Anti-Infective Dermal Integration Sleeves for Needle Free Dialysis Access Devices

描述(由申请人提供)：意义：终末期肾病(ESRD)影响着迅速增长的人口，到2020年，美国可能超过100万患者。每周3次的标准血液透析(HD)治疗具有很高的并发症发生率和感染风险，导致患者治疗不足，并且对卫生保健系统来说是不可持续的昂贵。传统的血管通路部位形成和维护问题导致超过25%的HD患者使用中心静脉导管(CVC)，通常时间较长，感染风险更高。成本更低、患者更友好的家庭腹膜透析(PD)和家庭血液透析(HHD)的替代方案尚未得到广泛采用，部分原因是出口部位感染风险(对于PD)，以及需要在家中反复使用困难的针头(对于HHD)。这一第二阶段SBIR方案的总体目标是为所有类型的无针透析通路(包括CVCS、PD导管和用于HD通路的下一代经皮放置端口)提供一种解决方案，以满足尚未满足的关键需求，即大幅提高抗感染能力。创新：我们正在开发一种多孔袖带，它可以在皮肤切割边缘和植入型经皮设备的表面之间形成紧密结合的密封。Healionics的STARcuffTM精确设计了毛孔几何结构(约35？m的毛孔由~15？m的孔喉相连)，允许巨噬细胞和真皮细胞进入每个毛孔。这种优化的结构促进了血管化的真皮整合和稳定的表皮整合，没有迁移、过度纤维化或窦道形成。其他开口较大(50-500米)的多孔袖带通过诱导纤维性内生实现机械固位，但容易发生袖带迁移和生物膜形成。孔径小于10？m的小孔袖套更容易感染，通过限制巨噬细胞和其他宿主防御细胞的进入，为渗透的细菌提供庇护。STARcuff生物界面阻止细菌生物膜的形成，并将稳定、静止的宿主巨噬细胞浓度招募到生物材料中，恢复自然皮肤屏障，并启用人体抵御细菌感染的自然防御机制。方法：我们已经成功地完成了第一阶段的目标：1)建立猪经皮植入物细菌挑战模型，2)建立用于监测出口部位感染的非侵入性技术(红外热像)，3)展示STARcuff在控制和减少这种感染方面的有效性。这些成功的第一阶段结果使我们能够将STARcuff技术推向高医疗影响经皮透析设备的商业实现。第二阶段的具体目标是1)证明改善的长期(9个月)感染抵抗力，2)评估皮肤密封的坚固性，以及3)将研究扩展到植入血管的完整CVC设备。项目的成功将为所有透析患者带来重大的积极经济影响和生活质量收益，降低急性感染成本，增加家庭透析使用，并创造更健康的患者群体。一家主要的导管公司已经表达了对这项技术的商业兴趣，并正在为该项目提供实物支持。

DESCRIPTION (provided by applicant): Significance: End Stage Renal Disease (ESRD) affects a rapidly growing population likely to exceed 1 million patients in the US by 2020. The standard treatment of 3 times per week hemodialysis (HD) has high complication rates and infection risks, results in undertreated patients, and is unsustainably costly to the health care system. Conventional vascular access site formation and maintenance issues result in more than 25% of HD patients using central venous catheters (CVCs), often for long periods and with even higher infection risks. Less expensive and more patient-friendly alternatives of home peritoneal dialysis (PD) and home hemodialysis (HHD) have not seen wide adoption, in part due to exit site infection risk (in the case of PD) and the need for repeated difficult needle sticks a home (in the case of HHD). The overall goal of this Phase II SBIR proposal is a solution for the critical unmet need of much-improved infection resistance for all types of needle-free dialysis access, including CVCs, PD catheters, and next-generation percutaneously placed ports for HD access. Innovation: We are developing a porous cuff that forms a tightly integrated seal between the cut edge of the skin and the surface of an implanted percutaneous device. Healionics' STARcuffTM has precisely engineered pore geometry (~35¿m pores interconnected by ~15¿m pore throats) that allows macrophage and dermal cell entry into every pore. This optimized structure promotes vascularized dermal integration and stable epidermal incorporation without migration, excessive fibrosis, or sinus tract formation. Other porous cuffs with larger (50-500¿m) openings achieve mechanical retention by inducing fibrotic ingrowth, but are prone to cuff migration and biofilm formation. Smaller-pored cuffs with pore sizes less than 10¿m are even more infection prone, providing shelter for infiltrated bacteria by restricting access for macrophages and other host defense cells. A STARcuff biointerface resists bacterial biofilm formation and recruits a stable, quiescent concentration of host macrophages into the biomaterial, restoring the natural skin barrier and enabling the body's natural defense mechanisms for fighting bacterial infection. Approach: We have successfully accomplished Phase I goals to 1) establish a porcine percutaneous implant bacterial challenge model, 2) establish a non-invasive technique (infrared thermography) for monitoring exit site infection and 3) demonstrate effectiveness of STARcuff in controlling and reducing this infection. These successful Phase I results position us to move STARcuff technology toward commercial realization on high medical impact percutaneous dialysis devices. Phase II specific aims are to 1) demonstrate improved long-term (9-month) infection resistance, 2) assess the robustness of the skin seal, and 3) extend studies to full CVC devices implanted into a blood vessel. Project success will result in major positive economic impact and Quality of Life benefit for all dialysis patients by reducing acute infection costs, increasing home dialysis use, and creating a healthier patient population. A major catheter company has already expressed commercial interest in the technology and is providing in kind support for the project.