The Foot in Diabetes - part 6 docx

At present, Dermagraft presents a new and exciting treatment for the indolent plantar neuropathic ulcer that has failed to respond to conventional treatment. GRANULOCYTE-COLONY STIMULATING FACTOR (GCSF) Foot infection is common in patients with diabetes mellitus. The incidence and severity of such infections is greater in people with diabetes than in the non-diabetic population. The higher risk may be related to abnormalities in host defence mechanisms, including defects in neutrophil function 4,5 . Effective neutrophil antimicrobial action depends on the generation of several oxygen-derived free radicals. These toxic metabolites, (e.g. super- oxide anion) are formed during the respiratory (or oxidative) burst that is activated after chemotaxis and phagocytosis. De®ciencies in neutrophil chemotaxis, phagocytosis, superoxide production, respiratory burst activity, and intracellular killing have been described in association with diabetes. Granulocyte-colony stimulating factor (GCSF) is an endogenous haemo- poietic growth factor that induces terminal differentiation and release of neutrophils from the bone marrow. The recombinant form is used widely to treat chemotherapy-induced neutropenia. Endogenous GCSF concentra- tions rise during bacterial sepsis in both neutropenic 6 and non-neutropenic states 7 ; these ®ndings suggest that GCSF may have a central role in the neutrophil response to infection 8 . In addition, GCSF improves function in both normal and dysfunctional neutrophils 9 . Since diabetes represents an immunocompromised state secondary to neutrophil dysfunction, we investigated the effect of systemic recombinant human GCSF (®lgrastim) treatment in diabetic patients with foot infection. The aims of the study were to assess the effects of the GCSF on the clinical response and to measure the generation of neutrophil superoxide in patients and healthy controls 10 . Patients received either GCSF or a similar volume of placebo (saline solution). GCSF or placebo was administered as a daily subcutaneous injection for 7 days. Glycaemic control was optimized with insulin in all participants, by means of a continuous intravenous infusion or a multiple- dose regimen. Primary study objectives were time to resolution of infection (cellulitis), intravenous antibiotics requirements, and time to hospital discharge. Secondary objectives were the need for surgery, effects of GCSF on the generation of neutrophil superoxide, and the time taken for pathogens to be eliminated from the wound. Forty diabetic patients with foot infections were enrolled in a double- blind placebo-controlled study. On admission, patients were randomly assigned to GCSF therapy (n=20) or placebo (n=20) for 7 days. There were 182 The Foot in Diabetes no signi®cant differences between the groups in clinical or demographic characteristics on entry to the study. Both groups received similar antibiotic and insulin treatment. Neutrophils from the peripheral blood were stimulated with opsonized zymosan, and superoxide production was measured by a spectrophotometric assay based on reduction of ferricyto- chrome c. The maximum skin temperature within the area of cellulitis was recorded with an infra-red thermometer. These readings were compared with those taken from the corresponding site on the non-infected foot. Any decisions about surgical debridement or amputation were based on clinical signs, including the presence of non-viable tissue, the development of gangrene, abscess formation, and lack of improvement despite optimum antimicrobial therapy. GCSF therapy was asociated with earlier eradication of pathogens from infected ulcers [median 4 (range 2±10) vs 8 (2±79) days in the placebo group; p=0.02], quicker resolution of cellulitis [7 (5±20) vs 12 (5±93) days; p=0.03], shorter hospital stay [10 (7±31) vs 17.5 (9±100) days; p=0.02], shorter duration of intravenous antibiotic treatment [8.5 (5±30) vs 14.5 (8±63) days; p=0.02].There was a signi®cant reduction in the temperature difference between the infected and non-infected foot by day 7 in the GCSF-treated group; by contrast, in the placebo group the reduction was not signi®cant. No GCSF-treated patient needed surgery, compared with four in the placebo group. Four patients had ulcers healed at day 7 in the GCSF group, compared with none in the placebo group ( p=0.09). After 7 days' treatment, neutrophil superoxide production was higher in the GCSF group than in the placebo group [16.1 (4.2±24.2) vs 7.3 (2.1±11.5) nmol per 10 6 neutrophils in 30 minutes; p50.0001]. GCSF therapy was generally well tolerated. Patients who received GCSF therapy had signi®cantly earlier eradication of bacterial pathogens from wound swabs, quicker resolution of cellulitis, shorter hospital