Application of Fibrin Associated with Photobiomodulation as a Promising Strategy to Improve Regeneration in Tissue Engineering: A Systematic Review

Fibrin, derived from proteins involved in blood clotting (fibrinogen and thrombin), is a biopolymer with different applications in the health area since it has hemostasis, biocompatible and three-dimensional physical structure properties, and can be used as scaffolds in tissue regeneration or drug delivery system for cells and/or growth factors. Fibrin alone or together with other biomaterials, has been indicated for use as a biological support to promote the regeneration of stem cells, bone, peripheral nerves, and other injured tissues. In its diversity of forms of application and constitution, there are platelet-rich fibrin (PRF), Leukocyte- and platelet-rich fibrin (L-PRF), fibrin glue or fibrin sealant, and hydrogels. In order to increase fibrin properties, adjuvant therapies can be combined to favor tissue repair, such as photobiomodulation (PBM), by low-level laser therapy (LLLT) or LEDs (Light Emitting Diode). Therefore, this systematic review aimed to evaluate the relationship between PBM and the use of fibrin compounds, referring to the results of previous studies published in PubMed/MEDLINE, Scopus and Web of Science databases. The descriptors “fibrin AND low-level laser therapy” and “fibrin AND photobiomodulation” were used, without restriction on publication time. The bibliographic search found 44 articles in PubMed/MEDLINE, of which 26 were excluded due to duplicity or being outside the eligibility criteria. We also found 40 articles in Web of Science and selected 1 article, 152 articles in Scopus and no article selected, totaling 19 articles for qualitative analysis. The fibrin type most used in combination with PBM was fibrin sealant, mainly heterologous, followed by PRF or L-PRF. In PBM, the gallium-aluminum-arsenide (GaAlAs) laser prevailed, with a wavelength of 830 nm, followed by 810 nm. Among the preclinical studies, the most researched association of fibrin and PBM was the use of fibrin sealants in bone or nerve injuries; in clinical studies, the association of PBM with medication-related treatments osteonecrosis of the jaw (MRONJ). Therefore, there is scientific evidence of the contribution of PBM on fibrin composites, constituting a supporting therapy that acts by stimulating cell activity, angiogenesis, osteoblast activation, axonal growth, anti-inflammatory and anti-edema action, increased collagen synthesis and its maturation, as well as biomolecules.


Introduction
The word fibrin, in etymology, derives from the Latin 'fibre' (fiber) and -in (chemical substance). It can be defined as a protein formed in blood plasma from the action of thrombin on fibrinogen, being the main component of blood clots (that is, fibrin aggregating produces clots). Wound healing depends entirely on the initial mechanisms of tissue homeostasis. When an injury occurs, the first tissue to respond is blood, as bleeding is a potentially serious risk to the body. There is a cascade of molecular and cellular reactions that lead to the sealing of the vascular lesion with an aggregate of platelets, which stop the hemorrhage by forming a tampon in the injured tissue, triggering the next steps of tissue regeneration. Stable blood clot, containing cross-linked and polymerized fibrin, is essential to prevent bleeding and lead to wound repair after vascular injury [1,2].
Fibrin is a viscoelastic polymer and its mechanical and structural properties as a fibrin scaffold determine its effectiveness in hemostasis and in the development and outcome of thrombotic complications. Fibrin polymerization comprises a series of consecutive reactions, each affecting the final structure of the 3D porous network. Structural features in the fibrin molecule determine the physical properties of clots, and it is important for the blood clot to support arterial flow, clot contraction by platelets, and other dynamic forces [3,4].
The three-dimensional structure of fibrin allows for a series of cellular interactions and provides a temporary matrix in which cells can proliferate, organize, and perform their functions, especially at injured or inflamed sites. Thus, fibrin has been used with the aim of accelerating healing and regeneration in several surgical procedures, especially in medicine in the areas of orthopedics [5,6], neurology [7][8][9], and plastic surgery [10,11], as well as in dentistry in the areas of periodontics [12,13], implantology [14,15], and oral and maxillofacial surgery [16,17].
One of the ways to use fibrin in tissue regeneration is platelet-rich fibrin (PRF) which, unlike platelet-rich plasma (PRP), PRF has a high concentration of fibrin and white blood cells, not platelets. PRP and PRF have the same ability to accelerate the healing of soft and hard tissues by increasing the concentration of growth factors, but PRF acts to release growth factors over a longer period, providing longer lasting benefits, as well as stimulating a faster healing process than PRP [18]. PRF increases the concentration of these factors, among which we can exemplify the platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), factors which help to accelerate neovascularization and cell differentiation [18,19].
