Support is growing, in the medical literature and in clinical practice, for the use of skin substitutes and other advanced biologic therapies in chronic diabetic foot ulcers. But researchers and practitioners remain uncertain as to which of these advanced products are best for which patients.
By Hank Black
Call them cellular and tissue-based products, bioengineered tissues, or skin substitutes. Regardless of the nomenclature, the use of advanced biologic therapies for treatment of diabetic foot ulcers (DFUs) has grown dramatically in recent years. And the options are welcomed as clinicians seek to cope with the large percentage of these wounds that fail to heal even with the most rigorous application of conventional techniques.
Skin substitutes can consist of bioengineered or artificial skin, autografts, allografts, xenografts, or a combination of these. They may provide an acellular scaffolding for the body to populate with its own biology, perhaps augmented by one or many growth factors and nutrients that can induce healing. They may supply living human cells that come with their own healing factors. And many experts see great promise for these and other products, such as mesenchymal stem cells that bring even more—and different—factors to the mix, including some necessary mechanisms for wound healing.
“It’s an interesting time for biologic products for chronic diabetic foot ulcers, because historically they were used to replace deficiencies in the wound, such as collagen, and now the approach is to use stem cells to give the wound factors it’s never had to begin with,” according to Adam S. Landsman, DPM, PhD, chief of podiatry at Cambridge Health Alliance and an assistant professor of surgery at Harvard Medical School in Boston.
The need to heal chronic ulcers is evident. Almost 30 million people in the US have diabetes.1 As many as one-fourth of patients with diabetes will develop a foot ulcer (DFU) during their lifetime.2 A DFU presents significant physical, social, and financial burdens, including a high risk of lower extremity amputation.2,3 Nonhealing ulcers are the leading cause of eventual amputation.4 And at least one third of the $176 billion in direct costs for treating diabetes and its complications is associated with DFU therapy.1,3
The standard of conventional wound care consists of sharp debridement, moist dressings, stringent offloading, and infection control.5,6 With conventional wound care, healing rates are typically low—a 1999 meta-analysis reported only 24% of ulcers healed at 12 weeks and only 31% at 20 weeks7—so it’s no wonder that excitement abounds over the technological advances developed during the past few years.
Six years ago, a consensus panel of multidisciplinary experts reviewed the evidence for various options available for DFU care. The panel concluded advanced wound care, including biologics, should be considered the new standard of care for slow-healing wounds rather than a last resort.8
“There has been a rapid expansion of interest in new advanced products in recent years, although there’s not an overall consensus on which are better than others,” according to Rajiv Nathoo, MD, a clinical dermatology resident at the University of Florida in Gainesville, who coauthored an overview of the advanced wound care field in 2014.
The review concluded that, though modern alternatives do increase healing rates by providing relevant matrix, growth factor, and paracrine signaling abilities, an ideal substitute does not yet exist.9 A recent Cochrane review10 that included 17 studies of skin grafts and tissue replacements in people with diabetes showed a higher healing rate and slightly fewer amputations compared with standard care alone, but the data were not sufficiently robust to conclude that one therapy was more effective than another. The review noted strong industry involvement in all but two studies. In addition, only four of the trials performed a head-to-head comparison of products.
Paul J. Kim, DPM, MS, director of research in the Department of Plastic Surgery at Georgetown University in Washington, DC, said that, until recently, his institution preferred to use proven cellular products. But results of a randomized controlled trial11 of a new placental product influenced a change. The new product provides a cellular matrix designed to preserve the native components of the human placental membrane in a cryopreserved product.
“This product showed value with its greater than sixty percent healing rate, but even more significant was that the majority of participants in the control group who did not heal and were crossed over to the treatment arm did go on to heal,” Kim said.
He also found value in the recent trial of an acellular bilayer product that uses shark chondroitin-6-sulfate, bovine type 2 collagen, and a silicone layer. It acts as a scaffold for vascular ingrowth and host fibroblast population.12
As an indication of the interest in the promise of placental products, Kim said, five such studies are underway at Georgetown.
