Evaluation of Epidermal Skin Grafts for the Treatment of Complex Wounds in a Wound Care Center: A 94-Patient Case Series

Background. In recent years, a new technology for autologous epidermal harvesting has been developed to produce epidermal skin grafts (ESGs) for use over wounds. This technology employs negative pressure and heat to raise the epidermal skin layer, allowing for consistent and reproducible epidermal harvesting. The aim of this case series is to present the authors’ experience using an automated, epidermal harvesting system to produce ESGs to treat wounds of patients with multiple comorbidities. Materials and Methods. This case series was conducted between January 1, 2013 and December 31, 2014. Patients with wounds (≤ 25 cm²) that failed to heal were treated with ESGs by a group of 3 wound care physicians in 2 outpatient wound care centers in a community health center setting. Results. A total of 94 patients with 102 wounds were identified. Of the 94 patients, 3 were noncompliant and 9 were lost to follow-up. Therefore, 82 patients with 90 wounds were included in the analysis. The majority of wounds demonstrated epithelialization (83/90, 92.2%). Of the 90 wounds, 75 (83.3%) healed following epidermal grafting, 4 (4.4%) wounds displayed improvement, and 11 (12.2%) did not heal. Minimal or no pain at the donor site was reported by the patients, and all donor sites healed without complications. Conclusion. This case series provides additional evidence for the use of ESGs for the treatment of wounds that fail to heal.

Patients with nonhealing wounds are a significant concern to the global health care community. In the United States alone, more than 7 million people annually will experience chronic skin ulcers caused by pressure, venous stasis, or diabetes mellitus.¹ This may be due to the expanding disabled and geriatric population who are more susceptible to chronic wounds as well as related skin ulcer complications. 

Wound care centers across the country typically serve patients with chronic wounds in a multidisciplinary setting where physicians and surgeons are available to provide specialty services such as dermatology, infectious disease, plastic surgery, and orthopedics. In other areas, the local community hospital serves as the only option for wound care treatment, especially in underresourced or rural settings. Patients from rural communities are likely to be uninsured and have lower incomes, and they are, on average, older and less healthy than patients from metropolitan areas.² Patients often have to travel long distances to seek care and at times lack reliable transportation. These factors contribute to their tendency to delay seeking care, which can exacerbate health problems and may lead to more expensive interventions upon receiving care.³ Noninvasive and low-cost wound management options to treat chronic wounds are ideally suited for patients with limited access to hospital resources.

Skin grafts can be utilized for closure when chronic wounds do not respond to traditional wound care treatments such as topical agents and/or wound dressings. Traditional harvesting for split-thickness skin grafts (STSGs) involves taking autologous skin from a donor site and creating a second wound. The procedure often requires a doctor with surgical training, use of an operating room, and anesthesia. Wound healing outcomes vary depending upon the thickness of the skin graft and the characteristics of the recipient site. In addition, donor site adverse events are fairly common with STSGs and include donor site pain, scar formation, infection, hypopigmentation, hyperpigmentation and, on occasion, delayed healing.^4,5 In contrast, harvesting epidermal skin grafts (ESGs) removes only the epidermis and does not affect pain fibers in the dermis. As a result, the procedure is relatively painless and can be performed in the outpatient setting, requiring no anesthesia.^6,7 There is minimal scarring to the donor site and no risk of graft rejection.⁸ 

In recent years, a new commercially available device for harvesting autologous ESGs has been developed.^8,9 This technology employs negative pressure and heat to raise microdomes on the epidermal skin layer, allowing for consistent and reproducible epidermal harvesting. The aim of this case series is to present the authors’ experience using an automated, epidermal harvesting system for patients with multiple comorbidities. 

Patient data
This case series was conducted between January 1, 2013, and December 31, 2014. Patients with wounds (≤ 25 cm²) that failed to heal after conservative treatment were treated with ESGs by a group of 3 wound care physicians from 2 outpatient wound care centers in a community health center setting. Institutional guidelines for the collection of existing de-identified patient data were followed. Informed consent was obtained from all patients for the epidermal harvesting and grafting procedures, including the possible use of photos without identifying marks or facial features.

