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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：
10458610
负责人：
Christopher Pino
金额：
$ 55.33万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458610
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

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。选择性细胞分离装置（SCD）是一种体外血液接触医疗器械用于治疗炎症性疾病适应症患者。SCD治疗与血液透析相似，导管和医用管用于使患者的血液通过该装置。病人的白色血白细胞（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（或活化）的WBC进行免疫调节相互作用。迄今为止，SCD已安全用于4项人体临床研究，3项成人试验和1项青少年试验患者，急性肾损伤（阿基）和多器官功能衰竭的重症患者的临床结局为阳性功能障碍（MOD）。长期目标：开发医用级纤维的专有配方，外径（OD）≤ 140 µm，用于低血液填充量（BFV）的第二代SCD（SCD 2）为了能够治疗儿科患者和危重成人患者，由于潜在的血流动力学不稳定而导致的狭窄。当前SCD（SCD 1）中的纤维由聚磺酰亚胺制成。（280）这些纤维太大而不能用于SCD 2，导致BFV 过高，对儿科患者和危重患者不安全。将实现<50 mL的安全BFV 对于SCD 2，使用~140 µm OD光纤。一个新的精品纤维制造工厂，通过ISO 13485认证（中空纤维系统）将用于制造医疗级纤维。纤维将在一系列测试中进行测试，研究，以快速开发SCD 2用于临床转化，以挽救重症患者的生命。在之前完成的I期项目期间，SCD 1在临床试验中的工作方式是这就是所谓的作用机制（MoA）。阐明的MoA的主要特征包括：粘附于SCD纤维，具有单核细胞（MO）和中性粒细胞（NE）的特异性粘附。为了推进正确的- 纤维开发，在纤维生产过程中添加到PSu材料中的亲水剂的最佳范围，成立了。在第二阶段的建议中，拟议的研究包括：目标1。描述专有药物- 定制生产的医用级纤维。评估小型化原型SCD 2中的光纤，体外血液回路（IVBC）。目标2.生产全尺寸儿科-SCD 2。评估SCD 2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.评价SCD 2 在临床相关的AKI相关严重脓毒症（SS）猪模型中。目标4。FDA监管生物相容性- SCD 2的稳定性、灭菌和有效期测试。健康相关影响：由此生成的临床前数据将在向FDA申请IDE批准以启动临床试验的监管提交资料中纳入一项提案评估SCD 2治疗急性和慢性疾病适应症的试验，从孤儿病开始病例：儿科阿基、非典型溶血性尿毒综合征（阿胡斯）和心肾综合征（CRS）患者左心室辅助装置（LVAD）目标治疗（DT）可能受益于SCD 2治疗。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Immunomodulatory therapy using a pediatric dialysis system ameliorates septic shock in miniature pigs.

DOI：
10.1038/s41390-022-02061-4
发表时间：
2023-01
期刊：
PEDIATRIC RESEARCH
影响因子：
3.6
作者：
Johnston, Kimberly A.;Pino, Christopher J.;Chan, Goldia;Ketteler, Skylar K.;Goldstein, Stuart L.;Humes, H. David
通讯作者：
Humes, H. David