Phase I/II Clinical Evaluation of StrataGraft: A Consistent, Pathogen-Free Human Skin Substitute

Skin provides an essential role in fluid homeostasis and prevention of infection. Widespread full-thickness loss of skin integrity is common after trauma, burns, and necrotizing soft-tissue infections and patients suffer from the inherent loss of barrier function resulting in massive fluid losses and invasive bacterial infections. Current standards of care recommend resurfacing of the patient as quickly as possible with autologous skin grafts to restore fluid homeostasis and prevent sepsis. Unfortunately, this is often delayed due to patient instability, malnutrition, ongoing infection, or because of insufficient healthy donor skin available for wound site coverage. Meshed cadaver skin is commonly used to promote vascularization and reduce bacterial bioburden in those cases where immediate autografting is not a viable option.1,2 Unfortunately, the cadaver skin supply is often contaminated, precluding its use and presenting serious safety concerns because of the risk of disease transmission.3,4 Physicians often must rely on cryopreserved cadaver skin which has limited viability. Development of new treatment alternatives are needed to provide safer, consistent, and more available wound dressings for complex skin wounds. The potential advantages to patient health are to eliminate the risk of disease transmission and to provide a readily available, more consistent allograft with biologically active keratinocytes for clinical use. The first generation of skin substitutes containing living cells were promising treatment options for the temporary coverage of cutaneous wounds. Replacement of both dermal and epidermal compartments is paramount and living skin substitutes are accepted as more beneficial than acellular or biosynthetic skin substitutes.5 However, cell sourcing for these skin substitutes is a well-recognized problem directly coupled to safety concerns.6 In addition, many of the first-generation living skin substitutes have poor handling characteristics and typically lack epidermal barrier function.7,8 The rapid deterioration observed for some of them in the wound bed9 may compromise the delivery of growth factors and other desirable bioactive molecules. For patients with large wounds, a living skin substitute with a multilayered, mature epidermis may restore the skin’s barrier function and deliver bioactive molecules for wound bed conditioning and tissue regeneration. Recent findings suggest that host defense peptides (HDPs) such as human β-defensins (hBD) are central to keratinocyte-mediated killing of pathogens. hBDs have potent antimicrobial activity and constitutive hBD-3 expression in the suprabasal layers is enhanced during epidermal differentiation of keratinocytes.10 Exposure to Staphylococcus aureus (S. aureus) induces hBD-3 cutaneous expression and this induction is associated with increased antimicrobial activity.11,12 A link between cutaneous hBD-3 levels and bacterial growth is also seen in atopic dermatitis where hBD-3 deficiency appears to be causally associated with S. aureus skin infections.13 Human skin substitutes possessing a mature, viable, fully-stratified epidermis may forestall infection through the expression and processing of HDPs. The characteristics of ideal wound dressings or biological skin substitutes were first suggested by Pruitt and Levine14 and have been expanded upon by others in recent years (Table 1)7,9. StrataGraft is a second-generation living skin substitute which possesses many of these characteristics. It contains both epidermis and dermis with tensile strength and barrier function comparable to that of intact human skin. The epidermal layer of StrataGraft skin substitute is generated from NIKS cells, a consistent source of pathogen-free human keratinocyte progenitor cells which are amenable to stable genetic modification with nonviral vectors (Thomas-Virnig et al.,15 and Rasmussen et al. [unpublished]). In this report, StrataGraft skin substitute was compared with cadaver allograft in patients undergoing sequential skin reconstruction procedures before autograft placement. The trial was conducted under an Investigational New Drug application with the US Food and Drug Administration (FDA). Table 1 Characteristics of the Ideal Biologic Skin Substitute*