Major advances in care have resulted in a marked decrease in mortality and also morbidity, especially with massive burns.  In addition to survival the current focus in burn care is on improving the long term function and appearance of the healed or replaced skin cover as well as quality of life.

This focus on quality has generated a significant interest in the use of skin substitutes to be used to improve wound healing, to control pain, to more rapidly close a burn wound, to improve functional and cosmetic outcome, and, in the case of massive burns, to increase survival.

To more effectively address these new roles, the new generation of skin substitutes is biologically active.  The bioactivity can modulate the burn wound instead of just covering the wound. The new products to be discussed have not displaced the more inert standard burn wound dressings but rather are used in conjunction and for quite specific indications.

The skin substitutes are initially classified according to whether they are to be used as a temporary wound covering to decrease pain and augment healing or a permanent skin substitute to add to or replace the remaining skin components.

The ideal properties and indications for these products will be better clarified after a discussion of the function of normal skin and the effect of a burn on skin integrity.^1-18

A.   Role Of Bioactive Skin Substitutes

The major stimulus for advances in skin substitutes is to improve the quality of the closed burn wound, control pain and avoid poor quality skin.^18-20 

Temporary skin substitutes can improve the healing while decreasing pain in superficial burns once the blisters and non-viable tissue has been removed. ^16,17     In deeper burns the dead tissue will cause an inflammatory response producing both local and systemic effects.  The systemic effects include a profound increase in metabolic rate with a marked increase in muscle wasting, and impairment in immune defenses.^1,2  Controlling this systemic response, by earlier removal of the dead burn tissue and closure of the wound, has markedly decreased overall mortality morbidity.^1l-13 

Permanent skin substitutes can then be used to permanently close the excised burn, especially in large burns where there isn’t enough remaining skin to completely close the wound.^18-21

The addition of biological activity to the skin substitute, improves the healing process with the intention of more rapidly healing a superficial burn and restoring valuable dermal components in a deeper burn wound bed thereby minimizing scarring and optimizing function.^18-21  A list of the non-cellular components of dermis, used in available skin substitute, is shown below.^22-26  Human epidermal and dermal cells are usually also added to dermal elements in permanent skin substitutes in addition to these dermal components.

DERMAL COMPONENTS STIMULATING HEALING22-26

Structural component or scaffolding Biologically active component stimulating all phases of healing Collagen (protein) - Scaffold for cell migration and matrix deposition - Cell guidance Elastin (protein) - Tissue elasticity Fibronectin (protein) - Cell to cell adherence - Contact orientation for cells - Increases epithelial cell division, migration - Chemo attractant for fibroblasts, macrophages Growth Factors (proteins) Stimulate all phases of wound healing Glycosaminoglycan (glycosylated protein) - Cell adherence properties - Conduit for healing factors - Deactivator of proteases - Scaffold or foundation for dermal elements Hyaluronic Acid (complex carbohydrate) - Maintaining matrix hydrated - Decreases inflammation - Stimulates healing  - Proper cell alignment

 

 

AVAILABLE BIOLOGICALLY ACTIVE SKIN SUBSTITUTES Naturally occurring tissues Cutaneous allografts Cutaneous xenografts Amniotic membranes Porcine small intestinal submucosa Composite Synthetic-Biological Collagen based dermal analogs           Integra Culture-derived tissue Bilayer human tissue Cultured autologous keratinocytes Fibroblast seeded dermal analogs Epithelial seeded dermal analog

Skin substitutes can also be categorized as to use and indication into temporary or permanent. 

Temporary skin substitutes are used to:

- Help heal the partial thickness burn (or donor site)

- Close the clean excised wound until skin is available for grafting

There are typically no living cells present.

Permanent skin substitutes are used:

- To replace lost skin providing either epidermis or dermis, or both

- To provide a higher quality of skin than a thin skin graft

Most permanent skin substitutes contain viable skin cells as well as components of the dermal matrix.

C.     Temporary Bioactive Skin Substitutes

The purpose of a temporary skin substitute is twofold.  Temporary skin substitutes are typically a bilayer structure.  There is an outer epidermal analog and a more biologically active inner dermal analog.^18-21  The first objective is to close the wound, thereby protecting the wound from environmental insults.^18,19,27-29   The second objective is to provide an optimal wound healing environment by adding dermal factors which activate and stimulate wound healing.^18-29  Biologically active dermal components naturally are typically provided to the inner layer, which is then applied to the remaining dermis in a partial thickness burn or to an excised wound.  Below is a list of the commonly available dermal matrix elements present in these products, and their actions.

The currently available products are listed below:

1. Human Allograft (Cadaver skin)

Human allograft is generally used as a split-thickness graft after being procured from organ donors.^30-32  When used in a viable fresh or cryopreserved state, it vascularizes and remains the “gold standard” of temporary wound closures.  It can be refrigerated for up to 7 days, but must be stored frozen for extended periods.  It is also used in a non-viable state after preservation in glycerol or after lyophilization: however, most existing data describe best results when it is used in a viable state.  The epidermal component provides a barrier until rejected by the host in 3-4 weeks.  The dermis revascularizes and incorporates.

