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）影响快速增长的人群，到2020年美国可能超过100万患者。每周3次血液透析（HD）的标准治疗具有较高的并发症发生率和感染风险，导致患者治疗不足，并且对医疗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），通常使用时间较长，感染风险甚至更高。家庭腹膜透析（PD）和家庭血液透析（HHD）的更便宜且更患者友好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（在PD的情况下）和需要重复困难的针刺家庭（在HHD的情况下）。本II期SBIR提案的总体目标是针对所有类型的无针透析通路（包括CVC、PD导管和下一代用于HD通路的经皮放置输液港）的显著提高的抗感染性这一关键未满足需求的解决方案。创新：我们正在开发一种多孔套囊，可在皮肤的切割边缘和植入的经皮器械表面之间形成紧密集成的密封。Healionics的STARcuffTM具有精确设计的孔几何形状（~35 μ m的孔由~15 μ m的孔喉互连），允许巨噬细胞和真皮细胞进入每个孔。这种优化的结构促进了血管化真皮整合和稳定的表皮整合，而不会发生迁移、过度纤维化或窦道形成。其他具有较大（50-500 μ m）开口的多孔套囊通过诱导纤维向内生长实现机械固位，但易于发生套囊迁移和生物膜形成。孔径小于10微米的小孔袖口更容易感染，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生物界面可抵抗细菌生物膜的形成，并将稳定的静止浓度的宿主巨噬细胞招募到生物材料中，恢复天然皮肤屏障，使身体的天然防御机制能够对抗细菌感染。方法：我们已成功完成I期目标，即：1）建立猪经皮植入物细菌挑战模型，2）建立监测出口部位感染的无创技术（红外热成像），3）证明STARcuff在控制和减少这种感染方面的有效性。这些成功的I期结果使我们能够将STARcuff技术推向高医疗影响经皮透析设备的商业实现。II期研究的具体目标是：1）证明长期（9个月）抗感染性的改善，2）评估皮肤凝闭的稳健性，3）将研究扩展至植入血管的完整CVC器械。项目的成功将通过降低急性感染成本、增加家庭透析使用和创造更健康的患者群体，为所有透析患者带来重大的积极经济影响和生活质量受益。一家主要的导管公司已经表示对这项技术有商业兴趣，并为该项目提供实物支持。 公共卫生相关性：终末期肾病（ESRD）影响着快速增长的人群，到2020年美国可能超过100万患者。患者的生活质量和经济问题是对20世纪70年代建立的当前透析治疗中心系统的主要挑战。所有现有的方法都需要穿透天然皮肤屏障以防止细菌。由此产生的感染的医学治疗已经变得比透析本身更昂贵，并且是通常用作血管通路针的备用导管的特殊问题。类似地，通过无针血管通路装置可以极大地提高对成本较低且更多患者控制的替代方案（例如家庭血液透析）的接受度，但是用于此的植入装置在皮肤界面处遭受感染问题。我们正在开发一种生物材料套管，在入路器械的皮肤出口部位表现出非常强的组织整合性和抗感染性。项目的成功将显著提高透析的有效性和效率。

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. PUBLIC HEALTH RELEVANCE: End Stage Renal Disease (ESRD) affects a rapidly growing population, likely exceeding 1 million patients in the US by 2020. Patient quality of life and economic issues are major challenges to the present dialysis treatment center system established in the 1970's. All present methods require penetration of the natural skin barrier to bacteria. Medical treatment of resultant infections has become more costly than the dialysis itself and is a special problem with the catheters often used as a backup to needles for vascular access. Similarly, acceptance of less costly and more patient controlled alternatives such as home hemodialysis could be greatly improved by a needle free vascular access means, but implanted devices for this have suffered from infection problems at the skin interface. We are developing a biomaterial sleeve exhibiting very strong tissue integration and infection resistance at the skin exit sites of access devices. Project success will lead to significant improvements in dialysis effectiveness and efficiency.