Best practice guidelines for wound care published in recent years acknowledge a role for skin substitutes in nonhealing foot ulcers, but do not delineate specifics.13,14 Some experts believe one key to success is the use of multiple growth and other factors.
“More is better,” said John S. Steinberg, DPM, professor of plastic surgery at Georgetown University and codirector of the Center for Wound Healing at MedStar Georgetown University Hospital. “We’ve moved away from the original, cellular-based matrix products because placental-based therapy seems to have some merit linked to its stem cell activity that provides a more robust biologic environment to the wound.”
Steinberg and Kim were coauthors of a recent publication15 that divided bioengineered alternative tissues into dermoconductive and dermoinductive categories. The former refers to products that include cells such as fibroblasts and keratinocytes, which provide essential growth factors into the wound to activate new tissue. The dermoconductive category includes products that provide a scaffold in the wound for ingrowth of the surrounding host tissue. A third category includes dermogenic products that utilize stem cells.
Kim noted that even the most rigorously performed studies have top healing rates between 60% and 70%.
“The smaller studies are for the most part not well designed or analyzed and had a significant amount of industry bias,” he said. “One trial reported a 90% success rate for healing, which is an obvious outlier.”
Too good to be true?
Indeed, much of the chatter in the field is about the 90% to 95% healing rate reported by Zelen et al for a dehydrated human amnion/chorion membrane allograft.16 Most specialists interviewed for this article noted the limitations of that trial (the authors did not respond to requests for comment). Landsman, for example, said some wounds in that study were as small as 1cm in diameter and may well have closed regardless of the biologic used.
“It’s not clear that the biologic was what made the difference in healing,” he said. “When you look at larger wounds and follow them for a long time, the data start to make more sense: You don’t see the ninety-percent healing rate any longer. There’s no way that an adequately powered study would ever have a ninety-percent closure rate; it’s too good to be true.”
Yet some clinicians are using that particular amnion/chorion technology in selected cases. Brandon J. Hawkins, DPM, CWS, medical director of the Stockdale Podiatry Group in Bakersfield, CA, includes it among other biologics for hard-to-heal chronic DFUs.
“There are different placental grafts out there and this is the only one with both amniotic and chorionic properties,” Hawkins said. “I was skeptical of the data at first, but its high rate of wound healing seemed consistent. We have had very satisfactory results, although real-life experience and wounds do not match that of clinical trials. I don’t have the luxury of screening for uniform off-loading compliance.”
Hawkins said he especially likes the micronized version of the product for use in tunnel wounds and those with irregular borders. He recently published a small series of such cases.17
“I think advanced biologic products are now being used mainly in specialized wound centers because of insurance issues, but costs should come down with greater availability of the new technologies,” he said. “I still use a lot of other types of grafts. If you put a certain graft on and it doesn’t work for that patient, you try another. There’s not one catch-all product for every wound.”
Landsman said the particular needs of the wound should dictate which biological treatment should be used.
“You can go with the product that only offers fibroblasts, the one that offers fibroblasts and keratinocytes, or something that offers both plus a full array of collagens that are found in the skin,” he said. “All things being equal, if you’re going to offer biologics at all you might as well go for the one that’s most complete, because there’s typically not much of a price difference. More is better, in that case.”
A potential advantage of placental products, Landsman said, is that they offer additional factors.
“You’re getting collagen that primarily is not the type found in the skin, for example. Traditional biologics offer large quantities of fibroblasts and keratinocytes, cell lines that primarily produce collagen and platelet-derived growth factor that stimulate blood vessel growth, cell division, and attract cells from the host into the wound,” he said. “An amniotic product, on the other hand, produces a different set of growth factors, ones that are not present in the wound bed. That includes one in particular called tIMP [tissue inhibitor of metalloproteinase], a potent anti-inflammatory and stimulator of blood vessel growth.”
Although clinicians need better means of diagnosing the full range of what a wound requires, they are getting better at determining what is keeping a wound from healing, Landsman said.
