Preface
Acknowledgments
Contents
About the Editors
Contributors
Part I: Basics of Vascular Biology
Angiogenesis: Basics of Vascular Biology
1 Introduction
2 Neovascularization in Early Development
3 Different Forms of Angiogenesis
4 Intussusceptive Angiogenesis
5 Dominant Growth Factors in Angiogenesis
6 Balancing Angiogenesis: Endogenous Inhibitors
7 Sprouting Angiogenesis: Initiation and Invasion
8 Extension and Stabilization of Sprouts: Dll4/Notch Signaling
9 Guidance of Tip Cells
10 Metabolic Control of Sprouting
11 Lumen Formation
12 Anastomosis and Vessel Stabilization
13 Pruning
14 Lymphangiogenesis
15 Postnatal Vasculogenesis
16 Generation of a Functional Microvascular Bed
17 Conclusion
References
Mechanical Regulation of Microvascular Growth and Remodeling
1 Introduction
2 Cell-level Description of Mechanical Perturbations in Microvasculatures
2.1 Mechanical Inputs to Cell-Based Systems and Their Biological Outcomes
2.1.1 Fluid Shear
2.1.2 Interstitial Flow
2.1.3 Tensile Stretch
2.1.4 Extracellular Matrix Deformation
2.2 Cell Mechanotransduction
2.2.1 Mechanosensory Systems
2.2.2 Mechanical Equilibrium and Force Transmission
2.3 Concerted Response of Multiple Cells and Integration of Multiple Mechanical Cues
2.3.1 Cell-Cell, Cell-Matrix, and Soluble Factors Coupling
2.3.2 Topography and Mechanics
3 Microvessel-Level Description of Mechanical Perturbations in Microvasculatures
3.1 Tip and Stalk Dynamics
3.2 Stroma-Neovessel Forces
3.2.1 Neovessel-Fibril Interactions
3.3 Mechanical Forces and Network Topology
3.3.1 Hemodynamic Forces
3.3.2 Interstitial Fluid Forces
3.3.3 Tissue Stresses
4 Integrated Computational Modeling of Vascular Growth and Topology
4.1 Modeling Approaches
4.1.1 Modeling Dynamic Systems
4.1.2 Modeling Growth Behaviors
4.1.3 Modeling Scales
4.1.4 Model Assessment
4.1.5 Commonly Used Modeling Paradigms
4.1.6 Cell and Matrix Interactions
4.1.6.0 Effects of Constraints/Boundaries
4.1.6.0 Durotaxis, Porosity, and ECM Density
4.1.6.0 Matrix Anisotropy
4.1.6.0 Luminal Flow
4.1.7 Biophysical Factors
4.1.7.0 Cytokine Distribution in ECM
4.1.8 Intercellular Interactions
4.1.8.0 Biochemical
4.1.8.0 Mechanical
4.1.8.0 Effects of Stromal Cells
5 Conclusions
References
Part II: Angiogenesis Induction
Therapeutic Angiogenesis in Regenerative Medicine
1 Introduction
2 Mechanism Leading to the Formation of New Blood Vessels
2.1 Vasculogenesis
2.2 Angiogenesis
2.2.1 Vessel Sprouting
2.2.2 Formation of Vessel Anastomosis
2.2.3 Vessel Maturation and Stabilization
2.2.4 Intussusceptive Angiogenesis
2.3 Arteriogenesis
3 Angiogenic Growth Factors: Importance of ECM Binding
4 Therapeutic Angiogenesis
4.1 Angiogenic Gene Therapy
4.2 Growth Factor Delivery from First-Generation Biomaterials
4.3 The Critical Importance of the Microenvironmental Growth Factor Dose
4.4 Key Requirements for Therapeutic Angiogenesis´´ Using Recombinant Growth Factors
5 Engineering Strategies to Deliver Growth Factors for Therapeutic Angiogenesis
5.1 Controlled Delivery of Angiogenic Growth Factors by Engineered Biomaterials
5.2 Engineering of Hydrogel Biomaterials with ECM-Derived Growth Factor Affinity Sites
5.3 Hydrogels with Covalently Bound Growth Factors
