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，最终会影响到约25%-50%的种植体 放置，导致软组织和骨骼破坏。目前的治疗针对的是口腔的生物失调 种植体表面的微生物群(成熟斑块)是PI疾病的主要致病因素。传统型 治疗方案包括机械和/或化学清创、激光治疗、超声波刮除和 植入成形术。尽管在生物膜去除方面有所改进，但去污可能会在不经意间使PI病恶化 通过破坏植入物表面，产生加剧宿主炎症的离子/颗粒来预测预后 免疫反应。此外，这些解毒方案不能解决慢性炎症 支持PI宿主组织破坏的环境。猪的疾病缺乏可控的免疫调节 部位会阻碍宿主组织与先前被生物膜污染的种植体表面的重新结合。因此， 理想的PI病治疗应(I)消除感染，(Ii)保存钛表面状况，(Iii)具备 有利于组织-种植体界面愈合的免疫调节活性。此前，我们的研究 小组演示了阳离子咪唑基离子液体(IonL)与氨基酸基阴离子的使用 部分作为牙科植入物的多功能涂层。特别是，我们展示了IONL的功能化 苯丙氨酸(IONL-Phe)在钛表面形成稳定的涂层，赋予宿主细胞兼容性，抗菌活性， 抗腐蚀能力，体外润滑性以及体内生物相容性和口腔骨整合 大鼠模型。在体内评估中，IONL-Phe涂层钛植入物也不同程度地上调了炎症 分辨率和骨基质标记基因与非涂层植入物的比较。这种观察到的免疫调节活性 IONL-Phe作为一种多功能治疗剂应用于PI病治疗的动机评估。至 评估IONL-Phe联合脱毒方案促进种植体再结合的潜力， 提出了以下目标。在目标1中，将确定使用IONL-Phe的标准方法 基于释放动力学研究及其对脱毒钛表面性能的影响。在目标2中，体外评估 应用IONL-Phe对血浆蛋白沉积及随后对哺乳动物细胞生长的影响 在脱毒后的钛上进行细菌挑战或多菌种粘连。在《目标3》中，体内 IONL-Phe应用对蛋白质层形成、宿主组织与钛种植体表面重新整合的影响 在诱发大鼠PI疾病后，将对口腔微生物组组成进行评估。建议进行的研究 将通过阐明IONL的能力来解决目前治疗PI疾病的临床空白：(I)保护 在急性愈合阶段的种植体表面，(Ii)减缓细菌生物膜的再生长，以及(Iii)积极 调节免疫反应，促进软组织愈合和骨整合。如果成功，这个项目 将使以IONL为基础的治疗方式与目前的戒毒方法相结合 PI疾病发病过程中的靶生物失调和免疫平衡。

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.