Early Osteoarthritis: State-of-the-Art Approaches to Diagnosis, Treatment and Controversies

Preface
Contents
Part I: Early OA Definition, Epidemiology and Risk
	1: Definition of Early Osteoarthritis
		1.1	 Introduction
		1.2	 Clinical Presentation of Early OA
		1.3	 Structural Definition of Early Osteoarthritis
		1.4	 A Short History on the Progress in the Clinical Definition of Early Osteoarthritis
		1.5	 ESSKA 2012 Consensus Criteria for a Definition of Early Osteoarthritis
		1.6	 First International Early Knee Osteoarthritis Workshop 2014 Toward Classification Criteria for Early Osteoarthritis of the Knee
		1.7	 Establishing Outcome Measures in Early Knee Osteoarthritis
		1.8	 Application of the Definition of Early OA
		1.9	 Outlook
		References
	2: MRI of Early OA
		2.1	 Morphological MRI
		2.2	 T2 Mapping
		2.3	 Sodium (23Na) MRI
		2.4	 dGEMRIC in OA
		2.5	 Conclusion/Future Perspective
		References
	3: MRI Relaxometry as Early Measures of OA
		3.1	 dGEMRIC: Delayed Gadolinium-Enhanced MRI of Cartilage
		3.2	 T2 and T2* Relaxation Time Measurements
		3.3	 T1ρ Imaging
		3.4	 Summary
		References
	4: Epidemiology of Post-traumatic Osteoarthritis of the Lower Extremity: Premature Aging of Youthful Joints
