Multimodal Therapy for Approaching Difficult-to-Heal Wounds:...
Multimodal Therapy for Approaching Difficult-to-Heal Wounds:...
Seven patients with leg ulcers of diverse etiology that had failed various therapies were treated with becaplermin plus living skin equivalent (LSE) along with standard therapy, which included compression, leg elevation, and regular debridements. Becaplermin was applied both prior to and following LSE application, with the cycle repeated as necessary. All patients had reduced pain, easier debridement (due to a softening of the fibrotic wound base), and some degree of wound closure as early as one month after starting therapy. Over a three- to ten-month follow up, four patients healed completely and three healed between 50 percent and 75 percent. Becaplermin and LSE appear to complement each other in the promotion of healing in this group of therapeutically resistant ulcers.
The vast majority of leg ulcers occur in patients with venous insufficiency; however, most patients with venous insufficiency do not develop leg ulcers. This observation suggests that additional factors may be involved in the etiology of leg ulcers. Data on leg ulcers from 1,380 patients revealed that over 70 percent of their ulcers could be classified as postthrombotic ulcers involving primary or secondary hypercoagulable states.
Other causes of leg ulcers, which may present with or without venous disease, include a diverse group of disorders including connective tissue diseases, peripheral vascular disease, vasculitis, cryoglobulinemia, cryofibrinogenemia, and lymphoproliferative disorders. Leg ulcers due to these disorders are often unresponsive to conventional therapy and frequently become chronic, exacting a financial and psychosocial burden. The use of newer agents that provide safe and effective treatment options for these difficult-to-heal wounds should result in substantial cost savings and improved quality of life.
Although the precise molecular mechanisms involved in healing chronic skin wounds have not been completely elucidated, it is understood that specific cytokines and growth factors participate in the process. Cell types found within wounds synthesize and express growth factor receptors, and topical application of growth factors can accelerate wound repair in vivo. A physiologic basis for treating chronic human wounds with exogenous recombinant human platelet-derived growth factor-BB (rhPDGF-BB) has been identified with the discovery of PDGF receptors in normal skin and granulation tissue. Becaplermin gel* contains human PDGF-BB produced by recombinant DNA technology, and has biological activity similar to that of naturally occurring PDGF. In the United States, the indication for becaplermin is restricted to use as an adjunct to good ulcer care practices in the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. The mechanism of action of becaplermin is thought to involve chemotactic recruitment and proliferation of endothelial cells and fibroblast-like cells in granulation tissue.
A living skin equivalent (LSE)** is an allogeneic, bilayered living skin construct that has been developed for the treatment of chronic, difficult-to-heal ulcers. This tissue-engineered skin consists of a well-differentiated and stratified epidermal layer with a distinct stratum corneum and a multilayer dermal matrix of collagen and fibroblasts. LSE is made from viable human dermal and epidermal cells derived from neonatal foreskin. The lack of professional antigen-presenting cells in LSE results in a low immunogenic profile, and there have been no clinically evident signs of rejection in patients treated with LSE.8 Because it contains living fibroblasts and keratinocytes, LSE produces cytokines, growth factors, and matrix proteins associated with normal wound healing. Biochemically, LSE expresses PDGF and at least 15 other cytokines and growth factors, which may act synergistically to promote healing. Recent studies indicate that cells within the wound bed of chronic ulcers are often unresponsive to growth-regulatory signals seen in normal wound healing, thus limiting the potential effectiveness of single growth factor agents. Application(s) of multiple growth factors in addition to the sequential use of single growth factors may accelerate the healing process of chronic wounds.
The case series reported here demonstrates the effectiveness of combined therapy (becaplermin plus LSE) to treat therapeutically resistant, multifactorial leg ulcers.
Seven patients with leg ulcers of diverse etiology that had failed various therapies were treated with becaplermin plus living skin equivalent (LSE) along with standard therapy, which included compression, leg elevation, and regular debridements. Becaplermin was applied both prior to and following LSE application, with the cycle repeated as necessary. All patients had reduced pain, easier debridement (due to a softening of the fibrotic wound base), and some degree of wound closure as early as one month after starting therapy. Over a three- to ten-month follow up, four patients healed completely and three healed between 50 percent and 75 percent. Becaplermin and LSE appear to complement each other in the promotion of healing in this group of therapeutically resistant ulcers.
The vast majority of leg ulcers occur in patients with venous insufficiency; however, most patients with venous insufficiency do not develop leg ulcers. This observation suggests that additional factors may be involved in the etiology of leg ulcers. Data on leg ulcers from 1,380 patients revealed that over 70 percent of their ulcers could be classified as postthrombotic ulcers involving primary or secondary hypercoagulable states.
Other causes of leg ulcers, which may present with or without venous disease, include a diverse group of disorders including connective tissue diseases, peripheral vascular disease, vasculitis, cryoglobulinemia, cryofibrinogenemia, and lymphoproliferative disorders. Leg ulcers due to these disorders are often unresponsive to conventional therapy and frequently become chronic, exacting a financial and psychosocial burden. The use of newer agents that provide safe and effective treatment options for these difficult-to-heal wounds should result in substantial cost savings and improved quality of life.
Although the precise molecular mechanisms involved in healing chronic skin wounds have not been completely elucidated, it is understood that specific cytokines and growth factors participate in the process. Cell types found within wounds synthesize and express growth factor receptors, and topical application of growth factors can accelerate wound repair in vivo. A physiologic basis for treating chronic human wounds with exogenous recombinant human platelet-derived growth factor-BB (rhPDGF-BB) has been identified with the discovery of PDGF receptors in normal skin and granulation tissue. Becaplermin gel* contains human PDGF-BB produced by recombinant DNA technology, and has biological activity similar to that of naturally occurring PDGF. In the United States, the indication for becaplermin is restricted to use as an adjunct to good ulcer care practices in the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. The mechanism of action of becaplermin is thought to involve chemotactic recruitment and proliferation of endothelial cells and fibroblast-like cells in granulation tissue.
A living skin equivalent (LSE)** is an allogeneic, bilayered living skin construct that has been developed for the treatment of chronic, difficult-to-heal ulcers. This tissue-engineered skin consists of a well-differentiated and stratified epidermal layer with a distinct stratum corneum and a multilayer dermal matrix of collagen and fibroblasts. LSE is made from viable human dermal and epidermal cells derived from neonatal foreskin. The lack of professional antigen-presenting cells in LSE results in a low immunogenic profile, and there have been no clinically evident signs of rejection in patients treated with LSE.8 Because it contains living fibroblasts and keratinocytes, LSE produces cytokines, growth factors, and matrix proteins associated with normal wound healing. Biochemically, LSE expresses PDGF and at least 15 other cytokines and growth factors, which may act synergistically to promote healing. Recent studies indicate that cells within the wound bed of chronic ulcers are often unresponsive to growth-regulatory signals seen in normal wound healing, thus limiting the potential effectiveness of single growth factor agents. Application(s) of multiple growth factors in addition to the sequential use of single growth factors may accelerate the healing process of chronic wounds.
The case series reported here demonstrates the effectiveness of combined therapy (becaplermin plus LSE) to treat therapeutically resistant, multifactorial leg ulcers.
