Year : 2018 | Volume
: 12 | Issue : 2 | Page : 46--49
An update on the effect of low-level laser therapy on growth factors involved in oral healing
Ashwini Savia Colaco
Department of Conservative Dentistry and Endodontics, A. J. Institute of Dental Sciences, Rajiv Gandhi University of Health Sciences, Mangalore, Karnataka, India
Dr. Ashwini Savia Colaco
Department of Conservative Dentistry and Endodontics, A. J. Institute of Dental Sciences, Rajiv Gandhi University of Health Sciences, Mangalore, Karnataka
Low-level laser therapy (LLLT) refers to irradiation with red-beam or near-infrared lasers that are typically of narrow spectral width to pathology to reduce inflammation, pain, and promote tissue regeneration. Lasers have varied and growing applications in the field of medicine. This technology has attracted major interest in the field of tissue engineering and healing. The goal of this review is to present the biological action of LLLT on various growth factors involved in oral healing. This article highlights the series of photochemical reactions, mechanism of action, and synthesis of several cytokines. Furthermore, it elucidates the cellular responses to LLLT providing insight into the current strategies that promote healing. This review was based on electronic search of scientific papers from 2000 to 2017 which was accomplished using PubMed and MEDLINE search engines to include relevant scientific citations from the peer-reviewed journals published in English. A total of 68 articles were included, of which 23 were excluded based on the exclusion criteria. The remaining 45 articles were evaluated, and specific information was retrieved from relevant 22 articles. The 22 articles included review articles and in vivo and in vitro studies that discussed in detail the effect of lasers on various growth factors. LLLT has a biomodulating effect on oral healing. LLLT influences the release of chemical mediators, reduces the duration of inflammation, and consequently promotes tissue repair. LLLT has therapeutic actions on the growth factors involved in oral healing and hence accelerates healing.
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Colaco AS. An update on the effect of low-level laser therapy on growth factors involved in oral healing.J Dent Lasers 2018;12:46-49
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Colaco AS. An update on the effect of low-level laser therapy on growth factors involved in oral healing. J Dent Lasers [serial online] 2018 [cited 2019 Aug 21 ];12:46-49
Available from: http://www.jdentlasers.org/text.asp?2018/12/2/46/247997
Light amplification by stimulated emission of radiation is a source of monochromatic, intense, coherent, and collimated light, whose emission of radiation is done by stimulating an external field, which in turn generates electromagnetic radiation that is relatively uniform in wavelength, phase, and polarization.
Low-level laser therapy (LLLT) refers to irradiation with red-beam or near-infrared lasers which are characterized by a wavelength of 600–1100 nm, an output power of 1–500 mW, and an energy density of 0.04–50 J/cm2.
In recent times, LLLT has attracted major interest in the field of tissue engineering, particularly in oral surgery. LLLT facilitates healing by increased neoangiogenesis, collagen fiber deposition, bone cell proliferation, and differentiation. All of these benefits stimulate bone regeneration after tooth extraction and surgical-assisted rapid maxillary expansion. It also accelerates healing in periapical surgeries and maxillofacial fracture consolidation and promotes bone remodeling during orthodontic movement of the teeth and osseointegration of implants.
Aim of this review
The aim of this review article is to gather and clarify the actual effects of LLLT on growth factors and its most effective application in wound healing.
Materials and Methods
A thorough search of the literature was performed through electronic search of scientific papers from the year 2000 to 2017. This was accomplished using PubMed and MEDLINE search engines to include relevant scientific citations from the peer-reviewed journals published in English. The words used in the literature search include LLLT, biostimulation, growth factors, oral healing, action spectrum of LLLT, and therapeutic application.
Articles from the year 2000 to 2017Articles in English were only acceptedArticles related to LLLT and its potential application in healing.
Articles before 2000Articles that not related to the title of literature and discuss other issuesArticles with unclear data and indistinct information.
A total of 68 articles were included, of which 23 were excluded based on the exclusion criteria. The remaining 45 articles were evaluated, and specific information was retrieved from relevant 22 articles. The excluded articles were those that did not provide precise data and distinguishable knowledge on the related topic. The 22 articles included review articles and in vivo and in vitro studies that discussed in detail the effect of lasers on various growth factors. Hence in this review, article compiles significant information on the therapeutic application of LLLT to promote healing.