Studies also evaluate "fibrin glues" that can be called fibrin adhesive, fibrin sealant or fibrin biopolymer in tissue regeneration [20][21][22][23]. Human fibrin glue is manufactured using two components, one of which is a concentrate of clotting proteins (fibrinogen, fibronectin and Factor XIII) and the other is thrombin, both lyophilized. The first component is reconstituted with an aprotinin solution that inhibits tissue fibrinolysis. Thrombin is mixed with calcium chloride, thus being a grouping of substances participating in hemostasis and wound repair, giving the product properties such as hemostatic action, sealant and biological stimulation, which favor the formation of new tissue matrix [24,25]. In Brazil, a group of researchers from the Center for the Study of Venoms and Venomous Animals (CEVAP/UNESP Botucatu) developed and has been using in several studies, a fibrin sealant without the presence of derivatives from human blood, being totally heterologous, which has components derived from snake venom and fibrinogen from buffalo blood. This sealant, due to its diversity of use, is currently called fibrin biopolymer [8,26].
However, in view of the search for a rapid morphological and functional recovery of the injured tissues, more than one type of therapy can be combined (in this case, a set of therapies complementary to the treatment). One of them is the low-level laser (LLLT), with tissue stimulation properties through red or infrared light with the ability to modulate the repair process, reducing pain, increasing tissue vascularization, promoting an increase in the production of mitochondrial ATP, and a series of biostimulatory effects, which led to the current name of photobiomodulation (PBM) therapy [27,28].
The combined use of fibrin glue with photobiomodulation has shown promising results in the repair of peripheral nerve injuries, being effective in the neurorrhaphy procedure, as well as providing a better quality of axonal regeneration to the interior of the distal stump [29]. In addition, this associated form of therapeutic use has demonstrated the ability to assist in the repair process of bone defects, stimulating angiogenesis and osteoblast proliferation, contributing to the formation of new bone in shorter postoperative periods and in greater volume [30].
However, there are still gaps in explaining the mechanisms of PBM therapy and its effects in combination therapies with fibrin. Therefore, this systematic review was designed from the PICO strategy (P: problem; I: intervention; C: control; O: outcome) [31,32], in order to analyze the relationship between PBM therapy and the use of fibrin compounds, such as PRF and fibrin sealants.

Materials and Methods
This systematic review was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, as well as other similar research [32][33][34]. For this, PubMed/MEDLINE, Scopus (Elsevier) and Web of Science databases were searched, with a specific search period (1 January 2002-30 April 2022), using the keywords: "fibrin AND low-level laser therapy" and "fibrin AND photobiomodulation".
With the crossing of keywords, a detailed analysis of the results was carried out, being important in the selection the title and the abstract. From there, the manuscripts were separated into included and excluded according to the eligibility criteria. The authors carried out this process impartially and independently.
-Eligibility Criteria: The inclusion criteria were: • restricted the articles only to the focus of the question in this review. Methodology, the results obtained, and the importance of these results were important to list the selected manuscripts. The selected articles on the topic were carefully read. In addition, two independent reviewers participated in the selection phases, ensuring that the inclusion and exclusion criteria were carefully followed, with the clear objective of minimizing bias.
Data related to the subject of this review were selected and extracted from the manuscripts by independent reviewers, taking into account the characteristics of the individual studies that contributed to their outcome as well as their aggregated results, without the objective of performing a meta-analysis.
The selection scheme, according to the PRISMA flow diagram [32,35,36], is shown in Figure 1.

•
Commentaries; • Unpublished abstracts; • Dissertations or theses from repositories Initially, the manuscripts with the title and abstract connected to the topic of the search were verified, with the terms: fibrin and PBM therapy, and then we evaluated and restricted the articles only to the focus of the question in this review. Methodology, the results obtained, and the importance of these results were important to list the selected manuscripts. The selected articles on the topic were carefully read. In addition, two independent reviewers participated in the selection phases, ensuring that the inclusion and exclusion criteria were carefully followed, with the clear objective of minimizing bias.
Data related to the subject of this review were selected and extracted from the manuscripts by independent reviewers, taking into account the characteristics of the individual studies that contributed to their outcome as well as their aggregated results, without the objective of performing a meta-analysis.
