burns 37 (2011) 1360–1366

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/burns

Fibrin sealant improves graft adherence in a porcine

full-thickness burn wound model

Ludwik K. Branski a,1, Rainer Mittermayr b,1, David N. Herndon a,

Marc G. Jeschke a,*, Martina Hofmann b, Oscar E. Masters a, William B. Norbury a,
Daniel L. Traber a, Stefan Tangl c, Heinz Redl b
a
Shriners Hospital for Children and University of Texas Medical Branch, Galveston, TX, USA
b
AUVA Research Center - Ludwig Boltzmann Institute for Experimental and Clinical Traumatology,
Austrian Cluster for Tissue Regeneration, Vienna, Austria
c
Department of Oral Surgery, University of Vienna Dental School, Vienna, Austria

article info abstract

Article history: Introduction: Autograft take and rapid wound closure is essential for the survival of severely
Accepted 9 August 2009 burned patients. Loss of skin grafts typically occurs during the first few days after coverage,
mainly due to shear forces and inadequate contact with the wound bed. Slow-clotting fibrin
Keywords: sealant, applied with a spray-on device, has been shown to improve healing of skin grafts in
Pig large wounds. However, its use in burn wounds has not been studied so far.
Wound healing Study aim: To evaluate the effectiveness of sprayed fibrin sealant in excised and grafted full-
Autograft thickness burns.
Skin substitute Material and methods: Ten female Yorkshire pigs (30–45 kg) received a full-thickness contact
burn of approximately 15% total body surface area. The burns were excised to the level of the
muscular fascia after 24 h and covered with meshed skin autograft (mesh ratio 1:3). Wounds
were randomized to either fibrin sealant (n = 20) or standard skin staples (n = 16) for graft
fixation. Fibrin sealant was used as a slow-clotting spray (4 IU thrombin/ml). Outcome
measurements included clinical scoring at days 2, 5, 9 and 14 postoperatively, planimetric
analysis of wound closure, and histological examination of epidermal and dermal thickness
14 days after autografting.
Results: In the fibrin sealant group, graft adherence scores were significantly increased
( p < 0.02) and graft dislocation scores significantly decreased ( p < 0.01) at days 2 and 5
postoperatively, when compared to controls. Planimetric analysis of remaining open mesh
interstices showed acceleration of wound closure in the fibrin sealant group but did not
reach statistical significance (day 14 p = 0.04 at significance level p < 0.025). Wound contrac-
tion, occurrence of hematoma, and dermal as well as epidermal thickness were not different
between the groups at 14 days postoperatively.
Conclusion: The results indicate that the use of slow-clotting fibrin sealant spray for auto-
graft fixation is advantageous over skin staples. Easy handling and reduced graft dislocation
at early time points are key qualities of this method.
# 2011 Published by Elsevier Ltd and ISBI.

