Download asernip-s review of bioengineered skin substitutes for the

ASERNIP S
Australian Safety
and Efficacy
Register of New
Interventional
Procedures - Surgical
Systematic Review
Bioengineered Skin Substitutes for the
Management of Burns:
A Systematic Review
ASERNIP-S REPORT NO. 46
August 2006
Australian Safety & Efficacy Register of
New Interventional Procedures – Surgical
The Royal Australasian College of Surgeons
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Bioengineered skin substitutes for the management of
burns: a systematic review
ISBN 0 909844 75 5
Published August 2006
This report should be cited in the following manner:
Pham CT, et al. Bioengineered skin substitutes for the management of burns: a
systematic review. ASERNIP-S Report No. 46. Adelaide, South Australia:
ASERNIP-S, August 2006.
Copies of these reports can be obtained from:
ASERNIP-S
PO Box 553,
Stepney, SA 5069
AUSTRALIA
Ph: 61-8-8363 7513
Fax: 61-8-8362 2077
E-Mail: [email protected]
http://www.surgeons.org/asernip-s
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
The Safety and Efficacy Classification for the
Systematic Review of Bioengineered Skin Substitutes for the
Management of Burns
was ratified by:
The ASERNIP-S Management Committee on
July 31, 2006
and
The Council of the Royal Australasian College of Surgeons on
August 26, 2006
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table of Contents
Executive Summary .......................................................................................... vi
The ASERNIP-S Classification System............................................................. x
The ASERNIP-S Review Group ...................................................................... xii
1.
Introduction ............................................................................................... 1
Objective...............................................................................................................................1
Context..................................................................................................................................1
Background ..........................................................................................................................2
Burns ...............................................................................................................................2
Burn management ...............................................................................................................4
Wound dressings and topical agents...........................................................................5
Biological skin replacements ........................................................................................5
Bioengineered skin substitutes.....................................................................................6
Summary ...............................................................................................................................8
2.
Methods.....................................................................................................12
Literature Search Protocol .............................................................................................. 12
Inclusion Criteria ........................................................................................................ 12
Literature Searches Strategies ......................................................................................... 14
Databases Searched and Search Terms Used ......................................................... 14
Methods of the Review.................................................................................................... 15
Literature Database .................................................................................................... 15
Ongoing and unpublished trials ............................................................................... 17
Data Extraction........................................................................................................... 17
Data Analysis............................................................................................................... 17
3.
Studies Included in the Review ................................................................19
Designation of Levels of Evidence and Critical Appraisal......................................... 19
Description of studies................................................................................................ 19
4.
Results ...................................................................................................... 28
Efficacy .............................................................................................................................. 28
Biobrane® ................................................................................................................... 28
TransCyte® ................................................................................................................. 32
Dermagraft® ............................................................................................................... 34
i
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Integra®........................................................................................................................36
Apligraf®......................................................................................................................38
Autologous cultured skin ...........................................................................................39
Allogeneic cultured skin .............................................................................................41
Complications ....................................................................................................................44
Biobrane® ....................................................................................................................44
TransCyte® ..................................................................................................................45
Dermagraft®................................................................................................................45
Integra®........................................................................................................................45
Apligraf®......................................................................................................................46
Autologous cultured skin ...........................................................................................46
Allogeneic cultured skin .............................................................................................46
Mortality .............................................................................................................................47
Biobrane® ....................................................................................................................47
Biobrane® ....................................................................................................................47
TransCyte® ..................................................................................................................47
Dermagraft®................................................................................................................47
Integra®........................................................................................................................47
Apligraf®......................................................................................................................48
Autologous cultured skin ...........................................................................................48
Allogeneic cultured skin .............................................................................................48
Cost considerations...........................................................................................................49
5.
Discussion ................................................................................................ 50
Limitations of the evidence .............................................................................................50
Efficacy outcomes.............................................................................................................51
Biobrane® ....................................................................................................................51
TransCyte® ..................................................................................................................52
Dermagraft®................................................................................................................53
Integra®........................................................................................................................53
Apligraf®......................................................................................................................54
Autologous cultured skin ...........................................................................................54
Allogeneic cultured skin .............................................................................................54
Biological skin replacements......................................................................................55
Safety outcomes.................................................................................................................55
ii
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Cost considerations .......................................................................................................... 56
Ethical considerations...................................................................................................... 56
Future research ................................................................................................................. 56
6.
Conclusions and Recommendations ....................................................... 58
Acknowledgments ............................................................................................................ 60
References .........................................................................................................61
Appendix A – Hierarchy Of Evidence.......................................................................... 68
Appendix B – Excluded Studies..................................................................................... 70
Appendix C – Methodological Assessment and Study Design Tables..................... 77
Appendix D – Mean Total Burn Surface Area for Included Studies ....................... 99
iii
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
List of Tables
Table 1. Classification of available skin substitutes ...........................................................9
Table 2. Databases searched................................................................................................14
Table 3. Summary of included randomised controlled trials*........................................20
Table 4. Losses to follow-up in Biobrane® for burn management studies .................22
Table 5. Losses to follow-up in Dermagraft® for burn management studies.............24
Table 6. Losses to follow-up in Integra® for burn management studies.....................25
Table 7. Losses to follow-up in Apligraf® for burn management studies...................26
Table 8. Wound healing time for burns managed with Biobrane® and comparators29
Table 9. Number of wounds requiring skin grafting to close the wound.....................29
Table 10. Wound pain scores for burns managed with Biobrane® and comparators30
Table 11. Wound healing time (days) for donor sites managed with Biobrane® and
comparators: part 1...............................................................................................................31
Table 12. Wound healing time (days) for donor sites managed with Biobrane® and
comparators: part 2...............................................................................................................31
Table 13. Percentages of sites completely healed by Day 32..........................................31
Table 14. Scar severity (mean scores) for Biobrane® versus OrCel™.........................32
Table 15. Wound infection for burns managed with TransCyte® and comparators .33
Table 16. Wound healing time for burns managed with TransCyte® and comparators
.................................................................................................................................................33
Table 17. Wound pain scores for burns managed with TransCyte® and topical
antibiotics ...............................................................................................................................34
Table 18. Percent graft take for burns managed with Dermagraft® and allograft .....36
Table 19. Proportion of patients with ≥75% wound closure for Integra® and
comparators ...........................................................................................................................37
Table 20. Proportion of patients with ≥75% wound closure for Apligraf® and
autograft .................................................................................................................................38
Table 21. Other patient-related outcomes for Waymack 2000 (n=40).........................39
iv
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table 22. Wound closure, graft take and number of patients requiring skin grafting 40
Table 23. Other patient-related outcomes for Boyce 2002 (n=45) .............................. 41
Table 24. Wound healing time (mean days) for donor sites managed with an
allogeneic cultured skin and comparators......................................................................... 42
Table 25. Percentage of epithelialisation for donor sites managed with allogeneic
cultured keratinocyte sheets and OpSite® ....................................................................... 43
Table 26. Breakdown of cost information from Demling & DeSanti 2002................ 49
v
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Executive Summary
Objective
To assess the safety and efficacy of bioengineered skin substitutes in comparison
with biological skin replacements and/or standard dressing methods in the
management of burns, through a systematic review of the literature.
Methods
Search strategy – Studies were identified by searching MEDLINE, EMBASE, The
Cochrane Library, Science Citation Index and Current Contents from inception to
April 2006. The Clinical Trials Database (US), NHS Centre for Research and
Dissemination, NHS Health Technology Assessment (UK), National Research
Register (UK), National Institute of Health (US) and Meta Register of Controlled
Trials were also searched in April 2006.
Study selection – Only randomised controlled trials in humans were included for
review. Efficacy outcomes included wound infection, wound closure, wound healing
time, and wound exudate. Patient-related outcomes included pain and cosmesis.
Safety outcomes included complications and mortality.
Data collection and analysis – Data from the included studies was extracted by an
ASERNIP-S researcher using standardised data extraction tables developed a priori
and checked by a second researcher. Statistical pooling was not appropriate due to
the study and result heterogeneity.
Results
A total of 20 randomised controlled trials were included in this review. Due to the
diversity of skin substitutes and methods for burn management and the way in which
outcomes were reported in the included studies, it was not possible to investigate
differences in the effectiveness of bioengineered skin substitutes in partial thickness
compared with full thickness burns, in paediatric patients compared to adult patients,
and for TBSA. However, from the available evidence it was possible to draw some
conclusions about the different bioengineered skin substitutes considered in the
review.
For partial thickness burns (less than 15%TBSA), Biobrane® and TransCyte®
appear to be more effective than silver sulfadiazine, avoiding the need for painful
daily dressing changes and prolonged hospital stay. Biobrane® may also offer cost
advantages over other bioengineered skin substitutes.
vi
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
For burns between 20% and 50% TBSA, allogeneic cultured skin and Apligraf®
combined with autograft both appear to be effective. Dermagraft® was also found to
be effective for partial and full thickness burns (as effective as allograft); however,
the validity of this comparison is questionable as Dermagraft® is permanently
integrated whereas allograft is a temporary biological dressing.
Integra® may be better suited to selected patients with burns less than 45% TBSA
due to the high rates of infection reported in one study managing patients with burns
greater than 45% TBSA. However, in clinical practice, Integra® is commonly used in
the treatment of major burn injury where a paucity of available donor area precludes
early autografting. Its successful take still has to be followed by definitive epidermal
closure (by autograft or cultured epithelial autograft).
TransCyte® appears to be good for facial burns, providing good adherence to the
contours of the face. However, considerations with the storage, pre-use preparation
and high cost of TransCyte® may limit its clinical use.
In terms of safety, no major complications were reported with the use of
bioengineered skin substitutes for the management of burns or donor sites. The
mortality rate was relatively high; however, it was unclear whether these deaths could
be attributed to the use of the bioengineered skin substitute or the actual burn injury.
In practical terms, this distinction would be difficult to assess since the use of
bioengineered skin substitutes is largely confined to patients with larger TBSA burn
areas, more complicated pathophysiological insults and significantly poorer
prognoses. The available evidence could not resolve the question of the long-term
safety of bioengineered skin substitutes with respect to viral infection and prion
disease. Thus, at present, autograft remain the gold standard for the management of
excised burns as it is effective at closing the wound and there are no issues with graft
rejection and viral contamination.
Classification and Recommendations
On the basis of the evidence presented in this systematic review, the ASERNIP-S
Review Group agreed on the following classifications and recommendations
concerning the safety and efficacy of bioengineered skin substitutes for the
management of burns:
Classifications
Evidence rating
The evidence-base in this review is rated as average. The included randomised
controlled trials were limited by small sample size and poor reporting of
methodological detail. The numerous sub-group analyses and the diversity of skin
substitutes limited the ability to draw any conclusions from it.
vii
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Safety
The evidence suggests that bioengineered skin substitutes, namely Biobrane®,
TransCyte®, Dermagraft®, Apligraf®, autologous cultured skin, and allogeneic
cultured skin, are at least as safe as biological skin replacements or topical
agents/wound dressings. The safety of Integra® could not be determined as one
study reported a high rate of infection and the trial was terminated early.
The long-term safety of the use of bioengineered skin substitutes, with respect to
viral infection and prion disease, could not be determined.
Efficacy
For the management of partial thickness burns, the evidence suggests that
bioengineered skin substitutes, namely Biobrane®, TransCyte®, Dermagraft®, and
allogeneic cultured skin, are at least as efficacious as topical agents/wound dressings
or allograft. Apligraf® combined with autograft is at least as efficacious as autograft
alone.
For the management of full thickness burns, the efficacy of autologous cultured skin
could not be determined based on the available evidence.
The efficacy of Integra® could not be determined based on the available evidence.
Clinical and Research Recommendations
Additional methodologically rigorous randomised controlled trials would strengthen
the evidence base for the use of bioengineered skin substitutes. However, it is
acknowledged that it is unlikely that randomised trials of patients with large, deep
burns will be carried out, as these burns are uncommon and usually involve complex
clinical decision pathways and possibly the use of several products, which may differ
between patients and make comparisons difficult. Therefore, it is recommended that
randomised trials of patients with smaller burns be undertaken as these burns are
more common and patient accrual should be easier. Furthermore, clinical equipoise
should be more easily obtained in these less life-threatening situations. Additionally,
studies with sufficient follow-up should be conducted to evaluate the long-term
safety of bioengineered skin substitutes and future studies should define and
document outcomes for partial and full thickness burns separately.
There is also a need for randomised controlled trials on cultured epithelial autograft,
in particular cultured epithelial autograft suspensions, as there is a lack of evidence to
support its safety and efficacy and its use largely based on anecdote.
Important note
The information contained in this report is a distillation of the best available evidence
located at the time the searches were completed as stated in the protocol. Please
viii
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
consult with your health care professional if you have further questions relating to
the information provided, as the clinical context may vary from patient to patient.
ix
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
The ASERNIP-S Classification System
Evidence Rating
The evidence for ASERNIP-S systematic reviews is classified as Good, Average or
Poor, based on the quality and availability of this evidence. High quality evidence is
defined here as having a low risk of bias and no other significant flaws. While high
quality randomised controlled trials are regarded as the best kind of evidence for
comparing interventions, it may not be practical or ethical to undertake them for
some surgical procedures, or the relevant randomised controlled trials may not yet
have been carried out. This means that it may not be possible for the evidence on
some procedures to be classified as good.
Good
Most of the evidence is from a high quality systematic review of all relevant
randomised trials or from at least one high quality randomised controlled trial of
sufficient power. The component studies should show consistent results, the
differences between the interventions being compared should be large enough to be
important, and the results should be precise with minimal uncertainty.
Average
Most of the evidence is from high quality quasi-randomised controlled trials, or from
non-randomised comparative studies without significant flaws, such as large losses to
follow-up and obvious baseline differences between the comparison groups. There is
a greater risk of bias, confounding and chance relationships compared to high-quality
randomised controlled trials, but there is still a moderate probability that the
relationships are causal.
An inconclusive systematic review based on small randomised controlled trials that
lack the power to detect a difference between interventions and randomized
controlled trials of moderate or uncertain quality may attract a rating of average.
Poor
Most of the evidence is from case series, or studies of the above designs with
significant flaws or a high risk of bias. A poor rating may also be given if there is
insufficient evidence.
x
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Safety and Efficacy Classification
Safety
At least as safe compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is at least as safe as the comparator.
Safety cannot be determined
This grading is given if the evidence is insufficient to determine the safety of the
new intervention.
Less safe compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is not as safe as the comparator.
Efficacy
At least as efficacious compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is at least as efficacious as the comparator.
Efficacy cannot be determined
This grading is given if the evidence is insufficient to determine the efficacy of
the new intervention.
Less efficacious compared to comparator* procedure(s)
This grading is based on the systematic review showing that the new
intervention is not as efficacious as the comparator.
Research Recommendations
It may be recommended that an audit or a controlled (ideally randomised) clinical
trial be undertaken in order to strengthen the evidence base.
Clinical Recommendations
Additional recommendations for use of the new intervention in clinical practice may
be provided to ensure appropriate use of the procedure by sufficiently qualified/
experienced centres and on specific patient types (where appropriate).
* A comparator may be the current ‘gold standard’ procedure, and alternative procedure, a nonsurgical procedure or no treatment (natural history)
xi
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
The ASERNIP-S Review Group
ASERNIP-S Director
Professor Guy Maddern
ASERNIP-S
Royal Australasian College of Surgeons
Stepney SA 5069
Protocol Surgeon
Mr John Greenwood
Director of Burns Unit, Royal Adelaide Hospital
North Terrace
Adelaide SA 5000
Advisory Surgeon
Dr Heather Cleland
Director of Burns Unit, The Alfred Hospital
Elizabeth Street
Melbourne VIC 3000
Other Specialty Surgeon
Associate Professor Peter Woodruff
Vascular Surgical Unit
Princess Alexandra Hospital
Woolloongabba QLD 4102
ASERNIP-S Researcher
Ms Clarabelle Pham
ASERNIP-S
Royal Australasian College of Surgeons
Stepney SA 5069
Conflict of Interest
None of the authors declared a conflict of interest.
xii
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
1. Introduction
Objective
To assess the safety and efficacy of bioengineered skin substitutes in comparison
with biological skin replacements and/or standard dressing methods in the
management of burns, through a systematic review of the literature.
Context
Burn injuries are amongst the most complex and harmful physical injuries to evaluate
and manage. In addition to pain and distress, a large burn injury will leave the patient
with visible physical scars and invisible psychological sequelae. Bioengineered skin
substitutes have been developed as an adjunct or alternative to the use of the
patient’s own skin (autograft), the current gold standard (Jones et al. 2002). They are
designed to close the wound, temporarily or permanently, providing a mechanical
barrier to infection and fluid loss. They also possess various biological and
pharmacological properties of human skin which allow and/or promote new tissue
growth and optimise the conditions for healing (Demling et al. 2000).
In Australia and New Zealand, approximately 1% of the population sustain burn
injuries annually (~220 000 people) (Australia and New Zealand Burn Association
Ltd. 1996). Of these, 50% will suffer restriction of their activities of daily living
(~110 000 people), 10% of those will require admission to hospital (~10 000 people)
and 10% of those will have burn injuries sufficiently severe to threaten life (~1000
people) (Australia and New Zealand Burn Association Ltd. 1996). In the United
Kingdom, approximately 0.42% of the population (~250 000 people) are burnt
annually with about 70% (~175 000 people) attending accident and emergency
departments and about 5% (~12 500) being admitted to hospital (Hettiaratchy and
Dziewulski 2004).
The type and severity of burn will determine the management required. Management
of superficial burns involves the use of antibacterial topical agents, dressings and
certain biosynthetic skin substitutes (epidermal replacements). However, for major
deep burns, management involves surgical debridement of the burn wound and the
additional use of autograft with or without other biological skin replacements
(allografts or xenografts) and bioengineered skin substitutes (biosynthetic skin
substitutes and autologous cultured/non-cultured skin engineering products). The
use of bioengineered skin substitutes is usually mandated by a deficiency of autograft.
However, there is uncertainty about the safety and effectiveness of the various types
of skin substitutes available.
SECTION 1
z
INTRODUCTION
1
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Background
Burns
Skin is the largest organ in the human body (Balasubramani et al. 2001). It consists of
a thin, cellular, superficial layer - the epidermis - which acts as a barrier against
infection and moisture loss, and a thick, deeper layer - the dermis - which is
responsible for the elasticity and mechanical integrity of skin. The dermis contains
adenexal structures and blood vessels responsible for the health and nutrition of the
epidermal cells (Jones et al. 2002) (see Figure 1).
Figure 1. The layers of the skin
If the dermis is exposed through a burn injury, the body’s innate wound healing
cascade is activated. Wound healing is a complex process with four main overlapping
phases (Hunt et al. 2000):
1. Coagulation – begins immediately after injury. Platelets are involved in the
release of cytokines and mediators which stimulate epidermal cell
proliferation and attract early debriding cell populations such as neutrophils
into the wound.
2. Inflammation – may last from a few days to weeks. Macrophages are
involved in the release of chemical messengers that stimulate angiogenesis
(necessary to re-establish a blood supply to the wound). Any factor which
leads to prolongation of the inflammatory phase will result in worsening of
the scar result; functionally, cosmetically and symptomatologically.
2
SECTION 1
z
INTRODUCTION
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
3. Proliferation and cell migration – periwound keratinocytes, and any
surviving keratinocyte nests around adenexal structures within the wound,
rapidly divide to increase their numbers. Their migration across the wound
results in epithelialisation, re-establishing the epidermal barrier. The
interaction of collagen and fibroblasts results in wound contraction reducing
the distance that epithelial cells need to migrate to effectively complete
epithelialisation.
4. Remodelling (maturation) – may last up to two years. This process of scar
tissue formation is facilitated by the presence of intermatrix ground
substances, glycosaminoglycans and proteoglycans, which maintain hydration
and support to the neo-collagen.
The agents capable of causing burn injuries are many and varied but can broadly be
placed into one of five groups: heat, cold, electricity, chemicals and ionising radiation
(Hettiaratchy and Dziewulski 2004).
Treatment will depend on the burn depth (see Figure 2). Burn injury depth is
classified as follows (Papini 2004):
™
Epidermal burns – cell death affects only the epidermal cells. These rapidly
dividing cell populations are capable of regeneration and, as such, these injuries
heal spontaneously and without scarring.
™
Superficial to mid partial thickness burns – affects the epidermis and upper
dermis. Healing again is spontaneous. Any injury involving the dermis
generates scar tissue, but in the more superficial cases the scar is almost
unnoticeable.
™
Deep partial thickness burns – all epidermal cell nests capable of
proliferation are lost, the healing process is slower and involves contraction if
injuries are extensive or in functionally or cosmetically sensitive areas.
™
Full thickness burns – all elements essential for skin regeneration have been
destroyed; contraction is marked, healing very slow and scarring unacceptable.
The products used to manage each burn wound will differ and depend on the depth
of the burn. For epidermal to superficial-mid partial thickness burns, a skin substitute
may be used as a definitive treatment and to potentially circumvent the need for
autografting. For deep partial to full thickness burns, a skin substitute will be used as
a temporised matrix when there is no alternative or as a material to hold the skin
graft in place.
SECTION 1
z
INTRODUCTION
3
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Figure 2. Burn depth
Burn management
The principle of burn management is to allow superficial burns to heal whilst
minimising discomfort, avoiding infection and producing no or negligible scar.
4
SECTION 1
z
INTRODUCTION
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Generally, burn injuries to the epidermis alone, or with a superficial amount of
dermis, will heal spontaneously and require only conservative management with
wound dressings and/or topical agents. However, deep dermal burns have a
protracted healing course which results in significant scarring and full thickness burns
(other than small injuries) are unlikely to heal spontaneously because the epidermal
cell nests responsible for re-epithelialisation are lost and there is deep destruction of
dermal collagen. Surgical management of deep burns involves the removal of nonviable, burn-injured tissue and permanently closing the burn wound in a timely
fashion designed to generate the best cosmetic, functional and symptomatological
result.
Wound dressings and topical agents
A variety of wound dressings are available which can be used alone, if appropriate, or
with topical agents. The properties of these dressing materials differ and include
(Demling et al. 2000):
™
antibacterial (to control infection)
™
absorbency (to control heavily exuding wounds)
™
non-adhesiveness (designed to not stick to the wound, thus minimising
discomfort on dressing changes)
™
occlusion/semi-occlusion (designed to provide a healing environment for a
clean, minimally exudative wound, whilst preventing bacterial contamination
and protecting the surrounding uninvolved tissue from wound exudate).
For the treatment of burns, antibacterial topical agents such as nanocrystalline silver
(impregnated in Acticoat™ dressings) (Dunn and Edwards-Jones 2004), silver
sulfadiazine (Dunn and Edwards-Jones 2004) and mafenide acetate (Brown et al.
2004) are used in the acute phase where there has been considerable contamination
of the burn wound, or where a lengthy delay is expected before the patient can
expect to receive definitive burn treatment.
These topical agents and wound dressings are only used to cover the wound and
provide a warm, moist environment, conducive to wound healing. They cannot
‘close’ the wound like skin replacements/substitutes.
Biological skin replacements
Biological skin replacements are defined as materials derived from wholly biological
sources. The gold standard for surgical repair after excision of a burn wound is the
use of a skin graft harvested from the patient’s own undamaged skin (an autograft).
Alternatively, if autograft is scarce, cadaver skin (an allograft) or a graft derived from
animal skin products (a xenograft) may be used to temporarily close and modulate
the wound bed.
SECTION 1
z
INTRODUCTION
5
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Of these, only autograft usually remains permanently. As allografts and xenografts
are allogeneic, they are rejected after a variable period and therefore can only be used
as a biological dressing until spontaneous skin repair occurs or definitive skin
replacement becomes available. Occasionally, dermal elements of cadaver allograft
may remain permanently.
The supply of cadaver skin is provided by registered, regulated skin banks. The
availability of cadaver skin is limited by the geographical location of skin banks, the
expense of processing and storage, and the potential difficulties associated with
emergency transport of such materials when needed. Their desirability may be
reduced by the potential for disease transmission (particularly prion-related) and the
quality of the material after the cryopreservation process (Eisenbud et al. 2004).
Currently, there are only two skin banking facilities that are licensed by the
Therapeutic Goods Administration (TGA) to provide human skin allografts; the
Donor Tissue Bank of Victoria and the Auckland Skin Bank, which operates under
the auspices of the New Zealand Red Cross Blood Transfusion Service (Hancock
1999).
Porcine skin products are the most commonly used xenografting materials,
particularly de-epidermised dermis such as EZ Derm™ (Brennen Medical, Inc., St.
Paul, Minnesota, USA). They are more readily available than cadaver allograft, but
their use is restricted to partial thickness burns (Demling et al. 2000). However, the
beliefs of certain religions must be considered when planning the use of these
materials. Although used on a widespread basis in the USA and Europe, they are not
yet licensed in Australia (J Greenwood: personal communication, 2005).
Bioengineered skin substitutes
Bioengineered skin substitutes have been designed to offer therapeutic alternatives
that are readily available and have some of the biological and pharmacological
properties of human skin (Herman 2002). There are two main categories of
bioengineered skin substitutes; biosynthetic skin substitutes and autologous cultured
and non-cultured skin engineering products. Table 1 is a summary and taxonomy of
skin substitutes available in Australia and internationally.
Biosynthetic skin substitutes
The biosynthetic skin substitutes are a family of materials which have been
developed to mimic a function of the skin and are designed to be used in situations
when full or variable thicknesses of skin have been lost (Eisenbud et al. 2004). Some
are designed to replace the functions of the epidermis, some to replace the functions
of the dermis and some to replace the functions of both epidermis and dermis. Most
are for use temporarily as highly specialised dressings to replace skin functions until
the skin barrier repairs spontaneously, or to ‘buy time’ until definitive skin
replacement is possible with autograft or cultured equivalent. Epidermal substitutes
allow re-epithelialisation to occur while permitting gas and fluid exchange, providing
6
SECTION 1
z
INTRODUCTION
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
both protection from bacterial ingress and mechanical coverage (aiding relief from
discomfort). A small number are designed to permanently incorporate into the
debrided wound, for example, by generating a neo-dermis. This large group of
materials may be completely synthetic in their composition but most have some
biological element incorporated into them (Demling et al. 2000). There are a large
number of biosynthetic skin substitutes available worldwide; however, in Australia
only Biobrane®, TransCyte® and Integra® are available (see Table 1). Of these,
TransCyte® and Integra® are licensed by the Therapeutic Goods Administration
(TGA) and are freely available. Smith & Nephew Pty. Ltd. have recently placed the
manufacturer of TransCyte® (Advanced Tissue Sciences, Inc., La Jolla, CA, USA) on
the market and as a result, it is expected that no new stock of TransCyte® will be
available from the beginning of 2006. Biobrane® is also available via the Special
Access Scheme (Therapeutic Goods Administration 2004a) requiring yearly
reapplication for permission to use an unapproved product (J Greenwood, personal
communication 2005).
Autologous cultured and non-cultured skin engineering products
In an attempt to address the expense and other disadvantages of allografts and
xenografts, methods for expanding the patient’s own cell populations have been
developed. Since 1975, a process for the culture of keratinocytes has been available
(Rheinwald and Green 1975). Keratinocytes are rapidly dividing epidermal cells and,
by sacrificing a small sample biopsy of uninjured skin, huge numbers of keratinocytes
can be grown in a relatively short time. Cultured and non-cultured skin engineering
products are a rapidly growing group of materials in which techniques have been
employed to expand available autograft, either by creating cultured keratinocyte
sheets or suspensions, or enzymatically generating non-cultured epithelial cell
suspensions (Eisenbud et al. 2004). Keratinocyte replacements require dermal support
and as such, they are at present used in an attempt to facilitate rapid reepithelialisation in superficial partial thickness burns (where dermal elements are
uninjured), as an adjunct to meshed autograft, or over bioengineered neo-dermis.
