As Aristidis Veves, MD and Thanh Dinh, DPM, point out, it is well-known that the chronic diabetic foot ulcer is stuck in the inflammation phase of the wound healing cycle. Research studies have shown that non-healing wounds may have specific biochemical imbalances, notes Liza Ovington, PhD. In particular, non-healing wounds have been shown to have excessively high levels of proteolytic enzymes such as matrix metalloproteases (MMPs).
While these enzymes are necessary in various aspects of the healing process, such as cellular migration, debridement and phagocytosis, Dr. Ovington notes that higher than normal levels of these enzymes contribute to non-healing via uncontrolled degradation of granulation tissue components and local destruction of growth factors.
With these things in mind, our expert panelists discuss what the future may hold for new advances in wound care.
Q: What product/technology do you see on the horizon as the next commercially available adjunct to help heal chronic wounds?
A: Dr. Ovington points to Promogran, a topical dressing composed of collagen and oxidized regenerated cellulose. She says this recent addition to the wound healing armamentarium is designed to reduce local levels of MMPs, a particular family of protein-degrading enzymes.
Oscar M. Alvarez, PhD, notes that a multi-center study proved that Promogran is effective for treating diabetic foot ulcers. He adds that in vitro studies have shown that this dressing modulates MMPs and protects growth factors from digestion. According to Dr. Alvarez, there is evidence in general that cellulose inhibits certain MMPs in chronic wounds, which reduces the proteolytic environment that is “so unfriendly to migrating epithelium.”
In the future, Gerit Mulder, DPM, says he expects to see modifications of current wound dressings that allow them to act as delivery systems for drugs and cell mediators.
ExCell is another wound dressing that can provide moisture to the wound if it is dry and absorb moisture from the wound if it is too moist. Dr. Alvarez says this microbially-derived cellulose dressing provides a good environment for autolytic debridement as well as healing. He adds that clinical studies on venous ulcers are underway.
Pre-clinical research with a nitric oxide releasing hydrogel dressing has been promising, according to Dr. Alvarez, who notes that impaired wound healing in diabetics has been associated with reduced nitric oxide synthesis. Dr. Alvarez also notes that noncontact, normothermic wound therapy with Warm-Up has recently been shown to significantly reduce healing time in diabetic foot ulcers when compared to standard care.
Q: What is the future of topical growth factors?
A: Dr. Mulder says growth factors are considered appropriate adjunctive treatment for difficult wounds when standard approaches have failed. Researchers have shown that using becaplermin gel augments chronic wound healing via the addition of recombinant platelet-derived growth factor (PDGF), according to Drs. Dinh and Veves. They also note that bioengineered tissue, such as Apligraf and Dermagraft, has been successful in treating chronic diabetic foot ulcers. Drs. Dinh and Veves say these bioengineered tissues introduce metabolically active fibroblasts and keratinocytes that facilitate the expression of growth factors and cytokines into the chronic wound.
Dr. Mulder believes tissue substitutes will evolve into biological materials, which will remain viable for longer periods of time, be more complex in structure and have broader indications than currently available products.
With the introduction of Promogran, which reduces MMPs, Dr. Ovington says “we may see improved results from existing topical growth factor therapies such as Regranex (becaplermin) and bioengineered tissues.”
All of the panelists agree that delivery of growth factors to the wound is a complicated issue and that future growth factor treatment will evolve to meet the changing environment in the wound. Instead of focusing on a single growth factor, the panelists agree that an appropriate sequential stimulation of growth factor expression and secretion may be more effective for facilitating the complex wound healing process.
According to Drs. Dinh and Veves, there have been studies that proved simultaneous applications of growth factors produced significantly greater wound stimulation than the addition of a single growth factor.
Although studies have demonstrated the efficacy of using topically applied PDGF for diabetic foot ulcers, Dr. Alvarez says this modality “requires a complicated treatment regimen to ensure greater than marginal efficacy.” He adds that it was recently shown that fibroblast proliferation can be significantly increased by platelet-rich lysates and PDGF that have been incubated in an acidic environment (pH 5.0). However, Dr. Alvarez points out that concentrations of TGF-b were lower at an acidic pH and more active at a pH of 7.5. He says these findings support the hypothesis that growth factor effects on chronic wounds are dependent on the sequence of delivery and wound bed stabilization.
Dr. Ovington says a potentially interesting idea is to use cells or even cells modified by gene therapy to deliver growth factors. She says this would enable the cells to respond to what is going on in the wound in a more precise fashion.
Q: How will genomics play a role in the future of wound care?
A: Gene therapy provides a means of altering the genetic activity in cells already in the wound environment, according to Dr. Mulder. He notes that altering gene expression or introducing a gene sequence necessary for healing in a living, yet inactive cell would offer a means of directly manipulating the wound environment.
Studies have shown that genetic modification of cells in bioengineered tissues is possible and even has an effect on local wound tissue, according to Dr. Ovington. For example, she says you may one day be able to “order up” a specific genetically modified bioengineered tissue for eschemic wounds, perhaps a Dermagraft which has been boosted with VEGF.
Drs. Dinh and Veves note that current clinical trials involving VEGF gene therapy for peripheral arterial disease have demonstrated improvements in ulcer size, ischemic pain and endothelial function.
They also note that gene therapy may eventually prove to be beneficial for microvascular ischemia in diabetic neuropathy. Drs. Dinh and Veves point out that it has been postulated that diabetic neuropathy results from ischemia of the vasa nervorum of peripheral nerves. Therefore, according to Drs. Dinh and Veves, the novel use of VEGF gene transfer to reverse this ischemia may potentially reverse the sensory neuropathy that is crucial in the development of diabetic foot ulcers.
Dr. Alvarez is Director of University Wound Healing Centers, LLC in Bronx, N.Y. and Hoboken, NJ.
Dr. Dinh is an Assistant Clinical Instructor of Surgery at Harvard Medical School and is the Assistant Director of Podiatric Residency Training at Beth Israel Deaconess Medical Center in Boston.
Dr. Mulder is the Director of the Wound Treatment and Research Center, Trauma/Burn Division at the University of California, San Diego.
Dr. Ovington is the President of Ovington & Associates, Inc., a wound care consulting company in Pittsburgh, Pa. She is an Adjunct Faculty Member in the Department of Dermatology and Cutaneous Surgery at the University of Miami School of Medicine.
Dr. Veves is the Research Director of the Microcirculation Lab Joslin-Beth Israel Deaconess Medical Center in Boston. He is an Assistant Professor at Harvard Medical School.
Dr. Karlock (pictured at the right) is a Fellow of the American College of Foot and Ankle Surgeons and practices in Austintown, Ohio.
Editor’s Note: For a related article, see “Growth Factors: Are They Worth The Gamble?” in the September 2000 issue of Podiatry Today.