Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 2023 24(11):957-973

www.jzus.zju.edu.cn; www.springer.com/journal/11585
E-mail: [email protected]

Review
https://doi.org/10.1631/jzus.B2200706

Photobiomodulation therapy assisted orthodontic tooth movement:

potential implications, challenges, and new perspectives
Jiawen YONG1,2, Sabine GRÖGER2, Julia VON BREMEN2, Márcia MARTINS MARQUES3,
Andreas BRAUN4, Xiaoyan CHEN1, Sabine RUF2, Qianming CHEN1*
1
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral
Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research
Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
2
Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, Giessen 35392, Germany
3
School of Dentistry, University of Sao Paulo, Sao Paulo 05508000, Brazil
4
Department of Operative Dentistry, Periodontology and Preventive Dentistry, RWTH Aachen University, Aachen 52074, Germany

Abstract: Over the past decade, dramatic progress has been made in dental research areas involving laser therapy. The
photobiomodulatory effect of laser light regulates the behavior of periodontal tissues and promotes damaged tissues to heal
faster. Additionally, photobiomodulation therapy (PBMT), a non-invasive treatment, when applied in orthodontics, contributes
to alleviating pain and reducing inflammation induced by orthodontic forces, along with improving tissue healing processes.
Moreover, PBMT is attracting more attention as a possible approach to prevent the incidence of orthodontically induced
inflammatory root resorption (OIIRR) during orthodontic treatment (OT) due to its capacity to modulate inflammatory,
apoptotic, and anti-antioxidant responses. However, a systematic review revealed that PBMT has only a moderate grade of
evidence-based effectiveness during orthodontic tooth movement (OTM) in relation to OIIRR, casting doubt on its beneficial
effects. In PBMT-assisted orthodontics, delivering sufficient energy to the tooth root to achieve optimal stimulation is
challenging due to the exponential attenuation of light penetration in periodontal tissues. The penetration of light to the root
surface is another crucial unknown factor. Both the penetration depth and distribution of light in periodontal tissues are
unknown. Thus, advanced approaches specific to orthodontic application of PBMT need to be established to overcome these
limitations. This review explores possibilities for improving the application and effectiveness of PBMT during OTM. The aim
was to investigate the current evidence related to the underlying mechanisms of action of PBMT on various periodontal tissues
and cells, with a special focus on immunomodulatory effects during OTM.

Key words: Photobiomodulation therapy; Low-level laser therapy (LLLT); Low-intensity laser therapy (LILT); Orthodontic tooth
movement; Orthodontics; Immunorthodontics

1 Introduction growing evidence regarding the clinical effects of laser

light, particularly in the field of dentistry. Lasers used
The introduction of laser (light amplification by in phototherapy to induce photobiomodulation (PBM)
stimulated emission of radiation) technology pro‐ therapy (PBMT) on periodontal tissues are classified
vided researchers and clinicians with the opportunity as class III (those with an output power of 500 mW
to use light in human biology, creating new opportun‑ or less) or class IV (those with an output power of
ities for its application in medicine (Chen et al., 2023). more than 500 mW) (Dompe et al., 2020).
After more than 50 years of ongoing research, there is It was previously believed that PBMT required
the use of coherent laser light, but recently, light-
* Qianming CHEN, [email protected]
emitting diodes (LEDs) have been serving as a cheaper
Qianming CHEN, https://orcid.org/0000-0002-5371-4432
Jiawen YONG, https://orcid.org/0000-0002-3021-075X
alternative (Chow et al., 2009). The use of a low-
Received Dec. 29, 2022; Revision accepted May 15, 2023;
power light source (lasers or LED lights) can induce
Crosschecked Aug. 18, 2023; Published online Sept. 27, 2023 a PBM effect to simulate host cells directly for the
© Zhejiang University Press 2023 purpose of accelerating tissue healing, promoting
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angiogenesis, reducing inflammation, relieving pain, the cellular and molecular levels to influence bone
and producing analgesia (Chung et al., 2012). Clin‑ and cementum remodeling mechanisms. The biologic‑
ically, PBMT entails exposure of cells or tissues to red al process triggered by PBMT mentioned above can
(600–700 nm) and near infra-red (NIR, 770–1200 nm) be used for improving the proliferation rate of osteo‐
lights. blasts, as well as cementum repair, allowing the devel‐
The key mechanisms involved in the intracellu‐ opment of new clinical approaches in orthodontics
lar responses include the stimulation of mitochondrial (Yong et al., 2022f).
metabolism and an increase in electron transport. Ad‐ In this review, we explore possibilities for im‐
enosine triphosphate (ATP) production elevated by ac‐ proving the application and effectiveness of PBMT
tivation of the electron transport chain and a short during orthodontic tooth movement (OTM). The aim
release of nitric oxide (NO) from its binding site on was to investigate the current status of evidence re‐
cytochrome c oxidase (CCO) results in increased cell lated to the underlying mechanisms of action of PBMT
respiration and transient synthesis of reactive oxy‐ on various periodontal tissues and cells, with a special
gen species (ROS) which in turn promote the conver‐ focus on the immunomodulatory effects during OTM.
sion of adenosine diphosphate (ADP) to ATP. An‐ The first goal of this review was to update knowledge
other hypothesis concerns the activation of light- of laser application in dentistry, mostly concerning
sensitive ion channels that allow calcium ions (Ca2+ ) how PBMT works at the molecular and cellular levels
to enter the cell leading to subsequent modulation of in relation to orthodontics. The second purpose was to
numerous signaling pathways via ROS, adenosine raise the awareness of researchers regarding the diffi‐
3',5'-cyclic-monophosphate (cAMP), NO, and Ca2+ re‐ culties and challenges of the application of PBMT in
lease, resulting in transcription factor production (Cron‐ orthodontics. The third objective was to promote PBMT-
shaw et al., 2020). These transcription factors are able assisted OT as an important complementary approach
to promote the expression of genes associated with to treat orthodontic-related problems that goes beyond
new protein synthesis, cell migration and prolifera‐ traditional methods. For future research, the working
tion, anti-inflammatory signaling, anti-apoptotic pro‐ mechanisms underlying the positive effects of PBMT
teins, and antioxidant enzymes (de Freitas and Hamb‐ on OTM should be investigated.
lin, 2016).
There are recent encouraging reports of the den‐
tal application of PBMT in a wide range of oral hard 2 Laser and PBMT
and soft tissues in endodontics, periodontics, pediatrics,
2.1 Basic concepts of laser
prosthodontics, orthodontics, and maxillofacial surgery
(de Freitas and Hamblin, 2016). Recently, PBMT has The development of lasers triggered a medical
been studied extensively in regard to orthodontic pain revolution in multiple branches of medicine (Svelto
management (pain reduction), tooth movement accel‐ et al., 2007). There are three significant characteristics
eration (faster alveolar bone remodeling and improved of laser light that set it apart from natural light: mono‐
collagen deposition) during fixed mechanotherapy, chromaticity, collinearity, and coherence (Ailioaie and
bone regeneration (improved osteoblast/osteoclast ac‐ Litscher, 2020). Due to these distinctive properties,
tivity) after rapid maxillary expansion, titanium im‐ laser light is ideal for stimulating chromophores in
plants (improved wound healing, attachment, and os‐ biological tissues that are sensitive only to certain
seointegration), external root resorption control, and specific wavelengths (Ailioaie and Litscher, 2020).
post-treatment retention (Nayyer et al., 2022). One In clinical laser practice, wavelength, power, energy,
of the commonly associated iatrogenic effects of fixed irradiation/exposure time, emission modes (continu‐
orthodontic treatment (OT) is the occurrence of ous or pulsed), power density, and energy density are
orthodontically induced inflammatory root resorption the most useful parameters and units of measurement
(OIIRR), which is gaining attention concerning its (Ailioaie and Litscher, 2020) (Table 1).
prevention and treatment (Yong et al., 2022e). Based A laser device emits light energy from stimulated
on the established mechanisms of PBMT, it is ex‐ photons into the irradiated target tissue that stimulates
pected that the energy emitted by PBMT may act at photothermal, photophysical, and/or photochemical
 J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973 | 959

