1056 O’NEILL ET AL Ann Thorac SurgHUMAN VS PORCINE LUNG ECM 2013;96:1046–56

GENERALTHORACIC

We’re going to have to comeupwith amultiflask system to growcells on a large scale to be able to deliver those cells to repopulate alung, which is why we go for repopulating a lobe first—youknow: go that way, evaluate function, and then step up further.

DR DANIEL BOFFA (New Haven, CT): Have you ever tried thisstrategy using the scaffold of end-stage lungs to see if just putting

� 2013 by The Society of Thoracic SurgeonsPublished by Elsevier Inc

stem cells into damaged matrix or architecture has any restor-ative capabilities?

DR SINGH: We have not gotten lungs and tried that. But we’rein the process of using a similar method for acute lung injury,and we hope that we’d be able to repair those lungs and evaluatethose in our next few apparatus, but we have not tried it yet.

INVITED COMMENTARY

Lung transplantation remains the only definitive treat-ment for end-stage lung disease. However, its clinicaleffect is limited by donor organ shortage, the need forimmunosuppression, and chronic rejection leading tograft failure. As of April 2013, 1,690 Americans werewaiting for a donor lung, and nearly half of them will bewaiting for more than 2 years [1]. Patient survival andgraft function after lung transplantation arecontinuously improving, but still reach only 50% to 60%at 5 years after transplantation [2]. A bioartificial lungderived from the patient’s cells that can be implantedsimilar to a donor organ could become a theoreticalternative to allotransplantation.

Tissue engineering relies on the concept of using anextracellular matrix scaffolds to place cells into theirphysiologic 3-dimensional context, thereby enabling theformation of functional grafts for implantation [3]. Oneapproach toward the engineering or “regeneration” offunctional lung grafts for transplantation is based onnative extracellular matrix scaffolds. These can begenerated by perfusion decellularization of cadavericorgans, a process that ideally removes all of the cells andleaves only extracellular matrix components behind. Insmall-animal experiments, such whole organ scaffoldshave been successfully repopulated with vascular andepithelial cells and matured to functional lung grafts [4, 5].In orthotopic transplant experiments, these grafts weremaintained by the recipient’s blood supply and functionedfor several days in vivo [6].

As a next step towardmoving this technology closer to apotential clinical validation, human-scale lung scaffoldshave to be generated. In the present report, O’Neilland colleagues [7] compare different decellularizationprotocols for human and porcine lung sections. Theauthors did not perfuse the cadaveric lung samplesbut submerged lung slices in different chemicals toexamine composition, mechanical properties, andbiocompatibility of the resulting tissue. Acellular scaffoldslices allowed for cell attachment and survival in a 2-dimensional culture system, suggesting nontoxicity ofthe native extracellular matrix. Importantly, human cellsthrived equally on porcine and human matrix sections, apromising finding considering the nearly unlimitedsupply of porcine lungs not only as a test bed for organregeneration but also as potential “off-the-shelf” organscaffolds. In this data set, all tested decellularizationprotocols led to a decrease in elastin content andchanges in mechanical properties, which is consistentwith other publications, and a detail that warrants

further investigations given the physiologic need forelasticity during ventilation [8, 9].As the authors suggest, the end goal of decellularizing

human or porcine lungs is to obtain native-like scaffoldsfor organ engineering. The use of perfusion as a deliverymethod for the tested decellularization agents may pro-vide the unique possibility to maintain the entire organ’sarchitecture, including a hierarchic vasculature and air-ways, while creating a biocompatible scaffold material forcell seeding. Scaling the data presented in their study towhole lungs of human size will provide further insightinto the choice of ideal decellularization protocol andhelp to assess the translational potential of lung engi-neering based on native extracellular matrix.

Harald C. Ott, MD, PD

Department of SurgeryDivision of Thoracic SurgeryMassachusetts General HospitalHarvard Medical SchoolHarvard Stem Cell Institute185 Cambridge St, CPZN 4812Boston, MA 02114e-mail: hott@partners.org

References

1. OPTN. Organ Procurement and Transplantation NetworkWebsite. Vol. 2012. Available at: http://optn.transplant.hrsa.gov/data/. Accessed April 1, 2013.

2. United States Organ Transplantation, OPTN & SRTR AnnualData Report 2011. U.S. Department of Health and HumanServices, Health Resources and Service Administration.December 2012. Available at: http://srtr.transplant.hrsa.gov/annual_reports/2011. Accessed April 1, 2013.

3. LangerR,Vacanti JP.Tissueengineering. Science1993;260:920–6.4. Ott HC, Clippinger B, Conrad C, et al. Regeneration and

orthotopic transplantation of a bioartificial lung. Nat Med2010;16:927–33.

5. Petersen TH, Calle EA, Zhao L, et al. Tissue-engineered lungsfor in vivo implantation. Science 2010;329:538–41.

6. Song JJ, Kim SS, Liu Z, et al. Enhanced in vivo function ofbioartificial lungs in rats. Ann Thorac Surg 2011;92:998–1006.

7. O’Neill JD, Anfang R, Anandappa A, et al. Decellularization ofhuman and porcine lung tissues for pulmonary tissue engi-neering. Ann Thorac Surg 2013;96:1046–56.

8. Petersen TH, Calle EA, Colehour MB, Niklason LE. Matrixcomposition and mechanics of decellularized lung scaffolds.Cells Tissues Organs 2012;195:222–31.

9. Wallis JM, Borg ZD, Daly AB, et al. Comparative assessment ofdetergent-based protocols for mouse lung de-cellularizationand re-cellularization. Tissue Eng Part C Methods 2012;18:420–32.

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