Introduction Ehlers-Danlos syndrome (EDS) is a group of heritable disorders with an incidence of approximately 1 in 5000 births.[1] It is associated with a defect in collagen formation leading to skin fragility and hyperelasticity of skin, hypermobility of joints, and poor wound healing with scarring.[2,3] It has been subdivided into separate types according to the predominant areas affected and the degree of abnormality (Table 1). Collagen plays an important part in the wound healing process, and patients with EDS have suboptimal wound healing and multiple complications following surgery secondary to defects in collagen metabolism.[4–6] The authors treated two patients with traumatic wounds of the lower extremities with a bioengineered skin equivalent (BSE) (Apligraf®, Organogenesis, Canton, Massachusetts). Both of these patients failed to heal their wounds normally with standard wound care. BSE consists of bovine collagen and human fibroblasts and keratinocytes.[7] The fibroblasts and keratinocytes in Bse produce growth factors and antibiotic peptides creating a physiological microenvironment that can stimulate wound healing.[8] Case Reports Case report #1. Patient #1 was an 11-year-old male with a history of EDS type II diagnosed at 10 years of age. His skin was flexible and loose around the joints. He was prone to large subcutaneous hematomas, and his skin was fragile and would easily tear after minor trauma. The skin held sutures, and his wounds healed with scarring. He presented to our office with a one-week-old soft tissue injury over the anterior aspect of his left lower extremity. This occurred while playing soccer. There was significant skin loss over the area with resultant eschar formation. On initial examination, the eschar had separated from the 5cm x 5cm wound bed, which contained some underlying granulation tissue (Figure 1A). The initial management consisted of wet-to-dry dressings with normal saline solution. One week later, the patient returned to the office. The wound bed appeared healthy with continued presence of granulation tissue but without other signs of healing or wound contraction. Due to suboptimal healing, the patient was taken to the operating room one week later where BSE was placed onto the wound (Figure 1B). A sterile dressing was applied, and a splint was fabricated for immobilization. The BSE was examined on post-operative Day 5 and appeared viable with adherence to the underlying wound. Daily dressing changes consisted of application of antibiotic ointment, nonstick gauze, and the splint. Weekly follow-up visits continued, and by post-op Day 30, the wound was completely healed with good cosmetic results (Figure 1C). Case report #2. Patient #2 was a nine-year-old female with EDS type I diagnosed at two years of age. She had the typical features of velvety skin that is hyperelastic and fragile. Her skin would tear, even after minor trauma, and would not hold sutures. Her parents reported that these minor wounds might take up to four months to heal and there was unsightly scarring of the healed wounds. She had a history of bilateral hip dysplasia and a left club foot. This patient presented to the authors’ office four weeks after a sutured repair of a laceration of the posterior aspect of the right lower extremity. The wound had dehisced. Necrotic tissue at the inferior aspect of the wound was debrided after suture removal, and daily dressings of collagenase and polysporin powder were prescribed and continued at home. On a follow-up visit a week later, the wound measured 3cm x 5cm with a granulating base (Figure 2A). Two weeks after the first visit and after re-evaluation and determination of poor healing, the wound was debrided in the operating room and Bse was placed onto the wound (Figure 2B). Antibiotic ointment and a nonstick gauze dressing were applied. The wound was examined on post-op Day 7 and was found to have good adherence of the BSE. The wound continued to heal and was approximately 75-percent reepithelialized by post-op Day 14 and was completely healed on post-op Day 28 with a good cosmetic result (Figure 2C). Discussion EDS is associated with skin fragility, poor wound healing, easy bruising, hypermobility of joints, and connective tissue fragility. It was first described in 1891 by Tschernogobow, a Russian dermatologist, in 1901 by Ehlers,[9] a Danish dermatologist, and in 1908 by Danlos,[10] a French dermatologist. The skin is often velvety in appearance and texture. It is hyperextensible but not lax. If stretched and released, it will resume its original position. The fragile nature of the skin leads to what has been termed dermatorrhexis. Over bony prominences like elbows, knees, and shins, there are often gaping or “fish-mouth” wounds as a result of minor trauma. The linear configuration of scars on the forehead and chin are notable. Skin splitting from minor trauma is common. There tend to be gaping wounds that heal slowly. Often stitches hold poorly in the skin. Slow healing and wound dehiscence is common. There are often wide scars that are shiny, parchment-thin, atrophic, and hyperpigmented. These have been described as “papyraceous” or “cigarette paper” scars. Molluscoid pseudotumors are calcification of superficial hematomas that frequently develop at pressure points like heels, knees, and elbows. In addition, there are subcutaneous spherules of fat, which often calcify over time. Although they cause no discomfort for the patient, these fat spherules are palpable and radiographically demonstrable.