Progress in Biophysics and Molecular Biology 188 (2024) 55–67

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Progress in Biophysics and Molecular Biology

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The role of photobiomodulation in accelerating bone repair

Ping Lu a, b, c, 1, Jinfeng Peng a, b, c, 1, Jie Liu a, b, c, Lili Chen a, b, c, *
a
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
b
School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
c
Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China

A R T I C L E I N F O A B S T R A C T

Keywords: Bone repair is faced with obstacles such as slow repair rates and limited bone regeneration capacity. Delayed
Photobiomodulation healing even nonunion could occur in bone defects, influencing the life quality of patients severely. Photo­
Low-level laser therapy biomodulation (PBM) utilizes different light sources to derive beneficial therapeutic effects with the advantage of
Light-emitting diode
being non-invasive and painless, providing a promising strategy for accelerating bone repair. In this review, we
Bone repair
Light parameters
summarize the parameters, mechanisms, and effects of PBM regulating bone repair, and further conclude the
Osteoblasts and osteoclasts current clinical application of PBM devices in bone repair. The wavelength of 635–980 nm, the output power of
40–100 mW, and the energy density of less than 100 J/cm2 are the most commonly used parameters. New
technologies, including needle systems and biocompatible and implantable optical fibers, offer references to
realize an efficient and safe strategy for bone repair. Further research is required to establish the reliability of
outcomes from in vivo and in vitro studies and to standardize clinical trial protocols.

1. Introduction et al., 2022). Bone formation is a gradual process that is triggered by

osteoclast apoptosis and osteoblast differentiation (Eriksen, 2010).
Bone is a rigid tissue that forms the vertebrate skeleton, maintaining During this process, osteoblasts secret the osteoid matrix (Palander
body structure for movement and defense against harm (Lopes et al., et al., 2022). After neoformation, some osteoblasts suffer apoptosis
2018). Bone repair is a postnatal regeneration process that follows a while others differentiate into osteocytes and bone lining cells to guar­
characteristic sequence of events, including inflammation, bone for­ antee the stability of the bone structure (Ponzetti and Rucci, 2021).
mation, and coupled bone remodeling (Einhorn and Gerstenfeld, 2015). Physiological bone remodeling develops constantly throughout life to
Studies have shown that bone repair capacity is attributed to a modulate bone metabolism caused by daily mechanical stress, hormonal
controlled balance of activity between bone formation and bone changes, and aging effects (Liang et al., 2021; Siddiqui and Partridge,
resorption (Salhotra et al., 2020), which is regulated by bone remodel­ 2016). The imbalance between bone resorption and bone formation can
ing. Bone remodeling is a tightly regulated procedure of replacing old cause bone loss and a high risk of fractures (Weivoda and Bradley,
bone with new bone to ensure the normal functions of bone (Karsenty 2023). Therefore, the methods of promoting bone repair by regulating
and Khosla, 2022). Fig. 1 describes the cellular events that occur at bone remodeling have attracted much attention and made great progress
different stages of bone remodeling. It occurs in the basic multicellular to some extent.
unit defined by Frost in 1990, the provisional functional group with four Nevertheless, the process of bone repair faces obstacles such as
types of cells: osteocytes, osteoclasts, osteoblasts, and bone lining cells delayed healing and nonunion caused by inadequate immobilization,
(Harrison et al., 2022). There are five major phases in bone remodeling: unsuccessful surgical intervention, insufficient biological response or
initiation, resorption, transversion, formation, and cessation (Bolam­ infection (Wildemann et al., 2021). Currently, there are two main stra­
perti et al., 2022). Bone resorption, a rapid process that involves tegies to accelerate bone repair: surgically facilitated treatments and
H+-mediated acidification and protease-mediated matrix degradation, is non-surgically facilitated treatments (Schuett et al., 2015). Surgery is
initiated by osteoclast apoptosis and osteoclast differentiation (Everts not the preferred method due to postoperative complications (Le

* Corresponding author. Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022,
China.
E-mail address: chenlili1030@[Link] (L. Chen).
1
Ping Lu and Jinfeng Peng contributed equally to this work.

[Link]
Received 14 October 2023; Received in revised form 3 March 2024; Accepted 8 March 2024
Available online 16 March 2024
0079-6107/© 2024 Elsevier Ltd. All rights reserved.
P. Lu et al. Progress in Biophysics and Molecular Biology 188 (2024) 55–67

