“…12 To explore this possibility, we tested the utility of the liver MPS for general drug development applications related to detecting drug toxicity, metabolism, and intracellular accumulation, which are key pharmacological determinants of drug development studies. 20 Reproducibility of MPS results was tested considering previously published work and the experimental outcomes from two test sites, from using different cell batches and from other cell culture platforms (spheroids and sandwich cultures).…”
Liver microphysiological systems (MPSs) are promising models for predicting hepatic drug effects. Yet, after a decade since their introduction, MPSs are not routinely used in drug development due to lack of criteria for ensuring reproducibility of results. We characterized the feasibility of a liver MPS to yield reproducible outcomes of experiments assaying drug toxicity, metabolism, and intracellular accumulation. The ability of the liver MPS to reproduce hepatotoxic effects was assessed using trovafloxacin, which increased lactate dehydrogenase (LDH) release and reduced cytochrome P450 3A4 (CYP3A4) activity. These observations were made in two test sites and with different batches of Kupffer cells. Upon culturing equivalent hepatocytes in the MPS, spheroids, and sandwich cultures, differences between culture formats were detected in CYP3A4 activity and albumin production. Cells in all culture formats exhibited different sensitivities to hepatotoxicant exposure. Hepatocytes in the MPS were more functionally stable than those of other culture platforms, as CYP3A4 activity and albumin secretion remained prominent for greater than 18 days in culture, whereas functional decline occurred earlier in spheroids (12 days) and sandwich cultures (7 days). The MPS was also demonstrated to be suitable for metabolism studies, where CYP3A4 activity, troglitazone metabolites, diclofenac clearance, and intracellular accumulation of chloroquine were quantified. To ensure reproducibility between studies with the MPS, the combined use of LDH and CYP3A4 assays were implemented as quality control metrics. Overall results indicated that the liver MPS can be used reproducibly in general drug evaluation applications. Study outcomes led to general considerations and recommendations for using liver MPSs.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Microphysiological systems (MPSs) have been designed to recreate organ‐ or tissue‐specific characteristics of extracellular microenvironments that enhance the physiological relevance of cells in culture. Liver MPSs enable long‐lasting and stable culture of hepatic cells by culturing them in three‐dimensions and exposing them to fluid flow.
WHAT QUESTION DID THIS STUDY ADDRESS?
What is the functional performance relative to other cell culture platforms and the reproducibility of a liver MPS for assessing drug development and evaluation questions, such as toxicity, metabolism, and pharmacokinetics?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The liver MPS systematically detected the toxicity of trovafloxacin. When compared with spheroids and sandwich cultures, this system had a more stable function and different sensitivity to troglitazone, tamoxifen, and digoxin. Quantifying phase II metabolism of troglitazone and intracellular accumulation of chloroquine demonstrated the potential use of the liver MPS for studying drug metabolism and pharmacokinetics. Quality control criteria for assessing chip function were key for reliably using the liver MPS.
HOW MIGHT THIS CHANGE CLINICAL PH...
“…12 To explore this possibility, we tested the utility of the liver MPS for general drug development applications related to detecting drug toxicity, metabolism, and intracellular accumulation, which are key pharmacological determinants of drug development studies. 20 Reproducibility of MPS results was tested considering previously published work and the experimental outcomes from two test sites, from using different cell batches and from other cell culture platforms (spheroids and sandwich cultures).…”
Liver microphysiological systems (MPSs) are promising models for predicting hepatic drug effects. Yet, after a decade since their introduction, MPSs are not routinely used in drug development due to lack of criteria for ensuring reproducibility of results. We characterized the feasibility of a liver MPS to yield reproducible outcomes of experiments assaying drug toxicity, metabolism, and intracellular accumulation. The ability of the liver MPS to reproduce hepatotoxic effects was assessed using trovafloxacin, which increased lactate dehydrogenase (LDH) release and reduced cytochrome P450 3A4 (CYP3A4) activity. These observations were made in two test sites and with different batches of Kupffer cells. Upon culturing equivalent hepatocytes in the MPS, spheroids, and sandwich cultures, differences between culture formats were detected in CYP3A4 activity and albumin production. Cells in all culture formats exhibited different sensitivities to hepatotoxicant exposure. Hepatocytes in the MPS were more functionally stable than those of other culture platforms, as CYP3A4 activity and albumin secretion remained prominent for greater than 18 days in culture, whereas functional decline occurred earlier in spheroids (12 days) and sandwich cultures (7 days). The MPS was also demonstrated to be suitable for metabolism studies, where CYP3A4 activity, troglitazone metabolites, diclofenac clearance, and intracellular accumulation of chloroquine were quantified. To ensure reproducibility between studies with the MPS, the combined use of LDH and CYP3A4 assays were implemented as quality control metrics. Overall results indicated that the liver MPS can be used reproducibly in general drug evaluation applications. Study outcomes led to general considerations and recommendations for using liver MPSs.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Microphysiological systems (MPSs) have been designed to recreate organ‐ or tissue‐specific characteristics of extracellular microenvironments that enhance the physiological relevance of cells in culture. Liver MPSs enable long‐lasting and stable culture of hepatic cells by culturing them in three‐dimensions and exposing them to fluid flow.
