History. Department of Dermatology and Venerology, Medical University of Silesia in Katowice Kierownik: prof. dr hab. L. Brzezińska-Wcisło POLSKI

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1 POLSKI PRZEGLĄD CHIRURGICZNY 2010, 82, 6, /v Biosurgery the future of non healing wounds Hubert Arasiewicz, Benita Szubryt, Mariola Wylędowska-Kania Department of Dermatology and Venerology, Medical University of Silesia in Katowice Kierownik: prof. dr hab. L. Brzezińska-Wcisło As our society is ageing the number of patients suffering from chronic wounds arising from diabetes and peripheral vascular disease is constantly growing. It places an enormous burden on our health care system. Chronic wounds require long-term treatment, what results in the increasingly higher costs. Biosurgery, as an alternative to a classic wound dressing, proved to be a very effective and quick method of wound cleansing. It hastens the healing process, and hence lowers the overall cost of the treatment (1). It uses sterile maggots Lucilia sericata. The simplicity and limited number of side effects makes it a very promising method of chronic wound dressing. This article aims to present a current practical and theoretical understanding of biosurgery. History The history of biosurgery dates back to the times of native tribes of New South Wales, Burmese highlanders as well as ancient Maya people. The first physician to observed a positive influence of maggots on the process of chronic wounds healing was a French surgeon, Ambroise Paré ( ). The turning point of his experience with biosurgery was during an observation of a patient with a severe head wound, where maggots significantly contributed to the recovery. Thereafter Paré allowed maggots to live in the open wounds, as a factor enhancing healing process. The first documented example of applying maggots at an open wound was a publication by a military physician, Forney Zacharias ( ), who described it during The Civil War. A real breakthrough however transpired in 1928, when William Baer, an American orthopedist from John Hopkins University applied facultative parasitism principles in a bone inflammation treatment of four children. In those days the therapy was deemed the quickest and the most effective method of bone inflammation treatment. In the thirties over three hundred American hospitals were using biosurgery as a standard in chronic wounds treatment, and over one hundred papers were published on the subject. However, an advent of sulfonamides and industrial technology of penicillin production in the forties ousted biosurgery from the heath care. Present renaissance of the method is caused by a growing antibiotic resistance and constantly increasing cost of the chronic wounds treatment. A significant contribution to the revival of biosurgery is attributed to Ronald Sherman, employee of the University of California Irvine Medicine School, USA. Together with his coworker, he conducted research that helped biosurgery back to the academic medicine. In 1996 International Biotherapy Society, an entity examining role of the living organisms in the wound healing process, was established. Nowadays, utilization of maggots Lucilia sericata for healing purposes is getting a growing number of supporters. The comeback of maggots therapy is an effect of a progressive ageing of the society. This demographic transformation prompts the increase of illnesses causing intractable wounds, and in effect imposes heavy costs on the overloaded health care system (2-6).

2 372 H. Arasiewicz i wsp. Mechanics Cornerstone of the intractable wounds treatment is a proper debridement, sustaining moist environment and preventing infection. Using maggots in the treatment helps to change the course of healing from chronic to to severe (normal wound healing phases)(7). During the process maggots devour bacteria along with liquid dead tissue, and subsequently bacteria are destroyed within their digestive system. The whole process is so efficient, that maggots are able to change the wound from rank and infected to clean and healthy within just few days. Numerous authors divide the mechanics into three stages: debridement, disinfection and stimulation of healing. Debridement Debridement is a stage thanks to which we gain control over an inflammation, limit bad odour and expose healthy vascularized tissue. Biosurgery enables debridement on the microscopic level, with minimal damage to a healthy tissue the quality that gives biosurgery an upper hand over traditional methods. Maggots Lucilia sericata are necrophagous organisms feeding on dead tissue and ooze coming from the wound (3). As an organism, maggot is devoid of teeth, and hence digest extracorporealy by secreting a number of enzymes including: carboxypeptidases A and B, leucine aminopeptidase, collagenase and serine proteases (trypsin-like and chymotripsin-like), aspartyl proteinase and metalloproteinase (8). Digested tissue is subsequently painlessly consumed by the maggot. One maggot consume approximately 0.15 gram of dead tissue a