Resorbable Antimicrobial Envelope to Prevent Infection of Implanted Cardiac Devices

项目总结 与植入心血管可植入电子设备(CIED)相关的感染发生在20%的 这些干预措施会使死亡率增加2倍。虽然术前使用抗生素 预防目前用于临床实践，建议针对局部感染病原体，以减少 抗生素耐药性的风险。使用由聚合物制成的抗菌封套(TYRX、美敦力) 涂有两种抗菌剂(米诺环素和利福平)的网片已被证明减少了40%的主要 CIED感染。尽管有这些积极的结果，该产品仍有几个缺点。信封有变量 对凝固酶阴性葡萄球菌有效，对真菌或生物膜缺乏有效性。 此外，几种耐甲氧西林金黄色葡萄球菌(Mrsa)菌株已经产生了抗药性。 反对它。因此，一种完全根除CIED相关疾病的抗菌抗真菌可吸收信封 感染仍然是一个未得到满足的临床需求。N8医疗公司正在开发一种新的可生物吸收聚合物CIED 含有专有角质蛋白的信封，这是一种新型的抗感染剂，不会产生 抵抗。这种新化合物是一种人工合成的非肽化合物，它模仿人体的活动 内源性抗菌肽(AMPs)，它对难以根除的菌株具有疗效，如 金黄色葡萄球菌和真菌。N8医疗公司的CIED信封是第一个防止真菌定植的外科信封 心脏装置，同时提供卓越的细菌生长抑制作用。在植入CIED后 N8医疗器械，封套实际固定和稳定植入的起搏器，并释放 Ceragenin在被身体完全吸收之前清除引起感染的病原体 在8-12周内。该SBIR第二阶段项目建立在第一阶段项目的结果基础上，该项目提供了初步的 对包膜在体外和体内的有效性进行验证，并确认其潜在的更广泛的光谱 活动与TYRX相比。该第二阶段项目的目标是执行关键的临床前研究，所需的 通过De Novo申请获得IDE和FDA设备批准。该项目有三个目标 两年多了。首先，工业产品开发将改进制造方法，以确保商业化 信封的生存能力(目标1)。最终设计将在GLP Pivotal安全性(目标2)和有效性方面进行验证 (目标3)研究。全面的生物相容性测试(包括细胞毒性、致敏性、致热性和 遗传毒性试验)，以及体内急性、亚慢性和慢性全身毒性评估。高潮 N8医疗公司的CIED信封在根除耐药细菌菌株、真菌和生物膜方面的效果将导致 在发病率和死亡率方面改善患者结局，减少与感染相关的并发症，以及 减少对额外干预措施的需要。

PROJECT SUMMARY Infections related to the implantation of cardiovascular implantable electronic devices (CIEDs) occur in 20% of the interventions and are associated with a 2-fold increase in mortality rate. While pre-operative antibiotic prophylaxis is currently used in clinical practice, targeting the infectious agents locally is recommended to reduce the risk of antibiotic resistance. The use of an antibacterial envelope (TYRX, Medtronic), made of a polymer mesh coated with two antibacterial agents (minocycline and rifampin), has been shown to reduce by 40% major CIED infections. Despite these positive results, the product has several drawbacks. The envelope has variable effectiveness against coagulase-negative Staphylococci and lacks effectiveness against fungi or biofilms. Moreover, several methicillin-resistant Staphylococcus aureus (MRSA) strains have developed resistance against it. Therefore, an antibacterial and antimycotic resorbable envelope that fully eradicates CIED-related infections remains an unmet clinical need. N8 Medical is developing a new bioresorbable polymeric CIED envelope that incorporates a proprietary ceragenin, a novel class of anti-infective agents that do not engender resistance. The new compound is a synthetic non-peptide compound that mimics the activity of the body’s endogenous antimicrobial peptides (AMPs) and it confers efficacy against difficult to eradicate strains, such as MRSA and fungi. N8 Medical’s CIED Envelope is the first surgical envelope to prevent fungal colonization of cardiac devices while providing superior inhibition of bacterial growth. Upon implantation of the CIED within the N8 Medical device, the envelope physically secures and stabilizes the implanted pacemaker and releases the ceragenin to eliminate infection-causing pathogens during the period before being fully resorbed by the body within 8-12 weeks. This SBIR Phase II project builds on the results of a Phase I project that provided preliminary validation of the efficacy of the envelope in vitro and in vivo and confirmed its potential broader spectrum of activity compared to TYRX. The goal of this Phase II project is to perform pivotal preclinical studies required to obtain an IDE and FDA device approval through a De Novo application. The project is articulated in three aims over 2 years. First, industrial product development will improve the fabrication method to assure the commercial viability of the envelope (Aim 1). The final design will then be validated in GLP pivotal safety (Aim 2) and efficacy (Aim 3) studies. Comprehensive biocompatibility tests (including cytotoxicity, sensitization, pyrogenicity, and genotoxicity assays), and in vivo acute and sub-chronic and chronic systemic toxicity will be assessed. The high efficacy of N8 Medical’s CIED Envelope in eradicating resistant bacterial strains, fungi, and biofilms, will lead to better patient outcomes in terms of morbidity and mortality, reduced infection-related complications, and reduction in the need for additional interventions.