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A Novel Method of Esophageal Lengthening in


a Large Animal Model of Long-Gap Esophageal
Atresia
Conference Paper in Journal of Pediatric Surgery October 2014
Impact Factor: 1.39 DOI: 10.1016/j.jpedsurg.2015.03.011

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Journal of Pediatric Surgery xxx (2015) xxxxxx

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

A novel method of esophageal lengthening in a large animal model of


long gap esophageal atresia
Veronica F. Sullins a,b, Peter K. Traum c, Samuel W. French c, Benjamin M. Wu d,
James C.Y. Dunn b,d, Steven L. Lee a,b,
a

Division of Pediatric Surgery, Department of Surgery, Harbor-UCLA Medical Center, Torrance, CA, USA
Division of Pediatric Surgery, Department of Surgery, University of California, Los Angeles, CA, USA
Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA, USA
d
Department of Bioengineering, University of California, Los Angeles, CA, USA
b
c

a r t i c l e

i n f o

Article history:
Received 20 February 2015
Accepted 10 March 2015
Available online xxxx
Keywords:
Esophageal atresia
Pure esophageal atresia
Long gap esophageal atresia
Animal model
Esophageal lengthening

a b s t r a c t
Purpose: Long gap esophageal atresia remains a signicant treatment challenge. We aimed to create the rst large
animal model of long gap esophageal atresia to test a degradable esophageal lengthening device.
Methods: The distal esophagus was divided 2 cm above the gastroesophageal junction in 6 minipigs. A
polycaprolactone (PCL) spring device was secured inside the distal esophageal segment, and the end was
oversewn. Nonexpanding PCL tubes served as controls. An esophagogastric anastomosis was created to restore
continuity. After 4 weeks, the distal esophageal pouch was analyzed.
Results: The distal esophageal pouch of experimental animals increased in length from 1.9 to 4.5 cm. Control
animals demonstrated no change. When comparing lengthened to native esophagus, there was no difference
in the thickness of muscularis mucosa or muscularis propria. Mechanically lengthened esophagus showed mild
to moderate supercial inammation and brosis. There were no differences in the number of myenteric or
submucosal ganglia.
Conclusion: We created the rst porcine model of long gap esophageal atresia and lengthened the distal esophagus
with an internally placed device. This model may be used to explore novel therapies in the management of long
gap esophageal atresia.
2015 Elsevier Inc. All rights reserved.

Esophageal atresia (EA) and tracheoesophageal stula (TEF) are


major congenital malformations that affect 1:3500 live-born infants
[1]. The described subtypes are based on extent of the atresia and location of the TEF. Type A, or pure EA, accounts for approximately 8% of all
EA/TEF [2]. Management of pure EA depends largely on the length of
gap between the proximal and distal atretic ends of the malformed
esophagus. While children with small gap EA can be managed with a
single surgical procedure, long gap atresias pose a signicant problem
because of the length of esophagus needed for repair.
Current surgical management of long gap EA is widely varied. Interposition grafts using the stomach, colon, and jejunum have been described, however most patients have signicant long-term sequelae
requiring additional procedures [3]. Most agree that preservation of
the native esophagus is best. To achieve this, there are several mechanical lengthening techniques described. Regardless of the method used,
children are subject to signicant morbidity and no single technique is
ideal. Major complications include anastomotic leak, stricture, infection,

Corresponding author at: Division of Pediatric Surgery, Harbor-UCLA Medical Center,


1000 West Carson St., Box 25, Torrance, CA, 90502-2004. Tel.: +1 310 222 2706; fax: +1
310 782 1562.
E-mail address: slleemd@yahoo.com (S.L. Lee).

dysphagia, and gastroesophageal reux disease [4,5]. Patients consequently suffer long hospitalizations and have signicant oral aversion.
Gastrointestinal tissue engineering has been a focus of investigation
with the goal of improving therapies for both short bowel syndrome
and EA. In regard to short bowel syndrome, recent animal models of distraction enterogenesis, or intestinal lengthening by mechanical means,
have been promising [6,7]. These models utilize internal propulsion
force, rather than external traction, to achieve lengthening. Given the
current clinical use of distractive force in esophageal tissue, there may
be a role for mechanical lengthening using similar devices in the treatment of long gap EA. Presently, there are no practical animal models of
pure EA. Our goal is to create a viable large animal model of long gap EA
for the purpose of testing a novel, internally placed, distal esophageal
lengthening device.

