How To Treat Diabetic Ulcers With Dermagraft

The prevalence of diabetic ulceration is alarmingly high and increasing. Currently, it is between 4 and 10 percent, depending on a host of factors including ethnicity, geographic region and duration of disease. Wounds are clearly associated with infection and a high risk of future amputation. The economic implications are overwhelming to the health care system. As clinicians, we must be able to rapidly identify, access and manipulate the factors necessary for wound healing.
Indeed, it is vital to approach the wound healing process as a whole body process when you’re treating a patient who has diabetes. You must address and influence the vascular and nutritional status of the patient. We must reduce the microflora of the wound through debridement and appropriate topical or systemic antimicrobials, and offload the ulcerated area to reduce repetitive shear and vertical pressure.
Until the approval of various bioengineered tissues, most recently Dermagraft, we had not been able to influence — on a molecular level — the quality of tissue produced at the wound site in a patient with diabetes. Studies have shown a decreased level of production and an increased level of abnormal collagen in a chronic wound. Diabetic patients have higher levels of collagen glycosylation, which produces abnormal crosslinking.1-3 Crosslinking forms the superstructure that provides the tensile strength to the wound base. This necessary requirement of wound healing must be influenced at the level of the fibroblast, which produces most of the collagen.
Dermagraft is a bioengineered living matrix of cultured neonatal fibroblasts seeded on an absorbable (polyglactin) mesh measuring 2x3 inches (5cm x 7.5cm).4-7 Once it is cultured, the mesh is then frozen and shipped in a cyroprotectant. After the rapid thawing procedure, then you can apply the graft to the wound. The graft provides a living matrix of neonatal fibroblasts that produce collagen, glycosaminoglycans and other proteins for approximately two weeks.
Keep in mind the cell lines used in this human dermal substitute are tested thoroughly for infective agents. They also undergo extensive genetic and antigenic testing. The only contraindications cited at this time are the presence of clinical infection or a hypersensitivity to bovine products.

What The Research Reveals
Researchers have completed several clinical trials. Gentzkow et. al., completed the earliest published study to assess the frequency and dosing requirements for Dermagraft.8 They found that using a tissue graft every week for a total of eight weeks resulted in a 50 percent rate of healing, while conventional care for the same duration resulted in only an 8 percent rate of healing.
Another multi-center clinical pivotal trial applied this dosing regime to a maximum of eight grafts over a 12-week evaluation period.9 The end point of the study was complete closure of the ulceration at 12 weeks and maintained closure at week 16. Closure rate of the Dermagraft group ranged between 22 to 38 percent and the control group ranged between 12 to 26 percent at the 95 percent probability level.9
Using a Markov cost-effectiveness model, Allenet et. al., suggested that using Dermagraft on all patients in a 100 patient cohort, would result in a long-term cost savings of approximately 6 percent.10 You might presume these savings would be even more substantial if the attending physician had discretion as to who might benefit from therapy and who would not.
Dermagraft received FDA approval for treating diabetic foot ulcers late last year.11,12 (See “News And Trends,” November, 2001, pg. 11.) Indications for use include the full thickness diabetic foot ulceration. It is recommended that you do not use Dermagraft over exposed tendon, capsule or bone.
Key Pearls And Insights For Applying Dermagraft Successfully
The procedure for applying Dermagraft often begins the week before you plan to use it. We begin with an aggressive debridement of the wound, as is the standard at our institution. Following this, we will attempt to pragmatically reduce the bacterial burden in the wound. First and foremost, we do this via debridement, but you can also use other modalities. We prefer using a silver-ion donating dressing (Acticoat) or a cadexomer-iodine based topical (Iodosorb).