Many centres are working towards engineered composite skin replacement utilising a
molecular scaffold (e.g. fibrin, fibronectin, vitronectin, or collagen) seeded with
autologous fibroblasts. This arrangement allows these cells to create an ‘autologous’
neo-dermis onto the ‘outer surface’ of which can be cultured autologous
keratinocytes. Though the use of autologous cells is immunologically safe, there are
issues with cost, short shelf-life, fragility and the need for custom preparation
(Eisenbud et al. 2004).
Cultured keratinocytes are now listed as a Class 3 Human Cell, Tissue and Cellular
and Tissue-Based Products, where laboratories manufacturing such products are
inspected, audited, licensed and regulated with subsequent monitoring (Therapeutic
Goods Administration 2004b). The Therapeutic Goods Administration’s Special
Access Scheme offers arrangements to provide for the import and/or supply of an
SECTION 1
z
INTRODUCTION
7
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
unapproved therapeutic good, such as cultured keratinocytes, for a single patient, on
a case by case basis (Therapeutic Goods Administration 2004a).
Enzyme-generated autologous non-cultured keratinocyte/melanocyte products and
are Class 1 Human Cell, Tissue and Cellular and Tissue-Based Products (i.e.
unregulated products), as they are produced completely within the operating theatre
during the operative procedure and involves no transport of tissue out of the
operating theatre (Therapeutic Goods Administration 2004a).
Summary
Currently autograft is the best replacement for lost skin. In clinical practice this is not
always possible, particularly in large total body surface area burns, as there is often an
insufficient amount of skin for autografting available at the time of burn excision or
the physiological condition of the patient precludes the harvesting of skin. Allografts
and xenografts can be used as temporary wound coverage but there are issues with
graft rejection, availability, cultural and ethical implications and the possibility of
disease transfer.
Biosynthetic skin substitutes provide immediate wound cover, are available in large
quantities and have a negligible risk of cross-infection (potentially associated with the
use of allografts and xenografts). Furthermore, the use of autologous cells in the
cultured skin products has the advantage of immunological safety. However, most
skin substitutes are expensive and considerable experience is required to decide
which material is appropriate for any given situation. No skin substitute, other than
full thickness autograft, replaces all lost skin elements.
Due to the rapid proliferation of bioengineered skin substitutes there is uncertainty
regarding their safety and effectiveness in comparison with standard wound
management, either with biological skin replacements or standard wound dressings.
This uncertainty may be compounded if comparisons are made between different
treatments without consideration of factors such as differences in the methods and
timing of application of the product (for example at different time points post-injury
when bacterial colonisation may be established). This review aims to assess the safety
and efficacy of bioengineered skin substitutes, compared with biological skin
replacements and/or standard dressing methods, in the management of burns, taking
into consideration these factors whereever possible.
8
SECTION 1
z
INTRODUCTION
Table 1. Classification of available skin substitutes
Classification
Duration of
Contact
Tissue Replaced
Layers
Status in Australia
Manufacturer
Permanent
Epidermal & Dermal
Full or variable thickness
Available
Temporary
Epidermal & Dermal
Full or variable thickness
Available
EZ Derm™
Temporary
Dermal
Biosynthetic, acellular, xenogeneic
(porcine) dressing
Not Available
Cutaneous Flaps
Permanent
Epidermal & Dermal
Full or variable thickness
Available
Alloderm®
Permanent
Dermal
Acellular, de-epithelialised cadaver
dermis
Not Available
LifeCell, Woodlands, TX, USA
Oasis™
Temporary
Dermal
Derived from porcine small
intestinal submucosa
Not Available
Healthpoint Ltd., Fort Worth, TX,
USA
Promogran™
Temporary
Dermal
Bovine collagen & oxidised
regenerated cellulose
Not Available
Johnson & Johnson, New Jersey,
USA
Temporary
Epidermal
Thin, transparent, synthetic
polyurethane membrane
Available
ITG Laboratories, Inc., CA, USA
Apligraf®
Temporary
Epidermal & Dermal
1. Neonatal keratinocytes
2. Collagen seeded with neonatal
fibroblasts
Only in clinical trials
Organogenesis, Inc., Canton, MA,
USA & Novartis Pharmaceuticals
Corp., East Hanover, NJ, USA
Biobrane®
Temporary
Epidermal
1. Silicone
2. Nylon mesh
3. Porcine polypeptides
Available
Dow Hickam/Bertek
Pharmaceuticals, Sugar Land, TX,
USA
Biological Skin Replacements
Grafts & Cutaneous Flaps
Autograft
Allograft
Cadaver Skin
Xenograft
Brennen Medical, Inc., St. Paul,
MN, USA
Biosynthetic Skin Substitutes
Biological
Synthetic
Omiderm®
Mixed
Table continued over …
9
10
Table 1. Classification of available skin substitutes (continued)
Classification
Duration of
Contact
Tissue Replaced
Layers
Status in Australia
Manufacturer
Dermagraft®
Permanent
Dermal
Polyglycolic acid (Dexon™) or
polyglactin-910 (Vicryl™) seeded with
neonatal fibroblasts
Not Available
Only available in Canada &
UK
Used in clinical trials in the
US
Advanced Tissue Sciences, Inc., La
Jolla, CA, USA
Integra®
Permanent
Dermal
1. Silicone
2. Collagen & glycosaminoglycan
Available
Integra Life Science Corp., Plainsboro,
NJ, USA
OrCel™
Permanent
Epidermal & Dermal
Collagen (bovine type I) seeded with
allogeneic fibroblasts & keratinocytes
Not Available
Ortec International, Inc., NY, USA
TransCyte®
Temporary
Epidermal
1. Silicone
2. Nylon mesh
3. Collagen seeded with neonatal
fibroblasts
Available
Advanced Tissue Sciences, Inc., La
Jolla, CA, USA
Hyalograft™
Permanent
Dermal
Cultured autologous fibroblasts on a
biomaterial derived from hyaluronic
acid
Not Available
Fidia Advanced Biopolymers, Italy
Autologous Cultured and Non-Cultured Skin Engineering Products
Cultured Keratinocytes
Cellspray®
Permanent
Epidermal
Spray on cultured epithelial autograft
Available on case-by-case
basis
Clinical Cell Culture Ltd., Bentley, WA,
Australia
Epicel™
Permanent
Epidermal
Cultured autologous keratinocytes
Not Available
Genzyme Tissue Repair Corp.,
Cambridge, MA, USA
EpiDex™
Permanent
Epidermal
Generated in vitro from the patient’s
hair (the outer root sheath cells of hair
follicle)
Not Available
Modex Therapeutiques, Lausanne,
Switzerland
Laserskin™
Permanent
Epidermal
1. Cultured autologous keratinocytes
2. Hyaluronic acid with laser
perforations
Not Available
Fidia Advanced Biopolymers, Italy
(aka Vivoderm™ by ER Squibb & Sons,
Inc.)
Table continued over …
Table 1. Classification of available skin substitutes (continued)
Classification
Duration of
Contact
Tissue Replaced
Layers
Status in Australia
Manufacturer
Non-Cultured Keratinocytes/Melanocytes
ReCell®
Permanent
Epidermal
Autologous cell harvesting kit
Available
Clinical Cell Culture Ltd., Bentley, WA,
Australia
Cellspray® XP
Permanent
Epidermal
Spray on non-cultured epithelial
autograft
Available on case-by-case
basis
Clinical Cell Culture Ltd., Bentley, WA,
Australia
Disclaimer: Every effort has been made to correctly assign design details and company names to the prostheses listed in Table 1.
11
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
2. Methods
Literature Search Protocol
Inclusion Criteria
Articles were selected for inclusion in this systematic review on the basis of the
following criteria:
Participants
Only studies in humans (adults and children) with burns (or donor sites used to treat
burn wounds) suitable for treatment with bioengineered skin substitutes and
reporting efficacy and/or safety data were included.
New Intervention
Biosynthetic skin substitutes
Autologous cultured and non-cultured skin engineering products
Comparative Intervention
Biological skin replacements
Standard methods (dressings and/or topical agents or compression therapy)
**Studies of one kind of new intervention versus another were also included.
Outcomes
The studies included reported at least one of the following outcomes of the new or
comparative interventions:
™ Extent of wound healing which could include, but not be limited to:
• Wound measurements
• Rate of re-epithelialisation
• Wound closure rate
™ Acceptance or failure of graft which could include, but not be limited to:
• Clinical take
• Failure rate
™ Convalescence of patients which could include, but not be limited to:
• Length of hospital stay
• Healing time
™ Perioperative and postoperative morbidity and mortality of patients
• Cosmesis (scarring)
12
SECTION 2
z
METHODS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
•
Toxic/adverse effects
™ Patient satisfaction factors which could include, but not be limited to:
• patient satisfaction
• pain
™ Cost/resource use
Types of studies
Systematic reviews of randomised controlled trials (RCTs) and RCTs were included
for review. Where appropriate, additional relevant published material in the form of
letters, conference material, commentary, editorials and abstracts were included as
background information.
Language Restriction
Searches were conducted without language restriction. Foreign language articles were
subsequently excluded unless the findings provided additional information over that
reported in well designed studies published in the English language.
SECTION 2
z
METHODS
13
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Literature Searches Strategies
Databases Searched and Search Terms Used
Searches are shown in Table 2.
Table 2. Databases searched
Database
Platform
Edition
Current Contents
Ovid
Searched 01/04/2006
EMBASE
Ovid
Week 1 1980 to 11/04/2006
Cochrane Library
Issue 2, 2006
MEDLINE
Ovid
1966 to 11/04/2006
CINAHL
Ovid
1982 to 10/04/2006
PubMed
Entrez
1953 to 11/04/2006
Clinical Trials Database (US)
Searched 12/04/2006
NHS CRD (UK) NHS HTA (UK)
Searched 12/04/2006
National Research Register (UK)
Issue 2, 2006
Current Controlled Trials (mRCT)
Searched 12/04/2006
Search Terms
Search terms used for The Cochrane Library:
artificial AND skin
Search terms used for the Clinical Trials Database, NHS CRD, NHS HTA, Current
Controlled Trials and the National Research Register:
burns
AND
tissue engineer* OR
bioengineer* OR
biosynthetic OR
keratinocytes
Search terms used for MEDLINE, EMBASE, CINAHL, PubMed and Current
Contents:
burns [MeSH]
AND
(tissue engineer$ OR bioengineer$ OR biosynthetic OR artificial)
OR ((human OR living) AND skin equivalent)
OR keratinocytes
OR artificial skin [MeSH]
In MEDLINE and PubMed limit by publication type: randomized controlled trial
OR Xenoderm
14
SECTION 2
z
METHODS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
OR Epicel
OR Laserskin
OR Vivoderm
OR EpiDex
OR Alloderm
OR TransCyte
OR Apligraf
OR Dermagraft
OR Oasis
OR E-Z-Derm
OR OrCel
OR Biobrane
OR Integra
OR Promogran
OR Cellspray
OR Recell
OR Hyalograft
Note: * is a truncation character that retrieves all possible suffix variations of the root
word e.g. surg* retrieves surgery, surgical, surgeon, etc. In Cochrane the truncation
character is *; in Current Contents, EMBASE, CINAHL and MEDLINE (Ovid) it is
$. # is a wildcard symbol that substitutes for one required character in Current
Contents, EMBASE, CINAHL and MEDLINE (Ovid).
Methods of the Review
Literature Database
Articles were retrieved if they were judged to possibly meet the inclusion criteria
based on their abstracts. Two ASERNIP-S Researchers independently applied the
selection criteria and any differences were resolved through discussion. The number
of articles retrieved for each search category is listed in Figure 1. In some cases, when
the full text of the article was retrieved, closer examination revealed that it did not
meet the inclusion criteria specified by the review protocol. Consequently these
papers were not used to formulate the evidence base for the systematic review (see
Figure 1 and Appendix B). However, relevant information contained in these
excluded papers was used to inform and expand the review discussion. The
bibliographies of all publications retrieved were manually searched for relevant
references that may have been missed in the database search (pearling).
SECTION 2
z
METHODS
15
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Figure 1. Process for selection of studies retrieved from the literature databases
Potentially relevant citations identified as a result of
the electronic and internet searches
(n=166)
Citations that provided general
background information
(n=78)
Citations excluded after
application of inclusion criteria
(n=39)
Studies retrieved for more detailed evaluation
(n=49)
Citations excluded after detailed
evaluation
(n=30)
Initial relevant studies included in systematic review
(n=19)
References of these included
studies were “pearled”.
7 relevant references were retrieved
for more detailed evaluation.
1 study met the inclusion criteria.
Relevant studies included in systematic reviews
(n=20)
Donor site treatment
(n=4)
16
Burns treatment
(n=16)
SECTION 2
z
METHODS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Ongoing and unpublished trials
Searches of the Clinical Trials Database, NHS CRD, NHS HTA, Current Controlled
Trials and the National Research Register identified one RCT in progress and two
unpublished RCTs. The details for each are provided below.
RCT in progress
Greenwood J. Adelaide, Australia: The use of melanocyte/keratinocyte cosuspension for the repigmentation of amelanotic patches in vitiligo. This randomised
controlled trial is in its final stages of investigating the effectiveness of CellStat on
surgically dermabraded apigmented wounds in vitiligo patients. It is hoped that the
results of this trial will determine the potential of CellStat for the management of
burns. Start Date: January 2005.
Unpublished RCTs
Myers S. Essex, UK: A randomised prospective comparison of Mepitel® and
Biobrane® in the treatment of paediatric partial thickness burn injury. Outcome
measures included: pain scores, time to healing, in-patient stay, hypertrophic scar
rate, and infective episodes. Start Date: March 2001. End Date: March 2002.
Freedlander E. Sheffield, UK: A randomised controlled trial of the effectiveness and
cost-effectiveness of Integra® in the management of severe burns. Outcome
measures included: length of stay, morbidity and mortality. Start Date: June 1999.
End Date: February 2003.
Data Extraction
Data from all included studies were extracted by one researcher and checked by a
second using standardised data extraction tables that were developed a priori. Data
were only reported if stated in the text, tables, graphs or figures of the article, or
could be accurately extrapolated from the data presented. If no data were reported
for a particular outcome, in particular adverse outcomes, then no value was
tabulated. This was done to avoid the bias caused by incorrectly assigning a value of
zero to an outcome measurement on the basis of an unverified assumption by the
reviewer. For example, if no mortality rate was reported the result was not assumed
to be zero.
Data Analysis
The included studies were categorised into type of bioengineered skin substitute,
then by management of donor sites and management of burns, and by age (paediatric
or adult). The data for the main outcomes were not suitable for statistical pooling or
meta-analyses and were therefore reported narratively.
SECTION 2
z
METHODS
17
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
3. Studies Included in the Review
Designation of Levels of Evidence and Critical
Appraisal
The evidence presented in the included studies was classified according to the
National Health and Medical Research Council (NHMRC) Hierarchy of Evidence
(See Appendix A). Study quality was assessed according to the methods given in
Section 6 of the Cochrane Reviewers’ Handbook (Higgins and Green 2005) on a
number of parameters such as the quality of the reporting of study methodology,
methods of randomisation and allocation concealment, blinding of patients or
outcomes assessors, attempts made to minimise bias, sample sizes and their ability to
measure ‘true effect’, applicability of results outside of the study sample as well as
examining the statistical methods used to describe and evaluate the study data. The
included studies are shown in Table 3, and the study profiles are given in Appendix
C. Several authors and/or centres have published numerous reports on their
experience with bioengineered skin substitutes. As a result, there are some studies
published by the same group where there are very likely to be common pools of
patients and such studies will be identified.
Description of studies
A total of 20 randomised controlled trials were included in this review. The
bioengineered skin substitutes from the included studies have been categorised in
this review by type, as each are comprised of different components, have different
functions and are used at different time points in the various clinical treatment
pathways for burns (see Table 3). Thus it would have been inappropriate to combine
the results of different products when discussing the outcomes.
In some of the studies, the use of the bioengineered skin substitute may be used at a
different stage in the clinical treatment pathway to the comparator product, and both
may differ in their components and function, which would affect the validity of the
comparison. Where appropriate, such studies will be identified and these issues
discussed.
SECTION 3
z
INCLUDED STUDIES
19
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table 3. Summary of included randomised controlled trials*
Study
Type of burn
Intervention
N patients
Type of
patients
Follow-up
(days)
Partial
thickness
Biobrane
41
Paediatric
NR
Silver sulfadiazine
48
Partial
thickness
Biobrane
10
Paediatric
16
Silver sulfadiazine
10
Partial
thickness
Biobrane
20 wounds
Paediatric
~11
TransCyte
17 wounds
Silver sulfadiazine
21 wounds
Partial
thickness
Biobrane
26 (30 wounds)
308 (44 weeks)
Silver sulfadiazine
26 (26 wounds)
Paediatric &
adult
Superficial and
mid-dermal
thickness
Biobrane
35
Paediatric
~17
Duoderm
37
Partial
thickness
Biobrane
82†
Paediatric &
adult
168 (24 weeks)
Partial and full
thickness
Biobrane
10†
Adult
23
14†
Paediatric &
adult
365 (12 months)
NR
~18
NR
~19
BIOBRANE
For the management of burns
Lal 2000
Barret 2000
Kumar 2004
Gerding 1990
Cassidy 2005
For the management of donor sites
Still 2003
Fratianne 1993
OrCel
Allogeneic cultured
keratinocyte sheets
TRANSCYTE
For the management of burns
Noordenbos
1999
Partial
thickness
TransCyte
Demling &
DeSanti 1999‡
Partial
thickness
(facial)
TransCyte
10
Bacitracin ointment
11
Demling &
DeSanti 2002†‡
Partial
thickness
(facial)
TransCyte
16
Antibiotic ointments &
creams§
18
10†
Paediatric &
adult
14
66†
Paediatric &
adult
28
Silver sulfadiazine
DERMAGRAFT
For the management of burns
Hansbrough
1997‡
Partial and full
thickness
Dermagraft
Purdue 1997‡
Full thickness
Dermagraft
Allograft
Allograft
Table continued over …
20
SECTION 3
z
INCLUDED STUDIES
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table 3. Summary of included randomised controlled trials*
Study
Type of burn
Intervention
N patients
Type of
patients
Follow-up
(days)
Spielvogel 1997
Full thickness
Dermagraft
65†
NR
14
149†
Paediatric &
adult
365 (1 year)
7†
Adult
Up to 150 (5
months)
40†
Paediatric &
adult
730 (2 years)
17† (34
wounds)
Paediatric &
adult
Up to 365 (1
year)
45† (90
wounds)
Paediatric
Up to 365 (1
year)
15† (16
wounds)
Adult
365 (1 year)
15†
Paediatric &
adult
240-690 (8-23
months)
Allograft
INTEGRA
For the management of burns
Heimbach 1988
NR
Artificial dermis
Auto-, allo- or xenograft
Peck 2002
Partial and full
thickness
Integra
Biobrane
Allograft
APLIGRAF
For the management of burns
Waymack 2000
Partial and full
thickness
Apligraf + autograft
Autograft
AUTOLOGOUS CULTURED SKIN
For the management of burns
Full thickness
Boyce 1995‡
Autologous epidermal
substitute
Autograft
Full thickness
Boyce 2002‡
Autologous epidermal
substitute
Autograft
ALLOGENEIC CULTURED SKIN
For the management of donor sites
Madden 1996
Partial and full
thickness
Cultured epidermal
allograft + Adaptic
Adaptic dressing
Duinslaeger
1997
NR
Allogeneic cultured
keratinocyte sheets
OpSite dressing
NR – not reported; * all included studies are level II, except for Boyce 2002 which is level III-1; † each patient served as
their own control (within-patient comparison); ‡ possibly some patient overlap; § particular antibiotic ointments and
creams used not specified.
Biobrane® for the management of burns
Five studies reported on the use of Biobrane® for the management of burns; three
comparing Biobrane® with silver sulfadiazine, one comparing Biobrane® with
TransCyte® or silver sulfadiazine, and one comparing Biobrane® with Duoderm®.
The reporting of methodological detail was generally inadequate in four of the five
studies. However, Gerding et al. (1990) reported adequate methodological detail.
SECTION 3
z
INCLUDED STUDIES
21
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Three of the five studies provided some description of randomisation. The
randomisation of patients was done by computer-generated codes or table in two
studies (Gerding et al. 1990; Lal et al. 2000) and Kumar et al. (2004) randomised
wounds by lottery. Gerding et al. (1990) was the only study that provided a
description of their method of allocation concealment, which was by the use of
sealed envelopes. The remaining studies did not state their methods of allocation
concealment. Four of the five studies reported no blinding of patients or assessors
(Barret et al. 2000a; Gerding et al. 1990; Kumar et al. 2004; Lal et al. 2000). Cassidy et
al. (2005) did not provide any information on blinding status.
All five studies with a parallel design performed appropriate statistical analyses
(Barret et al. 2000a; Cassidy et al. 2005; Gerding et al. 1990; Kumar et al. 2004; Lal et al.
2000). Barret et al. (2000a) and Cassidy et al. (2005) performed power analyses to
calculate the required sample sizes. However, Lal et al. (2000) reported a lack of
statistical power to determine an increase in infectious complications with
Biobrane®.
Losses to follow-up were reported in two studies (Table 4). The remaining three
studies retained all their patients (Barret et al. 2000a; Cassidy et al. 2005; Kumar et al.
2004).
Table 4. Losses to follow-up in Biobrane® for burn management studies
Study
Follow-up
(days)
Losses to follow-up
Reasons
Lal 2000
NR
Biobrane 7/41 (17%)
NR
Silver sulfadiazine 3/48 (6%)
NR
Biobrane 7/64 (11%)
Lost to follow-up (2)
Gerding
1990
308 (44 weeks)
Removed due to protocol violations by non-investigators (4)
Excluded due to scarlet fever (1)
Silver sulfadiazine 5/64 (8%)
Lost to follow-up (4)
Removed due to protocol violations by non-investigators (1)
NR – not reported.
In regards to sources of funding, two of the five studies received independent
funding (Cassidy et al. 2005; Lal et al. 2000) and no details were given for the
remaining three studies (Barret et al. 2000a; Gerding et al. 1990; Kumar et al. 2004).
Biobrane® for the management of donor sites
Two studies compared Biobrane® with two different comparators for the
management of donor sites in burns patients. The comparators were OrCel™ and
allogeneic cultured keratinocyte sheets.
The reporting of methodological detail in the two studies was generally good but
some information was not provided.
Still et al. (2003) reported use of a computer-generated schedule to randomise
wounds to receive treatment with either Orcel™ or Biobrane®. Fratianne et al.
(1993) did not state their method of treatment allocation. Both studies did not state
22
SECTION 3
z
INCLUDED STUDIES
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
their methods of allocation concealment. With regard to blinding status, three
independent burn experts assessed wound closure in the study by Still et al. (2003).
Fratianne et al. (1993) reported no blinding.
Statistical dependence (for comparison of two wounds in the same individual) was
accounted for in one study (Still et al. 2003). Fratianne et al. (1993) did not perform
any statistical analyses. Still et al. (2003) also used intention-to-treat (ITT) analysis for
efficacy, where all patients underwent randomisation of donor sites and received
treatment regardless of completion of study, and for safety, where a subset of the
ITT population received treatment with a study device regardless of completion of
study.
Both studies reported losses to follow-up (see Mortality section) (Fratianne et al.
1993; Still et al. 2003).
The study by Still et al. (2003) was funded by OrCel™ International, Inc., the
manufacturer of the material and Fratianne et al. (1993) did not report their funding
source.
A study by Prasad et al. (1987) comparing Biobrane® with scarlet red was identified
during the search for included studies. However, this study was excluded, as scarlet
red is no longer used to manage burn wounds due to its association with sarcoma
development in rats (Takeuchi et al. 1975).
TransCyte® for the management of burns
Three studies reported on the use of TransCyte® for the management of burns; one
comparing TransCyte® with silver sulfadiazine and two comparing TransCyte® with
antibiotic ointments and creams.
The reporting of methodological detail in the three studies was inadequate.
All three studies did not provide information on the methods of patient allocation or
the methods of allocation concealment. One study reported no blinding of patients
or assessors (Noordenbos et al. 1999) and the other two did not provide information
on the blinding status (Demling and DeSanti 1999; Demling and DeSanti 2002).
Statistical dependence was accounted for in the one within-patient comparison
(Noordenbos et al. 1999) and appropriate statistical analyses were performed in one
of the parallel design studies (Demling and DeSanti 2002). Demling and DeSanti
(Demling and DeSanti 1999) did not provide information on the statistical analyses
performed.
One study reported losses to follow-up with 3/14 (21%) patients lost to follow-up at
three and 12 months and 5/14 (36%) patients lost to follow-up at six months
(Noordenbos et al. 1999). The other two studies retained all their patients (Demling
and DeSanti 1999; Demling and DeSanti 2002).
Demling and DeSanti (Demling and DeSanti 1999) received independent funding for
their study. Demling and DeSanti (Demling and DeSanti 2002) and Noordenbos et al.
(1999) did not report their funding sources.
SECTION 3
z
INCLUDED STUDIES
23
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Dermagraft® for the management of burns
Three studies compared Dermagraft® with allograft for the management of burns.
The comparability of these two products is questionable, as Dermagraft® can be
permanently integrated, whereas allograft is a temporary biological dressing.
The reporting of methodological detail in the three studies was inadequate.
All three studies did not provide information on the methods of patient allocation
and the methods of allocation concealment. Two of the three studies provided some
information on the blinding status; Purdue et al. (1997) blinded the assessor who
analysed the wound biopsies and in Spielvogel (1997), the reviewer was blinded
regarding the clinical results. Hansbrough et al. (1997) did not provide information on
blinding status.
All three studies had within-patient comparisons; two accounted for this statistical
dependence (Hansbrough et al. 1997; Purdue et al. 1997). Spielvogel (1997) used
within-patient comparisons but did not perform any statistical analyses due to a very
small sample size.
Two of the three studies reported losses to follow-up (Hansbrough et al. 1997;
Purdue et al. 1997) (Table 5). Spielvogel (1997) retained all their patients.
Table 5. Losses to follow-up in Dermagraft® for burn management studies
Study
Follow-up
(days)
Losses to
follow-up*
Reasons
Hansbrough 1997
14
3/10 (30%)
NR
Purdue 1997
28
20/66 (30%)
Had treatment other than skin grafts (2)
Had temporary covering deviations (7)
Had premature removal of temporary coverings or autograft (3)
Death (8)
*only overall data was provided; NR – not reported.
The studies by Hansbrough et al. (1997) and Purdue et al. (1997) were funded by
Advanced Tissue Sciences, Inc., the manufacturer of Dermagraft®. Spielvogel
(Spielvogel 1997) did not report their funding source.
Integra® for the management of burns
Two studies reported on the use of Integra® (also known as artificial dermis) for the
management of burns; one comparing Integra® with autograft, allograft or xenograft
and the other comparing it with Biobrane® or allograft. The comparability of
Integra® with the other types of burn management is questionable. Integra® is a
permanent, integrable dermal substitute and has been compared with a temporary,
non-integrable epidermal substitute (Biobrane®) and temporary, biological skin
replacements (allograft and xenograft). In addition, Peck et al. (2002) included both
partial and full thickness burns in a trial of only seven patients, so the heterogeneity
of these groups render it difficult to make valid conclusions. Autograft and
Dermagraft® would allow valid comparisons in all of these groups for Integra®, as
they are both capable of permanent integration.
