Biomimetic Design and Construction of an Artificial Lung

描述(申请人提供)：该项目的最终目标是开发人工肺辅助装置技术来治疗急性和慢性肺衰竭。慢性肺病是美国第三大死因，仅次于心脏病和癌症。目前，除肺移植外，还没有针对慢性阻塞性肺疾病(COPD)等慢性病的长期解决方案，而供体器官的严重短缺限制了这种方法，使大多数患者依赖于家庭氧疗。对于成人呼吸窘迫综合征(ARDS)等急性疾病，通常需要机械通气，并发症和死亡率仍然非常高。替代疗法，如体外膜氧合器(ECMO)疗法，只能在有限的时间内使用，需要很高的抗凝水平，并且涉及许多复杂的操作。迫切需要在人工肺装置方面取得技术进步，包括简化和扩大装置的使用，减少对抗凝的需要，以及以紧凑的形式和低血量的高气体传输率。在这里，我们提出了一项探索性生物工程研究拨款，以追求生物人工肺技术的发展，基于仿生设计原则和微制造技术，建立能够在小而紧凑的结构中进行高水平气体传输的可扩展呼吸辅助结构。成功开发生物人工肺将需要几个关键要素，其中许多要素由于制造技术的限制在模拟自然肺生理方面存在困难而尚未实现。这项建议的具体目标是针对这些要素，包括能够设计一种具有小预充量和高气体渗透性的仿生结构，以及建立内皮化的微血管网络，以支持在没有抗凝剂的情况下顺畅的血液流动。这些目标与未来的临床目标是一致的，包括能够为患者提供长期的功能性呼吸辅助设备，这些设备不需要广泛的抗凝，并且可以以可穿戴或潜在的可植入形式启用。为了实现这些目标，我们的目标是1)进行仿生设计，并利用微制造技术构建包含微血管网络和透气膜的人工肺模块，2)在血管腔内建立内皮化微流体网络，并测定生物人工肺构建物的气体传输和血流凝固特性。 公共卫生相关性：该项目的最终目标是开发一种能够为急慢性肺病和心肺衰竭患者的血液充氧的医疗设备。目前的技术不能使用超过一个月，需要高水平的抗凝血剂，而且经常会损伤敏感的肺组织。这项新技术将模拟自然、健康的肺的结构和功能，并为患有急性肺损伤、慢性阻塞性肺疾病和其他导致缺氧的患者提供长期治疗。

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop artificial lung assist device technology to treat acute and chronic pulmonary failure. Chronic lung disease is the third-leading cause of death in the United States, exceeded only by heart disease and cancer. Currently there are no long-term solutions for chronic diseases such as Chronic Obstructive Pulmonary Disease (COPD) other than lung transplantation, and a severe shortage of donor organs limits this approach, leaving most patients relying on home oxygen therapy. For acute illnesses such as Adult Respiratory Distress Syndrome (ARDS), mechanical ventilation is typically required, and complications and mortality remain very high. Alternatives such as ExtraCorporeal Membrane Oxygenator (ECMO) therapy can only be used for a limited duration require high levels of anticoagulation and involve numerous operational complexities. There is an urgent need for technological advances in artificial lung devices, including simplification and extended use of devices, a reduced need for anticoagulation, and high gas transfer rates in a compact format with low blood volumes. Here we propose an Exploratory Bioengineering Research Grant to pursue the development of technology for a bioartificial lung, based on biomimetic design principles and microfabrication technology to build scalable respiratory assist architectures capable of high levels of gas transport in a small and compact structure. Successful development of a bioartificial lung will require several critical elements, many of which have not been realized because of difficulties in mimicking natural lung physiology due to limitations in fabrication technology. The specific aims of this proposal are directed towards these elements, including the ability to design a biomimetic structure with small priming volume and high levels of gas permeability, and the establishment of an endothelialized microvascular network to support smooth blood flow without clotting in the absence of anticoagulative agents. These goals are consistent with future clinical targets including the ability to provide patients with long-term functional respiratory assist devices that do not require extensive anticoagulation and that can be enabled in a wearable or potentially implantable format. To accomplish these goals, we aim 1) To generate a biomimetic design and utilize microfabrication technology to construct an artificial lung module comprising microvascular networks and gas-permeable membranes, and 2) To establish endothelialized microfluidic network in vascular chamber and determine gas transport and blood flow coagulation properties of bioartificial lung construct. PUBLIC HEALTH RELEVANCE: The ultimate goal of this project is to develop a medical device capable of oxygenating the blood of patients suffering from acute and chronic lung diseases and cardiopulmonary failure. Current technologies cannot be used for more than one month, require high levels of anti-clotting agents, and often damage sensitive lung tissues. This new technology will mimic the structure and function of natural, healthy lungs and provide a long- term treatment for patients suffering from acute lung injury, chronic obstructive pulmonary disease, and other conditions that cause hypoxia.