A whole-organ regenerative medicine approach for liver replacement

Alejandro Soto-Gutierrez*, Li Zhang, Chris Medberry, Ken Fukumitsu, Denver Faulk, Hongbin Jiang, Janet Reing, Roberto Gramignoli, Junji Komori, Mark Ross, Masaki Nagaya, Eric Lagasse, Donna Stolz, Stephen C. Strom, Ira J. Fox, Stephen F. Badylak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

272 Scopus citations

Abstract

Background & Aims: The therapy of choice for end-stage liver disease is whole-organ liver transplantation, but this option is limited by a shortage of donor organs. Cell-based therapies and hepatic tissue engineering have been considered as alternatives to liver transplantation, but neither has proven effective to date. A regenerative medicine approach for liver replacement has recently been described that includes the use of a three-dimensional organ scaffold prepared by decellularization of xenogeneic liver. The present study investigates a new, minimally disruptive method for whole-organ liver decellularization and three different cell reseeding strategies to engineer functional liver tissue. Methods: A combination of enzymatic, detergent, and mechanical methods are used to remove all cells from isolated rat livers. Whole-organ perfusion is used in a customized organ chamber and the decellularized livers are examined by morphologic, biochemical, and immunolabeling techniques for preservation of the native matrix architecture and composition. Three different methods for hepatocyte seeding of the resultant three-dimensional liver scaffolds are evaluated to maximize cell survival and function: (1) direct parenchymal injection, (2) multistep infusion, or (3) continuous perfusion. Results: The decellularization process preserves the three-dimensional macrostructure, the ultrastructure, the composition of the extracellular matrix components, the native microvascular network of the liver, and the bile drainage system, and up to 50% of growth factor content. The three-dimensional liver matrix reseeded with the multistep infusion of hepatocytes generated ∼90% of cell engraftment and supported liver-specific functional capacities of the engrafted cells, including albumin production, urea metabolism, and cytochrome P450 induction. Conclusions: Whole-organ liver decellularization is possible with maintenance of structure and composition suitable to support functional hepatocytes.

Original languageEnglish
Pages (from-to)677-686
Number of pages10
JournalTissue Engineering - Part C: Methods
Volume17
Issue number6
DOIs
StatePublished - 1 Jun 2011
Externally publishedYes

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