21 Living Skin Equivalents for the Diabetic Foot Ulcer

Living Skin Equivalents for the Diabetic Foot Ulcer

Thanh Dinh, DPM and Aristidis Veves, MD , DS c

INTRODUCTION

Foot ulceration remains the leading diabetic complication requiring hospitaliza- tion (1). Treatment of the diabetic foot ulcer is often a complex process that involves a multidisciplinary approach. Despite best efforts, failure to heal a diabetic foot ulcer can lead to amputation (2). As the incidence of diabetes in the general population is expected to rise, the prevalence of ulcerations and amputations will follow. The resulting cost to society can be measured in direct costs attributed to treatment, as well as indirect costs in lost productivity. The total cost of diabetic foot ulcerations in the United States has been estimated to approach $4 billion annually, as extrapo- lated from the costs of ulcer care and amputations (3). However the costs are meas- ured, diabetic foot ulcerations represent a major public health challenge of growing proportions.

TREATMENT

Over the last decade, significant strides have been made in the treatment of diabetic foot ulcerations. Prevention remains the best means of averting the potentially devastating results of diabetic foot ulcerations. It has been estimated that up to 80% of diabetic foot ulcers are preventable with routine clinical examination of the “at-risk” foot (4). In the event that a foot ulceration develops, a multi-disciplinary team approach to treatment has been demonstrated to be the most beneficial and cost-effective method, in addition to preventing amputation (5).

Treatment of diabetic foot ulcerations varies greatly depending on the severity of the ulceration as well as the presence of ischemia. However, the cornerstones of treatment for full-thickness ulcers should consist of: adequate debridement, offloading of pressure, treatment of infection, and local wound care. Despite good wound care incorporating all of the above treatment principles, one study demonstrated only 24% of ulcers healed after 12 weeks and only 31% of ulcers healed after 20 weeks (6).

Evidence of poor wound healing despite strict adherence to wound care guidelines has led to further investigation into the pathophysiology of the diabetic foot ulcer. The observed “faulty wound healing” has been attributed to a disruption in the normal healing process (7). This disruption results in cessation or stalling of wound healing, with a resultant hostile chronic wound environment.

From: The Diabetic Foot, Second Edition

Edited by: A. Veves, J. M. Giurini, and F. W. LoGerfo © Humana Press Inc., Totowa, NJ

459

IMPAIRED WOUND HEALING

The normal wound healing process involves the timely expression of numerous growth factors that promote cellular migration and proliferation, production of new connective tissue matrix and collagen deposition (8). All three of these physiological processes are altered in the diabetic state and contribute to the poor healing observed in diabetic foot ulcers. The importance of growth factors and their function in normal wound healing is discussed elsewhere in this book. However, in discussion of advanced wound care products, it is important to recognize the unique biochemical characteristics of the chronic diabetic foot ulcer in order to understand how living skin equivalents influence wound healing.

Normal wound healing transitions through three overlapping phases: inflammation, proliferation, and maturation. Instead of progressing in an orderly and timely fashion, it is now clear that diabetic ulcers are “stuck” in the inflammation phase of the wound healing process. During this delay there is a cessation of epidermal growth and migration over the wound surface (9). A common characteristic of all chronic wounds is the elevation of the levels of matrix metalloproteinases (MMPs) that results in increased proteolytic activity and inactivation of the growth factors that involved in the wound healing process (10). Additionally, these chronic wounds have been found to exhibit defi- ciencies in growth factors and cytokines along with elevated levels of inhibitory proteases.

As a result, impaired wound healing is manifested in aberrant protein synthesis, cellular activity, and growth factor secretion.

At present, the term chronic wound simply refers to a wound that has been disrupted during the normal, controlled inflammatory phase or the cellular proliferative phase.

However, a number of studies have attempted to describe the chronic wound based on the length of time present and failure to demonstrate significant improvement within that time interval. In a Consensus Development Conference, the American Diabetes Association defined a chronic wound as one that failed to “continuously progress towards healing.” Furthermore, wounds that remained unhealed after 4 weeks was a source of con- cern, and were associated with worse outcomes, including amputation (11). Regardless of the definition, what remains clear is the fact that the chronic wound fails to heal in a timely fashion and this can be attributed to an altered biochemical wound environment.

