Long-Term Broad-Spectrum Prevention of Implant-Related Infections

描述(由申请人提供)：全关节置换术后的深部伤口感染是医生和患者的毁灭性并发症，是发病率的主要原因，也是医疗保健系统的重大经济负担。随着人口老龄化和预期寿命的增加，关节成形术的数量预计将在未来20年大幅上升。越来越多的高危患者接受手术，进一步增加了败血症并发症和其他不良后果的严重程度。30多年来，抗生素已被加入骨水泥中用于预防和整形外科应用。然而，由于担心成本、长期机械性能，以及最重要的是可能产生抗生素耐药性，负载抗生素的骨水泥通常不被用于预防使用。银作为一种抗菌剂，因其特殊的安全性和有效性而被广泛研究。此外，银引发广泛细菌耐药性的风险被认为是微乎其微的。近年来，银纳米粒子(AgNP)在医疗器械中的应用得到了广泛的研究，但在将其均匀分散到生物材料中所遇到的问题以及合成所需的复杂工艺和苛刻的化学物质限制了它的应用。位于圣安东尼奥的德克萨斯大学健康科学中心的研究人员最近开发了一种创新的一步法，可以在聚甲基丙烯酸甲酯(PMMA)等不需要苛刻化学物质的丙烯酸树脂中原位合成AgNPs。初步研究表明，这种材料具有与不含AgNPs的树脂相当的力学性能，同时展示了分布均匀的AgNPs，提供了对几种病原体具有生物杀灭作用的Ag+离子的延长释放。因此，本项目的目标是开发一种长效、广谱、抗菌的骨水泥，利用这种新的方法在原位产生AgNPs。本研究第一阶段有五个具体目标：1.机械性能特异性目标的制定和评价2.体外银离子释放特异性目标3.体外抗菌活性特异性目标4.生物相容性特异性目标5.疲劳试验 公共卫生相关性：全膝关节和全髋关节置换手术后的感染对患者来说是一个毁灭性的并发症，对医疗保健系统来说非常昂贵。抗生素可以被加入骨水泥中以减少感染，但通常不能预防性使用，因为它们会对骨水泥的机械性能产生不利影响，价格昂贵，而且在微生物能够在抗生素下存活的情况下会导致耐药性。开发一种安全有效的含银纳米粒子的抗菌骨水泥，不会导致耐药性，并将克服现有产品的局限性，将对公众健康产生重大影响。

DESCRIPTION (provided by applicant): Deep wound infection following total joint arthroplasty is a devastating complication for physician and patient, a leading cause of morbidity, and a significant economic burden to the healthcare system. With an aging population and increased life expectancies, the number of arthroplasties is expected to rise dramatically over the next 20 years. The growing number of high-risk patients undergoing surgery further increases the severity of septic complications and other adverse outcomes. Antibiotics have been incorporated into bone cement for prophylaxis and orthopedic applications for more than 30 years. However, antibiotic laden bone cement is not generally indicated for prophylactic use due to concerns about cost, long-term mechanical performance, and most importantly, the potential for developing antibiotic resistance. As an antimicrobial agent, silver has been extensively researched because of its exceptional safety and efficacy. Further, the risk of silver inducing widespread bacterial resistance is considered to be remote. Recently, the incorporation of silver nanoparticles (AgNP) into medical devices has been investigated, but problems encountered with homogeneously dispersing AgNPs into biomaterials and the need for complex processes and harsh chemicals required for synthesis have limited its use. Researchers at the University of Texas Health Science Center at San Antonio have recently developed an innovative single-step method to synthesize AgNPs in situ in acrylic resins such as polymethylmethacrylate (PMMA) that requires no harsh chemicals. Preliminary studies show that this material possesses mechanical properties comparable to resins without AgNPs, while demonstrating well-distributed AgNPs that provide extended release of Ag+ ions that are biocidal to several pathogens. Thus, the goal of this project is to develop a long-lasting, broad-spectrum, antimicrobial bone cement using this novel method to generate AgNPs in situ. This Phase I study has five Specific Aims: Specific Aim 1. Formulation and Evaluation of Mechanical Properties Specific Aim 2. In Vitro Ag+ Ion Release Specific Aim 3. In Vitro Antimicrobial Activity Specific Aim 4. Biocompatibility Specific Aim 5. Fatigue Testing PUBLIC HEALTH RELEVANCE: Infection following total knee and total hip replacement surgery is a devastating complication for patients and very costly to the healthcare system. Antibiotics can be incorporated into bone cement to reduce infection, but are generally not used preventively because they can adversely impact the mechanical properties of the cement, are expensive, and can cause drug resistance where a microorganism is able to survive exposure to the antibiotic. The development of a safe and effective antimicrobial bone cement containing silver nanoparticles that would not induce drug resistance and would overcome the limitations of current products would have a significant impact on public health.