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Photobiomodulation in Periodontitis: Targeting Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Extracellular Matrix Remodeling

Submitted:

22 September 2026

Posted:

23 September 2026

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Abstract
Periodontitis is an inflammation-driven disease caused by dysbiosis, in which excessive host proteolytic activity contributes to connective tissue destruction and alveolar bone loss. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are key regulators of extracellular matrix turnover and potential molecular targets of photobiomodulation (PBM). This review summarizes the available clinical evidence on the effects of adjunctive PBM on MMP/TIMP-associated biomarkers in periodontitis. Nine clinical publications published between 2005 and 2023 were identified, together with one relevant systematic review. The included studies used PBM-compatible protocols or mixed laser studies with a PBM-related arm. There was considerable heterogeneity in irradiation parameters, treatment schedules, comparator therapies, follow-up period, and biomarker assessment. The most studied marker was MMP-8, showing a reduction after periodontal therapy, independent of PBM. Some studies reported a greater PBM-associated reduction, whereas others observed clinical improvement without changes in MMP-8 or related cytokines. Data supporting MMP-1, MMP-9, MMP-13, TIMP-1 and MMP/TIMP ratios were sparse and heterogeneous. Changes in biomarker production did not always correlate with clinical improvements in probing depth, clinical attachment level, gingival inflammation, bleeding indices, and early wound healing. In conclusion, PBM may influence MMP-related responses during periodontal healing, but a definite effect beyond conventional periodontal therapy has not been established. Future randomized trials should employ well-defined non-thermal PBM parameters, the same background treatment, quantitative evaluation of active MMPs and TIMPs, and standardized long-term clinical and biochemical follow-up.
Keywords: 
photobiomodulation
;  
periodontitis
;  
matrix metalloproteinases
;  
tissue inhibitors of metalloproteinases
;  
clinical trials
Subject: 
Medicine and Pharmacology  -   Dentistry and Oral Surgery

Introduction

Periodontitis is a chronic inflammatory disease of the supporting tissues of the tooth characterized by loss of connective tissue attachment and destruction of the alveolar bone. The disease is caused by the complex interaction between periodontal bacteria in a dysbiotic subgingival biofilm and a dysregulated host immune response that fails to adequately control either the infection or the associated inflammation [1,2]. Periodontitis is initiated by microorganisms, but the extent and progression of destruction of periodontal tissues is largely determined by the magnitude, persistence, and regulation of the host inflammatory response [1,2].
Matrix metalloproteinases (MMPs) have a central role in this destructive process. These proteolytic enzymes degrade collagen and other components of the extracellular matrix and regulate the activity of cytokines, chemokines, growth factors, and cell-surface receptors. MMP-8 and MMP-9 are particularly relevant to periodontitis because their excessive and prolonged activation contributes to the degradation of the gingival connective tissue and periodontal ligament. Under physiological conditions, MMP activity is controlled by tissue inhibitors of metalloproteinases (TIMPs), whereas disruption of the MMP/TIMP balance in favor of active MMPs promotes progressive connective tissue attachment loss and periodontal tissue destruction [2,3].
The cornerstone of nonsurgical periodontal treatment is the mechanical disruption and removal of the supra- and subgingival biofilm and calculus through professional mechanical plaque removal and subgingival instrumentation, together with effective self-performed oral hygiene and control of relevant risk factors [4]. Depending on the clinical indication, several adjunctive approaches have also been investigated, including locally or systemically administered antimicrobials, antiseptics, anti-inflammatory agents, other host-modulating agents, and different laser- and light-based modalities [4,5]. These approaches are intended to complement rather than replace conventional mechanical periodontal therapy.
Photobiomodulation (PBM), formerly referred to primarily as low-level laser therapy (LLLT), is a noninvasive approach based on the application of low-intensity red or near-infrared light to modulate cellular and tissue responses. In periodontitis, PBM has been investigated mainly as an adjunct to nonsurgical periodontal therapy. Available evidence suggests that it may reduce excessive production of proinflammatory mediators and oxidative stress, modulate NF-κB-dependent signaling and macrophage polarization, and support angiogenesis, fibroblast activity, collagen synthesis, periodontal ligament cell function, and osteogenic repair [6,7,8]. Some clinical studies and meta-analyses have reported additional short-term improvements in inflammatory and periodontal parameters. However, considerable heterogeneity in wavelength, irradiance, fluence, treatment schedule, and study design currently prevents the definition of a universally accepted clinical protocol [6,7].
Because MMPs and TIMPs are located at the interface between inflammation, extracellular matrix degradation, and tissue repair, they may represent important molecular targets and biomarkers of PBM-mediated host modulation. By influencing inflammatory and redox signaling, immune–stromal cell interactions, and tissue-remodeling pathways, PBM could potentially restore a more favorable MMP/TIMP balance, thereby limiting pathological matrix degradation while supporting periodontal repair. Nevertheless, direct evidence demonstrating how specific PBM protocols regulate individual MMPs and TIMPs in periodontitis remains fragmented and insufficiently integrated. Therefore, this review aims to summarize the roles of MMPs and TIMPs in periodontal pathogenesis and to critically evaluate the available evidence regarding their modulation by PBM as a potential host-directed adjunct to conventional periodontal therapy.

Review Methodology and Scope

This narrative review was conducted using a structured literature search of PubMed/MEDLINE, Scopus, Web of Science, the Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar. The search strategy combined controlled vocabulary and free-text terms related to periodontitis, photobiomodulation, laser-based periodontal therapy, extracellular matrix remodeling, matrix metalloproteinases, and their endogenous inhibitors. The main search terms were “periodontitis”, “periodontal disease”, “photobiomodulation”, “low-level laser therapy”, “laser therapy”, “matrix metalloproteinases”, “MMP”, “tissue inhibitors of metalloproteinases”, “extracellular matrix”, “collagen degradation”, “gingival crevicular fluid” and “host-modulation therapy”, both alone and in appropriate combinations. We searched for publications from the start of each database to June 2026. Additional references were identified by manual screening of the reference lists of relevant original articles and reviews. The broader mechanistic synthesis included experimental and clinical studies and peer-reviewed reviews concerned with the roles of MMPs, TIMPs, and extracellular matrix remodeling in periodontal pathogenesis and therapy. The clinical part comprised human studies that examined changes in MMP- and/or TIMP-related biomarkers after adjunctive PBM or other laser-based periodontal therapies. Studies examining gingival crevicular fluid (GCF), saliva, serum, or periodontal tissue biomarkers were considered. Only peer-reviewed articles published in English were included, whereas conference abstracts, editorials, case reports, non-peer-reviewed manuscripts, and studies without relevant biochemical or clinical outcomes were excluded.
Because the available clinical studies differed substantially in study design, patient characteristics, laser systems, irradiation parameters, treatment schedules, biomarker assays, and follow-up duration, quantitative pooling was not considered appropriate. The evidence was therefore synthesized narratively, with an emphasis on MMP-1, MMP-8, MMP-9, MMP-13, TIMP-1, and MMP/TIMP ratios, together with inflammatory mediators in GCF and corresponding periodontal clinical outcomes. Particular attention was given to distinguishing conventional PBM protocols from high-power ablative laser treatments and antimicrobial photodynamic therapy. Contradictory findings and limitations of the available evidence were explicitly discussed, and cautious terminology was used where mechanistic or clinical conclusions remained uncertain.

