j o u r n a l o f s u r g i c a l r e s e a r c h  j a n u a r y 2 0 1 7 ( 2 0 7 ) 1 0 2 e1 0 7

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.JournalofSurgicalResearch.com

Topical vanadate enhances the repair of median

laparotomy incisions

Sprague W. Hazard III, MD,a,b Charles F. Zwemer, PhD,b

Donald R. Mackay, MD,c Srinivas V. Koduru, PhD,c
Dino J. Ravnic, DO, MPH,c,* and H. Paul Ehrlich, PhDc
a
Department of Anesthesia, Penn State Hershey Medical Center, Hershey, Pennsylvania
b
Department of Biology, Dickinson College, Carlisle, Pennsylvania
c
Department of Surgery, Penn State Hershey Medical Center, Hershey, Pennsylvania

article info abstract

Article history: Background: There are over two million laparotomies performed in the United States each
Received 11 May 2016 year with an incisional hernia rate between 2% and 11%. A total of 100,000 ventral hernia
Received in revised form repairs are undertaken each year with recurrences as high as 50%.
1 August 2016 Materials and methods: Full thickness midline fascia incisions from the xiphoid to the pubic
Accepted 24 August 2016 symphysis were made in rats. The fascia and/or muscular layer was sutured closed and a
Available online 31 August 2016 gel with 300 mM of sodium orthovanadate or saline was placed over the suture line with the
skin closed over it. On day 10, 1-cm strips from the superior, middle, and inferior regions of
Keywords: the abdominal wall were tested for breaking strength and processed for histology.
Laparotomy Results: The mean wound breaking strength of vanadate-treated wounds was 18.6
2.7 N
Hernia compared with 9.4
3.6 N for controls (P < 0.0001). Similar quantities of granulation tissue
Wound healing were deposited in treated and control wounds. Fine green birefringence patterns, charac-
Scar teristic of immature connective tissue, were seen in control samples viewed with polarized
Vanadate light. In contrast, vanadate-treated wounds showed thick yellow-orange birefringence
patterns characteristics of more mature connective tissue. Using a-smooth muscle actin
immunostaining, myofibroblasts were prominent in control incisions, but few were iden-
tified in vanadate-treated incisions.
Conclusions: In rat laparotomy wounds, a single application of vanadate increases wound
breaking strength, through enhanced connective tissue organization. These combined data
suggest topical application of vanadate immediately after fascial closure will increase
wound strength, possibly reducing hernia recurrences in the repaired abdominal wall.
2016 Elsevier Inc. All rights reserved.

Introduction potential compromise of the intestinal blood supply.2 There is

In the United States, approximately 10% of patients under-
going laparotomy will develop an incisional hernia.1,2 Inci-
sional hernias are fraught with numerous complications such
as pain, intestinal obstruction, skin ulceration, fistula, and
little consensus in the literature on which approach (laparo-
scopic versus open), implantable mesh (synthetic versus bio-
logic), or suture material provides the strongest repair.
Implantable materials and reoperations each have their dis-
advantages. Therefore, a simpler solution may be given to