* Corresponding author at: Sunnybrook Health Sciences Centre, Department of Surgery, Division of Plastic Surgery University of Toronto,
Sunnybrook Research Institute, Rm D704, 2075 Bayview Ave. Toronto, ON, Canada M4N 3M5. Tel.: +1 (416) 480 6703; fax: +1 (416) 480 6763.
E-mail address: marc.jeschke@sunnybrook.ca (M.G. Jeschke).
1
Both authors contributed equally to this manuscript.
0305-4179/$36.00 # 2011 Published by Elsevier Ltd and ISBI.
doi:10.1016/j.burns.2009.08.011
 burns 37 (2011) 1360–1366
1. Background
Over the past 25 years, the breadth of burn surgery and new
techniques in burn care have improved outcome and
significantly reduced mortality [1–3]. Severe acute burn
wounds require early excision and appropriate coverage to
prevent hypothermia, protein/fluid loss, and risk of exogenous
infection. Autologous, meshed split-thickness skin grafts have
emerged as the standard treatment for extensive full-
thickness wounds [4–7]. In terms of graft fixation, sutures or
staples represent the current standard of care. However, the
use of these fixation methods is time-consuming and often
associated with complications and pain upon removal [8,9]. In
addition, it is often difficult to achieve full contact of graft and
underlying wound surface. Severely burned patients with
large grafted wound areas are particularly prone to graft loss.
Fibrin sealant has emerged as an alternative fixation
method for autografts. It consists mainly of thrombin and
fibrinogen, is biologically degradable and non-toxic to the
human tissue, and was primarily developed as a fast-clotting
agent for hemostatic purposes. In a slow-clotting version with
low amounts of thrombin (4–5 IU/ml instead of 500 IU/ml) it
was proven to be successful in the fixation of autografts [10].
Our group recently compared the slow-clotting version of
fibrin sealant to sutured grafts in a porcine wound healing
model, and found decreased seroma and hematoma forma-
tion, less graft dislocation and necrosis, and an improved graft
take [11]. Taking into account the specific clinical situation
after a burn injury, we have further developed the porcine
wound healing model into a model of burn, excision, and
grafting with meshed autologous skin [12].
Using this standardized burn and wound healing model,
the goal of the present study was to compare a sprayed, slow-
clotting fibrin sealant preparation to standard stapling in the
fixation of autologous split-thickness skin grafts. The influ-
ence of fibrin sealant on graft take, graft dislocation and
wound healing was examined.
2. Materials and methods
2.1. Animal model and preparation
A porcine model of burn, excision and grafting with meshed
autologous skin was developed by our group to serve as a tool in
burns research [12]. The project was approved by the Animal
Care and Use Committee of the University of Texas Medical
Branch (Protocol number ACUC 99-01-003). This study was
conducted in the large animal research facility of the Shriners
Hospital for Children and the University of Texas Medical
Branch. Housing and animal care were provided according to
the National Research Council (NRC) guidelines [13].
Surgical and burn procedures were performed as previously
described [12]. Briefly, class A 30–45 kg (3–4-month old)
Yorkshire pigs were purchased at a single breeding farm,
housed individually at the Animal Resource Facility for at least
one week for acclimatization, and transferred to our laboratory
for conduction of experiments. All animals received standard
porcine diet (LabDiet1 5084, PMI Nutrition, IN) once daily, water
1361
ad libitum, and were fasted overnight before procedures. After
premedication by intramuscular injection of Ketamine and
Xylazine, animals were intubated and inhalative anesthesia
delivered by isoflurane in a 2:1 oxygen:nitrous oxide mixture. A
venous catheter was placed into the right jugular vein and
remained in place for the entire length of the experiment.
Contact burns were created by placing a heated custom-
made aluminum bar on the dorsum of the animal, as previously
described [12]. Briefly, the bar was heated to 200 8C with a
Meeker gas burner, placed on the animal for 30 s at constant
pressure, creating burn sites of approximately 40 cm2 each with
4 cm between each site or from the spine. The total burn size did
not exceed 15% of the entire body surface area. The animals had
free access to fluids directly postoperatively. In order to mimic
the clinical situation, the burn was excised in healthy tissue to
the level of the underlying muscular fascia 24 h after the injury,
leaving the fascia intact. The average size of the resulting
defects was approximately 50 cm2.
Prior to graft harvesting, skin was lubricated with Jelonet1
gauze to facilitate the operation of the electric Padgett
dermatome (Integra Lifesciences, Inc.). Split-thickness skin
grafts (0.4 mm thickness) were harvested, meshed at a ratio of
1:3 and trimmed to the size of the defects.
2.2. Treatment groups and graft fixation
Prior to the study, wound sites were randomly assigned to two
groups: fibrin sealant (FS) and staples (surgical staples only).
No staples were used in the FS group. A physiological coarse
type two-component fibrin sealant [14], was used in the FS
group in a slow solidification format (Artiss1 Baxter Health-
care Inc., CA), which recently has been approved by the Food
and Drug Administration (FDA). While high thrombin concen-
tration (500 IU/ml) renders fibrin sealant ideal for hemostatic
purposes, for autograft fixation a slower solidification of FS is
desirable, which can be achieved by reducing the concentra-
tion of thrombin to 4 IU/ml [11]. Using a two-syringe
application device and a pressure controlled spray system
(DuplojectTM and TissomatTM, Baxter Healthcare Inc., CA), we
applied approximately 0.05 ml/cm2 of FS to the wound bed,
which resulted in a homogenous, thin layer (Fig. 1). In the
staples group, standard 35 mm surgical staples were used. The
staples were applied with a disposable skin stapler (Oasis Inc.,
IL), using 10–15 staples per wound field. Intraoperatively, fluids
were substituted with Ringer’s Lactate solution at 5 ml/kg/h
via the implanted venous jugular catheter.
2.3. Dressing application and postoperative care
A multi-layer dressing that protected wounds from contami-
nation was used after the grafting procedure. The dressing
layers consisted of non-sticking oil emulsion dressing, a
protective layer of antimicrobial ointment (1% Nystatin and 2%
Polymyxin B/Bacitracin, Shriners Hospital Pharmacy, Galves-
ton, TX), a double layer of Polyurethane film (Opsite1,
Smith&Nephew Inc., FL), elastic bandage (VetRap1, 3M Health
Care, MN), and a stocking hose (Goat tubeTM, Sullivan Supplies,
TX) made out of cotton and elastic fibers.
Dressing changes were performed at days 2, 5, and 9. At day
14 the animals were sacrificed. During surgical procedures and
1362 burns 37 (2011) 1360–1366
Small patches, up to 10% wound size