Pathogenesis of Periodontitis

A healthy periodontal biofilm is a part of the physiological oral ecosystem and is in balance with epithelial barrier function, the biochemical and humoral composition of GCF, and local immune mechanisms. But the build-up of dental plaque along the gingival margin changes local microenvironmental conditions. This is associated with an increase in GCF flow and a consequent decrease in the partial pressure of oxygen. At the same time, a microenvironment is created that favors the growth of proteolytic and anaerobic bacteria. This is especially important for those bacteria that have developed mechanisms to adhere to solid surfaces, including teeth covered with already formed plaque of other bacteria (co-aggregation) and to epithelial layers. The inflammatory exudate that accumulates provides additional nutrients for bacterial growth, such as peptides and heme. All these factors act synergistically to further promote dysbiosis of the microbiota and selection of pathogenic species of bacteria [1,9,10]. Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia are especially relevant to the immunopathogenesis of periodontitis. Porphyromonas gingivalis can interfere with the signaling pathways of the complement system and Toll-like receptors, as well as their crosstalk. The latter is followed by impaired effective clearance of microorganisms and maintenance of a proinflammatory response. Thus, Porphyromonas gingivalis facilitates not only its own survival but the persistence of the whole dysbiotic microbial community in the dental biofilm. The outcome is not just an uncontrolled proliferation or invasion of a single microbial species but a disruption of the general ecological and local immune balance, fostering conditions for polymicrobial synergistic activity [10,11].
The disease begins as gingivitis. Several variables, including smoking, diabetes mellitus, aging, and systemic inflammatory diseases, are associated with the progression to periodontitis. Furthermore, genetic and epigenetic characteristics of the host, especially those related to proinflammatory and immunoregulatory cytokines, are of paramount importance [1,9]. Cells of the periodontal ligament and the gingival epithelium form an active immune barrier. Innate immune cells recognize bacterial lipopolysaccharides, lipoproteins, and other pathogen-associated molecular patterns (PAMPs) via pattern-recognition receptors (PPRs), triggering nuclear factor (NF)-κB activation and associated signaling pathways. This is followed by increased production of interleukin (IL)-1β, tumor necrosis factor (TNF), IL-6, chemokines, prostaglandin E2, MMPs, and other bioactive molecules. These mediators increase vascular permeability, recruit circulating leukocytes to the inflamed tissue, and promote degradation of the extracellular matrix. This response initially restricts the growth of microorganisms. However, when prolonged, it becomes a major cause of collateral tissue damage [1,2,9].
Neutrophils are the most abundant immune cells in the inflamed periodontium and migrate continuously through the junctional epithelium toward the biofilm. Their protective function depends on phagocytosis, degranulation, generation of reactive oxygen species (ROS), and formation of neutrophil extracellular traps. However, both impaired neutrophil function and excessive neutrophil activation can contribute to disease development. Under chronic immune stimulation, the effects of released proteases, myeloperoxidase, ROS, and other mediators outweigh the local antioxidant and antiprotease defense capacity. This leads to oxidative stress, destruction of epithelium and connective tissue, activation of osteoclastogenic signaling, and further proliferation of microbes [12,13].
A major mechanism that connects microbial signals to destructive inflammation is the activation of the NLRP3 inflammasome. Inflammasomes are cytosolic multi-protein complexes that detect microbial and endogenous danger signals. NLRP3 is primed and activated by Porphyromonas gingivalis, Fusobacterium nucleatum, bacterial lipopolysaccharides, extracellular ATP, ionic disturbances, and ROS. The complex assembled activates caspase-1 to convert pro-IL-1β and pro-IL-18 into their biologically active forms and cleaves gasdermin D. The N-terminal fragment of gasdermin D forms pores in the cell membrane, enabling the release of cytokines and triggers pyroptosis, a proinflammatory form of programmed cell death [14,15]. NLRP3 is not only expressed in macrophages and monocytes in periodontitis. Its expression and activation have also been found to be increased in neutrophils, gingival fibroblasts, periodontal ligament cells, osteoblasts, and osteoclast precursors. IL-1β increases the production of proteolytic enzymes, local leukocyte recruitment, and osteoclastogenesis. Pyroptosis of fibroblasts and periodontal ligament cells further impairs the barrier and reparative capacity of periodontal tissues. At the same time, the release of intracellular danger-associated molecules activates surrounding cells and perpetuates local inflammation. This leads to a positive feedback loop between inflammation and cell death [15,16,17]. Experimental inhibition of NLRP3 reduces IL-1β activation, osteoclast differentiation, and alveolar bone loss, thereby confirming its functional, rather than merely associative, role in the disease [16].
Persistent antigenic stimulation activates dendritic cells and T and B lymphocytes, promoting the transition of the lesion to a chronic phase. Th1 cells, and particularly Th17 cells, contribute to the recruitment and activation of phagocytes. In addition, IL-17 stimulates chemokine production and granulopoiesis. This response may be protective when spatially and temporally restricted. However, within a dysbiotic microenvironment, it contributes to persistent neutrophilic inflammation. Regulatory T cells, IL-10, and TGF-β exert opposite effects by restraining inflammation and osteoclastogenesis. Disease progression is thus a change in the balance between regulatory and effector immune responses [2,9].
In advanced lesions, there is an increase in the number of B lymphocytes and plasma cells. Antibodies may help control bacteria, but activated B and T lymphocytes may also be an important source of receptor activator of nuclear factor κB ligand (RANKL). RANKL binds to the RANK receptor on osteoclast precursors, inducing their differentiation and activation. Osteoprotegerin is a soluble decoy receptor that inhibits this process. Proinflammatory cytokines, including IL-1β, TNF-α, and IL-17, and prostaglandin E2, shift the balance between RANKL and osteoprotegerin toward bone resorption. In parallel, the inflammatory microenvironment might inhibit osteoblast differentiation and mineralization. Hence, alveolar bone loss results from a coordinated osteoimmune disturbance characterized by increased osteoclastogenesis and insufficient bone formation [2,9,16].
As already mentioned, the MMP/TIMP balance plays an important role in periodontal connective tissue degradation and in regulating extracellular matrix remodeling. In this context, MMP and TIMP expression levels, as well as their ratio, may serve as potentially important biomarkers of active periodontal disease. In addition, polymorphisms in MMP genes seem to influence MMP expression or activity, thereby increasing susceptibility to periodontal disease [1,9,10,18].
Resolution of inflammation is an active biological program, not simply a passive termination of the inflammatory response, and comprises cessation of further neutrophil recruitment, clearance of apoptotic cells, phenotypic reprogramming of macrophages, and restoration of tissue homeostasis. Specialized pro-resolving lipid mediators, such as resolvins, restrict leukocyte recruitment but do not fully abrogate antimicrobial defense. Resolvin E1 decreases the expression of inflammatory genes and the number of osteoclasts, prevents bone loss, and may contribute to the reversal of dysbiosis in experimental periodontitis [19]. The present results suggest that chronicity of periodontitis is due not only to continuous microbial stimulation but also to the lack of or delayed activation of resolution pathways [1,19].
The present knowledge of the immunopathogenesis of periodontitis has allowed the identification of several possible therapeutic targets to modulate the host response. These include excessive complement activation, particularly signaling via C3 and the C5aR1 receptor, as well as synergistic interactions with Toll-like receptors that enhance proinflammatory cytokine production and sustain dysbiosis. Relevant targets also include the helper (Th)17/IL-17 axis; the cytokines TNF, IL-1β, IL-6, and IL-23; oxidative stress; excessive neutrophil activation; MMPs; and the RANKL/osteoprotegerin (OPG) ratio, which directly links inflammation to connective tissue degradation and alveolar bone resorption. In this context, the MMP/TIMP axis may represent an important therapeutic target for restoring the balance between extracellular matrix degradation and tissue repair. Therapeutic benefit may also be achieved by stimulating regulatory and pro-resolving pathways, in addition to blocking proinflammatory mechanisms. These include boosting the activity of regulatory T cells, encouraging more effective efferocytosis of apoptotic neutrophils, steering macrophages toward an anti-inflammatory and reparative phenotype, and leveraging the effects of specialized pro-resolving lipid mediators. The aim of this modulation is not the indiscriminate suppression of the immune response, but the interruption of the vicious cycle between inflammation and dysbiosis and the restoration of periodontal homeostasis [9].

Matrix Metalloproteinases and Their Tissue Inhibitors: A General Overview and Significance in Dentistry

MMPs are a family of endogenous zinc- and calcium-dependent endopeptidases that participate in the precise remodeling of the extracellular matrix (ECM). They are among the principal proteolytic systems responsible for the turnover of major ECM components, including collagens, elastin, fibronectin, proteoglycans, and gelatin [3,18]. Although they were initially described primarily as enzymes that degrade collagen and other structural proteins, MMPs are now known to have much broader functions. They process cytokines, chemokines, growth factors, receptors, adhesion molecules, and antimicrobial peptides, thereby regulating cell migration, inflammation, angiogenesis, wound healing, and bone remodeling [3,18,20,21,22,23,24]. By modifying these non-matrix substrates, MMPs may either activate or inactivate signaling mediators and thereby exert regulatory effects that extend well beyond ECM degradation [21]. Their activity is therefore not exclusively destructive. Physiological MMP activity that is spatially and temporally restricted is required for tooth development, periodontal ligament turnover, alveolar bone remodeling, and tissue repair. More broadly, tightly regulated MMP activity contributes to embryogenesis, morphogenesis, angiogenesis, tissue remodeling, and wound repair [3,18,20,21,22,23,24]. In contrast, prolonged or insufficiently controlled activation contributes to dental caries, degradation of the hybrid layer, pulpal and periapical inflammation, periodontitis, and peri-implant diseases [23,24].
The human MMP family comprises 23 members [21]. Most are synthesized as inactive proenzymes (pro-MMPs) containing a signal peptide, a propeptide with a conserved cysteine residue, a catalytic domain containing a Zn²⁺ ion, and, in most family members, a hemopexin domain that determines substrate binding and interactions with inhibitors. The catalytic and hemopexin domains are generally connected by a flexible linker or hinge region, although some smaller MMPs lack the hemopexin domain [18,20,21]. In the latent enzyme, the cysteine residue of the propeptide binds to the catalytic zinc ion and prevents substrate access, a mechanism known as the “cysteine switch.” Activation occurs through proteolytic removal of the propeptide or through its oxidative modification. According to their mode of localization, MMPs may also be broadly distinguished as enzymes secreted into the extracellular environment as latent proenzymes and membrane-associated MMPs positioned at the cell surface [3,18,21,22]. Within the inflammatory periodontal microenvironment, pro-MMPs may be activated by other host-derived proteases, ROS, hypochlorous acid generated by the neutrophil myeloperoxidase system, and certain bacterial proteases [20,21].
On the basis of substrate preference and structural organization, human MMPs are commonly classified into collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and several additional MMPs that are considered separately [3,18,21]. Collagenases include MMP-1, MMP-8, and MMP-13; gelatinases comprise MMP-2 and MMP-9; stromelysins include MMP-3, MMP-10, and MMP-11; and matrilysins comprise MMP-7 and MMP-26. The membrane-type group includes MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25. The six membrane-type MMPs can be further divided into transmembrane proteins—MT1-, MT2-, MT3-, and MT5-MMP—and glycosylphosphatidylinositol-anchored proteins—MT4- and MT6-MMP [21]. Through their cell-surface localization, these enzymes coordinate pericellular ECM degradation, activation of other MMPs, and cellular migration [12,13,14,15]. MT1-MMP may additionally support osteoclast-associated degradation and remodeling of the bone matrix, which may be relevant to alveolar bone changes in periodontitis [20,21]. Other MMPs, such as MMP-12, MMP-19, MMP-20, MMP-21, MMP-23B, MMP-27, and MMP-28 are generally considered individually [21].
According to their structure and function, collagenases MMP-1, MMP-8, and MMP-13 cleave fibrillar collagens, whereas gelatinases MMP-2 and MMP-9 subsequently degrade denatured collagen, type IV collagen of basement membranes, and numerous non-collagenous proteins, thereby sustaining the proteolytic cascade. Stromelysin MMP-3 acts on proteoglycans, laminin, and fibronectin and is also an important activator of other pro-MMPs. MMP-7 is a small secreted enzyme with a broad substrate spectrum, whereas MMP-12 is particularly associated with macrophages. Membrane-bound MMP-14, also known as membrane type 1 MMP (MT1-MMP), mediates pericellular proteolysis, cell migration through the ECM, and activation of pro-MMP-2 [18,20,21]. MMP-20, or enamelysin, has a specific role in enamel development [18,20,21]. MMP-25 and MMP-26 are among the latest members of MMPs. MMP-25 is mainly expressed by neutrophils and is involved in the turnover of ECM. MMP-26 (endometase) has the ability to degrade ECM and alpha1-antitrypsin and activate pro-MMP-9 [25].
MMP activity is regulated at several levels, including gene transcription, secretion of latent proenzymes, extracellular activation, localization at the cell membrane or within the ECM, and inhibition by endogenous inhibitors. The proinflammatory cytokines IL-1β and TNF, bacterial products, prostaglandin E2, oxidative stress, and mechanical loading can increase MMP expression through the mitogen-activated protein kinase (MAPK), NF-κB, and activator protein 1 (AP-1) signaling pathways. In contrast, anti-inflammatory and pro-resolving signals, restoration of redox homeostasis, and increased local activity of tissue inhibitors limit proteolysis. In circulation, active MMPs may be neutralized by α2-macroglobulin, whereas their primary direct regulators in tissues are the tissue inhibitors of metalloproteinases (TIMPs) [26,27,28].
The family of TIMPs includes TIMP-1, TIMP-2, TIMP-3 and TIMP-4. They are small proteins with an N-terminal domain that penetrates into the catalytic cleft of an MMP and coordinates the catalytic zinc ion, usually forming a reversible complex with the enzyme at a 1:1 molar ratio. The C-terminal domain mediates latent gelatinase binding as well as other protein-protein interactions [20,21,22]. TIMP-1, which is widely distributed, is a potent inhibitor of most secreted MMPs, including MMP-9. However, it is less effective against certain membrane-type MMPs. TIMP-2 inhibits active MMPs, but at the correct concentration, it also participates in the formation of the MMP-14-TIMP-2-pro-MMP-2 complex, thereby allowing a controlled activation of MMP-2 at the cell surface. TIMP-3 is ECM-bound and, besides MMPs, can inhibit some ADAM and ADAMTS proteases. TIMP-4 is less abundant in oral tissues, and its local role is less well characterized [21,22,24]. TIMPs are more than passive “switches” of proteolysis. They can inhibit cell proliferation, apoptosis, angiogenesis, and differentiation, independently of MMP inhibition. Thus, the biological outcome cannot be predicted by measuring the levels of a single MMP or TIMP. The local ratio of active enzyme to available inhibitor, the presence of activators and substrates, the cellular source, and the duration of the response are more important. Increased TIMPs in inflamed tissue may be a compensatory response, but may not be sufficient to neutralize a much greater increase in active MMPs. Therefore, the MMP-8/TIMP-1 or MMP-9/TIMP-1 ratios may be a better indicator of the net proteolytic potential than individual levels of these molecules [3,18,22,27].
MMPs are implicated in the development and degradation of mineralized and soft tissues in dentistry. MMP-20 is required for amelogenesis to enable controlled proteolysis of enamel matrix proteins. Different types of MMPs have been identified in dentin, such as MMP-2, MMP-8, MMP-9, and MMP-13, which can be entrapped in a latent form in the mineralized matrix. They are released and activated by acid-mediated demineralization occurring during caries progression or adhesive procedures, and then participate in the degradation of exposed collagen. This mechanism is relevant to the progression of dentin caries and the gradual degradation of the hybrid layer at the dentin-composite interface [18,22,24]. MMP-1, MMP-2, MMP-8, and MMP-9 are up-regulated in pulpitis and apical periodontitis and are involved in tissue remodeling, leukocyte migration, and damage of the periapical ECM. However, their regulated activity may also be required during healing and the formation of reparative dentin, as well as for the physiological remodeling of the periodontal ligament and alveolar bone during orthodontic tooth movement (OTM) [18,24,29]. These facts further suggest that complete, nonselective inhibition of MMPs is undesirable.

