We’ve seen 3D printable biomaterials before, but never any like the ones engineers at Rhode Island-based Brown University have been working on. They have developed a technique to make 3D printed biomaterials that are able to quickly degrade on demand. The research team made the degradable structures, which could have applications in making dynamically changing cell cultures and microfluidic devices with detailed patterns, using a stereolithography (SLA) 3D printing process. A biocompatible chemical trigger is used to degrade away the temporary structures.
Ian Wong, an assistant professor with Brown’s School of Engineering, explained, “It’s a bit like Legos. We can attach polymers together to build 3-D structures, and then gently detach them again under biocompatible conditions.”
[Image: Wong Lab, Brown University]
Wong and the other researchers wanted to work on making structures with ionic bonds that could be reversible, which has never been accomplished before with light-based 3D printing – SLA typically uses photoactive polymers that link together with strong, but irreversible, covalent bonds. The team used precursor solutions with sodium alginate, which is a compound derived from seaweed. Alginate, which can manage ionic crosslinking, has been combined with 3D printing technology before to fix bone defects, to improve hydrogel 3D printing, and to treat microtia; now, the team from Brown has shown that the compound can be used with SLA printing.
“The idea is that the attachments between polymers should come apart when the ions are removed, which we can do by adding a chelating agent that grabs all the ions. This way we can pattern transient structures that dissolve away when we want them to,” said Wong.
They also used multiple combinations of ionic salts, like barium, calcium, and magnesium, to make structures that had different levels of stiffness, which could be dissolved at various rates. The researchers published a paper on their work, titled “Stereolithographic Printing of Ionically-Crosslinked Alginate Hydrogels for Degradable Biomaterials and Microfluidics,” in the journal Lab on a Chip; co-authors include Thomas M. Valentin, Susan E. Leggett, Po-Yen Chen, Jaskiranjeet K. Sodhi, Lauren H. Stephens, Hayley D. McClintock, Jea Yun Sim, and Wong. The Department of Education, the National Institutes of Health (NIH), Brown University’s Hibbitt Postdoctoral Fellowship, and the Center for Cancer Research and Development at Rhode Island Hospital all supported the Brown University team’s research.
The abstract explains, “3D printed biomaterials with spatial and temporal functionality could enable interfacial manipulation of fluid flows and motile cells. However, such dynamic biomaterials are challenging to implement since they must be responsive to multiple, biocompatible stimuli. Here, we show stereolithographic printing of hydrogels using noncovalent (ionic) crosslinking, which enables reversible patterning with controlled degradation. We demonstrate this approach using sodium alginate, photoacid generators and various combinations of divalent cation salts, which can be used to tune the hydrogel degradation kinetics, pattern fidelity, and mechanical properties. This approach is first utilized to template perfusable microfluidic channels within a second encapsulating hydrogel for T-junction and gradient devices. The presence and degradation of printed alginate microstructures were further verified to have minimal toxicity on epithelial cells. Degradable alginate barriers were used to direct collective cell migration from different initial geometries, revealing differences in front speed and leader cell formation.”
Fabrication steps for agarose microfluidic channels. 3% alginate with 1:3 Ba2+: Mg2+ was SLA-printed in a 35 mm diameter Petri dish, and washed with DI water. Alginate template
structures were encapsulated in molten 1.5% agarose, and allowed to cool to form a hydrogel. Reservoirs were biopsy-punched and the alginate degraded with 100 mM EDTA. The source channel was filled with 0.2% Evans Blue and the sink channel with DI water.
The innovative research led the team to discover several different ways that temporary alginate structures could be of use, such as using them as templates for lab-on-a-chip devices that contain “complex microfluidic channels.”
Valentin, the study’s lead author and a PhD student in Wong’s lab at Brown, said, “It’s a helpful tool for fabrication.”
“We can print the shape of the channel using alginate, then print a permanent structure around it using a second biomaterial. Then we simply dissolve away the alginate and we have a hollow channel. We don’t have to do any cutting or complex assembly.”
In addition, the degradable structures made of alginate can also be used to make “dynamic environments” in order to run experiments using live cells, and the researchers demonstrated this by running multiple experiments that used human mammary cells to surround alginate barriers. When the barrier was fully dissolved, they then observed how exactly the cells migrated; this would be helpful when considering how to study cells migrating in cancer or wound-healing processes. As there was no “appreciable toxicity to the cells” in either the alginate barrier or the chelating agent that dissolves it, the researchers deduced that these types of experiments could work using degradable alginate barriers.
The researchers also explained that due to the alginate’s biocompatibility, it would be an ideal material for making artificial organ and tissue scaffolds as well.
Time-lapse video shows an intricately printed Brown logo dissolving away after the application of a biocompatible chemical trigger (speed 300X real time).
Wong said, “We can start to think about using this in artificial tissues where you might want channels running through it that mimic blood vessels. We could potentially template that vasculature using alginate and then dissolve it away like we did for the microfluidic channels.”
Experiments with the team’s degradable alginate structures will continue, and the researchers will focus next on fine-tuning the pace of degradation, as well as the structures’ stiffness and strength properties.
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[Source/Images: Brown University]