“If you see it needs collagen, I would recommend a biologic with a long-standing track record. But, if it needs blood vessel development and anti-inflammatory action, I might use an amniotic-derived product first, then transition to the traditional product,” he said. “I take my best guess as to what will heal a chronic ulcer, but if it’s not working after four weeks I check to see if there’s too much biofilm, if the patient is noncompliant, or something else. If those aren’t a problem, I change therapies monthly, cycling through my options.”
Diagnostics: The next wave
Researchers are looking for more robust diagnostic tests for chronic wounds, he said.
“That’s the next wave of wound care,” Landsman said. “Detection systems for MMP, a marker of inflammation, are clearly in development now. We are looking for a wound care ‘dipstick,’ a sensor to measure everything from pH to the bacterial level. For example, we are using microvascular analysis with infrared spectrophotometry to determine microcirculation in the wound surface. These are the types of tools that well-equipped, exceptional wound centers will have within the next few years.”
Yet, most agree that, even with the increased rates of healing with the alternative products, complete success and the ability to heal practically every wound awaits better models of who will benefit from which product, and how best to analyze wound conditions and build more predictive models from the many factors inherent in each chronic wound.
Steinberg said the most frequent users of biological alternatives when a wound stalls are in tertiary wound centers, but that the products are increasingly being used in smaller centers.
“Impediments to use might include cost, although reimbursement is generally available, and adequate monitoring and handling, especially as to temperature control for cryopreserved products,” he said. “And then there is the fact that the treatments address only the biology of the wound and not necessarily the underlying cause, which may be infection, ischemia, or biomechanics. There’s also concern about biofilm, which may reform within hours of debridement and promote inflammation. Perfusion may be stalled by micro- or macrovascular disease. And bony prominences, tendon contracture, or abnormal gait patterns can result in ulcer recurrence.”
Even with use of an advanced product with a multitude of stimulatory and healing factors, it’s rare to achieve more than a 65% to 70% complete healing rate after 12 to 20 weeks.
“There are host factors involved that no one understands well,” Kim said. “We haven’t identified the confounding autoimmune processes that are inhibiting wound healing, which may include nutritional factors and other inherent immune-compromising factors that will keep us from ever getting to one-hundred percent complete healing.”
Patient compliance may also be an issue, which is why most experts interviewed for this article say they advocate total contact casting or other nonremovable off-loading devices.
“Pressure offloading is crucial to healing of diabetic foot ulcers,” Nathoo said. “You can have the best graft, durable, with adnexal structures and stem cells, but if the patient is applying pressure—knowingly or not—the success of healing will be diminished.”
There are concentrated efforts to determine the factors involved in healing and develop models to predict which wounds can be successfully treated. A recent paper18 sought to pinpoint early which wounds would not heal with standard care and should be treated with advanced products such as skin substitutes.
“We know that the duration of the wound trajectory is a negative prognostic factor, so the earlier the treatment, the better off you are,” said coauthor Robert S. Kirsner, MD, PhD, professor and chair of the Department of Dermatology and Cutaneous Surgery at the University of Miami in Florida. “Almost everybody adheres in principle to the Peter Sheehan model of going to advanced products if the wound hasn’t achieved at least a fifty percent reduction in area in four weeks,19 but, in theory, if you knew at two weeks the wound wasn’t going to heal, that would be the even better time to apply advanced therapy. In our study we had a thousand different parameters from more than thirty-five thousand patients to develop a better predictive model. These data suggest that you could predict sixteen-week healing with eighty-five to ninety-percent accuracy.”
The high cost of biologic care is, of course, an inhibiting factor for many clinicians and patients. Standard care for a nonhealing ulcer carries an average cost per ulcer episode of $13,179, with higher grade ulcers costing as much as $27,600 per episode.20 Wu et al determined the costs associated with treating a DFU using advanced technologies can be as high as $45,000.21
Still, many believe the additional benefits of biologic therapies will justify the higher pricetag. But so far that remains to be demonstrated.