day. Depending on the number of maggots used and the time over which the dressing is applied, it enables to clean the wound to a substantial extent (9). Approximately 5 to 10 maggots a cm 2 is suggested (10). Disinfection Apprehension of the mechanics by which maggots can bring infection under control in scope of the wound was altering alongside the development of the research methods. The first theory implied that maggots activity intensify the oozing, and hence cause mechanical rinsing of the wound. Rich with proteolytic enzyms ooze was supposed to contribute to digestion of bacteria. It was also proved that bacteria consumed by the maggot die in its digestive system. Excreting ammoniac and calcium carbonate, maggots increase ph index of the wound, what constrains expansion of the bacteria and broadens an activity of the proteolytic enzyms (6, 8, 11). The antiseptic mechanics is not completely intelligible. Due to the ambiguous results of the research, the direct antiseptic in vitro effect could not be proved (12). Nevertheless, presence of at least two active antiseptic agents, characterized by a broad spectrum of activity G(+), G(-) including MRSA, has been proved. Modern methods of isolation allowed approximate stipulation of the antiseptic substances nature as thermostable and protease resistant (size <500 Da and 0,5-3-kDa) (13, 14, 15). Last researches indicate that maggots play a key role in breaking bacterial biofilm with Pseudomonas aeruginosa, what additionally promotes its usage for infected wounds (16). Stimulation of healing Maggots stimulate healing by draining a tissue, what enables better access to oxygen and enzymes. They excrete allantoin and urea, which are ingredients of numerous healing ointments (6). Experimental tests confirmed that maggots excretions/secretions (ES) causes increased activeness of fibroblasts in vitro (17, 18, 19), and also inhibits pro-inflammatory function of neutrophiles (20) and monocytes (21), without suppressing phagocytosis. Described was also immuno-moduling effect based on decreasing the production of TNF-a, IL- 12p40 (pro-inflammatory function) and increasing IL-10 (anti-inflammatory function). The latest research enabled isolation of IFN-gamma and beta-fgf from the ES maggots. Those agents have a fundamental role in philological healing processes (19). Wang and assoc. showed that ES induces human microvascular endothelial cell migration through AKT1 (22). Moreover, authors are unanimous regarding its beneficial effect on wound remodeling. Indications and contraindications for biosurgeral debridement Biosurgery is very effective with intractable wounds. Physicians all over the world use this

3 Biosurgery the future of non healing wounds 373 method especially willingly with diabetic wounds and other wounds with large amount of dead tissue, and get good clinical results (23-28). Some the applications of living wound dressings described in the literature (6) are as follows: diabetic ulcers, ulceration (venous, arterial, venous-arterial, naturopathic), pressure sores, thromboangiitis obliterans, tumour-related wounds, necrotizing fasciitis, pyoderma gangrenosum, osteomyelitis, burns, severe wounds, mastoiditis, pilonidal sinus, wound infected after breast operation, wounds after a knee joint endoprosthesis, non-healing wounds after surgeries, MRSA infected wounds, condition after removing medial malleolus abscess, infected gun shot wound. A few of them were not long ago disadvised, due to a problematic location of the dressing (what caused difficulties during disposal of maggots). This includes: cleansing of peritoneal cavity, glans penis or pleural space (29). Immuno-modulating mechanics described above justify treatment of pyoderma gangrenosum and other skin alterations with autoimmunologic background. Another thesis emphasize antiseptic property of maggots which contribute to good clinical results in infected wounds dressing MRSA (14). Another extremely important aspect is a tumour-related wounds treatment, where cleansing has a palliative character. It helps to eliminate an unpleasant odour, which is often embarrassing for a patient. Nowadays maggots are more willingly used for non-chronic severe wounds (29). Relative contraindications include dry wounds (maggots require humid environment), opening abdominal cavity and neighborhood of large blood vessels (Difficult disposal of maggots). There is also one strict contraindication allergy to maggots (6). Side effects Biosuregeral therapy is considerably safe and entails few possible side effects. One of the most dangerous is an infection transmitted by non-sterile maggots. However, ensuring proper breeding conditions and sterility minimize the problem considerably (30). In case of large amount of dead tissue a disagreeable oduor caused by engaging the wound is likely, but this can be mostly eliminated after first change of dressing. Very important factor is a technique and thoroughness of dressing application, as it determines the stability of dressing and prevent maggots from getting out, what