|Year : 2017 | Volume
| Issue : 2 | Page : 129-134
Photobiomodulation and oral wound healing
E Vinesh, S Marytresa Jeyapriya, M Sathish Kumar, M Arunachalam
Department of Oral Pathology, Karpaga Vinayaga Institute of Dental Sciences, Kanchipuram, Tamil Nadu, India
|Date of Web Publication||28-Dec-2017|
Dr. S Marytresa Jeyapriya
Department of Oral Pathology, Karpaga Vinayaga Institute of Dental Sciences, Palayanoor, Kanchipuram, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Wounds can be classified into different types based on the etiology, clinical presentation, degree of contamination, and the extent of involvement of overlying skin. Wound healing is a complex, dynamic, well-orchestrated biological process that plays a vital role in the survival of humans. Both wounding and wound healing may occur in any tissue or organ of the body. In adults, wound healing commences as a cascade and includes the following phases: 1. hemostasis, 2. inflammation, 3. proliferation, 4. angiogenesis, 5. re-epithelialization, and 6. cross linking of collagen. Photobiomodulation (PBM) or low level laser therapy employs light energy to produce biological cell response and to restore cell function. It uses nonionizing light sources such as light emitting diodes and lasers, in the visible and infrared spectrum, and it is found to elicit numerous therapeutic benefits such as immunomodulation, promotion of wound healing, and rapid regeneration of tissues. This review aims to explore the molecular mechanisms of PBM and its role in wound healing. Further studies on the molecular mechanisms of PBM and their pathways can preclude promising clinical interventions for wound care.
Keywords: Low-level laser therapy; oral wound healing; photobiomodulation therapy; wound healing; wounds
|How to cite this article:|
Vinesh E, Jeyapriya S M, Kumar M S, Arunachalam M. Photobiomodulation and oral wound healing. Indian J Multidiscip Dent 2017;7:129-34
| Introduction|| |
A wound is defined as damage or disruption to the normal anatomical structure and function.,
| Classification of Wounds|| |
Clinically, wounds can be classified into three types, namely acute wounds, chronic wounds, and complicated wounds [Table 1].
These wounds repair themselves and follow a normal, timely, and orderly healing course (from 5 to 10 days). They may occur as a result of a surgical procedure or trauma.,
These type of wounds fail to repair in an orderly, timely manner and do not follow the normal course of healing process., The healing is incomplete, and relapse frequently occurs., They may occur as a result of burns, vasculitis, and arterial/venous insufficiency.
A complicated wound is said to be a combination of an infection and a tissue defect. In these types of wounds, infection becomes a serious threat to the wound.
According to etiology, wounds can be classified into
- Stab wounds
- Shot wounds
Based on the degree of contamination, wounds can be classified into
- Aseptic wounds
- Contaminated wounds
- Septic wounds.,,
Wounds can also be classified into
- Open wounds: wounds where the skin is damaged and the underlying tissue is exposed
- Closed wounds: wounds where the underlying tissue is traumatized with the skin intact.,,,
Wound healing is a complex, precisely regulated, dynamic, well-orchestrated biological process that plays a critical role in the survival of humans.,,,,,,
Both wounding and wound healing may occur in any tissue or organ of the body.
| Phases of Wound Healing|| |
In adults, wound healing commences as a cascade and includes the following phases [Table 2]:
- Cross-linking of collagen.
Following a wound, a blood clot forms as a result of activated coagulation pathways. The clot releases cytokines and vascular endothelial growth factor (VEGF). Neutrophils are attracted by these secreted chemokines, and they migrate into the wound. The neutrophils release proteolytic enzymes and destroy the invading microorganisms, and they also secrete proteases and reactive oxygen species.
Macrophages infiltrate into the area and release cytokines, activate leucocytes, induce apoptosis, and clear the apoptotic cells. Subsequently, the macrophages stimulate keratinocytes, fibroblasts and induce angiogenesis., The above events are followed by the migration of T lymphocytes into the wound area. It is believed that CD4+ cells promote wound healing whereas CD8+ cells inhibit wound healing., During wound healing, dendritic epidermal T cells when activated produce fibroblast growth factor 7 (FGF– 7), chemokines, and other cytokines that enhance keratinocyte proliferation and regulate inflammation.
