Multifunctional Ionic Liquid Application for Treatment of Peri-implant Diseases

多功能离子液体治疗种植体周围疾病的应用

• 批准号: 10530033
• 负责人: Danieli Rodrigues
• 金额: $ 37.05万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530033
• 关键词: Acute; Address; Adsorption; Affect; Aftercare; Amino Acids; Antimicrobial Resistance; Bacteria; Bacterial Adhesion; Behavior; Biological Assay; Bone Matrix; Cells; Cellular Structures; Chemicals; Chitosan; Chlorhexidine; Chronic; Citric Acid; Clinical; Clinical Treatment; Coculture Techniques; Corrosion; Corrosives; Coupled; Debridement; Decontamination; Dental Implants; Deposition; Disease; Disease model; Drug Metabolic Detoxication; Enzyme-Linked Immunosorbent Assay; Equilibrium; Etiology; Evaluation; Excision; Exhibits; Fiber; Fibroblasts; Flow Cytometry; Formulation; Genes; Growth; Histology; Hydrogen; Immune; Immune response; Immunologics; Implant; In Vitro; Infection; Inflammation; Inflammatory; Ions; Kinetics; Lasers; Ligature; Liquid Chromatography; Liquid substance; Lubricants; Lubrication; Mammalian Cell; Mechanics; Mediating; Methods; Microbial Biofilms; Modality; Modeling; Molecular; Mucositis; Optics; Oral; Osseointegration; Pathogenicity; Phase; Phenylalanine; Plasma Proteins; Procedures; Proteins; Proteome; Protocols documentation; Raman Spectrum Analysis; Rattus; Recurrence; Regimen; Research; Resolution; Roentgen Rays; Saline; Sampling; Scanning Electron Microscopy; Site; Spectrum Analysis; Surface; Surface Properties; Symbiosis; Taxonomy; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Titanium; Treatment Protocols; Ultrasonics; Up-Regulation; antimicrobial; aqueous; base; biomaterial compatibility; bone; cell growth; clinical efficacy; confocal imaging; conventional therapy; disease prognosis; dysbiosis; healing; hydrophilicity; immunoregulation; implant coating; implant material; improved; in vitro testing; in vivo; inflammatory milieu; macrophage; metallicity; microCT; microbiome; microbiome composition; migration; mineralization; novel; oral microbiome; organic acid; osteoblast differentiation; oxidation; particle; pathogen; peri-implantitis; polymicrobial biofilm; preservation; response; soft tissue; subcutaneous; tandem mass spectrometry; ultraviolet

ABSTRACT Peri-implant (PI) diseases, mucositis and peri-implantitis, eventually affect ~25-50% of dental implants after placement, resulting in soft tissue and bone destruction. Current treatments target dysbiosis of the oral microbiome (mature plaque) on the implant surface as the primary etiological factor of PI diseases. Conventional treatment options include mechanical and/or chemical debridement, laser treatment, ultrasonic scaling, and implantoplasty. Despite improvements in biofilm removal, decontamination may inadvertently worsen PI disease prognosis by damaging the implant surface, generating ions/particles that exacerbate the host inflammatory immune response. Furthermore, these detoxification protocols do not address the chronic inflammatory environment sustaining PI host tissue destruction. The lack of controlled immunomodulation at the PI diseased site can hinder re-integration of host tissue with a previously biofilm-contaminated implant surface. Thus, the ideal PI disease treatment should (i) eliminate infection, (ii) preserve Ti surface condition, and (iii) possess immunomodulatory activity conducive towards healing at the tissue-implant interface. Previously, our research group demonstrated the use of dicationic imidazolium-based ionic liquids (IonLs) with amino acid-based anionic moieties as multifunctional coatings on dental implants. In particular, we showed that IonL functionalized with phenylalanine (IonL-Phe) formed stable coatings on Ti, imparting host cell compatibility, antimicrobial activity, anti-corrosive ability, and lubrication in vitro in addition to in vivo biocompatibility and oral osseointegration in a rat model. During in vivo assessment, IonL-Phe-coated Ti implants also differentially upregulated inflammation resolution and bone matrix marker genes versus non-coated implants. This observed immunomodulatory activity motivated evaluation of IonL-Phe application as a multifunctional therapeutic agent for PI disease treatment. To assess the potential of IonL-Phe in combination with detoxification regimens to promote implant re-integration, the following aims are proposed. In Aim 1, a standard method for application of IonL-Phe will be determined based on release kinetic studies and its effect on detoxified Ti surface properties. In Aim 2, an in vitro evaluation of IonL-Phe application on plasma protein deposition and subsequent effect on mammalian cell growth under bacterial challenge or multispecies bacterial adhesion on detoxified Ti will be performed. In Aim 3, the in vivo impact of IonL-Phe application on protein layer formation, host tissue re-integration with Ti implant surface, and oral microbiome composition will be assessed after induction of PI diseases in a rat model. The proposed study will address the current clinical gap in treatment of PI diseases by elucidating the ability of IonL to (i) protect the implant surface during the acute healing phase, (ii) mitigate regrowth of bacterial biofilm, and (iii) actively modulate the immune response towards soft tissue healing and re-osseointegration. If successful, this project will enable application of IonL-based treatment modality in combination with current detoxification methods to target dysbiosis and immune balance during the onset of PI diseases.