Epidermal harvesting
Healthy skin donor sites were selected and cleansed with 70% isopropyl alcohol. The harvester from the epidermal harvesting system (CELLUTOME Epidermal Harvesting System, KCI, An Acelity Company, San Antonio, TX) was attached to the donor site, and negative pressure (-400 mm Hg to -500 mm Hg) and warmth (37°C to 41°C) were applied to induce epidermal microdome formation (30-45 minutes). Microdomes were transferred onto 1 of 3 dressings (Tegaderm, 3M, St. Paul, MN; ADAPTIC TOUCH, Systagenix, an Acelity company, Gargrave, UK; and Mepilex, Mölnlycke Health Care, Gothenburg, Sweden) and applied over the wound. The graft site was bolstered with a calcium alginate dressing and covered with a nonadhering silicone dressing (ADAPTIC TOUCH, Systagenix), followed by a self-adhesive foam dressing (Mepilex, Mölnlycke Health Care). The donor site was covered with self-adhesive silicone foam dressing (AQUACEL Foam Dressing, ConvaTec, Deeside, UK). Wounds were considered healed when complete closure with full reepithelialization was observed by the physician. Patient noncompliance was defined as refusal to follow physician orders or the wound management plan. 

Statistical analyses
Continuous variables were presented as mean ± standard deviation. Categorical variables were presented as the number of patients or number of wounds and the corresponding proportion with respect to the group under study. Data management and analyses were performed using SAS 9.4 software (SAS Institute Inc., Cary, NC).

A total of 94 patients with 102 wounds were included. The patients included 46 females and 48 males with an average age of 56.1 years (standard deviation 20.5 years) (Table 1). The most common comorbidities in this patient group were hypertension (55/94, 58.5%), obesity (45/94, 47.8%), and peripheral vascular disease (44/94, 46.8%) (Table 1).

Wound descriptions are presented in Table 2. Of the 102 wounds that were treated, 77 (75.5%) were nontraumatic in primary origin. Traumatic wounds (25, 24.5%) included gunshot wound, dog bite (upper and lower extremities), right ankle (shrapnel), glass in toe (surgical removal), right leg trauma, third-degree burn, lower leg (due to fall), burn on back, left heel (torn on metal), and blood blister to hernia site (due to fall). The most common types of wounds presented by this patient group included diabetic foot ulcers (31/102, 30.4%) and surgical wounds (29/102, 28.4%). Wound locations were predominantly on the lower leg, foot, and ankle. All wounds had been debrided previously and prior treatments included adjunctive therapies, compression therapies, biological skin substitutes, and topical antimicrobials (Table 3). The majority of donor sites were located on either the arm (44/102, 43.1%) or the thigh (49/102, 48%) (Table 4). Of the 102 wounds, 72 (70.6%) received a single graft application. The remaining wounds received 2 or more graft applications (Table 4).

Of the 94 patients, 3 were noncompliant and 9 were lost to follow-up. Therefore, 82 patients with 90 wounds were included in the analysis (Table 5). The majority of wounds demonstrated epithelialization (83/90, 92.2%). Mean time to first observation of epithelialization was 5.6 ± 6.5 weeks (range 0.7-35.3 weeks) (Table 5). Of the 90 wounds, 75 (83.3%) healed following epidermal grafting, 4 (4.4%) wounds displayed improvement, and 11 (12.2%) wounds did not heal (Table 5). For those wounds that healed, the time to wound healing was 16.9 ± 17.5 weeks (range 1–74.7 weeks) (Table 5). Of the 90 wounds, 48 (53.3%) developed complications following ESG: infection (25/90, 27.8%), hypergranulation (23/90, 25.6%), reopened (7/90, 7.8%), and other (6/90, 6.7%). Of the 48 wounds with complications, 38 (79.2%) healed, 1 (2.1%) showed improvement, and 9 (18.8%) did not heal. The patients reported minimal or no pain at the donor site, and all donor sites healed without complications. 

Three cases are detailed further and included to illustrate the use of ESGs for wound closure.

Case study 1
A 68-year-old female presented with a failed mastectomy for breast cancer with significant wound breakdown (Figure 1A). Standard treatment involved antibiotics, weekly debridement, negative pressure wound therapy, and hyperbaric oxygen therapy. The patient received concurrent chemotherapy treatment, which likely created a significant barrier to wound healing. Epidermal skin grafts were applied after 25 weeks of standard treatment (Figure 1B). The wound was fully closed 1 week post-ESG (Figure 1C). 

Case study 2
A 67-year-old male patient with a history of hypothyroidism presented with a nonhealing, surgical abdominal wound resulting from an emergent surgical repair of an abdominal hernia (Figure 2A). Standard treatment involved weekly debridement, topical ointment, and 2 applications of ESGs. Following 13 weeks of standard treatment, a third ESG was applied to the wound (Figure 2B). The wound was fully closed 4 weeks post-ESG (Figure 2C). 

Case study 3
A 59-year-old female presented with a venous leg ulcer complicated by scleroderma (Figure 3A). Standard treatment involved living, bilayer skin substitute application (Apligraf, Organogenesis Inc, Canton, MA) and 2 applications of epidermal skin grafts (ESGs). Following 10 weeks of standard treatment, a third ESG was applied to the wound (Figure 3B). The wound was fully closed 4 weeks post-ESG (Figure 3C). 

