Commentary on the advance of organ regeneration for transplantation.
Last week an article appeared in Wired magazine about a recently paper published in Science Translational Medicine, “Production and transplantation of bioengineered lung into a large-animal model”. The Transplantation Society asked one of our own experts, Christopher Burlak from the University of Minnesota, to provide our readership with a commentary regarding the advancement of organ regeneration for transplantation.
- Bioengineers are Closer Than Ever To Lab-Grown Lungs. Wired – August 1, 2018.
- Production and transplantation of bioengineered lung into a large-animal model. Joan Nichols et al . Science Translational Medicine 01 Aug 2018
Commentary on the advance of organ regeneration for transplantation.
Christopher Burlak, Associate Professor of Surgery and Scientific Program Director of the Schulze Diabetes Institute at the University of Minnesota.
One of the most challenging organs to transplant is the lung. Because of a complex mucosal network riddled with immune cells, transplanted lungs are very sensitive to rejection during allo- or xeno-transplantation. If one could, however, grow a lung from cells of the future recipient, perhaps immune mediated rejection would not be an issue. The challenges of growing bioengineered organs are not trivial, as described by Dr. Joan Nichols and her colleagues in the recently published article in Science Translational Medicine titled, “Production and transplantation of bioengineered lung into a large-animal model”. Mr. Robbie Gonzalez has written a commentary for the magazine Wired that highlights their scientific achievement. I was inspired by Mr. Gonzalez’s commentary and reached out to Dr. Nichols to discuss the science, the challenges, and what comes next.
This project started 15 years ago and was a step wise approach. First, they needed to learn how to isolate the primary cells from viable lung tissue. Second, they needed to develop methods to create an appropriate scaffold. Last of all they designed the process to produce tissues repeatedly. They published the production of whole human scaffolds in 2013 and the first pig transplant was done on 2/5/15. Six lungs were produced in bioreactors but only 4 were transplanted. This was a feasibility pilot to show that the method of lung production was appropriate and that the animals would survive. Transplants were spaced weeks apart to allow time to prepare scaffolds and to allow the team time to discuss the procedures for management of the transplant. The last animal was done 3/7/16. That gave them a year to do analysis of histology, electron microscopy microvascular development, microbiome analysis, genomic and proteomic assessments. The first version of the manuscript was submitted to Science Translational Medicine in October of 2017, was returned for major editing and then finally accepted by the journal 2 months ago.
This work was accomplished by a dedicated group of basic scientists and clinicians that worked together try to solve a clinical problem regarding the lack of donated organs for people that need them. Dr. Nichols pointed out that many people played indispensable roles in support of this work. Dr. Nichols met Joaquin Cortiella MD, her research partner in 2001. He had a background in scaffolds and development of tissue engineered trachea and managed the transplant team. She met Jason Sakamoto, a nanoparticle specialist, in 2006 and Saverio La Francesca, the lead surgeon, in 2011 at scientific meetings. They had a very small budget and none of the staff were paid for their efforts. All of them took a vacation day when they performed a surgery. Dave Christiani at Harvard did the genome analysis, Gregg Hendricks at U Mass performed and analyzed the electron microscopy, Rich Pyles did the microbiome work. All three of these researchers did the work at cost or paid for the reagents/staff costs themselves. At the end of an enlightening conversation I was awestruck at the generosity of time and effort that Dr. Nichols and her colleagues put forth to complete this work.
One of the greatest hurdles throughout the 15-year course of this project at the lab at UTMB was frequently fabricating what was need from existing equipment or modify systems available commercially to fit their needs. The second big hurdle was funding. This is high risk work and federal grant agencies tend to be conservative in terms of funding research (as they should be). They have had some modest federal funding to model the lung and to engineer an ex vivo immune system but not to engineer lung for transplantation. Further preclinical studies are needed to prove that the bioengineered lung tissue can fully support oxygenation and gas exchange. Their immediate goal is to do a study where animals receiving a single bioengineered lung transplant would survive for 6 months to a year. After that time, Dr. Nichols and her colleagues will evaluate the ability of the matured bioengineered tissue to fully support the oxygen needs of the animal. These are the amazing procedures that they have developed for today’s science and with their mastery of bio-printing and knowledge of stem cell behavior they will likely develop better methods of bioengineering organs in the future.