* Corresponding author. Division of Plastic Surgery, The Pennsylvania State University, College of Medicine, H071, 500 University Drive,
Hershey, PA 17033. Tel.: 1 717 531 1019; fax: 1 717 531 4339.
E-mail address: dravnic@hmc.psu.edu (D.J. Ravnic).
0022-4804/$ e see front matter 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jss.2016.08.078
 hazard iii et al  use of vanadate in laparotomy incisions
make the primary repair stronger, lessening the likelihood of
an incisional hernia. To do so, this would require an alteration
in normal wound healing. Wound healing is a critical biolog-
ical process that restores tissue integrity from loss by trauma
or necrosis. The replacement of tissue is usually achieved by
scarring, where a patch of connective tissue holds the edges of
the defect together. A scar is not equivalent to the lost tissue in
terms of function, strength, suppleness, and appearance. In
most injuries, the scar is the consequence of wound repair
rather than regeneration. The repair process follows a pre-
dictable sequence of cell populations that enter the repair site.
Wound repair starts with the lag phase, where inflammatory
cells (neutrophils and macrophages) populate the site. The
proliferative phase follows, fibroblasts enter the wound site
and deposit a new connective tissue matrix composed mostly
of randomly organized collagen fiber bundles. During the final
remodeling phase, the myofibroblast is the major cell
phenotype. The myofibroblast contains stress fibers with
cytoplasmic filaments that contain an isoform of a-smooth
muscle (a-SM) actin.3 During this phase, collagen fibrils
condense into thicker collagen fibers and myofibroblasts
eventually undergo apoptosis. This transitioning of cell types
occurs in a complex milieu known as granulation tissue.
Granulation tissue is the transitional connective tissue matrix
that ultimately matures into the scar. Granulation tissue has a
high cell density, fine collagen fibrils enriched in type III
collagen, and a dense network of blood vessels necessary for
the elevated metabolic needs. After cellular apoptosis, the
final scar has limited vasculature, few fibroblasts, no myofi-
broblasts, and an unstable connective tissue matrix composed
of irregular-sized collagen fiber bundles arranged in random
arrays.4 This haphazard organization of collagen fiber bundles
within the scar is a major reason for its reduced tensile
strength. The uniform quality of the connective tissue matrix
that makes up the scar in vanadate-treated wounds is
responsible for increased strength, having qualities similar to
intact dermis.5-8
Surgical access to the abdominal cavity is typically via a
midline laparotomy incision made through the linea alba. The
linea alba is the aponeurosis of anterior and lateral abdominal
wall musculature that extends from the xiphoid to the pubic
symphysis.9 It is composed of connective tissue structures
rich in collagen. The repair of a damaged linea alba requires
both the synthesis of new collagen and its subsequent reor-
ganization into a connective tissue matrix can withstand
tensile stresses from the viscera pushing against the abdom-
inal wall. The strength of a healed laparotomy incision is
weaker than the virgin linea alba.10 In a cadaveric model,
Hollinsky and Sandberg demonstrated the tensile strength of
normal, uninjured epigastric regions of the linea alba ruptured
at a horizontal load of 10.0
3.4 N/mm2 as compared to
6.9
2.5 N/mm2 in repaired linea alba scar tissue (P  0.001).
Scar tissue thus has a significantly reduced loading capacity
than the intact ventral abdominal wall and therefore poses a
permanent risk for herniation.10
It is well documented, in fibroblasts and other cell types,
those intracellular signaling pathways can be controlled
through specific tyrosine phosphorylated residues in select
proteins. Protein tyrosine phosphatases (PTPs) primarily act to
downregulate signaling pathways. Thus, the inhibition of
103
PTPs could promote and or maintain the activities of native
signaling pathways. In fibroblasts, PTPs modulate mitogenic
signaling, regulate motility, and control mRNA levels of type I
and III procollagen.11-13 Vanadate is a broad PTP inhibitor and
acts as a phosphate analogue exerting its action by binding to
the transition state of specific PTPs.14
The purpose of this study was to demonstrate that fascial
repair responds to topical vanadate therapy similar to dermis;
where there is more uniform packing of collagen fiber bundles
within the repair site. It is the uniform packing of collagen
fiber bundles that is responsible for the doubling of dermal
wound-breaking strength. This is in contrast to the increased
deposition of connective tissue seen in dermal wounds
treated with transforming growth factor-beta (TGF-b).5-8,15
Materials and methods
All animal studies followed protocols compliant with our in-
stitutions guidelines outlined in the Guide for the Care and
Use of Laboratory Animals, authored by the Institute of Lab-
oratory Animal Resources and published by the National In-
stitutes of Health (NIH Publication #86-23, Revised 1985)
IACUC #2007-123.
Twelve adult female Sprague Dawley rats (350-400 g) were
randomly assigned to either treatment with vanadate or
normal saline (six in each group). The rats were placed into an
induction chamber of 5% isoflurane anesthesia with a balance
of oxygen and maintained via facemask consisting of 2-4%
isoflurane throughout the surgical procedure. The abdomen of
the animal was clipped and prepared with tincture of iodine. A
midline abdominal skin incision was made from the xiphoid
process to the pubic symphysis. The skin adjacent to the
incision was undermined for approximately 1 cm in all di-
rections off the anterior abdominal wall. Once hemostasis was
obtained, the linea alba was visualized, and a full thickness
incision was made into the peritoneum. The linea alba was
