p38-mediated cell growth and survival drive rapid embryonic wound repair.

Embryos repair wounds rapidly, with no inflammation or scarring, in a process that involves polarization of the actomyosin cytoskeleton. Actomyosin polarization results in the assembly of a contractile cable around the wound that drives wound closure. Here, we demonstrate that a contractile actomyosin cable is not sufficient for rapid wound repair in Drosophila embryos. We show that wounding causes activation of the serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) in the cells adjacent to the wound. p38 activation reduces the levels of wound-induced reactive oxygen species in the cells around the wound, limiting wound size. In addition, p38 promotes an increase in volume in the cells around the wound, thus facilitating the collective cell movements that drive rapid wound healing. Our data indicate that p38 regulates cell volumes through the sodium-potassium-chloride cotransporter NKCC1. Our work reveals cell growth and cell survival as cell behaviors critical for embryonic wound repair.

Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-α and MMP-3 in a mouse model.

There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production.

The critical roles of histone deacetylase 3 in the pathogenesis of solid organ injury.

Histone deacetylase 3 (HDAC3) plays a crucial role in chromatin remodeling, which, in turn, regulates gene transcription. Hence, HDAC3 has been implicated in various diseases, including ischemic injury, fibrosis, neurodegeneration, infections, and inflammatory conditions. In addition, HDAC3 plays vital roles under physiological conditions by regulating circadian rhythms, metabolism, and development. In this review, we summarize the current knowledge of the physiological functions of HDAC3 and its role in organ injury. We also discuss the therapeutic value of HDAC3 in various diseases.

Complex challenges of estimating the age and vitality of muscle wounds: a study with matrix metalloproteinases and their inhibitors on animal and human tissue samples.

The estimation of wound age and wound vitality is a recurring task in forensic routine work and has been subject of forensic research for a long time. By now, an unrestrictedly reliable marker or set of markers has not been found. In a study on myocardial infarctions, matrix metalloproteinases (MMP) 2 and 9 as well as tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) were detected immunohistochemically in mechanically wounded myocardium (ECG electrodes, vessel ligations). Against this background, the potency of MMP-9, MMP-2, and TIMP-1 as markers for the estimation of wound age and wound vitality was tested in a broad approach with human tissue samples drawn during autopsies and with an animal model, the isolated perfused Langendorff heart. The study comprised samples of injured human skeletal muscle, injured human myocardium, rats' hearts with vital wounds, and rats' hearts with postmortem-inflicted wounds that were all stained immunohistochemically. The results showed great scattering, leading to the conclusion that MMP-2, MMP-9, and TIMP-1 are not suitable for wound age estimation. Merely the results for TIMP-1 suggested that this marker might be able to differentiate between vital and postmortem-inflicted wounds. With a view to the promising results of the preceding study, the results underline the necessity to test possible markers of wound age/wound vitality on a large and diverse sample set.

Histochemical and Morphometrical Analyses of Scarless Wound Healing in Mouse Fetal Model.

OBJECTIVE: Scar formation is an inevitable outcome after craniofacial surgery in the congenital facial anomaly. Scarless healing is the ultimate treatment after the surgery. Therefore, we elucidate the mechanism underlying scarless healing during fetal development. METHODS: A full-thickness back skin excision (1 × 0.5 mm) was made at embryonic day 16.5 (E16.5) and 18.5 (E18.5) in fetal C57BL/6J mice and examined the histochemical and morphometrical findings of wound healing after 48 hours. RESULTS: The wound made at E16.5 showed almost complete re-epithelialization with fine reticular dermal collagen fibers, but not at E18.5. The ratio of CK5 positive area was significantly higher in the wound of E16.5 operation than in the E18.5. The wounds made at E18.5 showed granulation tissue formation which will lead to subsequent scar formation. The collagen fibers tended to be thinner in wound than in normal skin, while the decrease in the number of fibers but the increase in the straightness of fibers were evident in the wound at E18.5. CONCLUSION: Transition point of scarless healing seemed between E16.5 and E18.5 in mice, which may imply that the potential of epithelial regeneration and matrix formation was changed, possibly due to alteration of cell constitution and decrease in stemness, at that time.

