Orthobiologics: Injectable Therapies for the Musculoskeletal System

Description

This book presents the evidence related to the use of injectable biologics to provide faster and better healing for musculoskeletal lesions and conditions. The authors discuss approaches, such as blood derivatives and cell concentrates, applied to lesions of muscles, ligaments, tendons, bones, meniscus and cartilage, as well as osteoarthritis. Chapters are written by some of the most influential opinion leaders in the field, with up-to-date review of the current literature, where the authors explore both the potential and the limitations of these minimally invasive and promising treatments. The first section is devoted to the formulations and rationale for the use of injectable orthobiologics, while the second section reviews current treatment methods applied to specific joints and pathologies – ranging from tendinopathies through non-unions to articular degenerative processes – as well as the results of these treatment approaches. The third section explores future perspectives, such as pluripotent stem cells, gene therapy, and the stimulation of intrinsic stromal cell niches. Appealing to a broad readership, this book will be of interest to both laboratory research scientists and clinicians, including orthopedists, sports physicians, physiatrists, and regenerative medicine experts. Preface Contents Part I: Injectable Orthobiologics: Formulations and Rationale 1: The Stem and Progenitor Cell Paradigms and Engineering Principles Guiding the Clinical Use of Cells or Cell-Derived Products for Regenerative Medicine 1.1 Overview 1.2 Domains of Progress 1.2.1 Choice between Rapid Point of Care Processing and Cell Expansion 1.3 Conceptual Paradigm of Stem and Progenitor Biology in the Context of Regenerative Medicine: Cell Composition and Cellular Kinetics 1.3.1 Stem and Progenitor Cell Systems and Niches 1.3.2 Tissue-Specific Kinetics and Stem/Progenitor Populations 1.3.3 Tissue-Derived Cell Populations: Heterogeneous Mixes of Cells and Biological Potential 1.3.4 Tissue-Specific Connective Tissue Progenitors 1.4 Engineering Principles 1.4.1 Clinical Assessment Measurement 1.4.2 Defining the Cellular Product and Process 1.4.3 Cell Composition 1.4.4 Analytical Method for Cell Composition Analysis 1.4.5 Sampling Bias 1.4.6 Defining and Documenting the Process 1.4.7 Defining the Efficacy of Processes and Process Steps 1.5 Conclusion Glossary of Terms References 2: Bone Marrow as a Source of Cells for Musculoskeletal Cellular Therapies 2.1 Introduction 2.2 Bone Marrow as a Cell Source 2.3 Clinical Rationale for Bone Marrow-Derived Cells in Cellular Therapy 2.4 Bone Marrow Aspiration Technique 2.5 Aspirate Yield, Composition, and Efficiency 2.6 Processing Options for BMA 2.7 Standardized Measurement and Report of BMA Dose and Composition 2.8 Putting it all Together References 3: Adipose-Derived Stem/Stromal Cells, Stromal Vascular Fraction, and Microfragmented Adipose Tissue 3.1 Introduction 3.2 Adipose-Derived Stem/Stromal Cells and Adipose-Derived Products: Two Sides of the Same Moon 3.2.1 SVF and Microfat 3.2.2 Culture-Expanded Adipose-Derived Stem Cells (ASCs) 3.3 Influence of