stays, and shorter duration of intravenous antibiotic treatment than placebo recipients. Metabolic control did not differ signi®cantly between the groups. GCSF therapy was associated with the development of leukocytosis, due almost entirely to an increase in neutrophil count. Total white-cell and neutrophil counts increased signi®cantly after two doses of GCSF, and the increases were maintained until day 7. There were alsosigni®cant increases in lymphocyte and monocyte populations in patients receiving GCSF. All cell counts returned to near-baseline values within 48 hours of the end of treatment. CONCLUSION This study showed that in diabetic patients with foot infection, GCSF treatment signi®cantly accelerated resolution of cellulitis, shortened Dermagraft and Granulocyte-colony Stimulating Factor 183 hospital stay, and decreased antibiotic requirements. Thus, GCSF may be an important adjunct to conventional therapy. Clinical improvements with GCSF were supported by a signi®cant decrease in foot temperature difference, and a shorter time to negative wound culture. REFERENCES 1. Gentzkow G, Iwasaki S, Hershon K, Mengel M, Prendergast J, Ricotta J, Steed D, Lipkin S. Use of Dermagraft, a cultured human dermis, to treat diabetic foot ulcer. Diabet Care 1996; 19: 350±4. 2. Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Arti®cal Organs 1997; 21: 1203±10. 3. York Health Economics Consortium. Evaluation of the cost-effectiveness of Dermagraft in the treatment of diabetic foot ulcers in the UK. University of York, 1997. 4. Sato N, Shimizu H, Shimomura Y, Mori M, Kobayashi I. Myeloperoxidase activity and generation of active oxygen species in leukocytes from poorly controlled diabetic patients. Diabet Care 1992; 15: 1050±2. 5 Marphoffer W, Stein M, Maeser E, Frederlin K. Impairment of polymorpho- nuclear leukocyte function and metabolic control of diabetes. Diabet Care 1992; 15: 256±60. 6. Cebon J, Layton JE, Maher D, Morstyn G. Endogenous haemopoietic growth factors in neutropenia and infection. Br J Haematol 1994; 86: 265±74. 7. Selig C, Nothdurft W. Cytokines and progenitor cells of granulocytopoiesis in peripheral blood of patients with bacterial infections. Infect Immun 1995; 63: 104± 9. 8. Dale DC, Liles WC, Summer WR, Nelson S. Granulocyte colony stimulating factor (GCSF): role and relationships in infectious diseases. J Infect Dis 1995; 172: 1061±75. 9. Roilides E, Walsh TJ, Pizzo PA, Rubin M. Granulocyte colony stimulating factor enhances the phagocytic and bactericidal activity of normal and defective neutrophils. J Infect Dis 1991; 163: 579±83. 10. Gough A, Clapperton M, Tolando N, Foster AVM, Philpott-Howard J, Edmonds ME. Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet 1997; 350: 855±9. 184 The Foot in Diabetes 14 New Treatments for Diabetic Foot Ulcers (c) Larval Therapy STEPHEN THOMAS Princess of Wales Hospital, Bridgend, UK HISTORY In the treatment of infected or necrotic areas on the diabetic foot, as with most types of chronic wounds, it is axiomatic that before the process of healing can begin, the affected areas must be thoroughly cleansed of all devitalized tissue. If surgical intervention is not an option, most practitioners use hydrogels to promote autolytic debridement 1 or resort to the use of other agents of questionable value. These include preparations containing povidone iodine and other lotions and potions containing sodium hypochlorite. Enzymatic debriding agents such as those containing streptodornase and streptokinase have also been used, although results of clinical trials involving these preparations have been disappointing. Within the last few years, an alternative approach has been described that involves the use of sterile maggots, larvae of the common greenbottle, to effect wound debridement. This is not a new technique but a revival of a procedure that was widely used in the ®rst half of the century as a treatment for osteomyelitis and soft tissue infections. An early reference to the ability of maggots to cleanse wounds and prevent infection was made by Larrey, a military surgeon to Napoleon, who reported that when these creatures accidentally developed in wounds sustained in battle, they prevented the development of infection and accelerated the process of wound healing 2 . The Foot in Diabetes, 3rd edn. Edited by A. J. M. Boulton, H. Connor and P. R. Cavanagh. & 2000 John Wiley & Sons, Ltd. The Foot in Diabetes. Third Edition. Edited by A.J.M. Boulton, H. Connor, P.R. Cavanagh Copyright  2000 John Wiley & Sons, Inc. ISBNs: 0-471-48974-3 (Hardback); 0-470-84639-9 (Electronic) During the First World War, Baer, an American orthopaedic surgeon, also observed the cleansing action of maggots in extensive traumatic injuries. Some 10 years later, when Clinical Professor of Orthopaedic