Essential Insights On Bioengineered Alternative Tissues

Ryan H. Fitzgerald, DPM, Paul J. Kim, DPM, and John S. Steinberg, DPM

While bioengineered alternative tissue (BAT) products show promise in the management of complicated lower extremity ulcerations, the variety of these emerging modalities can lead to confusion on appropriate indications and proper use. Accordingly, these authors provide a timely update, suggest the use of new terminology and survey the most recent literature on the efficacy of BAT modalities.

   As physicians, we are facing a rising epidemic of limb loss due to the development of diabetic foot ulcerations (DFU). The consequences of major amputation in the lower extremity are well understood. Recent data suggests that the morality rate associated with lower extremity amputation indeed rivals most cancers.1

   In addition to advances in interdisciplinary treatment protocols that allow for rapid diagnosis and management of complex wounds in this high-risk patient population, there have been advances in bioengineering and a transition toward greater evidence-based research. These advances have provided the practitioner with numerous new technologies that can facilitate predictable healing for wounds in patients who previously would have faced the threat of limb loss.

   Additionally, as we have gained greater clarity on the etiologies for wound development and chronicity, we have seen the emergence of treatment modalities that can help address the specific local and systemic factors that can impede wound healing.

   While the development of these technologies serves as a windfall in the treatment of complex lower extremity ulcerations, the sheer numbers and variety of wound healing products that have become available in the last few years have led to some confusion. As a result, there may be hesitancy on the part of many physicians who consider using these products for their patients.

   A key point of confusion in the arena of new wound technologies begins with the labeling and terminology used to describe these products. We previously introduced a new term, “bioengineered alternative tissue” (BAT), which more accurately encompasses and describes these wound care products, and will help direct their use.

   While these products fill a specific niche in wound care, none of them is a panacea. Obviously, no one product will work for all types of wounds. While there is some overlap between these products, the greatest likelihood for successful wound healing lies with thorough wound evaluation and appropriate product selection.

A Primer On Wound Healing Fundamentals

   Within the context of wound healing, there are four important components: 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 it is at this layer that clinicians look for granulation tissue.

   The skin contains important growth factors (e.g. vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)) that stimulate tissue repair and angiogenesis during the process of wound healing. Bioengineered alternative tissues generally stimulate these processes in the wound bed or can often serve to deliver growth factors extrinsically when one applies these tissues 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 and help to stimulate the development of granulation tissue.

   When selecting a particular BAT product, it is important to keep in mind the different layers of tissue and their aforementioned architecture. In many cases, one can choose a specific product to match the wound depth and nature. Proper selection of BAT products increases the likelihood of successful wound closure.

Converting Chronic Wounds To Acute Wounds: What You Should Know

   The overall goal in using any of these products is the central concept of converting a chronic wound into an acute wound. With normal healing, acute wounds create a provisional wound matrix that contains fibrin and fibronectin, which act as chemical mediators. Fibrin and fibronectin direct cells to the site of injury and motivate the cells to proliferate and differentiate into new, provisional matrix structures.2

   However, in chronic wounds, increased levels of inflammatory cells and proteases degrade the extracellular matrix (ECM) components that are essential for healing.3 Among these proteases, matrix metalloproteases (MMPs) play an important role in damaging the ECM and the extracellular growth factors present in a chronic wound. These MMPs are synthesized by multiple cell types including neutrophils, fibroblasts and macrophages at the direction of chemical mediators such as inflammatory cytokines.4

   In the non-chronic wound environment, MMPs function to debride away denatured elements of the ECM, exposing areas of intact functional matrix that are needed for wound healing. This process is highly regulated and controlled via tissue inhibitors of metalloproteases (TIMPs).5

   With chronic wounds, in addition to an excess number of MMPs, there is a failure in the regulation of protease activity between the MMPs and TIMPs, which can result in further degradation of the ECM. This is followed by the the destruction of growth factors, inhibition of angiogenesis and breakdown of granulation tissue.6

   For wound healing to occur, a balance is necessary between the protein degrading activities of MMPs and other cellular activity that synthesizes and deposits protein components of granulation tissue. Many new advanced wound care products, including BATs, aim to reestablish balance in the wound environment and stimulate the conversion of a stagnant wound into an acute wound.

