Neurological Sciences

https://doi.org/10.1007/s10072-021-05478-7

REVIEW ARTICLE

Efficacy of low‑level laser therapy in nerve injury repair—a new era

in therapeutic agents and regenerative treatments
Xellen Cunha Muniz1 · Ana Carolina Correa de Assis2 · Bruna Stefane Alves de Oliveira2 ·
Luiz Fernando Romanholo Ferreira3,4 · Muhammad Bilal5 · Hafiz M. N. Iqbal6 · Renato Nery Soriano7

Received: 24 April 2021 / Accepted: 8 July 2021

© Fondazione Società Italiana di Neurologia 2021

Abstract
Background Traumatic nerve injuries may result in severe motor dysfunctions. Although the microenvironment of peripheral
axons favors their regeneration, regenerative process is not always successful.
Purpose We reviewed and discussed the main findings obtained with low-level laser therapy (LLLT), a therapeutic interven-
tion that has been employed in order to achieve an optimized regeneration process in peripheral axons.
Scope Disseminating the best available evidence for the effectiveness of this therapeutic strategy can potentially improve
the statistics of success in the clinical treatment of nerve injuries. We found evidence that LLLT optimizes the regeneration
of peripheral axons, improving motor function, especially in animal models. Nonetheless, further clinical evidence is still
needed before LLLT can be strongly recommended. Although the results are promising, the elucidation of the mechanisms
of action and safety assessment are necessary to support highquality clinical studies.
Conclusion The present careful compilation of findings with consistent pro-regenerative evidence and published in respected
scientific journals can be valuable for health professionals and researchers in the field, possibly contributing to achieve more
promising results in future randomized controlled trials and interventions, providing better prognosis for clinical practice.

Keywords Peripheral axon · Axon regeneration · Photobiomodulation · Pro-regenerative interventions

* Muhammad Bilal Introduction

bilaluaf@hotmail.com
* Renato Nery Soriano The literature regarding the prevalence of traumatic nerve
renato.soriano@ufjf.edu.br injury is sparse and variable according to the compromised
1 topography. Some recent cohort studies have shown a preva-
Department of Physical Therapy, Federal University of Juiz
de Fora, 35032‑620 Governador Valadares‑MG, Brazil lence of 1.8 to 3.3%, with a higher prevalence in the age
2 group of 16 to 59 years (82.7–86.1%), in men (78.6%–80%),
Department of Medicine, Federal University of Juiz de Fora,
35032‑620 Governador Valadares‑MG, Brazil mainly related to traffic accidents, involving motorcycles
3 and car collisions. An interesting finding is the fact that, on
Graduate Program in Process Engineering, Tiradentes
University (UNIT), Av. Murilo Dantas, 300, Farolândia, initial admission, trauma patients with concomitant nerve
Aracaju‑Sergipe 49032‑490, Brazil damage have a higher incidence of shock and length of hos-
4
Institute of Technology and Research (ITP), Tiradentes pital stay, when compared to patients without this type of
University (UNIT), Av. Murilo Dantas, 300, Farolândia, lesion [1, 2]. In response to trauma causing partial or total
Aracaju‑Sergipe 49032‑490, Brazil nerve rupture, a series of events results in morphological and
5
School of Life Science and Food Engineering, Huaiyin functional changes—neuroplasticity—that may or may not
Institute of Technology, Huaian 223003, China restore the functionality of the injured nerve(s). The neuron
6
Tecnologico de Monterrey, School of Engineering capacity of self-recovery is already well known and is par-
and Sciences, Campus Monterrey, Ave. Eugenio Garza Sada ticularly present (and not diminished) in autonomic, sensory,
2501, CP 64849 Monterrey, N.L., Mexico and motor neurons. In this context, regenerative neuroplas-
7
Division of Physiology and Biophysics, Department ticity can, therefore, promote the morphofunctional restora-
of Basic Life Sciences, Federal University of Juiz de Fora, tion of injured peripheral axons.
35010‑177 Governador Valadares‑MG, Brazil

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Vol.:(0123456789)

We do not address here scientific advances in the under-
standing of cellular and molecular phenomena inherent to
the axon regeneration process itself. However, it is worth
highlighting in the next three paragraphs fundamental
aspects of (1) Wallerian degeneration, (2) chromatolysis,
and (3) axonal growth cones.
(1) Wallerian degeneration. Degeneration of the distal
stump of the injured axon (Wallerian degeneration)
is engendered by the rupture of the axonal membrane
and the consequent and intense influx of calcium ions,
which promote depolarization of the neuron mem-
brane, activation of calcium-activated proteases, and
reshaping of the cytoskeleton [3]. Differently from
what was initially believed, the discovery of a spon-
taneous mutation in mice (the slow Wallerian degen-
eration gene, W­ lds) revealed that this is not a passive
phenomenon, but rather an active one [4]. Moreover, it
is worth mentioning that the lesion also compromises
the permeability of the blood-nerve barrier in the peri-
neural and endoneurial capillaries; consequently, there
is also a disturbance of homeostasis of this microen-
vironment [5]. Biochemical and cellular alterations
induced by injury—including the release of pro- and
anti-inflammatory cytokines, neurotrophins and growth
factors—are associated with the dedifferentiation and
proliferation of Schwann cells (SC) (which stimulate
axon regeneration) and also with the recruitment of
macrophages. The infiltration of pro-inflammatory
macrophages (also called M1) has been attributed to
the actions of interleukin-1β (IL-1β) and tumor necro-
sis factor (TNF-α), which are released into the injured
region [6, 7]. On the other hand, nerve-repairing M2
macrophages (M2), recruited and activated by expo-
sure to IL-4, IL-10, and IL-13 [7], seem to be associ-
ated with promotion of angiogenesis and suppression
of adaptive immunity. Due to intracellular alterations
and signaling, the distal stump of the injured axon is
subjected to the Wallerian degeneration process, which
occurs in parallel with the removal of cellular debris by
the phagocytic action of macrophages [8], favoring the
regenerative growth of the proximal stump (Fig. 1).
(2) Chromatolysis. After lesion, another cellular phenom-
enon occurs, known as chromatolysis: the pericary (cell
body) of the neuron exhibits alterations (Fig. 1). Stud-
ies indicate that in the course and after overcoming
chromatolysis (neuronal “suffering” phase), there is
an increase in the expression of genes encoding pro-
teins involved in the regeneration of the axon (growth-
associated protein (GAP-43), actin, tubulin, adhesion
molecules, and neurotrophic factors and their recep-
tors) and there is a reduction in the expression of genes
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Neurological Sciences
related to synaptic transmission and axonal stability [9,
10].
(3) Axonal growth cone. Finally, the third aspect that
deserves to be mentioned is the generation and pro-
gression of a growth cone—regenerative growth of the
proximal axonal stump (Fig. 1). This process is also
engendered by the influx of C ­ a2+ ions into the neuron
and presents three stages: protrusion, engorgement,
and consolidation. In protrusion, phylopodiums and
lamelipodiums filled with actin F extend from the main
edge of the growth cone; during engorgement, dynamic
microtubules enter the newly formed protrusions,
bringing vesicles and organelles; and, finally, consoli-
dation occurs with depolymerization of actin F in the
neck of the growth cone with the axonal axis estab-
lished by microtubule compaction. Thus, it is conceiv-
able that the regulation of the dynamics of cytoskeleton
components is a relevant factor for axon growth and is
an essential component to enable a functional restora-
tion [10].
As aforementioned, nerve injuries mainly affect the eco-
nomically active population, which leads to impacts on the
social security system. Besides that, it compromises the
patients’ quality of life, since pain related to neuropathic
mechanisms may persist for months or years, contributing
to poor physical function and, often, lifelong morbidity [11,
12]. With these in mind, there is no doubt about the major
challenges that nerve injuries represent for physicians and
other health professionals involved in the rehabilitation
process, since in general, the outcomes (the final functional
results) tend to be discouraging for both health professionals
and patients, especially in cases of more severe lesions with
complete sections of the nerve(s), in which, even after sur-
gical repair, only 25% of patients recover the lost functions
[13]. In view of this situation, in the search for a method
that optimizes the regeneration process and increases the
probability of a successful functional restoration, low-level
laser therapy (LLLT) has been used over the last decades.
In this context, the present article aimed to review, describe,
and discuss the most promising findings documented in the
literature, providing a refined analysis of scientific informa-
tion that can contribute to increase the LLLT success rate
and minimize risks.
Low‑level laser therapy
Scientific evidence indicates that the axonal regeneration
process can be optimized by non-pharmacological thera-
peutic strategies, among which we highlight the following:
ultrasound; extracorporeal shock wave therapy (ESWT);
LED (light-emitting diode); and a promising intervention
Neurological Sciences

