Changxue Xu's research is critical to the development of 3-D organ printing.
The survival of any living tissue, whether it's small in size or forms a complex network like a vital organ, depends on the delivery of vital nutrients and oxygen to survive. The thicker the tissue, and it could be by only a few hundred microns, the more vital a vascular structure becomes.
Researches are hard at work around the world trying to develop viable, transplantable replacement organs using 3-dimensional printing as a way to solve the shortage of donor organs, whether it's lungs, heart, kidneys or any other organ that can fail. But in order for 3-D organs to function properly, they have to have a strong vascular network that can deliver the vital nutrients necessary for their survival.
That is what Changxue Xu has been focused on for the last several years. An assistant professor in the Department of Industrial, Manufacturing and Systems Engineering in the Edward E. Whitacre Jr. College of Engineering at Texas Tech University, Xu has dedicated his research to the manufacturing of living cells and tissues through 3-D bioprinting that can be used to develop a living, working vascular network, possibly able to replace blood vessels in humans and animals.
“If part of the blood vessel is damaged, for whatever reason, it's very difficult to just rely on the body itself to recover intact,” Xu said. “You have to replace the entire part of the blood vessel. What we do is collect some cells from the patient, then culture the cells. That way there is no issue with immune rejection. We culture these cells and then we can use the cells from the patient to print this vascular structure and use it for transplantation.
“Another application is for drug delivery. If we can fabricate this vascular network, then we can be very efficient in using this for drug delivery. We can then use nanoparticles to study the permeability of the blood vessel to see what kind and size of particles can go through the blood vessel.”
While practical application of this research is still a way off, it might be a little closer than most think, thanks to Xu and fellow researchers' dedication to development of the manufacturing process.
3-D bioprinting technology
Several factors go into the ability to effectively print a 3-D structure of a living organism, and many of the usual 3-D printing technologies are not viable.
The printing of biological structures uses a different type of ink than what is used in most 3-D printing. Bioink is the combination of biological materials and living cells that have been cultured to form this printing material. But because living cells are suspended in the bioink, most of the normal methods of 3-D printing can't be used because they heat the ink to a temperature of 100 degrees or more, which kills the cells.
Other printing methods use lasers, which also are damaging to the cells in the bioink. Therefore, the most common method of printing with bioink, including what Xu uses, is inkjet printing, utilizing a printing nozzle with a piezoelectric actuator.
“We use a small signal to stimulate this actuator, and then this actuator will deform and eject some of the bioink out,” Xu said. “We can control the following deposition process. We also use microextrustion, which uses pressure to push the fluid out, and we use stereolithography, which uses a very low ultraviolet (UV) light and a very low concentration of photo initiator to process quality material to use for cell encapsulation.”
Through inkjet bioprinting, Xu is able to more easily control the microspheres that contain bioink. The microspheres then are ejected to form a two-dimensional pattern that becomes one layer. Then, numerous following layers are fabricated and stacked together to form a 3-D structure.
Time depends on the size of the vascular structure, but Xu said an average one can be fabricated in about 15 minutes.
But the bioink is only one aspect of the printing process. Xu has done extensive research into the manufacturing technology and processes themselves to develop the most optimal method for fabricating a vascular structure.
For inkjet printing, there are two methods used for fabricating a 3-D structure – Drop on Demand (DOD) and Continuous Inkjet (CIJ). In both cases, the ink is ejected through a printing nozzle to form a jet, but that's where the similarities stop.
With CIJ, the ejection of ink from the jet is continuous, which allows for less control of the ink, and the jet, Xu said, will eventually break up due to instability. DOD printing gives the researcher much more control as to the placement and intensity of the ink droplets. Plus, DOD reduces the chance for contamination of the ink.
Printing the vascular structure is only one step in the process. In order for it to be a viable alternative for use in transplantation or drug delivery, it's got to function like a blood vessel as well.
Because the material used for 3-D printing of vascular structures is very soft, it absorbs water very easily, and that causes an increase in weight that leads the vessel to collapse. So part of Xu's research involves studying the mechanical properties of the fabricated structure to analyze the stress strength of certain sections.
Vascular structures that have been printed both horizontally and vertically have presented different challenges when it comes to strength. Vertical printing has resulted in the collapse or buckling of vascular structures if there is no supporting material, like a scaffolding. For horizontal printing, the structure could collapse if the material strength is not enough.
That is where the second step of the fabrication process comes into play – testing it through fluid dynamics.
“Basically, we use fluid that could be considered like blood and put it through the fabricated structure to simulate blood,” Xu said. “Also, we control the pressure of the fluid, and it is not continuous. It is like blood pressure effects and it has a pulse. Then, we study how the cells and biological materials interact.”
If researchers can find areas where the strength of the vascular structure is not sound enough, they can then adjust the printing process for future attempts. It helps identify which areas in a vascular structure might have the most need for additional material support.
“Eventually, we can build this very beautiful shape without collapse,” Xu said. “That is based on the theoretical data and analytical calculations, and it incorporates that into our experiment design to try to compensate for the deformation.”
Hope for the future
Xu and his collaborators in the Texas Tech University Health Sciences Center are working tirelessly to bring this technology to use as a practical application. And though the path to being able to use 3-D printed blood vessel structures is still a way off, the attention the technology is drawing is a good sign for its future viability.
In addition to his work at Texas Tech, Xu also is collaborating with a researcher at the University of Central Florida among others on a proposal for a company called Microfab, which Xu said is the only company in North America working on inkjet printing of biological constructs.
As Xu continues to experiment with the different manufacturing technologies associated with 3-D printing, he hopes to soon begin working toward practical application of the technology, specifically starting with implantation of vascular structures in animals and then humans. That could result in a tremendous milestone in the evolution of medicine and engineering.
“It is a very promising technology and will have more and more applications as it develops, especially some commercial applications, hopefully very soon,” Xu said. “We're working to try to improve the technology and patent it, and then we can push our research into commercial production.”