Surgery at the Johns Hopkins Medical School, he remembered this experience and began to use maggots to treat cases of intractable osteomyelitis. He found that the wounds of many of his patients, which had failed to respond to all other therapies, healed within 6 weeks with the continued application of the larvae 3 . As a result of Baer's work, the clinical use of maggots became commonplace in the USA during the 1930s 4 and remained so for about a decade until the development of antibiotics offered an easier and more aesthetically acceptable form of treatment for serious wound infections. In recent years, however, multiresistant strains of bacteria such as Staphylococcus aureus (MRSA) have evolved. The clinical problems caused by these organisms, combined with a general recognition that conventional debriding agents are of limited ef®cacy in the management of problem or potentially limb-threatening wounds such as those on the diabetic foot, have caused some practitioners to revert to the use of maggots, often with impressive results. The revival of larval therapy began in the USA in 1983 when Sherman et al 5 used maggots for treating pressure ulcers in persons who had suffered spinal cord injuries. This was followed by further reports of the use of larval therapy in podiatry 6 and recurrent venous ulceration 7 . In the UK, sterile larvae under the brand name of LarvE are produced in the Biosurgical Research Unit in South Wales 8 . Over a 4 year period, about 10 000 containers of sterile larvae have been supplied by this unit to about 700 centres, mainly in the UK, but also in Sweden, Germany and Belgium. A signi®cant proportion of these larvae has been used in the treatment of wounds associated with diabetes. These vary in size from small neuropathic ulcers to more serious infected wounds involving one or more toes 9,10 as well as wounds such as leg ulcers and pressure sores 8,9,11±13 . A particularly graphic account of the use of larvae in the management of diabetic patients with extensive ulceration of the feet was published by Rayman et al 14 . These initial reports of the value of larval therapy are now being tested in randomized controlled trials to compare larvae with conventional treatments in the management of different types of necrotic wounds. Treatment times vary according to the severity of the wound and the number of larvae applied. A small wound may only require one application lasting 3 days, but for more extensive wounds containing large amounts of necrotic tissue additional treatments may be required. Experience suggests that the continued application of larvae to a chronic or indolent wound following complete debridement will help to prevent further infection and may actually promote healing. Although larvae are generally applied to 186 The Foot in Diabetes cleanse wounds in order to promote healing, they have also been used to improve the quality of life for terminally ill patients, for whom healing is not a realistic option. In such situations it has been reported that they may eliminate odour and reduce wound-related pain. One paper describes how larvae used in this way removed extensive amounts of necrotic tissue, including the toes, from a terminally ill gentleman with diabetes 15 . FLIES USED IN LARVAL THERAPY The maggots used clinically are the larvae of Lucilia sericata a member of the family Calliphoridae, also classi®ed as higher Diptera (Muscamorpha) 16 . The adult insects are a metallic coppery green colour, hence the common name, ``greenbottles''. They are facultative parasites, able to develop both on carrion and live hosts. In some animals such as sheep, greenbottle larvae produce serious woundsÐa condition known as sheep-strikeÐbut in human hosts the larval enzymes appear able only to attack dead or necrotic tissue. The life cycle of the insect involves four stages; the egg, the larval form, the pupa (in its puparium) and the adult. Adult ¯ies lay their eggs directly onto a food source and these hatch within about 18±24 hours, according to temperature, into larvae 1±2 mm long. These larvae immediately begin to feed using a combination of mouth hooks and proteolytic secretions and excretions. If conditions are favourable, the larvae grow rapidly, moulting twice before reaching maturity. The full-grown larvae, some 8±10 mm long, stop feeding and search for a dry place to pupate and complete the life cycle with the emergence of a new adult ¯y. Sterile larvae for clinical use are collected in the laboratory from eggs the outer surface of which have treated to remove the very high numbers of bacteria that are normally present. The absence of micro-organisms on these newly hatched larvae is subsequently con®rmed by a sterility test. MODE OF ACTION OF STERILE LARVAE Maggots remove dead tissue