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Continued From Part 1

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J Surg Res. 1999 Nov;87(1):6-13.

Effects of anastomosis of tissue-engineered neointestine to native small
bowel.

Kim SS, Kaihara S, Benvenuto MS, Choi RS, Kim BS, Mooney DJ, Vacanti JP.

Department of Surgery, Harvard Medical School and Children's Hospital,
Boston, Massachusetts, USA.

BACKGROUND: Our laboratory is investigating the tissue engineering of small
intestine using intestinal epithelial organoid units seeded onto highly
porous biodegradable polymer matrices. This study investigated the effects
of anastomosis of tissue-engineered intestine to native small bowel alone
or combined with small bowel resection on neointestinal regeneration.
METHODS: Intestinal epithelial organoid units harvested from neonatal Lewis
rats were seeded onto biodegradable polymer tubes and implanted into the
omentum of adult Lewis rats as follows: (1) implantation alone (n = 9); (2)
implantation followed by anastomosis to native small bowel at 3 weeks (n =
11); and (3) implantation after small bowel resection and anastomosis to
native small bowel at 3 weeks (n = 8). All constructs were harvested at 10
weeks and examined by histology. Morphometric analysis of the neomucosa was
obtained using a computer image analysis program. RESULTS: Cyst development
was noted in all animals. All anastomoses were patent at 10 weeks.
Histology revealed the development of a vascularized tissue with a
neomucosa lining the lumen of the cyst with invaginations resembling crypt-
villus structures. Morphometric analysis demonstrated significantly greater
villus number, villus height, crypt number, crypt area, and mucosal surface
length in groups 2 and 3 compared with group 1, and significantly greater
villus number, villus height, crypt area, and mucosal surface length in
group 3 compared with group 2 (P < 0.05, ANOVA, Tukey test). CONCLUSION:
Intestinal epithelial organoid units transplanted on biodegradable polymer
tubes can regenerate into complex tissue resembling small intestine.
Anastomosis to native small bowel combined with small bowel resection and
anastomosis alone contribute significant regenerative stimuli for the
morphogenesis and differentiation of tissue-engineered neointestine.
Copyright 1999 Academic Press.

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Tissue Eng. 1999 Aug;5(4):339-46.

End-to-end anastomosis between tissue-engineered intestine and native small
bowel.

Kaihara S, Kim S, Benvenuto M, Kim BS, Mooney DJ, Tanaka K, Vacanti JP.

Department of Surgery, Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts 02114, USA.

The purpose of this study was to demonstrate the feasibility of end-to-end
anastomosis between tissue-engineered intestine and native small bowel and
to investigate the effect of this anastomosis on their growth. Microporous
biodegradable polymer tubes were created from a fiber mesh of polyglycolic
acid sprayed with 5% polylactic acid. Intestinal epithelial organoid units
were harvested from neonatal Lewis rats and seeded onto polymers. These
constructs were implanted into the omentum of adult Lewis rats. Three weeks
after the implantation, the constructs (n = 7) were anastomosed to the
native jejunum in an end-to-end fashion. Ten weeks after implantation, the
tissue-engineered intestine was harvested. Four of 7 rats survived for 10
weeks and the overall patency rate of the anastomosis was 78% (11 of 14
anastomosis). The maximal length of the tissue-engineered intestine at week
3 and 10 was 1.80 +/- 0.32 and 1.93 +/- 0.39 cm (mean +/- SD).
Histologically, the tissue-engineered intestine was lined with a well-
developed neomucosal layer that was continuous with the native intestine.
We conclude that anastomosis between tissue-engineered intestine and native
small bowel had a moderately high patency rate and had a positive effect on
maintenance of the size of the neointestine and development of the
neomucosa.

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Transplantation. 1999 Jan 27;67(2):241-5.

Successful anastomosis between tissue-engineered intestine and native small
bowel.

Kaihara S, Kim SS, Benvenuto M, Choi R, Kim BS, Mooney D, Tanaka K, Vacanti
JP.

Department of Surgery, Children's Hospital & Harvard Medical School,
Boston, Massachusetts 02115, USA.

