Perspective: Pulmonary Tissue Engineering Advance Opens New Frontiers

Drs. Wagner and Griffith compare and contrast the new paradigm to other approaches for replacing lung function and highlight the intriguing potential for the new technology.

The current issue of Science magazine features the medicine perspectives piece entitled “Reconstructing the Lung.” McGowan Institute for Regenerative Medicine deputy director William Wagner, PhD (pictured top), Professor of Surgery, Bioengineering and Chemical Engineering at the University of Pittsburgh, Director of Thrombosis Research for the Artificial Heart and Lung Program, and Deputy Director of the NSF Engineering Research Center on “Revolutionizing Metallic Biomaterials,” and Bartley Griffith, MD (pictured bottom), Professor of Surgery, Chief, Division of Cardiac Surgery, and Director, Heart and Lung Transplantation, University of Maryland, are co-authors. The article provides context and background to the work of Yale University scientists who report in the same issue an important first step in regenerating fully functional lung tissue that can exchange gas, as well as for a similar report in Nature Medicine from Harvard Medical School and Boston University.

Per their article published in Science, “Tissue-engineered lungs for in vivo implantation,” and reported by Science Daily, the Yale team took adult rat lungs and first removed their existing cellular components, preserving the extracellular matrix and hierarchical branching structures of the airways and vascular system to use later as scaffolds for the growth of new lung cells. They then cultured a combination of lung-specific cells on the extracellular matrix, using a novel bioreactor designed to mimic some aspects of the fetal lung environment. Under the fetal-like conditions of the bioreactor, the cells repopulated the decellularized matrix with functional lung cells. When implanted into rats for short intervals of time (45-120 minutes), the engineered lungs exchanged oxygen and carbon dioxide similarly to natural lungs.

The Massachusetts researchers described their findings in the Nature Medicine article, “Regeneration and orthotopic transplantation of a bioartificial lung.” As reported by Reuters, Harald Ott and colleagues at Massachusetts General Hospital and Harvard Medical School in Boston removed the cells from rat lungs to leave a scaffolding or matrix. They soaked these in a bioreactor along with several types of human lung cells, creating pressures to simulate the pressure inside a body to make the lung workable and flexible. The cells took up residence and grew into different tissue sub-types seen in a lung, Ott's team reported. When transplanted into rats, the lung tissue worked for about six hours, although imperfectly. The researchers said it may be possible to try the experiment with more immature stem cells, the body's master cells. These could include embryonic stem cells, which can mature into any cell type in the body, or induced pluripotent stem cells -- ordinary cells with genes added to make them behave like flexible stem cells.

Drs. Wagner and Griffith compare and contrast the new paradigm to other approaches for replacing lung function and highlight the intriguing potential for the new technology. They also note that “although these recent reports open possibilities for treating pulmonary failure and studying the mechanisms underlying cell–extracellular matrix interactions, many issues remain to be addressed. Identifying cell sources from the patient that are most effective in repopulating the decellularized lung, achieving a sound blood-gas barrier and a completely endothelialized blood pathway, and providing long-term evaluation of cellularization and differentiation in situ are considerations. The use of extracellular matrix for connective tissue repair is effective in many applications, but there can be failures associated with tissue remodeling that result in mechanically inadequate structures. How will the lung extracellular matrix ultimately be remodeled? If replacement lung tissue is inappropriately fibrous or weak, long-term outcomes will be insufficient. Also, the level of phenotypic organ recapitulation that can be achieved and is functionally adequate remains open. Like the native organ, will the regenerated lung recruit vascular beds that will permit increasing blood flows with low resistance? The organ decellularization paradigm has opened a breach where multidisciplinary teams of biologists, clinicians, and engineers can explore new ways to engineer complex tissues. The next generation of artificial or bio-hybrid organs may provide temporary support for patients while patient-specific regenerative solutions are prepared and implanted.”

Illustration: McGowan Institute for Regenerative Medicine and University of Maryland.

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Science Daily (06/24/10)

Reuters (07/13/10)

Bio: Dr. William Wagner

Bio: Dr. Bartley Griffith

Abstract (Reconstructing the Lung. William R. Wagner and Bartley P. Griffith. Science 30 July 2010: Vol. 329, No. 5991, pp. 520 – 522)

Abstract (Regeneration and orthotopic transplantation of a bioartificial lung. Harald C Ott, Ben Clippinger, Claudius Conrad, Christian Schuetz, Irina Pomerantseva, Laertis Ikonomou, Darrell Kotton & Joseph P Vacanti. Nature Medicine, Published online 13 July 2010)

Abstract (Tissue-Engineered Lungs for in Vivo Implantation. Thomas H. Petersen, Elizabeth A. Calle, Liping Zhao, Eun Jung Lee, Liqiong Gui, MichaSam B. Raredon, Kseniya Gavrilov, Tai Yi, Zhen W. Zhuang, Christopher Breuer, Erica Herzog, and Laura E. Niklason. Science Express, online June 24, 2010; Science 30 July 2010: Vol. 329, No. 5991, pp. 538 - 541)