The selection scheme, according to the PRISMA flow diagram [32,35,36], is shown in Figure 1.

Results
The bibliography search found 44 articles in the PubMed/MEDLINE database, of which 26 were excluded since they were duplicates or due to inclusion/exclusion criteria. We also found 40 articles in Web of Science and selected 1 article, 152 articles in Scopus and no article selected, totaling 19 articles for qualitative analysis.
From the studies selected for a detailed description, we can see that, due to their physicochemical characteristics, fibrin compounds are widely used in several areas that mainly involve medicine and regenerative dentistry. In this way, three selected studies were selected in which the researchers used hydrogels or 3D fibrin, 3 with L-PRF, 10 with fibrin sealants (or also called glue, adhesive or biopolymers) and 3 with autologous PRF (Figure 2).
The bibliography search found 44 articles in the PubMed/MEDLINE database, of which 26 were excluded since they were duplicates or due to inclusion/exclusion criteria. We also found 40 articles in Web of Science and selected 1 article, 152 articles in Scopus and no article selected, totaling 19 articles for qualitative analysis.
From the studies selected for a detailed description, we can see that, due to their physicochemical characteristics, fibrin compounds are widely used in several areas that mainly involve medicine and regenerative dentistry. In this way, three selected studies were selected in which the researchers used hydrogels or 3D fibrin, 3 with L-PRF, 10 with fibrin sealants (or also called glue, adhesive or biopolymers) and 3 with autologous PRF (Figure 2).   In the photobiomodulation protocols of the selected studies, when the wavelengths were analyzed, the most used was 830 nm, in nine studies. Then, 810 nm in three studies; 475 nm, 516 nm, 635 nm, and 1064 nm in two studies each; 633 nm, 650 nm, 660 nm, 840 nm, 910 nm with one study each; and one study did not disclose the wavelength used ( Figure 4).  In the photobiomodulation protocols of the selected studies, when the wavelengths were analyzed, the most used was 830 nm, in nine studies. Then, 810 nm in three studies; 475 nm, 516 nm, 635 nm, and 1064 nm in two studies each; 633 nm, 650 nm, 660 nm, 840 nm, 910 nm with one study each; and one study did not disclose the wavelength used ( Figure 4).
Aluminum-Arsenide (GaAlAs) laser that presented greater use in the selected studies in tissue re generative processes (10 studies). Two studies did not specify the type of PBM used. One study used different types of PBM, therefore considered separately in the data in the figure.
In the photobiomodulation protocols of the selected studies, when the wavelengths were analyzed, the most used was 830 nm, in nine studies. Then, 810 nm in three studies 475 nm, 516 nm, 635 nm, and 1064 nm in two studies each; 633 nm, 650 nm, 660 nm, 840 nm, 910 nm with one study each; and one study did not disclose the wavelength used ( Figure 4).  Table 1. 830 nm tha presented greater use in the selected studies in tissue regenerative processes (nine studies). One study did not present the wavelength used. Studies that used different wavelengths were consid ered separately in the data in the figure.
The articles selected to compose this review are presented in Table 1.  Table 1. 830 nm that presented greater use in the selected studies in tissue regenerative processes (nine studies). One study did not present the wavelength used. Studies that used different wavelengths were considered separately in the data in the figure.
The articles selected to compose this review are presented in Table 1.

Discussion
This systematic review aimed to analyze published research on the association of photobiomodulation therapy, through the use of LLLT or LED, with fibrin scaffolds. The focus was on its use in tissue regeneration, mainly fibrin in the form of PRF and fibrin sealants (glues or adhesives) in order to verify the possible beneficial effects of PBM in three-dimensional fibrin scaffolds.
The initial description of fibrin comes from the classic coagulation cascade, proposed in 1964 by Macfarlane [55] and Davie and Ratnoff [56], documented in several articles. This model referred to as the "cascade" has been proposed to explain the physiology of blood clotting, whereby clotting occurs through sequential proteolytic activation of proenzymes by plasma proteases, resulting in the formation of thrombin, which then breaks down the fibrinogen molecule into fibrin monomers [57]. The fibrin network formed in the clot presents a particularly homogeneous and three-dimensional organization [58]. Furthermore, a progressive polymerization mode means increased incorporation of circulating cytokines in the fibrin meshes (intrinsic cytokines), providing an increase in the lifespan of these cytokines. Thus, cytokines are kept in situ for a convenient period when the scar cells begin to remodel the matrix, at which time they need to be stimulated to participate in the reconstruction of the injured site [59,60].
