国际口腔医学杂志

国际口腔医学杂志 ›› 2024, Vol. 51 ›› Issue (5): 572-584.doi: 10.7518/gjkq.2024070

• 种植专栏 • 上一篇    下一篇

抗菌肽在口腔钛种植体涂层中的研究进展

李佳敏1,2(),李毓晨1,2,葛张洁2,3,廖凌子1,2,郭鑫1,2,郭晓龙1,2,周平1,2,4()   

  1. 1.兰州大学口腔医学院 兰州 730000
    2.甘肃省牙颌面重建与生物智能制造重点实验室 兰州 730000
    3.甘肃省人民医院口腔科 兰州 730000
    4.兰州大学口腔医院颌面外科 兰州 730000
  • 收稿日期:2023-12-17 修回日期:2024-05-09 出版日期:2024-09-01 发布日期:2024-09-14
  • 通讯作者: 周平
  • 作者简介:李佳敏，学士，Email：lijm2019@lzu.edu.cn
  • 基金资助:
    中国博士后科学基金(2022M721443);兰州大学学生创新创业行动计划(20220150019)

Advancements in the study of antimicrobial peptides in the coating of oral titanium implants

Jiamin Li1,2(),Yuchen Li1,2,Zhangjie Ge2,3,Lingzi Liao1,2,Xin Guo1,2,Xiaolong Guo1,2,Ping Zhou1,2,4()   

  1. 1.School of Stomatology, Lanzhou University, Lanzhou 730000, China
    2.Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing in Gansu Province, Lanzhou 730000, China
    3.Dept. of Stomatology, Gansu Provincial Hospital, Lanzhou 730000, China
    4.Dept. of Oral and Maxillofacial Surgery, Hospital of Stomato-logy, Lanzhou University, Lanzhou 730000, China
  • Received:2023-12-17 Revised:2024-05-09 Online:2024-09-01 Published:2024-09-14
  • Contact: Ping Zhou
  • Supported by:
    China Postdoctoral Science Foundation(2022M721443);Lanzhou University College Students’ Innovation and Entrepreneurship Action Plan(20220150019)

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摘要：

口腔钛种植体的临床需求与日俱增，为预防种植体周疾病、提高种植成功率，种植体的表面修饰是目前研究的一大热点。影响种植体远期治疗效果的主要因素是种植体周炎所导致的骨丧失，理想的种植体应在具有良好的抗菌性能的同时，具备优异的骨整合性能。与传统涂层相比，抗菌肽（AMP）具有优良的抗菌性能等多方面优势。本文介绍了种植体周疾病的发病机制和AMP的分类及作用机制，并从增强抗菌性能、促进骨结合、响应种植体周围组织变化这三方面对现有种植体表面AMP涂层作一综述，以期为AMP涂层研究的优化及其临床转化指明方向。

关键词: 抗菌肽, 钛种植体, 种植体周炎, 表面改性, 抗菌, 骨整合

Abstract:

The demand for oral titanium implants is growing. Thus, strategies preventing peri-implant disease and improving the success rate of implantation through the surface modification of implants have been extensively studied. The main factor affecting the long-term therapeutic outcome of implants is bone loss due to peri-implantitis. Hence, an ideal implant should have not only good antimicrobial properties but also excellent osseointegration properties. Compared with conventional coatings, antimicrobial peptides (AMPs) have excellent antimicrobial properties. This paper introduces the pathogenesis of peri-implant diseases and the classification and mechanism of action of AMPs. In addition, existing AMP coatings on implant surfaces are examined in terms of their efficiency in enhancing AMPs, promoting osseointegration, and responding to changes in peri-implant tissues. This study is expected to provide a direction for the optimization of AMP coating research and its clinical translation.

