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

• 批准号: 10533877
• 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
• 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/10533877
• 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; Ensure; 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; Phenols; Plant Roots; 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; Time; 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

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.

项目摘要/摘要 人假体感染（PPI）发生在原发性总置换量的1-4％，最多30％的修订 关节置换术，由于细菌的趋势，尤其是葡萄球菌而难以预防或治疗 金黄色葡萄球菌（金黄色葡萄球菌），在植入物表面定居并形成生物膜并入侵周围的骨头 矩阵。常规的抗生素预防和治疗不能充分解决这一挑战。我们 最近表明，当ti6al4v肠内（IM）垂体接枝时，抗污染zwitterionic聚合物，当 与单一全身注入万古霉素结合，有效抑制金黄色葡萄球菌在植入物上定植 鼠股管中的表面和PPI，单独的两种治疗方法都明显优于任何两种治疗。在这里，我们的目标是 通过设计强大的反 - 污染块共聚物浸入涂层作为金属粉刷的现成产品，有效且安全 在初级植入物插入和植入物期间，协同抗生素预防方案，以持续保护 修订分别针对甲氧西林敏感和耐甲氧西林的（MRSA）金黄色葡萄球菌PPI。在AIM 1中， 高分子重量聚合物聚合物块共聚物与抗污染zwitterionic sidechains和金属 通过顺序反向添加碎片链转移（RAFT）来制备表面结合的侧链 聚合和铜催化叠氮化物环加成（CUAAC）。利用优秀 控制筏的聚合程度和高保真的CUAAC修饰， 金属合金表面结合残差的一级块长度和化学性质和空间密度为 模块化更改以识别最佳共聚物组成和浸入涂层方案以实现一致 以及在Ti6al4v上稳定的抗死涂层，可以维持洗流量，灭菌和货架上的存储空间。 涂层表面的特征是水接触天使，X射线光电子光谱和电阻 在体外进行非特异性蛋白吸附和细菌定植。在AIMS 2和3中，顶部的反污染倾角 - 在AIM 1中选择的涂层应用于Ti6al4v im销并进行检查，并与协同抗生素一起检查 预防，以实现由PPI和复发性PPI长期抑制的效率和安全性 在大鼠插入原发性和修订后，甲氧西林敏感的金黄色葡萄球菌或MRSA， 分别。 PPI或复发性PPI的程度是引脚涂层的函数以及的时间/频率 通过完整的血数和µCT定量来纵向监测协同抗生素预防 皮质骨增厚，以及通过检索的销钉，扭转测试和 在6个月的时间里，股骨外植物的组织学/电子显微镜特征。长期 未感染的股骨组织学和全身器官病理学都检查了涂层的安全性 控制。这项研究的成功将确定最佳的浸入涂层组成和协同抗生素 预防方案分别有效地对抗PPI和反复出现的PPI，从而确定了它们的 临床相关性是一种新的反佩比策略，并将其推进到其临床翻译的下一阶段。