Larval Therapy for Chronic Cutaneous Ulcers: Historical Review and Future Perspectives

Cutaneous ulcers tend to become chronic and have a profound impact on quality of life. These wounds may become infected and lead to greater morbidity and even mortality. In the past, larvae (ie, maggots) of certain common flies (Lucilia sericata and Lucilia cuprina) were considered useful in ulcer management because they only remove necrotic tissue while promoting healthy tissue in the wound bed, thus helping wounds heal faster. Recently, maggots from several other fly species (Calliphora vicina, Calliphora vomitoria, Phormia regina, Chrysomya albiceps, Sarcophaga carnaria, and Hermetia illucens) have been shown in vitro to possess characteristics (ie, debridement efficacy and putative antimicrobial potentialities) that make them suitable candidates for possible use in clinical practice. This review presents a historical analysis of larval debridement and speculates future directions based on the literature presented.

Chronic skin ulcers, such as diabetic ulcers, venous leg ulcers, and pressure ulcers, are increasing in prevalence, representing a costly problem in health care. A rapid rise in the treatment of chronic wounds has been linked to an aging population and an increasing incidence of diabetes and obesity.¹ Leg ulcers are most common, accounting for 43% of skin ulcers.¹ Chronic cutaneous ulcer treatment places a significant burden on the patient and the health care system; in addition, these nonhealing ulcers place the patient at much higher risk for lower extremity amputation. 

Treatment of chronic cutaneous ulcers includes a number of different regimens: glycemic control, revascularization, surgery, local wound treatment, offloading, and other nonsurgical treatments. Proper local wound care consists of tissue debridement, control of persistent inflammation or infection, and moisture balance before considering advanced therapies for wounds that are not healing at the expected rate (3 months).  

Maggot therapy is a simple and successful method for cleansing infected and necrotic wounds. The use of maggots has become increasingly important in the treatment of nonhealing wounds, particularly those infected with the multidrug-resistant pathogen, methicillin-resistant Staphylococcus aureus (MRSA). Indeed, it has been shown that excretions/secretions from the blowfly Lucilia sericata (LS) exhibit potent, thermally stable, protease-resistant antibacterial activity against in vitro MRSA.² The application of sterile LS larvae to an infected nonhealing wound results in the removal of necrotic tissue, disinfection, rapid elimination of infecting microorganisms, and enhancement of the healing process.³

Debridement refers to the removal of dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue. In order to debride necrotic tissue, larvae (ie, maggots) produce a mixture of proteolytic enzymes, including collagenase, that breaks down the necrotic tissue to a semi-liquid form to be absorbed and digested. Debridement is facilitated by wound disturbance as the larvae crawl around the tissue using their mouthhooks.⁴

Maggot therapy is administered by applying sterilized fly larvae to the wound at a density of 5 to 8 per cm². To apply larval therapy, a wound-sized hole is cut from a hydrocolloid dressing, a self-adhesive wafer with a semipermeable outer membrane. This both protects the skin from irritation by the maggot’s proteolytic enzymes and forms the base of the adhesive dressing. The sterile maggots are then moved from their container to a special piece of nylon netting placed on a nonwoven swab to draw away moisture. The netting is then bunched up to create a cage for the larvae, placed on the wound, and secured to the hydrocolloid dressing by waterproof adhesive tape. The dressing is finally covered with a simple absorbent pad held in place with adhesive tape or a bandage.³ Maggots are kept over the wound for cycles of about 48 hours; two 48-hour cycles are usually applied each week.

The aim of this paper is to review the history and mechanisms of action of larval therapy while speculating some future directions.

Larval debridement therapy has been utilized for medical purposes for hundreds, if not thousands, of years and is recorded in ancient folk medicine, such as the Chinese in Yunan, the hill people of Burma, the Aborigines in Australia, and the Mayans in Central America.³ Since the 1700s, surgeons have documented that the larvae of certain common blow flies or greenbottles (LS) only remove dead tissue while promoting healthy tissue in the wound bed, helping wounds heal faster.² The beneficial effects of using larvae in wounds were first noticed by Ambroise Paré in 1557.⁵ Dominique-Jean Larrey (1766–1842), another French surgeon, observed that maggots of the blue fly only removed dead tissue and had a positive effect on the remaining healthy tissue during the Egyptian expedition in Syria.³ The first officially documented application of maggots was performed by John Forney Zacharias (1837–1901), a surgeon from Maryland during the American Civil War (1861–1865).³ Later, William Baer refined the technique by using sterile maggots to prevent maggot-induced wound infection.⁵ The therapy became increasingly popular and was widely used for the treatment of infected or chronic wounds across Europe and North America during the 1930s.³