Increase of tyrosinase activity at the wound site in zebrafish imaged by a new fluorescent probe.

Tyrosinase plays a pivotal role in the hyperpigmentation of wounds. Here, we develop a new fluorescent probe and with it, we reveal an increase of tyrosinase activity at the wound site in zebrafish.

The Role of Astrocytes in the Modulation ofK+-Cl--Cotransporter-2 Function.

Neuropathic pain is characterized by spontaneous pain, pain sensations, and tactile allodynia. The pain sensory system normally functions under a fine balance between excitation and inhibition. Neuropathic pain arises when this balance is lost for some reason. In past reports, various mechanisms of neuropathic pain development have been reported, one of which is the downregulation of K+-Cl--cotransporter-2 (KCC2) expression. In fact, various neuropathic pain models indicate a decrease in KCC2 expression. This decrease in KCC2 expression is often due to a brain-derived neurotrophic factor that is released from microglia. However, a similar reaction has been reported in astrocytes, and it is unclear whether astrocytes or microglia are more important. This review discusses the hypothesis that astrocytes have a crucial influence on the alteration of KCC2 expression.

Kanglexin accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling.

Diabetic foot is one of the main causes of non-traumatic amputation. However, there is still lack of effective drugs to treat diabetic foot in clinical practice. Kanglexin (KLX) is a new anthraquinone compound with cardiovascular protective effects. Here we report that KLX accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling. Firstly, KM mice were injected (ip) with streptozocin to establish type 1 diabetic model. The full thickness wound with the diameter of 5 mm was prepared on the back of each mice. The wounds were treated with KLX once a day for 14 consecutive days. Results showed that KLX significantly accelerated the closure of diabetic wounds. Pathological studies of skin tissues around the wounds showed that KLX promoted the formation of granulation tissue and new blood vessels, increased collagen deposition and reduced inflammatory cell infiltration. Besides, KLX significantly alleviated advanced glycation end products (AGEs) - induced abnormal proliferation, migration and tubule formation of human umbilical vein endothelial cells (HUVECs), and up-regulated phospho-ERK1/2 both in the diabetic wound tissue and AGEs - treated HUVECs. Moreover, molecular docking results indicated that KLX had the potential to bind with FGF receptor 1 (FGFR1), and subsequent experiments confirmed that FGFR1 inhibitor PD173074 reversed the effect of KLX on promoting the phosphorylation of ERK1/2 and angiogenesis, suggesting that KLX promoted angiogenesis through FGFR1/ERK signaling. In conclusion, our study provides a new effective compound for treating diabetic wounds. More importantly, KLX has the potential to be developed as a topical drug to promote diabetic wound healing.

Effect of Horse-chestnut seed extract on matrix metalloproteinase-1 and -9 during diabetic wound healing.

The effects of aqueous-ethanol extract of Horse chestnut (HCE) on MMP-1 and MMP-9 expressions during cutaneous wound healing in diabetic rats were investigated in this study. The expressions of MMP-1 and MMP-9, wound closure, myeloperoxidase (MPO) activity, hydroxyproline, and malondialdehyde (MDA) levels in wound tissue were measured. Quercetin glucuronide in HCE was identified as main compound using a LC-MS/MS. The hydroxyproline level was significantly increased in the treated group versus control after the 3rd and 7th days (p < 0.05). The MDA level and MPO activity were significantly lower in the treatment group (p < 0.05). MMP-1 gene expression level in treated rats was increased in the 7th day while it was reduced in 14th day. MMP-9 gene expression level in treated rats was decreased in 7th, and 14th days compared to control (p < 0.05). These results show that HCE accelerated the cutaneous wound-healing process in diabetic rats via MMP-1 and MMP-9 regulation. PRACTICAL APPLICATIONS: The main function of MMPs is to degrade and deposite the various components of the extracellular matrix. Also, they participate physiological processes such as inflammation, angiogenesis, and tissue remodeling. Horse chestnut seeds (HC) are known to be rich in saponins and flavonoids. HC are used for the treatment of abdominal pain, stomach ache, cold, hemorrhoids, arterial stiffness, rheumatism, oedema, diarrhea, chronic venous insufficiency and also as an antihemorrhagic and antipyretic in traditional medicine. It has been shown that HC has anti-inflammatory, antioedema, vessel protective, and free radical scavenging properties. This study indicates that HCE could be an effective agent for wound healing in diabetic wound model via its ability to suppress the MMP-9 gene expression and regulates MMP-1 gene expression besides its antioxidative, anti-inflammatory effects.