and graft skin totally macerated

Wound fully covered with fibrin
Fibrin deposition

Thicker, confluent patches,

up to 20% wound size
None

Up to 100%, total graft loss

Up to 60% wound size,
Up to 10% wound size

Up to 20% wound size

Up to 40% wound size

Hematoma

partial graft loss

None
Hyper granulation
None

100%
10%

20%

40%

65%

Fully granulated wound, exceeds

Low level of granulation tissue

Granulation tissue level just

half of initial wound depth
Granulation tissue

level of surrounding tissue

None; full depth thickness

Granulation tissue level at

below surrounding tissue

Granulation at level with
Table 1 – Clinical wound assessment scale. Adapted from Branski et al. [12].
Fig. 1 – (A) Burn wound excision and application of

surrounding tissue
autograft. Wounds are excised to the level of muscle
fascia. (B) Application of meshed skin autograft with the
application of fibrin sealant.
dressing changes, heart rate and oxygen saturation were

Full graft adherence

Graft 20% adherent,

Graft 50% adherent,

Graft 75% adherent,

monitored. Postoperative analgesia was provided with trans-

Graft 90% adherent

Graft adherence
dermal fentanyl patches (Duragesic1 25, Janssen Pharmaceu-

50% graft loss

30% graft loss

20% graft loss

Full graft loss
tics, NJ) and with oral non-steroidal analgesics (Ibuprofen
500 mg). Intravenous perioperative antimicrobial prophylaxis
was provided with cephalosporin (Cefazol1 1 g, Bosch Phar-
maceuticals, IN), and oral postoperative antimicrobial pro-
phylaxis was continued for 7 days with levofloxacin 500 mg
tablets (Levaquin1, Ortho-McNeil Pharmaceuticals, TX).

25–50%, more than 20% tissue

50–80%, more than 50% tissue

5–10%, tissue still fully viable

Graft completely dislocated,

10–25%, one or two spots,
Graft dislocation
2.4. Outcome measurements

10% tissue not viable

During each dressing change and before euthanasia, stan-

full tissue loss

dardized digital photographs of the wound fields were
obtained (Sony Cybershot1 Digital Camera, Sony Inc., Japan)

not viable

not viable
and evaluated using planimetric software. For correct mea-

None
surement of the absolute area of each parameter by
planimetry, a calibrated benchmark was positioned adjacent
to each wound site during photographing.

Grade
Clinical evaluation of wounds was conducted using a scale

0
1

5
from 0 to 5. Parameters of the clinical evaluation included graft
 burns 37 (2011) 1360–1366 1363

adherence, graft dislocation, granulation tissue level, occur- Remaining Open Wound Area
Fibrin Sealant
50%
rence of hypergranulation and hematoma, and fibrin deposi- Staples

Percentage of Total Defect Size

tion (Table 1). This evaluation was conducted independently
by the two investigators during each dressing change. 40%

2.5. Histology 30%

A total of 12 skin specimens in each group were obtained at

20%
day 14 and stored in 10% buffered formaldehyde solution for at
least 24 h, embedded in paraffin, sectioned, and stained with
hematoxylin and eosin using standard procedures. Assess- 10%

ment of dermal and epidermal thickness was carried out as

previously described [12]. In brief, for each section, two 0%
random visual fields were chosen and three measurements of Da y 9 Da y 14

each dermal and epidermal thickness obtained.

