wound healing is a highly coordinated and carefully orchestrated process to promote proper healing [ 1 , 2 ] . this process forms the ecm that enhances cellular processes in the wound , including cell adhesion , migration , and tissue remodelling . matrix metalloproteinases ( mmps ) are zinc endopeptidases capable of degrading all components of the extracellular matrix ( ecm ) . they participate in all the phases of wound healing by removing damaged proteins and temporary ecm during the inflammatory phase , breaking down the capillary basement membrane in the proliferation phase for angiogenesis and cell migration , as well as contracting and remodelling tissue in the remodelling phase . in addition , mmps interplay the activity of a few growth factors and polymorphonuclear cells ( pmns ) [ 410 ] . the mmp family comprises enzymes based on their substrate specificity , collagenases ( mmp-1 , mmp-8 , mmp-13 , and mmp-18 ) , gelatinases ( mmp-2 and mmp-9 ) , stromelysins ( mmp-3 , mmp-10 , and mmp-11 ) , membrane type ( mt ) metalloproteinases ( mmp-14 , mmp-15 , mmp-16 , mmp-17 , mmp-24 , and mmp-25 ) , matrilysins ( mmp-7 and mmp-26 ) , and others ( mmp-12 , mmp-19 , mmp-20 , mmp-21 , mmp-23 , mmp-27 , and mmp-28 ) [ 11 , 12 ] . they are comprised of three histidines conserved on the zinc site as well as a conserved methionine below the active site . gelatinases ( mmp-2 and mmp-9 ) and collagenases ( mmp-1 and mmp-8 ) are particularly involved in the wound healing process . tissue inhibitor of metalloproteinase ( timp ) , of which there are four different subtypes ( timp-1 , timp-2 , timp-3 , and timp-4 ) , interrupts the action of mmps and thus regulates their action . timps attach to alternate or active sites of mmps and are capable of inhibiting all mmps , although their affinity levels may differ . even though the importance of mmps in wound healing can not be underestimated , they can negatively affect healing if not present in the correct amount [ 14 , 15 ] . under normal conditions , the interaction of mmps with growth factors and receptors is capable of maintaining the balance of the ecm . in such circumstances , however , predictors of healing will depend on the ratio between mmps and timps . within the ecm , an imbalance of these matrix proteins and their inhibitors may cause degradation of the matrix   and is associated with proteolytic enzymes distributed in several groups involved in disease development . it also increases the level of proteases and mmps , especially mmp-1 , mmp-2 , mmp-8 , and mmp-9 , and proinflammatory cytokines such as interleukin-1 ( il-1 ) and tumour necrosis factor - alpha ( tnf- ) released by neutrophils and macrophages . the imbalance is associated with abnormal wound healing conditions such as those in diabetes mellitus ( dm ) and other vascular complications [ 19 , 20 ] . mmps control the composition of ecm in various vascular and nonvascular inflammatory conditions [ 4 , 5 , 79 , 21 ] . when an injury occurs , in the vascular system , it initiates an inflammatory reaction . some of the events include inflammation , activation of pmns , and release of mmps . inflammatory cytokines such as il1- , il1- , il-2 , il-17 , c - reactive protein ( crp ) , insulin - like growth factor-1 ( ilgf-1 ) , and tgf- stimulate the production of neutrophil gelatinase - associated lipocalin ( ngal ) . this process occurs during the onset and healing phases of nonhealing venous ulcers [ 9 , 22 , 23 ] . this serves as a contributing factor to delayed wound healing even though it is not clear how many biochemical factors are involved . several studies have supported the central role played by ngal in the activation of mmps , especially mmp-9 in delayed wound healing [ 710 , 22 , 24 ] . observed that mmp-1 and mmp-8 are pivotal in normal wound healing ; however , overexpression was seen in patients with nonhealing chronic venous ulcers ( cvus ) as compared to patients with healing ulcers undergoing normal and physical treatment . similarly , serra et al .   also found mmp and ngal to be pivotal in arterial aneurysms due to high levels seen in patient 's plasma . they concluded that the use of mmps as molecular markers to prevent aneurysmal rupture was vital . in contrast , karlsson et al .   