By Corinna Wu
used to think that artificial devices were the way to go when someone
needed a new body part, but now they're finding that skin,
boneseven the heartcan be created using the body's
been called cyborgs, vital machines, and bionic men and women.
Characters who are part human and part machine have inspired countless
science-fiction stories. In that vision of the future, space-age
materials and electronics not only replace damaged flesh but make
it better than beforebestowing new strength and power on
the human body that nature alone might not ever provide.
at the beginning of the 21st century, scientists are crafting
another visionone that's more realistic but no less
fantastic. They've discovered that the body's own tissues
are really the superior materials, perfectly suited for their
intended purposes. Bone, for example, is strong, flexible, and
self-healinga characteristic that steel or titanium has
yet to acquire. Scientists and engineers are calling on all their
creative energies to replicate the physical and chemical properties
of materials that nature created, slowly, over millions of years.
been an evolution of thinking in this whole field, says
Michael Miller, a plastic surgeon at the M.D. Anderson Cancer
Center in Houston. In the past, everyone expected to have
artificial parts to replace living parts, but it's becoming
clearer that having a living part is going to be much superior
to having an artificial part.
To that end,
researchers are searching for ways to grow human tissues from
the bottom up: In the mid 1980s, the National Science Foundation
created a program called Emerging Technologies Initiation, whose
purpose was to fund high-risk research with strong potential in
the early stages. One of the first areas funded was tissue engineering.
NSF poured about $2 million into the project, and required the
research teams to include scientists from several disciplines.
By working together today, individuals with backgrounds in biology,
chemistry, medicine, and engineering are developing techniques
to encourage the body's own tissues to regenerate. They're
doing this by tapping into the potential of stem cellsimmature
cells that have the ability to develop into many different tissue
types in the body. Researchers are also making artificial scaffolds
to support and guide tissues during their growth. It will be many
years before scientists have the ability to create custom-made
organs and replacement parts, but they are closer than ever before.
has made many once life-threatening injuries and diseases almost
routine to cure. For the patient, however, the results of treatment
can sometimes cause as much distress as the initial trauma. A
treatment that involves surgery, perhaps removing a tumor or repairing
a wound, sometimes leaves large openings that the body simply
can't return to its original state.
surgeons do have ways to minimize these so-called defects. They
can perform what's known as an autograft, replacing missing
tissue with the patient's own by taking it from another part
of the body. Tissue engineers commonly describe this dilemma as
robbing Peter to pay Paul. This solution, while workable, is not
ideal. Sometimes, there simply isn't enough tissue to take,
and more importantly, a second defect is being created in order
to repair the first one. Take bone, for example. The limitations
of current surgical ways of replacing bone are that you have to
destroysacrificean existing bone in order to reconstruct
a more important bone somewhere else, says Miller. So
there's a loss involved that becomes a trade-off the patient
has to make.
more, Miller adds that remolding a bone is a difficult skill for
surgeons to learn and to get right. It's a technical
challenge to change the shape of a bone into the right shape that
you need. You have to take a straight bone, say, and make cuts
in it, and use plates and screws to create the right shape. It
would be better if we could actually have a bone of the right
shape grow in the patient.
is to use an allograft, which is tissue from another person, most
likely a cadaver. Although donated tissue might be in greater
supply, says Michael Yaszemski of the Mayo Clinic in Rochester,
Minn., it still has its limitations. We can take their femurs,
their tibias, their ribsbut again, that doesn't fill
all the needs that we have.
raises other troubling issues. It introduces the possibility of
rejection by the recipient's body, and although donated tissue
is screened and processed, the risk of disease transmission still
remains. When an entire organ needs to be replaced, the only option
is to get it from a living donor, which usually means being placed
on a long waiting list.
vision of bionics notwithstanding, for years doctors have used
artificial materials such as metals, ceramics, and polymers as
substitutes for tissues like bone, fat, and cartilage. Artificial
hips and joints, breast implantseven cavity fillingsare
all devices that restore the body's function or appearance.
But as sophisticated as those replacements may be, they are still
foreign objects, and the body will sometimes mount an immune reaction
even durable materials like stainless steel wear down eventually,
and without the ability to heal, those devices eventually will
need to be replaced. A metal stem in a person who's
70that's not a problem we're looking to solve,
says Yaszemski. That person gets an hour and a half operation,
and there's a high likelihood that is the end of their problem
for the rest of their life. But if you're 20 and break your
hip in a car accident, and you get a total hip [replacement] when
you're 22, you can count on many return trips to the operating
room in your life.
far the best solution is to fix a wound with real, living tissue
that becomes completely integrated with the patient, as if the body
healed of its own accord. And then that replacement tissue can keep
repairing itself long after an inorganic material has worn away.
have made great advances toward engineering implantable tissues
that work almost like the real thing. They're working on
ways to grow almost every tissue in the body: liver, bone, muscle,
cartilage, blood vessels, nerves, pancreatic cells, and more.