1. Materials and methods


Animal experimental protocols were approved by the Institutional
Animal Care and Use Committee (Protocol #20808-01) and complied
with all established regulations. Male Yucatan minipigs (S&S Farms,
Ramona, CA) weighing between 8 and 14 kg were used. All materials
used in device fabrication were FDA approved for use in humans.

http://dx.doi.org/10.1016/j.jpedsurg.2015.03.011
0022-3468/ 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Sullins VF, et al, A novel method of esophageal lengthening in a large animal model of long gap esophageal atresia, J
Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.011

V.F. Sullins et al. / Journal of Pediatric Surgery xxx (2015) xxxxxx

1.1. Device fabrication


Polymer springs made from polycaprolactone (PCL) were fabricated
using a 3.8% (w/w) PCL (Lactel, Birmingham, AL) solution mixed in chloroform and spray-coated onto a spinning 7 mm stainless steel mandrel
to form polymer tubes. PCL tubes measuring 1.52.0 cm were laser cut
into spirals, stretched and heat set at 50 C for 1 hour to form nal PCL
springs. Target spring constants were extrapolated from stress versus
strain curves of rat intestinal tissue and previously used spring constants from successful mechanical lengthening of rat intestine [6].
Spring constants were measured using an Instron electromechanical
testing system (Instron, Norwood, MA). PCL spring devices were compressed and placed into gelatin capsules (Torpac Inc., Faireld, NJ)
then coated with cellulose acetate phthalate as we have previously
described [8]. The capsule allows compression of the device and the
polymer coating delays full expansion until several days after it is
secured in the esophagus.
1.2. Surgical procedure
Animals were anesthetized with inhaled oxygen and 2.0% isourane.
The abdomen was entered through an upper midline laparotomy incision and the stomach was identied and eviscerated. The esophagus
was mobilized and ligated 1.52.0 cm above the gastroesophageal junction (GEJ) to create a distal esophageal pouch. To restore enteric continuity, a gastrotomy was made in the gastric cardia and a tension-free
anastomosis using 3-0 Maxon suture (Covidien, Manseld, MA) in simple interrupted fashion was created between the distal end of the proximal esophagus and the stomach (Fig. 1). In experimental animals, the
encapsulated PCL spring device was placed into the distal esophageal
pouch and the open end was closed with a 3-0 polypropylene running
suture (n = 4). A large vessel loop was wrapped around the gastroesophageal junction (GEJ) and clipped to secure the device inside the
distal esophageal pouch. PCL tubes measuring 2 cm in length were
placed into the distal esophageal pouch of control animals (n = 2).
For the rst postoperative day, animals were started on a low residue
diet (TestDiet, Purina, Richmond, IN) and water, then advanced to a
regular diet. They were observed closely for signs of distress. Animal
weights were recorded weekly.
1.3. Tissue analysis
Euthanasia was performed after 28 days and gross tissue was examined. The length and circumference of the distal esophageal stump
were measured and recorded. The GEJ was examined for evidence of
stenosis. The native esophagus from each animal was also harvested
and measured for comparison. Tissues were xed in 10% zinc formalin
for 24 hours, then representative sections were sampled and embedded
in parafn blocks. Four-micrometer sections were mounted on slides
and stained with hematoxylin and eosin (H&E), Sirius red special
chemical stain, and immunohistochemical stains for smooth muscle

