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A Closer Look At Bioengineered Alternative Tissues

   The medical management of wounds today is vastly different than wound management was a few years ago. Evidence-based research has provided the practitioner with new technologies that can predictably heal wounds that previously would have threatened limb loss.    The team approach to complex wound management has been widely embraced and many communities now have referral centers and hospital-based teams that provide multidisciplinary care. With an estimated 20.8 million people in the United States now affected by diabetes and a 15 percent lifetime incidence of foot ulceration in those diagnosed with diabetes, the public health impact of wound care is rapidly making its way into the spotlight. One can properly assume these concerns have a significant impact on the projection that Medicare is expected to be insolvent by the year 2018.    Recent advances in bioengineering have expanded the wound care treatment armamentarium with products that can stimulate healing where there was once a chronic or problem wound. However, the complexity and sheer number of bioengineered products now available for wounds has led to some confusion and hesitancy on the part of many physicians who contemplate their use. Clearly, there is no one perfect bioengineered product for all wounds. Accordingly, let us take a closer look at the current leading biotechnologies that clinicians may utilize for lower extremity wounds.

Redefining ‘Skin Substitutes’ With New Terminology

   A key point of confusion in the arena of new wound technologies begins with the labeling and terminology used to describe these products. Some terms that are commonly used include “bioengineered skin,” “bioengineered skin substitutes,” “biological skin substitutes,” “tissue-engineered skin” and “bioengineered skin equivalents.”1-9 The term “skin” generally does not apply because many of these products have no dermal or epidermal components. The term “equivalent” is especially erroneous because these products are not equivalent to skin and should not be used in such a manner.    The inconsistent, intermingled and sometimes arbitrary use of these terms has led to some difficulty. We believe these terms do not fully or accurately describe these products, and the role they play in wound closure.    Therefore, we propose a new term that more appropriately describes this group of products: “bioengineered alternative tissue” (BAT). We use the term “bioengineered” because these products have been produced artificially or modified in some way that alters the biology and its interaction with the wound bed. In many cases, bioengineered products are processed in such a way and infused with ingredients to optimize their ability to stimulate a positive wound healing wound environment when one places them into the clinical site. “Alternative” better delineates the difference between an autologous skin graft and the manufactured/engineered biologic products. We believe the term BAT more accurately encompasses and describes these wound care products, and would help direct their use in the correct types of wounds.    The overall goal in using any of these products is the central concept of converting a chronic wound into an acute wound (also see “Key Fundamentals For Successful Outcomes With BAT Products” at left). A chronic wound is a wound that does not heal or is retarded in healing and generally populated with senescent cells. Most often, one would determine whether a wound has become chronic through the clinical assessment of wound quality and through serial wound measurements. Some published criteria cite that a wound should have a 10 to 15 percent decrease in area each week or have a greater than 50 percent decrease over the period of one month.10    It is important to understand that one of the key roles of BAT products is to stimulate the conversion of a stagnant wound into an acute wound. This again emphasizes the fact that these products are not generally replacements for skin grafting. These products serve to stimulate and augment the wound’s intrinsic healing pathway. In deeper and larger wounds, it is commonplace for multiple applications or combinations of BAT products to be required for the conversion and eventual healing to occur.

Assessing The Impact Of Apligraf

   Apligraf® (Organogenesis). Apligraf is a bilayered tissue construct that microscopically resembles true skin. It is composed of bovine collagen and living human cells (keratinocytes and fibroblasts) derived from neonatal foreskin. After application, the living cells contained in the graft tissue continue to produce matrix proteins and growth factors that aid in the healing process.    This product is FDA approved for the indications of chronic venous ulcers and diabetic foot ulcerations. The use of Apligraf for these indications has been extensively researched and its efficacy is currently supported by numerous prospective clinical trials.6,13-16 Although it is an allogeneic product, the risk for disease transmission remains extremely low.8 The product has a 10-day shelf life and is shipped by overnight mail at room temperature. Disadvantages include the limited shelf life and cost.    Fivenson, et. al., examined the efficacy and economic data of 13 patients treated with Apligraf.17 They reported a 75 percent reduction in ulcer size and a significant decrease in total ulcer related costs when using Apligraf. It is important to remember that although the product is relatively expensive, lower costs are associated with the Apligraf therapy because the duration of treatment decreases significantly.15,17

