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Letters and Commentary

Letter to the Editor

Fetterolf, Donald MD, MBA, FACP; Koob, Thomas PhD

Author Information
doi: 10.1097/SAP.0000000000001235
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A recent publication of Johnson et al1 in the Annals titled “Understanding the Impact of Preservation Methods on the Integrity and Functionality of Placental Allografts” recently came to our attention. This industry-sponsored research makes a number of observations and conclusions that we think warrant further comment. As the reported manufacturer of the dehydrated human amnion/chorion membrane (dHACM) used in the study, we would note the following.

The study was extensively referenced, with some 60 references, yet these do not include any of the substantial 8 existing, peer-reviewed articles in the scientific literature on the properties and attributes of dHACM, a material oversight in such a study, especially given that the article purports to study dHACM.2–9

Furthermore, claims made about the MiMedx dHACM material were often unsupported, such as the degradation of the extracellular matrix in this product (which cannot be determined at the staining and magnification level shown) or the suggestion that the material contains maternal components. Literature that is cited discussing the various effects of dehydration on amniotic membrane is not relevant to dHACM in the material used, because the proprietary PURION Process developed by MiMedx was created to expressly avoid these issues. The suggestion that all amniotic membranes researched present the same properties is well known to be an incorrect statement.

The discussion of the various attributes tested appeared to imply that these attributes materially contributed to a superior result in actual clinical patients, which was not demonstrated. If anything, the observation that preclinical models demonstrate 92% cell death in transplanted viable allografts would seem to negate the argument that Grafix would continue to produce growth factors well after implantation.

The discussion of the significance of matrix metalloproteinase-9 appears to be a sponsor-related statement on an isolated area of their research. Individual markers of inflammation are well known to be insufficient indicators (or treatments) of the wound healing process, which in fact requires the full milieu of both pro-inflammatory and anti-inflammatory growth factors and cytokines in what Schultz et al10 describes as a process of “dynamic reciprocity.” Furthermore, immunoreactivity testing only notes the presence of these factors without noting whether they are clinically active. One of the scientific articles ignored in this article relates directly to matrix metalloproteinases in dHACM, which shows that it is not active.11

Interestingly, this article notes that the materials were placed on in vivo chronic wounds in an animal model, but clinical results were not discussed in detail. The implication that dHACM somehow does not work or works less effectively for whatever reason in animals or patients remains unproven.

The only claim cited at the end of the article that Grafix is a superior product seems to be derived from a small retrospective study in a rural hospital that suffered from numerous methodological issues.12 The study mentioned is far from a comparable standard. A level 3 nonrandomized, noncomparable, highly variable study groups created without a protocol can easily reflect any number of incorrect findings, good or bad. By definition, “comparative effectiveness research” seeks to truly compare equivalent groups for differences in effectiveness and/or cost. That discipline did not occur here. Clearly, it is inappropriate to use this study to counter multiple level 1 published randomized controlled trials using dHACM13–16 and other evidence published in formally peer-reviewed, indexed, well-recognized medical journals including the Annals of Plastic Surgery.17–23

Most of the observations reported relate to various in vitro comparisons of the Osiris “living” tissue versus the “nonviable” dHACM tissue. It would seem rather obvious and a spurious study design to subject these very different tissue grafts to various stimuli that would potentially elicit a response of some sort from viable tissue and then conclude unsurprisingly that the nonviable tissue did not respond to stimuli as well. This conclusion could have been made without a study, and this challenges the relevance of the entire data set. Interestingly, Osiris24 acknowledges the issues with live cell preservation to the extent it has introduced its own lyophilized product with its “Prestige Lyotechnology.”

Whereas Grafix may be dependent on the presence of live cells to promote healing, the mechanism of action by which EpiFix promotes healing is independent of the need for viable cells. Upon implantation, EpiFix delivers a diverse array of vital bioactive factors into the wound, and as EpiFix matrices are remodeled within the wound environment, additional matrix bound growth factors are continually released from the tissue. These factors recruit endogenous cells including reparative stem cells into the wound environment and stimulate cells to proliferate and secrete factors to reset the wound healing response by endogenous cells.8,9 Osiris, however, has not demonstrated these same bioactive mechanisms with Grafix, a single layer amnion product.

All in all, the article by Johnson et al1 is disappointing in that it clearly presents an industry-sponsored bias, is devoid of appropriate literature references, and implies conclusions from the work done that are not supported in actual clinical trials.

We are surprised that the article made it through the Annals review process.