 Oan E. Nichols, Saverio La Francesca, Jean A. Niles, Stephanie P. Vega, Lissenya B. Argueta, Luba Frank, David C. Christiani, Richard B. Pyles, Blanca E. Himes, Ruyang Zhang, Su Li, Jason Sakamoto, Jessica Rhudy, Greg Hendricks, Filippo Begarani, Xuewu Liu, Igor Patrikeev, Rahul Pal, Emiliya Usheva, Grace Vargas, Aaron Miller, Lee Woodson, Adam Wacher, Maria Grimaldo, Daniil Weaver, Ron Mlcak, Joaquin Cortiella.Science Translational Medicine 01 Aug 2018: Vol. 10, Issue 452, eaao3926 DOI: 10.1126/scitranslmed.aao3926
 Robbie Gonzalez. Bioengineers are Closer Than Ever To Lab-Grown Lungs. Wired – August 1, 2018.
Publications directly related to this project:
Nichols JE, Niles J, Riddle M, Vargas G, Schilagard T, Ma L, Edward K, Lafrancesca S, Sakamoto J, Vega S, Ogedegbe M, Mlcak R, Deyo D, Woodson L, McQuitty C, Lick S, Beckles D, Melo E, Cortiella J. Production and Assessment of Decellularized Pig and Human Lung Scaffolds.Tissue Eng Part A. 2013 May 2.
Nichols JE, ,LaFrancesca S, Vega SP, Niles JA, Argueta LB, Riddle M, Sakamoto J, Vargas G, Pal R, Woodson L, Seanor D, Campbell G, Schnadig V, Rhudy J, Cortiella J New Life for Old Lungs “Whole Human Lung Bioengineering: Production and Assessment of a Bioengineered Pediatric Lung” Journal of Tissue Engineering and Regenerative Medicine e-published, January, 2016.
Related publications that led to this work :
Kotov NA, Liu Y, Wang S, Cumming C, Eghtedari M, Vargas G, Motamedi M, Nichols J, Cortiella J: Inverted colloidal crystals as three-dimensional cell scaffolds. Langmuir. 2004 Sep 14;20(19):7887-92. 2004.
Nichols JE, Cortiella J, Lee J, Niles JA, Cuddihy M, Wang S, Bielitzki J, Cantu A, Mlcak R, Valdivia E, Yancy R, McClure ML, Kotov NA.In vitro analog of human bone marrow from 3D scaffolds with biomimetic inverted colloidal crystal geometry. Biomaterials. 2009 Feb;30(6):1071-9.
Cortiella J, Niles J, Cantu A, Brettler A, Pham A, Vargas G, Winston S, Wang J, Walls S, Nichols JE. Influence of Acellular Natural Lung Matrix on Murine Embryonic Stem Cell Differentiation and Tissue Formation. Tissue Eng Part A. 2010 Apr 21.
Nichols JE, Niles JA and Cortiella J. Journal of Biological Chemistry. Production and Utilization of acellular lung scaffolds for tissue engineering. Journal of Biological Chemistry. 2012. Accepted February 2012. E-published ahead of printing.
Luque T, Melo E, Garreta E, Cortiella J, Nichols J, Farré R, Navajas D.
Local micromechanical properties of decellularized lung scaffolds measured with atomic force microscopy.Acta Biomater. 2013 Jun;9(6):
Nichols JE, Niles JA, Dewitt D, Prough D, Parsley M, Vega S, Cantu A, Lee E, Cortiella J.Neurogenic and neuro-protective potential of a novel subpopulation of peripheral blood-derived CD133+ ABCG2+CXCR4+ mesenchymal stem cells: development of autologous cell-based therapeutics for traumatic brain injury. Stem Cell Res Ther. 2013 Jan 6;4(1):3.
Fernandez-Moure JS, Van Eps JL, Rhudy JR, Cabrera J, Acharya GS, Tasciotti E, Sakamotos, Nichols JE. Porcine acellular lung matrix for wound healing and abdominal wall reconstruction: a pilot study. Tissue Engineering and Regenerative Medicine, 2016, vol7; p1-8.
Melo E, Garreta E, Luque T, Cortiella J, Nichols J, Navajas D, Farré R.Effects of the Decellularization Method on the Local Stiffness of Acellular Lungs.Tissue Eng Part C Methods. 2013 Nov 6.
Farina M, Chua CYX, Ballerini A, Thekkedath U, Alexander JF, Rhudy JR, Torchio G, Fraga D, Pathak RR, Villanueva M, Shin CS, Niles JA, Sesana R, Demarchi D, Sikora AG, Acharya GS, Gaber AO, Nichols JE, Grattoni A. Transcutaneously refillable, 3D-printed biopolymeric encapsulation system for the transplantation of endocrine cells. Biomaterials. 2018 Sep;177:125-138.