24
SECTION 3
z
INCLUDED STUDIES
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
The reporting of methodological detail in the two studies was inadequate.
Both studies did not provide information on the methods of patient allocation and
the methods of allocation concealment. Both studies did not provide information on
blinding status (Heimbach et al. 1988; Peck et al. 2002).
Statistical dependence was accounted for in the within-patient comparison by
Heimbach et al. (1988). Peck et al. (2002) used within-patient comparisons but did not
perform any statistical analyses due to a very small sample size. The trial by Peck et al.
(2002) was stopped early due to a high infection rate.
Both studies reported losses to follow-up (Heimbach et al. 1988; Peck et al. 2002)
(Table 6).
Table 6. Losses to follow-up in Integra® for burn management studies
Study
Follow-up (days)
Losses to follow-up*
Reasons
Peck 2002
Up to 150 (5 months)
4/7 (57%)
Patient moved interstate after discharge (1)
Death (3)
Heimbach
1988
365 (1 year)
67/149 (45%)
Eliminated from analysis due to protocol violation (37)
Eliminated from analysis due to logistic reasons or longterm assessment was not possible (10)
Death (20)
*only overall data was provided.
Marion Laboratories (Kansas City, MO, USA) partly funded the study by Heimbach
et al. (1988) and provided in-house statisticians to perform the statistical analyses.
Peck et al. (2002) received independent funding for their study.
Apligraf® for the management of burns
One study reported on the use of Apligraf® combined with autograft compared with
autograft only for the management of burns.
The methodological detail reported in this study was inadequate. No information on
the method of patient allocation, the method of allocation concealment and blinding
status was provided.
Statistical dependence was accounted for in this within-patient comparison
(Waymack et al. 2000). The authors used last observation carried forward (LOCF)
analysis, where data from the prior evaluation point was carried forward to estimate
missing patient information.
Losses to follow-up were reported in Waymack et al. (2000) (Table 7).
SECTION 3
z
INCLUDED STUDIES
25
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table 7. Losses to follow-up in Apligraf® for burn management studies
Study
Follow-up (days)
Losses to follow-up*
Waymack 2000
730 (2 years)
24/40 (60%)
Reasons
Lost to follow-up (20)
Excluded due to non-compliance (2)
Due to Apligraf loss (1)
Data not collected after grafting (1)
*only overall data was provided.
Two of the investigators on the Waymack et al. (2000) trial were full-time employees
of Organogenesis Inc., the manufacturer of Apligraf®.
Autologous cultured skin for the management of burns
Two studies reported on the use of an autologous epidermal substitute compared
with autograft only for the management of burns. The comparability of these two
types of management is questionable, as autograft is comprised of both dermis and
epidermis and would have a different function to just a cultured epidermis. Ideally,
both groups should be comprised of a dermis and epidermis to enable valid
comparisons.
The reporting of methodological detail in the two studies was generally good but
some information was not provided.
Both studies reported randomisation methods; one study randomised wounds using
a computer-generated schedule (Boyce et al. 1995) and another was a pseudorandomised controlled trial, where wounds were randomised according to patient
enrolment number (Boyce et al. 2002). However, information on their methods of
allocation concealment was not provided. Both studies reported no blinding of
patients or assessors (Boyce et al. 1995; Boyce et al. 2002).
Both studies were within-patient comparisons and accounted for this statistical
dependence (Boyce et al. 1995; Boyce et al. 2002).
One of the two studies reported losses to follow-up (13/17 (76%) patients at one
year) (Boyce et al. 1995). The other study by Boyce et al. (2002) retained all their
patients.
Both studies received funding from independent sources.
Allogeneic cultured skin for the management of donor sites
Two studies reported on the use of allogeneic cultured skin for the management of
donor sites; one study compared cultured epidermal allograft combined with
Adaptic™ dressing and Adaptic™ dressing alone, and the other study compared
allogeneic cultured keratinocyte sheets and OpSite® dressing alone.
The methodological detail reported in the two studies was inadequate.
Both studies did not state the methods of treatment allocation and the methods of
allocation concealment (Duinslaeger et al. 1997; Madden et al. 1996). Whether
selection bias and reporting bias occurred in these studies could not be determined
26
SECTION 3
z
INCLUDED STUDIES
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
due to the lack of detail on the method of treatment allocation and allocation
concealment. In both studies, the assessor was blinded (Duinslaeger et al. 1997;
Madden et al. 1996)); Madden et al. (1996) stated that the trial was double-blinded but
only mentioned blinding of the assessor.
The two studies did not account for the lack of statistical independence; Madden et
al. (1996) reported the use of a signed rank test for comparisons of reepithelialisation, and Duinslaeger et al. (1997) did not provide any information on the
statistical tests performed. The lack of statistical analyses may have been due to the
small sample sizes, which would decrease the power of the study to detect any
differences.
Patients were lost to follow-up in Madden et al. (1996) (3/16, 19%) and Duinslaeger
et al. (1997) retained all their patients.
Madden et al. (1996) stated no financial ties and Duinslaeger et al. (1997) did not
report their funding sources.
SECTION 3
z
INCLUDED STUDIES
27
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
4. Results
Efficacy
Biobrane®
Biobrane® is a biosynthetic dressing composed of a knitted nylon mesh that is
bonded to a thin, silicone membrane and coated with porcine polypeptides (Hansen
et al. 2001). It can be used as a temporary covering for clean, debrided superficial and
mid-dermal burns and donor sites or as a protective covering over meshed
autografts. Biobrane® is designed to adhere to the burn wound and is trimmed away
as the burn wound heals (Hansen et al. 2001).
For the management of burns
Three studies compared Biobrane® with silver sulfadiazine (Barret 2000a; Gerding
1990; Lal 2000), one study compared Biobrane® and TransCyte® with silver
sulfadiazine (Kumar 2004) and another study compared Biobrane® with Duoderm®
(Cassidy 2005). All five studies had parallel comparisons. Follow-up times ranged
from 11 days to 44 weeks. Mean total burn surface area (TBSA) and mechanism of
burn injury are detailed in Appendix D. The mean TBSA varied across the studies
but did not appear to influence the outcomes reported.
Wound infection
Two studies reported on wound infection (Barret 2000a; Gerding 1990). Gerding
(Gerding 1990) reported similar numbers of cases of wound infection from both
groups (3/30 wounds (10%) treated with Biobrane® and 2/26 wounds (8%) treated
with silver sulfadiazine). None of the patients receiving Biobrane® or silver
sulfadiazine in the Barret (Barret 2000a) study had wound infection.
Kumar (Kumar 2004), Lal (Lal 2000) and Cassidy (Cassidy 2005) did not provide
information on wound infection.
Wound healing time
Wound healing time was measured by number of days to healing (Barret 2000a;
Cassidy 2005; Gerding 1990; Kumar 2004) or days per percent TBSA burned (Lal
2000).
Four studies reported a significantly shorter wound healing time with the use of
Biobrane® compared with silver sulfadiazine (Table 8). Gerding (Gerding 1990)
noted that in their sample, the greatest difference in healing time was observed in
grease/tar burns (8.4 [3.0] days (n=9 wounds) for Biobrane® vs. 18.5 [10.0] days
(n=4 wounds) for silver sulfadiazine, p<0.02), there was an average 4.4-day
difference in the healing of scald burns (but the difference was not significant due to
the small sample size for this sub-group) and no difference was observed in the
28
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
healing time for contact burns. Kumar (Kumar 2004) reported the shortest wound
healing time in paediatric patients with wounds treated with TransCyte®.
There was no significant difference in wound healing time between Biobrane® and
Duoderm® (Table 8) (Cassidy 2005).
Table 8. Wound healing time for burns managed with Biobrane® and comparators
Study
Biobrane
TransCyte
Silver sulfadiazine
Duoderm
P-value
Kumar 2004
9.5 (20)
7.5 (17)
11.2 (21)
…
<0.001*
Gerding 1990
10.6 [4.1] (26)
…
15.0 [6.1] (26)
…
<0.01
Barret 2000
9.7 [2.2] (10)
…
16.1 [1.9] (10)
…
<0.001
Cassidy 2005
12.24 [5.1] (35)
…
…
11.21 [6.5] (37)
0.47
…
<3 yrs: 2.35 [1.35] (31)
…
0.025
Number of days
Days / % TBSA burned
Lal 1999
<3 yrs: 1.52 [2.45] (26)
3-17 yrs: 1.00 [0.51] (8)
3-17 yrs: 2.40 [0.75] (14)
0.026
* P-value across all three groups. Ellipses indicate not applicable. Values expressed as Mean [Standard Deviation]
(sample size) unless stated otherwise.
Wound closure
Significantly more partial thickness burns sites treated with silver sulfadiazine
appeared to require skin grafting to close the wound than sites covered with
TransCyte® or Biobrane® (Kumar 2004) (Table 9). Kumar (Kumar 2004) reported
that wounds in the Biobrane® group (n=3) and TransCyte® group (n=1) required
autografting due to infection and loss of product, and wounds in the silver
sulfadiazine group (n=5) underwent grafting due to delayed re-epithelialisation. One
wound from each group required skin grafting in the Gerding (Gerding 1990) study.
Cassidy (Cassidy 2005) did not provide information on wound closure.
Table 9. Number of wounds requiring skin grafting to close the wound
Study
Biobrane
TransCyte
Silver sulfadiazine
P-value
Kumar 2004
3/17 wounds (18%)
1/20 wounds (5%)
5/21 wounds (24%)
<0.001*
Gerding 1990
1/30 wounds (3%)
…
1/26 wounds (4%)
NP
* P-value across all three groups; NP – statistical analysis not performed. Ellipses indicate not applicable.
Patient-related outcomes
Pain was assessed using scales of different magnitudes (Table 10). Significantly more
pain was reported from sites treated with silver sulfadiazine than sites covered with
Biobrane® in two studies (Barret 2000a; Gerding 1990). There was no significant
difference in pain scores for Biobrane® and Duoderm®.
SECTION 4
z
RESULTS
29
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table 10. Wound pain scores for burns managed with Biobrane® and comparators
Study
Biobrane
Silver sulfadiazine
Duoderm
P-value
Visual analogue scale and Faces scale (0, none to 4, severe)
Barret 2000
…
Admission
3.3 [0.3] (10)
3.8 [0.6] (10)
PNS
Day 1
2.4 [0.3] (10)
3.7 [1.3] (10)
<0.001
Day 2
2.6 [0.9] (10)
3.8 [1.3] (10)
<0.001
1.6 [4.1] (26)
3.6 [6.6] (26)
Score (1, none to 5, severe)
Gerding 1990
…
<0.001
2.37 [2.77]
0.993
Oucher scale (n=34) and Visual analogue scale (n=37)*
Cassidy 2005
2.36 [2.62]
…
* reported as a mean aggregate score; PNS – p-value not significant. Ellipses indicate not applicable. Values expressed
as Mean [Standard Deviation] (sample size) unless stated otherwise.
Patients who received Biobrane® also required significantly less pain medication
than those receiving silver sulfadiazine treatment in two studies: 0.6 [7.1] tablets vs.
3.0 [17.8] tablets (p<0.01) (Gerding 1990) and 0.5 [0.3] doses/person/day vs. 1.9
[1.3] doses/person/day (p<0.001) (Barret 2000a). Kumar (Kumar 2004) also
reported that patients who received Biobrane® or TransCyte® required significantly
fewer pain medications (narcotic analgesia) than those treated with silver sulfadiazine
(p=0.0001).
In regards to dressing changes, sites treated with silver sulfadiazine required a
significantly higher number of dressing changes (mean 9.2 dressing changes per
wound) than Biobrane® (mean 2.4 dressing changes per wound) and TransCyte®
(mean 1.5 dressing changes per wound) (Kumar 2004) (p=0.0001).
For the management of donor sites
Biobrane® was compared with two different products in two different studies. One
study compared Biobrane® with OrCel™ (Still 2003) and another with allogeneic
cultured keratinocyte sheets (Fratianne 1993). All three studies had within-patient
comparisons. Follow-up times were 23 days (Fratianne 1993) and 24 weeks (Still
2003). Mean TBSA and mechanism of burn injury are detailed in Appendix D. The
mean TBSA was comparable across the two studies.
Wound infection
No statistically significant differences were noted between sites covered with
Biobrane® and OrCel™ (Still 2003). Fratianne (Fratianne 1993) did not provide any
information on wound infection.
Wound healing time
The wound healing time for donor sites covered with Biobrane® was significantly
longer than for sites treated allogeneic cultured keratinocytes (Table 11) (Fratianne
1993).
30
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table 11. Wound healing time (days) for donor sites managed with Biobrane® and
comparators: part 1
Study
Biobrane
Allogeneic cultured keratinocyte sheets
P-value
Fratianne 1993
Median 14 (n=10)
Median 6 (n=10)
<0.005
(range 7-23)
(range 5-11)
Still (Still 2003) measured time to 100% wound closure using investigator,
planimetric and photographic assessments, and also reported significantly longer
wound healing times for sites covered with Biobrane® compared with those covered
with OrCel™ (Table 12).
Table 12. Wound healing time (days) for donor sites managed with Biobrane® and
comparators: part 2
Study
Biobrane
OrCel
P-value
Mean
Median
Mean
Median
Mean / Median
Investigator assessment
18.4
16.0
13.2
12.0
<0.0001 / <0.0001
Planimetric assessment
19.3
17.0
13.7
12.0
<0.0001 / <0.0001
Photographic assessment
22.4
22.0
18.0
15.0
<0.0001 / <0.0006
Still 2003
The median time required for the donor site to be ready for recropping was seven
days less for OrCel™ than the median time for Biobrane® (the mean time for
OrCel™ was five days less than the mean for Biobrane®) (Still 2003). The absolute
values were not provided.
Wound closure
Two studies reported wound closure (Fratianne 1993; Still 2003). Still (Still 2003)
reported significant differences in the rates of wound closure per day (by planimetric
assessments) during the 32-day post-surgical period in the ITT population (p<0.05).
The mean rate of wound closure for OrCel™ on days 6 through 16 was 61% faster
than Biobrane® (6.1 vs. 3.8cm2 per day, respectively), and on days 17 to 32 OrCel™
was 90% faster than Biobrane® (4.0 vs. 2.1cm2 per day, respectively) (Still 2003). The
percentage of donor sites covered with OrCel™ that completely healed by day 32
was significantly higher than donor sites covered with Biobrane® for all assessment
methods (Table 13).
Table 13. Percentages of sites completely healed by Day 32
Study
OrCel
Biobrane
P-value
Investigator assessment
79 / 82 (96.3%)
71 / 82 (86.6%)
<0.0047
Planimetric assessment
76 / 82 (92.7%)
66 / 82 (80.5%)
<0.0039
Photographic assessment
70 / 82 (85.4%)
50 / 82 (61.0%)
<0.001
Still 2003
SECTION 4
z
RESULTS
31
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
In 3/10 (30%) patients, the donor sites covered with allogeneic cultured keratinocyte
sheets had re-epithelialised and were reharvested (Fratianne 1993). No Biobrane®
sites were reharvested.
Wound exudate
No studies reported on wound exudate.
Patient-related outcomes
Still (Still 2003) assessed pain at the donor site for three different age groups: 0 to 10
scale (0 indicating no pain and 10 indicating worst pain possible) was used to rate
pain in patients eight years of age or older; the Wong-Baker Faces Pain Rating Scale
was used with patients aged three to seven; and objective measurements were used
for patients less than three years of age. The mean daily pain score was 1.4 for donor
sites covered with OrCel™ and 1.8 for donor sites covered with Biobrane® across
all three groups (i.e. less pain for OrCel™ group).
Scar severity was measured using two methods; the Vancouver Scar Scale and the
Hamilton Burn-Scar Rating Scale (Still 2003). For both methods, the total scores for
sites covered with OrCel™ were significantly lower (i.e. less scarring) than for sites
covered with Biobrane® at weeks 12 and 24 (Table 14). No statistically significant
difference between the sites was observed using the Vancouver Scar Scale at the
biannual follow-up visit.
The severity and incidence of donor site itching was similar for sites covered with
OrCel™ or Biobrane® (72.2% and 68.8%, respectively) (Still 2003).
Table 14. Scar severity (mean scores) for Biobrane® versus OrCel™
Study
Biobrane
OrCel
P-value
Vancouver
Hamilton
Vancouver
Hamilton
Vancouver / Hamilton
Week 12
3.07
4.95
2.26
3.89
<0.017 / 0.018
Week 24
3.79
3.5
2.56
2.46
<0.002 / 0.020
Biannual
3.95
NR
3.10
NR
PNS / NR
Still 2003
NR – not reported; PNS – p-value not significant.
TransCyte®
TransCyte® is a temporary, biosynthetic covering composed of a semi-permeable
silicone membrane and newborn human fibroblast cells cultured on a porcine
collagen coated nylon mesh (Hansen et al. 2001). It has been indicated for use as a
temporary covering for excised burns prior to autografting or burns that do not
require autografting (partial thickness burns) and its physical properties (pliability)
allow it to easily conform to the contours of the face (Hansen et al. 2001).
TransCyte® is applied to the burn using adhesive strips or surgical adhesives and will
peel away as the burn heals.
32
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
For the management of burns
TransCyte® was compared with silver sulfadiazine in one study (within-patient
comparison) (Noordenbos 1999) and antibiotic ointments and creams in two studies
(both had parallel comparisons) (Demling and DeSanti 1999; Demling and DeSanti
2002). Follow-up times ranged from 18 days to 12 months. Mean TBSA and
mechanism of burn injury are detailed in Appendix D. The mean TBSA did not
appear to influence the outcomes reported.
Wound infection
All three studies reported on wound infection (Table 15). Noordenbos (Noordenbos
1999) reported no cases of wound infection during treatment with TransCyte® and
mild cellulitis in six patients during silver sulfadiazine treatment, which responded to
intravenous antibiotics. No wound infections were reported for partial thickness
facial burns treated with TransCyte® or topical antibiotics in two studies (Demling
and DeSanti 1999; Demling and DeSanti 2002).
Table 15. Wound infection for burns managed with TransCyte® and comparators
Study
TransCyte
Silver sulfadiazine
Topical antibiotics
Noordenbos 1999
0/14 patients
6/14 patients (43%)
…
Demling & DeSanti 1999*
0/5 patients
…
0/6 patients
Demlind & DeSanti 2002
0/16 patients
…
0/18 patients
*for major burns only (patients were split into major and minor burns). Ellipses indicate not applicable.
Wound healing time
Wound healing time was reported in three different ways across the three studies
(Table 16). However, all the studies reported a shorter wound healing time for sites
covered with TransCyte®.
Table 16. Wound healing time for burns managed with TransCyte® and comparators
Study
TransCyte
Silver sulfadiazine
Topical antibiotics
P-value
Major: 8 [2] (5)
…
Major: 14 [4] (6)
<0.05
Minor: 12 [3] (5)
<0.05
18.14 [6.05] (14)
…
NS
…
15 [4] (18)
<0.05
Number of days
Demling & DeSanti 1999
Minor: 8 [1] (5)
Days until 90% healing
Noordenbos 1999
11.14 [4.37] (14)
Days to 95% re-epithelialisation
Demling & DeSanti 2002
9 [4] (16)
NS – not stated. Ellipses indicate not applicable. Values expressed as Mean [Standard Deviation] (sample size) unless
stated otherwise.
Wound closure
No skin grafts were required for sites covered with TransCyte® in two studies
(Demling and DeSanti 1999; Noordenbos 1999) and 2/14 (14%) patients in the silver
SECTION 4
z
RESULTS
33
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
sulfadiazine arm required skin grafting to close the wound (Noordenbos 1999). No
data was provided for sites treated with topical antibiotics (Demling and DeSanti
1999). For partial thickness facial burns, it was reported that the use of TransCyte®
had good adherence to the entire face including ears and there was no need for reapplication (Demling and DeSanti 1999).
Patient-related outcomes
Wound care time was reported in patients with major and minor burns to the face in
Demling and DeSanti (Demling and DeSanti 1999). The major and minor burns
covered with TransCyte® had significantly shorter wound care time than those
treated with topical antibiotics (major burns, 0.35 [0.5] hours/day vs. 1.9 [0.5]
hours/day; minor burns, 0.4 [0.1] hours/day vs. 2.2 [0.4] hours/day, p<0.05,
respectively).
The patients in the two studies by Demling & DeSanti (Demling and DeSanti 1999;
Demling and DeSanti 2002) reported significantly more pain during and between
dressing changes for sites treated with topical antibiotics than sites covered with
TransCyte® (Table 17).
Table 17. Wound pain scores for burns managed with TransCyte® and topical antibiotics
Study
TransCyte
Topical antibiotics
P-value
2 [1] (5) / 2 [1] (5)
5 [1] (6) / 5 [1] (5)
<0.05 / <0.05
2 [1] (5) / 1 [0.5] (5)
4 [2] (6) / 3 [2] (5)
<0.05 / <0.05
During dressing changes
3 [1] (16)
7 [2] (18)
<0.05
Between dressing changes
2 [1] (16)
4 [2] (18)
<0.05
Visual analogue scale (0, lowest to 10, highest)
Demling & DeSanti 1999
During dressing changes (major burns / minor burns)
Between dressing changes (major burns / minor burns)
Demling & DeSanti 2002
Values expressed as Mean [Standard Deviation] (sample size) unless stated otherwise.
Scar severity was measured in one study using the Vancouver Burn Scar Score (where
lower ratings indicate more normal skin appearance) (Noordenbos 1999). At all
follow-up time points, the sites covered with TransCyte® had significantly less
scarring than sites treated with silver sulfadiazine; 1.39 [1.14] vs. 4.82 [1.27] (p<0.001,
n=11) at three months, 0.8 [1.312] vs. 3.7 [1.373] (p<0.001, n=9) at six months, and
0.375 [0.744] vs. 2.125 [1.458] (p=0.006, n=11) at 12 months.
Dermagraft®
Dermagraft® is a bioabsorbable polyglactin mesh seeded with allogeneic neonatal
fibroblasts (Hansen et al. 2001). The fibroblasts proliferate and produce dermal
collagen, growth factors, glycosaminoglycans (GAGs) and fibronectin and the mesh
material is gradually absorbed (Hansen et al. 2001). It can be used as a temporary or
permanent covering to support the take of meshed split-thickness skin grafts on
34
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
excised burn wounds (Hansbrough 1997) and for venous ulcers and pressure ulcers
(Hansen et al. 2001).
For the management of burns
Three studies compared Dermagraft® with allograft (Hansbrough 1997; Purdue
1997; Spielvogel 1997) and all had within-patient comparisons. Follow-up times
ranged from 14 to 28 days. Mean TBSA and mechanism of burn injury are detailed in
Appendix D. The mean TBSA was greater in Purdue (Purdue 1997) than
Hansbrough (Hansbrough 1997).
Wound infection
Two studies reported on wound infection (Purdue 1997; Spielvogel 1997). No
significant differences were detected between the use of Dermagraft® and allograft
for full thickness burns in two studies (Purdue 1997; Spielvogel 1997). However,
Purdue (Purdue 1997) noted that infection was diagnosed in 5/66 (8%) wounds, a
mean 3.8 days (range 1-7) earlier for the Dermagraft® covered wound than for the
paired allograft covered wound, and in no case was an allograft covered wound
infection diagnosed before a Dermagraft® covered wound infection.
Wound healing time
Only one study reported wound healing time (Hansbrough 1997). Hansbrough
(Hansbrough 1997) compared Dermagraft® red (cultured fibroblasts were
cryopreserved by a method that maintains most of the metabolic activity),
Dermagraft® blue (cultured fibroblasts were frozen by a method that did not
maintain metabolic activity), and allograft. They reported no significant differences
between treatments and all partial and full thickness burns were completely healed by
day 21.
Wound closure
Granulation tissue formation was measured in two studies (Purdue 1997; Spielvogel
1997). Of the full thickness burns covered with allograft, 74% had granulation tissue
present compared with 51% in wounds covered with Dermagraft® (Purdue 1997). A
histologic study by Spielvogel (Spielvogel 1997) reported similar results with 78%
(40/51) of allograft treated full thickness burns and 51% (26/51) of Dermagraft®
treated burns having granulation tissue present.
In regards to graft take, allograft and Dermagraft® produced comparable results
(Hansbrough 1997; Purdue 1997) (Table 18).
SECTION 4
z
RESULTS
35
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Table 18. Percent graft take for burns managed with Dermagraft® and allograft
Study
Dermagraft
Hansbrough 1997
Allograft
P-value
Red
Blue
Day 5 (n=8)
93.8 [10.26]
98.8 [2.31]
98.8 [10.26]
0.19*
Day 9 (n=7)
97.1 [7.56]
99.3 [1.89]
97.9 [2.67]
0.72*
100 [0]
97.9 [3.93]
96.4 [3.78]
0.0527*
93.1
0.0001
Day 14 (n=7)
Purdue 1997 (n=46)
94.7
* across all three groups. Values expressed as Mean [Standard Deviation] unless stated otherwise.
Wound exudate
Purdue (Purdue 1997) reported minimal fluid accumulation under both coverings,
though it was significantly higher in the Dermagraft® group than the allograft group
on days 5, 9, 14, and on the day of removal (p<0.02). The mean fluid accumulation
score for the Dermagraft® red group was significantly higher than the scores for the
Dermagraft® blue and allograft groups on day 5 only (p=0.0074) (no specific scores
were provided) (Hansbrough 1997).
Patient-related outcomes
Ease of removal was recorded in two studies (Hansbrough 1997; Purdue 1997).
Dermagraft® was significantly easier to remove than allograft (p=0.0379), with 1/66
(1.5%) wounds requiring surgical excision of Dermagraft® and 11/66 (17%) wounds
requiring surgical excision of allograft (Purdue 1997). Hansbrough (Hansbrough
1997) noted that Dermagraft® blue was easier to remove than Dermagraft® red and
allograft.
Sloughing was reported in two studies (Hansbrough 1997; Purdue 1997). For
Hansbrough (Hansbrough 1997), no sloughing was required for Dermagraft®
treated wounds (both blue and red) compared with 4/10 (40%) allograft treated
wounds requiring sloughing of the epidermal layer. Purdue (Purdue 1997) reported
that the average amount of sloughing was 3.6% at day 5, which increased to 49.9% at
day 18, with more than half of the allograft wounds at day 9 and all of the allograft
wounds at day 18 exhibiting some epidermal sloughing.
In terms of patient satisfaction, the investigators in the study by Purdue (Purdue
1997) reported a significantly higher level of satisfaction with Dermagraft®
compared with allograft on the day of removal (p=0.0167). The technique used to
measure patient satisfaction was not stated.
Integra®
Integra® is composed of two layers; a bovine collagen-based dermal analogue, which
integrates with the patient’s own cells and a temporary epidermal silicone sheet that
is peeled away as the wound heals (Hansen et al. 2001). A very thin autograft is then
36
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
grafted onto the neo-dermis. Integra® is indicated for the post-excisional treatment
of full thickness or deep partial thickness burns (Hansen et al. 2001).
For the management of burns
Integra® was compared with autograft, allograft or xenograft (Heimbach 1988) and
Biobrane® or allograft (Peck 2002) in two studies. Both studies were within-patient
comparisons. Follow-up times ranged from five months to one year. Mean TBSA
and mechanism of burn injury are detailed in Appendix D. The mean TBSA was
greater in Peck (Peck 2002) than Heimbach (Heimbach 1988).