by means of complex mechanisms which involve both physical activity and the production of a broad spectrum of powerful enzymes that break down dead tissue to a semi-liquid form, which is then ingested by the larvae. Young et al 17 showed that the range of molecules secreted by larvae is complex and dynamic, changing quite dramatically over a short time frame of a few days. The majority of these agents belong to the serine class of proteases and some are developmentally regulated. Larval Therapy 187 In order to maximize the ef®ciency of their extra-corporeal digestive process, larvae tend to congregate into groups, feeding in the head-down position, concentrating initially on small defects or holes in the tissue. In human wounds it is believed that the enzymes produced by Lucilia sericata are inactivated by enzyme inhibitors in healthy tissue which are not present in necrotic tissue or slough. Some evidence for this hypothesis comes from the observation that if a signi®cant quantity of larval enzymes are allowed to escape from the area of the wound and spread onto the surrounding skin, they can cause severe excoriation, eventually penetrating right through the keratinized epidermal layer. Once the enzymes breach the epidermis, however, no further damage occurs 9 . It is therefore assumed that the enzymes are inactivated at this point by proteolytic enzyme inhibitors in the dermis. The mechanisms by which larvae prevent or combat infection are also complex. Pavillard, in 1957 18 , demonstrated that secretions of larvae of the black blow¯y contained an antibiotic agent that, when partially puri®ed and injected into mice, protected them from the lethal effects of intraperitoneal injection with a suspension of Type 1 pneumococci. It has been shown in studies conducted in the author's laboratory that actively feeding larvae produce a marked increase in the pH of their local environment, which is suf®cient to prevent the growth of some pathogenic Gram-positive bacteria. Furthermore, it has been shown that other bacteria which are not susceptible to pH changes within the wound are ingested by feeding larvae and killed as they pass through the insects' gut 19 . The early literature contained numerous references to the fact that maggots appeared to stimulate the production of granulation tissue 3,20,21 , and this effect has also been noted in more modern studies. There are a number of possible explanations for this observed effect. Prete 22 demon- strated the existence of intrinsic ®broblast growth-stimulating factors in the haemolymph and alimentary secretions of maggots which may have some stimulatory effects in vivo. It may also be that the presence of the larvae, or their metabolites, stimulates cytokine production by macrophage cells which initiate or potentiate the in¯ammatory response within the wound and thus enhance the ability of the body to resist the development of infection and initiate healing. LARVAE: METHOD OF USE Various techniques have been described for retaining larvae in a wound 7,12 . In the main these rely upon the use of a piece of sterile net anchored to a suitable substrate applied to the area surrounding the wound to form a simple enclosure. A simple absorbent pad completes the dressing system. The adhesive substrate, which may consist of a hydrocolloid dressing, a 188 The Foot in Diabetes zinc paste bandage or some other suitable alternative, ful®ls three important functions. It provides a sound base for the net, protects the skin from the potent proteolytic enzymes produced by the larvae, and prevents any tickling sensation caused by the larvae wandering over the intact skin surrounding the area of the wound. If larvae are applied to or between the toes, it is prudent to protect the areas between the adjacent toes with small amount of alginate ®bre to absorb any excess secretions. The outer absorbent dressing can be changed as often as required and, because the net is partially transparent, the activity of the larvae can be determined without removing the primary dressing. As a rule of thumb, about 10 larvae/cm 2 should be introduced into a small wound (a circular wound 35 mm in diameter has an approximate area of 10 cm 2 and could therefore be treated with about 100 larvae). The fully grown larvae are generally removed from the wound after 2±3 days. Studies have shown that larvae are unaffected by the concurrent administration of systemic antibiotics 23 but residues of hydrogel dressings within the wound may have an adverse effect upon their development 24 . Unpublished studies have shown that larvae appear to be unaffected by X- rays and therefore do not need to be removed if a patient requires such an investigation. CONCLUSIONS Larvae are living chemical factories that produce a complex mixture