QUAD #14 Future in Bioengineering Solutions with Dr. Michael Helmrath

The lab has developed methods to grow from a single stem cell drawn from the blood the entire GI tract from the mouth to the anus.

The first bowel made roughly 11 years ago was small bowel, which was able to be transplanted into the animal.

Colon transplants into animals but not as well as small bowel, and the antral structures, esophagus and stomach did not and do not readily transplant into the animal.

When a single organoid is grown in a dish for roughly a month and put into an animal, it is fully laminated and looks no different than a biopsy.

The transplanted organoid represents the patient from whom the stem cells were derived.

Nerves are not present in the initial grafts, which are just mesenchyme and endoderm, but nerves can be added by adding to the dish.

When nerves are present in transplanted grafts, they cause the ingrowth of vasculature that is human, with endothelial progenitors in the graft responding to nerve signals.

Vascular growth with nerves is important for tissue engineering of the esophagus, requiring both vascular and nervous components.

Growing cells in a confined space to make a long tube resulted in nerves being co-developed by progenitors within the typical HIO without adding neurospheres externally.

Nerves formed in confined space culture are very similar to human controls.

Peristalsis starts in the cells of Cajal in the mesenchyme and is then affected and modulated by the nerve.

The grafts demonstrate regular peristalsis that can be externally stimulated, and nerve function can be blocked with TTX.

Relaxation of the grafts can be blocked by L-NAME.

The lab can separate HIO into endoderm (epithelium, the inside) and mesenchyme (the outside), recombine them, and the result is fully faithful to the original.

The mesenchyme from HIO can be combined with other endoderms, including colon endoderm.

In a rat model where bowel was damaged with hot EDTA and a brush, HIO fragments were placed inside the lumen, with somatic stem cells (epithelial only) as controls.

At seven days after transplantation, control cells showed minimal engraftment, while IPS-generated fragments showed both epithelial and mesenchymal engraftment with cells migrating and proliferating beyond the confined space.

At 10 weeks after transplantation, nearly the entire epithelium was human, with muscle cells aligned with existing rat cells and fully functional.

Cincinnati Children's was awarded funding for Organoid Cure to compile data for growing human intestine for patient transplantation and obtain FDA approval.

The team has developed a hydrogel that polymerizes when exposed to UV light, acting like glue to hold tissue in place without killing cells, allowing cells to migrate out.

The first clinical step is tissue agnostic, with intestinal transplants serving as a tool to gather information.

Esophageal strictures are very applicable to this therapy, and Dr. Helmrath anticipates using this therapy in patients this decade.