Ultrasound-Triggered Prophylaxis as a Novel Paradigm for Preventing Spinal Infection

脊柱融合手术后的细菌感染是一个主要的临床问题，1-10%的患者 尽管进行了积极的围手术期抗生素治疗，仍发生感染。每年超过500万的脊髓损伤 手术预计在2030年完成。目前的临床标准包括使用无菌引流管和包装约1g 粉末状万古霉素（货车）进入伤口空间;然而，这种预防是短暂的（24-48小时）。左 未经治疗的持久性细菌在脊柱硬件上形成生物膜，使感染的治疗复杂化， 需要积极的全身抗生素治疗和移除感染的硬件，延长住院时间 入院和患者虚弱。更有效的方法来预防感染是临床上的当务之急。新 治疗方式必须在病原体粘附到脊柱硬件之前根除病原体 防止感染。基于我们以前的工作，我们的假设是，一个时间依赖的增强的 初始货车水平与对革兰氏阳性和革兰氏阴性有效的抗生素组合 细菌会降低脊柱感染率。我们建议开发一种可植入的水凝胶， 积极的抗菌预防的标准时期，通过（1）手术时持续释放货车， 手术引流管仍然存在时的部位，以维持预防性抗生素水平，以及（2）手术后 引流管移除，外部超声触发释放补充广谱抗生素 (VAN+妥布霉素）以提供针对存活细菌的广谱覆盖。 联合使用抗生素有望降低抗生素耐药病原体的风险，同时还 确保从手术部位根除所有污染病原体。科学的前提是 所做的工作是，拟议中的系统将允许快速、时空控制和完全释放抗生素 在超治疗水平，以减少外科硬件的细菌定植。有三个具体的 目的：1）表征水凝胶的释放动力学和稳定性以及超声触发的 使用优化的超声参数的预防性释放系统，2）评估超声的能力， 触发系统，以防止细菌在体外条件下定植于脊柱硬件，以及3）确定 超声触发系统在消除细菌和预防感染中的预防性效用， 脊柱手术体内模型。该项目旨在解决脊柱手术后的临床问题。 感染使用经过验证的材料的创新应用，并可以快速有效地转化为 项目完成后的临床。我们预计该项目将导致一种连续疗法 能够降低脊柱融合患者的感染率，有效减少疼痛、残疾和死亡率， 与脊柱融合手术后感染相关。在整个拟议项目中， 申请人将在每个领域接受适当的培训和支持，以执行研究任务，获得 宝贵的技能和经验，以帮助推进她的职业生涯作为一个独立的研究人员。

Bacterial infection following spinal fusion surgery is a major clinical concern, with 1-10% of patients developing infection despite aggressive peri-operative antibiotic treatments. Upwards of 5 million annual spinal surgeries are predicted by 2030. Current clinical standards involve the use of aseptic drains and packing of ~1g of powdered vancomycin (VAN) into the wound space; however, this prophylaxis is short-lived (24-48 h). Left untreated, persistent bacteria form biofilms on the spinal hardware, complicating treatment of the infection by requiring aggressive systemic antibiotic treatment and removal of the infected hardware, prolonging hospital admission and patient debilitation. More effective means to prevent infection are a clinical imperative. New treatment modalities must eradicate pathogens prior to their adherence to the spinal hardware to be effective in preventing infection. Based on our previous work, our hypothesis is that a time-dependent augmentation of the initial VAN levels with a combination of antibiotics effective against both Gram-positive AND Gram-negative bacteria will reduce spinal infection rates. We propose to develop an implantable hydrogel, which will augment the standard period of aggressive antimicrobial prophylaxis through (1) sustained release of VAN at the surgical site while surgical drains are still present to maintain prophylactic levels of antibiotics, and (2) following surgical drain removal, external ultrasound-triggered release of a bolus of complementary broad-spectrum antibiotics (VAN + tobramycin) from within the hydrogel to provide broad spectrum coverage against surviving bacteria. Use of a combination of antibiotics is expected to reduce the risk of antibiotic resistant pathogens, while also ensuring that all contaminating pathogens are eradicated from the surgical site. The scientific premise of this work is that the proposed system will allow rapid, spatiotemporally-controlled, and complete release of antibiotics at supra-therapeutic levels to reduce bacterial colonization of the surgical hardware. There are three specific aims: 1) Characterize the release kinetics and stability of the hydrogel as well as the ultrasound-triggered prophylactic release system using optimized ultrasound parameters, 2) Assess the ability of the ultrasound- triggered system to prevent bacterial colonization of spinal hardware under in vitro conditions, and 3) Determine the prophylactic utility of the ultrasound-triggered system in eradicating bacteria and preventing infection in an in vivo model of spinal surgery. This proposed project addresses the clinical problem of postoperative spinal infections using innovative applications of proven materials, and can quickly and effectively be translated to the clinical area upon completion of the project. We anticipate that the project will result in an adjunctive therapy capable of lowering infection rates in spinal fusion patients, effectively reducing the pain, disability, and mortality associated with postoperative infection following spinal fusion surgery. Throughout this proposed project, the applicant will receive training and support in each area as appropriate to perform the research tasks, gaining invaluable skills and experiences to help advance her career as an independent researcher.