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discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/267893885
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6 authors, including:
Peter K Traum
Samuel W French
4 PUBLICATIONS 7 CITATIONS
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James C Y Dunn
Steven L Lee
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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.
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.
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
Fig. 1. Schematic representation of the surgical methods and procedure. P = distal esophageal pouch; S = spring device; A = esophagogastric anastomosis.
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
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
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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Pediatr Surg (2015), http://dx.doi.org/10.1016/j.jpedsurg.2015.03.011
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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