did not find any correlation between mmp , ngal , and inflammatory cytokines in their investigation . most authors concluded and linked the association of mmp / ngal to the pathophysiology of chronic wounds during the inflammatory and proliferative phases , whereby proteases appear to be significantly high , resulting in repeated migration of neutrophils , pmns , and macrophages to the wound site . they concluded that overexpression of these proteins could have prolonged the inflammatory phase due to excessive collagenolytic properties and neutrophils resulting in delayed wound healing [ 810 , 22 , 24 ] . furthermore , the production of mmps and endotoxins , provoked by high metabolic activity of bacteria due to replication , has influenced the wound progression at different stages negatively . infections are predominant with improper regulation of the immune defence system and a factor favouring bacterial growth , which may cause the wound to remain chronic , except for the eradication of the causative agent . many studies have confirmed the major role of mmps in infectious diseases [ 10 , 2628 ] . during unfavourable conditions , mmp degrades the ecm causing immune cells to migrate to initiate inflammatory response or proteolysis to eradicate the pathogen [ 29 , 30 ] . the bacterial colonisation depends on several factors and patients with persistent infections are more predisposed to prolonged healing and care [ 31 , 32 ] . hyperglycaemia induces the majority of the micro- and macrovascular complications associated with dm   and increases mmp activity directly or indirectly through oxidative stress or advanced glycation end products ( ages ) ( figure 1 ) [ 14 , 20 , 34 ] . there are significantly higher levels of mmp in patients with metabolic syndrome as compared with normal individuals . the process of wound healing necessitates ecm degradation to be controlled ; thus an imbalance between ecm formation and the degradation process could lead to the development of chronic ulcers or fibrosis . cellular and biochemical imbalances , tissue damage , or other disease conditions may present varied effects in the healing process . this also upsets the proteases , cytokines , and growth factors leading to an absence or delay of wound closure preventing successful skin repair [ 14 , 15 , 36 ] . there is a serious concern in the health sector regarding the unresolved problems associated with venous leg ulcers ( vlu ) and diabetes , which may not only be associated with pain , depreciated life , and/or eventual death , but also pose a severe economic burden [ 3739 ] . diabetic foot ulcer is common among any age group   and is predominantly seen in those over the age of 65 years with an occurrence of more than 3%   and an incidence of more than 1% of the world population . an increased proteolytic environment provoked by an alteration in mmps and timps affects patients with diabetic ulcers . recent indications have shown the association of mmps and their inhibitors with diabetic development and progression to be poor [ 43 , 44 ] . increased activities and levels of mmp-1 , mmp-8 , and mmp-9 have been identified in slow - to - heal wounds , with relatively low timp levels . neutrophil derived mmp-8 may be up to 50100 times higher as compared to normal wounds due to chronic inflammation [ 15 , 4547 ] . mmp-9 degrades fibronectin into fragments , which further activates mmp , cell migration , and proliferation . mmp-1 , mmp-8 , and mmp-9 are highly expressed in venous wounds in the absence of timps [ 5 , 7 , 23 ] . studied the expression of mmp-8 and mmp-26 in human cutaneous wounds and concluded that mmp-8 and mmp-26 could be associated with both acute and chronic wounds . khattri and colleagues , after examining 388 subjects , found an overexpression of mmp-2 and mmp-9 in the serum of patients with metabolic syndrome as compared to controls . they concluded that altered expression of mmps may provoke pathogenesis in several tissues [ 13 , 50 , 51 ] . singh et al .   