Table 1 Irradiation parameters

Quantity Unit Definition
Power mW or W Energy (J) per second (s), peak and average when pulsed.
Energy mJ or J Produced energy is obtained by multiplying the laser output power (W) by
exposition time (s).
Irradiation/exposure time s or min The irradiation/exposure time varies significantly from a few seconds to many
minutes, but is often in the range of 30–150 s.
Beam area cm2 The correct way to measure the beam area is to use a beam profiler and report
the 1/e2 area.
Intensity (power density), mW/cm or W/cm Irradiance is the power (W) divided by the beam area (cm2).
2 2

irradiance
Fluence (energy density) mJ/cm2 or J/cm2 Calculated as power (W)×time (s)/beam area (cm2). The tissue dose is expressed
by the energy density (J/cm²).
Dose J/cm2 Examined another way, the dose is the power density multiplied by time (s).
The resultant dose in J/cm2 could be the consequence of several different
treatment options.
Dosage J Dosage (J) is the trickiest parameter in photobiomodulation (PBM) studies
especially when pulsing is involved. The use of Joules is advocated to specify
how much energy is delivered in a treatment, which is more important
clinically. Using dosage (J) rather than dose (J/cm2) will enable better
standardization of dosages and permit comparison across different treatment
regimens/protocols.

reactions at various biological levels, implicating en‐ of 700 –770 nm have been ineffective, as this region
dogenous chromophores (Ailioaie and Litscher, 2020). coincides with a trough in the absorption spectrum of
The effect of a laser is dependent on the light interac‐ CCO (de Freitas and Hamblin, 2016). Both absorp‐
tions in biological tissues including transmission, scat‐ tion and scattering decline significantly as the wave‐
tering, reflection, and absorption (Arora et al., 2021). length increases, so the penetration depth of NIR is
The penetration depth of a laser beam into tissue maximal at a wavelength of about 810 nm (Hamblin,
is governed by several factors, including the wave‐ 2017). At longer wavelengths, water molecules become
length, tissue composition, and forward- and back- the important absorber and the penetration depth de‐
scattering by structures and molecules present within clines (Hamblin, 2017).
the tissue (Keijzer et al., 1989). The success of laser In PBMT, emissive photonic fluxes from LEDs
treatment is determined by the selection of an appro‐ enter the cells, penetrate tissue, and initiate a cascade
priate laser resource for energy level quantification of photochemical reactions on specific signaling path‐
targeting and the correct setting of parameters (Ailio‐ ways due to endogenous photoreceptors. These reac‐
aie and Litscher, 2020). tions trigger molecular changes in the mitochondrial
respiratory chain, inducing reduction of nitrite to NO,
2.2 Mechanism action of PBMT
and enhancement of synthesis of CCO, an enzyme
Low-level laser therapy (formerly abbreviated as participating in the mitochondrial electron transport
LLLT), also known as low-intensity laser therapy chain (Osipov et al., 2018).
(LILT), was initially used in attempts to cure malig‐ Hamblin (2017) proposed that three key cellular
nant tumors in rats (MgGuff et al., 1965). However, and molecular stages are triggered when light photons
this term became replaced by “PBMT” because equiva‐ are absorbed by target photoreceptors modulating cel‐
lent beneficial biological effects can be obtained by lular functions. The primary biological chromophores
non-coherent LEDs with comparable parameters to (termed “photoreceptors”) have been identified as CCO
low power coherent monochromatic lasers for most in mitochondria (absorbing light mainly in the NIR re‐
medical applications (Hamblin, 2016). gion up to 950 nm), light-gated calcium ion channels,
In PBMT, numerous wavelengths in the red (600– and opsins (particularly responding to blue or green
700 nm) and NIR (770–1200 nm) spectral regions have light). Secondary effects of photon absorption in cells
produced desirable results, while those in the region include increases in ATP, a brief and modest burst of
960 | J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973

