Electromechanobiology of Cartilage and Osteoarthritis: A Tribute to Alan Grodzinsky on his 75th Birthday

Preface
Contents
Editors and Contributors
About the Editors
Contributors
Part I: Scientific Impact
1: Aggrecan and Hyaluronan: The Infamous Cartilage Polyelectrolytes – Then and Now
1.1 Introduction
1.2 Chondroitin Sulfate and Keratan Sulfate Fine Structure on Aggrecan
1.2.1 Aggrecan CS Chain Length and Sulfation Are Different in Skeletal Growth and Mature Cartilages
1.2.2 GAG Biosynthesis Is a Multienzyme Process That Takes Place During Core Protein Trafficking Through the ER and Golgi
1.2.3 Skeletal Disorders Caused by Defective Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans
1.2.4 Intracellular Localization and Topographical Organization of Enzymes for Aggrecan GAG Synthesis
1.2.5 ER/Golgi Topography and Organelle Microenvironment of GAG Synthesizing Enzymes
1.2.6 Alterations in CS Fine Structure by Biomechanical Stimuli – What Parts of the Post-translational Pathway Are They Targeting?
1.3 Aggrecan Metabolic Turnover in the ECM of Healthy and Osteoarthritic Cartilages
1.3.1 Enzymatic Mechanism of Aggrecanolysis
1.3.2 Targeted Inhibition of Aggrecanolysis – A Potential Treatment for Human Osteoarthritis?
1.4 Hyaluronan Metabolism and Its Relevance to Cartilage Structure and Function
1.4.1 Hyaluronan in Cartilage Matrix Structure and Articular Joint Mechanics
1.4.2 Engagement of Hyaluronan Receptors Modulates Cell Responses
1.5 HA Metabolism Pathways Support Cell Survival
1.5.1 Enzymatic Pathways in HA Synthesis and Catabolism
1.5.2 Synergy Between Glucose Metabolism and HA Synthesis Adjusts the Cellular Energy Status
1.5.3 Are Biophysical Stressors Important in Regulation of HA Metabolism by Chondrocytes?
1.6 Conclusion
References
2: Understanding the Influence of Local Physical Stimuli on Chondrocyte Behavior
2.1 Introduction
2.2 Static Stimulus
2.2.1 Mechanical Anchoring and Substrate Stiffness
2.3 Dynamic Stimuli
2.3.1 Dynamic Compression
2.3.2 Oscillatory Shear and Tension
2.3.3 Impact/Injurious Loading
2.4 Future Direction
2.4.1 Combined Loading
2.4.2 Big Data/Machine Learning
2.5 Conclusion
References
3: Multiscale In Silico Modeling of Cartilage Injuries
3.1 Introduction
3.2 Experiments to Study Tissue Alterations Following Cartilage Injury
3.2.1 General
3.2.2 Setup
3.2.3 Analysis of Structure and Composition
3.2.4 Biological Analysis
3.3 In Silico Models for Understanding Mechanisms Leading to Cartilage Degeneration
3.3.1 General
3.3.2 Theory
3.4 From In Vitro to In Vivo
3.4.1 General
3.4.2 In Vivo Experiments
3.4.3 In Vivo FE Analysis
3.4.4 Summary from In Vitro and  In Vivo Studies
3.5 Toward a Clinical Assessment Tool to Aid Decision Making
3.6 Future Plans
References
4: In Vitro Models and Proteomics in Osteoarthritis Research
4.1 Introduction
4.2 In Vitro Models in Osteoarthritis
4.3 Inflammatory Models
4.4 Mechanical Loading
4.5 Proteomics
4.6 Proteomics Applications Using In Vitro Models
4.6.1 Targeted Proteomics Applications
4.6.1.1 Explant Cultures
4.6.2 Discovery Proteomics Applications
4.6.2.1 Cell Cultures
4.6.2.2 Explant Cultures
4.7 Concluding Remarks and Future Perspectives
References
5: Nanomechanics of Aggrecan: A New Perspective on Cartilage Biomechanics, Disease and Regeneration
