To make a new intestinal mucosa

A number of clinical conditions are caused by disorders affecting the mucosal lining of the gastrointestinal tract. Some patients suffer from a loss of mucosal surface area due to congenital defects or due to surgical resections ("short bowel syndrome"). Other patients have inborn or acquired defects of certain mucosal functions (e.g., glucose-galactose malabsorption, bile acid malabsorption). Many patients with these mucosal disorders could be more effectively treated if healthy mucosa were available in larger quantities as a replacement or functional supplement. We therefore developed methods to transplant mucosal stem cells from one part of the intestine to another and to make bioengineered intestinal mucosa. We generated an animal model of bile acid malabsorption using rats that underwent resection of the distal 25% of their small intestine (ileum). This resulted in significant losses of bile acids with the fecal excretions in these animals. We subsequently harvested ileal stem cell clusters from neonatal donors, removed the mucosa from a segment of proximal intestine (jejunum), and implanted the stem cell clusters into the debrided segment of jejunum. After four weeks, the animals had developed a functional "neomucosa." We inserted the "neo-ileal" segment into continuity as a substitute ileum. Postoperative measurements of fecal bile acid excretion showed that we were able to reverse the malabsorption syndrome in this model. This was the first reported neo-mucosa-based treatment of a malabsorption syndrome in vivo. We subsequently studied different biodegradable PGA and PLLA scaffoldings to generate bioengineered intestinal mucosa. We implanted these materials into omentum of rats and were able to identify a PGA/PLLA hybrid material on which engraftment rates of 36% of the available surface area could be achieved. Most recently, we developed a novel technique that permits direct observation of cell-biomaterial interactions after implantation into omentum or intestine in vivo. This method will help to optimize engraftment conditions for stem cell clusters on biomaterials.