快猫短视频

EVEN a Rolls-Royce will eventually break down as a result of wear and tear.
The same is true of human bodies, as our ligaments, muscles and organs are
pulled, pumped and repeatedly prodded by disease, routine use and ageing.
Unfortunately for us, new body parts for worn-out or sick humans are at a far
more primitive stage of development than the purpose-built spare parts for a
car.

Organs such as livers and kidneys are shunted from dead people into live
ones, bringing with them infectious diseases and triggering reactions that would
kill many patients were it not for the arsenal of drugs used to calm the immune
system. Simpler bits and pieces such as replacement joints and heart valves are
manufactured from materials that bear no resemblance to the real thing, such as
plastic, metal and porcelain, or the higher-tech Teflon, Dacron (called Terylene
in Britain) or Gortex鈥攊n other words, the stuff of pots and pans, bras and
expensive raincoats. These materials can cause life-threatening inflammatory
reactions and blood clots, and the spares generally don鈥檛 function nearly as
well as the originals.

鈥淲e can do better,鈥� says James Anderson at Case Western Reserve University in
Cleveland, Ohio. Trained as both a doctor and an engineer, Anderson typifies the
multidisciplinary approach to spare part medicine. Tissue engineering, he says,
is teetering on the brink of finding new ways to patch up worn-out bodies. Soon
parts may be carefully crafted on a computer and then built in a lab flask from
a mix of living human cells and specially designed plastics. Indeed, tissue
engineering is already causing eyes to pop and investors鈥� pocketbooks to open
wide with spectacular devices such as artificial bladders for dogs, blood
vessels for pigs, human ears grown on the backs of mice and little kidney-like
organoids that produce urine that is ever so dilute, but urine nonetheless. The
engineers鈥� eventual aim, however, is far more audacious: to tailor-make a
complete and complicated solid organ鈥攁 liver, say, or a heart鈥攖hat
is fit to function in the human body.

This is no small undertaking. After all, a liver is not some slushy mess, but
an orderly three-dimensional structure made up of six different types of cells,
infiltrated by nerves, bile ducts, lymph and blood vessels, and capable of doing
everything from filtering toxins from the blood and orchestrating the body鈥檚
energy supplies to storing vitamins and producing bile. A heart may look
somewhat like your average pump, but it is a pump that tidily manages fluid
turbulence and beats faster or slower in response to minute changes in any one
of a repertoire of hormonal and nervous signals.

How to even begin? First, suggest the researchers, get yourself a good set of
blueprints. Using computer technology originally developed to manufacture engine
parts for airplanes, biomedical engineer Linda Griffith at the Massachusetts
Institute of Technology (MIT) has generated just such three-dimensional
blueprints for the liver. These do not describe exact copies of the real thing,
but rather a framework鈥攃omplete with minute channels, caverns and
crevices鈥攐n which Griffith hopes to grow small, liver-like organs.

A partially grown liver in a flask will need blood vessels to supply it with
oxygen and food, and flush away the waste. These vessels will grow along the
channels. Meanwhile, the caverns and crevices are there to provide lodging sites
for the 鈥渟eed鈥� liver cells that will grow and divide, eventually creating a
whole new organ. They will also increase the surface area of the skeleton,
making it easier for the organ鈥檚 minders to provide the growing cells with
oxygen and nutrients before real blood vessels have infiltrated the organ. This
is important, because cells that are starved of nutrients or kept in cramped
conditions lose their ability to perform specialised tasks. Imagine if someone
sealed all the doors and windows of a home, cut off the power and food supplies,
and plugged up the plumbing, says Larry Hench, a organic chemist at Imperial
College, London. 鈥淭he members of the family would dedifferentiate into a Stone
Age culture just to survive.鈥�

But while fine detail is important, aesthetics is not. 鈥淲e do not need to
make a liver that looks exactly like the real thing,鈥� Griffith says, 鈥渨hat is
critical is the microscopic structure鈥攖he arrangement of the cells.鈥� Once
the computer has generated its virtual skeleton, Griffith uses it to instruct a
printer-like device to assemble an actual skeleton by, in effect, gluing
together microscopically thin layers of polymer.

