Lasers in Medical Science

https://doi.org/10.1007/s10103-020-03159-z

REVIEW ARTICLE

Proposed mechanisms of low-level light therapy in the treatment

of androgenetic alopecia
Yilong Guo 1 & Qian Qu 1 & Jian Chen 1 & Yong Miao 1 & Zhiqi Hu 1

Received: 25 June 2020 / Accepted: 7 October 2020

# Springer-Verlag London Ltd., part of Springer Nature 2020

Abstract
Androgenetic alopecia (AGA) is a global challenge, affecting a large number of people worldwide. Efficacy of the existed
treatments can barely meet the demands of patients. Patients who are poorly responding to those treatments are seeking for a more
effective and suitable technique to treat their disease. Low-level light therapy (LLLT) is a newly developed technique, which has
been proved to stimulate hair growth. Based on the function principle of LLLT in other domains and refer to the published
literatures, we write this review to neaten and elucidate the possible mechanism of LLLT in the treatment of AGA. A review of
published literature which is associated with keywords LLLT, photobiomodulation, AGA, treatment, hair growth, and mecha-
nism was performed to elucidate the proposed mechanism of LLLT in the treatment of AGA. The present study shows that LLLT
can accelerate hair growth in AGA patients. The proposed mechanism of LLLT in treating AGA may vary among different
specialists. But we can summarize the consensual mechanisms as follows; low-level light absorbed by chromophores can lead to
the production of nitric oxide (NO) and the modulation of reactive oxygen species (ROS). These mobilized molecules subse-
quently activate redox-related signaling pathways in hair follicle cells and perifollicular cells. Finally, these activated cells
participate in the regrowth of hair follicle. Even though the efficacy of LLLT in the treatment of AGA in both men and women
has already been confirmed, the present studies focusing on discovering LLLT are still inadequate and unsystematic. More
studies are needed to standardize the optimum treatment parameters applied in promoting hair growth and determine the long-
term safety and efficacy of LLLT. Current recognitions about the mechanisms of LLLT, mainly focused on the molecules that
may take effect, neglected different cellular components that are functional in the hair follicle macro-environment.

Keywords Low-level light therapy . Photobiomodulation . Treatment . Androgenetic alopecia . Hair follicle . Mechanism

Features and pathogenesis of AGA the terminal hair gradually transforms into vellus hair, finally
results in “hair follicle miniaturization” [2]. AGA has been
AGA is a common form of hair loss that follows a defined confirmed to have a great impact on an individual’s psycho-
pattern caused by multiple factors, such as hereditary suscep- logical state and quality of life [3]. With the rise of people’s
tibility, endocrine disturbance, and aging [1]. It is character- living standards, the demand for treating AGA is getting more
ized by the progressive shortening of the duration of the urgent.
anagen phase, extending of the catagen phase, and changing
of the follicular morphology. With the shortening of anagen,
Treatments
Yilong Guo and Qian Qu are joint first authors.
The current treatment for AGA is hair transplant surgery and
* Yong Miao medication [4]. The surgical treatment has won a good repu-
[email protected]
tation among patients; a better appearance can be obtained
* Zhiqi Hu immediately after the operation. Meanwhile, the surgical out-
[email protected]
come is satisfactory in the long run. But the limited donor site,
1
Department of Plastic and Aesthetic Surgery, Nanfang Hospital of
post-operation shedding phase, and high cost hindered the
Southern Medical University Guangzhou, widespread popularity [5]. Two medications have been ap-
Guangzhou 510515, Guangdong Province, China proved by the US Food and Drug Administration (FDA) for
 Lasers Med Sci

Low level light regional adverse reactions also occur after the application of
PRP [8]. Therefore, a non-surgical, safe, and efficient therapy
is required to meet the demand of AGA patients.

