Chapter 3 Highlights and Issues
- An Opening Comment on an Amazing Industry
- Industry Issues
- In Vitro versus In Vivo
- Dimensionality
- The Research Chain for 2D and 3D Cell Culture
- Best Practices
- Standardization
- Regulation
- Genomics Forcing the Hand of the FDA
- Leachables and Extractables
- Broad Issues
- Research Talent Shortages
- The Shifting International Picture
- Pace and Diversification of Innovation
- A Comment on the "Other" Areas of Cell Culture
- Omics Everywhere
- Is 2020 a Watershed Year for the Cell Culture Industry?
- Preliminary Market Analysis
- Cell Culture Market Growth Rate Estimates
- Assessing Large-Scale Media Consumption Needs
- Modeling Future Growth in Biopharmaceuticals
- Base Case for the Cell Culture Market
- Challenges in Projecting Sales and Growth
- Cell Culture Media Market Estimates
- Cell and Gene Therapy Bioprocessing Segment
- Evaluating Media Consumption for Biosimilars
- What About CDMOs?
- Microfluidics
- Bioreactors
- Internal Cell Culture Resources
- Drug Development Costs: What to Believe?
- Is There Too Much Concentration of Ownership in Biotechnology?
- Characterizing Innovation in 3D Cell Culture
- Bioprinting Strategic Roadmap
- Impact of COVID-19 on the World of Cell Culture
- Clinical Trials on COVID-19
Chapter 4 Tissue and Cell Culture: Technology and Product Background
- Where did Tissue and Cell Culture Start?
- History and Early Applications
- Invention of Tissue Culture
- Development of Sustained Cell Lines
- First Cell Culture Flask and Rigorous Techniques
- Lindbergh: The Cell Culture Equipment Pioneer
- Establishing Continuous Cell Lines
- Key Developments in Equipment
- Terminology and Concepts
- Tissue and Cell Culture Industry
- Tissue
- Cells
- Cell Types
- Tissue Culture and Cell Culture Definitions
- Cell Lines
- Care and Growth of Cell Culture Systems
- Consumables
- Media, Sera and Reagents
- Gels and Scaffolds
- Microplates/Microtiter Plates
- Equipment
- Bioanalytical Instruments
- Bioanalytical Imaging
- Bioprinting
- Bioreactors
- Other Equipment for Cell Culture
- Adherent Approaches
- Traditional Roller Bottles
- Other Systems
- Information Technology: Software and Services for the Cell Culture Research Market
- Software for the Research Market in Cell Culture
- Software-Related Support Services
- Bioprocessing Consumables for Cell Culture
- Microcarriers for Large-Scale 3D Culture
- Sera for Large-Scale 3D Culture
- Media for Large-Scale 3D Culture
- Bioreactor Bags for Large-Scale 3D Culture
- Other
- Bioprocessing Equipment
- Analytical Equipment for Bioprocessing
- Automation Systems for Bioprocessing
- Support Equipment for Bioprocessing
- Aspects of Large-Scale Manufacturing of Biopharmaceuticals and Vaccines
- Suspension Proteins and Monoclonal Antibodies
- Adherent-Cell-Based Therapies and Vaccines
- Small-Scale Adherent to Make Somatic Cells, Stem Cells and Tissues
- Vaccines
- Vaccine Development as a Catalyst
- Vaccines Developed Using Human Cell Strains
- Exosome Manufacturing
- Viral Vector Manufacturing
- Lentivirus Manufacturing
- Plasmid Manufacturing
- Cell Culture End Users
- Pharma/Biopharma
- Universities
- Government
- CROs/CDMOS
- Other
- Cell Culture Applications
- Drug Discovery
- Clinical Development
- Toxicology
- Basic Research
- Bioprocessing Development
- Other
- Regional Markets
- The Americas
- Europe
- Asia-Pacific
- Rest of the World
Chapter 5 Assays, Imaging and Analysis
- Assays
- Assay Development for Mesenchymal Stem Cells
- In Vitro Testing of Adventitious Agents
- Assays and Assay Kits
