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Skin Substitutes
 the main requirement in burn wound management is an economical, easy to apply,
readily available dressing or method of coverage that will provide good pain relief,
protect the wound from infection, promote healing, prevent heat and fluid loss, be
elastic and non-antigenic and adhere well to the wound while waiting for
spontaneous epithelialization of superficial partial thickness burns or for permanent
coverage with autologous epithelium of deeper burn wounds.
 Methods for handling burn wounds have changed in recent decades. Increasingly,
aggressive surgical approach with early tangential excision and wound closure is
being applied.
 It is probably the most significant change in recent years leading to improvement
in mortality rates of burn victims at a substantially lower cost
 By shortening hospital stay, early wound closure reduces pain associated with local
burn wound care, number of operative procedures and infective complications.
 It also decreases the severity of hypertrophic scarring, joint contractures and
stiffness, and promotes quicker rehabilitation
 Irrespective of any other consideration, early healing is paramount for good
aesthetic and functional recovery.
 It has been clearly demonstrated that disruption of epidermal–mesenchymal
communication due to a delay in epithelialization, increases the frequency of
developing fibrotic conditions such as scar hypertrophy and contractures.
 successful artificial skin or skinlike material must replace all of the functions of
skin and, therefore, consist of a dermal portion and an epidermal portion.
 True closure is achieved only with living autografts or isografts (identical twins).
One exception, though, is human skin allografts in patients taking the usual
dosages of immunosuppressants for renal transplantation. In such category of
patients, skin allografts seem to survive indefinitely with minimal repopulation of
skin allografts by autogenous keratinocytes (KC) and fibroblasts. In case of
discontinuation of immunosuppression, the skin allograft does not reject acutely. It
persists clinically and the allograft cells are destroyed and replaced slowly with
autogenous cells
Classification
1. Dressing (synthetic)
2. Skin substitute (biosynthelic or allograft)
3. Autograft
Skin substitutes may be
1. permanent or temporary
2. biological or biosynthetic
3. dermal or epidermal or combined
Biological
Autologous
1. SSG
a. Limited in donor sites with major burns
b. creation of additional donor site wounds equivalent to second degree burns
thus further increasing the total body surface area
2. CEA
a. most important advantage of cultured keratinocyte allografts is the large
surface area obtained from a relatively small biopsy of healthy skin from the
patient.
b. Deep second degree burns remain an application of choice for the cultured
epithelia, as the presence of dermis limits retractions responsible for
functional complications usually observed in third degree burns where
dermis is absent
c. at least 3 weeks is needed for growth of cultured epidermal sheets in the
laboratory, thus delaying the coverage of wounds
d. epidermal sheets need to be grafted on a clean wound bed because they are
highly sensible to bacterial infection and toxicity of residual antiseptics;
e. best applied to intact dermis - the regeneration of the dermal compartment
underneath the epidermis is a lengthy process, and skin remains fragile for at
least 3 years and usually blisters
f. aesthetic aspect of the healed skin is less acceptable than the one obtained
with a split-thickness graft.
g. Storage and preservation of viable sheets have also been a major handicap
3. Keratinocytes delivery system
a. Many researches have been working on the development of alternative
systems for the delivery of cultured autologous keratinocytes
1. fibrin glue suspension
2. fibrin glue sheets
3. spray on cells
Allograft
1. Cadaveric allograft - temporary
a. Cryopreserved
b. Glycerolised
2. cultured allogeneic keratinocytes - temporary
a. survival appears to be related to presence of dermis (prolongs survival)
b. regarded as a wound cover (dressing) since they do not achieve wound
closure
3. lyophilized human dermis (Alloderm) - permanent
a. After processing, the skin is reduced to a basement membrane and properly
oriented dermal collagen matrix.
b. Preserved by freeze-drying
c. Result is an acellular human dermis that theoretically will not be rejected.
4. Amnion - temporary
a. efficiency of amniotic membrane in preserving healthy excised wound bed
and maintaining low bacterial count in contaminated wounds parallels that
of human skin allograft dressings
b. Contrary to human skin allograft, it has a fragile structure and is technically
more difficult to handle
c. special appeal in developing countries particularly where religious barriers
preclude the acceptance of bovine and porcine skin or cadaveric skin.
d. greater risk of contamination from pathogenic bacteria on placentas from
vaginal deliveries
e. proven to be impervious to micro-organisms and is usually free from toxic
material however, disease transmission remains a possibility as with any
biological material.
f. Unlike skin allografts, amniotic membranes do not get incorporated and
vascularised
g. Though amniotic membranes allow rapid epithelialization and early healing
in superficial and intermediate depth dermal burns, in deep dermal burns
the membrane is not adequate and usually disintegrates before healing
occurs
h. primarily used to cover debrided second degree burns until complete
healing, can provide a useful cover for microskin grafts as well or an overlay
of widely meshed autografts promoting early epithelialization and rapid
wound healing
Xenograft
1. Porcine skin is the most common source of xenograft because of its high
similarity to human skin.
2. Sterility is an essential concern with xenogeneic tissues transplanted on wounds.
Ionizing radiation appears to be the most suitable method for a guarantee of this
sterility and for application in mass production.
3. irradiation coupled with freeze-drying seems to decrease the antigenic properties
of the pigskin graft and to increase its potential to inhibit bacterial growth.