Treatment of the chronic wound initially focused on bolus doses of exogenous growth factors. Topically applied recombinant human platelet-derived growth factor (rhPDGF)-BB (becaplermin) in conjunction with good wound care, significantly increased the incidence of complete wound closure and significantly reduced the time to complete closure of chronic diabetic neuropathic ulcers (12). As a result of the prom- ising findings, the development of a replacement tissue to overcome the deficiencies found in chronic wounds was undertaken.

SKIN GRAFTING

Skin is an important organ, covering the entire body and providing the first line of

defense against many offending organisms. When skin integrity is lost, infection, illness,

major disability, and even death can occur. Therefore, coverage of large skin defects is

essential for protection against disease and disability. The birth of skin grafting can be

traced back to 1869, when a Swiss surgeon named Reverdin reported on the hastening

of the healing of granulating wounds by what he called “epidermic” grafts (13). These

“epidermic” grafts were allografts of superficial skin excised in small (approx 2 × 3 mm) pinches. Since its inception, the technique of skin grafting has been perfected to allow for coverage of skin defects in various scenarios such as burns, traumatic injuries with skin loss, epidermolysis bullosa, and chronic wounds.

Although skin grafting provides a valuable and immediate means of soft tissue coverage in most wounds, there are significant disadvantages to its use in the diabetic foot ulcer.

The most obvious advantage to skin grafting is the immediate provision of skin coverage.

In addition to immediate coverage, skin grafting also appears to stimulate wound healing with revascularization of the skin graft to the host bed. However, in the patient with dia- betes, the skin from the donor site may also exhibit faulty wound healing characteristics that could potentially result in secondary wound complications at the donor site. Therefore investigation into suitable skin substitutes with skin-like characteristics was undertaken for use in instances where a donor site was unavailable, or undesirable.

Since the 1970s, scientists have been able to grow human skin cells in vitro (14). With the advent of cultured epithelial autografts, the problem of allograft rejections was elim- inated, as was the problem of skin donor availability (15). However, cultured epithelial autografts could spontaneously blister and also took time to produce, typically a couple of weeks (16). And so the search for an optimal wound dressing with more immediate availability continued.

In 1987, the term “tissue engineering” was coined at a National Science Foundation meeting (17). This term described the application of engineering to the development of biological substitutes to restore, maintain, or improve function. The goal at this time was to create a readily available tissue replacement with the biological and pharmaco- logical properties of human skin (18). Advances in tissue engineering over the last decade has lead to the development of living skin equivalents (LSE) that have shown effectiveness in diabetic foot ulcers compared to standard care and has been used as adjunctive therapy for the difficult to heal wounds. LSEs have also demonstrated effectiveness in other wounds such as burns, venous ulcers, decubitus ulcers, and epidermolysis bullosa.

LIVING SKIN EQUIVALENTS Cadaveric Allograft

Cadaveric allograft skin has been used to provide temporary coverage for full-thickness burns by most burn centers in the United States (19). Cadaver skin closes and protects the wound, and therefore can be lifesaving in instances of large skin defects such as burns.

The cadaver skin is often removed at a later date, leaving a well-vascularized wound

base that makes subsequent skin grafting more readily to take. Unfortunately, the

demand for cadaver skin is high and is often not available for immediate use. It can

also pose problems with graft rejection and transmission of disease because many

transmittable diseases cannot be screened effectively and some diseases may not have

been expressed at the time the skin is harvested (20,21). Cadaver allograft skin can be

treated chemically to decrease fears of transmittable diseases, however, this results in

an inert acellular dermal matrix (22). Cryopreservation affords longer storage and

immediate availability, but also make the allograft more susceptible to sloughing off

the wound bed.

Epidermal Replacements

The technology for epidermal replacement was developed in the 1970s (23).

Epithelial cells were procured from a full-thickness skin biopsy, thus allowing the use of a patient’s own keratinocytes to promote wound closure. Serial cultivation resulted in expansion of the epithelial cells into broad sheets, which were recultured until confluent thin layers of undifferentiated cells were obtained. These sheets were then attached to a petroleum gauze carrier for easier handling.

There were high hopes that use of epidermal replacements would be beneficial in the treatment of burn patients. As a result, these cultured autologous grafts were used in a wide range of burn centers (24,25). However, engraftment rates were suboptimal and, when successful, the epithelium was fragile and showed a lack of durability (26).

At present, there exists only one cultured epidermal autograft produced and manufac- tured in the United States (Epicel, Genzyme Tissue Repair Corporation, Cambridge, MA).

