Resorbable Antimicrobial Envelope to Prevent Infection of Implanted Cardiac Devices

项目摘要 与心血管植入式电子设备（CIED）植入相关的感染发生在20%的 这些干预措施与死亡率增加2倍有关。虽然术前抗生素 目前在临床实践中使用预防，建议局部靶向感染因子，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，Medtronic） 涂有两种抗菌剂（米诺环素和利福平）的补片已被证明可减少40%的主要 CIED感染。尽管有这些积极的结果，该产品有几个缺点。信封具有可变的 对凝固酶阴性葡萄球菌有效，对真菌或生物膜无效。 此外，几种耐甲氧西林金黄色葡萄球菌（MRSA）菌株已产生耐药性 因此，一种抗菌和抗霉菌可吸收的信封，完全根除CIED相关的 感染仍然是未满足的临床需求。N8 Medical正在开发一种新的生物可吸收聚合物CIED 一种含有专有的ceragenin的包膜，这是一类新型的抗感染药物， 阻力这种新化合物是一种人工合成的非肽化合物，它模拟了人体的 内源性抗微生物肽（AMP），并且其赋予针对难以根除的菌株的功效，例如 MRSA和真菌。N8 Medical的CIED Envelope是第一个防止真菌定植的外科手术封套。 同时提供对细菌生长的上级抑制。在将CIED植入 N8医疗器械，包膜在物理上固定和稳定植入的起搏器， 在被身体完全吸收之前的一段时间内消除引起感染的病原体 8-12周内。该SBIR第二阶段项目建立在第一阶段项目的结果之上， 在体外和体内验证了包膜的功效，并证实了其潜在的更广谱的 与TYRX相比。该II期项目的目标是进行关键临床前研究， 通过De Novo申请获得IDE和FDA器械批准。该项目有三个目标 超过2年。首先，工业产品开发将改进制造方法，以确保商业化 信封的可行性（目标1）。然后将在GLP关键安全性（目标2）和有效性方面对最终设计进行确认 (Aim（3）研究。全面的生物相容性试验（包括细胞毒性、致敏性、致热原性和 遗传毒性试验），以及体内急性和亚慢性和慢性全身毒性。高 N8 Medical的CIED Envelope在根除耐药菌株、真菌和生物膜方面的功效将导致 在发病率和死亡率方面改善患者结局，减少感染相关并发症， 减少额外干预的必要性。

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.