Fig. 2 – Remaining open wound size, expressed as
percentage of initial total defect size. The remaining open
2.6. Statistical analysis
wound size on day 14 is decreased to 6.1% in the FS group
(n = 20) vs. 7.8% in the staples group (n = 16). Results of
Statistical analyses of planimetric measurements (total and
one-sided t-test: p = 0.046, level of statistical significance
remaining wound sizes) were performed with SAS Version 8.2
p < 0.025). Data expressed as means W standard error of
for Linux. A fixed location unbalanced complete randomized
the mean.
block design was used, where op_block was used as fixed
location factor, animal nested in op_block as random factor,
item, op_block and item-by-op_block as fixed factors as well as
base (i.e. the total defect size at day 0) as covariate. The null Day 2 - Graft Dislocation and Adherence
Fibrin Sealant
hypothesis of no superiority was tested against its one-sided
alternative at a level of 2.5% statistical significance. Statistical
5.0 A * Staples
Clinical Wound Assessment Grade

analyses of macroscopic scoring and microscopic measure-

ments were performed with SigmaStat1 software Version 3.11 4.0
(Systat Software Inc.). Macroscopic scoring data were evaluat-
ed using the Mann–Whitney Rank Sum Test for nonparametric 3.0
comparisons. Microscopic measurements of dermal and
epidermal thickness were evaluated using a two-sided t-test. 2.0
Statistical significance was accepted at a level of p < 0.05.
1.0

3. Results *
0.0
Graft Dislocation Graft Adherence
3.1. Wound healing and re-epithelialization

Day 5 - Graft Dislocation and Adherence

Wound contraction, induced by the wound healing process, Fibrin Sealant
revealed no statistical differences between the two study 5.0
B
* Staples
Clinical Wound Assessment Grade

groups. In both groups, total wound size decreased to app. 75%

of its original size (Table 2). Wound healing, assessed by 4.0
planimetric evaluation of open mesh interstices. Superiority
of FS over staples could not be shown (1-sided p-value for
3.0
superiority = 0.04) at the level of 2.5%, however, the open mesh

2.0

Table 2 – Total wound size on day 0, day 9, and day 14

postoperatively. Data are presented as means W stan- 1.0 *
dard deviation. Statistical comparison between Fibrin
Sealant and Staple groups is shown. ns = not significant.
0.0
Fibrin sealant Staples p Graft Dislocation Graft Adherence
(n = 20) (n = 16)
Fig. 3 – (A) Graft dislocation/adherence day 2. *p < 0.02 FS
mm 2 % mm 2 % (n = 20) vs. staples (n = 16). (B) Graft dislocation/adherence
Day 0 – grafting 5035  1212 100 4692  842 100 ns day 5. *p < 0.02 FS (n = 20) vs. staples (n = 16) (two-sided t-
Day 9 post-op 4185  761 86 3783  791 81 ns test, level of significance p < 0.05). Data expressed as
Day 14 post-op 3736  856 75 3410  788 73 ns
means W standard error of the mean.
1364 burns 37 (2011) 1360–1366

Table 3 – Measurements of dermal and epidermal thickness. Data are presented as means W standard deviation.
Fibrin sealant (n = 12) [mm] Staples (n = 12) [mm] p
Dermis Wound center 4109  1415 3806  1227 ns
Wound edge 4702  504 3856  1515 ns
Normal tissue 2440  546 2501  133 ns
Epidermis Wound center 177  45 163  41 ns
Wound edge 277  124 247  123 ns
Normal tissue 103  29 104  17 ns