Manach et al., 2015), high financial cost (Feller et al., 2019), and low 2. Basic concepts of photobiomodulation
patient compliance (Steinmetz et al., 2020) although its effectiveness
has been shown. Non-surgical treatments comprise pharmacological 2.1. The development of photobiomodulation
approaches and physiotherapy (Almpani and Kantarci, 2016). Para­
thyroid hormone was found to improve functional outcomes of bone Since the first laser of red light from solid ruby was designed by
repair but not the rate (Eastman et al., 2021). Other medications, such as Maiman in 1960, more research has focused on the interaction between
prostaglandin E2 (Cheng et al., 2021) and growth hormone (Iglesias light and tissue (Adelman et al., 2013). At the end of the eighteenth
et al., 2011), have been proven to adjust bone metabolism. However, the century, Niels Ryberg Finsen began to use light in the red and blue
long-term safety of pharmaceutical treatments is still in doubt due to spectrum for the treatment of human indisposition, particularly Lupus
their adverse side effects (Martiniakova et al., 2020). Thus, physio­ vulgaris (Anders et al., 2015). In 1967, Endre Mester successfully
therapy, including mechanical stimulus, photobiomodulation therapy applied a 694 nm laser at low power to promote hair growth and wound
(PBMT), low-intensity electrical stimulation, and pulsed electromag­ healing in rats, which suggested that low-dose light irradiation had no
netic fields, has been applied locally to accelerate bone repair for its carcinogenic effect (Mester and Mester, 2017). In the 1980s, researchers
non-offensive (El-Angbawi et al., 2015; Jin et al., 2020). Although a few began to focus on the laser-bone interaction. In 1982, studies found that
devices are available for accelerating bone repair in clinics, further osteogenesis was stimulated by monochromatic red light (Lomnitskiĭ
research on their safety and validity in humans has not been disclosed and Biniashevskiĭ, 1982). In 1983, it was observed that a low-dose laser
(Miles et al., 2018; Telatar and Gungor, 2021). Low-intensity electrical of 1064 nm played a positive role in promoting cartilage proliferation
stimulation is an emerging area that needs more evidence to prove the and regeneration in pig knees (Schultz et al., 1985). In 1987, research
effectiveness of bone repair acceleration (Yao et al., 2021). PBMT is reported that fractures in the tibia of mice consolidated faster after red
referred to a procedure of light treatment that harnesses different laser at 632 nm in doses of 2.4 J at one point, with an increase in
sources of light, comprising lasers and light-emitting diodes (LEDs) with vascularization and the metabolism and reaction of bone cells (Trelles
a broad light spectrum, which induces beneficial therapeutic effects and Mayayo, 1987). Furthermore, an in vitro experiment in 1988 sug­
including pain or inflammation reduction, immunomodulation, and gested that low-level laser irradiation of 1064 nm improved mature
tissue reconstruction and wound healing (Anders et al., 2015). It has normal bovine articular cartilage metabolism via DNA activation and
offered a better prospect for clinical applications due to its parameter cartilage proteoglycan, collagen, and non-collagen synthesis (Herman
flexibility and few side effects (Cheng et al., 2020). and Khosla, 1988). In 1989, Karu reported that cytochrome c oxidase
In recent decades, photobiomodulation (PBM) has become a prom­ (CCO), a component of the respiratory chain, was the primary photo­
ising method of promoting bone repair (Escudero et al., 2019; Schuett acceptor for red or near-red infrared (NIR) light (Karu, 1989). In the
et al., 2015). It has been shown to play a positive role in stimulating early twenty-first century, in vitro studies suggested that 1064 nm
osteoblasts and osteoclasts to shorten the duration of conventional low-power laser enhanced bone healing in rat femurs, with alkaline
treatment (Garzón et al., 2022b; Yang et al., 2019). Several studies have phosphatase/total protein (ALP/TP), calcium (Ca), and nitric oxide
investigated the light parameters of promoting bone repair in cell and (NO) increasing (Guzzardella et al., 2002) by biochemical measure­
animal experiments (Aihara et al., 2006; Garzón et al., 2022b), but the ments. Subsequently, it was demonstrated that PBM with 660 nm could
detailed parameters and safety of its application lack sufficient clinical enhance bone cell activity (both resorption and formation) and promote
information to further clarify. Additionally, the indicators to assess the bone repair in the femurs of rats (Nicola et al., 2003). With further
effectiveness of accelerating bone repair include the duration as well as research and applications of lasers, the term “Low-level laser therapy
the changes in bone density (Mirulla et al., 2021), which have been less (LLLT)” was gradually used to describe light therapy, which refers to
well described. Therefore, in this review, we highlight the light pa­ “treatment using irradiation with light of low power intensity so that the
rameters regarding the role of PBM in regulating bone repair and explain effects are a response to the light and not due to heat. A variety of light
the molecular and cellular mechanisms and effects of PBM on bone cells sources, especially low-power lasers, are used” (Tsai and Hamblin,
and bone-related cells. We further discuss the features and limitations of 2017).
current clinical PBM devices for bone repair and outlook novel PBM Since the 1990s, LEDs, a source producing non-coherent artificial
devices combined with new technology, providing a reference for light, have been shown to stimulate mitochondrial oxidative metabolism
achieving an efficient and safe strategy in bone repair acceleration. in vitro and enhance the repair process of cells and tissues in vivo (Desmet
et al., 2006; Enwemeka, 2006). Studies reported that low-dose LED of
637 nm wavelength had a similar biological effect compared with a red
and infrared laser, increasing rat calvaria osteoblasts (rGO lineage)

Fig. 1. The procedure of bone remodeling. Bone remodeling includes five main stages: Initiation, resorption, transversion, formation, and cessation. Stage 1:
osteocyte apoptosis and osteoclast differentiation. Stage 2: H+ and proteases secretion from osteoclasts, with a duration of several days. Stage 3: osteoclast apoptosis
and osteoblast differentiation. Stage 4: osteoid matrix secretion from osteoblast, lasting three to four months. Stage 5: osteoblast apoptosis or differentiation into
osteocytes and bone lining cells.

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P. Lu et al. Progress in Biophysics and Molecular Biology 188 (2024) 55–67