Fig. 1. Schematic representation of the surgical methods and procedure. P = distal esophageal pouch; S = spring device; A = esophagogastric anastomosis.

actin (SMA) and S100. Monoclonal mouse anti-SMA antibody (Cell


Marque Corp., Rocklin, CA), diluted at 1:3000 and polyclonal rabbit
anti S100 antibody (Cell Marque Corp., Rocklin, CA) diluted at 1:400
were visualized by horseradish immunoperoxidase staining using a
BenchMark XT automated immunohistochemistry/in situ hybridization
slide staining system (Ventana Medical Systems, Inc., Tucson, AZ) with
external controls. All four stains were performed following standard institutional operating procedures. All microscopic evaluation was performed under bright eld microscopy (Nikon Instruments, Inc.,
Melville, NY) and slides from at least 4 representative sections per tissue
block were examined. An initial unblinded analysis was followed by a
blinded review by a board certied anatomic pathologist. Histologic architecture was examined qualitatively on H&E stain. Degree of inammation seen on H&E, and degree of brosis seen on Sirius red stain
were graded semiquantitatively (none, mild, moderate, severe) with
comparison of lengthened to native esophagus. Muscularis mucosa
and muscularis propria thickness measurements were quantied
using microscopic length measurements of representative areas recorded
with the use of a reticle on anti-SMA antibody localized tissue. Anti-S100
localized ganglia cells counts were visualized under uorescent light
microscopy and recorded per unit area of submucosa and muscularis
propria as the number of cells per 5-m diameter high power eld
(HPF). At least 50 HPFs per sample were examined and then mathematically converted to a cell count per square millimeter.
1.4. Statistical analysis
Data were expressed as means standard deviations. Statistical signicance was determined using paired and unpaired Student's t-tests
where appropriate.
2. Results
All animals survived with an average weight gain of 164 57 grams
per day. The distal esophageal pouch of experimental animals increased
in length from 1.9 0.3 cm to 4.5 0.7 cm (p b 0.05) (Fig. 2). Control
animals had no signicant change in esophageal length (2.0 0 cm to
2.1 0.1 cm, p = 0.5). The native GEJ exhibited normal histology without evidence of stricture in all animals. Histologic examination of the
distal esophageal pouch revealed the presence of stratied squamous
esophageal epithelium and all layers of esophageal architecture were
present (Fig. 3). When comparing lengthened to native esophagus
there were no differences in the thickness of muscularis mucosa
(0.73 0.65 mm versus 0.65 0.19 mm, p = 0.78) or muscularis
propria (2.35 0.73 mm versus 2.53 0.74 mm, p = 0.42). Mechanically lengthened esophagus showed mild to moderate supercial inammation. Sirius red staining revealed a mild to moderate degree of
brosis in lengthened tissues. When comparing S100 immunohistochemical staining of lengthened to native esophagus, there were no

Fig. 2. Photographs of (A) initial placement of the device into the distal esophageal pouch
(P), and (B) lengthened distal esophagus 4 weeks after device placement.

Please cite this article as: Sullins VF, et al, A novel method of esophageal lengthening in a large animal model of long gap esophageal atresia, J
Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.011

V.F. Sullins et al. / Journal of Pediatric Surgery xxx (2015) xxxxxx

Fig. 3. Microscopic photographs of hematoxylin and eosin-stained (A) native and


(B) lengthened esophagus taken at 40 magnication. Numbers correspond to layers of
esophageal tissue: 1) squamous mucosa; 2) lamina propria; 3) muscularis mucosa; 4)
submucosa; 5) muscularis propria. Scale bars represent 1000 m.