The inflammatory phase is followed and overlapped by proliferative phase. It includes re-epithelialization. The subjacent fibroblasts and endothelial cells orchestrate angiogenesis, synthesis of collagen, and granulation tissue formation in the site of the wound. The fibroblasts begin to synthesize extracellular matrix (ECM). In the final remodeling phase, the newly formed capillaries regress and the ECM returns to its normal architecture. Contractile fibroblasts mediate the contraction of the wound.,
Oral wound healing
Wound healing in the oral cavity is a complex process and can be attributed to the complex interactions between oral keratinocytes, ECM of the oral mucous membrane, bacteria, saliva, and gingival crevicular fluid. Integrins such as α2 β1, α3 β1, αvβ5, αvβ6, vitronectin, tenascin–C, transforming growth factor β and wound fibroblasts, thrombospondin and secreted protein rich in cysteine/osteonectin play a vital role in the physiology of oral wound healing. As a result of these myriad interactions, oral mucosal wounds heal more rapidly with less scarring than dermal wounds.,,
Biophysical therapies for wound healing
Over the past few decades, several biophysical therapies have been employed to promote wound healing. A few commonly used biophysical interventions include microcurrent, electromagnetic fields, ultrasound, pressure, and light therapies. In 1968, Professor Endre Mestre demonstrated that high power lasers had the ability to rapidly heal experimental skin defects, diabetic ulcers, and infected wounds. This experimental research led to the discovery and development of photobiomodulation (PBM).
PBM or low-level laser therapy (LLLT) employs light energy to produce biological cell response and to restore cell function. PBM, a form of phototherapy, uses nonionizing light sources such as light emitting diodes and lasers in the visible and infrared spectrum and it is found to elicit numerous therapeutic benefits such as immunomodulation, promotion of wound healing, and rapid regeneration of tissues. PBM is based on Arndt–Schulz law. According to the law, a weak stimulus improves a specific biological function, and a stronger stimulus elevates the effect further. Once a peak response is attained, further increase in stimulus results in a negative response.,
PBM, when applied to pathology, promotes tissue regeneration, reduces inflammation, and relieves pain. PBM is considered to elicit a nonablative, nonthermal, photochemical, therapeutic effect in biological tissues.
| Molecular Mechanisms of Photobiomodulation|| |
Based on the time period from intervention, PBM mechanisms can be classified into the following two phases [Figure 1]:
- Primary phase
- Secondary phase.
Primary phase events are of two types
- Direct events (occur as a result of interaction of light energy with tissues)
- Indirect events (immediately follow direct events).
The primary phase events are transient, critical, and subsequently elicit biological tissue responses that lead to the secondary phase events.
According to the 1st law of photobiology, in order for PBM to be effective, the photos by generated by PMB therapy must be absorbed by molecular photoacceptors (chromophores) in the biological tissue.
A chromophore is a molecule (or a part of a molecule) which imparts a specific color to the biological compound of which it is a component, for example, hemoglobin and cytochrome Coxidase (CCO)., Some examples of biological, mammalian chromophores are 7 dehydrocholesterol, rhodopsin, photopsin, cytochrome oxidase, flavins, nicotinamide adenine dinucleotide phosphate, and so on. The “optical window” of the human tissue ranges from 650 nm to 1200 nm and within this spectrum, the tissue penetration of light is maximized. This necessitates the use of LLLT in the range of red and infrared light (600–1100 nm) in humans.
Primary phase events
These events occur within a few seconds/minutes of treatment and are photochemical and photophysical in nature.
Two distinct types of direct events can be elicited by LLLT:
In the first type, once LLLT is administered, the light energy is absorbed by a chromophore (in the biological tissue). A redox reaction results and electrons are released. Reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, and hydroxyl radicals are released and they initiate numerous biological responses.
In the second type of direct events, the LLLT administered results in change in conformational structure of biomolecules and favor its physiological function.
Both the events act as “sensors” and they occur within fractions of seconds of LLLT application.
The primary direct events are followed by a cascade of sequential, biological events, which occur within seconds to minutes of PBM.
| Role of Photobiomodulation-Generated Reactive Oxygen Species|| |
The ROS (superoxide, O2−) generated during the primary direct events reacts with nitric oxide (NO, produced by interaction of LLLT with nitrogen) to form ONOO − (peroxynitrite) which causes biological responses. PBM-generated ROS can produce modulation of antioxidants and induce protein modification and oxidative stress-mediated gene expression and lead to transcription of gene products. A classic example of protein modification is production of disulfide bonds by cysteine residues. This leads to alteration in the structure and functions of enzymes, notably phosphatases. Inactivated, structurally altered phosphatases can elicit transcriptional changes.
