Synergistic anti-fouling coating and minimal systemic antibiotic injections for combating periprosthetic infections

协同防污涂层和最少的全身抗生素注射可对抗假体周围感染

基本信息

批准号：
10667659
负责人：
Jie Song
金额：
$ 56.64万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667659
关键词：
Address Adsorption Alkynes Alloys Antibiotic Prophylaxis Antibiotic Therapy Antibiotics Azides Bacteria Bacterial Counts Bacterial Drug Resistance Binding Bone Marrow Bone Matrix Cell Proliferation Chemicals Complete Blood Count Copper Debridement Development Dose Electron Microscopy Engineering Environment Femur Frequencies Histology Implant In Vitro Infection Injections Invaded Length Measurement Metals Methicillin Methicillin Resistance Microbial Biofilms Modeling Modification Molecular Weight Monitor Mus Nature Operative Surgical Procedures Organ Orthopedics Osteogenesis Outcome Pathology Polymers Predisposition Prophylactic treatment Proteins Protocols documentation Rattus Recurrence Regimen Replacement Arthroplasty Resistance Risk Roentgen Rays Safety Spectrum Analysis Staphylococcus aureus Staphylococcus epidermidis Sterilization Stromal Cells Surface Testing Torsion Vancomycin Water bioluminescence imaging bone clinical translation clinically relevant combat copolymer cortical bone cycloaddition cytotoxicity density design efficacy evaluation implant associated infection implant coating improved in vivo infection rate manufacturing process metallicity methicillin resistant Staphylococcus aureus polymerization polymethacrylate prevent prophylactic side effect success surface coating

项目摘要

PROJECT SUMMARY/ABSTRACT Periprosthetic infections (PPIs) occur in 1-4% of primary total joint replacement and up to 30% of revision arthroplasty and are difficult to prevent or treat due to the tendency of bacteria, especially Staphylococcus aureus (S. aureus), to colonize and form biofilms on implant surfaces and to invade the surrounding bone matrices. Conventional antibiotic prophylaxis and treatments do not adequately address this challenge. We recently showed that anti-fouling zwitterionic polymers grafted from Ti6Al4V intramedullary (IM) implants, when combined with a single systemic injection of vancomycin, effectively inhibited S. aureus colonization on implant surfaces and PPI in murine femoral canals, significantly outperforming either treatment alone. Here, we aim to facilitate the clinical translation of this promising synergistic anti-PPI strategy by engineering a robust anti- fouling block copolymer dip-coating as an off-the-shelf product for metallic implants, and an effective and safe synergistic antibiotic prophylaxis regimen for sustained protection during primary implant insertion and implant revision, respectively, against methicillin-sensitive and methicillin-resistant (MRSA) S. aureus PPIs. In Aim 1, high-molecular weight polymethacrylate block copolymers with anti-fouling zwitterionic sidechains and metal surface-binding sidechains are prepared by sequential Reverse Addition Fragmentation Chain Transfer (RAFT) polymerization and copper-catalyzed azide-alkyne cycloaddition (CuAAC). Taking advantage of the excellent control over the degree of polymerization by RAFT and the high-fidelity CuAAC modification of sidechains, the respective block lengths and chemical nature and spatial density of metal alloy surface-binding residues are modularly altered to identify an optimal copolymer composition and dip-coating protocol to achieve consistent and stable anti-fouling coating on Ti6Al4V that can sustain flow wash, sterilization and over-the-shelf storage. Coated surfaces are characterized by water contact angels, x-ray photoelectron spectroscopy, and resistance to non-specific protein adsorption and bacterial colonizations in vitro. In Aims 2 and 3, the top anti-fouling dip- coating chosen in Aim 1 is applied to Ti6Al4V IM pins and examined, along with synergistic antibiotic prophylaxis, for the efficacy and safety in achieving long-term inhibition of PPI and recurrent PPI caused by methicillin-sensitive S. aureus or MRSA following the insertion of primary and revision implants in rats, respectively. The degree of PPI or recurrent PPI as a function of pin coating and the timing/frequency of synergistic antibiotic prophylaxis are longitudinally monitored by complete blood counts and µCT quantification of cortical bone thickening, and by endpoint quantification of bacteria on the retrieved pin, torsion test and histology/electron microscopy characterizations of explanted femurs over the course of 6 months. Long-term safety of the coating is examined by both femoral histology and systemic organ pathology in the uninfected control. Success of this study will identify an optimal dip-coating composition and synergistic antibiotic prophylaxis regimens to effectively combat PPI and recurring PPI, respectively, thereby establishing their clinical relevance as a new anti-PPI strategy and advancing them to the next stage of their clinical translations.

项目概要/摘要初次全关节置换术中发生假体周围感染 (PPI) 的比例高达 1-4%，翻修手术中发生率高达 30% 关节置换术，由于细菌，特别是葡萄球菌的倾向，难以预防或治疗金黄色葡萄球菌（S. aureus），在种植体表面定殖并形成生物膜并侵入周围的骨骼传统的抗生素预防和治疗不足以应对这一挑战。最近表明，从 Ti6Al4V 髓内 (IM) 植入物接枝的防污两性离子聚合物，当结合单次全身注射万古霉素，有效抑制金黄色葡萄球菌在植入物上的定植小鼠股管中的表面和 PPI 显着优于单独的治疗。通过设计强大的抗 PPI 策略，促进这一有前景的协同抗 PPI 策略的临床转化防垢嵌段共聚物浸涂作为金属植入物的现成产品，是一种有效且安全的方法协同抗生素预防插入方案可在初次植入和植入过程中提供持续保护分别针对甲氧西林敏感和耐甲氧西林 (MRSA) 金黄色葡萄球菌 PPI 进行修订。具有防污两性离子侧链和金属的高分子量聚甲基丙烯酸酯嵌段共聚物表面结合侧链通过顺序反向加成断裂链转移 (RAFT) 制备聚合反应和铜催化叠氮化物-炔环加成反应（CuAAC）的优异性能。通过RAFT控制聚合度和侧链的高保真CuAAC修饰，金属合金表面结合残基各自的嵌段长度和化学性质和空间密度为模块化改变以确定最佳的共聚物成分和浸涂协议以实现一致 Ti6Al4V 上的稳定防污涂层可承受流动清洗、灭菌和货架储存。涂层表面通过水接触角、X 射线光电子能谱和电阻来表征目标 2 和 3 中的非特异性蛋白质吸附和细菌定植。将目标 1 中选择的涂层应用于 Ti6Al4V IM 针并与协同抗生素一起进行检查预防，以实现长期抑制 PPI 和由以下原因引起的复发性 PPI 的有效性和安全性：在大鼠中插入初次和修复植入物后，对甲氧西林敏感的金黄色葡萄球菌或 MRSA，分别是 PPI 或复发性 PPI 的程度与针涂层和时间/频率的关系。通过全血细胞计数和 µCT 定量来纵向监测协同抗生素预防皮质骨增厚，并通过回收销钉上细菌的终点定量、扭转测试和 6 个月内移植股骨的组织学/电子显微镜特征。通过未感染者的股骨组织学和全身器官病理学检查涂层的安全性这项研究的成功将确定最佳的浸涂组合物和协同抗生素。分别有效对抗 PPI 和复发性 PPI 的预防方案，从而建立其各自的预防方案作为一种新的抗 PPI 策略的临床相关性，并将其推进到临床转化的下一阶段。