Watch for effective new treatments for diabetic foot ulcers to make their way into clinical use soon, thanks to recent wound care developments, experts say.
New interventions include a synthetic thrombin peptide-based material now in clinical trials and various approaches using growth factors to enhance ulcer healing. Among the factors being explored: fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF).
At present, the only FDA-approved drug for treating diabetic foot ulcers (DFU) is becaplermin, a gel made of a recombinant human platelet derived growth factor (Regranex).
“Both VEGF and FGF-2 are potent stimuli for angiogenesis, the growth of new capillary blood vessels … a critical step in all forms of wound healing that is impaired in diabetes and that can be pharmacologically promoted to heal DFUs,” said William W. Li, MD, president and medical director of the nonprofit Angiogenesis Foundation. He studied angiogenesis under Judah Folkman, MD, who pioneered the field.
Japan leads the way
In Japan FGF-2 has already made it into clinical use. Physicians there now spray a substance containing recombinant human FGF-2 onto wounds to create granulation tissue for healing.
“The spray approach makes sense in the era of molecular therapy — we are delivering protein molecules to cell receptors, so it only takes a small quantity of active drug. Spraying growth factors may be more efficient with less wastage and therefore cost less, issues that are critical in diabetic wound care” Li, an internist, told Orthopedics Today.
The product, Fiblast Spray (Kaken Pharmaceutical Co.), received regulatory approval in Japan in 2001 as a wound-healing drug and is indicated for treating burns.
Kaken officials said at the firm’s Web site that studies are underway into using FGF-2 for bone fractures. Kaken licenses Trafermin, the recombinant human FGF used in the spray, from Scios Inc.
Genentech has evaluated topical VEGF for DFUs and is preparing for phase 2 clinical trials, according to its Web site.
Scientists at EBI are considering a different approach to healing foot ulcers using the power of FGF-2 by applying pulsed electromagnetic fields (PEMF) to the site to increase the body’s local production of that growth factor.
Preclinical studies show that PEMF might indeed stimulate FGF activity, Bruce Simon, director of research at EBI, told Orthopedics Today. Recently, EBI officials decided to study its effect further, he said.
“We had a paper published in 2004 where we looked at the use of one of these signals, one of our bone healing signals, for treating diabetic foot ulcers. We’re in a clinical trial now looking at the effect of these fields on ulcer treatment,” Simon said.
Not only is this approach to allow DFU healing a bit more biologic, but also “now that we’re understanding which type of cells we stimulate with which signals, [and] what are the growth factors that are upregulated, we can begin to tailor ‘electro-pharmacologic’ signals to specific indications,” he said.
Improved healing rates
James T. Ryaby, PhD, senior vice president of research and clinical affairs at OrthoLogic Corp., said researchers at his company have studied yet another approach to DFU healing. “We hope to start our second clinical trial in 2006 on a peptide-based approach for diabetic ulcer healing. We have recently submitted a manuscript on the phase1/2 clinical trial we conducted evaluating the effect of the peptide on diabetic ulcer healing,” Ryaby said.
The prospective, randomized, double-blind, placebo-controlled trial involved 60 patients with Type I or II diabetes and full-thickness Wagner grade I, II or mild grade II ulcers. Ulcers that involved bone or tendon were excluded.
When investigators topically treated the patients’ ulcers with the synthetic thrombin peptide (Chrysalin, TP508) they found it safe and effective, according to the abstract of the submitted paper. Chrysalin also stimulates angiogenesis as part of its healing mechanism.
Improved closure rates
When investigators used Chrysalin in 1 µg and 10 µg treatments, they found DFU healing rates 45% and 72% greater than with placebo saline at 20 weeks. Chrysalin treatment more than doubled the complete 20-week healing (P<.05) and increased mean wound closure rate and time to complete closure by about 80% and 40%, respectively (P<.05), they noted.
Researchers reported no serious adverse events related to use of the peptide drug. They presented the preliminary results at the May 2002 Wound Healing Society meeting.
Researchers are also studying cartilage defect and fracture repair applications for the material.
Although the potential for new growth factors and other technologies is highly promising, Li emphasized the importance of using them in conjunction with best practices in wound care. That includes wound debridement, infection control, managing exudates, maintaining proper moisture in the wound environment and proper off loading.
“Debridement exposes cell receptors, while infection control decreases the level of protease enzymes released by bacteria into wound fluid that can destroy growth factors,” he said.
“Wounds have a complex microenvironment and there are no magic bullets. We know from experience that growth factors can accelerate healing, but applying one and doing nothing else for the diabetic foot is guaranteed to fail.”
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