Innovative robot microsurgeon shows how embryos grow

Combining biology and robotics, scientists at EPFL have created a robotic microsurgical platform that can perform micrometer-resolution, high-precision dissections to advance our understanding of how the vertebrate body is formed during embryonic development. (CREDIT: EPFL)

Understanding the developmental biology of the embryo is critical not only from a fundamental science standpoint, but also from a medical standpoint. However, we are in dire need of tools that can help us systematically explore embryonic development.

“The original experimental approach in embryology is microsurgery,” says Andy Oates of the EPFL School of Life Sciences. “But it used to be done with a very simple microscope and very simple instruments like cactus thorns or pointed pieces of wire. Another problem is that our hands naturally tremble, which makes microsurgery difficult for some people. It takes years of training and only a few people can do it, so productivity is very low.”

Combination of robotics and biology

In an effort to address the current limitations of microsurgery techniques, Oates joined forces with Professor Selman Sakar of the School of Engineering, an expert in microfabrication and small-scale robotics. “In my lab, we build robotic instruments for tissue micromanipulation,” says Sakar.

“Together with Andy [Oates]we asked if we could use some of these tools to facilitate research in embryology in general, to make it more reliable and increase its productivity, and in this case, to specifically understand the biomechanics of how tissue morphogenesis [the shaping and structuring of a developing tissue] in work with zebrafish”.

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Two professors have received funding for the iPhD, a specialized doctoral fellowship at EPFL that combines research in the life sciences with another discipline. PhD candidate Ece Ozelci has trained in both robotics and developmental biology.

“I think it’s a great program because, to be honest, otherwise I would never have taken up such interdisciplinary research,” she says. “It was pretty intense; it’s not like you’re focused on just one discipline. I’ve learned a lot in both areas and I think this is a really great opportunity if you’re looking to acquire a unique set of skills.”

New robotic platform

In a publication in Nature Communications, the researchers describe the new platform’s role as “robot-assisted tissue micromanipulation.” It is compact (200 x 100 x 70 mm3), high resolution (4 nm position and 25 µ° rotation), maneuverable, with multiple degrees of freedom. The tool can be positioned automatically without manual intervention and does so with high reproducible stability.

The researchers drew inspiration from related microsurgical systems from ophthalmology and neurology, which are also quite compact and accurate and also rely on microscopes, although their targets are often larger than the embryo.

The scientists tested the platform’s capabilities by using it to study the elongation of the zebrafish embryo’s body axis. “Our lab focuses on how the spine forms, and partly on how the body lengthens, grows and segments,” says Oates.

The robotic platform allows precise microsurgery of the zebrafish tail. (CREDIT: Nature Communications)

“We use the zebrafish embryo as a model, and the idea is to look at the contribution of different parts of the embryo to the developmental process. In this case, we are looking at how embryos elongate and segment themselves, and how these two processes interact. Our approach is to physically separate elongation and segmentation through microsurgery and see how each performs when the other is missing.”

Using the platform, Ozelchi and her colleagues were able to target specific regions of the zebrafish embryo. Robot-assisted microsurgery allowed them to remove the elongating tail of the embryo and grow it separately, a process called explantation that is often used in embryological research.

The dynamics of elongation and signaling in the anterior and posterior parts of the tail explant are independent. (CREDIT: Nature Communications)

“Our approach is to physically separate elongation and segmentation through microsurgery and see how each performs when the other is missing.” Andy Oates said.

The study revealed the surprising behavior of the notochord of the embryo, which acts as an early “backbone” for the larva as it begins to swim. “The notochord pushes so hard into the tail that it can bend,” says Oates. “Normally, the embryo would elongate uniaxially, but once we physically stopped this process, the notochord continued to elongate, creating compressive stresses that led to curvature.”

Biology for the development of technology – and vice versa

“In addition to embryology, our research allows us to revolutionize the development of tissue engineering programs,” says Sakar. “If we understand how forces drive tissue morphogenesis, we can replicate these conditions with engineered tissues in vitro. Similar to biochemical factors, providing the correct mechanical environment and signals is critical for proper tissue development and function.

“We are also interested in creating biological machines designed to perform specific engineering tasks. For example, we would like to develop mini hearts that serve as organic pumps with a much simpler architecture compared to a real heart. To this end, robotic microsurgery provides not only design principles, but also the means to produce machines from living matter by self-assembly under mechanical control.”

But will such platforms become more widespread? “I envision that such robotic micromanipulation tools will become an essential tool in every life science lab,” says Sakar. “Regardless of the biological model system chosen, from single cells to organisms, robotics and automation can empower scientists.”

“Medical robots are quite advanced,” he adds. “The time has come to bring the unique possibilities of surgical robotics to the biomedical research community. Automated processing of biological samples will increase the throughput, accuracy and repeatability of data collection, as well as simplify procedures that require high skills and years of experience. Combined with intelligent imaging and microscopy, the possibilities are endless.”

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Note. Materials provided above EPFL. Content can be edited for style and length.

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