A simple scratch on the foot in a person with diabetes or to the skin in a person with spinal cord injury (SCI) or multiple sclerosis (MS) can develop into a large wound that gradually spreads under the skin leading to osteomyelitis (bone infection) and sinus tract formation, i.e. bacteria and fungi boring tunnels into the tissue creating a network of interconnected tunnels with the possible presence of abscesses along the way – just like a huge underground mining area with tunnels and scattered holding chambers. In most cases, existing treatments are ineffective, and frequently the only option is surgery, but as the infection is not limited to the wound and tunnels but infiltrates the wider tissue as well, surgery is often unable to fully resolve the problem, except perhaps in diabetes where it is solved by amputation.
Diabetes, SCI and MS are seemingly very different conditions, but they actually share a characteristic that can explain why they all are associated with impaired wound healing – as well as other issues, but this discussion will focus on wound healing. This common characteristic is an impairment of the nervous system.
Wound healing requires a functional immune system, but the immune system is to a large extend controlled by the nervous system. The nervous system receives information about a wound or a local infection via local sensory fibres and in response it activates the immune cells in that area via the sympathetic nervous system, also called the fight and flight system. It is well known. that sensation in the foot is lost partly or fully in diabetics (neuropathy), in SCI it is lost in all areas below the site of injury and in MS sensation is known to be reduced. Studies have shown, that the sympathetic nervous system is impaired in diabetes and MS and it is not functional in SCI below the site of injury. Taken together, this means, that the nervous system is unable to sense an injury or an infection, and that it is unable to direct the immune cells to that area to produce an organised immune response. Interestingly, patients with amyotrophic lateral sclerosis (ALS), which mainly affect the motoneurons and not sensation nor the sympathetic nervous system, do not report wound healing as a significant problem, an observation that supports the above connection.
The immune response to a wound or a local infection consists of a local response that is activated by local factors, e.g. tissue damage, inflammation or the presence of foreign organisms; and a system-response that is controlled by the nervous system. In one study, it was shown that the number of macrophages, a type of immune cells, in an area of injury was 50% lower if the individual had a SCI and another study found that the properties of the healed skin was inferior in terms of strength and function in individuals with SCI. The inability of the nervous system to receive and send information to the area therefore has a huge effect on the body’s ability to fight an infection and to coordinate the tissue healing process.
There is one more factor that needs to be considered and that is the location and extend of the injury. Our skin contains a highly specialised “skin immune system”, which has evolved to protect us from the environment. The skin is our armour and the skin immune system is our weaponry. This protective armour also includes the skin microbiome, i.e. an ecosystem of bacteria, fungi, viruses and mites that live on and in our skin and that helps to keep unwanted organisms away. This skin microbiome is closely controlled by our immune system and forms an integral part of its defence system. Anatomically, the skin also contains several layers and membranes that makes it physically difficult for organisms to penetrate through the skin and into our body itself, which is sterile.
Given this information, it is also worth considering that the underlying cause of a pressure ulcer and a DFU may not be fundamentally different. It is known that diabetes causes vascular changes that may make vessels and capillaries prone to damage and the DFU is usually seen in areas exposed to extensive mechanical pressure. This is not fundamentally different to the cause of pressure ulcers, where tissue is damaged due to excessive mechanical pressure or prolonged pressure blocking the perfusion of the tissue. As the nervous system in diabetics is unable to register and react to this damage, this area will be at high risk of developing an injury. These events may occur in all diabetics with neuropathy, i.e. the loss of neurones, but it may be exacerbated if blood sugar levels are high as this will allow bacteria to spread faster as frequently seen in poorly controlled diabetic states. The resemblance between DFUs and pressure injuries may therefore also involve the initial events that cause the injury and not only the impaired healing which is a consequence of an impaired nervous system unable to direct the immune response and the healing process.
