Multifunctional Ionic Liquid Application for Treatment of Peri-implant Diseases

摘要 种植体周围（PI）疾病，粘膜炎和种植体周围炎，最终影响约25-50%的牙科种植体后， 放置，导致软组织和骨破坏。目前的治疗目标是口腔粘膜的生态失调， 种植体表面的微生物组（成熟菌斑）是PI疾病的主要病因。常规 治疗选择包括机械和/或化学清创术、激光治疗、超声刮除， 尿道成形术尽管生物膜去除有所改善，但去污可能会无意中使PI疾病恶化 通过损坏植入物表面、产生加剧宿主炎症的离子/颗粒来预后 免疫反应此外，这些解毒方案并不解决慢性炎症反应。 维持PI宿主组织破坏的环境。在PI患病时缺乏受控的免疫调节， 位点可能阻碍宿主组织与先前被生物膜污染植入物表面的重新整合。因此 理想PI疾病治疗应该（i）消除感染，（ii）保持Ti表面状态，和（iii）具有 免疫调节活性有助于组织-植入物界面处的愈合。此前，我们的研究 一组演示了使用双阳离子咪唑基离子液体（IonLs）与氨基酸基阴离子 部分作为牙科植入物上的多功能涂层。特别是，我们表明，IonL官能化与 苯丙氨酸（IonL-Phe）在Ti上形成稳定的涂层，赋予宿主细胞相容性，抗微生物活性， 抗腐蚀能力和润滑性，以及体内生物相容性和口腔骨整合， 大鼠模型在体内评估过程中，IonL-Phe涂层钛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种植体的比较。观察到的免疫调节活性 IonL-Phe作为PI疾病治疗的多功能治疗剂的应用的积极评价。到 评估IonL-Phe联合解毒方案促进植入物再整合的潜力， 提出了以下目标。在目标1中，将确定IonL-Phe应用的标准方法 基于释放动力学研究及其对解毒钛表面性质的影响。在目标2中，体外评价 IonL-Phe应用对血浆蛋白沉积和随后对哺乳动物细胞生长的影响 将在解毒钛上进行细菌挑战或多菌种细菌粘附。在目标3中，体内 IonL-Phe应用对蛋白质层形成、宿主组织与Ti植入物表面再整合以及 将在大鼠模型中诱导PI疾病后评估口腔微生物组组成。拟定研究 将通过阐明IonL的以下能力来解决目前在PI疾病治疗中的临床差距：（i）保护 在急性愈合阶段，（ii）减轻细菌生物膜的再生长，和（iii）主动 调节免疫应答以促进软组织愈合和重新骨整合。如果成功，这个项目 将使基于IonL的治疗模式与当前的解毒方法相结合， 靶向PI疾病发作期间的生态失调和免疫平衡。

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.