Patient-Specific Factors on Adipose-Derived Cells and Products 3.4 The Rationale for Using Injections of Culture-Expanded ASCs or Adipose-Derived Products 3.4.1 Paracrine Potential (Soluble Mediators and Exosomes/Microvesicles) 3.5 In Vitro and Preclinical Findings 3.5.1 Focus on Culture-Expanded ASCs and SVF/Microfat in Joint Degeneration 3.5.2 Focus on Culture-Expanded ASCs and SVF/Microfat in Tendon Repair 3.5.3 Focus on Culture-Expanded ASCs and SVF/Microfat in Bone Repair 3.5.4 Focus on Culture-Expanded ASCs and SVF/Microfat in Muscle Repair 3.6 Conclusions References 4: Injections of Synovial Mesenchymal Stromal Cells 4.1 Introduction 4.2 Generation of MSCs Starting with Heterogeneous Mixtures of Colony-Forming Progenitors from Synovial Tissues 4.3 In Vitro Chondrogenic Potential of Synovial MSCs 4.4 Culture of MSCs with Autologous Serum 4.5 Intra-Articular Injections of Synovial MSCs in a Rat OA Model 4.6 Localization of Synovial MSCs after Injection 4.7 Properties of Synovial MSCs after Migration to the Synovium 4.8 Species-Specific Gene Expression Analysis 4.9 Mechanism by which Injections of Synovial MSCs Delay OA Progression 4.10 Clinical Study of Synovial MSC Injections into OA Knees 4.11 Conclusions References 5: Placenta, Umbilical Cord, and Umbilical Cord Blood-Derived Cultured Stromal Cells 5.1 Structure and Function of the Placenta, Umbilical Cord, and Umbilical Vessels 5.2 Placenta-Derived Stromal Cells 5.2.1 Formulation 5.2.1.1 Collection 5.2.1.2 Isolation and Expansion 5.2.2 In Vitro and in Vivo Effects 5.3 Umbilical Cord-Derived Stromal Cells 5.3.1 Formulation 5.3.1.1 Collection 5.3.1.2 Isolation and Expansion 5.3.2 In Vitro and in Vivo Effects 5.4 Umbilical Cord Blood-Derived Stromal Cells 5.4.1 Formulation 5.4.1.1 Collection 5.4.1.2 Isolation and Expansion 5.4.2 In Vitro and in Vivo Effects 5.5 Conclusions References 6: Injectable Allogenic Mesenchymal Stromal Cells: Advantages, Disadvantages, and Challenges 6.1 Introduction 6.2 Theoretical Advantages of Allogeneic MSCs 6.3 Theoretical Disadvantages of Allogeneic MSCs 6.4 Challenges for the Future 6.5 Conclusions References 7: Injection of Steroid Hormones 7.1 Introduction 7.2 Corticosteroids in Orthopaedics 7.3 Side Effects 7.4 AAS Physiology 7.5 The Effects of AAS on Musculoskeletal Tissues 7.6 AAS Applications in the Treatment of Human Disease 7.7 AAS in Orthopaedics (Table 7.1) 7.7.1 Rotator Cuff Repair 7.7.2 Anterior Cruciate Ligament Reconstruction 7.7.3 Patellar Tendon 7.7.4 Total Knee Arthroplasty 7.7.5 Hip Fractures 7.8 Potential Side Effects 7.9 Future Directions 7.10 Conclusion References 8: Intra-articular Hyaluronic Acid Injections 8.1 HA Chemistry and Structure 8.2 Current Product Profile 8.3 Biologic Effects of HA 8.4 Mechanical Effects of HA 8.4.1 Viscosity 8.4.2 Lubrication 8.5 Future Directions 8.6 Conclusion References 9: Cytokines, Chemokines, Alpha-2-Macroglobulin, Growth Factors 9.1 Cytokines 9.1.1 Introduction 9.1.2 What Is Currently Available Clinically? 9.1.3 What Has Shown Promise in Preclinical Studies? 9.1.4 Future Directions 9.2 Chemokines 9.2.1 Introduction 9.2.2 What Is Currently Available Clinically? 9.2.3 What Has Shown Promise in Preclinical Studies? 