- Cell-Based Assays: Overview and Newer Developments
- Cells Used in Cell-Based Assays
- Notes on 3D Cell-Based Assays
- Kinetic Metabolism Assays
- Cell Proliferation
- Viability and Cytotoxicity
- Permeability Assays for Cell Viability and Survival
- Cell Invasion
- Cell Signaling and Communication
- Cytostatic
- Cell Death Assays
- Imaging Technology
- Imaging Assays
- Fluorescence as a Driver of Screening
- Analytical Systems Used in Tissue and Cell Culture
- Understanding ""Cellomics""
- HCS Support of 3D Cell Culture
- NGS Discovery Pools
- Multiplex Assays
- Predictive Toxicology
- Neuro Safety
- The Omics Invasion
- Transcriptomics
Chapter 6 Regulation and Standardization
- U.S. Regulatory Status of Bioprinted Products
- Basic Guidance for the Regulation of Biologics
- Guidance for Regenerative Medicine
- Guidance for Xenotransplants
- Guidance for Regenerative Medicine: Emergency Approval
- Regulating Bioprinted Products
Chapter 7 3D Models for Cancer
- Disease Modeling
- Cancer
- Main Classes of Models for Researching Cancer and Other Diseases
- Cell Lines
- Spheroids and Organoids
- Genetically Engineered Mouse Model (GEMM)
- Patient-Derived Tumor Xenografts (PDXs)
- Overview: Cancer at the Cellular Level
- In Vivo (Animal) Testing Standard
- Empire of the Mouse
- Humanized Mice
- 2D Culture
- 3D Requirements
- Cell Number and Viability
- Migration and Invasion
- Unmet Needs: Angiogenesis and Immune System Evasion
- Benefits of 3D Models to Cancer Research
- Greater Distinction in Cell Morphology and Proliferation
- Greater Gene Expression and Cell Behavior
- Better Models of Cell Migration and Invasion
- Cell Heterogeneity
- Breast Cancer as a Driver of 3D Cultures
- Structure, Polarity and Apoptosis
- Melanoma as a Driver of 3D Cultures
- Moving to Spheroid Configurations
- 3D Systems in Cancer Research
- Multicellular Tumor Spheroids
- Multilayered Cell Cultures
- 3D Engineered Scaffolds
- Natural Materials
- Synthetic Materials
- Human Cancer Model Initiative (HCMI)
- Next-Generation Human Cancer Models
- Drug Sensitivity and Resistance
- Altered Signaling and Sensitivity
- Drug Resistance
- Cellular Signaling
- Cellular Signaling Mediated by Integrins
- Drug Screening
- Approaches and Endpoints
- Spheroid Applications
- Metastasis via 3D Cell Migration Model
- Metastasis via Lung-on-Chip
- Cancer Metabolism
- Future Horizons
- Metastases
- Coculture
- Vascularization
- Cancer-Associated Fibroblasts
- Cancer Stem Cells
- Combination Therapies
- Biologics Development
- Tumor Recurrence
- Patient-Derived Cells
- Patient-Derived Tumor Xenografts (PDXs)
- Evolution of PDX Platforms
Chapter 8 Landscape for Toxicology and Drug Safety Testing
- Introduction
- Liver
- Cardiovascular Toxicity
- Toxicology Background
- Testing for Adverse Effects on the Skin
- New Assessment Methodologies Impact on 3D Cell Culture
- Toxicology Testing in Cosmetics
- Updated Regulatory Requirements
- Efficacy of Cosmetics and Cosmeceuticals
- Aspects of Cosmetic Toxicity Testing
- Skin Irritation
- Skin Corrosion
- Phototoxicity
- Skin Sensitization
- Eye Irritation
- Acute Systemic Toxicity
- Acute Toxicity Testing
- Cytotoxicity Assays for Acute Toxicity Testing
- Chronic and Repeated Dose Toxicity
- Carcinogenicity and Genotoxicity
- Overview
- In Vitro Methods: Background and Recent Developments
- Regulatory versus Drug Development Applications
- Efforts to Reduce False Positives
- Recent Innovations in Screening
- Future Challenge: Non-genotoxic Carcinogens
- Reproductive and Developmental Toxicity