Metalloproteinases in chronic and acute wounds: A systematic review and meta-analysis.

A systematic review and meta-analysis were undertaken in order to explore the influence of matrix metalloproteinases and their diagnostic methods in chronic and acute wounds. Searches were conducted in the PubMed (Medline) and Embase (Elsevier) databases from inception to late November 2017. We included clinical trials enrolling patients with cutaneous chronic and acute wounds where a validated diagnostic method was employed for metalloproteinases. We excluded in vitro, animal or preclinical studies, nonoriginal articles, and studies without available data for analysis. In addition, references of narrative and systematic reviews were scrutinized for additional articles. Eight studies met the inclusion criteria. Results revealed that the most frequently determined matrix metalloproteinases were MMP-2 and MMP-9, and were found in 54.5% of wounds. MMP-9 was present in more than 50% of the chronic wounds with a range from 37 to 78%. However, metalloproteinases were found in only 20% of acute wounds, and other types of metalloproteinases were also observed (MMP-2 and MMP-3). On the basis of the available evidence, high levels of metalloproteinases have been correlated with significantly delayed wound healing in wounds of a variety of etiologies.

SIRT1 activation promotes angiogenesis in diabetic wounds by protecting endothelial cells against oxidative stress.

OBJECTIVE: Chronic wounds are a devastating complication of diabetes and can lead to amputations or even death. Current medical therapies are insufficient to accelerate its repair. The objective of this study was to explore the role of Sirtuin1 (SIRT1) in diabetic wounds. METHODS AND MATERIALS: Perilesional skin tissue samples from diabetic ulcers and normoglycemic trauma wounds were used to detect SIRT1 expression and oxidative stress levels. In a diabetic mouse model, SIRT1 was pharmacologically activated to attenuate angiogenesis and accelerate wound closure. Finally, in vitro experiments were performed to elucidate some of the mechanisms by which SIRT1 activation promotes angiogenesis in diabetic wound healing. RESULTS: We found that skin tissue from diabetes patients showed lower expression of SIRT1 and severe oxidative stress. Decreased SIRT1 expression was observed in skin tissue from streptozocin (STZ)-induced diabetic mice and was associated with impaired wound healing. In addition, the wounds of STZ-induced diabetic mice treated with SRT1720 (a specific SIRT1 activator) demonstrated locally improved wound healing and angiogenesis. In the in vitro experiment, similar results were observed. Under hyperglycemia conditions, human umbilical vein endothelial cells (HUVECs) showed lower expression of SIRT1 and higher levels of reactive oxygen species (ROS) production. Furthermore, the migration, proliferation and in vitro tube formation ability of HUVECs were impaired under hyperglycemia conditions, and SRT1720 treatment rescued these impairments and decreased ROS production in HUVECs. CONCLUSIONS: This study provides experimental evidence that SIRT1 activation could improve angiogenesis in wounds in vitro and in vivo and that sirtuin1 activation accelerates wound healing in diabetic mice by promoting angiogenesis. These positive therapeutic effects may be mediated by protecting vascular endothelial cells from oxidative stress injury. This study suggested that SIRT1 may serve as a potentially important and potent therapeutic target for treating diabetic ulcers.

Quercetin Shows the Pharmacological Activity to Simultaneously Downregulate the Inflammatory and Fibrotic Responses to Tissue Injury in Association with its Ability to Target Multi-Kinases.

