Lung Tissue Engineering

肺组织工程

基本信息

批准号：
7765764
负责人：
LAURA E NIKLASON
金额：
$ 63.54万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7765764
关键词：
Accounting Address Adhesions Adhesives Adult Air Alveolar Alveolus American Lung Association Anatomy Architecture Area Autologous Biology Biomimetics Bioreactors Bladder Blood Blood Circulation Blood Vessels Bone Marrow Breathing Bronchi Carbon Dioxide Cartilage Cell Differentiation process Cell Therapy Cells Cessation of life Characteristics Chronic Obstructive Airway Disease Chronic lung disease Clinical Clinical Trials Complex Connective Tissue Data Detergents Differentiation and Growth Effectiveness Elements Endothelium Engineering Environment Epithelial Epithelial Cells Epithelium Event Exposure to Fibroblast Growth Factor 2 Future Gases Glean Goals Growth Growth and Development function Harvest Human In Vitro Infection Intervention Knowledge Liquid substance Location Lung Lung Transplantation Lung diseases Malignant neoplasm of lung Measurement Mechanics Microscopic Mission Mucous body substance Natural regeneration Neonatal Nutrient Organ Oxygen Pathologist Patients Perfusion Permeability Physiological Population Procedures Production Property Rattus Regenerative Medicine Research Personnel Resected Rodent Model Skin Source Staging Stem cells Sterility Structure of parenchyma of lung Support System Surface System Technology Testing Tissue Engineering Tissues Trachea Tretinoin Universities Ursidae Family Vascular Graft Vascular Permeabilities Work base cell growth embryonic stem cell improved in utero in vivo induced pluripotent stem cell insight lung injury mortality novel pressure public health relevance remediation repaired scaffold shear stress skills stem cell biology success surfactant three dimensional structure tissue regeneration vascular tissue engineering

项目摘要

DESCRIPTION (provided by applicant): Lung diseases, including lung cancer and chronic lung diseases such as chronic obstructive pulmonary disease, together account for some 280,000 deaths annually (American Lung Association). Contributing to this mortality is the fact that remediation of all forms of lung disease is hampered by the limited ability of lung to regenerate. Hence, lung tissue that is damaged by degeneration or infection, or lung tissue that is surgically resected, is not functionally replaced in vivo. Currently, the only way to replace lung tissue is to perform lung transplantation, an expensive procedure that is achieves only a 10% survival at 10 years, and one that is hampered by a severe shortage of organs. Over the past 3 years, we have worked to address some fundamental challenges in lung tissue engineering. In order to produce a lung scaffold that has suitable geometry and mechanics for lung regeneration, we have developed technologies to decellularize entire lung tissues. We have shown that these acellular lung matrices retain the gross mechanical properties of the original lung tissues, and provide outstanding support for the adhesion and growth of epithelial and vascular cells. We have developed a novel, "biomimetic" bioreactor that provides for long-term sterile lung culture, circulation of nutrient medium through the lung vascular compartment, and "breathing" of nutrient medium into the airway. As a cell source to repopulate the acellular lung matrix, we have utilized syngeneic neonatal rat lung cells, as these cells show significant potential for growth inside the developing lung. We have made substantial and exciting progress in this work, and have shown the feasibility of regenerating many characteristics of lung tissue, but there remain several important issues that must be studied and addressed before the functionality of such lung tissues can be tested in vivo. Most fundamentally, in order to exchange gas, the lung must comprise sufficient alveolar diffusional surface area, must be populated with functional and differentiated epithelial cell subsets at correct anatomic locations in the alveoli and elsewhere, and must be invested with a functional microvasculature that withstands physiological perfusion pressures and does not leak fluid into the alveolar compartment. In this proposal, we will study and refine the lung tissue engineering system in order to address each of these issues and advance the central mission of functional lung regeneration, which is the capacity for effective gas exchange. We hypothesize that the acellular lung matrix, when suitably re-populated with lung epithelium and vascular cells, will support the growth and differentiation of these cells and will produce a tissue that is effective for gas exchange, based upon in vitro measurements. PUBLIC HEALTH RELEVANCE: Lung diseases, including lung cancer and chronic lung diseases such as chronic obstructive pulmonary disease, together account for some 280,000 deaths annually. Over the past 3 years, we have worked to address some fundamental challenges in lung tissue engineering in order to provide lung tissue replacements for patients with lung disease. We hypothesize that an acellular lung matrix, when suitably re-populated with lung epithelium and vascular cells, will support the growth and differentiation of these cells and will produce a tissue that is effective for functional gas exchange.

描述（申请人提供）：包括肺癌和慢性肺部疾病，例如慢性阻塞性肺部疾病，每年约为280,000例死亡（美国肺协会）。导致这种死亡率的原因是，所有形式的肺部疾病的修复受到肺部再生能力有限的能力受到阻碍。因此，在体内未能替代因变性或感染而受损的肺组织或手术切除的肺组织。当前，替代肺组织的唯一方法是进行肺移植，这是一种昂贵的程序，在10年时仅可实现10％的生存，并且由于严重的器官短缺而受到阻碍。在过去的三年中，我们一直在解决肺组织工程方面的一些根本挑战。为了产生具有合适的几何形状和肺部再生力学的肺支架，我们开发了整个肺组织的技术。我们已经表明，这些细胞的肺部基质保留了原始肺组织的总机械性能，并为上皮和血管细胞的粘附和生长提供了出色的支持。我们已经开发了一种新型的“仿生”生物反应器，可提供长期无菌肺培养，营养培养基通过肺血管室的循环以及营养培养基的“呼吸”到气道中。作为重新填充细胞肺基质的细胞源，我们使用了同性新生儿大鼠肺肺细胞，因为这些细胞在发育中的肺内显示出显着的生长潜力。我们在这项工作中取得了重大和令人兴奋的进步，并显示了再生肺组织许多特征的可行性，但是在可以在体内测试此类肺组织功能之前，仍然存在一些重要问题。从根本上，为了交换气体，肺必须包括足够的肺泡扩散表面积，必须在肺泡和其他地方的正确解剖位置的功能和分化的上皮细胞亚群中填充，并且必须通过承受能够承受物理灌注压力的功能性微血管造影进行投资。在此提案中，我们将研究和完善肺组织工程系统，以解决这些问题中的每一个，并促进功能性肺部再生的核心使命，这是有效气体交换的能力。我们假设细胞细胞肺基质在适当地用肺上皮和血管细胞重新填充时，将支持这些细胞的生长和分化，并会根据体外测量产生有效的气体交换的组织。公共卫生相关性：肺癌，包括肺癌和慢性肺部疾病，例如慢性阻塞性肺部疾病，每年约为280,000例死亡。在过去的三年中，我们一直致力于解决肺组织工程中的一些基本挑战，以便为肺部疾病患者提供肺组织替代。我们假设，如果适当地用肺上皮和血管细胞重新填充细胞肺基质，将支持这些细胞的生长和分化，并会产生有效的功能性气体交换的组织。