Engineering Translational Models of Lung Homeostasis and Disease (Advances in Experimental Medicine and Biology, 1413)

Foreword
Preface
Contents
Chapter 1: An Introduction to Engineering and Modeling the Lung
	1.1 Introduction
	1.2 Broader Impacts of Understanding Lung Biology in Health and Disease
	1.3 Lung Physiology in Homeostasis and Disease
	1.4 Engineering Translational Models of Lung Homeostasis and Disease
	1.5 Conclusion
	References
Part I: Engineering and Modeling the Developing Lung
	Chapter 2: Simple Models of Lung Development
		2.1 Introduction
			2.1.1 Basics of Lung Development
		2.2 Models to Study Lung Development
		2.3 Models of Early Lung Development (Airways)
			2.3.1 Explant Cultures
			2.3.2 2D and 3D Imaging of Branching Morphogenesis
			2.3.3 Time-Lapse Imaging
			2.3.4 Organoids
		2.4 Models of Late Lung Development
			2.4.1 Saccular Phase Models
			2.4.2 Alveologenesis
			2.4.3 Other 3D Models of Alveologenesis
		2.5 Conclusion
		References
	Chapter 3: Lung Development in a Dish: Models to Interrogate the Cellular Niche and the Role of Mechanical Forces in Development
		3.1 Introduction
		3.2 Self-Assembled Organoid and Spheroid Models
			3.2.1 Creating Lung Organoid Models That Represent Regional Composition and Heterogeneity
			3.2.2 Advancing the Complexity of Organoids to Investigate Tissue Crosstalk
			3.2.3 Induction of Lung Organoids to Create Multiple Tissue Compartments
		3.3 Microfluidic and Organ-on-a-Chip Models to Study Lung Development
			3.3.1 Moving Toward More Complex Physiology with Multiple Channels
			3.3.2 Integration of Dimensionality and Biomaterials into Organ-on-a-Chip Platforms
		3.4 Whole Organ Models to Understand the Mechanics of Lung Development
		3.5 Conclusion
		References
	Chapter 4: Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis
		4.1 Introduction
		4.2 Overview of Embryonic Lung Progenitors
			4.2.1 Stage-Specific Epithelial Progenitors (Primordial, Distal Tip, Basal)
				Lung Primordial Progenitors
				Distal Tip Progenitors
				Airway Basal Cells
			4.2.2 Stage-Specific Mesenchymal Progenitors
		4.3 Ex Vivo Culture of Multipotent Embryonic Lung Progenitors
			4.3.1 Ex Vivo Culture of Mouse Embryonic Progenitors
			4.3.2 Ex Vivo Culture of Human Embryonic Progenitors
		4.4 In Vitro Derivation of Multipotent Embryonic Lung Progenitors
		4.5 Progenitor Cell Similarity Models
		4.6 Conclusion
		References
Part II: Engineering and Modeling Large Airways
	Chapter 5: Basic Science Perspective on Engineering and Modeling the Large Airways
		5.1 Introduction
		5.2 Proximal Airways: Composition and Function
		5.3 Regeneration of the Airways
			5.3.1 Endogenous Stem Cells
			5.3.2 The Stem Cell Niche
			5.3.3 Stem Cell Attrition with Disease and Aging
		5.4 Developing Cellular Therapies for Regeneration of Airway Tissues
		5.5 In Vitro Models of the Human Airways
			5.5.1 Transwell Air-Liquid Interface (ALI) Cultures
			5.5.2 Airway Spheroids: Tracheo/Bronchospheres
			5.5.3 Organoids
			5.5.4 Lung-on-a-Chip
			5.5.5 Xenografts
		5.6 Cell-Matrix Interactions
		5.7 Conclusion
		References
	Chapter 6: Computational, Ex Vivo, and Tissue Engineering Techniques for Modeling Large Airways
		6.1 Large Airways: Structure-Function Relationship
		6.2 Pathologies and the Need for Modeling the Large Airways
			6.2.1 Conditions That Cause Large Airway Dysfunction
			6.2.2 Need for Computational and Physiological Models of the Large Airways
		6.3 Computational Modeling
		6.4 Ex Vivo Testing
