The Use of Micronized Dehydrated Human Amnion/Chorion Membrane Allograft for the Treatment of Diabetic Foot Ulcers: A Case Series

Diabetic foot ulcers (DFUs) are a common problem in patients with diabetes and are associated with significant morbidity and mortality. Dehydrated human amnion/chorion membrane (dHACM) allografts have been shown to be effective in the treatment of DFUs. A micronization process produces a dHACM powder that can be sprinkled onto irregular wound surfaces or reconstituted with normal saline for injection into tunneling wounds or wound margins.The author presents a case review of 3 patients with chronic plantar surface DFUs treated with micronized dHACM over a 1-month period. Wound duration was at least 8 months, and 2 out of 3 wounds had failed to heal with cryopreserved human fibroblast-derived dermal substitute before treatment with dHACM. Micronized dHACM (40 mg) in powder form was sprinkled onto the plantar ulcers weekly after sharp debridement, followed by standard topical dressings. Weekly dressing change and wound assessment was conducted to determine the rate of closure. Off-loading shoes were provided. Within 4 weeks of the first dHACM application, all 3 wounds had healed: the first after 2 applications, the second after 3 applications, and the last after 4 applications. No adverse events were observed, and the wounds remained healed after 6 months. In the author’s practice, the micronized dHACM allograft was easily applied, clinically effective, and well tolerated as a treatment for plantar ulcers in patients with diabetes.

Diabetes affects 29.1 million people or 9.3% of the population in the United States.¹ Diabetic foot ulcers (DFUs) are a common problem in patients with diabetes and are associated with significant morbidity and mortality. The lifetime risk of developing a DFU has been reported to be as high as 25% among people diagnosed with diabetes.² Routine ulcer care, treatment of infections, amputations, and hospitalizations cost billions of dollars every year and place a tremendous burden on the health care system.³

There is an ongoing and urgent need for proper management of diabetes, including education and surveillance of good foot care and effective and timely treatment of foot ulcers in patients with diabetes. Each year in the United States, more than 80,000 amputations are performed on persons with diabetes, and approximately 50% of the people with amputations will develop ulcerations and infections in the contralateral limb within 18 months.⁴ While conservative treatment may heal some diabetic ulcers, they are frequently recalcitrant to treatment and slow to heal, often taking up to several months to heal.⁵ Especially difficult to treat are those irregular and tunneling wounds. Tunneling and irregularly contoured wounds may increase the risk for infections destroying soft tissues and leading to osteomyelitis.

The use of human amniotic membrane as a wound care treatment has been described in the literature since the early 1900s.⁶ Advances in the processing and preservation of the membrane have led to more widespread use in the clinical setting.⁷ PURION Processed dehydrated human amnion/chorion membrane (dHACM) allografts (EpiFix, MiMedx Group Inc, Marietta, GA) contain an array of growth factors known to play a critical role in the physiological processes of normal healing and tissue regeneration.^8,9 The dHACM allografts in sheet form are available in a variety of sizes and configurations. These allograft sheets are easily applied to most wounds. Prospective, randomized studies comparing dHACM allografts to standard care, and dHACM to a tissue-engineered skin substitute, have demonstrated the efficacy of dHACM as a treatment for chronic DFUs.^10,11 In these efficacy studies, the dHACM allograft used was in sheet form. A micronization process produces a dHACM powder that can be sprinkled onto irregular wound surfaces or reconstituted with normal saline for injection into tunneling wounds or wound margins. There is limited information on the use of the micronized dHACM available to clinicians. The author’s purpose is to evaluate the handling characteristics of micronized dHACM allograft and treatment outcomes of 3 patients with diabetic plantar ulcers.

The author performed a case review of patients (n = 3) with chronic plantar surface DFUs treated in his clinic with micronized dHACM over a 1-month period. Prior to treatment with dHACM, standard of care included regular sharp debridements, off-weight bearing, silver dressings, antibacterial creams and ointments, xenografts, and cryopreserved human fibroblast-derived dermal substitute (HFDDS). In each of the 3 cases, micronized dHACM (40 mg) was applied weekly to the DFU after sharp debridement, followed by standard topical dressings. The micronized powder graft was sprinkled uniformly across the wound with the use of a small spatula. A nonadherent, noncaustic inner dressing such as Adaptic (Systagenix, San Antonio, TX) was then applied over the graft as well as a standard dry dressing as the outer layer. 

