Essentials of Regenerative Medicine in Interventional Pain Management

Foreword by Steven E. Sampson
Foreword by Gabor B. Racz
Prologue
Preface
Important Notice
Contents
About the Editors
Part I: Basic Considerations
	1: Evolution of Regenerative Medicine in Managing Musculoskeletal and Spinal Disorders
		Introduction
		Historical Context
		Evolution
		Origin and Types of Regenerative Medicine
			Platelet-Rich Plasma (PRP)
			Mesenchymal Stem cell or Medicinal Signaling Cell Therapy
		Clinical Effectiveness
			Platelet Rich Plasma
			Mesenchymal Stem Cells or Medicinal Signaling Cells
		Ethical and Regulatory Challenges
			Human Cells, Tissues, and Cellular and Tissue-Based Products
			Minimal Manipulation
			Homologous Use
			Regulatory Scope and Compliance Policy
			FDA’s Comprehensive Framework for Regenerative Medicine
				Expediting the Development of New Therapies
				Implementation of Comprehensive Framework
			State Medical Board Regulations/Guidelines
		Current Applications and Future Directions
		References
	2: Principles of Evidence-Based Medicine
		Introduction
		History
		EBM in Regenerative Medicine in Chronic Pain
		Randomized Controlled Trials
			Assessment of the Bias and Quality of the Manuscripts
		Observational Studies
		Outcomes in Regenerative Medicine Studies in Chronic Pain
		Systematic Review and Meta-analysis
		Conclusion
		References
	3: Evidence-Based Regenerative Medicine
		Introduction
		Regenerative Therapies
			Platelet-Rich Plasma
			Mesenchymal Stem Cells or Medicinal Signaling Cells (MSCs)
			Other Biologic Preparations
		Regenerative Medicine for Spinal Pain
			Pain Generators in Spine
				Intervertebral Disc
			Evidence for PRP in Intervertebral Disc Degeneration (IVDD)
			Role of Alpha-2-Macroglobulin in Degenerative Disc Disease
			Evidence of Mesenchymal Stem Cells (MSCs) in Intervertebral Disc Degeneration
			Bone Marrow Concentrate for Cervical Disc
			Exosomes
				Radicular Pain
			Evidence for Lumbar Epidural PRP Injections
			Evidence for Intra-articular MSCs in Radicular Pain
				Facet Joint
			Evidence for PRP in Facet Joint Pain
			Evidence for Intra-articular MSCs in Facet Pain
				Sacroiliac Joint
				Evidence for PRP in Sacroiliac Joint Pain
			Evidence for Intra-articular MSCs in Sacroiliac Joint Pain
		Regenerative Medicine for Musculoskeletal Pain
			Tendinopathies
			Patellar Tendinopathy
			PRP Vs. Saline
			PRP Vs Dry Needling
			PRP Vs Extracorporeal Shock Wave Therapy (ESWT)
			Utilization of Cell-Based Therapy
			Rotator Cuff Tendinopathy
			PRP Vs Active Controlled Group
			PRP Vs Corticosteroid Injections
			Utilization of Cell-Based Therapy
			Common Extensor Tendinopathy
			PRP Vs Active Controlled Group
			PRP Vs Corticosteroid Injection
			PRP Vs ESWT
			Utilization of Cell-Based Therapy
			Achilles Tendinopathy
			PRP Vs Saline
			PRP Vs Sham Injection
			PRP Vs ESWT
			Utilization of Cell-Based Therapy
			Intra-articular Pathology
			Osteoarthritis of the Knee
				PRP Vs Corticosteroid Injection
			PRP Vs Hyaluronic Acid Products
			Utilization of Cell-Based Therapies
			Osteoarthritis of the Hip
				PRP Vs HA
			Utilization of Cell-Based Therapy
		Conclusion
		References
	4: Biologic and Cellular Therapies in the Clinical Setting: Standardization and Collaboration
		Introduction
		Hyaluronic Acid
		Platelet Rich Plasma
		Bone Marrow Concentrate
		Adipose Derived Mesenchymal Stem Cells
		Future Directions
		Conclusion
		References
	5: Fluoroscopy for Interventional Techniques in Regenerative Medicine
		History
		Technical Aspects
			Fluorescence
			The Fluoroscopic Imaging Chain
			The X-Ray Generator
			The X-Ray Tube
			Image Intensifier
			Flat-Panel Detectors
			Collimation
			Optical Coupling
			Analog to Digital Converter
			Fluoroscopy Table and Pad
			Configuration of Fluoroscopic Systems
			Advanced Radiographic Imaging for Complex Procedures
		Radiation Safety
		Indications and Clinical Applications
		Precautions
		References
	6: Principles of Ultrasound Imaging in Musculoskeletal Medicine
		Introduction
		Historical Background
		Ultrasound Equipment Overview