Key words: antimicrobial peptide, titanium implant, peri-implantitis, surface modification, antibacteria, osseointegration

中图分类号: 

  • R783.1

图 1

AMP作用机制的模式图"

图 2

AMP表面涂层的示意图"

图 3

负载AMP的钛种植体作用示意图"

表 1

AMP涂层的研究进展概述"

参考文献AMP类型氨基酸序列主要结果应用意义
[55]HHC36KRWWKWWRR有效抑制S. aureus的增殖，在体内具有生物相容性和抗菌性该策略可以提高经皮植入物的抗菌潜力，利于预防经皮植入物的细菌感染
[56]HHC36KRWWKWWRR体外实验表现出良好的细胞相容性，显著的短期抗菌性能；体内试验能够抑制细菌感染和炎症反应该涂层有望在钛种植体的应用过程中降低再感染的风险
[57]HHC36、QKKRWWKWWRR、IGKYKLQYLEQWTLK融合两肽修饰的种植体对S. aureus、E. coli、铜绿假单胞菌显示出很好的抗菌活性，同时促进细胞增殖、血管形成和骨整合该研究对临床上开发多功能钛种植体，以抑制细菌感染和促进骨整合大有裨益
[58]叠氮基修饰的PEGHHC-36N3-PEG12-KRWWKWWRR抗菌钛植入物对于S. aureus表现出良好且稳定的抗菌活性，对小鼠骨髓间充质干细胞的细胞毒性可忽略不计该方法在制备抗菌钛植入物和预防临床感染方面具有巨大潜力
[59]RGD修饰的HHC36KRWWKWWRR-Acp-RGD可杀灭99%以上的S. aureus和E. coli，并显著抑制细菌生物被膜的形成；同时还能显著促进小鼠成骨细胞的黏附和增殖，并显著促进成骨标志物的表达有望预防细菌感染，促进早期骨整合
[60]来源于LL-37的多肽KR-12的类似物KRIVQRIKDFLR、KIRVQRIKDFLR、KRIVRIKFR、KIRVRIKFR对E. coli、铜绿假单胞菌和S. aureus表现出良好的抗菌活性，HOS细胞在该材料表面有良好的附着和生长，对细胞无明显毒性这种表面处理方法显示出在许多金属和有机材料表面提供长期抗菌活性的潜力
[61]LL-37LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES对S. aureus有较强的体外抗菌作用，可防止细菌生物被膜的形成；还能显著破坏钛合金表面成熟、稳定的生物膜结构为治疗S. aureus在钛合金假体感染中的难治性感染提供了新的途径
[62]Pac-525Ac-KWRRWVRWI-NH2该涂层可阻碍细菌生物膜生成，抗菌性良好，可促进成骨细胞黏附及增殖为构建具有良好生物活性及抗菌功能的口腔种植体表面涂层提供依据
[63]Pac-525Ac-KWRRWVRWI-NH2对革兰阴性菌（E. coli）和革兰阳性菌（S. aureus）均有较强的细胞毒性作用，同时不影响成骨样细胞系MC3T3-E1的生长和黏附该涂层具有提高钛骨科种植体和口腔种植体的抗菌活性和生物活性方面的潜力
[64]GL13KGKIIKLKASLKLL-CONH2对M1巨噬细胞有抑制作用，对M2巨噬细胞有良好的细胞相容性，可以调节巨噬细胞的极化以及炎症和抗炎作用的表达，减轻炎症过程的影响该表面可能促进骨再生和骨整合的过程
[65]GL13KGKIIKLKASLKLL-CONH2具有良好的生物相容性、促成骨作用，抑制RAW264.7细胞的破骨细胞分化，并显著促进血管生成分化该涂层具有成骨、血管生成和抗破骨细胞生成的特性
[66]GL13KGKIIKLKASLKLL-CONH2对耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus，MRSA）、E. coli和S. aureus具有较强的接触和释放杀灭能力，在抗菌浓度下具有良好的细胞相容性该涂层有望控制MRSA引起的种植体相关感染