Cytochrome c oxidase
LLLT for prevention and reversal
of androgenetic alopecia

LLLT, also is known as photobiomodulation (PBM), is a

newly developed approach for the treatment of various clinical
circumstances, such as wound pain, edema, chronic ulcer, and
inflammation [9]. In the 1960s, it is firstly applied by the
National Aeronautics and Space Administration (NASA) to
wound healing in space [10]. Nowadays, LLLT devices for
the treatment of hair loss are widely acknowledged; various
Fig. 1 Cytochrome c oxidase (Cco) is the unit IV of the mitochondrial devices have been declared by the FDA since this technology
respiratory chain. It is proposed that LLLT can modulate the production
of nitric oxide (NO) and balance reactive oxygen species (ROS) became available.
Many clinical trials have been conducted to assess the ef-
ficacy of LLLT in the treatment of AGA (Table 1). Avram
the treatment of AGA: finasteride and minoxidil. However, conducted a research by using a laser device at a wavelength
medications are not effective for all types of patients, and side of 650 nm at a fluence of 5 mW. The assessment criteria
effects may occur after the application of drugs [6, 7]. Platelet- include vellus hair counts, terminal hair counts, and hair shaft
rich plasma (PRP) injection has been confirmed to accelerate diameter. However, these results showed no significant differ-
hair growth via releasing related stimulative cytokines. Qu ence between the test group and the control group, the hair
and Shi found that PRP is effective for grade II and grade III growth of these patients seems to have worsened identified by
in male pattern hair loss (MPHL) and grade I in female pattern a video microscopic photograph. Even so, the progress of
hair loss (FPHL). However, it is difficult to reverse the prog- LLLT research did not stop there [11]. In 2009, Leavit et al.
ress of patients who suffer from severe hair loss. Some conducted a double-blinded and control group trial with a

Before LLLT After LLLT

a

Apoptotic cell

Prolif eration ↑
Apoptosis ↓ Epidermis
Sebaceous
gland Dermis
Hair shaft Bulge stem cell
Nerve fiber
Outer root sheath

β-catenin
Inner r oot sheath
Hair shaft
c
b β-catenin β-catenin Prolif eration ↑
β-caten

β-catenin
β-catenin Dermal papilla
β-cate
β-catenin

β-catenin
β-catenin

β-catenin Hair matrix c ell

β-catenin Dermal papilla c ell

After LLLT Before LLLT After LLLT

Before LLLT

Fig. 2 LLLT can modulate cells in the hair follicles. (A) LLT can Wnt/B-certain signaling in hair matrix cells and promote hair growth.
accelerate the proliferation and reduction of apoptosis of ORS cells via (C) LLLT can regulate the proliferation of dermal papilla cells and hair
activating Wnt/B-certain and ERK pathways. (B) LLLT can activate follicles
Lasers Med Sci

Before LLLT After LLLT Before LLLT After LLLT

a b
Pro-inflammatory cytokine
BNDF
Anti-inflammatory cytokine
presynaptic
membrane

postsynaptic
Epidermis membrane
Sebaceous
gland Dermis
Hair shaft Bulge stem cell

Nerve fiber

Inflammatory cell

Before LLLT After LLLT

Dermal white Before LLLT After LLLT
adipose tissue
c FGF2
FGF2 d
HGF
VEGF VEGF
HGF
TNF/CHX TNF/CHX

Apoptosis Apoptosis

Adipocyte Vascular endothelial cell

Adipose derived
stem cell

Bothr ops jararaca venom

high blood sugar

Fig. 3 LLLT can modulate cells in the perifollicular region. (A) LLLT LLLT can enhance angiogenic factors production such as VEGF, HGF,
can downregulate inflammatory cells infiltration, pro-inflammatory and FGF2. (D) LLLT can prevent endothelial cells from TNF-a/
cytokines secretion, and upregulate anti-inflammatory cytokine cycloheximide-induced apoptosis and damages such as exposure to
secretion. (B) LLLT can modulate BNDP production in neurons. (C) Bothrops jararaca venom and high blood pressure

large number of patients enrolled. Experimental data showed growth of the group that received 655-nm red laser plus 808-
that patients treated with LLLT maintained a better hair den- nm infrared laser through a laser scanner was significantly
sity. Also, patients’ subjective assessment of hair growth was higher than 655-nm red light group and sham group [18].
also statistically significant [12]. In 2013, Kim et al. conduct- Fan et al. conducted a self-comparison study, one-half of the
ed a randomized, double-blind, device-controlled, and multi- scalp received LLLT and another half received sham light
center trial. LLLT group showed significant improvement in treatment. Compared with the sham side, hair thickness, hair
hair density and hair diameter. Investigator assessment also count, hair coverage, and investigators’ global assessment
showed a better outcome in LLLT-treated group [13]. (IGA) were significantly improved after LLLT [19]. In a study
Lanzafame and co-workers demonstrated LLLT can signifi- done by Suchonwanit focusing on the efficacy of LLLT for
cantly improve hair count in both male and female patients treating AGA in Thai men and women, hair density and hair
[14, 15]. A study also compared the use of LLLT in both men diameter were significantly improved in the study group [20].
and women, and increased hair density was observed after Also, LLLT can serve as adjuvant therapy; the combination of
LLLT [16]. Another multicenter, randomized, double-blind, LLLT with minoxidil can maintain a better result than mono-
controlled trial using the dome laser device achieved a 51% therapy [21].
increase of hair counts in the test group compared to that in the Summing up the above studies, LLLT appears to be an
control [17]. Light parameters can significantly affect the ex- effective option for the treatment of AGA. It can also serve
perimental outcome; a study aimed to evaluate the effective- as adjuvant therapy for medication and surgical therapy. And
ness of a different laser source (665 nm and 808 nm). The hair no severe side effects of LLLT have been documented so far.
 Lasers Med Sci