The authors evaluated the use of an automated epidermal harvesting system to harvest ESGs for use over complex, nonhealing wounds. To date, this is the largest case series examining the use of ESGs harvested with the automated harvesting system. The results of this study showed that the majority of chronic wounds displayed epithelialization (92.2%) and healed (83.3%) following epidermal grafting. Similar rates of wound healing, as seen in this cohort, have been reported in previous studies examining the use of epidermal grafting in chronic wounds. 

In a small case series presented by Gabriel et al,⁹ complete reepithelialization occurred in 3 of the 4 wounds that received an epidermal graft, and 50% wound size reduction occurred in a chronic diabetic foot ulcer of 8-year duration. Serena and colleagues¹⁰ presented a case series of 7 patients with lower extremity wounds. Six of the 7 patients were treated with epidermal grafts improved or achieved complete closure in 4 weeks. One patient had a 2-year-old thigh wound that did not improve as the graft could not be adequately secured. Richmond et al¹¹ presented a cohort of 5 patients with pyoderma gangrenosum, characterized by chronic, recurrent ulcers of the skin. Following epidermal grafting, 4 of the 5 wounds completely healed or reduced in size by 8 weeks, while 1 patient achieved complete healing within 12 weeks.¹¹ In 2 of the case studies presented here, serial ESG applications were required, which suggests that the initial graft may serve to stimulate wound bed preparation while the final graft serves to reepithelialize the wound.¹² In all mentioned studies, including this study’s cohort, minimal or no pain at the donor site was reported by patients during the harvesting procedure, eliminating the need for anesthetics. All donor sites healed without complications.^9-13 These results are supported by a healthy human study conducted by Osborne et al¹³ in which patients reported a mean pain score that did not exceed 1.3 on the Wong-Baker FACES Pain Rating Scale¹⁴ (scale of 1-5) throughout the epidermal harvesting process.

A multidisciplinary expert panel led by Kirsner¹² reviewed the scientific evidence and clinical utility of ESGs and provided guidance on the use of ESGs to achieve primary wound closure. In order to provide the best clinical outcome, all wounds should be thoroughly evaluated for blood flow, infection, edema, presence of nonviable tissue, and quality of the microenvironment prior to placement of ESGs.¹² Harvested microdomes from donor sites can be transferred onto perforated film dressings or nonadherent silicone dressings to manage wound exudates and help keep the graft from shifting on the wound bed. Secondary dressings are strongly recommended over the wound after application of ESGs. After the ESG has been applied, it should not be disturbed in any way for at least 1 week before dressing removal and initial compression/bolster dressing change. It may take up to 3 weeks after ESG application for visible graft take to occur. Unfortunately, the cohort in this study presented with multiple risk factors for delayed wound healing including hypertension, obesity, smoking, and peripheral vascular disease. Although several of the included patients also had a complication (ie, infection and hypergranulation), a majority of them went on to complete healing after the ESG application. These types of complications usually interfere with wound healing; however, only a small number of wounds did not heal or improve despite prior standard wound care treatments and epidermal grafting. 

Epithelialization is thought to occur through a process of keratinocyte reproduction and colonization and growth factor secretion that promotes cell migration such that the reepithelialization covers the entire wound area.^15-17 In epidermal graft-mediated wound closure, Richmond and colleagues¹¹ proposed that ESGs serve as a biological dressing and stimulate healing through the release of growth factors. In 2 studies, Osborne and coauthors^8,13 evaluated the cellular characteristics of ESGs from 15 healthy subjects. Harvested ESGs from 12 of the 15 patients were cultured, showing that the ESGs were capable of keratinocyte and melanocyte outgrowth, which proliferated and migrated between graft edges. Additionally, donor site specimens from 3 of 15 patients were earmarked for growth factor assays. The viable cells actively secreted growth factors that may help regulate the wound healing response cascade. The authors determined that because ESGs retained their original keratinocyte structure, this allowed for potential reepithelialization and repigmentation of the wound.⁸ 

Grafting with autologous tissues is effective for treating difficult-to-treat chronic wounds. However, the use of STSGs for such wounds is limited by various factors, including the need for anesthesia, STSG-trained surgeons, operating room availability, donor site adverse events, and patient comorbidities. At community wound care centers such as the authors’, many of these limitations, as well as the previously described challenges for patients from the rural setting, have been encountered. Fortunately, the epidermal harvesting system is minimally invasive and is designed for use in the office or outpatient setting. In the authors’ experience, use of this automated epidermal harvester does not require anesthesia at the donor site, and it makes ESGs less expensive to obtain than STSGs.¹² Therefore, the use of ESGs may represent a practical reconstructive option for patients with limited access to hospital resources.