[67]GL13K、MMP9-CPGKIIKLKASLKLL-NH2、KKGGGPLGMYS该表面显示出强大的抗生物膜活性，能够有效地促进成骨细胞和成纤维细胞的增殖，稳定性较好该表面有望降低经皮骨固定装置的感染率，并增强组织的再生能力
[68]GL13K、LamLG3GKIIKLKASLKLL-NH2、NH2-KKGGG-PPFLMLLKGSTRFC显示出抗戈登链球菌的生物膜活性，同时促进口腔来源角质形成细胞的增殖、半桥粒形成和机械附着多功能表面有望能够通过强大的抗菌活性和增强软组织对植入物的附着来降低种植体周炎的发生率
[69]LamLG3KN3-GGG-PPFLMLLKGSTRFC或KK-GGG-PPFLMLLKGSTRFC口腔角质形成细胞的增殖和半桥粒形成显著增加有助于开发更有效的生物医学涂层
[70]LamLG3、Netrin-1PPFLMLLKGSTR、QWRDTWARRLRKFQQREKKGKCRKA人口腔角质形成细胞TERT-2/OKF6在多肽涂层钛表面的增殖速度加快，促进了半桥粒标志物Col XVII和β-4整合素的表达；同时抑制了诱导型一氧化氮合酶的产生；内毒素刺激的小鼠巨噬细胞（RAW 264.7）中表达的促炎M1标志物以及与抗炎M2巨噬细胞表型相关的抗CD206的表达增加该设计可以帮助减轻炎症，促进黏膜/种植体周围软组织的封闭
[71]成骨生长肽ALKRQGRTLYGFGG能够促进成骨细胞的扩散和成骨分化，其抗菌性能明显提高该方法有望加快口腔种植体骨整合速度
[72]基于β氨基酸的AMP模拟物ACHC-β3hVal-β3hLys在体外成功地阻止了S. aureus生物膜的形成，不会显著降低前成骨细胞MC3T3-E1的活性，可在24 d内抑制S. aureus生物膜的形成有望减少与种植体相关的感染的发生
[73]PRELP衍生的AMP RRP9W4NRRPRPRPRPWWWW-NH2AMP具有与传统抗生素氯唑西林相当或更好的抗生物被膜性能，未观察到对骨结合的负面影响介孔二氧化钛具有作为AMP给药系统的潜力；有助于骨整合植入物感染的控制
[74]DJK-5VQWRAIRVRVRVIR对革兰阳性菌和革兰阴性菌的抑菌率均在90%以上，能够间接杀灭细菌、抑制炎症反应该方案有望在严重种植相关细菌感染中实现更好的骨整合
[75]NKC-DOPA5APKAMKLLKKLLKLQKKGIGGGGSGGGGSYYYYY在2 h内完全抑制了E. coli、铜绿假单胞菌和S. aureus的生长，包覆在底物表面的多肽的稳定性为84 d，该表面对人角质形成细胞系HaCaT没有细胞毒性黏附性AMP具有作为抗菌表面涂层的潜力，可以有效地杀灭接触的广谱细菌
[76]蜂毒肽GIGAVLKVLTTGLPALISWIKRKRQQ可促进MC3T3细胞释放碱性磷酸酶及MC3T3细胞的增殖；四环素和蜂毒肽复合涂层可杀灭所有MRSA该涂层具有良好的成骨和抗菌活性，有望成为一种多功能的骨植入涂层
[77]复合氧化石墨烯与AMP NaL-P-113Ac-AKR-Nal-Nal-GYKRKF-Nal-NH2具有缓慢、持续的体外释药特性，负载Nal-P-113的复合氧化石墨烯涂层对革兰阳性变异链球菌和革兰阴性P. gingivalis均表现出良好的抗菌性能，对人牙龈成纤维细胞无明显细胞毒性有望在钛基种植体跨黏膜成分的表面改性中得到应用
[78]Amino pepti-des、Carboxyl peptidesNGIVKAGPAIAVLGEAAL-GGGGS、GGGGS-KRLFRRWQWRMKKY该涂层具有灵敏的pH值响应特性；对S. aureus 21 d的抗菌实验中，抗菌率始终保持在99%以上，还有利于骨髓干细胞在表面的黏附、扩散和增殖，促进成骨基因的表达和胶原蛋白的分泌以及骨整合该涂层具有协同抑制细菌和促进骨整合的能力，在骨缺损和相关感染治疗中具有巨大的潜在应用前景
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