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

基本信息

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
项目类别：
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

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

展开

项目摘要

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（由适用提供）：金属侵入的周围感染是骨科手术中最严重的并发症之一，其事件已看到最近的全国上升趋势，它追求严格的预防和手术方法。植入物周围的生物膜形成是一种常见威胁，使这些严重的局部感染既可能发生，又更难放射。当前改善植入物表面或本地提供抗生素的抗污染特性的方法显示出一些短期益处，但是这些方法的长期结果不满足。拟议的研究的目的是通过协同提供具有稳定的抗污染和足够的细菌性特性的金属植入物表面来应对牙周感染的挑战，而不会损害整合性。这将通过将功能性聚合物刷包含具有可调化学成分，分子量的ZIDINIC和VATIRECIN和万古霉素的基序来实现“单击”化学。 zwitterionic主题的选择是由它们稳定的反污染特性以及我们最近发现其作为生物矿化潜在介体的新作用的动机。在AIM 1中，我们将使用强大的SI-ATRP和“ Click” Chemistry和“ Compartial Ti6Al4V尺寸”的模块化抗服和生物功能基序表面植根，这些均聚物库，随机和嵌段共聚物具有模块化的抗死和生物功能基序。通过X射线光电子光谱，水接触角度测量，热毛皮分析/凝胶渗透色谱以及表面划痕测试来表征和验证涂料的特性和鲁棒性。在AIM 2中，我们将筛选出最有效的细菌，抗污染但细胞相容的表面刷子组成，这些表面刷组合物数量通过对金黄色葡萄球菌（S. aureus）培养的体外抑制，通过非特异性蛋白质吸收的葡萄球菌培养物（S. aureus）培养物，并在适当的蛋白质上吸收，并在质量骨质质质体细胞上的易活性/增殖。在AIM 3中，将来自AIM 2选择的最高功能均聚物，块和随机共聚物表面刷组合物应用于TI6AL4V肠内（IM）杆。表面改性的IM杆以及未修饰的对照，并用万古霉素的单层修饰，将其植入大鼠股骨髓质管中，接种了金黄色葡萄球菌或盐水（未感染的对照）。表面聚合物刷涂层在还原短期（3周）和长期（长达6个月）的效率中，通过定量遵循的金黄色葡萄球菌对所检索的IM杆的固定，续集形成和股骨宽度和股骨宽度/股骨宽度（按microct）进行评估，以及探索性人的失败扭矩。对这些结果进行评分以指导选择表面刷成分的选择，从而提供了对周围感染的最持续抑制作用，并且对正常的股骨形态和机械完整性的扰动最少。表面刷成分的生物相容性还通过重要的/清道夫器官和股骨的病理（对于骨溶解的迹象，急性/慢性炎症反应以及对涂层的过敏反应的迹象），对涂层的涂层进行了过敏反应）。预计这项研究的成功完成将确定一种生物相容性的表面聚合物刷组成，可持续保护 /抑制人虚拟感染，可以广泛应用多种金属外科手术。