ROS generation, production of NO, and regulation of Thus, the final clinical outcomes of PBMT result not
calcium levels. Moreover, PBMT can normalize the only from the direct irradiation of the tissue, but also
oxygen levels through two enzymatic reactions of from its secondary and tertiary effects.
CCO, CCO/H2O and CCO/NO (Pruitt et al., 2022), PBMT presents a “biphasic dose-response” (also
which may play an important role in hypoxic condi‐ termed the “Arndt-Schulz curve”), where low doses
tions induced by orthodontic force during OTM. Ter‐ produce photobiostimulation and high doses produce
tiary effects include activation of a wide range of signal‐ photobioinhibition (Huang et al., 2011). Photobios‐
ing pathways that will improve cell survival and apop‐ timulation is associated with enhanced healing, whereas
tosis, increase proliferation and migration, and pro‐ photobioinhibition has been found to be optimal for
mote new protein synthesis (Hamblin, 2017) (Fig. 1). pain relief (Kate et al., 2018). As a result, it is widely
In vivo, PBMT has a potent anti-inflammatory effect applied in clinical practice for stimulation and wound
by activating nuclear factor-κB (NF-κB) in embry‐ healing (as values from 5 to 50 mW/cm2) and relief
onic fibroblasts, reducing pro-inflammatory cytokines of pain and inflammation or nerve inhibition (up to
in activated inflammatory cells, and decreasing mark‐ 1 W/cm2), noting that a key consideration for clini‐
ers of the M1-activated macrophage phenotype in cians is that an inappropriate dose may have the oppo‐
macrophages (von Leden et al., 2013). The cellular re‐ site therapeutic effects (Huang et al., 2011).
actions of PBMT also include the inhibition of cyclo‐ The use of PBMT may be an alternative treat‐
oxygenase (COX) resulting in a reduced production ment with good acceptance due to its well-proven
of prostaglandins (PGs), which act as core mediators characteristics, as well as being a type of therapy that
of the acute inflammatory response (Pruitt et al., 2022). can be widely used in different areas of dentistry. In