9.2.4 Future Directions 9.3 Alpha-2-Macroglobulin 9.3.1 Introduction 9.3.2 What Is Currently Available Clinically? 9.3.3 What Has Shown Promise in Preclinical Studies? 9.3.4 Future Directions 9.4 Growth Factors 9.4.1 Introduction 9.4.2 What Is Currently Available Clinically? 9.4.3 What Has Shown Promise in Preclinical Studies? 9.4.4 Future Directions 9.5 Conclusions References 10: Platelet-Rich Plasma: Processing and Composition 10.1 Introduction 10.2 Processing 10.2.1 Whole Blood 10.2.2 Anticoagulant 10.2.3 Isolation and Concentration Method 10.2.4 Activation 10.3 Product Composition 10.3.1 Growth Factors 10.3.2 Leukocytes 10.4 Conclusion References 11: Placental Tissue Extracts 11.1 Introduction 11.2 Clinically Relevant Anatomy 11.3 Evidence in Sports Medicine 11.3.1 Cartilage Injury and Osteoarthritis 11.3.1.1 Basic Science 11.3.1.2 Human Studies 11.3.2 Tendon Injury 11.3.2.1 Basic Science 11.3.2.2 Human Studies 11.3.3 Ligament Injury 11.3.3.1 Basic Science 11.3.3.2 Human Studies 11.3.4 Plantar Fasciitis 11.3.4.1 Basic Science 11.3.4.2 Human Studies 11.4 Conclusion References 12: Secretome, Extracellular Vesicles, Exosomes 12.1 Introduction 12.2 Composition of the Secretome and Its Extracellular Vesicle Fraction 12.2.1 Secretome: Preclinical and Clinical Evidence 12.2.2 Extracellular Vesicles: Preclinical and Clinical Evidence 12.3 Conclusions References Part II: Injectable Orthobiologics: Methods and Results Based on Anatomy and Pathology 13: Rotator Cuff Tendinopathy: Cell Therapy 13.1 Introduction 13.2 Rotator Cuff: From Mechanical to Biological Improvement 13.2.1 Early History 13.2.2 Biological Enhancement of Rotator Cuff Repair 13.3 The Theoretical Benefits of Cell Transplantation on Enthesis Healing 13.3.1 Reparative Process of the Enthesis 13.3.2 Rationale for the Use of Cells to Treat Tendon Disorders 13.3.3 Preclinical Studies 13.4 Benefit of Cell Transplantation for Rotator Cuff Repair: What Is the Current Evidence? 13.4.1 The First Trial: The Experience of the Senior Author 13.4.2 The Other Seven Trials 13.5 Conclusion References 14: Rotator Cuff Tendinopathy: Biologics 14.1 Introduction 14.2 Platelet-Rich Plasma (PRP) 14.3 Hyaluronic Acid (HA) 14.4 Cytokines and Growth Factors 14.5 Conclusions References 15: Orthobiologics for the Treatment of Tennis Elbow 15.1 Introduction 15.2 Pathophysiology 15.3 Evaluation of Tennis Elbow: Lateral Epicondylitis 15.4 Orthobiologic Treatment Options 15.4.1 Basic Mechanism of Action 15.4.2 Sites of Harvests and Source Materials 15.4.3 Biologic Selection 15.5 Clinical Results 15.5.1 PRP 15.5.2 Bone Marrow Aspirate (BMA) or Bone Marrow Aspirate Concentrate (BMAC) 15.5.3 Adipose Tissue-Derived Cells 15.5.4 Autologous Culture-Expanded Fibroblasts 15.5.5 Gold-Induced Cytokines Injection (Autologous Conditioned Serum) 15.6 Delivery of Orthobiologics 15.7 Conclusion References 16: Patellar Tendinopathy: Cell Therapy 16.1 Introduction 16.2 Current Treatments 16.3 Cell Therapy 16.4 In Vitro Isolation and Preparation of Culture-Expanded Cell Populations with Potential Value in Treating Tendinopathy 16.5 Preclinical In Vivo Evidence for Cellular Therapy for Tendinopathy 16.6 Clinical Evidence for Cellular