Bacteria-Triggered Antimicrobial Release from Microgel-Modified Surfaces

技术摘要：该项目结合了细菌触发释放、接触杀菌和差异细胞相互作用等新兴概念，构建了一种使接触组织的生物材料表面抵抗细菌定植的新方法。主要的科学目标是了解控制络合隔离阳离子抗菌剂触发释放的材料属性。该项目将：(1)确定一组具有不同电荷、电荷分布和疏水性的抗菌肽(AMP)，它们可以在模型内、表面固定的阴离子微凝胶(微凝胶)中在四周的生理缓冲条件下复合；(2)显示隔离的多肽被保护而不被蛋白质降解；(3)确定AMP是否可以通过与细菌的直接物理化学接触而从微凝胶中释放；(4)确定与组织细胞(例如巨噬细胞)的直接物理化学接触是否触发AMP的释放；以及(5)证明AMP负载的微凝胶修饰表面在抵抗细菌定植的同时仍然能够实现组织细胞的整合。这项研究工作的智力价值集中于这样一个事实，即该项目将提供关于小分子阳离子抗菌剂和合成阴离子微凝胶之间静电和疏水相互作用的相对作用的见解。这些基本信息将指导未来设计具有增强的电荷、电荷分布和疏水性的新型微凝胶，从而将细菌触发的释放机制扩大到更广泛的抗菌剂。值得注意的是，该项目还将涉及研究生和本科生，他们不仅将在史蒂文斯工作，还将与齐默Trabecular Metals的同事密切合作，并将从该项目的基本学术和应用工业视角中受益。非技术摘要：我们大多数人都认识做过髋关节或膝关节置换手术的人。这样的关节置换已经变得很常见，可以对生活质量产生非常积极的影响。然而，许多人没有意识到关节置换可能会失败，最常见的原因是感染。感染导致的失败也发生在其他植入物中，如疝气网片、起搏器和心脏瓣膜。当细菌附着在植入物表面并生长成称为生物膜的菌落时，就会发生感染，就像我们不刷牙时长在牙齿上的东西一样。重要的是，抗生素不能杀死生物膜中的细菌。因此，我们必须开发出抑制细菌黏附的植入物表面。然后，对于那些设法附着的细菌，我们需要在它们形成生物膜之前杀死它们。这不是一个容易解决的问题。可以理解的是，FDA不愿批准含有抗生素的植入式生物医学设备，这让问题变得更加复杂，因为在许多感染不成问题的情况下，不需要的抗生素有助于培养MRSA等耐药细菌。这项研究项目由国家科学基金会材料研究部生物材料计划资助，旨在了解能够使新技术预防植入物感染的基础科学。这个想法是在植入物表面覆盖一种名为微凝胶的显微镜颗粒，并在其中负载一种名为抗菌肽的杀菌分子。核心的科学问题是了解如何将这些抗菌肽困在微凝胶中，除非碰巧有细菌出现。在这一点上，也只有在那一点上，微凝胶必须被设计成释放多肽并杀死细菌。如果美国国家科学基金会资助的科学家能够弄清楚如何完成这项任务，需要生物医学植入物的人将有更大的机会获得手术成功和更健康的结果。

Technical Abstract: This project combines emerging concepts of bacteria-triggered release, contact bacterial killing, and differential cell interactions to construct a new means with which to render tissue-contacting biomaterial surfaces resistant to bacterial colonization. The primary scientific objective is to understand the materials properties governing the triggered release of complexation-sequestered cationic antimicrobials. This project will: (1) identify a set of antimicrobial peptides (AMPs) with varying charge, charge distribution, and hydrophobicity that can complex within model, surface-immobilized, anionic micro hydrogels (microgels) under four-week exposure to physiological buffer conditions; (2) show that sequestered peptides are protected from proteolytic degradation; (3) establish whether AMP release from the microgels can be triggered by direct physico-chemical contact with bacteria; (4) determine whether direct physicochemical contact with tissue cells (e.g. macrophages) triggers AMP release; and (5) demonstrate that AMP-loaded microgel-modified surfaces resist bacterial colonization while still enabling the integration of tissue cells. The intellectual merit of this research work centers on the fact that this project will provide insights into the relative roles of electrostatic and hydrophobic interactions between small-molecule cationic antimicrobials and synthetic anionic microgels. This basic information will guide the future design of new microgels with enhanced charge, charge distribution, and hydrophobicity that can broaden the bacteria-triggered release mechanisms to an even wider range of antimicrobials. Significantly, this project will also involve both graduate and undergraduate research students who will work not only at Stevens but also in close collaboration with colleagues from Zimmer Trabecular Metals and will benefit from both the basic academic and applied industrial perspectives of this project. Non-Technical Abstract: Most of us know someone who has had a hip or knee replacement. Such joint replacement has become common and can have a very positive impact on the quality of life. Many people are unaware, however, that joint replacements can fail, most commonly because of infection. Failure due to infection also occurs in other implants like hernia meshes, pacemakers, and heart valves. Infection occurs when bacteria adhere to the implant surface and grow into colonies called biofilms, like the stuff that grows on our teeth when we don?t brush. Importantly, antibiotics don't kill bacteria in a biofilm. So, we have to develop implant surfaces that inhibit bacteria fro' adhering. Then, for those bacteria that do manage to adhere, we need to kill them before they form a biofilm. This isn't an easy problem. The problem is further complicated by the fact that the FDA is understandably reluctant to approve implantable biomedical devices that incorporate antibiotics into them, because, in the many cases where infection is not a problem, the unneeded antibiotics help cultivate resistant bacteria like MRSA. This research project, funded by the Biomaterials Program within the National Science Foundation's Division of Materials Research, is designed to understand the fundamental science that can enable a new technology to prevent implant infection. The idea is to cover an implant surface with microscope particles called microgels and load them with bacteria-killing molecules called antimicrobial peptides. The central scientific problem is to understand how to keep these antimicrobial peptides trapped inside the microgels unless a bacterium happens to come along. At that point, and only at that point, the microgels have to be designed to release the peptide and kill the bacterium. If NSF-funded scientists can figure out how to accomplish this task, people needing biomedical implants will have a greater probability of surgical success with healthier outcomes.