Donald Fetterolf, MD, MBA, FACP

MiMedx, Inc

Marietta, GA

MiMedx [email protected]

Thomas Koob, PhD

MiMedx, Inc

Marietta, GA


1. Johnson A, Gyurdieva A, Dhall S, et al. Understanding the impact of preservation methods on the integrity and functionality of placental allografts. Ann Plast Surg. 2017;79:203–213.
2. Koob TJ, Lim JJ, Massee M, et al. Properties of dehydrated human amnion/chorion composite grafts: implications for wound repair and soft tissue regeneration. J Biomed Mater Res B Appl Biomater. 2014;102:1353–1362.
3. Koob TJ, Lim JJ, Massee M, et al. Angiogenic properties of dehydrated human amnion/chorion allografts: therapeutic potential for soft tissue repair and regeneration. Vasc Cell. 2014;6:10.
4. Koob TJ, Lim JJ, Zabek N, et al. Cytokines in single layer amnion allografts compared to multilayer amnion/chorion allografts for wound healing. J Biomed Mater Res B Appl Biomater. 2015;103:1133–1140.
5. Koob TJ, Rennert R, Zabek N, et al. Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing. Int Wound J. 2013;10:493–500.
6. Maan ZN, Rennert RC, Koob TJ, et al. Cell recruitment by amnion chorion grafts promotes neovascularization. J Surg Res. 2015;193:953–962.
7. Maan ZN, Rennert RC, Koob TJ, et al. Progenitor cell recruitment by dehydrated human amnion chorion grafts promotes neovascularization in a murine model of dermal ischemia. J Surg Res. Published online September 3, 2014.
8. Massee M, Chinn K, Lei J, et al. Dehydrated human amnion/chorion membrane regulates stem cell activity in vitro. J Biomed Mater Res B Appl Biomater. 2016;104:1495–1503. [Epub ahead of print].
9. Massee M, Chinn K, Lim JJ, et al. Type I and II diabetic adipose-derived stem cells respond in vitro to dehydrated human amnion/chorion membrane allograft treatment by increasing proliferation, migration, and altering cytokine secretion. Adv Wound Care (New Rochelle). 2016;5:43–54.
10. Schultz GS, Davidson JM, Kirsner RS, et al. Dynamic reciprocity in the wound microenvironment. Wound Repair Regen. 2011;19:134–148.
11. Lei J, Priddy LB, Lim JJ, et al. Identification of extracellular matrix components and biological factors in micronized dehydrated human amnion/chorion membrane. Adv Wound Care (New Rochelle). 2017;6:43–53. doi:10.1089/wound.2016.0699. [Epub ahead of print].
12. Johnson EL, Marshall JT, Michael GM. A comparative outcomes analysis evaluating clinical effectiveness in two different human placental membrane products for wound management. Wound Repair Regen. 2017;25:145–149.
13. Zelen CM, Serena TE, Denoziere G, et al. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10:502–507.
14. Serena TE, Carter MJ, Le LT, et al. 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;22:688–693.
15. 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;13:272–282. doi: 10.1111/iwj.12566. Epub 2015 Dec 23.
16. Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly versus biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. 2014;11:122–128. doi: 10.1111/iwj.12242. Epub February 21, 2014.
17. Zelen CM. An evaluation of dehydrated human amniotic membrane allografts in patients with DFUs. J Wound Care. 2013;22:347–348, 350–1.
18. Snyder RJ, Ead J, Glick B, et al. Dehydrated human amnion/chorion membrane as adjunctive therapy in the multidisciplinary treatment of pyoderma gangrenosum: a case report. Ostomy Wound Manage. 2015;61:40–49.
19. Wisco OJ. Case series: The use of a dehydrated human amnion/chorion membrane allograft to enhance healing in the repair of lower eyelid defects after Mohs micrographic surgery. JAAD Case Rep. 2016;2:294–297. doi: 10.1016/j.jdcr.2016. 06.002. eCollection July 2016.
20. Herndon DN, Branski LK. Contemporary methods allowing for safe and convenient use of amniotic membrane as a biologic wound dressing for burns. Ann Plast Surg. 2017;78(suppl 1):S9–S10.
21. Tenenhaus M. The use of dehydrated human amnion/chorion membranes in the treatment of burns and complex wounds: current and future applications. Ann Plast Surg. 2017;78(suppl 1):S11–S13.
22. Glat PM, Davenport T. Current techniques for burn reconstruction: using dehydrated human amnion/chorion membrane allografts as an adjunctive treatment along the reconstructive ladder. Ann Plast Surg. 2017;78(suppl 1):S14–S18.
23. Reilly DA, Hickey S, Glat P, et al. Clinical experience: using dehydrated human amnion/chorion membrane allografts for acute and reconstructive burn care. Ann Plast Surg. 2017;78(suppl 1):S19–S26.
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