- 01 February 2007
- From New Scientist Print Edition. Subscribe and get 4 free issues
- Celeste Biever
Jeff Borenstein holds up a piece of semi-transparent rubber, about half the size of a credit card. If all goes to plan this unassuming piece of rubber could become the building block for the first 3D artificial organs.
reposted from: New Scientist
my highlights / edits
Stacks of these bendy, biodegradable flaps are fused together to form structures snaked through with a network of interconnecting channels. When pumped with a solution of cells, nutrients and oxygen, these channels spring into life, forming a system of blood vessels and tissue that might one day be the basis of an artificial heart, kidney or liver.
Borenstein, a micro-machinist at the Draper Laboratory in Cambridge, Massachusetts, is just one of a number of people who are attempting to build sophisticated artificial organs complete with their own network of blood vessels, or vasculature.
So far simple organs including skin and bladders have been built by seeding a tissue scaffold with cells that are cultured in a nutrient-rich broth. Skin and bladder tissue is thin enough for oxygen and nutrients from the broth to reach all the cells, and a dedicated vascular system is unnecessary until the organs are transplanted when the body's own blood vessels take over.
But thicker organs such as the liver, heart and kidneys will need a vascular system while they grow in the lab, otherwise cells beneath the surface will die from lack of oxygen. "The major limiting factor for solid organs right now is vascularity," says Anthony Atala, a tissue engineer at Wake Forest University in Winston-Salem, North Carolina, who last year implanted the first lab-grown bladders in humans (New Scientist, 8 April 2006, p 10).
"The major limiting factor for solid organs right now is a vascular system
Borenstein's solution is to create a temporary scaffold of biodegradable polymer containing a network of channels, some of which become organ tissue and others blood vessels. The two sets of channels are linked via small pores, allowing nutrients and oxygen pumped through the blood vessels to reach the liver or heart tissue. "Channels help you to establish the organ and maintain function," he says. When the organ is implanted, these channels would be connected to the recipient's own blood vessels.
To create the channels, which are around 10 micrometres in diameter, Borenstein uses a process called soft lithography. A piece of silicon is etched as if to create a reverse cast of the channels, so when the biodegradable material is poured onto the "mould" and removed it has the desired shape. Two halves are fused together and then connected to other copies to create a network of channels (see picture).
So far Borenstein has created 8-centimetre cubes from a range of biodegradable materials, including dissolved spider silk and a polymer called polyglycerol-sebacate, or "biorubber". He can tune the scaffold to the needs of particular organs by using materials with different properties. For instance, cells that take a long time to grow will need a scaffold that degrades slowly after implantation and retains its structure, while others might require a structure that dissolves quickly.
To turn some channels into blood vessels Borenstein lines them with endothelial cells; for liver organ tissue he fills channels with liver cells called hepatocytes. He has also built 2-millimetre-sized hybrid cubes, seeded with both cell types, which filter blood in a similar way to the liver. The blood travels along a "vessel" lined with a single layer of endothelial cells, and passes through the pores into a layer of hepatocytes. These filter the blood and return it to the original vessel.
However, while building a simple cube of cell-lined channels is relatively straightforward, ensuring cells migrate throughout an entire organ so that they fill gaps between these channels may prove more difficult. "This is particularly critical for cells that don't divide or migrate readily like hepatocytes," says Sangeeta Bhatia, a tissue engineer at the Massachusetts Institute of Technology.
Bhatia is pursuing a different approach. Instead of flowing cells through a ready-made structure, she mixes liver cells with a light-sensitive polymer called polyethylene glycol, which she deposits on a surface and covers with a mask. She can build very precise structures by shining light onto the cell-filled polymer to harden those areas not covered by the mask and then washing the rest away (New Scientist, 4 January 2003, p 19). "We build living tissues with light rather than fabricating a scaffold and then occupying it with cells," Bhatia says. "This allows us to embed cells throughout the organ without coaxing the cells to migrate."
She has already used the technique to create liver tissue a few millimetres thick, a breakthrough that will appear in the Journal of the Federation of American Societies for Experimental Biology (FASEB). Although she did not build an entire vascular system to feed the tissue, she did create a network of channel-like voids - 50 micrometres wide - between the liver cells, through which she pumped a fluid rich in oxygen and nutrients. This kept the tissue alive for 10 days. "If we organised these voids into a branching network explicitly, it would look like a vascular system," she says.
Some researchers, however, doubt whether either technique will ever produce structures as intricate as those in the human body, where arteries and veins branch hundreds of times until they form tiny structures just 10 micrometres wide. "They could build such a branching structure but this is very complicated, so I have strong reservations," says Gabor Forgacs at the University of Missouri-Columbia. Forgacs believes that engineering the thicker vessels but leaving the smaller ones to develop on their own might prove more successful.
A group lead by Jens Kelm and Martin Fussenegger of the Swiss Federal Institute of Technology in Zurich has shown that cells can build their own vasculature. Last year they created balls of a mixture of animal and human heart cells and coated them with human umbilical vein endothelial cells. They found that as the heart cells on the inside ran short of oxygen, they released a chemical called VEGF that prompted the endothelial cells to migrate to the centre of the ball and form a network of cells resembling capillaries. When they attached a tissue made of multiple balls to a chicken embryo, the embryo blood vessels fused with those in the grafted tissue, showing that a vasculature formed like this could one day be hooked up to the human body.
But Forgacs believes it would not be possible for an entire heart to form in this way, as they are far too complex. Instead he hopes to combine this approach with a bioprinting technique he has developed. He uses a centrifuge to form clumps of cells, which are printed layer by layer onto a biodegradable gel to build 3D structures (New Scientist, 13 April 2006, p 19). He plans to print large tubes of cells to build veins and arteries, and he hopes the smaller vessels will form by themselves from clumps of heart or liver cells coated in endothelial cells in the space surrounding the larger vessels. Indeed, many of the new techniques being developed are likely to merge as more is learned about how to create the complex networks of cells needed to form hearts, livers and kidneys.
"It's a really exciting time because we are all learning the principles," says David Kaplan at Tufts University in Medford, Massachusetts. "If we can succeed, the impact on human health is immense."
