Novel outside-in dialyzer with long filter life and reduced anticoagulation therapies

7.项目摘要/摘要[修订] 在过去的60年里，所有的中空纤维透析器都有腔内血流。Novaflux自外向内过滤 (OIF)开创了中空纤维透析器的新设计范式，改变了透析器的流量分布，使血液 血液在纤维外流动，透析液在腔内空间流动。这一发展减少了 急性或慢性透析治疗需要抗凝，包括血液透析(HD)，并提供 延长连续性肾脏替代疗法(CRRT)的过滤器寿命。使用常规方法获得的体外数据 具有OIF流的透析器发现，与标准透析器的约24小时相比，过滤器的使用寿命延长到100小时以上 具有统计等值净空的流动。在OIF中，血栓对血流或滤器的影响很小 动态三维互联流动通道产生的压力、扩散间隙或滤液流量 在纤维间空间创造的。 Novaflux研究公司已经开发出逆转传统透析器膜的原型纤维 结构，以提供薄，紧凑，光滑的血液兼容的外层皮肤。OI纤维将防止对血液的损害 细胞或血小板聚集物的形成。Novaflux Oi过滤器外壳使用新型优化进血口设计 流动几何、建模和计算流动动力学以提供稳定的血流速度和均匀的血液 流量分配。OIF透析器将能够用现有的透析器生产设备生产 相对较小的修改。 OI透析器的价值主张是减少或消除慢性阻塞性肺疾病患者的抗凝需求 血液透析。这带来的主要好处包括：1)降低肝素相关并发症的风险，如 作为治疗后的出血和失血；2)为肝素诱导的非抗凝提供替代 血小板减少；3)由于减少使用，每次治疗费用降低0.70美元至1.60美元 肝素；4)减少可能从体外循环传给患者的微栓子，导致 脑等器官的缺血性损害，这可能导致透析性痴呆；以及5)低凝血 潜力促进了可穿戴式肾脏治疗的发展。 OI过滤器可以通过不提供或减少抗凝和 CRRT中的过滤器寿命更长，这意味着：1)降低了医疗保健提供者的成本和复杂性；以及2) 减少了对复杂抗凝疗法的需求，例如局部柠檬酸盐抗凝。 第二阶段将扩大OIF膜和外壳的规模，以生产用于IN的OI透析器原型 体外和动物研究，以表征性能和血液相容性。这些研究将量化 OI技术在消除或减少透析治疗的抗凝方面的潜力并为临床提供 与目前的急性和慢性疗法相比，收益和成本都有所降低。这两个项目的具体目标 年计划是：目标1：开发OI纤维的中试规模生产；目标2：为 基于CFD分析的自外向内过滤器及开发有限元透析器制造/施工工艺 生产运行；目标3：对OI膜和OI过滤器进行体外测试；以及目标4：执行 用绵羊模型进行活体动物实验。OI技术还将使可穿戴设备的开发成为可能 滤清器寿命更长的固有优势。

7. Project Summary/Abstract [Revised] For the past 60 years all hollow fiber dialyzers have had intraluminal blood flow. Novaflux outside-in filtration (OIF) creates a new design paradigm for hollow fiber dialyzers, changing dialyzer flow distribution so that blood flows on the outside of the fiber and dialysate flows in the intraluminal space. This development reduces the need for anticoagulation for acute or chronic dialytic therapies, including hemodialysis (HD) and provides increased filter life for continuous renal replacement therapies (CRRT). In vitro data using conventional dialyzers with OIF flow have found increased filter life to over 100 hours as compared to ~24 h with standard flow with statistically equivalent clearance. In OIF, thrombi have a minimal effect on the blood flow or filter pressure, diffusive clearance, or filtrate flux due to dynamic three-dimensional interconnected flow channels created in the inter fiber space. Novaflux research has developed prototype fibers that reverse the conventional dialyzer membrane structure to provide a thin tight smooth hemocompatible outer skin. The OI fiber will prevent damage to blood cells or formation of platelet aggregates. Novaflux OI filter housings optimize the blood inlet design using novel flow geometries, modeling and computation flow dynamics to provide steady blood velocity and uniform blood flow distribution. OIF dialyzers will be able to be produced by current dialyzer production equipment with relatively minor modifications. The value proposition of OI dialyzers is to reduce or eliminate the need for anticoagulation for chronic hemodialysis. This brings about key benefits including: 1) Lowering risk of heparin related complications such as bleeding and blood loss post treatment; 2) Providing a no-anticoagulation alternative for Heparin-Induced Thrombocytopenia; 3) Lowering the cost by $0.70 to $1.60 per treatment due to reduction in the use of heparin; 4) Reduction of microemboli which may pass from the extracorporeal circuit to the patient, causing ischemic lesions in organs such as the brain, which may contribute to dialysis dementia; and 5) Lower clotting potential facilitates development of wearable renal treatments. The OI filter can help acute dialytic renal treatments by providing no or reduced anticoagulation and longer filter life in CRRT, which translates into: 1) Lower cost and complexity for the healthcare provider; and 2) Reduced need for complex anticoagulation regimes, e.g., regional citrate anticoagulation. The Phase II will scale up the OIF membrane and housings to produce prototype OI dialyzers for in vitro and animal studies to characterize performance and hemocompatibility. These studies will quantify the potential of OI technology to eliminate or reduce anticoagulation for dialytic therapies and to provide clinical benefits and cost reductions compared to current acute and chronic therapies. The Specific Aims of this two year program are: Aim 1: Development of pilot scale production of OI fiber; Aim 2: Design the housing for the outside-in filter based on CFD analysis and develop the dialyzer manufacturing/construction process for limited production runs; Aim 3: To perform Ex vivo testing for the OI membrane and OI filter; and Aim 4: To perform in vivo animal testing in the sheep model. The OI technology will also enable the development of wearable technologies due to inherent benefits of longer filter life.