ASEE Prism Magazine - Oct 2001



Last Piece of the Puzzle

- By Corinna Wu

Researchers 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, bones—even the heart—can be created using the body's own tissue.

They've 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 before—bestowing new strength and power on the human body that nature alone might not ever provide.

But now, at the beginning of the 21st century, scientists are crafting another vision—one 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-healing—a 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.

“That's 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 cells—immature 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.


A Better Way?

Modern medicine 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.

Currently, 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 destroy—sacrifice—an 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.”

What's 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.”

Another solution 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 ribs—but again, that doesn't fill all the needs that we have.”

Using allografts 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.

The popular 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 implants—even cavity fillings—are 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 against them.

Moreover, 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 70—that'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.”


The Real Thing

By 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.

Researchers 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.

Human cells 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.

Scientists 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.

Many are 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 skin cells.

KGF induces 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.

One method 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.

In other 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 surface—a nontrivial problem. Yaszemski says that cartilage could benefit from research that takes a true engineering approach.

One tissue 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.

“Lay 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 tissue—so much so that every 10 years, the skeleton is completely replaced, he notes.

The challenge 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.


Laying the Groundwork

One approach to engineering tissue—whether it's bone or something else—relies 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.

But many 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.”

The materials 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.

Scientists 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.

These light, 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 down—leaving behind a juicy pink nose, looking like its owner took it off and put it down on the table for safekeeping.

One issue 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.

Some researchers 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.


Boning Up

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.

Even with 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.

Another approach 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.

One reason 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.

Miller and 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.”

The pelvis 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 body.

No matter 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.

Asked to 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.” Autografts—robbing Peter to pay Paul—are still the best choice at this point, he notes. Using tissue from donors is next.

And like 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.

The interdisciplinary 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 says.

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.”

Corinna Wu is a freelance writer based in Washington, D.C.