Peptide-mediated Attachment of Drug-loaded Microparticles to Medical Devices

描述（由申请人提供）：纵隔炎是心脏直视手术后常见的，有时是毁灭性的并发症。尽管使用预防性全身抗生素和改进的手术技术，细菌感染仍然是几乎所有外科手术（包括正中胸骨切开术）的严重并发症。当手术部位感染发生时，它们可能是毁灭性的，具有巨大的经济和心理成本，特别是在糖尿病患者，吸烟者，老年人和免疫功能低下的高危患者中。防止手术部位风险组织微生物定植的新技术可以通过降低感染率明显造福社会。对抗生素局部递送的进一步创新的需求是我们开发肽介导系统以将载药微粒附着到医疗设备的动机。Affinergy正在开发双功能亲和肽，称为界面生物材料（IFBM），可促进药物，蛋白质和细胞在医疗器械表面的附着和保留。使用噬菌体展示，我们已经确定了特定的肽序列，以高亲和力结合到许多材料和生物制剂。合成一对这些肽作为单个IFBM促进药物、蛋白质或细胞直接附着到医疗器械的表面。虽然我们已经观察到使用抗生素的这种技术的有希望的初步数据，但用载药微粒对医疗器械进行肽介导的涂层可能具有额外的优势。我们可能会用这种新型的微粒涂层策略来靶向其他药物和医疗器械。由于存在如此广泛的潜在肽-微粒装置组合，在本提案中，我们将专注于开发用于胸骨钢丝的微粒涂层以预防纵隔炎。因此，该I期研究计划的目标是首先在Affinergy优化载药聚乳酸-羟基乙酸共聚物（PLGA）微粒制剂。然后，我们将表征和优化候选PLGA：金属IFBM。最后，我们将检查IFBM靶向微粒的抗菌功效和生物相容性，确定微粒是否增加了Affinergy器械涂层技术的潜力。这里提出的目标代表了一个原理验证研究计划，该计划将在随后的第二阶段资助期间扩大到包括新的抗生素和商业化策略。在未来，微粒：医疗装置IFBM可用于附着载有各种治疗分子的微粒，所述治疗分子来自抗生素以防止手术后感染到局部麻醉剂以治疗手术后疼痛。 公共卫生相关性：术后感染是心脏直视手术后常见的，有时是毁灭性的并发症。尽管使用预防性全身抗生素和改进的手术技术，感染仍然是一个严重的并发症。在局部抗生素递送中进一步创新的需要是我们开发用于将载药微粒附着到医疗装置上的肽介导的附着系统的动机。Affinergy正在开发双功能亲和肽，称为界面生物材料（IFBM），可促进药物，蛋白质和细胞在医疗器械表面的附着和保留。虽然我们已经观察到使用抗生素的这种技术的有希望的初步数据，但用载药微粒对医疗器械进行肽介导的涂层可能具有额外的优势。我们可能会用这种新型微粒涂层策略靶向其他药物和其他医疗器械。在本提案中，我们专注于开发用于胸骨钢丝的微粒涂层，以在心脏直视手术后局部递送抗生素。在未来，微粒：医疗装置IFBM可用于附着载有各种治疗分子的微粒，所述治疗分子来自抗生素以防止手术后感染到局部麻醉剂以治疗手术后疼痛。

DESCRIPTION (provided by applicant): Mediastinitis is a common and sometimes devastating complication following open heart surgery. Despite the use of prophylactic systemic antibiotics and improved surgical techniques, bacterial infection remains a serious complication following almost all surgical procedures including median sternotomy. When surgical site infections occur, they can be devastating with immense financial and psychological costs especially in at-risk patients such as diabetics, smokers, the elderly, and immunocompromised. New technologies that prevent microbial colonization of the at-risk tissues in a surgical site could clearly benefit society by decreasing infection rates. The need for further innovation in the local delivery of antibiotics is our motivation to develop a peptide-mediated system to attach drug-loaded microparticles to medical devices. Affinergy is developing bifunctional affinity peptides, called interfacial biomaterials (IFBMs), that promote the attachment and retention of drugs, proteins, and cells on the surface of medical devices. Using phage display, we have identified specific peptide sequences that bind with high affinity to a number of materials and biologics. Synthesizing a pair of these peptides as a single IFBM promotes the attachment of drug, protein, or cell directly to the surface of a medical device. While we have observed promising preliminary data with this technique using antibiotics, peptide-mediated coating of medical devices with drug loaded microparticles may hold additional advantages. There are likely additional drugs and additional medical devices we might target with this novel microparticle-coating strategy. Because there exist such a wide range of potential peptide-microparticle device combinations, in this proposal we will focus on the development of a microparticle coating for sternal wires to prevent mediastinitis. Therefore, the goal of this Phase I research plan is to first optimize drug loaded poly (lactic-co-glycolic acid) (PLGA) microparticle preparations at Affinergy. We will then characterize and optimize candidate PLGA: metal IFBMs. Finally, we will examine the antimicrobial efficacy and biocompatibility of IFBM targeted microparticles, determining if the microparticles increase the potential of Affinergy device coating technology. The aims presented here represent a proof-of-principle research program, which would be expanded to include new antibiotics and commercialization strategies during a subsequent Phase II funding period. In the future, microparticles: medical device IFBMs could be used to attach microparticles loaded with a wide variety of therapeutic molecules from antibiotics to prevent post-operative infection to local anesthetics to treat post- operative pain. PUBLIC HEALTH RELEVANCE: Post-operative infection is a common and sometimes devastating complication following open heart surgery. Despite the use of prophylactic systemic antibiotics and improved surgical techniques, infection remains a serious complication. The need for further innovation in localized antibiotic delivery is our motivation to develop a peptide-mediated attachment system for drug-loaded microparticles onto medical devices. Affinergy is developing bifunctional affinity peptides, called interfacial biomaterials (IFBMs), that promote the attachment and retention of drugs, proteins, and cells on the surface of medical devices. While we have observed promising preliminary data with this technique using antibiotics, peptide-mediated coating of medical devices with drug loaded microparticles may hold additional advantages. There are likely additional drugs and additional medical devices we might target with this novel microparticle coating strategy. In this proposal we focus on the development of a microparticle coating for sternal wires to deliver antibiotics locally following open heart surgery. In the future, microparticle: medical device IFBMs could be used to attach microparticles loaded with a wide variety of therapeutic molecules from antibiotics to prevent post-operative infection to local anesthetics to treat post-operative pain.