Treatment of Chronic Leg Ulcers with a Human Fibroblast-Derived Dermal Substitute: A Case Series of 114 Patients
- 0 Comments
- 7701 reads
Leg ulceration is a common disorder, though the incidence and prevalence have not been well established. It is estimated that 0.12 to 0.19 percent of Western populations have leg ulcers, and in people aged 65 or older the prevalence of venous leg ulcers is estimated at 1.0 to 3.3 percent. Seventy to 81 percent of leg ulcers are caused by venous disease, and arterial disease accounts for another 10 to 25 percent, which may coexist with venous disease. Coexisting rheumatoid disease occurs in nine percent of wound patients, whereas diabetes mellitus is present in 5 to 12 percent of patients. Less commonly, trauma, pressure, inflammatory disorders, and infectious agents also are causes of leg ulcers. The overlap of various causes, as well as coexisting disease, occurs because these conditions are not mutually exclusive.[1–7]
Because leg ulceration is a condition characterized by chronicity and relapse, it gives rise to massive healthcare expenditure. In the European countries, the care of patients with venous leg ulcers consumes 1 to 2 percent of the overall healthcare resources. A chronic wound is predisposed to secondary infections, which can lead to amputations, which in turn are associated with increased mortality. Each person with a chronic wound suffers from pain and discomfort, and a chronic wound entails restrictions in a person’s everyday life and social activities.
Since most leg ulcers are of venous origin, they can be healed with compression therapy alone or combined with local treatments. In recent years, the concept of a clean, moist environment has been widely accepted in the treatment of leg ulcers. In some cases, however, a moist environment and compression therapy are not sufficient for the ulcer to heal, and for these hard-to-heal ulcers, the development of tissue-engineered products can offer new options for treatment.[10,11]
A tissue-engineered human dermal substitute (HDS) (Dermagraft®, Smith & Nephew Inc., Largo, Florida) is designed to replace the dermis and to provide essential stimulatory growth factors for wound healing. It contains living human fibroblasts obtained from neonatal foreskins seeded onto a bioabsorbable polyglactin mesh.[12,13] The HDS pieces are stored frozen at -70°C until used. Although the precise mechanism of action of tissue-engineered dermis is not completely understood, it has been shown to provide elements to the wound bed that are believed to be important in the repair process. HDS provides live, nonsenescent fibroblasts capable of colonizing the wound bed and persisting in situ for several weeks. The fibroblasts are capable of secreting a number of cytokines and growth factors, including platelet-derived growth factor, insulin-like growth factors I and II, heparin-binding epidermal growth factor, vascular endothelial growth factor, transforming growth factors a and b, and keratinocyte growth factor. Growth factors are known to stimulate fibroblasts, granulation tissue, matrix deposition, angiogenesis, and skin cell maturation. The fibroblasts also produce matrix proteins like collagen types I and III, fibronectin, and tenascin, as well as glycosaminoglycans, which bind growth factors and enhance their activity.[14,15]
The overall safety and lack of rejection reactions combined with the efficacy[16,17] encourages the use of HDS in addition to good wound care practices. In the present paper, the authors describe their experience in the treatment of leg ulcers of various origins with HDS.
Patients and Methods
This was an open, noncomparative, retrospective analysis to assess the use of HDS in the treatment of leg ulcers of various origins when conservative treatment with compression and various local treatments had proved ineffective.
1. Baker SR, Stacey MC, Singh G, et al. Aetiology of chronic leg ulcers. Eur J Vasc Surg 1992;6:245–51.
2. O´ Brien JF, Grace PA, Perry IJ, et al. Prevalence and aetiology of leg ulcers in Ireland. Ir J Med Sci 2002;2:110–2.
3. Ebbeskog B, Lindholm C, Ohman S. Leg and foot ulcer patients. Epidemiology and nursing care in an urban population in south Stockholm, Sweden. Scand J Prim Health Care 1996;4:283–93.
4. Öien RF, Håkansson A, Ovhed, I et al. Wound management for 287 patients with chronic leg ulcers demand 12 full-time nurses. Leg ulcer epidemiology and care in a well-defined population in Southern Sweden. Scan J Prim Health Care 2000;4:220–5.
5. Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology 2001;52:5–15.
6. Margolis DJ, Bilker W, Santanna J, et al. Venous leg ulcer: Incidence and prevalence in the elderly. J Am Acad Dermatol 2002;3:381–6.
7. Thurtle OA, Cawley MI. The frequency of leg ulceration in rheumatoid arthritis. J Rheumatol 1983;10:507–9.
8. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology 1997;48:67–9.
9. Phillips T, Stanton B, Provan A, et al. A study of the impact of leg ulcers on quality of life: Financial, social, and psychologic implications. J Am Acad Dermatol 1994;31:49–53.
