Organoids are miniature organs that can be grown in the lab from a person’s stem cells. They can be used to model diseases, and in the future could be used to test drugs or even replace damaged tissue in patients.
But currently organoids are very difficult to grow in a standardized and controlled way, which is key to designing and using them. EPFL scientists have now solved the problem by developing a patent-pending “hydrogel” that provides a fully controllable and tunable way to grow organoids. The breakthrough is published in Nature.
Organoids need a 3D scaffold
Growing organoids begins with stem cells — immature cells that can grow into any cell type of the human body and that play key roles in tissue function and regeneration. To form an organoid, the stem cells are grown inside three-dimensional gels that contain a mix of biomolecules that promote stem cell renewal and differentiation.
The role of these gels is to mimic the natural environment of the stem cells, which provides them with a protein- and sugar-rich scaffold called the “extracellular matrix”, upon which the stem cells build specific body tissues. The stem cells stick to the extracellular matrix gel, and then “self-organize” into miniature organs like retinas, kidneys, or the gut. These tiny organs retain key aspects of their real-life biology, and can be used to study diseases or test drugs before moving on to human trials.
But the current gels used for organoid growth are derived from mice, and have problems. First, it is impossible to control their makeup from batch to batch, which can cause stem cells to behave inconsistently. Second, their biochemical complexity makes them very difficult to fine-tune for studying the effect of different parameters (e.g. biological molecules, mechanical properties, etc.) on the growth of organoids. Finally, the gels can carry pathogens or immunogens, which means that they are not suitable for growing organoids to be used in the clinic.
A hydrogel solution
The lab of Matthias Lütolf at EPFL’s Institute of Bioengineering has developed a synthetic “hydrogel” that eschews the limitations of conventional, naturally derived gels. The patent-pending gel is made of water and polyethylene glycol, a substance used widely today in various forms, from skin creams and toothpastes to industrial applications and, as in this case, bioengineering.
Nikolce Gjorevski, the first author of the study, and his colleagues used the hydrogel to grow stem cells of the gut into a miniature intestine. The functional hydrogel was not only a goal in and of itself, but also a means to identify the factors that influence the stem cells’ ability to expand and form organoids. By carefully tweaking the hydrogel’s properties, they discovered that separate stages of the organoid formation process require different mechanical environments and biological components.
One such factor is a protein called fibronectin, which helps the stem cells attach to the hydrogel. Lütolf’s lab found that this attachment itself is immensely important for growing organoids, as it triggers a whole host of signals to the stem cell that tell it to grow and build an intestine-like structure. The researchers also discovered an essential role for the mechanical properties, i.e. the physical stiffness, of the gel in regulating intestinal stem cell behavior, shedding light on how cells are able to sense, process and respond to physical stimuli. This insight is particularly valuable – while the influence of biochemical signals on stem cells is well-understood, the effect of physical factors has been more mysterious.
Because the hydrogel is man-made, it is easy to control its chemical composition and key properties, and ensure consistency from batch to batch. And because it is artificial, it does not carry any risk of infection or triggering immune responses. As such, it provides a means of moving organoids from basic research to actual pharmaceutical and clinical applications in the future.
Lütolf’s lab is now researching other types of stem cells in order to extend the capacities of their hydrogel into other tissues.
Learn more: Taking miniature organs from lab to clinic
Biocompatible fibers could use light to stimulate cells or sense signs of disease
Researchers from MIT and Harvard Medical School have developed a biocompatible and highly stretchable optical fiber made from hydrogel — an elastic, rubbery material composed mostly of water. The fiber, which is as bendable as a rope of licorice, may one day be implanted in the body to deliver therapeutic pulses of light or light up at the first sign of disease.
The researchers say the fiber may serve as a long-lasting implant that would bend and twist with the body without breaking down. The team has published its results online in the journal Advanced Materials.
Using light to activate cells, and particularly neurons in the brain, is a highly active field known as optogenetics, in which researchers deliver short pulses of light to targeted tissues using needle-like fibers, through which they shine light from an LED source.
“But the brain is like a bowl of Jell-O, whereas these fibers are like glass — very rigid, which can possibly damage brain tissues,” says Xuanhe Zhao, the Robert N. Noyce Career Development Associate Professor in MIT’s Department of Mechanical Engineering. “If these fibers could match the flexibility and softness of the brain, they could provide long-term more effective stimulation and therapy.”
Getting to the core of it
Zhao’s group at MIT, including graduate students Xinyue Liu and Hyunwoo Yuk, specializes in tuning the mechanical properties of hydrogels. The researchers have devised multiple recipes for making tough yet pliable hydrogels out of various biopolymers. The team has also come up with ways to bond hydrogels with various surfaces such as metallic sensors and LEDs, to create stretchable electronics.
The researchers only thought to explore hydrogel’s use in optical fibers after conversations with the bio-optics group at Harvard Medical School, led by Associate Professor Seok-Hyun (Andy) Yun. Yun’s group had previously fabricated an optical fiber from hydrogel material that successfully transmitted light through the fiber. However, the material broke apart when bent or slightly stretched. Zhao’s hydrogels, in contrast, could stretch and bend like taffy. The two groups joined efforts and looked for ways to incorporate Zhao’s hydrogel into Yun’s optical fiber design.