Mechanism of action. Experiments performed by Barnes et al⁶ have demonstrated that LS excretions/secretions are able to inhibit bacteria growth in both stationary and exponential phases. For these reasons, maggot debridement was approved by the US Food and Drug Administration in 2004.⁵ 

Prete⁷ demonstrated that hemolymph and alimentary secretions of larvae were growth stimulatory for in vitro human fibroblasts. Both factors increased the proliferation of fibroblasts stimulated by epidermal growth factor or interleukin 6. Clinical observations provided evidence for growth stimulation in chronic wounds.⁸

Lucilia sericata larvae digest necrotic tissue and pathogens (Figure 1); they discriminate between necrotic and healthy (granulating) tissue. This technique is rapid and selective, although some of the evidence to support its use is still derived from anecdotal reports.⁹ Depending on the size and depth of the wound, 50 to 1000 sterile maggots, about 24 to 48 hours old, are applied 2 to 4 times per week and left on for a period of 24 to 72 hours.⁵ Several papers have described the utility of maggot debridement therapy,^10-22 though there is only 1 randomized, specific LS clinical debridement trial using maggot therapy.²³ Clinical studies have demonstrated maggot therapy to be safe and effective in patients both with and without diabetes and for many problematic wounds, including pressure ulcers, venous stasis leg ulcers, wound bed preparation prior to surgical closure, and a variety of other traumatic, infectious, and vascular wounds.^24-39 

Wayman et al⁴⁰ compared the cost of larval therapy with hydrogel dressings in the treatment of necrotic venous ulcers. Twelve patients with sloughy venous ulcers were randomized to receive either larval therapy or the control hydrogel therapy. Effective debridement occurred with a maximum of 1 larval application in all 6 experimental patients; 2 of the 6 hydrogel patients still required dressings at 1 month. The median cost of treatment of the larval group was £78.64 compared with £136.23 for the control group (P < .05). Thus, this study confirmed both the clinical efficacy and cost effectiveness of larval therapy in the debridement of sloughy venous ulcers.⁴⁰

In the present authors’ opinion, increased knowledge of fly biology and larval debridement benefits for chronic skin ulcer treatment as well as the clinical study focus on only 2 species (LS and Lucilia cuprina) call for an investigation of new optimal treatment protocols to find suitable, alternative maggot candidates. 

An investigation of new potential species for maggot therapy should be focused on the Diptera order of flies, specifically those families such as the Calliphoridae (blowflies) and Sarcophagidae (fleshflies) (Table); the evolutionary patterns of these 2 families have shifted from scavenging animal matter to parasitism, moving from purely saprophagous free-living larvae feeding on decaying animals to facultative parasitic free-living larvae feeding on necrotic tissues and live animal wounds.^41,42 Species with obligatory parasitic habits, with larvae only able to live on the tissues of living animals, and those causing malign myiasis (parasitic infestation of a live mammal by fly larvae that grows inside the host while feeding on its tissue; eg, all species in the Oestridae family, known as bot flies, or the screwworms Cochliomyia hominivorax and Chrysomya bezziana) must be excluded from this range. Nevertheless, it should be noted that since myiasis is defined as any infestation of live vertebrates (humans and/or animals) with dipterous (order of insects comprising the true flies, characterized by a single pair of membranous wings and a pair of club-shaped balancing organs) larvae which, at least for a certain period, feed in the host’s dead or living tissue, liquid body substances, or ingested food,⁴³ maggot therapy is otherwise known as therapeutic myiasis,⁵ an artificially induced, benign myiasis performed in a controlled environment by an experienced medical practitioner, where the risks are outweighed by the benefits of debridement, disinfection, and enhanced healing. 

Sherman et al⁴¹ listed a summary of biological properties that could make good candidates for maggot therapy, such as the absence of host specificity, the fast rate of larvae development in the host, the ability to feed on necrotic tissues without invading healthy ones, and the straightforward in vitro rearing. As sterilization is a crucial step in maggot therapy, egg laying also was included among positive properties, as eggs are usually much easier to sterilize than larvae; this is why the mainly oviparous Calliphoridae (producing eggs that hatch outside the body of the mother) were probably better candidates than the larviparous species (laying living larvae instead of eggs).

Besides these characteristics, the authors also suggest considering larvae that have higher chances to survive and thrive in infected wounds/ulcers, create a better environment for wound healing, and produce substances that are recognized as being potentially useful in clinical therapy, such as antimicrobial compounds. For these reasons, other members of saprophagous fly families could represent potential maggot therapy candidates, provided their biology is at least fairly well known and that they are easy to rear and obtain in sterilized conditions. Species of interest in forensic entomology are therefore among the best models to choose from due to the extensive studies performed to obtain the development curves useful for the postmortem interval estimates.

