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Combining Bioengineered Human Dermal Replacement and Multilayered Compression Dressings to Manage Ulcers in a Person with Diabetes Mellitus: A Case Study
The combination of diabetes mellitus and venous insufficiency contributes to a wide variety of complications; one of the most prevalent is chronic lower extremity wounds.1-3 These wounds may be caused by one or more factors such as pressure, ischemia, neuropathy, and venous congestion. Several potential treatment modalities exist for attempted resolution of pressure ulcers in persons with diabetes complicated by venous insufficiency. One product that has been found to facilitate healing of diabetic lower extremity ulcerations is the bioengineered human dermal implant (Dermagraft™, Smith & Nephew, Largo, Fla).
Current literature focuses on either dermal replacement or multilayered venous compression to help resolve ulcers in persons with diabetes. This case study illustrates the collaborative properties of a bioengineered human dermal implant used with multilayered compression dressings (ProFore™, Smith & Nephew, Largo, Fla) to achieve wound closure. The heel ulcer treated in this study had a multifactorial origin. Its location was typical of pressure ulcers but the primary focus of treatment was similar to the approach used when treating a classic venous ulcer on the medial aspect of the lower leg. The dermal implant employed has been shown to facilitate healing of diabetic foot ulcers.4 Multilayered compression dressings have been shown to improve venous insufficiency; thereby, facilitating the healing of venous ulcers.5 However, concomitant use of these two modalities for the treatment of diabetic ulcers complicated by the presence of venous insufficiency has not been reported in the literature.
Literature Review
Bioengineered human dermal implants provide a polymer scaffold consisting of multiple growth factors, cytokines, matrix proteins, and human glycosaminoglycans (GAGs).4 These structures have been found to stimulate a dermal framework that remains active after sterile application, encouraging wound healing and enhancing cell growth while re-establishing the dermal component of the integument.4,6 Matrix proteins, which patients with diabetes are often unable to produce in sufficient amounts, act to provide a lattice integral to wound healing.6-8 These proteins consist of collagen type I and type III fibers, fibronectin, and tenascin. The matrix proteins act collaboratively to function as the structural foundation of the dermis and in conjunction with growth factors, fibroblasts, and keratinocytes, enabling capillary in-growth.6,7 Growth factors assist in the development of granulation tissue and aid in crucial matrix deposition. In addition to growth factors and matrix proteins, dermal implants contain multiple GAGs that provide structural stability and enhance the wound resolution process.4-7 Lastly cytokines, immunoregulatory agents also contained within the implant product are reported to facilitate wound closure by stimulating fibroblasts and furthering angiogenesis.6-9
Bioengineered human dermal implants featuring the aforementioned properties are manufactured as stable, cryopreserved, ready-to-implant medical devices with US Food and Drug Administration approval for use in diabetic wound closure as an aide to promoting diabetic ulcer closure.
The human fibroblast-derived dermal replacement system used in this study has been reported to improve the healing rate of venous ulcers when compared to topical therapies with debridement alone.4 Recently, rates of healing were compared in a study10 involving 18 patients where 10 received a dermal replacement and compression therapy and eight used compression therapy alone. Patients receiving the dermal replacement not only healed significantly faster, but also displayed an increase in skin perfusion as measured by a laser Doppler.
Dermal layer expansion, which can be a direct cause of lower extremity ulceration, responds well to compression dressings. These dressings are an important component of treatment for patients with venous insufficiency. Providing care for the ulcer and underlying venous congestion and insufficiency should hold equal importance because ulceration has been linked to an increase in venous pressure in the leg during periods of activity or exercise.11 Various forms of compression products, including graded elastic stockings, Unna boots, and sequential pneumatic compression devices, are available to alleviate fluid collection, skin pressure, and ultimately breakdown.5,12-14 Compression pumps also have been linked to a decrease in the fibrin cuff formation around capillaries, ultimately increasing perfusion to the site of the venous ulcer.15
Multilayered compression dressings have well-documented success in closing ulcers associated with venous insufficiency.16 Gupta et al17 evaluated 15 patients with venous ulcers; 10 of the 13 participants who completed the study attained complete healing of the ulcer site. The treatment regimen becomes complicated when a patient with diabetes mellitus and venous insufficiency develops an ulcer on a lower extremity.
Indications for Product Use
Indications for bioengineered human dermal implant use include full-thickness diabetic foot ulcers secondary to pressure that are present for >6 weeks. These ulcerations usually extend through the dermis; however, the product is contraindicated if deeper soft tissue structures such as muscle, tendon, and osseous or capsular tissue are visible within the wound bed or margins. The dermal implant is recommended over other forms of local wound care for use as an adjunctive treatment modality.4 If a wound appears infected or co-exists with a chronic sinus tract, implant use is contraindicated. The presence of a known autoimmune response to bovine components is also a contraindication.4
The patient in this study also was selected to receive compression therapy due to significant bilateral chronic lower extremity edema as well as skin change typically seen with venous insufficiency. A clinical vascular evaluation of the patient was performed before initiating compression to ensure sufficient distal perfusion essential to healing capability.