migration and secretion (Cardoso et al., 2021). Oliveira et al. suggested Whereas red and NIR light was observed to enhance bone cell activity
that both LEDs and lasers are beneficial to bone metabolism, though (da Fonseca et al., 2022). It was demonstrated that the penetration,
their mechanisms of action probably differ (Oliveira et al., 2016). It depending on wavelength, played an essential role in the effects of PBM,
implied that the coherence of light was not essential during PBM and light with longer wavelengths had stronger penetration until
although stimulating effects upon biological objects were originally absorbed by water in the infrared portion, especially 970 nm (Finlayson
explained by the coherence (Vinck et al., 2003). Furthermore, it was et al., 2022). Studies showed that 1% incident light could achieve a
demonstrated that LED with relatively lower power output, reducing maximum penetration depth of 5 mm (Ash et al., 2017). Deep tissue such
invasion and detriment to targeted cells and tissues, provides a safer tool as bone, which required deep penetrations, performed better when
for further remedy (Sorbellini et al., 2018). To date, considering the irradiated by NIR light (780–950 nm) (Lima et al., 2020). Because NIR
diversity of light sources and therapeutic effects (Heiskanen and Ham­ light was highly penetrating, absorbed less in water and hemoglobin,
blin, 2018), photobiomodulation therapy is a more accurate term to be and less harmful to normal cells than UV or visible light (Zhou et al.,
utilized, referring to “A form of light therapy that utilizes non-ionizing 2016). Animal experiments suggested the in vivo efficacy of photo­
forms of light sources, including lasers, LEDs, and broadband light, in biomodulation with NIR light in promoting bone repair (Macedo et al.,
the visible and infrared spectrum. It is a nonthermal process involving 2020; Yılmaz et al., 2022) and alveolar bone regeneration (Ribeiro et al.,
endogenous chromophores eliciting photophysical (i.e., linear and 2022). It is worth noting that the absorption of light by water molecules
nonlinear) and photochemical events at various biological scales. This could release heat, and moderate heat is beneficial for bone metabolism
process results in beneficial therapeutic outcomes, including but not (Valente et al., 2017). Thus, taking into account the influence of both
limited to the alleviation of pain or inflammation, immunomodulation, penetration and heat, it was found that the wavelengths of 660 nm and
and promotion of wound healing and tissue regeneration” (Anders et al., 810 nm were preferred in the bone field (Wang and Li, 2019).
2015).
2.2.2. Dose
Dose was considered another significant light parameter affecting
2.2. Parameters of photobiomodulation the effects of PBM (Zhu et al., 2023). Beam area is a dose-related
parameter and has the potential to reduce lateral scattering and
Light parameters regarding bone repair are complex consisting of enhance penetration (Ash et al., 2017). The metrics to describe doses
wavelength, energy, energy density, power, irradiation time, beam area include power, energy, and energy density. After the middle period of
and emission pattern (Chen et al., 2022b). Table 1 describes the main the nineteenth century, Arndt–Schulz law was established to illustrate
physical quantities of light parameters about PBM. the link between doses and outcomes, suggesting that small stimulations
advance the action and heavy ones hinder it (Obodovskiy, 2015).
2.2.1. Wavelength Furthermore, PBMT was discovered to follow the biphasic
Wavelength is the inherent nature of electromagnetic waves. There is dose-response, precisely dose-time-response (Calabrese, 2016), which
an electromagnetic spectrum based on wavelengths: gamma rays (10− 12 was attributed to different concentrations of reactive oxygen species
m), X-rays (10− 9 m), ultraviolet (UV) rays (10− 7 m), visible light (10− 6 (ROS) responding to PBM in osteoblastic cells (Garzón et al., 2022a).
m), infrared light (10− 5 m), microwaves (10− 2 m), and radio waves (102 ROS was found to control cytology at a normal level and harm cells at a
m) (Zhong et al., 2021). Distinct physical properties are related to low or high level (Sies and Jones, 2020). Flores Luna et al. applied
wavelengths, which have an impact on application areas (Lin, 2016). different energies to investigate effects on the mitochondria activity and
Gamma rays, electromagnetic radiation of the shortest wavelength and found that 660 nm lasers of 0.84 and 1.40 J energy had a remarkably
highest energy, have harmful electro-ionization (Pei et al., 2020). positive impact compared with 5.88 and 6.72 J energy (Flores Luna
et al., 2020). Each cell had a unique optimal dose for its function. It was
Table 1 observed that 940 nm LEDs with a low energy density of 1 J/cm2 pro­
Main physical quantities of light parameters about PBM (Sliney, 2016; Song moted osteoblast (MC3T3-E1) proliferation, osteoclast (RAW264.7)
et al., 2023). differentiation, and bone repair activity in vitro, while a high dose of 5
Parameters Symbol Common Definition J/cm2 and a higher dose of 7 J/cm2 decreased osteoclast and osteoblast
unit activity respectively (Na et al., 2018). Similarly, data from
Wavelength λ nm The shortest length Borzabadi-Farahani, A. showed that 660 nm laser with energy densities
between a point and of 0.05, 0.30, 7, and 42 J/cm2 were ineffective in the proliferation of
another same point on a human dental mesenchymal stem cells, indicating that surpassing a
wave
specific dose threshold is necessary for achieving PBM therapy effects
Dose Energy Q J The amount of energy
emission, conversion, or (Borzabadi-Farahani, 2016). Furthermore, it was suggested that energy
reception density per day for PBM ranging from 1 to 6 J/cm2 in the red and NIR
Energy H J/cm2 Energy per unit area in the wavelength range of 600–1000 nm is valid and safe (Zecha et al., 2016).
density radiated surface Research showed that the total energy ranged from 16 to 3920 J in
Power Φ/P mW Energy per unit time in
radiated surface, equaling
animal experiments and ranged from 60 to 3240 J in clinical trials could
J/s be used to facilitate bone repair when utilizing wavelengths with the
Irradiation t s Length of radiation time at range of 660–904 nm (Cheng et al., 2020).
time a time
Beam area S cm2 The spot size related to the
2.2.3. Mode
beam width
Emission Continuous – – Continuous energy input Little attention has been paid to the light mode, including the
mode wave during processing continuous wave (CW) and pulse wave (PW) mode. In vitro research has
Pulse wave Φ/P W Intermittent energy output shown that pulsed light is a more effective pattern due to a different
ν/f Hz in a pulse structure during molecular mechanism compared to CW (Chen et al., 2021). Evidence has
t s processing, with three
main parameters to
indicated that light mode is attributed to the penetrating power and
describe pulse structure: high-frequency wave taking effect better than low-frequency wave and
peak power (W), pulse CW to some extent in a multilayered water-skin model (You et al., 2018).
frequency (Behrangi et al.), In vivo studies reported that PW is safer than CW at the same dose for
pulse width (s)
producing less heat damage on the radiation surface, which means the