Wound infection
In the study by Peck (Peck 2002), four patients had an Integra® covered wound
paired with a Biobrane® covered wound and three patients had an Integra® covered
wound paired with an allograft covered wound. The allograft covered sites had no
signs of infection, two of the four (50%) Biobrane® covered sites developed
infections, and all seven sites (100%) covered with Integra® developed infections.
Due to the high incidence of infectious complications associated with Integra®, as
well as the failure of Integra® to make a significant contribution to wound closure in
patients with burns greater than 45% TBSA, the trial was terminated after discussion
with the Committee on the Protection of the Rights of Human Subjects.
Heimbach (Heimbach 1988) did not report on wound infection.
Wound healing time
One study reported wound healing time (Heimbach 1988). Sites covered with
autograft, allograft or xenograft had a significantly longer wound healing time than
sites covered with Integra® (14.3 [6.9] days vs. 10.6 [5.8] days, p<0.001) (Heimbach
1988). Details on the number of patients who received autograft, allograft or
xenograft were not reported separately.
Wound closure
In regards to graft take, biological skin replacements (autograft, allograft, or
xenograft) had significantly better take than Integra® (Table 19) (Heimbach 1988).
Table 19. Proportion of patients with ≥75% wound closure for Integra® and comparators
Study
Integra
Auto-, allo- or xenograft
P-value
Heimbach 1988 (n=106)
62 [4] (median 80)
All: 79 [3] (median 95)
<0.0001
Allograft only*: 66 [8]
* sample size not specified. Values expressed as Mean [Standard Deviation] unless stated otherwise.
Patient-related outcomes
Heimbach (Heimbach 1988) reported patient and physician preferences. The
majority of patients (53/82, 64%) and physicians (37/82, 45%) found the Integra®
and biological skin replacement (autograft, allograft, or xenograft) sites equivalent.
SECTION 4
z
RESULTS
37
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Apligraf®
Apligraf® is a bilayered living skin equivalent composed of type I bovine collagen
and allogeneic keratinocytes and fibroblasts obtained from neonatal foreskin (Hansen
et al. 2001). It has to be applied “fresh”, as it has a shelf-life of five days at room
temperature (Hansen et al. 2001) and has been used as a temporary covering over
meshed expanded autograft for excised burn wounds (Waymack 2000).
For the management of burns
One study reported the use of Apligraf® with two years’ follow-up (Waymack 2000).
This study was a within-patient comparison with sites covered with either Apligraf®
combined with autograft or autograft only. Mean TBSA and mechanism of burn
injury are detailed in Appendix D.
Wound healing time
Waymack (Waymack 2000) reported a median eight days to greater than 75% closure
of interstices for Apligraf® and autograft combined compared with a median 13 days
for autograft only for the treatment of partial and full thickness burns.
Wound closure
The use of Apligraf® between the wound surface and the autograft appeared to
accelerate the rate of wound closure, with 53% (20/38) of patients having greater
than 75% closure compared with 37% (14/38) of patients who received autograft
only after the first week (Waymack 2000). By one month the proportion of patients
with greater than 75% closure was the same in both groups (Table 20).
Table 20. Proportion of patients with ≥75% wound closure for Apligraf® and autograft
Study
Apligraf + autograft
Autograft
P-value
Week 1
20/38 (53%)
14/38 (37%)
NP
Week 2
34/38 (89%)
33/38 (87%)
NP
Month 1
36/38 (95%)
36/38 (95%)
NP
Waymack 2000
NP – not performed.
There was no significant difference in the proportion of patients with greater than
75% graft take between Apligraf® and autograft combined and autograft only
(38/38, 100% vs. 37/38, 97%, respectively) (Waymack 2000).
Wound exudate
No significant differences were detected between autograft and Apligraf® combined
with autograft (Waymack 2000). However, wound exudate was reported in fewer
wounds treated with Apligraf® and autograft combined than with autograft only
(7/38, 18% vs. 10/38, 26%, respectively) (Waymack 2000).
38
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Patient-related outcomes
Compared with autograft only, the use of Apligraf® combined with autograft
resulted in scar tissue that was significantly closer to normal skin, a significantly
smoother (closer to normal) surface texture, and a greater proportion of wounds
with pigmentation closer to normal, at all follow-up time points (Waymack 2000).
The proportion of patients with normal pliability was also significantly greater for
Apligraf® combined with autograft than autograft only at all follow-up time points
except week 1 (Waymack 2000). Table 21 provides more detail on these outcomes.
Table 21. Other patient-related outcomes for Waymack 2000 (n=40)
Outcomes
Apligraf + autograft
Autograft
Cosmesis
Wk 1
Wk 2
Mth 1
Mth 2
Mth 6
Mth 12
Mth 24
Wk 1
Wk 2
Mth 1
Mth 2
Mth 6
Mth 12
Mth 24
4.81
4.89
4.89
5.26
5.13
4.76
4.89
<0.05
<0.05
<0.001
<0.001
<0.001
<0.001
<0.0001
Vancouver Scar Score
(0=normal, 13=abnormal)
4.38
4.32
4.18
4.16
3.79
3.08
2.55
P-value
Pigmentation
No. of patients with normal
pigmentation
Mth 6
Mth 12
Mth 24
5/38 (13%)
12/38 (32%)
17/38 (45%)
Mth 6
Mth 12
Mth 24
2/38 (5%)
5/38 (13%)
5/38 (13%)
PNS
Pliability (no. of patients
with normal pliability)
Wk 1
Mth 1
Mth 6
Mth 24
6/38 (16%)
20/38 (53%)
22/38 (58%)
23/38 (60.5%)
Wk 1
Mth 1
Mth 6
Mth 24
1/38 (3%)
7/38 (18%)
5/38 (13%)
5/38 (13%)
PNS
<0.001
<0.0001
<0.0001
Surface texture
Mth 0.5-1
Mth 2
Mth 3-6
Mth 7-12
Mth 13+
8.3 [1.3]
8.9 [0.6]
8.8 [0.6]
8.5 [1.9]
8.6 [2.5]
Mth 0.5-1
Mth 2
Mth 3-6
Mth 7-12
Mth 13+
7.2 [1.3]
7.0 [1.3]
6.9 [1.9]
7.3 [1.3]
7.7 [1.9]
<0.05
<0.05
<0.05
<0.05
<0.05
Score (0=rough,
10=smooth)
<0.05
<0.05
PNS – p-value not significant.
Autologous cultured skin
The preparation of autologous cultured skin involves the collection of biopsy
samples from the burns patient as early as possible after injury (Boyce 2002). The
keratinocytes and fibroblasts are isolated and grown in serum-free culture media,
harvested and prepared for grafting onto full thickness burn sites (Boyce 2002).
For the management of burns
Two studies with possible patient overlap compared an autologous epidermal
substitute with autograft only for full thickness burns (Boyce 1995; Boyce 2002).
Both studies had within-patient comparisons with up to one-year follow-up. Mean
TBSA and mechanism of burn injury are detailed in Appendix D. The mean TBSA
was comparable across the two studies.
SECTION 4
z
RESULTS
39
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Wound closure
There was no significant difference between the two groups in percent reepithelialisation for the first two weeks (Boyce 2002). However, autograft had a
higher percent re-epithelialisation and percent TBSA closed in the long-term (after
two weeks and up to one year) (Table 22) (Boyce 1995; Boyce 2002).
In regards to graft take, autograft had a high percentage and was superior to
autologous epidermal substitute (Boyce 1995; Boyce 2002).
A higher proportion of patients in the autologous epidermal substitute group
required regrafting as opposed to patients in the autograft only group (p<0.05)
(Boyce 1995; Boyce 2002). The first eight patients in the Boyce (Boyce 1995) trial
whose full thickness burns were covered with autologous epidermal substitute
experienced complete or nearly complete failure and required regrafting. However, as
experience was gained, graft take improved markedly (Table 22).
Table 22. Wound closure, graft take and number of patients requiring skin grafting
Study
Autologous epidermal substitute
Autograft
P-value
50-60 (17)
>80 (17)
<0.05†
Day 7
79.9 (45)
85.4 (45)
NP
Day 14
71.5 (45)
90.8 (45)
NP
Day 14
15.4 [7.6] (12)
60.0 [5.5] (12)
NP
Day 28
16.7 [9.0] (12)
58.7 [6.2] (12)
NP
Day 14
89.2 [8.7] (12)
94.9 [12.5] (12)
NP
Day 28
95.4 [6.2] (12)
99.0 [2.8] (12)
NP
11/17 (65%)
0/17
<0.05
16/45 (36%)
1/45 (2%)
<0.05
2/12 (17%)‡
0/12
NP
Percent re-epithelialisation
Boyce 1995
Boyce 2002
Percent TBSA closed
Boyce 2002*
Percent graft take
Boyce 2002*
Skin grafting required
Boyce 1995
Boyce 2002
*in the last 12 patients (total 45 patients); † at days 10, 11 and 14; ‡ regrafting was partial, not total; NP – statistical
analysis not performed. Values expressed as Mean [Standard Deviation] (sample size) unless stated otherwise.
Wound exudate
Although no significant differences were detected between autograft and autologous
epidermal substitute, the mean percentage of wounds with exudate was less for
autograft only than autologous epidermal substitute at day seven (33% (SE: 51.7) vs.
40
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
44% (SE: 52.3), respectively) and day 14 (18% (SE: 47.6) vs. 41% (SE: 55.7),
respectively) (Boyce 2002).
Patient-related outcomes
Scars from sites covered with autograft were significantly flatter (closer to normal
skin) than sites covered with autologous epidermal substitute up to 12 months
follow-up, but both sites were similar after 13 months (p<0.05) (Table 23) (Boyce
2002). The scar colour appeared to be better for autograft than autologous epidermal
substitute and this was significant at day 14 (p<0.05) (Table 23) (Boyce 2002).
Pigmentation scores increased progressively for sites covered with autologous
epidermal substitute or autograft (Boyce 2002). There was a significant difference
between the two groups, with pigmentation in the autologous epidermal substitute
group closer to normal than the autograft group at two to four weeks follow-up
(p<0.05) (Table 23).
Table 23. Other patient-related outcomes for Boyce 2002
Outcomes
Autologous epidermal
substitute (n=45)
Autograft (n=45)
P-value
Raised scar
Mth 0.5-1
Mth 2
Mth 3-6
Mth 7-12
Mth 13+
8.7 [1.3]
8.8 [1.3]
8.8 [1.7]
9.2 [0.7]
8.4 [1.3]
Mth 0.5-1
Mth 2
Mth 3-6
Mth 7-12
Mth 13+
8.0 [1.3]
7.5 [2.0]
7.1 [2.0]
7.9 [1.3]
8.4 [2.7]
<0.05
<0.05
<0.05
<0.05
PNS
Day 7
Day 14
5.43 [1.1]
6.20 [2.0]
Day 7
Day 14
6.04 [1.7]
7.75 [1.7]
PNS
<0.05
Mth 0.5-1
9.5 [1.3]
Mth 0.5-1
8.5 [2.0]
<0.05
Score (0 = 5mm, 10 = flat)
Colour
Score (0 = worst, 10 = best)
Pigmentation
Score*
* 0 = hyperpigmentation, 5 = normal pigmentation, 10 = hypopigmentation; PNS – p-value not significant.
No significant difference in pliability was reported between autologous epidermal
substitute and autograft and both sites were noted to be similar to normal skin
(Boyce 2002).
Erythema resolved progressively for sites covered with autologous epidermal
substitute or autograft with no significant differences between groups (Boyce 2002).
Allogeneic cultured skin
Allogeneic human epidermal cells are collected and the keratinocytes and/or
fibroblasts are isolated and cultured for the preparation of allogeneic cultured skin.
Duinslaeger (1997) used cadaveric donor skin to produce cultured sheets (fresh or
cryopreserved) which were grafted onto the wound site. Studies assessing allogeneic
cultured skin were only available for the management of donor sites.
SECTION 4
z
RESULTS
41
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
For the management of donor sites
Two studies compared an allogeneic cultured skin with a wound dressing
(Duinslaeger 1997; Madden 1996). Madden (Madden 1996) compared sites covered
with either cultured epidermal allograft combined with Adaptic™ or Adaptic™
dressing alone, with one-year follow-up. Duinslaeger (Duinslaeger 1997) compared
allogeneic cultured keratinocyte sheets with OpSite® dressing alone, with 8-23
months follow-up. Both studies were within-patient comparisons. Mean TBSA and
mechanism of burn injury are detailed in Appendix D. The mean TBSA was
comparable across the two studies.
Wound infection
One study reported rates of wound infection in which no cases of wound infection
were reported from sites treated with allogeneic cultured keratinocyte sheets or sites
treated with OpSite® dressings (Duinslaeger 1997).
Wound healing time
Wounds covered with OpSite® dressing took a significantly longer time to heal than
wounds covered with allogeneic cultured keratinocyte sheets (Table 24) (Duinslaeger
1997). No statistical analyses were performed for wound healing time in the Madden
(Madden 1996) study; however, the application of a cultured epidermal allograft in
between the donor site and Adpatic™ dressing appears to make the wound heal
faster (Table 24).
Table 24. Wound healing time (mean days) for donor sites managed with an allogeneic
cultured skin and comparators
Study
Bioengineered Skin
Substitute
Mean [SD]
Topical Agent /
Wound Dressing
Mean [SD]
P-value
Madden 1996
Cultured epidermal allograft +
Adaptic dressing (n=15)
7.8 [2.3]
Adaptic dressing (n=15)
9.2 [3.5]
NP
Duinslaeger
1997
Allogeneic cultured
keratinocyte sheets (n=15)
6.7
OpSite dressing (n=15)
13.6
<0.0001
NP - no statistical analyses were performed.
Wound closure
Both studies reported wound closure (Duinslaeger 1997; Madden 1996). In one
study, the percentage of re-epithelialisation (determined by visual estimation) was
significantly higher for wounds covered with allogeneic cultured keratinocyte sheets
than wounds covered with OpSite® dressing at first inspection (day 4, 5 or 6) and on
day 10 (p<0.01) (Table 25) (Duinslaeger 1997). In the other study, wound closure,
determined by visual assessment, was assessed in all 13 patients (Madden 1996).
Visual examination of the wound margin revealed no differences between sites
covered with cultured epidermal allograft and Adaptic™ dressing or Adaptic™
dressing alone (Madden 1996). Biopsies taken from the centre of each wound bed
revealed a greater degree of re-epithelialisation (p=0.039) and enhanced epithelial
42
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
differentiation (p=0.023) for sites covered with cultured epidermal allograft
compared with sites covered with Adaptic™ dressing alone (Madden 1996).
Table 25. Percentage of epithelialisation for donor sites managed with allogeneic cultured
keratinocyte sheets and OpSite®
Study
Allogeneic cultured keratinocyte
sheet
OpSite dressing
P-value
Day 4, 5 or 6
Mean 93.6 (range 75-100)
Mean 54.3 (range 30-70)
<0.01
Day 10
Mean 98.6 (range 85-100)
Mean 75.6 (range 40-100)
<0.01
Duinslaeger 1997
Wound exudate
Duinslaeger (Duinslaeger 1997) reported fewer wounds with exudate for sites
covered with allogeneic cultured keratinocyte sheets (4/16, 25%), than those covered
with OpSite® dressing (11/16, 69%). Madden (Madden 1996) did not provide data
on wound exudate.
Patient-related outcomes
Pain was reported in both studies in different ways. Madden (Madden 1996) reported
that pain assessments were equivalent between sites covered with cultured epidermal
allograft or Adaptic™ dressing. Duinslaeger (Duinslaeger 1997) used a Visual
Analogue Scale (VAS) (range, 0 to 20) to measure pain, where higher scores indicated
greater pain. The VAS could not be used in 3/15 (20%) patients due to age and/or
general anaesthesia. The mean score for donor sites covered with allogeneic cultured
keratinocyte sheets was 10.75 [3.25] (range 5-15) compared with 13.3 [3.1] (range 818) for sites covered with OpSite® dressing (p=0.000029).
Cosmetic outcome was also reported in both studies. Mild hypertrophic scarring
occurred at one site (1/16, 6.25%) covered with allogeneic cultured keratinocyte
sheets and two sites (2/16, 12.5%) covered with OpSite® dressing (Duinslaeger
1997). There were no differences in the quality of the scar after one month, except
for mild differences in colour (more redness and hypervascularity) in two sites (2/16,
12.5%) covered with OpSite® dressing (Duinslaeger 1997). Similar results from the
Vancouver Scale Scar assessments were reported for sites covered with cultured
epidermal allograft or Adaptic™ dressing, where both sites were hypopigmented and
either flat or less than 2mm in height up to one year after transplantation (Madden
1996). The sites were pink at one-month follow-up, returning to normal colouration
by three to six months, and remained supple and flexible after transplantation.
Unpleasant odour was reported in 4/16 (25%) sites covered with allogeneic cultured
keratinocyte sheets and 11/16 (69%) sites covered with OpSite® dressing
(Duinslaeger 1997).
SECTION 4
z
RESULTS
43
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Complications
The tables in this section provide information on the comparators and types of skin
substitutes in the studies for each category.
Biobrane®
For the management of burns
Study
Bioengineered Skin Substitute
Comparator
Lal 2000
Biobrane
Silver sulfadiazine
Biobrane
Silver sulfadiazine
Barret 2000
Gerding 1990
Kumar 2004
TransCyte
Cassidy 2005
Biobrane
Duoderm
No complications were reported in two studies comparing Biobrane® with silver
sulfadiazine (Barret 2000a; Gerding 1990) and one study comparing Biobrane®,
TransCyte® and silver sulfadiazine (Kumar 2004). Biobrane® failed in 2/34 (6%)
patients and was removed early due to non-adherence without suspicion of
underlying infection (Lal 2000). After removal, the affected wound area was treated
with twice daily silver sulfadiazine dressing changes (Lal 2000). No patients in either
group required hospital readmissions or skin grafts (Lal 2000).
Kumar (Kumar 2004) compared Biobrane®, TransCyte®, and silver sulfadiazine in
paediatric patients with partial thickness burns and reported no complications.
Cassidy (Cassidy 2005) did not provide information on complications.
For the management of donor sites
Study
Bioengineered Skin Substitute
Comparator
Fratianne 1993
Biobrane
Allogeneic cultured keratinocyte sheets
Still 2003
Biobrane
OrCel
No major complications were reported in the two studies; however, deaths were
reported (Fratianne 1993; Still 2003) (see Mortality section).
44
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
TransCyte®
For the management of burns
Study
Bioengineered Skin Substitute
Topical Agent / Wound Dressing
Noordenbos 1999
TransCyte
Silver sulfadiazine
Demling & DeSanti
1999
TransCyte
Antibiotic ointments and creams
Demling & DeSanti
2002
No complications were reported in one study comparing TransCyte® with silver
sulfadiazine (Noordenbos 1999). Demling and DeSanti (Demling and DeSanti 1999;
Demling and DeSanti 2002) did not provide information on complications.
Dermagraft®
For the management of burns
Study
Bioengineered Skin Substitute
Topical Agent / Wound Dressing
Hansbrough 1997
Dermagraft
Allograft
Purdue 1997
Spielvogel 1997
Hansbrough (Hansbrough 1997) reported no adverse reactions to Dermagraft®, and
no evidence of rejection, early deterioration, or separation from wound.
The premature removal of either temporary coverings or autograft occurred in 3/66
(4.5%) patients in the study by Purdue (Purdue 1997) but the reason for removal was
not specified. No adverse device effects were reported. No patterns were observed
that raised safety issues regarding Dermagraft® (Purdue 1997).
No information on complications were provided by Spielvogel (Spielvogel 1997).
Integra®
For the management of burns
Study
Bioengineered Skin Substitute
Topical Agent / Wound Dressing
Peck 2002
Integra
Allograft
Biobrane
Heimbach 1988
Artificial dermis
Autograft, allograft, or xenograft
No major complications were reported in the two studies (Heimbach 1988; Peck
2002). However, both studies did report deaths (see Mortality section).
SECTION 4
z
RESULTS
45
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Apligraf®
For the management of burns
Study
Bioengineered Skin Substitute
Topical Agent / Wound Dressing
Waymack 2000
Apligraf + autograft
Autograft
Waymack (Waymack 2000) reported no device-related adverse events, infections, and
humoral or cellular responses.
Autologous cultured skin
For the management of burns
Study
Bioengineered Skin Substitute
Topical Agent / Wound Dressing
Boyce 1995
Autologous epidermal substitute
Autograft
Boyce 2002
No complications were reported in the two Boyce studies (Boyce 1995; Boyce 2002).
Allogeneic cultured skin
For the management of donor sites
Study
Bioengineered Skin Substitute
Topical Agent / Wound Dressing
Madden 1996
Cultured epidermal allograft + Adaptic dressing
Adaptic dressing
Duinslaeger 1997
Allogeneic cultured keratinocyte sheets
OpSite dressing
There was no evidence of blister formation for donor sites covered with cultured
epidermal allograft combined with Adaptic™ dressing (Madden 1996). Blood clot
accumulation at a small part of the donor site was reported in 1/16 (6%) patients
treated with allogeneic cultured keratinocyte sheets and 2/16 (12.5%) patients treated
with OpSite® dressing (Duinslaeger 1997).
46
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Mortality
Biobrane®
For the management of burns
No deaths were reported from all five studies {Gerding, 1990 162 /id;Barret, 2000
144 /id;Lal, 2000 172 /id;Kumar, 2004 225 /id;Cassidy, 2005 257 /id}.
Biobrane®
For the management of donor sites
Two studies reported patient deaths (Fratianne 1993; Still 2003). Fratianne (Fratianne
1993) reported two patient deaths (2/10, 20%); one on post-burn day 14 and the
other on post-burn day 35. The cause of death was not stated for either patient. For
the patient who died on post-burn day 14, the site treated with allogeneic cultured
keratinocyte sheets healed in 11 days and the Biobrane® treated site was 50% healed
at the time of death, which was slightly longer than the median wound healing time
reported (wounds healed in a median six days for sites treated with allogeneic
cultured keratinocyte sheets and a median 14 days for the Biobrane® treated sites).
For the patient who died on post-burn day 35, the site treated with allogeneic
cultured keratinocyte sheets healed in nine days and the Biobrane® treated site
healed in 17 days, which was similar to the median wound healing time. Still (Still
2003) reported three patient deaths (3/82, 4%) during their study. However, none of
the deaths were considered to be related to the study treatment.
TransCyte®
For the management of burns
No deaths were reported in any of the three studies (Demling and DeSanti 1999;
Demling and DeSanti 2002; Noordenbos 1999).
Dermagraft®
For the management of burns
Purdue (Purdue 1997) reported eight patient deaths (8/66, 12%) before completion
of the study but the causes were not stated. No deaths were reported from
Hansbrough (Hansbrough 1997) and Spielvogel (Spielvogel 1997).
Integra®
For the management of burns
Deaths were reported in both studies (Heimbach 1988; Peck 2002). Of the seven
patients in the trial by Peck (Peck 2002), three died (43%); one was due to
complications related to smoke inhalation injury and the causes were not stated for
two (presumably sepsis).
SECTION 4
z
RESULTS
47
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Heimbach (Heimbach 1988) reported an overall mortality rate of 13% (20/149). The
mortality rate for patients with complete data was also 13% (14/106). These
mortality rates were age-related where the children in this study appeared to generally
respond well to treatment as opposed to the elderly patients who tolerated burns
quite poorly. Most of the deaths were in patients with massive burns or associated
with severe smoke inhalation.
Apligraf®
For the management of burns
Waymack (Waymack 2000) did not report any deaths.
Autologous cultured skin
For the management of burns
Boyce (Boyce 1995; Boyce 2002) did not report any deaths.
Allogeneic cultured skin
For the management of donor sites
No deaths were reported from Duinslaeger (Duinslaeger 1997) and Madden
(Madden 1996).
48
SECTION 4
z
RESULTS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Cost considerations
Integra®, TransCyte® and Biobrane® are currently available for use in Australia (J
Greenwood: personal communication, 2005). As of October 2005, the cost of
Integra® is $AUS 10.60 per cm2 and TransCyte® is $AUS 5.30 per cm2 (J
Greenwood: personal communication, 2005). Sheets of Biobrane® are available in
three sizes (5” x 5”, 5” x 15” and 10” x 15”) and the average cost across the three is
approximately $AUS 0.30 per cm2 (J Greenwood: personal communication, 2005).
Cadaver skin is approximately $AUS 1.70 per cm2 (J Greenwood: personal
communication, 2005).
Three of the included studies provided some cost information on the treatments
used (Demling and DeSanti 2002; Gerding 1990; Still 2003). The cost of OrCel™ is
$US 27.80 per cm2 (~$US 1000 per 36cm2), more expensive than Biobrane®, which
is $US 0.16 per cm2 ($US 25.15 per 161 cm2) (Still 2003). Gerding (Gerding 1990)
based their cost data collection on the assumption that patients followed all of their
instructions for wound dressings and kept all of their clinic follow-up visits. The
mean cost was significantly lower with the use of Biobrane® ($US 434 (SE: 14)) than
treatment with silver sulfadiazine ($US 504 (SE: 24)) for 44 weeks’ follow-up in
paediatric and adult patients with partial thickness burns (p<0.05).
Demling & DeSanti (Demling and DeSanti 2002) reported significantly lower costs
with the use of TransCyte® for partial thickness facial burns compared with the use
of antibiotic ointments and creams (Table 26).
Table 26. Breakdown of cost information from Demling & DeSanti 2002
Study
TransCyte
Antibiotics
P-value
Demling & DeSanti 2002
Mean [SD] US dollars
Total cost until healing
Nursing costs
Cost of supplies (incl. skin substitute cost)
Cost of medications
$2390 [$290]
$240
$1950
$210
$3020 [$350]
$1350
$1310
$390
<0.05
<0.05
<0.05
NS
NS – not significant.
Though cost was not a key search term in this review, a study on the cost of cultured
epidermal autografts (CEA) compared with conventional meshed autografts in 20
paediatric patients, with full thickness burns to more than 90% TBSA was found in
the initial search strategy (Barret et al. 2000b). Conventional meshed autografts were
superior to CEA in terms of total number of operations (8[0.9] vs. 13[1.3] (p<0.05),
respectively), length of hospital stay (89 [9.8] days vs. 128[14.3] days (p<0.05),
respectively), and cost per patient ($US 178 000[19000] vs. $US 304000[31000]
(p<0.05), respectively).
SECTION 4
z
RESULTS
49
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
5. Discussion
Limitations of the evidence
This review of bioengineered skin substitutes was limited by the quantity and quality
of the available evidence. Despite the inclusion of 20 RCTs, a number of factors
limited the conclusions which could be drawn and prevented statistical pooling: the
diversity of skin substitutes and management methods for burns; the lack of a
standard comparator; the differences in the techniques used to measure wound
healing time and wound closure across the studies. As a consequence, the included
studies were categorised into type of bioengineered skin substitute, then by
management of donor sites and management of burns, and by age (paediatric or
adult). Due to this categorisation, there were only a few studies for each sub-group.
This review recognises that due to the relatively rapid developments in burns
management and the sudden proliferation of materials, many of the included studies
compared bioengineered skin substitutes with what the ‘gold standard’ was at that
time, which may not be a valid comparator.
