Bioreactor device helps regrow legs on frogs

This image shows Xenopus laevis swimming in a tank pre-amputation. (Celia Herrera-Rincon/Tufts University)

Researchers have created a new device that can trigger partial limb regrowth in frogs. The findings could lead to limb regeneration in mammals somewhere off in the future.

Frogs are capable of regenerating lost limbs on their own, but the stumps grown are smaller and not that impressive. The wearable device, which kick–starts the tissue on the wound, drastically improved the quality of the limb.

“They are not (yet) full limbs, but very different from the thin, featureless spike that forms in frogs without our intervention,” senior study author Michael Levin of the Allen Discovery Center at Tufts University told Fox News. “They had improved shape, size, bone, innervation, and function.”

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The bioreactor, which is 3D printed from silicon, is filled with a sticky gel made from polymers. The gel contains progesterone, which has been shown to help repair nerves, blood vessels, and bone tissue.

After the adult African clawed frogs’ limbs were amputated, the bioreactors were immediately sutured on at the amputation site. For 24 hours, the devices released progesterone on the frogs’ wounds before being taken off. The frogs were then observed over a period of 9–10 months. Compared to frogs that weren’t fitted with the bioreactor after amputation, the regrown limbs were improved– they were paddle–like formations and closer to fully–formed legs. The group who didn’t wear the device regrew only the little thin spike. The device–improved limbs were also thicker, with more developed bones, nerves, and veins.

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According to analysis and RNA sequencing, the bioreactors altered the gene expression in cells at the amputation site– upregulating genes involved in oxidative stress, serotonergic signaling, and white blood cell activity. At the same time, scarring and immune responses were downregulated, indicating that the progesterone curtailed the body’s reaction to injury. This left the pathway open to improved regeneration.

Levin said that the limb wouldn’t have been improved any more if the device was left on for a longer period, and that 24 hours of exposure was sufficient to kickstart the leg growth process.

“The trick is to perfect the initiation trigger, which we are doing (improved cocktails for example),” he explained. “Our strategy is not to try to micromanage the process, but to find the right trigger - the body already knows how to make legs, [which] it does it during embryogenesis.”

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The team aisworking on limb regeneration in mammals, though aquatic animals are naturally better at regeneration. Mice, for example, have been shown to be able to partially regenerate lost fingertips, but the process is hampered when they walk around on the wound. Water is a lot kinder to the delicate regenerative cells.

Levin also hopes the research will eventually benefit humans.

“The limb work is an example of this bigger research program­– we need to figure out how to coax cells into forming specific complex structures,” he said.

“Once this is figured out, the results will benefit many biomedical needs: birth defects (remodeling), traumatic injury (regeneration), cancer (tumor reprogramming), aging (regenerate senescent tissues), degenerative disease– all of these will be revolutionized once we know how to control large-scale growth and form. Our lab is pursuing a number of directions, specializing in modulating the electric conversations that allow cells to decide what to build, to try to gain control over this process.”

The research is published in the journal Cell Reports.