5.4 Controlling Growth Factor Delivery by Biomaterials Stability
5.5 Engineering of Growth Factors with ECM Affinity
6 Combination Therapies for Enhanced Angiogenesis, Maturation, and Stabilization
7 Conclusions and Future Directions
References
Therapeutic Angiogenesis: Translational and Clinical Experience
1 Introduction
1.1 Therapeutic Angiogenesis
1.2 Myocardial Gene Therapy
1.3 Gene Therapy for Peripheral Artery Disease
2 Preclinical Studies
2.1 Translational Pathway in the Preclinical Setting
2.2 Animal Models
2.2.1 Small Animals
2.2.2 Large Animals
2.3 Delivery
2.3.1 Administration in Small Animal Models
2.3.2 Administration in Large Animals
2.3.3 Vectors
2.4 Transgenes
3 Clinical Trials
3.1 PAD Trials
3.1.1 VEGF Trials
3.1.2 HGF Trials
3.1.3 FGF Trials
3.2 Myocardial Trials
3.2.1 VEGF Trials
3.2.2 FGF Trials
3.2.3 Other Trials
4 Conclusions
References
Targeting the CellularOxygen Sensors´´: Hypoxia Pre-conditioning and Stabilization of Hypoxia-Inducible Factors
1 Introduction
2 The Biology of Hypoxia: Hypoxia-Inducible Factors as Key Players
3 Pharmacologically and Genetically Simulated Hypoxia
4 Potential Applications for Hypoxia-Based Strategies
4.1 Ischemia
4.2 Inflammatory Disease
4.3 Tissue Injury
5 Ex Vivo Hypoxia-Based Pre-conditioning Strategies in Tissue Engineering and Regenerative Medicine
6 In Vivo Hypoxia-Based Strategies in Tissue Engineering and Regenerative Medicine
7 Future Directions
8 Conclusion
References
Probing Vasculature by In Vivo Phage Display for Target Organ-Specific Delivery in Regenerative Medicine
1 Introduction
2 History
3 Vascular Address System
3.1 Molecular Features of Vessel Endothelium
3.2 Homing and Penetrating Peptides
4 Screening Method
4.1 Peptide Design
4.2 Biopanning Protocol
4.3 Target Molecule Recognition
4.4 Advantages and Disadvantages
5 Applications
5.1 Therapeutics Delivery
5.2 Imaging and Diagnostics
5.3 Examples of Applications in Regenerative Medicine
6 Conclusions
References
From Secondary Intent to Accelerated Regenerative Healing: Emergence of the Bio-intelligent Scaffold Vasculogenic Strategy for...
1 Introduction
1.1 Clinical Issues and Unmet Need
1.2 Current Products, Strategies, and Shortcomings
2 Bio-intelligent Scaffold Hypotheses
2.1 Synthetic Skin Biomaterials
2.2 Tissue Scaffold Modalities
2.3 Concept of a Pro-angiogenic Synthetic Dermal Replacement Scaffold
3 Development of a First-Generation Bio-intelligent Scaffold Product
3.1 Initial Identification of a Biomaterial Substrate
3.2 Development of a Fibrin-Based Biomaterial
3.3 Scaffold Structure
3.4 Proteolytic Stability
3.5 Cytotoxicity
3.6 Cyto-adhesion, Cell Ingress Assessments
3.7 Long-Term Fibroblast Regulation
3.8 In Vivo Evaluation and Optimization: Splinted Wound Healing
3.9 Evaluation of Formulation, Porosity, and Scaffold Structure
3.10 Single-Step Full-Thickness Reconstruction
3.11 Long-Term Outcome of Full-Thickness Reconstruction
4 First Step to Addressing Chronicity or Delayed Wound Healing
4.1 The Delayed Partial Burn Excision Model
4.2 Scaffold Treatment in the Delayed Wound Model
5 Conclusions
5.1 Emergent Development of a Bio-intelligent Scaffold for Dermal Reconstruction
5.2 Vascularization of Fibrin Scaffolds
5.3 The Bio-intelligent Biomaterial Scaffold Concept for Chronic Wounds