- Background
- Following the Reproductive Cycle
- Development and Reproductive Tox Testing Types
- Zebrafish Model for Developmental Toxicity Screening
- Combination of Zebrafish and Stem Cells
- Biomedical Frontiers: Male Testis
- Endocrine Disruptor Screening
- Background
- Environmental Toxicology Impacts In Vitro Methods
- High-Production Volume Chemicals
- ToxCast and Tox 21 Initiatives
- Future Challenge: Thyroid Disruption
- BG1 Assay
- Toxicokinetics and ADME
- In Vitro Developments
- Metabolism
- Pharmacokinetics of Low Turnover Compounds
- Organotypic Models
- 3D Models for Skin
- 3D Corneal System
- Absorption Barrier Models
- Gastrointestinal
- Lung
- Blood-Brain Barrier
- Real Architecture for 3D Tissue Barriers and Extracellular Matrix
- Liver Toxicity
- Uniqueness and Complexity of Liver
- Liver as a Key Driver for 3D Innovation
- In Vitro Liver Applications
- In Vivo Liver Function and Structure
- Liver Metabolism
- In Vitro Liver Models
- Cocultures of Hepatocytes and Macrophages
- 3D Liver Models
- Bioprinted Liver Tissue
- Detected Hepatosphere Structures and Functionality
- Ideal Criteria
- Drug Resistance
- Transporter Studies
- Achieving Heterotypic Cell-Cell Contacts
- Unmet Needs and Future Drivers of Innovation
- Morphogen Signaling
- Multi-donor Liver Cells
- Kidney Toxicity Applications
- Future Challenge: Stem-Cell Derived Kidney Cells
- Bioprinted Kidney Tissue
- Pancreatic Toxicology Applications
- Cardiovascular Toxicity
- Commercial Avenue
- Collaboration with Regulators
- Cardiovascular Drug Discovery
- Microelectrode Arrays (MEAs) Based on Impedance
- Surrogate for Aortic Ring Assay via Bioprinted Magnetics
- Vasodilator Activity
- 3D Engineered Heart Tissues
Chapter 9 Stem Cell Landscape
- A History of Stem Cells
- Major and Minor Research Areas for Stem Cells
- 3D Stem Cell Culture Systems
- Plate or Culture Dish
- Spinner Flask and Rotating Wall Vessel
- Perfusion Bioreactor and Microcarrier Systems
- Shortcomings
- Microfluidics and Stem Cells
- Short Review of Stem Cell Biology
- Embryogenesis
- Growth, Structure and Morphology of Stem Cells
- Stem Cell Differentiation
- Stem Cell Differentiation versus Proliferation
- Extracellular Matrix and Stem Cells
- Soluble Factors
- Manufacturing Stem Cells
- Controlling Embryoid Body Formation
- Forced Aggregation Cultures
- Hanging-Drop Approach
- Applications
- Stem Cell Markers for High-Throughput Screening
- Teratomas and the Teratoma Assay
- Fujifilm (Cellular Dynamics Inc.)
- Stem Cell Research Breakthroughs
- Stem Cells for Neuroscience Discovery and Development
- Example: Alzheimer's Research
- Background: B-Amyloid Cascade Hypothesis
- Human iPSC-Derived Models
- New 3D Model
- Other Advantages of 3D
- Envisioned Applications
- Other 3D Neuro Applications
- Stem Cells for Cardiovascular Discovery
- Stem Cells for the Development of Regenerative Medicine
- Background: Allogenic versus Autologous
- MicroRNAs
- Induced Pluripotent Stem Cells (IPS)
Chapter 10 Regenerative Medicine: Organ Transplants and Skin Substitutes
- Regenerative Medicine
- Need for Organ Transplants
- Applications in Regenerative Medicine
- Investments in Regenerative Medicine
- Skin Substitutes Industry
- Tissue Culture Allograft and Autograft Products
- Tissue Engineering in Regenerative Medicine
Chapter 11 Company Profiles
- 3D Biopinting Solutions
- 3D Biotek Llc
- 4D Technology
- Abcam
- Akron Biotechnology Llc
- Amsbio Llc
- Agilent Technologies
- Alpco
- Applikon Biotechnology
- Beckman Coulter Life Sciences
- Biogelx Ltd.
