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AUTHORS: Robert H. Demling, M.D. Leslie DeSanti R.N.,  Dennis P. Orgill, M.D. Ph.D.

BIOSYNTHETIC SKIN SUBSTITUTES:  PURPOSE, PROPERTIES & CLINICAL INDICATIONS

A) PURPOSE AND DESIGN CRITERIA OF ENGINEERED SKIN SUBSTITUTES

The evolution of biologic and synthetic dressings began with the recognition that burn wounds require a barrier protection to prevent infection and desiccation and cell guidance by dermal elements to maximize healing. Properties of both layers of skin are important to incorporate.

 

IMPORTANT DEVELOPMENT CRITERIA

  • bilayer concept of wound coverage
  • both epidermal and dermal analogs necessary for successful skin replacement
  • outer layer has a barrier function to facilitate healing
  • dermal elements important for cell guidance during re-epithelialization
  • dermal element will vary from an interface for healing (temporary substitute) to incorporation of dermal elements (permanent substitutes)
  • restore normal tissue architecture
  • avoid scar contracture

Increased understanding of the optimization of healing partial thickness wounds, occurred with the noted benefits of an adherent protective dressing, initiated the search for a temporary skin substitute which had barrier properties plus adherence properties. The addition of dermal components in particular collagen, have been added after recognition of the wound healing properties of this protein.

The increasing survival of massive burns, where available skin for auto grafting is very limited, has been the initial stimulus for the development of a permanent skin substitute. The increasing emphasis on rehabilitation and "quality of skin cover" has further accelerated this field. A skin substitute which has properties of a dermis is the marker for gauging a permanent substitute.

SKIN SUBSTITUTES

  • temporary - material designed to be placed on a fresh wound (partial thickness) and left until healed
  • semi-permanent-material remaining attached to the excised wound, and eventually replaced by autogeneous skin grafts
  • permanent incorporation of an epidermal analog, dermal analog, or both as a permanent replacement

 

REQUIREMENTS FOR SUCCESS (BIOSYNTHETIC SKIN SUBSTITUTE)

  • solve a clinical problem
  • approval by governmental regulatory agency
  • financially viable

 

AVAILABLE BIOLOGIC AND SYNTHETIC SKIN SUBSTITUTES

  • Naturally occurring tissues
    - Cutaneous allografts
    - Cutaneous xenografts
    - Amniotic membranes
  • Skin substitutes
    - Synthetic bilaminate
    - Collagen based composites
           Biobrane
           TransCyte
           Integra
  • Collagen based dermal analogs
    - Deepithelized allograft
    - Alloderm
  • Culture-derived tissue
    - Bilayer human tissue (Apligraf)
    - Cultured autologous keratinocytes
    - Fibroblast seeded dermal analogs
    - Collagen-glycosaminoglycan matrix
    - Polyglycolic or acid mesh
    - Epithelial seeded dermal analog

 

BIOLOGICALS (ALREADY MADE) Available biologic materials include allografts and xenografts.

Allograft (cadaver skin) has been considered the gold standard for temporary skin but eventual lack of an epidermis eliminates its barrier function and the outer layer will need to be added. Plus there is a major problem of availability. Its use in partial thickness wounds is not practical.

Xenografts (tissue from another species) is more accessible than allograft. However, xenografts cannot re-vascularizes from the wound so the tissue breaks down and sloughs off the wound.

B) RATIONALE FOR DEVELOPING BIOSYNTHETICS

Given the limitations of available biologic bilayer skin, the development of engineered skin substitutes became necessary using synthetics and incorporating biological active components. The biologically active agents have mainly been collagen and glycosamino glycan components of dermal matrix. More recently viable cells namely human keratinocytes and fibroblasts have become available through advances in bio-engineering and culture techniques. Therefore, current bilayer skin substitutes are usually composed of

  • a synthetic component
  • a biologically active component
 

C) SYNTHETIC MATERIALS

Advances in the technology of polymer chemistry has led to the develop of the epidermal analogs which are critical for the function of both temporary and permanent skin substitutes.

