Staphylococcus aureus auf Haut

Processes: Optimisation and Solutions

The biofilm mystery – Why do wounds fail to heal?

When wounds fail to close, medical assistance is needed. Proper wound management with thorough debridement and adequate local wound care can save patients a lot of suffering. Here, measures to prevent biofilms from forming in the wound play a decisive role. Bacteria can lead to delayed wound healing – and this occurs much more frequently than previously assumed.

A fall, an accident, an operation – in many situations, people can sustain wounds accompanied by significant tissue damage. In most cases, this is only a temporary and short-term problem. In others, however, an injury evades the normal healing process and the wound becomes chronic. Often, a microbial biofilm has formed in the wound that prevents it from closing and healing.

Roughly three per cent of the population in Germany have chronic wounds. Most of the people affected are 70 years and older. Venous leg ulcer, post-traumatic wounds, decubitus and diabetic foot syndrome are the most common conditions.

A total of 2.7 million people had to seek medical help for chronic wounds in 2012, according to a study conducted in 2015. Treating such patients is a great challenge for doctors and nurses – biofilm in the wounds makes this work more difficult.

Microbes communicate via chemical messengers

Biofilms in non-healing wounds are comprised of microorganisms embedded in a slimy matrix of various sugars and proteins. Initially, individual bacteria form microcolonies within a few hours, and adhere firmly to the wound surface. After two to four days, the microbial community has united to form a dense film. Immune cells and antimicrobial therapies cannot penetrate this film.

The biocoenosis is organised with the help of molecular communication, so-called “quorum sensing”. This describes the ability of bacteria to communicate via chemical messengers. Among other things, the cell density of their population can be measured.

Dr Thomas Bjarnsholt from Denmark is a leading researcher in the field of biofilms. He says, “Biofilms are most likely involved in all chronic wounds, even if they could be detected microscopically in only 60 to 80 per cent of cases so far.

This is why wounds that are closing poorly should be intensively treated from the beginning, so that their healing does not take weeks and months – which can lead to the risk of fatal sepsis. “This is particularly important for people whose health conditions promote chronic wounds, for example, obesity and diabetes, or when they are bedridden,” explains Bjarnsholt.

In his laboratory at the University of Copenhagen, the microbiologist is working on deciphering the biofilm’s secrets to ultimately find substances that are effective against the resistant bacterial mucus. “However, we still do not know enough about biofilms in chronic wounds,” says the scientist.

Biofilm is constantly changing

International research has identified some key characteristics of biofilms: For example, they are by no means just a covering, but penetrate deep into the wound bed. In addition, many different bacteria come together, as well as fungi and various other microorganisms. Every biofilm is therefore different – and each one is also constantly changing.

Another special feature is that the antibiotic resistance of the bacteria embedded in this protective mucus matrix can be up to 1,000 times higher than that of individual pathogens. And even if a therapeutic offensive is successful, surviving microbes can rebuild the biofilm within 24 hours.

Culture of the human pathogen Staphylococcus aureus.

However impenetrable bacterial biofilm may be in wounds, it does not survive long under laboratory conditions. Because of limitations accompanying the Petri dish, the significance of biofilms for chronic wounds has long been underestimated.

Today, this also makes it difficult for researchers to translate in vitro results into therapeutic practice. Thomas Bjarnsholt says, “Biofilms in the laboratory may react to molecules that attack the matrix. But with patients, things can look very different.” And, “First of all, we have to understand which processes take place in chronic wounds. Then we can develop new active ingredients.”

It’s particularly important to biofilm-researcher Bjarnsholt that “chronic wounds in medical care are taken more seriously than before, right from the start.” If a wound does not close after three months, the chances of healing drop significantly.

One of the most important approaches in the fight against biofilms is the destruction of the protective layer, and the key here may be lectins. These proteins enable the cohesion of bacteria. “Lectins link the components of biofilms,” explains Professor Alexander Titz from the Helmholtz Institute for Pharmaceutical Research in Saarbruecken. “They are the cement in the wall, so to speak.” Without a binding lectin function, a biofilm loses its hold and falls apart. The bacteria are then accessible again for the immune system and for antibiotics.

Following five years of research, the chemist and his team have developed a lectin-blocking molecule that suppresses the biofilm formation by the dangerous germ Pseudomonas aeruginosa. This bacterium is commonly resistant to antibiotics, is responsible for life-threatening infections of the respiratory and urinary tracts, and it contributes to open wounds.

These bacteria are most commonly found in biofilms on wounds

Studies have shown that both aerobic and anaerobic bacteria are found in wound biofilms. These are the most common germs that bind together in wounds:

Pseudomonas aeruginosa
Staphylococcus aureus
Staphylococcus epidermidis

Debridement against biofilm in wounds

Until such a therapeutic approach is ready for the market, physicians will continue their attempts to remove the biofilm in wounds through debridement*. The word originally comes from the French, where débridement means, “to free from reins”. Today, this term refers to the extensive removal of adhering, dead or contaminated tissue from a wound.

The fastest option is “sharp” surgical debridement, in other words, intensive cleaning of the wound with surgical instruments. However, there is a risk that healthy tissue will also be damaged during the procedure – and this in turn can delay the healing process.

The choice of the debridement method depends on, among other things, the individual wound situation. After debridement, the cleansed wound is treated locally with dressings that usually contain antimicrobial substances – such as silver, iodine or organic acids.

Wound dressings* enriched with PHMB (polyhexamethylene biguanide) are particularly effective. This substance acts quickly on a broad spectrum of pathogens (such as MRSA and VRE), not only in the dressing but also directly in the wound.

Studies have shown that the PHMB released from the wound dressing is effective against 99.99 per cent of germs within the first six hours.

Dressings with silver can also help to reduce the germ count directly in the wound bed. With absorption of excess exudate from the wound into the dressing, an ion exchange occurs, and a gel forms. During this process, silver ions that can kill bacteria are released.

Success only becomes apparent after several weeks

The debridement procedure demands great diligence, and also patience. Antimicrobial therapy must be repeated frequently, as a single wound cleansing cannot completely remove the biofilm. And the procedure has to use the small window of time before the biofilm reorganises and rebuilds itself from remaining fragments.

Whether a biofilm has been defeated can, in theory, be determined only following a biopsy. It can take many weeks and months for a wound to heal normally and finally close.

To give doctors even better weapons against chronic wounds, researchers including Thomas Bjarnsholt are deciphering the secrets of biofilms. But the Danish researcher also says, “In chronic wounds, we must focus not only on the elimination of bacteria. We must also consistently treat the underlying diseases of patients prone to such wounds.” Only through an overall therapeutic concept will it be more often possible to prevent chronic wounds in the first place.

Further information

  1. Abschlussbericht für MedInform – Informations- und Seminarservice Medizintechnologie, Köster I, Dr. Schubert I, PMV forschungsgruppe

  2. Understanding biofilm resistance to antibacterial agents, Davies D, Nature Reviews Drug Discovery

    *commercial communication

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