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Living Machines PUBLIC ACCESS

A Large NSF-Funded Research Team is Building Working Machines Out of Living Human Cells

[+] Author Notes

Monique Brouillette is a science and technology writer in Cambridge, Mass. For more about biomedical engineering visit aabme.org.

Mechanical Engineering 139(06), 44-47 (Jun 01, 2017) Paper No: ME-17-JUN3; doi: 10.1115/1.2017-Jun-3

This article provides an insight into National Science Foundation (NSF) funded research and development of biological machines. The goal of these research projects is to build living, multicellular machines that sense, move, and solve real-world health problems. One of the Emergent Behaviors of Integrated Cellular Systems (EBICS) group has developed a biobot that walks. Inspired by the structure of human joints, this walker has two short, stubby legs connected by a bridge. The skeleton is constructed from a soft Jell-O-like 3D-printed skeleton called hydrogel, and surrounded by a band of skeletal muscle. The group genetically engineered the cells to produce a protein called channel rhodopsin, a sensory photorecepter that enables the muscle to contract in response to blue light. This provides an easy on–off switch to activate the muscle spurring the bot to move its legs and walk. As biologists understand better how tissues develop, bioengineers will be able to reverse-engineer development to better program cells to self-assemble to create biological machines. Plans for future bots include different cell types and many more functionalities.

Blood vessels don’t pump blood, for example, but imagine ones that could. A blood vessel that supplies the heart could be engineered to sense rising pressure from a blood clot in a clogged artery, and start pumping to disperse the clot. A swimming, sperm-like robot powered by muscle cells could swim in a patient's bloodstream, seek out hidden tumors inside her body and deliver targeted doses of lifesaving drugs.

The first such biological machines are just now being built. Funded by the National Science Foundation, a consortium of researchers at major engineering schools have developed a handful of biological machines that can sense input, move, or both.

So far their devices are rudimentary, but the scientists are aiming for cellular machines that not only behave as simplified organs, but also improve upon their design.

Unlike today's tissue-engineered organ replacements, which seek to replace or repair damaged organs, these new machines harness the building blocks of lifelike muscle and nerve cells and, put them together in ways nature never has. The goal is to build living, multicellular machines that sense, move, and solve real-world health problems.

“When we put these building blocks together, we can capitalize on their individual functionalities and make something new to serve whatever purpose we want,” said Caroline Cvetkovic, a bioengineer from the University of Illinois, Urbana-Champaign, one of the 10 research institutions on a national Science Foundation-funded project called Emergent Behaviors of Integrated Cellular Systems (EBICS).

These new biological machine-building capabilities rely on recent advances in genetic engineering, bioinformatics, and stem cell engineering. Scientists can now genetically program cells to produce proteins that give cells prescribed functions, such as the ability to respond to light or pressure.

One of the first and most rudimentary biobots is the microswimmer, which is part animal, part machine and most closely resembles a sperm.

The microswimmer consists of a flexible microfilament string about the thickness of a human hair, with a bundle of cardiomyocytes—heart muscle cells—clustered at one end. As the cardiomyocytes beat in synchrony, they bend the string and propel the biobot forward.

“We used cardiomyocytes because they can self-organize, synchronize their beating and mimic a swimmer,” said Taher Saif, the designer of the bot and bioengineer at University of Illinois at Urbana-Champaign.

One day this bot may be programmed to sense chemical signals emitted from cancer cells, seek them out, and deliver tumordestroying chemicals, he said.

Skeletal muscle (dark band) contracts and extends on command, causes a hydrogel to flex repeatedly, which this biobot to walk.

Images: Rashid Bashir, University of Illinois, Urbana-Champaign

Grahic Jump LocationSkeletal muscle (dark band) contracts and extends on command, causes a hydrogel to flex repeatedly, which this biobot to walk.Images: Rashid Bashir, University of Illinois, Urbana-Champaign

Another EBICS group has developed a biobot that walks. Inspired by the structure of human joints, this walker has two short, stubby legs connected by a bridge. The skeleton is constructed from a soft Jell-O-like 3D-printed skeleton called hydrogel, and surrounded by a band of skeletal muscle. Just as a muscle in the body contracts and moves a bone, these muscles contract to move the hydrogel skeleton.

In building the walker, Rashid Bashir's team at the University of Illinois, Urbana-Champaign used skeletal muscle cells instead of heart cells. That's because heart cells beat on their own, whereas a skeletal muscle needs a stimulus to contract, which allows the engineer to actuate it on command.

A skeletal muscle contracts naturally in response to electrical current, and at first Bashir and his colleagues used electricity as the stimulus. But now their latest biobot responds to light. The group genetically engineered the cells to produce a protein called channel rhodopsin, a sensory photorecepter that enables the muscle to contract in response to blue light. This provides an easy on-off switch to activate the muscle, spurring the bot to move its legs and walk.

As the cardiomyocytes beat in synchrony, they bend the string and propel the biobot forward.

Why use biological materials to construct machines at all, as opposed to building machines with more traditional materials like metal and plastic? There are many advantages, Saif said. To start, you don’t need a motor. The heart cells that power the swimmer, for example, beat in synchrony and generate enough power to actuate the device.

In addition, individual cells self-organize and condense into tissues without much prompting from a scientist, a phenomenon called emergence. To make muscle for the walker, Bashir's team simply combined 1.5 million muscle stem cells, extracellular matrix proteins like collagen and fibrin, and the 3D-printed skeleton in a small mold. Within a day, the muscle stem cells had linked to the proteins, condensed and aligned themselves into a band of solid muscle the length of a staple that could actuate the skeleton as a human muscle actuates bone.

Birds flying in a flock, fish swimming in a school, and even civilizations organizing themselves around major riverways like the Nile or Ganges are other examples of emergence. Cells, too, organize themselves. During development, they sense, process, and act on each other to form tissues and organ systems.

As biologists understand better how tissues develop, bioengineers will be able to reverse-engineer development to better program cells to self-assemble to create biological machines. In the case of Saif's microswimmer, “we didn’t do much at all; we just put the cells in randomly,” he explained. “They had the power within themselves and were cross-talking to one another.”

Plans for future bots will include different cell types and many more functionalities. Bashir's team would like the walker to employ nerve cells, due to their built-in ability to sense and respond to chemical cues. Also in the works are artificial vascular systems that will be able to supply the interior of biological machines with oxygen and nutrients. In the future, biological machines could also repair themselves.

For now, the next milestone will be a biological machine containing a functional neuromuscular junction. Saif said: “This will be the first biological machine with multiple cell types and potential intelligence.”

As biologists understand better how tissues develop, bioengineers will be able to reverse-engineer development... to create biological machines.

A biobot called the microswimmer moves when heart muscle cells beat in synchrony, causing a microfilament to flex and extend.

Grahic Jump LocationA biobot called the microswimmer moves when heart muscle cells beat in synchrony, causing a microfilament to flex and extend.

Copyright © 2017 by ASME
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