A Closer Look At The Research On Bilayered Living Cell Therapy

Author(s): 
George Liu, DPM, FACFAS, and John Steinberg, DPM, FACFAS

   

Diabetic foot ulcers are among the many complications encountered with poorly controlled diabetes mellitus. Approximately 15 percent of all patients with diabetes will experience an ulcer in their lifetimes.1,2 Additionally, 85 percent of all nontraumatic lower extremity amputations are preceded by a preventable ulceration.3,4

   Diabetic foot ulcerations pose a considerable economic burden. In 1995, Medicare spent $1.5 billion on diabetic lower extremity ulcers.5 One retrospective analysis found that foot ulcer management averaged up to $27,987 two years from the time of diagnosis.6 Harrington, et al., suggested that if healing rates could increase by 9 percent at a 20-week time period, the cost savings would average $189 per episode.5

   Problem chronic wounds are defined as wounds that do not heal or respond to standard treatment. Prolonged wound exposure increases the risk for bacterial infection.Wound healing in patients with diabetes is physiologically impaired. Hyperglycemia delays phagocytosis and the migration of inflammatory cells pertinent to the acute phase of wound healing.7 Nonenzymatic glycosylation, altered endothelial cell proliferation and impaired collagen deposition prolong the inflammatory phase of wound healing, causing the wound to linger in the chronic stage.

   In chronic venous ulcerations, investigators have found alterations of the wound tissue phenotype that cause an unresponsiveness to specific growth factors needed to promote wound healing.8,9 In addition, chronic wounds often have abnormal expression of individual growth factors needed to stimulate granulation.

   While one may address the primary etiology of ulcerations with offloading for diabetic foot ulcerations and compression therapy for venous leg ulcerations, abnormal intrinsic wound physiology may still persist in prevention of progressive wound healing. Several advances address stagnant wound healing and these advances include recombinant human platelet-derived growth factors, collagen-alginate dressings and growth factors.10-15 These modalities have produced variable stimulation of wound healing.
   Over the years, more bioactive cellular analogs similar to skin were needed to stimulate healing effectively in diabetic wounds that were larger, deeper and chronic in duration. One of the few advances in human living cell therapy was cultured epidermal human keratinocytes, which were procured from a full-thickness biopsy of the patient’s own skin. One would cultivate the autogenic keratinocytes and subsequently apply them later to the wound in the form of sheets. Researchers believed this living allograft stimulated chronic wounds through the delivery of cytokines.16

   While the autogenic keratinocytes demonstrated encouraging success with venous stasis wounds, clinical trials were limited as the process of harvesting and culturing autologous keratinocytes required several weeks.17,18 Another major disadvantage of a keratinocyte sheet was its inherent fragility due to the absence of a dermal layer, which caused difficulty in the application to wounds.19 Evidence suggested that a dermal graft component was necessary to provide a collagen structural lattice and fibroblasts which play an important role in wound healing.20-22

Key Insights On The Makeup And Mechanisms Of Action For Bilayered Living Cell Grafts

   Apligraf (Organogenesis), also referred to as graftskin or human skin equivalent (HSE), is a living, bilayered skin substitute with an epidermal layer consisting of viable human keratinocytes and a dermal layer composed of viable human fibroblasts in a bovine type I collagen lattice. There are four components of the graft: epidermal keratinocytes, the stratum corneum, allogenic dermal fibroblasts and the extracellular matrix. Both keratinocytes and fibroblasts are harvested and cultured from a donor human neonatal foreskin.

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