An experimental treatment applied for 24 hours to a group of legless frogs has allowed their limbs to repairing almost completely and functionally in the long term. The results open the door to further research, this time in mammals.

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SYNC 26/1/2022 20:00 CEST

For millions of people who have lost their legs and arms for various reasons, such as diabetes or trauma, the possibility of regaining function through natural regeneration is still out of reach. This is still the preserve of salamanders, starfish, crabs or lizards.

The development of the legs took place over the next 18 months until the limb was almost fully and functionally restored.

Now, scientists at Tufts University (USA) and Harvard University’s Wyss Institute have moved a step closer to this goal of regenerative medicine in a paper published in the journal Science Advances.

The researchers regrew the amputated legs of African clawed frogs (Xenopus laevis), which are naturally unable to regenerate their limbs, using a combination of five drugs applied through a silicone plug that sealed the stump for just 24 hours.

After this brief treatment, the development of the legs took place over the next 18 months, until the limb was almost fully and functionally restored.

A silicone plug to close the stumps
To achieve their goal, Nirosha Murugan’s team at Tufts University’s Department of Biology designed a bioreactor called ‘BioDome’, which resembles a silicone plug, composed of a silk protein gel loaded with a cocktail of five cell regeneration-promoting drugs (1,4-DPCA, BNDF, and retinoic acid, among others).

Each of the drugs served a different purpose, such as reducing inflammation, inhibiting the production of collagen that would cause scarring, and promoting the growth of new nerve fibres, blood vessels and muscles.

That a brief exposure to the drugs sets in motion a months-long regeneration process suggests that frogs, and perhaps other animals, may have latent regenerative abilities that can be activated.

“It’s exciting to see that the drugs we selected helped create a nearly complete limb,” says Murugan, a researcher affiliated with the Allen Discovery Center at Tufts and first author of the paper.

The scientists worked with 115 amputated female frogs and divided them into three groups: one control, one with the bioreactor alone, and one with the bioreactor loaded with the drug cocktail. After 24 hours, the gel was removed and the team studied limb regeneration over 18 months.

“The fact that only a brief exposure to the drugs was needed to trigger a months-long regeneration process suggests that frogs, and perhaps other animals, may have latent regenerative abilities that can be activated,” she says.

A promising avenue
Until now, such work has focused on animals with a natural regenerative capacity, such as the salamander (Ambystoma mexicanum), but the results of this new study propose a way to initiate the recovery process in animals that are unable to regrow an amputated limb on their own, such as frogs.

This also provides a promising therapeutic avenue for studying limb regeneration in humans, but “it is unclear from a biomedical perspective whether the size of a human limb would affect the feasibility of endogenous regeneration,” the authors note.

It is unclear, from a biomedical perspective, whether the size of a human limb would affect the viability of endogenous regeneration.

In this case, people can close wounds by growing new tissue, and our livers have a remarkable ability to regenerate to full size after a 50% loss.

But the loss of a large, structurally complex limb, such as an arm or leg, cannot be restored by any natural regeneration process in humans or mammals. In fact, we tend to cover major injuries with an amorphous mass of scar tissue, which protects them from further blood loss and infection and prevents further growth.

For this reason, the regeneration of muscles, bones and nerves (morphogenesis) of an amputated limb has always been considered a milestone to be achieved in biomedicine, and work such as this one proposes new and promising avenues of research.

In this sense, although the results are very encouraging, the researchers stress the need to initiate new studies, changing the variables of the initial work. “This research is a very interesting starting point to initiate similar experiments in mammals,” they conclude.

Reference:

N. J. Murugan, et al. “Acute multidrug delivery via a wearable bioreactor facilitates long-term limb regeneration and functional recovery in adult Xenopus laevis”. Science Advances, 2022

Source: SINC