All patients were advised not to remove the dressing and to keep the dressing dry until their next office visit. The patients were dispensed home with a shower bag to prevent the wound from getting wet. As each patient rejected the use of total contact casting or a removable cast walker, a postoperative shoe for offloading (DH Offloading Post-Op Shoe, Ossur, Reykjavik, Iceland) was prescribed. Home health was contacted to follow-up with the patients, reinforce information provided, and record the patients’ compliance at home. Care was coordinated with each patient’s primary care physician and other health care providers as deemed necessary. All of the patients provided written consent for treatment, use of their de-identified health information and photographs used for this case series. The dHACM used for this product evaluation was provided free of charge by MiMedx.

Two female and 1 male patient, 35 years to 61 years of age with multiple comorbidities, participated in this study. At initiation of dHACM, wound duration was at least 8 months and 2 out of 3 wounds had received prior treatment with cryopreserved HFDDS. None of the wounds showed signs of infection at initiation of dHACM. No adverse events occurred in any of the patients treated. Individual cases are described and illustrated below.

Case 1. A 35-year-old male presented with a plantar ulcer on his left foot of 8-months duration. He had a history of uncontrolled type 2 diabetes for 17 years, hyperlipidemia, hypertension, associated peripheral neuropathy, atherosclerosis with peripheral arterial disease and venous insufficiency, and a stroke. The patient also had a history of alcohol and tobacco use. His body-mass index (BMI) was 34.1, ankle-brachial index (ABI) was 0.64, and A1c was 9.3%. Prior to dHACM therapy, the patient was treated with cryopreserved HFDDS. The ulcer reopened within 3 weeks of closure with the HFDDS graft. Wound size at first dHACM was 3.2 cm x 2.0 cm x 0.3 cm (Figure 1). Dressings and off-loading were conducted as described above. After 1 week, the ulcer reduced in size by 86%. The ulcer healed in 2 weeks with 2 applications of dHACM (Figure 2). The wound remained healed at 6-month follow-up.

Case 2. A 41-year-old female presented with a plantar ulcer on her right foot of 1-year duration. Patient history included uncontrolled type 2 diabetes, associated peripheral neuropathy, atherosclerosis with peripheral arterial disease and venous insufficiency, and high blood pressure. She also had a history of tobacco use and a previous revascularization with stents. At presentation, her BMI was 33.6 with an ABI of 0.71 and an A1c of 8.8%. The patient had a total of 6 cryopreserved HFDDS grafts with no signs of closure. Initial wound size was 1.5 cm x 1.5 cm (Figure 3). After 1 week the wound had reduced by 33%, and the ulcer healed with 4 applications of dHACM in 4 weeks (Figure 4). At 6-month follow-up, the patient had no reulceration of the wound site after treatment with dHACM. 

Case 3. A 61-year-old female presented with a plantar ulcer of 8-months duration on the first toe of her right foot. The patient had a history of uncontrolled type 2 diabetes, associated peripheral neuropathy, atherosclerosis with peripheral arterial disease and venous insufficiency, and an amputation of a toe on the same foot in 2012. Her BMI was 33.9 with an ABI of 0.61 and an A1c of 9.6%. Previous treatments included serial debridements, topical antibacterial ointments, and various silver dressings as well as various off-weight-bearing modalities. Wound size at first dHACM application was 1.0 cm x 0.5 cm x 0.2 cm (Figure 5). After 1 week, the wound had reduced by 67%. The patient was seen weekly, and the ulcer healed in 3 weeks with 3 applications of dHACM (Figure 6). A 6-month follow-up after healing with dHACM showed no reulceration to the site. 

The purpose of this report was to evaluate the use of micronized dHACM allograft applied weekly as a treatment for diabetic plantar ulcers in a case series of 3 patients in a clinical setting. To the author’s knowledge, this is the first paper showing results of patients treated solely with micronized dHACM in lieu of the dHACM in sheet form. Although the wounds were chronic and had failed multiple other treatments, all healed within 4 weeks of first micronized dHACM application. These results are similar to those reported in a randomized trial which reported an average time of 2.4 weeks until complete healing and 90% of DFUs with complete healing by 4 weeks with weekly dHACM allograft sheets.¹⁰ The author chose to use the micronized dHACM versus the sheet allograft believing this would better conform to the irregular wound outline and allow for the maximum amount of the allograft material to be applied to the wound versus trimming the sheet allograft to fit. The researcher chose to apply the material weekly based on results from a prospective, randomized, comparative study of 40 patients with DFUs of ≥ 4 weeks duration that did not heal with standard treatment.¹⁰ The patients in that study were randomized to receive either weekly (n = 20) or biweekly (n = 20) application of dHACM following surgical debridement. During the 12-week study period, 92.5% (37/40) of dHACM-treated ulcers completely healed. Number of grafts to healing were similar in both groups (P = 0.841), but mean time to heal was only 2.4 weeks ± 1.8 weeks in the weekly group compared to 4.1 weeks ± 2.9 weeks in the biweekly group (P = 0.039). Complete healing occurred in 90% of patients by 4 weeks in the weekly group and 50% of wounds in the biweekly group. 

