A new approach to wound healing

Dr Sylvie Meaume, Dermatologist - Geriatrics, France (Paris)

Let’s look at a few clinical case studies

• Around leg ulcers, the skin is often covered in oily or dry scales, which are a source of concern for the patient and/or nurse. They must be removed mechanically with tweezers after each dressing and can be prevented by
  using suitable emollients.
• Stasis dermatitis is not uncommon; it can be dry or oozing and is sometimes difficult to distinguish from allergic contact eczema, or even erysipelas.
  This type of dermatitis is essentially treated with compression therapy, as well as with 1% aqueous silver nitrate for oozing and with short courses of topical corticosteroids.
• Changes related to venous insufficiency can manifest themselves as ochre dermatitis, asteatotic eczema or white atrophy.
  - For ochre dermatitis, which is often scaly, emollients should be recommended. Management of the venous disease will be entrusted to the vascular physician.
  - Asteatotic eczema will not benefit from topical corticosteroids – the opposite is actually true – but it can be treated with emollients and reinforced compression therapy.
  - As for white atrophy, which is fragile and difficult to treat, it requires reinforced compression therapy and the application of emollients.
• Large amounts of exudate, a source of skin maceration, are likely to form around a colonised wound or in the absence of compression therapy, despite absorbent dressings.
  The wound must then be investigated for possible infection, which in some cases will require general antibiotic therapy or debridement if the infection is local, but the use of local antibiotics or antiseptics in general should be avoided. In the presence of oedema, look for a general cause: cardiac, hepatic, renal, nutritional, etc.
• The question often arises of how to distinguish between allergic contact dermatitis and irritant dermatitis.
  In the event of irritation, there is no prior sensitisation, the patient feels pain and burning rather than pruritus, and the lesions have sharp contours, limited to the contours of the dressing. The onset is rapid, occurring within a few minutes to a few hours. There is no spread of the lesions.
  Contact eczema, on the other hand, is due to an immune mechanism, is more pruritic than painful, is not always vesicular, has jagged borders, and may extend beyond the limits of the area to which the responsible product was applied. It is likely to become more widespread.

The treatment of contact dermatitis, whether allergic or not, involves identifying the product responsible, asking the patient about any self-medication with essential oils or other products, and carrying out use tests or allergy testing, after taking the precaution of giving the patient the list of products not to be used.
The doctor will suggest “barrier” creams, which are emollients with ceramides; in the event of allergy or discomfort, Class 2 topical corticosteroids are indicated, in a reasoned manner.

Are you familiar with MARSI?

This is the acronym for medical adhesive-related skin injuries, which are lesions caused by adhesive products applied to the skin surrounding a leg ulcer, a stoma opening or a surgical suture. These can take the form of dermabrasion-type wounds, bullae, skin tears, folliculitis, maceration, or allergic or irritant contact dermatitis.

There are several ways to prevent them:

• Look after your skin, but without excessive bathing and showering. Always use non-detergent products, syndet or oil (with a pH close to that of the skin), as well as emollients;
• Remove adhesives using silicone solvents – do not use alcohol or ether;
• Use skin protectors containing polymers, organic solvents or silicone;
• Choose the right adhesive depending on the desired result and whether or not there is a compression bandage;
• Train nurses in adhesive application and removal techniques, noting that adhesives should not be pulled vertically, as this could tear fragile skin, particularly the skin of the elderly.

Compression therapy can also cause skin lesions such as purpura or oedema. Shearing or friction bullae require protection of the underlying skin.
Eczema and irritant dermatitis are also possible, due to the compression devices that are nonetheless necessary for the healing of venous ulcers.

Occlusion can be responsible for erosive and pustular dermatitis of the leg:

• This particular condition, of inflammatory origin, occurs in the elderly and may or may not accompany a leg ulcer.
• It is characterised by non-follicular, amicrobial pustules in addition to scabs and erosions, on one or both legs, with some forms being purely erosive.
• Patients are often treated unsuccessfully for months or even years with various antiseptics, antibiotics and antifungal agents.
• Strong local corticosteroid therapy (Dermoval®, Clarelux®), continued for several weeks, is consistently effective.

Prof Brigitte Dréno, Dermatologist-oncologist, France (Nantes)

Among our organs, the skin stands out for its visibility and size. It is on its surface and in its appendices that a second organ develops, i.e. the skin microbiome, made up of a myriad of micro-organisms, bacteria, viruses and eukaryotes. The skin of foetuses is sterile, so the microbiome appears at birth, taking advantage of the environment to characterise itself and therefore differing depending on whether childbirth took place by vaginal delivery or by caesarean section. Bacterial density is higher on the surface of the epidermis: the composition of the microbiome sampled by scratch testing differs from that collected via biopsy.