Because the grafts are grown from a patient’s own skin cells, they are not rejected by the patient’s immune system. However, this technique is expensive, requires a biopsy and takes 2–3 weeks to culture sufficient epithelium for grafting. Furthermore, Epicel sheets are thin and fragile and must be handled with extreme care during and after appli- cation. Studies have found that healed epithelium can be very fragile and the skin prone to contraction and breakdown (26). Many of the imperfections associated with epithelial wound closure may be attributable to the absence of a dermal element because the epidermis is fragile without a dermal bed. The dermal element plays an important role in wound healing, affecting epithelial migration, differentiation, attachment, and growth. Therefore, efforts to develop dermal analogs were undertaken.

Dermal Replacements

Initial developments of dermal replacements consisted of a composite graft with a col- lagen-based dermal analog of bovine collagen and an outer temporary epidermal substi- tute layer of silicone (Integra, Integra Life Sciences Corporation, Plainsboro, NJ) (27).

The dermal replacement layer of Integra consists of a porous matrix of fibers of bovine type 1 collagen that is crosslinked with chondroitin-6-sulfate, and glycosaminoglycan (GAG) extracted from shark cartilage. The porous matrix is designed to serve as a tem- plate for infiltration of the patient’s fibroblasts, macrophages, lymphocytes, and capillar- ies. The outer silicone layer of Integra serves as a temporary epidermis and allows for water flux, protection from microbial invasion, and prevention of burn wound desic- cation. Although Integra has been successfully used on burns, it is not currently indicated for use in diabetic foot ulcers or other chronic wounds. It is also important to note that implantation is a two-stage procedure. After application of the Integra, the neodermis requires approx 3 weeks for vascularization to the wound bed. Following this, the tem- porary silicone layer is removed and a second operative procedure is required for appli- cation of an autograft. As a result, the process can be both lengthy and costly.

DERMAGRAFT

Dermal replacements underwent further evolution with the introduction of a living

dermal equivalent that contained allogenic neonatal fibroblasts impregnated on a bioab-

sorbable polyglactin mesh (Dermagraft, Advanced Tissue Sciences Inc, La Jolla, CA).

There are three major production steps in the manufacturing of Dermagraft. First, fibroblasts from human neonatal foreskin are screened, enzymatically treated, and either banked or placed into a tissue culture. Next, allogenic dermal fibroblasts are seeded onto a bioabsorbable polyglactin mesh. Finally, the cells proliferate and pro- duce dermal collagen, growth factors, GAGs, and fibronectin during a 2- to 3-week period.

The final structure is similar to the metabolically active papillary dermis of neonatal skin. Demagraft contains growth factors and matrix proteins instrumental to wound heal- ing such as: platelet-derived growth factor (PDGF)-A, insulin-like growth factor (IGF), mitogen for keratinocytes (KGF), heparin binding epidermal growth factor (HBEGF), transforming growth factors (TGF- α, TGF-β

, TGF- β

), vascular endothelial growth factor (VEGF), and secreted protein acidic and rich in cysteine (SPARC). The matrix proteins and growth factors remain active after implantation onto the wound bed (27,28). No exogenous human or animal collagen, GAG, or growth factors are added. Dermagraft has been shown to stimulate angiogenesis possibly by upregulating cellular adhesion molecules in response to growth factor stimulation (28). Preclinical studies in animals indicated that Dermagraft incorporates itself quickly into the wound and vascularized well. Preclinical data also indicated that Dermagraft might limit wound contraction and scarring.

Dermagraft is designed to replace the dermal layer of the skin and to provide stimu- lus to improve wound healing. The histological cross-section shows human collagen fibers arranged in parallel bundles (Fig. 1). Dermagraft is supplied as a 2-inch by 3-inch graft in a sealed plastic bag (Fig. 2) on dry ice. Dermagraft must be stored at –70°C.

Dermagraft must be rapidly thawed and warmed before application on to the wound.

The top of the package is cut and the tissue is rinsed with sterile saline. The package is translucent so the wound can be traced and Dermagraft is cut to the wound size. It is then can be removed form the package and applied to the wound. Secondary dressing is used to keep the implant in place and keep the wound moist. Dermagraft acts on wound by cell colonization and provision of growth factors and cytokines. Because of cryop- reservation, the cells can lose some viability and therapeutic effect (29).

Fig. 1. The cross section of Dermagraft showing collagen fibers in parallel bundles.

