Human Acellular Dermal Matrix Paired With Silver-zinc Coupled Electroceutical Dressing Results in Rapid Healing of Complicated Diabetic Wounds of Mixed Etiology: A Novel Case Series

Patients with diabetes are well known for having difficult-to-close wounds. When additional factors are added, such as gouty tophi or tumors, the difficulty is compounded and conventional care often fails to heal the wound. In this case series, an innovative wound modality that combined a human acellular dermal matrix with a silver-zinc coupled electroceutical wound dressing was used in 3 particularly difficult and complex cases. In all 3 cases, this alternative treatment provided full healing within 6 weeks in wounds that conventional care had been unable to close in up to 2 years.

Two common long-term complications of diabetes are neuropathy, which leads to poor sensation, and microvascular disease, which causes poor tissue perfusion, particularly in the extremities. These conditions can lead to the creation of the ulcers often observed on the lower extremities of patients with diabetes.¹ Caring for such ulcerations can be difficult and expensive. Additionally, these wounds are highly susceptible to infection which can extend both the duration and cost of treatment.  The consequences of failed conventional wound care can be serious and even include amputation of the limb.^2-4 These challenges make it necessary to explore alternative healing methods to improve conventional-care healing rates. Two innovative wound care modalities were paired in an attempt to increase healing potential in complicated diabetic neuropathic wounds of mixed etiology. The wound healing environment was improved by simultaneously using a matrix scaffold to promote new tissue creation and a microcurrent-generating dressing material to manage bioburden. The matrix scaffold utilized in this case was a human acellular dermal matrix (ADM) described in a review by Moore et al.⁵ Decellularized human skin has been used in a wide variety of medical procedures, including wound healing, sports medicine applications, and soft-tissue reconstruction.^6-9 The potent bactericidal activity of the silver-zinc coupled electroceutical wound dressing was shown effective against antibiotic-sensitive strains and multiple antibiotic-resistant strains of wound pathogens that commonly contribute to biofilm and infection formation in these types of wounds.¹⁰

All patients were brought into the operating room (OR) for the procedure. Patients were placed on the OR table in a supine position. Monitored anesthesia was used and a local block consisting of 10 mL 2% lidocaine plain and 0.5% Marcaine plain (Pfizer, New York, NY) in a 50/50 mix was infiltrated around the area of the wound bed. A pneumatic ankle tourniquet was set at 250 mm Hg to control intraoperative bleeding. The limb was then prepped with antiseptic skin cleanser and draped for sterility.

The area of the wound base was then debrided with a #15 blade to the level of the subcutaneous layer to remove all devitalized tissue. Bleeding was controlled with a topical hemostatic agent when necessary. Once the wound bed was free of contaminants and the bleeding was controlled, the DermACELL Advanced Decellularized Dermis graft (LifeNet Health, Virginia Beach, VA) was applied. One 2 cm x 2 cm fenestrated advanced decellularized dermis graft was used in each procedure. Care was taken to apply the graft with the reticular or white side against the wound bed and the papillary or dull side facing outward. Any graft overage was trimmed as needed with tenotomy scissors. The advanced decellularized dermis graft was then affixed in place utilizing skin staples. 

The advanced decellularized dermis graft was covered with a saline-moistened 5 cm x 5 cm electroceutical wound dressing (Procellera, Volmaris Wound Care, Inc, Tempe,  AZ). The dressing was secured with skin-prep, and quarter inch 3M steri-strips (Maplewood, MN) were used. A 7.6 cm x 7.6 cm piece of nonadherent dressing was then applied and fastened in place with skin-prep and steri-strips. A dry, bulky dressing consisting of 10 cm x 10 cm gauze, abdominal (ABD) pad, 7.6 cm rolled gauze, and 7.6 cm self-adherent wrap were then applied as the final wound bandage. The pneumatic ankle tourniquet was released and the digits were evaluated for return of perfusion. Patients were transferred to the postanesthesia care unit for a brief period of postoperative monitoring. Once stable, they were discharged to home. The patients were given strict orders to keep the postoperative bandage dry, clean, and intact for 1 week and return to the wound care center for follow-up.

At the first postoperative appointment, the bandages were removed and the wounds were evaluated, photographed, and measured. The dermis graft remained undisturbed during this process. A new saline-moistened electroceutical wound dressing was reapplied as previously described. Nonadherent dressing, steri-strips, 10 cm x 10 cm gauze, an ABD pad, rolled gauze, and self-adherent wrap were also reapplied. Patients were instructed to keep this bandage clean, dry, and intact until their next weekly wound care visit. This same process occurred on a weekly basis until the wounds were completely healed. 

This case series consisted of 3 patients ranging in age from 55 years to 90 years. These 3 patients presented with wounds that had histories of 4 months to 2 years of nonhealing despite various treatments and dressings. The patients had complex comorbidities including diabetes, war trauma, gout, and regressed melanoma. The combination of a single application of the advanced decellularized dermis graft and use of the electroceutical wound dressing completely healed all 3 wounds within 6 weeks. As the electroceutical dressing was used to accelerate healing and not to treat bioburden, quantitative cultures were not obtained since the wounds were clean. The cases are described below. 