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possibility of enhancing the radiated power peak and mitigating the 3. Biological mechanisms and effects of photobiomodulation on
effect of light scattering on penetration (Hashmi et al., 2010). In vivo bone repair
studies with 808 nm laser found that low-frequency pulsed light irra­
diation generated about four times the amount of adenosine-5′-­ The past decade has witnessed a significant breakthrough in the
triphosphate (ATP) than at CW, which could encourage mitochondrial mechanisms of PBM (Hamblin, 2018). There was no doubt that the ac­
function and certain biological processes (Lapchak and De Taboada, tion of PBM was broad-spectrum, suggesting it had an effect on all cells
2010). Chen et al. observed that 40-Hz pulse frequency light exposure at the irradiated site. Different types of bone cells and bone-related cells
with various wavelengths could inhibit in vitro B16F10 melanoma cells respond to PBM through different signaling pathways, forming a com­
through ROS/opsins-3 (OPN3)/Ca2+ signaling pathway (Chen et al., plex network of molecular signals (Hosseinpour et al., 2019). The
2023). However, pulse waves at a frequency range from 2 to 10 Hz are modular impact of PBM generally comprises three crucial events: light
recommended in clinical use (Hecox, 1994). Therefore, the more specific absorption, DNA activation, and cellular and tissue biology regulation
light frequency of PBM for bone repair still requires further investiga­ (Karu, 2008; Karu et al., 2004). Fig. 2 describes the penetration depth
tion. It has been suggested that variations in race and ethnicity could and the main photoacceptors at different wavelengths. Blue light
influence the outcomes of PBM due to pigmentation and genetics (Jag­ (400–470 nm), Green light (470–540 nm) and yellow light (about 540
deo et al., 2020). Different light parameters of PBM have different nm) have a lower penetration potential and are beneficial in the
mechanisms and characteristics of influence on bone repair. Much un­ epidermis layer of the skin (Sorbellini et al., 2018). Red light (630–700
certainty about the best parameters in clinical application still exists, nm) reveals useful in the dermis layer of the skin to activate fibroblasts,
which is worthy of further discussion. and NIR light (700–1200 nm) reaches maximum penetration in the skin
(Finlayson et al., 2022). Previous studies found that CCO in mitochon­
2.3. Side effects of photobiomodulation dria could be sensitized by red or NIR light (Karu and Afanas’eva, 1995).
CCO, a key enzyme located in the mitochondrial electron transport
In addition to the parameter-dependent effectiveness of PBM, safety chain, has been proven to elevate the mitochondrial membrane potential
is another important issue. It was suggested that bone mineral density (MMP) (Wu et al., 2014). Based on photodissociation of inhibitory NO, it
(BMD) is the most common indicator of bone repair, which is defined as promoted the generation of secondary mediators including ROS, cyclic
the amount of mineral per unit of bone (Mirulla et al., 2021). Some adenosine monophosphate (Escudero et al., 2019), NO as well as Ca2+
researchers found that low-level NIR light around 810 nm resulted in a (Brookes et al., 2002; Karu, 1999; Moncada and Erusalimsky, 2002).
notable enhancement in both bone density and biomechanical proper­ Furthermore, studies found that CCO was not necessary for the prolif­
ties in rats of osteoporosis (OP) (Shokri et al., 2023; Zhu et al., 2023). A eration effectiveness under light radiation at 660 nm in CCO-negative
systematic review suggested PBM applied postoperatively with wave­ cells (Lima et al., 2019), which suggested that other photoreceptions
lengths ranging from 500 to 1000 nm could improve bone density in existed in the body. Transient receptor potential (TRP) was proven to be
human maxillofacial bone defects (Santinoni et al., 2017). However, in another acceptor of infrared light with longer wavelengths (around 980
vivo studies have revealed a doubtful increase in biomechanical prop­ nm) (Fuchs et al., 2021), which altered the membrane voltage and
erties of the healing bone in rabbits after PBM (780 nm, 4 J/cm2, 5 worked through the Ca2+ signal path (Hasan and Zhang, 2018; Zhang
min/day) (Kazem Shakouri et al., 2009). A review about clinical trials of et al., 2018). Research found that the shorter wavelength of red or NIR
PBM on fracture healing suggested that PBM seemed to be associated light especially 670 nm could be absorbed by hemoglobin and
with the improvement in pain and physical function rather than bone myoglobin better (Keszler et al., 2018). Water was considered an
callus formation based on the evidence of low certainty (Neto et al., alternative chromophore for visible or infrared red light (Hamblin,
2020). 2017), resulting in a small increase in vibrational energy or charge
Additionally, studies found the side effects of light exposure were separation around sensitive proteins such as temperature-gated TRP
limited to the thermal effect, constant erythema, and mild pain in channels to perturb the tertiary protein and open the channels (Wang
clinical trials (Behrangi et al., 2022). However, chronic exposure to la­ et al., 2017). Studies reported that TRP channels in mitochondria based
sers (400–1400 nm) had adverse effects on the retina due to photoco­ on opsins (OPN)/G protein could be sensitized by blue and green light,
agulation or photodisruption damages (Juhasz et al., 2021). Shorter with ROS and NO production (Serrage et al., 2019). And the generation
wavelength light (less than 400 nm) could be absorbed by eye tissue and of ROS resulted from the absorption of blue light by a component of the
caused burns and photochemical damage (Ouyang et al., 2020). And mitochondrial respiratory chain, flavin (Yoshida et al., 2015). Although
longer wavelength invisible light (greater than 1060 nm) was more UVC light (less than 280 nm) caused serious side effects, UVA light
hazardous since it would not trigger the defensive blink reflex (Thomas (320–400 nm) was shown to be an effective method to increase intra­
and Isaacs, 2011). Thus, eye protection equipment including blackout cellular ROS and activate DNA polymerases (Tafur and Mills, 2008).
goggles is necessary to prevent damage. A systematic review among in Researchers found that heme P450 on mitochondrial complex I was the
vivo studies and clinical trials showed that there was no significant photoacceptor of UVA light at 375 nm (Golovynska et al., 2023).
correlation between light irradiation and cancer formation (Bensadoun
et al., 2020), which means normal cells were at a low risk of cancer after 3.1. Osteoblasts
irradiation. However, studies have found that repeated red-light expo­
sure (642 nm) has the potential to promote the proliferation of skin It was shown that PBM was a powerful regulator of osteoblast dif­
tumors in mice (Goo et al., 2021). Therefore, the long-term application ferentiation and proliferation. The upregulation of ROS would activate
of PBM in areas with diagnosed or probable tumors should be considered activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB), leading
with care (Klausner et al., 2021). Apart from the local irradiation site, to cell survival, cell proliferation, and cell migration (de Freitas and
Tuby et al. focused on histopathological alterations of distal organs after Hamblin, 2016). Green light (560–650 nm) was found to have no dif­
long-term PBM with an 804 nm wavelength and different power den­ ference in the numbers of cultured human osteoblast-like cells, and blue
sities and showed that there were no clear changes in a variety of organs light (420–580 nm) was demonstrated to decrease alkaline phosphatase
such as livers, kidneys, and brains in mice (Tuby et al., 2013). However, (ALP) activity but increase synthetic activity (according to the signifi­
there is little evidence to support this. Further research on the potential cantly higher osteocalcin content in the cells) (Rosenberg et al., 2020).
negative effects of PBM is needed. Studies reported PBM with 635 nm significantly up-regulate both
Runx-2 and ALP mRNA expression via Akt signaling activation and 808
nm resulted in an increase of Runx-2 but not of ALP on human
osteoblasts-like Saos-2 cells (Tani et al., 2018). Studies found that PBM