WHAT QUESTION DID THIS STUDY ADDRESS?
What is the functional performance relative to other cell culture platforms and the reproducibility of a liver MPS for assessing drug development and evaluation questions, such as toxicity, metabolism, and pharmacokinetics?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The liver MPS systematically detected the toxicity of trovafloxacin. When compared with spheroids and sandwich cultures, this system had a more stable function and different sensitivity to troglitazone, tamoxifen, and digoxin. Quantifying phase II metabolism of troglitazone and intracellular accumulation of chloroquine demonstrated the potential use of the liver MPS for studying drug metabolism and pharmacokinetics. Quality control criteria for assessing chip function were key for reliably using the liver MPS.
HOW MIGHT THIS CHANGE CLINICAL PH...
“…This rationale should include not only an evaluation of the animal model itself but also how it compares to other available options. Furthermore, agencies could review disease-specific guidance to include a more comprehensive account of efficacy assessment by exploring the use of disease models in safety studies [24,50]. The simultaneous evaluation of efficacy and safety can result in more informative studies, which are more likely to translate to the clinic.…”
Section: Levelling the Translational Gap For Animal To Human Efficacymentioning
confidence: 99%
“…This reflection is especially relevant for the discussion of alternatives to animal studies. Many in silico and in vitro (particularly organoids and organs-on-a-chip) approaches are in development, aiming to replace animal use in drug development partially or entirely, but they also have limitations [ 50 , 64 ]. For instance, organoids cannot simulate organ–organ interactions, and the organ-on-a-chip technology has not resolved the lack of a universal medium to connect different organs as well as its inability to replicate the immune response, endocrine system or gut-microbiome [ 65 ].…”
Section: Levelling the Translational Gap For Animal To Human Efficmentioning
Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and the general public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, we explore whether external validity is a factor in animal model selection in the Investigator’s Brochure (IB), and we use the IB-derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm.
“…Current neural MPSs are limited to assessing specific effects of drugs on neural cells, and it is not possible to reproduce entire neurobehaviors. However, the neural MPS still has the pharmaceutical potential for examining drug toxicity and chemical safety directly on the CNS, as an artificial tissue [ 138 , 139 ]. Moreover, advances in the physiological relevance of neural MPS can be used to recreate interactions in the CNS that can highly affect the pharmacokinetic effects of the drugs in the CNS.…”
Section: Conclusion and Future Perspectivesmentioning
Neurodegenerative diseases are among the most severe problems in aging societies. Various conventional experimental models, including 2D and animal models, have been used to investigate the pathogenesis of (and therapeutic mechanisms for) neurodegenerative diseases. However, the physiological gap between humans and the current models remains a hurdle to determining the complexity of an irreversible dysfunction in a neurodegenerative disease. Therefore, preclinical research requires advanced experimental models, i.e., those more physiologically relevant to the native nervous system, to bridge the gap between preclinical stages and patients. The neural microphysiological system (neural MPS) has emerged as an approach to summarizing the anatomical, biochemical, and pathological physiology of the nervous system for investigation of neurodegenerative diseases. This review introduces the components (such as cells and materials) and fabrication methods for designing a neural MPS. Moreover, the review discusses future perspectives for improving the physiological relevance to native neural systems.
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