ByDeborah Balthazar Dec. 7, 2023
Imagine getting surgery without ever being cut open. Researchers at Duke University and Harvard Medical School have successfully demonstrated a proof of concept in new research published Thursday in Science using a 3D printer that uses ultrasound to print biomaterials inside an organ.
Growing up, Junjie Yao, a bioengineer at Duke University and one of the primary investigators of the study, had heard stories about scientists coming up with great ideas over coffee or while chatting in the break room, but he never thought that would happen to him. About three years ago, Yao, and his co-primary investigator Yu Shrike Zhang, who have been friends and collaborators since their grad school days, were talking casually at an industry conference about big problems in their field. This included how to break the limit of bioprinting technologies used to create thinks like engineered tissue, flexible electronics, or medical devices.
They continually came across the same obstacle: most 3D printing technologies utilize light to transfigure the ink into a hard structure, which must be printed externally or on a set surface. This was thought to be unworkable for producing items intended to be minimally invasive, according to the experts.
In instances where surgeons wish to utilize 3D printed tissues, the dual challenge is that light does not permeate solid objects and the need for surgery to insert the printed structure. “This really is the limitation of existing bioprinting technology,” noted Yao. His team of researchers devised the concept of a printer employing ultrasound waves, which can traverse farther through non-transparent materials. Additionally, they had to design an ink that can be hardened using sound.
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“Therefore, we’re creating this ultrasound printer that utilizes ultrasound waves to convert the sono-ink—developed in Shirke’s lab—into three-dimensional structures right within the tissue itself, eliminating the need for extraction and reimplantation,” Yao informed STAT. This emerging technology, known as deep-penetrating acoustic volumetric printing, heralds a vast range of potential medical applications.
Yao, with a background in ultrasonic imaging, and his team developed a 3D printer that embodies a dedicated ultrasound transducer. This transducer can transform electrical energy into sound waves. Moreover, these waves can be controlled remotely to pass through tissue and create any structure, such as a honeycomb, a tube, or even an irregular figure like a patch, layer by layer.
Zhang, a biomaterials scientist, who is also an associate bioengineer at Brigham and Women’s Hospital and an associate professor at Harvard Medical School, produced an “ink cocktail.” This mixture is composed of different elements or a “concoction of polymers, particles and chemical initiators” that respond to sound waves. Depending on whether the ink needed to have bone-like characteristics or be as flexible as heart tissue, its constituents were altered. For the purpose of testing the principle, the researchers inserted the ink into several pig organs to check its functionality inside real tissue.
The unused ink that remains unactivated by the ultrasound will continue to be fluid, Yao informed STAT. The surplus liquid could either be cleaned out by the tissue itself or it could be removed using a catheter or a syringe.
The team of researchers successfully printed a bone-like structure through 10mm of pig skin and muscle, simulating bone reconstruction. Additionally, they showcased a feasible treatment method for atrial fibrillation by printing a patch on an ex vivo heart’s left atrial appendage. They filled the ink with a chemotherapy drug and printed it through a 14mm-thick pig liver.
“The innovative implementation of ultrasound to gel the materials so deep within the organ with a technology as non-invasive as ultrasound, which has marginal side effects, was exceptional,” says Adam Feinberg, a Carnegie Mellon University professor specializing in biomedical engineering and material science. Feinberg, an uninvolved party in the study, hails the research as a “unique” technological application.
Currently, the ink does not constitute tissue, and that might suffice. Intrinsic regenerative capacities are prevalent in numerous human body tissues, which might only require a scaffold to guide them appropriately. “Bone, muscle, fat tissue—these body parts are probably already equipped with the right cells; we just have to create the conducive environment,” Feinberg explained, referencing his previous research that used a collagen scaffold that required implantation. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine in North Carolina, suggests the technology could potentially be used to print other materials like medical devices or alternative drug delivery methods in the future.
Although the research shows promise, the researchers faced several challenges throughout the project.
One of the key challenges, according to Yao, was achieving “a balance between efficient printing and tissue safety.” Everyone is familiar with the photothermal effect or when you get a sunburn. Yao explained that the ink molecules can convert the ultrasound wave into heat, which is called the sonothermal effect and can lead to a “soundburn,” damaging tissue in the process if the temperature goes above 70 degrees Celsius. “So, how much temperature rise is tolerable, is safe, is compatible for the patient? That’s something we have to really pay attention to because we do want the printing process to be as efficient as possible,” Yao said.
Xuanhe Zhao, a professor of mechanical, civil and environmental engineering at the Massachusetts Institute of Technology, agreed. “While the biocompatibility and printing resolution of the method requires further improvement, there is great potential for future applications,” Zhao said by email. He was not part of the study.
Another concern raised is that since the sono-ink must be injected at high concentrations inside of the body, it may cause toxicity. Feinberg added that once this technology is tested in vivo, or in the body, there might be some regulatory hurdles with the biomaterials being used and how it could be regulated by the Food and Drug Administration.
“If you’re repurposing materials already used in vivo, that’s usually a much lower bar than if you’re introducing new materials that have never been in vivo in this kind of indication,” Feinberg said. In the future, he added that he expects 3D printed tissue scaffolds (printed outside the body) to be in clinical trials within the next five years. In June 2022, the regenerative medicine company 3DBio Therapeutics started Phase 1/2a clinical trials using an implantable living tissue scaffold to reconstruct the ears of people with congenital ear deformity.
Yao envisions a not-so-distant future where medical procedures are characterized by a heightened level of technology. He pictures patients set up comfortably on tables or chairs, while a robotic arm, wielding an ultrasound transducer, follows an exact pre-programmed pattern. Overseen remotely using artificial intelligence, precision is ensured. In place of traditional methods, the ‘ink’ is applied via catheter or small syringe.
Yao stresses the significance of the innovations at hand, notably the absence of the need for surgical impact. This reduction in the surgeon’s involvement will lead to fewer patient complications, such as inflammation, infections, and extended recovery periods.
Atala, sharing Yao’s enthusiasm, praises the potential the technology holds. He describes it as the integration of device manufacturing and therapy within the body, all conducted via remote control.
For Yao, this research stands out as the pinnacle of his career. According to him, the convergence of enthusiasm for the field, active conversations, and an open exchange of ideas sparking innovation. It highlights the importance of social gatherings like coffee breaks in catalyzing creative thinking.
Sharon Begley Science Reporting Fellow
Deborah Balthazar is the 2023-2024 Sharon Begley Science Reporting Fellow at STAT.
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“Why did the 3D printer go to therapy? Because it had too many layers of unresolved issues!”
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