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McGowan Institute for Regenerative Medicine, University of Pittsburgh, 100 Technology Dr, Suite 200, Pittsburgh, PA 15219
(Email: gilberttw{at}upmc.edu).
| Dr Gilbert discloses that he has a financial relationship with Acell Inc.
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I appreciate the comments by Schanz and colleagues [1] about our article [2]. We attempted to use acellular extracellular matrix (ECM) scaffolds derived from the porcine urinary bladder (UBM-ECM) and trachea to repair a window defect in the ventral surface of the canine trachea. Schanz and colleagues [1] have suggested that the insufficient findings could have been a consequence of inadequately addressing the concepts of decellularization, cell seeding, and vascular supply [1].
Acellular ECM scaffolds derived from the porcine small intestinal submucosa and UBM-ECM have been used widely in pre-clinical studies and in clinical applications [3]. The ECM scaffolds promote the formation of site-specific tissues in various locations through the process of cell infiltration, scaffold degradation, and host tissue deposition [4, 5]. These findings are in contrast with Walles and colleagues [6] who reported calcification of decellularized ovine carotid artery and aorta implanted subcutaneously in a rat model. Heterotopic calcification of small intestine submucosa-ECM and UBM-ECM scaffolds has not been reported.
Walles and colleagues [6] showed that cell-seeded ECM scaffolds were not calcified. Cell seeding has also been reported to improve the remodeling of ECM scaffolds in other applications [7, 8]. However, there are limitations to cell seeding. Survival of the cells in vivo is tenuous due to lack of vascularization. It has also been recently shown that the presence of cellular material in an ECM scaffold, regardless of the viability of the cells, adversely alters the phenotype of macrophages that respond to the scaffold [9, 10]. Finally, the inclusion of cells in a seeded scaffold necessarily increases the complexity and cost of any procedure. Therefore, it is important to explore possible methods for use of an ECM scaffold alone before including cells.
Decellularization of tissue and organs for use as biologic scaffolds is necessary to remove antigens that may lead to immune rejection [11]. However, several commercially available biologic scaffolds, including UBM-ECM, have been shown to contain detectable amounts of fragmented DNA (< 200 bp) [12]. These fragments are likely degraded along with the rest of the scaffold, and have not been shown to cause adverse responses in the clinical setting. The DNA content of the tracheal ECM would have been higher than UBM-ECM due to incomplete decellularization of the tracheal cartilage [2]. Additional studies are required to determine if cellular material in the cartilage adversely affected the remodeling results.
The lack of vascularization is an important consideration that was not addressed in our recent report. This was due to previous work that showed the presence of angiogenic factors in ECM scaffolds and rapid vascularization of ECM scaffolds after implantation [4, 5, 13, 14]. We are currently investigating methods to increase the vascularity of the ECM scaffolds for the tracheal application.
There is still a need for a tracheal replacement graft that will have widespread clinical acceptance. The form of this replacement is not clear at this time, so it is important to consider all options as potential strategies for tracheal replacement.
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