		6.5 Tissue Engineering Techniques for Modeling the Large Airways
			6.5.1 Biomaterial Scaffolds
				Decellularized Scaffolds
				Cellular, Synthetic, or Hybrid Biomaterial Approaches
			6.5.2 Manufacturing Techniques for Large Airway Models
		6.6 Tools for Functional Assessment of Large Airway Models
		6.7 Limitations and Future Considerations
		References
	Chapter 7: Engineering Large Airways
		7.1 Introduction
		7.2 Forces During Respiration and How They Can Influence Construct Design
		7.3 The Structure of the Trachea and Its Mechanical Properties
			7.3.1 Tracheal Cartilage
			7.3.2 Trachealis Muscle
			7.3.3 Annular Ligament
		7.4 Mechanical Properties of the Whole Trachea and the Implications of Mechanical Property Mismatch
			7.4.1 Compliance
			7.4.2 Extension and Bending
		7.5 Key Considerations and Summary of Recommended Mechanical Tests
		7.6 Conclusion
		References
Part III: Engineering and Modeling the Mesenchyme and Parenchyma
	Chapter 8: Engineering and Modeling the Lung Mesenchyme
		8.1 Introduction
		8.2 Advancing the Discovery of Fibroblast Heterogeneity
		8.3 The Organization and Heterogeneity of Lung Fibroblasts
			8.3.1 Platelet-Derived Growth Factor Receptor Alpha (PDGFRα)-Expressing Alveolar Fibroblasts 1 and 2
			8.3.2 Platelet-Derived Growth Factor Beta (PDGFRβ)-Expressing Pericytes
			8.3.3 Airway and Vascular Smooth Muscle (ASM and VSM)
		8.4 Other Fibroblast Subtypes
			8.4.1 Developmental Secondary Crest Myofibroblasts (SCMF)
			8.4.2 Fibrotic Disease-Associated Myofibroblasts (MyoF)
		8.5 Bioengineering Approaches to Characterize Complex Fibroblast Behaviors
			8.5.1 Organoids to Model Mesenchymal-Epithelial Interactions
			8.5.2 Lung-on-a-Chip to Model Human Lung Architecture and Environmental Forces
			8.5.3 Acellular Tissue Scaffolds to Model Fibroblast and ECM Interactions
		8.6 Targeting Fibroblasts with Nanoparticles as Strategy for Intervention
		8.7 Conclusion
		References
	Chapter 9: Engineering Dynamic 3D Models of Lung
		9.1 Introduction
		9.2 Building the Extracellular Microenvironment
			9.2.1 Biomaterials
			9.2.2 Lung Decellularization and Recellularization
			9.2.3 dECM Hydrogels
			9.2.4 Synthetic Hydrogels
			9.2.5 Hybrid-Hydrogels
		9.3 Constructing Relevant Tissue Geometries
			9.3.1 Precision-Cut Lung Slices
			9.3.2 Organoids
			9.3.3 Engineered 3D Hydrogel Constructs
			9.3.4 3D Bioprinting
		9.4 Incorporating Dynamic Mechanical Forces
			9.4.1 Biomechanical Modeling
			9.4.2 Lung-on-a-Chip
		9.5 Conclusion
		References
	Chapter 10: Lung-on-a-Chip Models of the Lung Parenchyma
		10.1 Introduction
		10.2 Lung Alveolar Cells and the Alveolar Environment
			10.2.1 Lung Alveolar Cells and Their Environment
			10.2.2 Lung Alveolar Epithelial Cells In Vitro
		10.3 Reproducing the Alveolar Barrier with a Lung-on-a-Chip
			10.3.1 Reproducing the Lung Alveolar Environment on Chip
				Scaffolds for the Alveolar Barrier: Engineering a Thin, Flexible and Soft Basement Membrane
				Mechanical Stress Induced by the Respiratory Movements
			10.3.2 Effects of Biochemical and Physical Cues on the Lung Alveolar Barrier
				Effects of Mechanical Forces on Alveolar Epithelial Cells
				Effects of Mechanical Forces on Lung Endothelial Cells
				Lung Alveolar Extracellular Matrix (ECM)
				Effects Induced by the Air-Liquid Interface
			10.3.3 Read-Outs: Extracting Information from a Lung-on-a-Chip
		10.4 Lung Disease-on-a-Chip Models
			10.4.1 Idiopathic Pulmonary Fibrosis (IPF)
			10.4.2 Emphysema
			10.4.3 Acute Respiratory Distress Syndrome (ARDS)
			10.4.4 COVID
