Commentary: A Prospective Comparison of Diabetic Foot Ulcers Treated With Either Cryopreserved Skin Allograft or Bioengineered Skin Substitute

  Comparative research and product evaluation is a new endeavor, which should be applauded and supported. Dr. Didomenico and colleagues are to be commended for their attempts to meet that goal. Before any meaningful data is to result from comparative product evaluation, the use of the products must be maximized if the data is to be useful. Unfortunately, the data collected leaves much to be desired. As reported, the treatment of diabetic foot ulcers with Apligraf resulted in a 12-week healing rate of 41.3% and a 20-week healing rate of 47.1%. For the other product, TheraSkin, the healing rate at 12 weeks was 66.7% and at 20 weeks was 66.7%. These healing rates for TheraSkin are reasonable and comparable to a retrospective evaluation of its effect where a healing rate for diabetic foot ulcers was 60% at 12 weeks and 74% at 20 weeks.¹ In light of previously reported data, the healing rates with Apligraf in this comparative study are surprisingly low. In the original clinical trials, Veves et al² treated diabetic foot ulcers with Apligraf and achieved a 56% healing rate at 12 weeks. In a subsequent study, Steinberg et al³ noted a 55% healing rate at 12 weeks, and Edmonds et al⁴ reported a 51% healing rate at 12 weeks with ulcers averaging 2.5 cm² and receiving an average of 1.8 applications per patient. Other studies have shown even more impressive healing rates. In a Phase IV, randomized, diabetic foot ulcer trial by Sheehan et al,⁵ the 12-week healing rate for diabetic foot ulcers was 70% utilizing 1.27 applications per patient. This compares favorably to the results of Treadwell et al⁶ who reported 72% healing at 12 weeks with an average of 1.4 applications per patient with an even higher healing rate of 80% at 12 weeks with appropriate wound bed preparation.   What could make the difference in the previously reported and the currently observed healing rates? Many times an apparent failure of a product is not the failure of the product, but a failure to use the product appropriately. In the manuscript the authors describe that care of the wounds post application involved “no dressing changes being performed during the first week” and “subsequently, dressings changes were performed every other day, or on a daily basis, as needed.” This may be a potential source of the problem.   The Application Protocol for TheraSkin recommends that the original dressing be left in place for 5–7 days and then “re-dress [the] wound if necessary.”⁷ It appears that daily or every other day dressing changes may not be indicated for TheraSkin. The Application and Aftercare instructions for Apligraf plainly state that at the first dressing change should be 5 to 10 days after application; the primary, non-adherent dressing should be left undisturbed and the primary dressing should be only removed 14 to 21 days after application with care being taken “not to disturb or debride the wound bed.” Subsequent dressing changes are recommended only at weekly intervals.⁸ These recommendations are made so that neither the tissue engineered skin nor the wound bed is disturbed while the living cells are interacting with the wound bed to produce a positive clinical outcome. If excessive drainage necessitates more frequent dressing changes, the bandage is only changed down to the non-adherent dressing, which is left undisturbed and only changed weekly. It is known that manipulating the wound bed or too frequent changes of the non-adherent dressing can lessen the effectiveness of the tissue engineered skin and damage the wound bed, resulting in prolongation of the inflammatory wound microenvironment and delaying healing. Is it possible that this recommendation of too frequent dressing changes led to reduced healing for patients treated with Apligraf? Is it possible that the outcomes using TheraSkin could have been even better with fewer dressing changes?   The manuscript states that each patient was seen on “a weekly basis for the first 12 weeks, and then bi-weekly through the 20th week.” This implies that the patient or family member may have been doing the daily or every other day dressing changes. It is our experience that patients are unable to change a dressing with the care and expertise required for the management of a wound treated with a skin graft, tissue engineered skin, or other advanced wound care product. If we, as clinicians, believe a wound is best treated with any advanced therapeutic product, it behooves us to invest the time and skill in managing the wound to ensure the best possible clinical outcome. There is considerable monetary investment in any of these products, and as such, we should strive to get the most from that investment; providing appropriate follow-up care is one way to assure that.   The authors are to be congratulated for completing this comparative effectiveness study. There is no doubt that TheraSkin is a good product for the treatment of diabetic foot ulcers with good outcomes being obtained. Unfortunately, this study does not appear to demonstrate a true superiority over the bi-layered tissue engineered skin substitute. We look forward to seeing more comparative effectiveness research, but we must strive to assure that the effectiveness of each product is maximized so that a true comparison is possible.

References

1. Landsman AS, Cook J, Cook E, et al. A retrospective clinical study of 188 consecutive patients to examine the effectiveness of a biologically active cryopreserved human skin allograft (TheraSkin®) on the treatment of diabetic foot ulcers and venous leg ulcers. Foot Ankle Spec. 2011;4(1):29–41. 2. Veves A, Fananga V, Armstrong DG, Sabolinski ML. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290–295. 3. Steinberg JS, Edmonds M, Hurley DP Jr., King WN. Confirmatory data from EU study supports Apligraf for the treatment of neuropathic diabetic foot ulcers. J Am Pod Med Assoc. 2010;100(1):73-77. 4. Edmonds M, Foster A. A randomized, open label, multicenter study to compare the safety and efficacy of bilayered cell therapy versus standard therapy in the treatment of diabetic foot ulcers [abstract]. WOUNDS. 2005;17(3):A43. 5. Phase IV Diabetic Foot Ulcer Study. Data on file. Organogenesis; Canton, MA. 6. Treadwell TA, Fuentes ML, Walker D. Wound bed preparation prior to the use of bi-layered tissue engineered skin: the role of protease modulation. Wound Repair Regen. 2008;16:A19. 7. Soluble Systems, LLC. TheraSkin Preparation Protocol. Available at: https://www.solublesystems.com/files/PDF/ TheraSkin-Use_Protocol.pdf. Accessed: June 25, 2011. 8. Organogenesis, Inc. [Apligraf] Application and Aftercare: Tips for Optimizing Wound Healing. Available at: https://apligraf.com/professional/pdf/Application_Poster.pdf. Accessed: June 25, 2011.