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Reuters Health recently featured this article on "Tissue-Engineered Colon"
which leads one to consider possible new novel approaches to treating
celiac disease and refractory sprue. You may need to register (free) with
Medscape to read this article:

Tissue-Engineered Colon Looks and Acts Like Real Intestine
http://www.medscape.com/viewarticle/459635

Replace your intestine?  Maybe not.  But replacing sections of the
intestine in a refractory sprue patient might restore enough intestinal
function to allow oral nutrition in place of total parenteral nutrition
(TPN) for seriously affected patients.  Perhaps one can even replace the
intestine or portions of it with one that is unaffected by gluten.

Also, a study on genetically engineered intestinal cells to produce isulin
for diabetics suggests that intestinal cells could be engineered and
permanently implanted in the intestine either to secrete enzymes to
breakdown gluten peptides into harmless entities or to secrete chemicals to
prevent T cell activation by gluten epitopes.  This could essentially be
a "cure" for CD.

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Biochem Biophys Res Commun. 2003 Apr 4;303(2):645-52.

Development of genetically engineered human intestinal cells for regulated
insulin secretion using rAAV-mediated gene transfer.

Tang SC, Sambanis A.

School of Chemical Engineering, Georgia Tech-Emory Center for the
Engineering of Living Tissues, and P.H. Petit Institute for Bioengineering
and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.

Cell-based therapies for treating insulin-dependent diabetes (IDD) can
provide a more physiologic regulation of blood glucose levels in a less
invasive fashion than daily insulin injections. Promising cells include
intestinal enteroendocrine cells genetically engineered to secrete insulin
in response to physiologic stimuli; responsiveness occurs at the exocytosis
level to regulate the acute release of recombinant insulin. In this work,
we established a human cellular model to demonstrate that meat hydrolysate
can simultaneously stimulate glucagon-like peptide-1 (GLP-1, an
enteroendocrine cell-derived incretin hormone) and recombinant insulin
secretion from the engineered human NCI-H716 intestinal cell line. Cells
were genetically modified using the recombinant adeno-associated virus
(rAAV)-mediated insulin gene transfer. Recombinant cells were then
differentiated to display endocrine features, in particular the formation
of granule-like compartments. A fusion protein of insulin and enhanced
green fluorescence protein (EGFP) was designed to reveal the compartments
of localization of the fusion protein and assess its co-localization with
endogenous GLP-1. Our work provides a unique human cellular model for
regulated insulin release through genetic engineering of GLP-1-secreting
intestinal cells, which is expected to be useful for cell-based therapies
of IDD.

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Ann Surg. 2003 Jul;238(1):35-41.

Tissue-engineered large intestine resembles native colon with appropriate
in vitro physiology and architecture.

Grikscheit TC, Ochoa ER, Ramsanahie A, Alsberg E, Mooney D, Whang EE,
Vacanti JP.

Department of Surgery, Center for the Integration of Medicine and
Innovation in Technology, Massachusetts General Hospital, 55 Fruit Street,
Boston, MA 02114, USA.

OBJECTIVE: Novel production and in vitro characterization of tissue
engineered colon. SUMMARY BACKGROUND DATA: The colon provides important
functions of short chain fatty acid production, sodium and water
absorption, and storage. We report the first instance of tissue-engineered
colon (TEC) production from autologous cells and its in vitro
characterization. METHODS: Organoid units, mesenchymal cell cores
surrounded by a polarized epithelia derived from full thickness sigmoid
colon dissection from neonatal Lewis rats, adult rats, and tissue
engineered colon itself, were implanted on a polymer scaffold into the
omentum of syngeneic hosts. TEC was either anastomosed at 4 weeks or
excised for Ussing chamber studies or histology, immunohistochemistry, and
terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-
digoxigenin nick end labeling assay. RESULTS: TEC was generated by 100% of
all animals without regard to tissue source, the first instance of
engineered intestine from adult cells or an engineered tissue. TEC
architecture is identical to native with muscularis propria staining for
actin, acetylcholinesterase detected in a linear distribution in the lamina
propria, S100-positive cells, ganglion cells, and a terminal
deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin
nick end labeling assay similar to native colon. Ussing chamber data
indicated in vitro function consistent with mature colonocytes, and a
positive short circuit current response to theophylline indicating intact
ion transfer. TEM showed normal microarchitecture. Colon architecture was
maintained in anastomosis with gross visualization of fluid uptake.
CONCLUSIONS: TEC can be successfully produced with fidelity to native
architecture and in vitro function from neonatal syngeneic tissue, adult
tissue, and TEC itself.

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Transplantation. 2002 Sep 15;74(5):619-23.

Tissue-engineered small intestine: ontogeny of the immune system.

Perez A, Grikscheit TC, Blumberg RS, Ashley SW, Vacanti JP, Whang EE.

Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.

BACKGROUND: Using tissue-engineering techniques, we have developed a
neointestine that regenerates structural and transporter properties of
native jejunum. The purpose of this study was to characterize the mucosal
immune system of the engineered neointestine. We hypothesized that the
neointestinal mucosa is capable of developing a mature immunocyte
population and that exposure to luminal stimuli is critical to this
development. METHODS: Neointestinal cysts were engineered by implanting
polymer-organoid constructs into syngeneic adult recipients. Neointestine
(cysts left nonanastomosed [NA] and cysts anastomosed to native bowel [AN])
and native jejunum were harvested serially (3-56 weeks postoperatively).
Immune cell subsets were characterized by the immunohistochemical detection
of cell-specific antigens (T cells [CD3], B cells [CD32], NK cells [CD56],
and macrophages [CD68]) combined with computer-based morphometry. RESULTS:
Intraepithelial and lamina propria immunocyte population densities and
subset distributions were identical in AN cysts harvested 20 weeks
postoperatively and in native jejunum. Mucosal immunocyte population
densities were lower in AN cysts harvested 10 weeks postoperatively and
only rudimentary in NA cysts, even those harvested 20 weeks
postoperatively. CONCLUSIONS: These results suggest that tissue-engineered
intestine has the capacity to develop a mucosal immune system with an
immunocyte population similar to that of native small intestine. The
development of this immune system is a function of both exposure to luminal
stimuli and the duration of this exposure. Tissue-engineered intestine
offers promise as a new therapeutic approach for patients who have
intestinal insufficiency.

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Continued in Part 2

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