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.

项目总结/摘要 超过20%的血液透析患者发生危及生命的中心静脉导管相关血流感染 （CLABSIs）。根据CDC的数据，在美国发生了> 250，000例CLABSI，死亡率为14- 40% 其中与血液透析中心静脉导管（CVC）直接相关的病例超过10万例。 目前用于减少CLABSI的工具之一是使用抗微生物CVC。但目前 抗微生物CVC仍然对生物污垢敏感（即，生物膜形成），因为它们不显示对 生物污染物换句话说，宿主生物分子和来自死亡微生物的细胞碎片可以积累 在它们的表面上，从而促进活微生物及其相关生物膜的粘附。此外，本发明还提供了一种方法， 大多数抗微生物CVC通过逐渐释放嵌入的杀生物剂/抗生素发挥作用， 抗菌素耐药性为了解决这些问题，我们假设， 两性离子部分与抗微生物双子双阳离子部分一起进入CVC表面， 效果可以实现。我们的初步研究证实了协同效应。技术创新是（1） 用双子双阳离子部分共价固定的新CVC表面，以提供同类最佳的抗微生物剂 性能而无需担心抗微生物抗性的发展;以及2）新的CVC表面 含有生物膜排斥剂和抗微生物部分以克服各自单独的缺陷， 防止CLABSI的根本原因。为了证明我们的技术的可行性，在目标1中，我们将 通过反复优化抗微生物剂和驱避剂之间的比例来最大化协同效应 在抗微生物功效、生物膜排斥性、涂层抗感染耐久性方面， 的时间表.在目标2中，我们将生产原型混合CVC，并比较它们相对于 商业抗微生物CVC针对导致>90%的CLABSI的病原体。在目标3中，我们 使用ISO 10993-4中规定的溶血试验评价原型的生物相容性和血液相容性， 凝血、补体激活和炎症以及沥滤液毒性。这方面的预期成果 I期包括增殖、抗微生物和生物膜测定减少>20%，具有相似/更好的血液 与目前的抗微生物CVC相比，我们的国家感染率降低20%以上 CVC产品将预防> 50，000例CLABSI，挽救> 16，000人的生命和> 5亿美元的直接医疗保健成本 每年.第二阶段将包括体内研究，以确保体外和离体特性的准确转换。 在第二阶段，我们还将在符合FDA cGMP的生产中开始生产原型CVC 机构，随后申请510（k）许可进行后续临床评价。我们的服务 SOM是美国CVC市场，预计到2026年将增长13亿美元。因为我们的混合涂层可以 适用于几乎所有类型的导管，包括IV和尿路导管，总可用市场（TAM） 是全球导管市场，预计到2028年将达到748亿美元。