Amniotic Membrane: Does It Have Promise For Diabetic Foot Ulcers?

Author(s): 
Karen Shum, DPM, and Lee C. Rogers, DPM

The prevalence of diabetes, estimated at 14 percent in 2010, is projected to increase to 21 percent of adults in the United States by 2050.1 The Centers for Disease Control and Prevention (CDC) has projected that as many as one out of three U.S. adults could have diabetes by 2050 if current trends continue.1

   The incidence of diabetic foot ulcers will likely parallel this trend and continue to rise. Those with diabetes have an annual incidence of 4 percent for the development of diabetic foot ulcers and up to 25 percent will develop a foot ulcer over their lifetime.2,3 The primary goal for these patients is to achieve quick wound closure to prevent complications such as infection and amputation.

   Due to the complex nature of the diabetic foot ulcer, treatment approaches are multipronged. These include pressure reduction, ensuring adequate blood flow and tissue perfusion, eradication of infection, correcting the deformity, and good nutritional status. Proper wound debridement is also a principal component that prepares the wound bed and stimulates the healing process. With optimal wound care, a steady decrease in wound size should occur.

   The percentage of reduction in foot ulcer area from baseline at four weeks is a strong predictor of healing at 12 weeks.4 Warriner and colleagues showed that a reduction in the size of foot ulcers by 90 percent at eight weeks resulted in a 2.7-fold higher incidence of healing at 12 weeks.5 If diabetic foot ulcers do not respond appropriately to standard care at four weeks, this requires re-evaluation of the current treatment plan. When wound healing stalls, one should consider adding advanced wound care therapies to the standard of care as chronic, non-healing diabetic foot ulcers are a common prequel to amputation.

   There are several biologic dermal replacement grafts available for the treatment of diabetic foot ulcers. These products are either cellular or acellular. The cellular products are derived from human fibroblasts and keratinocytes. Many of the acellular products are xenografts from bovine, porcine or equine tissue.

A Closer Look At How Amniotic Membranes Work

Amniotic membrane grafts are acellular human tissues with a variety of growth factors. The role and use of amniotic membranes in treating tissue defects has received much study.

   Since the early 20th century, human amniotic membrane allografts have been in widespread use in a variety of applications including burn care, dentistry, ophthalmic, ear, nose and throat, and spine surgery. This amniotic membrane allograft is most widely used in the field of ophthalmologic surgery, dating back to De Roth in 1940.6 More recently, research in early studies has shown human amniotic membrane allografts to be effective in healing diabetic foot ulcers.7 Amniotic membranes have biologically active cell products and growth factors, functioning as an extracellular collagen matrix that promotes cellular migration.

   There are two layers of the placental membrane, the amnion (in contact with the amniotic fluid and fetus) and the chorion (in contact with the maternal side of the placenta). Both layers are non-immunogenic and a combination of the chorion with the amnion contains more growth factors than the amnion alone. The combination is supplied as dehydrated human amnion/chorion membrane allograft and it can treat a variety of soft tissue defects, including chronic diabetic foot ulcers.

   Technological advances have occurred in preserving the amniotic tissue membrane along with its growth factors for use in wound healing. The amniotic tissue allograft is biologically active but does not have living cells. Its biologic activity comes from the effect of the growth factors in the graft on the host cells after implantation. The human amniotic membrane comprises the innermost layer of the placenta, which is composed of epithelial cells and connective tissue matrix of collagen and fibroblasts. Collagen types IV, V and VII make up the extracellular matrix and are substrates that are important for the integrity of the membrane and ingrowth of cells. The membrane also includes proteins such as fibronectin, proteoglycans, glycosaminoglycans and laminins.7 All of these are components of the extracelluar matrix scaffold, which aids in the organization of the body’s wound healing process.

   Epidermal growth factor, transforming growth factor, fibroblast growth factor, and platelet-derived growth factors make up the biomolecules in the amniotic membrane. Applying these growth factors to wounds can accelerate healing by stimulating angiogenesis and granulation tissue formation, and enhancing epithelialization.8
Manufacturers supply human amniotic grafts dehydrated at room temperature or frozen.