AIM: Previous studies have suggested that quercetin is effective for treating diverse chronic disorders including organ fibrosis and airway and cardiovascular disorders. To access the pharmacological background for its broad efficacy, we examined the ability of quercetin to modulate the inflammatory and fibrotic responses associated with organ injury that commonly underlie the pathogenesis of those disorders. METHODS: A cutaneous wound model on rabbit ear was used for in vivo study. Quercetin was topically applied to the wounds, and the number of macrophages and myofibroblasts and the size of the hypertrophic scar formed were estimated. An in vitro study examined the ability of quercetin to inhibit cell-signaling pathways that activate RAW264.7 macrophages and primary dermal fibroblasts and the tyrosine kinase activity of discoidin domain receptor 2. RESULTS: Quercetin reduced the population of macrophages and myofibroblasts and the scar formation in cutaneous wound healing. Quercetin suppressed the signaling pathways activating RAW264.7 macrophages and dermal fibroblasts, which is associated with its inhibition of multiple tyrosine kinases to regulate the pathways. This pharmacological activity of quercetin to simultaneously inhibit the inflammatory and fibrotic responses upon tissue damage by targeting multi-kinases could be the action mechanism to support its broad efficacy for various chronic disorders.

The influence of matrix metalloproteases and biofilm on chronic wound healing: a discussion.

Chronicity in wound healing is a challenge for health services financially and scientifically, with negative consequences on patients' lives. This paper seeks to explore why chronic wounds fail to heal in relation to the inflammatory cellular dysfunction associated with biofilm development. Findings demonstrate an association between chronic wounds failing to heal, the presence of devitalised tissue and abnormal immune cell activity with a consequential excessive release of harmful matrix metalloproteases (MMPs). This process perpetuates the cycle of wound chronicity and extracellular matrix destruction, which prolongs the inflammatory response, fuelling biofilm formation. Evidence suggests that 'trapping' MMPs may increase new tissue growth but, while devitalised tissue is present, phagocytic cells continue to secrete MMPs and chronicity persists. Consequently, by removing the trigger and implementing effective, sustained debridement of devitalised tissue, both MMP and biofilm production will be diminished, with positive healing outcomes.

Dracorhodin perchlorate regulates fibroblast proliferation to promote rat's wound healing.

In recent years, plant-derived extracts are increasing interest from researchers worldwide due to good efficacy and lower side effects. Among the different plant extracts, Dracorhodin perchlorate (DP) is originated from Dragon's blood which has long been used as a natural medicine with various pharmacological activities. In the present study, we have explored the potential regulation of DP on fibroblast proliferation which promotes wound healing both in vitro and in vivo. DP at treatment of 12-24 h significantly induced fibroblast proliferation which is associated with increasing level of phosphorylated-extracellular signal-regulated kinase (ERK). Moreover, if ERK is halted with siRNA, DP cannot induce fibroblast proliferation. In vivo, DP ointment treatment at low- (2.5 µg/mL), medium- (5 µg/mL) and high-(10 µg/mL) doses, rat wounds healed more rapidly compared with the control group. After DP treatment for 7 days, Serpin family H member 1 (SERPINH1) staining confirmed enhanced fibroblast proliferation in the wound tissue. Finally, phosphorylated-ERK in the wound tissue remarkably increased with DP ointment treatment. Therefore, DP may be developed into a potential lead compounds for the treatment of wounds in clinical trials in the near future.

Testing Elevated Protease Activity: Prospective Analysis of 160 Wounds.

