A team of Lawrence Livermore National Laboratory researchers and their external partners recently created what they’re calling the first living, 3D-printed brain aneurysm to ever exist outside of the human body—and they witnessed it react and mend following a medical procedure conducted to repair it.
Cerebral aneurysms are essentially thin points on a brain artery that bulge out and fill up with blood. They can be deadly if they rupture and are difficult to treat, but those involved in this work believe it could yield a novel testbed for surgical training and pave the way for innovative new healing options.
“By the end of it, we’re aiming to help build a computational model a neurosurgeon can turn to in order to help them decide their best course of action for treating a life-threatening brain aneurysm,” William “Rick” Hynes, an LLNL staff research engineer and the initial principal investigator for the work, recently told Nextgov via email.
Hynes came up with the original idea for the bioprinted aneurysm, and he and the project’s current principal investigator, LLNL biomedical engineer Monica Moya, detailed the promise the development holds for the future, and exactly how the experimental, “living” aneurysm device really came to life.
“I often remind my family members that the field of medicine is more art than science,” Moya explained. “While medicine is supposed to be scientific, its practice is very much an art.”
Producing and Treating the Aneurysm
Brain aneurysms, according to LLNL’s release on the work, come from a weakening in blood vessel walls and can be fatal if they burst. Roughly one in every 50 Americans are affected by them, but treatments can be invasive and their outcomes generally differ for each individual person.
Reflecting on the root of the current effort, Hynes explained that it all traces back to the moment he was approached by colleagues who asked if he could think up a method to help validate a computational model intended to simulate and predict the clotting response to aneurysm coiling treatments, in support in one of the researcher’s Ph.D work. When employing the coiling approach as a remedy, surgeons essentially feed catheters into the groin and up the body and into the aneurysm, and then pack it with coils that cause it to clot and eventually become safely walled off.
“After some thought, discussion, and research,” Hynes said he rapidly came to the conclusion that those he was working with were not the only researchers who needed help in validating their computational aneurysm models. “In fact, it represented a major capability gap in the field, with many groups facing this same issue, since the current best method is the use of animal models, which are less than ideal for numerous reasons,” he explained.
Hynes saw an opportunity to adapt a vascular printing process he was tapping into for a completely unrelated project—one aimed at predicting cancer metastasis to the brain led by Moya—to see if it could potentially be reworked for printing artificial aneurysms that might be well- suited for benchmarking computational simulations.
“One night, when I was done with my experiments for the day, I just decided ‘Why not?’ and gave the idea a try,” he said. When his first test demonstrated it could be “a successful research avenue,” he quickly contacted a former lab computational scientist at Duke University who made a code for simulating blood flow and another former LLNL scientist at Texas A&M who runs a company behind an experimental shape memory coil for treating aneurysms, to discuss it all. They both went on to become collaborators, and Hynes submitted a proposal to an internal lab-wide funding competition.
After that, as he put it, they “were off to the races.”
The work is financially backed by the Laboratory Directed Research and Development program, the release confirms, and the results were recently published in the journal, Biofabrication.
Hynes, Moya and their team replicated an aneurysm in vitro by 3D printing blood vessels with human cells sourced from science research product provider Cedarlane.
“To break it down a bit, it’s more of a combination of printing and molding process where we first cast a thin hydrogel that functions as the base layer of the device,” Hynes explained. “Then a sacrificial ink is printed onto this base layer in the shape of the aneurysm and its connecting vascular channels.”
After that, they casted another layer of the same hydrogel, “encapsulating the printed structure, which is then allowed to crosslink.” From there, the whole device was cooled so that the “sacrificial” material liquified and could be gently suctioned out of the device—“leaving its shape behind in the now solid piece of hydrogel.”
Endothelial cells form a walled layer called an endothelium, which is basically a tissue that lines blood vessels and other inner-parts of the body. A little further down the line, the team used a syringe to inject a solution of such cells, which Hynes noted were “suspended in cell growth media” and enabled them to attach to the walls of the vessels and new aneurysm “dome.” He said the “device is then connected to our perfusion system and cultivated for several days under flowing growth media, allowing the cells to grow and divide, eventually forming a fully confluent endothelium.”
The dome of the living aneurysm created for the experiments presented in the paper was designed to have a diameter of 3.6 mm, with the vessel leading toward it having a diameter of 2.4 mm, while the vessels leading away from the aneurysm were 1.8 mm in diameter.
