Globally, hard-to heal wounds have become a major public health problem that incur significant economic costs. They place a huge burden on patients, caregivers and society in general and are a major cause of patient morbidity. In 2012/12, out of a total estimated cost to the NHS of £5.3 billion to manage patients with wounds, £3.2 billion was spent on hard-to-heal wounds (Guest et al, 2015). In the UK, the number of people with a wound managed by the NHS was estimated at 2.2 million patients for 2012/13 (Guest et al, 2015), with the number of people across Europe living with a hard-to-heal wound across Europe estimated at 1.5-2 million (Lindholm and Searle, 2016. Meanwhile, in the USA, diabetic foot ulcers and other chronic wounds affect around 6.5 million people, costing around $25 billion a year (Dhall et al, 2014).
Wounds can be described as dynamic environments in which a triad of dead tissue, exudate and microbial load interact in a complex circle between both themselves and with the host tissue (Vyas and Wong, 2016). They should be approached as a serious medical issue because they may be contaminated with a high number of microorganisms, which delay wound healing and skin proliferation. Ultimately, death can occur as a result of a devastating systemic infection (Tian et al, 2015).
This article highlights:
Economic costs associated with hard-to-heal wounds
Wounds are a major cause of patient morbidity and high healthcare costs, which are increasing the stress on healthcare systems at a global level (Gupta et al, 2016). The reduction of infection associated with wounds could result in significant overall healthcare cost savings. According to the United Nations, chronic wounds account for 2% of the health budget in Europe, and 1-2% of the population in developed countries are expected to experience a hard-to-heal wound at some point in their lives (Böttrich, 2012).
The number of patients with hard-to-heal wounds is rising worldwide because of the ageing population and an increase in the number of people who are obese, have type 2 diabetes or cardiovascular disease. Furthermore, hard-to-heal wounds are related to psychosocial issues such as loss of mobility, decreased bodily function, social problems, poor quality of life and loss of participation in the workforce (Ennis et al, 2004).
Managing such a critical condition requires quicker solutions results with scarcer resources. Hospitals are looking for novel, effective approaches to identify and integrate cost-effective wound therapies without compromising care quality. Consequently, cost-effectiveness analyses have become a critical instrument for hospital administrators (Gupta et al, 2016). The challenge arises when trying to balance the initial higher costs of advanced wound-healing technologies with overall direct and indirect costs involved in wound care.
Hard-to-heal wounds
For many years the classification of wounds termed ‘chronic’ has proved a challenge. In 2018, there was an attempt to make the classification of such wounds consistent at a meeting that also discussed how they should be described. There was consensus that the most appropriate description for wounds previously described as chronic, complex, non-healing or hard-to-heal should be hard-to-heal wounds. A consensus document published following the meeting has recommended that any wound that has not healed by 40–50% after 4 weeks of good standard of care should be considered a hard-to-heal wound (Atkin et al, 2019).
In hard-to-heal wounds, the usual biological progression of inflammation, angiogenesis, matrix deposition and wound contraction followed by epithelialisation and scar remodelling is interrupted so healing is delayed (Jull et al, 2015). Delayed healing is usually related to microbial colonisation and/or infection, high levels of exudate, wide tissue loss or exposure of critical structures. Some features, such as the number of times that the wound is open and previous attempts to close it are useful when describing the timeline until closure. The most common hard-to-heal cutaneous wounds are venous, arterial and neuropathic leg ulcers and pressure ulcers (Gupta et al, 2016).
The key factors in promoting wound healing are debridement (surgical or chemical), infection control (local application of antiseptics or antimicrobials versus systemic administration) and wound dressings. Skin grafting or skin substitutes and growth factors could be valuable in some hard-to-heal ulcers.
A crucial step to treat any wound is debridement to remove all foreign material or necrotic tissue that may be harmful until the wound edges and base are formed of normal, healthy tissue. Debriding an acute wound enables it to go through the normal wound-healing phases, assuming that both systemic and local factors are working normally (Kirshen et al, 2006). Adequate surgical debridement is a prerequisite for the successful treatment of skin, soft tissue and bone infection (Diefenbeck et al, 2013). Aggressive debriding of a hard-to-heal wound aids its change into an acute wound so it can progress through the normal phases of wound healing. Recurrent debridement removes inhibitors of wound healing and allows growth factors to function more successfully (Trengove et al, 1999).