EFFICACY OF DERMAGRAFT IN DIABETIC FOOT ULCERS

A pilot study was performed to assess the efficacy of Dermagraft diabetic foot ulcers for the duration of 12 weeks (30). Fifty patients were enrolled and divided into four treatment groups. Group A patients received one piece of Dermagraft weekly for a total of eight pieces and eight applications plus control treatment. Group B patients received two pieces of Dermagraft every 2 weeks for a total of eight pieces and four applications plus control treatment. Group C patients received one piece of Dermagraft every 2 weeks for a total of four pieces and four applications plus control treatment. Group D patients received conventional treatment only. Patients in all groups had very similar demo- graphic characteristics. After 12 weeks, group A patients achieved more wound healing than other groups. Wound closure in the group A patients (50%) after 12 weeks was sig- nificantly better than the control group (8%, p = 0.03). There were no reported adverse events in this study.

As a result of the encouraging pilot study, a large, prospective, randomized control study was conducted to investigate the effectiveness of Dermagraft on diabetic foot ulcers (31). A total of 281 patients were enrolled at 20 centers. Patients were randomized to receive either Dermagraft weekly for a total of eight applications or only conventional wound care. One-hundred and twenty-six patients were enrolled in the standard wound care group, with 31.7% healing rate by the end of week 12. One-hundred and nine patients received Dermagraft treatment, resulting in a 38.5% healing rate by the end of week 12. The healing rates between the two groups were found to be a statistically nonsignificant result (p = 0.14).

Further analysis revealed that a specific range of metabolic activity of Dermagraft

was associated with higher complete healing rate by week 12 (32). Seventy-six patients

received metabolically active products at least at the first application, and 48.7% of

these achieved wound healing by week 12 (p = 0.008). Sixty-one patients received

Fig. 2. Dermagraft is supplied in a translucent bag. It can be used to trace the ulcer then cut

the specimen to fit the ulcer.

metabolically active products at the first two applications and as well as many of the subsequent applications, and 50.8% of these patient had complete wound closure by week 12 (p = 0.006). Thirty-seven patients received the correct metabolically active products at all applications, and they achieved the highest healing rate of 54.1% by week 12 (p = 0.0067) (Fig. 3). A supplemental study using Dermagraft within the ther- apeutic range reported healing rates of diabetic foot ulcers above 50% at 12 weeks (33).

A subsequent study involving more centers and larger patient population was concluded recently. In a randomized, controlled, multicenter study at 35 centers throughout the United States, 314 patients were randomized to either the Dermagraft treatment group or control (conventional therapy) (34). Except for the application of Dermagraft (applied weekly for up to 7 weeks), treatment of study ulcers was identical for patients in both groups. All patients received pressure-reducing footwear and were allowed to be ambu- latory during the study.

The results demonstrated that patients with chronic diabetic foot ulcers of more than 6 weeks duration experienced a significant clinical benefit when treated with Dermagraft vs patients treated with conventional therapy alone. With regard to complete wound closure by week 12, 30% of Dermagraft patients healed compared with 18.3%

of control patients (p = 0.023). The overall incidence of adverse events was similar for both the Dermagraft and control groups, but the Dermagraft group experienced signifi- cantly fewer ulcer-related adverse events.

COMPOSITE REPLACEMENTS

Composite replacements are allogenic, bilayered skin equivalents consisting of a well- differentiated human epidermis and a dermal layer of bovine collagen containing human fibroblasts. A composite cultured skin (CSS, Ortec International Inc, New York, NY) was developed that consists of neonatal keratinocytes and fibroblasts cultured in distinct bovine type 1 collagen layer. This has limited use and studied for patients with burns and epidermolysis bullosa (35).

Fig. 3. Results of Dermagraft study. A 32% of the control (CT) achieved wound healing

compared to 39% of patients who received Dermagraft (DG-All) treatment (p = 0.14). Patients

who received metabolically active products at the first two applications and the majority of the

following application (DG-TR) achieved 51% healing rate by week 12 (p = 0.006). Patients who

received metabolically active products at all time (DG-E) achieved 54% healing rate (p = 0.007).

