Chronic wounds are wounds that have not healed by themselves within a certain time period. They may be managed in a number of different ways such as specialised dressings, surgery (eg, skin grafts and flaps from the patient's own skin) or the use of bioengineered skin.
The development of bioengineered skin was motivated by the critical need to cover extensive burn injuries in patients with insufficient skin for grafting. Bioengineered skin substitutes have also been widely used for a variety of chronic wounds with the aim of faster healing, reduced infection, and better cosmetic appearance.
What is bioengineered skin?
Bioengineered skin consists of an outer epidermal layer and/or a dermal layer (the layer of skin between the epidermis and the subcutaneous tissue) embedded into an acellular matrix (a support structure) forming a biological skin substitute.
This ‘artificial’ tissue can be grown from the patient's own cells or from another ‘allogeneic‘ (non-self) sources. Most commercial bioengineered skin consist of sheets of cells derived from neonatal (allogenic) foreskin. Neonatal foreskin is chosen because:
- it is a convenient source obtained from healthy babies undergoing circumcision
- it has a high content of epidermal keratinocyte stem cells
- the cells grow vigorously with high metabolic activity
- allergic reactions against the cells are rare.
How does bioengineered skin work?
Bioengineered skin is designed to temporarily take over the functions of the epidermis and/or dermis until the patient's skin barrier repairs spontaneously or until definitive skin replacement is possible with a skin graft or cultured equivalent.
It is thought that bioengineered skin accelerates wound healing by introducing living cells to re-establish the conditions needed for repair including:
- Moist wound environment
- Structural support
- Cytokines and growth factors to stimulate immune response and tissue regeneration.
Important features for a biosynthetic skin substitute include:
- Rapid and sustained adherence to the wound surface
- Impermeability to external bacteria
- Allows water vapour transmission similar to normal skin
- Inner surface structure that permits cell migration/proliferation/in-growth of new tissue
- Flexible and pliable so it can conform to irregular wound surfaces
- Low cost
- Indefinite shelf life
- Minimal storage requirements
- Non-antigenic so not subjected to immune rejection by the host
- No local/systemic toxicity.
How does bioengineered skin compare with skin grafts?
Bioengineered skin substitutes represent artificial, off-the-shelf alternatives to skin grafts. Their advantages include:
- Less pain than skin grafting
- Fewer complications than skin grafting
- Always available in any quantity needed
- Can be applied in an office setting
- Negligible risk of cross-infection
- No requirement for graft harvesting and wound healing at the harvest site.
What is bioengineered skin used for?
Tissue-engineered skin substitutes have emerged as a potential alternative to skin grafting in patients with the following conditions:
- Stasis ulcer due to venous insufficiency
- Diabetic foot ulcers
- Ulcers associated with peripheral arterial disease
- Vasculitic ulcers
- Pressure ulcers (bedsores)
- Severe burns
- Epidermolysis bullosa (EB)
- Pyoderma gangrenosum
- Systemic sclerosis
- Breast reconstruction surgery
- Acute surgical wounds such as those caused by excision of skin cancer.
Commercial bioengineered skin products
Bioengineered skin products that are available commercially in USA and/or Europe are tabulated below.
|US FDA-approved indications
[LifeCell Inc. Woodlands, Texas, USA]
|Skin tissue donated from cadavers to make an acellular dermal matrix that has been freeze- dried after processing. It is used to serve as a scaffold for normal tissue remodeling. The collagen framework provides strength to the skin and contains no cells that can cause rejection or irritation. Duration of contact permanent.
Available in Australia on a case by case basis.
|Other formulations (Cymetra™, Repliform™) have been used to fill soft tissue defects in plastic, gynecologic, dental and urologic surgery
|Not rejected; no cases of viral trans-mission after >100,000 product application; 2 year shelf life
|Lacks cellular components
[Organogenesis Inc. Canton, MassachusettsUSA]
|Is a culture-derived human skin equivalent. Like human skin it has 2 layers. The upper epidermal layer is made of living human keratinocytes. The bottom dermal layer consists of human fibroblasts combined with bovine collagen to produce a matrix of proteins. This living skin construct is similar in cell proliferation to human skin. Duration of contact permanent.
Available in Australia for clinical trials only.
|Venous/ diabetic ulcers
|Epidermolysis bullosa; anecdotal reports, case studies and pilot trials in many other conditions such as recurrent hernia repair, major abdominal cavity re-constructio,burns and pressure sores
|Mimics function of dermis;cryo-preserved product
|5 day shelf life; awkward logistics of ordering and use
[Celadon Science LLC, Brookline, MassachusettsUSA]
|Is an allograft that contains active keratinocytes made from epithelial cells of neonatal foreskin. Although metabolically active they are not capable of proliferating.
|Partial and full thickness burns, venous wounds
|>6 month shelf life; relatively inexpensive; good results in many pilot studies
|Not FDA approved
[Smith and Nephew Inc. Largo, Florida, USA]
|Is a single layer biosynthetic dermal substitute made of human fibroblasts obtained from neonatal foreskin and cultured on a bioabsorbable polyglactin mesh for several weeks. Matrix proteins are secreted during the culture period and include human dermal collagens and soluble factors which create a three-dimensional matrix that is used as a dermal replacement or temporary skin substitute. Duration of contact permanent. Available in UK and Canada.
|Diabetic foot ulcers; ulcers secondary to epidermolysis bullosa
|Mimics function of dermis; cryo-preserved product
|Difficult logistics of ordering and application; short shelf life (unless stored cryopreserved)
[Genzyme Biosurgery, Cambridge, Massachusetts USA]
|Autologous keratinocytes from a patient’s healthy skin tissue are cultured to form cultured epidermal autografts. The autografts are processed into sheets that are attached to a petrolatum gauze backing using stainless steel surgical clips. Duration of contact permanent.
