Alginate-enhanced gel improves organoid development

Miniature organs grown in the lab can organize themselves into complex shapes. But they never do it the same way twice, which makes it hard to use these so-called 'organoids' to study disease. 

Now, scientists at UC San Francisco have created a new material that helps organoids grow in a more predictable way. They mixed microparticles of alginate, a complex carbohydrate derived from algae, into Matrigel, the standard gel used to grow organoids. This made the gel more akin to the soft but supportive environment inside the body that tissues normally grow in. 

It also enabled the team to 3D print stem cells into precise shapes in petri dishes before they began to mature. The organoids developed better and more consistently. The improved growing conditions could one day help with the manufacture of replacement tissues. 

"What turned out to matter most was how the material relaxes over time - something we call stress relaxation," said Zev Gartner, PhD, professor of Pharmaceutical Chemistry at UCSF and senior author of the paper, which was published in Nature Materials on Mar. 10. "It needs to give way at the same pace that tissues are reshaping themselves." 

Scientists have long imagined using printers to arrange stem cells into balls or tubes - like 3D printing, but for living tissue. It's already used to make flat sheets of skin and collagen for reconstructive surgery. But it doesn't work in Matrigel. 

"Liquid Matrigel is too runny to print into, and once it solidifies, it pushes back too much," said Austin Graham, PhD, a postdoctoral fellow in Gartner's lab who is the first author of the paper. "We wanted a material that lets us place cells exactly where we want them but still allows them to grow and organize themselves." 

The team considered how tissues develop naturally in embryos, where they push and pull on their surroundings as they grow. If the environment is too rigid, development stalls. If it's too fluid, development veers off course. 

Mixing alginate microparticles with liquid Matrigel made a wet sand-like material that supported stem cells that were printed in lines or clumps. This gave these cells a consistent shape and size to build on. As they cells grew, the material loosened its grip, allowing the organoids to expand and fold into more natural forms. 

The team tested the method with several organoid-forming tissues, including mouse intestinal and salivary gland cells, human vascular cells, and human stem-cell–derived brain cells. Printed clusters grew into healthy organoids and often matured by sprouting developmental buds. Intestinal cells that were printed in long lines formed tubes that could carry fluid, much like the human intestine. 

Rather than constructing tissues piece by piece, the method leverages the cells' natural abilities. 

We're not building tissues like Legos. We place cells where they need to be and let their developmental programs assemble the tissue. The goal is to reach a stage where an organ begins to build itself." 

Zev Gartner, PhD, Professor of Pharmaceutical Chemistry, UCSF