Table 1 Summary of the clinical trials that investigated the efficacy of LLLT for the treatment of androgenetic alopecia

Author (year) Subject Light source Therapeutic regimen Evaluation criterion Adverse reaction
group parameters

Avram et al. 2009 Both sexes 650 nm laser Treatment frequency: Vellus hair counts Itching
[12] 20 min/ 2 days per week 15 cm from glabella
Treatment course: Baseline 52.43 3 months
3 and 6 months 43.86
Delta 8.57 P value 0.3131
20 cm from glabella
Baseline 48.86 3 months
45.57
Delta −3.29 P value 0.6474
Terminal hair counts
15 cm from glabella
Baseline 64.14 3 months
71.71
Delta +7.57 P value 0.4183
20 cm from glabella
Baseline 82.14 3 months
88.29
Delta +6.14 P value 0.4441
Hair shaft diameter
15 cm from glabella
Baseline 27.98 3 months
28.98
Delta +1.00 P value 0.5351
20 cm from glabella
Baseline 29.74 3 months
28.77
Delta −0.97 P value 0.5161
Leavitt et al. 2009 Male 655 nm laser Treatment frequency: Hair density Paraesthesia
[13] 15 min/3 days per week LLLT: 17.3 ± 11.9 Urticaria
Treatment course: Control: −8.9 ± 11.7
26 weeks P value<0.0001
Kim et al. 2013 Both sexes 630 nm, 650 nm Treatment frequency: Hair density: Headache
[14] and 660 nm laser 20 min/ 2 days per week LLLT: 17.2 ± 12.1 Dermatologic
Treatment course: Control:-2.1 ± 18.3 problem
24 weeks P value = 0.003
Hair thickness
LLLT: 12.6 ± 9.4
Control: 3.9 ± 7.3
P value = 0.01
Lanzafame et al. 2013 Male 655 ± 5 nm laser Treatment frequency: Hair count No reported
[15] 25 min/ Every other day LLLT: 67.2 ± 33.4
Treatment course: Control:32.3 ± 44.2
16 weeks P < 0.0001
Lanzafame et al. 2014 Female 655 ± 5 nm laser Treatment frequency: Hair count No reported
[16] 25 min/ Every other day LLLT: 48.07 ± 17.61,
Treatment course: Control: 11.05 ± 48.30
16 weeks P = 0.011
Jimenez et al. 2014 Female 655 nm (± 5%) laser Treatment frequency: Hair density Dry skin
[17] 11 min / 3 times per LLLT: 20.2 ± 11.2, Pruritus
week Control: 2.8 ± 16.5 Scalp tenderness
Treatment course: P < 0.0001 Irritation
16 weeks Warm sensation
Female 635 nm/ 655 nm (±5%) Treatment frequency: Hair density
laser 18 min / 3 times per LLLT: 20.2 ± 11.6,
week Control: 3.0 ± 9.3
Treatment course: P < 0.0001
16 weeks
Male 655 nm (±5%) laser Treatment frequency: Hair density
15 min/ 3 times per week LLLT: 18.4 ± 13.7,
Treatment course: Control: 3.0 ± 9.3
16 weeks P < 0.0001
Lasers Med Sci

Table 1 (continued)

Author (year) Subject Light source Therapeutic regimen Evaluation criterion Adverse reaction
group parameters

Male 635 nm / 655 nm (±5%) Treatment frequency: Hair density

laser 8 min/ 3 times per week LLLT: 25.7 ± 17.1,
Treatment course: Control: 9.4 ± 12.9
16 weeks P < 0.0001
Friedman et al. 2017 Female 650 nm laser Treatment frequency: Terminal hair count No reported
[18] 30 min/ Every other day LLLT: 63.67 ± 50.9
Treatment course: Control: 12.48 ± 13.76
17 week P < 0.001
Barikbin et al. 2017 Both sexes 655 nm / 808 nm laser Treatment frequency: Terminal hair count Mild headache
[19] 3 times per week LLLT: 9.62 ± 9.46, Dry skin
Treatment course: Control: −1.81 ± 3.10
16 weeks P < 0.0001
Mai-Yi Fan et al. 2017 Both sexes 650 ± 10 nm/ Treatment frequency: Hair count Eczema
[20] 660 ± 5 nm laser 30 min/ 3 times per week LLLT: 6 ± 12.5, pruritus
Treatment course: Control: −2 ± 12.6 Acne
24 weeks P < 0.001
Suchonwanit et al. Both sexes 650 ± 20 nm laser Treatment frequency: Hair density Temporary hair
2018 20 min/ 3 times per week LLLT: 10.21 ± 3.25 shedding
[21] Treatment course: Control: 3.95 ± 1.32 Scalp pruritus
24 weeks P = 0.002
Hair diameter
LLLT: 6.11 ± 2.15
Control: 3.76 ± 1.24
P = 0.009