BACKGROUND: Previous work from this laboratory has shown that isolated
intestinal epithelial organoid units on porous biodegradable polymer
scaffolds formed vascularized cysts lined by a neomucosa. The purpose of
this study was to demonstrate anastomosis between tissue-engineered
intestine and the native small bowel and to observe the effect of this
anastomosis on cyst growth. METHODS: Intestinal epithelial organoid units
from neonatal Lewis rats were seeded onto porous biodegradable polymer
tubes made of polyglycolic acid, and they were implanted into the omentum
of adult male Lewis rats. Three weeks after implantation, the unit-polymer
constructs were anastomosed in a side-to-side fashion to the native jejunum
in 20 rats (group 1). The other 18 rats were closed without anastomosis
(group 2). All 38 tissue-engineered constructs were harvested 10 weeks
after implantation. Four rats underwent upper gastrointestinal (GI) study
before they were killed. RESULTS: The rats in group 1 increased their body
weights equal to those in group 2, and there was no statistically
significant difference between the two groups. Upper GI examinations
revealed no evidence of either bowel stenosis or obstruction at the
anastomotic site. Grossly, the patency of the anastomosis was 90% and the
lumen of the cyst was visualized by the upper GI study. At the second
operation, there was no significant difference in the size of the cysts in
either group: however, at the time the rats were killed, the length of the
cysts in group 1 was significantly longer than that in group 2 (P<0.05
using Mann-Whitney U test). Histological examination showed that cysts
after anastomosis were lined by a neomucosa in continuity to native small
bowel across the anastomotic site and also demonstrated crypt-villus
structures. Morphometric study demonstrated that cysts in group 1 had
significantly greater villus number, height, and surface length than did
those in group 2. CONCLUSIONS: Anastomosis between tissue-engineered
intestine and native small bowel resulted in no complications after the
operation, kept a high patency rate, and maintained mucosal continuity
between the tissue-engineered intestine and native small bowel.
Furthermore, anastomosis had a positive effect on cyst size and development
of the mucosa in the tissue-engineered intestine.

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Transplantation. 1999 Jan 27;67(2):227-33.

Regenerative signals for intestinal epithelial organoid units transplanted
on biodegradable polymer scaffolds for tissue engineering of small
intestine.

Kim SS, Kaihara S, Benvenuto MS, Choi RS, Kim BS, Mooney DJ, Taylor GA,
Vacanti JP.

Department of Surgery, Children's Hospital and Harvard Medical School,
Boston, Massachusetts, 02115, USA.

BACKGROUND: Our laboratory is investigating the tissue engineering of small
intestine using intestinal epithelial organoid units seeded onto highly
porous biodegradable polymer tubes. This study investigated methods of
stimulation for optimizing neointestinal regeneration. METHODS: Intestinal
epithelial organoid units harvested from neonatal Lewis rats were seeded
onto porous biodegradable polymer tubes and implanted into the omentum of
adult Lewis rats in the following groups: (1) the control group (group C),
implantation alone (n=9); (2) the small bowel resection (SBr) group, after
75% SBr (n=9); (3) the portacaval shunt (PCS) group, after PCS (n=8); and
(4) the partial hepatectomy (PH) group, after 75% PH (n=8). Neointestinal
cyst size was recorded using ultrasonography. Constructs were harvested at
10 weeks and were examined using histology. Morphometric analysis of the
neomucosa was obtained using a computer image analysis program (NIH Image,
version 1.59). RESULTS: Cyst development was noted in all animals. Cyst
lengths and diameters were significantly larger in the SBr group at 7 and
10 weeks compared with the other three groups (P<0.05; analysis of variance
[ANOVA], Fisher's protected least significant difference). Histology
revealed a well-vascularized tissue with a neomucosa lining the lumen with
invaginations resembling crypt-villus structures. Morphometric analysis
demonstrated a significantly greater villus number, height, area, and
mucosal surface in the SBr group compared with the other three groups and a
significantly greater crypt number and area in the PCS group compared with
group C (P<0.05; ANOVA, Fisher's protected least significant difference).
CONCLUSIONS: Intestinal epithelial organoid units transplanted on porous
biodegradable polymer tubes can successfully vascularize, survive, and
regenerate into complex tissue resembling small intestine. SBr and, to a
lesser extent, PCS provide significant regenerative stimuli for the
morphogenesis and differentiation of tissue-engineered small intestine.

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