5.1 Introduction
5.2 Ultrastructure and Nanomechanics of Aggrecan
5.3 Implications for Aging, Disease and Regeneration
5.4 Other Native and Biomimetic Proteoglycans
5.5 Summary and Outlook
References
6: Computational Modelling for Managing Pathways to Cartilage Failure
6.1 Introduction
6.2 Articular Cartilage, an Extraordinary Tissue
6.3 Cartilage Damage Mechanics
6.4 Role of Computational Modelling to Capture Complex Interactions
6.5 Using Models to Investigate Pathways to Cartilage Failure
6.6 Probabilistic Modelling and Osteoarthritis Risk Assessment
6.7 Conclusion
References
7: Gene Delivery to Chondrocytes
7.1 Introduction: Why Transfer Genes to Chondrocytes?
7.2 A Gene Transfer Primer
7.2.1 Viral Vectors
7.2.2 Non-viral Vectors
7.2.3 Gene Activated Matrices
7.3 Gene Delivery to Chondrocytes
7.4 Progress in the Clinical Application of Gene Transfer to Chondrocytes
7.4.1 Osteoarthritis
7.4.2 Cartilage Regeneration
7.5 Additional Considerations
7.6 Conclusions
References
8: Mechanical Articular Cartilage Injury Models and Their Relevance in Advancing Therapeutic Strategies
8.1 Introduction
8.2 From Electromechanobiological Structure-Function Relationships to Developing a Versatile Shear and Compression Model for Understanding the Injurious Response of Articular Cartilage
8.2.1 Unraveling Central Electrokinetic and Biomechanical Properties of Articular Cartilage – The Basis for Understanding Tissue Failure Under Injurious Compressive Loads
8.2.2 The Invention of a Successful In Vitro Cartilage Injury Model
8.2.3 The Effects of Mechanical Compressive Injury on Articular Cartilage Biomechanics, Metabolic Behavior and Cell Viability and Their Strain-, Strain Rate- and Peak Stress-Dependency
8.2.4 Understanding the Molecular Concept of Mechanical Injury by Studying Gene Expression, Signal Transduction and the Release of Potential Injury Biomarkers
8.2.5 Elucidating the Zonal, Age and Species-Dependency of Injurious Compression
8.2.6 Combining Mechanical Injury with Cytokine Exposure or Co-culture Systems for Generating a More Realistic Trauma Model
8.2.7 Predicting Articular Cartilage Properties and Injurious Damage on the Structural, Biochemical and Biomechanical Level
8.3 Therapeutic Modulation of the Injurious Response
8.3.1 Dexamethasone and 17b-Estradiol – Steroid Hormone Treatment of Mechanically-Injured Articular Cartilage and in an In Vivo PTOA Model Lead to Clinical Assessment
8.3.2 Interleukin 10 (IL-10) Treatment of Mechanically-Injured Articular Cartilage and Cell-Laden ACI Grafts
8.3.3 IGF-1 in Treatment of Mechanically-Injured Articular Cartilage and in an In Vivo PTOA Model
8.3.4 Anti-IL-6 Fab-Fragment in Treatment of Mechanically-Injured Articular Cartilage
8.3.5 Antioxidant Treatment of Mechanically-Injured Articular Cartilage
8.3.6 MMP Inhibitors and a VEGFR-2 Kinase Inhibitor in Treatment of Mechanically-Injured Articular Cartilage
8.3.7 Moderate vs. High Dynamic Compressive Loading of Mechanically-Injured Articular Cartilage
8.4 Final Remarks
References
9: Hip Osteoarthritis: Bench to Bedside Perspective
9.1 Introduction
9.2 Osteoarthritis or Osteoarthrosis – What Is the Role of Biological vs Mechanical Factors in the Development and Progression of Hip OA?
9.3 Articular Cartilage – Paradigm Shift from Inert Lubricating Cushion to Biologically Active and Mechanosensitive Tissue
9.4 Bench to Bedside – Use of dGEMRIC in Understanding the Effect of Pelvic Osteotomy on Hip Articular Cartilage
9.5 Summary
References
10: Harnessing Growth Factor Interactions to Optimize Articular Cartilage Repair
10.1 Introduction
10.2 Multiple Growth Factors
10.3 Multiple Combinations of Growth Factors
10.4 Multifunctional Growth Factors
10.5 Opportunities for Progress
10.6 Biochemical and Biophysical Factor Combinations
10.7 Growth Factor – Matrix Interaction: Role in Growth Factor Delivery
10.8 Conclusions
References
Part II Personal Tributes
A Toast to Al
A Letter to Alan
Tribute to Al from Finland
Rami “Trusted Astronaut” Korhonen
Cristina “Chief AFM Sailor” Florea
Petri “Paulaner Brother-in-Arms” Tanska
Atte “Duffman” Eskelinen
On Behalf of the Undergraduate Trainees
Mentor
Instructor
Supporter
Congratulations, Al
Ode to Al: A Tribute from the Boston Osteoarthritis Researchers (BOAR)
Grateful
Reflections from a Graduate Student
Thanks to Alan
A Thank You Note to Alan J. Grodzinsky from Germany
A Tribute to Al
Index