Mechanisms of low-level laser therapy
LLLT is based on biostimulation of the tissues with monochromatic light. The biostimulatory effects are attributed to the presence of cellular chromophores and the law of photobiology. The first law of photobiology states that for low-power visible light to have any effect on a living biological system, the photons must be absorbed by electronic absorption bands belonging to some molecular photoacceptors or chromophores. Chromophores are molecules or part of a molecule which imparts color to the compound. They are seen in hemoglobin, myoglobin, flavins, flavoproteins, and porphyrins. The other important factor is the optical properties of tissue. Hemoglobin is the principle tissue chromophore, and it has high absorption bands. The optical window for highest tissue penetration is in the red and near-infrared spectrum. Hence, LLLT involves using light in the red and near-infrared wavelength. However, the success is also dependent on power, dose, and time of application of LLLT.
The action spectrum and the cellular response to low-level laser therapy
At the cellular level, the biological action includes activation of protein complexes, manipulation of inducible nitric oxide synthase activity, upregulation of various growth factors, stimulation of protein kinase C, induction of reactive oxygen species, modification of extracellular matrix components, inhibition of apoptosis, stimulation of mast cell degranulation, upregulation of heat shock proteins, and suppression of inflammatory cytokines such as tumor necrosis factor-alpha and interleukins.
The components of the mitochondrial cytochrome system absorbed and near-infrared radiation. The inner mitochondrial membrane shuttles electrons from one complex to the next using two freely diffusible molecules. This stepwise transfer of electrons with the aid of protons forms water molecules. All of these lead to release of energy that is transferred to the pumping of protons from the matrix to the intermembrane space. The mitochondrial membrane contains five complexes of integral membrane proteins, namely, nicotinamide adenine dinucleotide dehydrogenase (NADH) (Complex I), succinate dehydrogenase (Complex II), cytochrome c reductase (Complex III), cytochrome c oxidase (Complex IV), and adenosine triphosphate (ATP) synthase (Complex V). The respiratory chain transfers electrons through these integral proteins that play a vital role in biostimulation. Complex I (NADH) and hydroquinone form of flavin adenine dinucleotide (FADH2) which are produced in the Krebs cycle transfer electrons to oxygen molecules harnessing energy channels to the protons. The protons can flow back down this gradient, re-entering the matrix, only through another integral protein complex of the inner membrane, and the ATP synthase complex.
Growth factors involved in oral wound healing
Growth factors are involved in all phases of wound healing. Growth factors are categorized as a subclass of cytokines, which are proteins that act as intracellular signals to allow cells to communicate with one another. They are released from some cells and act as mediators that specifically stimulate the migration and proliferation of cells and synthesis of new tissues.
Some of the important growth factors involved in intraoral wound healing are as follows:
Platelet-derived growth factor
Platelet-derived growth factor (PDGF) helps in new bone formation and functions as an anabolic factor in bone metabolism. It is primarily stored in the bone matrix and released on activation of osteoblasts. PDGF stimulates the proliferation and chemotaxis of osteoblasts. It also plays a vital role in neoangiogenesis. The stimulation of microcirculation causes vasodilatation, thus increasing local blood flow. This, in turn, brings in oxygen and also allows for greater traffic of immune cells. Foremost immune cells consist of macrophages at the healing site. Macrophage activation increases the phagocytic activity into the tissue, contributing to accelerate healing.
Transforming growth factors
Transforming growth factor (TGF)-beta facilitates wound healing under inflammatory conditions. It is a multifunctional growth factor which upon activation causes proliferation of gingival fibroblastic cells, which result in increased formation of granulation tissue. It is found at higher levels in the bone matrix and promotes remodeling of bone matrix. TGF plays a role in immunoregulation of the wounded tissue, formation of blood vessels, and collagen production thereby accelerates epithelial repair and facilitates the growth of granulation tissue. TGF exerts pleiotropic effects on wound healing by regulating cell proliferation migration and differentiation and extracellular matrix production and immune modulation.
Epidermal growth factor
Epidermal growth factor plays an essential role in wound healing by participating in the development and differentiation of skin appendages, tissue repair, and proliferation of epithelial cells in the oral cavity. It promotes the formation of granulation tissue and stimulates fibroblast motility and migration of keratinocytes. Elevated levels of epidermal growth factor (EGF) were found in humans for up to 48 h after oral surgery, which promoted faster healing. Furthermore, EGF increases apoptosis and angiogenesis and activates ectodermal and mesodermal markers. EGF has been found to induce the phosphorylation of extracellular signal-regulated kinase pathways and production of extracellular matrix.