5.4 Future Strategies for Bio-intelligent Scaffold Developments
5.5 Summary
References
Stimulation by Light
1 Introduction
2 History of Low-Level Light Therapy (LLLT)
3 Coherent Light (Laser) Versus Incoherent Light (LED)
4 Biphasic Dose Response
5 Interaction of Light with Tissue
6 General Mechanism of LLLT
7 In Vitro
7.1 Secondary Angiogenic Effects of Supporting Cells After Exposure to LLLT
8 In Vivo
9 Conclusion
References
Approaches for Generation of Lymphatic Vessels
1 Introduction
2 Biology and Functions of the Lymphatic System
3 Lymphatic Development
4 Lymph-Specific Markers
5 In Vitro Culturing of LECs
6 Scaffold-Based Approaches
7 Regenerative Approaches
8 Conclusion
References
Biomimetic Models of the Microcirculation for Scientific Discovery and Therapeutic Testing
1 Introduction
2 Motivation for Microvascular Research
3 Angiogenesis: Cell/System Dynamics Involved in Microvascular Growth
4 Need for Integrative Biomimetic Models of the Microcirculation
4.1 Biomimetic Experimental Models
4.2 Biomimetic Computational Examples
5 Conclusions
References
Part III: Prevascularization
Microvascular Networks and Models: In Vitro Formation
1 Introduction
1.1 The Microvasculature
1.2 Dynamics of Microvasculature Networks
1.3 The Microvasculature in Engineered Tissue
2 Cells and Model Systems to Generate a Capillary Network In Vitro
2.1 Role of Different Cell Types in Capillary Formation and Stabilization
2.1.1 Endothelial Cells
2.1.2 Pericytes
2.1.3 Mesenchymal Stem Cells
2.1.4 Smooth Muscle Cells
2.1.5 Hematopoietic Cells and Inflammation
2.2 In Vitro Models of Vasculogenesis and Angiogenesis
2.2.1 Vasculogenesis Models
2.2.2 Angiogenesis Models
2.3 Origin of Cells Used in In Vitro Models
2.3.1 Embryonic Stem Cell
2.3.2 Endothelial Progenitor Cells
2.3.3 Primary Endothelial Cells
2.3.4 Endothelial Cells from Adult Tissue (Lung, Brain, Colon, Mucus Membrane, Skin)
2.3.5 EC-iPSCs
2.3.6 Adipose Stromal Vascular Fraction/SVF-ECs for Prevascularization Approaches
2.3.7 Bone Marrow Stromal Vascular Fraction
3 Scaffold Materials that Enable the Formation of 3D Micro-Capillary Networks
3.1 Lesson from the Pioneers and the ECM
3.2 Natural Materials: Protein Polymers
3.3 Tuning Protein Polymers: Modified Collagen
3.4 Modified Natural and Synthetic Polymers
4 Advanced Bioengineering Approaches
4.1 3D-Printing of Blood Vessels
4.2 Acoustic Bioprinting
4.3 Microfluidic System
5 Conclusion and Outlook
5.1 Use of In Vitro Microvascularized Constructs
References
Co-culture Systems for Vasculogenesis
1 Introduction
2 Choice of Cells to Create Vascularized Systems
2.1 Endothelial Cells
2.2 Supporting Cells
3 Engineering Tissue-Specific Vasculature
3.1 Skin
3.2 Muscle
3.3 Cardiac Tissue
3.4 Pancreas
3.5 Bone
4 Construct Fabrication Techniques
4.1 Biomaterials
4.2 Decellularization
4.3 3D-Bioprinting
4.4 Microfabrication
5 Manipulation of External Forces
5.1 Cyclic and Static Strain
5.2 Flow-Induced Shear Stress
6 Conclusions
References
Cell Sorting, Culture, Preconditioning, and Modulation/Cell Aggregates: Sheets
1 Introduction
2 The Temperature-Responsive Cell Culture Surface
2.1 Conjugating Biomolecules onto the PIPAAm-Grafted Surface