A glance at the typical life cycle of the scavenging-necrophagous fly species (Figure 2) helps clarify its biology. The first instar larvae crawl on the substrate (dead tissue, cellular debris, exudates of wounds or corpses), probing and finely macerating it by means of their hook-like mouthparts. The larvae feed upon the substrate, performing an extracorporeal digestion by secreting proteolytic enzymes and ingesting the liquefied matter; by doing this, they grow bigger and molt twice. Upon maturity, the maggots cease feeding and leave the substrate, searching for a drier and suitably protected area to pupate; adult flies emerge 1 to 3 weeks later. The whole lifespan varies according to the species and is strictly related to the environmental temperature. The development of fly larvae is promoted by temperate climate temperatures and high humidity; wounds may, therefore, represent the optimum for maggot growth rate. Well adapted to living in habitats which typically contain a vast array of pathogenic microorganisms, these larvae have developed several effective mechanisms for survival in these conditions: physical removal of microorganisms by ingesting them, the release of antimicrobial substances by means of secretion/excretion, and specific adaptations of the cuticle and inner lipid.^44-49 

On the basis of these considerations, several other fly species have been shown in vitro to have qualities indicative of putative debridement, antifungal, and antibacterial potentialities.^50-56 These qualities make them potentially good candidates in clinical practice for chronic skin ulcer management. Among them are members of the Calliphoridae, Sarcophagidae, and Stratiomyidae families.

As such, the authors propose that larvae from Calliphora vicina, Calliphora vomitoria (Figure 3), Phormia regina, Chrysomya albiceps, Sarcophaga carnaria, and Hermetia illucens be investigated as new, useful biological agents for ulcer management as new maggot therapy species (NMTS). The authors hypothesize that the NMTS-debrided organic compounds found in salivary secretions and hemolymph, gut, cuticular, and internal lipids and the antimicrobial action of the aforementioned larvae may have the same as or greater therapeutic potentials than those of LS or conventional, mechanical debridement. These compounds include fatty acid methyl ester and alcohol fractions; defensin-like peptide 4; azelaic acid; phenylacetic and phenylpropionic acids; sebacic acid; 3-hydroxy-2-methyl-butanoic acid; (E,E)-2,4-decadienal; and synthetic BhSGAMP-1 peptide. 

Despite today’s high-tech medicine, basic principles that evolved in nature can still be efficacious and may help the physician combat specific medical problems. In selected cases, use of properly identified maggots, natural removers of necrotic and infected tissue, may result in adequate wound healing and prevent limb amputation.⁵⁷

Nonetheless, besides correct wound care management, several important factors determine a patient’s ability to heal. Most importantly, an adequate blood supply must be present. Whenever possible, it is important to treat the cause of an ulcer: pressure ulcers require pressure redistribution and attention to other cofactors such as friction, shear, mobility, nutrition, and control of external moisture, including feces; venous ulcers require edema control, the cornerstone being compression therapy and activity modifications to activate the calf muscle pump; and diabetic foot ulcers require pressure offloading and appropriate control of diabetes and its complications, including infection. There are personal and health care system factors that may prevent adequate correction of the cause; when it is not possible to provide the best practice, clinicians may consider treating the wound to prevent complications and to improve quality of life rather than have healing as the primary outcome.⁵⁸

Two of the most important cornerstones in the care of any ulcer are (1) debriding healable wounds by removing nonviable, contaminated, or infected tissue (through surgical, autolytic, enzymatic, mechanical, or biological methods); and (2) assessing and treating the wound for increased bacterial burden or infection.⁵⁸ Accordingly, the proposed hypothesis may prove to be useful for these purposes.

The authors believe that sufficient evidence exists to support the testing of NMTS as therapy agents, though studies on the in vivo effects and mechanisms of NMTS need to be carried out. Moreover, a cost-effectiveness comparative analysis of the different larval therapies proposed should be conducted.

Affiliations: Department of Medicine and Surgery, Plastic Surgery Chair, University of Parma, Parma, Italy; Cutaneous, Mininvasive, Regenerative and Plastic Surgery Unit, Parma University Hospital, Parma, Italy; Department of Life Sciences, University of Modena and Reggio Emilia, Reggio Emilia, Italy; and Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma

Correspondence:
Edoardo Raposio, MD, PhD, FICS
Director, Plastic Surgery Chair, 
Department of Medicine and Surgery
University of Parma
Via Gramsci 14
43126, Parma, Italy
edoardo.raposio@unipr.it