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End organ failure is the leading health care challenge in the Western World. Nearly six million Americans suffer from heart failure with about 550,000 new cases diagnosed annually; 25 million Americans suffer from chronic obstructive pulmonary disease (COPD) with an estimated 12 million new yearly diagnoses; and 530,000 Americans suffer from end stage renal disease.
Currently, organ transplantation is the only potentially curative therapy available. However, its outcomes are limited by shortage of donor organs and the side effects of harsh immunosuppressive treatments designed to prevent the body from rejecting the organ.
The Ott Laboratory is investigating tissue engineered organs as an alternative to donor transplantation. The goal is to create various whole organs that are derived from a patient’s own cells, and transplanting them into patients, avoiding the need for a donor. This process could address the donor shortages and eliminate the need for immunosuppressive drugs.
The Ott Laboratory developed and first reported a novel technique to isolate the whole organ extracellular matrix (ECM) scaffolds by a process called perfusion decellularization.
In preliminary studies, these ECM scaffolds supported engraftment of specialized cells to form viable and functional hearts, lungs, kidneys, pancreas, and composite tissue that could be transplanted and function in the body.
Harald C. Ott, MD Thoracic Surgeon, Massachusetts General Hospital Associate Professor of Surgery, Harvard Medical School Charles and Sara Fabrikant MGH Research Scholar
Sarah E. Gilpin, PhD Instructor in Surgery
Jacques P. Guyette, PhD Instructor in Surgery
Tong Wu, PhD Research Fellow in Surgery
Xi (Charlie) Ren, PhD Instructor in Surgery
Lisa M. Fitzgerald, PhD Lab Manager and Administrative Director
Philipp Moser, MD Research Fellow in Surgery
Kentaro Kitano, MD, PhD Research Fellow in Surgery
Daniele Evangelista Leite da Silva Research Assistant
Mattia F.M. Gerli, PhD Research Fellow
Dana M. Schwartz, MD Clinical Fellow in Surgery
Miyuki Sakuma, MD, PhD Research Fellow in Anesthesia
The human heart project in the Ott Laboratory aims to engineer a bioartificial heart for clinical application and transplantation. The lab uses the native cardiac extracellular matrix (ECM) to support cardiac cell types that work synergistically to generate sustainable ventricular pump function. This project draws from expertise in stem cell biology, developmental biology, physiology, cardiology, and biomedical engineering in pursuit of creating a bioartificial heart as an alternative treatment option for patients in need of heart transplants.
The lung project focuses on deriving a functioning, transplantable human lung by combining native extracellular matrix scaffolds and novel recellularization approaches. This project combines expertise in stem cell and developmental biology, molecular biology, lung repair, and bioengineering, and seeks to contribute to developing personalized medicine in whole lung regeneration.
Approximately 100,000 individuals in the United States are awaiting kidney transplantation, and 400,000 individuals are living with end-stage kidney disease requiring hemodialysis. The creation of a transplantable, bioengineered kidney that can permanently replace kidney function could address this severe organ shortage and, at the same time, allow recipients to avoid the side effects of immunosuppressant drugs.
The composite tissue project seeks to engineer complex soft tissue grafts, such as a whole forearm, for the treatment of devastating injuries.
The current treatment of benign and malignant tracheal disorders involves surgically removing the affected area and reconnecting the remaining tissue. This procedure is only possible if the length of the diseased segment is less than half of the trachea in adults or a third of the trachea in children. Conventional allotransplantation of a donor tracheal segment is technically feasible, but requires lifelong immunosuppression and can result in infection, cell death and the failure of the transplant due to improper revascularization and continuous contact with the external environment.
Lung cancer is the leading cause of cancer-related deaths in the United States and represents approximately 14 percent of all new cancer diagnoses. Survival rates have changed little in recent decades in spite of new chemotherapeutic and targeted molecular agents and advances in surgical treatment. Our lung cancer research efforts aim to gain a better understanding of human lung cancer biology by establishing biomimetic three-dimensional culture models that more closely resemble the microenvironment that cancer cells experience in vivo.
These models have the potential to provide new strategies for the treatment of lung cancer and to speed the translation of these strategies into clinical care. This project benefits from expertise in molecular biology, cancer biology, imaging and biomedical engineering.
Regenerative potential of human airway stem cells in lung epithelial engineering. Gilpin SE, Charest JM, Ren X, Tapias LF, Wu T, Evangelista-Leite D, Mathisen DJ, Ott HC. Biomaterials. 2016 Nov;108:111-9.