Fig. 1 Mechanisms underlying photobiomodulation (PBM) at the cellular and molecular levels. NIR: near infra-red;
NO: nitric oxide; ROS: reactive oxygen species; CCO: cytochrome c oxidase; ATP: adenosine triphosphate; cAMP:
adenosine 3', 5'-cyclic-monophosphate; Akt: protein kinase B; GSK-3β: glycogen synthase kinase-3β; NF-κB: nuclear
factor-κB; RANKL: receptor activator of NF-κB ligand; HIF-1α: hypoxia-inducible factor-1α; ERK: extracellular signal-
regulated kinase; PPAR: peroxisome proliferator-activated receptor; mTOR: mammalian target of rapamycin; RUNX-2:
Runt-related transcription factor 2.
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the field of periodontology, PBMT at wavelengths of light without causing damage (Domínguez and
810 nm (Abidi et al., 2021) and 660 nm (Lee et al., Velásquez, 2021).
2018) has anti-inflammatory effects on human perio‑ Researchers have found different ways to speed
dontal ligament cells (hPDLCs). Besides its non- up OTM through the stimulation of bone remodeling
invasive, safe, and effective properties, PBMT has (Nimeri et al., 2013). The approaches fall into three
been highlighted in the dental literature mainly for its broad categories: (1) biological pathways involving
pain inhibitory effects (Topolski et al., 2018) and tissue local or systemic drug delivery (local injections of PGs
repair mechanisms (Wagner et al., 2013). These modu‐ (Seifi et al., 2003), vitamin D (Kawakami and Takano-
latory effects are the result of the capacity of PBMT Yamamoto, 2004), osteocalcin (OCN) (Hashimoto
to induce metabolic changes and accelerate bone re‐ et al., 2001) around the alveolar socket, or the admin‐
sorption and neoformation, which are also necessary istration of muscle relaxants (Uribe et al., 2014));
for OTM (Ekizer et al., 2016). This prompted us (2) physical or mechanical stimulation (PBMT (Doshi-
to explore its potential applications and underlying Mehta and Bhad-Patil, 2012; Genc et al., 2013) or vi‐
mechanisms more deeply for future “PBMT-assisted bratory forces); and (3) surgically facilitated OT (de‐
orthodontics.” cortication, piezocision, or cortectomies) (Fernandes
et al., 2019). Based on randomized controlled trials re‐
lated to PBMT-assisted OTM acceleration, the ideal
3 PBMT in orthodontics range of PBMT wavelength is between 780 and 830 nm
(Domínguez Camacho et al., 2020a). Individual studies
Orthodontics is a dental specialty and, like all have reported positive results at 809 nm (Youssef
dental procedures, may have adverse effects. The et al., 2008), 780 nm (Cruz et al., 2004), 810 nm (Yo‐
most common side effects of OT are pain, oral ulcers shida et al., 2009; Doshi-Mehta and Bhad-Patil, 2012),
(Baricevic et al., 2011), white spot lesions and caries, 860 nm (Limpanichkul et al., 2006), and 980 nm (Da‐
periodontal changes, root resorption (specially termed kshina et al., 2019). The cascade of physiological re‐
“OIIRR”), pulpal changes, and temporomandibular actions triggered by applying an orthodontic force in
disorder (TMD) (Enaia et al., 2011; Talic, 2011). conjunction with PBMT allows an average increase in
Many studies have reported positive effects of speed of OTM of 24%–30% compared to applying
PBMT in the above common clinical adverse condi‐ force alone (Domínguez Camacho et al., 2020b).
tions in relation to OT, including reduction of orth‐ OTM induced by orthodontic force results in a
odontic pain (Sfondrini et al., 2020; Anicic et al., 2021; painful and sterile inflammatory adaptation process of
Mirhashemi et al., 2021), acceleration of OTM rate the alveolar bone modeling (Yong et al., 2023). Differ‐
(Kau et al., 2013; Yassaei et al., 2013; Shaughnessy ent medications and techniques have been proposed
et al., 2016; Yavagal et al., 2021), management of ex‐ to relieve pain during OT (Law et al., 2000), such as
ternal root resorption (da Silva Sousa et al., 2011; ibuprofen and naproxen sodium, chewing gum, anti-
Nimeri et al., 2014; al Okla et al., 2018; Khaw et al., inflammatory and preemptive valdecoxib therapy, acu‐
2018; Ng et al., 2018; Fernandes et al., 2019; Goymen puncture and acupressure techniques, salicylic acetyl
and Gulec, 2020; Eid et al., 2022), mitigation of oral acid, and rofecoxib (Domínguez Camacho et al.,
mucosal lesions/traumatic ulcers caused by appliances, 2020a). These alternatives can be helpful in relieving
as well as the prevention or treatment of TMD (Tunér pain, but they may also slow down the rate of OTM
et al., 2019; Alsarhan et al., 2022). Therefore, it seems (Bernhardt et al., 2001). The use of PBMT is able to
that PBMT presents many possible and potential clin‑ alleviate pain, accelerate wound healing, and have a
ical benefits for OT and its associated side effects. beneficial effect on inflammatory processes. Lim et al.
(1995) and Harazaki et al. (1998) both showed that
3.1 PBMT-assisted orthodontics
orthodontic pain levels were lower in PBMT group
PBMT-assisted orthodontics refers to the applica‐ compared to control group at different treatment
tion of this non-invasive therapy during OT, as it does stages. It has further been reported that PBMT within
not raise tissue temperature and stimulates biological a wavelength range of 800 to 850 nm may effectively
functions in a biphasic manner using monochromatic decrease orthodontic pain, temporomandibular joint
962 | J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973

(TMJ) pain, and TMD, at least in the short term (Esla‐ including increased production of mitochondrial ATP
mian et al., 2014; Panhoca et al., 2015). (Masha et al., 2013). Increased ATP levels are then in‐
Reducing orthodontic pain levels and the dura‐ volved in promoting alveolar bone remodeling through
tion of multibracket appliance treatment would ben‐ overall elevation of metabolic activity to achieve OTM
efit patient comfort and satisfaction (Seifi et al., 2007). acceleration. PBMT may also promote angiogenesis,
However, most PBMT research on OTM and the thus increasing the blood supply necessary for remod‐
concurrent cellular reactions has been conducted in eling (Eells et al., 2003). It has been theorized that
rodents (Saito and Shimizu, 1997; Yamaguchi et al., PBMT-induced ROS production may be associated
2007; Gama et al., 2010) and rabbits (Ozawa et al., with laser-induced analgesia (Ryu et al., 2010). These
1998; Kawasaki and Shimizu, 2000; Seifi et al., 2007). secondary mediators of PBMT (ROS, ATP, NO, and
Some clinical studies have reported the relief of pain cAMP) can activate the cellular response via transcrip‐
during treatment (Cruz et al., 2004; Limpanichkul tion factors and signaling pathways including NF-κB,
et al., 2006; Youssef et al., 2008; Mistry et al., 2020), receptor activator of NF-κB (RANK) ligand (RANKL),
but the cellular changes that occur following laser ap‐ hypoxia-inducible factor-1α (HIF-1α), protein kinase
plication were not fully investigated. B (Akt)/glycogen synthase kinase-3β (GSK-3β)/
β-catenin pathway, Akt/mammalian target of rapamy‐
3.2 Cellular and molecular mechanisms of PBMT
cin (mTOR)/cyclin-D1 pathway, extracellular signal-
in orthodontics
regulated kinase (ERK)/forkhead box protein M1
Domínguez and Velásquez (2021) proposed five (FOXM1), peroxisome proliferator-activated recep‐
fronts at which orthodontic force acts to induce OTM. tors (PPARs), and Runt-related transcription factor 2
Accordingly, an ideal acceleration technique should (RUNX-2) (de Freitas and Hamblin, 2016; Hamblin,
modulate all five fronts: blood vessels, non-mineralized 2018; Yong et al., 2021b, 2022a, 2022d).
tissues, mineralized tissues, nervous system, and im‐
3.2.1 Effects of PBMT on blood vessels
mune system (Fig. 2).
At the cellular level, PBMT in the NIR region During OTM, periodontal ligament and alveolar
activates the primary mitochondrial photoreceptors bone remodeling are two main alterations in response
(CCO) (Eells et al., 2004). The activation of CCO to orthodontic force. However, it is crucial to consider
triggers different cascades of cellular responses that there are also important alterations in the pulp

