Risk Factors Associated with Healing Chronic Diabetic Foot Ulcers: The Importance of Hyperglycemia

  • Wed, 9/3/08 - 10:25am
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Author(s): 
William A. Marston, MD, for the Dermagraft Diabetic Foot Ulcer Study Group

Diabetic foot ulcers (DFU) frequently precede limb loss1 and remain a difficult clinical problem to treat. Standard wound management protocols have not proven to result in rapid healing. Margolis et al2 reported the results of a meta-analysis of 10 prospective studies of DFU — the aggregate percentage of patients healed with standard care protocols was 24% at 12 weeks and 31% at 20 weeks. Numerous treatment strategies have been devised in an attempt to speed the healing process, including the use of topical growth factors, living human skin equivalents, hyperbaric oxygen, and electrical stimulation. Some, including platelet-derived growth factor and two living human skin equivalents, studied in prospective multicenter clinical studies,3-5 yielded significant benefit regarding wound closure compared to controls. However, the improvement in the percentage of patients healed in these trials has been disappointing, with an increase of 10% to 20% over standard treatment in each trial. Coupled with the high cost of these active therapies, the relatively moderate benefit has led to questions concerning the appropriate use of growth factors and skin equivalents.

Dermagraft (Smith and Nephew, Inc, Largo, Fla) is a living human dermal substitute consisting of neonatal human dermal fibroblasts (HDF) seeded onto an absorbable polyglactin mesh.6 It was found to significantly increase the rate of wound closure compared to control in a multicenter randomized clinical study of 245 patients.5

The effect of hyperglycemia on the critical components of wound healing in animal models has been studied extensively.7-10 Inhibition of angiogenesis by chronic hyperglycemia has been reported at multiple levels; it appears that consistent hyperglycemia negatively affects the potential for new capillary growth and other key components of the wound healing process.8 Because subgroup analysis and risk factors associated with the incidence of healing were not reported in the human dermal substitute study5 and in order to provide further information on the use of this active treatment modality, a secondary analysis of the study data was conducted to determine risk factors related to wound closure in the HDF and control groups. Specifically, the relationship of HgbA1c levels to wound closure was studied.


Study Design and Analysis

Human dermal substitute structure. The HDF utilized is a cryopreserved, human fibroblast-derived dermal substitute. Human neonatal dermal fibroblasts are cultured in vitro onto a bioabsorbable mesh. The fibroblasts proliferate across the mesh, secreting human dermal collagen, matrix proteins, growth factors, and cytokines to create a three-dimensional human dermal substitute containing metabolically active, living cells.11

Human dermal substitute DFU study. The specific inclusion and exclusion criteria, treatment particulars, and follow-up of the HDF diabetic foot ulcer study have been described in detail.5 Briefly, the study was a prospective, multicenter, single-blind, randomized, controlled investigation that compared an HDF regimen to a control regimen (frequent debridement and wound dressing with saline-moistened gauze) in the treatment of chronic diabetic foot ulcers. Between December 1998 and March 2000, 314 were enrolled in the study. At the screening visit, before randomization, study ulcers received sharp debridement. Following randomization and screening, weekly application of HDF occurred for up to 8 weeks or until ulcer closure, defined as “full epithelialization of the wound with the absence of drainage.”

References: 

1. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Diabetic neuropathic foot ulcers and amputation. Wound Rep Regen. 2005;12:230–236.
2. Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care.1999;22:692–695.
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4. Veves A, Falanga V, Armstrong D, Sabolinski M, for the Diabetic Foot Ulcer Group. Graftskin, a human skin equivalent, is effective in the management of non-infected neuropathic diabetic foot ulcers: a prospective randomized multi-center clinical trial. Diabetes Care. 2001;24:290–295.
5. Marston WA, Hanft J, Norwood P, Pollak R, for the Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers. Diabetes Care. 2003;26:1701–1705.
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