		4.1	 Epidemiology of Osteoarthritis
		4.2	 Overview of Mechanisms Linking Trauma to Osteoarthritis
		4.3	 Post-traumatic Knee Osteoarthritis
			4.3.1	 ACL Injury
			4.3.2	 ACL Reconstruction Surgery
			4.3.3	 Meniscal Tears
		4.4	 Post-traumatic Hip Osteoarthritis
		4.5	 Post-traumatic Ankle Osteoarthritis
		4.6	 Summary
		References
	5: Economic Aspects of Early Osteoarthritis
		5.1	 Introduction
		5.2	 Current Economic Burden of Osteoarthritis
		5.3	 Special Issues Associated with Early Osteoarthritis
		5.4	 Socioeconomic Characteristics of Patients with Early Osteoarthritis
			5.4.1	 Socioeconomic Distribution
			5.4.2	 Education
			5.4.3	 Work Status
		5.5	 Cost-Effectiveness of Treatments for Early Osteoarthritis
			5.5.1	 Knee
			5.5.2	 Hip
		5.6	 Conclusion
		References
	6: Early Osteoarthritis: Frequency, Epidemiology, and Cost of ACL Injuries
		6.1	 Introduction
		6.2	 Frequency and Incidence
			6.2.1	 Skeletally Immature Patients
			6.2.2	 Competitive Athletes
			6.2.3	 Recurrent ACL Injury
		6.3	 Cost-Effectiveness
			6.3.1	 Costs of ACL Reconstruction and Conservative Management
			6.3.2	 The Role of Time to Intervention
			6.3.3	 Costs of Concomitant Meniscus Pathology
			6.3.4	 The Role of the Surgical Setting
			6.3.5	 The Role of Anesthesia
			6.3.6	 Costs Based on Graft Type
			6.3.7	 Costs Based on Technique
			6.3.8	 Injury Prevention
		6.4	 Conclusion
		References
	7: The Human Anterior Cruciate Ligament Injury Model of Early Osteoarthritis
		7.1	 Prevalence of Osteoarthritis After Anterior Cruciate Ligament Injury
		7.2	 ACL Injury as a Model of Early Osteoarthritis
			7.2.1	 Persistent Inflammatory Response and Cartilage Breakdown
			7.2.2	 Changes to Underlying Bone
			7.2.3	 Muscular Changes
		7.3	 Patient and Injury Factors That Increase the Likelihood of Osteoarthritis After ACL Injury
			7.3.1	 Concomitant Meniscus Injury
			7.3.2	 Increased Age at the Time of Injury or Surgery
			7.3.3	 Increased Body Mass Index (BMI)
			7.3.4	 Female Sex
		7.4	 Conclusion
		References
Part II: Basic Science of Early OA
	8: Biomechanics of Instability and Its Relationship to OA
		8.1	 Introduction
		8.2	 Injury Patterns and the Prevalence of OA
			8.2.1	 Meniscus
			8.2.2	 Anterior Cruciate Ligament (ACL)
			8.2.3	 Posterior Cruciate Ligament (PCL)
			8.2.4	 Multi-ligament/Knee Dislocation
			8.2.5	 Collateral Ligaments
		8.3	 Limitations of Clinical Studies
			8.3.1	 Concomitant Injuries
			8.3.2	 Host-Related Variables
			8.3.3	 Operative vs. Non-operative Treatment
			8.3.4	 Variation in Outcome Metrics
		8.4	 Future Perspectives
			8.4.1	 Animal Models
			8.4.2	 In Vivo Kinematics
			8.4.3	 Advanced Imaging and Biomarkers
		8.5	 Conclusion
		References
	9: Early OA Following Synovial Joint Fracture
		9.1	 Joint Fractures and Post-traumatic Osteoarthritis
		9.2	 Evaluation of OA Risk Following Joint Fracture
			9.2.1	 Acute IAF Severity (Fracture Energy)
			9.2.2	 Chronic Overloading (Residual Joint Incongruity and Instability)
		9.3	 Biologic Mechanisms Responsible for PTOA Following Joint Fracture
			9.3.1	 Mitochondrial-ROS Pathway
			9.3.2	 Chondrocyte Senescence
		9.4	 Minimizing the Risk of OA Following Joint Fracture
			9.4.1	 Interruption of the Mitochondrial-ROS Pathway
			9.4.2	 Senolytics
		9.5	 The Potential of Chondrocyte Progenitor Cells to Restore Articular Cartilage Following Joint Fracture
		9.6	 Rehabilitation Following IAF
		9.7	 Future Advances Needed to Decrease the Risk of OA Following Joint Fracture
		References
	10: Inflammation After Anterior Cruciate Ligament Injury
		10.1	 Biochemical Response to Injury
		10.2	 Post-operative Response
		10.3	 Inflammatype
		10.4	 Treatment Considerations
		References
	11: T Cells in Early Osteoarthritis
		11.1	 Introduction
		11.2	 Orchestration of the T Cell Response in OA
		11.3	 CD8+ Cytotoxic T Cells (CTL)
		11.4	 T Helper 1 Cells (Th1)
		11.5	 T Helper 2 Cells (Th2)
		11.6	 T Helper 17 Cells (Th17)
		11.7	 Regulatory T Cells (Tregs)
		11.8	 Th17: Treg Phenotype Plasticity
		11.9	 T Cell-Targeted Immunotherapies for OA
		11.10	 Conclusion
		References
	12: Monocytes, Macrophages and Joint Inflammation in Osteoarthritis
		12.1	 Introduction
