Evaluation of the Effect of Commercial Processing on Artificial Lung Zwitterionic Coatings

摘要 在美国，超过1500万患者患有慢性肺部疾病。这些患者经历了一个渐进的 呼吸功能下降，伴有急性加重，导致短暂但危险的， 病情恶化。每年，这导致690万次急诊，70万次住院， 18万人死亡。不幸的是，每年只有不到2,400例肺移植。因此，其中大多数 患者将死于他们的疾病而不进行移植，因此非常需要一种安全、永久的方法 呼吸支持。为了满足这一需求，我们正在开发一种能够永久呼吸的人工肺。 肺辅助设备（PAD）。PAD是一种紧凑、高度生物相容的气体交换器， 当与心室辅助装置耦合时，可提供永久的、移动的、静脉-静脉的或静脉-动脉的 体外呼吸支持持续数月至数年。慢性肺病患者可以得到支持 在护理机构或家中，每2-3个月或更长时间返回医院进行计划的PAD 更换.为了实现这一目标，PAD必须具有比当前氧合器更大的生物相容性， 这会导致严重的出血并发症，同时也会在几周内由于凝块形成而失败。这是 通过一种新颖的专利PAD设计来实现，该设计专注于减缓凝块形成并对其进行涂层 具有聚羧基甜菜碱（DOPA-PCB）表面涂层。DOPA-PCB涂层可有效减少蛋白质 吸附、血小板结合和人工肺中的体内凝块形成。下一个商业阶段的 涂层的发展是为了检查是否保持其抗凝功能，在储存期长达3 个月因此，我们将确定（1）小的DOPA-PCB涂层纤维样品是否保持其抑制 纤维蛋白原吸附和（2）如果DOPA-PCB涂层电路含有微型人工肺保持其 在体内试验期间减缓凝块形成和器械功能退化的能力， 涂覆和灭菌。我们的第一阶段成功标准是DOPA-PCB涂层继续（1）减少 纤维蛋白原吸附大于80%，和（2）在长达3个月后，凝块重量减少大于50% 与未涂覆的对照相比，如果成功，第二阶段研究将扩展所描述的测试 在为期两个月的绵羊ECMO研究中， 涂有DOPA-PCB或市售肝素涂层的全尺寸PAD，储存时间长达6 个月在这些研究之后，涂层将在传统ECMO期间准备好商业应用 在重症监护病房外进行支持或长期目的性治疗。

Abstract Over 15 million patients in the U.S. suffer from chronic lung diseases. These patients experience a gradual decline in respiratory function that is coupled with acute exacerbations that lead to a transient, but dangerous, worsening of their disease. Yearly, this results in 6.9 million emergency room visits, 700,000 hospitalizations, and 180,000 deaths. Unfortunately, there are less than 2,400 lung transplants every year. Thus, most of these patients will succumb to their disease without a transplant, and there is a great need for a safe, permanent means of respiratory support. To address this need, we are developing an artificial lung capable of permanent respiratory support, the pulmonary assist device (PAD). The PAD is a compact, highly biocompatible gas exchanger that, when coupled with a ventricular assist device, can provide permanent, mobile, venovenous or venoarterial extracorporeal respiratory support lasting months to years. Patients with chronic lung disease could be supported within a nursing facility or at home and return to the hospital every 2-3 or more months for scheduled PAD replacement. To accomplish this goal, the PAD must have far greater biocompatibility than current oxygenators, which cause serious bleeding complications while also failing due to clot formation within a few weeks. This is accomplished by starting with a novel, patented PAD design focused on slowing clot formation and coating it with a polycarboxybetaine (DOPA-PCB) surface coating. The DOPA-PCB coating is effective at reducing protein adsorption, platelet binding, and in vivo clot formation in artificial lungs. The next commercial phase of the coating’s development is to examine if maintains its anticoagulation function over a storage period of up to 3 months. Thus, we will determine if (1) small, DOPA-PCB coated fiber samples maintain their ability to inhibit fibrinogen adsorption and (2) if DOPA-PCB coated circuits containing miniature artificial lungs maintain their ability to slow clot formation and device functional degradation during in vivo testing for up to 3 months after coating and sterilization. Our Phase I Success Criteria are that the DOPA-PCB coating continues to (1) reduce fibrinogen adsorption by greater than 80% and (2) reduces clot weight by greater than 50% after up to 3 months of storage when compared to the uncoated control. If successful, Phase II studies will extend the described tests out to six months of storage and examine coating effectiveness during two-month sheep ECMO studies using full-scale PADs coated with either DOPA-PCB or commercial heparin coatings and stored for periods of up to 6 months. Following these studies, the coating will be ready for commercial application during traditional ECMO support or longer-term, destination therapy outside of the intensive care unit.