have been grown outside the body for years. But simply letting
cells flourish inside a test tube isn't enough. The cells
need to arrange themselves in three dimensions, forming the complex
spatial and biochemical relationships that turn a conglomeration
of cells into functional tissue. That is what happens as a body
grows and develops. So now, the challenge for tissue engineers
is to decipher the myriad biochemical and physical conditions
necessary for duplicating that process.
have already had success growing certain types of tissues, like
skin and cartilage. Replacement skin is used for burn victims
or for people who have diabetic ulcers. These lab-grown skin products
have been in use for more than 10 years, but they aren't
much more than temporary covers, according to Miller.
made out of collagen gels, so they don't have good mechanical
stability, adds Stelios Andreadis of the University of Buffalo
in New York, so he and his colleagues are trying to take the technology
one step further by genetically engineering skin to promote its
healing potential. Building on work he did at the Shriner's
Hospital for Children in Boston, Andreadis and his colleagues
are transferring genes for keratinocyte growth factor (KGF) into
dramatic changes to the three-dimensional organization of the
skin, says Andreadis, promoting growth of skin cells and producing
much thicker tissue. Unlike existing types of lab-grown skin,
their engineered skin contains the basement membrane, or the matrix
molecules that epidermal cells like to sit on. So far, the engineered
skin has been tested only in animals and needs much improvement
before it can rival genuine human skin, he says. For instance,
the skin has no sweat glands, hair follicles, or nerves.
of implanting cartilage, called autologous chondrocyte transplantation,
is currently on the market, says Yaszemski. It consists of growing
cells in a solution that doctors can then transplant into a cartilage
defect. The cartilage that's available is just a space-filler
more than a living tissue, says Miller. In some ways, it's
been one of the easier tissues to engineer because all of its
nutrition is derived from diffusion from joint fluid, meaning
it doesn't need a blood supply.
ways, however, cartilage is just as challenging as any other tissue.
Cartilage is a whole different approach from an engineering
and biological perspective, says Yaszemski. If the
bone gets injured, if we can jump-start it, it does a pretty good
job. Fractures heal. But arthritis doesn't heal, so cartilage
damage doesn't heal. Mechanically, it has to provide
low friction movement at joints and attach to bone on one surfacea
nontrivial problem. Yaszemski says that cartilage could benefit
from research that takes a true engineering approach.
in particular that interests many researchers is bone because
there's such a great need for it. A doctor might want extra
bone to repair a congenital deformity, says Yaszemski. Other
needs we have are bone loss from trauma. A gunshot, a land mine,
a motorcycle accident may leave a person with a large defect in
an arm bone, a leg bone, or pelvis. We need some bone to fill
this in. Also, bone is the tissue many scientists feel is
next in line to being used in people.
people look at bone as an inanimate structure, but bone is very
vibrant, vital tissue, says Jeffrey Hollinger, a researcher
at the Bone Tissue and Engineering Center at Pittsburgh's
Carnegie Mellon University. Bone is a continuously renewing tissueso
much so that every 10 years, the skeleton is completely replaced,
for scientists is to tap into that self-renewing potential and
guide it. More so than other types of tissue, bone is a structural
material. It needs to hold a particular shape, and if it's
in an arm or leg, it needs to support weight. That is why scientists
are looking not only at the biology of bone but also its engineering.
to engineering tissuewhether it's bone or something
elserelies the most on the body's own resources, encouraging
the bone or other tissue to heal itself. The strategy is to identify
molecules that cause cells to migrate to a site, proliferate,
and connect together. Injecting those molecules into a wound can
then help enhance healing.
scientists prefer giving the cells something to grow on. Real
bone cells deposit themselves on a matrix that's a composite
of an organic material, collagen, and an inorganic material, calcium
phosphate. That's the central theme of tissue engineering:
working on the interaction between scaffolds, cells, and signals,
Yaszemski says. The signaling molecules exist in nature,
and by and large we try to use them. But the scaffold is the thing
that we have control over. We try to engineer its necessary mechanical
properties, its process properties, and its biologic properties.
used for these scaffolds vary. They can be natural materials like
collagen or synthetic materials like glasses, polymers, metals,
and ceramics. Polymers are the most useful by far, says Yaszemski.
Scientists can control the chemistry of polymers, so the materials
can be made to degrade harmlessly in the body. Researchers can
also choose appropriate chemical groups to modify a polymer's
surface in order to encourage the growth of cells.
like Antonios Mikos of Rice University in Houston are working
on making synthetic polymers that can serve as scaffolds for cells.
The idea is to seed the polymers with cells and to allow new tissue
to grow and take the shape of the scaffold. The materials can
be impregnated with bioactive molecules that slowly leach out
and encourage cell growth. Eventually, the synthetic material
would degrade, leaving the newly formed tissue behind.
porous polymers can be carved into precise shapes. A paper in
the May 2000 issue of the Proceedings of the National Academy
of Sciences showed remarkable before and after photos that demonstrated
the possibilities of this approach. Robert Langer and his group
at the Massachusetts Institute of Technology carved a nose out
of a porous polymer and seeded it with bovine cartilage cells.