of biologically active molecules, many of which have yet to be fully characterized. Long-term clinical experience with maggots in wounds has been extremely positive and the wealth of recorded observations concerning the ability of these creatures to debride wounds and stimulate healing are gradually beginning to be substantiated by structured clinical investigations. It has also been shown that the use of larvae produces a wound bed that is very suitable for grafting. Whilst some patients ®nd the use of larvae unacceptable, generally there is much less resistance to this form of treatment than might have been expected. Some medical and nursing staff initially ®nd the idea distasteful or consider that it represents an outmoded or unacceptable form of therapy, but once they have seen the bene®ts of larval therapy at ®rst hand many become enthusiastic converts. Although larval therapy has been used for all types of chronic wounds, the technique is of particular value in the treatment of the diabetic foot. The larvae are frequently able to remove all traces of necrotic tissue and eliminate wound infections in a fraction of the time taken by conventional therapies. The procedure may often be carried out in the patient's own Larval Therapy 189 home, thus reducing or eliminating the need for hospitalization, with important implications for overall treatment costs. At the present time larval therapy is regarded by some as a treatment of ``last resort''. For this reason it is only offered to patients when all other options have been exhausted and when some form of amputation is considered inevitable. If the technique were to be applied at an earlier stage, it might prevent relatively small isolated areas of infection extending to threaten a foot or even an entire limb. REFERENCES 1. Thomas S. Wound Management and Dressings. London: Pharmaceutical Press, 1990. 2. Livingstone SK, Prince LH. The treatment of chronic osteomyelitis with special reference to the use of the maggot active principle. J Am Med Assoc 1932; 98: 1143±9. 3. Baer WS. The treatment of chronic osteomyelitis with the maggot (larva of the blow¯y). J Bone Joint Surg 1931; 13: 438±75. 4. Robinson W. Progress of maggot therapy in the United States and Canada in the treatment of suppurative diseases. Am J Surg 1935; 29: 67±71. 5. Sherman RA, Wyle F, Vulpe M. Maggot therapy for treating pressure ulcers in spinal cord injury patients. J Spinal Cord Med 1995; 18: 71±4. 6. Stoddard SR, Sherman RM, Mason BE, Pelsang DJ. Maggot debridement therapy. J Am Podiat Med Assoc 1995; 85: 218±20. 7. Sherman RA, Tran JM-T, Sullivan R. Maggot therapy for venous stasis ulcers. Arch Dermatol 1996; 132: 254±6. 8. Thomas S, Jones M, Andrews A. The use of ¯y larvae in the treatment of wounds. Nursing Standard 1997; 12: 54±9. 9. Thomas S, Jones M, Shutler S, Jones S. Using larvae in modern wound management. J Wound Care 1996; 5: 60±9. 10. Mumcuoglu KY, Lipo M, Ioffe-Uspensky I, Miller J, Galun R. Maggot therapy for gangrene and osteomyelitis. Harefuah 1997; 132: 323±5, 382. 11. Thomas S. A wriggling remedy. Chem Ind 1998; 17: 665±712. 12. Thomas S, Jones M, Andrews M. The use of larval therapy in wound management. J Wound Care 1998; 7: 521±4. 13. Thomas S, Jones M, Shutler S, Andrews A. Wound care. All you need to know about . . . maggots. Nursing Times 1996; 92: 63±6, 68, 70 passim. 14. Rayman A, Stans®eld G, Woolard T, Mackie A, Rayman G. Use of larvae in the treatment of the diabetic necrotic foot. Diabet Foot 1998; 1: 7±13. 15. Evans H. A treatment of last resort. Nursing Times 1997; 93. 16 Crosskey RW. Introduction to the Diptera. In Lane RP, Crosskey RW (eds), Medical Insects and Arachnids. London: Chapman & Hall, 1995. 17. Young AR, Mesusen NT, Bowles VM. Characterisation of ES products involved in wound initiation by Lucilia cuprina larvae. Int J Parasitol 1996; 26: 245±52. 18. Pavillard ER, Wright EA. An antibiotic from maggots. Nature 1957; 180: 916±17. 19. Robinson W, Norwood VH. Destruction of pyogenic bacteria in the alimentary tract of surgical maggots implanted in infected wounds. J Lab Clin Med 1934;19: 581±6. 190 The Foot in Diabetes 20. Fine A, Alexander H. Maggot therapyÐtechnique and clinical application. J Bone Joint Surg 1934; 16: 572±82. 21. Buchman J, Blair JE. Maggots and their use in the treatment of chronic osteomyelitis. Surg Gynecol Obstet 1932; 55: 177±90. 22. Prete P. Growth effects of Phaenicia sericata larval extracts on ®broblasts: mechanism for wound healing by maggot therapy. Life Sci 1997; 60: 505±10. 23. Sherman RA, Wyle FA, Thrupp L. Effects of seven antibiotics on the growth and development of Phaenicia sericata (Diptera: Calliphoridae) larvae. JMed Entomol 1995; 32: 646±9. 