Matrix Metalloproteinases and Their Tissue Inhibitors in Periodontitis

As mentioned above, MMPs and TIMPs are relevant to the pathogenesis of periodontal disease. Microbial antigens and inflammatory mediators produced during periodontitis increase MMP production and activation. Chronic inflammation disturbs the balance between MMPs and TIMPs. This causes uncontrolled collagen degradation in the gingiva and periodontal ligament, and loss of connective tissue attachment, thus creating a microenvironment that perpetuates dysbiosis and inflammation. Because type I collagen is the predominant structural component of the periodontal ligament ECM, collagenases and gelatinases are particularly important in periodontal tissue destruction [3,18,21,26,27,28].
MMP-1 (collagenase-1) degrades mainly type I and type III collagens and is involved in physiological extracellular matrix turnover and connective tissue remodeling. It is produced mainly by fibroblasts, macrophages, keratinocytes, endothelial cells, and osteoblasts in response to inflammatory stimuli. The increased MMP-1 expression is involved in collagen degradation in periodontitis, but the role of MMP-1 in periodontal tissue destruction seems to be less evident than that of MMP-8 and MMP-13 [26,28,30].
MMP-8 (neutrophil collagenase, collagenase-2) is considered an important proteolytic enzyme in the destruction of periodontal tissue. It is stored in specific neutrophil granules as pro-MMP-8 and is rapidly released upon cell activation. MMP-8 is mainly produced by neutrophils in active periodontal lesions, but macrophages, plasma cells, fibroblasts, keratinocytes, endothelial cells, and osteoblasts may also produce it under inflammatory conditions [30]. Its release may be promoted by inflammatory mediators such as IL-1β, IL-8, TNF-α, complement components, fibrin-degradation products, and granulocyte colony-stimulating factor [21,30]. MMP-8 is the major collagenolytic enzyme measured in GCF in periodontitis [26,27,28] and efficiently degrades type I and type III collagens. In addition to fibrillar collagen, MMP-8 can process fibronectin, aggrecan, fibrinogen, serpins, bradykinin, angiotensin I, and substance P, suggesting that its activity may also modulate inflammatory and vascular signaling [21].
The active form, aMMP-8, is of particular pathogenetic importance, since measurements of total MMP-8 also include the latent proenzyme, which may not be involved in ongoing tissue destruction. Other MMPs, bacterial proteases, and serine proteases, as well as the neutrophil oxidative system, can activate pro-MMP-8, thus initiating and amplifying a proteolytic-oxidative cycle of tissue injury [31]. More specifically, pro-MMP-8 may be activated by MMP-3 and MMP-10, bacterial proteases from the dental biofilm, trypsin-like and other serine proteases, and ROS [31,32,33]. Non-proteolytic activation is particularly relevant in inflamed periodontal tissues, where neutrophil-derived myeloperoxidase generates hypochlorous acid, which disrupts the interaction between the prodomain cysteine residue and the catalytic zinc ion, thereby activating latent MMP-8 and MMP-9 [16,19,20,21,22]. MMP-8 can cleave certain inflammatory mediators. Therefore, its effects may not be detrimental in all experimental settings. From a clinical point of view, its excessive and prolonged activity is of utmost importance [3,18,27,28,32].
Active MMP-8 can also be detected in saliva, mouth-rinse samples, and peri-implant sulcular fluid. Its levels generally increase with periodontal disease severity, correlate with probing pocket depth, clinical attachment loss, and bleeding on probing, and decrease following successful periodontal therapy. Elevated MMP-8 concentrations have also been associated with a higher plaque index and with the presence of periodontal pathogens such as Fusobacterium nucleatum, Tannerella forsythia, and Treponema denticola [21]. Because aMMP-8 reflects ongoing collagen degradation rather than only previously accumulated tissue damage, it is considered a potentially useful biomarker for early detection, assessment of disease activity, and monitoring of the therapeutic response [33,34]. Importantly, elevated aMMP-8 appears to distinguish gingivitis from periodontitis more effectively than measurements of total or latent MMP-8 and may identify individuals at increased risk of attachment loss and disease progression [21,33,34]. Recent meta-analyses support the diagnostic potential of both MMP-8 and aMMP-8, although greater methodological standardization across different oral samples is still required before their routine clinical implementation [21]. In addition to its role in periodontal destruction, controlled MMP-8 activity may participate in physiological tissue remodeling and wound healing [35].
MMP-9, or gelatinase B, is released by neutrophils, macrophages, and other inflammatory cells. It degrades gelatin, type IV collagen, and basement membrane components, thereby facilitating leukocyte migration through tissues, microvascular remodeling, and the spread of the inflammatory infiltrate. It also degrades collagens V and XI, proteoglycans, and elastin []. MMP-9 is especially abundant in polymorphonuclear leukocytes and was found in increased levels in junctional epithelium, gingival epithelial cells, and connective tissues in advanced periodontitis [18,21,24]. In neutrophils, MMP-9 can be bound to lipocalin-2 or neutrophil gelatinase-associated lipocalin (NGAL), thereby preventing its inactivation and prolonging its proteolytic activity. Besides its role in connective tissue degradation, MMP-9 may also contribute to osteoclast recruitment, differentiation, and access to the bone surface, thus favoring alveolar bone resorption during periodontitis [24,28,30,36,37]. Within the acidic osteoclastic microenvironment, cathepsin K can activate pro-MMP-9 after mineral dissolution exposes collagen fibers, thereby linking gelatinase activation to degradation of the organic bone matrix. MMP-9 levels generally correlate with periodontal disease severity and decrease after successful periodontal treatment [18,21,24].
MMP-2, also known as gelatinase A, is more constitutively expressed by fibroblasts and other resident cells, and is involved in basal extracellular matrix turnover, although its activity can be increased during periodontal inflammation. MMP-13 has potent activity against fibrillar collagen and participates in the interface between connective tissue and bone remodeling. It can also activate pro-MMP-9. MMP-3 degrades non-collagenous matrix components during periodontitis and activates other pro-MMPs. MMP-7 is associated with epithelial tissues and the processing of several signaling molecules. MMP-12 is associated with activated macrophages, whereas MMP-14 is involved in pericellular invasion, cell migration, and MMP-2 activation, all of which are functions relevant for periodontal inflammation [18,24,26,27,28]. Periodontal bacterial proteases may further intensify this network. Proteases produced by T. denticola can activate MMP-2, promote fibronectin fragmentation, induce apoptosis, and suppress osteoblast differentiation, whereas P. gingivalis may enhance MMP-2 activity, monocyte migration, and MMP-9 expression [18,21,24].
MMP-13, MMP-2, and MMP-14 also cooperate in a proteolytic cascade to amplify extracellular matrix degradation. Pericellular proteolysis is controlled by the membrane-bound MMP-14 that activates latent MMPs, notably pro-MMP-2 and MMP-13. MMP-2 then degrades gelatin, type IV collagen, basement membrane components, and collagen fragments initially generated by collagenases [3,18,30]. These enzymes together contribute to the destruction of connective tissue and the remodeling of alveolar bone that occurs during periodontitis.
Destruction of the periodontal tissues does not occur solely by direct cleavage of matrix components. Proteolytic processing of cytokines, chemokines, receptors, and adhesion molecules can enhance, redirect, or inhibit inflammatory signaling. MMPs liberate entrapped growth factors from the extracellular matrix, alter chemokine gradients, and affect the recruitment and survival of leukocytes. Proteolytic fragments of collagen, fibronectin, and laminin can act as matrikines, i.e., biologically active signals that further modulate inflammation and angiogenesis [18,20,27]. MMPs are not directly responsible for the removal of the mineral component of bone but instead facilitate the removal of osteoid and organic matrix, osteoclast migration, and remodeling of the bone surface. Thus, their activity is functionally associated with the RANKL/OPG axis and cytokine-mediated stimulation of osteoclastogenesis.
Expression and activation of TIMPs are of high relevance to the pathogenesis of periodontitis. The TIMP family consists of four members (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) that are synthesized by fibroblasts, macrophages, endothelial cells, and other resident or infiltrating cells. TIMPs bind to the catalytic domains of active MMPs, limiting excessive proteolysis and thus contributing to extracellular matrix homeostasis and controlled periodontal tissue remodeling [26,28].
TIMP-1 and TIMP-2 in the healthy periodontium limit basal MMP activity and permit controlled collagen turnover. Both MMP and TIMP levels may be elevated in periodontitis, but the increase in inhibitors is usually insufficient to counteract the increased production and activation of proteases. A higher ratio of active MMPs to TIMPs, therefore, favors net extracellular matrix degradation.
TIMP-1 has been studied most extensively in GCF and saliva during periodontitis. TIMP-2 plays a particular role in the regulation of MMP-2 and pericellular proteolysis. TIMP-3 may have an important local protective role due to its broad inhibitory spectrum and binding to the extracellular matrix, although it has been investigated far less extensively in clinical periodontal samples [3,18,22,24,26,27]. Elevated TIMP levels should therefore not automatically be interpreted as protective. The magnitude of simultaneous MMP activity, the MMP/TIMP ratio, and the clinical stage of the disease must also be considered. It is important to note that both MMP and TIMP levels may be elevated in periodontitis, but the increase in inhibitors is usually insufficient to counteract the increased production and activation of proteases. A higher ratio of active MMPs to TIMPs, therefore, favors net extracellular matrix degradation. Thus, alterations in MMP/TIMP ratios may provide more biologically relevant information on net proteolytic activity than the levels of individual MMPs or TIMPs alone, and may serve as markers of periodontal disease activity and treatment response [26,28].
In addition to endogenous TIMPs, several synthetic, pharmacological, and naturally derived MMP inhibitors have been developed or investigated as adjunctive approaches in periodontal therapy. These include hydroxamate-based inhibitors; non-hydroxamate compounds such as carboxylates, sulfonamides, and phosphates; antibody-based inhibitors; bisphosphonates; chlorhexidine; and naturally occurring polyphenols such as proanthocyanidins [21]. However, the mechanisms, selectivity, clinical efficacy, and limitations of these exogenous MMP inhibitors are beyond the scope of the present review.
Most MMPs and TIMPs investigated in periodontitis are measured in GCF because it most directly reflects local periodontal inflammation and ECM degradation. MMP-8 is particularly suitable for non-invasive diagnostic assessment because it can also be reliably detected in saliva, mouth-rinse samples, and peri-implant sulcular fluid [38]. In contrast, MMP-14 is assessed mainly in periodontal tissue samples because of its membrane-bound localization, whereas most other MMPs are predominantly evaluated in GCF [3,18,26,28,30,33].

