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Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, 100 Technology Dr, Suite 200, Pittsburgh, PA 15219
(Email: badylaks{at}upmc.edu; gilberttw{at}upmc.edu).
Resection of tracheal tissue that spans more than approximately 6 cm in adults is not possible because of the lack of suitable artificial devices or replacement tissue that can perform the functions necessary to sustain life. An article by Seguin and colleagues [1] describes efforts to replace a 7-cm segment of the cervical trachea in a sheep model with the use of an aortic allograft; an approach that has been successfully used in a small number of selected human patients in France. Although the results of the present animal study are not entirely successful, the article does bring to the forefront some of the key issues that need to be addressed as the use of biologic tissue scaffolds for functional airway replacement receives increased attention. Based on the numerous failed efforts to replace major airways with artificial materials and from the adverse tissue inflammatory responses elicited by the various available stents, it seems obvious that any long-term solution to this problem must involve an approach in which the fundamental principles of biology for this anatomic location are used to the advantage rather than disadvantage of the patient.
Several key issues are addressed in the Sequin study including the donor tissue source, the preparation of the biologic source tissue, and the in-vivo remodeling events that direct the host cellular infiltrate. Both the present pre-clinical animal study, and the recent clinical report of successful left main bronchus replacement with allogeneic decellularized tracheal tissue [2] suggest that a biologic scaffold material that supports constructive remodeling by the recipient is key to long-term clinical success. Questions that remain to be answered include the optimal tissue source of the biologic scaffold material, the optimal method of preservation so that "off the shelf" use is made practical, and the need for autologous seeding of the scaffold with cells prior to implantation.
It seems that autologous tissue is not required as the starting scaffold material as long as nonself cellular elements are either eliminated through decellularization or devitalized to minimize an adverse immunologic response. Many tissue sources deserve investigation as the starting scaffold material including trachea, aorta, and the existing commercially available biologic materials, such as human dermis, porcine small intestinal submucosa, porcine urinary bladder, or pericardium. The limitation of most of these materials is inadequate mechanical integrity to support respiration during whatever process must occur to replace the native cartilaginous ring structures.
It seems that chemical cross linking by agents, such as glutaraldehyde in the Sequin study, is undesirable. This is likely due to the inhibition of host cell infiltration that is necessary for the constructive remodeling process or the inflammatory response that is elicited by cross linking procedures that yield nonresorbable foreign, almost artificial, material, or both. Alternative methods of preservation, such as cryopreservation, lyophilization, and various sterilization methods may prove to be acceptable.
Finally, and perhaps the biggest issue that requires investigation, is the need (or not) for seeding of these scaffold materials with an autologous cell population prior to implantation. If the key event in successful airway replacement is the complete remodeling by the host into a new airway structure, then it is imperative that the contribution of seeded cell populations to this process be determined. Are such cell populations necessary for success? If so, then which cell population is required? Is it mesenchymal stem cells, as suggested in the present sheep study? Is it chondrocytic precursors and epithelial cells that are used in the patient with the allogeneic tracheal tissue implant? It is abundantly clear that cells (ie, either host cells that infiltrate post-implantation or seeded autologous cells) are required to modulate a favorable airway remodeling process.
There is room for optimism that replacement of large segments of major airways will be possible in the foreseeable future. This solution will come through an understanding of how to promote a constructive remodeling response by the use of biologic scaffold materials and host derived cells. Traditional surgical approaches will be combined with tissue engineering and regenerative medicine strategies to achieve what neither can do independently.[2]
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