Wounds

According to the Cambridge Dictionary, a wound is “a damaged area of the body, such as a cut or hole in the skin or flesh”. The wound is therefore an opening of the skin, possibly with some tissue damage, that the body urgently needs to repair, because

  1. the body may lose vital resources through the opening, e.g. blood, and this may affect the ability of the body to continue functioning; and
  2. microbes such as bacteria and fungi may enter the body through the opening to inflict damage first in the wound and, if they succeed to enter the blood, to be carried around and cause harm in the entire body.

These microbes will seek to multiply inside the body and, for this process, they will use the body’s nutrients and often use and kill the cells of the body. The impact and weakening may be so severe, that the body is unable to function and the individual dies.

 

Dr. Karl Klose from The University of Texas at San Antonio explains how bacteria are an integral part of us and our environment and how we usually live in synergy with them. He also explains about the defence mechanisms of bacteria as well as about antibiotics and antibiotic resistance.

 

It is clear that wounds that face the body's surface are and will always be constantly exposed to bacteria. Therefore, it is also evident that the simple killing of all the bacteria, as is the intention of antibiotics and antiseptics, is no feasible solution to wound infections. On the contrary, the synergy between the bacteria and the skin needs to be restored.

Microbes’ Weapons and Protective Armour

Bacteria and fungi have developed very effective “weaponry” to protect themselves as they typically live in spaces where everyone is fighting for an area to live and grow.

These can be divided into:

  • Weapons - toxins and enzymes that are released to kill or inhibit the function of other microbes as well as of the immune cells of the body.
  • Protective armour – biofilm, which is a viscous layer secreted as a shield or fortress to protect themselves against the environment, e.g. drought. However, it will also protect them against the immune system as the immune cells are unable to penetrate the biofilm.

The bacteria and the fungi need to find spaces and sources of food that allow them to grow and multiply in order to ensure the survival of the species and in this respect an animal or human body represents an ideal place as it is warm, moist and in itself an ideal food source. Many microbes have, therefore, developed strategies to circumvent the defence systems of the body. To give an example, Staphylococcus aureus excretes a toxin that, if the bacterium is present in high numbers, intoxicates the body’s own immune cells and trick them into attacking the cells of its own body instead of the bacterium, i.e. they are fooled into protecting the bacterium. The toxins secreted by bacteria and fungi can enter the blood and be circulated throughout the body (toxaemia) and may affect the vital organs leading to shock (sepsis) often with lethal consequences. Wounds are one of the main origins of septicaemia and consequently main causes of sepsis.

Video of how a neutrophil (a specific type of immune cell) actively chases a bacterium and how the bacterium actively seeks to avoid the neutrophil. The video offers an impression of the type of fight that continously takes place in the wound. The bacteria will try to release toxins to put the neutrophil out of action - similiarly to a snake, spider or bee that uses venom as a defence.

The speed of the video has been increased x10.

Protection strategies

Our body employs two different strategies with respect to defending itself against potential harm caused by microbes, i.e. bacteria and fungi, present in the environment.
  • Internal regions not in direct contact with the environment, e.g. the blood and brain: The immune system keeps these areas sterile, i.e. all microbes are removed.
  • External areas in direct contact with the environment, e.g. the skin and gut: It is not possible for the immune system to keep these areas sterile. Instead, it works in synergy with selected microbes to protect our body against the microbes that can be dangerous to us.