|Deep partial-thickness and full-thickness burns; congenital naevi
|Autologous cells; no rejection, high incidence of uptake
|Fragile; custom preparation; one day shelf life; inferior cosmesis in many patients
|Endoform® Dermal Template
[Aroa Biosurgery, New Zealand, marketed by Hollister Inc.]
|An xenograft extracellular matrix (ECM) composed of a complex mix of biological molecules. Provides structure, substrates and signals for regenerative healing. Restores cell-ECM interactions, aids cell migration, encourages new blood vessel formation and neutralises enzymes. Patients’ cells migrate into the scaffold. Typically, patients are treated once a week for 6 to 12 weeks.
|Diabetic, venous, arterial and pressure ulcers. Partial and full-thickness wounds and surgical, trauma, draining, tunneled/undermined wounds
|Matrix metalloproteinase inhibition; fast healing; economical; no fixation required; accessible at all wound care treatment sites; 3 year shelf life
|Not to be applied if uncontrolled infection, acute inflammation, excessive exudate or bleeding; not indicated for third degree burns
[Brennen Medical Inc. Saint Paul, Minnesota, USA]
|Is a porcine (pig) derived xenograft (non-human skin graft) of collagen that has been chemically crosslinked with aldehyde to provide strength and durability.
|Partial-thickness burns, venous ulcers, diabetic ulcers, pressure ulcers
|Relatively long shelf life
|Potential immune response and/or disease transmission
[Integra LifeSciences Corp.Plains-boro, NJ, USA]
|Is a bilayered (two layers) membrane system made of a porous matrix of fibres that crosslink bovine tendon collagen and glycosaminoglycan. The epidermal substitute layer is made of a thin poly silicone layer to control moisture. Duration of contact permanent.
Product available in Australia.
|Deep partial-thickness and full-thickness burns
|Two layers; good barrier function; used in over 10,000 patients; moderate shelf life
|Operative removal of silicone layer required
[Fidia Advanced Biopolymers, Italy]
|This product is based on a biodegradable matrix composed of a benzyl esterified hyaluronic acid derivative with ordered laser-perforated microholes for the in-growth and proliferation of autologous keratinocytes. Autologous keratinocytes are isolated from a skin biopsy and cultured directly on the matrix. The graft can be removed from culture without disturbing the arrangement of basement membrane proteins. Duration of contact permanent.
Currently, this product is commercially available only in Europe.
|Partial thickness burns, chronic venous and pressure ulcers, vitiligo
|Autologous cells; no rejection; high incidence of permanent take
|Two day shelf life; custom preparation; fragile
|Is an acellular skin substitute made from porcine (pig) small intestine. The matrix is composed of acellular collagen and acts as a wound covering. Accommodates the remodelling of host tissue by providing an acellular dermal scaffold for tissue growth.
|Partial/full-thickness pressure, venous and diabetic wounds/ burns
|1.5 year shelf life
|Potential immune response
[Ortec International Inc. New York, New York, USA]
|Formally known as composite cultured skin, is a living skin equivalent. This bilayered cellular matrix is made of human dermal cells [containing neonatal foreskin-derived cultured keratinocytes and fibroblasts ] cultured in bovine collagen sponge. Duration of contact permanent.
|Hand reconstruction surgery in patients suffering from recessive dystrophic epidermolysis bullosa and for healing of autograft donor sites in burn patients.
|Venous and diabetic wounds
|Mimics cytokine expression of healing skin; 9 month shelf life; cryo-preserved
|Requires cryopreserved storage
[Smith and Nephew Inc. Florida, USA; Advanced Tissue Sciences Inc. La Jolla, California, USA]
|Is a bilaminate skin substitute made of human fibroblasts cultured on a silicone covered nylon mesh and combined with a synthetic epidermal layer. Duration of contact temporary.
Product available in Australia.
|Full- and partial-thickness burns
|1.5 year shelf life frozen
|Silicone membrane must be removed
Although the initial capital cost of the bioengineered skin substitute is greater than standard wound dressings, cost-effectiveness analysis has shown that the overall cost of the use of bioengineered skin may be less than standard care due to earlier resolution of the wound and the shorter time in hospital/supported care.
The following ethical and/or religious concerns associated with the use of skin substitutes should be considered in the management of patients with chronic wounds.
- Use of donor organs or animal tissue in the preparation of bioengineered skin may raise issues for ethnic or religious groups, vegans, vegetarians, and animal rights activists.
- Transmission of viral and prion diseases and use of material from neonates.
Patients should be advised of the product constituents in bioengineered skin to ensure their informed consent.
Bioengineered skin substitutes are considered at least as safe as standard therapies for burns and wound care, based on evidence from randomised controlled trials.
Apligraf® is contraindicated for use in the following situations:
- Infected wounds
- Known allergy to bovine collagen
- Known hypersensitivity to components in the product's agarose shipping medium.
Dermagraft® is contraindicated for use in the following situations:
- Ulcers that have signs of clinical infection
- Ulcers that have sinus tracts
- Patients with known hypersensitivity to bovine products.
Challenges and future directions
Technological improvements may result in better bioengineered skin products in the future. Three-dimensional bioprinting or 3D bioprinting is an emerging technology that uses 3D printing techniques to deposit biological material to create artificial tissues and organs.
Controversies and unanswered questions associated with the design of bioengineered skin products include:
- Does adding dermal tissue improve results compared with application of cultured epidermal keratinocyte sheets alone?
- Does adding keratinocytes improve results obtained using a cultured fibroblast-containing matrix alone?
- Does freezing, thawing, and rinsing the cells damage them or wash away potentially beneficial growth factors required in wound healing?