“There’ve been cost-utility analyses,” Kim said, “but nobody’s ever done cost-effectiveness studies, which require calculations of quality-adjusted life years utilizing quality of life surveys such as SF-36.” The SF-36 is the 36-item Short Form Health Survey used by Medicare and managed care organizations to monitor and assess care outcomes.22
The ability to make early predictions about which patients will benefit from biologics, without having to spend four weeks on standard care as is typically required for reimbursement now, could make an even stronger cost-benefit argument.
“Despite the higher up-front cost of these advanced products, we might be saving the economy money because of the higher cure rates and quicker resolution of chronic diabetic foot ulcers,” Nathoo said. “Payers need more long-term vision to recognize this fact.”
Hank Black is a freelance writer in Birmingham, AL.
- Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of diabetes and its burden in the United States, 2014. Centers for Disease Control and Prevention website. https://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed June 26, 2016.
- Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005;12;293(2):217-228.
- Driver VR, Fabbi M, Lavery LL, et al. The cost of diabetic foot: the economic case for the limb salvage team. J Vasc Surg 2010;52(3 suppl):17S-22S.
- Pecararo RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation. Basis for prevention. Diabetes Care 1990;13(5):515-521.
- Snyder R. Wound percent area reduction and making decisions about utilizing advanced therapies. Podiatry Manage 2010;29(3):197-201.
- Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen 2006;14(6):680-692.
- Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care 1999;22(5):692-695.
- Snyder RJ, Krisner RS, Warriner RA, et al. Consensus recommendations on advancing the standard of care for treating neuropathic foot ulcers in patients with diabetes. Ostomy Wound Manage 2010;56(4 Suppl):S1-S24.
- Nathoo R, Howe N, Cohen G. An overview of the key players in wound management. J Clin Aesthet Dermatol 2014;7(10):44-48.
- Santema TB, Poyck PPC, Ubbink DT. Skin grafting and tissue replacement for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev 2016;2:CD011255.
- Lavery LL, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix for the treatment of chronic diabetic ulcers: results of a multicenter, controlled, randomized, blinded, clinical trial. Int Wound J. 2014;11(5):554-560.
- Driver VR, Lavery LA, Reyzelman AM, et al. A clinical trial of Integra Template for diabetic foot ulcer treatment. Wound Rep Regen 2015;23(6):891-900.
- Best practice guidelines: Wound management in diabetic foot ulcers. Wounds International website. woundsinternational.com/media/issues/673/files/content_10803.pdf. Accessed June 26, 2016.
- An overview of advanced therapies in the management of diabetic neuropathic foot ulcers. Wound Care Canada website. http://www.woundcarecanada.ca/supplements/ DFU-Advanced-Healing-supplement-FINAL-320E.pdf. Accessed June 26, 2016.
- Garwood CS, Steinberg JS, Kim P. Bioengineered alternative tissues in diabetic wound healing. Clin Podiatr Med Surg 2015;32(1):121-133.
- Zelen CM, Serena TE, Snyder RJ. Dehydrated human amnion/chorion membrane allografts in patients with chronic diabetic foot ulcers: a long-term follow-up study. Wound Med 2014;4:1-4.
- Hawkins BJ. The use of micronized dehydrated human amnion/chorion membrane allograft for the treatment of diabetic foot ulcers: a case study. Wounds 2016;28(5):152-157.
- Jung K, Covington S, Chandan KS, et al. Rapid identification of slow healing wounds. Wound Rep Reg 2016;24(1):181-189.
- Sheehan P, Jones P, Caselli A, et al. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003;26(6):1879-1882.
- Stockl K, Vanderplas A, Tafesse E, Chang E. Costs of lower-extremity ulcers among patients with diabetes. Diabetes Care 2004;27(9):2129–2134
- Wu SC, Marston W, Armstrong DW, et al. Wound care: the role of advanced wound healing technologies. J Vasc Surg 2010;52(3 Suppl):595-665.
- Rand Medical Outcomes Study: 36-item short form survey. Rand.org website. http://www.rand.org/health/surveys_tools/mos/mos_core_36item.html. Accessed June 26, 2016.