		Basic Ultrasound Physics
		Biological Effects of Ultrasound
		Optimizing the Ultrasound Image
			Common Ultrasound Artifacts
			Scanning Technique Basics
			Tips to Keep in Mind
		Ultrasound Imaging
			Ultrasound of Stellate Ganglion
			Ultrasound of Sacroiliac Joint
			Ultrasound for Musculoskeletal Imaging
				Shoulder
				Elbow
				Hip
				Knee
				Ankle
				Peripheral Nerves
				Intercostal Nerves
				Iliohypogastric/Ilioinguinal Nerves
				Occipital Nerves
				Pudendal Nerve
		Conclusion
		References
	7: Platelet-Rich Plasma
		Introduction
			Platelet Functions
			Hemostasis
			Tissue Healing
		The Evolution of PRP for Clinical Use
			Describing Platelet Content in PRP
				Concentration Factor (How Concentrated Is the PRP Product?)
				Absolute Platelet Count (How Many Platelets Are in the PRP Product?)
			Treatment Volume
			Platelet Capture
			PRP Safety Profile
		Adding PRP to Clinical Practice
			Preprocedure Planning
				Lab Work
				Medications
			Comorbid Disease
			Preparing PRP in the Office
			Blood Draw
				Centrifugation Process
			Activation of PRP Prior to Treatment
			Scaffold and Gel Preparation
			Confusing Terminology Regarding PRP Formulations
		PRP Mechanism of Action
			Platelets
			Leukocytes
			Monocytes and Macrophages
			Neutrophils
			Lymphocytes
			Fibrinogen and Fibrin
			Erythrocytes (RBCs)
			Innate and Adaptive Immunity
			Opposing Inflammatory Effects After PRP Treatment
		PRP Analgesic Effects
		Conclusion
		References
	8: Platelet Lysate
		Introduction
		Methods of Producing Platelet Lysate
			Freeze-Thaw Method
			Ultrasonic Homogenization
			Final Centrifugation and Filtering
		Platelet Lysate and Releasate Current and Future Clinical Use: Spine and Musculoskeletal Conditions
			Spinal Pathology
			Refractory Lateral Epicondylitis
			Fracture Nonunion
		Platelet Lysate and Releasate: Current and Future Clinical Use: Non-Musculoskeletal Conditions
			Longstanding Diabetic Foot Ulcers
			Ocular Surface Disease (OSD) and Refractory Primary Sjogren’s Syndrome
			Other Potential Future Considerations
		Conclusion
		References
	9: Bone Marrow Concentrate
		Introduction
		Biologic Composition of Bone Marrow Aspirate
			Cellular Components
			Protein Components
		Harvesting of Bone Marrow Aspirate
		Preparation of Bone Marrow Concentrate
		Characterization of Bone Marrow Aspirate and Concentrate
			Clinical Efficacy and Safety of Bone Marrow Concentrate
				Osteoarthritis of the Knee
				Avascular Necrosis of the Hip
				Non-Union Fractures
				Rotator Cuff Tears
				Degenerative Disc Disease in Lumbar Spine
				Safety of Autologous Bone Marrow Concentrate Injections
		Regulatory Considerations for Use of Bone Marrow Concentrate
		Conclusion
		References
	10: Adipose Tissue-Derived Stromal Vascular Fraction
		Introduction
		Preparation and Biology
			Preparation of SVF
			Biology of SVF
		Mechanism of Action
		Clinical Applications and Safety
			Clinical Applications in Cosmetic Dermatology and Reconstructive Plastic Surgery
			Clinical Applications in Musculoskeletal Pathologies
			Safety of SVF
		Future Directions
		Conclusion
		References
	11: Wharton Jelly MSC for Treating Local and Systemic Illnesses
		Introduction
		Mechanism of Action
		Clinical Trials
		Safety
		Optimizing Clinical Outcomes
		Conclusion
		References
	12: Non-autologous Biologics
		Introduction
		History
		Regulatory Considerations
		Placental Tissue Associated Materials
			Placental Tissue-Derived Materials
				Clinical Studies of dHACM
				Clinical Studies of Micronized Placental Tissue-Derived Products
			Amniotic Fluid
				Clinical Studies of Amniotic Fluid
		Cadaveric Tissue Derived Products
		Cord Blood and Cord Tissue Derived Products
		Cultured Cell Products
			Cultured Cells
				Clinical Studies
				USFDA Approved Product
			Induced Pluripotent Stem Cells
			Cell Culture Fluid-Derived Products
		Exosome Containing Products
		Mechanisms of Therapeutic Action
			Evolving Therapeutic Benefit
			Pre-formed Therapeutic Benefit
		Conclusion
		References
	13: The Role of Exosomes in Regenerative Medicine
		Introduction
		What Are MSCS and Exosomes?
