Photobiomodulation Therapy (PBMT) in Peripheral Nerve Regeneration: A Systematic Review

Photobiomodulation therapy (PBMT) has been investigated because of its intimate relationship with tissue recovery processes, such as on peripheral nerve damage. Based on the wide range of benefits that the PBMT has shown and its clinical relevance, the aim of this research was to carry out a systematic review of the last 10 years, ascertaining the influence of the PBMT in the regeneration of injured peripheral nerves. The search was performed in the PubMed/MEDLINE database with the combination of the keywords: low-level laser therapy AND nerve regeneration. Initially, 54 articles were obtained, 26 articles of which were chosen for the study according to the inclusion criteria. In the qualitative aspect, it was observed that PBMT was able to accelerate the process of nerve regeneration, presenting an increase in the number of myelinated fibers and a better lamellar organization of myelin sheath, besides improvement of electrophysiological function, immunoreactivity, high functionality rate, decrease of inflammation, pain, and the facilitation of neural regeneration, release of growth factors, increase of vascular network and collagen. It was concluded that PBMT has beneficial effects on the recovery of nerve lesions, especially when related to a faster regeneration and functional improvement, despite the variety of parameters.


Introduction
Low-level laser therapy (LLLT), now commonly referred to as photobiomodulation therapy (PBMT), using low-level infrared light spectrum lasers is considered a therapeutic advance. Its effects are related to tissue biostimulation, presenting therapeutic responses from photoelectric, photoenergetic, and photochemical reactions [1]. Scientific research has shown the application of PBMT in bone tissue and peripheral nerves with good results whether or not it is associated with other supporting methods in tissue repair [2][3][4][5][6][7].
Laser photobiomodulation presents itself as an electromagnetic technology that is being inserted into clinical practice due to its characteristics that differ from other conventional thermal sources [8,9]. It was observed that there are several features of PBMT that are related to the reduction of tissue repair time and its capacity to increase cell proliferation [10].
In rehabilitative health, PBMT was inserted to promote the repair and recovery of tissues. For example, in physical therapy, the use of PBMT is applied in postoperative phases as an aid in the muscular, nervous, joint, and other functional recovery processes, and in dentistry it is applied in the processes of dental extraction, grafting, osteonecrosis, and periodontal lesions [11][12][13].
The wavelength of infrared irradiation is easily absorbed by tissues and the loss of intensity is minimal, affecting metabolic modifications, DNA activity, adenosine triphosphate (ATP) formation, and the mitochondrial chain. The effect of photobiomodulation is due to the absorption of the photons by cytochrome C oxidase in the mitochondrial respiratory chain, consequently increasing the cytochrome C oxidase activity and therefore ATP formation. ATP from injured or regions of impaired blood perfusion can reactivate injured cells and metabolic disorders [10]. PBMT is also related to pain and inflammation relief and prevention of tissue death to avoid neurological degeneration [14,15].
The wavelength is the key point that regulates the depth and penetration of the laser irradiance in the tissue, noting that the absorption and dispersion coefficients are larger at the lower wavelengths. Regarding the type of wave, whether continuous or pulsed, there are still divergences in which is the best and for which factors are the pulse parameters to be chosen [16]. PBMT presents difficulties in selecting the most suitable parameters for its application due to the lack of standardization, since wavelength, power density, irradiation time, and light polarization have repercussions on the biological effects [9].
Due to the photochemical and photobiological effects of PBMT at the cellular level, there is a relationship between the improvement of trophic conditions and the reduction of inflammatory processes, closely related to a more efficient nervous regeneration and, also, promoting the secretion of neural factors [16,17]. Thus, photobiomodulation therapy in the neurological area acts as an adjuvant in the treatment of traumatic brain degeneration/injury, spinal cord trauma, and in the process of peripheral nerve regeneration.
Peripheral nerve lesions are a reality today, but there is a deficit in relating effective treatments for recovery of the nerves, resulting in considerable functional changes in the daily life of the individual. When injured, the nerve can lose its function, causing motor or sensitive deficits. There is retrograde axonal degeneration to the area of the lesion, so regeneration occurs slowly and sometimes incompletely [18,19].
At the end of the 80's, the scientific interest in the therapeutic approach of rehabilitation for neural lesions was initiated [20], due to the good results with the use of PBMT in the recovery of injured peripheral nerves but, until the present day, there are still difficulties related to the application parameters [19,20]. Its beneficial effects are independent of the repair technique, neurorrhaphy techniques, and the use of fibrin sealants [3,6,7,21].
PBMT leads to changes in important vascular levels such as elevation of the secretion of antiapoptotic factors in ischemic organs, providing a better wound healing [22,23]; the presence of angiogenesis when ischemic organs were injured [24,25]; a decrease in the site of infarction in rats; as well as elevation in neurological scores following embolic stroke in rats [26,27].
Due to the high range of benefits that PBMT has shown and its clinical relevance of application, the aim of this research was to carry out a systematic review of the scientific papers published in the last 10 years verifying the relation of PBMT with the regeneration of injured peripheral nerves.