could discourage patients and medical personnel alike from using the therapy. Pain rarely accompany the therapy and is easily subjected to pharmacotherapy (31, 32). Mentions about bleeding from biosurgeraly cleansed wound seldom occur (33). Biosurgeral dressing Correctly applied dressing is a significant element of the biosurgeral therapy. Its main purpose is to keep maggots within the limits of the wound. It has to be thigh enough lest little surgeons escape, and airy enough to enable them their work. During the process of debridement wound usually become more soggy and oozy, hence extra gauze should be applied. Biosurgeral dressing should be applied for approximately 3-4 days. However, it is not possible to stipulate the exact time, as it is individually tailored to each patient. A good yardstick is a size of maggots. While applying, they are the size of a rice grain, and provided the debridement proceeds successfully, they grow 1 cm long. Varied techniques of living dressing application, depending on the location of the wound, are available. They all consist in constructing a cage which restrict maggots to the area of the wound. There is an alternative dressing called Biofoam, in which sterile maggots are mixed up with scraps of foam and put into a handy bag, what keeps them out of sight. Cage dressing is cheaper and more available than biofoam, and being equally effective, it is more frequently in use(9). General rules of cage dressing preparation boils down to four simple steps, which are: I. Covering healthy skin II. Applying maggots III. Securing maggots with cage IV. Applying outer dressing. It must be remembered that biosurgeral dressing, by virtue of its living nature, requires

4 374 H. Arasiewicz i wsp. exceptional precautions. Wetting, drying or squashing is strongly disadvised as it can disturb the debridement (30, 31). Costs Economic aspect of biosurgery was comprehensively described in British conditions. Among the publications we can find calculations unambiguously in favour of biosurgery, as well as those regarding it financially comparable with classic therapy. Wayman and assoc. presented result ranging from 79 to 136, whereas Thomas and assoc. put it between 82 and 503 (adding up nursing care cost) respectively for patients treating with biosurgeral and classic dressing (34, 35). Dumville and assoc. indicated that the time of wound debridement was considerable shortened, but it didn t entail lower cost of the therapy (36). As for polish conditions, breeding of sterile maggots Lucilia sericata is getting more and more common, what entails its market price drop. Appearance of local sellers has broken the barrier of expensive import. Some of the authors encourage hospitals to breed maggots independently in specially appointed spaces, what should additionally lower costs of the therapy (37). Discussion Nowadays, maggots are used in hospital as well as ambulatory treatment all over the world. Researchers form prestigious R&D centres publish another papers confirming the relevancy of biosurgery. Moreover, there are reports indicating new and broader applications of the therapy. According to present knowledge biosurgery is a good form of intractable wounds treatment. It is characterized by efficient wound debridement, safety, simple usage and low cost. Possible problems with implementation of presented therapy most probably result from epidemiologic reasons. Physicians of different specializations on many occasions had to do with quasi biosurgery, when treating extremely neglected patients. Unfortunately there is an abundance of mentioned cases, what definitely poses a barrier for practical application of maggots in medical treatment. Another hindrance is a limited availability of good quality local maggots breeding centres, what gives no alternative for imported material, and has an ill effect on economic side of the therapy. Mentioned by numerous authors yuck factor seems to be of no significance after appropriate acquaintance of patient and personnel with the method. Hopefully, as time passes, quasi surgery will become history, replaced by modern and acceptable form of chronic wound treatment. It is expected, that the number of high quality national maggots breeding centres will constantly grow, and hence biosurgeral therapy will become naturally and commonly worthwhile form of a chronic wound treatment. References 1. Gwynne B, Newton M: An overview of the common methods of wound debridement. Br J Nurs 2006; 15: S4-S Whitaker IS, Twine Ch, Whitaker MJ Et al.: Larval therapy from antiquity to the present day: mechanisms of action, clinical applications and future potential. Postgrad Med J 2007, 83: Sherman RA, Hall MJR, Thomas S: Medical Maggots: An Ancient Remedy for Some Contemporary Affilctions. Annu Rev Entomol 2000; 45: Orkiszewski M: Zastosowanie larw muchy Lucilia sericata w leczeniu trudno gojących się ran. Wiad Lek 2007; 60: Gupta A: A Review of the Use of Maggots in Wound Therapy. Ann Plast Surg 2008; 60: Chan D, Fong D, Leung J et al.: Maggot debridement