Peptide Enabled Self Assembled Reconfigurable Implant Coatings

描述(申请人提供)：植入物相关感染是骨科手术中的主要问题，需要高比率的膝关节和髋关节翻修和关节置换术。植入材料为细菌的生长提供了理想的环境，无论是在手术时还是在后来的阶段。这项计划的目标是开发基于多肽的多功能分子，这种分子可以在植入物表面自组装，同时通过其固有的可编程功能直接在植入部位产生抗菌效果。随着病原体在种植体表面的成核，抗生素对生物膜的渗透可能很弱，从而对健康的种植体-组织整合产生各种不利影响，例如骨骼的血管形成不良。目前的一些治疗方法甚至可能包括植入物取出、抗生素治疗，以及只有在很长一段恢复期后才重新植入。在与种植体相关感染的斗争中，迫切需要制定新的战略，特别是在种植体部位进行预防。最有吸引力的预防策略之一是在不损害骨整合的情况下在种植体部位提供抗菌活性。实现这一方法的主要前提是通过固定化生物活性分子来改变植入物的表面生化。然而，传统的固定化方法仅适用于有限范围的材料，并且需要存在特定的官能团和合成途径。使用组合选择的固体结合多肽，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属性。我们最近设计了针对钛基植入材料的多肽序列，成功地将它们与抗菌肽偶联，并测试了它们的杀菌效果。我们的初步研究表明，设计成双功能分子的多肽可以组装在植入材料上，并产生强大的抗菌效果。在这里，我们建议探索通过可编程的功能生物分子来控制细胞-表面相互作用的可能性，这些生物分子可以在种植体/生物界面诱导可预测的抗菌特性。设计的嵌合肽由单个结构域组成，用于在植入物表面结合和自组装，并具有抗菌性能，将被嫁接到坚固和稳定的载体蛋白上，用作分子抗菌战斗器，以防止感染。一旦开发出来，建议的技术将是模块化的，具有高效率，可能具有广泛的应用范围，包括在整形外科手术部位的药物输送。

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.