Some studies have emphasised the central importance of wound irrigation to the process of wound healing. Wound irrigation involves the steady flow of a solution across an open wound to create an optimal environment for healing, improving hydration and facilitating the removal of deep debris, wound exudate and metabolic waste (Rodeheaver, 1999; Fernandez and Griffiths, 2008).
Biofilms and hard-to-heal wound infection: a dynamic relationship
Unfortunately, wounds are highly susceptible to bacterial infection (Becerra et al, 2016). Bacterial infection in a wound follows an ‘exponential progression’, with bacterial replication and production of a polymeric matrix. This matrix promotes adherence to any inert or living surface, allowing bacteria to thrive in hostile environments (Davey and O'Toole, 2000). This forms a structure called a biofilm (Donlan and Costerton, 2002), which is highly resistant to topical and systemic antibacterial compounds unless disrupted by debridement (Gabriel et al, 2008).
Biofilms, which occur in nearly all environments around the world, are communities of independent cells with an extraordinary degree of organisation, linked by an extracellular polymeric matrix. All abiotic surfaces submerged in non-sterile water, such as seawater or fresh water, may develop bacterial biofilms. Within these surfaces, biofilm can cause major problems, disturbing pipelines and water supplies, and its adherence to ships' hulls reduces performance and increases fuel consumption. In respect to freshwater pipelines, this situation is worrying because Pseudomonas aeruginosa and Legionella pneumophila can easily multiply in water, becoming waterborne infectious agents (Di Pippo et al, 2018). Bacteria organised in a biofilm are particularly effective in promoting their own development by enhancing symbiotic relationships and granting survival in hostile environments.
Biofilm capacity is an important factor in microbial survival and pathogenicity, with intricate implications for wound treatment; for instance, antimicrobial resistance mechanisms in biofilm may involve increased cell density and physical exclusion of antimicrobials. Moreover, each individual microbial cell in a biofilm may undergo changes that increase resistance to biocides (Edmiston et al, 2016), such as:
The biofilm may also contribute to increased microbial resistance of the microorganism to the host immune system response by interfering with macrophage phagocytic activity (Wolcott et al, 2010) or by inactivating antibodies that mediate phagocytosis and the clearance of microbial cells (Thomsen et al, 2015).
A study by Wolcott et al (2016) showed that 60–90% of hard-to-heal wounds have biofilms compared with 6% of acute wounds. Akers et al (2014), in a study of US military trauma patients, found that bacterial biofilms were responsible for approximately 80% of chronic skin infections.
A systematic review of studies on biofilms in hard-to-heal wounds, including pressure ulcers, venous leg ulcers and diabetic foot ulcers, found that their prevalence was 78.2% (Malone et al, 2017).
In clinical practice, bacterial biofilms are a considerable challenge for health professionals and are widely recognised as a key factor in increasing patient morbidity. In patients who are confined to bed, recurrent pressure ulcers are particularly prone to developing biofilm by both aerobic and anaerobic bacteria; for that reason, healing is difficult to achieve (Donelli and Vuotto, 2014). Patients with diabetes are also susceptible to developing hard-to-heal dermal and subdermal wounds, which can be colonised by a high number of diverse bacteria. Data from the literature stresses that bacterial biofilms are invariably found in hard-to-heal wounds (Attinger and Wolcott, 2012). Diabetic foot ulcers, pressure ulcers and chronic venous ulcers usually contain Staphylococcus aureus biofilms. It is important to highlight that some chronic wounds do not heal despite successive therapeutic approaches, a fact that can be attributed to the presence of bacteria with a biofilm growth phenotype (Percival and Bowler, 2004; Davis et al, 2008).
James et al (2008), using scanning electron microscopy, found microbial aggregates were higher in hard-to-heal wounds than acute wounds. The interaction between biofilm and chronic wounds has been investigated using several in vitro models (Hill et al, 2010; Agostinho et al, 2011). According to Akers et al (2014), biofilm production is associated with a prolonged persistence of wound infection. While debridement is accepted as the gold standard intervention to promote wound healing, bacterial biofilm can resist debridement and act as a resistance reservoir, leading to considerable delays in wound healing.