   The determination of whether a wound has become chronic occurs primarily through clinical assessment of wound quality and serial wound measurements. When it comes to assessing wound improvement, the literature has demonstrated that a wound should decrease in area 10 to 15 percent each week or more than 50 percent in one month.7

   A topically placed collagen matrix can initiate wound healing by activating inflammatory cells and promoting increased vascularity to healing tissue.8 Other research has demonstrated that the physical three-dimensional structure of collagen has the ability to induce fibroblastic activity, which is essential in the formation of granulation tissue.

   Another key role of BAT products is the matrix component that can assist with rapid wound in-growth and building wound integrity by providing a temporary scaffold. This again emphasizes the fact that these products are not generally replacements for skin grafting but rather serve to stimulate and augment the wound’s intrinsic healing pathway.

   In deeper and larger wounds, multiple applications or combinations of BAT products may be required for the conversion to take place. Eventual healing will occur through the development of neodermis and the formation of healthy granulation tissue prior to complete healing via skin grafting or by intrinsic neo-epithelialization observed with secondary healing.

Providing Improved Clarity On BAT Products With New Terminology

   Two broad categories have been utilized to classify BAT products. “Living tissues” include products with cell impregnation. “Bioactive adjuncts” refer to products that serve as scaffolds for cell migration. These terms serve to identify BAT products but fall short in describing their function.

   In an attempt to describe and categorize BAT products more accurately, we have developed two new terms that should replace the previously utilized terms. To our knowledge, the following terms have not been utilized before in the literature in this context. The first term “dermoinductive” more accurately describes BAT products that previously fell into the category of living tissues. Dermoinductive denotes the fact that the impregnated cells within this category of products actively participate in the recruitment and activation of the tissue about the wound bed.

   The second term is “dermoconductive,” which better describes the BAT products that previously fell into the category of bioactive adjuncts. Dermoconductive describes the function of these products that serve as a scaffold matrix, which allows for an organized infiltration of cells from the surrounding wound tissue.

   These new terms are derived from the terms “osteoinductive” and “osteoconductive,” which are utilized in the bone healing arena to describe substances that serve in a similar manner of providing cells to the area or serving as bone scaffolds respectively. With the integration of this new categorization scheme, physicians should be better equipped to make a more appropriate selection of the available BAT products.

   While no specific evidence-based protocol has been established, general guidelines can be created for the use of BAT products. It is absolutely essential that prior to the application of these products, the wound is clear of infection, there is adequate blood supply, and there is minimal tension about the wound margins (this includes the use of adequate offloading).9 When the wound bed is properly prepared within a positive environment, BAT products are an effective means of promoting healing.

A Guide To Dermoinductive BATs

   Apligraf® (Organogenesis). This bilayered tissue construct 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 chronic venous ulcers and diabetic foot ulcerations. Numerous prospective clinical trials support the efficacy of Apligraf for these indications.10-14 Although it is an allogeneic product, the risk for disease transmission remains extremely low.7 The product has a 10-day shelf life and ships by overnight mail at room temperature. Disadvantages include the limited shelf life and cost.

   Fivenson and colleagues examined the efficacy and economic data of 13 patients who were treated with Apligraf. They reported a 75 percent reduction in ulcer size and a significant decrease in total ulcer related costs when patients received Apligraf.15 Edmonds and co-workers found that patients treated with Apligraf demonstrated a significantly higher incidence of wound closure at 12 weeks in comparison to the standard of care.16

   It is important to remember that although the product is relatively expensive, lower costs are associated with the Apligraf therapy because treatment duration decreases significantly.13,15

   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. Clinicians have used it for the temporary coverage of freshly excised full-thickness wounds as well as large donor sites.17 Frank and co-workers demonstrated a threefold decrease in rate of wound contracture when using Biobrane on freshly excised wounds in the rodent model.18 Benefits include a long shelf life, decreased wound contracture and immediate availability. Minimal research involving Biobrane’s use in diabetic wounds has been documented.19

   Dermagraft® (Advanced Biohealing). Dermagraft originates from growing living allogeneic fibroblasts on a polyglactin mesh. Fibroblasts come from neonatal foreskin. After implantation, the fibroblasts remain viable and continue to secrete matrix proteins and growth factors. The polyglactin mesh is biodegradable and reabsorbs after three to four weeks. The product serves as a dermal equivalent so one can use it in deeper wounds.