Proposed mechanisms of LLLT for treatment and re-epithelialization in an energy-dependent manner [25].
of hair lose Furthermore, Carrasco and co-workers demonstrated that low-
level light irradiation (636 nm, 2.5–10 J/cm2) can modulate
“Three-step principle” of LLLT ROS level in mouse skin; activate cell proliferation in epider-
mal, dermal layers, and hair follicle stem cell niche; and final-
Although the mechanism of LLLT is still controversial, the ly leads to the growth of hair follicle [26]. Therefore, based on
evidence-based mechanisms can be described as followed: current researches, it was proposed that LLLT might influence
firstly, visible red or near-infrared (NIR) light is absorbed by hair growth through the modulation of these molecules. Next,
endogenous chromophores, leading to the production of ATP we will expound them in detail (Table 2).
and NO as well as the modulation of ROS [22]. Secondly,
these mobilized molecules subsequently activate some The function of NO on influencing hair growth
redox-related signaling pathways; cellular responses such as
proliferation, migration, and inflammation were regulated The production of NO can be triggered by endogenous and
[23]. Thirdly, these activated cells participate in the regenera- exogenous stimuli. LLLT has been shown to induce NO syn-
tion of hair follicles (Image 1). thase [27]. Investigation of the exact role of NO after light
irradiation may provide a new insight for studying the mech-
The primary step: LLLT modulates the production of anism of LLLT on promoting hair growth. LLLT can induce
NO and ROS in hair follicle in vitro re-epithelialization via NO production, which is essen-
tial in the process of hair follicle morphogenesis [25]. Also,
Cytochrome oxidase (Cco) is known to be the complex IV in Ca2+-activated K+ channel in the cell membrane can be mod-
the mitochondrial respiration chain. Also, it is proposed to be ulated by nitric oxide derived from dermal papilla (DP) cells,
the primary photoreceptor in the photobiomudulation process which is essential in cytokine production and body fluid equi-
[24]. Evidence suggests that low-level light irradiation can librium [28]. The production of NO is able to modulate the
effectively trigger the production of NO and modulation of differentiation and survival of lymphocytes, acting as an
ROS in the hair follicles (Fig. 1). Manuela et al. has already assisting factor to fight against exogenous infection and mod-
confirmed the production of NO after laser irradiation ulate inflammation and immune response [29]. As a second
(980 nm wavelength, 649.35 mW/cm2) in epidermal messenger, NO exerts its function via lowering the concentra-
keratinocytes, leading to accelerated keratinocyte proliferation tion of Ca2+, consequently relax the smooth muscle cells in
 Lasers Med Sci

Table 2 Summary of the proposed molecular mechanisms of LLLT on promoting hair growth

Molecule Regulation References

NO Ion Channel: Modulate Ca2 + −activated K+ channel in dermal papilla cells [30]
Cellular behavior: Modulate the differentiation and survival of lymphocytes [31]
Vasodilation: Dilate blood vessels via stimulation of soluble guanylate cyclase to form cyclic-GMP (cGMP). [32]
Modulate stem cell behavior [33]
ROS Cellular behavior: Activate cell proliferation in mouse skin and the hair follicle stem cells in the bulge region. [27]

the vascular system, and increase blood flow of regional cir- The function of ROS on maintaining hair follicle redox
culation, so as to provide more oxygen and nutrients [30]. state
At present, the researches focus on the cellular behavior of
stem cells about NO encompasses cardiovascular, neuronal, ROS is a type of highly active adjustable small molecules as a
and immune systems; NO can trigger the cellular responses of consequence of cellular respiration. The good side of ROS is
stem cells via the NO-specific pathways [31]. As for hair that the effect on immunoreaction, cellular responses. The bad
follicle stem cells, no relevant studies about NO and hair fol- side about ROS is about the generation of an excess amount of
licle stem cell therapy were available for now, but discovering molecules that lead to the destruction of redox homeostasis,
a novel treatment strategy involved with hair follicle stem causing dysregulation of physiological cellular function [33].
cells and NO against androgenetic alopecia is promising and Previous studies have confirmed that LLLT is able to mod-
possible. ulate ROS production in vivo and in vitro. Alarmingly,
Confusingly, dihydrotestosterone can induce NO pro- Dillenburg et al. found that LLLT can trigger the upregulation
duction in DP cells, even though the functional differ- of ROS in human epithelial cells, resulting in accelerated
ences of basal and androgen-stimulated NO production wound healing but without inducing DNA damage [34].
has not been explained. Referring to published literature, Therefore, there is a significant difference between abundant
we can ascribe to the different concentrations of NO ROS production induced by pathological factors and ROS
[32]. production after low-level light irradiation.