The presence of bacteria in the wound bed can be divided into four categories based on the host response: contaminated; colonised; critically colonised; and infected. All wounds are contaminated at first, and progress up and down the wound bioburden in a continuum, depending upon the quantity and types of microorganisms present.
The most frequently isolated species in hard-to-heal wounds in humans are Staph aureus, Enterococcus faecalis, Pseudomonas aeruginosa, coagulase-negative Staphylococci spp and Proteus spp (Gjødsbøl et al, 2006). Hard-to-heal wounds provide an ideal culture medium for bacteria and, among inpatients with chronic leg ulcers and burn wounds, Staph aureus and P aeruginosa can colonise up to 93.5% and 52.2% of cases respectively (Serra et al, 2015). Regarding pressure ulcers, a diversity of colonising bacteria is evident but aerobic organisms are cultured more often than anaerobes (O'Meara et al, 2000). The most common species recovered are Staph aureus, Streptococcus spp, Proteus spp, Escherichia coli, Pseudomonas spp, Klebsiella spp and Citrobacter spp (Boulton et al, 2007). In the case of diabetic foot ulcers, P aeruginosa and anaerobes are frequently isolated, with anaerobes being commonly present in the discharge of chronic pilonidal sinuses.
It is increasingly recognised that biofilms are the principal cause of wounds becoming chronic. Progress in treatments for wound biofilms will increase the range of hard-to-heal wounds that can be healed and possibly save many patients' lives.
Wound healing management
Historically, one of the most elementary and crucial practices of human civilisation is healing wounds; this can be seen from Egyptian civilisation papyri to the battlefields of Crimea. Civilisations in the remote past created bandages and homemade dressings made from honey, grease and lint (Broughton et al, 2006), among many other substances and compounds.
The process of wound healing is complex, involving the reconstitution of several skin layers. This occurs through four overlapping phases: haemostasis; inflammation; proliferation; and remodelling. Haemostasis starts when blood components extravasate into the site of wound, with platelets being exposed to collagen and other extracellular components, leading to the release of clotting factors, growth factors and cytokines (Burnouf et al, 2013). During the inflammatory phase, blood cells such as neutrophils and macrophages infiltrate the wound bed, remove pathogenic organisms and secrete cytokines to promote the production of fibroblasts, endothelial cells and keratinocytes. Two days later, these factors penetrate the wound massively and increase phagocytic activity. This constitutes a critical phase leading to the next steps in the healing process.
Thereafter, the proliferation phase when new tissue is formed takes place, which includes stages such as fibroplasia, wound matrix deposition, angiogenesis and re-epithelialisation. The granulation tissue formed by this provides volume to the wound and facilitates closure by driving wound contraction. This phase also enables healing by promoting re-epithelialisation. Substantial angiogenesis is required for the healing process to occur within this tissue. At the same time, granulation tissue produces growth factors that favour proliferation and differentiation of epithelial cells, which restore epithelial barrier integrity. When the wound is filled, angiogenesis finishes and many newly formed blood vessels may undergo apoptosis. In the remodelling phase, a constant alteration occurs, such as collagen degradation and deposition in an equilibrium-producing manner.
In hard-to-heal wounds, the steps of this process are not complete and the tissue remains under oxidative stress owing to the production of reactive oxygen species, leading to DNA damage, gene dysregulation, cell death and the development of an aggressive proteolytic environment (Sen and Roy, 2008). Sen and Roy (2008) induced oxidative stress by inhibiting two antioxidant enzymes (catalase and glutathione peroxidase) in a diabetic mouse model (the db/db mouse model) at the time of injury. This mechanism was enough to cause wounds to become chronic.
As mentioned above, wounds may be colonised by a polymicrobial community with biofilm-producing bacteria becoming dominant. The expression of several genes is impaired when reactive oxygen species increases, which makes bacteria more able to produce virulent attributes involved in biofilm formation. After treatment with antioxidants such as α-tocopherol and N-acetylcysteine, oxidative stress may be reduced, with biofilms recovering at least partial sensitivity to antibiotics (Dhall et al, 2014).
