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Point of Care Attachment of Antibiotics onto Metal Implants

将抗生素即时附着在金属植入物上

基本信息

批准号：
7536980
负责人：
PAUL T HAMILTON
金额：
$ 89.34万
依托单位：
AFFINERGY ,INC
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-02 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7536980
关键词：
Address Affinity Animals Antibiotics Area Bacteria Behavior Binding Biocompatible Materials Biological Biological Assay Biomechanics Biopolymers Cardiovascular Surgical Procedures Caring Cells Ceramics Chemical Engineering Chemicals Chemistry Clinical Dental Implants Development Devices Diagnostic radiologic examination Drug Formulations Engineering Ensure Failure Friction Funding Growth Factor Implant In Vitro Infection International Investments Life Ligation Limb structure Liquid substance Mechanics Mediating Medical Metals Methods Microbial Biofilms Modeling Modification New Agents Numbers Operative Surgical Procedures Oral Orthopedics Peptide Antibiotics Peptides Phage Display Pharmaceutical Preparations Phase Plastics Point Mutation Polymers Process Public Health Range Rate Rattus Recovery Research Research Contracts Research Infrastructure Risk Rodent Model Series Societies Specific qualifier value Specificity Staining method Stainless Steel Stains Staphylococcus aureus Sterilization for infection control Structure Surface Techniques Technology Teflon Testing Time Tissues Titanium To specify Vancomycin Variant antimicrobial antimicrobial drug base biomaterial compatibility commercialization concept cost craniomaxillofacial design dosage experience improved in vivo insight interfacial medical implant microbial colonization new technology novel point of care prevent programs prototype shear stress tibia tool

项目摘要

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. Once biofilm is established on a medical implant, it is essentially impossible to eradicate by any means except explantation. New technologies that decrease microbial colonization and infection rates associated with metal implants would clearly improve care and reduce medical costs. In Phase I we proposed the development of a generalizable peptide coating, allowing a clinician to load an antibiotic onto an implant at point of care. Using phage display technology, Affinergy has identified a series of peptides that bind with high affinity to metals, including titanium and stainless steel, as well as peptides which bind the antibiotic vancomycin with high affinity. These peptides were synthesized as a single bifunctional peptide to serve as an "interfacial biomaterial" or IFBM designed to attach a coating of vancomycin on the surface of metal implants. The IFBM developed in Phase I retains the high affinity of its component peptides for metals and vancomycin, delivering an effective antimicrobial dosage to metal surfaces. We also demonstrated that this peptide coating for metal surfaces is stable in biological fluids, resists biomechanical and shear stress and does not alter cellular behavior on metal implants. With the successful completion of our Phase I aims, we are now eager to further optimize our vancomycin-binding sequences, as well as test new vancomycin:metal bifunctional peptides assembled using different ligation chemistries, peptide orientations and asymmetric ratios of peptide components. We will also initiate biocompatibility, storage and sterilization testing of our prototype vancomycin:metal IFBM to ensure this is a commercializable product concept. Finally, we are eager to test our prototype peptide in an in vivo infection model of metal implants. Upon completing these aims, we will have a well-characterized, commercializable antibiotic/peptide coating, ready for a Phase III large animal study likely funded by Affinergy and/or new potential partners. The insights gained from these studies will provide key information for the continued pursuit of a generalizable peptide coating that will promote attachment of antibiotics at point of care to a wide range of medical implants to decrease microbial colonization on their surfaces. PUBLIC HEALTH RELEVANCE: 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. Once biofilm-forming bacteria colonize metal hardware, they 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 the continued Phase II development of a generalizable peptide coating that will promote attachment of antibiotics at point of care to a wide range of medical 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。一旦生物膜在医疗植入物上形成，除了外植之外，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将明显改善护理并降低医疗成本。在第一阶段，我们建议开发一种通用的肽涂层，允许临床医生在护理点将抗生素加载到植入物上。利用噬菌体展示技术，Affinergy 鉴定了一系列与金属（包括钛和不锈钢）高亲和力结合的肽，以及与抗生素万古霉素高亲和力结合的肽。这些肽被合成为单个双功能肽，用作“界面生物材料”或 IFBM，旨在将万古霉素涂层附着在金属植入物的表面上。第一阶段开发的 IFBM 保留了其成分肽对金属和万古霉素的高亲和力，为金属表面提供有效的抗菌剂量。我们还证明，这种用于金属表面的肽涂层在生物液体中稳定，能够抵抗生物力学和剪切应力，并且不会改变金属植入物上的细胞行为。随着第一阶段目标的成功完成，我们现在渴望进一步优化我们的万古霉素结合序列，并测试使用不同的连接化学、肽方向和肽组分的不对称比例组装的新万古霉素：金属双功能肽。我们还将启动万古霉素原型：金属 IFBM 的生物相容性、储存和灭菌测试，以确保这是一个可商业化的产品概念。最后，我们渴望在金属植入物的体内感染模型中测试我们的原型肽。完成这些目标后，我们将拥有一种特性良好、可商业化的抗生素/肽涂层，为可能由 Affinergy 和/或新的潜在合作伙伴资助的 III 期大型动物研究做好准备。从这些研究中获得的见解将为继续追求通用肽涂层提供关键信息，这种肽涂层将促进抗生素在护理点附着到各种医疗植入物上，以减少微生物在其表面的定植。公共卫生相关性：金属硬件周围的感染是口腔、颅颌面 (CMF)、骨科和心血管外科等许多医学领域中植入物失败的常见原因，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。一旦形成生物膜的细菌在金属硬件上定殖，除了外植之外，基本上不可能通过任何方式根除它们。降低金属植入物相关感染率的方法显然将使社会受益。我们建议继续进行通用肽涂层的第二阶段开发，该涂层将促进抗生素在护理点附着到各种医疗植入物上，以减少其表面的微生物定植，并最终降低植入物感染率。