Biofilms and Wounds: An Overview of the Evidence.

Significance: Microorganisms can exist both in the planktonic and biofilm state. Each phenotypic state has a role to play in delaying healing and causing infections of both acute and chronic wounds. However, the virulent biofilm state is the fundamental reason that chronic wounds do not heal in a timely manner. We hypothesize that because microorganisms attach to any surface, biofilms can be found in all chronic wounds. However, it is not the biofilm per se that represents the greatest obstacle to the healing of a chronic wound, but its virulence and pathogenicity. Recent Advances: Numerous studies with animals and humans have identified biofilms in wounds. In particular, these studies have highlighted how biofilms impede host fibroblast development, inflammatory responses, and the efficacy of antimicrobial therapy. Despite this, the role biofilms play in affecting the healing of wounds is still vigorously debated. Critical Issues: Clinicians must understand the role that pathogenic biofilms play in impairing the healing of chronic wounds and in increasing the risk for wound infection, with its potentially catastrophic outcomes. The composition of the biofilm, its physiochemical properties, the climaxed indigenous microbiota and their virulence/pathogenicity, microbial numbers and the host's pathophysiology, and immunological fitness will govern the sustainability of a pathogenic biofilm in a wound and its resistance to interventions. Future Directions: Establishing which specific pathogenic biofilms delay wound healing should help guide better wound care practices.

Silver and Alginates: Role in Wound Healing and Biofilm Control.

Significance: Chronic wounds are known to be a significant issue globally. Of concern in wounds are the numbers and types of residing microorganisms and the ability of the host's immune system to control their proliferation. Wound healing is impeded by colonizing microorganisms growing within the biofilm phenotypic state. In this state microorganisms are recalcitrant to routinely impeded by used antimicrobial interventions. Recent advances: Silver has been reported to demonstrate efficacy on planktonic microorganisms both within the in vitro and in vivo environments. However, when silver is incorporated into a wound dressing, its antimicrobial efficacy on biofilms within the in vivo environment remains contentious. Critical Issues: Unequivocal evidence of the efficacy of silver, and wound dressings containing silver, on biofilms in clinical situations is lacking. This is principally due to the deficiency of definite biofilm definitions, markers, and evidence in the chronic wound environment. Future Direction: Research studies demonstrating antimicrobial efficacy on in vitro biofilms can be used to generate data and information appropriate for extrapolation and applicability to the in vivo environment. It is very important that inventors of antimicrobial wound dressings ensure efficacy against both planktonic and sessile microorganisms, within the in vitro and in vivo environments.

The role of polyphosphates in the sequestration of matrix metalloproteinases.

This study outlines the potential of a novel therapeutic dressing for the management of chronic wounds. The dressing incorporates polyphosphate, a non toxic compound with a number of beneficial characteristics in terms of wound healing, in a foam matrix. The aim of this study was to identify the potential of polyphosphate incorporated in the foam dressing to sequester the activity of matrix metalloproteinases (MMPs) and proteases derived from Pseudomonas aeruginosa. Methods used included gelatin zymography and milk-casein agar plate analysis. Results have shown that this dressing is effectively capable of reducing the levels of MMP-2 and MMP-9 in both their active and latent forms using an in vitro model. The dressing also demonstrated the compound's potential in the regulation of P. aeruginosa derived proteases.

Proteases and Delayed Wound Healing.

SIGNIFICANCE: Proteases and their inhibitors contribute to the balance between extracellular matrix (ECM) degradation and deposition, creating an equilibrium that is essential for the timely and coordinated healing of cutaneous wounds. However, when this balance is disrupted, wounds are led into a state of chronicity characterized by abundant levels of proteases and decreased levels of protease inhibitors. RECENT ADVANCES: Researchers have sought to investigate the roles of proteases within both acute and chronic wounds and how the manipulation of protease activity may aid healing. Indeed, numerous wound dressings have been developed that target such proteases in an attempt to promote wound healing. CRITICAL ISSUES: The normal tissue response to injury involves a complex interaction between cells and cellular mediators. In particular, the inflammatory response is augmented in chronic wounds which are characterized by elevated levels of proinflammatory cytokines and proteases. While controlling levels of inflammation and protease expression is a critical part of normal wound healing, elevated and prolonged expression of proteases produced during the inflammatory phase of healing can lead to excessive ECM degradation associated with impaired healing. FUTURE DIRECTIONS: It seems plausible that future research should aim to investigate the ways in which proteases may be targeted as an alternative therapeutic approach to wound management and to assess the benefits and draw-backs of utilizing wound fluids to assess wound progression in terms of proteolytic activity.

The role of endogenous and exogenous enzymes in chronic wounds: a focus on the implications of aberrant levels of both host and bacterial proteases in wound healing.

Cutaneous wound healing is orchestrated by a number of physiological pathways that ultimately lead to reformation of skin integrity and the production of functional scar tissue. The remodeling of a wound is significantly affected by matrix metalloproteinases (MMPs), which act to control the degradation of the extracellular matrix (ECM). Regulation of MMPs is imperative for wound healing as excessive levels of MMPs can lead to disproportionate destruction of the wound ECM compared to ECM deposition. In addition to human MMPs, bacterial proteases have been found to be influential in tissue breakdown and, as such, have a role to play in the healing of infected wounds. For example, the zinc-metalloproteinase, elastase, produced by Pseudomonas aeruginosa, induces degradation of fibroblast proteins and proteoglycans in chronic wounds and has also been shown to degrade host immune cell mediators. Microbial extracellular enzymes have also been shown to degrade human wound fluid and inhibit fibroblast cell growth. It is now being acknowledged that host and bacterial MMPs may act synergistically to cause tissue breakdown within the wound bed. Several studies have suggested that bacterial-derived secreted proteases may act to up-regulate the levels of MMPs produced by the host cells. Together, these findings indicate that bacterial phenotype in terms of protease producing potential of bacteria should be taken into consideration during diagnostic and clinical intervention of infected wound management. Furthermore, both host MMPs and those derived from infecting bacteria need to be targeted in order to increase the healing capacity of the injured tissue. The aim of this review is to investigate the evidence suggestive of a relationship between unregulated levels of both host and bacterial proteases and delayed wound healing.

Influence of the human leukocyte antigen complex on the development of cutaneous fibrosis: an immunogenetic perspective.

A number of aesthetically and physically distressing disorders of the skin come under the general term "cutaneous fibrosis", all sharing a common abnormal wound healing process. These disorders are often incurable and effective treatments remain to be established and, as such, they present a significant burden for patients and a therapeutic challenge for clinicians. The aim of this review is to investigate the evidence of either positive or negative associations of the human leukocyte antigen (HLA) system with various types of cutaneous fibrosis, focussing in particular on keloid scars, hypertrophic scars and scleroderma. A standard systematic literature search was performed. The strengths and limitations of studies were evaluated in terms of significance, methodology and reproducibility. There is a clear association between specific HLA alleles and predilection or protection to cutaneous fibrosis. Of these candidate HLA alleles, the class II loci seem to be the most promising in terms of a genetic biomarker, with the DQ and DR alleles having significant associations with abnormal wound healing and cutaneous fibrosis. There is strong evidence of a significant immune component in the pathogenesis of each type of fibrotic disorder explored in this review. However, the exact mechanisms remain to be elucidated, since the pathogenesis of cutaneous fibrosis and abnormal wound healing are not fully understood.