IDEAL PROPERTIES OF BIOSYNTHETIC SKIN SUBSTITUTE

  • rapid and sustained adherence to wound surface*
  • impermeable to exogenous bacteria
  • water vapor transmission similar to normal skin
  • inner surface structure that permits cell migration, proliferation and in growth of new tissue
  • flexibility and pliability to permit conformation to irregular wound surface, elasticity to permit motion of underlying body tissue
  • resistance to linear and shear stresses
  • prevention of proliferation of wound surface flora
  • tensile strength to resist fragmentation when removed
  • biodegradability (important for "permanently" implanted membranes
  • low cost
  • indefinite shelf life
  • minimal storage requirements
  • absence of antigenicity
  • tissue compatibility
  • absence of local and systemic toxicity

* The most important criteria is Adherence

 

AVAILABLE SYNTHETIC MATERIALS FOR SKIN SUBSTITUTES

SOLID SILICONE POLYMERS

  • uniquely permeable to water vapor
  • impermeable to bacteria and toxins
  • control evaporative water loss
  • flexible, durable, non-antigenic

POLYURETHANE, POLYVINYL

  • impermeable to bacteria, toxins
  • minimally permeable to water vapor which can lead to fluid collections
  • some flexibility
  • difficult to add pores without weakening structure

NYLON

  • can make into a fine weave markedly increasing surface area for contact
  • can control adherence by type of weave
  • can bond collagen
  • durable, non-allergenic
 

D) THE IMPORTANCE OF COLLAGEN

The phenomenon of contact guidance of cells to restore normal tissue anatomy is well recognized. Some cell alignment properties can be provided with a micro filamentous synthetic material such as nylon.

However numerous studies have demonstrated the importance of a collagen contact interface with the wound to guide the "healing process". Type one collagen provides contact guidance for epithelial cells and fibroblast allowing optimal migration and cell orientation.

Initial collagen based products lacked an outer synthetic protective layer and were prone to environmental insults. The rate of biodegradability which is related to the degree of cross-linking, is controlled by increasing cross-linking. However, the denser the cross-linking, the less the surface adherence and the stiffer the product. In addition, porosity is decreased leading to fluid accumulation and less adherence.

PROGRESSION OF COLLAGEN BASED DRESSINGS


Various views of laminated collagen sponge dressing in scanning electron microscopy. Left-top view showing multifilamentous gauze made of polyesther (A) attached to self-adhesive film (B). This lamination is permeable to air and secretions and has high tensile strength. Middle-bottom layer of collagen sponge matrix (700x). Right-side view, showing at the top cross-section through the gauze filaments (A) and a continuous film of a self-adhesive lamination (700x).

An advance was the addition of glycosaminoglycan to provide more porosity and a more durable structure. A further advance was the development of a bilaminar structure with an outer synthetic layer acting as a barrier and controlling water vapor while the inner layer acting as a dermal analog.

Characteristics of Collagen Utilized in Skin Substitutes
Physical Physical-Chemical Biological
high tensile strength

low extensibility

complex surface

morphology

 controllable

cross linking

regulating

solubility

swelling

tissue resorption

antigenicity

 minimal antigenicity by cross linking

chemotactic

stimulation of cell migration

adhesion site for cells through fibronectin
     

 

With the separation of skin substitute into temporary and permanent the structure of the dermal collagen analog has changed.

  • Temporary skin substitute
    - dermal analog not incorporated
    - a collagen protein or collagen peptide provides epithelial cell direction
  • Permanent skin substitute
    - dermal analog is incorporated to varying degrees to restore a dermis

E) TEMPORARY SKIN SUBSTITUTES FOR THE PARTIAL THICKNESS BURN

The objective of this approach is to actively alter the quality and rate of healing of a partial thickness burn. The approach is quite different from the standard treatment, where the rate of healing is patient dependent and treatment is focused mainly on infection control.

TEMPORARY SKIN SUBSTITUTES

  • control the wound healing environment
  • protection from healing retardants (epidermal analog)
  • biological enhancement of the healing process (dermal analog)

 

TEMPORARY SKIN SUBSTITUTES VERSUS TOPICAL ANTIBIOTICS

  • Clinical Advantages Skin Substitutes
    - Markedly reduces pain
    - Decreased heat, water loss
    - Decreases wound inflammation, drainage
    - Prevents surface drying in superficial wounds
    - Increases rate of epithelialization
    - Decreases surface infection
  • Disadvantages
    - Does not control deep infection
    - Can seal bacteria in as well as out
    - Biologicals can transmit infection
  • Indications
    - Superficial to mid second degree burn
    - Clean, excised wound
    - Skin donor sites

There are a number of products advertised as temporary skin substitutes, only two are truly a skin substitute having a bilayer with and epidermal and dermal components. These two products are discussed briefly in this section and in detail in later sections.

