Point of Care Attachment of Antibiotics onto Metal Implants

描述(申请人提供)：在口腔、颅颌面(CMF)、矫形外科和心血管外科等领域，金属种植体周围的感染是导致种植体失败的常见原因，有时甚至是毁灭性的。这些感染是由于在设备表面建立生物膜而引起的，不仅需要进行新的手术，而且本身就对生命和肢体构成了重大威胁。一旦在医学植入物上建立了生物膜，除了植入物之外，基本上不可能通过任何手段来根除它。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型多肽涂层，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，AffinEnergy已经鉴定出一系列与金属(包括钛和不锈钢)高亲和力结合的多肽，以及与抗生素万古霉素高亲和力结合的多肽。这些多肽被合成成一个单一的双功能多肽，作为一种“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。在第一阶段开发的IFBM保留了其组成多肽对金属和万古霉素的高亲和力，为金属表面提供了有效的抗菌剂剂量。我们还证明了这种金属表面的多肽涂层在生物流体中是稳定的，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。随着我们第一阶段目标的成功完成，我们现在迫切希望进一步优化我们的万古霉素结合序列，并测试新的万古霉素：使用不同的连接化学、肽取向和不对称比例的肽组分组装的金属双功能肽。我们还将启动我们的原型万古霉素：金属IFBM的生物兼容性、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多肽。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/多肽涂层，为可能由AffinEnergy和/或新的潜在合作伙伴资助的第三阶段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一种通用型多肽涂层提供关键信息，该涂层将促进在护理点将抗生素附着到广泛的医疗植入物上，以减少其表面的微生物定植。公共卫生相关性：金属五金件周围的感染是口腔、颅颌面(CMF)、矫形外科和心血管外科等多个医疗领域植入物失败的常见原因，有时甚至是毁灭性的。由于在设备表面建立了致病生物膜，这些感染不仅需要进行新的手术，而且本身就对生命和肢体构成了重大威胁。一旦形成生物膜的细菌定居在金属硬件上，除了植入法外，基本上不可能通过任何手段将其根除。降低与金属植入物相关的感染率的方法显然将使社会受益。我们建议继续第二阶段开发一种通用型多肽涂层，该涂层将促进抗生素在护理点附着到广泛的医疗植入物上，以减少其表面的微生物定植，最终降低植入物感染率。

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.