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

基本信息

批准号：
10080065
负责人：
Christopher Pino
金额：
$ 56.34万
依托单位：
INNOVATIVE BIOTHERAPIES, INC.
依托单位国家：
美国
项目类别：
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/10080065
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 pre-clinical preclinical study prototype safety testing success

项目摘要

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。选择性细胞生育装置（SCD）是体外，血液接触的医疗装置针对治疗患有炎症性疾病适应症的患者。 SCD疗法类似于血液透析导管和医用管用于通过设备传递患者的血液。病人的白血细胞（WBC），也称为白细胞（LE），与SCD内的血流相相纤维接触。这些纤维能够与患者的过度活性（或激活）WBC进行免疫调节性相互作用。迄今为止，SCD已在4项人类临床研究中安全地使用，成人3次试验，青少年试验患者患有急性肾脏损伤（AKI）和多机构的重症患者的临床结果阳性功能障碍（mod）。长期目的：开发具有医学级纤维的专有配方外径（OD）≤140µm，用于低血液填充体积（BFV）的第二代SCD（SCD2）为了治疗儿科患者和危重的成年患者血容量清除的患者由于潜在的血流动力不稳定性而导致的细胞。当前SCD（SCD1）中的纤维由多孔制成 Fone（PSU），OD为280 µm。这些纤维太大，无法在SCD2中使用，导致BFV为太高，对于儿科患者和重症患者而言是不安全的。将实现<50毫升的安全BFV 用于使用〜140 µm OD纤维的SCD2。具有ISO 13485认证的新型精品纤维制造设施（空心纤维系统）将用于制造医疗级纤维。纤维将通过一系列测试研究迅速开发SCD2进行临床翻译，以挽救严重患者的生命。在先前完成的I期项目期间，临床试验中使用的SCD1的方式是表征，称为作用机理（MOA）。阐明的MOA的主要特征包括：LE 对SCD纤维的粘附，具有特异性的单核细胞（MO）和中性粒细胞（NE）的粘附力。提高原则 Etary纤维发育，一种最佳的亲水剂范围，可在纤维生产过程中添加到PSU材料中 - 建立了。在此II阶段提案中，提出的研究包括：目标1。由定制制造产生的ICal级纤维。使用IN评估微型原型SCD2的纤维体外血回路（IVBC）用人血回路。 AIM 2。产生全尺寸的小儿SCD2。评估SCD2设计 IVBC对猪血的研究以评估SCD-LE相互作用和血流相容性。目标3。评估SCD2 在严重败血症（SS）相关的临床相关猪模型中。 AIM4。FDA调节生物兼容 SCD2的耐药性，灭菌和保质期测试。与健康相关的影响：从此产生的临床前数据建议将包括在监管提交中，以申请FDA的IDE批准以启动临床在急性和慢性疾病适应症中评估SCD2治疗的试验，并用孤儿凝视方面：小儿AKI，非典型溶血性尿毒症综合征（AHUS）和心脏综合征（CRS）患者左心室辅助装置（LVAD）目的地治疗（DT）可能受益于SCD2治疗。