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P. Lu et al. Progress in Biophysics and Molecular Biology 188 (2024) 55–67

Fig. 2. The penetration depth and the main photoreceptors at different wavelengths during PBM. Different wavelengths of light have various photoreceptors in the
body, causing changes in the second messengers. Blue light (400–470 nm), Green light (470–540 nm) and yellow light (about 540 nm) has a lower penetration
potential and shows beneficial in the epidermis layer of the skin. Red light (630–700 nm) reveals useful in the dermis layer of the skin to activate fibroblasts, and NIR
light (700–1200 nm) reaches maximum penetration in the skin. Red and NIR light could activate CCO, while blue light could trigger flavins in mitochondrial, with
the production of NO, ROS or Ca2+. TRP, another significant acceptor, could absorb longer wavelengths of NIR light directly or green and blue light via OPN/G
protein to regulate Ca2+.

at 980 nm wavelength could enhance the expression of Runx-2, Osterix, (Cardoso et al., 2021). Besides, it was observed that the PI3K/Akt/Bcl-2
and Dlx5 on MC3T3-E1 pre-osteoblasts (mouse calvarian pathway, triggered by PBM (980 nm, 45 J/cm2), promoted mouse
pre-osteoblasts) via Wnt signaling and the Smads 2/3-β-catenin pathway MC3T3-E1 pre-osteoblasts proliferative markers expressions such as
with or without the transforming growth factor-β (TGF-β) stimulation c-myc, CDK4, and cyclin D3 (Agas et al., 2021). A systematic review
(Hanna et al., 2019). Our studies found PBM with 810 nm inspired the showed that PBM had little effect on osteoblastic-like cells proliferation,
ubiquitination-dependent degradation of a cryptochrome 1 in the nu­ but higher irradiance showed detrimental effects on their proliferation
cleus, thereby promoting ALP expression and activity via the bone (Deana et al., 2018). More research is needed to investigate them. Fig. 3
morphogenetic protein (BMP)-2/Smads 1/5/9 pathway on mouse oste­ deals with the mechanism of osteoblast differentiation after PBM. The
oblastic MC3T3-E1 cells (Peng et al., 2022). Researchers reported that activation of signaling pathways, including Ca2+, ROS, Wnt,
PBM with 660 nm was beneficial to osteogenic induction by itself, while TGF-β/Smads 2/3-β-catenin, and BMP-2/Smads 1/5/9, may occur in
the alizarin red S staining assay found that PBM with 808 nm could not pre-osteoblasts. It subsequently led to the initiation of Runx2, Osterix,
motivate the production of mineralized nodules without osteogenic NF-κB, and AP-1, which play a crucial role in promoting osteoblast
medium potentializing on rat calvaria osteoblasts (rGO lineage) differentiation and mineralization.

Fig. 3. The mechanism of osteoblast differentiation triggered by PBM. Ca2+, ROS, Wnt, TGF-β/Smads 2/3-β-catenin, and BMP-2/Smads 1/5/9 pathway could be
activated in pre-osteoblast, resulting in the initiation of Runx2, Osterix, NF-κB, and AP-1. Thus, osteoblast differentiation and mineralization could be achieved
during PBM.

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3.2. Osteoclasts Ptger2) and pro-inflammatory interleukins (IL-1, IL-6, IL-8, IL-18), can
be modulated in different phases during PBM at 830 nm (Tim et al.,
More studies have confirmed that osteoclast (TRAP) foramtion can 2016), thereby facilitating vessel generation in rat bone defects.
be activated by red (660 nm) and NIR (830 nm) light to accelerate bone Research found that PBM at 650 nm could initiate human umbilical
repair in vivo (Garcia et al., 2022; Ribeiro et al., 2022). Research found vascular endothelial cells (HUVECs) proliferation, migration and tube
that PBM (810 nm, 3.5 J/cm2) could facilitate rat osteoclast precursor formation through the PI3K/Akt pathway, with elevating levels of
cells which had been purified from rat bone marrow cells differentiation HIF-1α, eNOS, and VEGFA (Li et al., 2020). PBM with 632 nm was also
to increase the number of TRAP-positive cells via receptor activator of found to enhance cell viability, migration, proliferation and tube for­
nuclear factor-kappa B (RANK) expression (Aihara et al., 2006). Studies mation via VEGFA/VEGFR2/STAT3 pathway on HUVECs (Zhang et al.,
showed that PBM with 810 nm promoted c-fms mRNA expression on rat 2022). Previous studies reported that PBM at 808 nm led to a
osteoclast precursor cells and increased the cells stained with macro­ ROS-dependent rise in vessel formation with an increase of HIF-1α,
phage colony-stimulating factor (M-CSF) (Yamaguchi et al., 2019). vascular endothelial grow factor (VEGF), and TGF-β in co-cultured bone
Studies found that the elevation of secreted osteoclastogenic factor of marrow mesenchymal stem cells (BMMSCs)/HUVECs (Bai et al., 2021),
activated T cells (SOFAT) by PBM (810 nm, 100 mW) could promote the Vessel generation is a procedure that couples osteogenesis via TGF-β
production of osteoclastogenic cytokines, including interleukin (IL) - 6, secretion in vitro after PBM with 808 nm (Kusumbe et al., 2014). VEGF
IL-10, and granulocyte-macrophage colony-stimulating factor was found to increase collagen accumulation on murine osteoblastic
(GM-CSF), instead of receptor activator of nuclear factor-kappa B ligand MC3T3-E1 (subclone 4) cells (Hu and Olsen, 2016a). The mechanism of
(RANKL) (Jettar et al., 2018; Napimoga et al., 2015). The triggered PBM-induced angiogenesis and enhanced blood flow is explained in
HIF-1α/RANKL/Notch1 pathway acted primarily to promote osteoclasts Fig. 5. The production of NO led to vasodilatation and increased vascular
formation by enhancing the fusion and maturation of the murine cell activity. Different inflammatory mediators could be activated to
monocytic cell lines RAW264.7 macrophages, rather than stimulating promote vessel generation. VEGFA/VEGFR2/STAT3 and PI3K/Akt
resorptive activity (Chen et al., 2022a). However, research about the pathway were found to enhance vascular cell proliferation and migra­
responsive osteoclast by light radiation still remains controversial to tion during PBM.
date. The mechanism to promote osteoclast formation by PBM is
described in Fig. 4. Osteoclast formation could be stimulated via 3.4. Stem cells
increasing RANKL and RANK during PBM. SOFAT was a
RANKL-independent manner to promote osteoclast differentiation via Exosomes from mesenchymal stem cells (MSCs) were found to pro­
osteoblast excreting IL-6, IL-10, and GM-CSF when irradiation. More­ mote proliferation and migration of HUVECs and mouse MC3TE-E1 pre-
over, light exposure led to an increase in M-CSF and c-fms, which could osteoblasts through BMP-2/Smad1/Runx-2 signaling pathway (Zhang
promote differentiation. et al., 2020). A review suggested that MSCs and their exosomes pro­
moted bone repair by increasing the factors including BMP-2/4, insulin
3.3. Vascular endothelial cells like growth factor (IGF)-1, TGF-β and activating macrophages (Maqsood
et al., 2020). BMMSCs play a crucial role in bone repair, as their capacity
Since bone is a highly vascularized organ, vascular endothelial cells to differentiate into osteoblasts (Chen et al., 2019). Studies showed that
have a significant effect on the promotion of bone repair activated by PBM (890 nm, 80 Hz, 1.5 J/cm2) significantly increased viability and
PBM (Hu and Olsen, 2016b). In vivo studies found that PBM-induced NO cell proliferation of BMMSCs in vivo (Mostafavinia et al., 2017).
(780 nm) in a dose-dependent manner plays an essential role in Hypoxia-inducible factor-1 (HIF-1) and TGF-β could also be upregulated
enhancing vascular reactivity and blood flow (Guzzardella et al., 2002; by a subsequent increasing level of ROS when active mitochondria cause
Kashiwagi et al., 2023). Studies observed that the expressions of hypoxia during PBM (808 nm) on mouse BMMSCs (Bai et al., 2021). In
different inflammatory genes, including monocytes to macrophage vivo research suggested that PBM (632.8 nm, 3 mW, 0.6 J/cm2) stimu­
differentiation-associated gene, prostaglandin genes (PTGIR, PTGS2, lated the osteogenic potential of BMMSCs by higher TGF-β, IGF-1, and

