Zev J. Gartner, Ph.D., and his team of researchers at the University of California in San Francisco have developed a new tissue modelling technique that has allowed them to create precise 3D shapes out of living human and mouse tissues that could potentially be used in regenerative medicine.
Over the past few years, significant advances have been made in 3D bioprinting. Scientists have managed to print shapes out of living cells which could be potentially be used in vivo, but there are limitations to what can be printed. Bioprinting fully functional living tissues with all the structural features of the tissues they are attempting to recreate is still extremely problematic.
One area where bioprinting falls down is the creation of folding patterns in tissues, which can play an important role in the functioning of the tissue. The researchers explain in the paper that “Tissue folds are a widespread and crucially important structural motif because they contribute to tissue function in adults.”
Growing tissues in vitro that incorporate these naturally occurring folding structures is a major challenge for tissue engineers. “Folding is difficult to control in vitro because it emerges from spatially patterned cell dynamics that span micro- to millimeter scales.”
However, the researchers believe they have solved these issues and have created a range of complex 3D shapes. The researchers used thin layers of extracellular matrix (ECM) fibers and patterned mechanically active cells into the ECM. The cells are able to interact with each other through the fibers, and in response to stresses and strains applied by the researchers, the team was able to mimic the natural folding process seen in development in vivo.
“Tissue folding derives from a mismatch in strains between two adjacent tissue layers, which in vertebrate embryos are often an epithelium and the underlying ECM in a loose connective tissue layer known as the mesenchyme,” explained the researchers.
Compressive and tensile stresses can act across entire organ systems, or smaller areas of tissues. The team studied tissues in vivo to determine how they developed and folded, such as the folding of the gut to create villi, and identified mechanisms that they were able to incorporate into their patterning technology.
One mechanism studied was the condensation of mesenchymal cells, which generates the strains required to produce curves and folds in developing tissues in vivo. The researchers then used these mechanisms to guide their patterning process along a defined trajectory, allowing them to create a wide range of different 3D shapes.
“The process requires cell contractility, generates strains at tissue interfaces, and causes patterns of collagen alignment around and between condensates… We demonstrate the robustness and versatility of this strategy for sculpting tissue interfaces by directing the morphogenesis of a variety of folded tissue forms from patterns of mesenchymal condensates,” wrote the authors.
“By breaking the complexity of development down into simpler engineering principles, scientists are beginning to better understand, and ultimately control, the fundamental biology,” said Gartner, “In this case, the intrinsic ability of mechanically active cells to promote changes in tissue shape is a fantastic chassis for building complex and functional synthetic tissues.”
The new tissue modeling technique is detailed in the paper –Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme.- published in the journal Developmental Cell.