4. pigskin is a well-suited temporary dressing for the coverage of second-degree
burns, especially after early excision. It usually promotes scar-free healing, with
an average healing period of about 10 days.
5. In addition, pigskin provides a suitable overlay to cover widely meshed (1:8 to
1:12) autografts.
6. Because freeze-drying and irradiation are expensive, a low-cost alternative
preservation technique was successfully developed by using 98% glycerin as the
antiseptic followed by storage at room temperature for 20-300 days
Biosynthetics
Cell Free matrices
1. Integra
a. Dermal regeneration template
b. Bilaminar structure – cross-liked
bovine collagen and shark
glycosaminoglycan with a silicone
membrane that provides a
temporary epidermal function
c. Pore size 70-200m to allow
migration of patient’s own
keratinocytes and fibroblasts
d. Histology shows gradual dermal
remodelling resembling papillary
and reticular dermis but failing to
show rete ridges.
e. Graft take lower than SSG (80 vs 95%) but the same as allograft take
f. Advantages
i. Heals quicker
ii. Less scarring
iii. Better aesthetic result
iv. Reduced donor site morbidity – able to use thinner autografts. Use with
CEA reported, and said to be more durable than if CEA used alone.
g. Disadvantages
i. High learning curve
ii. Expensive
iii. 2 stage
2. Biobrane
a. Bilaminate membrane – nylon mesh fabric bonded to a thin layer of silicone,
b. Nylon mesh is coated with peptides derived from porcine type 1 collagen in
order to aid adherence to the wound bed and fibrovascular ingrowth
c. As the wound heals, Biobrane separates and can readily be peeled away
d. Adherence is slightly less than that of allografts before day five, but after a
further 72 hours it is greater.
e. Recommended for use on donor sites and superficial partial-thickness burns
within the first 6 hours
f. Has been used for temporary cover for freshly excised full-thickness wounds
g. Advantages
i. The single application reduces pain and costs.
ii. adherence of Biobrane reduces the incidence of infection
iii. allows bathing of the patient
iv. adapts to any body surface
v. Epithelialization is visible beneath Biobrane.
Cell containing matrices
1. Transcyte
a. No longer available
b. Biobrane seeded with neonatal fibroblasts in order to improve healing
properties
c. Outer layer: synthetic epidermal layer is biocompatible and protects the wound
surface from environmental insults. It is semi-permeable to allow fluid and
gas exchange.
d. The Inner layer: bio-engineered human dermal matrix, contains structural
proteins (type I, III, and V collagen), provisional matrix proteins (fibronectin,
tenascin, SPARC,), glycosaminoglycans (versican, decorin), and growth
factors (TGF-B1, KGF, VEGF, IGF-1).
e. Fibroblasts allowed to grow for 17 days producing fibronectin, type I collagen,
proteoglycans and growth factors
f. Then frozen to -70C which does not maintain metabolic activity of the
fibroblasts, however, the tissue matrix and bound growth factors are left intact.
g. Stored at -20C in specially designed cartridges (2 sheets/cartridge)
h. recommended for use as a temporary wound covering for surgically excised
full thickness and deep partial thickness thermal burn wounds prior to
autograft placement.
i. Autograft adherence as good with transcyte as with allograft
j. Transcyte easier to remove than allograft and with less bleeding
k. Heals quicker and less scarring
l. No trials comparing Transcyte vs Biobrane
2. Apligraf
a. Most sophisticated and expensive skin substitute
b. Outer layer: Neonatal allogeneic keratinocytes
c. dermal layer: composed of human fibroblasts in a bovine Type I bovine
collagen lattice. While matrix proteins and cytokines found in human skin are
present in Apligraf, Apligraf does not contain Langerhans cells, melanocytes,
macrophages, lymphocytes, blood vessels or hair follicles.
d. Primary role for treatment of chronic ulcers – three times more effective than
compression therapy alone
e. Donor fibroblasts probably last longer than keratinocytes but will eventually
be replaced. The matrix will remain
3. Dermagraft
a. Cryopreserved living dermal structure
b. Cultivated neonatal allogeneic fibroblasts on a polymer scaffold (Dexon or
Vicryl)
c. Cells secrete growth factors and dermal matrix proteins
d. Remain viable and metabolically active after implantation
e. Facilitates healing by stimulating the ingrowth of fibrovascular tissue from the
wound bed and reeithelialisation from the wound edges
f. Like Apligraf, is marketed for healing diabetic ulcers and not for burns
The future
Cytokine/ Gene therapy
 Local application of cytokines as proteins (transforming growth factor-TGFb,
heparin binding epidermal growth factor-like growth factor-HB-EGF, etc.) has
been shown to be ineffective and of little clinical value due to enzymes and
proteases locally present in the wound and because of lack of adequate receptors
 Large amounts of systemic IGF-I needed for the desired therapeutic effects result,
however, in serious side-effects, such as hypoglycemia, mental status changes,
edema, fatigue and headache. These adverse side-effects limit the therapeutic
utility of IGF-I in the treatment of burns
 Gene therapy is emerging as an effective therapeutic approach to improve clinical
outcomes after thermal injury
 Particle-mediated gene transfer in burnt skin is feasible and may provide a means
of introducing biologic agents into injured tissue capable of enhancing bacterial
clearance and improving wound healing.
 Hurdles include
o Ensuring therapeutic genes are expressed at the correct level for the
right amount of time.
o Ensuring that delivery vehicle that is taken up by cells