2.2 Micropatterned Temperature-Responsive Cell Culture Surface
3 Building Functional 3D Tissues with Cell Sheets
3.1 Cell Sheet Manipulation Technology
3.1.1 Manual Methods
3.1.2 Automated Manufacture Systems
3.2 Fabrication of Thick Cardiac Tissues with Functional Vasculature
3.3 Fabrication of Organ-like Structures
4 Application of Cell Sheet-Based Tissue Engineering
4.1 Heart
4.2 Liver
4.3 Cornea
4.4 Esophagus
4.5 Periodontal Tissue
4.6 Cartilage
4.7 Lung
4.8 Other Applications
5 Conclusions
References
In Vitro and In Vivo Approaches for Prevascularization of Three-Dimensional Engineered Tissues
1 Introduction
1.1 Extrinsic Vascularization
1.2 Addition of Angiogenic Growth Factors
1.3 Vascular Pedicle Capillary Sprouting and Its Use in Surgical Prefabrication
1.4 The Rat Arteriovenous Loop Chamber Model
1.5 Versatility and Modifications of the AVL Chamber Model
1.6 Alternative Animal Chamber Models
1.7 The Concept of Pre-vascularization
1.8 3D Printing of Capillary Networks
1.9 Combining Vascular Pedicles with Pre-vascularized Scaffolds
2 Conclusion
References
Perfusion Bioreactors for Prevascularization Strategies in Cardiac Tissue Engineering
1 Introduction
2 Factors Influencing Vascularization and Tissue Development
2.1 Cells
2.2 Oxygen
2.3 Perfusion
2.4 Artificial Lumen Versus Donor Vessel
2.5 Shear Stress
3 Additional Bioreactor Features for Promoting Tissue Development
3.1 Mechanical Strain
3.2 Quality Control in Advanced Bioreactor Systems
4 Conclusion
References
Past and Future Prevascularization Strategies with Clinical Relevance: Leading to a Dual Approach
1 Introduction
2 Vascularization Strategies and the Development of a Dual Approach
2.1 In Vitro Pre-vascularization Techniques
3 The Importance of Choosing the Most Appropriate Scaffold, Cell Type, and Mechanical Stimulation
4 The Dual Approach: First Successes and Challenges
5 Conclusions
References
Microsurgical Approaches for In Vivo Prevascularization
1 Introduction
2 Prevascularization Strategies
2.1 Surgical Approaches for In Vivo Prevascularization
3 Prefabrication and Prelamination
4 The Arteriovenous Loop Model
4.1 AV Loop Chamber
4.2 Chamber Modifications
4.3 Matrix Modifications
4.4 Quantification of AV Loop Associated Angiogenesis
4.5 AV Loop as a Model of De Novo Angiogenesis
4.6 Clinical Implications and Translational Approaches
5 Further Microvascular Approaches
6 Future Perspectives
7 Conclusion
References
From Autologous Flaps to Engineered Vascularized Grafts for Bone Regeneration
1 Introduction
2 Approaches in Plastic and Reconstructive Surgery
2.1 Description of Flaps
2.2 Categories of Flaps
2.3 The Donor Site Problem and the Drawbacks of Grafting
3 Bone Grafting
3.1 Fibula Bone Graft
3.2 Iliac Crest Bone Graft
3.3 Scapula Bone Flap
3.4 Costal Bone Graft
3.5 Distal Radius Pedicled Bone Flap
3.6 Medial Femoral Condyle Flap
4 Engineering Vascularized Grafts
5 Ectopic Prefabrication of Engineered Bone Grafts
5.1 Angiogenic Ingrowth
5.2 Flap Technique
5.3 AV Loop Technique
5.4 AV Bundle Technique
6 Future Directions
6.1 Graft Prefabrication Using Adipose-Derived Cells
6.2 Graft Prefabrication Using Microvascular Fragments
6.3 Graft Prefabrication Using 3D Printing and Microfluidic Systems
7 Conclusions
References
Index