Though all evidence was from RCTs (Level II and III-1), the methodological quality
of these studies was generally inadequate. Of the 20 included studies, 13 were withinpatient comparisons and seven were parallel comparisons. The advantage of withinpatient comparisons is that it overcomes the potential problems of comparing groups
of different patients and the carry-over effects and treatment by period interactions
that are inherent in crossover trials have been circumvented, due to the concurrent
administration of treatments in the included studies.
The majority of the included studies had relatively small sample sizes (all but one
study had fewer than 100 patients) and may have lacked the power to detect
significant differences between treatments. Follow-up times ranged from 11 days to
two years. In most cases, the effects of age on the reported outcomes were unclear,
as the results for the paediatric and adult population were grouped together.
However, in the studies that categorised patients into age groups, patient age did not
appear to significantly influence wound healing time, wound closure and wound
infection. The reporting and the percentages of mean TBSA varied and were
therefore not good predictors of outcome. It was also not possible to evaluate the
effectiveness of bioengineered skin substitutes by burn depth, as outcomes were not
reported separately for partial thickness and full thickness burns.
Key outcomes, including wound healing time, wound closure, wound infection, pain
and cosmesis (scarring) were reported. However, some included studies did not
report on all of these outcomes, suggesting the possibility of publication/reporting
bias in favour of the experimental groups.
50
SECTION 5
z
DISCUSSION
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Several methods were used to measure pain. The Vancouver Scar Scale, Hamilton
Burn Scar Rating Scale, Wong-Baker Faces Pain Rating Scale, Oucher Scale and
Visual Analogue Scale were validated tools used in most of the studies. However,
some studies measured pain subjectively, which may have introduced bias in favour
of a particular treatment if the patient or assessor was not blinded.
Efficacy outcomes
From the included studies, Biobrane® and TransCyte® were used for the
management of burns <15% TBSA; TransCyte® was used for the management of
burns <20% TBSA; TransCyte®, Dermagraft®, Integra®, Apligraf® and allogeneic
cultured skin were used for the management of burns 20-50% TBSA; and Integra®
and autologous cultured skin were used for the management of burns >50% TBSA.
Biobrane®
For the management of burns
From the evidence available in the five studies, Biobrane® produced as good results
as the comparators (silver sulfadiazine and TransCyte®), with regard to wound
infection and wound healing time. The use of Biobrane® required significantly fewer
dressing changes and less pain medication than silver sulfadiazine.
The rates of wound infection with the use of Biobrane® were comparable to those
obtained with silver sulfadiazine, the type of infections reported tended to be local
and easily controlled. It has been recommended that Biobrane® should be removed
if it is non-adherent, as leaving it in place may increase the risk of invasive wound
infection (Lal et al. 2000). Wound infection may be related to the mechanism of burn
injury, as this influences the severity of the wound. The reporting of wound
infections in Gerding et al. (1990) and the lack of wound infections in Barret et al.
(2000a) suggests that wound infections are more likely to occur in grease-related
injuries rather than scalds. The higher temperatures, increased viscosity and enhanced
heat transfer associated with burns caused by grease may induce deeper injuries than
aqueous-based scalds; whereas contact burns generally have a limited depth of heat
penetration and are less likely to deepen with time and become infected (Gerding et
al. 1990). Therefore the outcomes reported from different causes of burn injury may
not be comparable.
Unlike silver sulfadiazine, Biobrane® is not toxic to keratinocytes, which may explain
the significantly faster wound healing time reported for partial thickness burns
covered with Biobrane® than those covered with silver sulfadiazine. Partial thickness
burn sites on paediatric patients treated with silver sulfadiazine tended to require skin
grafting to close the wound compared with sites covered with Biobrane® or
TransCyte®. Kumar et al. (2004) noted that paediatric patients appeared to respond
better with the use of Biobrane® or TransCyte®, as the dressings were usually left
SECTION 5
z
DISCUSSION
51
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
intact on the wound until separation; this reduced the pain and anxiety associated
with dressing changes and allowed the wound to heal undisturbed underneath,
resulting in the shorter wound healing times reported. Wound healing times were
comparable for Biobrane® and Duoderm®.
Biobrane® required significantly fewer dressing changes than silver sulfadiazine. As a
result, patients reported less pain at the Biobrane® site and significantly less pain
medication was required. Patients who received silver sulfadiazine treatment were not
as compliant as the Biobrane® treated patients, which may have been attributable to
the more frequent and painful dressing changes required with silver sulfadiazine
treatment.
For the management of donor sites
Although Biobrane® is not frequently used for the management of donor sites,
evidence was obtained from two studies, as they provided evidence on the properties
of Biobrane® on a clean and controlled wound.
From the evidence available in the two studies, Biobrane® did not produce results as
good as the other products (allogeneic cultured keratinocytes and OrCel™), with
regard to wound healing time, wound closure, pain and scar severity. Wound
infection appears to be comparable for Biobrane® and OrCel™.
Donor sites covered with Biobrane® took a longer time to heal than sites covered
with allogeneic cultured keratinocyte sheets or OrCel™. Compared with Biobrane®,
a higher percentage of OrCel™ sites were completely healed and had a faster rate of
wound closure, enabling these sites to be ready for recropping earlier (none of the
Biobrane® sites were reharvested). The scar severity score was lower for OrCel™
and patients reported less pain from OrCel™ covered sites. There were no
significant differences in wound infection between OrCel™ and Biobrane®.
The outcomes reported with the use of OrCel™ and the allogeneic cultured
keratinocyte sheets suggests that the presence of cytokines and growth factors
produced by the proliferating keratinocyte and fibroblast donor cells may have a
positive influence on the wound healing process.
TransCyte®
From the evidence available in the three studies, TransCyte® performed more
favourably than topical antibiotics in terms of wound healing time, wound care time
and pain. Similarly, TransCyte® produced more favourable results over silver
sulfadiazine, in terms of wound infection, wound healing time, wound closure and
scar severity.
For facial burns, TransCyte® appeared to be superior to antibiotic ointments and
creams, with a significantly shorter wound healing time and fewer dressing changes
required. The physical properties of TransCyte® are very similar to skin and allow it
52
SECTION 5
z
DISCUSSION
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
to mould to the facial contour. TransCyte® reportedly had good adherence to the
entire face including the ears, which could be attributable to biochemical bonding; in
particular, the bonding of the adhesion protein, fibronectin, to the wound surface
(Demling and DeSanti 1999).
Dermagraft®
From the evidence available in the three studies, Dermagraft® appeared to produce
results as good as allograft, with regard to wound infection, wound exudate, wound
healing time, wound closure and graft take.
Dermagraft® had comparable results with allograft, but was easier to remove; a
significantly higher level of patient satisfaction with Dermagraft® was also reported.
A higher proportion of wounds covered with allograft had granulation tissue present,
but removing the allograft required surgical excision and de-sloughing (removal of
necrotic tissue). The advantages of Dermagraft® are that it is transparent, which
allows direct visual monitoring of the wound bed and therefore permits earlier
detection of clinical signs of wound infection, and it induces less granulation tissue
formation and less bleeding on removal.
Hansbrough et al. (1997) also compared two different Dermagraft® products:
Dermgraft® red, which was cryopreserved by a method that maintains high viability
of the cultured fibroblasts, and Dermagraft® blue, which was frozen by a method
that did not retain metabolic activity. Both were functionally equivalent, suggesting
that continued fibroblast viability is not required for these skin substitutes to
function as a temporary wound cover.
Integra®
From the evidence available in the two studies, Integra® did not produce as good
results as the other products (autograft, allograft, xenograft, Biobrane®), with regard
to wound infection and graft take. However, Integra® appeared to be better than
autograft, allograft or xenograft in terms of wound healing time.
Results from the trial by Peck et al. (2002) appeared to be in favour of Biobrane®
and allograft, as all Integra® covered sites developed infections and, as a
consequence, the trial was terminated early. This suggests that Integra® may not be
effective on patients with burns more than 45% TBSA due to host
immunosuppression and may be better suited to selected patients with smaller burns
(Peck et al. 2002). However, in clinical practice, the use of Integra® is usually limited
to major burns when there is no alternative due to a lack of available donor area for
autografting and would therefore not be used on smaller burns.
Heimbach et al. (1988) reported a significantly shorter wound healing time with
Integra®; however, covering the wound with either an allograft or xenograft, prior to
SECTION 5
z
DISCUSSION
53
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
grafting, resulted in significantly better graft take. There appeared to be a learning
curve with the use of Integra®, and graft take improved as the surgeons became
more experienced (Heimbach et al. 1988).
Apligraf®
From the evidence available in the one study, Apligraf® combined with autograft
produced more favourable results than autograft only. The rate of wound closure
was accelerated, and scar tissue, pigmentation, pliability and smoothness were
significantly closer to normal with Apligraf®.
Autologous cultured skin
From the evidence available in the two studies, autograft appeared to be superior to
autologous epidermal substitute in terms of graft take, wounds with exudate and scar
appearance. More sites covered with autologous epidermal substitute required
regrafting.
The main disadvantage with the use of cultured and non-cultured skin products is
that these take weeks to prepare after collection of the biopsy for cell culture. For
burns this is not ideal but these may be more suitable for elective procedures, such as
reconstruction of burn scar or congenital skin lesions (Boyce et al. 2002).
Allogeneic cultured skin
From the evidence available in the one study, allogeneic cultured keratinocyte sheets
produced favourable results compared with OpSite® dressing, with regard to wound
healing time, re-epithelialisation rates, wounds with exudate and pain score. In
another study, cultured epidermal allograft combined with Adaptic™ dressing
produced comparable results when compared with Adaptic™ dressing only.
The use of allogeneic cultured keratinocytes resulted in a significantly shorter wound
healing time and significantly greater percentage of epithelialisation compared with
the use of OpSite® dressing (Duinslaeger et al. 1997). However, the degree of
epithelialisation was determined by visual estimation in this RCT and such subjective
methods could result in possible errors that could influence the wound healing time.
Sites covered with OpSite® dressing took the longest time to heal, had a higher
proportion of wounds with exudate and unpleasant odour, and a significantly higher
pain score. This would have been associated with the frequent dressing changes
required, which are often painful and may injure viable tissue and remove the
delicate, newly formed epithelial cells, and as a result, would make the wound
susceptible to infection. For both treatment sites, there were a few cases of mild
hypertrophic scarring but no cases of infection were reported.
Madden et al. (1996) developed a method to cryopreserve cultured epidermal
allografts suitable for grafting because, until recently, the use of cultured epidermal
54
SECTION 5
z
DISCUSSION
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
allografts was limited; they could only be supplied fresh to the surgeon. Sites covered
with cultured epidermal allograft plus Adaptic™ dressing had a significantly greater
degree of re-epithelialisation and enhanced epithelial differentiation, and a
significantly shorter wound healing time compared with those covered with
Adaptic™ dressing alone. Pain assessment and scar assessment results were
equivalent between the two groups.
Biological skin replacements
The most commonly used temporary cover is frozen cadaver allograft (Heimbach et
al. 1988). It is often used as an overlay on widely spread autografts to close the
wound and as the autografted epidermis spreads, it gradually dislodges the allograft
(the Alexander technique). Though the wound usually closes successfully, the
cosmetic and functional results remain poor (Heimbach et al. 1988). Xenografts are
commonly of porcine origin and are generally effective at preparing the wound bed
for a short time (seven days) but do not vascularise and thus offer little resistance to
infection (Heimbach et al. 1988).
Autografts are still the gold standard for the management of burns, as there are no
issues with graft rejection and viral contamination. However, some bioengineered
skin substitutes can be used with autograft; (i) as temporary coverings with/without
other dressings to prepare and maintain the post-burn excision wound until the time
for autografting, (ii) as agents to hold meshed autograft in areas of shear or to
stimulate the wound bed in the interstices of meshed autograft and (iii) as permanent
dermal replacements to provide a neo-dermal base onto which autograft can be
applied.
Safety outcomes
No major complications were reported with the use of Biobrane®. One RCT
reported Biobrane® failure in 6% of patients due to non-adherence without
suspicion of underlying infection. After the removal of Biobrane®, the sites healed
uneventfully with silver sulfadiazine dressings. The mortality rate was high with
patient deaths reported in the Biobrane®/allogeneic cultured keratinocyte sheets
study and in the Biobrane®/OrCel™ study. However, there was no evidence that
mortality was influenced by the choice of dressing.
Early removal was required in 4.5% of patients with Dermagraft® or allograft
coverings, but reasons for removal were not stated. Patient deaths were also reported
in the Dermagraft®/allograft study but the causes were not stated.
The mortality rate was also very high for the studies involving the use of Integra®,
and was associated with smoke inhalation injury or large TBSA.
The remaining studies did not report any major complications or deaths.
SECTION 5
z
DISCUSSION
55
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Cost considerations
Though cost was not a key search term in this review, a U.S. cost study published in
2000 was found in the initial search strategy (Barret et al. 2000b). Barret et al. (2000b)
reported that the mean cost for conventional meshed autografts, which included total
number of operations and length of hospital stay, was significantly lower per patient
than for mean cultured epidermal autografts per patient.
As of October 2005, Biobrane® appears to be the least expensive bioengineered skin
substitute available in Australia (J Greenwood: personal communication, 2005). In
the U.S., Biobrane® was also less expensive than OrCel™ (per cm2) (Still et al. 2003)
and treatment with silver sulfadiazine (total cost over 44 weeks) (Gerding et al. 1990).
Demling & DeSanti (Demling and DeSanti 2002) reported significantly lower total
costs with the use of TransCyte® for 19 days than the use of topical antibiotics over
the same period of time. Further investigation of the cost-effectiveness of the
bioengineered skin substitutes available in Australia compared with conventional
methods of burns management are required.
Ethical considerations
There are ethical and or religious concerns associated with the use of skin substitutes,
which should be considered in the management of burns patients. The use of donor
organs or animal tissue may raise issues for ethnic or religious groups, vegans,
vegetarians and animal rights activists. A U.K. study (Enoch et al. 2005) found that
religious leaders, representing 13 religious groups encompassing 75% of the U.K.
population, had concerns regarding bioengineered skin substitutes including the
transmission of viral and prion diseases, cruelty to animals, and derivation of material
from neonates. These leaders emphasised the need to inform the patient of the
constituents of the biological products and obtain informed consent. However,
healthcare professionals may be unfamiliar with all the constituents of bioengineered
skin substitutes (Enoch et al. 2005), which would make it difficult to appropriately
inform patients when obtaining consent. Thus, hospitals, regulatory authorities and
product manufacturers should address this issue and take adequate measures to
ensure that healthcare professionals are aware of the constituents of these products
in order to obtain informed patient consent, as the failure to do so could have
potentially serious ramifications.
Future research
Obtaining useful evidence from comparative studies of the use of bioengineered skin
substitutes for burns management is difficult. Although 20 RCTs were included in
this systematic review, the numerous types of bioengineered skin substitutes available
have prevented statistical pooling of the results. There is a need to develop a tool to
non-invasively and objectively measure the biophysical properties of skin to avoid
56
SECTION 5
z
DISCUSSION
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
biases associated with the use of subjectively scoring wound closure. More rigorous
RCTs are required comparing burn coverings with similar properties to enable valid
comparisons of outcomes. Studies should also specify where in the clinical decision
pathway is the bioengineered skin substitute employed and report separate outcomes
for partial thickness and full thickness burns.
There are also a number of autologous cultured and non-cultured skin engineering
products available, such as CellSpray®, Cellspray® XP and ReCell® (Clinical Cell
Culture Ltd., Bentley, Australia) and EpiDex™ (Modex Therapeutiques, Lausanne,
Switzerland) (Table 1). However, there is a paucity of published, high quality
evidence to allow the safety and efficacy of these products to be evaluated.
Randomised controlled trials are needed before the safety and efficacy of these
products can be determined.
SECTION 5
z
DISCUSSION
57
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
6. Conclusions and Recommendations
This review compared bioengineered skin substitutes and biological skin
replacements or topical agents/wound dressings in terms of safety and efficacy.
Despite the inclusion of 20 randomised controlled trials, which should have
minimised bias in the reporting of outcomes, these trials were characterised by
generally poor reporting of methodological detail and small sample sizes.
Consequently, it was difficult to be confident in the validity of some of the findings.
More rigorous RCTs are required comparing burn coverings with similar properties
to enable valid comparisons of outcomes.
Overall conclusions regarding the suitability of BSS for burns management could not
be formulated based on the evidence in this review, due to the diversity of skin
substitutes and methods for burn management. Due to the way in which outcomes
were reported in the included studies, it was not possible to investigate differences in
the effectiveness of bioengineered skin substitutes in partial thickness compared with
full thickness burns, in paediatric patients compared to adult patients, and for TBSA.
However, from the available evidence it was possible to draw some conclusions
about the different bioengineered skin substitutes considered in the review.
For partial thickness burns (less than 15%TBSA), Biobrane® and TransCyte®
appear to be more effective than silver sulfadiazine, avoiding the need for painful
daily dressing changes and prolonged hospital stay. Biobrane® may also offer cost
advantages over other bioengineered skin substitutes.
For burns between 20% and 50% TBSA, allogeneic cultured skin and Apligraf®
combined with autograft both appear to be effective. Dermagraft® was also found to
be effective for partial and full thickness burns (as effective as allograft); however,
the validity of this comparison is questionable as Dermagraft® is permanently
integrated whereas allograft is a temporary biological dressing.
Integra® may be better suited to selected patients with burns less than 45% TBSA
due to the high rates of infection reported in one study managing patients with burns
greater than 45% TBSA. However, in clinical practice, Integra® is commonly used in
the treatment of major burn injury where a paucity of available donor area precludes
early autografting. Its successful take still has to be followed by definitive epidermal
closure (by autograft or cultured epithelial autograft).
TransCyte® appears to be good for facial burns, providing good adherence to the
contours of the face. However, considerations with the storage, pre-use preparation
and high cost of TransCyte® may limit its clinical use.
In terms of safety, no major complications were reported with the use of
bioengineered skin substitutes for the management of burns or donor sites. The
58
SECTION 6
z
CONCLUSIONS AND RECOMMENDATIONS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
mortality rate was relatively high; however, it was unclear whether these deaths could
be attributed to the use of the bioengineered skin substitute or the actual burn injury.
In practical terms, this distinction would be difficult to assess since the use of
bioengineered skin substitutes is largely confined to patients with larger TBSA burn
areas, more complicated pathophysiological insults and significantly poorer
prognoses. The available evidence could not resolve the question of the long-term
safety of bioengineered skin substitutes with respect to viral infection and prion
disease. To address this issue, long-term follow-up is required as the incubation
period for viral infection and prion disease has been estimated to be approximately
15 to 18 years (Ghani 2002). Thus, at present, autograft remain the gold standard for
the management of excised burns as it is effective at closing the wound and there are
no issues with graft rejection and viral contamination.
Classification and Recommendations
The evidence-base in this review is rated as average. The included randomised
controlled trials were limited by small sample size and poor reporting of
methodological detail. The numerous sub-groups analyses and the diversity of skin
substitutes limited the ability to draw any conclusions from it.
Safety
The evidence suggests that bioengineered skin substitutes, namely Biobrane®,
TransCyte®, Dermagraft®, Apligraf®, autologous cultured skin, and allogeneic
cultured skin, are at least as safe as biological skin replacements or topical
agents/wound dressings. The safety of Integra® could not be determined as one
study reported a high rate of infection and the trial was terminated early.
The long-term safety of the use of bioengineered skin substitutes, with respect to
viral infection and prion disease, could not be determined.
Efficacy
For the management of partial thickness burns the evidence suggests that
bioengineered skin substitutes, namely Biobrane®, TransCyte®, Dermagraft®, and
allogeneic cultured skin, are at least as efficacious as topical agents/wound dressings
or allograft. Apligraf® combined with autograft is at least as efficacious as autograft
alone.
For the management of full thickness burns, the efficacy of autologous cultured skin
could not be determined based on the available evidence.
The efficacy of Integra® could not be determined based on the available evidence.
SECTION 6
z
CONCLUSIONS AND RECOMMENDATIONS
59
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Clinical and Research Recommendations
Additional methodologically rigorous randomised controlled trials would strengthen
the evidence base for the use of bioengineered skin substitutes. However, it is
acknowledged that it is unlikely that randomised trials of patients with large, deep
burns will be carried out, as these burns are uncommon and usually involve complex
clinical decision pathways and possibly the use of several products, which may differ
between patients and make comparisons difficult. Therefore, it is recommended that
randomised trials of patients with smaller burns be undertaken as these burns are
more common and patient accrual should be easier. Furthermore, clinical equipoise
should be more easily obtained in these less life-threatening situations. Additionally,
studies with sufficient follow-up should be conducted to evaluate the long-term
safety of bioengineered skin substitutes and future studies should define and
document outcomes for partial and full thickness burns separately.
There is also a need for randomised controlled trials on cultured epithelial autograft,
in particular cultured epithelial autograft suspensions, as there is a lack of evidence to
support its safety and efficacy and its use largely based on anecdote.
Acknowledgments
The authors wish to acknowledge Dr Rebecca Tooher, Ms Amber Watt and Ms
Philippa Middleton for their assistance during the preparation of this review. The
ASERNIP-S project is funded by the Australian Government Department of Health
and Ageing.
60
SECTION 6
z
CONCLUSIONS AND RECOMMENDATIONS
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
References
Australia and New Zealand Burn Association Ltd. Emergency Management of
Severe Burns Course Manual. 5th Edition Edition. 1996.
Balasubramani M, Kumar TR, Babu M. Skin substitutes: a review. Burns 2001; 27:
534-544.
Barret JP, Dziewulski P, Ramzy PI, Wolf SE, Desai MH, Herndon DN. Biobrane
versus 1% silver sulfadiazine in second-degree pediatric burns. Plastic &
Reconstructive Surgery 2000a; 105(1): 62-65.
Barret JP, Wolf SE, Desai MH, Herndon DN. Cost-efficacy of cultured epidermal
autografts in massive pediatric burns. Annals of Surgery 2000b; 231(6): 869-875.
Boyce ST, Goretsky MJ, Greenhalgh DG, Kagan RJ, Rieman MT, Warden GD.
Comparative assessment of cultured skin substitutes and native skin autograft
for treatment of full-thickness burns. Annals of Surgery 1995; 222(6): 743-752.
Boyce ST, Kagan RJ, Yakuboff KP, Meyer NA, Rieman MT, Greenhalgh DG,
Warden GD. Cultured skin substitutes reduce donor skin harvesting for
closure of excised, full-thickness burns. Annals of Surgery 2002; 235(2): 269279.
Brown TP, Cancio LC, McManus AT, Mason AD, Jr. Survival benefit conferred by
topical antimicrobial preparations in burn patients: a historical perspective.
Journal of Trauma 2004; 56(4): 863-866.
Burn treatment for burn victims. Skin grafts for scar management in burn victims.
Ethicon, Inc. Last updated 2003.
http://www.skinhealing.com/3_2_burntreatments.shtml [Accessed
September 2004].
Cassidy C, St Peter SD, Lacey S, Beery M, Ward-Smith P, Sharp RJ, Ostlie DJ.
Biobrane versus duoderm for the treatment of intermediate thickness burns
in children: a prospective, randomized trial. Burns 2005; 31(7): 890-893.
Demling RH, de Santi L, and Orgill DP. Use of skin substitutes module. Burn
Surgery. Last updated 2000.
http://www.burnsurgery.com/Modules/skinsubstitutes/ [Accessed June
2004].
REFERENCES
61
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Demling RH and DeSanti L. Management of partial thickness facial burns
(comparison of topical antibiotics and bio-engineered skin substitutes). Burns
1999; 25(3): 256-261.
Demling RH and DeSanti L. Closure of partial-thickness facial burns with a bioactive
skin substitute in the major burn population decreases the cost of care and
improves outcome. Wounds - A Compendium of Clinical Research & Practice 2002;
14(6): 230-234.
Duinslaeger LA, Verbeken G, Vanhalle S, Vanderkelen A. Cultured allogeneic
keratinocyte sheets accelerate healing compared to Op-site treatment of
donor sites in burns. Journal of Burn Care & Rehabilitation 1997; 18(6): 545-551.
Dunn K and Edwards-Jones V. The role of ActicoatTM with nanocrystalline silver in
the management of burns. Burns 2004; Supplement 1: S1-S9.
Eisenbud D, Huang NF, Luke S, Silberklang M. Skin substitutes and wound healing:
current status and challenges. Wounds 2004; 16(1): 2-17.
Enoch S, Shaaban H, Dunn KW. Informed consent should be obtained from
patients to use products (skin substitutes) and dressings containing biological
material. Journal of Medical Ethics 2005; 31(1): 2-6.
Fratianne R, Papay F, Housini I, Lang C, Schafer IA. Keratinocyte allografts
accelerate healing of split-thickness donor sites: applications for improved
treatment of burns. Journal of Burn Care & Rehabilitation 1993; 14(2 Pt 1): 148154.
Gerding RL, Emerman CL, Effron D, Lukens T, Imbembo AL, Fratianne RB.
Outpatient management of partial-thickness burns: Biobrane versus 1% silver
sulfadiazine. Annals of Emergency Medicine 1990; 19(2): 121-124.
Ghani AC. The epidemiology of variant Creutzfeldt-Jakob disease in Europe.
Microbes and Infection 2002; 4(3): 385-393.
Hancock W. Skin Banking in Australia. Summit Meeting to investigate the
establishment of a National Human Tissue Processing Centre in Australia.
Last updated November 1999.
http://www.menziesfoundation.org.au/conferences/tissue%201999/it04han
cock.html [Accessed May 2006].
Hansbrough JF, Mozingo DW, Kealy GP, Davis M, Gidner A, Gentzkow GD.
Clinical trials of a biosynthetic temporary skin replacement, DermagraftTransitional Covering, compared with cryopreserved human cadaver skin for
62
REFERENCES
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
temporary coverage of excised burn wounds. Journal of Burn Care &
Rehabilitation 1997; 18(1 Pt 1): 43-51.
Hansen SL, Voigt DW, Wiebelhaus P, Paul CN. Using skin replacement products to
treat burns and wounds. Advances in Skin and Wound Care 2001; 14(1): 37-44.
Heimbach D, Luterman A, Burke J, Cram A, Herndon D, Hunt J, Jordan M,
McManus W, Solem L, Warden G. Artificial dermis for major burns. A multicenter randomized clinical trial. Annals of Surgery 1988; 208(3): 313-320.
Herman AR. The history of skin grafts. Journal of Drugs in Dermatology 2002; 1(3): 298301.
Hettiaratchy S and Dziewulski P. ABC of Burns: Introduction. BMJ 2004; 328(7452):
1366-1368.
Higgins JPT and Green S. Cochrane Handbook for Systematic Reviews of
Interventions 4.2.4 [updated March 2005]. In: The Cochrane Library, Issue 2,
2005. Chichester, UK: John Wiley & Sons, Ltd.
Hunt TK, Hopf H, Hussain Z. Physiology of wound healing. Advances in Skin and
Wound Care 2000; 13(Suppl 2): 6-11.
Jones I, Currie L, Martin R. A guide to biological skin substitutes. British Journal of
Plastic Surgery 2002; 55(3): 185-193.
Kumar RJ, Kimble RM, Boots R, Pegg SP. Treatment of partial-thickness burns: A
prospective, randomized trial using Transcyte (TM). ANZ Journal of Surgery
2004; 74(8): 622-626.
Lal S, Barrow RE, Wolf SE, Chinkes DL, Hart DW, Heggers JP, Herndon DN.
Biobrane improves wound healing in burned children without increased risk
of infection. Shock 2000; 14(3): 314-318.