Table 3 Summary of the proposed cellular mechanisms of LLLT on promoting hair growth

Regulation References

1. Hair 1.1 Outer root sheath Apoptosis: Accelerate proliferation and migration and inhibite apoptosis via stimulation of the [43]
follicle cell cell Wnt5a/β-catenin and ERK signaling pathway.
1.2 Hair matrix cell Gene expression: Upregulate Wnt10b and β-catenin expression in hair matrix cells and stimulate [42]
hair growth.
1.3 Dermal papilla Cellular behavior: Regulate the proliferation of human dermal papilla cells and hair follicles growth [45]
cell via Wnt/β-Catenin and the Extracellular Signal-Regulated Kinase Pathways.
Cellular transcription: Modulate biological processes of dermal papilla cells such as: cellular [46]
transcription, protein biosynthesis, cell energy, lipid homeostasis, extracellular matrix, ECM
structural constituent, cell-cell/cell-matrix adhesion and angiogenesis.
2. 2.1 Dermal white Angiogenesis: Enhance angiogenic factors production such as VEGF, HGF and FGF2. [50]
Perifollic- adipose tissue Cellular behavior: Increase cellular viability, proliferation, and expression of β1-integrin of [51]
ular cells adipose-derived stem cells.
Inflammation: Suppress inflammatory response of human adipose-derived stem cells by [49]
modulating cyclic AMP level and NF-κB activity.
2.2 Inflammatory Inflammation: Limite perifollicular inflammation. [56]
cell
2.3 Vascular Cellular behavior: Accelerate proliferation, migration, and angiogenesis of human umbilical [60]
endothelial cells vascular endothelial cell (HUVECs) via activation of the PI3K/Akt signaling pathway.
Apoptosis: Prevent vascular endothelial cells from TNF-α/cycloheximide-induced apoptosis. [64]
Protective factor: Protect vascular endothelial cells against Exogenous injury factors such as [62, 63]
othrops jararaca venom and high blood sugar.
2.4 Nerve cells Gene expression: Modulate BNDP mRNA transcription and then induce calcium-dependent [70]
activation of the ERK/CREB pathway.
Lasers Med Sci