		Benefits of Extracellular Vesicles
		Difference Between Stem Cells and Exosomes in Regenerative Medicine Application
		Extracellular Vesicles in Musculoskeletal Regeneration
			Arthritis
			Tendonitis
			Bone Fractures
			Muscle Conditions
		Exosomes in Neurological Regeneration
		References
	14: Platelet Rich Plasma, Bone Marrow Concentrate and Adipose Derived Cells: Quantitative Analysis and Quality Control—What Does It All Mean?
		Introduction
		Why Should We Measure?
		What Should We Measure?
			Platelet Rich Plasma
			Bone Marrow Concentrate
			Microfragmented Adipose Tissue (MFAT)
			Stromal Vascular Fraction
		How Should we Measure?
			Counting Cells: Manual Method
			Counting Cells: Automated Method
			Counting MSCs: Colony Forming Unit Assays (CFU-F)
			Counting Cells: Flow Cytometry
		Correlation with Published Data
			Intradiscal BMC Data
			BMC in Rotator Cuff Repair
			BMC in Knee Osteoarthritis
			PRP Dosing: “Low Dose” Vs “High Dose”
		Validation of Bone Marrow Aspiration Technique
		Quality Control Considerations
			Proficiency Testing
			Benefits of Measurement
		Conclusion
		References
	15: Antiplatelet and Anticoagulant Therapy in Regenerative Medicine
		Prevalence and Risk Assessment of Studies
		Reports of Thromboembolic Events
			Reports of Bleeding Complications
			Guidelines and Recommendations
				Risk Stratification
			Pharmacologic Aspects and Hemostasis Monitoring
		Effects of Antithrombotic Therapy on Injection of Biologics
			Recommendations
		References
Part II: Regenerative Medicine in Musculoskeletal Disorders
	16: Pathophysiology and Mechanisms of Chronic Musculoskeletal Pain
		Background
		Definitions
		Pathophysiology of Pain
		Pain Mechanisms
			Nociceptors
			Algesic Substances
			Arachidonic Acid Pathway
			Pain Pathway
		Modulation of Pain
			Augmentation
			Inhibition
		Chronic Pain
		Biopsychosocial Experience of Pain
		References
	17: Regenerative Medicine for the Shoulder
		Introduction
		Anatomy
		Rotator Cuff Tendinopathy
			Brief Overview of Rotator Cuff Tendinopathy
			Platelet-Rich Plasma for Rotator Cuff Tendinopathy
			Bone Marrow Aspirate Concentrate for Rotator Cuff Tendinopathy
			Adipose Tissue-Derived Cells for Rotator Cuff Tendinopathy
		Glenohumeral Osteoarthritis
			Brief Overview of Glenohumeral Osteoarthritis
			Platelet-Rich Plasma for Glenohumeral Osteoarthritis
			Bone Marrow Aspirate Concentrate for Glenohumeral Osteoarthritis
		Adhesive Capsulitis
			Brief Overview of Adhesive Capsulitis
			Platelet-Rich Plasma for Shoulder Adhesive Capsulitis
			Cellular Treatments for Shoulder Adhesive Capsulitis
		Technique Considerations for Orthobiologic Injections in the Shoulder
		Timing Considerations for Orthobiologic Injections in the Shoulder
		Conclusion
		References
	18: Regenerative Medicine for the Elbow
		Introduction
		Lateral Epicondylitis
			Randomized Controlled Trials
			Meta Analyses
			Alternative Orthobiologics
		Medial Epicondylitis
			Alternative Procedures
		Ulnar Collateral Ligament
		Distal Biceps Tendinopathy
			Elbow Injection Technique Considerations
		Conclusion
		References
	19: Regenerative Therapy of Hip and Related Joints, Ligaments, and Tendons
		Introduction
		Anatomy
			Osteology
			Musculature
			Tendons/Ligaments
			Nerve Supply
			Vascular Supply
		Pathophysiology
			Osteoarthritis
			Labral Tear
			Femoroacetabular Impingement
			Osteonecrosis
			Greater Trochanteric Pain Syndrome/Gluteal Tendinopathy
