Table of Contents

1 Introduction

1.1 General

1.2 Light Sources

1.3 Physics and Tissue Optics

1.4 Irradiation Parameters

1.5 Penetration Depth

1.6 Research in PBM/LLLT

1.7 Present Status

1.8 Clinical and Biomedical Applications of PBM

References

2 History of LLLT and Photobiomodulation

2.1 History of Photomedicine

2.2 Development of the Laser

2.3 Discovery of Photobiomodulation

References

3 Molecular Mechanisms of LLLT

3.1 Chromophores

     3.1.1 Cytochrome c oxidase

     3.1.2 Retrograde mitochondrial signaling

     3.1.3 Light-sensitive ion channels

     3.1.4 Direct cell-free light-mediated effects on molecules

3.2 Signaling Molecules

     3.2.1 Adenosine triphosphate

     3.2.2 Cyclic AMP

     3.2.3 Reactive oxygen species

     3.2.4 Calcium

     3.2.5 Nitric oxide

3.3 Activation of Transcription Factors

     3.3.1 Nuclear factor kappa B

     3.3.2 RANKL

     3.3.3 Hypoxia-inducible factor

     3.3.4 Akt/GSK3β/β-catenin pathway

     3.3.5 Akt/mTOR/CyclinD1 pathway

     3.3.6 ERK/FOXM1

     3.3.7 PPARy

     3.3.8 RUNX2

3.4 Effector Molecules

     3.4.1 Transforming growth factor

     3.4.2 Oxidative stress

     3.4.3 Pro- and anti-inflammatory cytokines

     3.4.4 Brain-derived neurotrophic factor

     3.4.5 Vascular endothelial growth factor

     3.4.6 Hepatocyte growth factor

     3.4.7 Basic fibroblast growth factor and keratinocyte growth factor

     3.4.8 Heat-shock proteins

References

4 Cellular Mechanisms

4.1 Inflammation

4.2 Cytoprotection

4.3 Proliferation

4.4 Migration

4.5 Protein Synthesis

4.6 Stem Cells

References

5 Tissue Mechanisms

5.1 Muscles

5.2 Brain

5.3 Nerves (Repair and Pain)

5.4 Healing (Bones, Tendons, and Wounds)

5.5 Hair

5.6 Skin

5.7 Fat

5.8 High-Fluence Low-Power Laser Irradiation

References

6 Biphasic Dose Response

6.1 Dose Dependence and Dose Rate Effects: The Biphasic Curve

6.2 Biphasic Response: Irradiance

6.3 Biphasic Response: Time or Energy Density

6.4 Beam Measurement Reporting Errors

6.5 Biphasic LLLT Dose Response Studies

     6.5.1 in vitro activation of NF-kB

     6.5.2 Mouse wound healing

     6.5.3 Rat arthritis

6.6 Possible Explanations for Biphasic Dose Response in LLLT

     6.6.1 Excessive ROS

     6.6.2 Excessive NO

     6.6.3 Activation of a cytotoxic pathway

6.7 Summary and Conclusion

References

7 Pre-conditioning

7.1 Introduction

7.2 Mechanisms of IPC

7.3 Other Modalities for Pre-conditioning

7.4 Similarities between IPC and LLLT

7.5 Skeletal Muscle Pre-conditioning through Light

7.6 Improving Inflammation and the Analgesic Effect

7.7 Reducing Damage after Heart Attack

7.8 Protecting Cells from Toxins

7.9 Wound Healing

7.10 Central Nervous System

7.11 Protecting Skin from Ultraviolet Damage

7.12 Conclusion

References

8 Low-Level Laser Therapy and Stem Cells

Qi Zhang, Tingting Dong, and Chang Zhou

8.1 Effects of LLLT on Stem Cells

     8.1.1 Hematopoietic stem cells

     8.1.2 Mesenchymal stem cells

     8.1.3 Adipose-derived stem cells

8.2 Clinical Applications of LLLT for Stem Cells

     8.2.1 Stem-cell transplantation

     8.2.2 Wound healing and skin restoring

     8.2.3 Neural regeneration

     8.2.4 Treating hair loss

References

9 Edema and Lymph Flow

References

10 Augmenting Wound Healing with Photobiomodulation Therapy

Asheesh Gupta

10.1 Introduction

10.2 Light-Based Healing Therapy: Photobiomodulation

10.3 Mechanisms of PBM Action

10.4 PBM Therapy for Acute and Chronic Wound Healing

     10.4.1 Acute wound healing

     10.4.2 Chronic wound healing

10.5 Pre-conditioning with PBM Therapy before Surgery

10.6 Conclusions and Future Perspectives

References

11 Photobiomodulation in Human Muscle Tissue for Better Sports Performance

11.1 Introduction

11.2 Literature Review

     11.2.1 Acute responses in exercises with biceps brachii muscles

     11.2.2 Acute responses in exercises with quadriceps femoris muscles

     11.2.3 Acute responses during exercise on a treadmill

     11.2.4 Chronic responses in clinical trials