Fig. 2 Therapeutic effects in photobiomodulation therapy (PBMT)-assisted orthodontics are multifactorial, with positive
reactions in blood vessels, mineralized tissues, non-mineralized tissues, nervous system, and immune system. OTM:
orthodontic tooth movement; TMD: temporomandibular disorder.
 J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973 | 963

and gingival tissues as a result of vascular changes of the cells are indirectly affected by bioactive molecules
inflammatory origin. Vascularization plays a key role released from the stimulated cells (Carroll et al., 2014).
in OTM because both frontal and undermining alveo‐ In hypoxic microenvironments induced by com‐
lar bone resorptions require blood vessel supply (Yas‐ pressive force, mitochondria synthesize NO, which
saei et al., 2013). competes with and displaces oxygen for binding to
PBMT in rats, particularly at 660 nm, promotes CCO, leading to two negative effects: reduced ATP
angiogenesis and decreases oral wound level of tumor synthesis and increased oxidative stress, causing in‐
necrosis factor-α (TNF-α) while increasing level of in‐ flammation via NF-κB, an inflammatory “master
terleukin-1β (IL-1β) (Wagner et al., 2016). Cury et al. switch” transcription factor (Carroll et al., 2014). Thus,
(2013) demonstrated in rats that 660 and 780 nm of PBMT is able to circumvent these negative effects be‐
PBMT have a pro-angiogenic effect through HIF-1α cause it releases NO from CCO, restoring ATP forma‐
and vascular endothelial growth factor (VEGF) expres‐ tion. Then, PBMT contributes to the dilation of blood
sion, as well as by a decrease in matrix metalloproteinase- vessels and improves blood circulation through the ac‐
2 (MMP-2). Szymanska et al. (2013) reported that vas‐ tion of the signaling molecule NO released from CCO,
cular endothelial cells exposed to 635-nm irradiation increasing ATP synthesis and reducing oxidative stress
proliferated faster than non-irradiated cells and had a (de Freitas and Hamblin, 2016). NO, a well-known
decreasing VEGF level, while 830-nm irradiation de‐ vasodilator, acts via stimulation of soluble guanylate
creased transforming growth factor-β (TGF-β) secre‐ cyclase to form cyclic guanosine monophosphate
tion by endothelial cells. PBMT has also been shown (cGMP), which later activates protein kinase G to re‐
to stimulate angiogenesis during OT in the pulp at a sult in Ca2+ reuptake and the opening of calcium-
wavelength of 830 nm (100 mW, 2.2 J/palatine, for activated potassium channels (de Freitas and Hamblin,
22 s/point) (Domínguez et al., 2013). PBMT using 2016). The fall in concentration of Ca2+ prevents myo‐
LED illumination at 5 J/cm2 also showed favorable re‐ sin light chain kinase (MLCK) from phosphorylating
sults regarding angiogenesis (Corazza et al., 2007). the myosin molecule, which causes relaxation of the
PBMT facilitates epithelial healing and new blood smooth muscle cells in the lining of blood vessels and
vessel formation through activation of the mTOR sig‐ lymphatic vessels (Murad, 2004). Additional mech‑
naling pathway (Pellicioli et al., 2014) and ROS accu‐ anisms have also been proposed by which NO could af‐
mulation without inducing extra DNA damage (Dil‐ fect signaling pathways, including activation of iron-
lenburg et al., 2014). ROS is a classical “Janus-face” regulatory factors in macrophages (Drapier et al.,
mediator; beneficial at low concentrations and with 1993), modulation of proteins such as ribonucleo‐
brief exposures, but harmful at high concentrations tide reductase (Lepoivre et al., 1991) and aconitase
and with prolonged and chronic exposures (Popa- (Drapier and Hibbs, 1996), stimulating ADP-ribosylation
Wagner et al., 2013). PBMT application initially re‐ of glyceraldehyde-3-phosphate dehydrogenase (Dim‐
duces the production of prostaglandin E2 (PGE2) by meler et al., 1992), and nitrosylation of protein sulfhy‐
inhibiting the tissue arachidonic acid cascade, which dryl group (Stamler et al., 1992).
affects the secretion of inflammatory cytokines (Mizu‐
3.2.2 Effects of PBMT on non-mineralized tissues
tani et al., 2004).
The consequences of PBMT on hypoxic cells are The biological response of non-mineralized tis‐
dependent on four classes of effects. The first class of sues during OTM includes the synthesis of collagen
effect is induced by enzyme CCO, which transfers fibers and the proliferation of periodontal ligament
light energy to the cell, triggering a series of down‐ (PDL) cells, PDL stem cells (PDLSCs), and fibroblasts.
stream effects. The second class of effect is induced Also, specific biomarkers that modulate mineralized
by changes in NO, ATP, and ROS levels. The third tissue remodeling (bone/cementum) must be consid‐
class of effect refers to downstream intracellular ge‐ ered (Yong et al., 2021a).
netic transcription and cellular signaling to regulate Indicators of mechanisms required to increase
cell hemeostasis in processes such as proliferation, mi‐ the turnover in periodontal fibers are the increases in
gration, necrosis, and inflammation. The fourth class of expression of TGF-β, fibroblast growth factor (FGF),
effect is determined by the cells in the blood, where insulin-like growth factor-2 (IGF-2), and receptor of
964 | J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973