Case Report
Mr. J was a 53-year-old man with insulin-dependent diabetes and a medical history of hypertension, coronary artery disease, venous insufficiency, and osteoarthritis. When he was seen at the Edward J. Hines, Jr. Veterans Administration Hospital’s outpatient podiatry clinic, he had two chronic ulcers located on his left lower extremity — one at the posterior, lateral aspect of the left calcaneus that measured 8.1 cm x 4.9 cm x 3 mm on initial evaluation and the other on the posterior medial aspect of the left heel that measured 3.1 cm x 3.0 cm x 1 mm on initial evaluation. Previous attempts over 6 months to heal both ulcers included wet-to-dry dressing changes when the wound initially presented with necrotic tissue, cadexomer iodine 0.9% topical wound gel, and weekly full-thickness sharp debridement. These may not be “best practice” approaches and these interventions failed to resolve the ulcers, even with close follow-up and routine sharp debridement of any residual fibrous tissue. After initial debridement at the wound clinic, the ulcers were clean and granular and no osseous, capsular, or tendinous tissue was exposed. Mr. J’s ulcers exhibited no clinical signs of infection or evidence of purulent discharge or exudate and no necrotic tissue was present in the wounds.
In addition to the ulcers, both lower extremities exhibited dermatological changes consistent with the clinical appearance of venous insufficiency. Pedal pulses were faintly palpable and +1 to +2 pitting edema was noted for both extremities. Biphasic pulses also were noted using a hand held Doppler. In addition, clinical examination revealed warm, pink toes with immediate capillary refill and positive hair growth on the dorsum of the distal digits. Neurological examination showed sensation absent to testing with a 5.07 (10 g) Semmes-Weinstein monofilament.
A bioengineered human dermal implant was applied initially and weekly for 8 weeks thereafter using the published, standardized technique for tissue implantation.4 The dermal implant was covered with a layer of silver-impregnated absorbent dressing (Acticoat®, Smith & Nephew, Largo, Fla). With each dressing application, a multilayered compression dressing was applied. Throughout the course of the treatment, both ulcers demonstrated a marked reduction in area and depth (see Table 1). Left leg edema also improved and ultimately resolved. Edema on the contralateral extremity remained unchanged and after 8 weeks compression therapy on the right leg was changed to graded compression stockings. The posterior medial ulcer closed completely and has remained closed for more than 6 months. The posterior lateral ulcer substantially decreased in area and depth with closure anticipated after completion of the 8-week bioengineered implant treatment. Subsequent wound care consisted of serial full-thickness debridement and application of cadexomer iodine 0.9% topical gel to the lateral ulcer.
Discussion
Wound healing is mediated by a variety of intricate mechanisms. Generally, wound healing is subdivided into three distinct phases: inflammatory (lag/substrate) during day 0 through days 3 to 5; proliferation/granular phase, which typically starts at day 3 and persists up to day 10; and wound contract/healing/remodeling, which extends to day 30 and beyond.6,7 The inflammatory phase is requisite for wound healing to occur. In individuals without healing limitations, wound resolution is initiated less than 24 hours after wound appearance by the aggregation of neutrophils at the margins of the soft tissue deficit. This, in turn, leads to basal cell mitotic activity necessary to establish basement membrane and granulation tissue.6 Twenty-four (24) to 48 hours post injury, epithelial basement membrane differentiation occurs. Approximately 3 days after wounding, granulation tissue appears in conjunction with collagen fiber differentiation and early epithelialization. Around day 5, proliferation of granulation tissue, further epithelialization, and the initiation of neovascularization increase.6 In stark contrast, patients with diabetes mellitus often exhibit healing patterns that are deleterious to wound closure and they often present with atherosclerosis and/or microvascular disease in addition to venous insufficiency.6,7 Peripheral vascular disease, in combination with inherent cellular derangements (including a decrease in neutrophil and lymphocyte function, opsonization deficiency, and limited phagocytosis), leads to a delay or a complete lack of wound healing.6,7
In the inflammatory phase of wound healing, the components of the bioengineered human dermal implant are reported to promote closure by acting as a proliferative stimulus for neutrophil aggregation.4,10 This proliferative response increases further endogenous chemotactic activity of neutrophils and monocytes. Ultimately, the growth factors, cytokines, GAGs, and matrix proteins in the dermal implant have been found to provide an exogenous source of healing factors lacking in patients with diabetes, addressing the cause of chronic and acute wounds.4,6,10
Mr. J had venous insufficiency in addition to ulcers secondary to pressure and complications of diabetes mellitus (loss of sensation). Multilayered compression system use was initiated as a supplementary but critical treatment modality after local treatment modalities without compression therapy, such as debridement and topical wound gels, failed to facilitate healing. This case demonstrates the significance of evaluating the entire patient and identifying and addressing co-existing factors that can impede healing.
Conclusion
Large, deep ulcers secondary to diabetes mellitus can be difficult to resolve, especially in the presence of comorbidities such as venous insufficiency. Standard local wound care and failure to address comorbidities may not provide enough endogenous stimulation for closure to occur in a timely fashion. This case study demonstrates the feasibility of using two different treatment modalities simultaneously to facilitate wound closure in patients with complex conditions. Combining bioengineered human dermal replacement with multilayered compression dressings, previously not discussed in the current literature, offered a viable alternative in a clinical situation where resolution was considered doubtful on initial evaluation. Had the ulcers not improved, they would have increased the risk for infection and/or proximal amputation. Instead, patient limb salvage was achieved. New uses for and combinations of therapies may provide adjunctive solutions to the challenges of wound care.
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