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What Does The Future Hold For Amniotic Membrane Products?
Offering insights from the literature on the role of amniotic membrane modalities to facilitate wound healing, this author also notes that forthcoming regulatory changes could affect the use of these products in the near future.
Placenta-derived amniotic membrane modalities have gained increased popularity in the treatment of chronic wounds over the past decade.1 Readily available following cesarean delivery via a donor donation program, placental tissue contains essential growth factors and extracellular matrix components that have implications in reducing inflammation and scar tissue while providing low immunogenicity without adverse effects.2
Amniotic membrane, as a means of natural human allografts emerged in 1910 when it was first used to treat burns.1 Amniotic membrane has subsequently gained value in tissue regeneration and wound healing due to an increased availability for use in the clinical outpatient setting, owing to advanced preservation techniques.3-7
Chronic wounds are those that fail to proceed through an orderly and timely reparative process. According to the four-week model, chronic wounds are those that do not reduce in size by 50 percent four weeks after the use of the appropriate standard of care.8,9 Advanced treatment modalities often come into play for chronic non-healing wounds to facilitate wound closure. Recent advances in wound care technologies, especially the advent of bioengineered alternative tissue, have proven to offer an optimized wound environment but have varying efficacy rates.10,11
Assessing The Potential Of Amniotic Membrane In Wound Healing
The amnion is one of two layers comprising the human placenta with chorion being the other. The amnion is the innermost layer closest to the fetus and chorion is the layer adjacent to the uterus of the mother.2 The function of the amnion is to protect and support the fetus during the gestation period. The amnion is a translucent, avascular structure lacking nerves, muscles and lymph vessels, and it modulates metabolic activity by growth factors, cytokines and other biological factors.12 The amnion also has antibacterial properties and offers protection from adhesions.
Amniotic membranes are made of structural collagen and extracellular matrix, regenerative molecules (including the growth factors and cytokines inhibited in diabetic foot ulcers (DFUs)) and biologically active cells, all of which interact with one another to regulate the healing processes.13,14 The amnion is made up of five layers: the epithelium, basement membrane, the compact layer, the fibroblast layer and the intermediate layer.15 All of the layers, excluding epithelium, contain collagen, which is known for its scaffold possessing properties for enhancing tissue growth.16
The basement membrane is a combination of polymeric hyaluronan, glycoproteins, proteoglycans, collagen and sparse mesenchymal cells. The basement membrane not only acts as a barrier but plays a role in the wound healing process by contributing to cell differentiation, proliferation and migration.3,6,16-19 Chorion membrane has a reticular layer (which contributes to the placental tissue being three to four times thicker than amnion), a basement membrane and a trophoblast layer.15,20-23
Amniotic membrane is rich in endogenous growth factors, including epidermal growth factor (EGF), keratinocyte growth factor (KGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).6 Growth factors are proteins that bind to receptors on the cell surface with the primary result of activating cellular proliferation and/or differentiation. Amniotic membranes also contain antimicrobial proteins including neutrophil gelatinase-associated lipocalin and defensins.6
In the complex cascade of wound healing, a hallmark of a chronic non-healing wound is prolonged inflammation. This creates a disruption in the healing cycle, leading to a decrease in normal proliferation of growth factors as well as an imbalance in protective versus degradative enzymes favoring destruction of the extracellular matrix.6,24 Amniotic membrane can help facilitate wound healing by providing the necessary growth factors and other healing cascades that adhere to the extracellular matrix to enhance tissue growth and healing.6,25 This modality ultimately works to overcome the interruption in the series of healing events.6,25
In patients with diabetes or other immunocompromised patients, the ability of the body to produce the proteins needed for wound healing no longer exists so the application of placental products has shed new light on the ability of these patients to heal and survive. At one point, there was a perception that amniotic membrane tissue was impractical for office or outpatient use due to a short or limited shelf life and severe risk of disease transmission. However, the advent of several preservation methods overcame these limitations. In order to maintain the regenerative properties of amniotic membranes, commercially available amniotic products adopted either cryopreservation or dehydration preservation methods. Depending on the wound care technology, some manufacturers opt to utilize more than one part of the human placenta containing solely amnion, amnion and chorion, or amnion and umbilical cord. Currently, there are more than 80 commercial placenta membrane products available on the market. The most common products are dehydrated amniotic membranes.