   Marston and co-workers examined 314 patients with chronic diabetic foot ulcers of greater than six weeks in duration.20 They reported that patients treated with Dermagraft experienced a significantly greater decrease in ulcer size and ulcer related adverse events in comparison 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.21-23 Others have reported the beneficial effects of Dermagraft in the treatment of hard to heal venous ulcers.24

   As Dermagraft has no epidermal component, physicians may use it with a subsequent application of a split thickness skin graft. One may also use it alone as well. Advantages include a lack of host immune response, ease of application and resistance to tearing.25 A potential disadvantage is the need for serial applications, which can escalate its cost.

   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 thus suited for more superficial wounds.

   In terms of advantages for this product, it serves as a permanent skin replacement and is very unlikely to cause an adverse host reaction or transmit disease.26 It can also cover a large wound area.

   Disadvantages include cost and delay of application due to graft cultivation (approximately three weeks). 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.27,28 There is minimal published research on the use of Epicel.

   GammaGraft® (Promethean Health Sciences). GammaGraft is a gamma irradiated cadaveric allograft. This product 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.

   Studies have reported GammaGraft to have good results in smaller wounds on the dorsal aspect of the foot and lower leg.29 Several reports have described deceases in the length of hospital stay, pain and the rate of recurrent infection in comparison to alternative wound healing therapies.29 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). Also marketed as Vivoderm (ER Squibb and Sons), Laserskin utilizes a manufacturing technique involving a laser. The material is made of hyaluronic acid, a natural glycosaminoglycan present in all soft tissues that plays a role in a number of biological functions. One would perforate this material and seed it on both sides with autologous keratinocytes from a biopsy of the patient’s own skin.30 The pores within this product 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 slowly remodels in exchange for the body’s native tissue.

   Lobmann and colleagues 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.31

   Orcel® (Ortec International). Ortec 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 and stimulate tissue regeneration.

   Windsor and colleagues demonstrated that the polytetrafluoroethylene ring inhibited graft sloughing and provided a more favorable environment for the skin substitute to regenerate a substantially normal human skin in their SCID mouse model.32 Researchers have investigated it for the closure of split-thickness donor sites in severely burned patients. Still and co-workers found that in comparison to Biobrane, Orcel exhibited reduced scarring and more rapid healing.33 Benefits include immediate availability, good cosmetic result and rapid wound closure.

A Closer Look At Dermoconductive Products

   AlloDerm® (Life Cell Corp.). AlloDerm is an acellular, non-living dermal replacement comprised of human cadaveric skin in which salt processing has removed the epidermis. The product is freeze-dried and clinicians have used it in both acute and chronic wounds. It serves as a dermal scaffold and is intended for use in deeper wounds.10

   There is no epidermal component so physicians commonly utilize this product with a split-thickness skin graft. In the porcine model, researchers report that AlloDerm induces a decrease in wound contracture and scar formation.34

   The majority of research has evaluated AlloDerm’s efficacy in the treatment of full-thickness burns. It has exhibited excellent elasticity and good pigmentation with minimal wound contracture and scarring.35 Researchers have also shown that AlloDerm provides safe and reliable temporary soft tissue coverage over critical neurovascular structures prior to definitive soft tissue reconstruction.36 Advantages include a long shelf life (because it is freeze dried), immediate availability and minimal risk for host immunologic response.

   EZ-Derm® (Brennen Medical). EZ-Derm is composed of cross-linked porcine collagen. One may purchase it either perforated or non-perforated. Benefits include a long shelf life and immediate availability. Disadvantages include increased amounts of wound exudate.25 Research is sparse regarding its efficacy and the advantages and disadvantages of EZ-Derm.

