Biological dressings – larval therapy. Treatment with fly larvae (Lucilia sericata, green bottle fly)
Beneficial role of green bottle fly, Lucilia sericata, in the treatment of difficult-to-heal wounds (e.g. diabetic foot or pressure ulcers) has been known for millennia. Nowadays, thanks to the advancement in material technology, especially the development of a mesh with precisely selected holes, it is possible to produce advanced biological dressings, where the sterile cultures of larvae grown in medical standards can be enclosed in net coatings and applied directly on the patient’s wound.
Larval therapy – the history of treatment with fly larvae
Larvae were used by the ancient Aborigines and Maya. The first documented uses of maggots in wound healing can be found in the Old Testament (Book of Job, 7:5). The first information about the beneficial healing effects of maggots can be read in reports from the battle of Saint Quentin (1557), or in the journals from Napoleon’s campaign to Egypt (1799). Dr John Forney Zacharias, a surgeon, was the first to use larvae as deliberate treatment of necrosis during the American Civil War. However, it is William S. Baer, who should be considered the father of contemporary larval therapy. During the First World War, he noticed rapid healing of wounds in soldiers infested with green bottle fly larvae. Soon after that, he started to incorporate his experience into practice in Baltimore Hospital. In 1930, he described in a medical journal the efficacy of the treatment with maggots in bone inflammation in children. Unfortunately, the medical environment did not respond positively to his work, which was overshadowed by the invention of antibiotics by Alexander Fleming (1928). By 1944, antibiotics had become commercially used drugs. That event, along with the ongoing development of surgical science, completely erased the larval therapy from the list of efficient treatment methods.
In the 1990s, the crisis of antibiotic therapy began. The medical environment slowly started to return to the methods well-known by folk medicine – the larval therapy. The first prospective and retrospective studies from 1990-1995 showed the increased effectiveness of wound healing after the repeated applications of maggots as compared to mainstream medical methods. Since then, due to very high efficacy, the ease of use and the lack of toxicity, the interest in the maggot therapy reemerged, which resulted in the establishment of the International Biotherapy Society (1996). At that time, studies on the development of the larval therapy in wound management commenced. They were based on medical standards involving patients’ safety and the possibility of the repeatability of the therapy. Currently, this method is used in many countries all over the world. In 2004, FDA registered biological larval dressings as a medical device for the purpose of treatment in the United States. In many clinics in Europe new specialised units are being established in order to treat patients with larvae.
Novel biological dressings
Carefully selected materials allow larvae to work efficiently by preventing them from uncontrolled wandering out of the wound and reducing painful sensations. It is equally important that the patient can neither see nor feel the maggots.
Procedure and effectiveness
So far, it has been believed that the main task of maggots involves the mechanical debridement of the wound and removal of dead tissue with mandibles (mouthpieces) and hydrolytic enzymes secreted externally during the exploration of a wound bed. Beneficial antibacterial effects of wound biofilm eradication and the stimulation of the healing process and tissue regeneration are also well-known. Since the beginning of the 21st century, numerous intensive studies have been carried out. Recent research has distinguished at least 70 active substances secreted by larvae while working in a wound bed. Such discovery has allowed for a multifaceted management and healing of wounds.
At the beginning of the 1990s, the studies on an efficient method of the management of chronic wounds began. It was called the Wound Bed Preparation.
For the healing process to begin, 4 important conditions must be met. They are referred to as TIME:
T – Tissue. The wound must be completely debrided of any dead tissue,
I – Infection. The wound must be free of infection,
M – Moisture. Proper moisture and liquid balance in the wound must be maintained
E – Edge. The wound edge must be healthy as its cells are necessary for further division in the wound bed.
In order to prepare the wound all the above-mentioned conditions must be met, what requires great coordination of many medical professionals and various actions, which can efficiently determine the successful termination of particular processes.
Larvae caged in a dressing influence simultaneously all the processes in the TIME procedure, what makes this method highly effective, fast and safe for the patient.
T – Living organisms mechanically remove dead tissue from the wound bed and support the healing process with hydrolytic enzymes (mainly proteolytic, glycolytic, lipolytic and endonucleases). The enzymes are highly selective in the wound debridement process, because they “dissolve” only dead tissue and leave healthy tissue unaltered. The mechanism of selective debridement is very simple: serine protease, which is secreted in high concentration, is inhibited by proteins present in blood. At the border between living and dead tissue, at the site of vascularisation, the enzymes activity is inhibited.
I – Larvae of green bottle fly, L. sericata, secrete and release antimicrobial peptides (AMP) into the wound bed. The peptides efficiently fight microorganisms such as Gram-positive bacteria (lucifensin, seraticin, MAMP), Gram-negative bacteria (proline dimer, hydroxybenzoic acid), and fungi (lucimycin peptide). The production and synthesis of these substances depends on the type of microorganisms present in the wound. Moreover, as early as after the first 42 hours of the therapy, it can be easily noticed, that unidentified substances contained in larval secretion efficiently reduce inflammation in the wound, inhibiting the production of proinflammatory cytokines and promoting the production of anti-inflammatory cytokines by phagocytes.
M – Larval secretion inhibits the production of hydrogen peroxide and elastase enzyme by neutrophils. Both substances destroy living cells in the wound bed, what is of great importance especially in chronic wounds. The environment in the wound is also changed due to the action of hydrolytic enzymes and proteins targeted at microorganisms. Such action allows for a successful removal of bacterial-fungal biofilm.
E – Serine proteases from larval secretion efficiently influence the fibroblasts migration in the wound. This is the key factor contributing to the initiation of the healing process. Cell growth factors (basic fibroblast growth factor, endothelial cell growth factor) influence the rapid division of fibroblasts, keratinocytes, and cells which build blood vessels. As a result, the wound bed quickly fills with granulation tissue cells, and tiny blood vessels start to appear. Both events guarantee a fast healing process.
Application – free-range and bagged larvae
The application of dressings is very simple. The dressing is placed in the wound bed for 24-72 hours. During this time the wound is debrided, all necrotic cells and microorganisms are removed, and the regeneration process begins. Wounds with extensive necrosis require multiple applications of dressings. The therapy must be continued until a complete debridement is reached. This process can be supported with a surgical debridement. Biological material in a dressing must be alive. Thus, it is very important to protect dressings from organic fluids (the larvae will die without air), physical pressure and high temperature. If these occur, the risk of failure and the necessity of the repetition of the whole procedure must be taken into account. Studies on the effectiveness of the larval therapy show that the average healing time of 50% of wounds does not exceed 4 weeks. In case of conventional surgical methods, the same process may last up to 30 weeks and usually it does not finish with a complete closing of the wound.