Emerging Treatments in Diabetic Wound Care
- 3 Comments
- 35495 reads
Treatment of diabetic foot ulceration is much more complex than simply putting a dressing over a wound. Diabetic foot ulceration is a significant cause of morbidity and is the most common reason for hospital admission in diabetic patients. Annually, two to three percent of diabetic patients1,2 will develop foot ulcers, and up to 15 percent of diabetic patients will develop chronic ulcers during their lifetimes.3 In those who require lower-limb amputation, 70 to 90 percent will be preceded by a foot ulceration.
Physiology of Wound Healing
The three general phases involved in wound healing are the acute inflammatory phase, the proliferative phase, and the maturation phase. The initiation and transition of these phases have no clear-cut boundaries but are descriptors on a continuum of events. The initial phase, inflammation, involves transient vasoconstriction of local arterioles and capillaries followed by an influx of inflammatory cells and plasma proteins to mediate the repair process. The next phase is proliferation, where fibroblastic activity and angiogenesis by the endothelial cells begin. The maturation phase may last for up to two years and involves collagen synthesis and breakdown.
Developments in Physiological Aspects of Wound Healing
Chronic diabetic foot ulcers have been shown to result from a number of causes, one of which involves faulty wound healing. The normal wound healing process entails a complex interplay between connective tissue formation, cellular activity, and growth factor activation. All three of these physiologic processes are altered in the diabetic state and contribute to the poor healing of diabetic foot ulcers. More specifically, the chronic diabetic foot ulcer is stalled in the inflammation phase of the normal wound healing process.4 During this delay, there is a cessation of epidermal growth and migration over the wound surface.5,6 Analyses of fluid from chronic wounds have demonstrated elevated levels of matrix metalloproteinases (MMPs) directly resulting in increased proteolytic activity and inactivation of the growth factors that are necessary for proper wound healing. A number of recent studies have investigated these alterations in an attempt to better understand the wound healing abnormalities in diabetes and to target therapy specifically aimed at correcting these deficiencies, as described below.
Collagen. Collagen, the most abundant protein in connective tissue, is an integral component of dermis, bones, tendons, and ligaments. Collagen synthesis and degradation in wound repair are complex processes that continue at the wound site long after the injury. The resulting scar tissue following wound repair never fully regains the tensile strength of the original intact skin. Instead, scar collagen retains only 70- to 80-percent tensile strength of the original collagen.7 The balance between collagen synthesis and degradation in wound repair is tenuous, and disease states, such as diabetes, can shift the balance to one side, disrupting the wound healing process.
In diabetes, collagen synthesis is markedly decreased, resulting in chronic connective tissue complications. The defect in collagen metabolism in diabetes is present at both the collagen peptide production level as well as the posttranslational modification of collagen degradation. The resultant collagen production deficits can be observed in several systems, including thickening of the vascular basement membrane, limited joint mobility, and poor wound healing.
Cellular activity. The inflammatory stage of wound repair involves an orchestrated interaction of resident cells, such as epithelial cells, fibroblasts, dendritic cells, and endothelial cells, with biochemical activity. In addition to these resident cells, platelets, neutrophils, T-cells, natural killer cells, and macrophages are recruited to the wound site.
1. Borssen B, Bergenheim T, Lithner F. The epidemiology of foot lesions in diabetic patients aged 15-50 years. Diabetic Med 1990;7:438–44.
2. Kumar S, Ashe HA, Fernando DJS, et al. The prevalence of foot ulceration and its correlates in type 2 diabetic patients: A population-based study. Diabetic Med 1994;11:480–4.
3. Palumbo PJ, Melton LJ III. Peripheral vascular disease and diabetes. Diabetes in America. NIH Publ. No. 85-1468. Washington, DC: US Government Printing Office, 1985.
4. Loots MA, Lamme EN, Zeegelaar J, et al. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 1998;111:850–7.
5. Jude EB, Boulton AJ, Ferguson MW, Appleton I. The role of nitric oxide synthase isoforms and arginase in the pathogenesis of diabetic foot ulcers: Possible modulatory effects by transforming growth factor beta 1. Diabetologia 1999;42:748–57.
6. Loots MA, Lamme EN, Mekkes JR, et al. Cultured fibroblasts from chronic diabetic wounds on the lower extremity (non-insulin-dependent diabetes mellitus) show disturbed proliferation. Arch Dermatol Res 1999;291:93–9.
7. Schilling JA. Wound healing. Physiol Rev 1968;48:374–423.
8. Zykova SN, Jenssen TG, Berdal M, et al. Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice. Diabetes 2000;40:1451–8.
9. Spravchikov N, Sizyakov G, Gartsbein M, et al. Glucose effects on skin keratinocytes. Diabetes 2001;50:1627–35.
10. Cooper DM, Yu EZ, Hennesey P, et al. Determination of endogenous cytokines in chronic wounds. Ann Surg 1994;219:688–92.
11. Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (Becaplermin) in patients with chronic neuropathic diabetic ulcers. Diabetes Care 1998;21(5)822–7.
12. Broadley K, Aquino A, Woodward S, et al. Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. Lab Invest 1989;61:571–5.
