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3D printing of living responsive devices

(Nanowerk Spotlight) Most 3D-printing applications today are using 'dead matter' such as thermoplastics, resins or metals. However, by embedding bacteria in a biocompatible and functionalized 3D printing ink, researchers already have demonstrated the ability to print 'living materials' capable of degrading pollutants and of producing medically relevant bacterial cellulose (read more: "3D-printed living minifactories").
Now, researchers at MIT's Soft Active Materials Laboratory, led by Professor Xuanhe Zhao, have demonstrated a new paradigm in 3D-printing by using genetically programmed living cells as active components to print living materials and devices.
As the team reports in Advanced Materials ("3D Printing of Living Responsive Materials and Devices"), the living cells are engineered to light up in response to a variety of stimuli. When mixed with a slurry of hydrogel and nutrients, the cells can be printed, layer by layer, to form three-dimensional, interactive structures and devices.
These printed large-scale (3 cm) high-resolution (30 µm) living materials accurately respond to signaling chemicals in a programmed manners. The design of the 3D-printed structures is guided by quantitative models accounting for cell responses and chemical diffusion in matrices.
"3D-printed architectures of programmed cells will not only mimic highly organized, time-evolving biological constructs, but also provide new functions as living responsive materials and devices," Xinyue Liu, the paper's first author, tells Nanowerk.
There is a growing body of research that exploits living cells as active components for instance for tissue-engineered soft robotics (read more: "Biohybrid robots built from living tissue start to take shape") or a breathing lung-on-a-chip.
"However, nearly most of these works focus on extracting the cells from nature without any genetic editing," notes Liu. "Our previous work on stretchable devices (PNAS, "Stretchable living materials and devices with hydrogel–elastomer hybrids hosting programmed cells") adopted genetically programed bacteria; we followed this up with the current paper where we demonstrate using 3D-printing to fabricate large-scale high-resolution living devices."
"Besides, our technique can fabricate more complicated macro geometries and more precise microstructures due to the rheological and mechanical properties of the ink materials, leading to more interesting functions," she adds.
There are two main challenges for 3D printing of living responsive devices. The first and most important one is how to keep them alive and responsive. For instance, researchers have tried to use live mammalian cells, but with little success. Because mammalian cells are basically lipid bilayer balloons, they easily get damaged during processing and die.
In contrast, bacterial cells have tough cell walls that are able to survive relatively harsh conditions, such as the forces applied to ink as it is pushed through a printer’s nozzle. Furthermore, bacteria, unlike mammalian cells, are compatible with most hydrogels, which provides an aqueous environment that can keep them alive.
The second challenge is how to 3D-print programmed cells into macroscopic structures with high precision, i.e. high-resolution printing. To that end, the MIT team developed a quantitative model to predict the spatiotemporal response of the living materials.
"We developed a recipe for our 3D ink, using a combination of bacteria, a hydrogel with pluronic acid, and nutrients to sustain the cells and maintain their functionality," says Liu. "With this ink formula we can print at a high resolution of about 30 micrometers per feature."
The 3D printing procedure itself consists of two steps: 1) direct writing of multiple hydrogel inks with various types of cells and chemicals using nozzle diameters between 30 and 200 µm, and 2) ultraviolet curing of the printed constructs.
To demonstrate the capability of printing large-scale and complex structures with multimaterial inks, Zhao's team printed various 3D architectures including a cuboid, a pyramid, a dome, and hollow pyramids.
High printability of the hydrogel ink into large-scale, high-resolution structures with chemicals and bacterial cells
Optical images of various architectures generated by 3D printing, including (from left to right) a cuboid, a pyramid, a dome, and hollow pyramids. Red color denotes hydrogel ink with rhodamine B, and green color denotes hydrogel ink with fluorescein (scale bars 5 mm). (Reprinted with permission by Wiley-VCH Verlag) (click on image to enlarge)
"The 3D printing of living materials and devices enables us to explore novel functions, including logic gates, spatiotemporally responsive patterning, and wearable devices," Zhao points out. "With the rapid development in synthetic biology, single cells have now been engineered to have new functions such as logic, memory, oscillator, and classifier."
To enable multicellular logic and guide signaling transmission for cell–cell communication, the researchers print multiple types of cells and chemicals into 3D architectures and allow communication between different cell types to follow the well-defined networks of hydrogel matrices, thus achieving logic gates in the 3D-printed living materials and devices.
"Each cell in the structure performs a simple computational operation," adds Liu. "However, combined with their spatial distributions in the 3D architectures, the interactions among different cell types and chemicals in different regions can induce the emergence of informative patterns and achieve complex logic operations."
To demonstrated their technique's potential, the researcher printed a 'living tattoo' for chemical detection on human skin. The tattoo is printed with live bacteria cells as a tree-like pattern on a thin elastomer layer, which is then adhered to human skin.
Each branch of the tree is lined with cells sensitive to a different chemical or molecular compound. When the patch is adhered to skin that has been exposed to the same compounds, corresponding regions of the tree light up in response.
3D-printed living tattoo for chemical detection on human skin
3D-printed living tattoo for chemical detection on human skin. The design of the living tattoo. The tattoo is printed as a tree-like pattern on a thin elastomer layer, which is then adhered to human skin. Hydrogels with different colors illustrate the different types of cells encapsulated. Inset: Schematic illustration of living sensors embedded in the tattoo, which can respond to different chemicals by emitting fluorescence. (Reprinted with permission by Wiley-VCH Verlag)
Going forward, the team plans to pursue realistic biomedical applications. "Along this line, it is intriguing to envision a robust and personalized implant in which different cell types are programed to monitor inflammatory biomarkers and release growth factors to promote angiogenesis," says Liu. "Further, new ingestible devices based on our 3D printing of living materials may be able to modulate the gut microbiota and treat microbe mediated disease such as obesity and diabetes."
"The integrative technology of 3D living printing has the potential to be used as a general platform where a range of genetically programed cells (for example, cells with therapeutic production), matrices (for example, biodegradable hydrogels), and structures (for example, a cartilage shape) can be applied to design more customized living materials and devices with predictable dynamic functionalities," Zhao concludes.
By Michael is author of two books by the Royal Society of Chemistry: Nano-Society: Pushing the Boundaries of Technology and Nanotechnology: The Future is Tiny. Copyright © Nanowerk

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