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The Scientific Basis and Differentiating Features of Dermagraft

Christopher Roberts, PhD, MBA Jonathan Mansbridge, PhD

Can J Plast Surg. Volume 10, Suppl A, January/February 2002

abstract The large extent to which chronic wounds share causes and deficiencies in the overall repair process may support common approaches to treatment, such as those being developed by genetic and tissue engineering. As in many areas of biology, the mechanism of ulcer formation and maintenance probably involves synergy between several different mechanisms and redundancy, so that the same apparent result may develop by several different pathways. Optimal approaches to healing chronic wounds are likely to include multiple avenues of targeting the abnormalities to facilitate eventual closure. Dermagraft is derived using the emerging science of tissue engineering. It consists of a living, three-dimensional, neonatal human fibroblast-derived dermal implant and has been demonstrated, in randomized clinical

conclusions trials, to improve the healing of chronic wounds. It has been shown to provide key elements that are believed to be important in the wound repair process, including the provision of live, nonsenescent fibroblasts capable of colonizing the wound bed and persisting in situ; the production of growth factors, particularly angiogenic factors; the provision of a permissive substrate for keratinocyte migration; and the production of cytokines that are capable of modifying the inflammatory state of the ulcer. The aim of this review is to describe how new technologies such as Dermagraft can help to restore critical deficiencies in the repair of a chronic wound. In combination with appropriate wound care, Dermagraft may provide improved healing outcomes and a better quality of life for patients suffering from chronic wounds.

The clinical approach to impaired wound repair is advancing greatly with the development of products containing single growth factors and other biologically based systems, including living human cells. The use of human fibroblast-derived dermal substitutes, such as Dermagraft presents an innovative and potentially effective approach to healing chronic wounds. These new approaches are not ‘magic bullets’, but must always be used in combination with the basics of good wound care. These include correction of perfusion, aggressive debridement, infection control, provision of a moist-would environment and the off-loading of pressure.

comparison of fibroblast activity in culture systems and granulation tissue Granulation tissue

Scaffold-based, three-dimensional

Collagen gel, three-dimensional

Proliferation

High

High

Low

High

Collagen deposition

High

High

Low

Low

Provisional matrix proteins

High

High

Present

High

Angiogenic cytokines

High

High

Low

Moderate

Inflammatory cytokines

High

High

...

Low to Moderate

key points

Hemostasis

Dermagraft

Platelet Aggregation

Fills wound with normal tissue

Neutrophil Immigration G-CSF

Monocyte Immigration

IL-8 e

Normal Active Fibroblasts

Collagens Fibronectin GAG

Granulation Tissue

IL-6

e

Dermagraft

e e

e

Re-epithelialization

Anglogenesis

Substrate for Keratinocyte migration

e

TGF-ß

e

VEGF

e

• Dermagraft’s single layer dermal matrix may be all that is necessary for keratinocytes to adhere, proliferate, differentiate, and migrate across the wound bed

dermagraft healed wound

e e

• Keratinocytes aid in re-epithelialization and are generally found in abundance surrounding an ulcer. What they lack is a substrate on which they can migrate

Roberts & Mansbridge. Can J Plast Surg. 2002;10:11A.

e

• Cryopreservation enables Dermagraft to be rigorously tested prior to shipment and may improve clinical efficacy through the induction of a cellular stress response that enhances the ability of fibroblasts to survive in woundbeds

e

• Dermagraft’s three-dimensional scaffold optimizes the contribution of fibroblasts

e

• The wound healing process is orchestrated by the activity of fibroblasts in the dermal layer

Monolayer culture

Wound Closure HGF KGF

Scar Formation Remodeling

The contribution of Dermagraft (Advanced Tissue Sciences—Smith & Nephew Dermagraft Joint Venture) to targeting deficiencies of repair in chronic wounds. GAG Glycos-aminoglycan; G-CSF Granulocyte colony stimulating factor; HGF Hepatocyte growth factor; IL Interleukin; KGF Keratinocyte growth factor; TGF-b Transforming growth factorbeta; VEGF Vascular endothelial growth factor. Adapted from: Mansbridge et al. Diabetes Obes Metab. 1999;1:265. Roberts & Mansbridge. Can J Plast Surg. 2002;10:6A.

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