Fig. 4. The mechanism of osteoclast differentiation initiated by PBM. Osteoclast differentiation could be stimulated via increasing RANKL and RANK during PBM.
The elevation of RANKL was derived from osteoblasts and osteocytes. SOFAT secreted by activated T cells was a RANKL-independent manner to promote osteoclast
differentiation via osteoblast excreting IL-6, IL-10, and GM-CSF when irradiation. Moreover, light exposure led to an increase in M-CSF, which could promote
differentiation.

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P. Lu et al. Progress in Biophysics and Molecular Biology 188 (2024) 55–67

Fig. 5. The mechanism of PBM-induced angiogenesis and enhanced blood flow. The production of NO led to vasodilatation and increased vascular cell activity.
Different inflammatory mediators could be activated to promote vessel generation. VEGFA/VEGFR2/STAT3 and PI3K/Akt pathway were found to enhance vascular
cell proliferation and migration during PBM.

ALP (Fallahnezhad et al., 2018). Bone marrow-derived macrophages M (PKM) on mouse MC3T3-E1 pre-osteoblasts to enhance bone meta­
(BMMs) have the potential to differentiate into osteoclasts activated by bolism (Ma et al., 2023).
M-CSF and RANKL (Chen et al., 2020). However, Studies reported that In conclusion, different cells could be regulated by PBM to some
635 nm wavelength LED exposure significantly hindered extent. Under optimal illumination parameters, PBM has a noticeably
RANKL-mediated osteoclastogenesis by reducing ROS generation on progressive effect on reducing the duration of bone repair with
mouse BMMs (Sohn et al., 2015, 2017). Researchers observed a notable increasing bone density.
downregulation of osteoclast differentiation in co-culture groups be­
tween mouse calvaria pre-osteoblasts and BMMs via a lower RAN­ 4. Clinical applications of photobiomodulation for accelerating
KL/OPG ratio compared with single-cell groups of BMMs when exposed bone repair
to 808 nm (Hong et al., 2022). More research is needed to explain them.
In addition to the regulation of bone cells and bone-related cells, the
effects of PBM include relieving pain, edema, and inflammation,
3.5. Other cells
increasing collagen production, promoting nerve regeneration, and
reducing complications (Reis et al., 2022). Thus, clinical studies have
Other cells, including bone lining cells, osteocytes, and fibroblasts,
focused on bone repair by PBM, such as orthodontic tooth movement
could be affected by PBM. Osteocytes were considered crucial receptor
(OTM) (Zheng and Yang, 2021), after extraction (Rosero et al., 2020),
cells for regulating the balance between osteoclasts and osteoblasts,
bone fractures (Chang et al., 2014) and after rapid maxillary expansion
including mechanical force, hormones, and light (Bellido, 2014). Oste­
(RME) (Ferreira et al., 2016). Table 2 provides a comprehensive over­
ocytes, also a kind of endocrine cell, might excrete more RANKLs to
view of the light parameters, related patient counts, and outcomes of the
encourage osteoclast formation than osteoblasts (Nakashima et al.,
clinical trials for bone repair during PBMT. It was found that researchers
2011). Research showed that mouse MLO-A5 osteocyte proliferation
prefer the laser in the wavelength range of 635–980 nm. The output
(the ratios of the number of proliferating (EdU+) and all cells) could not
power was mostly in the range of 40–100 mW, except Matos et al. used
be activated by PBM at 940 nm (Na et al., 2018). However, in vivo
300 mW (Matos et al., 2021). Although the energy density selected by
studies demonstrated that osteocytes apoptosis due to osteoclasts
each researcher varied considerably, most were less than 100 J/cm2 per
recruitment could also be inhibited by PBM at 660 nm (Ko et al., 2013).
spot apart from (Matos et al., 2021) and Pereira et al. (2022). The
Adipose-derived stem cells-derived exosome marker proteins, including
excessive output power or energy density might have been the cause of
HSP70 and CD9, could increase to inhibit mouse MLO-Y4 osteocytes
the negative results of clinical trials. Even though 3 min per spot was the
apoptosis after PBM (Yang et al., 2020; Zhu et al., 2017). In 2012, re­
optimal exposure time in animal studies, researchers often chose shorter
searchers reported that the activation of bone lining cells was accom­
time in clinical trials. Light exposure was less frequent during therapy
panied by osteoclast formation through similar signal molecules (Kular
than in animal tests, which not only increased patient compliance but
et al., 2012). But there is no direct evidence to show changes in the
also reduced the side effects of light exposure, such as skin burns
function of bone lining cells in PBM. A systematic review showed that
(Behrangi et al., 2022). Lasers were more commonly used compared to
PBM could stimulate fibroblasts proliferation (Ren et al., 2016). In vitro
LEDs. In terms of OTM, it was observed that the laser (810 nm, 100 mW)
experiments showed that PBM with 2940 nm upregulated the expression
was more effective than the LED (640 nm, 40 mW/cm2) in accelerating
of genes related to bone metabolism on fibroblasts, including
tooth movements (Farhadian et al., 2021). But additional clinical data is
cyclooxygenase-2 (COX-2), IL-1β, tumor necrosis factor-α (TNF-α),
still required to confirm this.
BMP-2, and BMP-4 (Tsuka et al., 2020). Additionally, it has been
Previous studies found an increase in bone density, neoformation,
observed that skeletal muscle released extracellular vesicles to increase
mineralization, or bone condensation during PBMT (Noba et al., 2018).
the expressions of lactate dehydrogenase A (LDHA) and pyruvate kinase

