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）：金属植入物周围的感染是口腔、颅颌面（CMF）、骨科和心血管外科等许多领域中植入物失败的常见原因，有时甚至是毁灭性的原因。这些感染是由设​​备表面生物膜的形成引起的，不仅需要新的手术，而且其本身对生命和肢体构成重大威胁。除了外植之外，在植入物上建立的生物膜细菌基本上不可能通过任何方式根除。减少与金属植入物相关的微生物定植和感染率的新技术显然将使社会受益。我们建议开发一种通用的肽涂层，使临床医生能够从不止一类抗生素中进行选择，以在护理点加载到植入物上。利用噬菌体展示技术，Affinergy 已鉴定出一系列能够与多种金属（包括钛和不锈钢）以高亲和力结合的肽。这些金属结合肽将作为设计抗生素结合肽涂层的基础。第一阶段 SBIR 提案的目标是验证“界面生物材料”(IFBM) 方法，将抗生素附着在金属植入物表面，以减少植入物定植。我们最初将万古霉素作为“原理证明”，因为它具有相当大的结构复杂性。这种复杂性提供了更大的“化学空间”，从中可以找到结合肽；使得噬菌体展示淘选更有可能在短时间内取得成功。在目标 1 中，我们将合成对万古霉素具有结合亲和力的候选肽。在目标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 在生物体液中的稳定性，测试它们结合和保留抗生素的能力，验证它们不会抑制成骨细胞附着，并量化金属表面上肽和抗生素的涂层密度。在目标 3 中，我们将表征肽涂层金属结合和释放的万古霉素的抗菌活性和释放动力学。如果成功，第二阶段工作将涉及对另外两种抗生素靶点（氨基糖苷类和四环素）进行生物淘选，这些抗生素靶点通常用于局部和全身预防或治疗植入物相关感染。包含所有三类抗生素的结合模块的分支IFBM将被组装并在体外检查功效，然后在体内植入感染模型中检查。 在口腔、颅颌面 (CMF)、骨科和心血管外科等许多医学领域，金属硬件周围的感染是植入失败的常见原因，有时甚至是毁灭性的原因。由于在设备表面建立致病性生物膜，这些感染不仅需要新的手术，而且本身对生命和肢体构成重大威胁。除了外植之外，在金属硬件上建立的生物膜细菌基本上不可能通过任何方式根除。降低金属植入物相关感染率的方法显然将使社会受益。我们建议开发一种通用的肽涂层，该涂层将促进多种抗生素在护理点附着到各种金属植入物上，以减少微生物在其表面的定植，并最终降低植入物感染率。