IGF-1 (IGF binding protein 3 (IGFBP3)) (Saygun et al., Interaction between the mineralized structure
2008). At this point, the positive effects of PBMT start and PBMT induces osteoblast proliferation and acti‐
to overlap on various fronts on which the application vates the NF-κB and RANK/RANKL/osteoprotegerin
of force has its effect. For example, PBMT results in (OPG) system (Fujita et al., 2008). More osteoblasts
an increase in the expression of FGF, which is a cyto‐ express more circulating RANKL (Katagiri and Taka‐
kine involved in angiogenesis, tissue remodeling, and hashi, 2002), which is a factor promoting osteoclasto‐
stimulation of osteoblasts and osteoclasts. Kim et al. genesis. The receptor RANK, located on the cell sur‐
(2009) reported that PBMT at 808 nm increases fibro‐ face of precursors of osteoclasts, transduces signaling
nectin and type I collagen levels to facilitate the turn‐ inside the osteoclasts. OPG, a decoy receptor with the
over of connective tissue during OTM. Faria et al. capacity to competitively combine RANK and RANKL
(2020) demonstrated that PBMT at 830 nm with 3 with RANK, inhibits osteoclastogenesis to decrease
and 30 J/cm2 alters B-cell lymphoma-2 (BCL-2) and osteoclast formation. Thus, RANKL and OPG regu‐
caspase-6 levels to modulate cell survival and re‐ late alveolar bone resorption by exerting a positive or
duce DNA fragmentation in PDL cells. PDL also con‐ negative control on RANK on osteoclasts (Blair et al.,
tains PDLSCs that can differentiate into cementum/ 2007).
PDL-like structures in vivo to promote repair of OIIRR After application of orthodontic forces, alveolar
(Seo et al., 2004). Gholami et al. (2022) reported that bone resorption is induced on the compressed side by
PBMT at 940 nm using a diode laser at 4 J/cm2 im‐ RANK signaling in osteoclast precursors. Kim et al.
proved mineralized deposition by bone morphogenetic (2007) reported that PBMT increased the expression
protein-2 (BMP-2) and VEGF levels on PDLSCs. A of both RANK and RANKL in the irradiated area
recent systematic review indicated that PBMT can around the moved tooth, which are two components
enhance the differentiation capacities of PDLSCs, but necessary for the induction of tooth movement and osteo‑
there is no agreement on the protocol (Mylona et al., clastogenesis. Experimental evidence showed that
2022). In terms of the energy density applied by clini‐ PBMT stimulates osteoblast proliferation and induces
cians, it should not exceed 8 J/cm2 when using LED de‐ osteoclast differentiation during OTM, and acceler‐
vices, and 4 J/cm2 when using lasers (Mylona et al., 2022). ates alveolar remodeling (Fujita et al., 2008). Marcos
et al. (2011) showed that PBMT irradiated at 810 nm
3.2.3 Effects of PBMT on mineralized tissues
decreased the gene expression of COX-2 and subse‐
When orthodontic force and PBMT are applied, quently inhibited the production of PGE2 in a rat
the periodontal ligament is no longer the only mechano‑ model, both of which led to pain reduction. When
transducive organ that enables the acceleration of PBMT at 630 and 810 nm stimulates proliferation and
OTM. At that point, it is the change in alveolar bone differentiation of osteoblasts, it is accompanied by in‐
turnover that will speed up OTM (Yoshida et al., creased alkaline phosphatase (ALP) and OCN expres‐
2009). Studies using an experimental tooth movement sion (Chang et al., 2019). According to Fujimoto et al.
rat model have shown that PBMT irradiation in‐ (2010), this effect can be stimulated by 1.91 J/cm2
creases the velocity of OTM by induction of the PBMT and be attributed to an increased expression of
RANK/RANKL system (Fujita et al., 2008) and the RUNX-2 and Osterix (Osx), although other differen‐
c-fms/macrophage colony-stimulating factor (M-CSF) tiation factors, such as BMP-2, BMP-4, BMP-6, and
system (Yamaguchi et al., 2007). Kawasaki and Shi‐ BMP-7, might also be involved. Another major find‐
mizu (2000) reported that PBMT stimulated the ing is that PBMT at 2 J/cm2 irradiation influences ce‐
amount of OTM and the formation of osteoclasts on mentoblast migration, proliferation, and differentia‐
the compressed side during experimental tooth move‐ tion, and activates MAPK signaling, depending on the
ment in vivo in rats, indicating that PBMT can accel‐ pulse duration. This suggests that PBMT could be
erate OTM. However, PBMT also increases osteoblas‐ considered as an adjunctive therapy to be applied in
tic cell proliferation and can therefore stimulate osteo‐ prevention or treatments involving dental roots, such
genesis and increase bone density on the compressed as OIIRR (Yong et al., 2022f).
side during OTM (Yassaei et al., 2013), which could Yamaguchi et al. (2010) showed in their rat model
in turn reduce the speed of OTM. that increments in the expression of MMP-9, cathepsin
 J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973 | 965

