Fluorescence and Biomarkers in Prosthetic Joint Infection

摘要 全膝关节置换术（TKA）是医疗保险报销的最常见的外科手术之一， 提供改善的功能和疼痛缓解。与此手术相关的最具破坏性的并发症是 感染，也称为人工关节感染（PJI）。PJI的推荐管理取决于 许多因素，但理想情况下包括关节和周围组织的外科清创术。尽管 手术干预和静脉注射抗生素的长期疗程，这些治疗的失败率可达 60%，这导致多次手术，给患者和医疗保健系统带来巨大成本。有一个 我们目前对什么是充分清创的理解存在很大差距。这个假设 建议是生物标志物浓度、局部血管分布和免疫细胞存在变异性， 反应取决于清创术的深度和是否存在感染。内评价 临床环境和临床前PJI模型将允许开发检测适当性的方法 清创和改善显着的失败率在治疗PJI。 所提出的目标将证明感染和非感染组织中组织环境的可变性。 感染的环境。该变异性的结果将在两种临床样本中得到证实， 丢弃的手术组织和临床前模型，以允许进一步开发转化治疗 和技术。该提案的初步结果表明，有能力检测区域变化， 炎症生物标志物，通过激光辅助荧光血管造影检测局部血管分布的能力，以及 通过细胞外通量分析评估免疫细胞活化。在目标1中，来自翻修的临床样本 将在存在或不存在感染的情况下并根据感染的深度比较膝关节置换术。 清创术将使用从临床样本中获得的结果对临床前模型进行验证。目标2将 评估清创前后的局部血管环境，以证明 由于感染和手术清创导致的灌注。在目标3中，细胞的生物能量分布位于 在翻修膝关节的组织床内，将定义临床前模型。这些信息将进一步 了解翻修膝关节的局部环境，并允许与临床前模型进行比较。 这一雄心勃勃的研究计划是在一个 由受人尊敬的研究人员和各自领域的领导人组成的多学科导师团队。导师团队和 咨询小组是根据长期的关系，已知的专业知识和跟踪记录， 对初级教员和研究人员的成功指导。概述的职业发展目标将是 通过教学班，研讨会和会议，除了直接指导的 组获得的初步数据和培训将使Dietz博士能够独立使用R01 资助的研究。

Abstract Total knee arthroplasty (TKA), one of the most common surgical procedures reimbursed by Medicare, provides improved function and pain relief. The most devastating complication related to this surgery is infection, also known as prosthetic joint infection (PJI). The recommended management for PJI depends on a number of factors but ideally involves a surgical debridement of the joint and surrounding tissues. Despite surgical intervention and long courses of intravenous antibiotics, the failure rate for these treatments can reach 60% which leads to multiple surgeries and significant cost to the patient and health care systems. There is a large gap in our current understanding of what constitutes an adequate debridement. The hypothesis of this proposal is that variability exists in the concentration of biomarkers, regional vascularity, and immune cell response dependent on the depth of debridement and the presence or absence of infection. Evaluation in the clinical setting and in a preclinical PJI model will allow for the development of methods to detect the adequacy of debridement and improve significant failure rates in the treatment of PJI. The proposed aims will demonstrate the variability in the tissue environment in the infected and non- infected setting. The results of this variability will be demonstrated in both clinical samples obtained from discarded surgical tissue and in a preclinical model to allow for further development of translational treatments and techniques. Preliminary results in this proposal demonstrate the ability to detect regional variations in inflammatory biomarkers, the ability to detect local vascularity via laser assisted fluorescent angiography, and the assessment of immune cell activation via extracellular flux analysis. In Aim 1, clinical samples from revision knee arthroplasties will be compared in the presence or absence of infection and according to the depth of debridement. A preclinical model will be validated with the results obtained from the clinical samples. Aim 2 will assess the regional vascular environment before and after debridement to demonstrate the alteration of perfusion as a result of infection and surgical debridement. In Aim 3, the bioenergetic profile of cells located within a tissue bed in a revision knee and a preclinical model will be defined. This information will further the understanding of the local environment of a revision knee joint and allow for comparison to a preclinical model. This ambitious research plan has been developed with the assistance and guidance of a multidisciplinary mentor team of respected investigators and leaders in their fields. The mentor team and advisory panel were selected based on longstanding relationships, known expertise, and track record of successful mentorship of junior faculty and investigators. The career development goals outlined will be achieved through didactic classes, workshops, and conferences in addition to the direct mentoring of the group. The preliminary data and training acquired will position Dr. Dietz to achieve independence with R01 funded research.