Epidermal skin grafting

Abstract

Autologous skin grafts, such as full‐ and split‐thickness, have long been part of the reconstructive ladder as an option to close skin defects. Although they are effective in providing coverage, they require the need for a trained surgeon, use of anaesthesia and operating room and creation of a wound at the donor site. These drawbacks can be overcome with the use of epidermal skin grafts (ESGs), which can be harvested without the use of anaesthesia in an office setting and with minimal to no scarring at the donor site. ESGs consist only of the epidermal layer and have emerged as an appealing alternative to other autologous grafts for the treatment of acute and chronic wounds. In this article, we provide an overview of epidermal grafting and its role in wound management.

Introduction

Achieving complete wound healing in the shortest time period with the least morbidity is the goal that wound care clinicians strive for in the care of patients who have the potential for healing. Use of autologous tissue has been theorised and used to reach this goal. One procedure using autologous tissue, known as epidermal grafting, has significantly less morbidity associated with it than other treatment options. In this article, we will provide an overview of epidermal grafting and its role in wound management.

Types of skin grafts

Skin grafting has been part of the therapy for acute and chronic wounds for millennia. As part of the rationale on the reconstructive ladder to close skin defects 1, autologous grafts work both as tissue replacement as well as providing a pharmacological stimulus for healing 2. For chronic wounds, the intent of these therapies is to achieve closure of the wound with functional recovery of the skin, while in acute wounds, additional improvement in the aesthetic outcome can be expected when full‐thickness skin grafts (FTSGs) are used in the treated area. Classification of autologous skin grafts is based on the depth of the skin harvested 3. From a practical standpoint, several types of skin grafts have been used for wound closure. When the entire epidermis and dermis are harvested (with associated adnexal structures), the graft is an FTSG, which helps prevent skin contracture and thus can improve the cosmesis of the treated area. Alternatively, grafts that contain the entire epidermis but only part of the dermis (and associated adnexal structures) are called partial‐thickness or split‐thickness skin grafts (STSGs). These provide and promote wound coverage and closure while promoting return of proper skin function. However, they do not prevent wound contracture because of their relative thinness. A study by Yi and Kim showed that the simultaneous application of acellular dermal matrix and autologous STSG produced better outcomes than autologous STSG alone in terms of scar appearance in traumatic full‐thickness skin defects of the extremities 4.

Factors that must be considered when choosing the type of graft to use include: (i) reason for using the graft (i.e. restoring function or improved cosmesis), (ii) depth of the defect to be closed, (iii) donor site availability and (iv) ability of the recipient area to sustain the graft. For these reasons, FTSGs are preferred for acute full‐thickness wounds, where cosmesis is important, and the wound can nourish a thick graft. For chronic wounds, STSGs are preferred as restoring functional integrity of the skin is the primary concern, and the wound bed may not have the ability to support and maintain thicker grafts. Wound bed preparation may be implicated in variable rates of success of the grafting procedure. Even after initial ‘take’, graft failure may occur over time 5. This failure is likely related to the failure to control the underlying pathogenesis of disease (i.e. venous hypertension for venous ulcers) or because of failure to protect the graft site from trauma.

However, these grafts (FTSGs, STSGs) are associated with donor site morbidity. Attempts to limit donor site morbidity exist. As an example, a new experimental approach for harvesting FTSGs employs taking exceedingly small columns of full‐thickness skin using a custom‐made, single‐needle, fluid‐assisted harvesting device. A prototype device can harvest hundreds of full‐thickness columns of skin tissue (700 µm diameter) that can subsequently be applied directly to the wound. Donor sites heal with little scarring, but long‐term data are not yet available 6.

Another approach to limit donor site morbidity is the use of grafts composed solely of the epidermal layer of the skin, including epidermal cells (e.g. keratinocytes and melanocytes). These are called epidermal skin grafts (ESGs). Envisioned to restore epidermal coverage and stimulate healing. A significant advantage of this type of graft compared to STSGs and other forms of grafting is that ESGs are easily harvested without requiring donor site anaesthesia. The epidermis generally heals quickly without scarring, and overall, there is reduced morbidity to the donor area 7, 8. In addition to providing coverage and functional skin cells to the wound, ESGs stimulate wound closure likely through growth factors and cytokines from the cell populations in the graft 1, 2, 7, 8, 9. Limited donor site morbidity makes ESGs the best option in wounds when it is challenging to harvest other types of autologous grafts, as is the case in pyoderma gangrenosum 9, 10.

Practical issues in skin grafting

In general, all types of skin grafting can be performed in the office setting or in an operating room, depending on ability to provide anaesthesia and obtain haemostasis, availability of equipment and the extent of the planned procedure 1. Although many promising ready‐to‐use techniques have been developed, autologous ESGs harvested with some of the new tools on the market appear to be the most practical, with promising results.