The exact composition of that polymer is perhaps the most crucial factor of
all and certainly the one that garners the most research effort. One undisputed
expert on polymers for tissue engineering is Robert Langer, a chemical and
biomedical engineer, also at MIT. Back in 1983, Langer teamed up with Joseph
Vacanti, a transplant surgeon at Harvard Medical School in Boston, to try to do
the seemingly impossible鈥攎ake plastics that would act as a scaffold for a
body part grown in the lab. The scaffold would be placed in an incubator
containing sterile physiological fluid, kept at body temperature, supplied with
oxygen, nutrients and growth factors, and then seeded with the different types
of cells needed to grow an organ.

Erector set

The trick was to find a scaffold material that contained pores that, much
like the caverns in Griffith鈥檚 skeleton, would accommodate the sorts of cells
they wanted to grow. The material would also have to stay up long enough for the
new organ to take shape and could not provoke an immune response. Polymers made
of molecules such as lactic acid and glycolic acid, which crumble into their
component parts on contact with water and so don鈥檛 hang around long enough in
the body to trigger much of an immune response, fitted the bill.

Using their porous polymers, Langer, Vacanti and their colleagues have grown
sheets of skin and pieces of cartilage, and have even combined the two to
fashion ears and finger-like appendages. 鈥淵ou can make an ear or a blood vessel,
anything. The whole idea is to create a substrate that is ideal for cells to
grow on,鈥� says Langer.

And while the eventual goal of providing ears to replace human ones that are
missing because of injuries or birth defects is some years off, in 1997 Vacanti
and his brother Charles Vacanti, director of the Center for Tissue Engineering
at the University of Massachusetts Medical Center in Worcester, made quite a
splash when they successfully transplanted a bioengineered 鈥渉uman ear鈥� onto the
back of a mouse. Meanwhile, companies such as Advanced Tissue Sciences in La
Jolla, California, which has licensed the rights to Langer鈥檚 technology,
and Genzyme Corporation in Cambridge, Massachusetts, are growing skin and
cartilage that are used in hospitals to treat burns and repair joints.

In the past few years, however, the tissue engineers have set their sights
far higher than mere cartilage and skin: growing whole organs. As part of that
quest, they have had to find ways to reproduce a growing organ鈥檚 natural
environment in the lab. Take blood vessels. Grown from pig muscle and
artery-lining cells, they are stronger and resemble their natural counterparts
more closely if, as they grow, they are attached to a pump that simulates a
beating heart and streaming blood (Science, vol 284, p 489). The
vessels even contract鈥攁lbeit weakly鈥攚hen treated with
vasoconstricting drugs.

Longer lasting

鈥淲e grew an artery that has contractile function from individual cells thrown
in a dish,鈥� says an elated Laura Niklason, the anaesthesiologist and biomedical
engineer at Duke University in Durham, North Carolina who, along with Langer,
created the blood vessels. When the vessels were transplanted into pigs, they
lasted at least four weeks without triggering clots鈥攎uch longer than
vessels grown without the benefit of a simulated blood flow.

Clots are by far the most vexing problem for artificial blood vessel
engineers. Large arteries containing Dacron or Gortex are a staple of most
cardiology wards, but narrower versions of less than 3 millimetres in diameter,
about the size needed to patch up the leg of a diabetic patient, are not
available because they would clog up almost instantly. 鈥淭hey don鈥檛 even try to
make them that small,鈥� Niklason says. This means that the only way to replace
the smaller blood vessels is to take a healthy one from somewhere else in the
patient鈥檚 body, which is not always an option.

Researchers elsewhere are experimenting with other ways to recreate different
aspects of an organ鈥檚 natural environment. For example, Langer鈥檚 colleague
Prasad Shastri has worked with a polymer called polypyrrole, which conducts
electricity. He used it as an implant to help reconnect severed sciatic nerves
in rats (Proceedings of the National Academy of Sciences, vol 94, p
8948). By carrying electricity between the spinal cord and the severed end of
the nerve, the polymer encourages nerve cells to grow across the gap. Shastri
and Langer hope to use polypyrrole as a way of persuading nerves to grow into a
flask-grown organ.

Then there are attempts to more accurately recreate an organ鈥檚
microenvironment. A range of biodegradable polymers are being created that
provide the biological stimuli that will make different sorts of cells grow. In
the body, proteins on the surface of cells act like molecular Velcro, helping
cells stick to other cells and to connective tissue, which in turn helps them to
develop into the correct type of tissue. By spiking different parts of the
scaffold with particular proteins, or even by creating microscopic indentations
in the polymers that fit proteins on the surface of particular cells (
Nature, vol 398, p 593), tissue engineers may one day be better able to
direct the growth of, for example, blood vessels in one part of an organ and
hormone-secreting cells in another. With this end in mind, one of Langer鈥檚
latest polymers combines molecules of lactic acid with the amino acid lysine,
providing a natural attachment site for any protein you care to add.

