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Scaffolds, antibiotics show promise in treating diabetic foot sores

Re-amputation rate falls with Vacuum Assisted Closure. Osteoset-T beads and KeraPac dressing show potential benefits.

Issue: February 2006

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Existing technologies such as acellular tissue scaffolds offer safe and effective ways to treat diabetic foot ulcers. Now some new products, including negative pressure wound therapy, living-tissue scaffolds and topical treatments, may offer physicians even more ammunition in the fight against bone infection and amputation.

One new treatment method, Vacuum Assisted Closure, a form of negative pressure wound therapy (NPWT), is a potential �blockbuster� treatment for partial diabetic foot amputation wounds, said David Armstrong, DPM, PhD, professor of surgery, chair of research and assistant dean at the Dr. William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science in North Chicago, Ill. NPWT may yield a higher percentage of healed wounds, faster healing rates and fewer re-amputations than standard care, Armstrong said.

Armstrong, considered a leading expert on diabetic foot ulcers, teamed up with Lawrence Lavery, DPM, of the Texas A&M University Health Science Center College of Medicine, on a 16-week randomized controlled clinical trial comparing NPWT to standard therapy for partial foot amputation wounds in people with diabetes. They published their findings in The Lancet.

NPWT provides intermittent or continuous subatmospheric pressure through a pump connected to foam dressing, with an adhesive drape to maintain a closed environment.

�Essentially, what that [VAC] device does is it sucks out a lot of fluid and so in reducing edema and also in agitating and deforming the local cells, it stimulates new vessel formation,� Armstrong told Orthopedics Today. �And in doing that, it forms healthy granulation tissue, which then can allow us to apply skin grafts and other technologies.�

Secondary amputation wounds are complex and difficult to heal, Armstrong and Lavery wrote.

Armstrong and Lavery enrolled 162 patients in the 18-center trial. Patients were aged 18 and older, with partial foot amputation wounds up to the transmetatarsal level and evidence of adequate perfusion. Most study participants were men.

The researchers assigned 77 patients to NPWT and dressing changes every 48 hours, and 85 patients to standard moist wound care. Physicians treated wounds until they achieved healing or completed a 112-day active treatment period. (Kinetic Concepts Inc., maker of VAC Therapy Systems, funded the study.)

Faster healing

More patients healed in the NPWT group than in the control group (56% and 39%, respectively, P=.040), the authors reported. The NPWT group also healed faster than the control group (P=.005), they said. Granulation tissue, based on the time needed to attain 76% to 100% formation in the wound bed, formed faster in the NPWT group than in the control group (P=.002).

Both groups had similarly frequent and severe adverse events, with wound infection the most common event. No infections correlated with NPWT treatment, the authors said.

The NPWT patients were only 25% as likely as control group patients to need a second amputation. Three percent of NPWT patients and 11% of control group patients had a second amputation, the authors said.

The VAC trial differed from earlier studies of advanced wound healing technologies tested on the diabetic foot. For example, the patients in the VAC trial had larger and more complex wounds than patients in earlier studies of such technologies as bioengineered tissues and growth factors. Also, earlier studies of �advanced modalities� focused mainly on superficial neuropathic foot wounds that were seven or eight times smaller than those in the newer study (20.7 cm and 2.4 cm to 2.9 cm, respectively). The VAC study was also much larger than an earlier randomized controlled trials of the same technology.

�Biological duct tape�

Armstrong and other surgeons have combined VAC with tissue scaffolds and biological agents. One leading scaffold is the GraftJacket (Wright Medical Technology Inc.), a piece of skin, or dermis, from which the cells have been removed. Armstrong likened the scaffold to a building�s superstructure, or skeleton. The matrix loses antogenicity, reducing potential rejection, he said.

�Essentially, what happens is the body identifies this as part of its own and then � it morphs into that tissue,� Armstrong said.

The GraftJacket is useful in treating both foot wounds and various orthopedic conditions, such as rotator cuff and Achilles tendons tears. �It can be considered biological duct tape,� he said.