differences in number of myenteric ganglia (4.7 1.0 cells/mm2 versus


4.4 1.1 cells/mm2 p = 0.47) or submucosal ganglia (3.1 1.8 cells/mm2
versus 3.8 1.8 cells/mm2 p = 0.41).
3. Discussion
The initial treatment of long gap EA involves gastrostomy tube
placement, proximal esophageal pouch decompression, and imaging
to estimate the magnitude of the gap between the proximal and distal
esophagus. Denitive surgical management is delayed to allow growth
of the esophagus with the patient's development. Existing lengthening
procedures attempt to capitalize on the increased rate of spontaneous
esophageal growth in the rst few months of life. Most management
strategies result in prolonged hospitalizations while patients are kept
nil per os, and patients may have signicant oral aversion.
Distraction enterogenesis has been investigated in multiple ways to
develop a feasible model for the treatment of SBS. Recent success using
an internally placed PCL spring to lengthen rat jejunum led us to investigate the potential for its use in pure EA [9]. The use of traction force on
esophageal tissue is the basis for esophageal lengthening techniques in
current clinical practice; however, all exhibit varying degrees of success
[1014]. The most widely used is the Foker technique, which involves
placement of intrathoracic traction sutures into each end of the atretic
esophagus with externalization through the chest wall [11]. The sutures
are serially pulled in opposite directions over 1014 days until the
esophageal ends approximate. Although it has allowed preservation of
the native esophagus in many patients, complications including traction
suture rupture, anastomotic leak, stricture, and gastroesophageal reux
requiring additional surgery are common and patients must endure
multiple thoracotomies [5,15]. Kimura describes lengthening by serial
translocation of a cutaneous cervical esophagostomy down the anterior
chest wall as the child grows [12]. Although this technique preserves
the patient's ability to swallow by allowing sham feeding, there is loss
of length from the proximal esophageal pouch each time the
esophagostomy is moved. Again, multiple procedures are required, the
time interval until denitive esophageal repair is lengthy, and most patients develop strictures and gastroesophageal reux disease requiring
fundoplication [16]. Furthermore, the successes of both Foker and
Kimura techniques are not consistent across all institutions. Upper and/
or lower pouch bougienage is performed by placement of a weighted
bougie into the pouch with application of manual pressure once or

twice daily for 612 weeks [10]. In addition to the aforementioned complications, this technique is associated with signicant patient discomfort
and pouch rupture may result in an emergency operation. Many other innovative techniques such as circular or spiral myotomy and use of magnets have also been described [13,14]. Electromagnetic bougienage was
initially promising however results have been difcult to replicate and
the accompanying machinery is cumbersome and expensive.
Currently, mechanical bougienage is the only commonly attempted
technique to apply internal force to the distal esophageal pouch.
While bougienage of the proximal pouch is widely practiced and technically simple to perform, access to the distal pouch is challenging and
must be performed under uoroscopy [10]. In addition to electromagnetic bougienage, some authors have reported successful lengthening
using transgastric hydrostatic pressure through a balloon catheter
[17,18]. Several case reports of the rare combination of pure EA and duodenal atresia describe a severely dilated and enlarged proximal duodenum, stomach and distal esophagus [1921]. Authors point out that
antenatal distention of the distal esophageal pouch permitted a
tension-free primary esophageal anastomosis. Another report described
creation of a tension-free anastomosis after lower pouch bougienage
alone in a patient with long gap EA [22].
The combined results of current esophageal lengthening techniques
and reports of past observations point to the distal esophageal pouch as
a target for potential lengthening techniques. It is easily accessed
through the stomach during initial gastrostomy tube placement and
placement of an internal lengthening device at that time would preclude entry into the chest before the denitive repair is performed. Currently, only murine models of EA/TEF exist but size constraints, inability
to survive beyond the neonatal period, and a lack of control over resultant phenotypes make these models inadequate for testing treatment
strategies for long gap EA [23,24].
Minipigs are the preferred large animal species for conducting translational research [25]. They are most ideal for surgical models because
they are comparable to humans in both size and physiology. Like dogs,
they are easy to feed but are more robust and can tolerate multiple survival surgeries. In fact, they are most often used to practice surgical technique
and test clinical devices. Specic to our model, minipigs demonstrate a
prominent gastric cardia allowing for a tension-free esophagogastric anastomosis and gastric ulceration owing to stress is rare. Minipigs are more
expensive than small animals to purchase and maintain, although the
cost is comparable to other large animals such as dogs. Another drawback
to this surgical model is that we observed signicant adhesion formation
after open surgery, particularly in proximity to the liver. These adhesions
may make additional surgeries more challenging.
With this in mind, we successfully created a large animal model of
long gap EA and used a degradable spring device to lengthen the distal
esophageal pouch. We observed a nearly 2.5-fold increase in length of
the distal esophagus while preserving the native architecture of the
esophagus. While this lengthening process took place over the course
of 4 weeks, one animal required early euthanasia owing to abscess formation and we found that the esophageal pouch had lengthened from
2.0 cm to 4.5 cm at 10 days. Therefore, we believe that the duration of
lengthening using our device may be signicantly shorter than current
treatment modalities. The time to esophageal lengthening in our
model has yet to be tested and will be the subject of future research.
Placement of an intraluminal device into the distal esophageal pouch
requires occlusion of the GEJ in order to secure it in place. In our model,
the use of a vessel loop placed around the esophagus at the GEJ proved
to be safe method of securing the device inside the distal esophageal
pouch and no strictures were seen. While occlusion of the GEJ may at
rst seem problematic, in practice it can assist with dilation or elongation. One report of a very low birth weight infant with EA and a distal
TEF demonstrated dilation of the distal esophageal segment after closure of the gastroesophageal junction to prevent reux when the stula
could not be accessed for ligation [26]. Enlargement of the distal end
allowed the surgeon to perform a primary repair with ease. This again