According to the research of Lemasters and his colleagues, study conducted by Yu et al. confirmed that LLLT is able to
mitochondrial and oxidative metabolism is tightly related to accelerate the differentiation of melanocyte stem cells, migra-
growing hair follicle [35]. The generation of ROS provides an tion of immature melanoblasts, and melanogenesis and migra-
appropriate oxidative environment for the communication of tion of differentiated melanoblasts, which will eventually result
epithelial-mesenchymal in the hair follicles to occur. Carrasco in the segmental repigmentation in vitiligo [44]. It may provide
et al. found that ROS production after PBM can stimulate cell a new clue for restoring grey hair to its natural color.
proliferation in mouse skin and the hair follicle stem cells in Furthermore, it may be able to activate hair follicle stem cells
the bulge region and consequently accelerate the hair growth located in the bulge region as well.
[26]. In contrast, wounded mouse skin is highly active in the
production of ROS. Intriguingly, the oxidative stress in the Perifollicular cells
skin is significantly lower than the control after low-level laser
irradiation [36]. This kind of modulatory phenomenon of ROS Dermal white adipose tissue The low-level light irradiation can
after LLLT is also commonly seen in the circulation and res- penetrate and act on perifollicular cells as well. The effects of
piration system [37]. LLLT on perifollicular cells are shown in (Fig. 3). Dermal white
Therefore, the function of LLLT in the modulation of ROS adipose tissue (DWAT) is thought to affect the onset and prog-
in hair follicle is not nondirectional upregulating or downreg- ress of AGA. The hair follicle and DWAT are in close contact
ulating the amount of ROS; it is more likely to modulate and with each other in each hair cycle stage [45]. Low-level light
balance the amount of good and bad ROS. irradiation can suppress the inflammatory response of hADSCs
by modulating cyclic AMP level and NF-κB activity [46]. Park
The secondary step: mobilization of hair follicle cells et al. discovered that low-level light irradiation on the adipose-
and perifollicular cells after LLLT derived stromal cells can lead to enhanced angiogenic factors
production such as vascular endothelial growth factor (VEGF),
The altered molecules after light irradiation are confirmed to hepatocyte growth factor (HGF), and fibroblast growth factor-2
be able to modulate the redox related to signaling pathways. (FGF-2) and increase capillary density in the skin [47]. Besides,
LLLT devices can deliver energy to the epidermis, dermis, cellular viability, proliferation, and β1-integrin, a stem cell mark-
and subcutaneous layers and achieve large penetration depth er expressed in adipose-derived stem cells, are increased after
to act on deep tissues effectively and safely [38]. The cells LLLT [48]. In the field of stomatology, LLLT can affect the
regulated by LLLT can be divided into two types: hair follicle composition and ultrastructure of the ECM [49]. Similarly, in
cells and perifollicular cells (Table 3). hair follicle micro-environment, ECM of adipose tissue which
is essential for maintaining the stable structure may also be af-
Hair follicle cells fected by LLLT. In a word, LLLT can modulate cellular behav-
ior, enhance angiogenesis, suppress the inflammatory response,
The effects of LLLT on hair follicle cells are shown in (Fig. 2). and ECM composition in dermal white adipose tissue.
The hair matrix cell is critical in the process of the generation of
the hair shaft. Zhang et al. found that LLLT can accelerate hair Inflammatory cell Perifollicular inflammation and fibrosis
regrowth by the induction of anagen phase via upregulation of are more significant in AGA patients compared to healthy
Wnt10b and β-catenin expression in hair matrix cells of C3H/ control [50]. Christine and co-workers demonstrated that
HeJ mice [39]. Outer root sheath cell (ORSC) surrounds most thickening of hair follicle adventitial sheaths accompanied
components of the hair follicle and has enormous significance by mast cell degranulation and fibroblast activation is ob-
in maintaining DP cells and hair matrix cells. LLLT can accel- served in AGA hair follicle. Besides, they also observed
erate the proliferation and migration of ORS cells via activating the activated T cell infiltration in follicular bulge [51].
Wnt/β-catenin and ERK pathways [40]. DP is a type of spe- Researches about the pathogenesis and treatment of AGA
cialized mesenchymal cells that is critical for instructing the are now focusing more on the microscopic follicular in-
epithelial compartment to generate hair shaft periodically [41]. flammation process. Referring to previously published lit-
Joo et al. found that LLLT can accelerate the proliferation of DP erature, LLLT is able to decrease inflammatory response in
cells via Wnt/β-Catenin and the extracellular signal-regulated muscle cells, nerve cells, and skin [52]. Diabetic wounded
kinase pathways [42]. Furthermore, after LLLT treatment of rats exhibit significant necrosis and inflammatory cell in-
DP cells from AGA patients, the cellular transcription, protein filtration with the increase in serum pro-inflammatory cy-
biogenesis, extracellular matrix (ECM) production, angiogene- tokines such as interleukin 1β (IL-1β) and tumor necrosis
sis, etc. are all significantly upregulated [43]. Vitiligo is a type factor-alpha (TNF-α) and inflammatory cytokines prosta-
of acquired depigmentary disorder due to the dysfunction of glandin E2 (PGE-2) and leukotrieneB-4 (LTB-4) and the
melanocytes derived from melanocyte stem cells located in decrease in anti-inflammatory cytokine such as IL-10,
the bulge region of hair follicles in the lesion skin. A recent which indicates the preponderance of T helper cells type
 Lasers Med Sci