- Bioinspired Solutions
- Biotime Inc.
- Biovision Inc.
- Cell Applications Inc.
- Cellink
- Cellspring
- Corning Life Sciences
- Cyprotex Plc
- Cytiva
- Cytoo Sa
- Emd Millipore
- Emulate Inc.
- Envisiontec Inc.
- Epithelix Sarl
- Eurofins Sas
- Greiner Bio-One
- Hamilton Robotics
- Hubrecht Organoid Technology
- Hurel Corp.
- Insphero Ag
- Invitrocue Ltd.
- Kiyatec Inc.
- Lifenet Health
- Lorem Cytori
- Mattek Corp.
- Mimetas Inc.
- Mitra Biotech Inc.
- N3D Biosciences Inc.
- National Center For Advancing Translational Sciences (Ncats)
- Organovo
- Pandorum Technologies
- Perkinelmer
- Plasticell Ltd.
- Pluristem Therapeutics, Inc.
- Poietis Sas
- Promega Corp.
- Qualyst Transporter Solutions Llc (Subsidiary Of Bioivt)
- Regenhu Ltd.
- Regenovo Biotechnology
- Screen Holdings Co. Ltd.
- Seahorse Bioscience
- Stemcell Technologies Inc.
- Stratatech Corp.
- Synvivo Inc.
- Tap Biosystems
- Tecan Group Ltd.
- Tevido Biodevices
- Thermo Fisher Scientific
- Zen-Bio Inc.
List of Tables
Summary Table: Global Market for Cell Culture, by Segment, Through 2025
Table 1: Dimensionality of Cell Culture
Table 2: WHO R&D Roadmap of Priority Infectious Diseases
Table 3: 3D Bioprinting Roadmap
Table 4: Selected Online Prices for Bioreactors
Table 5: Current Clinical Trials on Remdesivir
Table 6: Tissue Types
Table 7: Cell Types Based on Developmental Origin
Table 8: Leading Cell Line Suppliers, April 2020
Table 9: Commonly Used Transformed Cells Lines
Table 10: Major Primary Cell Lines
Table 11: Leading Primary Cell Suppliers, April 2020
Table 12: Main Types of Stem Cells
Table 13: Stem Cell Services
Table 14: Areas of Interest in 3D Spheroid Research
Table 15: Global Market for Cell Culture Consumables in Research, Through 2025
Table 16: Selected Nanoparticle Products Used in Life Science Research
Table 17: Results of Liver-Chip Drugs Halted in Previous Clinical Trials Based on Animal Studies
Table 18: Companies and Universities Involved in the Organ-on-a-Chip Industry
Table 19: Global Market for Cell Culture Equipment, by Type, Through 2025
Table 20: Microfluidics Companies
Table 21: Selected Recent Patents Issued on Microfluidic Devices Related to Cell Culture Applications
Table 22: Selected Papers Published on Recent Microfluidic Advances in Cell Culture
Table 23: High-Content Screening Suppliers and Key Attributes, April 2020
Table 24: Selected Patents Issued Related to Flow Cytometers
Table 25: Thermo Fisher Imaging Products
Table 26: Publicly Disclosed Funding of Bioprinting Companies, 2017-2020*
Table 27: Bioprinting Company Deals and Strategic Partnerships, 2019 and 2020
Table 28: Bioprinting Modalities
Table 29: Maintaining Cell Viability During Printing
Table 30: Bioprinting Instrument Industry
Table 31: Biomaterial Components
Table 32: Bioink Types
Table 33: Classes of Matrix Bioink Hydrogels
Table 34: Matrix Bioink Selection Criteria
Table 35: Selected Bioink Companies, 2020
Table 36: Projected Unit Sales of Research Bioreactors, <10 Liters, 2020
Table 37: Leading Bioreactor Suppliers, 2020
Table 38: Label-Free Technologies and Suppliers, April 2020
Table 39: Global Market for Software and Services for Cell Culture Research, Through 2025
Table 40: Global Market for Bioprocessing Consumables for Cell Culture, Through 2025
Table 41: Global Market for Cell Culture Bioprocessing Equipment, by Type, Through 2025
Table 42: Global Market for Software for Cell Culture in Bioprocessing, Through 2025