But perhaps the simplest way to make sure that an engineered organ is exposed
to just the right influences is to start it off in a lab flask and then transfer
it into a body to finish off its development. A few months ago, Anthony Atala, a
paediatric urologic surgeon at the Children鈥檚 Hospital in Boston, and his
colleagues reported in Nature Biotechnology (vol 17, p 149) how they
used this strategy to grow a dog bladder that worked well enough to replace the
dog鈥檚 own organ for up to a year.

First, they surgically removed from adult dogs small amounts of smooth muscle
cells and urothelial cells, which line the bladder. Then, using the right mix of
growth factors鈥攁nd it took over a decade of work to hit on the correct
combination鈥攖hey cajoled the cells into growing in a flask on each side of
a springy polymer mould. To complete their development, the bladders were
implanted into dogs who had had their own removed.

At first, catheters were used to empty the bladders, but within months the
bladders were able to function by themselves. They looked indistinguishable from
normal bladders, says Atala, and had even hooked themselves up to nearby blood
vessels. 鈥淎n astonishing feat of tissue engineering,鈥� is how Jeffrey Hubbell of
the University of Zurich described the accomplishment in Nature.

Even so, Atala and Hubbell would probably be the first to admit that a
bladder is only a small, tottering step towards spare-part medicine鈥檚 grand goal
of creating a solid organ in a flask. Hollow organs have a simpler structure
and, because the layers of tissue are thinner, it is easier to ensure that the
cells are well fed before the blood supply is in place.

Vital functions

So what of the dreams of growing whole solid organs? Well, about three years
ago, Griffith teamed up with Vacanti to use her blueprints to grow an artificial
liver. A liver is made up of six different types of cells, but the two
researchers seeded a scaffold with just two: rat hepatocytes鈥攖he workhorse
cells of the liver鈥攁nd cow endothelial cells, which line blood vessels.
Their hunch was that these two cell types should be able to perform at least a
few of the vital functions of a normal liver.

The two types of cells did manage to organise themselves on the scaffold into
liver-like cavities, and the hepatocytes kept the physical appearance of
functional liver cells, proving that it is possible to grow the basic structural
unit of the organ in the lab. But by the standards of the clinic, the experiment
was not an overwhelming success. The organ never developed to the stage where it
could be easily transplanted into animals.

Atala has also tried to grow whole solid organs鈥攔at and mice
kidneys鈥攊n a flask. Although he managed to grow kidney-like 鈥渙rganoids鈥�
that appeared to produce urine when sewn into an animal upstream of its own
kidneys, the organoids are still a long way from being able to replace an
animal鈥檚 own. 鈥淭here are many unknowns. It is going to require huge advances to
make [solid] organs, and we don鈥檛 know when they will come,鈥� says Griffith.

But if you thought these hurdles would put off the tissue engineers, you鈥檇 be
wrong. They have simply toughened their resolve and are methodically attacking
each and every problem. Researchers such as Anderson are working to improve the
polymer skeletons, which in some cases do not dissolve completely in the body,
triggering inflammatory responses or interfering with the organ鈥檚 growth and
development. Different compositions could solve this problem.

Then there鈥檚 the issue of where you get your cells from in the first place.
鈥淵ou can have all the polymers you want, but if you don鈥檛 have the technology to
generate cells to replicate in large quantities, you are not going to be able to
get to the next step,鈥� says Atala. For the time being, the best option would be
to take cells from the person you want to make the organ for, eliminating
problems of organ rejection. But this would not be possible if the organ to be
replaced was badly diseased. And even if it was possible, getting adult cells to
grow and divide can be exceedingly difficult. In the future, it may be possible
to persuade cells taken from early embryos to develop into the types of tissues
you need, or coerce one adult cell type to transform into another (鈥沦耻辫别谤肠别濒濒鈥�,
快猫短视频, 24 April, p 32).

We will have to wait a while to see whether the tissue engineers will achieve
their goal鈥攍ivers, hearts and other complex organs engineered to
perfection like so many Rolls-Royce spare parts. But despite the roller-coaster
ride of successes and failures, this scenario does not seem quite as improbable
as it did 10 years ago. 鈥淭issue engineering is not ready for prime time,鈥� says
Niklason. 鈥淏ut it鈥檚 no longer just a pipe dream.鈥