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，有1-10%的患者 尽管围术期接受积极的抗生素治疗，但仍发生感染。每年超过500万的脊椎 手术预计将在2030年前完成。目前的临床标准包括使用无菌引流管和包装~1g 粉状万古霉素(VAN)进入伤口间隙；然而，这种预防是短暂的(24-48小时)。左边 未经治疗的持久性细菌在脊柱硬件上形成生物膜，使感染的治疗变得复杂 需要积极的系统抗生素治疗和移除受感染的硬件，延长住院时间 入院和病人虚弱。预防感染的更有效手段是临床上的当务之急。新的 治疗方式必须在病原体附着到脊柱硬件之前将其根除，才能在 预防感染。基于我们以前的工作，我们的假设是，随着时间的推移， 联合使用抗生素对革兰氏阳性和革兰氏阴性均有效的初始VAN水平 细菌将降低脊柱感染率。我们建议开发一种可植入的水凝胶，它将增强 侵袭性抗菌药物预防的标准期是通过(1)在外科手术时持续释放凡士林 当手术引流管仍然存在以保持预防性抗生素水平时，以及(2)手术后 引流管清除，体外超声波触发的补充性广谱抗生素的释放 (凡+妥布霉素)从水凝胶内提供广谱覆盖，以对抗存活的细菌。 联合使用抗生素有望降低抗药性病原体的风险，同时也 确保所有污染病原体从手术部位被根除。这其中的科学前提是 研究工作是，拟议的系统将允许快速、时空控制和完全释放抗生素。 在超治疗水平，以减少手术硬件的细菌定植。有三个具体的 目的：1)表征水凝胶的释放动力学和稳定性，以及超声引发的 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- 触发系统以防止体外条件下脊柱硬件的细菌定植，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作用 脊柱外科活体模型。本项目旨在解决脊柱手术后的临床问题。 使用经过验证的材料的创新应用程序进行感染，并可以快速有效地转换为 项目竣工后的临床区。我们预计该项目将导致一种辅助治疗。 能够降低脊柱融合患者的感染率，有效地减少疼痛、残疾和死亡率 与脊柱融合术后感染有关。在整个拟议的项目中， 申请者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 帮助她作为一名独立研究人员推进职业生涯的宝贵技能和经验。

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.