Implant surface modification strategies against periprosthetic infections

针对假体周围感染的种植体表面修饰策略

• 批准号: 9102901
• 负责人: Jie Song
• 金额: $ 36.85万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102901
• 关键词: Acute; Address; Alkynes; Allergic Reaction; Alloys; Antibiotics; Azides; Bacterial Adhesion; Betaine; Biocompatible; Bone Marrow; Budgets; Chemicals; Chemistry; Chronic; Clinical; Coupled; Development; Drug resistance; Encapsulated; Evaluation; Expenditure; Failure; Femur; Focal Infection; Gel Chromatography; Goals; Health; Health Care Costs; Implant; In Vitro; Incidence; Infection; Inflammatory Response; Libraries; Life; Measurement; Mechanics; Mediator of activation protein; Medicare; Microbial Biofilms; Modification; Molecular Weight; Morphology; Operative Surgical Procedures; Organ; Orthopedic Surgery procedures; Osteolysis; Outcome; Pathology; Patients; Polymers; Property; Prophylactic treatment; Proteins; Quality of life; Rattus; Replacement Arthroplasty; Reproducibility; Risk; Roentgen Rays; Role; Saline; Side; Spectrum Analysis; Staphylococcus aureus; Stromal Cells; Surface; Surface Properties; System; Testing; Thick; Torque; Vancomycin; Water; Wettability; absorption; bactericide; biomaterial compatibility; biomineralization; copolymer; cycloaddition; density; feeding; improved; in vivo; killings; microCT; mineralization; monolayer; monomer; novel; polymerization; retinal rods; screening; surface coating; trend

 DESCRIPTION (provided by applicant): Periprosthetic infection of metallic implants is one of the most serious complications in orthopedic surgeries and its incidence has seen a recent nationwide upward trend despite rigorous prophylaxis and surgical approaches. Biofilm formation surrounding the implant is a common threat that makes these serious local infections both more likely to occur and more difficult to eradicate. Current approaches in improving the anti-fouling property of implant surfaces or locally delivering antibiotics have shown some short-term benefits, but the long-term outcomes of these approaches are not satisfactory. The goal of the proposed study is to address the challenge of periprosthetic infections by synergistically affording metallic implant surfaces with stable anti- fouling and sufficient bactericidal propertie without compromising osteointegration. This will be realized by grafting functional polymer brushes containing zwitterionic and vancomycin-bearing motifs with modularly tunable chemical compositions, molecular weights, and spatial arrangements of the functional motifs from metallic alloy surfaces using surface initiated "living" atom-transfer radical polymerization (SI-ATRP) and bioorthogonal azide/alkyne cycloaddition "click" chemistry. The choice of the zwitterionic motif is motivated by their stable anti-fouling properties and our recent discovery of their novel role as potent mediators of biomineralization. In Aim 1, we will surface-graft a library of homopolymers, random and block copolymers with modularly presented anti-fouling and bactericidal functional motifs from commercial Ti6Al4V substrates using the robust SI-ATRP and "click" chemistry. The properties and robustness of the coatings are characterized and validated by X-ray photoelectron spectroscopy, water contact angle measurements, thermo-gravimetric analysis/gel permeation chromatography as well as surface scratch test. In Aim 2, we will screen for the most effective bactericidal and anti-fouling yet cytocompatible surface brush compositions by quantification of in vitro inhibition of Staphylococcus aureus (S. aureus) cultures by, non-specific protein absorptions on, and viability/proliferation of adherent bone marrow stromal cells on the modified surfaces. In Aim 3, the top functional homopolymer, block and random copolymer surface brush compositions chosen from Aim 2 are applied to Ti6Al4V intramedullary (IM) rods. The surface modified IM rods, along with unmodified control and that modified with a monolayer of vancomycin, are implanted in rat femoral medullary canals inoculated with either S. aureus or saline (uninfected control). The efficacy of the surface polymer brush coatings in reducing short-term (3 weeks) and longer-term (up to 6 months) periprosthetic infections are evaluated by quantification of S. aureus adhered on the retrieved IM rod, sequestrum formation and femur widening/cortex thinning (by microCT), and the failure torque of explanted femurs. These outcomes are scored to guide the selection of the surface brush composition affording the most sustained inhibition to periprosthetic infections and minimal perturbation to normal femoral morphology and mechanical integrity. Biocompatibility of the surface brush compositions are also examined by the pathology of vital/scavenger organs and femurs (for signs of osteolysis, acute/chronic inflammatory responses and allergic reactions to the coating) of the rats receiving implants without bacterial inoculum. Successful completion of this study is expected to identify a biocompatible surface polymer brush composition affording sustained protection against / inhibition of periprosthetic infections that can be broadly applied o a wide range of metallic surgical implants.

 描述（由申请人提供）：金属植入物的假体周围感染是骨科手术中最严重的并发症之一，尽管采取了严格的预防和手术方法，但其发病率最近在全国范围内呈上升趋势，植入物周围的生物膜形成是一种常见的威胁。这些严重的局部感染更容易发生，也更难以根除。目前改善植入物表面防污性能或局部施用抗生素的方法已显示出一些短期效益，但长期效果却不佳。这些方法并不令人满意。所提出的研究的目标是通过协同提供具有稳定的防污和足够的杀菌性能而不损害骨整合的金属植入物表面来解决假体周围感染的挑战，这将通过移植含有两性离子的功能性聚合物刷来实现。和万古霉素承载基序，具有模块化可调的化学成分、分子量和使用表面引发的金属合金表面功能基序的空间排列“活性”原子转移自由基聚合（SI-ATRP）和生物正交叠氮化物/炔环加成“点击”化学 两性离子基序的选择是。 受到它们稳定的防污特性以及我们最近发现它们作为生物矿化的有效介质的新作用的启发，在目标 1 中，我们将表面接枝具有模块化呈现的防污和杀菌功能基序的均聚物、无规和嵌段共聚物库。使用强大的 SI-ATRP 和“点击”化学从商用 Ti6Al4V 基材制备涂层的特性和坚固性通过 X 射线光电子进行表征和验证。光谱、水接触角测量、热重分析/凝胶渗透色谱以及表面划痕测试在目标2中，我们将通过定量体外抑制来筛选最有效的杀菌和防污且细胞相容的表面刷组合物。通过修饰表面上贴壁骨髓基质细胞的非特异性蛋白质吸收和活力/增殖来培养金黄色葡萄球菌（S. aureus）。在目标 3 中，将从目标 2 中选择的顶部功能均聚物、嵌段和无规共聚物表面刷组合物应用于 Ti6Al4V 髓内 (IM) 棒。表面改性的 IM 棒以及未改性的对照和用单层万古霉素改性的 IM 棒。植入接种有金黄色葡萄球菌或盐水（未感染对照）的大鼠股骨髓管中。 表面聚合物的功效。通过量化粘附在取回的肌内杆上的金黄色葡萄球菌、死骨形成和股骨加宽/皮质变薄（通过 microCT）来评估刷涂减少短期（3 周）和长期（长达 6 个月）假体周围感染的作用，以及外植股骨的失效扭矩，对这些结果进行评分，以指导表面刷组合物的选择，从而对假体周围感染提供最持久的抑制和最小的扰动。表面刷组合物的生物相容性也通过接受植入物的大鼠的重要/清道夫器官和股骨的病理学（骨质溶解、急性/慢性炎症反应和对涂层的过敏反应的迹象）进行检查。这项研究的成功完成预计将鉴定出一种生物相容性表面聚合物刷组合物，可提供持续的保护/抑制假体周围感染，可广泛应用于各种金属手术植入物。