Point of Care Attachment of Multiple Antibiotics onto Metal Implants

将多种抗生素即时附着在金属植入物上

• 批准号: 7325622
• 负责人: PAUL T HAMILTON
• 金额: $ 26.41万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-02 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7325622
• 关键词: Address; Affinity; Aminoglycosides; Antibiotics; Bacteria; Bacteriophages; Binding; Biocompatible Materials; Biological; Biological Assay; Biopolymers; Cardiovascular Surgical Procedures; Cells; Ceramics; Chemical Engineering; Chemicals; Chemistry; Class; Clinical; Dental Implants; Devices; Drug Kinetics; Engineering; Failure; Goals; Growth Factor; Implant; In Vitro; Infection; Investments; Kinetics; Life; Limb structure; Link; Liquid substance; Mediating; Medical; Metals; Methods; Microbial Biofilms; Modeling; New Agents; Numbers; Operative Surgical Procedures; Oral; Orthopedics; Osteoblasts; Pan Genus; Peptide Antibiotics; Peptides; Phage Display; Pharmaceutical Preparations; Phase; Plastics; Polymers; Process; Range; Rate; Research Infrastructure; Risk; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Societies; Specific qualifier value; Specificity; Stainless Steel; Sterilization for infection control; Surface; Technology; Teflon; Testing; Tetracycline; Tetracyclines; Time; Tissues; Titanium; To specify; Vancomycin; Work; antimicrobial; antimicrobial drug; aqueous; base; biomaterial compatibility; commercialization; cost; craniomaxillofacial; density; in vivo; in vivo Model; interfacial; manufacturing process; microbial colonization; new technology; novel; point of care; prevent; success

DESCRIPTION (provided by applicant): Infection surrounding metal implants is a common and sometimes devastating cause of implant failure in a number of fields including oral, craniomaxillofacial (CMF), orthopedic, and cardiovascular surgery. These infections, which arise from the establishment of biofilms on device surfaces, not only necessitate new surgeries but in themselves present a significant threat to life and limb. The biofilm bacteria that establish themselves on implants are essentially impossible to eradicate by any means except explantation. New technologies that decrease microbial colonization and infection rates associated with metal implants would clearly benefit society. We propose to develop a generalizable peptide coating that will allow a clinician to choose from more than one class of antibiotics to load onto an implant at point of care. Using phage display technology, Affinergy has identified a series of peptides that bind with high affinity to a number of metals, including titanium and stainless steel. These metal-binding peptides will serve as the basis for engineering an antibiotic binding, peptide coating. The goal of this Phase I SBIR proposal is to validate an "Interfacial Biomaterials" (IFBM) approach to attach an antibiotic onto metal implant surfaces to decrease implant colonization. We initially targeted vancomycin for "proof of principle" because it has a significant amount of structural complexity. This complexity provides a larger "chemical space" from which a binding peptide can be found; making the success of phage display panning more likely within a short time frame. In aim 1, we will synthesize candidate peptides that have binding affinity for vancomycin. In aim 2, we will synthesize a series of vancomycin:metal IFBM's. We will verify the stability of these candidate IFBM's in biological fluids, test their ability to bind and retain antibiotics, verify that they do not inhibit osteoblast attachment, and quantify the coating density of peptide and antibiotic on metal surfaces. In aim 3, we will characterize the anti-microbial activity and release kinetics of vancomycin bound and released from peptide coated metal. If successful, Phase II work would involve biopanning of two more antibiotics targets (an aminoglycoside and a tetracycline) commonly used both locally and systemically to prevent or treat implant associated infections. Branched IFBM's containing binding modules for all three classes of antibiotic would be assembled and examined for efficacy in vitro and then in an implant infection model in vivo. Infection surrounding metal hardware is a common and sometimes devastating cause of implant failure in a number of medical fields including oral, craniomaxillofacial (CMF), orthopedic, and cardiovascular surgery. Arising from the establishment of pathogenic biofilms on device surfaces, these infections not only necessitate new surgeries but in themselves present a significant threat to life and limb. The biofilm bacteria that establish themselves on metal hardware are essentially impossible to eradicate by any means except explantation. Methods that decrease infection rates associated with metal implants would clearly benefit society. We propose to develop a generalizable peptide coating that will promote attachment of multiple antibiotics at point of care to a wide range of metal implants to decrease microbial colonization on their surfaces and ultimately lower implant infection rates.

描述（由申请人提供）：围绕金属植入物的感染是在许多领域的常见原因，有时是造成植入物失败的原因，包括口腔，颅骨骨膜（CMF），骨科和心血管外科手术。这些感染是由在设备表面上建立生物膜的，不仅需要新的手术，而且还需要对生命和肢体构成重大威胁。基本上不可能通过任何方式根本不可能消除自植入物的生物膜细菌。降低与金属植入物相关的微生物定植和感染率的新技术显然会使社会受益。我们建议开发可推广的肽涂料，该肽将允许临床医生从多种类别的抗生素中进行选择，可以在护理点上加载到植入物上。使用噬菌体显示技术，Affinergy确定了一系列与许多金属（包括钛和不锈钢）结合的肽。这些金属结合肽将作为工程抗生素结合，肽涂层的基础。该阶段I SBIR提案的目的是验证“界面生物材料”（IFBM）方法，以将抗生素连接到金属植入物表面上以减少植入物定植。我们最初以“原理证明”为目标，因为它具有相当多的结构复杂性。这种复杂性提供了一个更大的“化学空间”，可以从中找到结合肽。在短时间内使噬菌体显示的成功更有可能。在AIM 1中，我们将合成对万古霉素具有结合亲和力的候选肽。在AIM 2中，我们将合成一系列万古霉素：金属IFBM。我们将验证这些候选IFBM在生物流体中的稳定性，测试它们结合和保留抗生素的能力，验证它们不抑制成骨细胞附着，并量化肽的涂层密度和抗生素在金属表面上。在AIM 3中，我们将表征抗微生物活性并释放万古霉素结合并从肽涂层金属释放的动力学。如果成功的话，II期的工作将涉及对两个抗生素靶标（氨基糖苷和四环素）的生物塑料，则通常在本地和系统上使用，以预防或治疗相关的植入物相关感染。分支的IFBM包含所有三类抗生素的结合模块将在体外组装并检查是否有效性，然后在体内植入感染模型中。 围绕金属硬件的感染是在许多医疗领域中发生植入物衰竭的常见原因，包括口腔，颅颌面（CMF），骨科和心血管手术。这些感染是由在装置表面上建立致病性生物膜的，不仅需要新的手术，而且还对生命和肢体构成了重大威胁。除了露天外，基本上不可能通过任何方式根除在金属硬件上建立自己的生物膜细菌。降低与金属植入物相关的感染率的方法显然会使社会受益。我们建议开发可推广的肽涂料，该肽将在护理点上促进多种抗生素的附着，以减少其表面上的微生物定植，并最终降低植入物感染率。