In vitro models for liver toxicity testing
ABSTRACT Over the years, various liver-derived in vitro model systems have been developed to enable investigation of the potential adverse effects of chemicals and drugs. Liver tissue slices, isolated microsomes, perfused liver, immortalized cell lines, and primary hepatocytes have been used extensively. Immortalized cell lines and primary isolated liver cells are currently most widely used in vitro models for liver toxicity testing. Limited throughput, loss of viability, and decreases in liver-specific functionality and gene expression are common shortcomings of these models. Recent developments in the field of in vitro hepatotoxicity include three-dimensional tissue constructs and bioartificial livers, co-cultures of various cell types with hepatocytes, and differentiation of stem cells into hepatic lineage-like cells. In an attempt to provide a more physiological environment for cultured liver cells, some of the novel cell culture systems incorporate fluid flow, micro-circulation, and other forms of organotypic microenvironments. Co-cultures aim to preserve liver-specific morphology and functionality beyond those provided by cultures of pure parenchymal cells. Stem cells, both embryonic- and adult tissue-derived, may provide a limitless supply of hepatocytes from multiple individuals to improve reproducibility and enable testing of the individual-specific toxicity. This review describes various traditional and novel in vitro liver models and provides a perspective on the challenges and opportunities afforded by each individual test system.
- SourceAvailable from: Apeksha Damania[Show abstract] [Hide abstract]
ABSTRACT: Liver extracellular matrix (ECM) composition, topography and biomechanical properties influence cell-matrix interactions. The ECM presents guiding cues for hepatocyte phenotype maintenance, differentiation and proliferation both in vitro and in vivo. Current understanding of such cell-guiding cues along with advancement of techniques for scaffold fabrication has led to evolution of matrices for liver tissue culture from simple porous scaffolds to more complex 3D matrices with microarchitecture similar to in vivo. Natural and synthetic polymeric biomaterials fabricated in different topographies and porous matrices have been used for hepatocyte culture. Heterotypic and homotypic cell interactions are necessary for developing an adult liver as well as an artificial liver. A high oxygen demand of hepatocytes as well as graded oxygen distribution in liver is another challenging attribute of the normal liver architecture that further adds to the complexity of engineered substrate design. A balanced interplay of cell-matrix interactions along with cell-cell interactions and adequate supply of oxygen and nutrient determines the success of an engineered substrate for liver cells. Techniques devised to incorporate these features of hepatic function and mimic liver architecture range from maintaining liver cells in mm-sized tailor-made scaffolds to a more bottoms up approach that starts from building the microscopic subunit of the whole tissue. In this review, we discuss briefly various biomaterials used for liver tissue engineering with respect to design parameters such as scaffold composition and chemistry, biomechanical properties, topography, cell-cell interactions and oxygenation.Hepatology International 04/2013; 8(2):185-197. DOI:10.1007/s12072-013-9503-7 · 2.47 Impact Factor
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ABSTRACT: Drug-induced liver toxicity dominates the reasons for pharmaceutical product ban, withdrawal or non-approval since the thalidomide disaster in the late-1950s. Hopes to finally solve the liver toxicity test dilemma have recently risen to a historic level based on the latest progress in human microfluidic tissue culture devices. Chip-based human liver equivalents are envisaged to identify liver toxic agents regularly undiscovered by current test procedures at industrial throughput. In this review, we focus on advanced microfluidic microscale liver equivalents, appraising them against the level of architectural and, consequently, functional identity with their human counterpart in vivo. We emphasise the inherent relationship between human liver architecture and its drug-induced injury. Furthermore, we plot the current socio-economic drug development environment against the possible value such systems may add. Finally, we try to sketch a forecast for translational innovations in the field.Lab on a Chip 05/2013; DOI:10.1039/c3lc50240f · 5.75 Impact Factor
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ABSTRACT: Introduction: Drugs are indispensable for human welfare nevertheless there is a lack of safe drugs. Obtaining pharmacokinetics information, especially metabolism, is a requirement during preclinical and clinical drug development so that in vitro tools represent a simple path where it is possible to assess drug toxicity and predict drug safety in humans. Areas covered: This review covers the latest in vitro tools developed for assessing drug toxicity in different organs. A special focus is given to hepatic models, as it is the main organ responsible for drug metabolism and consequently bioactivation and detoxification reactions. Three-dimensional culture models have been widely developed, resembling in vivo-like conditions, and are also discussed in this review. Expert opinion: Several in vitro tools to assess hepatic drug metabolism have been developed, however, novel in vitro methods to investigate extra-hepatic drug metabolism still need to be improved. These methods are able to reduce the number of animal used in preclinical experiments, but in vivo tests are mandatory for drug approval and commercialization.Expert Opinion on Drug Metabolism & Toxicology 11/2013; DOI:10.1517/17425255.2014.857402 · 2.93 Impact Factor