Fig. 1  Peripheral axon degen-

eration and regeneration. A
Intact neuron and Schwann cells
(SC) (yellow) myelinating the
axon. B Axon injury (scissors)
inducing Wallerian degenera-
tion, macrophage and SC migra-
tion, and chromatolysis (see text
for details). C Axon regenera-
tion with magnification of the
growth cone to highlight the
presence of M1 macrophages
(red; induced by the release
of IL-1β and TNF-α), M2
macrophages (pink; induced
by the release of IL-4, IL-10,
and IL-13), and the presence of
dedifferentiated SC (yellow). D
Regenerated axon remyelinated
by SC (yellow)

contemplated in the present work, low-level laser therapy
(LLLT), also known as light therapy or photobiomodulation.
A critical literature review article found that more than 80%
of the experimental studies conducted with LLLT had led
to a positive result in functional recovery of nerves in the
postoperative period [14].
Focusing our attention to lasers, let us mention some
basic aspects. Light is generated in a device through an
optical amplification process based on the stimulated emis-
sion of electromagnetic radiation. Lasers can be classified
as defined by the International Engineering Consortium
(Table 1; IEC standard 60,825–1:2001). Class 1 involves
lasers that are not dangerous, even for long exposures and
with the use of optical instruments—they have been consid-
ered very low power lasers (40 μW). Class 1 M is charac-
terized by presenting potential risks to the eyes if observed
with optical magnifiers—and are considered very low power
lasers (40 μW). Class 2 presents risks of unintentional expo-
sures and non-prolonged observations (< 0.25 s)—it is con-
sidered low power and its light is visible (1 mW). Class 2 M
presents potential risks to the eyes if observed with optical
magnifiers—and are also considered low-power lasers (1

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Table 1  Classification of lasers according to the International Engineering Consortium (IEC standard 60,825–1:2001)
Class Characteristics Power

1 Not dangerous, even for long exposures and with the use of optical instruments Very low
(40 μW)
1M Potentially dangerous to the eyes if observed with optical magnifiers Very low
(40 μW)
2 Risk of unintentional exposures and non-prolonged observations (< 0.25 s); its light is visible Low
(1 W)
2M Potentially dangerous to the eyes if observed with optical magnifiers Low
(1 W)
3R Low-risk when handled with care and is potentially dangerous to the eye if observed with optical Low
(antique 3A) instruments (200 μW to 5 mW)
3B Dangerous to naked eyes if observed directly (beam or specular reflections) Medium
(5 to 500 mW)

M, optical magnifiers; R, reduction of the original class 3A requirements

mW). The letter M of classes 1 M and 2 M indicates the use
of optical magnifiers. Class 3 was subdivided into classes
3A and 3B; however, class 3R is currently used instead of
class 3A. Class 3R (“R” means reduction of the original
class 3A requirements) presents low risk when handled with
care and is potentially dangerous to the eyes if observed with
optical instruments—it is considered low power (ranging
from 200 μW to 5 mW). 3B presents risks to naked eyes
if observed directly (beam and specular reflections)—it is
considered of medium power (ranging from 5 to 500 mW)
(IEC standard 60,825–1:2001) [15].
LLLT consists of the application of light with a power
range from 10 to 500 mW; therefore, as a class 3B laser,
it can damage the naked eye, requiring eye protection.
Although LLLT is not a pharmacological approach, it is
important to emphasize the need to describe and report
potential side effects of any therapeutic approach [16]. Light
with wavelength in the red or near-infrared region of the
electromagnetic spectrum (660 to 905 nm) is generally cho-
sen because these wavelengths can penetrate the skin and
soft tissues, and their effects result from biological responses
with repercussion on physical and chemical changes in irra-
diated tissues [16].
LLLT and possible mechanisms favoring axonal
regeneration
Laser therapy presents important therapeutic results on
the remodeling of scar tissue, as it has been able to reduce
inflammatory processes, reduce edema, promote analge-
sic effects, stimulate phagocytosis by macrophages, and
increase collagen synthesis by fibroblasts. Besides, LLLT
can stimulate myofibroblastic differentiation in the early
stages of healing by increasing mitotic velocity and tissue
repair efficiency [17]. It is believed that the mechanism of
action consists of the absorption of photons by the cell,
which possibly accelerates the activity of the electron
transport chain, increasing the synthesis of adenosine
triphosphate (ATP) in the mitochondria and thus favors
pro-regenerative cellular reactions [18]. Also, a spinal
cord injury model confirmed that this photon-cell interac-
tion may reduce glial scar and cavity area and decrease
the inhibitory response to remyelination by suppressing
chondroitin sulfate proteoglycans (CSPG) expression [19].
Other studies point to actions mediated by the increased
blood supply and cell proliferation [20]. These mecha-
nisms are illustrated in Fig. 2. As mentioned in the context
of Wallerian degeneration, macrophages play an important
regulatory role at the lesion site. LLLT appears to reduce
the relative abundance of M1 macrophages while increases
the proportion of nerve repairing M2 macrophages at the
site of injury [21]. Exploring the mechanisms involved in
this action, an experimental study using an in vitro model
of low-level laser irradiation indicated that LLLT can pro-
mote the secretion of several neurotrophic factors by acti-
vating the PKA-CREB pathway in macrophages, promot-
ing axon regeneration [21]. Moreover, another study using
an injured sciatic nerve model (adult male Wistar rats)
reported that LLLT attenuated the Wallerian degeneration,
increased the axonal density and the blood supply, and
accelerated the revascularization and angiogenesis [22].
The selection of correct parameters is crucial to achiev-
ing successful treatments. The main parameters that should
be considered and established are wavelength, light beam
energy, energy density, and laser application time [21].
Table 2 summarizes the main findings of treatments with
LLLT in injured nerves, and Table 3 reports the parameters
adopted in each article.

