Device for Eradicating /Controlling Biofilm in Dialysis

描述（由申请人提供）：近年来，暴露于内毒素的血液透析患者慢性促炎反应的临床意义已成为肾脏病学的中心问题。欧洲肾脏协会敦促常规使用细菌和内毒素水平分别< 0.1 cfu/ml和< 0.03 EU/ml的超纯透析液。美国医疗器械进步协会（AAMI）考虑为美国提出类似的建议，但当时选择不这样做，因为许多透析诊所如果不对设备和操作程序进行重大改变，就无法达到如此高水平的透析液纯度。最近，AAMI将其推荐的透析液细菌水平从2000 cfu/ml降至200 cfu/ml，并引入了2 EU/ml的内毒素限量。在欧洲，细菌和内毒素的可比水平分别为100 cfu/ml和0.25 EU/ml。为了在透析液中始终达到如此高的纯度水平，透析诊所需要克服两个主要挑战，即：1)防止与用于制造透析液的液体接触的水系统表面形成生物膜，以及ii)遵守标准化维护协议以满足如此低水平污染的能力。在第一阶段的研究中，我们开发了一种基于湍流两相流清洗方法的新技术，该技术被证明可以从模拟透析中心水系统（DCWS）的分布回路中去除99%以上的成熟生物膜，并完全杀死任何剩余的表面细菌。在第二阶段的研究中，我们建议完成两阶段清洁工艺的开发，并开发一种自动就地清洁/就地消毒（CIP/SIP）系统，该系统能够为DCWS的所有组件提供有效的清洁/消毒循环，包括：反渗透分配回路、碳酸氢盐分配回路、与透析机的连接、反渗透膜单元和储罐。根据我们的计划，透析机的分配回路和连接管将采用两相流工艺清洗和消毒，储罐将采用喷雾系统清洗，但不需要填充储罐。整个清洗/消毒将通过自动化CIP/SIP系统进行。拟议的系统将以最少的人力需求和更短的时间执行经过验证的维护协议。具体目标是：目标1 -使用第一阶段研究中开发的模拟系统，为DCWS的每个组件开发清洁程序和分析方法；目标2 -开发自动化就地清洁/就地消毒（CIP/SIP）系统，包括：流量和化学控制，循环步骤和顺序，工艺指标和参数；目标3 -验证每个透析水系统组件的清洗程序，包括：分配回路，与透析机的连接，储罐和ro膜装置；目标4 -在临床环境中验证有效的清洁流程和方案；目标5 -定义水系统设计和清洁/消毒方案，以便在临床环境中始终如一地提供高质量的透析液。

DESCRIPTION (provided by applicant): The clinical significance of chronic pro-inflammatory reactions in hemodialysis patients due to exposure to endotoxins has become a central issue in nephrology in recent years. The European Renal Association urges the routine use of ultrapure dialysate with bacteria and endotoxin levels < 0.1 cfu/ml and < 0.03 EU/ml, respectively. The American Association for the Advancement of Medical Instrumentation (AAMI) considered making similar recommendations for the United States, but chose not to do so at the time since many dialysis clinics would not be able to achieve this high level of dialysate purity without major changes in equipment and operating procedures. Recently, AAMI reduced its recommended levels of dialysate bacteria level from 2000 cfu/ml to 200 cfu/ml, and introduced an endotoxin limit of 2 EU/ml. The comparable European levels are 100 cfu/ml and 0.25 EU/ml for bacteria and endotoxins, respectively. To consistently achieve such high-purity levels in dialysate, two major challenges need to be overcome by dialysis clinics, namely: i) prevention of biofilm formation on surfaces of water systems in contact with liquids used to make the dialysate, and ii) ability to adhere to a standardized maintenance protocol to satisfy such low level of contamination. During the Phase I study, we developed a new technology based on the turbulent two-phase flow cleaning method that proved to remove more than 99% of mature biofilm from the distribution loops of a simulated dialysis center water system (DCWS), and with complete killing of any remaining surface bacteria. In the Phase II study, we propose to complete the development of the two-phase cleaning process and to develop an automated clean-inplace/ sanitize-in-place (CIP/SIP) system capable of delivering a validated cleaning/disinfecting cycle to all the components of the DCWS, including: RO distribution loop, bicarbonate distribution loop, connections to dialysis machines, RO-membrane unit and storage tanks. According to our plan, the distribution loops and connection tubing to dialysis machines will be cleaned and disinfected with the two-phase flow process, while storage tanks will be cleaned with a spray system, but without the need to fill such tanks. The entire cleaning/disinfection will be performed with the automated CIP/SIP system. The proposed system will perform a validated maintenance protocol with minimal labor requirements and in shorter times. The Specific Aims are: Aim 1 - To develop the cleaning procedure and analytical methodologies for each component of the DCWS using the simulated system developed in the Phase I study; Aim 2 - To develop an automated clean-in-place/sanitize-in-place (CIP/SIP) system, including: flow and chemical control, cycle steps and sequence, process indicators and parameters; Aim 3 - To validate the cleaning procedure for each dialysis water system component, including: distribution loops, connections to dialysis machines, storage tanks, and RO-membrane unit; Aim 4 - To verify the validated cleaning process and protocol in the clinical setting; and Aim 5 - To define water system designs and cleaning/disinfecting protocols necessary to consistently deliver high quality dialysate in the clinical setting.