> http://www.medscape.com/viewarticle/457932_print
>
>
> Two Cases of Traumatic Wounds in Patients With Ehlers-Danlos Syndrome
> Successfully Treated With a Bioengineered Skin Equivalent
> Babak Abai, MD, Dena Thayer, DO, Paul M. Glat, MD
>
> Wounds 15(6):201-207, 2003. © 2003 Health Management Publications, Inc.
> Posted 07/22/2003
>
> Abstract and Introduction
> Abstract
>
> The authors present two cases in which traumatic wounds in patients with
> Ehlers-Danlos syndrome (EDS) were successfully treated with a
bioengineered
> skin equivalent (BSE) (Apligraf®, Organogenesis, Canton, Massachusetts).
Due
> to defects in collagen metabolism, it has been reported that patients with
> EDS have poor wound healing and unsightly scarring. Considering this, it
is
> important to look into alternate ways to improve the healing process while
> avoiding donor site morbidity. The authors have demonstrated, in these two
> cases, the successful use of BSE as an option for use in the healing of
> wounds in patients with this syndrome.
>
> 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.
>
>
>
> Figure 1A. Pictured here is the wound before the application of the BSE.
> Note the good granulation tissue and no sign of infection.
>
> 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.
>
>
>
> Figure 1B. This is the wound after the application of the BSE.
>
> 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).
>
>
>
> Figure 1C. This is the appearance of the wound after healing is almost
> complete.
>
> 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).
>
>
>
> Figure 2A. Pictured here is the wound before the application of the BSE.
> Note the good granulation tissue and no sign of infection.
>
> 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).
>
>
>
> Figure 2B. This is the wound after the application of the BSE.
>
>
> Figure 2C. This is the appearance of the wound after healing is almost
> complete.
>
> 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-), 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,[22,23] 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.
>
>
> Tables
>
> Table 1. Subtypes of Ehlers-Danlos syndrome (EDS)[3,11,12]
>
> Type Synonym Molecular
> Defect Genetics Clinical Features Diagnosis Skin/Wound
> I Gravis COL5A1 in some/
> Unknown AD Hyperelastic fragile skin, lax joints Clinical
Severe
> skin splitting tendency, wide gaping scars, moderate bruising tendency,
> subcutaneous spheroid and molluscoid pseudotumors.
> II Mitis Unknown AD Mild version of type I Clinical
> Moderate skin splitting tendency, less scarring, mild bruising, mild
> spheroid, molluscoid pseudotumors.
> III Hypermobile Unknown AD Gross laxity of both large and
small
> joints Clinical Limited skin splitting, little scarring, spheroids
and
> pseudotumors uncommon.
> IV Vascular COL3A1 AD
> (recessive variants) Arterial, bowel, and uterine rupture Fibroblast
> culture Skin thin, pale, prominent veins, gross bruising tendency with
> minor trauma, dark pigmented scars.
> V X-linked Unknown X-linked Similar to type II Clinical
> Skin splitting, scarring, and bruising moderate, spheroids and
pseudotumors
> present.
> VI Ocular-
> scoliotic Lysyl
> hydroxylase AR Similar to type I with eye and spine involvement
> Lysyl hydroxylase activity assay Similar to type I.
> VII Arthrochalasis
> Multiplex
> Congenita COL1A1
> Procollagen
> N-Proteinase AD
> (recessive
> variants) Multiple joint laxity and dislocations Biochemical
analysis
> Skin manifestations mild.
> VIII Periodontosis COL1A1 in some/Unknown AD Early teeth loss,
> mild cutaneous and joint laxity Clinical Skin fragility, pigmented
> scars over bony prominences.
> IX Cutaneous
> Laxa No longer considered EDS
> X Fibronectin
> defect Fibronectin AR Similar to type II Biochemical Skin
> thin, extensible, and fragile with scarring and bruising tendency.
>
> References
>
> 1. Prockop D, Kuivaniemi H, Tromp G. Heritable disorders of connective
> tissue. In: Isselbacher K, Braunwald E, Wilson J, et al. (eds). Harrison's
> Principles of Internal Medicine, Thirteenth Edition. New York, NY:
> McGraw-Hill, 1994:2105-17.
> 2. Pyeritz R. Ehlers- Danlos syndrome. N Engl J Med 2000;342(10):730-2.
> 3. Maltz SB, Fantus RJ, Mellett MM, et al. Surgical complications of
> Ehlers-Danlos syndrome type IV. J Trauma 2001;51(2):387-90.
> 4. Lindgren VV, Hollister DW, Marshall WR. Wound healing and
> unsatisfactory scars. Plast Reconst Surg 1987;80(2):321-2.