then closed using 5-0 polydioxanone suture in a running
locking fashion. A running horizontal mattress suture was
started from the caudal most portions of the skin incision and
continued cephalad until a skin opening of approximately
1 cm remained. At that time, a mixture of Pluronic (BASF Corp,
Florham Park, NJ) with saline or Pluronic plus 300-mM sodium
orthovanadate (Sigma Chemical Co, St. Louis, MO) was layered
onto the repaired abdominal wall through the skin opening
starting from xiphoid extending to the pubis. With the gel in a
subcutaneous pocket, immediately anterior to abdominal
wall, the skin incision was sutured closed. Postoperative
analgesia was maintained with bupinorphine every 12 h as
needed for pain, and the animals were given free access to
food and water. On postoperative day 10, each rat was anes-
thetized with isoflurane and euthanized by an intracardiac
injection of sodium pentobarbital (150 mg/kg).
The abdominal wall was harvested en bloc, and a 1-cm strip
of tissue was cut from the superior, middle, and inferior re-
gions in a transverse fashion. These strips of tissue were then
subjected to testing using a custom built tensiometer. A Har-
vard apparatus PhD 2000 infusion pump (Holliston, MA) was
used to provide a constant linear force (3.0  10.4 m/s).
Machined aluminum posts were mounted onto the existing
104 j o u r n a l o f s u r g i c a l r e s e a r c h  j a n u a r y 2 0 1 7 ( 2 0 7 ) 1 0 2 e1 0 7
fixed and mobile brackets of the infusion pump. On the sta-
tionary end of the pump, interlocking jaws were mounted on
an aluminum rod. Directly opposite to this, a Grass FT03 force
transducer was mounted (West Warwick, RI) with the same
serrated interlocking jaws. Using a Biopac MP100 (Goleta, CA),
analog to digital oscillographic converter and analyzed with
an Apple Macintosh computer (Cupertino, CA), the signal from
the force transducer was digitally converted. Unpaired two-
tailed t-tests and a two-way analysis of variance with
HolmeBonferroni correction was used to determine differ-
ences in the mean breaking strength and anatomic specific
breaking strength. These tests were performed using Graph
Pad Prism software (LaJolla, CA).
Tissues samples were taken for histologic analysis. A
portion of the tissues were fixed in 10% formaldehyde,
embedded in paraffin in a transverse orientation, sectioned,
stained with hematoxylin and eosin (H&E) or Sirius red as
previously described.16 H&E sections were viewed with light
microscopy. The birefringence pattern of collagen fiber bun-
dles of Sirius-red-stained sections were elucidated by polarized
light microscopy. Other tissue samples were placed in cas-
settes, Tissue-Tek OCT Compound (Miles Laboratory, Elkart,
IN) was added, and then frozen in liquid nitrogen and stored at
80 C. Six micron sections were cut with a cryostat, fixed in 4%
paraformaldehyde and permeabilized with 0.1% Triton X-10.
The specimens were then incubated with an a-smooth muscle
actin monoclonal antibody (Sigma Chemical Co), followed by a
secondary rhodamine conjugated goat anti-mouse IgG anti-
body (Jackson Immuno Research Laboratory, West Grove, PA).
Samples were then counterstained with Alexa-Phalloidin for
identifying actin microfilaments and 40 ,6-diamidino-2-phe-
nylindole to identify nuclei (Invitrogen, Carlsbad, CA).
Results
Wounds tested to breaking strength showed a profound dif-
ference between the vanadate-treated and untreated groups.
Fig. 1 e Total force (left) and group-specific breaking strength in relation to anatomic location (right). (Color version of figure
is available online.)
The repair at the superior aspect of the abdominal wall of
vanadate-treated rats had a mean breaking strength of
23.1
5.9 N as compared to 11.0
4.3 N for the saline controls.
The statistical difference using an unpaired two-tailed t test
was P 0.0024. The repair sites in the middle and inferior
aspects from vanadate-treated rats had wound breaking
strength means of 15.6
5.7 N and 17.0
5.2 N, respectively.
The breaking strength of the same wound sites from control
rats was 7.5
3.5 N and 9.8
5.7 N, respectively. These dif-
ferences were statically significant using an unpaired two-
tailed t test (P 0.013 and 0.047, respectively). The mean
wound breaking strength of combined vanadate-treated
wounds (n 18) was 18.6
2.7 N compared with 9.42
3.6 N
for saline controls (n 18). The statistical significance was
P 0.0024 using an unpaired two-tailed t test. Two-way
analysis of variance showed differences between the mean
of vanadate-treated rats as compared with the mean of con-
trol treated rats with a P value less than 0.0001 Significant
differences across all three anatomic locations were seen
using HolmeBonferroni corrections (Fig. 1, right). In summary,
vanadate-treated abdominal wall repairs were 97% stronger
than controls (Fig. 1, left).
H&E sections showed the distance between the two su-
tured rectus abdominis muscles, i.e., the width of granulation
tissue deposited in the wound site, was similar in both
groups. The cell density and connective tissue deposited at
the wound site also appeared similar (Fig. 2). Sirius-red-
stained sections viewed with polarized light demonstrated
differences in the birefringence patterns in granulation tis-
sues from control compared with vanadate-treated rats. The
more organized and uniform packing of the collagen fiber
bundles, the greater the intensity of the tissues birefrin-
gence. As the collagen fiber bundles increases in thickness
and length; the birefringence color changes from green (thin
collagen fiber bundles typical of young and immature gran-
ulation tissue) to an orange birefringence color (characteristic
of thicker and longer collagen fibers). The birefringence in-
tensity of the granulation tissue from vanadate-treated rat
 hazard iii et al  use of vanadate in laparotomy incisions 105