The Microbiome

Over 1000 different species of bacteria live on our skin and they extend from the surface and down into the deeper dermal layers. These together with fungi, viruses and mites make up the skin microbiome. The microbiome is individual to each person, it varies in composition across different locations on the body, and it is influenced by a large number of external and internal factors. The presence of these organisms helps to protect us, e.g. by producing biofilm which protects our skin. Studies have found that several disease conditions are associated with abnormalities in the skin microbiome, e.g. it was recently discovered that the chronic skin disease Hidradenidis suppurativa is associated with a lack of bacteria and biofilm on the skin (Ring et al. 2017) and that people with diabetic foot ulcers have a reduced variability in their microbiome (Gardiner et al. 2017). However, not all bacteria and fungi are beneficial and their presence therefore needs to be governed, supervised and controlled by the immune system. In this respect, there are three main factors to consider:
  • If microbes encounter an empty space, they will seek to colonise it.
  • Some microbes are always dangerous to humans and need to be removed, e.g. Anthrax.
  • Other microbes are only dangerous if they gain a dominant position, e.g. Staphylococcus aureus.
Our immune system therefore aims to ensure that all body surfaces in direct contact with the environment are populated by
  • microbes that are non-pathogenic (not intrinsically disease causing)
  • a mix of many different species. These will keep each other at bay and, consequently, prevent anyone, benign in low numbers, suddenly becoming dominant and pathogenic (disease causing).
New RNA/DNA sequencing techniques have made it possible to identify most of the organisms present in a wound. With this new technology, it has been realised that the usual techniques of measuring the wound colonisation only identified around 5% of the organisms present, whereas new technology has increased the number to an estimated 85%. Using these new techniques, it has been possible to map the distribution of microbes across the body and the layers of the skin, and this has resulted in an enormous amount of new data. The probem, however, is that nobody knows how to interpret these findings, e.g. the relevance of changes in the microbiome during wound healing, what a "normal" microbiome is, what should be the target of a possible treatment etc. Most of the research at this stage is therefore mainly descriptive and it will be some time before it progresses towards targeted manipulations of the microbiome in order to understand how it actually functions.

Wound colonisation

The generation of a wound means opening up a new uninhabited area, which begs for microbial invasion. There will be microbes present on and in the skin, which are already accepted by the person’s immune system and which rapidly can invade the area. This will help to reduce the risk of invasion by pathogens, but it necessitates that the immune system is in control and can determine the proportion and distribution of the individual microbes to prevent a specific species of microbes from becoming dominant and out-of-control, as this would lead to an infection. In burns, all or most of the microbes in the deeper structures and the surrounding skin will have been killed, which means that there is not a pool of microbes acceptable to the immune system that can invade the area. This increases the risk of undesirable organisms gaining a foothold and can explain why burns are so susceptible to infection. In either case, it is clearly very important that the immune system is able to control the microbiome.

Wound healing

The natural wound healing process is normally divided into 3 phases:
  • Inflammatory Phase (response to injury) - Immediate to 2-5 days
  • Proliferative Phase (tissue regeneration) - 2 days to 3 weeks
  • Maturation Phase (improving strength) - 3 weeks to 2 years
It is during the inflammatory phase that microbes and dead (necrotic) tissue are removed in preparation for the generation of new tissue to fill up and subsequently close the wound - which will occur during the proliferative phase. It is therefore important, that the immune system is able to govern, supervise and control the wound from very early on in the process to prevent the development of infection. In cases, where the immune system lost the battle for control, infection or critical colonisation will develop as a result and the wound will usually remain stuck in the inflammatory phase or alternating between the inflammatory and proliferative phases. In order to get the wound to heal, it now needs help to put the immune system back in control. Once this happens, the healing process will proceed normally and the time to wound closure will be more or less constant (Thomas 2006) as shown schematically below.

Factors influencing wound healing

Infection or critical colonisation

A wound with an out-of-control microbiome will not heal and it is therefore necessary to assist the wound in regaining control of the microbiome. However, the microbiome extends deep into the dermis (Nakatsuji et al. 2013) and data seem to indicate that different bacterial species have different preferences (Costello et al. 2009; Grice and Segre 2011; Pellegatta et al. 2016) with regard to which layers they prefer. This may explain why some wounds seem to have cleared an infection on the surface but still do not heal.

 

Old wounds

The older the wound, the wider and the deeper the infection will have had the time to spread. This process of spreading and becoming increasingly firmly embedded in the affected tissues can continue for years, leading to an extensive penumbra, i.e. an affected region around and underneath the actual wound. The longer the process has been on-going (months – year – several years), the more difficult it becomes to re-establish a microbiome that allows for healing to proceed and the longer the healing process will often take. The healing process, once it starts, is usually visible by regular deposits of mucky waste on the wound surface as this is the only place the body can dispose of the waste originating from tidying up the penumbral area. Finally, it is not unusual that old wounds ache when the restoration process is being undertaken.

 

Osteomyelitis

Osteomyelitis (bone infection) can ensue as a result of an infection on top of a bone. Osteomyelitis is very difficult to treat and needs surgical intervention. If osteomyelitis has developed, the wound on top cannot heal. The microbes causing the infection in the bone generate waste and this must be able drain to the surface. The wound serves as the area of waste disposal.

 

Underlying diseases

The presence of underlying diseases in the tissue can cause the emergence of a wound, e.g. cancers, or impair healing and, consequently, lead to a wound growing in size or severity, as e.g. can be the case in diabetes.