An Official American Thoracic Society Workshop Report 2015. Stem Cells and Cell Therapies in Lung Biology and Diseases. Wagner DE, Cardoso WV, Gilpin SE, Majka S, Ott H, Randell SH, Thébaud B, Waddell T, Weiss DJ; ATS Subcommittee on Stem Cells and Cell Therapies. Annals of the American Thoracic Society. 2016 Aug;13(8).
Bioengineering Lungs for Transplantation. Gilpin SE, Charest JM, Ren X, Ott HC. Thorac Surg Clin. 2016 May;26(2):163-71.
Bioengineering Human Myocardium on Native Extracellular Matrix. Guyette JP, Charest JM, Mills RW, Jank BJ, Moser PT, Gilpin SE, Gershlak JR, Okamoto T, Gonzalez G, Milan DJ, Gaudette GR, Ott HC. Circ Res. 2015 Oct 26. doi: 10.1161/CIRCRESAHA.115.306874.
Engineering pulmonary vasculature in decellularized rat and human lungs. Ren X, Moser PT, Gilpin SE, Okamoto T, Wu T, Tapias LF, Mercier FE, Xiong L, Ghawi R, Scadden DT, Mathisen DJ, Ott HC. Nat Biotechnol. 2015 Sep 14. doi: 10.1038/nbt.3354. [Epub ahead of print]
Perfusion Decellularization of Discarded Human Kidneys: A Valuable Platform for Organ Regeneration. Ott HC. Transplantation. 2015 Sep;99(9):1753. doi: 10.1097/TP.0000000000000810.
Assessment of Proliferation and Cytotoxicity in a Biomimetic Three-Dimensional Model of Lung Cancer. Tapias LF, Gilpin SE, Ren X, Wei L, Fuchs BC, Tanabe KK, Lanuti M, Ott HC. Ann Thorac Surg. 2015 Aug:100(2):414-21. doi: 10.1016/j.athoracsur.2015.04.035. Epub 2015 Jul 2.
Engineered composite tissue as a bioartificial limb graft. Jank BJ, Xiong L, Moser PT, Guyette JP, Ren X, Cetrulo CL, Leonard DA, Fernandez L, Fagan SP, Ott HC. Biomaterials. 2015 August;61:246-256. doi: 10.1016/j.biomaterials.2015.04.051
Ex vivo non-invasive assessment of cell viability and proliferation in bio-engineered whole organ constructs. Ren X, Tapias LF, Jank BJ, Mathisen DJ, Lanuti M, Ott HC. Biomaterials. 2015 June;52:103-112. doi: 10.1016/j.biomaterials.2015.01.061. Epub 2015 Feb 21.
Using Nature’s Platform to Engineer Bio-Artificial Lungs. Gilpin SE, Ott HC. Ann Am Thorac Soc. 2015 Mar;12 Suppl 1:S45-9. doi: 10.1513/AnnalsATS.201408-366MG
Design and validation of a clinical-scale bioreactor for long-term isolated lung culture. Charest JM, Okamoto T, Kitano K, Yasuda A, Gilpin SE, Mathisen DJ, Ott HC. Biomaterials. 2015 June;52:79-87. doi: 10.1016/j.biomaterials.2015.02.016. Epub 2015 Feb 23.
Recellularization of organs: what is the future for solid organ transplantation? Moser PT, Ott HC. Curr Opin Organ Transplant. 2014 Dec;19(6):603-9. doi: 10.1097/MOT.0000000000000131.
Bioengineering kidneys for transplantation. Madariaga ML, Ott HC. Semin Nephrol. 2014 Jul;34(4):384-93. doi: 10.1016/j.semnephrol.2014.06.005. Epub 2014 Jun 13.
Enhanced lung epithelial specification of human induced pluripotent stem cells on decellularized lung matrix. Gilpin SE, Ren X, Okamoto T, Guyette JP, Mou H, Rajagopal J, Mathisen DJ, Vacanti JP, Ott HC. Ann Thorac Surg. 2014 Nov;98(5):1721-9. doi: 10.1016/j.athoracsur.2014.05.080. Epub 2014 Aug 19.
Perfusion decellularization of whole organs. Guyette JP, Gilpin SE, Charest JM, Tapias LF, Ren X, Ott HC. Nat Protoc. 2014 Jun;9(6):1451-68. doi: 10.1038/nprot.2014.097. Epub 2014 May 29.
