Researchers can create functional organ tissue in small quantities, building few-millimeter-sized structures known as organoids. Yet because there is still no reliable approach to the creation of the capillary networks required to support thick tissue sections, this cannot yet scale up to the production of full-size replacement organs. That may not be a roadblock for organs such as the liver and kidney, which are responsible for what are essentially chemical manufacture and filtration tasks; in this case the large-scale structure of the organ isn't as important as the small-scale structure, and much of the organ might be thought of as countless tiny factories operating independently in response to circumstances. The arrangement of those factories can vary.
Thus it should be possible to rescue a failing liver or kidney by transplanting scores or hundreds of functional organoids grown from the patient's own cells. The organoids will integrate with the existing tissue, and blood vessel networks will growth into and through them - that much has been demonstrated in animal studies for single organoids in a number of different organs. The only challenge standing in the way of this vision for the near future is the cost and time required to create organoids, a process that has yet to be scaled up for mass manufacture.
Researchers report creating a biologically accurate mass-production platform that overcomes major barriers to bioengineering human liver tissues suitable for therapeutic transplant into people. The new process allows researchers to bioengineer single batches of up to 20,000 genetically matched, three-dimensional and highly functional liver micro-buds. When combined, the batch has a sufficient quantity of liver cells and size feasibility for transplant into a person with liver failure, or for drug testing. The liver tissues were also generated entirely from human induced pluripotent stem cells (iPSCs), making the process free of animal feeder byproducts used to make cells for research purposes - a barrier to the cells being used therapeutically.
"Because we can now overcome these obstacles to generate highly functional, three-dimensional liver buds, our production process comes very close to complying with clinical-grade standards. The ability to do this will eventually allow us to help many people with final-stage liver disease." The researchers stress continued research and refinement of their process is required before initial clinical trials could begin, and estimate this might occur in the next two to five years.
Over the past five years the reseearch published several studies that made continuous progress into defining the precise genetic and molecular blueprints needed to mimic natural human development. This allows the researchers to develop and bioengineer functional, three-dimensional human mini livers in the laboratory. To help overcome the biological challenge of animal-product feeder cells in the current study, the team used their fine-tuned formula of genetic and molecular components to generate the liver tissues in custom-designed, U-shaped bottom micro-well cell plates. The plates use a combination of chemistry techniques to form a finely structured film inside the micro-wells, designed to nurture the developing liver buds.
But prior to this step, the researchers started mass production by initially using the donor-derived iPSCs to grow three critical types of liver progenitor cells needed to generate healthy livers. These include hepatic endoderm cells and both endothelial and septum mesenchyme cells. Study data show this generates robust and highly functional progenitor cells that are placed into the custom-designed, film-coated micro-wells. The progenitor cells then engage in high levels of molecular cross-communication to form into self-organizing, three-dimensional liver buds.