Hybrid repellant-antimicrobial gemini coatings for prevention of catheter-associated bloodstream infections

用于预防导管相关血流感染的混合排斥剂-抗菌 Gemini 涂层

• 批准号: 10697071
• 负责人: Kollbe Ahn
• 金额: $ 27.35万
• 依托单位: ACATECHOL, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697071
• 关键词: Address; Adherence; American; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Biocide; Biological Assay; Biotechnology; Blood; Catheters; Certification; Coagulation Process; Complement Activation; Cyclic GMP; Data; Development; Ensure; Equilibrium; Frequencies; Goals; Health Care Costs; Healthcare Systems; Hemodialysis; Hemolysis; Heparin; Hybrids; Immobilization; In Vitro; Infection; Inflammation; Kidney Diseases; Knowledge; Licensing; Life; Manufacturer; Marketing; Mechanics; Medical Device; Microbial Biofilms; Outcome; Pain; Pathology; Patients; Phase; Play; Polymers; Predisposition; Prevention; Production; Proliferating; Property; Public Health; Relative Risks; Resistance; Risk; Sepsis; Small Business Innovation Research Grant; Specific qualifier value; Surface; Technology; Toxic effect; Translations; United States; Urinary tract; Venous; antimicrobial; biological systems; biomaterial compatibility; commercial application; commercialization; cost; experience; hemocompatibility; hydrophilicity; in vivo; induced pluripotent stem cell; infection rate; infection risk; innovation; manufacturing facility; microbial; microorganism; mortality; novel; pathogen; phase 1 study; prevent; prototype; research clinical testing; surface coating; synergism; technological innovation; tool

Project Summary/Abstract Over 20% of the hemodialysis patients develop life-threatening central line-associated bloodstream infections (CLABSIs). According to the CDC, >250,000 CLABSIs, having mortality rates of 14-40%, occur in the US annually, and among them >100,000 cases are directly related to hemodialysis central venous catheter (CVC). One of the tools currently used to reduce CLABSIs is the use of antimicrobial CVCs. However, the current antimicrobial CVCs remain susceptible to biofouling (i.e., biofilm formation) as they do not display repellency to biofoulants. In other words, host biomolecules and cellular debris from dead microorganisms can accumulate upon their surface, thereby facilitating adherence of living microbia and their associated biofilms. In addition, most antimicrobial CVCs function by gradually releasing embedded biocides/antibiotics with risk of developing antimicrobial resistance. To address the problems, we hypothesized that incorporating biofilm-repellent zwitterionic moieties together with antimicrobial gemini dicationic moieties into CVC surfaces, a synergistic effect could be realized. Our preliminary study confirmed the synergetic effect. Technology innovation is 1) the new CVC surface covalently immobilized with gemini dicationic moieties to provide best-in-class antimicrobial properties without concerns of development of antimicrobial resistance; and 2) the new CVC surface containing both biofilm-repellant and antimicrobial moieties to overcome the deficiencies of each alone to prevent the root cause of CLABSIs. To demonstrate the feasibility of our technology, in Aim 1, we will maximize the synergetic effect by iteratively optimizing the ratio between the antimicrobial and repellent moieties with respect to antimicrobial efficacy, biofilm repellency, coating anti-infective durability, over varying timeframes. In Aim 2, we will produce prototype hybrid CVCs, and compare their infection risks relative to commercial antimicrobial CVCs against pathogens responsible for >90% of CLABSIs. In Aim 3, we will evaluate bio- and hemo-compatibility of the prototypes using assays specified in ISO 10993-4 for hemolysis, coagulation, complement-activation, and inflammation as well as leachate toxicity. Expected outcomes in this Phase I include >20% reductions in proliferation, antimicrobial, and biofilm assays with a similar/better blood compatibility compared to current antimicrobial CVCs. >20% reduction in the national infection rate with our CVC product would prevent >50,000 CLABSIs, saving >16,000 lives and >$500 million direct healthcare costs each year. Phase II will include in-vivo studies to ensure accurate translation of in-vitro and ex-vivo properties. In Phase II, we will also initiate production of our prototype CVCs at a FDA cGMP compliant manufacturing facility, subsequently apply for 510(k) clearance for subsequent clinical evaluation. Our serviceable obtainable market (SOM) is the US CVC market, estimated to grow $1.3 billion in 2026. As our hybrid-coating can be applied to nearly all types of catheters including IV and urinary tract catheters, the total available market (TAM) is the global catheter market, expected to reach $74.8 billion by 2028.

项目摘要/摘要 超过20％的血液透析患者发展了威胁生命的中枢性血液感染 （Clabsis）。根据疾病预防控制中心，> 250,000个clabsis，死亡率为14-40％，发生在美国 每年，其中> 100,000例与血液透析中央静脉导管（CVC）直接相关。 当前用于减少clabsis的工具之一是使用抗菌CVC。但是，电流 抗菌CVC仍然容易受到生物污染的影响（即生物膜形成），因为它们不显示驱逐 生物食品。换句话说，死去微生物的宿主生物分子和细胞碎片可以积累 从表面上看，从而促进了生物微生物及其相关生物膜的依从性。此外， 大多数抗微生物CVC通过逐渐释放出具有发展风险的嵌入式杀菌剂/抗生素 抗菌耐药性。为了解决这些问题，我们假设结合生物膜固定物 际离子部分以及抗菌双子座的毒性部分中的CVC表面，一种协同作用 效果可以实现。我们的初步研究证实了协同作用。技术创新是1） 新的CVC表面与双子座疾病部分共价固定，以提供一流的抗菌剂 不关心抗菌耐药性发展的特性； 2）新的CVC表面 含有生物膜 - 替代剂和抗微生物部分，以克服每个人的缺陷 防止clabsis的根本原因。为了证明我们技术的可行性，在AIM 1中，我们将 通过迭代优化抗菌和驱虫剂之间的比率来最大化协同效应 关于抗菌功效，生物膜驱除性，涂层抗感染耐用性的部分 时间范围。在AIM 2中，我们将产生原型混合CVC，并将其感染风险相对于 针对> 90％clabsis的病原体的商业抗菌CVC。在AIM 3中，我们将 使用ISO 10993-4中指定的溶血的测定法评估原型的生物兼容性， 凝结，补体激活和炎症以及渗滤液毒性。预期的结果 第一阶段的增殖，抗菌和生物膜分析的降低> 20％ 与当前的抗菌CVC相比，兼容性。我们的国家感染率降低了20％ CVC产品将防止> 50,000个clabsis，挽救> 16,000个生命和5亿美元的直接医疗费用 每年。第二阶段将包括体内研究，以确保对体外和前体特性的准确翻译。 在第二阶段，我们还将在FDA CGMP制造业中启动CVC的原型CVC 设施，随后申请510（k）间隙，以进行随后的临床评估。我们可以获得的可获得 市场（SOM）是美国CVC市场，估计在2026年增长13亿美元。因为我们的混合涂层可以是 应用于几乎所有类型的导管，包括IV和尿路导管，可用市场（TAM） 是全球导管市场，预计到2028年将达到748亿美元。