24. Thomas S, Andrews A. The effect of hydrogel dressings upon the growth of larvae of Lucilia sericata. J Wound Care 1999; 8: 75±7. Larval Therapy 191 [...]... used in addition to simple balloon PTA, and these are directed towards improving initial success rates and maintaining long-term patency following the initial intervention Thrombolytic therapy has a particular role in the management of critical ischaemia Balloon Angioplasty Dotter and Judkins ®rst described the technique of balloon angioplasty (PTA) in 1 964 20 A non-deformable balloon mounted on a low-pro®le... achieve full size The choice of stent depends on a number of factors, including vessel tortuosity and lesion length 2 06 The Foot in Diabetes Figure 15.10 (a) Popliteal angiogram showing severe stenosis at the origin of the peroneal artery (b) Following angioplasty Stents are used in two main clinical settings The ®rst of these is in the presence of a suboptimal PTA result or when there is an immediate... angiographic catheter is introduced into the stenosed or occluded portion of 204 The Foot in Diabetes the vessel over a previously positioned guidewire The PTA balloon is then in ated using radio-opaque contrast medium to allow visualization, and pressures of 4±10 atmospheres are then usually suf®cient to bring the balloon to its predetermined diameter Heparin is given at the time of PTA to reduce the risk... IMAGING Early and accurate diagnosis of infection or neuropathy is the key to successful management of the diabetic foot In addition, it is essential that developing angiopathy be treated early in order to avoid ischaemia This requires high quality imaging of the arterial supply to the leg and foot Spin echo MRI combined with 2D time-of-¯ight sequences can 198 The Foot in Diabetes Figure 15.5 Infection... radiology departments in the UK and increasingly by radiologists who have undergone specialist training in these techniques Continued improvements in catheter and guidewire technology have contributed signi®cantly to the reduction in morbidity and complication rates associated with radiological treatment of vascular disease The principal indications for such endovascular intervention in the diabetic... system, the roles of 202 The Foot in Diabetes duplex ultrasound and magnetic resonance angiography continue to increase in importance Within the next few years, the use of diagnostic angiography will decrease and the use of non-invasive techniques, in both diagnosis and intervention, will predominate Duplex Ultrasound Duplex ultrasound combines cross-sectional imaging of arteries and veins with simultaneous... marked periosteal thickening of the underlying bone indicates that it was infected provide all this information The time-of-¯ight sequences look at blood ¯ow rather than blood vessels Thus, blood ¯owing in both arteries and veins is imaged Because this would be confusing, a system of saturation bands is used in order that the blood returning to the heart (i.e venous Role of Radiology in Assessment and Treatment... accurately delineates 200 The Foot in Diabetes Figure 15.8 Magnetic resonance (MR) angiography Time-of-¯ight MR images showing a distal peroneal artery that was not visible on digital subtraction angiography the limits of the infection, reducing the incidence of recurrent infection post surgery This makes MRI extremely cost effective13 Magnetic resonance angiography is a useful non-invasive tool in the assessment... manifestations in diabetic foot disease result from a combination of neuropathy, infection and vascular disease, all of which are present to a greater or lesser extent in diabetic foot problems The disease affects all parts of the diabetic foot, including skin, soft tissues, muscles, blood vessels and bones It is the neuropathy which is the foundation upon which the other aspects of the diabetic foot are... thrombotic closure of the vessel, and antiplatelet therapy is started before treatment and usually continued inde®nitely The mechanism of balloon PTA is complex and involves disruption and moulding of the atheromatous plaque, longitudinal splitting of the vessel endothelium and disruption of the elastic media PTA causes mechanical stretching of the vessel, and also results in healing taking place at a cellular . imaging in infection. A transverse image taken through the heads of the metatarsals. The head of the ®fth metatarsal gives a very high-intensity signal, indicating infection the limits of the infection,. all other therapies, healed within 6 weeks with the continued application of the larvae 3 . As a result of Baer's work, the clinical use of maggots became commonplace in the USA during the. for the net, protects the skin from the potent proteolytic enzymes produced by the larvae, and prevents any tickling sensation caused by the larvae wandering over the intact skin surrounding the