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Neurological Sciences
Fig. 2  Possible mechanisms of action of low-level laser therapy
(LLLT) through which remodeling of scar tissue occurs. LLLT
with 690 to 900 nm (red or near-infrared region of electromagnetic
spectrum) may penetrate the tissue and cause physical and chemi-
cal changes associated to increased synthesis of ATP, blood supply,
and cell proliferation. LLLT, low-level laser therapy; ATP, adenosine
triphosphate
Efficacy of LLLT in clinical trials
In the last 10 years, seven clinical studies have investigated
the efficacy of LLLT in enhancing the regeneration and
functional restoration of peripheral nerves. In one of the
studies, sixty patients who presented symptoms of carpal
tunnel syndrome (CTS) less than 6 months ago (with diag-
nosis confirmed by sensory and motor conduction studies)
were submitted to laser application in doses of 0.6 or 1.2 J
per painful point per session, at five points of application in
the median nerve [22]. Laser power was 50 mW and wave-
length was 830 nm. Patients in the experimental group 1
received a total dose of 6 J (10 min per session); patients in
the second experimental group received a total dose of 3 J
(5 min per session); and the other patients formed the third
group: placebo (LLLT device switched off). For the three
groups, the analyses included the following: pain intensity,
grip strength, symptom severity score (SSS), functional
status score (FSS), electrophysiological conduction studies,
and cross-sectional area (CSA) of the median nerve meas-
ured by ultrasound. The results revealed that the applica-
tion of LLLT in the two experimental groups increased the
speed of sensory conduction; the other parameters showed
no statistically significant difference compared to placebo.
The authors concluded, then, that LLLT was not effective in
improving CTS symptoms compared to placebo; however,
they stated that the results differ from those of most previ-
ous studies with LLLT (the studies were cited by the authors
but were not cited here because they were published more
than 10 years ago). The authors argued that data analysis
was done in the short term and that, perhaps, the long-term
effects could bring better results. Furthermore, they attested
that different lasers may have different efficacies in different
diagnoses and that a limitation of the study may have been
the selection of doses and wavelength [22].
Another study evaluated in patients with CTS the effect
of LLLT compared to Fascial Manipulation (FM) [23]. In
the study, the authors used wavelengths of 780 and 830 nm
and power of 1000 and 3000 mW in 5 daily sessions last-
ing 10 min each. Pain (through the visual analog scale,
VAS), functional status, and severity of symptoms (through
the Boston Carpal Tunnel Questionnaire, BCTQ) were
performed before treatment, 10 days and 3 months after.
The results showed better effects of FM on both pain and
functional status compared to LLLT. The improvement of
functional status and reduction in symptom severity were
observed only at the end of treatment in the group treated
with LLLT, not being sustained at the 3-month follow-up
after treatment. The authors concluded, then, that FM was
more effective than LLLT for patients with CTS [23].
Different (and therefore positive) findings were observed
in a study that investigated the long-term efficacy of LLLT
[24]. The study evaluated the results of LLLT applied to
patients with CTS and compared them with those of another
therapeutic method: pulsed magnetic field (PMF) (whose
details are beyond the scope of this review). Parameters
adopted in the study are as follows: wavelength, 904 nm;
frequency, 10,000 Hz; total energy per treatment, 50 J. The
application time was 5 min and 33 s, precisely, which was
lower than that of the PMF, which was 15 min (and fre-
quency of 10 to 40 Hz; much lower than that of LLLT).
Clinical evaluation was performed in the following stages:
before treatment; after the first grade; after a 2-week interval
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Table 2  Pro-regenerative effects Lesioned nerve Results Reference

of low-level laser therapy
Median nerve (humans) ↑ Sensory conduction speed [22]
Median nerve (humans) Inferior to fascial manipulation [23]
↓ severity of symptoms and ↑ functional status (BCTQ)
Median nerve (humans) ↓ Pain and paresthesia (day and night) [24]
↓ Phalen Symptoms
Median-ulnar mixed nerve (humans) ↓ Pain, symptom severity and functional status scales [25]
↑ Grip and Pinch strength
↓ Distal sensory and motor latency
↑ CMAP and SNAP amplitude
Median nerve (humans) ↓ Pain [26]
↓ SNAP latency
↓ CMAP latency
↑ CMAP conduction speed
↑ CMAP and SNAP amplitude
Median nerve (humans) ↓ Pain [27]
↓ Median distal motor latency
↑ Median sensory nerve conduction speed
Ulnar nerve (humans) ↓ Pain [28]
↑ Grip strength
↓ Short segment conduction latency
Sciatic nerve ↑ Functionality (IFC; 3 e 8 J/cm2) [21]
(Sprague–Dawley Rats) ↑ Range of motion (8 J/cm2)
↑ Myelin sheath thickness
↑ Levels of GAP43 (3 e 8 J/cm2)
Sciatic nerve ↑ Nerve regeneration (10 J/cm2) [30]
(Wistar Rats)
Sciatic nerve ↑ Neuromuscular recovery [31]
(Wistar Rats) (660 nm a 10 or 60 J/cm2)
Sciatic nerve ↑ MMP-2 [32]
(Wistar Rats) ↑ Neuromuscular recovery
↑ Mechanical resistance
Sciatic nerve ↑ NGF e BDNF (RNAm) [33]
(Wistar Rats) ↓ iNOS activity
Sciatic nerve ↑ Functionality (IFC, Tibial e Fibular) [34]
(Sprague–Dawley Rats) ↓ HIF-1α, TNF-α e IL-1β
↑ VEGF, NGF e S100
Sciatic nerve Lack of significant results [35, 36]
(Wistar Rats)
Sural nerve ↑ Peripheral axonal regeneration [17]
(Wistar Rats) (associated with fibrin glue)
Sciatic nerve ↑ Functionality (IFC) [37]
(Sprague Dawley-Rats) ↑ CMAPs
↑ Number of axons
↑ Axonal diameter
↑ Myelin sheath thickness
Sciatic nerve ↑ S100 [38, 39]
(Wistar Rats/Sprague–Dawley Rats) ↑ Functionality (IFC)
↓ Muscle Atrophy
↑ Diameter and quantity of axons
↑ Myelin sheath thickness
↑ Reinnervation rate
↑ Neuromuscular recruitment
Sciatic nerve ↑ Functionality (IFC) [40]
(Sprague Dawley-Rats) ↑ Nerve regeneration
↑ Area of neural tissue
↑ Axonal diameter
↑ Myelin sheath thickness