			Iliopsoas Tendinopathy
			Iliotibial Band Syndrome
			Hamstring Tendinopathy
			Differential Diagnosis
		Clinical Assessment
			History and Physical Examination
			Diagnostic Imaging Studies
				Diagnostic Ultrasound
		Regenerative Medicine
			Joint OA
			Tendon Tear and Tendinopathy
			Femoral Head Osteonecrosis
		Technical Considerations in Performing Interventional Procedures in the Hip
			Femoral-Acetabular Joint Injection
			Tendon Injections
				Tendon Fenestration
				Iliopsoas Tendon and Bursa Injection
				Gluteus Medius Tendon Injection
		Conclusion
		References
	20: Regenerative Medicine for Knee Joint Disorders
		Introduction
		Treatment of Anterior Cruciate Ligament (ACL) with Biologics
			Diagnosis of ACL Injury
			Treatment
				Nonsurgical
			Interventional Treatments
				Percutaneous Bone Marrow Concentrate (BMC) Infiltration to Treat ACL Injuries
				Procedure for Percutaneous Infiltration of ACL
		Posterior Cruciate Ligament (PCL)
			PCL Injury
			Diagnosis of PCL Injury
			Treatment
				Non-surgical Treatment
			Biologics for PCL Injuries
			Procedure for Percutaneous Infiltration of PCL
		Knee Menisci
			Anatomy
			Classification of Meniscal Tears
				Types of Tears [19] (Fig. 20.9)
			Diagnosis
			Treatment of Meniscal Injuries
				Surgical Augmentation with PRP for Meniscus Tears
				Percutaneous Infiltration of Meniscal Tear with PRP
			Stem Cells in Meniscal Injuries
			Procedure for Percutaneous Meniscal Injury Infiltration
		Medial and Lateral Collateral Ligaments
			Treatment
				Interventional Treatment
		Knee Osteoarthritis
			Pathophysiology
			Diagnosis
			Surgical Treatments
			Interventional Treatments
		Mesenchymal Stem Cell Injection
		Percutaneous Subchondral Knee Procedure
		Conclusion
		References
	21: Regenerative Therapy of Ankle and Foot and Related Joints, Ligaments and Tendons
		Introduction
		Anatomy
			Bones, Joints, and Ligaments
			Muscles and Tendons
			Nerves
			Vascular
			Movement
		Pathophysiology
		Physical Examination
			Imaging (Fluoroscopy and Ultrasound)
			Diagnosis
			Biologic Basis
		Evidence
			Achilles Tendinosis
			Bunion
			Plantar Fasciitis
			Osteoarthritis and Osteochondral Lesions
			Tendinosis/Fasciitis
			Intraosseous Injections
		Technical Considerations
		Complications
		Regulatory Considerations
		Conclusion
		References
Part III: Regenerative Medicine in the Spine
	22: Radiology of the Spine for the Interventionalist
		Introduction
		Imaging Modalities
			Plain X-Rays and Fluoroscopy
			Nuclear Medicine
			Computed Tomography (CT)
			Magnetic Resonance Imaging (MRI)
			Myelography
		Degenerative Lumbosacral Spine
			Intervertebral Disc Disease
			Inflammatory Reaction to Intervertebral Disc Disease
			Facet Disease
			Combination: Central Canal Stenosis
			Neural Foraminal Narrowing
			Degenerative Sacroiliac (SI) Joint Disease
			Post-Operative Spine
		Degenerative Thoracic Spine
			Disc Protrusion
			Costochondral Joint Abnormalities
			Kyphosis
		Degenerative Cervical Spine Disease
			Disc Protrusion
			Disc Extrusion
			Chronic Disc/Osteophyte Complex
			Central Cervical Spinal Canal Stenosis
			Facet Joint Degenerative Disease with Osteophytic Spurring
			Narrowed Neural Foramen from Disc/Osteophyte Complex Affecting the Uncinate Process
		Traumatic Injuries
		Infectious Diseases of the Spine and Cord
		Regenerative Medicine and the Intervertebral Disc
		Disc Anatomy [41]
		Pathomechanism of Disc Degeneration