Yun’s design consists of a core material encased in an outer cladding. To transmit the maximum amount of light through the core of the fiber, the core and the cladding should be made of materials with very different refractive indices, or degrees to which they can bend light.
“If these two things are too similar, whatever light source flows through the fiber will just fade away,” Yuk explains. “In optical fibers, people want to have a much higher refractive index in the core, versus cladding, so that when light goes through the core, it bounces off the interface of the cladding and stays within the core.”
Happily, they found that Zhao’s hydrogel material was highly transparent and possessed a refractive index that was ideal as a core material. But when they tried to coat the hydrogel with a cladding polymer solution, the two materials tended to peel apart when the fiber was stretched or bent.
To bond the two materials together, the researchers added conjugation chemicals to the cladding solution, which, when coated over the hydrogel core, generated chemical links between the outer surfaces of both materials.
“It clicks together the carboxyl groups in the cladding, and the amine groups in the core material, like molecular-level glue,” Yuk says.
The researchers tested the optical fibers’ ability to propagate light by shining a laser through fibers of various lengths. Each fiber transmitted light without significant attenuation, or fading. They also found that fibers could be stretched over seven times their original length without breaking.
Now that they had developed a highly flexible and robust optical fiber, made from a hydrogel material that was also biocompatible, the researchers began to play with the fiber’s optical properties, to see if they could design a fiber that could sense when and where it was being stretched.
They first loaded a fiber with red, green, and blue organic dyes, placed at specific spots along the fiber’s length. Next, they shone a laser through the fiber and stretched, for instance, the red region. They measured the spectrum of light that made it all the way through the fiber, and noted the intensity of the red light. They reasoned that this intensity relates directly to the amount of light absorbed by the red dye, as a result of that region being stretched.
In other words, by measuring the amount of light at the far end of the fiber, the researchers can quantitatively determine where and by how much a fiber was stretched.
“When you stretch a certain portion of the fiber, the dimensions of that part of the fiber changes, along with the amount of light that region absorbs and scatters, so in this way, the fiber can serve as a sensor of strain,” Liu explains.
“This is like a multistrain sensor through a single fiber,” Yuk adds. “So it can be an implantable or wearable strain gauge.”
The researchers imagine that such stretchable, strain-sensing optical fibers could be implanted or fitted along the length of a patient’s arm or leg, to monitor for signs of improving mobility.
Zhao envisions the fibers may also serve as sensors, lighting up in response to signs of disease.
“We may be able to use optical fibers for long-term diagnostics, to optically monitor tumors or inflammation,” he says. “The applications can be impactful.”
“Hydrogel fibers are very interesting and provide a compelling direction for embedding light within the human body,” says Fiorenzo Omenetto, a professor of biological engineering at Tufts University, who was not involved in the work. “These efforts in optimizing and managing the physical and mechanical properties of fibers are necessary and important next steps that will enable practical applications of medical relevance.”
Washington State University researchers have developed a novel nanomaterial that could improve the performance and lower the costs of fuel cells by using fewer precious metals like platinum or palladium.
Led by Yuehe Lin, professor in the School of Mechanical and Materials Engineering, the researchers used inexpensive metal to make a super low density material, called an aerogel, to reduce the amount of precious metals required for fuel cell reactions. They also sped up the time to make the aerogels, which makes them more viable for large-scale production.
Their work is published in Advanced Materials (http://onlinelibrary.wiley.com/doi/10.1002/
Hydrogen fuel cells are a promising green energy solution, producing electricity much more efficiently and cleanly than combustion engines. But they need expensive precious metals to fuel their chemical reactions. This need has limited their acceptance in the marketplace.
Aerogels, which are sometimes also called liquid smoke, are solid materials that are about 92 percent air. Effective insulators, they are used in wet suits, firefighting gear, windows, paints and in fuel cell catalysts. Because metal-based aerogels have large surface areas and are highly porous, they work well for catalyzing in fuel cells.
The WSU team created a series of bimetallic aerogels, incorporating inexpensive copper and using less precious metal than other metal aerogels.
Researchers introduced the copper in the bimetallic system through their new, one-step reduction method to create hydrogel. The hydrogel is the liquid-filled form of aerogel. The liquid component is carefully and completely dried out of the hydrogel to create aerogel. Their method has reduced the manufacturing time of hydrogel from three days to six hours.
“This will be a great advantage for large scale production,” said Chengzhou Zhu, a WSU assistant research professor who created the aerogel.
Water-based “Band-Aid” senses temperature, lights up, and delivers medicine to the skin.
MIT engineers have designed what may be the Band-Aid of the future: a sticky, stretchy, gel-like material that can incorporate temperature sensors, LED lights, and other electronics, as well as tiny, drug-delivering reservoirs and channels. The “smart wound dressing” releases medicine in response to changes in skin temperature and can be designed to light up if, say, medicine is running low.
When the dressing is applied to a highly flexible area, such as the elbow or knee, it stretches with the body, keeping the embedded electronics functional and intact.
Read more: Stretchable hydrogel electronics