When Clinicians May Consider Integra

   Integra® (Integra Life Sciences). This non-living matrix, composed of bovine Type 1 tendon collagen and chondroitin-6-sulfate, has been used extensively for the management of acute burn wounds.24-29 Additionally, it displays a potential for use in the healing of deep postsurgical wounds and deep chronic diabetic ulcers of the lower extremity.30-31 The bilayered form of Integra comes adhered to an epidermal silastic top cover, which one removes approximately two to three weeks after application.    Podiatrists may use Integra alone or subsequently apply a split-thickness skin graft or other superficial product. Advantages include immediate wound coverage, a long shelf life and it is unlikely to cause a host immunologic reaction or transmit disease. In addition, one may apply Integra directly over bone.32-34    Dantzer, et. al., reported simplicity and reliability of technique as well as excellent pliability and cosmetic appearance of the resulting grafts after using Integra in both burn scars and for general reconstructive surgery.35 The disadvantages of Integra include the possibility of incorrect application and subsequent fluid entrapment beneath the graft surface.1 To prevent fluid entrapment, the product generally requires fenestration before application.    Voigt and colleagues examined the economic data in a comparison of patients who were treated with Integra versus a split-thickness skin graft.30 They concluded that Integra is an economically viable alternative when compared to a split-thickness skin graft for the closure of chronic wounds.

Examining The Pros And Cons Of Alloderm And Graft Jacket

   Alloderm® (Life Cell). Alloderm is an acellular, non-living dermal replacement composed of human cadaveric skin in which the epidermis has been removed by salt processing. The product is freeze-dried and has been used in both acute and chronic wounds. It serves as a dermal scaffold and is accordingly intended for use in deeper wounds.6 There is no epidermal component so clinicians commonly use the product with a split-thickness skin graft. In the porcine model, researchers report that Alloderm induces a decrease in wound contracture as well as scar formation.36    The majority of research has evaluated Alloderm’s efficacy in the treatment of full-thickness burns. Researchers have found that it exhibits excellent elasticity and good pigmentation with minimal wound contracture and scarring.37 The advantages of Alloderm include a long shelf life because it is freeze dried, immediate availability and minimal risk for host immunologic response. Disadvantages of this product include the risk of disease transmission.    Graft Jacket® (Wright Medical Technology). The Graft Jacket is derived from cadaveric skin. Its successful use has been reported on a variety of wound types including deep or superficial wounds. The allogeneic human tissue is processed with technology that removes the epidermis and all cellular components while preserving the matrix and biochemical components. Graft Jacket is cryogenically preserved and has a two-year shelf life. It is available in 0.4- to 0.8-mm and is pre-meshed for ease of application in the office setting. The company reports that only a single application is necessary. Graft Jacket is a newer product so independent research on its efficacy is limited.

Key Insights On Options For Burn Wound Coverage

   Biobrane® (Dow Hickam/Bertek Pharmaceuticals). Biobrane is a bilayered membrane consisting of nylon mesh fabric adhered to a thin layer of silicone. Peptides, embedded within the mesh, promote wound bed adherence and fibrovascular ingrowth. With time, Biobrane separates and one can readily remove it from the wound bed.    The product is intended mainly as a wound cover and clinicians have used it for the temporary coverage of freshly excised full-thickness wounds. Frank, et. al., demonstrated a threefold decrease in the rate of wound contracture when using Biobrane on freshly excised wounds in the rodent model.38 Benefits include a long shelf life, decreased wound contracture and immediate availability. Unfortunately, there is currently minimal documented research on the use of Biobrane for diabetic wounds.    Orcel® (Ortec International). Orcel is made of allogeneic neonatal fibroblasts and keratinocytes, which are cultured onto opposite sides of a matrix of cross-linked bovine collagen. The matrix contains viable cells that secrete growth factors and cytokines to promote healing. Researchers have investigated it for the closure of split-thickness donor sites in patients with severe burns. In a comparison of Biobrane and Orcel, Still, et. al., found that Orcel exhibited reduced scarring and more rapid healing.40 The benefits of Orcel include immediate availability, good cosmetic results and rapid wound closure.