elucidated altered gene expression in mmp-9 as a cause of nonhealing diabetic ulcers , whereby diabetic wounds as compared to the controls had significant unmethylated mmp-9 gene promoter status that could be a result of impaired mmp expression in such wounds . according to lobmann , mmp-1 , mmp-2 , mmp-8 , and mmp-9 were highly expressed in normal and chronic diabetic wounds with a decrease in timp-2 . they concluded that this could be due to high proteolytic surroundings promoting poor healing in diabetes . similarly , there was an overexpression of mmp-1 and mmp-9 , as well as timp-1 , in keratinocytes derived from foot ulcers in diabetic type 1 patients . in addition , menghini and colleagues   found mmp-9 to be increased and timp-3 to be decreased in diabetic type 2 patients . they suggested that the progression of ulcers could be due to a poor proteolytic environment . they concluded that new therapeutic strategies should focus on increasing the expression levels of timp-3 . dinh and colleagues   found increased expression of mmp-9 , tnf- , and other growth factors in diabetic foot ulcers and concluded that they could be linked with slow - to - heal ulcers in diabetics and therefore a target for new therapeutic management . these studies have all ascertained that mmps and timps are elevated in chronic wounds ; however , they may also play a role in determining the level of chronicity . uccioli et al .   elucidated that chronicity is associated with an increase mainly in mmp-9 and mmp-8 and elastase activity that may eventually alter collagen synthesis and the release of growth factor and cytokines into the site of injury . death and colleagues   found that hyperglycaemia affected the regulation of mmp / timp and increased the activities of mmp-1 , mmp-2 , and mmp-9 in vascular cells , stimulating the degradation of the ecm and causing an imbalance in diabetes . chung and colleagues   elucidated that an increase in expression of mmp-2 and mmp-9 as well as protein expression of timp-1 may be a resulting factor in impaired wound healing and might provide an explanation for human arterial vasculature in type 2 dm . some of the pathophysiological events responsible for initiating cvus are inflammation , pmn activation , and the release of proteases , especially mmps . many different compounds incorporated into conventional treatment have improved the quality of life in patients suffering from difficult - to - heal wounds . compounds such as bioflavonoids , nutraceuticals , and glycoaminoglycans such as sulodexide ( sdx ) and cilostazol , together with conventional treatments , have improved healing and clinical conditions of patients [ 4 , 5 , 10 ] . in a recent study done by serra and colleagues   on the effects of new nutraceutical substances , the researchers found that there was an overexpression of mmps , ngal , and inflammatory cytokines in cvus on treating patients conventionally . they introduced a nutraceutical substance together with compression therapy and surgical correction for 8 months and found a decrease in inflammatory cytokines with improved wound healing . their findings explained that there is a correlation between the pathophysiology and impaired wound healing probably due to the overexpression of mmps , ngal , and inflammatory cytokines . their findings are consistent with other studies using glycoaminoglycans such as sulodexide ( sdx ) and cilostazol [ 4 , 5 ] . the authors concluded that inhibition could be a possible therapeutic intervention . in addition to these compounds , the use of biomarkers would be vital when clinical signs are misleading [ 58 , 59 ] . however , mimicking the action of mmp inhibitors could possibly assist in managing infected wounds or wounds activated through mmp or cytokine release [ 4 , 5 , 10 , 60 ] . pbm is a noninvasive form of light therapy for wound healing , whereby several biological , chemical , and cellular processes are stimulated to speed up healing ( figure 2 ) . the adequacy of this therapy is specific to a spectral range of 5001,100  nm and power output ranging within 10200  mw . studies have also established its effect on wounded cell models in vitro using various wavelengths and dosages [ 6567 ] . in addition , studies performed on mice , rats , and humans showed a stimulatory effect of pbm in diabetic wound healing [ 62 , 63 , 6871 ] . the application of pbm in altering the gene expression in cell cultures is evident [ 72 , 73 ] . pbm is able to alter the expression of mmps in diabetic wounds and enhance collagen production [ 64 , 74 , 75 ] . however , experiments done on human skin fibroblasts demonstrated variations in gene expression [ 75 , 76 ] . ayuk and colleagues   found that pbm altered 49 genes involved in the ecm in vitro , with