Photobiomodulation and Its Application in Dentistry

PBM is the use of low-intensity light to modulate the biological activity of cells and tissues without ablation, coagulation, or significant temperature increase. The previously used term low-level laser therapy (LLLT) refers primarily to laser sources, whereas PBM is a broader term that also includes light-emitting diodes (LEDs) and other sources of non-coherent light. Red and near-infrared light, typically within the approximate range of 600–1100 nm, is most commonly used because it penetrates soft tissues relatively well and can initiate photophysical and photochemical reactions within cells [39,40,41,42]. The biological effects of PBM are determined not only by wavelength but also by a combination of power, irradiance, energy density (fluence), exposure time, irradiated area, continuous or pulsed mode, the number and frequency of treatment sessions, and the optical properties of the target tissue. Consequently, the same nominal dose may not produce the same effect when device power, applicator diameter, distance from the tissue, or irradiation time differ. Red light primarily affects more superficial structures, whereas near-infrared light penetrates more deeply. However, the actual amount of energy reaching the target cells depends on absorption and scattering within the epithelium, connective tissue, blood, and mineralized structures [41,43,44]. Precise reporting of all dosimetric parameters is therefore essential for study reproducibility and for the safe translation of experimental findings into clinical practice.
Cytochrome c oxidase, complex IV of the respiratory chain, located in the inner mitochondrial membrane, is considered the most widely accepted primary photoreceptor for red and near-infrared light. Photon absorption may facilitate the dissociation of inhibitory nitric oxide from the enzyme, improve electron transport, and transiently increase mitochondrial membrane potential, ATP synthesis, and the production of low signaling levels of ROS. Besides mitochondria, early cellular responses that promote Ca2+ influx may involve photosensitive and thermosensitive ion channels, especially members of the transient receptor potential (TRP) family [39,41,42]. ATP, ROS, nitric oxide, and Ca2+ then act as second messengers, linking the energy of the absorbed light to changes in metabolism, gene expression, and downstream physiological processes within the cell.
Early redox and calcium signaling induce a plethora of interconnected pathways like MAPK/extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR), NF-κB, AP-1, cAMP response element-binding protein (CREB), hypoxia-inducible factor 1 alpha (HIF-1α), nuclear factor erythroid 2-related factor 2 (Nrf2), transforming growth factor beta/Smad signaling pathway (TGF-β/Smad), and wingless-related integration site/beta-catenin (Wnt/β-catenin) signaling pathway [8,39,40]. The relative importance of these pathways depends on cell type, metabolic state, presence of inflammation, and dose applied. Effects include increased ATP synthesis, activation of antioxidant enzymes, altered expression of cytokines and growth factors, stimulation of cell proliferation and migration, and modulation of stem and progenitor cell differentiation [8,39,42]. PBM has a biphasic (hormetic) dose–response curve. Low and optimal doses can stimulate cellular functions, whereas very high doses may be ineffective or even inhibitory to the desired response. This principle explains why increasing the power or total energy delivered does not necessarily lead to better clinical outcomes. The therapeutic window may be narrow and variable between healthy and inflamed, hypoxic, or metabolically compromised tissues, and between superficial and deeper target structures [40,43,44,45]. The results obtained with one protocol cannot blindly be transferred to another device, anatomic region, or disease.
PBM exerts significant immunomodulatory and anti-inflammatory activities. This therapeutic modality is not a diffuse, universal inhibitor of inflammation but rather a modulator of its intensity and duration. Experimental models and clinical studies showed decreased excessive activation of NF-kB, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2, with reduced production of TNF-a, IL-1β, IL-6, prostaglandin E2, and reactive nitrogen and oxygen species. At the same time, PBM may also increase Nrf2-mediated antioxidant responses, IL-10 production, and mechanisms of resolution of inflammation [40,42]. However, these effects are time- and dose-dependent. Mild stimulation of inflammatory and phagocytic functions during the early phase of tissue repair may be beneficial, whereas PBM may facilitate the transition toward an anti-inflammatory and reparative phenotype at later stages. Of particular interest are the modulation and functional plasticity of macrophages. Under appropriate conditions, PBM may inhibit prolonged M1 polarization and promote M2-like reparative programs, thereby contributing to the clearance of cellular debris, angiogenesis, extracellular matrix remodeling, and tissue restoration. In periodontal and bone models, these processes are closely associated with signaling interactions among immune cells, fibroblasts, endothelial cells, osteoblasts, osteoclasts, and mesenchymal stromal cells [8,46].
In tissue repair, PBM can improve fibroblast survival, proliferation, and migration, increase synthesis of collagen and other extracellular matrix components, and stimulate VEGF expression and neovascularization. Changes in the expression of RUNX2, BMP-2, alkaline phosphatase, osteopontin, and osteocalcin, along with a possible increase in matrix maturation and mineralization, have been reported in osteogenic cells and mesenchymal stromal cells. The systematic analysis of studies involving periodontal ligament stem cells (PDLSCs) shows, in most cases, positive effects on proliferation and osteogenic differentiation, but also confirms significant heterogeneity among studies and the lack of a single optimal treatment protocol [42,46]. The analgesic effects of PBM are probably a combination of reduced local inflammation and edema, modulation of peripheral nerve fiber excitability, alterations in axonal transport, and transient effects on mitochondrial activity in nociceptors. The clinical effect seems to be most prominent in acute or subacute pain and depends on direct light delivery to the target tissue at an appropriate dose. PBM is generally well tolerated, and serious adverse effects are rarely reported. Eye protection, choice of an appropriate applicator, and strict adherence to standardized safety procedures are mandatory [42,43,47,48].
In dentistry, LLLT/PBM is used as an adjunctive modality in periodontology, oral and maxillofacial surgery, implantology, and the management of oral mucositis, temporomandibular disorders, and dentin hypersensitivity, as well as to reduce postoperative pain and promote wound healing [47,48,49,50,51,52]. In orthodontics, it has been investigated for reducing early treatment-related pain, potentially accelerating tooth movement, and supporting periodontal and bone remodeling; however, its effects on the rate of tooth movement are generally moderate and highly protocol-dependent [8]. PBM should therefore be regarded as an adjunctive rather than a replacement therapy, with the selection of indications and irradiation parameters guided by the quality of the available evidence.
In periodontitis, PBM primarily modulates the excessive host inflammatory response by attenuating sustained NF-κB activation and reducing the production of proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), and promoting a more favorable redox balance [6,8,40,53]. PBM may facilitate a shift in macrophage polarization from the proinflammatory M1 phenotype toward pro-resolving and reparative M2-like phenotypes, improve the MMP/TIMP balance, and regulate the RANKL/OPG axis. Through these mechanisms, it may limit extracellular matrix degradation, osteoclastogenesis, and inflammatory resorption of alveolar bone [6,7,8,53]. At the same time, stimulation of fibroblast and periodontal ligament cell proliferation and migration, angiogenesis, collagen synthesis, and osteogenic differentiation may accelerate the repair and regeneration of periodontal tissues. PBM is therefore applied as an adjunct to, rather than a substitute for, conventional periodontal therapy [6,8,53].