Madden MR, LaBruna AA, Hajjar DP, Staiano-Coico L. Transplantation of
cryopreserved cultured epidermal allografts. Journal of Trauma, Injury, Infection
& Critical Care 1996; 40(5): 743-750.
Noordenbos J, Dore C, Hansbrough JF. Safety and efficacy of TransCyte for the
treatment of partial-thickness burns. Journal of Burn Care & Rehabilitation 1999;
20(4): 275-281.
Papini R. ABC of burns: Management of burn injuries of various depths. BMJ 2004;
329(7458): 158-160.
REFERENCES
63
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Peck MD, Kessler M, Meyer AA, Bonham Morris PA. A trial of the effectiveness of
artificial dermis in the treatment of patients with burns greater than 45% total
body surface area. Journal of Trauma, Injury, Infection & Critical Care 2002; 52(5):
971-978.
Prasad JK, Feller I, Thomson PD. A prospective controlled trial of Biobrane versus
scarlet red on skin graft donor areas. Journal of Burn Care & Rehabilitation 1987;
8(5): 384-386.
Purdue GF, Hunt JL, Still JM, Jr., Law EJ, Herndon DN, Goldfarb IW, Schiller WR,
Hansbrough JF, Hickerson WL, Himel HN, Kealey GP, Twomey J,
Missavage AE, Solem LD, Davis M, Totoritis M, Gentzkow GD. A
multicenter clinical trial of a biosynthetic skin replacement, Dermagraft-TC,
compared with cryopreserved human cadaver skin for temporary coverage of
excised burn wounds. Journal of Burn Care & Rehabilitation 1997; 18(1 Pt 1): 5257.
Rheinwald JG and Green H. Serial cultivation of strains of human epidermal
keratinocytes: the formation of keratinising colonies from single cells. Cell
1975; 6(3): 331-343.
Spann CT, Tutrone WD, Weinberg JM, Scheinfeld N, Ross B. Topical antibacterial
agents for wound care: a primer. Dermatologic Surgery 2003; 29(6): 620-626.
Spielvogel RL. A histological study of Dermagraft-TC in patients' burn wounds.
Journal of Burn Care & Rehabilitation 1997; 18(1 Pt 2): S16-S18.
Still J, Glat P, Silverstein P, Griswold J, Mozingo D. The use of a collagen
sponge/living cell composite material to treat donor sites in burn patients.
Burns 2003; 29(8): 837-841.
Subrahmanyam M. A prospective randomised clinical and histological study of
superficial burn wound healing with honey and silver sulfadiazine. Burns
1998; 24(2): 157-161.
Takeuchi J, Miura K, Usizima H, Katoh Y. Histological changes in the
submandibular glands of rats after intraductal injection of chemical
carcinogens. Acta Pathologica Japonica 1975; 25(1): 1-13.
Therapeutic Goods Administration. Access to unapproved therapeutic goods via the
special access scheme. Department of Health and Ageing. Last updated
October 2004a. http://www.tga.gov.au/docs/html/sasinfo.htm [Accessed
May 2006a].
64
REFERENCES
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Therapeutic Goods Administration. Regulatory impact statement for human cell,
tissue and cellular and tissue-based products. Department of Health and
Ageing. Last updated September 2004b.
http://www.tga.gov.au/consult/2004/hctpris.htm#pdf [Accessed May
2006b].
Waymack P, Duff RG, Sabolinski M. The effect of a tissue engineered bilayered
living skin analog, over meshed split-thickness autografts on the healing of
excised burn wounds. The Apligraf Burn Study Group. Burns 2000; 26(7):
609-619.
REFERENCES
65
APPENDIX A – HIERARCHY OF EVIDENCE
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Appendix A – Hierarchy Of Evidence
Level of Evidence
Study Design
I
Evidence obtained from a systematic review of all relevant randomised
controlled trials.
II
Evidence obtained from at least one properly designed randomised
controlled trial.
III-1
Evidence obtained from well-designed pseudo-randomised controlled
trials (alternate allocation or some other method).
III-2
Evidence obtained from comparative studies (including systematic
reviews of such studies) with concurrent controls and allocation not
randomised, cohort studies, case-control studies, or interrupted timeseries with a control group.
III-3
Evidence obtained from comparative studies with historical control, two
or more single arm studies, or interrupted time series without a parallel
control group.
IV
Evidence obtained from case-series, either post-test or pre-test/post-test.
National Health and Medical Research Council. How to use the evidence: assessment
and application of scientific evidence. Canberra, ACT: Biotext, 2000.
68
APPENDIX B – EXCLUDED STUDIES
69
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Appendix B – Excluded Studies
The following articles were excluded from the methodological assessment as outlined
in the methods section of the review.
Excluded Studies
Study
Reason for exclusion
Arnold K. Out-patient care of scalds and burns with SYSpur-derm.
Dermatologische Monatsschrift 1981; 167(10): 647
Assessment of outpatient care – no useful
outcomes
Asai S, Ino K, Ebisawa K, Torii S. Simultaneous grafting for burn injuries
using artificial dermis and skin. [Japanese]. Japanese Journal of Plastic
& Reconstructive Surgery 2001; 44(1): 27-34
Not a comparative study
Asato H, Harii K, Nozaki M. Clinical evaluation of Pelnuc (Artificial
dermis) for full-thickness skin defects. [Japanese]. Japanese Journal of
Plastic & Reconstructive Surgery 2001; 44(4): 359-376
Not a comparative study
Barret JP, Wolf SE, Desai MH, Herndon DN. Cost-efficacy of cultured
epidermal autografts in massive pediatric burns. Annals of Surgery 2000;
231(6): 869-875
Non-randomised comparative study
Berger A and Burke JF. Autologous skin transplantation versus artificial
skin. Langenbecks Archiv fur Chirurgie 1987; 372: 343-348
Non-randomised comparative study
Bortolami PA, Guerrini P, Sanna A. A new type of dressing for skin
donor areas. Rivista Italiana di Chirurgia Plastica 1983; 15(1): 50-53
Not a comparative study
Boyce ST, Kagan RJ, Meyer NA, Yakuboff KP, Warden GD. Cultured
skin substitutes combined with integra artificial skin to replace native skin
autograft and allograft for the closure of excised full- thickness burns.
Journal of Burn Care & Rehabilitation 1999; 20(6): 453-461
Not a comparative study
Bugmann P, Taylor S, Gyger D, Lironi A, Genin B, Vunda A, La Scala G,
Birraux J, Le Coultre C. A silicone-coated nylon dressing reduces
healing time in burned paediatric patients in comparison with standard
sulfadiazine treatment: a prospective randomized trial. Burns 1998;
24(7): 609-612
No comparison with a bioengineered skin
substitute
Carsin H. Cultured skin in the treatment of burns. Pathologie Biologie
1999; 47(8): 776-779
Not a comparative study
Carsin H, Ainaud P, Le Bever H, Rives JM, Lakhel A, Stephanazzi J,
Lambert F, Perrot J. Cultured epithelial autografts in extensive burn
coverage of severely traumatized patients: a five year single-center
experience with 30 patients. Burns 2000; 26(4): 379-387
Not a comparative study
Caruso DM, Foster KN, Hermans MHE, Rick C. Aquacel Ag (R) in the
management of partial-thickness burns: Results of a clinical trial. Journal
of Burn Care & Rehabilitation 2004; 25(1): 89-97
Non-randomised comparative study
Caruso DM, Schuh WH, Al Kasspooles MF, Chen MC, Schiller WR.
Cultured composite autografts as coverage for an extensive body
surface area burn: case report and review of the technology. Burns
1999; 25(8): 771-779
Not a comparative study
Chan ESY, Lam PK, Liew CT, Lau HCH, Yen RSC, King WWK. A new
technique to resurface wounds with composite biocompatible epidermal
graft and artificial skin. Journal of Trauma-Injury Infection & Critical Care
2001; 50(2): 358-362
Not a comparative study
Chen X, Soejima K, Kikuchi Y, Nozaki M. Effects of artificial dermis
seeded with cryopreserved allogenic cultured dermal fibroblasts on
wound healing. [Japanese]. Japanese Journal of Plastic &
Reconstructive Surgery 2002; 45(11): 1061-1067
Not in humans (rats)
70
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Dantzer E and Braye FM. Reconstructive surgery using an artificial dermis
(Integra): results with 39 grafts. British Journal of Plastic Surgery 2001;
54(8): 659-664
Not a comparative study
Dantzer E, Queruel P, Salinier L, Palmier B, Quinot JF. Dermal
regeneration template for deep hand burns: clinical utility for both early
grafting and reconstructive surgery. British Journal of Plastic Surgery 2003;
56(8): 764-774
Not a comparative study
Degenhardt P, Marzheuser S, Mau H. First experiences with use of artificial
dermis (Integra) on soft tissue wounds in children. [German]. Zentralblatt fur
Kinderchirurgie 2002; 11(1): 17-21
Not a comparative study
Druecke D, Lamme EN, Hermann S, Pieper J, May PS, Steinau HU,
Steinstraesser L. Modulation of scar tissue formation using different dermal
regeneration templates in the treatment of experimental full-thickness
wounds. Wound Repair and Regeneration 2004; 12(5): 518-527
Not in humans
Elliott M and Vandervord J. Initial experience with cultured epithelial
autografts in massively burnt patients. ANZ Journal of Surgery 2002;
72(12): 893-895
Not a comparative study
Feldman DL, Rogers A, Karpinski RH. A prospective trial comparing
Biobrane, Duoderm and xeroform for skin graft donor sites. Surgery,
Gynecology & Obstetrics 1991; 173(1): 1-5
Not on burns
Fitton AR, Drew P, Dickson WA. The use of a bilaminate artificial skin
substitute (Integra) in acute resurfacing of burns: An early experience.
British Journal of Plastic Surgery 2001; 54(3): 208-212
Not a comparative study
Frame JD, Still J, Lakhel-LeCoadou A, Carstens MH, Lorenz C, Orlet H,
Spence R, Berger AC, Dantzer E, Burd A. Use of dermal regeneration
template in contracture release procedures: A multicenter evaluation.
Plastic & Reconstructive Surgery 2004; 113(5): 1330-1338
Not a comparative study
Gerding RL, Imbembo AL, Fratianne RB. Biosynthetic skin substitute vs.
1% silver sulfadiazine for treatment of inpatient partial-thickness thermal
burns. Journal of Trauma 1988; 28(8): 1265-1269.
Non-randomised comparative study
Gohari S, Gambla C, Healey M, Spaulding G, Gordon KB, Swan J, Cook B,
West DP, Lapiere JC. Evaluation of tissue-engineered skin (human skin
substitute) and secondary intention healing in the treatment of full thickness
wounds after Mohs micrographic or excisional surgery. Dermatologic
Surgery 2002; 28(12): 1107-1114
Not on burns
Healy CM and Boorman JG. Comparison of E-Z Derm and Jelonet
dressings for partial skin thickness burns. Burns, Including Thermal Injury
1989; 15(1): 52-54
No comparison with a bioengineered skin
substitute
Heitland A, Piatkowski A, Noah EM, Pallua N. Update on the use of
collagen/glycosaminoglycate skin substitute - Six years of experiences with
artificial skin in 15 German burn centers. Burns 2004; 30(5): 471-475
Not a comparative study
Hunt JA, Moisidis E, Haertsch P. Initial experience of Integra in the
treatment of post-burn anterior cervical neck contracture. British Journal of
Plastic Surgery 2000; 53(8): 652-658
Not a comparative study
Kaiser HW, Stark GB, Kopp J, Balcerkiewicz A, Spilker G, Kreysel HW.
Cultured autologous keratinocytes in fibrin glue suspension, exclusively and
combined with STS-allograft (preliminary clinical and histological report of a
new technique). Burns 1994; 20(1): 23-29
Not a comparative study
71
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Kashiwa K and Minato S. The clinical use of a new artificial dermis
(PELNAC(TM)). Japanese Pharmacology & Therapeutics 1996; 24(8): 229241
Not a comparative study
Kashiwa N, Ito O, Ueda T, Kubo K, Matsui H, Kuroyanagi Y. Treatment of
full-thickness skin defect with concomitant grafting of 6-fold extended mesh
auto-skin and allogeneic cultured dermal substitute. Artificial Organs 2004;
28(5): 444-450
Not a comparative study
Khan U, Rhoer S, Healy C. Use of biobrane in pediatric scald burns experience in 106 children by L. F. Ou, S.Y. Lee, Y.C. Chen, R.S. Yang,
Y.W. Tang. Burns 1998; 24(8): 770
Not a comparative study (letter)
King P. Artificial skin reduces nutritional requirements in a severely burned
child. Burns 2000; 26(5): 501-503
Not a comparative study
Klein RL, Rothmann BF, Marshall R. Biobrane. A useful adjunct in the
therapy of outpatient burns. Journal of Pediatric Surgery 1984; 19(6): 846847
Not a comparative study
Kurihara K, Goto S, Namikawa H, Takahaski M, Nakamura J, Sasaki Y.
Clinical experiences using an artificial dermis. Japanese Journal of Plastic
& Reconstructive Surgery 1995; 38(6): 567-573
Not a comparative study
Lei X, Wu J-J, Zhu T-Y, Lu Y-G. Effects of composite chitosan artificial skin
in accelerating wound healing. Zhongguo Linchuang Kangfu 2004; 8(17):
3300-3302
Not a comparative study
Leicht P, Muchardt O, Jensen M, Alsbjorn BA, Sorensen B. Allograft vs.
exposure in the treatment of scalds--a prospective randomized controlled
clinical study. Burns, Including Thermal Injury 1989; 15(1): 1-3
No comparison with a bioengineered skin
substitute
Loss M, Wedler V, Kunzi W, Meuli-Simmen C, Meyer VE. Artificial skin,
split-thickness autograft and cultured autologous keratinocytes combined to
treat a severe burn injury of 93% of TBSA. Burns 2000; 26(7): 644-652
Not a comparative study
Lukish JR, Eichelberger MR, Newman KD, Pao M, Nobuhara K, Keating M,
Golonka N, Pratsch G, Misra V, Valladares E, Johnson P, Gilbert JC,
Powell DM, Hartman GE. The use of a bioactive skin substitute decreases
length of stay for pediatric burn patients. Journal of Pediatric Surgery 2001;
36(8): 1118-1121
No comparison with a bioengineered skin
substitute
Mann R, Gibran NS, Engrav LH, Foster KN, Meyer NA, Honari S, Costa
BA, Heimbach DM. Prospective trial of thick vs standard split-thickness skin
grafts in burns of the hand. Journal of Burn Care & Rehabilitation 2001;
22(6): 390-392
No comparison with a bioengineered skin
substitute
Medina J, de Brugerolle dF, Chibout SD, Kolopp M, Kammermann R, Burtin
P, Ebelin ME, Cordier A. Use of human skin equivalent Apligraf for in vitro
assessment of cumulative skin irritation potential of topical products.
Toxicology & Applied Pharmacology 2000; 164(1): 38-45
Not on burns – investigating skin
irritations in healthy volunteers
Moiemen NS, Staiano JJ, Ojeh NO, Thway Y, Frame JD. Reconstructive
surgery with a dermal regeneration template: Clinical and histologic study.
Plastic and Reconstructive Surgery 2001; 108(1): 93-103
Not a comparative study
Monstrey S, Beele H, Kettler M, Van Landuyt K, Blondeel P, Matton G,
Naeyaert JM. Allogeneic cultured keratinocytes vs. cadaveric skin to cover
wide-mesh autogenous split-thickness skin grafts. Annals of Plastic Surgery
1999; 43(3): 268-272
No comparison with a bioengineered skin
substitute
Ohura T. The clinical study of NEOMATRIX (artificial dermis) for full
thickness skin defects. Japanese Pharmacology & Therapeutics 1995;
23(6): 171-184
Not a comparative study
72
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Ou LF, Lee SY, Chen YC, Yang RS, Tang YW. Use of Biobrane in
pediatric scald burns - experience in 106 children. Burns 1998; 24(1): 4953
Not a comparative study
Paddle-Ledinek JE, Cruickshank DG, Masterton JP. Skin replacement by
cultured keratinocyte grafts: an Australian experience. Burns 1997; 23(3):
204-211
Not a comparative study
Pandya AN, Woodward B, Parkhouse N. The use of cultured autologous
keratinocytes with integra in the resurfacing of acute burns. Plastic and
Reconstructive Surgery 1998; 102(3): 825-828
Not a comparative study
Pape SA. Safety and efficacy of TransCyte for the treatment of partialthickness burns. Journal of Burn Care & Rehabilitation 2000; 21(4): 390
Not a comparative study (letter)
Phillips TJ, Provan A, Colbert D, Easley KW. A randomized single-blind
controlled study of cultured epidermal allografts in the treatment of splitthickness skin graft donor sites. Archives of Dermatology 1993; 129(7):
879-882
Not on burns
Porter JM. A comparative investigation of re-epithelialisation of split skin
graft donor areas after application of hydrocolloid and alginate dressings.
British Journal of Plastic Surgery 1991; 44(5): 333-337
Not on burns
Prasad JK, Feller I, Thomson PD. A prospective controlled trial of Biobrane
versus scarlet red on skin graft donor areas. Journal of Burn Care &
Rehabilitation 1987; 8(5): 384-386
RCT but scarlet red is no longer used and
is therefore not a valid comparator
Purdue GF, Hunt JL, Gillespie RW, Hansbrough JF, Dominic WJ, Robson
MC, Smith DJ, MacMillan BG, Waymac JP, Herndon DN. Biosynthetic skin
substitute versus frozen human cadaver allograft for temporary coverage
of excised burn wounds. Journal of Trauma-Injury Infection & Critical Care
1987; 27(2): 155-157.
Non-randomised comparative study
Putland M, Snelling CFT, Macdonald I, Tron VA. Histologic comparison of
cultured epithelial autograft and meshed expanded split-thickness skin
graft. Journal of Burn Care & Rehabilitation 1995; 16(6): 627-640
Not a comparative study
Qaryoute S, Mirdad I, Hamail AA. Usage of autograft and allograft skin in
treatment of burns in children. Burns 2001; 27(6): 599-602
Not a comparative study
Rose JK, Desai MH, Mlakar JM, Herndon DN. Allograft is superior to
topical antimicrobial therapy in the treatment of partial-thickness scald
burns in children. Journal of Burn Care & Rehabilitation 1997; 18(4): 338341
No comparison with a bioengineered skin
substitute
Rubis BA, Danikas D, Neumeister M, Williams WG, Suchy H, Milner SM.
The use of split-thickness dermal grafts to resurface full thickness skin
defects. Burns 2002; 28(8): 752-759
Not in humans
Rue III LW, Cioffi WG, McManus WF, Pruitt Jr BA. Wound closure and
outcome in extensively burned patients treated with cultured autologous
keratinocytes. Journal of Trauma-Injury Infection & Critical Care 1993;
34(5): 662-668
Not a comparative study
Ryan CM, Schoenfeld DA, Malloy M, Schulz III JT, Sheridan RL, Tompkins
RG. Use of Integra artificial skin is associated with decreased length of
stay for severely injured adult burn survivors. Journal of Burn Care &
Rehabilitation 2002; 23(5): 311-317
Not a comparative study
Sheridan RL, Hegarty M, Tompkins RG, Burke JF. Artificial skin in massive
burns - Results to ten years. European Journal of Plastic Surgery 1994;
17(2): 91-93
Not a comparative study
Soejima K, Nozaki M, Mizuno M. Artificial skin grafts with cryopreserved
allogenic cultured dermal fibroblasts. Japanese Journal of Plastic &
Reconstructive Surgery 2001; 44(1): 35-41
Not a comparative study
73
- ASERNIP-S REVIEW OF BIOENGINEERED SKIN SUBSTITUTES FOR THE MANAGEMENT OF BURNS AUGUST 2006 -
Soejima K, Nozaki M, Sasaki K, Takeuchi M, Negishi N. Reconstruction of
burn deformity using artificial dermis combined with thin split-skin grafting.
Burns 1997; 23(6): 501-504
Not a comparative study
Steenfos HH and Agren MS. A fibre-free alginate dressing in the
treatment of split thickness skin graft donor sites. Journal of the European
Academy of Dermatology & Venereology 1998; 11(3): 252-256
Not on burns
Stern R, McPherson M, Longaker MT. Histologic study of artificial skin
used in the treatment of full-thickness thermal injury. Journal of Burn Care
& Rehabilitation 1990; 11(1): 7-13
Not a comparative study
Still JM and Craft-Coffman B. Graftskin (APLIGRAF) in the management
of thermal injury. Wounds: A Compendium of Clinical Research and
Practice 2000; 12(5): Suppl-63A
Not a comparative study
Subrahmanyam M. A prospective randomised clinical and histological
study of superficial burn wound healing with honey and silver sulfadiazine.
Burns 1998; 24(2): 157-161
No comparison with a bioengineered
skin substitute
Suzuki S. Clinical application of NEOMATRIX for deep dermal defect.
Japanese Pharmacology & Therapeutics 1995; 23(6): 185-194
Not a comparative study
Suzuki S, Matsuda K, Maruguchi T, Nishimura Y, Ikada Y. Further
applications of 'bilayer artificial skin'. British Journal of Plastic Surgery
1995; 48(4): 222-229
Not a comparative study
Takami Y, Tanaka H, Wada T, Shimazaki S, Ogo K. Clinical trial of
artificial dermis transplantation and simultaneous autologous skin graft
overlay. Japanese Journal of Plastic & Reconstructive Surgery 2001;
44(1): 21-26
Not a comparative study
Unglaub F, Ulrich D, Pallua N. Reconstructive surgery using an artificial
dermis (Integra((R))): Results with 19 grafts. Zentralblatt fur Chirurgie
2005; 130(2): 157-161
Not a comparative study
van Zuijlen PPM, van Trier AJM, Vloemans JFPM, Groenevelt F, Kreis
RW, Middelkoop E. Graft survival and effectiveness of dermal substitution
in burns and reconstructive surgery in a one-stage grafting model. Plastic
and Reconstructive Surgery 2000; 106(3): 615-623
Non-randomised comparative study
van Zuijlen PPM, Vloemans JFP, van Trier AJM, Suijker MH, van Unen E,
Groenevelt F, Kreis RW, Middelkoop E. Dermal substitution in acute burns
and reconstructive surgery: A subjective and objective long-term followup. Plastic and Reconstructive Surgery 2001; 108(7): 1938-1946
Non-randomised comparative study
Vloemans AF, Soesman AM, Suijker M, Kreis RW, Middelkoop E. A
randomised clinical trial comparing a hydrocolloid-derived dressing and
glycerol preserved allograft skin in the management of partial thickness
burns. Burns 2003; 29: 702-710
No comparison with a bioengineered
skin substitute
Wang NZ, Reynolds PS, Coumbe A, Frame JD. Microskin grafting with
Biobrane: A new application. European Journal of Plastic Surgery 1995;
18(4): 157-161
Not a comparative study
Weber RS, Hankins P, Limitone E, Callender D, Frankenthaler RM, Wolf
P, Goepfert H. Split-thickness skin graft donor site management. A
randomized prospective trial comparing a hydrophilic polyurethane
absorbent foam dressing with a petrolatum gauze dressing. Archives of
Otolaryngology -- Head & Neck Surgery 1995; 121(10): 1145-1149
Not on burns
Wisser D and Steffes J. Skin replacement with a collagen based dermal
substitute, autologous keratinocytes and fibroblasts in burn trauma. Burns
2003; 29(4): 375-380
Not a comparative study
Yamaguchi Y, Hosokawa K, Sumikawa Y, Kakibuchi M, Yoshikawa K. The
use of autologous and bioengineered epidermis to control fibrosis and
improve cosmesis. Wounds-A Compendium of Clinical Research and
Practice 2000; 12(3): 68-75
Not a comparative study
74
APPENDIX C – METHODOLOGICAL ASSESSMENT AND
STUDY DESIGN TABLES
Appendix C – Methodological Assessment and Study Design Tables
Appendix C.1 Study design tables – Biobrane® for the management of burns
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Lal 2000
Biobrane® vs. Silver Sulfadiazine
Randomised controlled trial.
Paediatric patients with superficial partial
thickness scald burns.
Initial Preparation:
Wounds were debrided to remove overlying epidermis using sharp and blunt dissection,
and cleaned with Betadine® followed by copious irrigation.
Randomisation was achieved by a
computer-generated randomisation table.
No blinding.
Pain Medication: Intravenous morphine every 2-4 hrs as needed to control pain.
Level of Evidence: II
Biobrane®
Layers of Dressing:
▪ Biobrane® sheets (hands were covered with Biobrane® gloves and maintained in an
elevated position)
▪ Fine mesh gauze impregnated with 2% polymyxin B-bacitracin ointment and 1%
nystatin ointment
▪ Dry cotton dressings
▪ Elastic bandages
Fixation: Stapled to the skin or wrapped circumferentially around the extremities and the
torso
Dressing Changes: Dressing remained intact for 12-24 hrs, then if Biobrane® was
adherent without signs of underlying infection, wounds were covered with dry gauze
once a day or left open at the attending surgeon’s discretion.
Follow-up: Not stated.
Mean Age: (years)
Biobrane 2.8 (SE: 0.5) (n=34)
SSD 3.4 (SE: 0.6) (n=45)
Inclusion criteria:
▪ superficial 2nd degree hot
fluid scald burns that were
5-25% TBSA
▪ within 48 hrs of injury
▪ did not appear to need
grafting
▪ showed no initial signs of
cellulitis.
Lost to Follow-up: 10/89 (11%)
Biobrane 7/41 (17%)
SSD 3/48 (6%)
All 10 patients were excluded from
analysis.
Gender Mix: (M/F)
Biobrane 19/15 (n=34)
SSD 30/15 (n=45)
Location
Department of
Surgery, University
of Texas Medical
Branch, and
Shriners Burns
Hospital,
Galveston, Texas,
USA
Silver Sulfadiazine (SSD)
Layers of Dressing:
▪ SSD impregnated fine mesh gauze
▪ Dry cotton dressings
▪ Elastic bandages
Fixation: NA
Dressing Changes: Twice a day
Definition of Success
Full wound healing.
When Biobrane® was adherent without signs of underlying infection. If Biobrane® did
not adhere to the wound surface, it was removed and conservative treatment was
implemented.
Study Period: 1994 to 1999.
Operator Details:
While in hospital, dressing changes were
done by hospital staff. Upon discharge,
parents were given instructions for its
application.
Outcome Measures:
▪ Length of hospital stay
▪ Number of days for wound to heal
▪ Need for oral antibiotics after acute
hospital discharge
▪ Hospital readmission for infection/sepsis
▪ Need for skin grafting
Sample Size: 89 patients
Biobrane 41 patients
SSD 48 patients
Mean Total Burn Surface Area (TBSA)*:
(%)
Biobrane 11.8 (SE: 1.1) (n=34)
SSD 11.5 (SE: 0.9) (n=45)
*excludes head and neck
Mechanism of Burn Injury:
Not stated.
Burn Location: (%)
Biobrane
Extremity
19
Trunk
14
Extremity + Trunk
66
SSD
24
7
69
Exclusion criteria:
▪ burns <5% TBSA or >25%
TBSA
▪ later than 48 hrs from injury
▪ 3rd degree burns in addition
to 2nd degree injuries
▪ burned by grease.
77
78
Appendix C.1 Study design tables – Biobrane® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Barret 2000
Biobrane® vs. Silver Sulfadiazine
Randomised controlled trial.
Paediatric patients with partial thickness burns.
Initial Preparation:
All patients were sedated with ketamine and received superficial
debridement of blisters and debris.
