Skin substitutes, which are also called bioengineered alternative tissues (BAT), are becoming more commonly used to help facilitate wound closure. Accordingly, our expert panelists discuss indications for these modalities and the timing of their use. They also weigh the benefits of skin substitutes versus skin grafts.
What is an appropriate wound condition for applying a skin substitute?
Eric Lullove, DPM, cites several appropriate wound conditions for the application of dermal skin replacement products. He says one may apply skin replacements in diabetic foot ulcers, venous stasis ulcers, burns of partial to full thickness, trauma, pressure ulcerations and for postoperative secondary wound closure.
Kazu Suzuki, DPM, CWS, and Desmond Bell, DPM, note the importance of ensuring the wound is thoroughly clean, free of infection and is covered with granulation tissue. Proper debridement, typically in serial fashion, can promote clean granulation tissue in the wound bed, according to Dr. Bell.
Kathleen Satterfield, DPM, concurs. “The recipient wound bed should look like the same surface on which we would apply a human skin graft — beefy red, non-fibrotic and clean with no signs of infection and callused edges debrided away,” she says.
However, Dr. Suzuki notes an exception may be Integra (Integra Life Sciences), a bovine collagen with silicone sheeting to prevent desiccation. He says one may apply Integra over some of the exposed bone and tendons, and then place another round of skin graft after Integra “takes” to the wound bed.
In addition, Dr. Bell notes that perfusion to the ulcer must be adequate and if it is not, one must address this prior to the use of a skin substitute. One should also rule out malignancy prior to use so he recommends a biopsy if the wound is suspicious based on history. Dr. Bell cautions against applying skin substitutes over ulcers in which there is necrotic tissue or a hyperkeratotic rim.
Is there appropriate timing for applying a skin substitute in chronic wounds?
The panelists cite research by Sheehan and colleagues that one should use skin substitutes in patients in whom ulcer size fails to reduce by half over the first four weeks of treatment.1 Dr. Bell says such patients are unlikely to achieve wound healing over a reasonable period. He adds that the study found that the percent change in foot ulcer area at four weeks’ observation is a robust predictor of healing at 12 weeks. Dr. Suzuki cites a similar study by Warriner and co-workers.2
Drs. Satterfield and Lullove note the importance of converting a chronic wound to an acute wound before using skin substitutes. Otherwise, Dr. Satterfield notes that one will only “totally misuse some excellent cutting-edge biotechnology” and the treatment will not work because the practitioner did not give it a chance to work. Dr. Lullove adds that one should assess arterial blood supply before any attempt at skin substitute replacement.
Is earlier use of skin substitutes warranted? Dr. Suzuki cites recent research by Kirsner and colleagues suggesting that the earlier one initiates an advanced biological therapy such as a skin substitute, the sooner the wound is likely to heal.3
“In other words, we probably should not ‘hold back’ these advanced biologic therapy but employ them proactively to get the wound to close as soon as possible,” argues Dr. Suzuki.
Dr. Bell agrees. “In an at-risk population, such as those with diabetes or venous disease, we know that nothing magical or good is going to happen by delaying more proactive treatment,” explains Dr. Bell. “Earlier use of skin substitutes should be encouraged as a way to ultimately help reduce morbidity and mortality.”
Furthermore, from a reimbursement standpoint, Dr. Bell says skin substitute application would be appropriate when an ulcer of diabetic and/or venous etiology has been present for a duration set forth in the policies of the patient’s insurance company or payer.
What is the rationale for using a skin substitute versus a skin graft?
As Dr. Satterfield notes, the key reason to use skin substitutes rather than grafts in patients with diabetes is the enhanced potential for healing as well as additional growth factors and living cells that the bioengineered substitute brings to the wound.
“By making this new deposit of living cells that include not only growth factors but proteins and collagen — all cells required to heal a wound — we are, we hope, giving them a wealth of cellular mass to heal that wound,” says Dr. Satterfield.
Dr. Lullove says one should use skin substitutes rather than autologous skin grafting in cases in which the patient is immunocompromised, has poor skin turgor or in those who are unable to undergo major surgery to harvest the graft. Dr. Suzuki says most patients who present to his wound care centers are of advanced age with very fragile skin quality and an autologous skin graft would be an inappropriate therapy option.