Table 43: Developmental Issues Facing the Commercialization of Exosomes
Table 44: Companies Working on Exosome Products
Table 45: Global Market for Cell Culture, by End User, Through 2025
Table 46: Global Market for Cell Culture, by Application, Through 2025
Table 47: Global Market for Cell Culture, by Region, Through 2025
Table 48: Typical Assay Endpoints and Tests
Table 49: U.S. Patents on Assays Systems, 2019 and 2020
Table 50: Selected U.S. Patents on Assay Imaging, 2019 and 2020
Table 51: Recently Issued U.S. Patents on Cellomics, 2017-2019
Table 52: Toxicology Issues That Need to Be Addressed for FDA-Regulated Products
Table 53: Overview of Federal Regulation of the Cell Culture Markets
Table 54: FDA List of Cell, Biologic and Tissue Products Regulated Under CBER and CDRH
Table 55: FDA “Talking Point” Recommendations for Regenerative Medicine Advanced Therapies (RMATs)
Table 56: U.S. Regulatory Considerations
Table 57: Main Types of Models for Researching Cancer and Other Diseases
Table 58: Goals of Funding Opportunity Announcement RFA-CA-19-055
Table 59: Common 3D Assays
Table 60: 3D Tumor Models Developed for Drug Discovery, June 2017
Table 61: Summary of the Benefits and Advantages of EV3D
Table 62: ECVAM List of Current Activities, 2020
Table 63: In Vitro Testing in Cosmetics, by Test Class
Table 64: In Vitro and In Vivo Assays in the Tier 1 Screening Battery, January 2014
Table 65: Timeline of Key Developments in Stem Cell Research, 1978-2006
Table 66: Major and Minor Research Areas in Stem Cells
Table 67: Stem Cell Usage in Research
Table 68: Recent U.S. Patents Granted on Stem Cell Technologies
Table 69: Papers Published on Selected Stem Cell Research Trends
Table 70: Comparison of the Number of Citations in the Literature on Cell Culture versus Stem Cell Culture
Table 71: Number of Organ Transplants Performed in the United States, 2018 and 2019
Table 72: Total Global Financing of Regenerative Medicine
Table 73: Total Financing of Regenerative Medicine, by Therapeutic Area
Table 74: Leading Tissue Products and Suppliers, April 2020
Table 75: Printed Tissue and Organs: Commercialization Timeframe
Table 76: Tissue/Organ Complexity
Table 77: New Bioassay Kits Introduced by BioVision
Table 78: Partial List of Specialty Media Formulations Sold by Cell Applications Inc.
List of Figures
Summary Figure: Global Market for Cell Culture, by Segment, 2020-2025
Figure 1: Research Chain for Cell Culture
Figure 2: A Model for The Evolution of FDA Regulation
Figure 3: An Innovation Matrix
Figure 4: Bioprinting Strategic Roadmap
Figure 5: Gastrointestinal Organotype Cultures
Figure 6: iCELLis Nanoreactor: Example of Commercial 2D Cell Culture Systems
Figure 7: Prototype of 3D Model Lung-on-a-Chip from Wake Forest
Figure 8: Recent Photos of the HepaChip
Figure 9: Recent Photos of the HepaChip-MWP
Figure 10: University of Toronto Handheld Bioprinting Device
Figure 11: Collaborative Experiment Conducted by American, Russian and Israeli Scientists
Figure 12: Smart Marbles Concept for Quantifying Process Heterogeneity
Figure 13: Porcine Intestinal Organoids
Figure 14: Diagram of the Components of a Predictive Toxicology System
Figure 15: Gleason’s Pattern
Figure 16: Diagram of PDXs, Cell Lines and Organoid/Spheroid Xenografts
Figure 17: Cell Heterogeneity and Its Function
Figure 18: Electron Micrograph of Porous Microcarrier for Stem Cell Production
Figure 19: Photograph of Apligraf