   GraftJacket® (Wright Medical Technology). An acellular collagen matrix, GraftJacket 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 using technology that removes the epidermis and all cellular components while preserving the matrix and biochemical components. GraftJacket 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 manufacturer reports that only a single application is needed.

   Integra® (Integra Life Science). Integra is a non-living matrix composed of bovine type 1 tendon collagen and chondroitin-6-sulfate. Physicians have used this extensively in the management of acute burn wounds.37-42 Additionally, it displays a potential for use in the healing of deep post-surgical wounds and deep, chronic diabetic ulcers of the lower extremity.43,44

   The bilayered form of Integra comes adhered to an epidermal silicone top cover, which one removes approximately two to three weeks after application. Studies have demonstrated that vascular ingrowth into the matrix occurs maximally between seven and 14 days, allowing for the rapid generation of granulation tissue.45 One may use Integra alone or employ a subsequent split-thickness skin graft or other superficial product.

   Advantages include immediate wound coverage and a long shelf life. Integra is also unlikely to cause a host immunologic reaction or transmit disease. In addition, one may apply it directly over bone.46-48 Dantzer and colleagues reported the simplicity and reliability of the 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.49

   The disadvantages include the possibility of incorrect application and subsequent fluid entrapment beneath the graft surface.25 To prevent fluid entrapment, the product generally requires fenestration before application.

   Voigt and colleagues examined the economic data of patients who were treated with Integra versus a split-thickness skin graft.44 They concluded that Integra is an economically viable alternative in comparison to split-thickness skin graft for the closure of chronic wounds.

   Additionally, this product is available in a “flowable” or injectable form that can provide a collagen and glycosaminoglycan matrix to difficult to manage wounds with tunneling or tracking components. Often one can use this modality in conjunction with the conventional bilayered graft to provide three-dimensional reconstruction at complex wound sites.

   Oasis® (Healthpoint). Oasis is composed of porcine small intestine submucosa that provides a scaffold for the growth of new tissue. While the product is acellular, it contains collagen and growth factors.

   Research has demonstrated that Oasis wound matrix provides a collagen scaffolding for dermoconduction. It also selectively absorbs bioactive molecules. This increases their concentration in the wound and limits protease denaturation of important wound healing growth factors (such as PDGF from serum), thus providing some for some element of dermoinduction.50 It is supplied in both hydrated and dried sheets.

   Mostow and colleagues examined the efficacy of Oasis in 120 patients with chronic venous ulcer of the lower extremity.51 They reported that 55 percent of the ulcers in the group treated with Oasis healed completely in comparison with 34 percent in the group that was 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 a relatively low cost, immediate availability and a long shelf life.

In Conclusion

   When considering the use of BAT products, it is important that the physician recognize the importance of proper wound bed preparation prior to product placement. Equally important is the post-application wound bed environment. In addition to an absence of infection and appropriate moisture control, one must ensure suitable offloading of the wound site to reduce shear and direct forces across the BAT.

   Often we prefer to apply negative pressure wound therapy (NPWT) to the site immediately after placing the graft onto the wound bed. As with split thickness skin grafting, the use of NPWT on top of a BAT product will promote better adherence to the wound bed and its underlying vascular supply while also promoting proper wound fluid drainage.

   Ultimately, the success of any of these products may depend on factors that lie outside the control of the physician. Psychosocial and economic influences may dictate which of the products one chooses for the patient. However, a working knowledge of the advantages and disadvantages of each product will better enable the physician in the selection of the appropriate BAT.

Dr. Fitzgerald is the Chief Resident at the Washington Hospital Center in Washington, DC.

Dr. Kim is an Associate of the American College of Foot and Ankle Surgeons. He is an Associate Professor at Midwestern University College of Health Sciences.

Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons.

Editor’s note: For related articles, see “A Closer Look At Bioengineered Alternative Tissues” in the July 2006 issue of Podiatry Today, “Exploring The Potential Of Bioengineered Alternative Tissues” in the September 2006 issue, “A Closer Look At The Research On Bilayered Living Cell Therapy” in the July 2008 issue or “Combining VAC Therapy With Advanced Modalities: Can It Expedite Healing?” in the September 2005 issue.

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