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Neurological Sciences

Table 2  (continued) Lesioned nerve Results Reference

Dorsal root ganglion L4–L5 ↓ Mechanical and thermal hyperalgesia [41]
(Sprague–Dawley Rats) ↓ TNF-α
↓ IL-1β
↑ GAP-43

GAP43, growth-associated protein 43; DRG, dorsal root ganglion; TNF-α, tumor necrosis factor α; MMP-2,
matrix metalloproteinase 2; mRNA, messenger ribonucleic acid (RNA); BDNF, brain-derived neurotrophic
factor; NGF, neural growth factor; iNOS, inducible isoform of nitric oxide synthase; HIF-1α, hypoxia-
induced factor 1-alpha; IL-1β, interleukin-1beta; VEGF, vascular endothelial growth factor; S100, saturated
solution soluble protein (100%) ammonium sulfate; CMAPs, compound muscle action potentials; P1, natu-
ral latex protein; SCSS, a sensitive and specific diagnostic test for ulnar nerve compression; BCTQ, Boston
Carpal Tunnel Questionnaire; SFI, Sciatic Functional Index; SNAP, sensory nerve action potential

between sets; after the second grade; and, finally, 6 months
after the second grade. Both the first and second series were
composed of 10 sessions, performed 5 times a week for
2 weeks. The authors observed clinical improvement after
treatment with LLLT or PMF, with a significant reduction in
pain and daytime and nocturnal paresthesia at each stage of
treatment. A reduction in Phalen symptoms (median nerve
compression) was also observed, with significant improve-
ment only in the group treated with LLLT [24].
A double-blinded randomized controlled study analyzed
the efficacy of LLLT in sixty-six patients with mild to mod-
erate CTS (diagnosed by clinical exams and electrodiagno-
sis; classified by nerve conduction studies (NCS) and the
guidelines of the American Association of Electrodiagnostic
Medicine). The patients were randomly allocated into two
groups: one received the LLLT, and the other received a
placebo treatment, both with a neutral wrist splint. In the
LLLT group, 15 sessions of a gallium-aluminum-arsenide
laser treatment at a dosage of 18 J per session (wavelength
of 810 nm and a power output of 50 mW) over the carpal
tunnel area were used. For evaluation, the following param-
eters were used: VAS for pain, SSS, FSS, and pinch and grip
strength (clinical parameters); NCS were performed with
a Medelec Synergy electrodiagnostic device: distal sen-
sory latency (DSL), sensory nerve action potential (SNAP)
amplitude, distal motor latency (DML), compound muscle
action potential amplitude (CMAP) (electroneurophysiologi-
cal parameters). The results showed that the LLLT-treated
group had significantly more evident improvements. Spe-
cifically, the authors concluded that both LLLT and splints
improved the clinical parameters, but LLLT was electroneu-
rophysiologically superior to splints with regard to the con-
duction of the median motor nerve fibers. As a limitation of
the study, they mentioned that the patients’ responses may
differ from different kinds and varying magnitude of wrist-
hand activities [25].
Another study, also with positive results, compared the
dose-dependent effect of LLLT and high intensity laser ther-
apy (HILT) regarding pain and electrophysiological studies,
in patients with moderate CTS confirmed by the evaluation
of sensory and motor fibers by electroneuromyography. In
this trial, participants were divided into five groups: LLT
with low fluency (50 mW- 8 J/cm2), LLT with high fluency
(50 mW- 20 J/cm2), HILT with low fluency (1/6 W- 8 J/cm2),
HILT with high fluency (50 mW-20 J/cm2), and control
group. All groups received standardized exercises, with the
first four, undergoing five laser therapy sessions for 2 weeks.
In the LLLT groups, the authors used the following param-
eters: laser with an average power of 50 mW, wavelength
860 nm, frequency of 10 Hz, duration of exposure of 32
or 76 s per point (total of 10 points). Pain was assessed by
VAS and studies of conduction of the median nerve (CMAP,
CMAP latency, conduction velocity, amplitude, SNAP) by
an electroneuromyography device conducted by a neurolo-
gist, both were assessed before and after 3 weeks of the
treatment. The reduction in pain was observed in all groups,
but it was greater in the laser therapy groups, with empha-
sis in the HILT group. In relation to electrophysiological
studies, CMAP latency decreased in all groups, with greater
decreases, in the HILT group when compared to the other
groups, the CMAP conduction speed increased in the HILT
groups, the CMAP and SNAP amplitude increased in all
groups, except the control, and, finally, the SNAP latency
decreased in all groups, except in the control. The conclu-
sions were that both laser therapies improve electrophysi-
ological studies and reduce pain in these patients, with bet-
ter effects seen with HILT. The absence of control groups
without interventions, the lack of long-term evaluation, and
the non-evaluation of functional and ultrasound aspects were
some of the limitations of this study [26].
Positive results were also found in a double-blind
placebo-controlled study which included seventy-nine
patients with mild to moderate CTS (less than a year of
symptoms), proven by clinical symptoms, ENM, and NCS.
Patients were separated into two groups: experimental and
control groups. Both groups were instructed to perform
nerve and tendon gliding exercises during the study period
and underwent 20 sessions for 5 weeks (in the case of
the control group with the laser off). In the active laser
group, the following parameters were adopted: GaAIAs