genes in a diabetic wounded cell model mostly downregulated , among which were mmp-1 , mmp-2 , mmp-8 , mmp-12 , mmp-14 , and mmp-16 . pbm in another study ( 1 or 3  j / cm with 810  nm ) was shown to reduce the gene expression of mmp-3 , mmp-9 , and mmp-13 in achilles tendons of rats as well as prostaglandin , implying that it was able to reduce tendon inflammation and preserve elasticity and resistance . casalechi and colleagues   investigated a nonconventional treatment for tendinopathies and found that pbm ( 780  nm ; 107  mw / cm ; 7.5  j / cm ) alongside various inflammatory treatments modulated mrna gene expression of mmp-1 , mmp-13 , and il-10 and vascular endothelial growth factor ( vgef ) in a wistar rat model . conducted an experiment using sixty male wistar rats which were irradiated at 660 and 780  nm with a fluence of 30 and 40  j / cm and found a decrease in mmp-2 activity and increased expression in angiogenesis markers such as vegf . therefore , pbm was associated with promoting healing of skin flaps in a dose dependent manner . pbm also plays a role in regulating inflammatory cytokines . in a study conducted by laraia and colleagues   to analyze the role of pbm ( 660  nm ; 100  mw ) on protein expression levels in rat achilles tendons with their main focus on the inflammatory mediators , they found that the group treated with lasers showed positive responses on il-6 and il-10 after 6 , 24 , and 72  h compared to the control . used three different dosages ( 0 , 0.6 , 1.5 , and 2.5  j / cm ) at 1064  nm on the dorsal skin of sprague - dawley rats and showed an increase in collagen content , as well as the upregulation of the gene expression of collagen type 1 ( col-1 ) and collagen type 3 ( col-3 ) and timp-1 and timp-2 , and a significant decrease in mmp-2 and mmp-3 . they concluded in their study that irradiation at 1064  nm could markedly increase collagen production and prevent degradation and activate the erk1/2 and jnk - mapk pathway . in addition , lee et al .   found that long - pulsed nd : yag laser ( 1064  nm ) decreased the expression of mmp-1 at low energy dosages ; meanwhile there was an increase in dermal collagen and transforming growth factor - beta ( tgf- ) with no significant difference in the expression of timp-1 in hairless mice . a similar study using cultured human skin fibroblasts after two successive irradiations with 1.5  j / cm at wavelengths of 1064 and 532  nm significantly increased col-1 and col-3 at 24 and 48  h after irradiation . this study also found an increase in the expression of timp-1 and timp-2 and a decrease in mmp-1 and mmp-2 . it ascertained that 1064  nm was more effective as compared to 532  nm in promoting molecular activities . kim et al .   found pbm ( 780  nm ; 1.75  w / cm ; 5  j / cm ) to modulate the gene expression of five mmps ( mmp-1 , mmp-2 , mmp-8 , mmp-9 , and mmp-13 ) in the periodontal ligament of sprague - dawley rats and inhibited immunoreactivity of timp-1 . similarly , pbm ( 780  nm ; 125  mw / cm ; 0 , 0.5 , 1.0 , 2.5 , 5.0 , and 20  j / cm ) with different energy densities modulated the gene expression of mmp-2 and mmp-9 as well as the oxidative metabolism of the masseter muscle in rats , indicating possible ecm remodelling . the biostimulatory effect of pbm in the near infrared ( nir ) range modulates wound healing events in various cells . .   found that pbm ( 780  nm , 1 or 2  j / cm ) increased collagen activity twofold , increased mmp-2 activity , upregulated mmp-1 and timp-2 expression , and downregulated mmp-2 and il-1. their findings may be of therapeutic importance in situations with depleted smooth cells , weakened ecm , and increased proinflammatory markers as major pathological components . migliario et al .   