Fig. 2 e H&E staining showed similar patterns of granulation tissue between control (left) versus the vanadate-treated rats
(right). (Color version of figure is available online.)

wounds was more intense than controls. Granulation tissue
from controls showed mostly a fine green birefringence
pattern with only occasional areas of yellow birefringence
(Fig. 3, left). Figure 3 right is the typical birefringence pattern
of granulation tissue from vanadate-treated wounds. A major
proportion of the granulation tissue had an intense yellow-
eorange birefringence. The birefringence pattern of granu-
lation tissue from vanadate-treated rats was typically more
mature, and the stronger uniform packing of collagen fibers
bundles appeared responsible for the increase in wound
breaking strength.
The presence of myofibroblasts within the granulation
tissue is demonstrated by the fluorescence of a-SM actin.
Granulation tissue from saline-treated control rats revealed
prominent green fluorescent phalloidin-stained stress fibers
(Fig. 4, left). The control samples also revealed SM cells (within
blood vessels) and myofibroblasts: each identified by their red
fluorescent a-SM actin within cytoplasmic stress fibers. The
granulation tissue from the control abdominal wall repair
sites had high densities of red fluorescent stress fibers iden-
tifying them as myofibroblasts. In contrast, the granulation
tissue in vanadate-treated rats had red fluorescent SM cells
within blood vessel walls, but there were few red fluorescent
stress fibers indicating a paucity of myofibroblasts (Fig. 4,
right). Vanadate-treated incisional fascia wounds showed lit-
tle differences with H&E staining but showed more uniformly
packed collagen fibers (as seen by polarized light microscopy)
and the absence of myofibroblast populations demonstrated
by immunofluorescence microscopy.
Discussion
In our study, laparotomy wounds tested to breaking strength
in the immediate postoperative period, showed a significant
difference between the vanadate-treated and untreated
groups. Vanadate-treated wounds had nearly double the
breaking strength of control wounds on postoperative day 10.
Dynamic testing correlated with histological differences;
specifically, the vanadate-treated wounds demonstrated
more organized and thicker collagen fiber bundles. We hy-
pothesize that these histologic changes led to the difference in
wound breaking strength.
Suture repaired fascia shares some of the qualities of
dermal repair, whereas granulation tissue is the provisional
matrix that replaces fibrin in the early repair process and
subsequently matures into a scar. Scar tissue is the patch that
holds the healed incisional wound together. Our speculation
is that the increase in breaking strength of vanadate-treated
sutured closed fascia incisional wounds results from the
more uniform packing of collagen fiber bundles in the im-
mediate postoperative period. We believe that our data have
direct implications into the way clinicians approach the
reapproximation of primary laparotomy incisions. It is

