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Abstract
Primary hepatocytes are commonly used as liver surrogates in toxicology and tissue
engineering fields, therefore, maintenance of functional hepatocytes in vitro is an
important topic of investigation. This paper sought to characterize heparin-based
hydrogel as a three-dimensional scaffold for hepatocyte culture. The primary rat hepatocytes
were mixed with a prepolymer solution comprised of thiolated heparin and acrylated
poly(ethylene glycol) (PEG). Raising the temperature from 25 degrees to 37 degrees
C initiated Michael addition reaction between the thiol and acrylated moieties and
resulted in formation of hydrogel with entrapped cells. Analysis of liver-specific
products, albumin and urea, revealed that the heparin hydrogel was non-cytotoxic to
cells and, in fact, promoted hepatic function. Hepatocytes entrapped in the heparin-based
hydrogel maintained high levels of albumin and urea synthesis after three weeks in
culture. Because heparin is known to bind growth factors, we incorporated hepatocyte
growth factor (HGF)-an important liver signaling molecule - into the hydrogel. HGF
release from heparin hydrogel matrix was analyzed using enzyme linked immunoassay
(ELISA) and was shown to occur in a controlled manner with only 40% of GF molecules
released after 30 days in culture. Importantly, hepatocytes cultured within HGF-containing
hydrogels exhibited significantly higher levels of albumin and urea synthesis compared
to cells cultured in the hydrogel alone. Overall, heparin-based hydrogel showed to
be a promising matrix for encapsulation and maintenance of difficult-to-culture primary
hepatocytes. In the future, we envision employing heparin-based hyrogels as matrices
for in vitro differentiation of hepatocytes or stem cells and as vehicles for transplantation
of these cells.
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