Case 1. A 55-year-old, noninsulin-dependent male with diabetes originally presented to the wound care facility with a 5-month history of a nonhealing diabetic foot wound on the plantar lateral aspect of his fifth metatarsal. The patient’s podiatrist had treated him for this condition with standard wound care and diabetic shoes. A recent magnetic resonance image scan showed an abscess present in the subcutaneous space, at which time he was referred to the wound center for further evaluation and treatment. His past medical history was significant due to chronic active hepatitis C successfully treated with interferon, morbid obesity, noninsulin-dependent diabetes mellitus with neuropathy, hypertension, and osteoarthritis of the lower extremities. The patient was diagnosed with a Wagner Grade 3 diabetic ulcer plantar surface of the right fifth metatarsal. He subsequently underwent a series of weekly wound care visits, numerous excisional debridements, 3 courses of doxycycline, and multiple dressing materials including calcium alginates, enzymatic debriding agents, and various foam dressings. After 5 months of therapy at the wound care center with little improvement in the wound, the patient was transferred to this author’s service for a second opinion. Upon initial evaluation, the wound measured 2.6 cm x 1.7 cm x 0.2 cm (Figure 1A). The wound base was granular and free of clinical indications of infection. Recent radiographs were negative for osteomyelitis. Surgical intervention consisted of surgical debridement and the applications of the advanced decellularized dermis graft and the electroceutical wound dressing, based on the chronic recalcitrant nature of the wound coupled with the healthy character of the wound base. The patient was seen weekly for postop bandage changes and reapplication of the electroceutical dressing (Figure 1B). 

The simultaneous use of a single application of the graft combined with weekly applications of the wound dressing to optimize the wound healing environment resulted in rapid and complete healing of this chronic, recalcitrant, Wagner Grade 3 diabetic neuropathic wound in 6 weeks (Figure 1C).

Case 2. A 90-year-old male with noninsulin-dependent diabetes presented with a 4-month history of a draining wound on his left posterior lower leg. The patient had a remote history of trauma related to a wartime injury. Aside from diabetes and neuropathy, his past medical history was otherwise unremarkable. He related this area had recently become painful and began draining a milky white fluid. His primary care physician treated him using several rounds of oral Bactrim DS (AR Scientific, Philadelphia, PA) and 100 mg doxycycline with no improvement (each therapy was used for 1 week). Two days before his initial evaluation, the patient stated the area opened up and began draining heavily. He was initially evaluated at the wound center, and the wound measured 1.5 cm x 1.5 cm x 0.8 cm. The drainage appeared to be white and tophaceous in nature. A radiograph of the lower leg showed multiple large areas of calcification within the subcutaneous tissues adjacent to the wound (Figure 2A). Polarized light microscopy analysis of the wound aspirate confirmed the presence of birefringent crystals consistent with gout. The patient was subsequently taken to the OR where an aggressive incision and drainage of the wound was performed to remove all gouty tophi from the soft tissues. After aggressive surgical debridement and excision of all gouty crystals, the wound measured 3 cm x 1.8 cm x 1 cm (Figure 2B). He was placed on negative pressure wound therapy immediately postoperative. Two weeks after initial incision and drainage, the patient had combined treatment with the advanced decellularized dermis graft and weekly applications of the electroceutical wound dressing (Figure 2C). The advanced age of the patient in combination with the several months duration of the wound made it imperative to heal the area as fast as possible and restore function to the limb to ward off systemic complications such as infection, deep vein thrombosis, and pulmonary issues. 

This extremely complicated wound of mixed etiology was completely healed in 4 weeks after using a combined therapy consisting of a single application of the graft and weekly applications of the dressing (Figure 2D). 

Case 3. A 63-year-old female with noninsulin-dependent diabetes presented to the wound center with a 2-year history of a nonhealing wound on her right ankle. The patient, who was referred by her primary care physician, stated this area had opened and healed numerous times over the past 2 years but had recently become larger. Her past medical history was positive for noninsulin-dependent diabetes mellitus with neuropathy, gastroesophageal reflux disease, and hypertension. Upon initial exam, the wound measured 1 cm x 0.8 cm (Figure 3A). The base was comprised of raised skin plaques and nodules with open areas of serosanguineous drainage present. A shave biopsy was performed due to the irregular appearance of the wound. The initial pathology report showed an “orthokeratotic hyperkeratosis with intracorneal melanin pigment having a high suspicion of melanocytic neoplasm.” Subsequently, the patient was taken to the OR for a wide excision and frozen section of the wound area. Pathology results were consistent with a nodular basal melanosis. This type of benign lesion is considered a rare manifestation of a completely regressed melanoma. The histopathological features included confluent dermal nodular aggregates of heavily melanized polygonal cells consistent with melanophages. After pathology results were confirmed, the advanced decellularized dermis graft and the electroceutical wound dressing was applied to the area of excision to augment healing and prevent further complications or adverse reactions (Figure 3B). 

A single application of the graft and weekly applications of the dressing maximized healing for this patient with a rare skin tumor, resulting in complete closure of this wound in 3 weeks (Figure 3C).

