Many of us have contemplated buying a reconditioned phone. It might be that bit older but it has a new screen and works as well as those in the shop-front. I’m not sure, however, that any of us have thought of investing in a reconditioned liver – but it could be coming to a body near you.
Researchers based in São Paulo’s Institute of Biosciences have been developing a technique to create and repair transplantable livers. The proof-of-concept study published in Materials Science and Engineering by the Human Genome and Stem Cell Research Centre (HUG-CELL) is based on tissue bioengineering techniques known as decellularisation and recellularisation.
The organs of some donors are sometimes damaged in traffic accidents, but these may soon be transplantable if the HUG-CELL team realises its goal.
The decellularisation and recellularisation approach involves taking an organ from a deceased donor and treating it with detergents and enzymes to remove all the cells from the tissue. What remains is the organ’s extracellular matrix, containing its original structure and shape.
This extracellular matrix is then seeded with cells from the transplant patient. The theoretical advantage of this method is that the body’s immune system won’t rile against the new organ as it already contains cells from the patient’s own body, thereby boosting the chance of long-term acceptance.
However, the problem with the decellularisation process is that it removes the very molecules that tell cells to form new blood vessels. This weakens cell adhesion to the extracellular matrix. To get around this, the researchers have introduced a stage between decellularisation and recellularisation. After decellularising rat livers, the scientists injected a solution that was rich in the proteins produced by lab-grown liver cells back into the extracellular matrix. These proteins then told the liver cells to multiply and form blood vessels.
These cells then grew for five weeks in an incubator that mimicked the conditions inside the human body. According to the researchers, the results showed significantly improved recellularisation.
“It’s comparable to transplanting a ‘reconditioned’ liver, said Mayana Zatz, HUG-CELL’s principal investigator and co-author of the article. “It won't be rejected because it uses the patient’s own cells, and there’s no need to administer immunosuppressants.”
Extracellular matrix of a decellularised liver | Image Credit: HUG-CELL/USP
Obviously, there is a yawning gap between proof of concept and the operating theatre, but the goal is to scale up the process to create human-sized livers, lungs, hearts, and skin for transplant patients.
“The plan is to produce human livers in the laboratory to scale,” said lead author Luiz Carlos de Caires-Júnior to Agência FAPESP. “This will avoid having to wait a long time for a compatible donor and reduce the risk of rejection of the transplanted organ."
This technique could also be used to repair livers given by organ donors that are considered borderline or non-transplantable. “Many organs available for transplantation can’t actually be used because the donor has died in a traffic accident,” Caires-Júnior added. “The technique can be used to repair them, depending on their status.”
Even if we are at the early stages of this approach, it bodes well for future research. And for those on the organ transplant list, a reconditioned liver would be as good as a new one – complete with their very own factory settings.
Read the paper here: https://www.sciencedirect.com/science/article/abs/pii/S0928493120337814
A shortage of donor organs for transplant surgery is fueling research to develop artificial livers and hearts, but how closely do they match up to the real thing?
Liver failure due to alcohol abuse, drug overdose and hepatitis is a growing problem. In 2016, 1220 Americans died waiting for a liver transplant, with the cost of treating cirrhosis – late stage liver scarring – is estimated at nearly $10bn/year.
‘In 2017, if you have liver failure, we don’t have a backup system,’ says Fontes. ‘But my group has a potential backup system. We are not ready for prime time yet, but we’ve some really good data.’
Liver failure can be hereditary or caused by excessive drinking. Image: Pixabay
Transplant surgeon Paulo Fontes at the University of Pittsburgh, US, regularly meets patients who ask what their options are aside from a liver transplant.
His group has attempted to build a new bioartificial liver, by seeding liver cells onto a liver scaffold. However, others working in this area have so far met with little success.
Now Fontes, working at the Starzl Transplantation Institute, has hit on a different strategy: to grow mini livers in living organisms. The work is in collaboration with Eric Lagasse, a stem cell biologist at the University of Pittsburgh, who showed lymph nodes are excellent ‘bioreactors’ for growing different types of cells, including liver cells.
The liver – made up of hepatocytes – has the capacity to regenerate after surgery. Image: Ed Uthman/Flickr
Lymph nodes filter damaged cells and foreign particles out of the body’s lymph system, which transports fluids around the body. When someone is ill, T cells from the immune system move to the lymph nodes to be cloned and released back to the bloodstream en masse to take on the microbe causing the illness.
For the past five years, Fontes and Legasse have been working with large animal models, infusing hepatocytes into the lymph nodes of pigs. ‘Within two months, it is amazing, but you have mini livers in the lymph nodes,’ he explains. ‘When you compare the mini liver with normal livers, they look very similar.’
Pigs are common animal models as they have similar organ systems to humans. Image: Pixabay
The mini livers weigh a few grams and would not offer a complete replacement for failed livers, but rather a supplement of liver tissue in patients with end stage liver disease who are too sick to undergo a transplant.
‘A lot of these patients have significant heart and lung problems, so would not sustain a full transplant,’ says Fontes. ‘The idea is to sustain their life by increasing their liver mass by creating new small ectopic livers within their lymph nodes.’
Compared with artificial livers, artificial heart technology is much further along the road to the clinic. To date, around 2000 artificial hearts have been implanted in patients, with demand driven similarly by an acute shortage of donors.
‘We wanted an artificial heart very similar to the natural human heart,’ explains Nicolas Cohrs at ETH Zurich in Switzerland. ‘Our hypothesis is that when you mimic the human heart in function and form you will have fewer side effects.’
Cohrs and his colleagues aim to print their artificial hearts so that they fit precisely into an individual patient. This is not yet close to clinic, but promises a tailored heart.
‘We take a CT scan of a patient, put it in a computer file and design an artificial heart around it, so it closely resembles the patient heart,’ says Cohrs. ‘We use these 3D printers and print a mould in ABS [acrylonitrile butadiene styrene], which is the plastic Lego is made of, fill it with silicone and then dissolve the mould with acetone to leave behind the silicone heart.’
Testing a soft artificial heart. Video: ETH Zurich
The plastic heart deflates and inflates with pressurised air. The first-generation device, made from silicone, has two chambers but survived for only 2000 beats. ‘This is only half an hour, so there is a lot of improvement needed,’ adds Cohrs.
A new prototype made from a more resistant [so far, undisclosed] polymer has managed more than a million beats, which is the equivalent of 10 days for a human heart. The goal is to develop a four-chamber heart that beats for 10 years, so a lot more work is still needed.