In spite of many advances in liver transplant surgery, an increasing number of patients with terminal liver disease are dying while awaiting transplants. Consequently, further advances in the storage of donor livers, as well as alternative replacement options and mechanisms for supporting liver function while awaiting a donor liver are needed. A very promising area of research and development is in the development of engineered solutions to the problems of liver support for either natural donor organs or bioartificial livers. However, efforts undertaken within a single discipline are hampered by the complexity of both the engineering and biological aspects of such projects. This proposal constitutes a partnership between bioengineers, biologists and a liver transplant surgeon with the goal of combining their expertise to devise improved methods of liver support via bioartificial livers and improved preservation of donor livers via machine perfusion preservation (MPP). The partnership encompasses three inter-related projects. The first project focuses on delivery of oxygen and other nutrients to the cells in in vitro systems such as the bioartificial liver. The approach involves the modification of the support matrix to facilitate enhanced mass transport. The second project addresses the hypothesis that improved bioartificial liver function can be attained by providing a more physiological combination of cell types in the support device. Specifically, we will investigate the relationship between Kupffer cells and hepatocytes in maintaining prolonged hepatic-specific function in culture. The final project focuses on development of methods for optimization of microvascular perfusion in machine-perfused livers. This project uses a combination of intravital microscopy and mathematical modeling. In all of the projects, engineering and biological approaches, as well as clinical experience, are combined to address focused, clinically relevant problems. Moreover, the unique environment that supports the partnership will maximize the potential for success in this interdisciplinary approach and provide an avenue for potential clinical application of laboratory advances.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058503-03
Application #
6617830
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (02))
Program Officer
Serrano, Jose
Project Start
2001-09-30
Project End
2006-05-31
Budget Start
2003-08-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$423,660
Indirect Cost
Name
University of North Carolina Charlotte
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
066300096
City
Charlotte
State
NC
Country
United States
Zip Code
28223
Niu, Mei; Hammond 2nd, Paul; Coger, Robin N (2009) The effectiveness of a novel cartridge-based bioreactor design in supporting liver cells. Tissue Eng Part A 15:2903-16
Niu, Mei; Clemens, Mark G; Coger, Robin N (2008) Optimizing normoxic conditions in liver devices using enhanced gel matrices. Biotechnol Bioeng 99:1502-12
Xu, Hongzhi; Lee, Charles Y; Clemens, Mark G et al. (2008) Inhibition of TXA synthesis with OKY-046 improves liver preservation by prolonged hypothermic machine perfusion in rats. J Gastroenterol Hepatol 23:e212-20
Lee, Sang-Ho; Coger, Robin N; Clemens, Mark G (2006) Antioxidant functionality in hepatocytes using the enhanced collagen extracellular matrix under different oxygen tensions. Tissue Eng 12:2825-34
Zinchenko, Yekaterina S; Culberson, Catherine R; Coger, Robin N (2006) Contribution of non-parenchymal cells to the performance of micropatterned hepatocytes. Tissue Eng 12:2241-1251
Zinchenko, Yekaterina S; Schrum, Laura W; Clemens, Mark et al. (2006) Hepatocyte and kupffer cells co-cultured on micropatterned surfaces to optimize hepatocyte function. Tissue Eng 12:751-61
Zinchenko, Yekaterina S; Coger, Robin N (2005) Engineering micropatterned surfaces for the coculture of hepatocytes and Kupffer cells. J Biomed Mater Res A 75:242-8
Jain, Shailendra; Xu, Hongzhi; Duncan, Heather et al. (2004) Ex-vivo study of flow dynamics and endothelial cell structure during extended hypothermic machine perfusion preservation of livers. Cryobiology 48:322-32
McClelland, Randall E; Coger, Robin N (2004) Effects of enhanced O(2) transport on hepatocytes packed within a bioartificial liver device. Tissue Eng 10:253-66
Xu, Hongzhi; Lee, Charles Y; Clemens, Mark G et al. (2004) Pronlonged hypothermic machine perfusion preserves hepatocellular function but potentiates endothelial cell dysfunction in rat livers. Transplantation 77:1676-82

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