Abstract
As drug-induced hepatotoxicity represents one of the most common causes of drug failure, three-dimensional (3D) in vitro liver platforms represent a fantastic toolbox to predict drug toxicity and thus reduce in vivo animal studies and lessen drug attrition rates. The aim of this study is to establish a functional porcine hepatocyte culture using a biofunctionalized 3D inverted colloidal crystal (ICC) hydrogel platform. The performances of non-adhesive bare poly(ethylene glycol)diacrylate (PEGDA) ICCs and PEGDA ICCs coated with either collagen type I or fibronectin have been investigated. Porcine hepatocytes viability, morphology, hepatic-specific functions and patterns of gene expression have been evaluated over a period of two weeks in culture to test diclofenac, a well-known hepatotoxic drug. Interestingly, cells in the fibronectin-functionalized scaffold exhibit different aggregation patterns and maintain better liver-specific function than those in bare ICCs and in collagen functionalized scaffold. We concluded that the 3D cell culture environment and the presence of extracellular matrix (ECM) proteins, especially fibronectin, facilitate hepatocyte viability and maintenance of the liver-specific phenotype in vitro, and enable us to predict hepatotoxicity.
Highlights
Drug-induced liver injuries (DILIs) still is a major concern for the pharmaceutical industry and regulatory authorities as well as for patients and clinicians.[1,2] drug-induced hepatotoxicity is among the most common reasons for drug failure at the clinical and post-marketing phases.[1,3,4] It has been reported that, among the medicinal products withdrawn between 1953 and 2003 due to adverse drug reactions, around 60% were removed from the market because of toxicity issues, 30% of which related to hepatotoxicity.[5]
poly(ethylene glycol)diacrylate (PEGDA)-based inverted colloidal crystal (ICC) hydrogels were fabricated by the inverse replica of a highly ordered array of monodisperse microspheres, as previously described in detail.[27,28,29,35,43]
The microbeads packed in a hexagonal manner accounted for the highly ordered porous structure of the ICC hydrogels, as well as for the high degree of interconnected pores, as visible in the Scanning Electron Microscopy (SEM) images (Fig. 1C)
Summary
Drug-induced liver injuries (DILIs) still is a major concern for the pharmaceutical industry and regulatory authorities as well as for patients and clinicians.[1,2] drug-induced hepatotoxicity is among the most common reasons for drug failure at the clinical and post-marketing phases.[1,3,4] It has been reported that, among the medicinal products withdrawn between 1953 and 2003 due to adverse drug reactions, around 60% were removed from the market because of toxicity issues, 30% of which related to hepatotoxicity.[5]. In vivo studies usually involve single or multiple administrations of the pharmaceutical compounds to two mammalian species (one of which should be non-rodent) and observation of the drug effects over a period of several weeks or months, depending on the proposed usage in humans. These studies are highly costly and time-consuming, as they require a large number of animals over extended periods of time, and are not always predictive of human toxicity.[10,11]
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