Due to its characteristics and properties, fibrin has been used in several areas, one of which is tissue regeneration in medical and dental procedures. Among the forms presented, in this review, three studies were selected for qualitative analysis that used hydrogels or 3D fibrin, 3 with L-PRF, 10 with fibrin sealants and 3 with autologous PRF (Figure 2). The production of autologous platelet concentrates (APCs) occurs by centrifuging the patient's own blood, injecting isolated plasma, which is rich in growth factors. In tissue regeneration, two generations of APCs have been used: PRP, which are first generation, produced by double-spin centrifugation of blood; and PRF, the second generation, produced by singlespin centrifugation and has the fibrin matrix network intact. The effectiveness of platelet concentrates in promoting wound healing and tissue regeneration is at the center of recent academic discussion [61].
In a preclinical study, using LLT, PRF and Nano-HA nanohydroxyapatite graft (Fisiograft ® , Ghimas, Italy) as variables, Hemaid et al., (2019) observed that the use of PRF + NanoHA mix results in an increase in bone fill and density regarding the radiographic outcomes in induced periodontal intrabony defects in rabbits, and LLLT may improve the results [44]. To prepare the PRF, five-milliliter blood samples were collected from each rabbit and then centrifuged at 30,000× g RPM for 15 min. The PRF was separated into two pieces; one was used as a membrane and the other was cut into pieces to be added with Fisiograft ® plus Nano-HA. However, the study by Doan et al., (2020) the clinical applicability of the combination of autologous concentrated growth factors (CGF) and photobiomodulation (PBM) was made. Lateral sinus windows were created using piezoelectric surgery (PES) and the dental implants were concurrently fixated and wrapped with autologous fibrin (AF) rich CGF. Wound sites PBM treatment using a multiwave locked system laser. Bovine demineralized freeze-dried bone (Bio-Oss ® , Chatswood, Australia) and hydroxyapatite and calcium triphosphate (Genoss ® , Seoul, Korea) were incorporated into CGF for grafting. The application of AF offers benefits such as being a safe procedure, easy to perform and low cost [54] (Figure 5).
Three studies used L-PRF, developed in 2001 in France by Dr. Joseph Choukroun [62], during the production technique an attempt was made to accumulate platelets and release cytokines in a fibrin clot. This technique does not require anticoagulants, bovine thrombin or any other gelling agent, unlike other platelet concentrates; it is simply centrifuged natural blood without additives [58,63]. When using L-PRF, there are different methods and protocols in its production. In a pre-clinical study, in critical defects in the calvaria of rats, two methods of obtaining the concentrate were analyzed, by means of high (L-PRF) or low speed (A-PRF) centrifugation. The L-PRF and A-PRF groups had significantly higher bone volume and newly formed bone area than the control group (clot only) and reduced bone porosity values, but with no significant difference between them in the histomorphometric and microtomographic analysis. Therefore, L-PRF and A-PRF potentiated the healing of critical defects, and high and low-speed centrifugation protocols did not produce PRF matrices with different biological impacts on the amount of new bone formation [64]. Three studies used L-PRF, developed in 2001 in France by Dr. Joseph Choukroun [62], during the production technique an attempt was made to accumulate platelets and release cytokines in a fibrin clot. This technique does not require anticoagulants, bovine thrombin or any other gelling agent, unlike other platelet concentrates; it is simply centrifuged natural blood without additives [58,63]. When using L-PRF, there are different methods and protocols in its production. In a pre-clinical study, in critical defects in the calvaria of rats, two methods of obtaining the concentrate were analyzed, by means of high (L-PRF) or low speed (A-PRF) centrifugation. The L-PRF and A-PRF groups had significantly higher bone volume and newly formed bone area than the control group (clot only) and reduced bone porosity values, but with no significant difference between them in the histomorphometric and microtomographic analysis. Therefore, L-PRF and A-PRF potentiated the healing of critical defects, and high and low-speed centrifugation protocols did not produce PRF matrices with different biological impacts on the amount of new bone formation [64].