Materials and Methods
A search was performed in the PubMed/MEDLINE database, combining low-level laser therapy AND nerve regeneration keywords, over the last 10 years and restricted to the English language. The next step was to restrict the verification and consultation of articles that used animals as a study object (non-human species).
We verified those articles that presented titles and summaries that approached the subject of this research, as well as methodology, results, and relevance for its practical application.
The articles included should necessarily be presented with full access to the text. The acquired texts were analyzed and synthesized in a reflexive way in order to obtain consistent information on the subject.

Results
Initially, 54 articles were obtained from the PubMed/MEDLINE database, of which 28 were excluded because they were not included in the search criteria (in English, study in animals, and full access to content). At the end, 26 articles related to the subject were included. Figure 1 schematizes the search system, according to PRISMA Flow Diagram [28].   On the sciatic nerve.
Application 1st day post-operatory during 10 successive days.
LLLT accelerated the nerve regeneration due to the larger neural tissue, larger diameter and thicker myelin sheath, motor function, electrophysiology and muscular innervation. On the sciatic nerve. 10 sessions every 10 days.
On the surgery site.
Sene et al. [48] GaAsAl LLLT associated to the F1 protein did not present positive results and did not potentialize the effects of this protein.

Discussion
With the evolution of the technology in the health field and the evolution of the adjunct methods for rehabilitation and functional restoration of injured nerves [3,[6][7][8][9], the PBMT has shown a wide range of benefits with clinical relevance. Thus, the aim of this research was to carry out a review of the scientific papers published in the last 10 years in order to verify the relation of PBMT in the regeneration of injured peripheral nerves. Regarding the varied benefits of PBMT, the highlight is the reduction of regeneration time and the aid in nerve function.
Among the effects of PBMT on nerve injury, it was verified that the laser minimized the side effects of bupivacaine on the nerve and on the muscle [29], potentiated the process of nerve regeneration observed by morpho-quantitative analysis of the axons and of the nerve fibers [2,3,19,[30][31][32][33][34][35], in addition to assisting muscular reinnervation [36].
Photobiomodulation in the nerve injury was also related to a decrease in inflammatory cytokine levels, in pain, and to the facilitation of neural regeneration, demonstrated by the levels of TNF-a, IL-1b, and GAP-43 [32,37].
It has been observed that the diversity of PBMT application protocols in nerve lesions is large, with the wavelength varying from 632.8 to 904 nm, a varied range of energy and energy density, in addition to the time of application, despite the similarity in the type of lesion targeted in each experiment. As shown, the infrared spectrum has good experimental results. The red spectrum (600 to 700 nm) [50] was seen in 15 studies with satisfactory morphological and electrophysiological results, immunological factors, and tissue markers [2,30,31,[33][34][35][36]38,39,[41][42][43][44]46,47]. It was also possible to verify the lack of standardization in relation to the application protocols, noting that 6 studies were discarded due to lack of data information regarding energy density and time of application of PBMT.
In a general critical analysis of the articles for the detailed study, a consensus was observed on the effectiveness of PBMT, with the use of low-level laser therapy on the improvement of the morphological and morphometric aspects of the regenerated peripheral nerve, as well as on the reduction of events inflammatory and painful sensitivity, providing faster and higher quality functional recovery [51,52].
In the perspective of new fronts of study, in the last decade, optogenetic and chemogenetic techniques have been used more frequently in the investigation of neuronal circuits, as well as in the study of non-neuronal cells in the brain and peripheral nerves. Optogenetics is effective in generating patterns that mimic neuron responses using a pulse generator that produces lights with different frequencies and pulse durations. Photostimulation can be performed in different subcellular regions, being useful for the study of neuronal circuits in the brain. Chemogenetics are less invasive in animal experiments and do not require the installation of a fiber optic cable into the brain or the connection of the cable to a light source, such as a laser or a light emitting diode (LED).

Conclusions
At the end of the present study, it can be seen that the data presented in the current articles helped us to understand the beneficial and helpful effects of photobiomodulation on regeneration and functionality after nerve injury. In spite of the great variety of parameters presented, great results were observed, mainly when related to the faster nervous regeneration process.

Conflicts of Interest:
The authors declare that they have no conflicts of interest.