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Organs on demand: the future of transplants

Researchers in the US have transplanted lab-grown kidneys into animals that are functional and produce urine, though not as efficiently as the real thing

Organs on Demand 

Ridley Scott's 1982 dystopian thriller describes a world in which bioengineered human beings or 'replicants' can be made using genetic engineering and tissue culture techniques.

Widely regarded as a science fiction classic, Blade Runner arguably brought the concept of genetic engineering more firmly into the public eye than any work of fiction preceding it and sparked concerns about the ethical and moral implications of human control over biological life and enthusiasm over its potential in almost equal measure.

We can build you
More than 30 years after Blade Runner was first screened – complete with the memorable image (to me anyway!) of eyeballs being grown in a jar - the news that researchers in the US have successfully created and implanted a semi-functional kidney into an animal suggests medical science may have taking a small step towards making bioengineering of human tissues and organs a reality.

The work carried out at Massachusetts General Hospital's Center for Regenerative Medicine and Harvard Medical School in the US - published in Nature Medicine - is still a long way even from clinical trials in humans. However, it provides a tantalising glimpse into an approach that could in time have a dramatic impact on the hundreds of thousands of people around the world on the kidney transplant waiting list.

Harald Ott and colleagues have sidestepped one of the major barriers to the creation of synthetic organs - reproducing the fantastically complex organisational structure of the cells and tissues within them - by developing a way to use harvested organs themselves as a supporting framework for donor cells.

The simulacra
The team took kidneys from recently deceased rats and flushed them with a detergent solution that removed the cells, leaving behind the extracellular matrix (ECM), a network of supportive connective tissues that serves as a biocompatible scaffold that can be seeded with new cells.

Critically, ECM scaffolds made via decellularisation retain the architecture of a kidney, such as the vascular network, the outer cortex that is involved in blood filtration and the inner medullary structures, which help balance salt and water levels in the blood.

The scaffold was then re-seeded with two types of cells: endothelial cells (which line the blood vessels and lymph ducts in the body) were introduced via the renal artery, while neonatal kidney cells (NKCs) - a mixture of various different cell types - were delivered through the ureter. The scaffold was suspended in a vessel during re-seeding so a vacuum could be applied, as the resulting pressure encouraged the introduced cells to penetrate the entire structure.

It's tantalising glimpse into an approach that could impact hundreds of thousands of people ...

Thereafter re-seeded kidneys were cultured to allow the donor cells to grow and repopulate the organ, a process which typically takes three to five days. Amazingly, Ott et al found that the cells organised themselves and grew into the fine structures present in the kidney, including the microtubules which produce urine.

The scientists then subjected the bioengineered kidneys to a battery of in vitro tests, discovering that the regenerated construct was able to carry out a number of kidney functions, such as albumin retention, reabsorption of glucose and electrolytes and excretion of urea, as well as urine production.

Penultimate truth
The acid test came when the scientists transplanted the regenerated kidneys into rats that had one kidney removed;  the team was not disappointed. The transplanted kidneys began producing urine as soon as the blood supply was restored, with no evidence of bleeding or clot formation.

“What is unique about this approach is that the native organ's architecture is preserved, so that the resulting graft can be transplanted just like a donor kidney and connected to the recipient's vascular and urinary systems,” said Ott.

If this technology can be scaled to human-sized grafts, patients suffering from renal failure could theoretically receive new organs ...

And while the overall function of the regenerated organs was significantly reduced compared with healthy kidneys, this was probably at least in part down to the immaturity of the NKCs used to repopulate the scaffold. A better result may be achieved with different cell types or by allowing the cells to mature for longer, suggest the scientists.

“If this technology can be scaled to human-sized grafts, patients suffering from renal failure who are currently waiting for donor kidneys or who are not transplant candidates could theoretically receive new organs derived from their own cells,” he added. 

The research team has already shown that decellularisation of pig and human kidneys is feasible, and have also applied the technique to make scaffolds of other organs such as the lungs, heart and liver, and are now gearing up to try to transplant regenerated pig kidneys into live animals.

At the moment there are around 18,000 kidney transplants carried out each year in the US, but 100,000 people are on the waiting list at any time and 400,000 patients who require dialysis because they are in end-stage renal disease (ESRD).

Eye in the sky
There is no doubt that Ott et al have taken an important step towards a major advance in medicine, with three milestones achieved: the creation of the acellular scaffolds, the repopulation of the scaffolds with viable cells that form organised structures; and the excretory function of the resulting graft. 

Meanwhile, although the regenerated kidneys only exhibited around 5 per cent of the function of a healthy kidney, the target for a replacement organ may not be that high. Typically, people with ESRD are only put forward for dialysis when their renal function dips below 15 per cent, so a replacement organ that can top that level of function could be used to keep patients free of the dialysis machine.

However, the researchers freely concede that any practical application of the approach is many years away and there are a number of serious obstacles to overcome. Some cells ended up in the wrong place, for example, and re-seeding organs gets almost exponentially harder with increasing size. It is also unclear whether the scaffold left behind after decellularisation is unaffected by the detergent flushing.

Gather yourselves together
Nevertheless, the work is a starting point and Ott now wants other research teams to get on board to take a multidisciplinary approach to refining the technique. It also raises intriguing possibilities with potentially significant impact on the healthcare industry.

Drugs to treat chronic kidney disease alone (antihypertensives, erythropoietin, phosphate binders etc) represent a multibillion dollar market that could be effectively negated if functional kidneys could be engineered and implanted. 

Using donor cells from the patients would mean there would be no need for lifelong and often hard-to-tolerate immunosuppressant drugs, while dialysis centres would become redundant. Extend the concept to other organs - pancreas, lung, liver etc - and healthcare provision becomes a very different and perhaps even a largely non-pharmacological proposition.

In fact, what if a limitless supply of organs could be grown easily from stem cells harvested and frozen in childhood? Would routine replacement of failing organs and tissues allow humans to live almost disease-free and have dramatically increased life spans? It remains to be seen whether that always stays in the realms of science fiction.

Article by
Phil Taylor

is a freelance journalist specialising in the pharmaceutical industry

29th May 2013

From: Research

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