Organotypic models in drug development / / Monika Schäfer-Korting, Silvya Stuchi Maria-Engler, Robert Landsiedel, editors

• Record Nr.: UNINA9910483160603321
• Pubbl/distr/stampa: Cham, Switzerland : , : Springer, , [2021]; ©2021
• ISBN: 3-030-70063-1
• Descrizione fisica: 1 online resource (viii, 323 pages) : illustrations
• Collana: Handbook of experimental pharmacology
• Disciplina: 615.19
• Soggetti: Drug development; Drugs - Testing; Desenvolupament de medicaments; Cultiu cel·lular; Llibres electrònics
• Lingua di pubblicazione: Inglese
• Formato: Materiale a stampa
• Livello bibliografico: Monografia
• Nota di bibliografia: Includes bibliographical references.
• Nota di contenuto: Intro -- Preface -- Contents -- Part I: General Topics - Quality Assurance and Predictability -- Human-Derived In Vitro Models Used for Skin Toxicity Testing Under REACh -- 1 Introduction -- 2 Validation and Regulatory Acceptance -- 3 Regulatory-Accepted Human-Derived In Vitro Models -- 3.1 Skin Irritation and Corrosion -- 3.1.1 Testing Methods: Reconstructed Human Epidermis (RhE) Used in OECD Test Guidelines No. 431 and 439 -- 3.1.2 Combination of Methods to Assess Skin Irritation and Skin Corrosion -- 3.2 Phototoxicity -- 3.3 Eye Irritation -- 3.3.1 Testing Methods: Reconstructed Human Cornea-Like Epithelium Models (RhE) Used in OECD Test Guideline No. 492 -- 3.3.2 Testing Methods: Immortalized Corneal Epithelial Cells Used in OECD Test Guideline No. 494 -- 3.3.3 Defined Approaches: Combination of Methods to Assess Eye Irritation and Serious Eye Damage -- 3.4 Skin Sensitization -- 3.4.1 Testing Methods: Synthetic Peptides Used in OECD Test Guideline No. 442C -- 3.4.2 Testing Methods: Human-Derived Keratinocytes Used in OECD Test Guideline No. 442D -- 3.4.3 Testing Methods: Human-Derived Dendritic-Like Cells Used in OECD Test Guideline No. 442E -- 3.4.4 Defined ; Approaches: Combination of In Vitro Methods to Assess Skin Sensitization -- 3.5 Genotoxicity -- 3.6 Dermal Penetration and Absorption -- 4 Limitations -- 4.1 Technical Limitations -- 4.2 Predictive Limitations -- 4.2.1 Mechanistic Limitations -- Metabolic Capacity -- Water Solubility and Lipophilicity -- 4.2.2 Agrochemical Formulation in In Vitro Skin and Eye Irritation Tests -- 4.3 Uncertainty -- 4.3.1 Reference Data and Validation Sets -- 4.3.2 Borderline Range: Uncertainty Arising from Technical and Biological Variance -- References -- How Qualification of 3D Disease Models Cuts the Gordian Knot in Preclinical Drug Development -- 1 Current Efficiency in Preclinical Research.; 1.1 Phases of Preclinical Research -- 1.2 Models and Test Methods -- 2 Reasons for Poor Translational Success -- 3 From Validation to Qualification -- 3.1 Validation -- 3.2 Quality Function Deployment: Learning from Industry -- 3.3 Qualification -- 3.4 Qualification of 3D In Vitro Models -- 3.5 Qualification of Test Methods -- 3.6 Selection of Relevant Drug Doses -- 4 Current Strategies to Rethink Preclinical Drug Research -- 4.1 Strategy 1: Characterized Cell Lines -- 4.2 Strategy 2: Primary Cells to Recapitulate Human Heterogeneity -- 4.3 Strategy 3: Patient-Derived Cells -- 4.4 Strategy 4: New Technologies in Tissue Engineering -- 4.5 Strategy 5: Comparing New Test Methods to Current Standards -- 5 Phases of Innovative Preclinical Drug Research -- 5.1 Preclinical Phase I -- 5.2 Preclinical Phase II -- 5.3 Preclinical Phase III -- 6 The Price of Quality -- References -- Standardised Reconstructed Skin Models in Toxicology and Pharmacology: State of the Art and Future Development -- 1 Introduction -- 2 Industrial Production of the 3D Skin Models in Standardised Conditions -- 2.1 Barrier Properties -- 2.2 Histology and Immunohistochemistry -- 2.3 Lipid Profile Characterisation -- 2.4 Tissue Viability and the Effects of Transport -- 3 Industrial Production of 3D Disease Tissue Models -- 4 Safety and Ethical Concerns in the Industrial Production of Normal and Disease Models -- 5 Innovative Approaches to the Production of the Standardised 3D Skin Models -- 6 Outlook -- References -- Part II: Models For Drug Research -- In Vitro Models of the Blood-Brain Barrier -- 1 The Blood-Brain Barrier -- 2 In Vitro Methods to Study the Blood-Brain Barrier -- 3 Cell Sources for Cell Culture Models -- 3.1 Criteria for Blood-Brain Barrier In Vitro Models in Drug Development -- 3.2 Stem Cell-Derived Brain Capillary Endothelial Cells -- 4 Cell Culture Models.; References -- Neural In Vitro Models for Studying Substances Acting on the Central Nervous System -- 1 Introduction into In Vitro Neurotoxicity Evaluation -- 1.1 Stem Cell-Based Human 2D Neuronal and Mixed Neuronal/Astrocyte Models -- 1.2 In Vitro Cultures of Microglia -- 1.3 Moving In Vitro Cultures into the Third Dimension with Brain Organoids -- 1.4 3D Bioprinted In Vitro Neural Models -- 1.5 CNS Disease Models -- 2 Summary and Conclusion -- References -- Engineered Heart Muscle Models in Phenotypic Drug Screens -- 1 Introduction -- 2 Macro-scale Heart Muscle Models for Drug Discovery -- 3 Pros and Cons of Tissue-Engineered Myocardium in Drug Screening Applications -- 4 Conclusion -- References -- Disease Models: Lung Models for Testing Drugs Against Inflammation and Infection -- 1 Introduction -- 2 Morpho-functional Characteristics of the Lung -- 3 Requirements to Model the Lung In Vitro -- 3.1 Technical Prerequisites -- 3.2 Sources of Cells -- 4 Modeling Pulmonary Diseases In Vitro -- 4.1 Asthma -- 4.2 Chronic Obstructive Pulmonary Disease (COPD) -- 4.3 Pulmonary Fibrosis -- 4.4 Bacterial Infections in the Context of Cystic Fibrosis and Pneumonia -- 4.4.1 Modeling the Treatment of Bacterial Infections on Cells In Vitro -- 4.4.2 ; Experimental Conditions to Build an In Vitro Model of CF -- 4.4.3 Testing Drug Efficacy on Infected Cell Lines -- 4.5 Tuberculosis -- 5 Outlook -- References -- Skin Disease Models In Vitro and Inflammatory Mechanisms: Predictability for Drug Development -- 1 Introduction -- 2 History -- 3 Monogenic Diseases -- 3.1 Monolayer Versus Three-Dimensional Cultures -- 3.2 Patient-Derived 3D Models -- 3.3 Knockdown and Knockout Models -- 4 Atopic Dermatitis -- 4.1 Barrier Function -- 4.2 Monolayer Cultures -- 4.3 Knockdown and Knockout Models -- 4.3.1 Filaggrin -- 4.3.2 TMEM45A -- 4.4 The Role of Cytokines -- 5 Psoriasis.; 5.1 Barrier Function -- 5.2 Cell Signalling -- 5.3 Immune Cells -- 6 Infection and Immunity -- 7 Immunocompetent Skin Models -- 8 Drug Development and Testing -- 8.1 Retinoic Acid Metabolism Blocking Agents (RAMBA) -- 8.2 Antifungal Compounds -- 8.3 Protein Replacement -- 9 Future Directions -- References -- Immunocompetent Human Intestinal Models in Preclinical Drug Development -- 1 Introduction -- 2 Inflammatory Responses in the Intestine -- 3 Human In Vitro Models for Intestinal Inflammation -- 3.1 Coculture Models -- 3.2 Intestinal Organoids -- 3.3 Microfluidic Gut-on-a-Chip Models -- 4 Limitations of Current In Vitro Models of the Inflamed Intestine -- 5 Conclusions and Outlook -- References -- Tissue Engineering for Musculoskeletal Regeneration and Disease Modeling -- 1 Introduction -- 2 Key Elements of Musculoskeletal Tissue Models -- 2.1 Biomaterials and Scaffolds -- 2.2 Cells -- 2.3 Signaling Molecules -- 3 Musculoskeletal Microphysiological Systems -- 4 Summary and Future Perspectives -- References -- Tumor Models and Cancer Systems Biology for the Investigation of Anticancer Drugs and Resistance Development -- 1 Introduction -- 2 Methods for Modeling and Overcoming Resistant Tumors -- 2.1 2D Models -- 2.2 3D Models -- 2.3 Microfluidic Devices -- 2.4 Bioinformatics/System Biology -- 2.4.1 Sequencing Technologies -- RNA Sequencing -- Single-Cell Sequencing -- ChIP Sequencing -- Reverse-Phase Protein Array -- 2.4.2 Public Genomic Databases -- The Cancer Genome Atlas -- The International Cancer Genomics Consortium -- The Gene Expression Omnibus -- Drug Response Databases -- 3 Challenges and Future Directions -- References -- The CAM Assay as an Alternative In Vivo Model for Drug Testing -- 1 General Remarks: Development and Structure of the Chick Chorioallantoic Membrane (CAM) -- 2 CAM Model: History and Regularities.; 3 CAM Model in Cancer Research -- 4 The CAM Model Compared to the Mouse Xenograft Model -- 5 Analysis of CAM Xenografts -- 6 The CAM and Study of Hallmarks of Cancer -- 6.1 Angiogenesis -- 6.2 Tumor Invasion and Metastasis -- 6.3 Visualization and Detection of Tumor Cells (Table 4) -- 7 The CAM Model and Molecular Pathways -- 7.1 Pharmacological Inhibition of Angiogenesis -- 7.2 Pharmacological Inhibition of Tumor Growth -- 8 CAM Use in Drug Delivery Studies -- 9 The CAM Model and Personalized Medicine -- 10 Outlook -- References.