13

Table 3  Parameters and protocols adopted in each study
Reference Parameters
[22] Wavelength: 830 nm
Energy density: not reported
Total energy emitted: 3 or 6 J
Stimulus duration per point: 1 or 2 min
Duration of a session: 5 or 10 min
[23] Wavelength: 780 and 830 nm
Energy density: not reported
Total energy emitted: not reported
Duration of stimulus per point: not reported
Duration of a session: 10 min
[24] Wavelength: 904 nm
Energy density: 6 J/cm2
Total energy emitted: 50 J
Stimulus duration per point: 200 ns
Duration of a session: 5 min and 33 s
[25] Wavelength: 810 nm
Energy density: not reported
Total energy emitted: 270 J
Stimulus duration per point: not reported
Duration of a session: not reported
[26] Wavelength: 860 nm
Energy density: 8 or 20 J/cm2
Total energy emitted: not reported
Stimulus duration per point: 32 s or 76 s
Duration of a session: not reported
[27] Wavelength: 780 nm
Energy density: 2.7 to 3.4 J/cm2/point
Total energy emitted: not reported
Stimulus duration per point: 80 s
Duration of a session: not reported
[28] Wavelength: 905 nm
Energy density: 0.8 j/cm2
Total energy emitted: not reported
Stimulus duration per point: 30 s
Duration of a session: not reported
13
Neurological Sciences
Protocol
Session frequency: 5 times a week for 15 days
Analysis period: 1st and 15th days of treatment
Power: 50 mW
Power density: not reported
Area per point: not reported
Application points: 5
Mode: continuous
Session frequency: 5 sessions per day (total time not reported)
Period of analyses: before treatment. (T0), 10 days after the last treat. (T1) and
3 months after the last treat
Frequency: not reported
Power: 1000 and 3000 mW
Power density: not reported
Area by point: not reported
Application points: not reported
Mode: not reported
Frequency of sessions: 1st grade (10 sessions, 5 times a week for 2 weeks); after
2-week break: 2nd grade (10 sessions, 5 times a week for 2 weeks)
Period of the analyses: before, after the 1st grade, after an interval of 2 weeks,
after the 2nd grade, and after 6 months of the last series
Frequency: 10,000 Hz
Power: 150 mW
Power density: not reported
Area by point: not reported
Application points: not reported
Mode: pulsed
Frequency of sessions: 3 times per week for 5 weeks; 15 sessions in total
Frequency: not reported
Power: 50 mW
Power density: not reported
Area by point: not reported
Application points: not reported
Mode: continuous
Frequency of sessions: five sessions for 2 weeks
Frequency: 10 Hz
Power: 50 mW
Power density: not reported
Area by point: not reported
Application points: 10
Mode: not reported
Frequency of sessions: 20 sessions for 5 weeks
Frequency: not reported
Power: 30 mW
Power density: 38,2 mW/cm2
Area by point: 0.785 c­ m2
Application points: 4
Mode: continuous
Frequency of sessions: 5 times a week for 2 weeks
Frequency: not reported
Power: 25 mW
Power density: not reported
Area by point: not reported
Application points: 4
Mode: pulsed
Neurological Sciences

Table 3  (continued)
Reference Parameters Protocol

[21] Wavelength: 808 nm Frequency of sessions: daily for 20 days

Energy density: 3; 8 or 15 J/cm2 Analysis period: 20 days after injury
Total energy emitted: not reported Frequency: not reported
Stimulus duration per point: 67.2; 179; or 335.6 s Power: 170 mW
Duration of a session: not reported Power density: 44.7 mW/cm2
Area per point: 3.8 ­cm2
Application points: not reported
Mode: continuous
[30] Wavelength: 780 nm Session frequency: 6 sessions on alternate days
Energy density: 4; 10 or 50 J/cm2 Analysis period: 2 weeks after injury
Total energy emitted: 0.48; 1.2 or 6 J Frequency: not reported
Stimulus duration per point: 4; 10 or 50 s Power: 40 mW
Duration of a session: not reported Power density: 1 W/cm2
Area per point: 0.04 ­cm2
Application points: 3
Mode: continuous
[31] Wavelength: 660 or 780 nm Frequency of sessions: daily for 10 days
Energy density: 10, 60 or 120 J/cm2 Period of analysis: after 28 days of injury
Total energy emitted: 8; 48 or 96 J Frequency: not reported
Stimulus duration per point: 0.3; 1 or 2 min Power: 40 mW
Duration of a session: not reported Power density: not reported
Area per point: 4 ­mm2
Application points: 2
Mode: continuous
[32] Wavelength: 830 nm Frequency of sessions: daily for 21 days
Energy density: 35; 70; 140 or 280 J/cm2 Analysis period: before, 7, 14, and 21 days after injury
Total energy emitted: 3.3; 6.6; 12.12 or 24.24 J Frequency: not reported
Stimulus duration per point: 11, 22, 44 or 88 s Power: 100 nW
Duration of a session: not reported Power density: 3086.4 nW/cm2
Area per point: 0.0324 ­cm2
Application points: 3
Mode: continuous
[33] Wavelength: 632.8 nm Frequency of sessions: Daily for 7, 14, and 21 days
Energy density: 10 J/cm2 Analysis period: 7, 14, and 21 days after injury
Total energy emitted: not reported Frequency: not reported
Stimulus duration per point: 20 s Power: 5 mW
Duration of a session: not reported Power density: 0.5 mW/cm2
Area per point: 0.10 ­cm2
Application points: 10
Mode: continuous
[34] Wavelength: 660 nm Frequency of sessions: daily for 7 days
Energy density: 9 J/cm2 Period of analysis: before, immediately after and 7, 14 days after injury
Total energy emitted: not reported Frequency: not reported
Stimulus duration per point: 60 s Power: 30 mW
Duration of a session: not reported Power density: not reported
Area per point: 0.2 ­cm2
Application points: 4
Mode: continuous
[35] Wavelength: 780 nm Session frequency: 6 sessions on alternate days
Energy density: 15 J/cm2 Analysis period: 4 and 8 weeks after injury
Total energy emitted: 1.8 J Frequency: not reported
Stimulus duration per point: 20 s Power: 30 mW
Duration of a session: not reported Power density: 0.75 W/cm2
Area per point: 0.04 ­cm2
Application points: 3
Mode: continuous