Fig. 3 e Typical birefringence pattern of granulation tissue from vanadate-treated wounds (right). Note the more organized
and uniform packing of the collagen fiber bundles and the greater the intensity of the tissues birefringence representing
more mature collagen fiber bundles as compared to control (left). (Color version of figure is available online.)
106 j o u r n a l o f s u r g i c a l r e s e a r c h  j a n u a r y 2 0 1 7 ( 2 0 7 ) 1 0 2 e1 0 7
Fig. 4 e There are prominent green fluorescent phalloidin-stained stress fibers seen in both control (left) and vanadate-
treated (right) rats; however, note there were few red fluorescent myofibroblasts present in the vanadate-treated samples.
(Color version of figure is available online.)
possible to extrapolate that vanadate-treated fascial repairs,
being twice as strong, would limit the number of incisional
hernias.
Granulation tissue from vanadate-treated wounds has an
absence of cytoplasmic stress fibers within wound fibroblasts.
In the closure of open full thickness wounds in rats by wound
contraction, the oral consumption of vanadate in the rats
drinking water prevents the appearance of cytoplasmic stress
fibers expressing a-smooth muscle actin in granulation tis-
sue.17 Vanadate-treated rats contract their open wounds in
the absence of myofibroblasts. In addition, techniques such as
polarized light and transmission electron microscopy
revealed the granulation tissue in vanadate-treated rats is
composed of collagen fiber bundles of equal diameters orga-
nized in uniform parallel arrays. These collagen fiber bundles
are thicker and longer than typical granulation tissue, which
has irregular collagen fiber bundles. Suture-closed incisional
skin wounds in vanadate-treated rats have a doubling in
wound breaking strength at 7 d without an increase in the
amount of granulation tissue deposited between the wound
edges.6 TGF-b treatment of incisional wounds also increases
wound breaking strength up to 80%.15 The mechanism for the
gain in wound breaking strength in TGF-b-treated rat wounds
is believed to be mediated by the increased deposition of
collagen within the wound site.15 Vanadate on the other hand
promotes the uniformity in the packing of collagen fibers
without increased deposition of collagen.5 The topical
administration of vanadate promotes the more uniform or-
ganization of collagen fiber bundles.
In dermis and tendon, the organization of connective tis-
sue matrix is dictated by the orientation of fibroblasts. During
wound repair, a disorganized collagen matrix contains pop-
ulations of randomly oriented cells. Fibrin provides hemo-
stasis at the site of initial injury, and it also provides a scaffold
or framework for the migration of neutrophils, macrophages,
and fibroblasts. Fibroblast outgrowth from untreated chick
embryo tendon explants onto a fibrin clot proceeds in a
random fashion. In contrast, fibroblasts from vanadate-
treated chick embryo tendon explants migrated in linear
arrays.7 These findings support the notion that vanadate
promotes the deposition of regular, parallel collagen fiber
bundles by advancing the orientation of fibroblasts in parallel
arrays early in the wound repair process in effect ignoring the
organization of the fibrin scaffolding.7 Furthermore, this
observation suggests that vanadates mechanism of action
may be to accelerate the normal wound healing process
causing functional remodeling to occur much earlier. In other
words, vanadate may modulate the traditional paradigm of
wound healing by compressing the time between phases or
causing an overlap of the remodeling phase with earlier
phases. Whatever the mechanism, fascial wounds healed in
the presence of a single topical application of vanadate were
twice as strong as saline-treated controls at 10 d.
Although these preliminary results are exciting, it is evident
that several limitations to our study exist. There are striking
differences in wound healing between mammalian species
and as such choosing a species to study has a profound effect
on the outcome of the investigation. Although large animal
models may more closely resemble human wound healing, in
regard to cellularity and timeline, practical limitations such as
cost and facilities limit their use. Rats, more specifically female
Sprague Dawley rats, were chosen for this study due to their
wide availability and relatively low cost. The timeline for har-
vest also serves as another limitation to this study. A 10-
d harvest was chosen due to a number of published predicate
studies regarding laparotomy wounds in rats which ranged
from 7 to 28 d postoperatively.18,19 The snapshot into the early