APLIGRAF

Apligraf is a composite graft is made up of a cultured living dermis and sequentially cultured epidermis, derived from neonatal foreskin (Graftskin, Organogenesis Inc., Canton, MA). Apligraf is a bilayered skin construct, consists of four components:

extracellular matrix, viable allogenic dermal fibroblasts, epidermal keratinocytes, and a stratum corneum. The extracellular matrix of Apligraf consists of type-1 bovine colla- gen (acid-extracted from bovine tendon and subsequently purified) organized into fibrils and fibroblast-produced proteins. This matrix promotes the ingrowth of cells, provides the scaffold for the three-dimensional structure of Apligraf, and provides mechanical stability and flexibility to the finished product.

The dermal fibroblasts produce growth factors to stimulate wound healing, con- tribute to the formation of new dermal tissue, and provide factors that help to maintain the overlying epidermis. The epidermal keratinocytes form the epidermis. They pro- duce growth factors to stimulate wound healing and achieve biological wound closure.

The stratum corneum provides a natural barrier to mechanical damage, infection, and wound desiccation. The dermal fibroblasts and keratinocytes are separated from nor- mally discarded infant human foreskin. Apligraf is processed under aseptic conditions and thus requires similar handling. Blood samples of the maternal parent of the fore- skin donor is tested and compared to normal ranges. Test for many infectious agents are performed and include anti-HIV virus antibody, HIV antigen, Hepatitis, Rapid Plasma Reagin, Glutamic pyruvic transaminase, Epstein–Barr, and Herpes simplex.

The cells are also tested for many infectious agents and also for their lack of tumori- genic potential.

Apligraf is supplied as a circular sheet approx 3 inch in diameter (44 cm

) in a plastic container with a gel-cultured medium (Fig. 4). Apligraf looks and feels like human skin.

Histological sections showed that Apligraf only lacks blood vessels, sweat glands, and

hair follicles when compared to human skin (Fig. 5). Apligraf contains all cytokines

present in human skin (Table 1). The specimen is in a sealed plastic bag that can be kept

at room temperature for up to 5 d. Once the bag is opened, the product must be applied

Fig. 4. Apligraf is manufactured in a culture medium disk approx 3 inch in diameter. It looks

and feels like human skin. In can be lifted off the disk and transferred to the wound.

within 30 minutes. The color of the gel medium will change to indicate when the prod- uct is no longer usable. The epidermal layer is closest to the lid of the plastic container, and has a matted or dull finish. The dermal layer rests on the insert membrane closest to the gel medium, and has a glossy appearance.

Apligraf can be trimmed to size and applied to the ulcer with the dermal layer in con- tact with the wound bed. The wound bed should be debrided extensively to be free of necrotic tissue. Apligraf can overlap the wound edge onto normal surrounding tissues without causing any harm. Apligraf can be “mesh” to cover larger wound. Apligraf does not need to be sutured in but it can be done to ensure the implant does not shift of the Fig. 5. Histology comparison between Apligraf and human skin. They are very similar.

Apligraf lack Langerhans’ cell and melanocyte at the epidermis level. In the dermis level, Apligraf does not contain any hair follicle, sweat gland, endothelial cell, or any blood cells.

Table 1

Cytokine Expression in Apligraf and Human Skin

Human Human dermal

keratinocytes fibroblasts Apligraf Human skin

FGF-1 + + + +

FGF-2 – + + +

FGF-7 – + + +

ECGF – + + +

IGF-1 – – + +

IGF-2 – + + +

PDGF-AB + + + +

TGF- α + – + +

IL-1 α + – + +

IL-6 – + + +

IL-8 – – + +

IL-11 – + + +

TGF- β1 – + + +

TGF- β3 – + + +

VEGF + – + +

Apligraf contains all the cytokines of those present in human skin.

target wound. Secondary dressings are used to keep the implant in place and to maintain a moist wound environment.

EFFICACY OF APLIGRAF IN DIABETIC FOOT ULCERS

A multicenter, prospective, randomized control clinical trial was conducted to study the efficacy of Apligraf in the treatment of chronic diabetic foot ulcers (35). Two-hundred and eight patients enrolled in 24 centers across the country. The efficacy of the treatment was studied for 12 weeks, followed by another 3 months of safety follow-up. Ninety- six patients were randomized to control group. This group received saline moistened gauze treatment in addition to good wound care and offloading techniques. One-hun- dred and twelve patients were randomized to the treatment group. These patients received Apligraf once a week for the first 4 weeks with a maximum of five applica- tions. After week number four, patients in the treatment groups received similar dress- ing regiments as the control group.