observed a decrease in mmp-9 in normal keratinocytes exposed to laser irradiation at 635.2  nm and a fluence of 82.5 or 112.4  j / cm , a very high dosage , which could influence the production of enzymes during wound healing and probably explain the decrease in cell proliferation . in addition , irradiation using a diode laser prototype ( 780  3  nm , 40  mw ) at different doses of 0.5 , 1.5 , 3.5 , and 7  j / cm over 24  h showed that a dose range of 0.53  j / cm promotes a biostimulatory effect on keratinocytes . luo and colleagues   found that intense pulse light ( ipl ) irradiation had a time dependent effect on mouse skin at 2 weeks up to 8 weeks with mmp-1 and mmp-2 showing a decrease in mrna expression after irradiation , and the authors concluded that irradiation with ipl modulated collagen synthesis as well as ecm degradation . after treating patients with laser therapy ( 660  nm ; power output 25  mw ; dose 6.2  j / cm ) , oton - leite and colleagues   found that there was a trend in the reduction levels of il-1 , il-10 , tnf- , tgf- , mmp-2/timp-2 , and mmp-9/timp-2 as compared to the untreated group , even though there was no significant difference . silva and colleagues   performed a randomized preliminary study to evaluate pbm using saliva and blood from haematopoietic stem cell transplantation patients and found a positive response in mmp-2 in the saliva and il-10 in the blood . they found out that pbm is clinically effective in reducing chemotherapy induced oral mucositis ; however , there was no mechanism linked with inflammatory cytokines , growth factors , and mmps . furthermore , some researchers performed a controlled randomized clinical trial and found that after treatment for chronic periodontitis there was a significant difference in the levels of mmp-1 , mmp-8 , and timp-1 between the various groups as compared with the controls . they found a significant decrease in the total amount of il-1 , il-6 , mmp-1 , mmp-8 , and timp-1 with mmp-8 significantly affected . the researchers concluded that mmp-8 has the most effective impact for use as an adjunct laser treatment on nonsurgical periodontal therapy . in addition , qadri et al .   used two wavelengths , 636 and 830  nm , on patients with moderate gingival periodontitis and their results showed a decrease in the total amount of mmp-8 as compared to the placebo . from their study , they found pbm to ameliorate periodontal gingival inflammation . in a similar study , qadri and colleagues   found that scale and root application together with nd : yag laser irradiation significantly reduced il-1 and mmp-8 and therefore improved clinical signs linked with periodontal inflammation as compared to the treatment alone . pbm is known for its stimulatory effects and promotes mmp activity and gene expression ; hence maintaining a dynamic balance between the proteolytic activity and degradation could be a target for therapeutic advancement . suggestions of further research in timps and mmps would be very important for the selection of these as indicators of early disease , in order to deduce standard protocols and improve clinical regimen . this review covers the relationship between mmps and their inhibitors in diabetic wound healing in relation to pbm and the ecm in both human and animal models , in vivo and in vitro . given the fact that mmps are known for degradation of the ecm and have been shown to be upregulated in most pathologies , they have been recognised as potential targets for new therapeutic measures . however , it is necessary to further elucidate the relationship between pbm , diabetic wound healing , and mmps .
the integration of several cellular responses initiates the process of wound healing . 
 matrix metalloproteinases ( mmps ) play an integral role in wound healing . 
 their main function is degradation , by removal of damaged extracellular matrix ( ecm ) during the inflammatory phase , breakdown of the capillary basement membrane for angiogenesis and cell migration during the proliferation phase , and contraction and remodelling of tissue in the remodelling phase . 
 for effective healing to occur , all wounds require a certain amount of these enzymes , which on the contrary could be very damaging at high concentrations causing excessive degradation and impaired wound healing . 
 the imbalance in mmps may increase the chronicity of a wound , a familiar problem seen in diabetic patients . 
 the association of diabetes with impaired wound healing and other vascular complications is a serious public health issue . 
 these may eventually lead to chronic foot ulcers and amputation . 
 low intensity laser irradiation ( lili ) or photobiomodulation ( pbm ) is known to stimulate several wound healing processes ; however , its role in matrix proteins and diabetic wound healing has not been fully investigated . 
 this review focuses on the role of mmps in diabetic wound healing and their interaction in pbm .