Insulin-like growth factor
Insulin-like growth factor (IGF) is chemotactic to fibroblast and thus enhances regeneration by stimulating the formation of mesenchymal tissues. IGF binds to a membrane-bound receptor and stimulates the tyrosine kinase receptor which generates signals needed for cellular response.
Fibroblast growth factors
Fibroblast growth factor (FGF) promotes healing of specialized tissue by the proliferation of fibroblast, vascular smooth muscle cells, capillary endothelial cells, and other cells such as chondrocytes and myoblasts. All of these enhance healing.
Vascular endothelial growth factor
Vascular EGF (VEGF) is produced by the endothelial cells, fibroblasts, smooth muscle cells, and many of the inflammatory cells such as macrophages, lymphocytes, neutrophils, and eosinophils. VEGF gene is highly expressed in the early stage of skin injury and is the only specific mitogen for endothelial cells. VEGF stimulates collagen deposition, angiogenesis, and epithelization promoting wound healing.
Bone morphogenetic proteins
Bone morphogenetic proteins are involved in bone formation, root cementum formation, and periodontal ligament formation. They encourage bone nodule formation by increasing alkaline phosphatase (ALP) activity and ALP gene expression.
Effect of low-level laser therapy on growth factors involved in wound healing
When there is tissue injury growth factors are released and brought to the traumatized area by macrophages, neutrophils, or the harbored blood clot. Growth factors participate in soft and hard tissues healing by increasing cellular chemotaxis which involves the directional movement of specific cell types and stem cells in response to a chemical concentration gradient to the wounded area. They induce differentiation of mesenchymal precursor cells to mature secreting cells and stimulate mitosis of relevant cells and synthesis of extracellular matrix.
The benefits of LLLT in wound healing are multifold. LLLT causes biomodulation effects on different types of cells, such as keratinocytes, fibroblasts, osteoblasts, odontoblasts, cardiomyocytes, and endothelial cells. This, in turn, increases cell proliferation, matrix synthesis, increased granulation tissue, enhanced neovascularization, early epithelialization, anti-inflammatory, and antiedema effect. All of these occur through acceleration of microcirculation, resulting in changes in capillary hydrostatic pressure with edema reabsorption, and disposal of the accumulation of intermediary metabolites. LLLT brings about a photostimulatory effect in mitochondria processes of the cells which enhances growth factor release and ultimately hastens healing.
Various studies established that there is a significant increase in basic FGF release from both keratinocytes and fibroblasts when cultured keratinocytes and fibroblasts were irradiated with 0.5–1.5 J/cm2 helium–neon (HeNe) laser. Furthermore, studies showed evidence of a more advanced bone tissue repair in the irradiated group when compared to the nonirradiated groups suggestive of the biomodulation effects. The cytokines released act on differentiated cells increasing both cell proliferation and secretion of components of the bone matrix. TGF is also upregulated by LLLT. TGF has potent effects on precursor cells of the osteoblast lineage and has a direct stimulatory effect on the bone collagen synthesis, thereby enhancing the quality of bone formation. Therefore, optimal laser therapy should promote the production and release of local factors at levels that enhance bone formation.
An in vitro study on the effect of low-power HeNe laser irradiation on endothelial cells concluded that LLLT increases VEGF. VEGF is critically important mediator of vasculogenesis, which is responsible for the neovascularization necessary for wound healing. Hypoxia is the main stimulus of angiogenesis. In response to hypoxia, hypoxia-inducible factor-1 is activated which is transported to the nucleus to be able to take part in the induction of VEGF gene. The activation of the VEGF gene stimulates the proliferation and chemotaxis of endothelial cells leading to angiogenesis. There have been reports on low-power laser irradiation increasing both protein and mRNA levels of interleukin-1-alpha and interleukin-8 from cultured human keratinocytes. Interleukins are pro-inflammatory cytokine known to be up-regulated during the early phases of inflammation.
LLLT can be indicated as an important therapeutic tool in wound healing. It stimulates the release of various growth factors that are mediators of a well-integrated inflammatory response thereby coordinating subsequent activity in the wound bed. Although studies have extensively covered the effects of LLLT on tissue, there is a need for research for better understanding of the true benefits of LLLT on different stages of oral healing.
I wish to express my appreciation to Manipal University and staff of A. J. Institute of Dental Sciences.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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