Method of allocation not stated. No
blinding.
Sample Size: 20 patients
Biobrane 10 patients
SSD 10 patients
Location
Shriners Burns
Hospital and the
University of Texas
Medical Branch,
Galveston, Texas,
USA
Pain Medication: For procedural pain - 0.3mg/kg/dose morphine
by mouth; for background pain – 15mg/kg/dose acetaminophen by
mouth every 4 hrs. Lorazepam 0.03mg/kg/dose by mouth every 4
hrs was given for anxiety.
Biobrane®
Layers of Dressing:
▪ Biobrane® was applied to open wound
Fixation: Not stated
Dressing Changes: Biobrane® was left intact until wounds were
considered to be healed.
Silver Sulfadiazine (SSD)
Layers of Dressing: Not stated
Fixation: NA
Dressing Changes: Twice daily
Definition of Success
Wounds were considered healed when all areas affected in the
initial injury were closed.
Level of Evidence: II
Follow-up: (days to complete wound
healing)
Biobrane mean 9.7 (SE: 0.7)
SSD mean 16.1 (SE: 0.6)
Lost to Follow-up: 0
Study Period: Not stated.
Operator Details:
Wounds were inspected within 24 hrs and
patients were discharged home when
parents were ready to assume wound care.
Outcome Measures:
▪ Pain
▪ Pain medication requirements
▪ Infection
▪ Healing time
▪ Length of stay in hospital
Mean Age: (years)
Biobrane 3.1 (SE: 0.5)
SSD 3.7 (SE: 0.6)
Gender Mix: (M/F)
Biobrane 7/3
SSD 8/2
Mean Total Burn Surface Area (TBSA): (%)
Biobrane 8.9 (SE: 4.9)
SSD 7.8 (SE: 0.9)
Mechanism of Burn Injury: (Flame/Scalds)
Biobrane 2/8
SSD 3/7
Inclusion/Exclusion Criteria
Inclusion criteria:
▪ 0-17 years old
▪ thermal flame or scald
injury
▪ TBSA burned between 2
and 29%
▪ admitted within 24 hrs after
the injury
▪ clean non-infected wound
as diagnosed by the
attending physician.
Exclusion criteria:
▪ >17 years old
▪ causes other than thermal
flame or scald injuries
▪ full thickness burns
▪ admission time >24 hrs
after the injury
▪ wounds noted to be
contaminated or infected.
Appendix C.1 Study design tables – Biobrane® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Kumar 2004
TransCyte® vs. Biobrane® vs. Silver Sulfadiazine
Randomised controlled trial.
Paediatric patients with partial
thickness burns.
Initial Preparation:
Wounds were debrided within 24 hrs of burn injury using appropriate topical and systemic
analgesia.
Randomisation by lottery. No blinding.
Pain Medication: Narcotic analgesia during dressing changes.
Follow-up: mean 11 days
TransCyte®
Layers of Dressing:
▪ TransCyte® (thawed at 37°C prior to application)
▪ A dry bulky dressing (Melolin; Smith & Nephew)
▪ Compression dressing or elastic wrap to maintain contact with the wound until the product
was adherent
Fixation: Sterile adhesive (Hypafix; Smith & Nephew) or staples to form a cuff if the wound site
was on a limb
Dressing Changes: After 24 hrs, if not adherent the outer dressings were replaced for a further
24 hrs and re-evaluated at that time.
Lost to Follow-up: 0
Inclusion criteria:
▪ wounds deemed to be
partial thickness in depth
▪ laser Doppler criteria of
perfusion values of
between 32 and 65%
▪ equivalent flux values of
between 250 and 600
random units.
Location
Stuart Pegg Burns
Unit, Royal
Children’s
Hospital, Brisbane,
Queensland,
Australia
Biobrane®
Layers of Dressing:
▪ Biobrane®
▪ A dry bulky dressing (Melolin; Smith & Nephew)
▪ Compression dressing or elastic wrap to maintain contact with the wound until the product
was adherent
Fixation: Sterile adhesive (Hypafix; Smith & Nephew) or staples to form a cuff if the wound site
was on a limb
Dressing Changes: After 24 hrs, if not adherent the outer dressings were replaced for a further
24 hrs and re-evaluated at that time.
Silver Sulfadiazine (SSD)
Layers of Dressing:
Once the wound area was clean with no eschar, SSD use was stopped and the wound covered
with a hydrocolloid dressing (Duoderm Thin; Smith & Nephew).
Fixation: NA
Dressing Changes: Daily
Definition of Success
The product provided wound coverage until re-epithelialisation.
Level of Evidence: II
Study Period: June 2000 to June 2001.
Operator Details:
2 independent observers assessed burn
depth and percentage of closure.
Outcome Measures:
▪ Time to re-epithelialisation
▪ Number of wounds requiring
autografting
▪ Number of dressing changes and
local wound care required (e.g.
medical intervention, pain medication)
▪ Burn depth (laser Doppler imaging
system)
▪ Percentage of closure (rated by visual
estimation)
Sample Size: 33 patients (58
wounds)
TransCyte 20 wounds
Biobrane 17 wounds
SSD 21 wounds
Mean Age: (years)
3.60
Gender Mix: (M/F)
Not stated.
Mean Total Burn Surface Area
(TBSA): (%)
5
Mechanism of Burn Injury:
“predominantly via hot water scalds”
Exclusion criteria:
▪ burn injury occurred >24
hrs prior to commencement
of treatment
▪ wounds identified as study
areas were full thickness in
depth
▪ wounds to be studied
exhibited clinical signs of
infection.
79
80
Appendix C.1 Study design tables – Biobrane® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Gerding 1990
Biobrane® vs. Silver Sulfadiazine
Randomised controlled trial.
Patients with partial thickness burns.
Initial Preparation:
All wounds were completely debrided of blisters and loose tissue and cleansed
with sterile saline before randomisation.
Randomisation was achieved by computergenerated codes within sealed, numbered
envelopes that were opened in sequential
fashion. No blinding of patients, physicians
or assessors.
Sample Size: 64 patients were enrolled.
Data available on 52 patients* (56 wounds)
Biobrane 26 patients (30 wounds)
SSD 26 patients (26 wounds)
Inclusion criteria:
▪ >2 months old
▪ not pregnant
▪ fresh partial thickness
wounds
▪ no history of sulfa
sensitivity
▪ wounds with a moist,
sensate surface and
prompt capillary refill.
Location
Departments of
Surgery and
Emergency
Medicine,
MetroHealth
Medical Centre,
Case Western
Reserve
University,
Cleveland, Ohio,
USA
Pain Medication: Adult patients were given prescriptions for acetaminophen with
codeine. Children were treated with acetaminophen alone.
Biobrane®
Layers of Dressing:
▪ Porous (green label) material was applied under moderate tension in a wrinklefree manner to the wound
▪ Dry gauze
▪ Elastic wraps
Fixation: Steri-Strips® or 1-inch paper tape
Dressing Changes: Wounds were inspected after 24 to 36 hrs. Non-adherent
Biobrane® was aspirated or reapplied at the 1st dressing change if the wound
appeared clean, free of eschar, and uninfected. The fabric was removed and not
replaced if the Biobrane® was discovered to be loose or have fluid collections on
subsequent inspections.
Silver Sulfadiazine (SSD)
Layers of Dressing:
▪ Dry gauze
▪ Elastic wraps
Fixation: NA
Dressing Changes: Patients were instructed to change their dressings twice daily,
to remove all old cream, and to apply a thick coat of cream with each new
application.
Definition of Success
Healing time was defined as the time required to fully re-epithelialise the burn
surface.
Infected and skin-grafted wounds were considered failures of therapy and
excluded from healing time analysis.
Level of Evidence: II
Follow-up: 44 weeks.
Lost to Follow-up: 12/64 (19%)
Biobrane
2/12 (17%) lost to follow-up
4/12 (33%) removed due to protocol
violations by non-investigators
1/12 (8%) excluded as patient was
suffering from scarlet fever
SSD
4/12 (33%) lost to follow-up
1/12 (8%) removed due to protocol
violations by non-investigators
Study Period: Not stated.
Operator Details: Not stated.
Outcome Measures:
▪ Healing time
▪ Wound infection
▪ Pain
▪ Compliance with scheduled visits
▪ Costs
Wounds were inspected at 24-36 hrs after
initiation of therapy.
Mean Age: (years)
Biobrane 18.3 (SE: 2.6) (range 10 months-55
years)
SSD 22.1 (SE: 3.5) (range 8 months-79 years)
Gender Mix: (M/F)
Biobrane 19/11
SSD 18/8
Mean Total Burn Surface Area (TBSA): (%)
Biobrane 2.0 (SE: 0.3) (range 0.5-5.0)
SSD 2.4 (SE: 0.5) (range 0.5-10.0)
Mechanism of Burn Injury:
Aqueous
Grease
Contact
Scald
Biobrane
17
9
2
SSD
17
4
3
*data extracted from Figure 1 (appears to be
number of wounds not patients).
Exclusion criteria:
▪ chemical or electrical burns
▪ grossly contaminated
wounds
▪ wounds more than 24 hrs
old
▪ wounds treated by any
topical agent before
presentation to the
emergency department.
Appendix C.1 Study design tables – Biobrane® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Cassidy 2005
Biobrane® vs. Duoderm®
Randomised controlled trial.
Initial Preparation:
Wounds were debrided before application of coverage material.
Method of allocation not stated. Blinding
status not stated.
Consecutive paediatric patients with
superficial or mid-dermal partial
thickness burns.
Location
Pain Medication: No topical or prophylactic antibiotics were utilised.
Level of Evidence: II
Inclusion criteria:
▪ 3-18 years old
▪ superficial or mid-dermal
partial thickness burn
<10% TBSA.
Department of
Pediatric Surgery,
The Children’s
Mercy Hospital,
Kansas City,
Missouri, USA
Biobrane®
Layers of Dressing:
▪ Followed nursing instruction included in the manufacturer guidelines (no other details given).
Fixation: Not stated
Dressing Changes: Not stated
Follow-up: Not stated.
Duoderm®
Layers of Dressing:
▪ Followed nursing instruction included in the manufacturer guidelines (no other details given).
Fixation: Not stated
Dressing Changes: Not stated
Definition of Success
Complete healing was defined as complete re-epithelialisation as assessed by an experienced
burn surgeon or nurse.
Lost to Follow-up: 0
Study Period: Not stated.
Operator Details:
Not stated.
Outcome Measures:
▪ Time to complete healing
▪ Pain scores (Oucher Score or Visual
Analogue Scale)
▪ Institutional cost of materials until
healing was complete
Sample Size: 72 patients
Biobrane 35 patients
Duoderm 37 patients
Mean Age: (years)
Not stated.
Gender Mix: (M/F)
38/34
Mean Total Burn Surface Area
(TBSA): (%)
Not stated.
Mechanism of Burn Injury:
Scald – 44
Contact – 24
Flame – 2
Miscellaneous – 2
Exclusion criteria:
▪ Burns involving the face,
hands, feet, or perineum.
81
82
Appendix C.2 Study design tables – Biobrane® for the management of donor sites
Authors
Intervention
Study Design
Study Population
Still 2003
OrCel™ vs. Biobrane®
Randomised controlled trial – within-patient
comparison.
Patients with partial thickness burns.
Inclusion criteria:
Sample Size: 82 patients
▪ ≥12 months of age
▪ burns involving 10 to 80%
Mean Age: (years)
31.7 (range 1-88)
▪ anticipated life expectancy
Gender Mix: (M/F)
63/19
Exclusion criteria:
Not stated.
Pain Medication: Not stated
Location
Physicians
Multispecialty
Group, Augusta,
Georgia, Division
of Plastic Surgery,
St. Christopher’s
Hospital for
Children,
Philadelphia,
Pennsylvania,
University of
Oklahoma Health
Sciences Centre,
Oklahoma City,
Oklahoma,
Timothy J. Harnar
Burn Centre,
Texas Tech
Medical Centre,
Lubbock, Texas,
Department of
Surgery, Shands
Burn Centre,
University of
Florida Health
Sciences Centre,
Gainesville,
Florida, USA
OrCel™
Layers of Dressing:
▪ OrCel™, a porous collagen sponge containing co-cultured
allogeneic donor epidermal keratinocytes and dermal fibroblasts
from human neonatal foreskin tissue
▪ Non-adherent, moisture-retentive, synthetic materials, such as
Adaptic™ or Vaseline™ gauze
▪ Gauze wrap
▪ Ace bandage
Fixation: Staples were used at the discretion of the investigator
Dressing Changes:
▪ On the 3rd postoperative day, the outer layers were removed.
The backing material was left in place and normal saline
irrigation to remove any debris was permitted.
▪ Thereafter, removal and replacement of the outer dressing wrap
on the OrCel™ was permitted every 48-72 hrs until day 7 when
attempts were begun to remove the backing.
Biobrane®
Layers of Dressing:
▪ Biobrane®, a synthetic wound dressing composed of an
ultrathin, semi-permeable silicone membrane and a flexible
monofilament nylon fabric
▪ Gauze wraps
Fixation: Staples
Dressing Changes: Removal of the outer dressing layers was
generally performed 24-48 hrs following surgery
Definition of Success
100% re-epithelialisation as measured by blinded photographic
assessment.
Randomisation was based on a computer
generated scheme and concealed from the
investigator. Blinded assessment of
percent re-epithelialisation by 3
independent burn experts.
Level of Evidence: II
Follow-up: 24 weeks.
Total Burn Surface Area (TBSA):
0/82 (0%) had <10%
61/82 (74%) had >20%
Lost to Follow-up: 3/82 (4%) died
Study Period: Not stated.
Operator Details: Not stated.
Outcome Measures:
▪ Complete wound closure (planimetry)
▪ Pain (Wong-Baker Faces Pain Rating
Scale)
▪ Itching
▪ Blister formation/site breakdown
▪ Wound infection
▪ Scarring (Vancouver Scar Scale and
Hamilton Burn-Scar Rating Scale)
Mean Surface Area for Donor Sites: (cm2)
OrCel 94.4
Biobrane 94.3
Mechanism of Burn Injury:
Not stated.
Inclusion/Exclusion Criteria
TBSA
of ≥6 weeks.
Appendix C.2 Study design tables – Biobrane® for the management of donor sites (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Fratianne 1993
Allogeneic cultured keratinocyte sheets vs. Biobrane®
Randomised controlled trial – within-patient
comparison.
Patients with partial and full thickness burns.
Inclusion criteria:
Not stated.
Location
Departments of
Surgery,
Pathology, and
Paediatrics, Case
Western Reserve
University,
MetroHealth
Medical Centre,
Cleveland, Ohio,
USA
Initial Preparation:
Keratinocyte strains were developed from the foreskins of infants
whose mothers tested negative for HIV, Hep B, and Herpes at
delivery and at 3 months after delivery. Keratinocytes were grown
in the presence of lethally irradiated 3T3 cells.
Sample Size: 10 patients
Method of allocation not stated. No
blinding.
Level of Evidence: II
Pain Medication: Not stated
Follow-up: 23 days.
Allogeneic cultured keratinocyte sheets (Keratinocytes)
Layers of Dressing:
▪ Keratinocyte sheets on a Vaseline (Chesebrough Ponds, Inc.,
Greenwich, Conneticut) gauze carrier measuring 4x7cm
▪ Red label Biobrane®
Fixation: Staples
Dressing Changes: NA
Lost to Follow-up: 2/10 (20%) died
Biobrane®
Layers of Dressing:
▪ Red label Biobrane®
Fixation: Staples
Dressing Changes: NA
Definition of Success
Complete healing.
Mean Age: (years)
44.3 (range 21-86)
Gender Mix: (M/F)
7/3
Mean Total Burn Surface Area (TBSA): (%)
35.8 (range 3-90)
Study Period: Not stated.
Operator Details: Not stated.
Outcome Measures:
▪ Wound healing
▪ Healing time
▪ Histologic examinations (3mm punch
biopsies at postop day 7)
Mechanism of Burn Injury:
Not stated.
Exclusion criteria:
Not stated.
83
84
Appendix C.3 Study design tables – TransCyte® for the management of burns
Authors
Intervention
Study Design
Study Population
Noordenbos 1999
TransCyte® vs. Silver Sulfadiazine
Randomised controlled trial – within-patient
comparison.
Patients with partial thickness burns.
Pain Medication: Narcotic analgesia was used as required during
dressing changes.
Location
Department of
Surgery, University
of California, San
Diego Medical
Centre, California,
USA
TransCyte®
Layers of Dressing:
▪ TransCyte® (human dermal fibroblasts were isolated from
newborn foreskins and grown aseptically on the nylon mesh of
Biobrane®)
Fixation: Sterile adhesive tape strips (Suture Strip Plus, abco
Dealers, Nashville, TN) or surgical staples
Dressing Changes: After 1 or 2 days, the outer dressings were
usually removed and the sites were left open to air.
Silver Sulfadiazine (SSD)
Layers of Dressing:
▪ Topical therapy with SSD
▪ When the wound was clean of necrotic tissue and debris, a
semi-occlusive dressing (Xeroform, Kendall Inc., Mansfield,
MA) was used
Fixation: NA
Dressing Changes: Twice daily
Definition of Success
Epithelial closure of at least 90% of the study site wound, or the
day on which excision and grafting was performed.
Method of allocation not stated. No
blinding.
Level of Evidence: II
Follow-up: 12 months.
Lost to Follow-up:
3/14 (21%) at 3 and 12 months.
5/14 (36%) at 6 months.
Study Period: Not stated.
Operator Details:
1 of the clinical research study nurses
evaluated scar formation.
Outcome Measures:
▪ Number of days until epithelial closure
▪ Wound infection
▪ Scar formation (Vancouver Burn Scale)
Sample Size: 14 patients
Mean Age: (years)
23.4 [19.4] (range 1.1-52)
Gender Mix: (M/F)
Not stated.
Mean Total Burn Surface Area (TBSA): (%)
13.3 [7.2] (range 4-30)
Mean TBSA covered: (%)
TransCyte 3.18 [2] (range 1.5-9)
SSD 3.66 [3.4] (range 1.5-15)
Mechanism of Burn Injury:
Not stated.
Inclusion/Exclusion Criteria
Inclusion criteria:
▪ burns of 2% to 30% TBSA
▪ 1 to 70 years old
▪ 2 comparable-sized
wounds judged by the
clinicians to be moderate to
deep partial thickness in
depth.
Exclusion criteria:
▪ wounds of the hands, face,
buttocks, feet and genitalia
▪ >24 hrs after injury.
Appendix C.3 Study design tables – TransCyte® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Demling and
DeSanti 1999
TransCyte® vs. Bacitracin
Randomised controlled trial.
Consecutive patients with mid-partial
thickness burns to the face.
Patients were initially categorised into 2 groups:
- major burns: require at least 7 days hospitalisation
- minor burns: have the potential for outpatient care.
Method of allocation not stated.
Blinding status not stated.
Inclusion criteria:
▪ >18 years of age
▪ partial thickness (middermal) burns of at least
50% of the facial surface.
(possible patient
overlap with
Demling and
DeSanti 2002)
Location
Trauma and Burn
Centre, Brigham
and Women’s
Hospital, Harvard
Medical School,
Boston,
Massachusetts,
USA
Initial Preparation:
All patients underwent complete debridement of non-viable epidermis and upper dermis using
blunt debridement (moist gauze) using systemic and topical analgesia.
No tangential excision was performed.
Pain Medication: For minor burns –
TransCyte® All required non-steroidal anti-inflammatory agent for wound care & in between
care
Bacitracin 100% required oral narcotics for wound care & 75% required oral narcotics for in
between care
TransCyte®
Layers of Dressing:
▪ TransCyte® sheets were thawed and placed on the wound
▪ A fluffed soft gauze was then applied to fit the facial contours for 3-4 hrs after which the gauze
was removed and the wound treated open
Fixation: Not stated
Dressing Changes: Not stated
Bacitracin
Layers of Dressing:
▪ Bacitracin ointment was used for the mid-dermal areas
▪ SSD was used only on deeper areas for 1-2 days, before initiation of bacitracin treatment
Fixation: NA
Dressing Changes: Wound was cleansed and antibiotics re-applied 2-3 times a day depending
on the degree of exudate build-up
Definition of Success
Healing time was defined as the point in time when 90% of the wound was re-epithelialised.
Level of Evidence: II
Follow-up: ~18 days.
Lost to Follow-up: 0
Study Period: Not stated.
Operator Details: Not stated.
Outcome Measures:
▪ Daily wound care time
▪ Pain between and during wound
care
▪ Healing time
▪ Discharge time
▪ Wound infection
▪ Wound conversion
Sample Size: 21 patients
TransCyte 10 patients (5 major, 5
minor)
Bacitracin 11 patients (6 major, 5
minor)
Mean Age: (years)
Major burns –
TransCyte 44 [10]
Bacitracin 40 [8]
Minor burns –
TransCyte 31 [8]
Bacitracin 29 [7]
Gender Mix: (M/F)
Not stated.
Mean Total Burn Surface Area (TBSA):
(%)
Major burns –
TransCyte 32 [9]
Bacitracin 30 [8]
Minor burns –
TransCyte 10 [3]
Bacitracin 7 [2]
Mechanism of Burn Injury:
Not stated.
Exclusion criteria:
Not stated.
85
86
Appendix C.3 Study design tables – TransCyte® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Demling and
DeSanti 2002
TransCyte® vs. Topical Antibiotics
Randomised controlled trial.
Patients with mid-partial thickness burns to the face.
Inclusion criteria:
Not stated
Initial Preparation:
For wounds receiving Transcyte®, the burn wound was initially
debrided under conscious sedation.
Method of allocation not stated. The burn
centre nurse coordinator and nurse
research assistant collected the data.
Blinding status not stated.
Sample Size: 34 patients
TransCyte 16 patients
Antibiotics 18 patients
(possible patient
overlap with
Demling and
DeSanti 1999)
Location
Pain Medication: Increased narcotics and sedation were needed
in the Topical Antibiotics group.
Burn Centre,
Brigham &
Women’s Hospital,
Boston,
Massachusetts,
USA
TransCyte®
Layers of Dressing:
▪ TransCyte® (thawed)
▪ Light gauze dressing (removed after 12-24 hrs)
Fixation: Not stated
Dressing Changes: Not stated
Topical Antibiotics
Layers of Dressing:
▪ Antibiotic ointment was used for facial burns
▪ SSD was used on burns to the ears
Fixation: NA
Dressing Changes: Twice daily
Definition of Success
Time to 95% re-epithelialisation.
Level of Evidence: II
Mean Age: (years)
TransCyte 39 [9]
Antibiotics 40 [8]
Follow-up: ~19 days.
Lost to Follow-up: 0
Study Period: Not stated
Operator Details: Not stated
Outcome Measures:
▪ Pain (0-10 pain scale, 0=no pain;
10=worst pain)
▪ Healing time
▪ Wound infection
▪ Nursing time
▪ Cost
Gender Mix: (M/F)
Not stated
Mean Total Burn Surface Area (TBSA): (%)
TransCyte 24 [8]
Antibiotics 21 [9]
% Full Thickness:
TransCyte 12 [7]
Antibiotics 10 [6]
Mechanism of Burn Injury: (Flame/Scald)
TransCyte 11/5
Antibiotics 12/6
Exclusion criteria:
Not stated
Appendix C.4 Study design tables – Dermagraft® for the management of burns
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Hansbrough 1997
Dermagraft® vs. Allograft
Randomised controlled trial – within-patient
comparison.
Patients with partial and full thickness burns.
Inclusion criteria:
▪ burn wounds requiring
surgical excision
▪ temporary wound closure
was clinically necessary.
Location
Department of Surgery, the
University of California, San
Diego Medical Centre, The
US Army Institute of
Surgical Research, Fort
Sam Houston, the
University of Iowa Burn
Treatment Centre, Iowa
City, and Advanced Tissue
Sciences, Inc., La Jolla,
California, USA
Sample Size: 10 patients (3 sites per patient)
Initial Preparation:
Wound haemostasis was achieved with topical thrombinepinephrine solution and electrocoagulation.
Method of allocation not stated. Blinding status not
stated.
Pain Medication: Not stated
Level of Evidence: II
Dermagraft®
Layers of Dressing:
▪ Dermagraft® Red (cryopreserved by a method that maintains
most of the metabolic activity of the cultured fibroblasts)
OR
▪ Dermagraft® Blue (frozen by a method that does not maintain
metabolic activity of the product)
Fixation: Staples
Dressing Changes: Not stated
Follow-up: 14 days.
Allograft
Layers of Dressing:
▪ Cryopreserved human cadaver allograft skin (obtained from
tissue banks)
Fixation: Staples
Dressing Changes: Not stated
When clinically indicated, Dermagraft® and allograft dressings were
removed.
Autograft skin was harvested from appropriate donor sites, and
meshed at a ratio of either 1.5:1 or 2:1.
Definition of Success
Autograft take defined as the percentage of autograft that was
present, adherent, and vascularised.
Lost to Follow-up: 3/10 (30%)
Study Period: Not stated.
Operator Details: All sites were excised to similar
depth in individual patients (subcutaneous fat,
fascia, or deep dermis/fat).
Outcome Measures:
▪ Adherence of wound coverings
▪ Fluid accumulation under the temporary covering
▪ Quantity and quality of the drainage
▪ Colour of the wound bed
▪ Ease of removal of the temporary covering
▪ Vascularity of the wound before autografting
▪ Autograft take
▪ Wound closure
▪ Investigator’s overall assessment
Mean Age: (years)
33.5 (range 7-62)
Gender Mix: (M/F)
Not stated.
Mean Total Burn Surface Area (TBSA): (%)
Partial thickness burn: 20.3 (range 8-56)
Full thickness burn: 19.6 (range 0-45)
Mechanism of Burn Injury:
Not stated.
Location of Study Wound Sites:
Legs (n=4)
Arms (n=2)
Flank (n=1)
Chest/abdomen (n=2)
Back (n=1)
Exclusion criteria:
Not stated.
87
88
Appendix C.4 Study design tables – Dermagraft® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Purdue 1997
Dermagraft® vs. Allograft
Randomised controlled trial – within-patient
comparison.
Patients with full thickness burns on adjacent sites.
Inclusion criteria:
Not stated.
Location
University of Texas
Southwestern Medical
Centre, Dallas, Texas,
Augusta Regional Medical
Centre, Augusta, Georgia,
Shriners Burn Institute,
Galveston, Texas, The
Western Pennsylvania
Hospital, Pittsburgh,
Pennsylvania, Maricopa
Medical Centre, Phoenix,
Arizona, UCSD Medical
Centre, San Diego,
California, University of
Tennessee, Medical Group,
Memphis, Tennessee,
University of Virginia Health
Sciences Centre,
Charlottesville, Virginia,
University of Iowa Burn
Treatment Centre, Iowa
City, Iowa, Hennepin
County Medical Centre,
Minneapolis, Minnesota, UC
Davis Medical Centre,
Sacramento, California, St
Paul-Ramsey Medical
Centre, St Paul, Minnesota,
and Advanced Tissue
Sciences, Inc., La Jolla,
California, USA
Initial Preparation:
Wounds were excised within 2 weeks of the burn.
Both sites were excised in the same manner to
viable deep dermis, subcutaneous fat, fascia, or
muscle.