When only the epidermis will suffice and the wound is relatively small, ESGs are a suitable alternative to traditionally harvested skin grafts. Important factors for re‐epithelialisation to occur through the successful take of the ESG are related to wound bed receptiveness, such as adequate granulation tissue and minimal bioburden 10, as recipient environment plays a role in determining the phenotypic state of cells in the newly placed graft. Harvesting techniques have been evolving over the past few years, and recently, a new option has been developed to further facilitate this process 7, 10. ESGs can be performed in the outpatient setting without the need to schedule an operating room procedure, and there is no need for anaesthesia, potentially making it cost and time effective 11. STSGs are traditionally harvested with an electrically or mechanically powered dermatome set to selectively harvest partial thickness skin. For these grafts, interstices are created in the graft through meshing or fenestration prior to application, which will allow for skin size expansion and extravasation of fluid or exudate through these spaces. Meshing may allow for a more effective interaction between the graft and the wound bed.

However, when the defect is small and only needs a small graft, a punch or pinch graft technique can be performed free‐hand. This method consists of the skin of the donor area being harvested using a scalpel or other type of blade or using a punch biopsy tool.

History of skin grafting

Skin grafting dates back to 1500 bc in India where mutilation practices took place as a form of punishment and necessitated the development of techniques for tissue reconstruction. In Europe, church dogma impeded the evolution of graft surgery as it was considered an interference with God's work 12. However, by 1500 and 1600 ad, Italians became leading authorities on grafting techniques. Gaspare Tagliacozzi of Bologna (1546–1599) published his book De Curtorum Chirurgia per Insitionem (Surgery of the Mutilated by Grafting) in 1597, although its influence was stunted because of religious beliefs of that time. It was not until 1794 that other publications on the subject of grafting appeared, related to the practices in India. Scientific experiments and writings from researchers around the world evolved into what are now considered modern grafting techniques.

Descriptions of epidermal grafting were first mentioned in the work of Jacques‐Louis Reverdin (1842–1929) of Switzerland. In 1869, he was the first person to use small, full‐thickness skin pieces as grafts for wound healing 13. He became known as the father of skin transplantation because of his descriptions and purported use of skin grafts from his own arm to treat the burns on a patient's back 12. In 1964, Kiistala et al. 14 introduced a form of ESG called suction blister epidermal grafting (SBEG), using suction to harvest epidermal sheets. This technique has evolved and its use has been expanded beyond the treatment of vitiligo 15, 16, 17, 18, 19 and lesions of chronic discoid lupus erythematosus 20 to include acute and chronic wounds 21, 22, 23, 24, 25, 26. Papers published by several authors 21, 22, 23, 24, 25, 26 were successful in demonstrating that SBEGs were potentially cost effective with minimal morbidity, such as pain and discomfort. Further development of grafting techniques was stunted because the methods of application involved a considerable amount of work and time. Complicated systems required syringes, 3‐way connectors, vacuum pumps 21, 22, 23, 24, suction cups and pumps 25, 26, 27, and thermal‐regulated suction chambers connected to vacuum sources to harvest epidermis 28, 29. However, despite harvesting challenges, successful outcomes and brought SBEGs into limited clinical practice. Other techniques for using epidermal grafts were developed, with some capitalising on new keratinocyte culture techniques 30. One example is cultured epidermal autografts, which are grown in the lab from keratinocytes and used over burns and wounds 31, 32.

Various efforts at creating less cumbersome but cost‐ and time‐effective skin graft procedures have been attempted. In 2015, several researchers 33 revisited the concept of thin STSGs, publishing work on a small sample of patients about the use of ‘microskin grafting’ for repigmentation of vitiligo areas. This technique harvests skin with a blade and cuts it in minute pieces, which are then mixed with normal saline and sprayed onto the defect. A small series of case reports demonstrated graft success with the described technique.

The process of epidermal grafting largely has been facilitated by the recent development of a minimally invasive technique using an automated device (CELLUTOME™ Epidermal Harvesting System, KCI, an ACELITY Company, San Antonio, TX). It uses suction and heat to homogeneously harvest epidermis. The system consists of a control unit, vacuum head and harvester. The selected donor site is prepared with an alcohol swab; the disposable harvester is positioned and strapped around the selected donor area. The vacuum head is hermetically connected to it. Microdome formation can be visualised through the vacuum head, and once formed, a transparent film dressing is placed on top of the microdomes and then transferred to the recipient area. A study in 15 healthy volunteers showed viable cells within the lamina lucida (n = 3) at the dermal/epidermal junction (n = 12) as well as secretion of growth factors (n = 3) that are important in the wound‐healing process 34, 35. Keratinocytes and melanocytes from these grafts (n = 12) proliferated in culture and type IV collagen was present in these grafts (n = 12) 35. This technique once again highlighted the advantages of ESG, with no need for anaesthesia, minimal to no discomfort and easy feasibility. This new device created neither scarring nor morbidity to the donor site, and skin returned to its previous appearance within 2 weeks 34.

In October 2014, an expert panel of physicians from several specialties (i.e. podiatry, plastic surgery, dermatology and wound care specialists) met to discuss the scientific evidence for and the clinical application of ESGs in wound care 5. One of the experts (Kirsner, RS) described that at donor sites where the epidermal harvest system was used, dermoscopy images showed healing of a single microdome site as early as 2 days after the procedure 5.

Practical aspects of ESG

The expert panel proposed best practices regarding the use of ESGs, including a stepwise approach to improve success rates of the ESG technique 5.