Clinical Evidence on the Effects of Photobiomodulation on Matrix Metalloproteinases and Their Tissue Inhibitors in Periodontitis

Ten clinical publications were identified as relevant to the effects of PBM or PBM-related irradiation on MMP/TIMP biomarkers in periodontitis. Based on the characteristics of the interventions, they can be divided into two groups: PBM-compatible studies and mixed laser studies containing a distinct or potentially PBM treatment arm. The main methodological characteristics, patient populations, irradiation parameters, treatment schedules, and analytical methods are presented in Table 1, whereas the narrative part focuses on the relationships between MMP/TIMP-related findings, other GCF biomarkers, and clinical periodontal outcomes.
Seven publications evaluated PBM-compatible protocols. The first clinical evidence that adjunctive LLLT could modulate collagenolytic activity in non-surgical periodontal therapy was shown by Qadri et al. [54]. PBM was associated with greater reductions in probing depth, plaque index, gingival index, and GCF volume than the placebo-treated side. MMP-8 levels increased in the placebo-treated arm but decreased slightly after treatment with PBM. However, the difference between groups was marginally significant. No significant differences between the two sides were observed with regard to elastase activity, IL-1β levels and microbiological findings. Therefore, no widespread suppression of inflammatory or collagenolytic mediators was observed to accompany the clinical response and reduction in GCF flow.
Aykol et al. [55] assessed the effect of PBM as an adjunct to nonsurgical periodontal therapy in smokers and nonsmokers. They showed that PBM produced greater improvements in probing depth, clinical attachment level, and sulcus bleeding index than conventional treatment alone. Clinical benefits were particularly apparent in smokers. Despite these clinical differences, MMP-1, TIMP-1, and the MMP-1/TIMP-1 ratio did not differ significantly between groups. In both groups, MMP-1 and the MMP-1/TIMP-1 ratio decreased during follow-up. These changes were mainly attributable to the resolution of inflammation after mechanical biofilm removal. TGF-β1 also decreased in both groups, whereas basic fibroblast growth factor (bFGF) initially declined and subsequently increased during the later follow-up period. This temporal dynamic of change may represent an early reduction in the inflammatory response, followed by increased reparative activity. However, because none of the GCF biomarker changes differed significantly between the groups, the enhanced clinical response to PBM could not be directly attributed to modulation of MMP-1, TIMP-1, TGF-β1, or bFGF.
Ismaili and Bokonjić [56] reported a distinctly different biochemical response following short-term LLLT. Significant decreases in GCF concentrations of IL-1α and IL-1β and improvements in clinical indices of periodontal inflammation. Conversely, MMP-9 increased after PBM. This indicates that clinical improvement and suppression of the main proinflammatory cytokines are not necessarily accompanied by a decrease in all MMPs. Following treatment, IL-1α correlated positively with MMP-9, whereas MMP-9 correlated negatively with the plaque index and papillary bleeding index. The negative association between MMP-9 and clinical inflammation suggests that its short-term increase may not have represented continuing periodontal destruction. Instead, increased MMP-9 may have been related to leukocyte migration, basement membrane remodeling, angiogenesis, or other processes involved in early tissue repair. Nevertheless, the absence of measurements distinguishing latent from active MMP-9 and the short follow-up period prevent a definitive interpretation of whether this increase in MMP-9 levels represented reparative remodeling or sustained proteolytic activity.
Chen et al. [57] assessed LED-delivered PBM applied either during the active phase of scaling and root planing or during the subsequent healing phase. All treatment protocols significantly improved probing depth, clinical attachment level, gingival bleeding, plaque score, and treatment-associated discomfort. At sites with the greatest initial probing depth and attachment loss, both LED protocols provided greater probing-depth reduction and attachment gain than conventional treatment alone, suggesting that PBM may be particularly beneficial in initially severe periodontal defects. IL-1β and MMP-8 decreased after treatment in all groups, without significant intergroup differences for either biomarker. The protocol applied after completion of mechanical treatment resulted in a numerically greater reduction in MMP-8, although the difference was not statistically significant. Therefore, the clinical benefit observed at the deepest sites was not consistently accompanied by an additional reduction in IL-1β or MMP-8. These findings suggest that the timing of PBM may influence clinical healing, but they do not establish a corresponding timing-dependent effect on the measured GCF biomarkers.
The most complete combined clinical and biochemical assessment of PBM studies included was that of Misra et al. [58]. After open flap debridement, both PBM-treated and control sites showed significant improvements in plaque index, gingival index, probing depth and clinical attachment level, with no significant intergroup differences in the conventional periodontal parameters. In contrast, early wound healing assessed using the Landry index was significantly better at PBM-treated sites during the first and second postoperative weeks. The biochemical findings also indicated a more favorable long-term tissue environment after PBM. MMP-8 and TNF-α decreased in both groups but were significantly lower at PBM-treated sites after six months, whereas OPG increased in both groups and reached significantly higher levels in the PBM group. IL-6 also declined, but neither its intragroup nor intergroup changes were statistically significant. The concomitant reduction in MMP-8 and TNF-α, together with increased OPG, suggests that PBM may attenuate collagenolytic inflammation and favor a less osteoclastogenic local environment. These biochemical changes, accompanied by improved early wound healing, were not reflected in additional long-term gains in probing depth or clinical attachment level.
The two studies by Sopi et al. [59,60] used very low-power intrapocket diode-laser irradiation compatible with the PBM effect. Rather than comparing the laser with an identical nonirradiated protocol, they assessed its clinical effectiveness against SRP or modified Widman flap surgery. Although this design does not isolate a PBM-specific effect, it provides clinically relevant comparative evidence regarding whether low-power laser treatment may be an effective, potentially less invasive alternative to conventional periodontal procedures.
In the earlier study [59], all three approaches (basic periodontal therapy followed by SRP, intrapocket diode-laser treatment, or modified Widman flap surgery) improved periodontal status, but the laser group showed greater improvements in probing depth, clinical attachment level, gingival recession, gingival index, and radiographic bone outcomes. MMP-8 was assessed qualitatively using a dipstick immunoassay. After six months, 96.3% of samples in the laser group were MMP-8-negative, compared with 86.3% in the surgical group and 75.0% in the SRP group. The parallel clinical, radiographic, and biomarker results are in favor of a good treatment response, although no other GCF mediators or direct correlations were found between MMP-8 positivity and clinical outcomes.
The subsequent study [60] similarly found greater probing-depth reduction, clinical attachment gain, and resolution of gingival inflammation after low-power laser treatment than after flap surgery. MMP-8-positive GCF samples decreased from 80% to 4% in the laser group and from 82% to 20% in the surgical group over six months. Such results further confirm the clinical and biochemical effectiveness of the low-power laser protocol. However, the qualitative assay does not reveal information about the MMP-8 concentration or its molecular activity.
Two publications involved mixed laser protocols containing a PBM-related treatment arm. Yang et al. [61] compared SRP alone with SRP combined with Er debridement, Nd irradiation described as PBM, or both modalities. Because Er was used for calculus and granulation-tissue removal, only the SRP plus Nd arm can be considered PBM-related. All laser protocols improved clinical parameters, with the greatest probing-depth reduction and attachment gain in the combined Er plus PBM group. Melatonin increased in all laser-treated groups, whereas MMP-8 showed a different temporal pattern: it decreased in the Er- and PBM-only groups at one month but remained unchanged in the combined group. By three months, MMP-8 had decreased in all groups without significant intergroup differences. Thus, the superior clinical response to the combined protocol was not accompanied by a greater reduction in MMP-8, and the specific contribution of PBM could not be separated from that of Er debridement.
Sayar et al. [62] compared a potentially PBM diode-laser protocol with Er,Cr laser treatment and SRP alone. Clinical parameters improved similarly in all groups, without a significant long-term advantage of either laser protocol over SRP. In contrast, MMP-13 decreased more in both laser groups, particularly after Er,Cr treatment, which also produced the greatest increase in IL-10. These biochemical changes suggest reduced collagenolysis and a more anti-inflammatory local environment but were not accompanied by superior clinical outcomes. Because the stronger response followed Er,Cr treatment and the diode protocol was insufficiently characterized as non-thermal PBM, the study provides only limited evidence for a PBM-specific effect.
In addition to the nine clinical publications, the systematic review by Akram et al. [63] evaluated adjunctive photodynamic therapy and “laser therapy (LT) alone” in relation to inflammatory proteins in GCF, including MMPs. In that review, LT referred broadly to laser irradiation applied without a photosensitizer as an adjunct to scaling and root planing and was not synonymous with PBM. Among the LT studies assessing MMP/TIMP-related outcomes, only Qadri et al. [54] and Aykol et al. [55], which we have already analyzed, could be clearly classified as PBM studies. The remaining LT studies involved pulsed Nd or higher-output intrapocket diode-laser procedures with potential thermal, antimicrobial, or debridement effects and therefore should not be considered unequivocal PBM. The review is relevant to the present analysis because it illustrates how earlier literature grouped mechanistically different laser procedures under the broad LT category.
Overall, MMP-8 was the most studied biomarker in the nine clinical studies and one review, and its levels were generally decreased after periodontal treatment regardless of PBM application. Some studies linked PBM to a greater reduction, while others reported clinical improvement without further changes in MMP-8 or related cytokines. There was limited and inconsistent evidence for MMP-1, MMP-9, MMP-13 and TIMP-1. Biomarker changes did not consistently correlate with clinical outcomes. The results indicate that individual MMPs cannot be reliably used to represent the biological response to PBM. Their interpretation becomes more informative when considered alongside inflammatory cytokines, TIMPs, markers of bone remodeling, wound-healing indices, and conventional clinical parameters.

