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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098220-03
Application #
8206739
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Blaisdell, Carol J
Project Start
2010-01-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$620,474
Indirect Cost
$245,565
Name
Yale University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Mendez, Julio J; Ghaedi, Mahboobe; Steinbacher, Derek et al. (2014) Epithelial cell differentiation of human mesenchymal stromal cells in decellularized lung scaffolds. Tissue Eng Part A 20:1735-46
Tsuchiya, Tomoshi; Balestrini, Jenna L; Mendez, Julio et al. (2014) Influence of pH on extracellular matrix preservation during lung decellularization. Tissue Eng Part C Methods 20:1028-36
Calle, Elizabeth A; Ghaedi, Mahboobe; Sundaram, Sumati et al. (2014) Strategies for whole lung tissue engineering. IEEE Trans Biomed Eng 61:1482-96
Sun, Huanxing; Calle, Elizabeth; Chen, Xiaosong et al. (2014) Fibroblast engraftment in the decellularized mouse lung occurs via a *1-integrin-dependent, FAK-dependent pathway that is mediated by ERK and opposed by AKT. Am J Physiol Lung Cell Mol Physiol 306:L463-75
Ghaedi, Mahboobe; Mendez, Julio J; Bove, Peter F et al. (2014) Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor. Biomaterials 35:699-710
Calle, Elizabeth A; Vesuna, Sam; Dimitrievska, Sashka et al. (2014) The use of optical clearing and multiphoton microscopy for investigation of three-dimensional tissue-engineered constructs. Tissue Eng Part C Methods 20:570-7
Ghaedi, Mahboobe; Calle, Elizabeth A; Mendez, Julio J et al. (2013) Human iPS cell-derived alveolar epithelium repopulates lung extracellular matrix. J Clin Invest 123:4950-62
Petersen, Thomas H; Calle, Elizabeth A; Colehour, Maegen B et al. (2012) Matrix composition and mechanics of decellularized lung scaffolds. Cells Tissues Organs 195:222-31
Petersen, Thomas H; Calle, Elizabeth A; Colehour, Maegen B et al. (2011) Bioreactor for the long-term culture of lung tissue. Cell Transplant 20:1117-26
Calle, Elizabeth A; Petersen, Thomas H; Niklason, Laura E (2011) Procedure for lung engineering. J Vis Exp :

Showing the most recent 10 out of 11 publications