Leukocyte and platelet-rich fibrin (L-PRF) also have been used widely for bone tissue engineering. L-PRF has the potential to, in cases of bone loss, collaborate in osteogenic differentiation, increase osteoblast proliferation, tissue neovascularization and lower risk of local contamination [65,66]. The three studies in Table 1 that used L-PRF were combinations with PBM for the treatment of jaw osteonecrosis, all with good and promising results for use in the treatment of this type of bone disease [38,45,48]. Among the growth factors stored in platelets, which are essential for the tissue repair, are PDGF. Also present are VEGF-A, transforming growth factor-beta (TGF-β1), FGF-2, epidermal growth factor (EGF), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) [67]. It Figure 5. Schematic overview of fibrin applications in tissue regeneration. Fibrin is a plasma protein formed by the action of thrombin on fibrinogen, and constitutes a natural component of the blood coagulation cascade. The three-dimensional structure of the fibrin matrix serves as a natural scaffold that favors cell adhesion, migration, proliferation and differentiation, in addition to favoring the interaction with biomolecules and growth factors. Thus, fibrin has been used to promote tissue regeneration in various segments of medicine, in the form of sealants, hydrogels, PRF or L-PRF.
Leukocyte and platelet-rich fibrin (L-PRF) also have been used widely for bone tissue engineering. L-PRF has the potential to, in cases of bone loss, collaborate in osteogenic differentiation, increase osteoblast proliferation, tissue neovascularization and lower risk of local contamination [65,66]. The three studies in Table 1 that used L-PRF were combinations with PBM for the treatment of jaw osteonecrosis, all with good and promising results for use in the treatment of this type of bone disease [38,45,48]. Among the growth factors stored in platelets, which are essential for the tissue repair, are PDGF. Also present are VEGF-A, transforming growth factor-beta (TGF-β1), FGF-2, epidermal growth factor (EGF), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) [67]. It should be taken into account the fact that L-PRF does not use the inclusion of anticoagulant and activating agents (CaCl 2 ) to obtain the platelet concentrate. The inclusion of these agents and activators, in addition to hard-centrifugation (≥210 g), can affect the amount and quality of platelet recovery and growth factor release, which can significantly influence healing behavior compared to natural fibrin clotting [68].
Three studies were used hydrogels or 3D fibrin [37,41,42], associated with PBM, being incorporated into the fibrin matrix endothelial cells [41], stromal vascular fraction (SVF) and mesenchymal stromal cells (MSCs) isolated from human gingival mucosa [37]. These studies agree that photobiomodulation combined with fibrin enhances the improvement of results, collaborating in cell and vascular proliferation.
Fibrin sealants were most commonly used in combination with PBM, in ten studies [29,39,40,43,47,[49][50][51][52][53]. One of the studies used the fibrin sealant derived from human plasma (Tisseel Lyo ® (Baxter Healthcare Ltd., Norfolk, UK) [43] and the others a heterologous fibrin sealant (HFS). This bioproduct (HFS) is composed of a thrombin-like enzyme purified from the venom of Crotalus durissus terrificus snake and a cryoprecipitate rich in fibrinogen extracted from Bubalus bubalis buffaloes (produced by CEVAP/UNESP-Center for the Study of Venoms and Venomous Animals, Botucatu, Brazil). HFS has several advantages in its use, such as a fast production process, low cost, potential to act as a scaffold for stem cells [69][70][71] and biomaterials [50,72], and as a new drug delivery system [73]. Its indications are in medical, veterinary and dental practice, due to the possibility of personalized formulation and replacement of conventional sutures. Considering all of the properties described for this bioproduct, which go beyond the adhesive capacity, the name "sealant" was reconsidered, and it has recently been called "fibrin biopolymer" [74,75].