interstices were 1.7% lower with FS than with staples after 14
days (Fig. 2).
3.2. Clinical evaluation
Using the clinical scale for wound assessment of graft
dislocation and graft adherence (Table 1), we found that graft
adherence was significantly increased in the FS group on days
2 and 5. Graft dislocation was correspondingly lower in the FS
group on days 2 and 5 (Fig. 3A and B). No significant differences
were noted in the evaluation of granulation tissue level,
occurrence of hypergranulation and hematoma, and fibrin
deposition between the groups. Local infection was noted in
one wound field in each group at day 9.
3.3. Histology
In the histological evaluation, we did not observe differences
in the thickness of epidermis or dermis between the study
groups (Table 3). In the H&E staining, both groups showed the
typical pattern of rete ridges and papillary dermis (Fig. 4). A
well organized dermal–epidermal junction, that also showed a
regular, stained basal cell layer, was present in all sections. In
both groups we saw the fragile, newly formed epidermis over
the former mesh interstices, with no difference in epithelial
thickness. In all groups, a similar number of small vessels
were present underneath the outgrowing epithelial exten-
sions and within the organizing granulation tissue.

4. Discussion

In the last decades, fibrin sealant has proven to be a valuable

Fig. 4 – Cross section of wound at day 14, FS group. Wound
center. Hematoxylin/eosin staining, 200T magnification.
(A) Dermal tissue with three measurement markings. (B)
Epidermal tissue with three measurement markings.
tool for hemostasis in various surgical applications. Its use in
reconstructive and burn surgery, as well as in plastic and
aesthetic operations, is still under clinical evaluation, but has
already shown great potential [15]. We performed a prospec-
tive, randomized and controlled large animal study that
clearly shows the benefit of sprayed fibrin sealant for the
fixation of meshed skin autografts.
The selection of animal models for wound healing studies
mainly depends on availability, costs, ease of handling, and
investigator familiarity with the object. Therefore, rodents
are often used in wound healing studies. However, the dense
layer of body hair and thin dermis and epidermis of rodents,
make it hard to translate results of these studies into
clinically applicable data. Furthermore, wounds in rodents
heal primarily through wound contraction, not via re-
epithelialization, due an underlying muscular structure
( panniculus carnosus) and a high amount of adnexal struc-
tures. For translational studies in wound healing it is
therefore paramount to choose an animal model that more
closely represents human skin.
Porcine skin is anatomically and physiologically similar to
human skin and therefore more suitable to serve as a wound
healing model. The thickness of human epidermis is 50–
120 mm, compared to 30–140 mm in the pig [16]. The vasculari-
zation of porcine skin is similar to that of human skin [17], as is
the collagen content and elasticity [18]. Both human and pig
show sparse body hair [19], similar epidermal turnover time,
type of keratins and stratum corneum [20]. In a comparative
review of over 180 studies related to wound healing, Sullivan
et al. [21] found concordance of 78% in the results of human
and porcine wound healing studies, vs. only 53% in human and
rodents. Their results suggested that the porcine model is an
 burns 37 (2011) 1360–1366
excellent tool for the evaluation of therapeutic agents destined
for use in human wounds.
Only few groups have, however, extended their wound
healing model to the more complex situation of a burn injury.
Middelkoop et al. [22] introduced a model of partial and full-
thickness burn in Yorkshire Swine; Danilenko et al. [23] used
adult minipigs for burn and excision studies. These studies
showed the general applicability of porcine burn wound
models. Only Singer and McClain [24] standardized a porcine
burn and autograft model. Mittermayr et al. [11] developed a
porcine wound excision model and tested the use of fibrin
sealant. For the use in further wound healing studies, our
group has recently developed a reliable and reproducible
model of burn, excision and autografting [12].
We chose two groups according to the clinical situation:
skin staples are the method of choice for the fixation of
autografts in the severely burned patient, as large wound
surfaces have to be covered in a timely fashion. They served
as controls in our study. Fibrin sealant was the test
substance. Its slow-clotting version and the application of
a thin layer of fibrin sealant (0.05 ml/cm2) have been shown
effective in both human [15,25] and porcine [11] studies.
Moreover, spray application of fibrin sealant results in an
equal ratio of thrombin and fibrinogen, and facilitates the
formation of a homogenously thin fibrin layer [26]. We have
previously shown that the specific fibrin sealant (TisseelTM)
used in this study (physiological coarse type fibrin sealant) is
superior to the fine type fibrin sealant and to autologous