ROS also modulates mitochondrial respiration and activates NF-κB signaling pathway. ROS tends to activate Src, a nonreceptor tyrosine kinase, which in turn enhances cell proliferation, attachment, migration, and cell survival. PBM-generated ROS interacts with methionine 253 on latent TGF-β1 and leads to its activation. This in turn contributes to oral mucosal wound healing.
| Role of Cytochrom C Oxidase|| |
Another biological photoacceptor CCO absorbs LLLT and disrupts electron transfer process, resulting in increase in ATP production. This, in turn, modulates a spectrum of biological effects that include synthesis/activation of DNA, proteins, RNA, enzymes and also aids in the repair and regeneration of cells and tissues.
Photoabsorption by CCO also leads to dissociation of NO from Fe/Cu redox centres., The NO released leads to vasodilation and also activates Ca-sensitive K (kc) channels. Dissociated NO promotes wound healing by enhancing keratinocyte proliferation, migration of endothelial cells, lumenization, macrophage function, vasodilation, and stem cell differentiation.
Secondary phase events
The primary phase events are followed by induced secondary phase pathways that occur hours to days after PMB therapy. These secondary phase responses have a long-term effect on biological tissue. The secondary phase events in wound healing include signaling of autocrine/paracrine hormones, migration, proliferation and differentiation of cells, angiogenesis, and synthesis of ECM.
Secondary phase events and their relation to the phases of wound healing
PBM stimulates platelet aggregation and activates coagulation pathways and thus plays a critical role in hemostasis.
PBM is known to promote proliferation of mast cells and also plays an active role in the degranulation of mast cells.
PBM therapy has direct effects on pro-inflammatory factors and anti-inflammatory factors such as interleukin [IL]-1, IL-8, COX 1 and COX 2., The inflammatory phase of wound healing is characterized by clearing of debris and migration of keratinocytes and fibroblasts. PBM therapy modulates inflammation and also regulates immune microenvironment. It induces cytokines and growth factors such as basic fibroblast growth factor (FGF), FGF-1, FGF-2, transforming growth factor-β, and VEGF over a period of hours to days after exposure to therapy. These factors in turn play a key role in wound healing by inducing proliferation of keratinocytes, proliferation and migration of fibroblasts, wound contraction, inflammation, neovascularization, matrix synthesis, and remodeling.,,
PBM induces proliferation of oral keratinocytes, fibroblasts, chondrocytes, and also ECM synthesis.
PBM aids in neovascularization, angiogenesis and improves the tensile strength of wounded tissues and restores functional structure of repaired tissues. It thus stimulates reorganization, repair, and wound healing.
PBM tends to aid in enhancing epithelialization and improves wound healing especially in gingivectomy and gingivoplasty wounds.
Downstream cellular and tissue effects of photobiomodulation
In the cellular level, PBM acts on mitochondria and increases ATP synthesis, RNA and protein synthesis and membrane potential.,
NO produced by the mitochondria binds to COX (the primary photo acceptor for mammalian cells) and inhibits respiration. LLLT dissociates NO from COX and reverses inhibition of respiration.,, NO can also be released by LLLT from nitrosylated hemoglobin and nitrosylated myoglobin. This may in turn result in vasodilation.,
PBM prevents cellular apoptosis and enhances cell proliferation, migration, and adhesion in keratinocytes., PBM also stimulates neovascularization, promotes angiogenesis, increases collagen synthesis, and promotes healing of wounds.,
| Conclusion|| |
Numerous randomized controlled trials have proved that the use of PBM contributes significantly to wound healing. The primary phase events and the secondary phase events in PBM therapy play a critical role in healing of wounds by photodissociation of ROS and CCO. These dissociated intermediates play an active role in each phase of the wound healing process. In the cellular level, PBM increases synthesis of ATP and RNA. In addition, PBM prevents apoptosis, enhances angiogenesis, and induces synthesis of ECM. All these events exert a synergistic influence on wound healing. Further studies on the molecular mechanisms of PBM and their pathways can preclude promising clinical interventions for wound care.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Robson MC, Steed DL, Franz MG. Wound healing: Biologic features and approaches to maximize healing trajectories. Curr Probl Surg 2001;38:72-140.
Velnar T, Bailey T, Smrkolj V. The wound healing process: An overview of the cellular and molecular mechanisms. J Int Med Res 2009;37:1528-42.
Lazarus GS, Cooper DM, Knighton DR, Margolis DJ, Pecoraro RE, Rodeheaver G, et al.
Definitions and guidelines for assessment of wounds and evaluation of healing. Arch Dermatol 1994;130:489-93.
Szycher M, Lee SJ. Modern wound dressings: A systematic approach to wound healing. J Biomater Appl 1992;7:142-213.
Degreef HJ. How to heal a wound fast. Dermatol Clin 1998;16:365-75.