			12.1.1	 Joint Inflammation in OA: A Role for Monocytes and Macrophages
			12.1.2	 Osteoclasts in Bone Marrow Lesions and Subchondral Bone Loss in OA
		12.2	 What Can Animal Models of Osteoarthritis Teach Us About the Role of Myeloid Cells in OA
			12.2.1	 Naturally Occurring Osteoarthritis
			12.2.2	 Induced and Invasive Models of Osteoarthritis
		12.3	 Human Osteoarthritis and Translational Research
			12.3.1	 Identification of Myeloid Cells in Human OA Biopsies
		12.4	 Targeting Myeloid Cells to Treat OA
			12.4.1	 Clinical Therapies Targeting Inflammatory Cytokines in OA
				12.4.1.1 Targeting Interleukin Pro-inflammatory Cytokines, IL-1 and IL-6
				12.4.1.2 JAK Inhibitors
				12.4.1.3 Targeting TNF
			12.4.2	 Osteoclast Targeted Therapies
				12.4.2.1 Bisphosphonates
				12.4.2.2 Cathepsin K Antibody
				12.4.2.3 Denosumab
				12.4.2.4 Strontium Ranelate.
			12.4.3 Additional Therapies with Actions on Myeloid Cells
				12.4.3.1 Targeting NGF
				12.4.3.2 Targeting MMPs
		12.5	 Conclusion
		References
	13: Mesenchymal Stromal Cells and Extracellular Vesicles
		13.1	 Introduction
			13.1.1	 Early Osteoarthritis Pathogenesis
			13.1.2	 Regenerative Medicine Approach to Early Osteoarthritis
		13.2	 Mesenchymal Stromal Cells
			13.2.1	 Definition and Classification of MSCs
			13.2.2	 MSC Tissue Source
			13.2.3	 Autologous Versus Allogeneic MSCs
			13.2.4	 Heterogeneity Within MSCs Populations
		13.3	 MSC-Based Strategies for the Treatment of Early OA
			13.3.1	 Intra-articular Injection of MSCs
			13.3.2	 MSC-Based Repair of Focal Cartilage Lesions
		13.4	 Proposed Therapeutic Mechanism of MSCs
			13.4.1	 Direct Engraftment and Differentiation
			13.4.2	 The MSC Secretome
			13.4.3	 Immunomodulation
			13.4.4	 MSC Priming/Licensing
			13.4.5	 Mitochondrial Transfer
		13.5	 Extracellular Vesicles
			13.5.1	 Biology of Extracellular Vesicles
			13.5.2	 EVs and Immunomodulation
			13.5.3	 EVs in OA Pathogenesis
		13.6	 MSC-Derived Extracellular Vesicles
			13.6.1	 Bioengineered Vesicles
		13.7	 Challenges to the Development of MSC-EV Therapies
			13.7.1	 EV Characterization
			13.7.2	 EV Isolation and Storage
		13.8	 Summary and Conclusion
		References
Part III: Treatment of Early OA
	14: Role of Injection Therapy in Early Osteoarthritis: Cortisone, Viscosupplement, PRP?
		14.1	 Introduction
		14.2	 Corticosteroids
		14.3	 Viscosupplementation
		14.4	 Platelet-Rich Plasma
		14.5	 Take Home Message
		References
	15: The Current Role of Stem Cell Therapy and iPS Cells
		15.1	 Introduction
		15.2	 Mesenchymal Stem Cells in OA
		15.3	 Embryonic Stem Cells in OA
		15.4	 Induced Pluripotent Stem Cells in OA
		15.5	 Review of Clinical Trials Using MSCs in OA
			15.5.1	 Intra-articular Injections
			15.5.2	 Tissue Engineering Approaches
		15.6	 Conclusion
		References
	16: Fat-Derived Stem Cells
		16.1	 Mesenchymal Stem Cells: New Biological Insights to Face Early OA Degenerative Environment
		16.2	 Features of ASCs: Adipose Tissue (Fat) Stem Cells
		16.3	 Fat-Derived Cell Products in the Treatment of Early OA
			16.3.1	 Preclinical Findings
				16.3.1.1	 Expanded ASCs
				16.3.1.2	 Nonexpanded (Minimally Manipulated) Adipose-Derived Cell Products
		16.4	 Clinical Trials
		16.5	 Conclusion
		References
	17: Bone Marrow Aspirate Concentrate for the Treatment of Early Osteoarthritis
		17.1	 Introduction
		17.2	 Harvest and Processing of BMAC
		17.3	 BMAC Components and Possible Mechanism of Action
		17.4	 Clinical Outcomes
		17.5	 Perspectives
			17.5.1	 Augmentation of BMAC with Additional Factors
			17.5.2	 Allogeneic or Autologous BMAC
			17.5.3	 Cellular Composition
			17.5.4	 Dosage
			17.5.5	 Safety and Limitations of the BMAC Technique
		17.6	 Conclusions
		References
	18: The Role of Alignment Correction With and Without Chondral Repair
		18.1	 Introduction
		18.2	 The Association of Load and Cartilage Health
			18.2.1	 Cartilage Strain and Activity
			18.2.2	 Changes in Chondrocyte Function in Response to Loading
		18.3	 Biomechanics of Gait and Coronal Plane Alignment
		18.4	 Realignment Osteotomy
			18.4.1	 Indications
			18.4.2	 Medial Opening High Tibial Wedge Osteotomy
			18.4.3	 Medial Closing Wedge Distal Femoral Osteotomy