If a person with diabetes, SCI or MS sustains an injury to the skin, the local immune response combined with the structure of the skin will in many cases be able to restrict the injury to the skin, e.g. there are many cases of small wounds and ulcers that persist for years without closing, but which do not seem to advance further either. However, once an injury breaks through the ultimate layer of the skin into the underlying structures (with adipose tissue, muscles, tendon, bone etc.), the skin immune system can no longer contain the infection and the microorganisms can now freely spread into the underlying tissue. The internal areas of the body have not evolved to deal with the presence of a microbiome and it lacks the specialised immune system and the anatomical structures of the skin to prevent the spread of infection. This combined with an impaired nervous system preventing the activation of a systemic immune response leaves the body in a highly precarious state. The situation is not so different to a fortress where the enemy has penetrated the outer defence structures and can now freely roam the castle. The result is, that an infection will spread as it overpowers the immune defence and slowly but steadily generates large wounds complicating them with osteomyelitis, sinus tract formation and high probability of septicaemia (blood poisoning), which is the precursor to septic shock.
Individuals with diabetes, SCI and MS therefore effectively suffer from an immune-deficiency-syndrome (IDS) and it is obviously essential to treat any wounds as early and as effectively as possible, but what are the treatment options? These wounds will typically be infected, because the immune system will have difficulty fighting an infection. The FDA in 2016 concluded that dressings with antibiotics and antiseptics are ineffective in treating an infected wound and in supporting healing. In the UK, NICE has concluded that antibiotics, antiseptics and NPWT (vacuum therapy) should not be used routinely for treating pressure ulcers, because they are ineffective. In a series of studies by Guest et al. (2017, 2018) covering the treatment of diabetic foot ulcers and pressure ulcers, it was found that, for patients treated with an antibiotic, only 16% of DFUs and 14% of pressure ulcers were healed after 12 months, respectively. In addition to the limited efficacy in treating these wounds, it has recently been discovered that antiseptics and disinfectants, just like antibiotics, cause the development of antimicrobial resistance and that antiseptics and disinfectants may also cause bacteria to become resistant to antibiotics (cross-resistance), leaving the patient in a vulnerable state if they later contract an internal infection and need antibiotic treatment. To pile even more problems on top, most antiseptics are toxic to human tissue, where they will damage newly formed cells that try to regenerate lost tissue and to close the wound. Furthermore, they will kill the few immune cells that the body has been able to mobilise in the area in a scenario with already impaired systemic immune response, as discussed above.
In all of this, it is important to keep in mind that antibiotics are very effective for treating infections inside the body, which is meant to be sterile, but, as outlined above, they are not effective for the treatment of infections in or on surfaces that involve a microbiome. Wounds also require a microbiome, because they are part of the skin and are exposed to the external environment. The immune system will therefore try to install a microbiome that fulfils its requirements, but antibiotics and antiseptics will disrupt these efforts and therefore work against the body.
There is a new passive immunotherapy, which acts by helping the immune system. This treatment is also effective in immune-deficient individuals, because their immune system is still active, even if impaired, but needs a helping hand as it easily gets overwhelmed. This wound treatment – micropore particle technology or MPPT – removes wound infections 60% quicker than antibiotics and antiseptics and it has been shown to be effective in people with SCI and diabetes (it remains to be evaluated in MS). It is a fully approved wound treatment that is available over-the-counter (without prescription). In the UK, SIA, the national Spinal Injuries Association, is actively working to make it available through the public healthcare system due to the high frequency of nonhealing wounds and ulcers in their members. Cases have shown that MPPT can help even very old wounds and ulcers in SCI and diabetes towards healing and, depending on underlying complications, to closure. The aim is to use MPPT for early intervention to prevent these devastating and life-threatening wounds from ever developing. MPPT is also highly effective in people with intact immune systems, e.g. surgical wounds, trauma wounds, venous leg ulcers, etc. Data have shown that MPPT is highly cost-saving. Due to its mode-of-action, it is also effective in anti-microbial-resistant wound infections and will not contribute to AMR. It is non-toxic, hypoallergenic and only contains natural components.
The founder and president of SIA, Baroness Masham of Ilton, Countess of Swinton recently highlighted the need for this new treatment during a debate in the House of Lords: https://parliamentlive.tv/event/index/51528574-7679-4697-a3de-c04193b58013?in=13:26:12&out=13:27:56
Furthermore, a SIA-Trustee recently wrote an article about this new treatment: https://www.boltburdonkemp.co.uk/news-blogs/spinal-injury-blogs/have-you-heard-of-acapsil-for-treatment-of-pressure-sores-and-if-not-why-not/.
More information about MPPT can be seen here: https://b8e.5eb.myftpupload.com