		Pfirrmann Classification: Disc Degenerative Scoring Based on T2-Weighted MRI Changes
		Regenerative Therapies
		MSC Therapy for IVD Regeneration
		References
	23: Intradiscal Injections of Biologics
		Introduction
		History
		Pathophysiology
		Regenerative Medicine Therapy in Disc Repair
		Evidence Base of Intradiscal Biologics
			Platelet Rich Plasma
			Intradiscal Autologous Bone Marrow Cells
		Indications
		Anatomy
		Technical Aspects
			Lumbar Discography and Disc Injections
				Disc Injection
				Intradiscal Injection of Biologics
			Cervical Discography and Disc Injection
				Anterior Approach
				Anterolateral Approach
				Disc Injection
				Intradiscal Injection of Biologics
			Thoracic Discography and Injection of Biologics
				Disc Injection
				Intradiscal Injection of Biologics
		Side Effects and Complications
		Precautions
		Conclusion
		References
	24: Epidural Administration of Biologics
		Introduction
		History
		Pathophysiology
		Epidural Biologics
		Evidence Base
		Indications
		Anatomy
		Technical Considerations
			Lumbar Interlaminar Epidural Injections
			Lumbar Transforaminal Epidural Injections
			Clinical Anatomy
			Technical Implications
				Safe Triangle Approach
				Infraneural or Kambin Triangle Approach
				First Sacroiliac Transforaminal
			Caudal Epidural Injections
			Percutaneous Adhesiolysis and Catheterization
			Cervical Epidural Injections
				Interlaminar Epidural Injections
				Extra-Epidural Placement
				Cervical Transforaminal Epidural Injections
			Thoracic Epidural Injections
				Thoracic Interlaminar Epidural Injections
				Extra-Epidural Placement
				Thoracic Transforaminal Epidural Injections
		Side Effects and Complications
		Precautions
		References
	25: Lumbar Facet Joints and Intraarticular Injection of Biologics
		Introduction
		History
		Pathophysiology
		Regenerative Medicine
		Evidence Base
		Clinical Presentation
		Anatomy
		Technical Considerations
			Lumbar Facet Joint Intraarticular Injections
			Facet Joint Nerve Branch Blocks
			L1 to L4 Facet Joint Nerve Blocks
				Prone Position Oblique
				Prone Position Anteroposterior
				Dorsal Ramus Blocks
		Indications
		Side Effects and Complications
		Precautions
		Conclusion
		References
	26: Cervical Facet Joints and Intraarticular Injection of Biologics
		Introduction
		History
		Pathophysiology
		Regenerative Medicine
		Evidence Base
		Clinical Presentation
		Anatomy
		Technical Considerations
			Intraarticular Cervical Facet Joint Injections
				Posterior Approach
				Lateral Approach
			Cervical Medial Branch Blocks
				Posterior Approach
				Lateral Approach
		Indications
		Side Effects and Complications
		Precautions
		Conclusions
		References
	27: Thoracic Facet Joints and Intraarticular Injection of Biologics
		Introduction
		History
		Pathophysiology
		Regenerative Medicine
		Evidence Base
		Clinical Presentation
		Anatomy
		Technical Considerations
			Intraarticular Thoracic Facet Joint Injections
				Medial Branch Blocks
		Indications
		Side Effects and Complications
		Precautions
		Conclusion
		References
	28: Regenerative Medicine for Sacroiliac Joint Dysfunction
		Introduction
		Pathophysiology
		Regenerative Medicine
		Evidence-Base
		Clinical Presentation
			Symptoms and Signs
			Diagnosis
		Anatomy
			Ligaments
			Muscles
			Innervation
		Technical Considerations
			Classic Technique
			Technique Without Oblique Angulation
			Benyamin Technique
			Double Needle Technique
			Modified Technique by Daitch et al.
