Martin H. Villet & Nicolette Bouwer
Department of Zoology & Entomology, Rhodes University, Grahamstown, South Africa
In the 2000 film version of Gladiator that starred Russell Crow, there is a scene where the hero passes out after being wounded in a battle, and when he awakes, he find his wound filled with maggots that had been put there by his closest friend. The maggots cleaned out the wound and helped it to heal faster and remarkably neatly. The dramatic image is not for faint-hearted viewers, but it is also not purely fiction: maggots really can help to heal wounds.
Modern medicine is very interested in this this biotechnological opportunity, sometimes called biosurgery, which has been effective in healing diabetic sores, skin ulcers, burns, gangrene, osteomyelitis and related chronic conditions that have resisted other standard contemporary medical procedures. The maggots appear to secrete antibiotics, removed dead tissue that bacteria might otherwise breed in, and stimulate the cellular processes of healing. They are able to explore all parts of most wounds, cleaning minute areas without harming surrounding healthy tissue, effectively performing microsurgery.
Biosurgery Through Time
The use of maggots or larvae in maggot debridement therapy, as biosurgery is more technically known, has been recorded in many cultures and goes back at least several centuries. In western history, the French barber-surgeon Ambroise Parè is generally credited as the first to note, in the 16th Century, the beneficial effects of maggot infestations on the wounds of soldiers. Almost 300 years later, Baron Dominique Jean Larrey reported that the healing of Napoleonic soldiers’ battle wounds was enhanced and accelerated by the presence of maggots in a wound. The first recorded clinical use of biosurgery occurred during the American Civil War, and it was used again with high success during World War I, when William Baer introduced the medical use of maggots as an antiseptic. During the 1930s biosurgery became medically popular in Europe, Canada and the United States. However, the discovery and development of antibiotics and the rise of aggressive surgical debridement led to a sharp fall in the popularity of biosurgery.
Renewed interest in biosurgery was sparked when widespread occurrences of antibiotic-resistant “supergerms” undermined antibiotic technology. For example, the bacterium occurring most commonly in wounds, Staphylococcus aureus, acquired resistance to methicillin in 1961, within two years of its introduction as a substitute for the rapidly defeated penicillin. This case of bacterial evolution led to prolonged hospitalization and treatment of some patients with chronic wounds, which contributed to the estimated cost of treating chronic wounds in the United Kingdom in 2004 to £1 billion. On the other hand, the antibiotic secretions of maggots are still effective, even against methacilin-resistant Staphylococcus aureus. As a result, since about 1990 maggots have again been considered in the treatment of certain otherwise intractable wounds in the USA, the UK, Israel, India and South Africa.
The larvae used in biosurgery usually belong to a species of greenbottle fly known to science as Lucilia sericata. A couple of recent reports successfully used two other species of blow fly, Lucilia cuprina and Chrysomya albiceps. The characteristics of greenbottle maggots make them particularly suitable for biosurgery. They are easy to culture in sterile conditions, have convenient life cycles, and are relatively hardy, withstanding the harsh and variable environments of wounds that may also contain drugs. Lucilia sericata, in particular, appears to avoid feeding on live tissue, which forestalls enlargement of the wound. In addition, they can also be cooled for transport in sterilized containers and stored at 5°C, which allows for round-the-clock availability.
About 8-10 sterilised first-instar larvae per square centimetre of cleaned wound are applied in a special gauze bag that allows them to reach the tissue being treated, but prevents them from leaving the wound. Blow fly larvae are highly mobile, hence the need to contain them carefully. A dressing may be secured over the bag to absorb excess fluids, and is changed regularly. Two hundred maggots can consume an impressive 15g of necrotic tissue in a day. The progress of the treatment is checked twice daily, and the maggots are changed at least every three days because of their rapid growth and short life cycle at human body temperatures.
So how do these animals achieve their beneficial effects? Can these processes be developed into biotechnological products? Several mechanisms are being studied and they are not mutually exclusive. Insight into each one could provide a new opportunity for biotechnological advances. In this regard, three things appear to be significant about maggots: they consume dead tissue voraciously; they secrete or excrete proteolytic digestive enzymes, cell growth stimulating factors, allantoin, urea, ammonia and calcium bicarbonate; and they are physically active.
The competitive feeding of blow fly larvae quickly removes a food source for bacteria, and many bacteria are eaten and digested in the process. This retards the growth rate of the bacterial populations and acts as a natural sanitation process. The removal of dead tissue also allows better diffusion of oxygen into the healthy tissues, which prevents the proliferation of anaerobic bacteria. The microsurgical feeding of larvae seems to have only minimally disruptive effects on the structure of healthy tissues, unlike surgical debridement, so that healing tissue is not set back by this way of removing dead tissue and bacteria.
The secretions of maggots have medical significance in several ways. One involves the mixture of proteolytic enzymes that maggots secrete to convert dead tissue to a nutrient-rich fluid that they can feed from. This proteolytic activity is an intrinsic component of tissue repair, haemostasis, thrombosis, inflammatory cell activation and tissue reconstruction, all of which are needed for healing in the extracellular matrix of the wound. Proteins in the extracellular matrix of wounds, such as fibrin, fibronectin, laminin and acid-solubilised collagens I and III, form blocking structures that restrict the flow of growth factors and nutrients between the patient’s plasma and their dermis and thus hinder the wound-healing process. Four distinct proteinases in the larval secretions degrade these extracellular blocking proteins, thus promoting access of growth factors and nutrients to the healing wound. The proteinase activity of larval secretions is greatest in their first instar or first larval stage (of which there are three), which supports the current clinical practice of selecting first-instar larvae for introduction into the wound.
The liquefaction of tissues and the removal of blocking proteins promote the mechanical washing of bacteria from the wound, especially if these are soaked up by dressings.
Additionally, proteinases secreted by the larvae and by human fibroblast cells already present within the wound are associated with inducing fibroblast migration, proliferation and tissue remodelling. Fibroblast proliferation is important to wound healing and helps to return the disrupted tissue’s structure to normal. Larval secretions also modify fibroblasts’ adhesion to extracellular matrix products after the digestion of fibronectin. Through these three means – the attraction, multiplication and anchoring of fibroblasts – a positive feedback loop is created between the extracellular matrix and fibroblasts that speeds up recovery.A
llantoin excreted by maggots has several known therapeutic effects in wounds, including improving hydration of the extracellular matrix, enhancing the shedding of superficial layers of dead cells (making them easier for the maggots to eat), promoting cell proliferation and wound healing, and acting as a soothing agent by forming complexes with potential allergens.
Urea, ammonia and calcium carbonate secreted by maggots all raise the pH of the wound, which has an antibacterial effect. In this way maggots compete with bacteria directly for the nutrient resource and indirectly by interfering with their populations by predation and poisoning, which is an interesting example of fine-scale ecology.
Finally, maggots might promote tissue growth through physically stimulating the wound tissue by their physical activity. The most likely mechanism seems to be that this motion helps to stir and spread the maggots’ secretions and to assist in the mechanical breakdown of dead tissue and blocking proteins. The disruption of blocking proteins like fibronectin would promote the formation of granulation tissue by fibroblasts as already discussed. The flow of serous exudates, with its benefits, might also be stimulated by the movement of maggots in the wound.
There are obviously tricks to be learned from how blow fly maggots, and opportunities to refine the way that biosurgery is carried out. For this reason, the natural infestation of wounds of humans and animals by flies, which is termed myiasis, is currently being studied at Walter Sisulu University and some related quality assurance protocols for biosurgery have been developed at Rhodes University in South Africa. Biotechnologists can draw inspiration for unexpected places!