Please cite this article as: Sullins VF, et al, A novel method of esophageal lengthening in a large animal model of long gap esophageal atresia, J
Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.011

V.F. Sullins et al. / Journal of Pediatric Surgery xxx (2015) xxxxxx

demonstrates the clinical potential of mechanical stress applied to the


distal esophageal pouch.
Similar spring devices used to lengthen isolated segments of rat jejunum resulted in signicant thickening of the muscularis layers with decreased numbers of both submucosal and myenteric ganglia [6,9]. In our
model of esophageal lengthening, the thickness of the muscularis mucosa
and muscularis propria was similar to native esophagus and numbers of
ganglia were also preserved. The preservation of the muscularis thickness
and numbers of ganglia in lengthened esophageal tissue may be related to
the preservation of the GEJ and its continuity with the stomach. However,
experimental lengthening studies of rat jejunum that remains partly in
continuity also results in thickening of the muscularis layers with fewer
submucosal ganglia [27]. Mechanical stress applied to esophageal tissue
may induce different growth factors and subsequent tissue effects compared to intestinal tissue. The molecular mechanisms of esophageal tissue
lengthening should be the focus of further exploration.
As expected, mechanical lengthening induced a mild to moderate
degree of inammation and brosis. It is not clear what clinical implication these ndings may have, however when we used the same spring
device to mechanically lengthen rat jejunum, we observed some degree
of brosis. Although we did not specically quantify the degree of brosis, several histologic changes occurred after the lengthened intestinal
segment was restored into continuity and function of the lengthened
then restored segment was not altered [8]. On the contrary, lengthening
methods currently used in patients likely induce some inammation
and brosis that may contribute to the development of esophageal
dysmotility, GERD, and anastomotic stricture. Future studies should
investigate the motility and function of the mechanically lengthened
distal esophageal segment as well as the potential for anastomotic stricture
after restoring esophageal continuity.
It is also unknown what clinical signicance the numbers of submucosal and myenteric ganglia hold. However, esophageal dysmotility and
GERD are common after repair of EA. In a histologic analysis of neural elements of esophageal tissue in patients with pure EA there were similar
numbers of neurons per ganglia when compared to control specimens
[27,28]. The authors attributed some of the esophageal dysmotility seen
in pure EA to a denser brilar network and larger ganglia. Although we
have not performed functional studies on experimental tissue, it appears
that mechanical lengthening in our model does not destroy submucosal
or myenteric ganglia. While esophageal dysmotility in patients with pure
EA may not be worsened by mechanical lengthening, it is likely caused
by a combination of intrinsic neurologic dysfunction and damage to the
extrinsic innervation during mobilization and repair of the esophagus.
Although this study demonstrates that a spring device can be used to
lengthen the distal esophagus, other devices targeting the distal esophageal pouch may also be explored. Prior to the clinical use of such devices,
the mechanically lengthened segment must rst be restored into continuity. Function and motility testing must also be performed to ensure
feasibility of the device. As mentioned previously, further testing of
the spring device itself is necessary to determine the optimal time to
complete lengthening.
In summary, we created the rst large animal model of long gap EA
and used a degradable spring device to mechanically lengthen the distal
esophagus. Native esophageal architecture and histology were preserved during this process. This device may easily be inserted at the
time of gastrostomy tube placement. Our ndings support the use of
an internally placed lengthening device in the treatment of long gap
esophageal atresia.
Acknowledgments
We extend many thanks to Doug Steinberger for his assistance with
device fabrication, and Catalina Guerra and Jenny Dancourt for their assistance with anesthesia and animal care. This work was supported by
Sun West Company, LA Biomed and the Department of Pediatrics at
Harbor-UCLA Medical Center.