抽象的 植入植物（PI）疾病，粘膜炎和植入植入术，最终影响约25-50％的牙齿植入物 放置，导致软组织和骨破坏。目前的治疗靶向口腔营养不良 植入物表面上的微生物组（成熟斑块）是PI疾病的主要病因因子。传统的 治疗方案包括机械和/或化学清创术，激光治疗，超声缩放以及 植入术。尽管去除生物膜，但净化可能会无意中恶化PI病 通过损坏植入物表面的预后，产生加剧宿主炎症性的离子/颗粒 免疫反应。此外，这些解毒方案无法解决慢性炎症 维持PI宿主组织破坏的环境。 PI患病缺乏受控免疫调节 位点可以阻止具有先前被生物膜污染的植入物表面的宿主组织重新集成。因此， 理想的PI疾病治疗应（i）消除感染，（ii）保存Ti表面状况，（iii）拥有 免疫调节活性有助于组织植入物界面的愈合。以前是我们的研究 组证明了使用基于氨基酸的阴离子的基于咪唑的离子液体（离子）的使用 部分是牙科植入物上的多功能涂料。特别是，我们表明IONL与 苯丙氨酸（IONL-PHE）在Ti上形成稳定的涂层，赋予宿主细胞兼容性，抗菌活性，抗菌活性， 除体内生物相容性和口服骨整合外，抗腐蚀能力和体外润滑 大鼠模型。在体内评估期间，离子涂层Ti植入物也差异上调炎症 分辨率和骨基质标记基因与非涂层植入物。这种观察到的免疫调节活性 对IONL-PHE应用作为PI疾病治疗的多功能治疗剂的动机评估。到 评估离子phe与排毒方案结合的潜力，以促进植入物重新整合， 提出了以下目标。在AIM 1中，将确定应用IONL-PHE的标准方法 基于释放动力学研究及其对排毒Ti表面特性的影响。在AIM 2中，体外评估 在血浆蛋白沉积和随后对哺乳动物细胞生长的影响下，对哺乳动物细胞生长的影响 将进行细菌挑战或多种细菌在排毒Ti上的细菌粘附。在AIM 3中，体内 IONL-PHE应用对蛋白质层形成，宿主组织与Ti植入物的重新整合的影响，以及 在大鼠模型中诱导PI疾病后，将评估口服微生物组成分。拟议的研究 将通过阐明IONL（i）保护IONL的能力来解决当前治疗PI疾病的临床差距 急性愈合阶段的植入物表面，（ii）减轻细菌生物膜的再生，（iii）积极地 调节对软组织愈合和重新结合的免疫反应。如果成功，这个项目 将使基于IONL的治疗方式与当前的排毒方法结合使用 PI疾病发作期间的靶向失调和免疫平衡。