CRITERIA FOR USE

  • since adherence is essential for effectiveness, wound bed must be debrided to viable tissue
  • since temporary skin substitutes have no intrinsic bacteriocidal properties, the wound surface must not be infected

 

GOOD CANDIDATES FOR TEMPORARY BIOSYNTHETIC SKIN SUBSTITUTES

Superficial 2° burn after debridement

Scald burn in child

Clean superficial mid-dermal burn

Superficial hand burn

Clean excised wound

Wide meshed skin graft

2) NOT GOOD CANDIDATES FOR TEMPORARY SKIN SUBSTITUTES

Mid-deep dermal burn: too deep to allow for the necessary adherence as non-viable tissue on the surface

Alkali burns: appear less deep than the actual degree of tissue damage. Wound conversion is occurring for hours after exposure. Surface typically is non-viable.

 

BILAYER TEMPORARY SKIN SUBSTITUTES

BIOBRANE

  • bilaminar skin substitute
  • outer epidermal analog constructed of a thin silicone film with barrier functions comparable to skin
  • small pores present in silicone to allow for exudate removal, permeability to topical antibiotics
  • inner dermal analog composed of a three dimensional irregular nylon filament weave upon which is bonded type I collagen peptides
  • surface binding of inner membrane potentiated by collagen-fibrin bonds as well as fibrin deposition between nylon weave
  • subsequently fibronectin, produced by migrated fibroblasts, enhances binding to the fibrin entrapped in mesh 
  • new epithelial cells growing along mesh measures adherence
  • thin water layer at surface maintained for epidermal cell migration
  • removed after re-epithelialization (or prior to skin graft on excised wound)
  • silicone and nylon weave provides flexibility
  • long shelf life: maintained at room temperature

* Bertek Pharmaceuticals Inc.

 

TRANSCYTE

  • bilayer skin substitute
  • outer epidermal analog is a thin nonporous silicone film with barrier functions
  • inner dermal analog is layered human fibroblast products mainly collagen type I, fibronectin and glycosaminoglycan
  • subsequent cryo-preservation destroys fibroblasts but preserves activity of fibroblast derived products.
  • thin water layer at surface maintained for epidermal cell migration
  • removed after re-epithelialization (or prior to skin graft or excised wound
  • silicone provides flexibility
  • must be kept frozen until use (Smith and Nephew Wound Management)

 

E) COMPARISON OF TEMPORARY SKIN SUBSTITUTE PROPERTIES

COMPARISON OF THE ADHERENCE, PROPERTIES OF COMMONLY USED TEMPORARY SKIN SUBSTITUTES (BIOSYNTHETICS VS. BIOLOGICALS)

     
Biobrane Allograft Pigskin

24 hrs 72 hrs

* Adherence measured in g/cm2

(At 72 hrs: Biobrane adherence significantly greater than biologic grafts)

EVAPORATIVE WATER LOSS (EWL) (EXCISED WOUND)

       
Open Wound Biobrane Allograft Pigskin

1 day 3 days 5 days

At Day 1: Biobrane and pigskin reduced EWL by 90% , while at 5 days Biobrane and Pigskin had EWL comparable to normal skin.  Note: marked EWL of open wound (Pigskin-not meshed)

Antibiotic Permeability (Biobrane with Pores) Permeability to 1% Silver Sulfadiazine

Click the Image to Enlarge

(A new Composite Skin Prosthesis, Travis M, Bartlett R, Woodroof E., Burns 1979; 7:123)

Adherence, Pain, Infection Control

Comparative Ranking of Skin Substitutes
  Adherence Pain Control Infection Control Durability
Biobrane 1 same same 1
Pigskin 2 same same 2
Allograft 1 same same 2
 

Biobrane demonstrated improved adherence and durability compared to porine xenograft and allograft. Pain and infection control were comparable. (Comparison of Biobrane Porine and Human Allograft as Biologic Dressings for Burn Wounds, Frank D. Wachlor T., et al., Surg Forum 1980; 31:552) 

 

F) PERMANENT SKIN REPLACEMENT (FULL THICKNESS SKIN LOSS)

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

This area can be arbitrarily divided into two approaches. The first approach is the use of a bilayer skin substitute with the inner layer being incorporated as a dermis rather than removed like a temporary product. The outer layer is either a synthetic to be replaced by autograft (epidermis) or both together. The outer layer of these products is usually not sufficiently developed to act as a barrier upon initial placement.

The second approach is the provision of either an epidermal or dermal components or simply a co-culture of cells containing elements of both. These products are technically not skin substitutes upon initial placement as there is no bilayer structure. Both approaches will be discussed.