Homograft, another term for human allograft, can only be obtained from a tissue bank as strict protocols are required for harvesting and storage.  Donors must be rigidly screened for potential viral and bacterial disease to avoid any transmission of disease.  The product is in limited supply and very expensive.

The primary indication for use is to cover a large excised burn wound until an autogenous skin or a permanent skin substitute becomes available.  Allograft is also used to cover a wide meshed skin graft, sealing the interstices during the healing process.

2.     Xenografts

Although various animal skins have been used for many years to provide temporary coverage of wounds, only porcine xenograft is widely used today.^33-34  The epidermis of the porcine xenograft is removed and the split thickness dermis is provided in rolls.  Split-thickness porcine dermis can be used after cryopreservation, or after glycerol preservation.  It effectively provides temporary coverage of clean wounds such as superficial second degree burns and donor sites.^33,34  Porcine xenograft does not vascularize, but it will adhere to a clean superficial wound and can provide excellent pain control while the underlying wound heals. 

In general, xenograft is not as effective as homograft but is more readily available and less expensive. 

Primary indications are for coverage of partial thickness burns during healing and used burn wounds prior to skin grafting.

3.     Human Amnion

Human amniotic membrane is used in many parts of the world as a temporary dressing for clean superficial wounds such as partial-thickness burns, donor sites, and freshly excised burns.^35,36  Amniotic membrane is generally procured fresh and used after brief refrigerated storage.  It can also be used in a nonviable state after preservation with glycerol.  Amnion does not vascularize but still can provide effective temporary wound closure.  The principal concern with amnion is the difficulty in screening the material for viral diseases.  The risks of disease transmission must be balanced against the clinical need and the known characteristics of the donor.  The primary indications are the superficial burn and the excised wound.

Human Amnion Membrane Advantages Acts like biologic barrier of skin Decreases pain Easy to apply, remove Transparent Disadvantages Difficult to obtain, prepare and store Need to change every 2 days Disintegrates easily Risk of disease transfer

4. Oasis Wound Matrix® 

This product is a two-layer membrane.^39,40  The outer epidermal analog is constructed of a thin silicone film with barrier functions comparable to skin.  Small pores present in silicone allow for exudates removal and has permeability to topical antibiotics. 

The inner dermal analog is composed of a three-dimensional irregular nylon filament weave upon which is bonded type I collagen peptides.  The surface binding of inner membrane is potentiated by collagen-fibrin bonds as well as fibrin deposition between the nylon weave.  A thin water layer is maintained at the wound surface for epidermal cell migration maintaining moist wound healing.

Excellent adherence to the wound significantly decreases pain in the superficial partial thickness burns. The silicone and nylon weave provides flexibility.  The biobrane is removed once the partial thickness wound has re-epithelialized or the covered excised burn wound is ready for grafting.  However, if left in place for more than 2 weeks the product is difficult to remove as tissue grows into the inner layer.  Biobrane L contains a nylon fabric woven from monofilament threads that provide a less dense matrix and less adherence, preferred e.g. on a donor site.  There is likely very little direct bioactivity from the collagen peptides.⁴⁰  The product has a long shelf life and can be stored at room temperature.  It is also relatively inexpensive.

The primary indication is for closure of the clean superficial burn or the excised burn wound. 

Biobrane Advantages Bilayer analog Excellent adherence to a superficial burn Decreases pain Maintains flexibility Easy to store with long shelf life Relative inexpensive Disadvantages Has very little direct bioactivity Difficult to remove if left in place over 2 weeks

Components of Biobrane showing silicone layer and amino nylon mesh coated with collagen peptides

Outer surface shown.  Note pores

Biobrane on modest stretch: surface smooth

Scald Burn

Biobrane on Debrided Scald

Day one: nicely adherent to wound

Superficial thigh burn

Covered with Biobrane (Day 10)

Biobrane removal

Opaque appearance indicates burn wound has re-epithelialized

Temporary Skin Substitute Covering Mesh Graft

The coverage avoids damage to the interstices as re-epithelialization occurs

6.     TransCyte™

This product is also a bilayer skin substitute.^41,42  The outer epidermal analog is a thin nonporous silicone film with barrier functions comparable to skin.  The inner dermal analog is layered with human neonatal foreskin fibroblasts which produce products mainly collagen type I, fibronectin and glycosaminoglycans.

 A subsequent cryo-preservation destroys the fibroblasts but preserves the activity of fibroblast-derived products on the inner surface.  These products do stimulate the wound healing process.  A thin water layer is maintained at the wound surface for epidermal cell migration.

 The nylon mesh provides flexibility and excellent adherence properties significantly decrease pain in the partial thickness burn.  The product is peeled off after the wound has re-epithelialized. 