Armstrong noted that antimicrobial agents also prove beneficial. Delivering antibiotics locally avoids problems associated with systemic delivery such as toxicity and resistance formation, Armstrong said.

PMMA vs. Osteoset-T

Physicians have used local antibiotics in bone and joint surgery for decades. Polymethylmethacrylate (PMMA) beads with antibiotics are a proven treatment method. Newer treatments include Osteoset-T (tobramycin-loaded calcium sulfate) beads, which elute high antibiotic levels into local tissue for about six weeks, depending on the blood supply. They require replacement less often than PMMA beads, said Alastair Younger, MD, FRCSC of Vancouver.

Younger has used Osteoset-T with good results since 1998. In one study of 65 transmetatarsal amputations, Osteoset-T had a 75% success rate. Saving the patient�s leg was the main success criterion, Younger told Orthopedics Today.

Osteoset-T and other products may replace PMMA beads as the antibiotic carrier of choice. �I think that we also, in time, are much more likely to use local antibiotic carriers because it allows us to get more effective local treatment without having all the antibiotic resistance creation and the systemic complications of long-term intravenous antibiotics,� Younger said.

For one thing, Osteoset-T is more cost effective than other carriers, Younger said. �They�re extremely cost-effective by preventing people from coming back into the operating room and having to have repeat surgeries,� he explained.

Products like Osteoset-T may also represent a new generation orthopedic treatment, Younger said.

�I think that there may well be other carriers that may be more effective,� he said. �There�s all sorts of ways where local antibiotic and enzyme release may change the way we do orthopedics.� For example, future carriers may deliver growth hormones, bone-stimulating hormones or bone inhibiting hormones for stimulation or prevention of bone formation.

�So, there�s all sorts of potential applications in local drug delivery in orthopedics that I think we�re only at the very, very edge of actually beginning to understand,� Younger said.

An even newer product is on the horizon: KeraPac, an interactive dressing of non-woven fabric with porous polyethylene/silica microcarrier beads and human keratinocytes (skin cells). It is placed directly on the wound and removed several days later.

Riley S. Rees, MD, professor of surgery at the University of Michigan, Ann Arbor, was one of the original investigators in creating the product. KeraCure licensed the technology from the university and developed it for clinical trials.

�The KeraPac is considered a combination product, having a dressing function as well as a biological effect from living keratinocytes,� Rees told Orthopedics Today. �The keratinocytes are grown on the beads and placed in a bag, similar to a tea bag.�

Rees had used topical glutathione, a chemical found in every human cell. However, despite some promising animal studies in the late 1990s, glutathione �turned out to be a compound which was not conducive to the development of a product for [the] diabetic foot,� Rees said. Getting glutathione, an intracellular molecule, into cells is very difficult, he added.

The therapeutic potential of cultured skin cells has been well demonstrated in a number of published studies by academic researchers, and clinical studies have shown that wounds treated with keratinocytes healed significantly faster than wounds treated with conventional passive wound dressings, Rees said.

Simple and easy to use

With this in mind, the inventors of the KeraPac technology developed a product that focused on simplicity, cost of manufacturing, ease of use and off-the-shelf availability.

With about 10% of Americans having diabetes, and 10% of that group having at least one diabetic foot ulcer, Reese wanted to find an effective treatment.

Gretchen Johnson, KeraCure�s president and chief operating officer, said KeraCure recently concluded a small pilot safety study at the University of Michigan and recently received FDA approval to conduct a multicenter pivotal trial in 16 U.S. clinical sites. The study should be completed in approximately one year.

�KeraCure then plans to file a premarket approval application with the FDA,� she said. Because of a conflict of interest, Rees will not be an investigator in the trial.

Drs. Armstrong and Younger are consultants for Wright Medical Inc.

For more information:

• Armstrong D, Lavery L. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomized controlled trial. The Lancet. 2005;366:1704-1710. Also available on www.thelancet.com. Accessed December 2005.

• For more details about KeraPac, a trademark of KeraCure, visit www.keracure.com.