In order to improve the tissue repair process, studies in the area of regenerative science seek the association of different therapies to accelerate and improve morphological recomposition and faster functional recovery. Among these conjunctions, light-based therapies, such as the use of low-power lasers and LEDs, have expanded their use in clinical and pre-clinical practices. The laser consists of a pure and well-defined color, while the LED can display different shades of colors at once. Therefore, the laser is a monochromatic light (only a well-determined color) and the LED is a polychromatic light, being able to present all of the shades of a specific color. Currently called photobiomodulation (PBM), consists of the application of light (Laser or LED) with therapeutic effect for tissue modulation (activation or inhibition). It has important potentialities such as angiogenesis and neovascularization [76], increase in collagen production [77], increase in muscle regeneration and decrease in its atrophy [78], favors nerve regeneration [9,79], increases cartilage production [80], and decreases inflammation, edema and pain [81] (Figure 6). In the studies selected for Table 1, according to the eligibility criteria, three used the red LED, 1 infrared LED, 1 GaAs laser, 10 GaAlAs laser, 2 ND: YAG laser, 1 InGaAlP laser and two studies did not identify the type of laser used (Figure 3). Handler et al. (2021) carried out a study to investigate the effects of photobiomodulation at wavelengths of 660 nm (Aluminium-gallium-indium-phosphide laser, AlGaInP) and 830 nm (Arsenide-Gallium-Aluminum laser, AsGaAl) at different numbers of application points on the healing Figure 6. Schematic overview of beneficial properties of photobiomodulation therapy in regenerative medicine. The application of laser therapy favors angiogenesis, collagen synthesis, mitochondrial ATP production, cytokines and growth factors synthesis, in addition to inducing cell proliferation and differentiation. Additionally, photobiomodulation therapy has anti-inflammatory, analgesic and biostimulating effects, acting mainly in the initial stages of tissue healing.
In the studies selected for Table 1, according to the eligibility criteria, three used the red LED, 1 infrared LED, 1 GaAs laser, 10 GaAlAs laser, 2 ND: YAG laser, 1 InGaAlP laser and two studies did not identify the type of laser used (Figure 3). Handler et al. (2021) carried out a study to investigate the effects of photobiomodulation at wavelengths of 660 nm (Aluminium-gallium-indium-phosphide laser, AlGaInP) and 830 nm (Arsenide-Gallium-Aluminum laser, AsGaAl) at different numbers of application points on the healing of open wounds in mice. Photobiomodulation with total energy of 3.6 J was applied at 1, 4, 5 and 9 points for 14 days. When comparing the photobiomodulation wavelength, the 830 nm (AsGaAl) groups were more effective, and the groups irradiated at 5 points stand out, which showed improvement in macroscopic analysis and epidermis thickness, increased number of vessels and lower number of fibroblasts on the 14th day after the skin lesion [82].
Regarding the wavelength, the most used was 830 nm, in nine studies. Then 810 nm in three studies; 475 nm, 516 nm, 635 nm, and 1064 nm in two studies each; 633 nm, 650 nm, 660 nm, 840 nm, and 910 nm with one study each; and one study did not disclose the wavelength used (Figure 4). A study conducted by Ma et al. (2018), to determine the effect of low-level laser therapy (LLLT) on diabetic wound healing and confirm its effect on the activity of healthy human fibroblasts, used PBM with an 830 nm (IR) wavelength, 635 nm (Red) and 635 nm + 830 nm (FX) with the same fluency of 60 J/cm 2 . Irradiation in the FX and IR groups showed a significant increase in fibroblast proliferation and collagen synthesis compared to the control and RED groups. However, there was no significant difference in collagen synthesis and fibroblast proliferation between the FX group and the IR group. These data allowed the authors to conclude that healthy human fibroblasts showed better cell proliferation and collagen synthesis when irradiated at the wavelength of 635 nm + 830 nm or 830 nm [83].
The use of LED photobiomodulation is more recent than laser therapy. Current research advances in the evaluation of the separate or combined use of the two therapies in tissue repair. Doses ranging from 0.1 to 10 J/cm 2 and wavelengths from 405 to 1000 nm promote therapeutic benefits in tissue regeneration. Ranges of light energy sources, from lasers to LEDs, have been used and have specific advantages and limitations. There is no consensus on standardized treatment parameters such as wavelengths, therapeutic outcomes and doses, which limits direct comparison and clinical protocol recommendation [84][85][86][87][88][89][90].
The use of combined therapies that involve the use of fibrin associated with photobiomodulation therapy has shown to be a promising strategy to favor the regeneration of injured tissues with better quality and less time. When fibrin is applied to the lesion site, it forms a bioactive matrix in the microenvironment that exerts a hemostatic effect, in addition to favoring interactions between cells and biomolecules ( Figure 7). These effects, added to those of PBM, constitute a supporting therapy that acts by stimulating cell activity, angiogenesis, and the synthesis of collagen and biomolecules [49,[91][92][93][94][95][96][97][98][99][100].