1 (Th1). After being treated with LLLT, significant sup- Ultimate result after the synergy of multiple
pression of inflammatory cell infiltration and improve- factors: the growth of hair follicle
ments of wound healing were observed in the skin [53].
AA is a type of autoimmune disease of the hair follicle due Since the marketing of LLLT devices, it has been applied in
to the damage caused by T cells [54]. Many clinical trials many areas for tissue regeneration, such as muscle recovery,
have demonstrated that LLLT can accelerate hair growth in brain damage recovery, and nerve healing [9]. One of the most
alopecia areata (AA) patients [55]. There have been many successful applications of LLLT is promoting hair growth in
speculations about the mechanism, and the most accepted AGA patients. The mobilized cells from hair follicle and
one is the modulation of perifollicular inflammation. perifollicular region contribute to the promotion of hair cycle
and growth of hair follicles. Improved hair count, hair thick-
Vascular endothelial cell The vascular endothelial cell is ness, hair shaft diameter, anagen/telogen ratio, and subjective
essential in the process of angiogenesis. LLLT treatment assessment by patient and investigator were improved after
can improve angiogenesis of ischemic skin flap mediated LLLT [15–19].
by VEGF, hypoxia-inducible factor 1α (HIF-1α), and ma-
trix metalloproteinase 2 (MMP-2) [56]. LLLT can accel-
erate the proliferation, migration, and angiogenesis of hu-
man umbilical vascular endothelial cells (HUVECs) via Conclusion
activation of the PI3K/Akt signaling pathway [57].
Amaroli et al. found that LLLT can act against With this review, we aimed to organize the existed literature to
inflammation-induced human endothelial cells (HECV) provide a feasible clue for unveiling the possible mechanism
dysfunction by modulating ROS production and stimulat- of LLLT in the treatment of AGA. There are different hypoth-
ing mitochondrial activity [58]. In some special condi- eses about the mechanism of LLLT on promoting hair growth;
tions, LLLT can prevent vascular endothelial cells from the exact mechanism of action is still controversial. We sum-
damages such as exposure to Bothrops jararaca venom marize the evidence-based mechanisms as followed: LLLT
and high blood sugar [59, 60]. Besides, Chu et al. found can mobilize molecules such as ROS, NO, and ATP through
that LLLT can prevent endothelial cells from TNF-α/cy- the interaction with mitochondrial chromophores such as Cco.
cloheximide-induced apoptosis [61]. Therefore, LLLT can These molecules can subsequently activate some signaling
mobilize endothelial cells and protect them when exposed pathways and modulate various cellular behaviors of irradiat-
to injury risk factors. ed cells, which eventually lead to the growth of hair follicles.
An ever-growing number of researches confirmed the efficacy
Nerve cell The nervous system and hair follicle epithelium of LLLT on promoting hair growth. Furthermore, LLLT can
share a common ectodermal origin. Many neurotrophins perform as adjuvant therapy of hair transplant surgery for its
have already been proven to be involved in hair growth ability to promote graft survival. Also, many clinical trials
control [62, 63]. The past decade has witnessed that pe- focus on the combination of LLLT with other medications
ripheral nerve damage was commonly associated with fol- for promoting hair growth showed a surprisingly positive out-
licle atrophy along the distribution zone of damaged nerve come. Nowadays LLLT has become more and more popular
[64]. Also, an unusual distribution of follicle innervation in the treatment of AGA for its convenience and effectiveness.
was observed in the stem cell region [65]. Brain-derived Most studies have used the optimum wavelengths that range
nerve factor (BDNF) is a type of neurotrophic factor from 635 to 650 nm; hair growth was observed after the ap-
which is critical for the differentiation and survival of plication of LLLT. Most of the patients who are poorly re-
neurons during development. A recent study revealed that sponsive to LLLT are mainly due to the choice of improper
BDNF expression was upregulated by approximately 12- light irradiation parameter or lack of continuous application.
fold in DP cells from bald patients as compared with In some cases, mild regional adverse reactions occurred such
nonbalding DP cells [66]. It turns out that BNDP might as acne, paresthesias, headache, and pruritus. Therefore, to
be critical for mediating the effects of androgens on hair define an optimum light irradiation parameter as well as to
follicles, acting as a negative regulating signal. Yan et al. elucidate LLLT’s mechanism of action, well-controlled clini-
discovered that LLLT modulates BDNF mRNA transcrip- cal trials are urgently required.
tion and then induces calcium-dependent activation of the
ERK/CREB pathway [67]. This might provide new in- Acknowledgments The authors thank the Guangdong Provincial Key
Laboratory of Construction and Detection in Tissue Engineering for pro-
sight into the mechanism of LLLT in the regulation of
viding experimental instruments.
hair growth. In general, LLLT can affect hair growth in
many aspects. Meanwhile, more and more possible cellu- Authors’ contributions Not applicable
lar mechanisms are waiting to be explored.
Lasers Med Sci