therapy in chronic wound care. Honk Kong Med J 2007; 13: Steenvoorde P, Calame JJ, Oskam J: Maggottreated wounds follow normal wound healing phases. Int J Dermatol 2006; 45: Nigam Y, Bexfield A, Thomas S et al.: Maggot Therapy: The Science and Implication for CAM Part I-History and Bacterial Resistance. Evid Based Complement Alternat Med 2006; 3(2): Blake FAS, Abromeit N, Bubenheim M et al.: The biosurgical wound debridement: Experimental investigation of efficiency and practicability. Wound Repair Regen 2007; 15: Thomas S, Jones M, Shutler S et al.: Wound care: all you need to know about maggots. Nurs Times 1996; 92: Wollina U, Liebold K, Schmidt WD et al.: Biosurgery supports granulation and debridement in chronic wounds-clinical data and remittance spectroscopy measurement. Int J Dermatol 2002; 41:

5 Biosurgery the future of non healing wounds Cazander G, Veen KEB, Bernards AT et al.: Do maggots have an influence on bacterial growth? A study on the susceptibility of strains of six different bacterial species to maggots of Lucilia sericata and their excretions/secretions. J Tissue Viability 2009; 18: Bexfield A, Nigam Y, Thomas S et al.: Detection and partial characterization of two antibacterial factors from the excretions/secretions of the medical maggot Lucilia sericata and their activity against methicillin-resistant Staphylococcus aureus (MRSA). Microbes Infect 2004; 6: Beasley WD, Hirst G: Making a meal of MRSAthe role of biosurgery in hospital-acquired infection. J Hosp Infect 2004; 56: Bexfield A, Bond AE, Roberts EC et al.: The antibacterial activity against MRSA strains and other bacteria of a <500 Da fraction from maggot excretions/secretions of Lucilia sericata (Diptera: Calliphoridae). Microbes Infect 2008; 10: Cazander G, Veen KEB, Bouwman LH et al.: The Influence of Maggot Excretions on PAO1 Biofilm Formation on Different Biomaterials. Clin Orthop Relat Res 2009; 467: Prete PE: Growth effects of Phaenicia sericata larval extracts on fibroblasts: mechanism for wound healing by maggot therapy. Life Sci 1997; 8: Horobin AJ, Shakesheff KM, Pritchard DI: Maggots and wound healing: an investigation of the effects of secretions from Lucilia sericata larvae upon the migration of human dermal fibroblasts over a fibronectin-coated surface. Wound Repair Regen 2005; 13: Nigam Y, Bexfield A, Thomas S et al.: Maggot Therapy: The Science and Implication for CAM Part II-Maggots Combat Infection. Evid Based Complement Alternat Med 2006; 3: Plas MJA, Does AM, Baldry M et al.: Maggot excretions/secretions inhibit multiple neutrophil pro-inflamatory responses. Microbes Infect 2007; 9: Plas MJA, Baldry M, Dissel JT et al.: Maggot secretions suppress pro-inflamatory responses of human monocytes through elevation of cyclic AMP. Diabetologia 2009; 52: Wang S, Wang K, Xin Y et al.: Maggot excretions/secretions induces human microvascular endothelial cell migration through AKT1. Mol Biol Rep 2009; Published online: 16 Sep. 23. Sherman RA: Maggot Therapy for Treating Diabetic Foot Ulcers Unresponsive to Conventional Therapy. Diabetes Care 2003; 26: Jukema GN, Menon AG, Bernards AT et al.: Amputation-Sparing Treatment by Nature: Surgical Maggots Revisited. Clin Infect Dis 2002; 35: Sherman RA, Shimoda KJ: Presurgical Maggot Debridement od Soft Tissue Wounds Is Associated with Decreased Rates of Postoperative Infection. Clin Infect Dis 2004; 39: Sherman RA: Maggot versus conservative debridement therapy for the treatment of pressure ulcers. Wound Repair Regen 2002; 10: Steenvoorde P, Jacobi CE, Doorn L et al.: Maggot debridement therapy of infected ulcers: patient and wound factors influencing outcome a study on 101 patients with 117 wounds. Ann R Coll Surg Engl 2007; 89: Mumcuoglu KY, Ingber A, Gilead L et al.: Maggot therapy for the treatment of intractable wounds. Int J Dermatol 1999; 38, Sherman RA, Shapiro CE, Yang RM: Maggot Therapy for Problematic Wounds: Uncommon and Off-label Applications. Adv Skin Wound Care 2007; 20: Wollina U, Karte K, Herold C et al.: Biosurgery in wound healing the renaissance of maggot therapy. J Eur Acad Dermatol Venereol 2000; 14: BioTherapeutics, Education and Research Foundation Maggot Debridement Therapy: Draft Policy and Procedure. org. 32. Claxton MJ, Armstrong DG, Short B et al.: 5 Questions and Answers about Maggot Debridement Therapy. Adv Skin Wound Care 2003; 16: Steenvoorde P, Doorn LP: Maggot Debridement Therapy: Serious Bleeding Can Occur. J Wound Ostomy Continence Nurs 2008; 35: Waymen J, Nirojogi V, Walker A et al.: The cost effectiveness of larval therapy in venous ulcers. J Tissue Viability 2000; 10: Erratum in: J Tissue Viability 2001; 11: Thomas S, Jones M: Wound debridement: evaluating the costs. Nurs Stand 2001; 15: Dumville JC, Worthy G, Bland M et al.: Larval therapy for leg ulcers (VenUS II): randomized controlled trial. BMJ 2009; 338:b773 doi: /bmj. b Sherman RA, Wyle RA: Low-cost, low-maintenance rearing of maggots in hospitals, clinics, and schools. Am J Trop Med Hyg 1996; 54: Received: r. Adress correspondence: Katowice, ul. Francuska 20/24