13. Richard JL, Parer-Richard C, Daures JP, et al. Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. Diabetes Care 1995;18(1):64–9.
14. Robson MC, Phillips LG, Lawrence T, et al. The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores. Ann Surg 1992;216:401–8.
15. Detmar M, Brown LF, Berse B, et al. Hypoxia regulates the expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptor in human skin. J Invest Dermatol 1997;108:263–8.
16. Frank S, Hubner G, Breier G, et al. Regulation of vascular endothelial growth factor expression in cultured keratinocytes: Implication for normal and impaired wound healing. J Biol Chem 1995;270:12607–13.
17. Schaffer MR, Tantry U, Efron PA, et al. Diabetes-impaired healing and reduced wound nitric oxide synthesis: A possible pathophysiologic correlation. Surgery 1997;121(5):513–9.
18. Shi HP, Efron DT, Most D, Barbul A. The role of iNOS in wound healing. Surgery 2001;130(2):225–9.
19. Field FK, Kerstein MD. Overview of wound healing in a moist environment. Am J Surg 1994;167(1A):2S–6S.
20. Hansson C. Interactive wound dressings: A practical guide to their use in older patients. Drugs & Aging 1997;11:271–84.
21. Wijetunge DB. Management of acute and traumatic wounds: Main aspects of care in adults and children. Am J Surg 1194;167(1A)suppl:56s–60s.
22. Lawrence C. Dressings and wound infection. Am J Surg 1994;167(1A)suppl:21s–24s.
23. Thomas S. Hydrocolloids update. J Wound Care 1992;1:27–30.
24. Ono I, Gunji H, Zhang JZ, et al. Studies on cytokines related to wound healing in donor site wound fluid. J Dermatol Sci 1995;10:241–5.
25. Jones V. Alginate dressings and diabetic foot lesions. Diab Foot 1999;2:8–14.
26. Thomas S, Hay NP. Assessing the hydroaffinity of hydrogel dressings. J Wound Care 1995;3:89–91.
27. Geronemus RG, Mertz PM, Eaglstein WH. Wound healing: The effects of topical agents. Arch Dermatol 1979;115:1311–3.
28. Kashyap A, Beezhold D, Wiseman J, et al. Effect of povidone-iodine ointment on wound healing. Am J Surg 1995;61:486–91.
29. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999;341:738–46.
30. Witte MB. General principles of wound healing. Surg Clin North Am 1997;77:509–28.
31. Muhart M, McFalls S, Kirsner RS, et al. Behavior of tissue-engineered skin. Arch Dermatol 1999135:913–8.
32. Teepe RGC, Koebrugge ED, Ponec M, Vermeer BJ. Fresh versus cryopreserved allografts for the treatment of chronic skin ulcers. Br J Dermatol 1990;122:81–9.
33. Teepe RGC, Roseeuw DI, Hermans D, et al. Randomized trial comparing cryopreserved cultured epidermal allografts with hydrocolloid dressings in healing chronic venous ulcers. J Am Acad Dermatol 1993;29:982–8.
34. Phillips TJ. Cultured skin grafts: Past, present, future. Arch Dermatol 1988;124:1035–8.
35. Phillips TJ, Gilchrest BA. Clinical applications of cultured epithelium. Epith Cell Biol 1992;1:39–46.
36. Phillips T, Bhawan J, Leigh IM, et al. Cultured epidermal allografts: A study of differentiation and allograft survival. J Am Acad Dermatol 1990;23:189–98.
37. Phillips T. Cultured epidermal allografts: A temporary or permanent solution? Transplantation 1991;51:937–41.
38. Clark RAF. Basics of cutaneous wound repair. J Dermatol Surg Oncol 1993;19:693–706.
39. Krant D, Eckhardt M, Patton ML, et al. Combined simultaneous application of cultured epithelial autograft and Alloderm. Wounds 1995;7:137–42.
40. Kolenik SA III, Leffell DJ. The use of cryopreserved human skin allografts in wound healing following Mohs surgery. Dermatol Surg 1995;21:615–20.
41. Hansbrough JF, Dore C, Hansbrough WB. Clinical trials of a living dermal tissue replacement placed beneath meshed, split-thickness skin grafts on excised burn wounds. J Burn Care Rehabil 1992;13:519–29.
42. Hansbrough JF, Cooper ML, Greenleaf G, et al. Evaluation of a biodegradable matrix containing cultured human fibroblasts as a dermal replacement beneath meshed split-thickness skin grafts. Surgery 1992;11:438–46.
43. 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 or polyglactin mesh. Biomaterials 1991;12:243–48.
44. Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of Dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 1996;19(4):350–4.
45. Eaglstein WH, Iriondo M, Laszio K. A composite skin substitute (Graftskin) for surgical wounds: A clinical experience. Dermat Surg 1995;21:834–9.
46. Brem H, Balledux J, Bloom T, Kerstein M, Hollier L. Healing of diabetic foot ulcers and pressure ulcers with human skin equivalent. Arch Surg 2000;135:627–34.
47. Veves A, Falanga V, Armstrong DG, Sabolinski ML. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers. Diabetes Care 2001;24(2):290–5.