Funding This study was funded by the National Natural Science Facial Plast Surg 18:413–418. https://doi.org/10.1001/jamafacial.
Foundation of China (Grant No. 81772104, No. 81701929, No. 2016.0546
81971889, No. 81902013), the Natural Science Foundation of 6. Venkataram M, Shashikumar BM (2016) Guidelines on the use of
Guangdong Province (Grant No. 2017A030310120), the Guangdong finasteride in androgenetic alopecia. Indian J Dermatol Venereol
Basic and Applied Basic Research Foundation (Grant No. Leprol 82:128–134. https://doi.org/10.4103/0378-6323.177432
2019A1515012170), the Science and Technology Program of 7. Poonkiat S, Sasima T, Kanchana L (2019) Minoxidil and its use in
Guangzhou (Grant No. 201904010480), and the Medical Scientific hair disorders: a review. Drug Des Devel Ther 13:2777–2786.
Research Foundation of Guangdong Province (Grant No. C2019112). https://doi.org/10.2147/DDDT.S214907
8. Pietro G, Simone G (2020) Systematic review of platelet-rich plas-
Availability of data and material Not applicable ma use in androgenetic alopecia compared with minoxidil, finaste-
ride, and adult stem cell-based therapy. Int J Mol Sci 21:undefined.
https://doi.org/10.3390/ijms21082702
Compliance with ethical standards 9. Wickenheisser VA, Marta ZE, Mary RE, Ho LH, Lawrence DS,
Kathleen TT (2019) Laser light therapy in inflammatory, musculo-
Conflicts of interest The authors declare that they have no conflict of skeletal, and autoimmune disease. Curr Allergy Asthma Rep 19:37.
interest. https://doi.org/10.1007/s11882-019-0869-z
10. Cotler HB (2015) A NASA discovery has current applications in
Ethics approval This article does not contain any studies with human orthopaedics. Curr Orthop Pract 26:72–74. https://doi.org/10.1097/
and animal experiments performed by any of the authors. BCO.0000000000000196
11. Avram MR, Rogers NE (2009) The use of low-level light for hair
growth: part I. J Cosmet Laser Ther 11:110–117. https://doi.org/10.
Consent to participate Not applicable
1080/14764170902842531
12. Matt L, Glenn C, Eugene H, David M (2009) HairMax LaserComb
Consent for publication Not applicable laser phototherapy device in the treatment of male androgenetic
alopecia: a randomized, double-blind, sham device-controlled,
Code availability Not applicable multicentre trial. Clin Drug Investig 29:283–292. https://doi.org/
10.2165/00044011-200929050-00001
List of abbreviations AGA, Androgenetic alopecia; LLLT, Low-level- 13. Hyojin K, Woong CJ, Young KJ, Won SJ, Lee S-J, Chang-Hun H
light therapy; NO, Nitric oxide; ROS, Reactive oxygen species; FDA, (2013) Low-level light therapy for androgenetic alopecia: a 24-
Food and Drug Administration; PBM, Photobiomodulation; PRP, week, randomized, double-blind, sham device-controlled multicen-
Platelet-rich plasma; Cco, Cytochrome oxidase; MPHL, Male pattern hair ter trial. Dermatol Surg 39:1177–1183. https://doi.org/10.1111/dsu.
loss; FPHL, Female pattern hair loss; NASA, National Aeronautics and 12200
Space Administration; IGA, Investigators’ global assessment; DP, 14. Lanzafame RJ, Blanche RR, Bodian AB, Chiacchierini RP, Adolfo
Dermal papilla; NIR, Near-infrared; ORSC, Outer root sheath cell; F-O, Kazmirek ER (2013) The growth of human scalp hair medi-
ECM, Extracellular matrix; DWAT, Dermal white adipose tissue; ated by visible red light laser and LED sources in males. Lasers
hADSCs, Human adipose-derived stem cells; VEGF, Vascular endotheli- Surg Med 45:487–495. https://doi.org/10.1002/lsm.22173
al growth factor; HGF, Hepatocyte growth factor; FGF-2, Fibroblast 15. Lanzafame RJ, Blanche RR, Chiacchierini RP, Kazmirek ER, Sklar
growth factor-2; IL-1β, Interleukin 1β; TNF-α, Tumor necrosis factor- JA (2014) The growth of human scalp hair in females using visible
alpha; PGE-2, Prostaglandin E2; LTB-4, Leukotriene B-4; Th1, T helper red light laser and LED sources. Lasers Surg Med 46:601–607.
cells type 1; AA, Alopecia areata; HIF-1α, Hypoxia-inducible factor 1α; https://doi.org/10.1002/lsm.22277
MMP-2, Matrix metalloproteinase 2; HUVECs, Human umbilical vascu- 16. Jimenez JJ, Wikramanayake TC, Wilma B, Maria H, Hickman JG,
lar endothelial cell; HECV, Human endothelial cells Hamblin MR, Schachner LA (2014) Efficacy and safety of a low-
level laser device in the treatment of male and female pattern hair
loss: a multicenter, randomized, sham device-controlled, double-
blind study. Am J Clin Dermatol 15:115–127. https://doi.org/10.
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