TransCyte must be stored at –70 C° in order to preserve the bioactivity of the dermal matrix products.

The primary indication is for closure of the clean superficial to mid-dermal burn, especially useful in children.  TransCyte is also indicated for the temporary closure of the excised wound prior to grafting.  Tissue growths tends to be less of a problem even if the product is kept in place for over two weeks.

TransCyte Advantages Bilayer analog Excellent adherence to a superficial to mid-dermal burn Decreases pain Provides bioactive dermal components Maintains flexibility Good outer barrier function Good Disadvantages Need to store frozen till use Relatively expensive

 

Components of TransCyte
Schema demonstrating the two-layer structure, the inner layer being bioactive.
TransCyte in Sealed Cassette
Stored at -70°Centigrade
TransCyte for Partial Thickness Hand Burn
Cutting the sheet to fit with a small overlap followed by initial immobilization until adherent
TransCyte on Foot Burn (3 days)
Note flexibility of the dressing
TransCyte on Leg Burn (10 days)
Opaque appearance indicating re-epithelialization beneath dressing for removal
TransCyte (Day 12)
Skin substitute being removed

D.     Permanent Skin Substitutes

The purpose of these products is to replace full thickness skin loss as well as to improve the quality of the skin, which has been replaced after a severe burn.^20-23

As opposed to the bilayer concept of the ideal temporary skin substitute, permanent skin replacement is much more complex.

There are two approaches to developing a permanent skin substitute.^21-23  The first approach is the use of a bilayer skin substitute, with the inner layer being incorporated into the wound as a neodermis, rather than removed like a temporary product.  The outer layer is either a synthetic to be replaced by autograft (epidermis) or actual human epithelial cells.  The epithelial cells, which will form epidermis barrier function, is not often sufficiently developed at placement to act immediately as an epidermal barrier.

The second approach is the provision of either just an epidermal or a dermal analog, i.e. a one layer tissue.  These products are technically not permanent skin substitutes upon initial placement as there is no bilayer structure.

1. Epicel

Epicel Advantages Patients own keratinocytes expanded several thousand fold Small skin biopsy required Can cover very large surfaces with reasonable graft take Used in large burns Disadvantages 2 to 3 week lag time for production Provides only the epidermal layer Epithelial layer can be quite fragile for some time Needs to be used immediately on delivery Very expensive

 

Epicel Placement

The epidermal cells are placed on the wound on pieces of 50cm2 petroleum gauze.  The pieces are then secured to the wound bed and immobilized for 2-3 weeks

Epicel at 3 weeks

Note new epithelium (whitish patches) on the upper leg where the gauze has been removed

2.     Alloderm

This product is basically treated human allograft with the epidermis removed.^50-52  The dermis is treated to produce a co preserved lyophilized allodermis, which incorporates.  The product is used as a dermal implant.  Therefore application of a thin epithelial autograft is required. Primary indication is for use in the replacement of soft tissue defects.  This product is not commonly used in large burns.  A period of incorporation is required before the epithelial skin graft can be applied.  The product has a long shelf life in its lyophilized form.  It requires re-hydration prior to use.

 

3.     Integra

This product is composed of a dermal analog made of a biodegradable bovine collagen-glycosaminoglycan copolymer matrix  The collagen and glycosaminoglycan is cross linked to attempt to maximize ingrowths of the patients own cells.^53-55

The epidermal analog is a thin silicone elastomer providing temporary barrier protection.  After the dermal analog incorporates and the surface revascularizes, at about 2-3 weeks, the silicone layer is removed and replaced with a very thin skin graft from the patient (or CEA cells).  The Integra needs to be carefully immobilized for the first 2 weeks as movement will cause devascularization and loss of the product.

The primary indication is the treatment of large deep burns as well as reconstruction procedures.  The incorporated neodermis appears to improve the function of the final skin once the epithelial graft is applied.  The product is provided in a number of sizes and sheets stored in 70% isopropyl alcohol.  Shelf life is very good.

SUMMARY

The scientific principles and practical approaches, to replacing skin either temporarily or permanently are advancing at a rapid rate.  Much of these advances can be attributed to both advances in the field of bioengineering as well as increasing interest in optimizing the outcome of the burned skin.

The ideal properties of a bioactive temporary and a permanent skin substitute have been well defined.

As expected, the properties of temporary skin substitutes are more concrete, easier to categorize and determine efficacy.  A bilayer structures is the current standard with the dermal component being bioactive.   Permanent skin replacement on the other hand is much more complex.  A variety of approaches are being used which can be loosely categorized as either use of bilayer products (usually the outer layer to be replaced by epidermal autograft) or replacement of either dermal or epidermal elements separately.  The terminology of the latter approach is difficult because these component products are really not permanent skin substitutes on initial application but become so only when all the elements are in place.

An understanding of the properties of each product is essential for the user to optimize outcome.

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