Does amniotic membrane represent a promising technology that can speed the healing of complicated wounds such as diabetic foot ulcers? These authors take a closer look at how amniotic membranes work and offer several case study examples.
Diabetic foot ulcers continue to be a challenge for podiatrists and other healthcare providers. With the diagnosis of diabetes increasing in prevalence year after year, we continue to find ways to heal these wounds as quickly, efficiently and economically as possible.
Recently, there has been an increase in interest in the use of amniotic membranes for wound healing. Even though this technology has been around for years, it has had a recent surge of popularity. Ophthalmologists have used amniotic membranes dating back to 50 years ago. The use of amniotic membrane for other applications started in the 20th century but dropped out of favor with the discovery and rise of human immunodeficiency virus (HIV).
Clinicians should reserve amniotic membrane and any advanced biological dressing for wounds that are considered “chronic.” Sheehan and Jones defined a chronic wound as a wound that is still present after 30 days and has less than 50 percent reduction in size during this timeframe.1 It is important to get these wounds healed as quickly as possible in order to reduce the risks of infection and limb loss, and return patients to activity and work. Unfortunately, it does not appear that this definition of chronic wound will change nor will the criteria for use of these products become any easier.
There are many products on the market that physicians have utilized in healing wounds but not all products are created equally. Of these products, only a few are FDA approved. Hopefully with continued prospective studies, more products will gain approval not only for diabetic wounds but for those challenging postoperative wounds as well.
However, advanced biologics should not replace the basic tenets of wound care management. If one does not address these basics, even the best biologic dressing will fail. When treating a wound, appropriate wound debridement is essential but we must not forget to treat the entire patient and not just the wound.
Of course, one must first start with a thorough history and physical. As simple as this sounds, if one forgets these basics, the standard of care will often go overlooked. There are many things that impact healing: age, medical history (especially diabetes, rheumatoid arthritis, etc.), and social history (smoking, alcohol use and poor nutrition). While we cannot change some of these factors, one must address the variable items in the equation. All too often we downplay the amount of influence nutrition can play in healing.
In addition, our physical exam will also help guide us to define what type of wound we are treating so we can implement the best options to obtain rapid healing. Clinicians should also perform a vascular exam, a neurologic exam and ascertain the patient’s overall health by obtaining lab work. It is also important to control the amount of edema as it has a huge impact on wound healing.
There is a wealth of literature that has demonstrated the financial burden that managing diabetic wounds has on our economy. Even with this understanding and evidence-based medicine to support advanced biologics, insurance companies still make it difficult for physicians to implement and utilize these products. Therefore, we want to make sure that we utilize the appropriate dressings and advanced biologics for each scenario to heal our patients as quickly as possible.
Amniotic membrane is placental tissue that comes from donated placenta after childbirth. It consists of the innermost layer of tissue that is comprised of a thin epithelial layer, a thick basement membrane and an avascular stroma.2
There are several unique properties of amniotic membrane that make it ideal for wound healing.
• Amniotic membrane has abundant stem cells that one can harvest without moral and ethical concerns.
• Amniotic membrane lacks immunogenicity via a low expression or lack of expression of histocompatibility antigens.
• Amniotic membrane has the ability to produce healing with little to no scarring. Along with the indirect contribution of amniotic membrane’s anti-inflammatory effects, there has been evidence of direct reduction of scarring. Tseng and colleagues demonstrated in a laboratory study that there was a direct anti-scarring action on ocular surface fibroblasts by suppressing transforming growth factor beta (TGF-b).3 The TGF-b is responsible for activation of fibroblasts and by down-regulating this process, there is a reduction and prevention of adhesion and fibrosis.
• Amniotic membrane has the ability to impart anti-inflammatory effects by mediating pro-inflammatory cytokines such as interleukin (IL-6) and TNF-alpha. Tseng and colleagues noted that enzyme-linked immunosorbent assay (ELISA) extracts have high levels of IL-10, which counteracts inflammatory effects.3 In addition, they have found amniotic membrane down-regulates the expression and production of IL-1, and up-regulates interleukin-1 receptor antagonist (IL-1RA).
Given all these properties of amniotic membrane, one can imagine what a great benefit it is to have this type of product available to heal these ever challenging diabetic wounds.
Currently, there are two methods of preserving amniotic tissue, dehydration (Purion, MiMedx) and cryopreservation (CryoTek, Bio-Tissue/Amniox Medical).
The Purion method uses a series of rinsing the amniotic tissue in hypertonic salt solutions and dehydration under elevated temperatures. The concern with this type of processing is that it can lead to the destruction of the very elements of the amniotic membrane that are integral in healing.
The new CryoTek process claims to maintain the structures of amniotic membrane. A recent study not yet published by Tan and coworkers demonstrated histologically that the CryoTek process preserved the extracellular matrix and structural proteins of amniotic membrane.4 However, when evaluating the dehydration method results, the study researchers found the morphology of the tissue was compacted, which implies structural changes to the matrix. In addition, both processes demonstrated the presence of hyaluronan.