stages of the wound healing cycle that this study provides was
chosen because fascial dehiscence tends to manifest early in
the postoperative period. Future studies will look at the impact
of vanadate in a more prolonged fashion.
Conclusions
Our study demonstrates that the single application of topical
vanadate immediately following fascial closure nearly
doubled wound breaking strength through the reorganization
 hazard iii et al  use of vanadate in laparotomy incisions
of connective tissue. This research may offer therapeutic
significance to optimize the healing of laparotomy wounds.
Acknowledgment
The authors would like to thank Gretchen Allison and Greg
Saggers for their insight and technical support. They would
also like to thank Rick Lindsey; the talented machinist that
moved data collection from an idea to a possibility.
Authors contributions: S.W.H., C.F.Z., and P.E. contributed
to the design of the work and the acquisition of data. All of the
authors contributed to the interpretation of data and the
drafting of the manuscript. All of the authors approve of this
final version for publication and are in agreement to be
accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the
work are appropriately investigated and resolved.
Disclosure
None of the authors have any financial and personal re-
lationships with other people or organizations that could
potentially and inappropriately influence (bias) their work and
conclusions.
references
1. Leber GE, Garb JL, Alexander AI, Reed WP. Long-term
complications associated with prosthetic repair of incisional
hernias. Arch Surg. 1998;133:378e382.
2. Flum DR, Horvath K, Koepsell T. Have outcomes of incisional
hernia repair improved with time? A population-based
analysis. Ann Surg. 2003;237:129e135.
3. Darby I, Skalli O, Gabbiani G. Alpha-smooth muscle actin is
transiently expressed by myofibroblasts during experimental
wound healing. Lab Invest. 1990;63:21e29.
4. Cohen IK, Keiser HR. Disruption of healed scars in
scurvydthe result of a disequilibrium in collagen
metabolism. Plast Reconstr Surg. 1976;57:213e215.
5. Chen J, Iosifidis M, Zhu J, Tatarintsev I, Wang JH.
Vanadate ingestion enhances the organization and
collagen fibril diameters of rat healing medical collateral
107
ligaments. Knee Surg Sports Traumatol Arthrosc.
2006;14:750e755.
6. Ehrlich HP, Keefer KA, Maish 3rd GO, Myers RL,
Mackay DR. Vanadate ingestion increases the gain in
wound breaking strength and leads to better organized
collagen fibers in rats during healing. Plast Reconstr Surg.
2001;107:471e477.
7. Lee MY, Ehrlich HP. Influence of vanadate on migrating
fibroblast orientation within a fibrin matrix. J Cell Physiol.
2008;217:72e76.
8. Mackay DJ, Moyer KE, Saggers GC, Myers RL, Mackay DR,
Ehrlich HP. Topical vanadate optimizes collagen organization
within granulation tissue. Wound Repair Regen.
2003;11:204e212.
9. Moore KL, Dalley AF. Clinically oriented anatomy. 5th ed.
Baltimore, MD: Lippincott Williams and Wilkins; 2006.
10. Hollinsky C, Sandberg S. Measurement of the tensile
strength of the ventral abdominal wall in
comparison with scar tissue. Clin Biomech (Bristol, Avon).
2007;22:88e92.
11. Duncan MR, Hasan A, Berman B. Pentoxifylline, pentifylline,
and interferons decrease type I and III procollagen mRNA
levels in dermal fibroblasts: evidence for mediation by
nuclear factor 1 down-regulation. J Invest Dermatol.
1995;104:282e286.
12. Chernoff J. Protein tyrosine phosphatases as negative
regulators of mitogenic signaling. J Cell Physiol.
1999;180:173e181.
13. Garton AJ, Tonks NK. Regulation of fibroblast motility by the
protein tyrosine phosphatase PTP-PEST. J Biol Chem.
1999;274:3811e3818.
14. Huyer G, Liu S, Kellyi J, et al. Mechanism of inhibition of
protein-tyrosine phosphatases by vanadate and pervanadate.
J Biol Chem. 1997;272:843e851.
15. McGee GS, Broadley KN, Buckley A, et al. Recombinant
transforming growth factor beta accelerates incisional wound
healing. Curr Surg. 1989;46:103e106.
16. Junqueira LC, Bignolas G, Brentani RR. Picrosirius staining
plus polarization microscopy, a specific method for
collagen detection in tissue sections. Histochem J.
1979;11:447e455.
17. Ehrlich HP, Keefer KA, Myers RL, Passaniti A. Vanadate and
the absence of myofibroblasts in wound contraction. Arch
Surg. 1999;134:494e501.
18. Xing L, Culberston EJ, Wen Y, Robson MC, Franz MG. Impaired
laparotomy wound healing in obese rats. Obes Surg.
2011;21:1937e1946.
19. Hoer JJ, Junge K, Schachtrupp A, Klinge U, Schumpelick V.
Influence of laparotomy closure technique on collagen
synthesis in the incisional region. Hernia. 2002;6:93e98.