Permanent Skin Replacement

  • bilayer structures with biologic dermal analog and either synthetic or biologic epidermal analog
  • skin components
    - epidermal cells alone
    - dermis alone
    - co-culture of epidermal cells and fibroblasts
 

BILAYER PERMANENT SKIN SUBSTITUTES

INTEGRA (BILAYER WITH BIOACTIVE DERMAL ANALOG
  • dermal analog of a biodegradable collagen-glycosaminoglycan co-polymer matrix
  • epidermal analog is a thin silicone elastomer providing environmental barrier protection and water flux similar to normal skin
  • collagen type I and glycosaminoglycan have biologic wound healing activity
  • collagen and the GAG is cross linked in such a manner as to maximize in growth of cells and control the rate of matrix degradation
  • after neodermis formation, the epidermal analog (silicone) is removed and replaced with thin epidermal autograft or cultured epithelial cells
  • major causes of loss of dermal analog are infection and shearing with devascularizatin
  • stored in 70% isopropyl alcohol
  • development in progress is seeding of dermal analog with epidermal cells which could then produce epidermis (a one step skin replacement process)
  • clinical trials have been performed in burns

(* Integra Life Sciences)
 

 

APLIGRAF (BILAYER HUMAN EPIDERMIS & DERMAL ANALOG)
  • dermal analog is collagen matrix populated with fibroblasts which produced a dermal layer
  • dermal elements obtained from neonatal foreskin
  • dermal layer incorporates
  • epidermis is stratified and multilayer providing biologic barrier function
  • epidermis also obtained from neonatal foreskin
  • composite repopulated by host cells
  • clinical trials data in burns not yet available

(Apligraf Living Skin Equivalent, Organogenesis Inc., Canton MA)
 

 

COMPOSITE CULTURED SKIN (NOT TRUE BILAYER ON APPLICATION)
  • keratinocyte, fibroblast co-culture in cross linked bovine collagen sponge
  • non-porous side of sponge is seeded with keratinocytes from neonatal foreskin
  • porous side of sponge seeded with fibroblasts from neonatal foreskin
  • epidermal analog or protective barrier requires 14 days to develop with full adherence to dermis reported
  • multicenter trial on use in burns is underway

(Composite cultured skin: Ortec International, NY, NY)
 


EPIDERMIS ONLY

Cultured Epithelial Autograft (CEA)
  • epidermal layer replacement only
  • use of cell culture technology to grow small sample of patients keratinocytes up to 10,000 fold in surface area
  • 2-3 week period to produce desired amount
  • application on excised wounds or over incorporated allograft dermis
  • multilayer confluent epithelial sheet forms
  • epidermal-wound junction has incomplete basement membrane and low resistance to sheer forces
  • graft take on excised wound (28-50%) and on incorporated allograft dermis is 45-75%
  • clinical data available on use in burns

(Epicel-CEA Genzyme Tissue Repair, Cambridge, MA)
 

DERMAL REPLACEMENTS ONLY

Alloderm - Allograft Dermis
  • allograft epithelium removed
  • dermis treated to produce a cryopreserved lyophilized allodermis
  • not a bilayer product but acts strictly as a dermal transplant
  • no protective epidermal analog
  • product incorporation
  • requires application of thin epithelial autograft
  • potential problem of limited supply of allograft
  • no comparative studies as yet with other permanent skin substitutes

(Alloderm Life Cell Corp, Woodlands, Texas)
 

 

COLLAGEN MATRIX ALONE

  • not bilayer product
  • collagen matrix dermal analog fabricated with cross linked bovine collagen and denatured collagen (gelatin)
  • no epidermal analog
  • thin autograft applied after incorporation
  • not available in the United States

(Terudermis Terumo Co., Kanagawa, Japan)

 

EPIDERMAL CELLS AND FIBROBLASTS PLACED AS A CO-CULTURE

CULTURED EPITHELIAL AUTOGRAFT PLUS CULTURED FIBROBLAST

  • confluent sheet of keratinocytes plus fibroblasts
    - (neonatal foreskins)
  • no real barrier function on application
  • bilayer to be developed after application
  • no clinical studies in burns yet available

(Lifeskin Culture Technology, Sherman Oaks, CA)

 

SUMMARY

The scientific principles and practical approaches to replace skin temporarily or permanently are advancing at a rapid rate. Much of these advances can be attributed to both advances in the field of bio-engineering as well as increasing interest in optimizing the outcome of the burn wound.

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

As expected, the arena of temporary skin substitutes is more concrete, easier to categorize and determine efficacy with a bilayer structure being the current standard. 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. The terminology of the latter approach is difficult because these component products are nearly not skin substitutes on initial application but become so only when all the elements are in place.

For now, understanding the properties of each product is essential for the user to optimize outcome.

 

 
 

 


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