K, and subunits of integrin are detectable after PBMT research is needed to fully characterize this complex
application, facilitating the velocity of OTM. Yamagu‐ mechanism of action (NIR light exerts a protective ef‐
chi et al. (2007) also reported that PBMT can increase fect on neurons, but the mechanisms are still not fully
M-CSF and c-fms on the compressed side and may understood).
also increase osteoclastogenesis leading to tooth move‐ Depending on the various energy densities reach‐
ment. Additional PBMT shortened the duration of ing the tissue or cell, PBMT may activate immune
OTM by accelerating OTM during molar intrusion by cells (Viegas et al., 2007; Moriyama et al., 2009).
modulating the levels of cytokines (IL-1β, IL-6, and Macrophages are important antigen-presenting cells
IL-8) in irradiated areas, which were elevated in com‐ that play a role in the induction of the primary im‐
parison to non-irradiated lesions throughout the entire mune response. The M1 profile is characterized by
experimental period (Fernandes et al., 2019). Taken the production of high levels of pro-inflammatory cy‐
together, these in vivo and in vitro findings point to a tokines (such as IL-6, TNF-α, and COX-2), low levels
potential favorable effect of PBMT on accelerating of anti-inflammatory cytokines, strong microbicidal
the rate of OTM via positive effects on mineralized activity, high ROS generation, and promotion of the
tissue remodeling. Th1 immune response (Labonte et al., 2014). In con‐
trast, the M2 profile is characterized by the produc‐
3.2.4 Effects of PBMT on the nervous and immune
tion of high levels of anti-inflammatory cytokines to
systems
attenuate the effects of the M1 population as well as
PBMT applied along with orthodontic force is enzymes and growth factors that stimulate tissue re‐
also used to impact the nervous system to aid in pain modeling and regeneration, and expression of the Th2
management. One proposed hypothesis involves a immune response (Martinez et al., 2009).
conduction block of central and peripheral nerve fi‐ Chen et al. (2014) reported that PBMT at 660 nm
bers to increase the release of endorphins (de Freitas and 1 J/cm2 promoted optimal M1 polarization of
and Hamblin, 2016). This process includes the absorp‐ monocytes. This effect was concomitant with histone
tion of mitochondria leading to vasodilation, stimula‐ modification at the TNF-α gene locus and mitochon‐
tion of cell division, release of NO, a rise in cortisol drial biogenesis (Chen et al., 2014). According to a
levels, accumulation of intracellular calcium, activity study by de Brito Sousa et al. (2020), PBMT irradi‐
of the antioxidant enzyme superoxide dismutase, and ated at 660 nm and 17.5 J/cm2 decreased the gene ex‐
new protein synthesis (Domínguez Camacho et al., pression of the macrophage inflammatory protein-1α
2020a; Yong et al., 2022b, 2022c). Yan et al. (2011) (MIP-1α, also known as C-C motif chemokine ligand
postulated that PBMT could suppress afferent fiber 3 (CCL3)), MIP-2α (also known as C-X-C motif che‐
signaling as well as modulate synaptic transmission to mokine ligand 2 (CXCL2)), and TNF-α to modulate
dorsal horn neurons, including inhibition of substance the expression of the M1-related markers. This indi‐
P, which can contribute to long-term pain suppression. cates important inhibitory effects in the promotion, mi‐
Chan et al. (2012) applied PBMT by 0.30–0.45 J/cm2 gration, and activation of monocytes and neutrophils
in their clinical trial and demonstrated its efficacy on in the initial stage of inflammation (de Brito Sousa et
pulpal analgesia of premolar teeth by suppressing the al., 2020). M1-related immunoregulation is important
intradental nerve response to electrical and mechan‑ for the pathogenesis of inflammation in autoimmune
ical stimuli. conditions. Hence, PBMT regulation of M1-related
It has also been reported that, when absorbed by immunological factors could be useful to promote
nociceptors, PBMT with an irradiance higher than control of autoimmune conditions. On the other hand,
300 mW/cm2 can inhibit Aδ and C pain fibers, decrease Liao et al. (2021) reported that NIR irradiated at high
conduction velocity, reduce the compound action po‐ energy density (30–360 J/cm2) epigenetically regu‐
tential amplitude, and suppress neurogenic inflamma‐ lates macrophage M2 polarization, resulting in anti-
tion (Carroll et al., 2014). PBM light can block antero‐ inflammatory effects by TGF-β1. Thus, NIR irradiation
grade transport of ATP-rich mitochondria in dorsal not only alters the homeostasis between M1 and M2
root ganglion neurons. This inhibition is entirely re‐ macrophages, but also decreases the M1-mediated de‐
versible within 48 h (Yan et al., 2011). However, more fense mechanism in unstimulated macrophages.
966 | J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973

