Peptide Enabled Self Assembled Reconfigurable Implant Coatings

肽支持的自组装可重构植入涂层

• 批准号: 8228799
• 负责人: Candan Tamerler-Behar
• 金额: $ 20.86万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228799
• 关键词: Address; Affinity; Alloys; Antibiotic Therapy; Antibiotics; Antimicrobial Effect; Binding; Biochemistry; Bioinformatics; Biology; Carrier Proteins; Cell surface; Ceramics; Chemicals; Chemistry; Computational Biology; Coupled; Drug Delivery Systems; Engineering; Environment; Epidermis; Escherichia coli; Excision; Exhibits; Generations; Goals; Growth; Higher Order Chromatin Structure; Hip region structure; Immobilization; Implant; Incidence; Individual; Infection; Infection prevention; Interphase; Knee; Medicine; Methods; Microbial Biofilms; Molecular; Operative Surgical Procedures; Orthopedic Surgery procedures; Outcome; Pathway interactions; Penetration; Peptides; Performance; Pharmaceutical Preparations; Population; Prevention strategy; Preventive; Preventive Medicine; Property; Recovery; Replacement Arthroplasty; Site; Solid; Staging; Surface; Technology; Testing; Therapeutic; Time; Tissues; Titania; Titanium; Vascularization; Zirconium; antimicrobial; antimicrobial peptide; bactericide; base; bone; combat; combinatorial; computerized tools; crosslink; design; functional group; implant coating; implant material; implantation; improved; knowledge base; novel strategies; pathogen; protein aminoacid sequence; self assembly; structural biology; targeted delivery; tool; zirconium oxide

DESCRIPTION (provided by applicant): Implant-associated infections are of major concerns in orthopedic surgery requiring a high rate of knee and hip revisions and joint replacements. The implant materials provide an ideal environment for bacterial growth, acquired at the time of surgery or at a later stage. The goal of this proposal is to develop peptide-based multifunctional molecules that can self-assemble on implant surfaces and simultaneously induce antimicrobial effects directly on the site through their inherent programmable functions. Following the nucleation of pathogens at the implant surface, antibiotic penetration into the biofilm can be weak resulting in various detrimental effects for healthy implant-tissue integrations such as poor vascularization of the bone. Some of the current treatments may even include implant removal, antibiotic therapy and, only after along recovery period, re-implantation. In the combat of implant-associated infections, there is an urgency to develop new strategies that can be preventive specifically at the implant site. Among the most attractive preventive strategies would be to provide an antimicrobial activity at the implant site without impairing the osseous-integration. The major prerequisite to realize this approach is by modifying the surface biochemistry of the implant via immobilization of biologically active molecules. Conventional immobilization methods, however, are only applicable to a limited range of materials and require the presence of specific functional groups and synthetic pathways. Using combinatorially-selected solid-binding peptides we tailor multifunctional properties with nanoMolar affinities through computational biology tools. We recently engineered peptide sequences that are specific to titanium based implant material, successfully coupled them with antimicrobial peptides, and tested their bactericidal efficacy. Our preliminary studies suggest that peptides engineered as bi-functional molecules can assemble on the implant materials and inducing potent antimicrobial effects. Here, we propose to explore the potential of controlling cell-surface interactions through programmable functional biomolecules that can induce predictable antimicrobial property at the implant/bio interface. The designed chimeric peptides, composed of individual domains for binding and self assembly on the implant surfaces and having antimicrobial property, will be grafted onto carrier proteins that are robust and stable for use as molecular antimicrobial combater to prevent infection. Once developed, the proposed technology will be modular with high efficacy potentially having a broad range of applications including drug delivery at the site of orthopedic surgery. PUBLIC HEALTH RELEVANCE: Implant-associated infections are of major concerns in orthopedic surgery requiring a high rate of knee and hip revisions and joint replacements. The implant materials provide an ideal environment for bacterial growth, acquired at the time of surgery or at a later stage. The goal of this proposal is to develop peptide-based multifunctional molecules that can self-assemble on implant surfaces and simultaneously induce antimicrobial effects directly on the site through their inherent programmable functions.

描述（由申请人提供）：植入物相关感染是需要高频率膝关节和髋关节翻修和关节置换的骨科手术中的主要问题。植入材料为手术时或后期获得的细菌生长提供了理想的环境。该提案的目标是开发基于肽的多功能分子，这些分子可以在植入物表面上自组装，同时通过其固有的可编程功能直接在该部位诱导抗菌作用。病原体在植入物表面成核后，抗生素对生物膜的渗透可能较弱，从而对健康的植入物-组织整合产生各种有害影响，例如骨血管化不良。目前的一些治疗方法甚至可能包括植入物移除、抗生素治疗，以及仅在恢复期后重新植入。在对抗植入相关感染的过程中，迫切需要开发新的策略，专门针对植入部位进行预防。最有吸引力的预防策略之一是在植入部位提供抗菌活性而不损害骨整合。实现这种方法的主要先决条件是通过固定生物活性分子来改变植入物的表面生物化学。然而，传统的固定化方法仅适用于有限范围的材料，并且需要特定官能团和合成途径的存在。使用组合选择的固体结合肽，我们通过计算生物学工具定制具有纳摩尔亲和力的多功能特性。我们最近设计了钛基植入材料特有的肽序列，成功地将它们与抗菌肽偶联，并测试了它们的杀菌功效。我们的初步研究表明，设计为双功能分子的肽可以在植入材料上组装并诱导有效的抗菌作用。在这里，我们建议探索通过可编程功能生物分子控制细胞表面相互作用的潜力，这些生物分子可以在植入物/生物界面诱导可预测的抗菌特性。设计的嵌合肽由用于在植入物表面结合和自组装的各个结构域组成并具有抗菌特性，将被移植到坚固且稳定的载体蛋白上，用作分子抗菌战斗机以预防感染。一旦开发出来，所提出的技术将是模块化的，具有高效能，可能具有广泛的应用，包括骨科手术现场的药物输送。 公共卫生相关性：植入物相关感染是需要大量膝关节和髋关节翻修及关节置换的骨科手术中的主要问题。植入材料为手术时或后期获得的细菌生长提供了理想的环境。该提案的目标是开发基于肽的多功能分子，这些分子可以在植入物表面上自组装，同时通过其固有的可编程功能直接在该部位诱导抗菌作用。