In this review, among preclinical studies, the most researched association of fibrin and photobiomodulation was the use of fibrin sealants in bone or nerve injuries. In clinical studies, the association of PBM with medication-related treatments osteonecrosis of the jaw (MRONJ). All experimental protocols concluded that the association is effective; promoting a more effective repair of lesions, in a shorter period of time and with effectiveness that can reinforce the indication of its use. In peripheral nerves, PBM therapy accelerated morphological and functional nerve repair. In bone tissue [51], PBM allowed for an improvement in the formation of new bone, with a more organized deposition of collagen fibers in the defect area [50]; and in osteonecrosis of the jaw, PBM may effectively contribute to MRONJ management [38,45,101].
In this way, we can see that few studies used the association fibrin + PBM, but given the good results, the technique is promising, with the potential to collaborate in tissue repair. The difficulty in comparing the different types of PBM can be considered as a limitation, due to the different protocols reported in the experiments. Therefore, protocols with favorable results are generally standardized and reused by the same researchers in an attempt to reduce this limitation. In addition, the scarcity of randomized clinical trials in the scope of this review can also be considered a limitation. sensus on standardized treatment parameters such as wavelengths, therapeutic outcomes and doses, which limits direct comparison and clinical protocol recommendation [84][85][86][87][88][89][90].
The use of combined therapies that involve the use of fibrin associated with photobiomodulation therapy has shown to be a promising strategy to favor the regeneration of injured tissues with better quality and less time. When fibrin is applied to the lesion site, it forms a bioactive matrix in the microenvironment that exerts a hemostatic effect, in addition to favoring interactions between cells and biomolecules ( Figure 7). These effects, added to those of PBM, constitute a supporting therapy that acts by stimulating cell activity, angiogenesis, and the synthesis of collagen and biomolecules [49,[91][92][93][94][95][96][97][98][99][100]. Figure 7. The application of fibrin combined with photobiomodulation therapy constitutes a promising strategy to favor regeneration in tissue engineering. Fibrin applied to the injury site forms a bioactive matrix that exerts a hemostatic effect, in addition to favoring interactions between cells and biomolecules. Photobiomodulation constitutes a coadjuvant therapy that acts by stimulating cell activity, angiogenesis and the synthesis of collagen and biomolecules. Thus, the application of fibrin associated with photobiomodulation therapy may have a beneficial effect, accelerating tissue healing.
In this review, among preclinical studies, the most researched association of fibrin and photobiomodulation was the use of fibrin sealants in bone or nerve injuries. In clinical studies, the association of PBM with medication-related treatments osteonecrosis of the jaw (MRONJ). All experimental protocols concluded that the association is effective; promoting a more effective repair of lesions, in a shorter period of time and with effectiveness that can reinforce the indication of its use. In peripheral nerves, PBM therapy accelerated morphological and functional nerve repair. In bone tissue [51], PBM allowed for an improvement in the formation of new bone, with a more organized deposition of collagen Figure 7. The application of fibrin combined with photobiomodulation therapy constitutes a promising strategy to favor regeneration in tissue engineering. Fibrin applied to the injury site forms a bioactive matrix that exerts a hemostatic effect, in addition to favoring interactions between cells and biomolecules. Photobiomodulation constitutes a coadjuvant therapy that acts by stimulating cell activity, angiogenesis and the synthesis of collagen and biomolecules. Thus, the application of fibrin associated with photobiomodulation therapy may have a beneficial effect, accelerating tissue healing.

Conclusions
This review was designed and carried out with the objective of analyzing studies, both clinical and pre-clinical, that used the association of photobiomodulation and fibrin. This association occurs with the purpose of tissue regeneration, in the search for its possible beneficial effects on morphophysiological and functional rehabilitation. The fibrin matrix, with its three-dimensionality, is a natural scaffold, which enables events that favor the repair of injured tissues, which is desired in tissue engineering procedures, through adhesion, migration, proliferation, and cell differentiation, in addition to contributing to the interaction with biomolecules and local tissue growth factors.
In the findings of this study, it can be shown that PBM contributed to improve tissue regeneration that used fibrin composites as scaffolds, constituting an important adjuvant therapy that acts by stimulating cell activity, angiogenesis, osteoblastic activation, axonal growth, anti-inflammatory and anti-edema action, increased collagen synthesis and its maturation, as well as biomolecules. More studies should be carried out in order to seek standardization in PBM protocols, in the same way that new fibrin concentrates will be developed with the same objective of recovering injured organs and tissues.