Dr. Lullove also cautions against using skin substitutes when the wound does not indicate for an autologous skin graft but might do better with secondary collagen filling. Drs. Bell and Suzuki note that the harvesting of skin graft creates another trauma that the patient has to heal. “The rationale is strong for considering a skin substitute over a skin graft for this reason alone,” says Dr. Bell.
Additional factors to consider are the potential pain, expense to the patient and insurers (due to operating room time and costs), and overall logistics of a bedside or office treatment versus a trip to the OR, according to Dr. Bell. He says skin substitutes are his preferred first line treatment due to their safety and efficacy.
Dr. Suzuki emphasizes informing patients of all of the treatment options. He says they often choose to go with skin substitute as opposed to the skin graft, given the excellent safety and efficacy data on wound closure demonstrated by some of the skin substitute products, such as Apligraf (Organogenesis) and Dermagraft (Advanced BioHealing).4,5
Do you differentiate the use and timing of skin grafts and skin substitutes, or do you use them as separate products?
Citing the acuity of his patients and their overall successful outcomes, Dr. Bell favors skin substitutes over skin grafting. However, in an acute setting, he says skin grafting would be the gold standard.
Dr. Suzuki believes that an autologous skin graft is for the wound that has granulated to the skin surface and is ready to be closed. On the other hand, he says skin substitutes may also be considered as “growth factor supplements” to further promote the granulation tissue and wound closure at the same time, based on the biological studies and multiple growth factors found in many skin substitutes.
One should make every attempt in most cases involving geriatric patients to prevent surgical procedures that would increase the risk of infection, according to Dr. Lullove. As he notes, skin substitutes allow the application and surgical fixation of dermal regenerative products. These products can supply the wound with needed type I or III collagen matrices to allow the wound to contract itself to healing. Dr. Lullove says one can also apply skin substitutes in an outpatient office setting as opposed to the operating room.
Dr. Satterfield has not often used the autograft in patients with diabetes to cover a non-healing ulcer. In her opinion, the patient with chronic wounds is deficient in many of those biochemical factors needed to heal the ulcer in the first place. “To use an autograft to heal an ulcer would be akin to using a patch from a blown-out tire to cover another blowout on that same tire,” she concludes.
Dr. Bell is a board certified wound specialist of the American Academy of Wound Management and a Fellow of the American College of Certified Wound Specialists. He is the founder of the “Save a Leg, Save a Life” Foundation, a multidisciplinary, non-profit organization dedicated to the reduction of lower extremity amputations and improving wound healing outcomes through evidence-based methodology and community outreach.
Dr. Lullove is in private practice in Boca Raton and Delray Beach, Fla. He is a staff physician at West Boca Medical Center in Boca Raton. Dr. Lullove is a Fellow of the American College of Certified Wound Specialists.
Dr. Satterfield is an Associate Professor at the Western University College of Podiatric Medicine in Pomona, Calif. She is a Fellow and President-Elect of the American College of Foot and Ankle Orthopedics and Medicine.
Dr. Suzuki is the Medical Director of Tower Wound Care Center at the Cedars-Sinai Medical Towers. He is also on the medical staff of the Cedars-Sinai Medical Center in Los Angeles and is a Visiting Professor at the Tokyo Medical and Dental University in Tokyo, Japan.
1. Sheehan P, Jones P, Giurini JM, 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.
2. Warriner R, Cardinal M, Snyder S. delayed progress in wound area reduction after four weeks of standard care predicts failure to heal diabetic foot ulcers. DFCON 2010 Poster Presentation. Los Angeles.
3. Kirsner RS, Warriner R, Michela M, et al. Advanced Biological Therapies for Diabetic Foot Ulcers. Arch Dermatol 2010; 146(8):857-862.
4. Veves A, Falanga V, et al. Graftskin, a human skin equivalent, is effective in management of non-infected neuropathic diabetic foot ulcers. Diabetes Care 2001; 24(2):290-295
5. Marston WA, Hanft J, Norwood P et al. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003 Jun; 26(6):1701-5.