OBJECTIVE: Given that local elevated protease activity (EPA) has been implicated in impaired wound healing, a prospective single-center study was conducted to assess protease activity in various wound types. METHODS: Protease activity was determined using an easy-to-use test system (Woundchek Protease Status Test Kit; Systagenix, Gatwick, United Kingdom) in 160 wounds in 143 patients. The assay detects the combined activity of inflammatory proteases, mainly matrix metalloproteinases 8 and 9 and human neutrophil elastase. RESULTS: Local EPA was detected in 29 of 153 validly tested wounds (18.95%). No difference was detected between acute and chronic wounds, regardless of associated or causative conditions, with the sole exception of surgical wounds. Surgical wounds showed EPA significantly less frequently than nonsurgical wounds. Among nonsurgical wounds, EPA was detected more frequently in acute compared with chronic wounds. Wounds with signs of unimpeded healing (granulation or epithelialization) showed EPA less often than wounds covered with necrotic tissue or a fibrin layer. However, 14% of wounds with epithelialization or granulation exhibited EPA potentially impeding wound healing. Wounds treated with moisture-retentive wound dressings showed EPA significantly less frequently compared with wounds bandaged with dressings with less moisture-retentive properties. Remarkably, none of the wounds treated with collagen/oxidized regenerated cellulose/silver, which is a protease-modulating dressing, showed EPA. CONCLUSIONS: To the study authors' knowledge, this is the largest study assessing EPA in various wound types. The convenient applicability of the test system provides a basis for future studies assessing the pathophysiologic relevance of EPA. In some unsuspicious wounds, early detection of EPA might precede impaired healing and prompt protease-modulating treatment before failure to heal becomes apparent.

Avaliação das fibras colágenas de feridas dérmicas de coelhos tratadas com diferentes fontes de plasma rico em plaquetas / Evaluation of collagen in dermal wounds of rabbits treated with different sources of platelet-rich plasma

Para comparar a regeneração tecidual de feridas dérmicas em coelhos tratados e não tratados, de forma seriada, com diferentes fontes de plasma rico em plaquetas (PRP) gel, biópsias dérmicas foram feitas na região dorsal, com auxílio de um punch de 8mm, em que o lado direito foi tratado com NaCl 0,9%® e o lado esquerdo recebeu aplicação de diferentes fontes de PRPs (autóloga, heteróloga e homóloga), nos dias zero, três, sete, 10, 14, tendo sido acompanhadas durante 17 dias. Ao final do 17º dia, foi realizada avaliação histopatológica das feridas. Do total de 24 animais, seis coelhos (três machos e três fêmeas) foram utilizados somente como doadores para obtenção do PRP homólogo gel. Um cão adulto, saudável, foi utilizado como doador durante o experimento para o preparo do PRP gel do grupo heterólogo. As médias das fibras dos grupos autólogo e homólogo foram muito semelhantes (75,0±13,7 e 73,1±10,2, respectivamente), quando comparadas às médias obtidas no grupo controle (71,5±10,8). Já as fibras colágenas do grupo heterólogo foram inferiores (P<0,05) às dos demais grupos (59,4±11,3). Conclui-se que a fonte heteróloga produz fibras colágenas menos organizadas e menos homogêneas, sendo o último recurso a ser utilizado para promover uma cicatrização de boa qualidade.(AU)

In order to compare the tissue regeneration of dermal wounds in treated and untreated rabbits serially with different sources of platelet rich plasma (PRP) gel, dermal biopsies were made in the dorsal region with the aid of an 8mm punch. The right side was treated with 0.9% NaCl and, on the left side, the different sources of PRPs (autologous, heterologous and homologous) on days 0, 3, 7, 10, 14 were applied and monitored for 17 days. At the end of the 17th day, histopathological evaluation of the wounds was performed. From the total of 24 animals, six rabbits (3 males and 3 females) were used only as donors to obtain the homologous PRP gel. A healthy, adult dog was used as a donor during the experiment to prepare the PRP gel from the heterologous group. The mean values of the fibers of the autologous and homologous groups were very similar (75.0±13.7 and 73.1±10.2, respectively), when compared to the means obtained in the control group (71.5±10.8). The collagen fibers of the heterologous group were inferior (P<0.05) to the other groups (59.4±11.3). It is concluded that the heterologous source produces less organized and homogeneous collagen fibers and should be the last resource to be used in order to promote good quality healing.(AU)

14-Day thawed plasma retains clot enhancing properties and inhibits tPA-induced fibrinolysis.