Liu and coworkers demonstrated that hyaluronan in amniotic tissue is present in the form of a heavy chain of inter-alpha-inhibitor-hyaluronan (HC-HA) complex. The authors believe this complex plays a role in anti-angiogenic activity as well as stabilizing the extracellular matrix.4,5 Results of the study via western blot analysis demonstrated high levels of HC-HA using the CryoTek process. The dehydrated process had the presence of HC-HA but it was minimal or with an altered band appearance. Accordingly, it certainly appears that the way the tissue is processed also makes a difference in maintaining the integrity of the amniotic membrane.
We have started using amniotic membrane for wounds that have been a particular challenge. We have seen great results with just one application. Below are some case studies to demonstrate the process of application, the different forms of the product we have used and the patient outcomes.
Case study 1. A 70-year-old female presented 12 weeks after ankle fusion with an anterior ankle wound dehiscence and exposure of the tendon. The patient had a history of diabetes, chronic kidney disease, obesity, gastrointestinal esophageal reflux disease, depression and hypertension. Some additional challenges with this case were the development of deep vein thrombosis and infection after surgery, which led to two incision and drainage (I&D) procedures.
The patient went back to the OR for I&D and application of an amnion graft. We placed the graft within the wound and wrapped it around the tendon. The dressing we applied consisted of Adaptic (Systagenix) 4x4 and a four-layered compression dressing.
We saw the patient weekly but did not perform debridement. We continued to apply a four-layered compression dressing to control edema and occasionally used a collagen (Prisma, Systagenix) dressing.
The patient went on to heal completely and is now back to pre-surgical activity.
Case study 2. A 72-year-old patient presented with a long history of rheumatoid arthritis and alcoholism. Even though this patient does not have diabetes, his pertinent medical history presents similar barriers to healing that are just as challenging. He had previous amputations and similar difficultly healing wounds. The patient had amputation of the left second and third digits secondary to infection on April 23, 2013. He went on to wound dehiscence and had various treatment modalities prior to amnion grafting.
In this case, we used one application of lyophilized particulate placental tissue with weekly evaluation. Prior to application, we performed sharp wound debridement to good, healthy granulation tissue. We placed the lyophilized placental tissue within the wound bed and used a dressing consisting of Adaptic 2x2, Kling and Ace wrap. The dressings remained in place until weekly follow-up appointments in which we applied a new Adaptic 2x2 and Kling. No further debridement occurred. The patient’s wound went on to heal completely in seven weeks with no further application of additional amnion or debridement.
Case study 3. As we all know, these wounds, diabetic or not, tend to be very challenging. Even if the wound is relatively small, it can become chronic and difficult to heal. In this case, a 46-year-old male had an insertional Achilles tendon repair on April 9, 2013. The patient started physical therapy and at eight weeks post-op presented with a new wound, drainage and pain. The patient’s pertinent medical history was pretty benign with only hypertension noted.
The patient had weekly debridement and subsequent use of Silvercel (Systagenix), VAC therapy (KCI) and Prisma dressing from June 5 to June 20.
On June 20, the patient had application of lyophilized particulate placental tissue followed by weekly evaluation. Prior to application, the wound had sharp debridement to good, healthy granulation tissue. We placed the lyophilized placental tissue within the wound bed and applied a dressing consisting of Adaptic 4x4, Kling and a layered compressive dressing. We applied new dressings weekly. No further debridements were necessary. The patient’s wound went on to heal completely in four weeks with no further application of additional amnion or debridement.
Case study 4. A 58-year-old male presented with a history of post-traumatic arthritis to the right ankle. He had a significant history of gout and arthritis. The patient’s past surgical history is significant for six ankle surgeries, including a most recent total right ankle replacement on May 1, 2013. The patient developed a wound on the medial aspect of the right ankle and got a referral to the senior author on May 21. His attempted treatments were Silvercel, Prisma and compression dressings.
On June 20, the patient received an application of lyophilized particulate placental tissue with weekly evaluation. Prior to applying this modality, we performed sharp debridement to good, healthy granulation tissue. We placed the lyophilized placental tissue within the wound bed and applied a dressing consisting of Adaptic 4x4, Kling and a layered compressive dressing. We applied new dressings weekly. No further debridement was necessary. His wound went on to heal completely in 16 days with no further application of amnion graft or debridement to this site.
In regard to the application of amnion graft, we noted that minimal disturbance of the wound provided a more optimal outcome. In addition, it was imperative to control the amount of edema with each of these patients for the wounds to heal.
Dr. Swan is in private practice at the Orthopedic Foot and Ankle Center in Westerville, Ohio.
Dr. Hyer is a Fellow of the American College of Foot and Ankle Surgeons, and serves on its Board of Directors. He is the Fellowship Director and an attending physician at the Orthopedic Foot and Ankle Center in Westerville, Ohio.
1. Sheehan P, Jones P. A percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete wound healing in a 120-week prospective trial. Diabetes Care. 2003;26(6):1879-1882.
2. 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): 215-228.
3. Tseng CG, Espana EM, Kawakita T, et al. How does amniotic membrane work? Ocul Surf. 2004;2(3):177-187.
4. Tan EK, Cooke M, et al. Wet vs. dry amniotic membrane tissue grafts: a comparison of cryopreserved and dehydrated tissue processing methods in preserving bioactivity. Tissue Tech Inc. Miami, Fla.
5. Liu J, Sheha H, Fu Y, et al. Update on amniotic membrane transplantation. Expert Rev Ophthalmol. 2010; 5(5):645-661.