> 5. Zarem H, Lowe N. Benign growths and generalized skin disorders. In:
> Aston S, Beasley R, Thorne C (eds). Grabb and Smith's Plastic Surgery,
Fifth
> Edition. Philadelphia, PA: Raven-Lippencott, 1997:141-59.
> 6. Freeman RK, Swegle J, Sise MJ. The surgical complications of
> Ehlers-Danlos syndrome. Am Surg 1996;62:869-73.
> 7. Atillasoy E. Current and investigative uses of Graftskin (Apligraf)
in
> wound care. WOUNDS 2000;12(5 Suppl A):3A.
> 8. Schmid P. Immunuhistologic characterization of Graftskin (Apligraf).
> WOUNDS 2000;12(5 Suppl A):4A-11A.
> 9. Ehlers E. Cutis laxa, neigung zu haemorrhagien in der haut,
lockerung
> mehrerer artikulationen. Derm Zschr [Denmark]1901;8:173-5.
> 10. Danlos M. Un cas de cutis laxa avec tumeurs par contusion chronique
> des coudes et des genoux. Bull Soc Franc Dermatol Syphiligr
> [France]1908;19:70-2.
> 11. Beighton P. The Ehlers-Danlos syndromes. In: Beighton P. Mckusick's
> Heritable Disorders of Connective Tissue, Fifth Edition. St. Louis, MO:
> Mosby, 1993:189-251.
> 12. Beighton P. The Ehlers-Danlos Syndrome. London, England: Heinemann
> Medical, 1970:15-42, 109.
> 13. Ablaza VJ, Berlet AC, Manstein ME. An alternative treatment for the
> split skin-graft donor site. Aesth Plast Surg 1997;21:207-9.
> 14. Bell E, Ehrlich HP, Buttle DJ, et al. Living tissue formed in vitro
> and accepted as skin-equivalent tissue of full thickness. Science
> 1981;211:1052-4.
> 15. Eaglstein WH, Falanga V. Tissue engineering for skin: An update. J
Am
> Acad Dermatol 1998;39(6):1007-10.
> 16. Milstone LM, Asgari MM, Schwartz PM, et al. Growth factor
expression,
> healing, and structural characteristics of Graftskin (Apligraf). WOUNDS
> 2000;12(5 Suppl A):12A-19A.
> 17. Atillasoy E. The safety and efficacy of Graftskin (Apligraf) in the
> treatment of venous leg ulcers: A multicenter, randomized, controlled
> clinical trial. WOUNDS 2000;12(5 Suppl A):20A-26A.
> 18. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous
> ulcers and lack of clinical rejection with an allogenic cultured human
skin
> equivalent. Arch Dermatol 1998;134:293-300.
> 19. McGinnis T. Significant FDA approvals in 2000. Am Fam Phys
> 2001;63(10).
> 20. Sabolinski ML, Veves A. Graftskin (Apligraf) in neuropathic
diabetic
> foot ulcers. WOUNDS 2000;12(5 Suppl A):33A-36A.
> 21. Eaglstein WH, Iriondo M, Laszlo K. A Composite skin substitute
> (Graftskin) for surgical wounds. Dermatol Surg 1995;21:839-43.
> 22. Waymack P, Duff RG, Sabolinski M. The effect of a tissue engineered
> bilayered living skin analog over meshed split-thickness autografts on the
> healing of excised burn wounds. Burns 2000;26:609-19.
> 23. Still JM, Craft-Coffman B. Graftskin (Apligraf) in the management
of
> thermal injury. WOUNDS 2000;12(5 Suppl A):58A-63A.
> 24. Falabella A, Valencia I, Eaglstein W, et al. Tissue-engineered skin
(
> Apligraf) in the healing of patients with epidermolysis bullossa wounds.
> Arch Dermatol 1999;135:1219-22.
> 25. Streit M, Bohlen LM, Braathen LR. Ulcerative sarcoidosis
successfully
> treated with Apligraf. Dermatology 2001;202:367-70.
> Reprint Address
>
> Paul Glat, MD, Division of Plastic Surgery, St. Christopher's Hospital for
> Children, Erie Avenue at Front Street, Philadelphia, PA 19134-1095, Phone:
> (215) 427-5093; Fax: (215) 427-4616; E-mail: pglatmd@...
> Babak Abai, MD, Dena Thayer, DO, Paul M. Glat, MD
> >From the Division of Plastic Surgery, St. Christopher's Hospital for
> Children, Philadelphia, Pennsylvania
> ------------------------------------------------------------------------
>