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Table 2
Parameters and outcomes of PBMT in clinical trials for bone repair.
Application areas Light Wavelength Output Energy density Beam area Radiation Light Control Application stages Outcomes Ref.
source (nm) power (J/ (cm2) time (s/ protocal protocal
(mW) (cm2•spot)) spot) (n) (n)

After rapid Laser 780 40 10 0.04 10 10 4 Days 1–5 of activation, 3 Bone regeneration (+); Cepera et al. (2012)
maxillary consecutive days at screw acceleration of bone healing
expansion locking, 7, 14, and 21 days (+)
after
Laser 780 70 35 0.04 20 14 13 Twice a week in the first Bone regeneration (+); Ferreira et al. (2016)
month and once a week in acceleration of bone repair
the second month (+)
Laser 980 300 238.85 1.26E3 10 18 16 1, 5, 10, and 15 days, and Bone regeneration (− ); pain Matos et al. (2021)
once a week for 8 weeks relief (− )
Bone fractures Laser 830 60 9.7 3.7 600 25 25 Five times per week for 2 Pain relief (+); acceleration Chang et al. (2014)
weeks of bone healing (+);
enhancement of physical
function and grip strength
(+)
Laser 808 100 8/4/12 1 80/40/120 7 7 24 h and 48 h after Rehabilitation of oral Dos Santos et al. (2022)
surgery, and weekly for 4 functions (+); pain relief (+)
weeks after hospital
discharge
Acceleration of Laser 650/910 50 (650 2 0.5 10 3 3 Days 0, 3, 7, and 14 over a Acceleration of OTM (+) Impellizzeri et al. (2020)
tooth nm); 500 month
movements (910 nm)
Laser 658 8 2.29 – 10 39 26 Days 0,3,7,14 in the first Acceleration of OTM (+) Lalnunpuii et al. (2020)
month, and every 15th day
62

from the second month

Laser 810 100 6.29 – 40 6 6 0, 7, 14, and 21, after Acceleration of OTM (+), Zheng and Yang (2021)
loading the canine with increases in IL-1β and
retraction forces RANKL.
LED 850 60 – 1 300 10 10 Everyday over 12 weeks Acceleration of OTM (− ) Al-Shafi et al. (2021)
Laser 980 300 – Optical 30 5 5 1, 3, 5, 7, and 14-day Acceleration of OTM (+), Jivrajani and Bhad Patil
fiber(D = intervals in the first month with higher MMP-9. (2020)
40 μm) and every 15 days after
Laser 808 100 25 0.002826 10 17 17 immediately, 24 h, 72 h, 1 Acceleration of OTM (+), by Murakami-Malaquias-Silva
and 2 months after higher IL-1β. et al. (2023)

Progress in Biophysics and Molecular Biology 188 (2024) 55–67

Laser 980 20 0.71 0.28 10 10 10 Days 0,3,7,14,21,42, and Acceleration of OTM (+) Özsoy et al. (2023)
63 after activation (slightly)
After extraction Laser 660/808 100 141.32 0.0283 40 10 10 Immediately, 3 and 7 days Edema relief (+); soft tissue Pereira et al. (2022)
after surgery repair (+); acceleration of
bone repair (− ); bone
formation (− )
Laser 808 100 75 0.04 30 10 10 Immediately, 24 h, 48 h, Acceleration of bone repair Romão et al. (2015)
72 h, 96 h, 7 days, and 15 (+); bone formation (+)
days after surgery
Laser 808 100 89 0.028 25 10 10 Immediate postoperative Acceleration of bone repair Rosero et al. (2020)
and after 1, 2, 3, 4, 7, and (+); bone formation (+)
15 days
After maxillary Laser 830 40 76 0.07 133 6 6 – Acceleration of bone repair Theodoro et al. (2018)
sinus floor (+); bone formation (− )
augmentation
Sternotomy Laser 660 40 6 0.4 60 15 15 Three times a week, for Decrease in upper-sternal Helmy et al. (2019)
healing four consecutive weeks separation (+); acceleration
of bone healing (+)
P. Lu et al. Progress in Biophysics and Molecular Biology 188 (2024) 55–67

