Cationic Steroidal Antimicrobial-13 for Use as an Orthopedic Device Coating

描述 用作整形外科设备涂层的阳离子类固醇抗菌剂-13摘要相关性：一级职业发展奖将为辛克莱博士提供必要的指导和培训，使他成为一名独立的退伍军人管理局职业科学家。这项工作，利用新型聚合物释放的抗菌剂传递系统来解决目前抗生素治疗的局限性，并将与他的导师的合作将是基础 辛克莱博士将在此基础上建立他的退伍军人管理局研究生涯。疾病控制中心报告说，美国每年发生近50万例确诊的金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌(MRSA)。耐甲氧西林金黄色葡萄球菌病例的增加可以归因于细菌对抗生素治疗的进化耐药性。为了解决这些问题，阳离子类固醇抗菌剂-13(CSA-13)将被加入到有机硅(Si)聚合物涂层中，并检测其用作整形外科设备涂层时的杀菌潜力。初步的体外测试表明，与涂有18%w/w硅聚合物释放的CSA-13抗菌剂的钛(Ti)塞植入物接触后，MRSA在24小时内下降了99%以上。目标：1)为辛克莱博士提供必要的指导和培训，以确立他作为退伍军人管理局职业科学家的地位。2)通过使用硅聚合物释放的CSA-13抗菌剂来对抗与常见骨科设备操作相关的耐药细菌菌株感染。这项工作的长期目标是促进辛克莱博士在获得退伍军人管理局职业科学家奖方面继续取得进展，并利用他在CSA-13工作中获得的知识来减少与设备相关的感染的发生率，最大限度地减少住院所需的时间，减少退伍军人管理局医疗保健系统和患者的费用，并减少修订程序所需的阶段数量。假设：1)CsA-13抗菌剂(18%w/w)从多孔涂层钛种植体表面的硅聚合物涂层中洗脱出来后，可预防体内MRSA感染。2)CsA-13抗菌剂的释放不会对假体周围骨生长的速度和数量产生不利影响。手术方法：4组，每组7只绵羊，将股骨柄内侧植入多孔涂层钛骨塞。第1~3组接种L 1×108浮游MRSA 200株。实验组(第1组)将在硅聚合物(18%w/w)中涂覆一层CsA-13薄膜的多孔涂层钛骨塞，聚合物对照组(第2组)将仅使用硅涂层(不含CsA-13)，以确认感染信号(第3组)将仅使用不含CsA-13或硅涂层的骨塞，而第4组将作为手术对照；既不添加CsA-13，也不添加硅涂层，也不添加细菌。功效分析的结果表明，要达到统计学意义，效应大小需要为7。研究结果的意义：这种新型抗菌药的成功有可能显著改善退伍军人管理局的临床护理，因为它降低了由围手术期设备相关感染引起的初次手术和翻修手术的相关成本。这项研究还将通过消除或显著限制退伍军人对手术前器械相关感染的敏感性，极大地提高退伍军人的生活质量，减少住院和康复所需的时间。

DESCRIPTION Cationic Steroidal Antimicrobial-13 for Use as an Orthopedic Device Coating Abstract RELEVANCE: The Career Development Award-Level 1 will provide Dr. Sinclair with the mentoring and training necessary to establish him as an independent VA Career Scientist. This work, utilizing the novel polymer released antimicrobial delivery system to address the current limitations of antibiotic therapies, and the collaborations with his mentors will be the foundation on which Dr. Sinclair will establish his VA research career. The Center for Disease Control reports nearly 500,000 confirmed incidences of S. aureus and methicilin-resistant S. aureus (MRSA) occurring in the United States per year. This increasingly high number of MRSA cases can be attributed to the bacteria's evolved resistance toward antibiotic therapy. To address these issues, Cationic Steroidal Antimicrobial- 13 (CSA-13) will be incorporated into a silicone (Si) polymer coating and examined for its bactericidal potential when used as an orthopedic device coating. Preliminary in vitro testing has demonstrated greater than a 99% reduction of MRSA within 24 hours with exposure to titanium (Ti) plug implants coated with the 18% w/w Si polymer released CSA-13 antimicrobial. OBJECTIVES: 1) Provide Dr. Sinclair with the mentoring and training necessary to establish himself as a VA Career Scientist. 2) Combat resistant bacteria strain infections associated with common orthopedic device procedures through the use of the Si polymer released CSA- 13 antimicrobial. The long-term goals of this work are to foster Dr. Sinclair's continued progress toward the award of VA Career Scientist and to use the knowledge gained from his work with CSA-13 to reduce the incidence of device-related infection, minimize the time required for hospitalization, decrease the expense incurred by the VA health care system and patient, and reduce the number of stages required for revision procedures. HYPOTHESES: 1) The CSA-13 antimicrobial (18% w/w) will prevent infection caused by MRSA in vivo when eluted from the Si polymer coating on a porous coated titanium implant. 2) The rate and amount of periprosthetic bone ingrowth will not be adversely affected by the release of the CSA-13 antimicrobial. PROCEDURES: Four groups, each utilizing seven sheep, will receive a porous coated Ti bone plug in the medial aspect of the femoral condyle. Groups 1-3 will be inoculated with 200 ¿l of 1x108 planktonic MRSA. The experimental group (Group 1) will have a porous coated Ti bone plug coated with a thin film of CSA-13 in a Si polymer (18% w/w), the polymer control (Group 2) will use only the Si coating (without CSA-13), to confirm an infection signal (Group 3) will use only the bone plug without CSA-13 or the Si coating, and Group 4 will serve as the surgical control; having neither CSA-13, Si coating, or bacteria added. The results of a power analysis indicated that an effect size of seven was required for statistical significance. SIGNIFICANCE OF FINDINGS: The success of this novel antimicrobial has the potential to significantly improve VA clinical care by reducing costs associated with primary and revision surgeries caused by perioperative device related infections. This research would also greatly improve the veteran's quality of life and reduce time required for hospitalization and rehabilitation by eliminating or significantly limiting the vetera's susceptibility to preoperative device related infections.