Pain Medication: Not stated
Dermagraft®
Layers of Dressing:
▪ Dermagraft® (thawed in its cassette immediately
before use and washed 4 times with normal
saline solution)
▪ When the wound was clinically ready,
Dermagraft® was removed and autografts were
applied
Fixation: Staples
Dressing Changes: Not stated
Allograft
Layers of Dressing:
▪ Allograft skin (obtained from each centre’s usual
tissue bank and prepared in the manner typical
for that centre)
▪ When the wound was clinically ready, the
allograft was removed and autografts were
applied
Fixation: Staples
Dressing Changes: Not stated
Definition of Success
Percent autograft take.
Sample Size: 66 patients.
Method of allocation not stated. Only wound
biopsy specimens were analysed in a blind
manner.
Level of Evidence: II
Mean Age: (years)
36.3 [22.4] (median 32.5; range 2-89)
Gender Mix: (M/F)
45/21
Follow-up: 28 days.
Lost to Follow-up: 20/66 (30%) were not
available for percent autograft take evaluation.
8/66 (12%) died
2/66 (3%) had treatment other than skin grafts
7/66 (11%) had temporary covering deviations
3/66 (4.5%) had premature removal of temporary
coverings or autograft.
Study Period: Not stated.
Operator Details: Not stated.
Outcome Measures:
▪ Percent autograft take
▪ Percent adherence and fluid accumulation
▪ Investigators’ global assessments
▪ Method and ease of removal
▪ Bleeding
▪ Percent wound closure
▪ Rejection/loss of allograft and reapplications
▪ Safety assessments such as wound
infections, intercurrent events, and adverse
device effects
▪ Immunological safety (wound biopsy
specimens)
Mean Total Burn Surface Area (TBSA): (%)
44.3 [20.0] (median 42.3; range 4-95)
Full thickness burn: 27.8 [21.3] (median 24.8; range 0-95)
Mechanism of Burn Injury:
Not stated.
Exclusion criteria:
Not stated.
Appendix C.4 Study design tables – Dermagraft® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Spielvogel 1997
Dermagraft® vs. Allograft
Randomised controlled trial – this was a
histologic study.
Sample Size: 65 patients.
Dermagraft 51 histologic specimens
Allograft 51 skin allograft control specimens
Inclusion criteria:
Not stated.
Biopsies were done at the time of removal of the temporary
covering.
Location
Pain Medication: Not stated
Allegheny
University of the
Health Sciences,
Philadelphia,
Pennsylvania,
USA
Dermagraft®
Layers of Dressing: Not stated
Fixation: Not stated
Dressing Changes: Not stated
Method of allocation not stated.
The slides were reviewed in a blind fashion
(blind regarding the clinical results, not in
terms of not being able to distinguish
between control and study specimens).
Definition of Success
Not stated.
Gender Mix: (M/F)
Not stated.
Level of Evidence: II
Follow-up: Not stated.
Allograft
Layers of Dressing: Not stated
Fixation: Not stated
Dressing Changes: Not stated
Mean Age: (years)
Not stated.
Lost to Follow-up: 0
Study Period: Not stated.
Operator Details:
Full thickness specimens were obtained by
excision biopsy through Dermagraft® or
allograft into the wound bed.
Outcome Measures:
▪ Histologic examinations (specimens
were reviewed for technical quality,
consistency of wound bed, and
description of covering, including its
interface with the wound bed)
Mean Total Burn Surface Area (TBSA): (%)
Not stated.
Mechanism of Burn Injury:
Not stated.
Exclusion criteria:
Not stated.
89
90
Appendix C.5 Study design tables – Integra® for the management of burns
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Heimbach 1988
Artificial Dermis vs. Biological Skin Replacement
(several types)
Randomised controlled trial – within-patient
comparison.
Sample Size: 149 patients.
Complete data available for 106 patients (136 wounds).
Pain Medication: Not stated
Method of allocation not stated. Blinding status not
stated.
Age:
27/106 (25%) patients were <15 years
59/106 (56%) patients were 15-60 years
20/106 (19%) patients were >60 years
Inclusion criteria:
▪ admitted to hospital with
extensive flame or scald
burns
▪ burns were considered to
be life-threatening
▪ burns not likely to heal
within 3 weeks
▪ burns were amenable to
early excision and grafting
▪ initial excision within 7
days after burn.
Location
University of
Washington, Seattle,
Washington,
University of South
Alabama, Mobile,
Alabama, Harvard
University, Cambridge,
Massachusetts,
University of Iowa,
Iowa City, Iowa,
University of Texas at
Galveston, Galveston,
Texas, University of
Texas at Dallas,
Dallas, Texas, George
Washington
University,
Washington, D.C., US
Army Institute of
Surgical Research,
San Antonio, Texas,
St. Paul-Ramsey,
University of
Cincinnati, Cincinnati,
Ohio, and the
University of Southern
California, Los
Angeles, California,
USA
Artificial Dermis (AD)
Layers of Dressing:
▪ Artificial dermis (Marion Laboratories, Kansas City, MO)
composed of a porous collagen-chondroitin 6-sulfate
fibrillar mat covered with a thin sheet of Silastic
▪ After vascularisation, the artificial dermis was grafted with
epidermal grafts taken at the thinnest dermatome setting
Fixation: Sutured or stapled
Dressing Changes: NA
Control
Layers of Dressing:
▪ Meshed autograft, or, if donor sites were not available,
other conventional temporary wound coverings (allograft,
xenograft, or synthetic dressings)
▪ After vascularisation, the materials other than autograft
were eventually replaced with autografts
Fixation: Not stated
Dressing Changes: Not stated
Definition of Success
Graft take – take of the collagen mat and take of the
subsequent epidermal graft.
Level of Evidence: II
Follow-up: up to 1 year.
Lost to Follow-up: 67/149 (45%)
Of the initial 149 patients 6/149 (4%) died
37/149 (25%) eliminated from analysis due to
protocol violation
Of the 106 patients (136 wounds) left 14/106 (13%) died
10/106 (9%) eliminated from analysis due logistic
reasons or long-term assessment was not possible.
Patients followed-up: 82 patients; 59 patients had
9-month follow-up and 26 patients had 1-year
follow-up.
Study Period: Not stated.
Operator Details: Not stated.
Outcome Measures:
▪ Wound infection
▪ Mechanical problems
▪ Time to wound closure
▪ Skin function
▪ Wound appearance
▪ Patient preference
Gender Mix: (M/F)
79/27
Mean Total Burn Surface Area (TBSA): (%)
46 [19]
Mechanism of Burn Injury:
Not stated.
Exclusion criteria:
Not stated.
Appendix C.5 Study design tables – Integra® for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Peck 2002
Integra® vs. Biobrane® vs. Allograft
Randomised controlled trial – within-patient
comparison.
Patients with partial and full thickness
burns.
Method of allocation not stated. Blinding status
not stated.
Sample Size: 7 patients.
Integra vs. Biobrane 4 patients
Integra vs. Allograft 3 patients
Inclusion criteria:
▪ adult patients aged 18 to
65 years
▪ deep partial or full
thickness wounds or both
totalling at least 45%
TBSA.
Location
North Carolina
Jaycee Burn
Centre and the
Department of
Surgery, University
of North Carolina
Health Care,
Chapel Hill, North
Carolina, USA
Initial Preparation:
Sequential excisions of burn eschar were performed so that all deeply burned skin
was removed by 2 weeks after injury.
Excision of the burns was performed under general anaesthesia after sterile
preparation of the wounds with chlorhexidine gluconate 4% (Calgon Vestal, St
Louis, MO).
Level of Evidence: II
Follow-up: up to 5 months?
Mean Age: (years)
41.1 (range 19-54)
Pain Medication: Not stated
Integra®
Layers of Dressing:
Phase 1 of the study ▪ Integra® sheets meshed at a 1:1 ratio with a non-crushing mesher (Brennen
Medical, Inc., St. Paul, MN)
▪ Mafenide acetate dressings (kept moist postoperatively with application of
mafenide acetate 5% solution every 2-6 hours)
Phase 2 of the study ▪ Silver-coated burn dressings (applied along the seams of the Integra® sheets)
Fixation: Staples and Stretch-Net dressings (DeRoyal, Powell, TN)
Dressing Changes:
▪ Mafenide acetate dressings were removed for observation of the grafts and
applied fresh daily
▪ Silver-coated burn dressings were moistened with sterile water twice daily
Biobrane®
Layers of Dressing:
Phase 1 of the study ▪ Biobrane®
▪ Mafenide acetate dressings (kept moist postoperatively with application of
mafenide acetate 5% solution every 2-6 hours)
Fixation: Staples
Dressing Changes: These dressings were removed for observation of the grafts
and applied fresh daily
Lost to Follow-up: 4/7 (57%)
1/7 (14%) patient moved interstate after
discharge
3/7 (43%) died.
Study Period: Not stated.
Operator Details:
Treatment sites were inspected daily by the
attending, the burn fellow, or the clinical
research nurse.
Outcome Measures:
▪ Wound closure
▪ Wound infections
▪ Complications
Gender Mix: (M/F)
Not stated.
Mean Total Burn Surface Area (TBSA): (%)
63.1 (range 47-80)
Mechanism of Burn Injury:
All patients had thermal injuries.
2/7 (29%) also had inhalation injuries.
Exclusion criteria:
▪ electrical injuries and
severe exfoliating skin
disorders
▪ treatment areas were not
selected from the following
sites: over joints; on the
head and neck; on the
buttocks, back, and
posterior thighs; and on the
hands and feet.
91
92
Appendix C.5 Study design tables – Integra® for the management of burns (continued)
Authors
Intervention
Peck 2002
(continued)
Allograft
Layers of Dressing:
Phase 2 of the study ▪ Cadaver homograft (Ohio Valley Tissue and Skin Centre, Cincinnati, OH)
meshed at a 1:1 ratio with a non-crushing mesher (Brennen Medical, Inc.,
St. Paul, MN)
▪ Gauze soaked with silver nitrate 0.25% solution (kept moist every 2-6
hours)
Fixation:
Dressing Changes: Daily
Location
North Carolina
Jaycee Burn
Centre and the
Department of
Surgery, University
of North Carolina
Health Care,
Chapel Hill, North
Carolina, USA
Definition of Success
Wound closure.
Study Design
Study Population
Inclusion/Exclusion Criteria
Appendix C.6 Study design tables – Apligraf® for the management of burns
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Waymack 2000
Apligraf® + Autograft vs. Autograft + Allograft
Randomised controlled trial – within-patient comparison.
Patients with partial thickness and full thickness burns.
Once all wounds were grafted, bandaging was
performed according to standard methodology as
determined by the investigator.
Method of allocation not stated. Blinding status not stated.
Pain Medication: Not stated
Follow-up: up to 24 months.
Sample Size: 40 patients enrolled.
Apligraf 40 patients
Autograft 36 patients*
Auto + Allo 2 patients*
Inclusion criteria:
▪ burns covering at least 2%
but not more than 97%
TBSA
▪ expected to survive at least
2 years.
Apligraf® + Autograft (Apligraf)
Initially the experimental arm involved the
application of Apligraf® directly onto the excised
wound bed. However, significant graft loss occurred
with the initial patients, so the protocol was
amended to treat patients with Apligraf® applied
over meshed autograft.
Layers of Dressing:
▪ Meshed (≥2:1), expanded autograft
▪ Meshed (1:1.5), unexpanded Apligraf®
Fixation: Not stated
Dressing Changes: Not stated
Lost to Follow-up: 24/40 (60%)
20/40 (50%) lost to follow-up
2/40 (5%) excluded due to non-compliance
1/40 (2.5%) due to Apligraf® loss
1/40 (2.5%) data not collected after grafting.
* A last observation carried forward (LOCF) approach was used for
primary statistical analysis, where data from the prior evaluation
point was carried forward to estimate missing patient information.
Autograft + Allograft
Layers of Dressing:
▪ Meshed (≥2:1), expanded autograft alone
OR
▪ Meshed (≥2:1), expanded autograft
▪ Meshed (1.5:1), unexpanded allograft
Fixation: Not stated
Dressing Changes: At each follow-up visit
Study Period: Not stated.
Location
University of
Washington Burn
Centre,
Harborview
Medical Centre,
Seattle, WA,
University of
California at San
Diego, San Diego,
CA, University of
South Alabama
Burn Centre,
Mobile, AL,
Massachusetts
General Hospital,
Boston, MA,
Shriners Hospital
for Crippled
Children,
Galveston Unit,
Burns Institute,
Galveston, TX,
USA
Definition of Success
Wound healed.
*Control site grafting information was missing for 2 patients.
Level of Evidence: II
Patients followed-up:
38 patients at week 1, 36 patients at week 2, 23 patients at month 6,
21 patients at month 12, and 16 patients at month 24.
Operator Details:
For each patient, autografts were meshed identically for both
treatment and control sites.
Outcome Measures:
▪ Overall cosmetic appearance
▪ Graft take
▪ Wound closure
▪ Wound exudate
▪ Pigmentation, vascularity, pliability, height, and scarring
▪ Safety (immunological tests, reporting of adverse events)
Mean Age: (years)
36.3 (range 3-78)
Gender Mix: (M/F)
36/4
Mean Total Burn Surface Area (TBSA): (%)
23.6 (range 5-90)
Type of Burn:
33/40 (82.5%) patients had both partial and full
thickness burns
6/40 (15%) patients had partial thickness burns only
1/40 (2.5%) patient had full thickness burns only.
Mechanism of Burn Injury: (Thermal/Chemical/Both)
38/1/1
Exclusion criteria:
▪ heavily contaminated
wounds
▪ known allergy or
hypersensitivity to bovine
proteins
▪ history of abnormal
bleeding
▪ medical conditions that
would impair healing
▪ taking medications that
would interfere with
treatment compliance or
the evaluation of the
Apligraf® graft.
93
94
Appendix C.7 Study design tables – Autologous cultured skin for the management of burns
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Boyce 2002
Autologous Epidermal Substitute vs. Autograft
Pseudo-randomised controlled trial – withinpatient comparison.
Paediatric patients with full
thickness burns.
(possible patient
overlap with Boyce
1995)
Initial Preparation:
Burn eschar was excised as early as possible.
Sites were initially covered with cadaveric allograft or the dermal substitute Integra®.
These temporary dressings were removed 1 day before grafting.
On the day of grafting, wounds were irrigated with a solution of nutrients and antimicrobials.
Wound sites were randomised according to
patient enrolment number. No blinding.
Sample Size: 45 patients (90
wounds).
Inclusion criteria:
▪ >50% TBSA full thickness
cutaneous burns.
Level of Evidence: III-1
Mean Age: (years)
10.6 (SE: 1.6) for all patients.
8.0 (SE: 1.5) for last 12 patients.
Location
Shriners Hospitals
for Children in
Cincinnati, Ohio,
and Sacramento,
California, and the
Department of
Surgery, University
of Cincinnati,
Cincinnati, Ohio,
USA
Pain Medication: Not stated
Follow-up: up to 1 year.
Autologous Epidermal Substitute (AES)
Layers of Dressing:
▪ AES
▪ Fine mesh gauze
▪ Bulky gauze containing perforated red rubber catheters
▪ Spandex stretched to apply gentle pressure and to immobilise the grafted sites
▪ After days 5-7, AES was treated with a Neosporin/Bactroban/Nystatin ointment and
covered with a dry bulky gauze
Fixation: Staples and N-terface (Winfield Laboratories, Richardson, TX)
Dressing Changes: on days 2, 4, 5, and daily thereafter until day 7 to 9
Lost to Follow-up: 0
Autograft
Layers of Dressing:
▪ Expanded split thickness autografts, meshed at ratios between 1:1.5 and 1:4
▪ Fine mesh gauze
▪ Bulky gauze containing perforated red rubber catheters (autograft was routinely irrigated
for 5 days with alternating solutions of 5% (w/v) mafenide acetate in water and
neomycin/polymyxin B in saline)
▪ Spandex stretched to apply gentle pressure and to immobilise the grafted sites
▪ On day 5 staples were removed, irrigations were discontinued, and dry dressings
(consisting of Adaptic™ coated with silver sulfadiazine/bacitracin/nystatin ointment) were
applied
Fixation: Staples
Dressing Changes: on day 2 and 5
Definition of Success
Graft take.
Study Period: April 1990 to July 1999.
Last 12/45 (27%) patients were enrolled
between April 1998 and July 1999.
Operator Details: Not stated.
Outcome Measures:
▪ All patients were assessed by ordinal scoring
(0, worst; 10, normal) for erythema, pliability,
raised scar, epithelial blistering, pigmentation,
and surface texture
For the last 12 patients only:
▪ Percentage of engraftment
▪ Ratio of closed wound:donor skin areas
▪ Percentage of TBSA closed with dressing
Gender Mix: (M/F)
34/11 for all patients.
8/4 for last 12 patients.
Mean Total Burn Surface Area
(TBSA): (%)
64.6 (SE: 2.0) for all patients.
76.9 (SE: 2.76) for last 12 patients.
Mechanism of Burn Injury:
Not stated.
Exclusion criteria:
▪ burns to joints, hands, or
faces.
Appendix C.7 Study design tables – Autologous cultured skin for the management of burns (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Boyce 1995
Autologous Epidermal Substitute vs. Autograft
Randomised controlled trial – within-patient
comparison.
Patients with full thickness burns.
(possible patient
overlap with Boyce
2002)
Initial Preparation:
One day before skin grafting, eschar was excised to viable tissue that most
frequently was subcutaneous fat. Excised wounds were irrigated overnight in
a solution of 5% (w/v) mafenide acetate, and grafted the following day.
On the day of grafting, excised wounds were irrigated thoroughly with saline
to reduce the residual concentration of mafenide acetate.
Inclusion criteria:
▪ required skin grafting at
least 3 weeks after hospital
admission
▪ >50% TBSA.
Location
Shriners Burns
Institute and the
Department of
Surgery, University
of Cincinnati,
Cincinnati, Ohio,
USA
Sample Size: 17 patients (34 wounds).
Wound sites were randomised according to
enrolment number by a computer-generated
schedule. No blinding.
Level of Evidence: II
Pain Medication: Not stated
Follow-up: up to 1 year.
Autologous Epidermal Substitute (AES)
Layers of Dressing:
▪ AES consisting of collagen-glycosaminoglycan substrates populated with
autologous fibroblasts and keratinocytes
▪ Polypropylene mesh (N-Terface, Winfield Laboratories, Richardson, TX)
▪ Fine mesh gauze
▪ Bulky gauze containing red rubber catheters for delivery of irrigation fluids
▪ Spandex fabric that was stretched across the graft site
Fixation: Surgical staples
Dressing Changes: Not stated
Lost to Follow-up: 13/17 (76%) at 1 year.
Autograft
Layers of Dressing:
▪ Meshed or unmeshed split thickness autograft
▪ Fine mesh gauze
▪ Bulky gauze containing red rubber catheters for delivery of irrigation fluids
▪ Spandex fabric that was stretched across the graft site
Fixation: Surgical staples
Dressing Changes: Not stated
Definition of Success
Graft take.
Patients followed-up:
17 patients for days 2-14, 11 patients for days 1530, 10 patients for months 1-2, 9 patients for
months 3-4, 5 patients for months 5-12, and 4
patients for 1 year and later.
Study Period: Not stated.
Operator Details: Not stated.
Outcome Measures:
▪ Wound exudate
▪ Colouration
▪ Keratinisation
▪ Percent of site covered by graft
▪ Wound qualitative outcomes such as erythema,
pigmentation, epidermal blistering, surface
texture, skin suppleness and raised scar
Mean Age: (years)
12.7 (SE: 3.3) (range 1-50)
Gender Mix: (M/F)
Not stated.
Mean Total Burn Surface Area (TBSA): (%)
68.8 (SE: 2.4) (range 51-87)
Mechanism of Burn Injury:
Not stated.
Exclusion criteria:
▪ burns to joints, hands, or
faces.
95
96
Appendix C.8 Study design tables – Allogeneic cultured skin for the management of donor sites
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Madden 1996
Cultured Epidermal Allograft + Adaptic™ vs. Adaptic™
dressing
Randomised controlled trial – within-patient
comparison.
Patients with partial or full thickness burns.
Inclusion criteria:
Not stated.
Method of CEA preparation:
Specimens of split thickness human skin were obtained from the
Skin Bank. Human epidermal cells were cultured for at least 20
days before preparation of cultured sheets. A programmable
controlled rate freezer was used to freeze the cell sheets.
Method of allocation not stated.
All wounds and wound margins were
visually inspected and scored by blinded
observer.
Location
Departments of
Surgery,
Otolaryngology,
and Pathology,
The New York
Hospital Cornell
Medical Centre,
New York, USA
Pain Medication: Not stated
Cultured Epidermal Allograft (CEA) + Adaptic™
Layers of Dressing:
▪ Sheets were thawed and grafted onto the wound site
▪ Adaptic™ dressing
Fixation: Not stated
Dressing Changes: NA
Adaptic™ dressing
Layers of Dressing:
▪ Adaptic™ dressing alone
Fixation: NA
Dressing Changes: Not stated
Definition of Success
Complete healing as determined by visual assessment.
Level of Evidence: II
Follow-up: up to 1 year.
Lost to Follow-up: 3/16 (19%)
Study Period: Not stated.
Operator Details:
The same individual created both donor
sites to minimise variation in the depth of
each wound.
Outcome Measures:
▪ Visual and histologic examinations
(biopsies taken on postoperative day 7)
▪ Scarring (Vancouver Scale Scar
assessments)
▪ Pain assessments
Sample Size: 15 patients (16 paired donor sites at mirror image
locations)
Mean Age: (years)
43.7 (SE: 2.5) (range 21-72)
Gender Mix: (M/F)
7/8
Mean Total Burn Surface Area (TBSA): (%)
21.8 (SE: 5.0) (range 3.5-49)
Mechanism of Burn Injury: (Flame/Scalds/Chemical)
9/6/1
Exclusion criteria:
Not stated.
Appendix C.8 Study design tables – Allogeneic cultured skin for the management of donor sites (continued)
Authors
Intervention
Study Design
Study Population
Inclusion/Exclusion Criteria
Duinslaeger 1997
Allogeneic Cultured Keratinocytes vs. OpSite® dressing
Randomised controlled trial – within-patient
comparison.
Sample Size: 15 patients (30 legs)
Inclusion criteria:
Not stated.
Pain Medication: Not stated
Location
Burn Centre
Brussels and
Military Hospital,
Brussels, and
Innogenetics,
Ghent, Belgium
Allogeneic Cultured Keratinocytes
Layers of Dressing:
▪ Allogeneic cultures (6 patients received fresh cultured sheets
and 9 patients received cryopreserved cultured sheets)
▪ Paraffin bandage (Jelonet; Smith & Nephew)
▪ Velpeau bandages
Fixation: NA
Dressing Changes: NA
OpSite® dressing
Layers of Dressing:
▪ OpSite® dressing (Smith & Nephew, York, UK)
▪ Cotton Velpeau bandages
Fixation: NA
Dressing Changes: Not stated
Definition of Success
Wound closure (re-epithelialisation) as determined by visual
estimation.
Method of allocation not stated.
An independent experienced evaluator
(biologist) blinded to the treatment.
Level of Evidence: II
Follow-up: 8-23 months.
Lost to Follow-up: 0
Study Period: Not stated.
Operator Details:
All donor sites were taken by the same
surgeon, using the same dermatome, and
preoperative treatment was similar on both
legs.
Outcome Measures:
▪ Rate of re-epithelialisation
▪ Wound healing time
▪ Pain
▪ Complications
▪ Cosmesis
Mean Age: (years)
42.2 (range 2-78)
Gender Mix: (M/F)
5/10
Mean Total Burn Surface Area (TBSA): (%)
21 (range 6-95)
Mechanism of Burn Injury: (Flame/Scalds)
10/5
Depth of Excision on Donor Site: 0.3 mm
Exclusion criteria:
Not stated.
97
APPENDIX D – MEAN TOTAL BURN SURFACE AREA
Appendix D – Mean Total Burn Surface Area for Included Studies
Study
Intervention
Mean total burn surface area (%)*
Mechanism of injury
Lal 1999
Biobrane
Silver sulfadiazine
Biobrane 11.8 (SE: 1.1) (34/41 patients)
SSD 11.5 (SE: 0.9) (45/48 patients)
NS
Barret 2000
Biobrane
Silver sulfadiazine
Biobrane 8.9 (SE: 4.9
SSD 7.8 (SE: 0.9)
Flame / scalds
Kumar 2004
Biobrane
TransCyte
Silver sulfadiazine
5
Scalds
Gerding 1990
Biobrane
Silver sulfadiazine
Biobrane 2.0 (SE: 0.3) (range 0.5-5.0)
SSD 2.4 (SE: 0.5) (range 0.5-10.0)
Scalds / grease / contact / other
Cassidy 2005
Biobrane
Duoderm
NS
Scalds / contact / flame / miscellaneous
BIOBRANE
For the management of burns
For the management of donor sites
Still 2003
OrCel
Biborane
21/82 (26%) had 10-20%
61/82 (74%) had >20%
NS
Fratianne 1993
Allogeneic cultured keratinocyte sheets
Biobrane
35.8 (range 3-90)
NS
TransCyte
Silver sulfadiazine
13.3 [7.2] (range 4-30)
% TBSA covered Transcyte 3.18 [2] (range 1.5-9)
SSD 3.66 [3.4] (range 1.5-15)
NS
TRANSCYTE
For the management of burns
Noordenbos 1999
Table continued over …
99
100
Appendix D: Mean total burn surface area for included studies (continued)
Study
Intervention
Mean total burn surface area (%)
Mechanism of injury
Demling & DeSanti 1999
TransCyte
Bacitracin ointment
Major burns –
Transcyte 32 [9]
Bacitracin 30 [8]
Minor burns –
Transcyte 10 [3]
Bacitracin 7 [2]
NS
Demling & DeSanti 2002
TransCyte
Antibiotic ointments & creams
Transcyte 24 [8]
Antibiotics 21 [9]
Flame / scalds
Hansbrough 1997
Dermagraft
Allograft
Partial thickness burn: 20.3 (range 8-56)
Full thickness burn: 19.6 (range 0-45)
NS
Purdue 1997
Dermagraft
Allograft
44.3 [20.0] (median 42.3; range 4-95)
Full thickness burn: 27.8 [21.3] (median 24.8; range 095)
NS
Spielvogel 1997 (histologic study)
Dermagraft
Allograft
NS
NS
Heimbach 1988
Artificial dermis
Auto-, allo- or xenograft
46 [19]
NS
Peck 2002
Integra
Biobrane
Allograft
63.1 (range 47-80)
Thermal / inhalation
DERMAGRAFT
For the management of burns
INTEGRA
For the management of burns
Table continued over …
Appendix D: Mean total burn surface area for included studies (continued)
Study
Intervention
Mean total burn surface area (%)
Mechanism of injury
Apligraf + Autograft
Autograft
23.6 (range 5-90)
Thermal / chemical / both
Boyce 2002
Autologous epidermal substitute
Autograft
64.6 (SE: 2.0) for all patients
76.9 (SE: 2.76) for last 12 patients
NS
Boyce 1995
Autologous epidermal substitute
Autograft
68.8 (SE: 2.4) (range 51-87)
NS
APLIGRAF
For the management of burns
Waymack 2000
AUTOLOGOUS CULTURED SKIN
For the management of burns
ALLOGENEIC CULTURED SKIN
For the management of donor sites
Madden 1996
Cultured epidermal allograft + Adaptic
Adaptic dressing
21.8 (SE: 5.0) (range 3.5-49)
Flame / scalds / chemicals
Duinslaeger 1997
Allogeneic cultured keratinocyte sheets
OpSite dressing
21 (range 6-95)
Flame / scalds
* mean TBSA was reported across all groups unless stated otherwise.
101