Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures

辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载

• 批准号: 10735964
• 负责人: Jonathan T Elliott
• 金额: $ 48.28万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735964
• 关键词: Adjuvant; Adjuvant Therapy; Amber; Animal Model; Antibiotics; Bacitracin; Bacteria; Biomedical Engineering; Bone Tissue; Cannulas; Catheters; Cells; Cementation; Collaborations; Data; Debridement; Dose; Effectiveness; Engineering; Exposure to; FDA approved; Formulation; Fracture; Free Radicals; Goals; Hospitalization; Human; Implant; In Vitro; Infection; Infection prevention; Infrastructure; Injury; Irrigation; Light; Limb structure; Mechanics; Microbe; Microbial Biofilms; Modality; Modeling; Morbidity - disease rate; Multiple Trauma; Nutritional; Open Fractures; Operative Surgical Procedures; Orthopedic Surgery; PUVA Photochemotherapy; Patients; Perioperative; Photosensitizing Agents; Polymethyl Methacrylate; Porphyrins; Positioning Attribute; Postoperative Period; Povidone-Iodine; Predisposition; Preparation; Prevention strategy; Rattus; Reactive Oxygen Species; Recovery; Research; Risk Reduction; Saline; Singlet Oxygen; Site; Soft Tissue Injuries; Source; Staphylococcus aureus; Surface; Time; Titanium; Translating; Translations; Trauma; Trauma patient; United States; Work; bioluminescence imaging; cost; efficacy evaluation; experience; fluorescence-guided surgery; fracture risk; high risk; in vivo; infection rate; infection risk; innovation; irradiation; limb loss; loss of function; metallicity; methicillin resistant Staphylococcus aureus; microbial; microbicide; multidisciplinary; musculoskeletal injury; optical imaging; sample fixation; soft tissue; tissue trauma; treatment strategy; wound

PROJECT SUMMARY This proposal aims to evaluate and optimize Photodynamic Therapy (PDT) as an adjuvant treatment for contaminated high-energy open fractures to reduce bacterial bioburden and, thus, reduce rate of infection. Infection following fracture treatment is one of the most challenging complications facing musculoskeletal trauma patients. Infection can be catastrophic, leading to prolonged morbidity, loss of function, and potential loss of limb. Several factors make high-energy open trauma particularly susceptible to infection: the presence of traumatized tissues, contamination of the fracture, poor soft tissue coverage, poor nutritional state due to polytrauma, prolonged hospitalization with exposure to nosocomial bacteria, and presence of metallic implants. Infection prevention strategies currently employed include systemic antibiotics, thorough surgical debridement of open fracture, local antibiotics, mechanical stability of the extremity with metallic implants as well as soft tissue coverage. However, despite these prevention strategies, infection occurs in 10-60% of open fractures. This is due, at least in part, to inadequate eradication of contaminating bacteria, particularly in the context of hardware at the fracture site. Thus, the overall goal of this proposal is to evaluate the efficacy of PDT at reducing wound bioburden in contaminated high-energy open fracture, thus reducing the risk of fracture related infection in preparation for translation into human patients. The scientific premise of this proposal is underpinned by data from our prior in vitro studies demonstrating enormous efficacy, killing >90% of bacteria in mature established biofilm, which is far superior to currently utilized adjuvant treatment, and our in vivo studies showing eradication of MRSA from contaminated open fracture. To attain our overall objective, three aims will be pursued. In Aim 1 we will optimize the formulation, light dose, and timing of PDT; in Aim 2 we will determine the efficacy of adjuvant topical PDT on two different fixation strategies, which have different consequences in terms of biofilm formation (intramedullary fixation and plate fixation); in Aim 3 we will develop and preliminarily assess the efficacy of repeat PDT administration through a surgically placed extraosseous catheter. Integration of PDT into treatment of high-risk contaminated high-energy open fractures has the potential to revolutionize treatment of these injuries, resulting in a reduction in wound bioburden and, thus, a reduction in risk of infection. This project leverages an extensive infrastructure and experience in fluorescence-guided surgery as well as longstanding collaborations between orthopaedic surgery and biomedical engineers.

项目摘要 该建议旨在评估和优化光动力疗法（PDT）作为辅助治疗 受污染的高能开放裂缝，以减少细菌性生物负担，从而降低感染率。 骨折治疗后的感染是肌肉骨骼面临的最具挑战性的并发症之一 创伤患者。感染可能是灾难性的，导致发病率延长，功能丧失和潜力 肢体丧失。几个因素使高能开放创伤特别容易感染：存在 受伤的组织，骨折污染，软组织覆盖率不佳，营养状态不良 多发性，长时间住院，暴露于医院细菌以及金属植入物的存在。 当前采用的感染预防策略包括系统性抗生素，彻底的手术清创术 开放裂缝，局部抗生素，肢体的机械稳定性以及金属植入物以及柔软的 组织覆盖范围。但是，尽管采取了这些预防策略，但仍有10-60％的开放性骨折发生感染。 这至少部分是由于根除污染细菌的根除不足，特别是在 骨折网站的硬件。因此，该提案的总体目标是评估PDT的功效 减少受污染的高能开放裂缝中的伤口生物负担，从而降低了与裂缝相关的风险 感染以准备转化为人类患者的感染。该提议的科学前提是 受到我们先前的体外研究数据的基础，证明了巨大疗效，杀死了> 90％的细菌 成熟建立的生物膜，远比当前使用的辅助治疗要好得多，我们的体内研究 从污染的开放裂缝中消除了MRSA。为了实现我们的整体目标，三个目标将 被追捕。在AIM 1中，我们将优化PDT的配方，轻剂量和时机；在AIM 2中，我们将确定 辅助局部PDT对两种不同的固定策略的功效，在两种不同的固定策略中都有不同的后果 生物膜形成的术语（内部固定和板固定）；在AIM 3中，我们将开发和初步 通过手术放置的外体导管评估重复PDT给药的功效。 将PDT整合到高风险污染的高能开放裂缝的处理中有可能 彻底改变了对这些伤害的治疗，导致伤口生物负担减少，因此减少了 感染的风险。该项目利用荧光引导的广泛基础设施和经验 手术以及骨科手术与生物医学工程师之间的长期合作。