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January 18, 2021
Imagine going to a surgeon to have a diseased or injured organ changed for a fully functional, lab-grown replacement. This remains science fiction and not reality because researchers today find it difficult to organize cells in complex 3D arrangements that our bodies can master on their own.
There are two major hurdles to overcome in the way of laboratory-grown organs and tissues. The first is to use a biologically compatible 3D scaffold in which cells can grow. The second is to decorate this scaffold with biochemical messages in the correct configuration to trigger the formation of the desired organ or tissue.
In a major step towards turning that hope into reality, researchers at the University of Washington have developed a technique to modify natural biological polymers with protein-based biochemical messages that affect cellular behavior. Their approach, published the week of Jan. 18 in the Proceedings of the National Academy of Sciences, uses a near infrared laser to trigger the chemical adhesion of protein messages to a scaffold made from biological polymers such as collagen, a connective tissue. found throughout our body.
Mammalian cells responded as expected to protein signals adhered to the 3D scaffold, according to lead author Cole DeForest, UW associate professor of chemical engineering and bioengineering. The proteins present on these biological scaffolds triggered changes in the messaging pathways in cells that affect cell growth, signaling, and other behaviors.
These methods could form the basis of biological scaffolds that could one day make functional lab-grown tissue a reality, said DeForest, who is also a faculty member at UW Molecular Engineering and Sciences Institute and UW Institute. for Stem Cell and Regenerative Medicine. .
“This approach gives us the opportunities we have been waiting for to exert better control over the function and fate of cells in naturally occurring biomaterials – not only in three-dimensional space but also over time,” said DeForest. “In addition, it uses exceptionally precise photochemistry that can be controlled in 4D while uniquely preserving protein function and bioactivity.”
DeForest colleagues on this project are lead author Ivan Batalov, former UW postdoctoral researcher in chemical engineering and bioengineering, and co-author Kelly Stevens, UW assistant professor of bioengineering and medicine and pathology. laboratory.
Their method is a first in the field, spatially controlling cell function within natural biological materials as opposed to those that are synthetically derived. Several research groups, including DeForest, have developed light-based methods to modify synthetic scaffolds with protein signals. But natural biological polymers may be a more attractive scaffold for tissue engineering because they naturally possess biochemical characteristics that cells rely on for structure, communication, and other purposes.
“A natural biomaterial like collagen inherently includes many of the same signaling signals found in native tissue,” DeForest said. “In many cases, these types of materials keep cells ‘happier’ by providing them with signals similar to those they would encounter in the body.”
They worked with two types of biological polymers: collagen and fibrin, a protein involved in blood clotting. They each assembled in fluid-filled scaffolds called hydrogels.
The signals the team added to the hydrogels are proteins, one of the primary messengers in cells. Proteins come in many forms, all with their own unique chemical properties. As a result, the researchers designed their system to use a universal mechanism to attach proteins to a hydrogel – the bond between two chemical groups, an alkoxyamine and an aldehyde. Prior to assembly of the hydrogel, they decorated the collagen or fibrin precursors with alkoxyamine groups, all physically blocked by a “cage” to prevent the alkoxyamines from reacting prematurely. The cage can be removed with ultraviolet light or a near infrared laser.
Using methods previously developed in DeForest’s lab, the researchers also installed aldehyde groups at one end of the proteins they wanted to attach to the hydrogels. They then combined the aldehyde-carrying proteins with the alkoxyamine-coated hydrogels and used a brief pulse of light to remove the cage covering the alkoxyamine. The exposed alkoxyamine readily reacted with the aldehyde group on the proteins, attaching them to the hydrogel. The team used masks with cutout patterns, along with modifications to laser scanning geometries, to create intricate patterns of protein arrangements in the hydrogel – including an old UW logo, the Seattle Space Needle, a monster and the 3D layout of the human. heart.
The attached proteins were fully functional, delivering the desired signals to the cells. Rat liver cells – when loaded onto collagen hydrogels containing a protein called EGF, which promotes cell growth – showed signs of DNA replication and cell division. In a separate experiment, the researchers decorated a fibrin hydrogel with motifs of a protein called Delta-1, which activates a specific pathway in cells called Notch signaling. When they introduced human bone cancer cells into the hydrogel, cells in the Delta-1 patterned regions activated Notch signaling, while cells in the non-Delta-1 areas did not.
These experiments with multiple biological scaffolds and protein signals indicate that their approach could work for almost all types of protein signals and biomaterial systems, DeForest said.
“We can now begin to create hydrogel scaffolds with many different signals, using our understanding of cell signaling in response to specific protein combinations to modulate critical biological function in time and space,” he added.
With more complex signals loaded onto the hydrogels, scientists could then try to control stem cell differentiation, a key step in turning science fiction into scientific reality.
The research was funded by the National Science Foundation, the National Institutes of Health, and Gree Real Estate.
For more information, contact DeForest at [email protected].
Tag (s): Cole DeForest • College of Engineering • Department of Bioengineering • Department of Chemical Engineering • Institute of Stem Cells and Regenerative Medicine • Institute of Molecular Engineering and Sciences • School of Medicine
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