13

Table 3  (continued)
Reference Parameters
[36] Wavelength: 780 nm
Energy density: 15 J/cm2
Total energy emitted: 1.8 J
Stimulus duration per point: 20 s
Duration of a session: not reported
[17] Wavelength: 830 nm
Energy density: 4 J/cm2
Total energy emitted: not reported
Stimulus duration per point: 16 s
Duration of a session: not reported
[37] Wavelength: 660 nm
Energy density: 3.84 J/cm2
Total energy emitted: 15 J
Duration of stimulus per point: not reported
Duration of a session: 5 min
[38, 39] Wavelength: 660 nm
Energy density: not reported
Total energy emitted: not reported
Stimulus duration per point: 2 min
Duration of a session: not reported
[40] Wavelength: 660 nm
Energy density: 5.76 or 0.96 J/cm2
Total energy emitted: not reported
Duration of stimulus per point: not reported
Duration of a session: 30 min or 5 min
[41] Wavelength: 808 ± 5 nm
Energy density: 0 or 8 J/cm2
Total energy emitted: not reported
Stimulus duration per point: 207 s
Duration of a session: not reported
diode laser, 780 nm, 30 mW with continuous waves, 0.785
­c m 2, 38.2 mW/cm 2, 90 s per point (4 points—2.7 J, 3,
4 J/cm2/point). Clinical and NCS aspects were assessed
at baseline and 3 weeks after treatment. The first included
pain assessment using VAS, provocative maneuvers (Hoff-
man and Tinnel’s sign); the second, median distal motor
latency (MDL) and median sensory nerve conduction
speed (SNCV). The results were a decrease in pain in
both groups, but with a statistically significant difference
13
Neurological Sciences
Protocol
Session frequency: 6 sessions on alternate days
Analysis period: 4 and 8 weeks after injury
Frequency: not reported
Power: 30 mW
Power density: 0.75 W/cm2
Area per point: 0.04 ­cm2
Application points: 3
Mode: continuous
Session frequency: 3 times a week for 5 weeks
Period of analysis: after 10 weeks of injury
Frequency: not reported
Power: 30 mW
Power density: not reported
Area per point: 0.116 ­cm2
Application points: 3
Mode: continuous
Frequency of sessions: daily for 21 days
Period of analysis: after 8 weeks of injury
Frequency: 50 Hz
Power: 50 mW
Power density: 0.0032 W/cm2
Area per point: 314 ­cm2
Application points: not reported
Mode: continuous
Frequency of sessions: daily for 10 days
Analysis period: 12 weeks after injury
Frequency: not reported
Power: 50 mW
Power density: not reported
Area per point: 0.1 ­cm2
Application points: 2
Mode: continuous
Frequency of sessions: daily for 9 days
Analysis period: 12 weeks after implantation
Frequency: not reported
Power: 50 mW
Power density: not reported
Area per point: 314 ­cm2
Application points: not reported
Mode: continuous
Frequency of sessions: daily for 8 days
Analysis period: 4th and 8th days after injury
Frequency: not reported
Power: 190 mW
Power density: 380 mW/cm2
Area per point: 0.5 ­cm2
Application points: not reported
Mode: continuous
between the groups and greater reductions in the experi-
mental group; as for clinical signs, they were less evi-
dent and no statistical differences were found between
the groups. In relation to conduction studies, there was a
decrease in the MDL in the experimental group and the
SNCV increased in both groups, but with a statistically
greater increase in the experimental one. The short follow-
up period was one of the limitations mentioned by the
authors, but the absence of a group without intervention
Neurological Sciences
was also a limitation in this case, although the article
claims to be a placebo-controlled study [27].
Unlike the articles previously discussed, in a sim-
ple-blind randomized study, the peripheral neuropathy
addressed was Ulnar Nerve Entrapment at the elbow
(UNE). Thirty-two patients with motor and sensory
impairment and diagnosis confirmed by clinical and elec-
trophysiological studies were divided into two treatment
groups: ultrasound (US) and LLLT. Both groups per-
formed 5 sessions per week for 2 weeks and were assessed
at the beginning of the study, one and 3 months after.
The evaluation included Tinel’s signal, VAS, handgrip
strength, Semmes Weinstein (SW) monofilament, patient
satisfaction scale and short segment conduction study
(SCSS), in which the latencies of the motor and sensory
components were observed. Regarding the laser group, the
parameters were 905 nm, 25 mW, 0.8 j/cm2, and 30 s per
point (4 points). As for the results, VAS score decreased
only in the first month for the LLLT group, while in the
US group, this remained in the third month; gain of hand-
grip strength occurred in both groups without statistical
difference between them; SSCS, reduction in latency, was
also observed in both groups; SW monofilament test, there
was an improvement only in the US group, and, finally,
patient satisfaction was greater in the US group. Authors
concluded that both methods had satisfactory efficacy in
patients with UNE, in the short term. The limitations of
this study were the absence of a control group, the small
sample size, and disparities between the groups in terms
of grip strength and monofilament, which requires greater
care in analyzing the results of the study, especially when
comparing the two treatments [28].
LLLT in animal models
Studies conducted with experimental animals have evalu-
ated functional, histological, morphological, and electro-
physiological aspects of LLLT, providing evidence of its
beneficial effects on nerve regeneration after injury [29].
Axonal regeneration was investigated in a study in which
the thickness of the myelin sheath of the sciatic nerve of
rats was measured and the expression of the protein asso-
ciated with growth 43 (GAP43) was analyzed [21]. This
pro-regenerative protein is highly expressed during the ini-
tial periods of ontogenetic development, but its expression
becomes greatly reduced in adulthood, except in peripheral
neurons. The results indicated that the application of LLLT
(808 nm at 3 and 8 J/cm2 for 20 days) favored the regenera-
tion of the sciatic nerve; however, the optimal duration of
treatment and the long-term effects of LLLT has not been
evaluated.
LLLT at different energy densities
In another study [30], the morphological and morphomet-
ric effects of LLLT applied to rats at three different energy
densities (4.10 and 50 J/cm2) on sciatic nerve regeneration
were investigated. The animals were allocated into five
groups (C, wounded group; L0, with lesion and without
irradiation; L4, nerve injury with LLLT at 4 J/cm2; L10,
nerve injury with LLLT at 10 J/cm 2; L50, nerve injury
with LLLT at 50 J/cm2) being the LLLT parameters char-
acterized by a wavelength of 780 nm, a power of 40 mW,
and an area per point of 0.04 ­c m 2 over three points of
the injured nerve region: the proximal, distal, and cen-
tral regions of the lesion. Two weeks after the injury, the
findings revealed that LLLT induced improvement in all
energy densities used, with the energy density of 10 J/
cm2 being the most effective treatment for sciatic nerve
regeneration after crushing [30].
The effects of LLLT with energy densities of 10, 60, and
120 J/cm2 combined with wavelengths of 660 and 780 nm
were evaluated on neuromuscular and functional recovery
of the sciatic nerve of rats [31]. The authors observed that
LLLT with low (10 J/cm2) or moderate energy densities
(60 J/cm2) at a wavelength of 660 nm for 10 consecutive
days was able to accelerate neuromuscular recovery 28 days
after injury by crushing the sciatic nerve of rats. The study
also investigated the activity of matrix metalloproteinase
(MMP), considering that to be successful in regeneration,
the action of proteolytic enzymes that play a critical role
in the reorganization of the extracellular matrix (ECM) is
required. The results were positive and revealed acceleration
in the remodeling of the ECM via MMP-2 and -9; however,
it was unable to amplify functional restoration after crush-
ing injury [31].
Increased MMP-2 activity and neuromuscular restoration
of the sciatic nerve were observed in a study that analyzed
the level of MMP-2 activation of the anterior tibial mus-
cle, gait functionality (Sciatic Functional Index), and bio-
mechanical resistance (determined by the maximum load
supported by the anterior tibial muscle until its rupture)
[31]. LLLT was applied at a wavelength of 830 nm at dif-
ferent energy densities (35, 70, 140, and 280 J/cm2) for 21
consecutive days. Functional results revealed a progressive
improvement in gait (~ 60%) 3 weeks after the injury; this
happens to all groups submitted to crushing injury of the
sciatic nerve and treated with LLLT on the 21st day (regard-
less of the energy density used). All treated groups showed
a superior functional improvement compared to the groups
that did not receive the treatment. The maximum load until
the rupture of the anterior tibial muscle on the 21st day was
significantly higher in all irradiated groups, thus revealing
that LLLT stimulated the neuromuscular recovery process.
The authors reported that LLLT was able to promote the
13