sealants [14,27].
Our main finding is the improved handling and reduced
graft dislocation/increased adherence in the fibrin sealant
group. We observed a significantly higher level of graft
adherence, and, correspondingly, less graft dislocation in
the FS group. This significant difference is visible at postoper-
ative days 2 and 5, and clearly indicates that the application of
fibrin sealant provides better graft attachment to the wound
surface than skin staples. When skin staples are used for the
fixation of widely meshed autografts, only one strand of the
mesh can be grasped with each staple, making the graft nets
even more prone to graft loss than sheet grafts. Graft loss even
occurs when large amounts of staples are used, appropriate
pressure dressings are applied, and experienced surgeons
conduct the operation. The main reason for the loss is that a
continuous contact of graft and recipient bed cannot be
guaranteed. Graft loss occurs mainly during the first three
postoperative days, and particularly when placed in exposed
anatomical locations [28]. The application of thin layers of
fibrin sealant does not only provide complete contact between
wound bed and graft, but also acts as a scaffold for collagen
producing fibroblasts, provides a matrix for vascularization,
and possibly creates a barrier against infection [10,29].
Therefore, we believe that the advantage of a good graft
adherence and re-vascularization in the early postoperative
phases translates into an accelerated wound closure in the
late phase, and represents a strong argument for the use of
fibrin sealant in the fixation of widely meshed autografts.
A significant acceleration in re-epithelialization, repre-
sented by a reduction of remaining open wound area, could
not be observed in this study. At day 14, the last day of our
observation, 94% of the initial open wound in the FS group was
1365
healed, as opposed to 92% in the staples group. Both groups
showed a similar amount of wound contraction. While this
difference in wound healing did not reach statistical difference
in this study, we believe that in a severely burned patient, even
slightly accelerated wound healing translates into less time in
the burn unit, less susceptibility to infection, less use of
analgesics, and avoidance of further reconstructive surgery.
Taking into account the immense costs of burn treatment, every
day less in the burn ICU is also an important economic factor.
We did not see any significant differences in the occurrence
of hematoma in this study and attribute this to good operative
technique and the fact that the study was conducted by only
two surgeons who had experience with this animal model.
The even level of granulation tissue indicates a healthy wound
healing which is not influenced by systemic factors. Finally,
hypergranulation did only occur in some wound fields where
partial graft loss was present, but there were no differences
between the study groups.
There are some limitations to this study. Wound fields of
50 cm2 cannot be directly translated to severely burned patients,
where large areas of the skin are burned and wound healing is
generally compromised by the systemic response. A porcine
model of delayed wound healing (aged or diabetic pig) may have
more clearly demonstrated the advantage of wound healing
acceleration with fibrin sealant or whether it needs addition of
growth factors to further improve healing like in other models
[30]. Finally, an extended observation period would have
shown the effect of FS on scarring and graft stability.
Graft fixation with slow clotting, coarse type fibrin sealant
is an adequate alternative for skin staples. Our findings
indicate that graft adherence improved and graft dislocation
minimized. The application of only 0.05 ml/cm2 FS with an
advanced spraying device also facilitates handling. We
achieved these results in a porcine model of full-thickness
burn that is similar to the clinical situation in humans. Thus,
the use of FS in the fixation of split-thickness skin autografts
on excised burn wounds can be recommended.
Conflict of interest
HR is a consultant to Baxter Innovations, Vienna.
Acknowledgements
We would like to acknowledge the entire staff of the large
animal facility of the Shriners Hospital for Children, especially
Thomas Miszalkiewski and John R. Salsbury, for their great
support in the conduction of the animal studies. We also want
to thank Zafar Khakpour, LBI Vienna, for the design and
construction of the burn apparatus, and Pat Sellers of the
Pathology core lab for the preparation of histological slides.
We would like to thank Dipl.-Math. John-Philip Lawo for the
statistical analysis of the planimetric data as well as Andreas
Goppelt, Ph.D., Johannes Regenbogen, Ph.D., Sabine Fraiss,
Ph.D. and Melitta Bilban, Ph.D. for the support and valuable
discussions. The work was supported by a Shriners Hospital
for Children Research Fellowship Grant and an unrestricted
research grant by Baxter AG Vienna.
1366 burns 37 (2011) 1360–1366
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