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Spie Press Book

Low-Level Light Therapy: Photobiomodulation
Author(s): Michael R. Hamblin; Cleber Ferraresi; Ying-Ying Huang M.D.; Lucas Freitas de Freitas; James D. Carroll
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Book Description

Low-level light therapy (or photobiomodulation therapy) is a rapidly growing approach to treating a wide range of diseases and disorders that afflict humanity. This Tutorial Text covers the basic molecular and cellular mechanisms of action, applications for treating diseases in animal models, and its use in clinical trials and therapeutic practice in patients. Other topics include the two basic chromophores and how they trigger the signaling pathways, activation of transcription factors, and mobilization of stem cells; how the light-source design and the relevant energy parameters can affect the outcome of therapy; and the physics and tissue-optics principles that concern LLLT.

Book Details

Date Published: 20 January 2018
Pages: 388
ISBN: 9781510614154
Volume: TT115

Table of Contents
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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

2 History of LLLT and Photobiomodulation
2.1 History of Photomedicine
2.2 Development of the Laser
2.3 Discovery of Photobiomodulation

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

4 Cellular Mechanisms
4.1 Inflammation
4.2 Cytoprotection
4.3 Proliferation
4.4 Migration
4.5 Protein Synthesis
4.6 Stem Cells

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

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

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

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

9 Edema and Lymph Flow

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

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

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

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

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

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

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

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

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

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

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

Appendix: Review of LLLT Applications


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

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