What You Should Know About Porcine Products

   EZ-Derm® (Brennen Medical). Composed of cross-linked porcine collagen, EZ-Derm is available either perforated or non-perforated. Benefits include a long shelf life and immediate availability. Disadvantages include the possibility of disease transmission and increased amounts of wound exudate.1 Research is sparse regarding the efficacy and the advantages and disadvantages of this product.    Oasis® (Healthpoint). Likewise, Oasis is composed of porcine small intestine submucosa, which provides a scaffold for the growth of new tissue. The product is acellular yet it contains collagen and growth factors. It is available in both hydrated and dried sheets.    Mostow, et. al., examined the efficacy of Oasis in 120 patients with chronic venous ulcer of the lower extremity.41 They reported that 55 percent of the ulcers in the group treated with Oasis healed completely, in comparison to 34 percent in the group who were treated with compression therapy alone. In addition, none of the patients treated with Oasis experienced recurrence at six months follow-up. Benefits of Oasis include relatively low cost, immediate availability and long shelf life.

Other BATs To Keep In Mind

   Epicel® (Genzyme Tissue Repair). Epicel is a cultured autograft composed of living keratinocytes. The product is made from a biopsy of the patient’s own skin, which is subsequently cultured for three weeks. It has no dermal component and is accordingly suited for more superficial wounds. In addition to serving as a permanent skin replacement, Epicel is very unlikely to cause an adverse host reaction or transmit disease. It can also cover a large wound area.    Disadvantages include cost and delay of application due to the three-week graft cultivation. In addition, the product is fragile and may incompletely anchor itself, leading to spontaneous blistering, contractures and an increased risk of infection months after graft application.42,43 There is minimal documented research on the use of Epicel.    GammaGraft® (Promethean Life Sciences). A gamma-irradiated cadaveric allograft, GammaGraft contains both epidermal and dermal components, and is stored in a penicillin/gentamycin solution. This product is primarily used as a temporary dressing and may require multiple applications. GammaGraft has been reported to have good results in smaller wounds on the dorsal aspect of the foot and lower leg.44 Although disease transmission from this product has not been reported, patients may resist this treatment option due to its human skin origin.    Laserskin® (Fida Advanced Biopolymers) and Vivoderm® (ER Squibb and Sons Inc.). These products utilize a manufacturing technique involving a laser. Material made of hyaluronic acid is perforated and subsequently seeded on both sides with autologous keratinocytes from a biopsy of the patient’s own skin. The pores within these products enhance drainage of fluid from the wound bed.    Laserskin is a thin, transparent membrane that incorporates itself into the wound. Like most other BAT products, it is slowly remodeled in exchange for the body’s native tissue. Lobmann, et. al., examined the long-term outcome of using Laserskin on the chronic wounds of 14 patients with diabetes. They reported a 79 percent wound closure rate at a 64-day post-graft application follow-up.45

What About Dermagraft And TransCyte?

   As this issue went to press, Advanced BioHealing had acquired the rights to Dermagraft and TransCyte from Smith and Nephew. The company indicated it would restart manufacturing both next year. Accordingly, let us take a look at the nature of these products and the current research.    Dermagraft®. Dermagraft is comprised of living allogeneic fibroblasts on a polyglactin mesh. The fibroblasts come from neonatal foreskin and remain viable after implantation, continuing to secrete matrix proteins and growth factors. The polyglactin mesh is biodegradable and is reabsorbed after three to four weeks. The product serves as a dermal equivalent and clinicians have used it to treat deeper wounds.    Marston, et. al., examined 314 patients with chronic diabetic foot ulcers of greater than six weeks duration.18 They reported that patients treated with Dermagraft experienced a significantly greater decrease in ulcer size and ulcer related adverse events compared with conventional therapy. In addition, they reported closure of 30 percent of the ulcers treated with Dermagraft at 12 weeks versus an 18.3 percent closure with conventional therapy alone. Numerous studies have supported the use of Dermagraft in the healing of chronic diabetic wounds.19-22 Others have reported the beneficial effects of Dermagraft in the treatment of hard to heal venous ulcers.23    As Dermagraft has no epidermal component, clinicians have used it with a subsequent application of a split thickness skin graft. However, practitioners may use Dermagraft alone. Advantages include a lack of host immune response, ease of application and resistance to tearing.1 Some disadvantages are the need for multiple applications and a higher price than comparable products.    TransCyte®. TransCyte is a nylon mesh fabric of Biobrane seeded with allogeneic human dermal fibroblasts. This cryopreserved matrix contains high levels of proteins and growth factors with no viable cells. Since nylon is not biodegradable, this product serves only as a temporary wound cover. Clinicians have used this product for the coverage of partial-thickness burns.    Kumar, et. al., compared the efficacy of TransCyte to Biobrane for partial-thickness burns in children. They report that TransCyte had a faster rate of reepithelialization and required less dressing changes during the course of treatment.39 The disadvantages of TransCyte include the need for frozen storage, the requirement of multiple applications and a relatively high cost.1