BACKGROUND: Plasma-first resuscitation attenuates trauma-induced coagulopathy (TIC); however, the logistics of plasma-first resuscitation require thawed plasma (TP) be readily available due to the obligatory thawing time of fresh frozen plasma (FFP). The current standard is storage of TP for up to 5 days at 4°C, based on factor levels at outdate, for use in patients at risk for TIC, but there remains a 2.2% outdated wastage rate. However, the multitude of plasma proteins in attenuating TIC remains unknown. We hypothesize that TP retains the ability to enhance clotting and reduce tPA-induced fibrinolysis at 14-day storage. METHODS: FFP was thawed and stored at 4°C at the following intervals: 14, 10, 7, 5, 3, and 1-day prior to the experiment. Healthy volunteers underwent blood draws followed by 50% dilution with TP stored at previously mentioned intervals as well as FFP, normal saline (NS), albumin, and whole blood (WB) control. Samples underwent tPA-modified (75 ng/mL) thrombelastography (TEG) with analysis of R-time, angle, maximum amplitude (MA), and LY30. RESULTS: TEG properties did not change significantly over the thawed storage. 14-day TP retained the ability to inhibit tPA-induced hyperfibrinolysis (median LY30% 9.6%) similar to FFP (5.6%), WB (14.6%), and superior to albumin (59.3%) and NS (58.1%). 14-day TP also retained faster clot formation (median angle, 66.2°) and superior clot strength (MA, 61.5 mm) to albumin (34.8°, 21.6 mm) and NS (41.6°, 32.2 mm). CONCLUSIONS: TP plasma stored for 14 days retains clot-enhancing ability and resistance to clot degradation similar to FFP. A clinical trial is needed to validate these in vitro results.

Matrix metalloproteinases: The sculptors of chronic cutaneous wounds.

Cutaneous wound healing is a complex mechanism with multiple processes orchestrating harmoniously for structural and functional restoration of the damaged tissue. Chronic non-healing wounds plagued with infection create a major healthcare burden and is one of the most frustrating clinical problems. Chronic wounds are manifested by prolonged inflammation, defective re-epithelialization and haphazard remodeling. Matrix metalloproteinases (MMPs) are zinc dependent enzymes that play cardinal functions in wound healing. Understanding the pathological events mediated by MMPs during wound healing may pave way in identifying novel drug targets for chronic wounds. Here, we discuss the functions and skewed regulation of different MMPs during infection and chronic tissue repair. This review also points out the potential of MMPs and their inhibitors as therapeutic agents in treating chronic wounds during distinct phases of the wound healing. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.

MAPK signaling pathways in eye wounds: Multifunction and cooperation.

As is widely distributed in eukaryotic cells, the mitogen-activated protein kinase (MAPK) signaling pathway family plays an inevitable role in diverse cellular processes, being capable of responding to particular physiological reactions induced by multiple extracellular signals or stimuli, such as protean concentrations, ischemia/reperfusion, and inflammation. The physiological reactions mediated by the MAPK signaling pathway contribute to the progression and healing of eye wounds. Meanwhile, several pathways in the MAPK family can cooperate with each other and establish distinct responses to different, or even the same, stimuli and, thus, more attention may be paid to the pathway in future research.

Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence.

OBJECTIVE: In the past 20 years, research and clinical trials on the healing process of chronic wounds have highlighted the key role of the family of enzymes called matrix metalloproteinases (MMPs). If a strong correlation between the course of healing of chronic wounds and the levels of a biological marker can be demonstrated, then it may be possible to: i) identify the best marker threshold to predict the clinical evolution of the pathology; and ii) if causality has been found between the marker and pathology, to improve the healing outcome, to change the marker level. METHOD: The databases Medline and Embase were searched to identify clinical trials pertaining to the assessment of MMPs in chronic wounds with the following keywords 'metalloproteinase' or 'metalloprotease' and 'wound healing'. Clinical trials were considered for inclusion if they enrolled patients with cutaneous chronic wounds and were published in English. More than 50 clinical trials, consensus documents and guidelines were assessed for this review. RESULTS: MMPs play key roles in the wound healing process, and excessive expression and activation of some of these enzymes is seen in chronic cutaneous wounds where healing is delayed. Levels of MMPs are affected by a number of factors, including patient and wound characteristics. CONCLUSION: Levels of MMPs can be used to indicate the prognosis of chronic wounds and protease modulating treatments used to improve healing rates. DECLARATION OF INTEREST: The authors report no conflicts of interest in this work.