References

12 Photobiomodulation in Bone: Studies in vitro, in vivo, and Clinical Applications

Cleber Ferraresi, Fernanda Freire, and Michael R. Hamblin

12.1 Photobiomodulation in Bone

12.2 in vitro Studies with Bone Cells

12.3 Bone Injury in Animal Models

     12.3.1 Laser versus ultrasound

     12.3.2 Osteoporotic rats

     12.3.3 Biomaterials

     12.3.4 Gene expression

     12.3.5 Diabetic rats

12.4 Bone Healing in Clinical Trials

References

13 Photobiomodulation in Cartilage: in vitro, in vivo, and Clinical Trials

Cleber Ferraresi, Fernanda Freire, and Michael R. Hamblin

13.1 Photobiomodulation in Cartilage

13.2 in vitro Studies with Cartilage-Related Cells

13.3 Cartilage Injury in Animal Models

     13.3.1 Osteochondral injury

     13.3.2 Arthritis and osteoarthritis

13.4 Cartilage Healing in Clinical Trials: Arthritis and Osteoarthritis

References

14 Photobiomodulation in Tendons: Effects in vitro, in vivo, and Clinical Use

Cleber Ferraresi, Fernanda Freire, and Michael R. Hamblin

14.1 Photobiomodulation in Tendons

14.2 in vitro Studies with Tendon Cells

14.3 Achilles Tendon Injury in Animal Models

     14.3.1 Achilles tendon healing in diabetic rats

14.4 Tendon Healing in Clinical Trials

References

15 Dermatology and Aesthetic Medicine Applications

15.1 Effects of LLLT on Skin

     15.1.1 Skin rejuvenation

     15.1.2 Acne

     15.1.3 Herpes virus infections

     15.1.4 Vitiligo

     15.1.5 Pigmented lesions

     15.1.6 Hypertrophic scars and keloids

     15.1.7 Burns

     15.1.8 Psoriasis

15.2 LLLT for Treatment of Hair Loss

     15.2.1 Hair and types of hair loss

     15.2.2 Existing treatments

     15.2.3 Androgenetic alopecia

     15.2.4 Alopecia areata

     15.2.5 Chemotherapy-induced alopecia

15.3 LLLT for Fat Reduction and Cellulite Treatment

     15.3.1 Lipoplasty and liposuction

     15.3.2 Fat reduction and cellulite treatment

     15.3.3 Combination treatments including LLLT

     15.3.4 LLLT for treating cellulite

15.4 Conclusion

References

Bibliography

16 Dental Applications

16.1 Musculoskeletal Pain: Temporal Mandibular Joint Disorder

16.2 Neuropathic Pain

16.3 Post-extraction Pain, Swelling, and Trismus

16.4 Nerve Injuries

16.5 Orthodontic Pain

16.6 Orthodontic Tooth Movement

16.7 Dentine Hypersensitivity

16.8 Herpes Simplex Infection

16.9 Cancer Therapy Side Effects

16.10 Post-operative Wound Healing

16.11 Endodontics

16.12 Analgesia

16.13 Lichen Planus

16.14 Stem Cells

References

17 LLLT Treatment of Pain: Clinical Applications

Roberta Chow

17.1 Background

17.2 Pain

17.3 Types of Pain and Mechanisms

17.4 Mechanisms Underlying Pain Relief

     17.4.1 Neural blockade

     17.4.2 Reduced inflammation

     17.4.3 Reduced edema

     17.4.4 Reduced muscle spasm

     17.4.5 Tissue repair

     17.4.6 Release of neurotransmitters

17.5 Conditions in which LLLT is Used, and Evidence

     17.5.1 Reviews of LLLT and pain

     17.5.2 Evidence for specific conditions

17.6 Pre-treatment Pain Relief

17.7 Unique Effects of LLLT on Pain

17.8 Practical Considerations

     17.8.1 Example: treating knee osteoarthritis

     17.8.2 Factors influencing outcomes

17.9 Laser Factors

     17.9.1 Wavelength

     17.9.2 Correct dose

     17.9.3 Application technique

     17.9.4 Treatment protocol

     17.9.5 Length of treatment

17.10 Patient Factors

17.11 Disease Factors

17.12 Goals of Treatment

     17.12.1 Monotherapy versus adjunctive treatment

17.13 Patients Unresponsive to LLLT

17.14 Practice Points

17.15 "Tip of the Iceberg" Principle

17.16 Prognostic Factors

17.17 Side Effects of Treatment

17.18 Conclusion

References

18 Applications to the Central Nervous System

18.1 Mechanisms of Photobiomodulation in the Central Nervous System

18.2 Human-Skull Transmission Measurements

18.3 PBM for Stroke

     18.3.1 Stroke

     18.3.2 PBM application

     18.3.3 PBM for stroke in animal models

     18.3.4 Clinical trials for acute stroke

18.4 PBM for Traumatic Brain Injury

     18.4.1 Introduction