Limitations of the Review

This narrative review is limited by the small number of eligible studies and the substantial heterogeneity in PBM protocols, comparator treatments, follow-up periods, and biomarker assessment methods. In addition, several studies used PBM-compatible or mixed laser protocols rather than unequivocally defined PBM, thereby limiting direct comparisons and the attribution of observed effects specifically to PBM. These methodological differences precluded a meaningful quantitative synthesis and formal meta-analysis; therefore, the available evidence was considered more appropriate for a structured narrative evaluation.

Conclusion

Current clinical evidence suggests that PBM may modulate MMP-related responses during periodontal healing, but a consistent biomarker effect beyond that achieved with conventional periodontal treatment has not been established. MMP-8 appears to be the most frequently investigated and treatment-responsive marker, although its reduction is not specific to PBM and depends on treatment context, sampling time, molecular form, and analytical method. Evidence for MMP-1, MMP-9, MMP-13, and TIMP-1 remains limited and heterogeneous.
Clinical improvements were frequently observed without corresponding increases in MMP or TIMP levels, whereas certain biochemical effects occurred without superior long-term clinical outcomes. These findings indicate that MMP/TIMP responses represent only one component of the complex periodontal healing process and should be interpreted together with inflammatory cytokines, regulators of bone remodeling, wound-healing parameters, and conventional clinical indices. Future randomized trials should use clearly defined non-thermal PBM parameters, identical background periodontal treatment in test and control groups, quantitative assessment of active MMPs and their corresponding TIMPs, and standardized long-term clinical and biochemical follow-up.

Author Contributions

Conceptualization, B.I, D.B. and M.Č.; resources, B.I, D.B. and M.Č.; writing—original draft preparation, B.I., M.E. and B.K.; writing—review and editing, M.Č.; visualization, B.I., M.E. and B.K.; funding acquisition, B.I, D.B. and M.Č.; All authors have read and agreed to the published version of the manuscript.

Funding

This co-operative project was funded by the Faculty of Dental Medicine, International Balkan University, Skopje, North Macedonia, and the Medical Faculty Foča, University of East Sarajevo, Bosnia and Herzegovina.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