4 Challenges and difficulties of PBMT-assisted due to its higher penetration depth than red laser light
orthodontics (Anders and Wu, 2016). Su et al. (2020) reported that
an 830-nm laser was more suitable than a 660-nm laser
4.1 What is the exact energy density applied to
for deeper tissues such as the attached gingiva stimu‐
the tooth root? lation, suggesting that the real required power density
For PBMT, selection of the correct irradiation pa‐ on the attached gingiva can be reached by radiating
rameter determines the effectiveness of the treatment NIR laser light from the outside (Na et al., 2018). Fur‐
outcome because of the “biphasic dose-response” thermore, the significant difference in light attenua‐
(Lanzafame et al., 2007; Su et al., 2020). Goulart et al. tion between soft and hard tissues indicates the need
(2006) observed that a high intensity of laser therapy for reassessment of PBMT parameters when treating
decreased the rate of tooth movement, while a low in‐ different orthodontic-related tissues such as gingiva,
tensity had the opposite effect by a dog model. As alveolar bone, and tooth root. Only in this manner
noted previously, different wavelengths have been re‐ can optimal clinical outcomes be precisely controlled
ported to have distinct biological effects and mecha‐ and achieved. However, exact data regarding light
nisms. Therefore, determining the optimal irradia‐ penetration and distribution during PBMT in peri‐
tion parameter for each range of wavelengths in the odontal hard and soft tissues under real clinical condi‐
red-to-NIR region is critical (Salehpour et al., 2018). tions have been lacking. Moreover, the real distribu‐
Besides, the energy and power densities reaching the tion or value of laser irradiation when the light pen‐
tissue are the key parameters influencing the thera‐ etrates to the tooth root region has not been studied at
peutic effects of PBMT. Na et al. (2018) found that all. Therefore, it should be emphasized that the
the responses of PBMT on osteoblasts, osteoclasts, quantitative re-measurement of energy density pen‐
and osteocytes differ under different energy densities. etration to these periodontal structures should be per‐
The “biphasic dose-response” indicates that the en‐ formed to help increase the efficiency of evidence-
ergy density must exceed a certain threshold to stimu‐ based clinical research (Su et al., 2020).
late any biological effects (Mester et al., 1978). If so,
4.3 What other exact parameters should be tested
after light attenuation in various tissues, the power
in PBMT-assisted orthodontics?
density must be high enough to reach the depth
of the cellular components responsible for tooth Also, new studies are needed to measure the ef‐
movement or OIIRR (Hamblin et al., 2015). When fects of power density and application time of PBMT
sufficient energy density reaches the tooth root, it on the rate of tooth alignment. The exact parameters
is possible that excessive energy density may be de‑ of optical spot size at surface tissue, irradiance, radi‐
trimental to the gingiva or alveolar bone. Thus, the ant exposure, total energy delivered, operator tech‐
exact calculation and the effectiveness of energy den‐ nique, and clinical outcomes should be systematically
sity are critical issues for orthodontics that remain evaluated. Testing these important variables on large
unresolved. and varied treatment groups will provide insights into
the threshold levels and energy optimal for the gen‐
4.2 What is the real penetration depth of light
eral population of orthodontic patients (Fig. 3).
applied in orthodontics?
Another important issue is the real penetration
depth of PBMT in the related periodontal structures in 5 Conclusions, unanswered questions, and
orthodontics. Light penetration in tissues is deter‐ further research
mined by several optical parameters such as wave‐
length, irradiance, exposure time, beam spot, and PBMT boosts energy by inducing self-organizing
pulse mode (Henderson and Morries, 2015). In skin phenomena and tissue repair, alleviating physical pain
(epidermis), the red-light spectrum (600–660 nm) is or symptoms, and regulating the interplay of oxidative
usually applied due to the low penetration depth (about stress. In the field of orthodontics, PBMT has been
1–2 mm (Avci et al., 2013)) of light required, whereas used to prevent pathological conditions associated with
NIR light is applied to deep tissue (about 1–3 mm) orthodontics throughout the clinical treatment period.
 J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2023 24(11):957-973 | 967

ensure the efficacy and safety of PBMT in conjunc‐

tion with OT, in so-called PBMT-assisted orthodontics.
The datasets used and/or analyzed during the cur‐
rent study are available from the corresponding author
on reasonable request.

Acknowledgments
This work was supported by the National Natural Science
Foundation of China (Nos. 81991500 and 81991502).

Fig. 3 Different regions of interest for light delivery to Author contributions

achieve photobiomodulation therapy (PBMT). The core Writing ‒ original draft: Jiawen YONG and Sabine GRÖGR.
concern is that the real energy density and penetration Writing ‒ review & editing: Julia VON BREMEN, Márcia
depth required for the light to reach the tooth root are MARTINS MARQUES, Andreas BRAUN, and Sabine RUF.
currently unknown. Project administration and supervision: Xiaoyan CHEN, Sabine
RUF, and Qianming CHEN. Conceptualization, data curation,
The therapeutic effects in PBMT-assisted orthodon‐ and figures and tables processing: Jiawen YONG, Sabine
tics should be considered multifactorial, with positive GRÖGR, and Xiaoyan CHEN. All authors have read and
reactions in blood vessels, mineralized tissues, non- approved the final manuscript, and therefore, have full access
mineralized tissues, nervous system, and immune to all the data in the study and take responsibility for the integrity
system. and security of the data.
PBMT regulates OTM and alveolar bone remod‐
eling at the same time, with the proper parameters. It Compliance with ethics guidelines
Jiawen YONG, Sabine GRÖGER, Julia VON BREMEN,
has also been reported to induce an innovative modu‐ Márcia MARTINS MARQUES, Andreas BRAUN, Xiaoyan
lation of immune cells related to OTM. Because ce‐ CHEN, Sabine RUF, and Qianming CHEN declare that they
mentoblasts interact with PBMT, application of red to have no conflict of interest.
NIR lights for OIIRR is highly attractive. The main This article does not contain any studies with human or
problem so far is deciding the approach and the dose animal subjects performed by any of the authors.
delivered to accomplish beneficial effects.
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