		18.5	 Clinical Outcomes of Realignment Osteotomy With and Without Chondral Repair
			18.5.1	 Osteotomy in Isolation
			18.5.2	 Non-Comparative Series of Osteotomy in Combination With Cartilage Surgery
			18.5.3	 Comparative Series of Osteotomy With and Without a Chondral or Biologic Intervention
			18.5.4	 Comparative Series of Cartilage Surgery With and Without an Osteotomy
		18.6	 Treatment Algorithm
			18.6.1	 Our Decision-Making Process
		18.7	 Conclusion
		References
	19: Meniscus Injury and Early Osteoarthritis
		19.1	 Introduction
		19.2	 Meniscal Injury
		19.3	 Biomechanics of the Meniscus
		19.4	 Biomechanics Post-Meniscal Injury
		19.5	 Biochemical Changes Post-Meniscal Injury
		19.6	 Early OA
		19.7	 Meniscal Injuries and Early OA
		19.8	 Meniscal Surgery and OA
		19.9	 Conclusion
		References
	20: The Role of Arthroscopic Debridement, Microfracture and Surface Procedures
		20.1	 Introduction
			20.1.1	 Background
			20.1.2	 Clinical Evaluation
				20.1.2.1	 History
				20.1.2.2	 Exam
				20.1.2.3	 Imaging
			20.1.3	 Surgical Management
		20.2	 Cartilage Injuries
			20.2.1	 Articular Cartilage and the Osteochondral Unit
			20.2.2	 Prevalence and Natural History of Chondral Injuries
		20.3	 Arthroscopic Lavage, Debridement and Chondroplasty
			20.3.1	 Techniques
				20.3.1.1	 Arthroscopic Lavage and Debridement
				20.3.1.2	 Arthroscopic Chondroplasty
				20.3.1.3	 Abrasion Arthroplasty
				20.3.1.4	 Radiofrequency Chondroplasty
			20.3.2	 Post-operative Rehabilitation
			20.3.3	 Outcomes
		20.4	 Microfracture and Marrow Stimulation Techniques
			20.4.1	 Background
			20.4.2	 Indications/Contraindications
			20.4.3	 Technique
			20.4.4	 Postoperative Management and Rehabilitation
			20.4.5	 Complications
			20.4.6	 Outcomes
			20.4.7	 Augmentation of Microfracture
		20.5	 Conclusion
		References
	21: Osteochondral Allografts in Early Osteoarthritis
		21.1	 Introduction
		21.2	 Indications and Contraindications
		21.3	 Preoperative Planning
		21.4	 Surgical Technique
		21.5	 Post-operative Management
			21.5.1	 Outcomes
		21.6	 Complications
		21.7	 Summary
		References
	22: Cell-Based Procedures for Early Osteoarthritis
		22.1	 Introduction
		22.2	 Factors to Consider before Cell-Based Procedures
			22.2.1	 Importance of the Intact Subchondral Unit
			22.2.2	 Defect Characteristics
		22.3	 Technical Aspects of Cell-Based Treatment Options
			22.3.1	 Autologous Matrix-Induced Chondrogenesis (AMIC)
			22.3.2	 Autologous Chondrocyte Implantation (ACI)
			22.3.3	 Particulated Juvenile Allograft Transplantation (PJACT)
		22.4	 Postoperative Rehabilitation After Cell-Based Procedures
		22.5	 Definition of Partial and Complete Cartilage Repair Failure
		22.6	 Conclusion
		References
	23: Coral-Based Bioscaffold for the Treatment of Osteochondral Lesions of the Knee
		23.1	 Introduction
		23.2	 Chemical–Physical Composition of Agili-C
		23.3	 Scaffold Preparation and Sterilization
		23.4	 Patient Selection and Evaluation
		23.5	 Surgical Technique and Rehabilitation Protocol
		23.6	 Histology
		23.7	 Results
		23.8	 Adverse Events
		23.9	 Conclusion
		References
	24: Potential Gene Therapy Options for Early OA
		24.1	 Introduction
		24.2	 Principles of Gene Therapy for Early Osteoarthritis
		24.3	 The Normal Osteochondral Unit
			24.3.1	 Articular Cartilage
			24.3.2	 Subchondral Bone
		24.4	 Structural Changes to the Osteochondral Unit in Early OA
		24.5	 Gene Delivery Methods to Articular Cartilage
			24.5.1	 Viral Vectors
			24.5.2	 Nonviral Vectors
			24.5.3	 Strategies of Gene Therapy for Early OA
		24.6	 Gene Transfer to Articular Chondrocytes In Vitro
		24.7	 Translational Investigations of Gene Therapy for Early OA In Vivo
		24.8	 Current Clinical Gene Therapy Trials for Osteoarthritis
		24.9	 Outlook
		24.10	 Competing Interest Statement
		References
	25: Surgical Management for Early Arthritis in the Shoulder
		25.1	 Introduction
		25.2	 Arthroscopic Debridement (Chondroplasty) and Biceps Tenotomy
		25.3	 Microfracture
		25.4	 Autologous Chondrocyte Implantation (ACI)
		25.5	 Osteochondral Autologous Transfer System
		25.6	 Platelet Rich Plasma (PRP)
		25.7	 Summary
			25.7.1	 Osteoarthritis in the Shoulder
		References