When it comes to the human body, form and function work together. The shape and structure of our hands enable us to hold and manipulate things. Tiny air sacs in our lungs called alveoli allow for air exchange and help us breath in and out. And tree-like blood vessels branch throughout our body, delivering oxygen from our head to our toes. The organization of these natural structures holds the key to our health and the way we function. Better understanding and replicating their designs could help us unlock biological insights for more effective drug-testing, and the development of new therapeutics and organ replacements. Yet, biologically engineering tissue structures that are organized across multiple scales, from the arrangement of small cells all the way to the architecture of a large organ, has proven challenging using current fabrication technologies.
Now, Christopher Chen and his team at Boston University and the Wyss Institute at Harvard University have invented a new approach to solve this complex problem called ESCAPE (engineered sacrificial capillary pumps for evacuation). In new research published in Nature , the multidisciplinary team demonstrates how they used gallium, a soft silvery metal that melts just above room temperature, as a molding material for generating cell structures in a wide range of shapes and sizes that can be used to engineer tissue.
Senior author Christopher Chen, director of BU's Biological Design Center and Core Faculty member at the Wyss Institute, explains how ESCAPE works and how their research will enable future advances in tissue engineering.
What is ESCAPE and how does it work?
Before we dive into ESCAPE, I think it is important to take a step back and talk about why building tissue itself is so difficult.
Why is building tissue a challenge?
There are two main hurdles when trying to engineer tissue. The materials themselves are incredibly fragile, and there is not a one-size fits all process.
First, biological materials, such as the extracellular matrix (ECM)—a complex network of proteins and other molecules that comes together to form cells and tissues—must be maintained in highly controlled environments. They cannot be exposed to high temperatures, harsh solvents or squeezed through tiny spaces. So, the way you must handle them is very limited.
The second challenge is finding a building process that works well for both small structures as well as large ones.
How did you overcome these challenges?
Inventing a single process that can handle the fragile materials and can build well at different scales is a hurdle. We wondered: could we decouple these two problems?
First, we examined building the geometry, the shape, using any material we wanted. Then, we copied the geometry over to the fragile biological material through molding. This approach allows us to build tissue successfully in many different shapes, using soft materials. That's the heart of the ESCAPE work.
How does ESCAPE copy shapes?
First, the desired shape is generated using fabrication processes and materials designed for patterning. Gallium is then used to form a solid metal cast of the shape. Next, the desired biomaterial is polymerized around the gallium cast. Finally, gallium is melted and removed cleanly, leaving behind an intact biomaterial scaffold. Cells can then be added to this scaffold and cultured to form tissue architectures.
Why did you decide to use gallium?
Gallium is truly the perfect material for this. It is solid at room temperature, so it can be handled easily and works well as a casting material. But what makes it so special is that it is biocompatible and can be melted at cell-friendly, low temperatures. So, it is easy to extract gallium without destroying a delicate mold. Even better yet, Gallium can be switched to a high surface tension state, which means that it can easily be triggered to pump itself out of confinement. This process is called capillary pumping, the "CAPE" of "ESCAPE" (engineered sacrificial capillary pumps for evacuation).
What structures have you built using ESCAPE?
ESCAPE can be used on several tissue architectures, but we started with vascular forms because blood vessel networks feature many different length scales. Engineering the vascular tree (and its hierarchies) is a well-known challenge in the field of biological engineering.
Our blood vessel demonstrations include trees with many branches, including dead ends and portions that experience fluid flow. This allows us to model a range of healthy structures as well as diseased abnormalities.
Another approach involves independent tissue networks that are interwoven with each other. Most tissues feature not one, but many distinct networks that come near each other, yet are not in direct contact. These networks are lined with different cells. To showcase this, we fabricated interwoven blood and lymphatic networks.
Finally, vascular networks nourish other cells within a tissue. To capture this, we built cavities packed with cardiac cells that have high nutrient needs that were met with blood vessels in close proximity.
What's next for ESCAPE?
We envision using ESCAPE with new cell types and new shapes representative of different organs. We also want to use it in organoid cultures. Then, we plan to expand to more materials beyond the three we tried in this research.
With this research, we have the basic design rules in place to predict the reliability of ESCAPE. Simulating the capillary pumping process will allow us to test different designs computationally in advance.
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