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

抽象的。选择性细胞遗传学装置(SCD)是一种体外接触血液的医疗装置 有针对性地治疗有炎症性疾病指征的患者。SCD疗法与血液透析的相似之处在于 导管和医用管道被用来将患者的血液通过该设备。病人的白血 细胞(WBC)，也称为白细胞(LE)，与SCD内的血液相容纤维接触。 这些纤维能够与患者过度活跃(或激活)的白细胞进行免疫调节相互作用。 到目前为止，SCD已安全地用于4项人类临床研究，3项成人试验和1项青少年试验 临床转归为急性肾损伤(AKI)和多器官功能障碍的危重患者 功能障碍(MOD)。长期目标：开发一种医用级纤维的专利配方 外径(OD)≤140µm，用于第二代充血容量(BFV)较低的SCD2 使儿科患者和危重成人患者的治疗能够再次进行血容量去除。 由于潜在的血流动力学不稳定而引起的狭窄。目前SCD(SCD 1)中的纤维是由聚硫醚- Fone(PSU)和外径为280微米。这些光纤太大，无法在SCD2中使用，导致BFV 太高，这对儿科病人和危重病人来说是不安全的。将实现50毫升的安全BFV 用于使用~140微米外径光纤的SCD2。通过国际标准化组织13485认证的新的精品纤维制造设施 (中空纤维系统)将被用于制造医用级纤维。纤维将在一系列 研究快速开发用于临床翻译的SCD2，以挽救重症患者的生命。 在之前完成的第一阶段项目期间，临床试验中使用的SCD1的工作方式是 特征，称为作用机制(MOA)。阐明的MOA的主要特征包括：LE 与SCD纤维的粘附性，具有单核细胞(MO)和中性粒细胞(NE)的特异性粘附性。推进普罗旺斯-- 纤维发展，在纤维生产过程中添加到PSU材料中的最佳亲水剂范围- 成立了国家安全局。在这项第二阶段提案中，拟议的研究包括：目标1.描述专利医疗-- 通过定制生产的医用级纤维。评估SCD2小型化样机中的光纤 人血体外循环(IVBC)。目的2.研制全尺寸儿科SCD2。评估SCD2设计 用猪血进行体外循环研究以评估SCD-LE的相互作用和血液相容性。目标3.评估SCD2 在一个临床相关的严重败血症(SS)相关AKI的猪模型中。目标4.FDA规定的生物兼容性- SCD2的脱脂、灭菌和保质期测试。与健康相关的影响：由此产生的临床前数据 提案将包括在监管提交的文件中，以申请FDA对IDE的批准以启动临床 SCD2治疗在急性和慢性病适应症中的评价试验，以孤儿疾病为起点。 病例：儿童AKI、非典型溶血性尿毒症综合征(AHUS)和心肾综合征(CRS)患者 使用左心室辅助装置(LVAD)的目的疗法(DT)可能受益于SCD2疗法。

Abstract. The Selective Cytopheretic Device (SCD) is an extracorporeal, blood contacting medical device targeted to treat patients with inflammatory disease indications. SCD therapy is similar to hemodialysis in that catheters and medical tubing are used to pass the patient’s blood through the device. The patient’s white blood cells (WBC), also called leukocytes (LE), come in contact with the hemocompatible fibers inside the SCD. These fibers are capable of immunomodulatory interactions with the patient’s over-active (or activated) WBC. The SCD has been safely used in 4 human clinical studies to date, 3 trials in adults and 1 trial in adolescent patients, with positive clinical outcomes for critically ill patients with acute kidney injury (AKI) and multiorgan dysfunction (MOD). Long term objective: Develop a proprietary formulation of medical grade fibers with an outer diameter (OD) ≤ 140 µm, for use in a second generation SCD (SCD2) with low blood fill volumes (BFV) to enable the treatment of pediatric patients and critically ill adult patients with blood volume removal re- strictions due to potential hemodynamic instability. Fibers within the current SCD (SCD1) are made of polysul- fone (PSu) and have an OD of 280 µm. These fibers are too large to be used in SCD2, causing the BFV to be too high, which is not safe for pediatric patients and critically ill patients. A safe BFV of <50 mL will be achieved for SCD2 using ~140 µm OD fibers. A new, boutique fiber manufacturing facility with ISO 13485 certification (Hollow Fiber Systems) will be utilized to manufacture medical grade fibers. Fibers will be tested in a series of studies to rapidly develop SCD2 for clinical translation to save severely ill patients' lives. In the previously completed Phase I project period, the way the SCD1 used in clinical trials works was characterized, called the mechanism of action (MoA). Main features of MoA that were elucidated include: LE adhesion to SCD fibers, with a specific adhesion of monocytes (MO) and neutrophils (NE). To advance propri- etary fiber development, an optimal range of hydrophilic agent to add to the PSu material during fiber produc- tion was established. In this Phase II proposal, proposed studies include: Aim 1. Characterize proprietary med- ical grade fibers produced by custom manufacture. Evaluate fibers in miniaturized prototype SCD2 utilizing in vitro blood circuit (IVBC) with human blood. Aim 2. Produce full-size pediatric-SCD2. Evaluate SCD2 design in IVBC studies with porcine blood to assess SCD-LE interactions and hemocompatibility. Aim 3. Evaluate SCD2 in a clinically relevant porcine model of severe sepsis (SS) associated-AKI. Aim 4. FDA regulatory biocompati- bility, sterilization and shelf-life testing of SCD2. Health Related Impact: Preclinical data generated from this proposal will be included in regulatory submissions 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, staring with orphan dis- eases: pediatric AKI, atypical hemolytic uremic syndrome (aHUS) and cardiorenal syndrome (CRS) patients with left ventricular assist device (LVAD) destination therapy (DT) that may benefit from SCD2 therapy.