On the road to bioartificial organs. Ren X, Ott HC. Pflugers Arch. 2014 Oct;466(10):1847-57. doi: 10.1007/s00424-014-1504-4. Epub 2014 Apr 2.
Decellularized scaffolds as a platform for bioengineered organs. Tapias LF, Ott HC. Curr Opin Organ Transplant. 2014 Apr;19(2):145-52. doi: 10.1097/MOT.0000000000000051.
Perfusion decellularization of human and porcine lungs: bringing the matrix to clinical scale. Gilpin SE, Guyette JP, Gonzalez G, Ren X, Asara JM, Mathisen DJ, Vacanti JP, Ott HC. J Heart Lung Transplant. 2014 Mar;33(3):298-308.
Injury-Specific Ex Vivo Treatment of the Donor Lung: Pulmonary Thrombolysis Followed by Successful Lung Transplantation. Machuca TN, Hsin MK, Ott HC, Chen M, Hwang DM, Cypel M, Waddell TK, Keshavjee S. Am J Respir Crit Care Med. 2013 Oct 1;188(7):878-880.
Invited commentary. Ott HC. Ann Thorac Surg. 2013 Sep;96(3):1056. doi: 10.1016/j.athoracsur.2013.04.067.
Cell therapy for lung diseases. Report from an NIH-NHLBI workshop, November 13-14, 2012. Matthay MA, Anversa P, Bhattacharya J, Burnett BK, Chapman HA, Hare JM, Hei DJ, Hoffman AM, Kourembanas S, McKenna DH, Ortiz LA, Ott HC, Tente W, Thébaud B, Trapnell BC, Weiss DJ, Yuan JX, Blaisdell CJ. Am J Respir Crit Care Med. 2013 Aug 1;188(3):370-5. doi: 10.1164/rccm.201303-0522WS.
Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC. Nat Med. 2013 May;19(5):646-51. doi: 10.1038/nm.3154. Epub 2013 Apr 14.
Perspectives on whole-organ assembly: moving toward transplantation on demand. Soto-Gutierrez A, Wertheim JA, Ott HC, Gilbert TW. J Clin Invest. 2012; 122(11):3817–3823 doi:10.1172/JCI61974.
Engineering tissues for children: building grafts that grow. Ott HC. J Clin Invest. 2012; 122(11):3817–3823 doi:10.1172/JCI61974.
Human lung cancer cells grown on acellular rat lung matrix create perfusable tumor nodules. Mishra DK, Thrall MJ, Baird BN, Ott HC, Blackmon SH, Kurie JM, Kim MP. Ann Thorac Surg. 2012 Apr;93(4):1075-81. Epub 2012 Mar 2.
Bioartificial tissues and organs: are we ready to translate? Ott HC, Mathisen DJ. Lancet. 2011 Dec 10;378(9808):1977-8. Epub 2011 Nov 24. No abstract available.
Pulmonary resection of metastatic sarcoma: prognostic factors associated with improved outcomes. Kim S, Ott HC, Wright CD, Wain JC, Morse C, Gaissert HA, Donahue DM, Mathisen DJ, Lanuti M. Ann Thorac Surg. 2011 Nov;92(5):1780-6; discussion 1786-7. doi: 10.1016/j.athoracsur.2011.05.081. Epub 2011 Oct 31.
Bioartificial lung engineering. Song JJ, Ott HC. Am J Transplant. 2012 Feb;12(2):283-8. doi: 10.1111/j.1600-6143.2011.03808.x. Epub 2011 Oct 25.
Enhanced in vivo function of bioartificial lungs in rats. Song JJ, Kim SS, Liu Z, Madsen JC, Mathisen DJ, Vacanti JP, Ott HC. Ann Thorac Surg. 2011 Sep;92(3):998-1005; discussion 1005-6.
Organ engineering based on decellularized matrix scaffolds. Song JJ, Ott HC. Trends Mol Med. 2011 Aug;17(8):424-32. Epub 2011 Apr 21. Review.
Regeneration and orthotopic transplantation of a bioartificial lung. Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, Kotton D, Vacanti JP. Nat Med. 2010 Aug;16(8):927-33. Epub 2010 Jul 13.
Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Conrad C, Niess H, Huss R, Huber S, von Luettichau I, Nelson PJ, Ott HC, Jauch KW, Bruns CJ. Circulation. 2009 Jan 20;119(2):281-9. Epub 2008 Dec 31.
Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Nat Med. 2008 Feb;14(2):213-21. Epub 2008 Jan 13.
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