regeneration of the anterior tibial muscle and stimulate the
activity of MMP-2 [32].
Effects of LLLT on anti‑apoptotic molecules
and inflammatory process
In addition to MMP-2, antiapoptotic molecules, known as
neurotrophic factors, such as nerve growth factor (NGF) and
brain-derived neurotrophic factor (BDNF), are capable of
playing an important role in the process of axonal regen-
eration, since they are directly associated with the promo-
tion of neuronal survival. It is known that complete nerve
regeneration depends on trophic conditions which are highly
favorable to neuronal protein synthesis, and neurotrophic
factors represent, therefore, one of the factors that contrib-
ute to the pro-regenerative microenvironment. Through
its photochemical and photobiological effects produced at
the cellular level, it has been shown that LLLT can favor
the development of pro-regenerative trophic conditions by
increasing the expression of neurotrophic factors and may
also inhibit the inflammatory process. Using LLLT with a
wavelength of 632.8 nm and an energy density of 10 J/cm2,
a higher expression of BDNF and NGF mRNA was observed
after 14 days of LLLT, with peak expression on the 21st day
after injury, in addition to inhibition of nitric oxide synthase
(iNOS), but without significant changes in the expression of
neurotrophin-3 mRNA [33].
LLLT and neuropathic pain
LLLT also promoted important modulatory effects on
hypoxia-induced factor 1α (HIF-1α), TNF-α, and IL-1β [33].
The authors demonstrated that these molecules controlled
neuropathic pain by favoring the activation of vascular
endothelial growth factor (VEGF) and NGF, after a chronic
constrictive injury in animals. They used LLLT with a wave-
length of 660 nm and energy density of 9 J/cm2 for 7 days
after injury. The findings revealed a potentially applicable
approach to clinical practice aiming at reducing hypoxia and
tissue inflammation in neuropathic conditions [34].
LLLT and natural latex protein (F1)
The expressions of VEGF and NGF factors as well as the
ultrastructural morphology of the injured sciatic nerve were
investigated after the application of LLLT associated with
natural latex protein (F1) four and 8 weeks after injury [35].
The animals were allocated into six groups: control (ani-
mals only anesthetized), exposed (anesthetized animals and
submitted to sciatic nerve exposure), injury (anesthetized
animals and submitted to sciatic nerve crushing), LLLT
(anesthetized animals, submitted to crushing of the sciatic
nerve, and treated with LLLT), F1 (anesthetized animals,
13
Neurological Sciences
subjected to crushing of the sciatic nerve followed by the
application of local F1 protein), and LLLT associated with
F1 (animals that received both interventions). The treat-
ment was performed with LLLT at a wavelength of 780 nm,
energy density of 15 J/cm2, and power of 30 mW in a total
of six sessions on alternate days. Four weeks after the injury,
the analyses showed that only the F1 group presented low
NGF expression and better morphological characteristics,
with more densely organized axons and that VEGF expres-
sion was significantly higher in the lesion groups: F1 and
F1 associated with LLLT. Eight weeks after the injury, the
expression of NGF in the injured groups decreased; mor-
phological characteristics were more similar to non-injured
groups and VEGF expression remained high only in groups
receiving F1 protein (F1 and F1 associated with LLLT). In
this sense, the authors argued that the interaction between
F1 protein and LLLT was negative since the results observed
in the groups receiving LLLT (LLLT and F1 associated with
LLLT) were worse compared to the F1 group [35].
Previously, the authors had investigated the effect of
LLLT associated with F1 protein on injured sciatic nerves
of rats [36] allocated in groups in the same way and using
the same LLLT parameters as the most recent study, but
under morphometric analysis and high-resolution scanning
microscopy. The treatments proposed with LLLT and F1
protein resulted in improvement of axonal characteristics
after injury: increased thickness of myelin sheath and better
axonal organization, more compactly and with larger dimen-
sions. The recovery of the lesion was time-dependent, since
the injured groups presented better results 8 weeks after the
injury, compared to those observed after 4 weeks. Morpho-
metric data revealed that the group that received only F1
protein exhibited better characteristics when compared to
the other injured groups both 4 and 8 weeks after the injury,
regardless of whether it was associated with LLLT. Besides,
the group treated only with LLLT presented similar results
to the injured group that did not receive treatment. In this
context, the authors suggested that treatment with F1 protein
was higher (it achieved better results), and the treatment with
LLLT failed to achieve positive results [36].
LLLT associated with guides for axon growth
Positive results were found in a study in which LLLT was
applied at a longer wavelength (830 nm) and combined
with the use of fibrin glue derived from snake venom [17].
Three different application points were selected through-
out the surgical site; the application of LLLT was done
1 day after surgery and for 5 weeks in the postoperative
period, at an energy density of 4 J/cm2 and exposure time of
16 s per point [17]. After 10 weeks, transmission electron
microscopy analyses revealed the presence of regenerated
axons, mainly myelinated ones [17]. In another study, the
Neurological Sciences
application of LLLT to rats was associated with the use of a
guide (biodegradable conduit) for axonal growth. Histomor-
phometric evaluations revealed that tissue regeneration was
qualitatively and quantitatively superior in the group treated
with LLLT compared to the group irradiated by simulation.
Laser irradiation was performed at a wavelength of 660 nm
and an energy density of 3.84 J/cm2 for 5 min daily for 21
consecutive days and covered an extensive area of the sciatic
nerve (314 ­cm2) [37].
Two years later, the authors proposed a new combination
of parameters for LLLT, also associating it with the use of a
guide (biodegradable conduit) for axonal growth [38]. The
study developed a biodegradable composite (GGT conduit),
genipin cross‐linked gelatin annexed with β‐tricalcium phos-