Four categories (phyla) of bacteria colonise the skin

• Actinobacteria, Firmicutes, Bacteroidetes and Proteobacteria.
• Cutibacterium and Staphylococcus are of particular interest to dermatologists.

The composition of the microbiome changes over time:

On the face, Firmicutes predominate in children, while Proteobacteria are more numerous in adults. Biodiversity also changes over time, leading to chronic inflammation in the elderly. Diversity is a crucial element of the normal skin microbiome, which must be successfully maintained. The microbiome profile is obtained using traditional cultures, 16S RNA gene sequencing and, more recently, shotgun metagenomic sequencing.

The microbiome is involved in all the key phases of wound healing

A rupture in the skin barrier destroys the microbiome that exists on the skin and creates an area rich in skin nutrients that favours the growth of opportunistic commensal or pathogenic microbes that compete with one another. This leads to an increase in skin pH and water loss, promoting the development of pathogens.

Dysbiosis in a wound varies according to its origin and the terrain in which it occurs (leg ulcer, burn, diabetic foot ulcer, etc.). For example, diabetic ulcers are mainly colonised by Streptococcus, burns by Gram-negative bacteria, and pressure ulcers by anaerobic bacteria: these different microbiomes require different treatments.

What happens when there is a wound?

A neo-microbiome appears two weeks after a wound forms, resembling that of the dermis and the deep layers of the epidermis. A healed lesion therefore does not have the same microbiome as the normal surrounding skin. The stratum corneum is covered in antimicrobial peptides (AMPs) called “antibiotic-like peptides” and thus forms an antimicrobial barrier.
If a pathogenic microbe penetrates the stratum corneum, the epidermis develops a new defence strategy: during the healing
process, there are constant interactions between commensal bacteria, their antimicrobial peptides and keratinocytes: therapeutically, the aim is to restore this balance.

To summarise, there are three targets in the skin microbiome for wound healing:

• Commensal bacteria prevent pathogenic invasions by producing antimicrobial peptides;
• Accelerate healing by limiting the duration of inflammation via the innate immune system;
• Induce the production of T-cells specific to the commensal microbes, which promote tissue repair.

Each commensal bacterium has a skin barrier protection function: it protects the skin from invasion by other pathogenic microbes

• Cutibacterium acnes interacts with Staphylococcus epidermidis, with both bacteria having self-regulating capacities.
• C. acnes maintains the skin pH at 5.
• Streptococcus thermophilus and Staphylococcus epidermidis are involved in ceramide production.

Lastly, many commensal bacteria act to inhibit the development of S. aureus. Activation of the innate immune system by the skin microbiome can have a negative impact:

• Excessive production of proteases, reactive oxygen species and other bio-active substances that delay healing;
• Certain external factors can alter the activity of the skin microbiome: age, nutrition, comorbidities, genetic factors, etc.
• Induction of chronic inflammation when acute inflammation has not been controlled;
• Formation of biofilms by certain bacteria.

This means efforts need to be made to strike a balance. In 60% of wounds, chronic activation of the innate immune system is accompanied by the development of a biofilm by the bacteria in the wound bed, which maintains chronic inflammation and delays wound healing.

Stress, whether physiological or psychological, modifies the profile of the skin microbiome, alters the innate immune system and stimulates the formation of a biofilm, resulting in the development of chronic neurogenic inflammation. Discovery of an injury causes the brain to send signals to the nerve endings around the sebaceous glands to produce substance P. Substance P receptors in these glands cause sebum to be produced; this in turn leads to changes in the microbiome, particularly as regards Staphylococcus aureus and epidermidis.

Therapeutic approaches take account of the fact that a healed wound does not regain the microbiome of normal skin. The aim of treatment is to restore a skin microbiome as close as possible to the normal microbiome.

• Thanks to bacteriophages, which are intra-bacterial viruses capable of targeting resistant bacteria, Anglo-Saxons have developed topical and oral bacteriotherapy using bacterial transplants, probiotics (live bacteria), prebiotics (bacterial extracts), a combination of pro- and prebiotics, and postbiotics (antimicrobial peptides). Bacterial resistance, particularly that of C. acnes, can thus be reduced by phages, which should reduce the need for antibiotics.
• Probiotics from lactic acid bacteria: induce the migration and differentiation of keratinocytes and fibroblasts, stimulate the formation of collagen, reduce the inflammatory phase and accelerate wound healing in rats.