A meta-analysis on a sample of 374 patients (mean age, 28.5 years) or LEDs to curtail the duration of bone repair. PBM has shown effec­
suggested that the postoperative application of PBMT resulted in tiveness in facilitating superficial bone repair in closed bone injuries,
enhancing bone density and promoting anti-inflammatory and analgesic such as oral and maxillofacial defects (Santinoni et al., 2017) and wrist
effects in maxillofacial bone defects (Santinoni et al., 2017). Another fractures (Chang et al., 2014). Limited by the penetrating capacity of
systematic review found that osteoblast and fibroblasts proliferation light, PBM may not be able to directly affect the repair of deep bone
could be activated in the early stage to promote bone formation in PBMT injury with thick tissue layers. Instead, it is activated by the response of
(Kheiri et al., 2020). Higher concentration of osteogenesis markers, dermis and subcutaneous layers during PBM. The utilization of
osteocalcin (OCN) and Runx2, were reported to promote bone density biocompatible and implantable optical fiber has been employed in the
and bone trabeculae percentage after tooth extraction in a systematic treatment of open bone injuries, opening up new avenues in biomedicine
review (Kulkarni et al., 2019). Although Short (visible; 635–650 nm) (Nazempour et al., 2018; Wang et al., 2021). Also, the minimally inva­
and longer (invisible; 810–850 nm and 915–980 nm) near-infrared sive laser needle system has been developed, which could deliver light to
wavelengths have been commonly used, a meta-analysis showed that the bone site directly by applying fine hollow needles to guide 100-μm
1064 nm PBMT could provide effective pain relief, increase OTM, optical fibers, to diminish light scattering in biological tissue and
improve functional scores and increase the quality of life in knee oste­ enhance therapeutic efficacy (Kang et al., 2012). A novel LED micro­
oarthritis and spinal disorders to some extent (Qu et al., 2022). Addi­ needle patch has been designed, breaking through the limitations of the
tionally, PBMT were found to promote osseointegration around dental low penetration of blue and green light (Kittigul et al., 2022). PBM
implants in animal models, but more clinical trials suggested that PBMT combined with biomaterials has emerged as a promising strategy in the
played a negative role in influencing bone structure around implants field of bone repair, with the potential to expedite the repair process and
(Bozkaya et al., 2021; Camolesi et al., 2023; Lobato et al., 2020). A enhance the structural integrity of neoformation bone (Hanna et al.,
meta-analysis revealed that PBMT was not effective in alleviating 2021; Magri et al., 2021).
postoperative pain or increasing BMD around implants but was limited However, the optimal parameters for a specific disease to accelerate
to reducing facial swelling (Qu et al., 2022). It is a novel field to apply bone repair remain in doubt, as there are relatively few clinical reports
PBM to regulate bone repair in patients with OP (Wan et al., 2020). In to support clinical applications. More clinical research is needed in the
2018, it was observed that 1064 nm laser irradiation alone did not future to investigate the therapeutic effects and side effects of PBM on
improve BMD in patients with OP, but the laser combined with exercise accelerating bone repair in humans from the known light parameters in
played a better role in increasing BMD compared with exercise alone cellular and animal experiments. Considering the differences between
after a year of treatment. Significantly, this trial was conducted by a the different ethnic groups in the physiological structure, the choice of
high-intensity laser with an average power of 10.5 W (Alayat et al., parameters might be varied, which is needed to be aware of. It is found
2018), which suggested that low-intensity laser therapy was not the only that the majority of current clinical PBM equipment has no relevance. It
form for clinical application. However, the number of clinical trials is not targeted to a specific disease. The feature possibly increases the
available is small, and more clinical data is needed to assess the effects of complexity of medical operations carried out by medical staff. Thus, the
PBM more precisely. trend is to develop a PBM device to accelerate bone repair which is
wearable and efficient to administer, similar to the helmet-type device
5. Conclusions and perspectives for androgenetic alopecia treatment (Yoon et al., 2020) and the sleeping
bag-type device for neonatal jaundice (Montealegre et al., 2020).
Previous studies have deepened the understanding of chromophores Additionally, most clinical PBM equipment is not portable due to the
during PBM at different wavelengths, including CCO, TRP, hemoglobin, controller of the light output, and patients must visit the hospital
myoglobin, water, opsins, flavins, and heme P450. The mechanisms of regularly for PBMT. Studies have found that portable light devices with a
PBM were discovered, including inhibition of photodissociation, pro­ battery faced power decay trouble caused by battery aging and voltage
motion of charge separation, and enhancement of vibrational energy. declining (Sampurna et al., 2020). Fortunately, fuzzy logic controller to
Research suggested biological effects of bone repair acceleration by maintain the invariable light energy yield was proposed (Phan et al.,
PBM, involving regulation of osteoblast differentiation and prolifera­ 2020), providing a progressive insight to guarantee preconcerted
tion, promotion of osteoclast formation, enhancement of vascular remedial outcomes. Therefore, more research is needed in the future to
epithelial cell proliferation and migration, and inhibition of osteocyte confirm the safety of new technologies, achieving precise and person­
apoptosis. Fibroblasts and MSCs also exerted beneficial effects in alized therapy.
accelerating bone repair. However, there are still some controversial
questions. First, most studies focused on the cellular and molecular ef­ CRediT authorship contribution statement
fects of PBM rather than the photoacceptors of light. There is a separa­
tion between the studies on mechanisms and effects. Cryptochromes, Ping Lu: Writing – review & editing, Writing – original draft,
which rely on flavin, have been studied mainly in plants and insects. Conceptualization. Jinfeng Peng: Writing – review & editing, Concep­
Recent evidence indicated that mammalian cryptochromes were essen­ tualization. Jie Liu: Writing – review & editing. Lili Chen: Writing –
tial for the regulation of the circadian clock (Hamblin, 2017), providing review & editing, Project administration.
new insight for further research. Second, studies found that PBM could
activate osteoclast differentiation via the production of SOFAT (Jettar Declaration of competing interest
et al., 2018) and M-CSF (Yamaguchi et al., 2019) during bone remod­
eling such as orthodontic tooth movement. However, there are no direct The authors declare that they have no known competing financial
in vitro studies to illustrate the relationship between the production of interests or personal relationships that could have appeared to influence
these molecules and PBM. Finally, studies suggested that the work reported in this paper.
anti-inflammation is a major response of PBM (Reis et al., 2022), while
angiogenesis mediated by inflammatory mediators is an important Data availability
process of bone repair (Tim et al., 2016). Previous studies on the process
of repairing of rat bone found that PBM suppressed the inflammatory Data will be made available on request.
process and increased the proliferation of cells responsible for bone
repair (Rodrigo et al., 2011). Therefore, more in vitro and in vivo studies Acknowledgments
are needed to focus on them.
Current studies have highlighted the practicability of applying lasers This work was financially supported by the National Natural Science

63
P. Lu et al. Progress in Biophysics and Molecular Biology 188 (2024) 55–67

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