10. Braddock M, Campbell CJ, Zuder D. Current therapies for wound healing: Electrical stimulation, biological therapeutics, and the potential for gene therapy. Int J Dermatol 1999;38:808–17.
11. Falanga V. Classifications for wound bed preparation and stimulation of chronic wounds. Wound Repair Regen 2000;8:347–52.
12. Cooper ML, Hansbrough JF, Spielvogel RL, et al. In-vivo optimization of a living dermal substitute employing cultured human fibroblasts on a biodegradable polyglycolic acid polyglactin mesh. Biomaterials 1991;12:243–8.
13. Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of Dermagaft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 1996;4:350–4.
14. Naughton G, Mansbridge J, Gentzkow GD. A metabolically active human dermal replacemnet for the treatment of diabetic foot ulcers. Artif Organs 1997;21:1203–10.
15. Roberts C, Mansbridge J. The scientific basis and differentiating features of Dermagraft. Can J Plast Surg 2002;10(Suppl A):6A–13A.
16. Cuono CB, Langdon R, Birchall N, et al. Composite autologous-allogeneic skin replacement: development and clinical application. Plast Reconstr Surg 1987;80:626–7.
17. Eaglstein WH. Dermagraft treatment of diabetic ulcers. J Dermatol 1998;25:803–4.
18. Margolis DJ, Kantor J, Santanna J, et al. Risk factors for delayed healing of neuropathic diabetic foot ulcers. Arch Dermatol 2000;136:1531–5.
19. Margolis DJ, Berlin JA, Strom BL. Which venous leg ulcers will heal with limb compression bandages? Am J Med 2000;132:15–9.
20. Brassard A. A prospective, multicentre, randomized, controlled clinical investigation of Dermagraft in patients with venous leg ulcers: A feasibility study. Can J Plast Surg 2002;10(Suppl A):17A–22A.
21. Lammintausta K, Viitala S, Vuori A-L, et al. Treatment of venous leg ulcers with Apligraf® [Finnish]. Suom Lääkäril 2002;57:1493–5.
22. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 1998;134:293–300.
23. Kirsner RS, Matta SM, Falanga V, et al. Split-thickness skin grafting of leg ulcers. J Dermatol Surg 1995;21:701–3.
24. Öien RF, Hansen BU, Håkansson A. Pinch grafting of leg ulcers in primary care. Acta Derm Venereol (Stockh) 1998;78:438–9.
25. Hafner J, Schaad I, Schneider E, et al. Leg ulcers in peripheral arterial disease (arterial leg ulcers): Impaired wound healing above the threshold of chronic critical limb ischemia. J Am Acad Dermatol 2000;43:1001–8.
26. Kantor J, Margolis DJ. Expected healing rates for chronic wounds. Wounds 2000;12:155–8.
27. Kaminski MJ. Skin disorders associated with rheumatic disease. Clin Podiatr Med Surg 1996;13:139–53.
28. Öien RF, Håkansson A, Hansen BU. Leg ulcers in patients with rheumatoid arthritis: A prospective study of aetiology, wound healing and pain reduction after pinch grafting. Rheumatology 2001;40:816–20.
29. McRorie ER. The assessment and management of leg ulcers in rheumatoid arthritis. J Wound Care 2000;9:289–92.
30. de Imus G, Golomb C, Wilkel C, et al. Accelerated healing of pyoderma gangrenosum treated with bioengineered skin and concomitant immunosuppression. J Am Acad Dermatol 2001;44:61–6.
31. Long RE, Falabella AF, Valencia I, et al. Treatment of refractory, atypical lower-extremity ulcers with tissue-engineered skin (Apligraf). Arch Dermatol 2001;137:1660–1.
32. Blume PA, Paragas LK, Sumpio BE, et al. Single-stage surgical treatment of noninfected diabetic foot ulcers. Plast Reconstr Surg 2002;109:601–9.
33. Puonti H, Seljavaara S, Hietanen H, et al. Excision and skin grafting of leg ulcer. Ann Chir Gyneacol 1998;87:219–23.
34. Cooper DM, Yu EZ, Hennessey P, et al. Determination of endogenous cytokines in chronic wounds. Ann Surg 1994;219:688–92.
35. Blakutny R, Jude EB, Martin GJ, et al. Lack of insulin-like growth factor 1 (IGF1) in the basal keratinocyte layer of diabetic skin and diabetic skin ulcers. J Pathol 2000;190:589–94.
36. Robson MC, Hill DP, Smith PD, et al. Sequential cytokine therapy for pressure ulcers. Clinical and mechanistic response. Ann Surg 2000;231:600–11.
37. Dinh T, Pham H, Veves A. Emerging treatments in diabetic wound care. Wounds 2002;14:2–10.