Fiber design and assessment for development of a novel biomimetic medical device

 描述（由申请人提供）：选择性细胞分离装置（SCD）是一种体外医疗器械，用于治疗炎症性疾病适应症患者。当患者血液通过SCD时，它与SCD内的血液相容性纤维接触。这些纤维能够与患者过度活跃的白色血细胞（活化的白细胞）进行免疫调节相互作用。迄今为止，SCD已用于三项人体临床研究，对急性肾损伤（阿基）和多器官功能障碍（MOD）的重症成人患者具有积极的临床结局。长期目标：开发一种生产外径（OD）= 140 µm的纤维的工艺，用于第二代SCD（SCD 2），血液填充量低，能够治疗因潜在血流动力学不稳定而导致血容量清除受限的儿科患者和危重成人患者，以及通过外周插入中心静脉导管（PICC）通路在门诊进行治疗，这需要低的血液流速。当前SCD中的纤维由聚砜（PSu）制成，OD为280 µm。血液透析纤维制造中的当前技术限于制造OD在280至600 μm之间的纤维。这些纤维太大而不能用于SCD 2，这将导致血液预充量很高，因此对于儿科患者和危重患者不安全。为了使这些患者的血液填充量<50 mL，纤维必须制成=140 µm。弗吉尼亚理工大学的一个实验室将用于制造SCD 2设备所需规格的纤维，这将使纤维制造工艺的快速发展成为SCD 2的临床转化，以挽救重症患者的生命。在这个项目中， SCD的工作原理，称为作用机制（MoA），将通过使用来自当地屠宰场的新鲜牛血，具体观察白色血细胞（WBC）如何与装置中的纤维相互作用（具体目标1）来探索。将通过寻找聚合物的正确平衡来开发=140 µm OD纤维的生产方法，以改变纤维的表面，从而实现与WBC的最佳相互作用，也用牛血进行了测试（具体目标2）。目标2中生产的纤维将在特定目标3中采用不同方法灭菌，并将使用牛血进行试验。这些经过优化的无菌纤维将准备用于医疗设备，以在临床前大型动物模型中进行测试，以证明功效。如果它们是安全的并且工作良好，那么最终的设备可以用于人体临床试验。健康相关影响：该提案产生的数据将推动生产SCD 2所需的PSu纤维制造的关键制造工艺的开发。它还将提供临床前数据，以纳入监管提交文件，申请FDA的IDE批准，以启动临床试验，评价SCD 2治疗急性和慢性疾病适应症，包括孤儿疾病：抗中性粒细胞胞浆抗体（ANCA）血管炎、皮肌炎、格林-巴利综合征（GBS）和儿科阿基。

 DESCRIPTION (provided by applicant): The Selective Cytopheretic Device (SCD) is an extracorporeal medical device targeted to treat patients with inflammatory disease indications. As patient blood passes through the SCD, it comes in contact with the hemocompatible fibers inside the SCD. These fibers are capable of immunomodulatory interactions with the patient's over-active white blood cells (activated leukocytes). The SCD has been used in three human clinical studies to date, with positive clinical outcomes for critically ill adult patients with acte kidney injury (AKI) and multiorgan dysfunction (MOD). Long term objective: to develop a process to manufacture fibers with an outer diameter (OD) = 140 µm, for use in a second generation SCD (SCD2) with low blood fill volumes to enable the treatment of pediatric patients and critically ill adult patients with blood volume removal re- strictions due to potential hemodynamic instability, as well as treatment in out-patient clinics via peripherally inserted central catheter (PICC) access, which require low blood flow rates. Fibers within the current SCD are made of polysulfone (PSu) and have an OD of 280 µm. Current technology in hemodialysis fiber manufacturing is restricted to fabricating fibers with OD of between 280 to 600 µm. These fibers are far too large to be used in the SCD2, which would cause the blood priming volumes to be high, and therefore not safe for pediatric patients and critically ill patiens. In order to make the blood fill volumes <50 mL for these patients, the fibers must be made =140 µm. A lab at Virginia Tech will be used to manufacture fibers of the required specifications for the SCD2 device, which will enable the rapid development of the fiber making process toward clinical translation for the SCD2 to save severely ill patients' lives. In this project, the way in which the SCD works, called the mechanism of action (MoA) will be explored by specifically looking at how white blood cells (WBC) interact with the fibers in the device (Specific Aim 1) by using fresh cow blood from a local slaughterhouse. Production methodology for =140 µm OD fibers will be developed by finding just the right balance of polymers to change the surface of the fibers for the best interaction with WBC, also tested with cow blood (Specific Aim 2). The fibers produced in Aim 2 will be sterilized by different methods in Specific Aim 3, and will be tested with cow blood. These optimized, sterilized fibers would be ready for use in a medical device to test in a preclinical large animal model, to prove efficacy. If they are safe and work well, then the finalized devices could be used in a human clinical trial. Health Related Impact: The data generated from this proposal will advance the development of a critical manufacturing process for fabrica- tion of PSu fibers needed to produce SCD2. It will also provide preclinical data for inclusion of regulatory sub- missions to apply for IDE approval from the FDA to initiate clinical trials for the evaluation of SCD2 therapy in both acute and chronic disease indications, including orphan diseases: anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, dermatomyositis, Guillian-Barre Syndrome (GBS), and pediatric AKI.