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.

抽象的 假体围关节感染（PJI）是关节置换的毁灭性并发症。预防感染 仍然是最好的策略，因为一旦建立了PJI，就很难治愈，并且复发率超过17％。 手术后立即将关节浸入术后血清液（SSF）中。 随着时间的流逝，粘稠的蛋白质和蛋白聚糖的关节液会改变。我们的数据显示 抗生素敏感性，细菌粘附和骨髓细胞功能（Synf），血清和血清和 近似伤口液/SSF的血清稀释液。重要的是，我们的数据表明流体成分 在这种进化中，不同的调节细菌的粘附，抗生素敏感性，并暗示着 免疫反应。令人兴奋的是，我们的数据进一步表明，应用超声触发的微泡应用 破坏（UTMD）会影响细菌代谢，从而增强随着抗生素的敏感性 关节液的演变。那就是我们假设存在术后SSF的“黄金窗户” 允许通过抗生素的综合作用和免疫来消除污染细菌 响应虽然合成的过渡限制了两者的效率。我们进一步建议这个金色的窗户 可以通过使用UTMD激活细菌代谢来增强和扩展。我们将（1）确定 SSF和SYNF液对抗生素活性和髓样细胞功能的影响，（2）确定UTMD对 SSF和Synf关节液中的细菌根除和髓样功能，（3）防止PJI通过体内 合并的微生物/抗生素处理。此信息将用于创建组合疗法 将防止PJI在体内。重要的是，我们的新型策略将与当前的临床感染无缝整合 缓解策略，可以立即转化为一种预防PJI的新治疗方法。