     18.4.2 Studies of PBM for TBI in mice

     18.4.3 Effect of different laser wavelengths in PBM for TBI

     18.4.4 Effect of pulsing PBM for TBI

     18.4.5 Effects of PBM regimen for TBI

     18.4.6 PBM has more effect on IEX knockout mice

     18.4.7 PBM in combination with metabolic inhibitors

     18.4.8 PBM increases neuroprogenitor cells

     18.4.9 PBM increases BDNF and synaptogenesis

     18.4.10 PBM in humans with TBI

18.5 PBM for Neurodegenerative Diseases

     18.5.1 Neurodegenerative diseases

18.6 PBM for Psychiatric Disorders

18.7 Conclusion

References

19 Intravascular Laser Irradiation of Blood

Daiane Thais Meneguzzo, Leila Soares Ferreira, Eduardo Machado de Carvalho, and Cássia Fukuda Nakashima

19.1 Introduction

19.2 History of ILIB

19.3 Antioxidant Action of ILIB

19.4 Modified ILIB Techniques

     19.4.1 Intranasal irradiation

     19.4.2 Wrist skin irradiation

19.5 ILIB Side Effects and Contraindications

References

20 Future Directions and the Path Forward

20.1 Disappointment at Current Lack of Progress

20.2 New Indications

     20.2.1 Stem cells

     20.2.2 Transcranial LLLT for brain disorders

     20.2.3 Ophthalmology

     20.2.4 Autoimmune diseases

     20.2.5 Lung disease

     20.2.6 Performance enhancement

20.3 New Light Sources

     20.3.1 Wearable LLLT devices: bandages and clothing

     20.3.2 Implantable LEDs for brain and spine

     20.3.3 Swallowable battery-powered LED capsule for GI diseases

20.4 Marketing Hype

20.5 Negative Publication Bias

20.6 The Path Forward

References

Appendix: Review of LLLT Applications

Preface

For almost 50 years, the medical therapy formerly known as "low-level laser therapy" and now known as "photobiomodulation" has had a somewhat checkered history. This approach has been promoted by some of its aficionados with almost missionary zeal, while doubters and skeptics have regarded it as "junk science" and "alternative and complementary medicine." This Tutorial Text intends to convey to the contemporary scientific reader that photobiomodulation is becoming increasingly well-founded based on the accepted principles of photochemistry, cellular and molecular biology, and physiology. The text covers in some detail the basic mechanisms of action of photobiomodulation at the cellular and molecular level because we have found that by far the question posed most often by scientists outside the field is "How does it really work?" The well-known biphasic dose response is covered because we believe that failure to take account of this phenomenon contributes to many of the negative studies that have been published. The ability of photobiomodulation to be used as a pre-conditioning regimen before some medical or surgical procedure or for performance enhancement is intriguing. This Tutorial Text (larger than most) includes original and previously published material. The majority of the book focuses on a critical analysis of the various diseases and disorders of different human and animal tissue and organ systems that can be beneficially treated by photobiomodulation therapy. Chapters cover well-established applications in muscles and orthopedic conditions (bone, tendon, cartilage). Applications of photobiomodulation in dentistry have historically been important because dentists are accustomed to using lasers and light sources in their clinical practice. In addition to the foregoing, more systemic disorders are addressed, such as stem cells, lymph flow and edema, and laser irradiation of blood. One of the most important growing areas of medical application is photobiomodulation to the brain. Many common disorders - such as stroke, traumatic brain injury, psychiatric diseases, and dementia - may all benefit. Finally, one of the commercially successful areas of photobiomodulation involves its applications to aesthetic medicine, including skin appearance, hair regrowth, and fat removal.

Michael R. Hamblin
Cleber Ferraresi
Ying-Ying Huang
Lucas Freitas de Freitas
James D. Carroll
December 2017