Bischoff M, Kinzl L, Schmelz A. The complicated wound. Unfallchirurg 1999;102:797-804.
Broughton G 2nd
, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg 2006;117 7 Suppl: 12S-34S.
Komarcević A. The modern approach to wound treatment. Med Pregl 2000;53:363-8.
Attinger CE, Janis JE, Steinberg J, Schwartz J, Al-Attar A, Couch K, et al.
Clinical approach to wounds: Débridement and wound bed preparation including the use of dressings and wound-healing adjuvants. Plast Reconstr Surg 2006;117:72S-109S.
Hunt TK, Hopf H, Hussain Z. Physiology of wound healing. Adv Skin Wound Care 2000;13:6-11.
Glat PM, Longaker MT. Wound healing. In: Aston SJ, Beasley RW, Thorne CH, editors. Grabb and Smith's Plastic Surgery. 5th
ed. Philadelphia: Lippincott-Raven; 1997. p. 3-12.
Nauta A, Gurtner G, Longaker MT. Wound healing and regenerative strategies. Oral Dis 2011;17:541-9.
Rajendran A, Sivapathasundaram B. Shafer's Textbook of Oral Pathology. 7th
ed. India: Elsevier Health Sciences; 2014. p. 591.
Häkkinen L, Uitto VJ, Larjava H. Cell biology of gingival wound healing. Periodontol 2000 2000;24:127-52.
Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res 2010;89:219-29.
Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 8th
ed. India: Elsevier Health Sciences; 2010. p. 102-6.
Meszaros AJ, Reichner JS, Albina JE. Macrophage-induced neutrophil apoptosis. J Immunol 2000;165:435-41.
Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008;8:958-69.
Swift ME, Burns AL, Gray KL, DiPietro LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 2001;117:1027-35.
Park JE, Barbul A. Understanding the role of immune regulation in wound healing. Am J Surg 2004;187:11S-16S.
Jameson J, Havran WL. Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol Rev 2007;215:114-22.
Gosain A, DiPietro LA. Aging and wound healing. World J Surg 2004;28:321-6.
Campos AC, Groth AK, Branco AB. Assessment and nutritional aspects of wound healing. Curr Opin Clin Nutr Metab Care 2008;11:281-8.
Sciubba JJ, Waterhouse JP, Meyer J. A fine structural comparison of the healing of incisional wounds of mucosa and skin. J Oral Pathol 1978;7:214-27.
Yang J, Tyler LW, Donoff RB, Song B, Torio AJ, Gallagher GT, et al.
Salivary EGF regulates eosinophil-derived TGF-alpha expression in hamster oral wounds. Am J Physiol 1996;270:G191-202.
Khan I, Arany P. Biophysical approaches for oral wound healing: Emphasis on photobiomodulation. Adv Wound Care (New Rochelle) 2015;4:724-37.
Gáspár L. Professor Endre Mester, the father of photobiomodulation. J Laser Dent 2009;17:146-8.
Ross G, Ross A. Photobiomodulation: An invaluable tool for all dental specialties. J Laser Dent 2009;17:117-24.
Huang YY, Chen AC, Carroll JD, Hamblin MR. Biphasic dose response in low level light therapy. Dose Response 2009;7:358-83.
Sutherland JC. Biological effects of polychromatic light. Photochem Photobiol 2002;76:164-70.
Karu T. Primary and secondary mechanisms of action of visible to near-IR radiation on cells. J Photochem Photobiol B 1999;49:1-7.
Karu TI, Afanas'eva NI. Cytochrome c oxidase as the primary photoacceptor upon laser exposure of cultured cells to visible and near IR-range light. Dokl Akad Nauk 1995;342:693-5.
Arany PR. Photobiomodulation: Poised from the fringes. Photomed Laser Surg 2012;30:507-9.
Liebert AD, Bicknell BT, Adams RD. Protein conformational modulation by photons: A mechanism for laser treatment effects. Med Hypotheses 2014;82:275-81.
Assis L, Moretti AI, Abrahão TB, Cury V, Souza HP, Hamblin MR, et al.
Low-level laser therapy (808 nm) reduces inflammatory response and oxidative stress in rat tibialis anterior muscle after cryolesion. Lasers Surg Med 2012;44:726-35.
Liu H, Colavitti R, Rovira II, Finkel T. Redox-dependent transcriptional regulation. Circ Res 2005;97:967-74.
Denu JM, Tanner KG. Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: Evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 1998;37:5633-42.
Chen AC, Arany PR, Huang YY, Tomkinson EM, Sharma SK, Kharkwal GB, et al.
Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts. PLoS One 2011;6:e22453.
