TRAUMA, INFECTION, AND PROSTHETIC BIOMATERIALS

以生物材料为中心的感染是导致治疗失败的重要原因。 假体植入物和器官。 几乎所有这些感染，早期和 晚期，发生在假体周围空间，由低水平的 手术时植入的微生物污染。 的 宿主不能消灭相对较少的细菌是最有可能的 由于中性粒细胞的氧化性杀伤作用的失败， 异物。 我们仔细研究了，在以前的补助金中， 期间，嗜酸性呼吸爆发之间的直接相互作用 和各种生物材料。 我们的证据和其他人的证据都支持 吸附在某些聚合物上的蛋白质与特定的 受体的中性粒细胞，并引发它过度生产 活性氧中间体（ROI），当被污染物触发时 细菌产物（葡萄球菌或脂多糖）或炎症 细胞因子如肿瘤坏死因子。 由于过度 在ROI的产生过程中，中性粒细胞的功能可能会受损。 杀死细菌的能力。 支持这一观点的事实是， 吸附的蛋白质不仅可以结合和启动中性粒细胞，但它们 也可以特异性结合（调理）细菌和细菌产物。 这类蛋白质包括血浆蛋白（纤维蛋白原）、细胞外基质蛋白（纤维蛋白原）、蛋白质和蛋白质。 基质蛋白（纤连蛋白，层粘连蛋白），血小板衍生蛋白 （血小板反应蛋白）和脂多糖结合蛋白（LBP）。 的 假体表面将成为感染的平台，因为它 吸附结合细菌和中性粒细胞的蛋白质， 配置，导致大规模和长期生产的投资回报率 这反过来又下调氧化杀伤。 此外，这样的 复杂的生物材料/蛋白质/细菌表面可能刺激 巨噬细胞：1）分泌细胞因子，下调吞噬细胞 杀死;和2）分泌一氧化氮，其具有反应能力， 并抑制杀死细菌所需的ROI。 现时的建议 旨在系统地阐明一些 选择的生物材料和可疑的调理蛋白，以确定 这些蛋白质如何与生物材料结合，以及复合物如何固定细菌 聚合物表面。 一旦发现某些调理剂 蛋白质可以吸附在生物材料上并在那里结合细菌， 生物材料/蛋白质/细菌复合物对中性粒细胞和 可以测定巨噬细胞应答。 最终目标是一个更 完全理解这些相互作用对 在假体植入物存在的情况下氧化杀死细菌。

Biomaterial centered infection is an important cause of the failure of prosthetic implants and organs. Almost all such infections, early and late, occur in the periprosthetic space and are caused by low levels of contamination with microbes implanted at the time of surgery. The inability of the host to eliminate relatively few bacteria is most likely due to failure of oxidative killing by the neutrophil in the presence of the foreign body. We have carefully explored, in the previous grant period, the direct interactions between neutrophilic respiratory burst and various biomaterials. Our evidence and that of others supports the idea that proteins adsorbed to certain polymers bind to specific receptors on the neutrophil and prime it to excessive production of reactive oxygen intermediates (ROI) when triggered by contaminating bacterial products (Staphylococcus or lipopolysaccharide) or inflammatory cytokines like tumor necrosis factor. As a result of excessive production of ROI, the neutrophils are likely to be impaired in their capacity to kill bacteria. In support of this idea is the fact that may adsorbed proteins can not only bind and prime neutrophils, but they can also specifically bind (opsonize) bacteria and bacterial products. Such proteins include the plasma protein (fibrinogen), the extracellular matrix proteins (fibronectin, laminin), the platelet derived protein (thrombospondin), and lipopolysaccharide binding protein (LBP). The prosthetic surface would then become a platform for infection because it adsorbs proteins which both bind the bacteria and the neutrophil into a configuration which leads to massive and prolonged production of ROI which in turn downregulates oxidative killing. Furthermore, such a complex biomaterial/protein/bacterial surface is likely to stimulate macrophages: 1) to secrete cytokines which will downregulate phagocytic killing; and 2) to secrete nitric oxide which has the capacity to react with and quench the ROI needed to kill bacteria. The present proposal is designed to systematically elucidate the interactions between a few selected biomaterials and suspect opsonic proteins in order to determine how such proteins bind to biomaterial and how the complexes fix bacteria to the polymeric surface. Once it becomes clear that certain opsonic proteins can be adsorbed onto biomaterials and bind bacteria there, the effects of the biomaterial/protein/bacterial complex on neutrophil and macrophage responses can be determined. The ultimate goal is a more complete understanding of the net effect of these interactions on oxidative killing of bacteria in the presence of a prosthetic implant.