The cells proliferated while the polymer broke downleaving
behind a juicy pink nose, looking like its owner took it off and
put it down on the table for safekeeping.
doctors have to consider with this approach is having access to
the site of the defect, says Yaszemski. To make an enormous
access hole would be to make more damage to the person.
Doctors don't want to create a bigger wound just to put a
new piece of bone or other tissue in, so he and his colleagues
have been working on injectable polymers that can take the shape
of the wound.
have even tried more creative scaffolding materials. In the May
17 New England Journal of Medicine, Charles Vacanti and his colleagues
at the University of Massachusetts Medical School replaced a missing
thumb bone with one carved from a piece of coral.
will be many years before scientists have the ability to create
custom-made organs and replacement parts, but they are closer than
a well-chosen scaffold, the replacement tissue is only as good
as the cells that grow to fill the space. Some groups are considering
stem cells as seeds to be planted on these synthetic scaffolds.
Many scientists feel that stem cells taken from embryos and fetuses
hold the most potential, but those sources have also raised the
most controversy. Stem cells have also been identified in adults
for many tissue types. Recently, researchers at the University
of Pittsburgh and the University of California at Los Angeles
found that stem cells taken from human fat could grow into bone,
muscle, and cartilage, as well as fat. And if the stem cells are
harvested from the patient, there's no risk of rejection.
is to simply put chemical attractants on the scaffolds to draw
the body's own cells to the defect, says Yaszemski. If
I had to say what's the ideal strategy, I would think that's
ideal because it could all be done at one operation and wouldn't
require harvest of cells from the person. But he adds that
these approaches are early enough in their conception that each
could be useful in different situations.
why the first successes in tissue engineering occurred in skin
and cartilage was because they could be made viable even without
a blood supply. But for bone and other tissues, that's not
an option. They need to constantly exchange nutrients, waste products,
and chemical messengers with the blood to be truly functional.
One of the biggest challenges for tissue engineers is hooking
up these tissues to the body's circulatory system. Adding
molecular factors that encourage blood vessel growth, or angiogenesis,
to the mix could be the key.
his colleagues are working on a technique of growing bone that
automatically incorporates a blood vessel network into the tissue.
Their concept is to allow the body to grow a new piece of bone
in a healthy, uninjured area of the body. To do this, they implant
shaped plastic molds under the periosteum, which is tissue that
lines bones. It's specialized tissue that has all the
equipment to make bone, Miller says. Our thought has
been to take advantage of that property, and try tpinduce and
guide bone formation from it.
would be a good place to carry this out, Miller says, since it's
protected and has a healthy periosteum. In sheep, growth of a
piece of bone takes about 6 to 9 weeks. Just how long to leave
in the mold is one question the researchers are trying to answer.
Leaving it in longer results in a more mature bone, but leaving
it in too long allows some of the bone to be reabsorbed by the
how well-engineered a piece of tissue might be, there are many
limits to how much a patient can benefit from it. Even after implanting,
the age or general health of the patient could hinder the body's
ability to heal and integrate that tissue, says Hollinger. Older
people have fewer and poorer functioning bone cells than a young
person, and there's sometimes an imbalance between bone resorption
and bone forming, which can lead to osteoporosis. Any bone replacement
strategy will have to take that into account.
assess the state of the tissue engineering field, Hollinger says,
If you're looking at kindergarten to post-grad, we're
still in third grade. Autograftsrobbing Peter to pay
Paulare still the best choice at this point, he notes. Using
tissue from donors is next.
so many other fields, advances in computer simulation will walk
hand-in-hand with advances in biology and materials science. That
is going to be an important part of whatever we do in tissue engineering,
says Miller. We're going to have to individualize the
recipes that we devise for tissues so that in any particular patient,
we know exactly how much of each ingredient we need to make tissue
for them. In addition to working on surgical methods, Miller
and his group are developing scanning techniques to calculate
how much tissue is needed to repair a defect.
nature of tissue engineering brings up other challenges that can't
be solved at the lab bench. In addition to exploring the mystery
of cell communication, scientists also need to improve communication
among themselves, Yaszemski says. Researchers with expertise in
a wide variety of fields need to learn how to talk to each other
at every step along the process. If you have a lapse of
communication anywhere along the line, every one of those things,
minus one, could be perfect, and it won't work, Yaszemski
For the researchers
like Yaszemski and Miller who see patients in addition to working
in the lab, their work takes on a particular urgency. Practically
every patient I see, I envision how if we had this technology
available, it would make taking care of that person so much more
predictable and so much less risky, says Miller. It
might take a number of years to work out details before it becomes
a routine thing, but I feel confident we'll arrive at a point
where this does become a routine way to replace tissues in the
future. But we have to be patient.
Wu is a freelance writer based in Washington, D.C.