HepatoPac® Microliver Technology

HepatoPac is an in vitro liver model designed for both short and long-term ADME, toxicology and efficacy studies during pre-clinical drug discovery. Its proprietary patterning of hepatocyte "islands" with supportive stromal cells replicates the physiological microenvironment of the liver, promoting hepatocyte health and enabling stable metabolic activity for over four weeks.

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From Liver to Micropatterned Hepatocyte co-cultures

HepatoPac technology was invented by Howard Hughes Medical Institute Investigator, Sangeeta Bhatia, at MIT, and is centered on the concept that "architecture is important." Cryopreserved primary hepatocytes from a species-of-interest (human, rat, monkey or dog) are micropatterned within industry-standard microwell plates creating hepatocyte islands which are surrounded by supportive stromal cells.  This proprietary architecture is the key to HepatoPac's longevity and superior predictive power.

HepatoPac is an architected co-culture of hepatocyte islands surrounded by fibroblasts to promote optimal metabolite health and activity

Key HepatoPac Features:

  • Long-term Stability and Functionality (> 4 weeks)
  • Extensively Characterized & Validated
  • Multi-species Platform
  • Superior Predictive Power Over Other Models
  • High Throughput Format

 

HepatoPac Validation

Hepatocyte health, functionality and liver enzyme activity are extensively characterized for each donor.  Shown below are examples of typical HepatoPac validation.  Results for individual donors are available in Specification Sheets.

Morphology

Human

Human HepatoPac morphology shows hepatocyte island surrounded by stromal cells and robust bile canalicular network with no substantial change after culturing times

Rat

Rat HepatoPac morphology shows hepatocyte island surrounded by stromal cells and robust bile canalicular network with no substantial change after culturing times

Monkey

Monkey HepatoPac morphology shows hepatocyte island surrounded by stromal cells and robust bile canalicular network with no substantial change after culturing times

Fresh Dog

 Dog HepatoPac morphology shows hepatocyte islands surrounded by supportive stromal cells.

Human, Rat, Monkey and Dog HepatoPac Co-cultures were created and maintained in vitro.  No substantial changes to the morphology of micropatterned co-cultures with the maintenance of the polygonal shape. Transport of a fluorescent dye via MRP-2 demonstrates the robust network of bile canaliculi between hepatocytes.  Dog hepatocyte islands have been optimized at a larger size to promote the ideal ratio of homo and heterotypic interactions between cells.

Liver Function Read-out

HepatoPac Co-cultures remain viable and highly functional for 4 weeks in culture, unlike alternative model systems such as primary hepatocyte suspensions which lose functionality (i.e. albumin and urea secretion) within several hours to a few days.

HepatoPac albumin and urea levels remain consistent over time

Maintenance of Phase I CYP Activity & Phase II Enzymes

HepatoPac CYP activity peaks at day 7 after recovery period and remains steady and high over culture time

Various CYP and Phase II enzyme activities were measured over time in culture of human HepatoPac co-cultures.  Metabolites were assessed using mass spectrometry.

 

Technical Resources

Type Title
Application Note HepatoPac® A Bioengineered Micro-Liver Platform for Predictive Drug Metabolism and Toxicity Studies. A Predictive, In Vitro Micro-Liver Co-culture System Providing In Vivo Performance
Publication A Micropatterned Hepatocyte Coculture Model for Assessment of Liver Toxicity Using High-Content Imaging Analysis. Assay Drug Dev Technol., Vol. 12 (1), p 16-27, (2014).
Publication Bridging in vitro and in vivo metabolism and transport of faldaprevir in humans using a novel cocultured human hepatocyte system, HepatoPac®. Drug Metab and Dispos. Early Access. December 2013.
Publication Meeting the challenge of predicting hepatic clearance of compounds slowly metabolized by cytochrome P450 using a novel hepatocyte model, HepatoPac® Drug Metab and Dispos. Vol. 41(12), p 2024-2032 (2013).
Publication Bioactivation and Toxicity of Acetaminophen in a Rat Hepatocyte Micropatterned Coculture System. Journal of Biochemical and Molecular Toxicology. Early Release Epub, August 5, 2013.
Publication Long-Term Stability of Primary Rat Hepatocytes in Micropatterned Co-Cultures. Journal of Biochemical and Molecular Toxicology, Vol. 27(3), p 204-212 (2013).
Publication The Use of Micropatterned Co-Cultures to Detect Compounds that Cause Drug induced Liver Injury in Humans. Toxicol. Sci. 132 (1): p 107-117, (2013).
Publication Assessment of MicroPatterned Hepatocyte Co-culture System to Generate Metabolites. Drug Metabolism and Disposition, Vol. 38(10), p 1900-1905 (2010).
Poster Microscale culture of human liver cells for drug development. Nat Biotechnol, 26(1), 120-126 (2007).