Appendix A. Discussions
Presenter: Veronica Sullins, MD (Los Angeles, CA)
Discussant: DR. RUSTY JENNINGS Boston, MA As you know, we're the
only center in the world who's absolutely committed to the
Foker process, and we'll be presenting a paper later. The question always arises are we stretching it like a rubber band,
making the distal and proximal esophagus thinner and less
viable, or are we growing it with all the normal layers that
are increasing in size with blood ow and nerves and mucosa.
So what do you think?
Response: DR. SULLINS That's a great question. Some of the studies that
we've done, at least in intestinal tissue, have shown that it actually grows. We looked at the amount of tissue present, the
growth factors, and actually measured some of those things,
both on the bench and also just microscopically looking at
the histology.
We haven't done the studies yet. That will be the topic of future study. But there's no reason to believe that this wouldn't
also be the case with esophageal tissue, in particular because
also the thicknesses, even though they're the same in intestinal tissue, they're a little bit thicker in the muscle layers as
well. But in esophageal tissue, it wasn't thinner. But, the number of subjects was also very low.
DR. JENNINGS I also want to commend you on coming up with a new
technique. The Foker process is a little crude, but everything
is FDA approved. So anything we can do to make it less invasive, techniques like this are certainly celebrated.
Discussant: DR. DANIEL VAN ALLMEN (Cincinnati, OH) It's a wonderful, interesting approach. Two questions; I had the same question Rusty had, but also what was the age of the pigs, and do
you think that that would potentially make a difference? And
second, people, including David van der Zee in Utrecht, The
Netherlands and others, have shown in the esophagus
and other people have shown in other tissues that
lengtheningor there's growth with tension, it's very rapid,
and you waited four weeks. Did you try anything earlier
than that, or is there a reason that you waited a month for
that lengthening to occur?
Response: DR. SULLINS So the mini-pigs were 8 to 10 kilos. They were
anywhere from eight to ten weeks old is my understanding. I
don't know if that makes a difference, the age of the pig. It certainly could, especially because this wasn't a genetic model.
This was a surgically created model, so we had to choose
mini-pigs that were about the same size or a little bit bigger
than neonates.
As to your second question, yes we did wait four weeks based
on the protocol that we used with the lengthening springs in
intestine. However, we know after exploration of a mini-pig
at seven to ten days that the lengthening actually occurs in
that period of time.

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Please cite this article as: Sullins VF, et al, A novel method of esophageal lengthening in a large animal model of long gap esophageal atresia, J
Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.011