The authors would like to express their gratitude to Maja Čolić for her help in the literature search.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. López-Valverde, N.; Quispe-López, N.; Blanco Rueda, J.A. Inflammation and immune response in the development of periodontal disease: A narrative review. Front. Cell. Infect. Microbiol. 2024, 14, 1493818. [Google Scholar] [CrossRef] [PubMed]
  2. Hajishengallis, G.; Chavakis, T.; Lambris, J.D. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol. 2000 2020, 84, 14–34. [Google Scholar] [CrossRef] [PubMed]
  3. Elgezawi, M.; Haridy, R.; Almas, K.; Abdalla, M.A.; Omar, O.; Abuohashish, H.; Elembaby, A.; Wölfle, U.C.; Siddiqui, Y.; Kaisarly, D. Matrix metalloproteinases in dental and periodontal tissues and their current inhibitors: Developmental, degradational and pathological aspects. Int. J. Mol. Sci. 2022, 23, 8929. [Google Scholar] [CrossRef] [PubMed]
  4. Sanz, M.; Herrera, D.; Kebschull, M.; Chapple, I.; Jepsen, S.; Berglundh, T.; Sculean, A.; Tonetti, M.S. Treatment of stage I–III periodontitis—The EFP S3 level clinical practice guideline. J. Clin. Periodontol. 2020, 47 (Suppl. 22), 4–60. [Google Scholar] [CrossRef] [PubMed]
  5. Donos, N.; Calciolari, E.; Brusselaers, N.; Goldoni, M.; Bostanci, N.; Belibasakis, G.N. The adjunctive use of host modulators in non-surgical periodontal therapy. A systematic review of randomized, placebo-controlled clinical studies. J. Clin. Periodontol. 2020, 47 (Suppl. 22), 199–238. [Google Scholar] [CrossRef] [PubMed]
  6. Ren, C.; McGrath, C.; Jin, L.; Zhang, C.; Yang, Y. The effectiveness of low-level laser therapy as an adjunct to non-surgical periodontal treatment: A meta-analysis. J. Periodontal Res. 2017, 52, 8–20. [Google Scholar] [CrossRef] [PubMed]
  7. Dalvi, S.; Benedicenti, S.; Hanna, R. Effectiveness of photobiomodulation as an adjunct to nonsurgical periodontal therapy in the management of periodontitis—A systematic review of in vivo human studies. Photochem. Photobiol. 2021, 97, 223–242. [Google Scholar] [CrossRef] [PubMed]
  8. Marković, J.; Čolić, M. Photobiomodulation meets mechanotransduction: Immune–stromal crosstalk in orthodontic remodeling. Biomedicines 2025, 13, 2495. [Google Scholar] [CrossRef] [PubMed]
  9. Łasica, A.; Golec, P.; Laskus, A.; Zalewska, M.; Gędaj, M.; Popowska, M. Periodontitis: Etiology, conventional treatments, and emerging bacteriophage and predatory bacteria therapies. Front. Microbiol. 2024, 15, 1469414. [Google Scholar] [CrossRef] [PubMed]
  10. Lamont, R.J.; Hajishengallis, G. Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol. Med. 2015, 21, 172–183. [Google Scholar] [CrossRef] [PubMed]
  11. Maekawa, T.; Krauss, J.L.; Abe, T.; Jotwani, R.; Triantafilou, M.; Triantafilou, K.; Hashim, A.; Hoch, S.; Curtis, M.A.; Nussbaum, G.; Lambris, J.D.; Hajishengallis, G. Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 2014, 15, 768–778. [Google Scholar] [CrossRef] [PubMed]
  12. Bassani, B.; Cucchiara, M.; Butera, A.; Kayali, O.; Chiesa, A.; Palano, M.T.; Olmeo, F.; Gallazzi, M.; Dellavia, C.P.B.; Mortara, L.; Parisi, L.; Bruno, A. Neutrophils’ contribution to periodontitis and periodontitis-associated cardiovascular diseases. Int. J. Mol. Sci. 2023, 24, 15370. [Google Scholar] [CrossRef] [PubMed]
  13. Sczepanik, F.S.C.; Grossi, M.L.; Casati, M.; Goldberg, M.; Glogauer, M.; Fine, N.; Tenenbaum, H.C. Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol. 2000 2020, 84, 45–68. [Google Scholar] [CrossRef] [PubMed]
  14. Aral, K.; Milward, M.R.; Kapila, Y.; Berdeli, A.; Cooper, P.R. Inflammasomes and their regulation in periodontal disease: A review. J. Periodontal Res. 2020, 55, 473–487. [Google Scholar] [CrossRef] [PubMed]
  15. Zhao, Y.; Quan, Y.; Lei, T.; Fan, L.; Ge, X.; Hu, S. The role of inflammasome NLPR3 in the development and therapy of periodontitis. Int. J. Med. Sci. 2022, 19, 1603–1614. [Google Scholar] [CrossRef] [PubMed]
  16. Chen, Y.; Yang, Q.; Lv, C.; Chen, Y.; Zhao, W.; Li, W.; Chen, H.; Wang, H.; Sun, W.; Yuan, H. NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation. Cell Prolif. 2021, 54, e12973. [Google Scholar] [CrossRef] [PubMed]
  17. Chen, Q.; Liu, X.; Wang, D.; Zheng, J.; Chen, L.; Xie, Q.; Liu, X.; Niu, S.; Qu, G.; Lan, J.; Li, J.; Yang, C.; Zou, D. Periodontal inflammation-triggered by periodontal ligament stem cell pyroptosis exacerbates periodontitis. Front. Cell Dev. Biol. 2021, 9, 663037. [Google Scholar] [CrossRef] [PubMed]
  18. Franco, C.; Hernández-Ríos, P.; Sorsa, T.; Biguetti, C.; Hernández, M. Matrix metalloproteinases as regulators of periodontal inflammation. Int. J. Mol. Sci. 2017, 18, 440. [Google Scholar] [CrossRef] [PubMed]
  19. Lee, C.-T.; Teles, R.; Kantarci, A.; Chen, T.; McCafferty, J.; Starr, J.R.; Brito, L.C.N.; Paster, B.J.; Van Dyke, T.E. Resolvin E1 reverses experimental periodontitis and dysbiosis. J. Immunol. 2016, 197, 2796–2806. [Google Scholar] [CrossRef] [PubMed]
  20. Visse, R.; Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ. Res. 2003, 92, 827–839. [Google Scholar] [CrossRef] [PubMed]
  21. Mendoza-Juárez, D.; Sánchez-Gutiérrez, M.; Izquierdo-Vega, A.J.; Madrigal-Santillán, E.O.; Velázquez-González, C.; Izquierdo-Vega, J.A. Matrix metalloproteinase inhibitors and their potential clinical application in periodontitis. Diseases 2025, 13, 296. [Google Scholar] [CrossRef] [PubMed]
  22. Brew, K.; Nagase, H. The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochim. Biophys. Acta 2010, 1803, 55–71. [Google Scholar] [CrossRef] [PubMed]
  23. Sorsa, T.; Tjäderhane, L.; Salo, T. Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis. 2004, 10, 311–318. [Google Scholar] [CrossRef] [PubMed]
  24. Charles, K.; Honibald, E.N.; Raghavendra, R.N.; Palani, A.K.P.; Ramamurthy, R.D.; Sankaralingam, T. Role of matrix metalloproteinases (MMPs) in periodontitis and its management. J. Indian Acad. Dent. Spec. Res. 2014, 1, 65–69. [Google Scholar] [CrossRef]
  25. Emingil, G.; Kuula, H.; Sorsa, T.; Atilla, G. Gingival crevicular fluid matrix metalloproteinase-25 and -26 levels in periodontal disease. J. Periodontol. 2006, 77, 664–671. [Google Scholar] [CrossRef] [PubMed]
  26. Checchi, V.; Maravic, T.; Bellini, P.; Generali, L.; Consolo, U.; Breschi, L.; Mazzoni, A. The role of matrix metalloproteinases in periodontal disease. Int. J. Environ. Res. Public Health 2020, 17, 4923. [Google Scholar] [CrossRef] [PubMed]
  27. Radzki, D.; Negri, A.; Kusiak, A.; Obuchowski, M. Matrix metalloproteinases in the periodontium—Vital in tissue turnover and unfortunate in periodontitis. Int. J. Mol. Sci. 2024, 25, 2763. [Google Scholar] [CrossRef] [PubMed]
  28. Sorsa, T.; Tjäderhane, L.; Konttinen, Y.T.; Lauhio, A.; Salo, T.; Lee, H.M.; Golub, L.M.; Brown, D.L.; Mäntylä, P. Matrix metalloproteinases: Contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann. Med. 2006, 38, 306–321. [Google Scholar] [CrossRef] [PubMed]
  29. Behm, C.; Nemec, M.; Weissinger, F.; Rausch, M.A.; Andrukhov, O.; Jonke, E. MMPs and TIMPs expression levels in the periodontal ligament during orthodontic tooth movement: A systematic review of in vitro and in vivo studies. Int. J. Mol. Sci. 2021, 22, 6967. [Google Scholar] [CrossRef] [PubMed]
  30. Toby Thomas, J.; Joseph, B.; Waltimo, T.; Anil, S. Matrix metalloproteinases (MMPs) in periodontium: Is it a boon or a bane? In Advances in Gingival Diseases and Conditions; Sufaru, I.-G., Solomon, S.M., Eds.; IntechOpen: London, UK, 2024; Volume 20. [Google Scholar] [CrossRef]
  31. Mendoza-Juárez, D.; Sánchez-Gutiérrez, M.; Izquierdo-Vega, A.J.; Madrigal-Santillán, E.O.; Velázquez-González, C.; Izquierdo-Vega, J.A. Matrix metalloproteinase inhibitors and their potential clinical application in periodontitis. Diseases 2025, 13, 296. [Google Scholar] [CrossRef] [PubMed]
  32. Räisänen, I.T.; Aji, N.R.A.S.; Sakellari, D.; Grigoriadis, A.; Rantala, I.; Pätilä, T.; Heikkilä, P.; Gupta, S.; Sorsa, T. Active matrix metalloproteinase-8 (aMMP-8) versus total MMP-8 in periodontal and peri-implant disease point-of-care diagnostics. Biomedicines 2023, 11, 2885. [Google Scholar] [CrossRef] [PubMed]
  33. Zalewska, E.A.; Ławicka, R.; Grygorczuk, P.; Nowosielska, M.; Kicman, A.; Ławicki, S. Importance of metalloproteinase 8 (MMP-8) in the diagnosis of periodontitis. Int. J. Mol. Sci. 2024, 25, 2721. [Google Scholar] [CrossRef] [PubMed]
  34. Fatemi, K.; Rezaee, S.A.; Banihashemrad, S.A.; Keyvanfar, S.; Eslami, M. Importance of MMP-8 in salivary and gingival crevicular fluids of periodontitis patients. Iran. J. Immunol. 2020, 17, 236–243. [Google Scholar] [CrossRef] [PubMed]
  35. Nwomeh, B.C.; Liang, H.X.; Diegelmann, R.F.; Cohen, I.K.; Yager, D.R. Dynamics of the matrix metalloproteinases MMP-1 and MMP-8 in acute open human dermal wounds. Wound Repair Regen. 1998, 6, 127–134. [Google Scholar] [CrossRef] [PubMed]
  36. Fuller, K.; Kirstein, B.; Chambers, T.J. Regulation and enzymatic basis of bone resorption by human osteoclasts. Clin. Sci. 2007, 112, 567–575. [Google Scholar] [CrossRef] [PubMed]
  37. Delaissé, J.M.; Andersen, T.L.; Engsig, M.T.; Henriksen, K.; Troen, T.; Blavier, L. Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities. Microsc. Res. Tech. 2003, 61, 504–513. [Google Scholar] [CrossRef] [PubMed]
  38. Domokos, Z.; Simon, F.; Uhrin, E.; Szabó, B.; Váncsa, S.; Varga, G.; Hegyi, P.; Kerémi, B.; Németh, O. Evaluating salivary MMP-8 as a biomarker for periodontal diseases: A systematic review and meta-analysis. Heliyon 2024, 10, e40402. [Google Scholar] [CrossRef] [PubMed]
  39. de Freitas, L.F.; Hamblin, M.R. Proposed mechanisms of photobiomodulation or low-level light therapy. IEEE J. Sel. Top. Quantum Electron. 2016, 22, 7000417. [Google Scholar] [CrossRef] [PubMed]
  40. Hamblin, M.R. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys. 2017, 4, 337–361. [Google Scholar] [CrossRef] [PubMed]
  41. Heiskanen, V.; Hamblin, M.R. Photobiomodulation: Lasers vs. light emitting diodes? Photochem. Photobiol. Sci. 2018, 17, 1003–1017. [Google Scholar] [CrossRef]
  42. Dompe, C.; Moncrieff, L.; Matys, J.; Grzech-Leśniak, K.; Kocherova, I.; Bryja, A.; Bruska, M.; Dominiak, M.; Mozdziak, P.; Ishimine Skiba, T.H.; Shibli, J.A.; Angelova Volponi, A.; Kempisty, B.; Dyszkiewicz-Konwińska, M. Photobiomodulation—Underlying mechanism and clinical applications. J. Clin. Med. 2020, 9, 1724. [Google Scholar] [CrossRef] [PubMed]
