本了解方面的知识差距，以及缺乏设计防污染地形的指导原则。锡拉丘兹大学和FDA的团队将合作应对这一挑战，并通过互补性研究获得关键的新知识。具体地说，该团队将合作研究细菌在附着过程中如何对表面形貌做出反应，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提供关于哪些类型的表面更有可能被定植的新知识和有价值的信息，这将有助于FDA对新型抗生物被膜形貌的监管。除了研究，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；并培养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，以改善人类健康和福祉。技术摘要：细菌使用鞭毛、菌毛和其他因素(如粘附素)附着在植入的医疗设备上。微生物的附着导致生物膜的后续形成，生物膜是一种表面附着的多细胞结构，由附着的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(与浮游生物细胞相比高出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黏附，因此可以通过调整这些特性来抑制生物膜的形成。然而，以前通过改变表面地形来控制生物膜的研究在很大程度上是经验性的，缺乏对细菌如何通过感知和响应表面地形来在浮游生长和生物膜形成之间做出决定的机制理解。此外，迄今为止设计的防污地形基本上是静态的，不能移动。即使有少量细菌细胞附着，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垢，重要的是设计出能够根据环境提示改变表面形貌的新的动态材料。一种动态材料既可以防止细菌的初始黏附，又可以破坏已建立的生物膜，使定殖者分散成浮游生物，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，可以合理地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黏附。它还假设，已建立的生物膜可以通过在需要时按需触发，通过这种表面形貌的动态变化来移除。该团队将以大肠杆菌、铜绿假单胞菌和金黄色葡萄球菌为模式物种，通过研究细菌对不同表面形貌的反应来检验这些假设。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.