Therapy for Patellar Tendinopathy 16.7 Conclusions References 17: Patellar Tendinopathy: Biologics 17.1 Introduction 17.2 Evaluation and Diagnostic Workup 17.3 Treatment Options 17.3.1 Nonoperative Management 17.4 Surgical Treatment 17.5 Role of Injectable Biologics 17.5.1 Overview 17.5.2 Number of Injections 17.6 PRP Formulations 17.7 Conclusion References 18: Orthobiologics for the Treatment of Achilles Tendinopathy 18.1 Introduction 18.2 Pathophysiology 18.3 Role of Biologic Therapies 18.4 Corticosteroids 18.5 Sodium Hyaluronate 18.6 Platelet-Rich Plasma 18.7 Autologous Blood Products 18.8 Peripheral Blood Mononuclear Cells 18.9 Bone Marrow Aspirate and Bone Marrow Aspirate Concentrate 18.10 Processing of Adipose Tissue as a Cellular Preparation 18.11 Culture-Expanded Mesenchymal Stromal Cells 18.12 Culture-Expanded Adipose-Derived Stromal Cells (ADSCs) 18.13 Growth Factors 18.13.1 Transforming Growth Factor-β 18.13.2 Vascular Endothelial Growth Factor 18.13.3 Bone Morphogenetic Proteins (BMPs) 18.13.4 Interleukin-6 (IL-6) 18.13.5 Combination Treatment with Growth Factors 18.14 Proteinase Inhibitors 18.15 Conclusions References 19: Orthobiologics for the Treatment of Plantar Fasciitis 19.1 Introduction 19.2 Platelet-Rich Plasma (PRP) 19.3 AWB vs PRP 19.4 Corticosteroid vs PRP 19.5 Prolotherapy 19.6 Bone Marrow Aspirate Concentrate (BMAC) 19.7 Placenta Tissue Extracts 19.8 Conclusions References 20: Ligament Lesions: Cell Therapy 20.1 Introduction 20.1.1 Native Ligament Healing 20.1.2 Relevant Osseous and Soft Tissue Anatomy 20.1.3 Differences in Healing Between the Collateral Ligaments and Cruciate Ligaments 20.2 Types of Cellular Therapies 20.3 Outcomes and Reasons for Cell Therapy 20.3.1 Cell Therapies for Anterior Cruciate Ligament 20.3.1.1 Preclinical Evidence 20.3.1.2 Clinical Evidence 20.3.2 Cell Therapies for Collateral Ligaments 20.3.2.1 Preclinical Evidence 20.3.2.2 Clinical Evidence 20.3.3 Cell Therapies for Ulnar Collateral Ligament 20.4 Current Indications and Contraindications 20.5 Conclusions References 21: Ligament Lesions: Biologics 21.1 Introduction 21.2 PRP Use in Anterior Cruciate Ligament Injuries 21.3 PRP Use in Medial Collateral Ligament Injuries 21.4 PRP Use in Ankle Sprains 21.5 Conclusion 21.6 Summary Table References 22: Meniscal Lesions: Cell Therapy 22.1 Introduction 22.2 Cell Selection 22.3 Mechanism(S) of Action of MSCs 22.4 Preclinical Studies 22.5 Clinical Studies 22.6 Future Directions 22.7 Conclusion References 23: Meniscal Lesions: Biologics 23.1 Introduction 23.2 The Management of Meniscal Lesions 23.3 The Rationale of Orthobiologics Injections 23.4 Corticosteroid Injections 23.5 Hyaluronic Acid Injections 23.6 Platelet-Rich Plasma Injections 23.7 Conclusions References 24: Orthobiologics for the Treatment of Muscle Lesions 24.1 Introduction 24.2 Muscle Injuries 24.2.1 Epidemiology and Mechanism of Injury 24.2.2 Muscle Lesions: Classification 24.2.3 Treatment Strategies and Burdens 24.3 Healing Process of Muscle Injuries 24.4 Platelet-Rich Plasma (PRP) in Muscle Injury 24.4.1 PRP: Biological Rationale and Formulations 24.4.2 PRP: Clinical Evidence 24.5 Other Biological Approaches 24.5.1 Culture-Expanded