			Upper One-Third Joint Injection
			Injection of the Middle Portion of the Joint
			True Anteroposterior View
		Precautions
		Conclusion
		References
Part IV: Miscellaneous Applications
	29: Regenerative Therapy for Chronic Pelvic Pain Syndromes
		Introduction
		Pathophysiology
		Anatomy
			Anterior (Abdominal) Cutaneous Nerve
			Ilioinguinal, Iliohypogastric and Genitofemoral Nerves
			Pudendal Nerve
			Piriformis Muscle
		Regenerative Medicine
		Diagnosis
			Examination
			Anterior (Abdominal) Cutaneous Neuralgia
			Ilioinguinal, Iliohypogastric and Genitofemoral Neuralgia
			Pudendal Neuralgia
			Piriformis Syndrome
			Associated Syndromes Characterized by Hypersensitivity and Psychological Distress
		Technical Considerations
			Conventional Therapy
			Imaging
			Anterior (Abdominal) Cutaneous Nerve Blocks
			Ilioinguinal, Iliohypogastric, and Genitofemoral Nerve Blocks
				Landmark Guided Techniques
				Fluoroscopic and CT-Guided Technique for Ilioinguinal, Iliohypogastric and Genitofemoral Nerve
				Ultrasound-Guided Technique for Ilioinguinal, Iliohypogastric and Genitofemoral Nerves
			Pudendal Nerve Block
				Transgluteal Pudendal Nerve Block
				Technique
				Dual Site Block
				Ultrasound-Guided Pudendal Nerve Block
			Piriformis Injection
			Pelvic Floor Myotendinous Injections
		Hormone Therapy
		Conclusion
		References
	30: The ABC of Stem Cell Therapies for Neurological Disorders
		Basic Concepts in Cell Therapy for Neurological Disease
		Neurogenesis
		Mesenchymal Stem Cells and the Brain
		Stem Cell Therapy for Stroke
		Stem Cell Therapy in Multiple Sclerosis
		Stem Cell Therapy in Amyotrophic Lateral Sclerosis
		Cell Therapies for Parkinson’s Disease
		Cell-Based Therapy in Traumatic Brain Injury
		Stem Cell Therapies as Potential Approaches to Reverse Aging
		Stem Cell Therapy in Alzheimer’s Disease
		Conclusions
		References
	31: Nerve Blocks for Regional Anesthesia for Regenerative Interventional Treatment
		Introduction
		Risks and Precautions of Peripheral Nerve Blocks for Orthobiologic Procedures
		General Nerve Block Techniques
		Common Nerve Block Techniques
			Peripheral Nerve Block for Rotator Cuff Interventions
			Peripheral Nerve Block for Elbow Common Extensor Tendon Procedures
			Peripheral Nerve Block for Ankle Interosseus and Achilles Tendon Procedures
			Peripheral Nerve Blocks for Medial Knee Intraosseous Procedures
		Conclusion
		References
	32: Rationale and Clinical Guidelines for Post-Orthobiologic Rehabilitation
		Tissue Healing
		Bioformulations
		Therapeutic Guidelines for Post Orthobiologic Rehabilitation
			Phase I-II (Homeostasis/Inflammatory Phases)
			Phase II (Inflammatory/Early Proliferative Phase)
			Phase III (Proliferative/Reparative Phase)
			Phase IV (Remodeling Phase)
		Summary
		References
	33: Regulatory Aspects of Regenerative Therapy and Stem Cell Therapy: Current Perspectives
		Introduction
			Background
		Current Regulatory Framework Overview
		Biologics License Applications
			21 CFR 1271 and PHS Act Pathways
			Expedited Tracks
		Platelet-Rich Plasma
			Bone Marrow
			Adipose Tissue
		References
	34: Ethical and Policy Issues in Practices of Regenerative Medicine for the Treatment of Chronic Pain
		Introduction
		Stem Cells
		Ethical Issues
		Policy Issues
		Current and Future Vistas
		References
Index