Point of Care Attachment of Multiple Antibiotics onto Metal Implants

描述（由申请人提供）：金属种植体周围的感染是口腔、颅颌面外科（CMF）、骨科和心血管外科等许多领域种植体失败的常见原因，有时是毁灭性的原因。这些感染是由器械表面生物膜的形成引起的，不仅需要进行新的手术，而且本身对生命和肢体构成重大威胁。在植入物上建立的生物膜细菌基本上不可能通过任何手段根除，除了外植。减少微生物定植和与金属植入物相关的感染率的新技术显然对社会有益。我们建议开发一种通用的肽涂层，使临床医生可以从不止一类的抗生素中选择，在护理点加载到种植体上。利用噬菌体展示技术，Affinergy已经确定了一系列肽，这些肽与许多金属（包括钛和不锈钢）具有高亲和力。这些金属结合肽将作为工程抗生素结合肽包被的基础。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种植体表面，以减少种植体的定植。我们最初将万古霉素作为“原理证明”的目标，因为它具有大量的结构复杂性。这种复杂性提供了一个更大的“化学空间”，从中可以找到结合肽；使噬菌体展示在短时间内更有可能成功。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在生物液体中的稳定性，测试它们结合和保留抗生素的能力，验证它们不会抑制成骨细胞的附着，并量化金属表面上肽和抗生素的涂层密度。在目标3中，我们将表征万古霉素结合和从肽包覆金属释放的抗菌活性和释放动力学。如果成功，第二阶段的工作将包括对另外两种抗生素靶点（氨基糖苷和四环素）进行生物筛选，这些靶点通常用于局部和全身预防或治疗种植体相关感染。分枝IFBM包含所有三类抗生素的结合模块，将在体外组装并检查其有效性，然后在体内植入物感染模型中进行检测。

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.