Stromal Cell Therapy 24.5.2 Glycosaminoglycans 24.5.3 Anti-Fibrotic Therapy 24.5.4 Actovegin 24.6 Conclusions References 25: Cartilage Lesions and Osteoarthritis: Cell Therapy 25.1 Introduction 25.2 Osteoarthritis (OA) 25.3 Cell Therapies for Repair of Cartilage Lesions and OA Damage 25.4 Mesenchymal Stromal Cells (MSCs) 25.5 MSCs and the Immune System 25.6 Clinical Studies of MSC Injection 25.7 Lessons from Preclinical Animal Studies 25.8 One-Step Approaches 25.8.1 Bone Marrow Aspirate Concentrate (BMAC) 25.8.2 Stromal Vascular Fraction (SVF) and Micro-Fragment Adipose Tissue (MFAT) 25.9 Conclusions References 26: Cartilage Lesions and Osteoarthritis of the Knee: Biologics 26.1 Introduction 26.2 Clinical Evidence 26.2.1 Corticosteroids 26.2.2 Hyaluronic Acid 26.2.3 Platelet-Rich Plasma 26.3 Conclusions References 27: Cartilage Lesions and Osteoarthritis of the Hip and Ankle: Orthobiologics 27.1 Introduction 27.2 State of the Art of the Injective Therapies in the Hip 27.2.1 Hyaluronic Acid 27.2.2 Platelet-Rich Plasma 27.2.3 Cell-Based Therapies 27.3 State of the Art of the Injective Therapies in the Ankle 27.3.1 Hyaluronic Acid 27.3.2 Platelet-Rich Plasma 27.3.3 Cell-Based Therapy 27.4 Conclusions References 28: Injectable Orthobiologics for the Treatment of Subchondral Insufficiency Fractures of the Knee (SIFK) and Related Pathogenic Processes 28.1 Introduction 28.2 Etiology and Pathogenesis 28.2.1 Pathophysiology 28.2.2 Role of Demographic Risk Factors 28.2.3 Role of Anatomic Risk Factors 28.2.4 Role of Procedural Risk Factors 28.3 Injectable Orthobiologic Treatments 28.3.1 Calcium Phosphate 28.3.2 Bone Marrow Aspirate Concentrate (BMAC) 28.3.3 Platelet-Rich Plasma (PRP) 28.3.4 Other Biological Approaches 28.4 Conclusions References 29: Injections: Orthobiologics and the Power of Placebo 29.1 Introduction: A Historical Note on the “Placebo Effect” 29.2 Mechanisms of the Placebo Effect 29.3 Placebo and Musculoskeletal Injections 29.4 Conclusions References Part III: Future Directions 30: Pluripotent Stem Cells: Embryonic/Fetal Stem Cells and Induced Pluripotent Stem Cells 30.1 Introduction 30.2 Generation of iPSCs 30.2.1 Methods Used to Reprogram Somatic Cells into iPSCs 30.2.2 Epigenetic Signature of iPSCs 30.3 Induction of Chondrogenesis from iPSCs 30.3.1 Co-Culture with Primary Chondrocytes 30.3.2 Via Embryoid Body Formation 30.3.3 Through Intermediate iMSC 30.3.4 Direct Differentiation Using Growth Factors 30.4 The Use of iPSCs for Cartilage Regeneration 30.5 Strategy for Clinical Application: iPSC Banking 30.6 Direct Conversion to Chondrocytes Without the Need for iPSCs 30.7 Conclusions References 31: Gene Therapy 31.1 Introduction 31.2 Gene Therapy: Principles 31.3 Injectable Gene Therapy for Musculoskeletal Applications 31.3.1 Cartilage Repair 31.3.2 Bone Healing 31.3.3 Tendon and Ligament Healing 31.3.4 Meniscal Repair 31.4 Perspectives 31.5 Conclusion References 32: In Situ Targeting of Stem and Progenitor Cells in Native Tissues 32.1 Introduction 32.2 Mobilization of Stem/Progenitor Cells 32.3 Homing of Stem/Progenitor Cells into Sites of Tissue Repair and Regeneration 32.4 Differentiation of Stem/Progenitor Cells 32.5 Conclusions References