Pharmaceutical Applications of Tissue Engineered Liver Models

Throughout the drug discovery/development phase there is a continual need for rapidly evaluating the pharmacokinetic properties (absorption, distribution, metabolism and elimination; ADME) of novel drugs. At present, the effects of novel compounds on hepatic metabolism are initially screened in 2D cultures of hepatocytes, followed by testing of a reduced/limited number of promising candidates in animal experiments. Since the number of promising compounds that can be tested in animals is very small, in comparison to the thousands of compounds generated daily in medicinal chemistry laboratories, this method is not efficient for large-scale screening but, rather, is reserved for selected lead compounds. A possible solution would be to accelerate the elimination process by using high-fidelity 3D in-vitro tissue models.

In 2D hepatic cultures the expression of the different cytochrome P-450 (CYPs) isoforms is limited, and other relevant functions are missing [81]. Therefore, it is assumed that more complex (and hence more realistic) 3D hepatic constructs may be more relevant for high-throughput drug metabolism screening in pharmaceutical research and development programs. Although measurements of cytochrome P-450 isoform expression/activity constitute important criteria for assessing the functionality of hepatocytes grown on various scaffolds [82, 83], to date very few studies have considered the pharmaceutical applications of engineered liver constructs as pharmacological models in assessing drug metabolism. However, the few published studies do reveal several pharmaceutical trends:

• In hepatic spheroids grown on a 3D peptide scaffold, the expression of CYP isoforms, such as CYP 1A1, 1A2, 1E1, can be induced by 3-methylcholanthrene. The ability to induce these CYP isoforms indicates that the chosen scaffold elicits and/or supports a physiologically correct cell response; hence, this particular scaffold might be useful for pharmaceutical evaluations [81].

• Newer engineering technologies are available to grow hepatocytes in 3D hollow-fiber bioreactors [83]. These assemblies may be useful for pharmaceutical screening purposes, and also serve as clinically relevant extracorporeal bioartifi-cial liver (BAL) devices which can support patients with liver failure [84].

• Recently, small and large animal models of liver disease have been developed, which employ implanted hepatocytes seeded on engineered scaffolds [85, 86]. These models might be useful in the initial steps of hepatic drug discovery.

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