The ability to inject or fill tunneled and irregular wounds with an advanced wound care product may reduce the need for more extensive surgical intervention. Products that can be applied in this manner are desirable to clinicians. Brigido et al¹² sought to evaluate the healing rates at 12 weeks of patients with deep tunneling wounds in a series of 12 patients treated with a flowable soft tissue scaffold (Graftjacket Xpress FSTS, KCI Inc, San Antonio, TX) and found a 50% wound reduction for all patients after 2 weeks, with 83% of patients having complete wound healing within 12 weeks. In the current evaluation of micronized dHACM, patients exhibited an average of 67% wound reduction in 1 week and all healed within 4 weeks.

Other studies have shown that dHACM is both clinically and cost-effective in the treatment of DFUs.^11,13 In a prospective, randomized, single-center clinical trial, Zelen et al¹¹ compared wound reduction and rates of complete healing in patients with diabetic foot ulcers treated with dHACM versus standard of care. Patients were randomized to receive standard of care alone or standard of care with the addition of dHACM. Healing characteristics were evaluated after 4 and 6 weeks. Significant differences were observed in wound reduction at 4 weeks, with wounds reducing in size by a mean of 32.0% ± 47.3% in the standard of care group (n = 12) versus 97.1% ± 7.0% (P < 0.001) for the patients receiving dHACM (n = 13). At 6 weeks, the difference between the groups was even greater. In the standard of care group, mean wound size had increased 1.8% ± 70.3% versus a mean wound size reduction of 98.4% ± 5.8% in the dHACM group, P < 0.001. After 4 and 6 weeks of treatment, the overall healing rates with dHACM were 77% and 92%, respectively, compared to 0% and 8.0%, respectively, with standard of care (P < 0.001). 

The use of advanced therapies should be considered if wound size has not been reduced after 4 weeks of standard wound care. While the body of evidence is a growing concern for the clinical and cost effectiveness of dHACM allograft in clinical trials, it is important to see how the material performs in its various configurations and outside of the tightly controlled study environment where treatment, follow-up, and strict levels of off-loading are enforced. The author found dHACM to be effective in patients with poor diabetes control and in cases where other advanced modalities had failed. This is not a total surprise in that a recent prospective, randomized, multi-center clinical trial was conducted by Zelen et al¹³ at 3 sites to compare the healing effectiveness of chronic lower extremity diabetic ulcers treated with weekly applications of either bioengineered skin substitutes (BSS) (Apligraf, Organogenesis Inc, Canton, MA), dHACM (EpiFix, MiMedx Group Inc, Marietta, GA), or standard wound care with collagen-alginate dressing. A total of 60 patients were randomized with 20 in each group. After 4 weeks of treatment with either dHACM or BSS, 85% of wounds treated with dHACM achieved complete healing compared to only 35% of patients receiving BSS. After 6 weeks, 95% of wounds treated with dHACM were healed compared to 45% of BSS treated wounds. Median time to healing was significantly faster with dHACM (13 days) compared to BSS (49 days). There was an 81.9% lower cost for graft material in the dHACM group. 

In summary, in this small case series of 3 patients, micronized dHACM was simple to use and allowed for coverage of larger surface area wounds as well as application into deep tunneling wounds. Patients tolerated the grafts well with no adverse events noted throughout the treatment. Using micronized dHACM in a real world clinical setting, the author obtained similar healing results compared to the randomized controlled trial performed by Zelen et al¹¹ using the dHACM sheet configuration. Although there are obvious limitations regarding conclusions drawn from a small case series, these early results provide the clinician with information relative to the various forms of dHACM which may be appropriate for varying wound characteristics and suggest that micronized dHACM yields similar treatment outcomes to those previously reported. Future studies in larger numbers of patients will better elucidate the generalizability of these results. 

In this evaluation of 3 patients, the author found micronized dHACM allografts to be easily applied, clinically effective, and well tolerated as a treatment for plantar ulcers in patients with diabetes.

From Stockdale Podiatry Group, Bakersfield, CA

Address correspondence to:
Brandon Hawkins, DPM, CWS, FACCWS
Stockdale Podiatry Group
3857 Stockdale Highway
Bakersfield, CA  93309
bjhawkdpm@icloud.com

Disclosure: MiMedx Group Inc. (Marietta, GA) supplied the allograft product used in this case series free of charge. The author has no financial or other conflicts of interest to disclose.