[6,11,12] There are nine well-known types of EDS with their own characteristic skin findings (Table 1). Type I is associated with the characteristic cigarette-paper or papyraceous scars, fish-mouth wounds, and sutures that commonly tear through skin. There is also significant joint hyperextensibility. Type II is a milder version of type I. Type III has mild skin features and more joint hypermobility. In Type IV, the skin appears almost translucent with superficial veins easily visible. Hyperpigmentation is often present over bony prominences, and significant scarring occurs. This type has a high morbidity and mortality due to vascular and gastrointestinal catastrophes. Type V is X-linked recessive and has minimal joint hypermobility, while skin hyperextensibility and fragility are prominent. Ocular complications are prevalent in type VI, often leading to blindness. This type also has the same skin and joint features as type I. Type VII is marked by joint laxity with multiple dislocations and sometimes stunted stature and mandibular micrognathia. Skin manifestations are mild. Type VIII is associated with fragile skin, and wounds heal with atrophic, hyperpigmented scars corrugated by fine wrinkles. Finally, type X has similar features to type I with the addition of petechiae during upper respiratory tract infections or after trauma to the skin.[11,12] All the different subtypes have various kinds of metabolic derangement that lead to susceptibility to minor trauma and result in slow and poor wound healing.[12] Because of the poor healing in patients with EDS, it is imperative to find a way to promote healing in these patients. One such modality is the use of skin equivalents. A skin equivalent has to meet certain criteria in order to justify its use in the clinical setting. It has to be safe, hasten the wound closure rate, improve closure success, and provide better cosmetic results. In addition, using an autograft has its own problems. Full-thickness donor sites are limited. The partial-thickness donor site that is created during the harvesting of split-thickness skin graft is prone to a number of complications and morbidities. These include fluid loss, excessive pain, infection, prolonged period for healing, delayed mobility, hypertrophic scarring, undesirable pigment aesthetics, and thin skin poorly resistant to everyday trauma.[13] These are magnified in patients with defects in wound healing, such as EDS. BSE is the first true composite skin equivalent of combined dermal and epidermal living cells. It consists of a bovine type I collagen matrix, which is combined with keratinocytes and fibroblasts harvested from human neonatal foreskin to form a dermis-like substance.[14,15] In addition, BSE has many characteristics and similarities to human skin and to acute wounds that make it ideal for use to promote wound healing. There is histological evidence of markers of activated fibroblasts in both healing wounds and BSE. Transforming growth factor-beta (TGF-b), platelet-derived endothelial cell growth factor (PD-ECGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), fibronectin, and tenascin are also found both in healing wounds and in BSE. Markers of activated keratinocytes like keratin 16 and Ki67, as well as antibiotic peptides, like defensins, are also present in both. The keratinocytes and fibroblasts in the Bse produce chemotactic factors, growth factors, cytokines, and antibiotic peptides to ward off infection.[8,16] These findings suggest that the microenvironment created by the application of BSE stimulates and aids the healing of wounds. Bse was approved by the Food and Drug Administration in 1998 for the treatment of chronic venous stasis ulcers, and studies have demonstrated a significant improvement in the healing of this type of wound.[17,18] BSE has also been successfully used to treat other types of wounds, including diabetic foot ulcers,[19,20] after full-thickness excision of skin cancer,[21] in burns,[22,2]3 and in patients with epidermolysis bullosa and sarcoidosis.[24,25] This is the first reported use in wounds in patients with EDS. There are several advantages to using BSE in patients with EDS. It is a skin substitute containing both dermal and epidermal components that can promote wound healing in many wound types. BSE has been shown in several studies to be immunologically inert[8,18,20,25] due to its lack of antigen-presenting Langerhans cells. Rejection, therefore, does not occur. Since there is no donor skin required, there is no morbidity associated with skin-graft harvest sites. This is particularly beneficial in EDS patients who already have an underlying wound healing deficiency. The BSE also provides a biological dressing that covers the wound. In addition, the patients may have a rapid wound recovery period, less discomfort and pain, and a better final result. Cosmetically, the wounds of patients with EDS heal with wide scars that are shiny, parchment-thin, atrophic, and hyperpigmented. This was not true of the wounds the authors treated with BSE. The resulting scar was far better cosmetically than has been described for these patients without care with Bse (Figure 1C and Figure 2C). Advances in wound care are benefiting patients with acute and chronic wounds in terms of scarring, pain, and speed of recovery. Skin equivalents can also decrease hospital stays and morbidities associated with chronic wounds and the care they require. Skin equivalents are especially desirable in patients with defects in wound healing, such as patients with EDS. The authors have demonstrated in these two case studies that BSE can be used with desirable outcome. However, these are antecdotal cases that demonstrate the usefulness of this product. In order to better analyze, quantify, and understand the benefits of BSE in the treatment of wounds in patients with EDS, a randomized, prospective, controlled trial would be necessary. This could prove to be a difficult study due to the low incidence of EDS.