The purpose of this investigation was to explore the healing potential of combining 2 alternative treatments for chronic wounds that conventional treatments have failed to close. Wounds presented here had proved extremely difficult to treat with duration histories ranging from 4 months to 2 years. The patients also presented with complex comorbidities that likely contributed to preventing the closure of the wounds through conventional means. These complicating conditions included an abscess adjacent to the target wound, trauma from an old wartime injury, gouty tophi, and a rare manifestation of a completely regressed melanoma. In marked contrast to the failure of conventional treatment, the combination of the advanced decellularized dermis graft and the electroceutical wound dressing completely healed all wounds in 3 to 6 weeks.

An advanced decullarized dermis graft is an acellular dermis that provides a scaffold to allow host recellularization, revascularization, and cellular infiltration.¹¹ The unique decellularization process allows this ADM to be stored fully hydrated at ambient temperature and sterile with a sterility assurance level (SAL) of 1 x 10⁶ while still retaining biomechanical and biocompatible properties.⁵ The graft has been used successfully in wound healing for both burn repair¹² and breast reconstruction following mastectomy.^13,14 The use of the graft for wound repair of chronic diabetic foot ulcers (DFUs) has also been explored with favorable preliminary results.^15,16 The success of an advanced decellularized dermis graft in treating a variety of wound types prompted the investigation of its use on the complex and treatment-resistant wounds presented here.

The dressing is a silver-zinc coupled electroceutical wound dressing. The dressing contains silver and zinc elements that generate an electric field similar to the microcurrent found in skin injuries.¹⁷ This dressing is also able to inhibit biofilm formation by generating superoxides, and it can overcome bacterial antibiotic resistance by disrupting quorum sensing.¹⁸ Preliminary clinical studies^19,20 have shown a significant increase in healing speed over standard wound care for a variety of acute and chronic wound types (34.6%, P = 0.015; 45.4%, P = 0.036, respectively). Infection is a constant concern when treating chronic wounds, and the ability of the electroceutical wound dressing to disrupt biofilm formation provides a strong tool for protecting open, treatment-resistant wounds.

The cases presented here display a variety of extremely complex wounds. Diabetic foot ulcers are notoriously difficult to close and a successful healing method will integrate both revascularization and removal of pathogens.²¹ An aid to assist in revascularization, such as an ADM, may be useful as there are more than 100 physiological factors that can cause healing deficiencies in patients with diabetes.²² Diabetic foot ulcers create an environment receptive to chronic infections caused by biofilms, a symbiotic and synergistic colony of multiple species of bacteria that traditional antibiotics may be ineffective against.^23,24 A treatment that can successfully target biofilms, such as an electroceutical dressing, may allow the wound to heal without the interference of chronic infection. To date, to the best of the author’s knowledge, no studies in the literature have been found to combine ADMs with electroceutical dressings to treat DFUs. While this paper only focused on these 3 patients with unusual wounds, it is the author’s experience that these 2 products used in combination result in a greater decrease in healing time than in instances of individual use. The decrease in healing times reduces the overall cost of wound care despite the initial higher cost compared to standard of care. As an example, the patient in Case 1 received more than 1 year of standard of care treatment without healing but was able to finally heal in just 6 weeks using the application of the combined therapy presented here.

There is also a paucity of research concerning gout and delayed wound healing, although a recently published case series²⁵ indicated there may be evidence of delays in ulcers with gouty tophi. The patient in Case 2 suspected the hard areas he felt in his leg were retained shrapnel, although it’s now known it was actually gout deposits. Unusual presentations of gouty tophi formation may be connected to local tissue changes related to previous tissue trauma or necrosis.^26,27 The patient’s previous injury probably predisposed him to have gout in this area. 

Completely regressed melanoma tumors are extremely rare with only 34 known cases as of 2005.²⁸ It seems likely there is some mechanism at work in the regressed tumor that prevented earlier healing of the wound. Tumors are able to grow and progress through a process called angiogenesis or blood vessel growth, which is partly driven by the structural protein perlecan.^29,30 In metastatic melanoma tumors, elevated perlecan messenger RNA levels may be correlated to the degree of the invasiveness of the cancer cells.³¹ It is possible that a regressed melanoma tumor contains abnormally high amounts of perlecan, though lower levels than a metastatic tumor, which prevents the healing of the wound through ongoing angiogenesis; but more research would be needed in this area. Regardless of what mechanism caused the tumor to be treatment resistant, the advanced decellularized dermis graft and the electroceutical wound dressing were able to rapidly close this 2-year-old wound in just 3 weeks. 

Given the obscure and complicated nature of the cases presented herein and the rapid healing achieved, it is reasonable to suggest similar healing outcomes may occur with the use of these products in more commonly presenting wound types. The successful outcomes presented here support the need for further studies with larger patient samples. 

Affiliation: Akron General Medical Center, Akron, OH

Correspondence:
Windy Cole, DPM
1533 South Water Street
Kent, OH  44240
drwec@yahoo.com 

Disclosure: Dr. Cole is a consultant for LifeNet Health (Virginia Beach, VA) and Arthrex (North Naples, FL) but has received no compensation for this study.