Apligraf quickly showed the difference in treatment (Fig. 6). After 4 weeks, 20% of patients who received Apligraf achieved wound healing compared to 3% in the control group. After 8 weeks, 45% of patients who received Apligraf treatment healed their ulcers compared to 25% of the control group. By the end of week 12, 56% (63/112) of Apligraf-treated patients had complete wound closure compared to 39% (36/96) of the control (p = 0.0026). Among the patients who had complete wound closure, the median time to 100% wound closure for Apligraf group was 65 days compared to 90 days for the control group. The recurrence rate was similar in both treatment groups. By 6 months after initiation of therapy, 8% (5/63) of the Apligraf-treated patients had recurrent ulcer compared to 17% (6/36) of the control group.

Because Apligraf could heal more ulcers in a shorter time, safety data also revealed that patients treated with Apligraf had a lower incidence of osteomyelitis and lower frequency of amputation. The incidence of adverse events was similar in the two treatment groups during the study.

Fig. 6. Results of Multicenter Apligraf study. The difference between the control and Apligraf treatment is apparent early in the study. At week 4, 3% of patients who received control treat- ment had wound healing compared to 20% of patients who received Apligraf once a week for the first 4 weeks. At week 8, 25% of control patients achieved wound healing compared to 45%

of the Apligraf treated patients. By 12 weeks, 39% of the control patients achieved complete

wound healing compared to 56% of the patients who received Apligraf treatment (p = 0.0026).

CLINICAL APPLICATION

The exact mechanism of action of living skin equivalents is still under much discus- sion and research. It is believed that LSEs act as a “smart matrix” by inducing the expression of growth factors and cytokines that contribute to wound healing (36). This concept is substantiated by the observation that wounds treated with LSEs exhibit wound healing from the edges of the wound bed.

It is postulated that the donor allogenic cells from LSEs are responsible for the delivery of growth factors and cytokines integral to wound healing. What remains unclear is how long these donor allogenic cells remain active in the wound site. Using polymerase chain reaction analysis, Phillips et al. detected allogenic donor cell DNA after the initial month of grafting (37). However, the allogenic DNA did not appear to persist after 2 months of grafting.

Some LSEs may become vascularized with time and lead to graft integration analogous to autologous skin grafting. Using laser Doppler imaging, Newton et al. assessed blood flow in seven diabetic foot ulcers treated with eight applications of Dermagraft on a weekly basis (38). It was found that blood flow increased by an average of 72% at the base of five out of seven diabetic foot ulcers. This angiogenesis may be responsible for the effectiveness of LSEs in the treatment of diabetic foot ulcers.

Rejection of the LSE or development of immune sensitization does not appear to be a problem. It is thought that this may be because of the fact that neonatal fibroblasts lack the HLA-DR surface antigens, which are responsible for generating allograft rejection (39).

As in many studies, patients with severe medical conditions such as end-stage renal failure on dialysis are often excluded. Some of the authors’ patients with diabetes who had end-stage renal disease on hemodialysis were able to achieve complete wound heal- ing on their chronic ulcers using Apligraf in addition to normal good wound care and offloading technique.

COST EFFECTIVENESS AND QUALITY OF LIFE

A major criticism of LSEs is the significant cost associated with their use. This has been a difficult issue to study because of the variation in healthcare cost from one region to another.

However, recent investigation has found that treatment with Apligraf is more cost effective because of its greater effectiveness offsetting the added cost of the product (40).

The investigators concluded that the cost effectiveness benefit was realized at the 5- month mark and treatment with Apligraf resulted in a 12% reduction in costs over the first year of treatment compared to standard wound care. Using modeling techniques over a 52-week period, Dermagraft treated diabetic foot ulcers was also felt to be more cost effective than standard wound care based on its ability to heal more wounds over that time period.

A similar conclusion was reached with the use of Apligraf for venous stasis ulcerations.

Schonfeld et al. (41) estimated that ulcers treated with Apligraf cost $20,041 annually, compared to $27,493 for those treated with compression therapy and wound care.

Furthermore, they found that treatment with Apligraf led to 3 months more in the

healed state.

Obviously, faster wound healing can lead to reduction in treatment costs. What is more difficult to measure, however, is the health-related quality of life. Mathias et al.

attempted to evaluate whether the use of Apligraf contributed to improved quality of life in patients. Based on a telephone questionnaire, 79% of respondents felt that their health was “much better” following treatment with Apligraf (42). The respondents also reported that the greatest improvement was reported in pain symptoms.

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