Prevention and effective management and control of infection are critical for the normal wound-healing process. When bacteria on the wound surface start replication and increase their metabolic activity, the byproducts formed, such as endotoxins and metalloproteinases, all negatively affect every phase described above (Warriner and Burrell, 2005). Wound pathogens such as Staph aureus, P aeruginosa and ß-haemolytic streptococci cause delayed healing. Causing further direct damage to the host, bacteria attract leukocytes, with subsequent amplification of inflammatory cytokines, proteases and reactive oxygen species, thus both initiating and maintaining inflammatory cascades (Schreml et al, 2010). The resulting proteases and reactive oxygen species from both host and bacteria degrade the extracellular matrix and growth factors, disrupting cell migration and inhibiting wound closure (Demidova-Rice et al, 2012).
Data from the literature show that numerous risk factors can complicate wound healing and consequently increase healthcare costs; these include, in particular, patient age, pulmonary and vascular disease, haemodynamic instability, hypoalbuminemia, obesity, uraemia, ascites, nutritional deficiencies, malignancy, hypertension, the length and depth of wound, the presence of foreign bodies in the wound, anaemia, diabetes and smoking, with radiation therapy, steroid use among several possible iatrogenic factors (Riou et al, 1992; Abbas and Hill, 2009).
Options to manage and treat hard-to-heal wounds are invariably intended to:
Possible treatments for hard-to-heal wounds
Dressings/advanced dressings
Dressing selection is important and the market is vast (Frykberg and Banks, 2015; Westby et al, 2017). This includes dressings that deliver debriding or antimicrobial agents (Gould et al, 2015), maintain a moist wound environment and minimise skin irritation or friction (Jones et al, 2018).
Many advanced wound dressings are available, including those containing alginates, foams, hydrocolloids and hydrogels. These should be chosen carefully according to the wound type. Alginate and foam dressings are used to absorb excess exudate.
Silver dressings decrease microbial contamination to enable a normal healing course (Kalan et al, 2017). Dressings incorporating iodide and carbon can also reduce the microbial bioburden (Bansal and Goyal, 2005; Fitzgerald et al, 2017).
Negative pressure wound therapy
Negative pressure wound therapy, which is also called vacuum-assisted wound closure, is a wound dressing system that continuously or intermittently applies subatmospheric pressure to the surface of the wound. It is a suggested treatment for the management of hard-to-heal wounds such as leg ulcers because its application is thought to promote the healing process (Vuerstaek et al, 2006). However, the evidence is lacking as to its benefits in treating other wound types (Mendonca et al, 2006).
Biofilm inhibitors
Exogenous delivery of nitric oxide with a prodrug vehicle is effective against clinically relevant multispecies biofilm (Craven et al, 2016). Recent studies have examined other biofilm inhibitors, such as antimicrobial peptides, metal chelators, quorum-sensing inhibitors and amino acids (Bala et al, 2011; Sanchez et al, 2014) and nitric oxide (Craven et al, 2016).
D-amino acids were described as inhibiting bacterial biofilm growth of Gram-positive species such as Bacillus subtilis and Staph aureus (Kolodkin-Gal et al, 2010; Hochbaum et al, 2011).
Conclusion
The number of patients with hard-to-heal wounds continues to increase worldwide, mainly because the population is ageing and an increasing number of people are obese, or have type 2 diabetes, or cardiovascular disease. Preventing or controlling infections is essential for the normal wound-healing process to occur.
In hard-to-heal wounds, the usual biological progression is interrupted so healing is delayed. Delayed healing is usually related to severe microbial colonisation or infection, high levels of exudate, wide tissue loss or exposure of critical structures. The extent of biofilm formation is an important factor in microbial survival and pathogenicity, with complex implications for wound treatment; for instance, antimicrobial resistance mechanisms in biofilm may include increased cell density and physical exclusion of antimicrobials. It is therefore essential to prevent wounds from becoming chronic and this may involve many approaches and strategies.