This application addresses broad Challenge Area (11) Regenerative Medicine, and specific Challenge topic, 11-EB-104: Living Human Tissue Microarrays, aimed at generating "organotypic platforms that are complex yet modular, hardened, standardized, simplified, and validated against traditional animal models." Animal studies are proving to be insufficient for predicting human liver responses primarily due to significant species-specific differences in liver functions. Therefore, a plethora of in vitro human liver models have been developed over the last three decades to supplement testing on animals. Of the several liver models currently available, those utilizing primary hepatocytes strike a good balance between their potential to predict the diverse human responses seen in vivo and their simplicity of use in various culture formats. However, primary hepatocytes are notoriously difficult to maintain in conventional models as their phenotypic functions display a precipitous decline within a few hours after isolation from the native microenvironment of the liver. Indeed, unstable hepatocytes in these models have been shown to be poor predictors of clinical outcomes. We have utilized microfabrication technologies and tissue engineering techniques to develop a human liver model with precise microscale cytoarchitecture and optimal stromal interactions that displays phenotypic stability for several weeks in vitro as compared to a few hours in conventional cultures. Here, we propose to further develop and optimize these microscale human liver cultures and couple them with miniaturization strategies and assay technologies for cost-effective high-throughput screening (HTS) applications. Since drug-induced liver injury (DILI) is a leading cause of acute liver failures and the high attrition rate of pharmaceuticals, we will optimize our miniaturized human livers specifically for the in vitro screening of genotype-specific and clinically- relevant drug disposition and coupled DILI. The technologies we develop here may find broad utility in the development of several classes of therapeutic compounds (drugs, biologics), in evaluating the disposition and injury potential of environmental toxicants, in fundamental investigations of liver physiology and disease, and in personalized medicine for liver disease. In the future, continued combination of microtechnology with tissue engineering may spur the development of other tissue models and their integration into the so-called 'human- on-a-chip'.
Public Health Relevance: The studies proposed in this project are aimed towards developing a miniaturized human liver microarray for high-throughput screening applications, specifically for evaluating drug disposition and drug- induced liver injury, a serious challenge for patients, regulatory agencies and the pharmaceutical/biotech industry. In the future, our miniaturized human liver HTS system may eliminate problematic compounds much earlier in the drug development pipeline towards reducing patient exposure to unsafe drugs. The technologies we develop here may also find utility in assessing the injury potential of environmental toxicants, in basic research, and in personalized medicine for patients with liver disease.
Public Health Relevance Statement: Project Narrative The studies proposed in this project are aimed towards developing a miniaturized human liver microarray for high-throughput screening applications, specifically for evaluating drug disposition and drug- induced liver injury, a serious challenge for patients, regulatory agencies and the pharmaceutical/biotech industry. In the future, our miniaturized human liver HTS system may eliminate problematic compounds much earlier in the drug development pipeline towards reducing patient exposure to unsafe drugs. The technologies we develop here may also find utility in assessing the injury potential of environmental toxicants, in basic research, and in personalized medicine for patients with liver disease.
NIH Spending Category: Alcoholism; Bioengineering; Biotechnology; Digestive Diseases; Liver Disease; Substance Abuse
Project Terms: Abnormal Assessment of Metabolism; Acute Liver Failure; Address; Allergic; animal data; Animal Model; Animal Models and Related Studies; Animal Testing; Animals; Architecture; Area; Assay; balance; balance function; Basic Research; Basic Science; Biliary; Bioassay; Biologic Assays; Biological Assay; Biological Models; biological signal transduction; body system, hepatic; Body Tissues; Boxing; Cell Communication and Signaling; Cell Signaling; Clinical; Clinical Data; clinical relevance; clinically relevant; Complex; Computational Technique; cost; Coupled; cytokine; Development; Disease; disease/disorder; Disorder; Dose; Drug Compounding; drug development; Drug Evaluation, Preclinical; Drug Exposure; Drug Interactions; drug market; drug metabolism; Drug Preparation; Drug Screening; drug/agent; Drugs; ELIG; Eligibility; Eligibility Determination; Employee Strikes; engineered tissue; Engineering; Engineering / Architecture; Engineerings; environmental toxicant; Environmental Toxin; Equilibrium; Evaluation Studies, Drug, Pre-Clinical; Evaluation Studies, Drug, Preclinical; Exposure to; fulminant hepatic failure; Fulminating Hepatic Failure; Fulminating Liver Failure; Future; Genotype; Hepatic Cells; Hepatic Disorder; Hepatic Failure, Acute; Hepatic Failure, Fulminant; Hepatic Parenchymal Cell; Hepatocyte; hepatopathy; hepatotoxicant; hepatotoxin; High Throughput Assay; high throughput screening; Hour; Human; human tissue; Human, General; Image; imaging; In Vitro; in vivo; Industry; Inflammatory; Injury; Intermediary Metabolism; Intracellular Communication and Signaling; Investigation; Kinetic; Kinetics; Life; Liver; Liver Cells; Liver diseases; liver disorder; Liver Failure, Acute; Liver Failure, Fulminant; liver function; Man (Taxonomy); Man, Modern; Measures; Medication; Medicine; metabolic abnormality assessment; Metabolic Processes; Metabolic Studies; Metabolism; Metabolism Studies; METBL; Methods and Techniques; Methods, Other; Microfabrication; Miniaturisations; Miniaturization; Miniaturizations; miniaturize; model organism; Model System; Modeling; Models, Biologic; National Institutes of Health; National Institutes of Health (U.S.); NIH; Noise; novel; organ system, hepatic; Outcome; pathway; Pathway interactions; Patients; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Physiology; Preclinical Drug Evaluation; Protocol Screening; public health relevance; Regenerative Medicine; Research; response; Route; Science of Medicine; screening; Screening procedure; screenings; Sensitivity and Specificity; Series; Signal Transduction; Signal Transduction Systems; Signaling; Strikes; Strikes, Employee; System; System, LOINC Axis 4; Techniques; Technology; Testing; Therapeutic; Time; Tissue Arrays; Tissue Chip; Tissue Engineering; Tissue Microarray; Tissue Model; Tissues; Toxic effect; Toxic Environmental Agents; Toxic Environmental Substances; Toxicities; Toxin; United States National Institutes of Health; Validation
