The joint environment and periprosthetic joint infection

关节环境与假体周围感染

• 批准号: 10744580
• 负责人: Noreen J Hickok
• 金额: $ 68.31万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744580
• 关键词: Adherence; Anti-Infective Agents; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Bacteria; Bacterial Adhesion; Bacterial Antibiotic Resistance; Bathing; Behavior; Cell physiology; Cells; Characteristics; Clinical; Clinical Treatment; Combined Modality Therapy; Consensus; Data; Effectiveness; Environment; Evolution; Family suidae; Immune; Immune response; Immune system; Immunology; Implant; In Vitro; Incidence; Infection; Infection prevention; Inflammatory; Joints; Liquid substance; Macrophage; Measures; Metabolic; Metabolism; Microbial Biofilms; Microbubbles; Modeling; Myelogenous; Myeloid Cells; Natural regeneration; Operative Surgical Procedures; Orthopedics; Perioperative; Periprosthetic joint infection; Phagocytes; Phagocytosis; Phenotype; Postoperative Period; Prevention; Prevention approach; Procedures; Production; Productivity; Proteins; Proteoglycan; Recurrence; Replacement Arthroplasty; Serum; Staphylococcus aureus; Synovial Fluid; Testing; Time; Translating; Virulence Factors; Viscosity; adverse outcome; aggregation factor; antimicrobial; bacterial metabolism; cytokine; image guided therapy; immune activation; immune clearance; immune function; immune phagocytosis; in vivo; infection rate; joint function; joint infection; novel strategies; novel therapeutic intervention; operation; pathogen; prevent; recurrent infection; success; synergism; traumatic wound; treatment effect; ultrasound; wound

ABSTRACT Peri-prosthetic joint infections (PJI) are devastating complications of joint replacements. Prevention of infection remains the best strategy as once a PJI has established, it is difficult to cure and recurrence rates exceed 17%. Immediately following surgery, the joint implants are bathed in a post-operative serosanguinous fluid (SSF) which over time changes to a viscous, protein- and proteoglycan-rich joint fluid. Our data show differences in antibiotic sensitivity, bacterial adhesion, and myeloid cell function between synovial fluid (SynF), serum, and serum dilutions that approximate wound fluid/SSF. Importantly, our data suggest that the fluid composition across this evolution differentially modulates bacterial adherence, antibiotic sensitivity, and by implication, immune response. Excitingly, our data further suggest that application of ultrasound-triggered microbubble disruption (UTMD) can impact bacterial metabolism to enhance the antibiotic sensitivity that was lost with the evolution of the joint fluid. Thus, we hypothesize that a “golden window” exists in which the post-operative SSF permits eradication of contaminating bacteria through the combined actions of antibiotics and the immune response while the transition to SynF limits the efficacy of both. We further propose that this golden window can be enhanced and extended through the use of UTMD to activate bacterial metabolism. We will (1) determine the effects of SSF and SynF fluid on antibiotic activity and myeloid cell function, (2) determine UTMD effects on bacterial eradication and myeloid function in SSF and SynF joint fluid and (3) prevent PJI in vivo through combined microbubble/antibiotic treatments. This information will be used to create combination therapies that will prevent PJI in vivo. Importantly, our novel strategy will seamlessly integrate with current clinical infection mitigation strategies and can be immediate translated into a new therapeutic approach for prevention of PJI.

摘要 假体周围关节感染（PJI）是关节置换术的毁灭性并发症。预防感染 这仍然是最好的策略，因为一旦PJI建立，就很难治愈，复发率超过17%。 手术后立即将关节植入物浸泡在术后血清血性液体（SSF）中 随着时间的推移，它会变成粘稠的、富含蛋白质和蛋白聚糖的关节液。我们的数据显示了 滑膜液（SynF）、血清和 接近伤口液/SSF的血清稀释液。重要的是，我们的数据表明， 在这一进化过程中，差异性地调节细菌粘附、抗生素敏感性，并且通过暗示， 免疫反应令人兴奋的是，我们的数据进一步表明，超声触发微泡的应用 破坏（UTMD）可以影响细菌代谢，以提高抗生素敏感性，这种敏感性随着UTMD的出现而丧失。 关节液的演变。因此，我们假设存在一个“黄金窗口”，在这个窗口中， 允许通过抗生素和免疫的联合作用根除污染细菌， 反应，而过渡到SynF限制了两者的功效。我们进一步建议， 可以通过使用UTMD激活细菌代谢来增强和延长。我们将（1）确定 SSF和SynF流体对抗生素活性和骨髓细胞功能的影响，（2）确定UTMD对 SSF和SynF关节液中的细菌根除和骨髓功能，以及（3）通过以下途径预防体内PJI： 联合微泡/抗生素治疗。这些信息将用于创建联合疗法， 将防止体内PJI。重要的是，我们的新策略将与当前的临床感染无缝整合 缓解策略，可以立即转化为预防PJI的新治疗方法。