Zhang J, Xing D, Gao X. Low-power laser irradiation activates Src tyrosine kinase through reactive oxygen species-mediated signaling pathway. J Cell Physiol 2008;217:518-28.
Jobling MF, Mott JD, Finnegan MT, Jurukovski V, Erickson AC, Walian PJ, et al.
Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res 2006;166:839-48.
Szor JK, Topp R. Use of magnet therapy to heal an abdominal wound: A case study. Ostomy Wound Manage 1998;44:24-9.
Brown GC. Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta 2001;1504:46-57.
Karu TI, Pyatibrat LV, Afanasyeva NI. Cellular effects of low power laser therapy can be mediated by nitric oxide. Lasers Surg Med 2005;36:307-14.
Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK, et al.
Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A 1994;91:7583-7.
Fathabadie FF, Bayat M, Amini A, Bayat M, Rezaie F. Effects of pulsed infra-red low level-laser irradiation on mast cells number and degranulation in open skin wound healing of healthy and streptozotocin-induced diabetic rats. J Cosmet Laser Ther 2013;15:294-304.
Pallotta RC, Bjordal JM, Frigo L, Leal Junior EC, Teixeira S, Marcos RL, et al.
Infrared (810-nm) low-level laser therapy on rat experimental knee inflammation. Lasers Med Sci 2012;27:71-8.
Oliveira MC Jr., Greiffo FR, Rigonato-Oliveira NC, Custódio RW, Silva VR, Damaceno-Rodrigues NR, et al.
Low level laser therapy reduces acute lung inflammation in a model of pulmonary and extrapulmonary LPS-induced ARDS. J Photochem Photobiol B 2014;134:57-63.
Peplow PV, Baxter GD. Gene expression and release of growth factors during delayed wound healing: A review of studies in diabetic animals and possible combined laser phototherapy and growth factor treatment to enhance healing. Photomed Laser Surg 2012;30:617-36.
Avci P, Gupta A, Sadasivam M, Vecchio D, Pam Z, Pam N, et al.
Low-level laser (light) therapy (LLLT) in skin: Stimulating, healing, restoring. Semin Cutan Med Surg 2013;32:41-52.
Posten W, Wrone DA, Dover JS, Arndt KA, Silapunt S, Alam M, et al.
Low-level laser therapy for wound healing: Mechanism and efficacy. Dermatol Surg 2005;31:334-40.
Desmet KD, Paz DA, Corry JJ, Eells JT, Wong-Riley MT, Henry MM, et al.
Clinical and experimental applications of NIR-LED photobiomodulation. Photomed Laser Surg 2006;24:121-8.
AlGhamdi KM, Kumar A, Moussa NA. Low-level laser therapy: A useful technique for enhancing the proliferation of various cultured cells. Lasers Med Sci 2012;27:237-49.
Enwemeka CS, Parker JC, Dowdy DS, Harkness EE, Sanford LE, Woodruff LD, et al.
The efficacy of low-power lasers in tissue repair and pain control: A meta-analysis study. Photomed Laser Surg 2004;22:323-9.
Ozcelik O, Cenk Haytac M, Kunin A, Seydaoglu G. Improved wound healing by low-level laser irradiation after gingivectomy operations: A controlled clinical pilot study. J Clin Periodontol 2008;35:250-4.
Greco M, Guida G, Perlino E, Marra E, Quagliariello E. Increase in RNA and protein synthesis by mitochondria irradiated with helium-neon laser. Biochem Biophys Res Commun 1989;163:1428-34.
Karu TI, Kolyakov SF. Exact action spectra for cellular responses relevant to phototherapy. Photomed Laser Surg 2005;23:355-61.
Lane N. Cell biology: Power games. Nature 2006;443:901-3.
Shiva S, Gladwin MT. Shining a light on tissue NO stores: Near infrared release of NO from nitrite and nitrosylated hemes. J Mol Cell Cardiol 2009;46:1-3.
Grossman N, Schneid N, Reuveni H, Halevy S, Lubart R 780 nm low power diode laser irradiation stimulates proliferation of keratinocyte cultures: Involvement of reactive oxygen species. Lasers Surg Med 1998;22:212-8.
Hopkins JT, McLoda TA, Seegmiller JG, David Baxter G. Low-level laser therapy facilitates superficial wound healing in humans: A Triple-blind, sham-controlled study. J Athl Train 2004;39:223-9.
Yu W, Naim JO, Lanzafame RJ. Effects of photostimulation on wound healing in diabetic mice. Lasers Surg Med 1997;20:56-63.
[Table 1], [Table 2]