			10.4.5 Lung Adenocarcinoma
		10.5 Challenges of Lung-on-a-Chip Technologies
		10.6 Perspectives for Lung-on-a-Chip Technologies
		References
	Chapter 11: Assessment of Collagen in Translational Models of Lung Research
		11.1 Introduction
		11.2 Quantification of Collagen
			11.2.1 The Sircol Assay
			11.2.2 Hydroxyproline Quantification
			11.2.3 Immuno-Based Methods
		11.3 Mass Spectrometry Characterization of Collagen
			11.3.1 Assessment of Collagens in Proteomics Analyses of Pulmonary ECM
			11.3.2 Analysis of Posttranslational Modifications of Collagen
			11.3.3 Assessment of Enzymatic Crosslinks in Collagen
		11.4 Assessment of Collagen Architecture In Situ
			11.4.1 Masson’s Trichrome Staining
			11.4.2 Picrosirius Red Staining
			11.4.3 Second Harmonic Generation Microscopy
			11.4.4 Immunohistochemistry
			11.4.5 Transmission Electron Microscopy
			11.4.6 Selected Complementary and Emerging Techniques
				Confocal Reflection Microscopy (CRM)
				Atomic Force Microscopy (AFM)
				Imaging Probes for Magnetic Resonance Imaging (MRI)
		11.5 Monitoring Fibril Formation in Real Time Using Purified Collagen
		11.6 Assessment of Collagen Turnover by Peripheral Markers
		11.7 Conclusion
		References
Part IV: Engineering and Modeling the Pulmonary Vasculature
	Chapter 12: Understanding and Engineering the Pulmonary Vasculature
		12.1 Pulmonary Vasculature in Development and Diseases
		12.2 Pulmonary ECs and Their Angiocrine Functions
		12.3 Engineering the Pulmonary Vasculature
			12.3.1 Generation of Vascularized Organoids
			12.3.2 Bioengineered Lung and Vasculature Using Acellular Native Lung Scaffold
			12.3.3 Vascularized Lung-on-a-Chip
			12.3.4 Guided Vascularization Through 3D Bioprinting
		12.4 Pulmonary Vascular Diseases
		12.5 Conclusion
		References
	Chapter 13: An Overview of Organ-on-a-Chip Models for Recapitulating Human Pulmonary Vascular Diseases
		13.1 Introduction
		13.2 Microfluidics and Organ-on-a-Chip
			13.2.1 Concepts
				Microfluidics in Vascular Biology
				Patterning Microvascular Networks
		13.3 OoC for Pulmonary Vascular Diseases
		13.4 Conclusion
		References
	Chapter 14: Clinical Translation of Engineered Pulmonary Vascular Models
		14.1 Introduction
		14.2 Brief Overview of Pulmonary Vascular Physiology
		14.3 Reconstituting Microenvironmental Cues to Improve Model Fidelity
		14.4 ECM Substrates
		14.5 Cell-Cell Crosstalk
		14.6 Shear Stress
		14.7 Cyclic Stretch
		14.8 Translational Potential of Current Models
		14.9 Organ Chips
		14.10 Organoids
		14.11 Conclusion
		References
Part V: Engineering and Modeling the Interface Between Medical Devices and the Lung
	Chapter 15: Extracorporeal Membrane Oxygenation: Set-up, Indications, and Complications
		15.1 Introduction to Modes of ECMO
			15.1.1 Veno-Venous ECMO
			15.1.2 Veno-Arterial ECMO
			15.1.3 VVA- and VAV-ECMO
			15.1.4 ECCO2R ECMO
			15.1.5 Other Components of the ECMO System
		15.2 Thrombosis and Bleeding
		15.3 Infection
		15.4 Inflammatory Response
		15.5 Bridge to Transplant
		15.6 Conclusion
		References
	Chapter 16: Current and Future Engineering Strategies for ECMO Therapy
		16.1 Introduction
		16.2 Blood Oxygen
		16.3 Advances in ECMO Circuit
			16.3.1 Cannula and Circuit Tubing
			16.3.2 Pumps
			16.3.3 Membrane Oxygenator
		16.4 Experimental Strategies
		16.5 Membrane Surface Coatings
			16.5.1 Bioactive Coatings
			16.5.2 Biopassive Coatings
		16.6 Endothelialization of ECMO Membrane: Biohybrid Approach
		16.7 Miniaturization of ECMO Circuit
		16.8 Conclusion
		References