Chapter 3 Biofilms in Health and Medicine
Section 5 Towards a Unified Theory of Chronic Wounds
Page 2 Steps toward a unified wound theory

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Are all chronic wounds essentially the same?

Steps toward a unified wound theory

The arbitrary division of wounds into different etiologic categories such as diabetic foot ulcers, venous leg ulcers, pressure ulcers, arterial ulcers, nonhealing surgical wounds and others may not be warranted. Common barriers to healing have been discussed previously (Section 3: Absolute and relative barriers to healing). The reason for the arbitrary division of these wounds was that certain barriers tend to present more severely and more frequently in certain wounds than others. For example, diabetic foot ulcers tend to have barriers related to neuropathy, poor perfusion, white cell dysfunction, poor nutrition and pressure issues, which, when added together, lead to a very high barrier to healing. However, venous leg ulcers may also have pressure issues as well as arterial disease (poor perfusion) contributing to poor healing. Therefore, all barriers to healing need to be addressed in every wound at every visit regardless of the etiology.

Although any one of these barriers can be sufficient in itself to prevent wound healing, this is rarely the case in clinical wounds. These barriers are additive, and their combinations vary from wound to wound. Therefore, these barriers (perfusion, oxygen, pressure, malnutrition, systemic disease), either singly or in combination, do not explain the cellular and biochemical similarity of wounds. It is interesting to note that regardless of the etiologic category assigned to a nonhealing wound, all chronic wounds possess identical clinical phenomena, identical cellular impairments and identical biochemical patterns.

There is increasing evidence to believe that biofilm formation in wounds is the best unifying explanation for the failure of chronic wounds to heal. Anecdotal clinical evidence indicates improved healing when chronic wounds are treated with the assumption that biofilm is the cause of the failure to heal. This treatment can comprise a number of approaches: use of antibacterial biofilm agents, debridement, anti-biofilm dressings, phages, biocides and advanced technologies. More case histories, to come.

Alternative biofilm control strategies

The recent rapid growth in the biofilm field has spawned a number of new strategies for controlling biofilms. Below are descriptions of a few of these emergent strategies.

For some years it has been known that bacteria communicate with each other via diffusible signal molecules in a process termed “quorum sensing.” The discovery that quorum sensing regulates biofilm formation opens the door to interdicting normal biofilm development through the use of quorum sensing inhibitors. This strategy of jamming communication is now moving towards application. One example of such inhibitors are the brominated furanones that block quorum sensing by acyl homoserine lactones, signal molecules used by Gram-negative bacteria. These furanones were first isolated from a marine algae and are thought to be part of the plant’s natural defense against microbial biofouling. Furanone-based quorum sensing inhibitors have been shown to increase antibiotic sensitivity of Pseudomonas aeruginosa biofilms and improve clearance of these same bacteria from a mouse model of lung infection. Gram-positive bacteria use cyclic peptides as quorum sensing signals. A synthetic peptide termed RIP interferes with the normal reception of these signals and has shown efficacy in combating biofilm infections in a number of animal models.

Iron is emerging as an important signal in normal biofilm development. Iron concentrations are very low in vivo. The availability of iron appears to govern the rate of staphylococcal biofilm development on venous catheters. An early stage of Pseudomonas aeruginosa biofilm development involves the association of bacteria with the surface in an active state of twitching motility. When sufficient iron is available, the bacteria cease twitching and begin building stationary cell clusters. When there is not sufficient iron available, for example in the presence of added lactoferrin or some other iron chelator, the bacteria continue twitching motility and never settle down to construct a three-dimensional biofilm. The use of natural or synthetic iron scavenging compounds could be a way of limiting biofilm formation in a wound in vivo.

One attractive, and still underdeveloped, strategy for biofilm control is to target the gelatinous matrix of the biofilm rather than the cells themselves. If the extracellular polymers that hold the biofilm together could be disrupted or degraded, the biofilm would disperse and its innate defenses would be subverted. Enzymes are one way this might be realized. For example, a hexosaminidase that specifically cleaves the primary extracellular polymer of many staphylococcal biofilms has been recently described. This enzyme, termed Dispersin B, has demonstrated remarkable efficacy in disrupting and removing Staphylococcus epidermidis biofilms in the Stewart laboratory. An enzyme cocktail could be considered for topical wound treatment as a way of loosening and removing biofilm.

Weak electric fields enhance the efficacy of antibiotics against bacterial biofilms. This phenomenon, termed the “bioelectric effect,” was discovered by Dr. J.W. Costerton and has been further investigated by Drs. McLeod and Stewart. Because of the ready accessibility for the placement of small wires or coils, a chronic wound may be a relatively straightforward context within which to test this technology.

Summary: Chronic wounds and biofilms

The biofilm concept explains many features of persistent infections and is consistent with clinical experience in treating chronic wounds. The care of chronic wounds poses enormous material and patient costs. If even a fraction of these cases stem from infection by a microbial biofilm, and effective anti-biofilm treatments are developed that accelerate wound healing, the impact will be very significant indeed.