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

摘要 美国有超过1500万名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，加上急性加重，导致短暂的，但危险的， 他们的病情不断恶化。每年，这导致690万急诊室就诊，70万人住院， 以及18万人死亡。不幸的是，每年的肺移植手术不到2400例。因此，这些中的大多数 如果不进行移植，患者将死于自己的疾病，因此迫切需要一种安全、持久的手段。 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 支持，肺辅助装置(PAD)。该衬垫是一种紧凑的、高度生物兼容的气体交换器， 当与脑室辅助装置配合使用时，可以提供永久性、移动性、静脉静脉或静脉动脉。 持续数月至数年的体外呼吸支持。慢性肺病患者可以得到支持 在护理机构或家中，每隔2-3个月或更长时间返回医院接受预定的PAD 替补。为了实现这一目标，这种垫子必须比目前的氧合器具有更好的生物兼容性， 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 从一种新颖的、获得专利的垫子设计开始，专注于减缓血栓形成并覆盖它 具有聚羧基甜菜碱(DOPA-PCB)表面涂层。DOPA-PCB涂层在降低蛋白质方面是有效的 人工肺中的吸附、血小板结合和体内凝块形成。的下一个商业阶段 涂层的开发是为了检查在长达3年的保存期内是否保持其抗凝血功能 月份。因此，我们将确定(1)DOPA-PCB涂层的小纤维样品是否保持其抑制能力 纤维蛋白原吸附和(2)如果包含微型人工肺的DOPA-PCB涂层电路保持其 能够在体内测试期间减缓血栓形成和设备功能退化，最长可达3个月 涂布和杀菌。我们第一阶段的成功标准是DOPA-PCB涂层继续(1)减少 纤维蛋白原吸附超过80%和(2)在长达3个月后减少血栓重量超过50% 与未涂覆的对照相比，具有更高的存储效率。如果成功，第二阶段研究将延长所描述的测试 在为期两个月的绵羊ECMO研究中，使用 全尺寸衬垫，涂有DOPA-PCB板或商用肝素涂层，储存时间长达6 月份。在这些研究之后，涂层将准备好在传统的ECMO期间用于商业应用 在重症监护病房之外支持或更长期的目的地治疗。

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.