On the day of the procedure, you may apply a standard surgical scrub to the area, with the addition of a final rinse with generous amounts sterile normal saline. You should excise all undermining, hyperkeratotic and necrotic tissue. We will often curette the base of the wound to promote an acute wound environment. Bleeding should be controlled by pressure only. Our staff recommends preparing the wound base and following up with the application of a compressive dressing, consisting of gauze and an elastic conforming bandage.
Remember, the graft is shipped at subzero temperatures and must undergo a rapid thaw procedure. It is necessary to have all the required equipment and liquids ready prior to removing the graft from the shipping container. The manufacturer of Dermagraft supplies a reusable starter kit that contains all the necessary thawing equipment.
The thawing process is reasonably straightforward, but you should perform it within two to three minutes of removing the graft from the refrigerated box. Viability of the dermis tends to degrade after the three-minute period. Once the graft has thawed, you may apply it to the patient within a 30-minute window. Be aware that if you apply the graft after the 30-minute window, it may yield less predictable results because of a decreased prevalence of viable fibroblasts.
Take care to handle the plastic bag only by the edges and avoid the central portion containing the graft. After the thawing process is complete, place the bag over the wound and trace the outline of the wound onto the bag. Add a small tab to the outline to allow for handling. Then you cut on the outline of the bag containing the graft. Separate the graft from the plastic bag and implant it directly in the wound base. You may remove the tab with sterile scissors. It is not necessary to mesh the graft, since it is liquid permeable. You may then place a non-adherent dressing layer over the graft and follow up with a wet to dry dressing. Generally, the graft should not be disturbed for a minimum of 72 hours.
Case Study: When You Have To Modify The Procedure
While the technique (described in “A Six Step Approach To Using Dermagraft” on page 34) is ideal, you may need to make minor modifications to the procedure when faced with other eventualities. For example, consider the following case study.
A 58-year-old Hispanic woman with diabetes came in with an ulceration on the anterior distal tibia region of the left leg. She had the ulcer for several months. We chose Dermagraft as the wound healing modality for this patient. We scheduled the patient for surgical debridement and application of the graft. Upon performing surgical debridement of the wound, we noted the patient had exposed deep fascia but this did not change our treatment plan.
Due to untimely shipping, the starter kit did not arrive with the Dermagraft. However, we used a sterile surgical bowl for the thawing tub and submerged the bag by hand. Once we completed the initial thawing in the water bath, we held the plastic bag upright by the edges and cut open on the printed cutting lines. Then we poured the cryopreservative out and poured sterile saline into the bag for the required rinses. Finally, we filled the bag with sterile normal saline to facilitate removal of the post-debridement compressive dressing.
Due to the excessive handling of the bag, we cut the bag open down the sides and removed the graft in toto. We noted four areas where the graft had adhered to the bag. Using saline-moistened sterile swabs, we gently teased the graft from this adhesive site. We transferred the graft to a saline-saturated 4x4 inch gauze, which we flipped over on top of the wound and placed in the wound base. Using swabs, we spread the graft into the wound base and, using sterile surgical scissors, we trimmed the graft to the wound size.
We applied a non-adherent layer, followed it with Acticoat and then Allevyn, which we cut to the size of the graft. We centered the remaining oversized piece of Allevyn over the cutout and secured it with Hypofix tape. Then we applied gauze and an ace wrap. We recommend this dressing protocol but keep in mind that many surgery centers and hospitals do not routinely stock these items. You may have to order these items and the Dermagraft at the same time.
Three days later, we removed the patient’s dressing and noted a significant improvement in the depth of the wound. All prior areas of exposed fascia were covered. The circumference of the wound remained the same, but we did see a 1cm decrease a week and a half post-graft.
The manufacturer of the graft recommends regrafting every two weeks. However, our results have been rather variable in this regard. Some patients have required as few as one application to achieve the desired stimulatory effect. We have used Dermagraft synergistically with a host of other products, including but not limited to Apligraf (asynchronously), maggots (asynchronously), the VAC Therapy device (concomitantly) and Hyaff (concomitantly).
Final Notes
There are several benefits to using Dermagraft. A primary benefit is being able to provide a superstructure of healthy, normal collagen that can be implemented in the wound base. We and other investigators have noted a rapid decrease in the depth of wounds when using this modality. Another advantage is the ease of application of the graft. As there is only a dermal component, you can apply the graft with either side facing up. Meshing is not necessary either.
We believe this modality has unique advantages that may assist it in staking a claim on the ever-broadening wound care landscape.

Dr. Armstrong is the Director of Research and Education within the Department of Surgery, Podiatry Section at the Southern Arizona Veterans Affairs Medical Center in Tuscon, Ariz
Dr. Abu-Ramman is a Senior Resident within the aforementioned department. Dr. Aung is in private practice in Tuscon, Ariz. She is also the Chairperson for the Arizona Department of Health’s Diabetes Council.

References:

References

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2. Brownlee M. Glycation products and the pathogenesis of diabetic complications. Diabetes Care. 1992;15:1835-1843.

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10. Allenet B, Paree F, Lebrun T, et al. Cost-effectiveness modeling of Dermagraft for the treatment of diabetic foot ulcers in the french context. Diabetes Metab. Apr 2000;26(2):125-132.

11. Nicholls H. FDA approves Dermagraft(R) for diabetic foot ulcers. Trends Endocrinol Metab. Dec 2001;12(10):433.

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