What You Should Know About FDA Regulation And The Future Of Amniotic Products
All placental-based products are currently designated by the U.S. Food and Drug Administration (FDA) as human cell, tissue, and cellular and tissue-based products (HCT/Ps). There are a couple of categories that the products we use fall into and there will be further regulation of these products occurring as of May 31, 2021.1
Section 361 of the Public Health Service Act defines the use of amniotic products for homologous use only. This means that products must be minimally manipulated and used for repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues via implantation, transplantation, infusion, or transfer into a human recipient.1 These products are subject to the “Current Good Tissue Practices” (CGTP) Guidelines. These products include the dried, lyophilized or cryopreserved sheet amnion, chorion, amnion/chorion and similar umbilical cord products that we now use. These products will require FDA review of their randomized controlled trials and an investigational new drug or device exemption (IND/IDE) filing for their use.1
Section 351 of the aforementioned Public Health Service Act defines a different set of products as more than minimally manipulated and therefore adequate for non-homologous use. These products follow the “Current Good Manufacturing Practices” (CGMP) Guidelines. These include the granular, injectable and further processed placental products that we now use. These products will require a Biologics License Application (BLA) filing and phase I, II and III studies prior to their widespread use.
As a result of these forthcoming regulations, only those products that have been studied in randomized controlled trials in the past and are committed to further study going forward (with the manufacturer filing for an IND) will be allowed to be used after May 2021.1 This will dramatically reduce the plethora of products marketed to providers by companies that have not produced unbiased studies.
In February 2020, the Department of Health and Human Services (HHS) prepared a technical brief on “Skin Substitutes for Treating Chronic Wounds.”26 This collection of data included over 164 articles and 81 packets of information from manufacturers, equaling 245 sources of information. This represented 76 commercial products from 48 manufacturers.26
Out of all the studies submitted, only 22 met the HHS inclusion criteria and were assessed for bias in the study outcomes. Of those 22 studies, 10 had a moderate risk of bias and just 12 were assessed as having a low risk of bias.26 Some, but not all, of these studies had to do specifically with amniotic products. Moving forward, we must be especially vigilant when it comes to the science and data for these types of products. That task will become much easier after May as many of the “fly by night” skin substitute manufacturers will disappear as they will not be able to provide good science for their products.
What Do The Current Studies Say About Amniotic Membrane Products?
Tettelbach and colleagues compared a dehydrated human umbilical cord allograft (dHACM) (EpiCord, MiMedx) to alginate wound dressings for chronic, non-healing DFUs.27 EpiCord-treated DFUs were more likely to heal within 12 weeks in comparison to those treated with alginate dressings, and researchers identified no adverse events associated with EpiCord.27 In another study by Tettelbach and coworkers, patients treated with the dHACM allograft were twice as likely to heal within 12 weeks in comparison to those who did not have dHACM treatment.28
Another dHACM, EpiFix (MiMedx) study, showed a higher probability of complete healing within 12 weeks for full-thickness venous leg ulcers when researchers used it as an adjunct to multilayer compression therapy.29 Also regarding venous leg ulcers, Serena and colleagues found that those treated with dHACM allografts and multilayer compression therapy reduced in size by 48.1 percent in comparison to 19.0 percent in those using multilayer compression alone.30
In another study involving a 100-patient cohort, Zelen and colleagues found that EpiFix had the highest wound healing probability among the treatments studied along with less applications to healing and less cost of overall treatment.31
Comparing hypothermically-stored amniotic membrane to the standard of care for diabetic foot ulcers, Serena and team found that DFUs treated with hypothermically-stored amniotic membrane had a higher rate of closure (60 versus 38 percent) at 12 weeks.32 Additionally, the authors noted greater than than a 60 percent reduction in wound area and depth at 12 weeks in the active treatment group.32
Lavery and colleagues found that 62 percent of DFUs closed when patients were treated with Grafix (Osiris Therapeutics) in comparison to 21 percent of DFUs closing with standard wound care alone.33 The median healing time was 42 days for Grafix and 69.5 days for the control group. The researchers noted fewer adverse events and wound-related infections in the Grafix group, and 82.1 percent of that group who healed remained healed at the end of the 12 week study.33
Concluding Thoughts
Placental-based products can be beneficial in the healing of difficult chronic wounds. Not all placental products are processed in the same way. Therefore, providers should use care in selecting the appropriate product based upon the most non-biased studies available. Clinicians should make sure that any regenerative medicine product they use is FDA-approved, studied under an IND and that manufacturers follow all regulatory processes for use of these products.
Dr. Garoufalis is a Past President of the American Podiatric Medical Association, Past President of the International Federation of Podiatrists and Co-Chair of the Alliance of Wound Care Stakeholders. He is in private practice in Chicago.
Dr. Garoufalis discloses that he is a member of the Speakers Bureau for OrthoBiologics, Horizon Therapeutics and MiMedx. He also discloses he is a consultant for 3M/Acelity, Modulim, AOTI, Uluru, RenovoDerm, Olaregen, Sanuwave and Orpyx.
1. U.S. Food and Drug Administration. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use. Available at: https://www.fda.gov/media/109176/download . Published July 2020. Accessed February 23, 2021.
2. Niknejad H, Peirovi H, Jorjani M, Ahmadiani A, Ghanavi J, Seifalian JM. Properties of the amniotic membrane for potential use in tissue engineering. Eur Cell Mater. 2008;15:88-99.
3. Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care. 2015;4(9):560-582.
4. Davis JS. Skin transplantation. Johns Hopkins Hosp Reports. 1910;15:307-396.
5. Cooke M, Tan EK, Mandrycky C, He H, O’Connell J, Tseng SCG. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465-474, 476.
6. Litwiniuk M, Grzela T. Amniotic membrane: new concepts for an old dressing. Wound Repair Regen. 2014;22(4):451-456.
7. Branski LK, Kulp G, Jeschke MG, Norbury WB, Herndon DN. Amniotic membrane as wound coverage: the effects of irradiation and different processing methods on growth factor content. J Surg Res. 2007;137(2):339.
8. Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: A major and snowballing threat to public health and the economy: perspective article. Wound Repair Regen. 2009;17(6):763-771.
9. Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders: a clinical practice guideline (2006 revision). J Foot Ankle Surg. 2006;45(5):S1-S66.
10. Gibbons GW. Grafix®, a cryopreserved placental membrane, for the treatment of chronic/stalled wounds. Adv Wound Care. 2015;4(9):534-544.
11. Maxson S, Lopez E, Yoo D, Danilkovitch-Miagkova A, Leroux MA. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 2012;1(2):142-149.
12. Mamede A, Carvalho M, Abrantes A, Laranjo M, Maia CJ, Motelho MF. Amniotic membrane: from structure and functions to clinical applications. Cell Tissue Res. 2012;349(2):447-458.
13. Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502-507.
14. Schultz GS, Davidson JM, Kirsner RS, Bornstein P, Herman IM. Dynamic reciprocity in the wound microenvironment. Wound Repair Regen. 2011;19(2):134-148.
15. Koob TJ, Lim JJ, Massee M, Zabek N, Denozière G. Properties of dehydrated human amnion/chorion composite grafts: Implications for wound repair and soft tissue regeneration. J Biomed Mater Res B Appl Biomater. 2014;102(6):1353-1362.
16. Ilancheran S, Moodley Y, Manuelpillai U. Human fetal membranes: a source of stem cells for tissue regeneration and repair? Placenta. 2009;30(1):2-10.
17. Lintzeris D, Yarrow K, Johnson L, et al. Use of a dehydrated amniotic membrane allograft on lower extremity ulcers in patients with challenging wounds: a retrospective case series. Ostomy Wound Manage. 2015;61(10):30–36.
18. Hodde J. Naturally occurring scaffolds for soft tissue repair and regeneration. Tissue Eng. 2002;8(2):295-308.
19. Toda A, Okabe M, Yoshida T, Nikaido T. The potential of amniotic membrane/amnion-derived cells for regeneration of various tissues. J Pharmacol Sci. 2007;105(3):215-228.
20. Bourne G. The foetal membranes. A review of the anatomy of normal amnion and chorion and some aspects of their function. Postgrad Med J. 1962;38(438):193-201.
21. Parry S, Strauss JF. Premature rupture of the fetal membranes. New Engl J Med. 1998;338(10):663-670.
22. Oyen ML, Cook RF, Calvin SE. Mechanical failure of human fetal membrane tissues. J Mater Sci Mater Med. 2004;15(6):651-658.
23. Chua WK, Oyen ML. Do we know the strength of the chorioamnion? A critical review and analysis. Eur J Obstet Gyn Reprod Biol. 2009;144(Suppl 1):S128-133.
24. Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clin Dermatol. 2007;25(1):19-25.
25. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83(3):835-870.
26. Centers for Medicare and Medicaid Services. Agency for Healthcare Research and Quality Technology Assessment Program “Skin Substitutes for Treating Chronic Wounds. Technical Brief Project ID: WNDT0818.” Available at: https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id109TA.pdf . Published February 2, 2020. Accessed February 25, 2021.
27. Tettelbach W, Cazzell S, Sigal F, et al. A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers. Int Wound J. 2019;16(1):122-130.
28. Tettelbach W, Cazzell S, Reyzelman AM, Sigal F, Caporusso JM, Agnew PS. A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: a prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics. Int Wound J. 2019;16(1):19-29.
29. Bianchi C, Cazzell S, Vayser D, et al. A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix®) allograft for the treatment of venous leg ulcers. Int Wound J. 2018;15(1):114-22.
30. Serena TE, Carter MJ, Le LT, Sabo MJ, DiMarco DT, EpiFix VLU Study Group. A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen. 2014;22(6):688-693.
31. Zelen CM, Serena TE, Gould L, et al. Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. Int Wound J. 2016;13(2):272-282.
32. Serena TE, Yaakov R, Moore S, et al. A prospective multicenter randomized controlled clinical trial of a hypothermically stored amniotic membrane for the management of diabetic foot ulcers [manuscript]. Adv Wound Care. 2019 Feb 26;32 p.
33. Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix(®) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. 2014;11(5):554-560.