“Typically, aneurysms in the body that are likely to require medical intervention are about twice this size and don’t tend to be this symmetrical in appearance,” Hynes noted, adding that the device used in this case was meant to be of an “idealized” aneurysm shape and is smaller in size to make initial flow measurements and computational modeling more tractable.
Still, he confirmed that the team “can, and will, print a great variety of different aneurysm geometries and sizes using this process as we move forward to further challenge the more complex predictions generated by modeling simulations.”
As for the object’s color, the engineer noted that the vessels produced in the process appear to be off-white and are semi-transparent due to heavy cell growth along the vessel walls.
“They don’t superficially resemble the color of vessels in the body as you might encounter them during surgery, since there is no blood present within them, but if you were to remove a blood vessel from a patient, rinse it well and fill it with clear fluid, they would look very similar to our printed vessels,” he explained.
Once the device completely took shape, Hynes went on to perform a coiling procedure on it that LLNL said is “believed to be the first surgical intervention ever performed on an artificial living tissue.” The researchers involved saw the endothelium start to improve eight days after.
“If you have an idea that you might first think is crazy, but also could possibly work, don’t hesitate to run it down and give it an honest go,” Hynes said. “It’s always better to know it’s a failure, rather than never knowing its potential.”
What This Might Mean for Medicine
The research and unfolding outcomes could one day drive forward both how doctors decide to—and ultimately treat—brain aneurysms. In fusing the 3D-printed platform with computational models, the team thinks this could mark the beginning of an innovative tool through which surgeons can pre-select the best coil types to use on particular aneurysms to garner the best effects, as well as test run operations before attempting them on human patients.
Generally, to verify computational models of aneurysms, scientists will often induce them in animals, and then perform surgery. The lab’s newly developed platform offers a possibly enhanced means for validating those computational models.
Hynes made it a point to note that such models sparked the very conception of all this work and are really at the heart of it. He added the team works incredibly close with the researchers at Duke to “regularly tap into their vast knowledge of physiological flow dynamics” and continuously tune both the living aneurysm device—while also helping the university officials to evaluate the accuracy of their advanced flow models.
“We can then go back and forth, performing an experiment, modeling the experiment, and comparing the results of each to help develop a clearer picture of biological events neither can capture completely on their own,” Hynes said. “The relationship is very symbiotic, and it’s something the field of tissue engineering should be striving for more and more as we continue into the future.”
Next steps of the work are unfolding, and a lot has to happen before this can all be applied in clinical environments. But in pairing both the model and 3D bioprinted aneurysm, researchers also have high hopes to help clinicians better predict the outcome of their potential approaches.
Moya likened it all to how tech giant Amazon works.
“They know what I will want to buy next, or the next book I will enjoy because they’ve developed incredible algorithms based on my data, what I spend on and what I read,” she explained. “We want to essentially use this living aneurysm to create the datasets needed to build up a computational model that could have the predictive capability that Amazon has—but for medical outcomes.”
Though clinical data could be tapped as part of the involved data stream, the living aneurysm platform allows for boosted feedback, and a mechanism to assess the prediction, which Moya noted is critical in developing these computer models.
“It’s not enough to just tell Amazon what I like—they have to make recommendations that I then try out and provide feedback on what they predicted I would like,” she said.
Putting it another way, Hynes further iterated that the team intends for the research to serve as a solid groundwork for the creation of a highly advanced, patient-specific predictive computational model that can inform aneurysm-centered surgical treatments. When treating the ailments, doctors frequently only have very small windows of time when they can act, and “simulations like these can help [them] make very challenging decisions” in those fast-pace, serious moments, or “in situations where choosing the wrong treatment option could make the situation worse,” he noted.
When the work is all completed, Hynes hopes to see a next-level computational model that can be used to shed light on people’s unique, individual aneurysm cases. A patient’s brain scan and clinical data would be uploaded into that future model, which would then simulate the person’s blood flow dynamics before the treatment, the clot formation as it is likely to proceed in response to the surgery, and the resulting blood flow dynamics after the treatment is complete
“By enabling clinicians to play out a variety of different treatment methods and predict their outcomes before the patient even arrives for treatment, the model we’re envisioning will enable neurosurgeons to give their patients the best personalized treatment and the best possible result,” Hynes said.