  43. Parker, S.; Cronshaw, M.; Anagnostaki, E.; Bordin-Aykroyd, S.R.; Lynch, E. Systematic review of delivery parameters used in dental photobiomodulation therapy. Photobiomodul. Photomed. Laser Surg. 2019, 37, 784–797. [Google Scholar] [CrossRef] [PubMed]
  44. Cronshaw, M.; Parker, S.; Anagnostaki, E.; Mylona, V.; Lynch, E.; Grootveld, M. Photobiomodulation dose parameters in dentistry: A systematic review and meta-analysis. Dent. J. 2020, 8, 114. [Google Scholar] [CrossRef] [PubMed]
  45. Huang, Y.-Y.; Chen, A.C.-H.; Carroll, J.D.; Hamblin, M.R. Biphasic dose response in low level light therapy. In Dose-Response; Hamblin, Ed.; 2009; Volume 7, pp. 358–383. [Google Scholar] [CrossRef]
  46. Mylona, V.; Anagnostaki, E.; Chiniforush, N.; Barikani, H.; Lynch, E.; Grootveld, M. Photobiomodulation effects on periodontal ligament stem cells: A systematic review of in vitro studies. Curr. Stem Cell Res. Ther. 2024, 19, 544–558. [Google Scholar] [CrossRef] [PubMed]
  47. da Silva, R.C.M.; da Silva, L.G.C.; Martins, A.A.; de Araújo, C.M.; Martins, A.R.L.A. Adjunctive photobiomodulation to basic periodontal therapy using different low-power laser application techniques: A systematic review and meta-analysis. Lasers Med. Sci. 2024, 39, 207. [Google Scholar] [CrossRef] [PubMed]
  48. Zadik, Y.; Arany, P.R.; Fregnani, E.R.; Bossi, P.; Antunes, H.S.; Bensadoun, R.-J.; Gueiros, L.A.; Majorana, A.; Nair, R.G.; Ranna, V.; Tissing, W.J.E.; Vaddi, A.; Lubart, R.; Migliorati, C.A.; Lalla, R.V.; Cheng, K.K.F.; Elad, S. Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. Support. Care Cancer 2019, 27, 3969–3983. [Google Scholar] [CrossRef] [PubMed]
  49. Hosseinpour, S.; Tunér, J.; Fekrazad, R. Photobiomodulation in oral surgery: A review. Photobiomodul. Photomed. Laser Surg. 2019, 37, 814–825. [Google Scholar] [CrossRef] [PubMed]
  50. Xu, G.Z.; Jia, J.; Jin, L.; Li, J.H.; Wang, Z.Y.; Cao, D.Y. Low-level laser therapy for temporomandibular disorders: A systematic review with meta-analysis. Pain Res. Manag. 2018, 2018, 4230583. [Google Scholar] [CrossRef] [PubMed]
  51. Saini, R.S.; Kanji, M.A.; Okshah, A.; Alshadidi, A.A.F.; Binduhayyim, R.I.H.; Vyas, R.; Aldosari, L.I.N.; Vardanyan, A.; Mosaddad, S.A.; Heboyan, A. Comparative efficacy of photobiomodulation on osseointegration in dental implants: A systematic review and meta-analysis. Photodiagnosis Photodyn. Ther. 2024, 48, 104256. [Google Scholar] [CrossRef] [PubMed]
  52. Giansiracusa, A.; Parrini, S.; Baldini, N.; Bartali, E.; Chisci, G. The effect of photobiomodulation on third molar wound recovery: A systematic review with meta-analysis. J. Clin. Med. 2024, 13, 5402. [Google Scholar] [CrossRef] [PubMed]
  53. Zhang, R.; Ma, X.; Song, J.; Guo, X.; Chen, Z.; Liu, T.; Wu, M. Effects of laser regulation on anti-inflammatory and osteogenic differentiation of periodontal ligament stem cells though NF-κB signaling pathway. BMC Oral Health 2025, 25, 1822. [Google Scholar] [CrossRef] [PubMed]
  54. Qadri, T.; Miranda, L.; Tunér, J.; Gustafsson, A. The short-term effects of low-level lasers as adjunct therapy in the treatment of periodontal inflammation. J. Clin. Periodontol. 2005, 32, 714–719. [Google Scholar] [CrossRef] [PubMed]
  55. Aykol, G.; Baser, U.; Maden, I.; Kazak, Z.; Onan, U.; Tanrikulu-Kucuk, S.; Ademoglu, E.; Issever, H.; Yalcin, F. The effect of low-level laser therapy as an adjunct to non-surgical periodontal treatment. J. Periodontol. 2011, 82, 481–488. [Google Scholar] [CrossRef] [PubMed]
  56. Ismaili, B.; Bokonjić, D. Short-term low-level laser therapy attenuates inflammation and production of interleukin-1, but elevates the level of matrix metalloproteinase-9 in chronic periodontitis. J. Int. Dent. Med. Res. 2014, 7(1), 7–13. [Google Scholar]
  57. Chen, Y.-W.; Hsieh, O.; Chen, Y.-A.; Chiou, L.-L.; Chang, P.-C. Randomized controlled clinical effectiveness of adjunct 660-nm light-emitting diode irradiation during non-surgical periodontal therapy. J. Formos. Med. Assoc. 2020, 119 1 Pt 1, 157–163. [Google Scholar] [CrossRef] [PubMed]
  58. Misra, P.; Kalsi, R.; Arora, S.A.; Singh, K.S.; Athar, S.; Saini, A. Effect of low-level laser therapy on early wound healing and levels of inflammatory mediators in gingival crevicular fluid following open flap debridement. Cureus 2023, 15(2), e34755. [Google Scholar] [CrossRef] [PubMed]
  59. Sopi, M.; Koçani, F.; Bardhoshi, M.; Meqa, K. Clinical and biochemical evaluation of the effect of diode laser treatment compared to the non-surgical and surgical treatment of periodontal diseases. Open Dent. J. 2020, 14, 281–288. [Google Scholar] [CrossRef]
  60. Sopi, M.; Koçani, F.; Bardhoshi, M.; Meqa, K. The effect of periodontal therapy on the level of MMP-8 in patients with chronic periodontitis. Eur. J. Dent. 2023, 17(1), 70–75. [Google Scholar] [CrossRef] [PubMed]
  61. Yang, B.; Li, H.; Zhang, P.; Wang, B. Effectiveness of Er:YAG laser combined with photobiomodulation on periodontitis based on 3-month observation. Oral Health Prev. Dent. 2022, 20, 193–198. [Google Scholar] [CrossRef] [PubMed]
  62. Sayar, F.; Hashemi, S.; Chiniforush, N.; Seyed Jafari, E.; Jandaghi, A. Effects of diode and erbium lasers as an adjunct to scaling and root planing on clinical and immunological parameters in non-surgical periodontal treatment: A split-mouth randomized controlled clinical trial—“Effects of lasers on immunological parameters”. Lasers Med. Sci. 2022, 37(7), 3021–3030. [Google Scholar] [CrossRef] [PubMed]
  63. Akram, Z.; Abduljabbar, T.; Sauro, S.; Daood, U. Effect of photodynamic therapy and laser alone as adjunct to scaling and root planing on gingival crevicular fluid inflammatory proteins in periodontal disease: A systematic review. Photodiagn. Photodyn. Ther. 2016, 16, 142–153. [Google Scholar] [CrossRef] [PubMed]
Table 1. Clinical publications evaluating PBM or PBM-related irradiation effects on MMP/TIMP biomarkers in periodontitis.
Table 1. Clinical publications evaluating PBM or PBM-related irradiation effects on MMP/TIMP biomarkers in periodontitis.
Study Population/design PBM-related protocol Biomarker(s) MMP/TIMP findings Clinical/other findings
Qadri et al., 2005 [54] Moderate CP; n=17; split-mouth, double-blind RCT Bilateral SRP; PBM 635 nm/10 mW/90 s + 830 nm/70 mW/25 s, weekly ×6; contralateral placebo GCF MMP-8; IL-1β; elastase PBM: slight ↓MMP-8; placebo: ↑; between-group p=0.052 (NS) PBM: greater ↓PD/GI/PI/GCF volume; IL-1β, elastase and microbiology ↔
Aykol et al., 2011 [55] Moderate–advanced CP; n=36; RCT; smokers/non-smokers SRP ± 808-nm GaAlAs PBM (0.25 W; 4 J/cm²; non-contact), d1, d2, d7; FU 1, 3, 6 mo GCF MMP-1; TIMP-1; ratio; TGF-β1; bFGF Both: ↓MMP-1 and ↓MMP-1/TIMP-1; TIMP-1 ↔; between-group ↔ PBM: greater ↓SBI/PD and ↑CAL, strongest in smokers; TGF-β1 ↓; bFGF early ↓ then ↑; between-group ↔
Ismaili & Bokonjić, 2014 [56] CP; n=36; RCT Scaling ± 635-nm LLLT (100 mW/cm²), daily ×9; FU d10 GCF MMP-9; IL-1α; IL-1β PBM: ↑MMP-9; +corr with IL-1α; −corr with PI/PBI PBM: ↓IL-1α/IL-1β and improved periodontal indices/gingival inflammation
Chen et al., 2020 [57] Severe CP; n=19; randomized split-mouth crossover NSPT + 660-nm LED (10 J/cm²; 3 min/d) during SRP, after SRP, or no LED GCF MMP-8; IL-1β All groups: ↓MMP-8 and ↓IL-1β; between-group ↔; greatest numerical ↓MMP-8 with post-SRP LED All improved; LED: greater ↓PD/↑CAL at deepest sites and ↓discomfort
Misra et al., 2023 [58] CP; n=40; split-mouth RCT OFD ± 890-nm diode PBM (1.5 W; 30 s ×2; baseline, d3, d7); FU 6 mo GCF MMP-8; TNF-α; IL-6; OPG Both: ↓MMP-8; PBM: greater ↓ at 6 mo Both: ↓PI/GI/PD and ↑CAL; PBM: ↑early healing, ↓TNF-α, ↑OPG; IL-6 ↔
Sopi et al., 2020 [59] CP; n=80; CCS Basic therapy + intrapocket 980-nm laser (10 mW; 1 min/tooth) vs SRP vs MWF; FU 6 mo GCF MMP-8 dipstick (+/−) MMP-8-negative at 6 mo: laser 96.3%; MWF 86.3%; SRP 75.0% Laser: greater ↓PPD/GR/GI and ↑CAL/bone gain; other GCF markers NA
Sopi et al., 2023 [60] Generalized Stage III periodontitis; n=100; randomized single-blind study Basic therapy + intrapocket 980-nm laser (10 mW; 1 min/pocket) vs MWF; FU 6 mo GCF MMP-8 dipstick (+/−) MMP-8-positive samples: laser 80%→4%; MWF 82%→20% Both improved; laser: greater ↓PPD/GI and ↑CAL; other GCF markers NA
Yang et al., 2022 [61] Severe periodontitis; n=50; randomized split-mouth, 4 arms SRP alone, +Er:YAG debridement, +Nd:YAG PBM, or combined; FU 1 and 3 mo GCF MMP-8; melatonin 1 mo: combined ↔, other arms ↓; 3 mo: ↓ in all arms; between-group ↔ Laser arms improved; combined: greatest ↓PD/PLI/BI and ↑CAL; melatonin ↑ in all laser arms (max combined); pain ↓ at d7
Sayar et al., 2022 [62] Periodontitis; n=17; split-mouth RCT SRP + 940-nm diode (1 W; CW) or Er,Cr:YSGG 2780 nm (1.5 W; 30 Hz); FU 2 and 6 mo GCF MMP-13; IL-10 Both lasers: ↓MMP-13 vs SRP; greater ↓ with Er,Cr:YSGG All groups improved; long-term clinical superiority ↔; IL-10 ↑ most with Er,Cr:YSGG
Akram et al., 2016 [63] Systematic review; 8 aPDT + 10 LT studies; search through Jul 2016 LT = laser without photosensitizer + SRP; heterogeneous protocols; LT ≠ PBM GCF inflammatory proteins incl. MMP-8 and TIMP-1 LT: significant ↓MMP-8 in 3 studies and ↓TIMP-1 in 1; overall evidence inconclusive Clear PBM among LT MMP/TIMP studies: Qadri 2005 and Aykol 2011; other LT protocols not unequivocal PBM
Symbols: ↓, decrease/reduction; ↑, increase/improvement; ↔, no significant change/difference; +/−, positive/negative; NS, not significant; +corr/−corr, positive/negative correlation. Abbreviations: aPDT, antimicrobial photodynamic therapy; bFGF, basic fibroblast growth factor; CAL, clinical attachment level; CCS, comparative clinical study; CP, chronic periodontitis; CW, continuous wave; d, day; FU, follow-up; GCF, gingival crevicular fluid; GI, gingival index; GR, gingival recession; LED, light-emitting diode; LLLT, low-level laser therapy; LT, laser therapy without a photosensitizer; MMP, matrix metalloproteinase; mo, month; MWF, modified Widman flap; NA, not assessed; NSPT, non-surgical periodontal therapy; OFD, open flap debridement; OPG, osteoprotegerin; PBI, papillary bleeding index; PBM, photobiomodulation; PD/PPD, probing depth/probing pocket depth; PI/PLI, plaque index; RCT, randomized controlled trial; SBI, sulcus bleeding index; SRP, scaling and root planing; TIMP, tissue inhibitor of metalloproteinases; TNF-α, tumor necrosis factor-α.
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