The first step is to assess the patient's baseline health status and ensure that the patient has the ability to heal. The recipient site must have adequate vascular supply for the graft to be successful. The wound bed should be optimised, such that there is adequate granulation tissue to support living cell therapy. In order to ensure an optimal wound environment (i.e. one that does not contain high levels of proteolytic enzymes and inflammatory mediators), the wound bed should be debrided, infection controlled and bioburden reduced. The standard of care for each particular wound [e.g. diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs)] should be optimised before the procedure in order to prepare the recipient site and maximise chances of graft success. The patient should be assessed periodically after grafting to evaluate the evolution of the wound (healing rate, reduction in wound size, stimulus to healing, limb preservation).

The second step is the actual application of the ESG. The donor site does not need significant preparation; however, the area can be wiped with alcohol. The panel recommended that the donor site be warmed and/or moistened (with brief application of warm water) prior to application of the harvesting device, which potentially accelerates the process of microdome formation. After application of the harvesting device and microdome formation, the microdomes are then transferred with a transparent film dressing that is fenestrated manually or with a non‐adherent silicone dressing. Based on some panel members' experiences, double‐density ESGs may be created by cutting the transfer dressing and reorienting it over the harvest, so that all microdomes are on the dressing, before applying it to the wound.

The third step is the application of secondary dressings. These include bolstering materials (e.g. foam dressings, gauze wraps) and the standard of care for each wound type (e.g. compression wraps in the case of VLUs and offloading devices in the case of DFUs). The secondary dressing ensures that the graft maintains contact with the wound. This interaction may be further improved with the use of negative pressure wound therapy (NPWT; V.A.C.® Therapy or SMART NEGATIVE PRESSURE™ Therapy, KCI, an ACELITY Company, San Antonio, TX).

The fourth and final step in applying ESGs is follow‐up and appropriate care after the procedure. The primary dressing should be left alone for the first week. The secondary dressings can be changed after the initial week, as determined by the health care professional. The wound should be assessed weekly, and debridement should not be performed, unless necessitated by the presence of infection, necrosis or excessive maceration. Visualisation of successful graft take may not be apparent for 3 weeks after application because of its reduced thickness.

Discussion

For many centuries, skin grafts have been used to promote wound healing. With time, newer and less invasive tools and techniques have been developed. Recently, a new tool has become available to harvest autologous epidermis with reduced discomfort to the patient and with ease of performance in an office‐based setting. The major factors in favour of this technique for ESG are the broad spectrum of wounds that can be treated, the availability of a vast donor area, minimal morbidity related to the procedure and the possibility of repeated sessions of this treatment.

One study by Yamaguchi et al. 36 demonstrated that ESGs assume the recipient site's phenotype as opposed to maintaining the donor site's phenotype, which is the case with STSGs and FTSGs 36. This is likely because keratinocytes respond to signals provided by underlying fibroblasts. ESGs do not bring donor site fibroblasts as part of the graft and thus, are more responsive to recipient site fibroblasts. As an example, when palmoplantar wounds received ESGs from non‐palmoplantar donor sites, the ESGs developed the phenotypic characteristics of the palmoplantar surface cells, as seen histologically and by keratin protein expression that mimicked normal palmoplantar skin. When STSGs and FTSGs were used, the cells maintained the phenotype of the donor site rather than acquiring the phenotype of the recipient site 2. Given these findings, it is possible in some circumstances that wounds treated with ESGs rather than other types of skin grafts may have better long‐term prognoses.

Among unanswered questions is whether cells from the ESG remain in the wound bed for a prolonged period of time or serve only as a stimulus for healing by supplying or inducing growth factors and other signalling molecules. It is hypothesised that wound bed characteristics influence duration of the wound. For example, when the tissue bed is of better quality (i.e. less bioburden and controlled inflammation), cells may persist, while in more hostile environments, cells may only produce, deliver or stimulate healing 5. Further investigations are warranted to validate the best practices and techniques of using ESGs in order to optimise wound healing outcomes and patient satisfaction.

Kirsner et al. 5 suggest that epidermal grafts can be used like STSGs as a one‐time application intended to cover the wound through re‐epithelialisation or applied through serial applications because they are readily available, easy to harvest, and there is low morbidity for the donor site. It is not yet clear how frequently reapplication should be performed, but it appears that at least several weeks between applications are needed for visualisation of graft take. Serial application of ESGs may function to improve wound bed quality without precluding the use of other forms of grafts, if necessary.

Conclusion

The armamentarium to combat the costly and time‐consuming process of wound care and wound healing has evolved over time. Today, we have more effective and less cumbersome options available. ESGs have emerged as an efficacious, appealing alternative to other therapies for the treatment of acute and chronic wounds. ESGs can be performed in the office/clinic setting and are less invasive, easier to harvest, require less time and are well tolerated with less discomfort and morbidity in patients than traditional skin grafting techniques, making ESGs an excellent therapeutic option. While unanswered questions exist, including the frequency of application and factors that affect graft success, ESGs are a promising new therapeutic approach for the treatment of acute and chronic wounds.