What You Should Know About The Healing Properties Of Amniotic Membrane Allografts

The dehydrated amniotic/chorionic membrane allograft has both matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The balance in activity of biomolecules and MMPs by TIMPs is a key component to the wound healing process.9 The amniotic membrane allograft has both MMPs and TIMPs, which potentially enable this regulation.

   This natural human tissue scaffold acts as a medium that enables cell proliferation and differentiation. It not only promotes and enhances wound healing, but also reduces inflammation and scar tissue formation. The human derived amniotic allograft is non-immunogenic and has low antigenicity.

   Only a few older reports highlight the use of amniotic membranes in foot and wound surgery.10,11 A recent but not yet published randomized controlled study compared standard therapy to the use of one of the human amniotic membranes (EpiFix, MiMedx) in chronic diabetic foot ulcers.12 Patients had weekly wound care and physicians applied dehydrated amniotic/chorionic membrane every two weeks until the wound healed. There was a healing rate of 92 percent while standard treatment only healed 8 percent over a short period of six weeks.

In Conclusion

Chronic diabetic foot ulcers display, among many things, a decreased production of growth factors within the wound. Oftentimes, biological cell therapy is what is needed to jump-start a stalled ulcer. The dehydrated amniotic membrane allograft by MiMedx provides these growth factors that a chronic diabetic foot ulcer lacks to activate the natural wound healing process. This product is entirely derived from human tissue and has few contraindications. We have mainly discussed the product’s use in treating chronic diabetic foot ulcers but one can also use the amniotic membrane in a wide range of wounds that include surgical wounds, pressure ulcers, venous and arterial ulcers.

   Dr. Shum is a third-year resident at Cedars-Sinai Medical Center in Los Angeles.

   Dr. Rogers is the Co-Director of the Amputation Prevention Center at Valley Presbyterian Hospital in Los Angeles.

References

1. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the U.S. adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Population Health Metrics. 2010;8:29.
2. Mayfield JA, Reiber GE, Sanders LJ, Janisse D, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care. 1998;21(12):2161-77.
3. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293(2):217-28.
4. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. 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):1879-82.
5. Warriner RA, Snyder RJ, Cardinal MH. Differentiating diabetic foot ulcers that are unlikely to heal by 12 weeks following achieving 50% percent area reduction at 4 weeks. Int Wound J. 2011;8(6):632-7.
6. De Roth A. Plastic repair of conjunctival defects with fetal membranes. Arch Ophthalmol. 1940;23(3):522-525.
7. Fetterolf D, Snyder R. Scientific and clinical support for the use of dehydrated amniotic membrane in wound management. Wounds. 2012;24(10):299-307.
8. Steed DL, Donohoe D, Webster MW, et al. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers: Diabetic Ulcer Study Group. J Am Coll Surg. 1996;183(1):61-4.
9. Armstrong DG, Jude EB. The role of matrix metalloproteinases in wound healing. JAPMA. 2002;92(1):12-18.
10. Kasi N, Durrani KM, Siddiqui MA. Human amniotic membrane as a versatile biologic dressing—a preliminary report. J Pak Med Assoc. 1987;37(11):290-2.
11. Boc SF, Chairman EL, Freed EL. Implications for the use of amnion and chorio in podiatric medicine and surgery. J Foot Surg. 1985;24(4):236-42.
12. Zelen CM, Serena T, Fetterolf D. Human amniotic membrane in the treatment of non-healing diabetic foot ulcers: a randomized controlled trial. Abstract presentation, Clinical Symposium on Advances in Skin and Wound Care, Orlando, FL, 2012.

Comments

The article made a very informative read regarding placental allograft application in wound healing. Incidentally I am part of a team that has been working on this for quite some time. It is indeed the growth factor and other bioactive molecules that are majorly responsible for the angiogenesis (chorionic side), followed by the epithelialization (amniotic side), but most of these are lost by 4 hours of the placental extraction, gamma IFN by 45 mins and Il10 by 4th hour. Hence, we prefer freshly collected and screened placental allograft, which has shown very effective results.

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