[Image from University of Michigan Health Lab]
Hydrogels have been permeating medtech recently – with researcheres using them for tasks as varied as gluing detached retinas back together to stopping bleeding. Now, University of Michigan and Georgia Institute of Technology researchers are using the engineered polymeric material to heal intestinal damage caused by diseases like Crohn’s and ulcerative colitis.
A problematic method of growing stem cell clusters called organoids could be greatly improved by using hydrogels.
“Before, we were only able to grow mini-intestines in a matrix derived from a mouse tumor cell line,” Miguel Quiros Quesada, lead author of the study, said in a press release.
The composition of the matrix is variable and indeterminate, according to the research. The proteins could also have immunogenic, pathogenic and metastatic side effects if they are used in humans.
“We have shown that the hydrogel matrix helps the human intestinal organoids (HIOs) engraft into the intestinal tissue; they differentiate and accelerate the healing of the wound,” said Andrés J. García, professor in the Woodruff School of Mechanical Engineering at Georgia Tech. “This work provides a proof of principle for using stem cell-derived human intestinal organoids in a therapeutic setting.”
The researchers used hydrogels to form a matrix that can give HIOs a temporary structure while providing signals that allow cell clusters to differentiate and grow.
“The fully defined nature of these synthetic bioengineered hydrogels could make them ideal for use in human patients in the event that HIOs are used for therapy in the future,” Asma Nusrat, director of experimental pathology at the University of Michigan, said. “In this work, we demonstrated that the hydrogels facilitate the transplantation of HIOs into an injured intestine, suggesting that this technique has significant implications for treating intestinal injuries caused by diseases such as inflammatory bowel disease.”
The Georgia Tech-developed synthetic matrix uses an adhesive peptide and allows growing cells to cut through polymer crosslinks. It is able to be made consistently over and over again, independent of any cell line and with parts that can be characterized.
In the University of Michigan lab, researchers delivered the hydrogels with organoids into intestine wounds in immune-compromised animals using a tiny colonoscope. The cells were labeled so they could later be identified.
After four weeks, the HIOs completely engrafted into the wounds and created 3D structures. The hydrogels disappeared and were replaced by natural extracellular matrix that the cells made themselves.
“HIOs provide a powerful platform that recapitulates important features of the intestine — making them suitable to study normal and diseased tissue — and they are a potential tool for human therapy,” Jason Spence, associate professor of internal medicine at the University of Michigan Medical School, said. “These studies are proof of concept that HIOs embedded in the synthetic matrix might be used therapeutically to enhance mucosal wound repair in gastrointestinal diseases.”
Hydrogel properties can be modified to best fit the needs of the cells being hosted. The hydrogels used in the research were based on a four-armed, maleimide-terminated polyethylene glycol macromer that could support the expansion of HIOs and could support reproducible in vitro growth.
“Because our hydrogel system is modular, we can just plug in the peptide that is needed and alter other parameters to create the mechanical properties desired,” Ricardo Cruz-Acuña, graduate research assistant at Georgia Tech, said. “The specifics may be different for other cells intended for different applications.”
The researchers now hope to test their hydrogel matrix in animals that have a normal and healthy immune system and in disease models. They also hope to reduce the labor used to deliver the hydrogel material with HIOs. The researchers also add that research in larger animals would be needed before they could begin human trials.
Down the road, the researchers envision similar methods being used to repair damage in other organs, including the kidneys, lungs, liver and pancreas.
The research was published in the journal Nature Cell Biology.