Key Fundamentals For Successful Outcomes With BAT Products

   In order to use BAT products successfully, it is important to have a strong understanding of the fundamental characteristics of skin. Within the context of wound healing, there are four important components to consider. These components are the epidermis, dermis, hypodermis (subcutaneous adipose tissue) and underlying tissue. The epidermis is the most superficial component of skin. It has no direct vascular supply and sloughs continuously. The dermis is often regarded as the most important skin component to wound healing and this is where clinicians look for granulation tissue. As a key marker for healing potential, granulation tissue is literally a collection of newly formed vascular buds.    As part of the standard of care, wound bed debridement involves removing nonviable tissue and inhibitory factors such as proteases and collagenases. The mechanical action of debridement disrupts the vascular buds at the surface of the wound base, causing bleeding. A bleeding wound base often indicates a viable base, which is a positive predictor for wound healing.11,12 It is also important to understand that adipose tissue and other deep tissues (fascia, tendon, bone and muscle) have the potential to form granulation tissue. Accordingly, proper debridement of these deep wound components can be essential to overall healing potential.11    The skin contains important growth factors (e.g. VEGF, PDGF) that stimulate tissue repair and angiogenesis during the process of wound healing. Bioengineered alternative tissue products generally stimulate these processes in the wound bed or can often serve to deliver growth factors extrinsically when one applies them to the wound.    Some BATs contain living fibroblasts and keratinocytes in addition to growth factors. These living cell components can play an important role through the continued production of growth factors after their delivery to the wound bed. Another key role of BAT products is the matrix component, which can assist in rapid wound ingrowth and building wound integrity by providing a temporary scaffold.    When selecting a particular BAT product, it is important to keep in mind the different layers of tissue and their architecture as described above. In many cases, one can choose a specific product to match the wound depth and nature. When clinicians use BAT products incorrectly, the results have a lesser degree of predicted success and the clinician may wrongly conclude that the product is ineffective or inferior. Proper selection of BAT products increases the likelihood of successful wound closure.    Prior to applying these products, it is absolutely essential that the wound is clear of infection, there is adequate blood supply and there is minimal tension about the wound margins (this includes adequate offloading). When the wound bed is properly prepared for a positive wound environment, BAT products offer an effective means of promoting healing.

In Conclusion

   Ultimately, the success of any of these products may depend on factors that are outside the control of the clinician. Psychosocial and economic influences may dictate which product one chooses for the patient. However, a working knowledge of the advantages and disadvantages of each product will better enable the clinician to select the appropriate bioengineered alternative tissue.    Additionally, it should be emphasized that proper wound bed preparation and stable wound environment are often the most important steps to achieving a successful BAT treatment. It is imperative that one should delay applying these products until the wound base is properly prepared to receive them. One key way to control the post-application environment is to apply negative pressure wound therapy (VAC®, KCI) to the site immediately after placing the graft onto the wound bed. As with split thickness skin grafting, using VAC therapy on top of a BAT graft will promote better adherence to the wound bed and its underlying vascular supply while also promoting proper wound fluid drainage.    Clearly, the horizon is bright when one looks at the future of bioengineering. There are many new products currently under development and we are still refining the proper use of the currently available technologies. This all should add up to faster, more reliable and more predictable wound healing for many of our most complicated patients. Dr. Kim is an Associate of the American College of Foot and Ankle Surgeons. He is an Assistant Professor at Midwestern University College of Health Sciences. Ms. Dybowski is a podiatry student at the Midwestern University School of Podiatric Medicine. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons. He is an Assistant Professor at the Georgetown University School of Medicine. For further reading, see “Closing Difficult Wounds” in the March 2006 issue of Podiatry Today, “Are Tissue Replacements Cost Effective?” in the July 2003 issue of Podiatry Today or “Can A New Biologic Matrix Facilitate Improved Wound Healing?” in the February 2005 issue of Podiatry Today. Also be sure to check out the archives at


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By Paul J. Kim, DPM, Karolina S. Dybowski, BS, and John S. Steinberg, DPM
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