phate (β‐TCP) ceramic particles to increase the mechani-
cal strength as a nerve guidance channel‐material for axon
regeneration. The authors used the same wavelength as the
previous study (660 nm), but with a shorter application time
(2 min) and treatment (10 consecutive days), over a smaller
area (0.1 ­cm2) in the rat sciatic nerve. The results showed
significant improvement in motor function: there was an
increase in functionality (calculated through the Sciatic
Functional Index), in electrophysiological reactions (evalu-
ated by gastrocnemius muscle response to electrical stimu-
lation at the proximal end of the grafts), and in the amount
of protein soluble in saturated solution (S100); and there
was also a reduction in muscle atrophy and more compact
and complete neural histomorphometric recovery compared
to the animals in the placebo group (simulated irradiation).
These data supported the authors’ hypothesis that LLLT
facilitates the recovery of injured nerves. The combination
of LLLT with the biodegradable conduit accelerated the
reinnervation rate and improved muscle recruitment [38].
In the same year, the authors [39] proposed a novel bio-
degradable nerve conduit comprising 1‐ethyl‐3‐(3‐dimeth-
ylaminopropyl) carbodiimide (EDC) cross‐linked gelatin,
annexed with β‐tricalcium phosphate (TCP) ceramic parti-
cles (EDC‐Gelatin‐TCP, EGT). On the implant site, LLLT
was applied at a wavelength of 660 nm and a power of 50
mW to verify its influence on the regeneration of the sciatic
nerve of rats. The animals were divided into three groups:
a control group submitted to autologous nerve graft (auto-
graft); a group that received LLLT in a simulated manner
and an experimental group submitted to laser stimulation.
Treatment was performed on two points of the surgical inci-
sion for 2 min daily for 10 consecutive days. After 12 weeks
of implantation, motor function, electrophysiological reac-
tion, muscle reinnervation, and histomorphometric evalu-
ations demonstrated that LLLT improved peripheral nerve
repair by 15 mm in rats after bridging with EGT, leading
to the conclusion that the combination of LLLT with EGT
can accelerate the reinnervation rate and improve muscle
recruitment [39].
The same conduit was investigated [40] using LLLT with
the same wavelength of 660 nm and power of 50 mW on
the sciatic nerve of rats allocated in the same distribution of
groups previously described. However, other parameters were
determined for LLLT: immediately after the surgical procedure
of conduit implantation, an extensive area of the injured nerve
(314 ­cm2) was irradiated at an energy density of 5.76 ­cm2 for
30 min and, subsequently, a smaller energy density (0.96 J/
cm2) in a shorter time (5 min) was applied for nine consecutive
days. Twelve weeks after the surgical procedure, functional
and histomorphometric analyses revealed an increase in the
sciatic functional index, faster nerve regeneration, larger neural
tissue area, larger axon diameter, and thicker myelin sheath in
the group that received the conduit and LLLT compared to the
group that was only submitted to the surgical procedure [40].
Possible pro‑regenerative mechanisms of LLLT
Using similar protocols, some studies have indicated that
there are no significant differences concerning the time of
use of LLLT as a facilitator of axonal regeneration. Other
beneficial effects attributed to the use of LLLT are linked
to its ability to induce the proliferation of SC, increasing
the remyelination capacity. The pro-regenerative efficacy of
LLLT was also evaluated in dorsal root ganglia (DRG) neu-
rons, more specifically in L4 and L5 roots [41]. An L-shaped
needle was inserted into the intervertebral foramen of L4 and
L5. After removal, a stainless-steel rod was inserted along
the needle path to produce a constant compression against
DRG L4 and L5. The parameters adopted for LLLT were as
follows: wavelength, 808 ± 5 nm; power, 190 MW; area per
point, 0.5 ­cm2; stimulus duration, 207 s. Rats were allocated
in control and experimental groups which in turn were ran-
domly divided into two subgroups: one placebo subgroup
(not submitted to LLLT) and another subgroup treated with
LLLT at 8 J/cm2. The animals received (or not) LLLT for 4
or 8 consecutive days after the injury, with half of the rats
in each group being sacrificed on the 4th day, and the other
half, on the 8th day after injury. These findings indicated a
decrease in mechanical and thermal hyperalgesia, reduction
in pro-inflammatory cytokines (TNF-α and IL-1β), and an
increase in GAP-43 expression in the group treated with
LLLT (both on the 4th and 8th day), suggesting that the
therapeutic effects of LLLT on DRG seem to involve the
suppression of the inflammatory response and the induction
of genes of neuronal repair [41].
Conclusion and perspectives
The efficacy of LLLT has been tested in a number of animal
models studies—most of them performed on rats submit-
ted to sciatic nerve injury—and some evidence of positive
13

effects has been achieved (LLLT optimizes regeneration of
peripheral axons, improving motor function). The animal
models findings are, therefore, promising, although elucida-
tion of the mechanisms of action and safety assessment are
relatively scarce. Clinical studies with high methodological
quality are quite necessary to provide evidence of clinical
efficacy and effectiveness of different electrostimulation
parameters. Systematic reviews and meta-analyses will then
be capable of evaluating the relevance of the published clini-
cal trials and define whether and which parameters generate
robust and reproducible positive effects, thereby circum-
venting two remaining obstacles: the great discrepancy of
parameters found in the literature and the still questionable
clinical efficacy of LLLT.
Acknowledgements Consejo Nacional de Ciencia y Tecnología (CON-
ACYT) is thankfully acknowledged for partially supporting this work
under Sistema Nacional de Investigadores (SNI) program awarded
to Hafiz M.N. Iqbal (CVU: 735340). The listed author(s) thankfully
acknowledge the literature access provided by their respective institu-
tions/ organizations.
Declarations
Conflict of interest The authors declare no competing interests.
Ethical approval None.
Informed consent statement Not applicable.
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