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

用于开发新型仿生医疗设备的纤维设计和评估

• 批准号: 10238170
• 负责人: Christopher Pino
• 金额: $ 76.4万
• 依托单位: INNOVATIVE BIOTHERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238170
• 关键词: Acute Disease; Acute Renal Failure with Renal Papillary Necrosis; Adherence; Adhesions; Adolescent; Adult; Advanced Development; Affinity; Age; Animal Model; Animals; Anticoagulation; Area; Biofeedback; Biological; Biological Response Modifier Therapy; Biomimetics; Biotechnology; Blood; Blood Volume; Blood capillaries; CD14 gene; Caliber; Catheters; Certification; Child; Childhood; Chronic Disease; Citrates; Clinical; Clinical Research; Clinical Trials; Critical Illness; Custom; Data; Destinations; Development; Devices; Dialysis procedure; Disease; Etiology; Evaluation; Excision; Exhibits; FCGR3B gene; Family suidae; Fiber; Formulation; Functional disorder; Funding; Future; Generations; Goals; Government; Health; Hemodialysis; Hemofiltration; Hemolytic-Uremic Syndrome; Hepatorenal Syndrome; Human; ITGAM gene; Immune system; In Vitro; Inflammation; Inflammatory; Investigation; Kidney Diseases; Left; Leukocytes; Life; Medical; Medical Device; Methodology; Modeling; Organ failure; Outcome; Patients; Performance; Peripheral; Persons; Pharmaceutical Preparations; Pharmacopoeias; Phase; Phenotype; Production; Rare Diseases; Renal Replacement Therapy; Research; Safety; Sepsis; Series; Sterilization; Surface; Syndrome; System; Technology; Testing; Therapeutic Equivalency; Time; United States; Ventricular; Work; adolescent patient; base; biomaterial compatibility; cell type; clinical efficacy; clinical translation; clinically relevant; commercialization; design; hemocompatibility; hemodynamics; hydrophilicity; immunoregulation; improved; in vivo; innovation; insight; left ventricular assist device; manufacturing facility; manufacturing process; miniaturize; monocyte; mortality; multiorgan injury; neonate; neutrophil; novel; off-label use; patient population; pediatric patients; porcine model; pre-clinical; preclinical study; prototype; safety testing; success

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.

抽象的。选择性细胞分离装置 (SCD) 是一种体外、血液接触医疗装置 有针对性地治疗有炎症性疾病适应症的患者。 SCD 疗法与血液透析的相似之处在于 导管和医用管用于使患者的血液流过该设备。患者的白血 细胞 (WBC)，也称为白细胞 (LE)，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（或激活）的白细胞进行免疫调节相互作用。 迄今为止，SCD 已在 4 项人体临床研究中安全使用，其中 3 项针对成人试验，1 项针对青少年试验 患者，对患有急性肾损伤（AKI）和多器官的危重患者具有积极的临床结果 功能障碍（MOD）。长期目标：开发具有专利性的医用级纤维配方 外径 (OD) ≤ 140 µm，用于低血液填充量 (BFV) 的第二代 SCD (SCD2) 使儿童患者和危重成人患者的治疗能够重新去除血容量 由于潜在的血流动力学不稳定而导致的限制。当前 SCD (SCD1) 中的纤维由聚硫制成 fone (PSu)，OD 为 280 µm。这些光纤太大，无法在 SCD2 中使用，导致 BFV 无法使用 太高，对儿科患者和重症患者不安全。将实现 <50 mL 的安全 BFV 对于 SCD2，使用 ~140 µm OD 光纤。拥有 ISO 13485 认证的全新精品纤维制造工厂 （中空纤维系统）将用于制造医用级纤维。纤维将接受一系列测试 研究快速开发 SCD2 进行临床转化，以挽救重症患者的生命。 在之前完成的一期项目期间，SCD1用于临床试验的工作方式是 特征，称为作用机制（MoA）。已阐明的 MoA 的主要特征包括： LE 与 SCD 纤维的粘附，具有单核细胞 (MO) 和中性粒细胞 (NE) 的特异性粘附。为推进适当 etary 纤维开发，在纤维生产过程中添加到 PSu 材料中的最佳亲水剂范围 化成立。在此第二阶段提案中，拟议的研究包括： 目标 1. 描述专有药物的特征 由定制生产生产的ical级纤维。评估小型化原型 SCD2 中的光纤 使用人血的体外血液回路（IVBC）。目标 2. 生产全尺寸儿科 SCD2。评估 SCD2 设计 使用猪血进行 IVBC 研究，以评估 SCD-LE 相互作用和血液相容性。目标 3. 评估 SCD2 在临床相关的严重脓毒症 (SS) 相关 AKI 猪模型中。目标 4. FDA 监管生物相容性 SCD2 的能力、灭菌和保质期测试。健康相关影响：由此生成的临床前数据 该提案将包含在监管提交中，以申请 FDA 的 IDE 批准以启动临床 评估 SCD2 疗法在急性和慢性疾病适应症中的试验，以孤儿疾病为中心 缓解：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) 的目标治疗 (DT) 可能会受益于 SCD2 治疗。