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December 2001
Vol. 4, No. 12, pp 34–38.
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Focus: Bioanalytical Methods
Feature Article
The mechanics of tissue engineering

CHRISTEN BROWNLEE

Just like spare parts for your car, science may someday provide replacement organs.

opening artWhether you drive the clunkiest clunker or the hottest hot rod, one thing is for certain: As mileage goes up, parts wear out and break. Even if your car is under warranty, pieces can lose their function early. And an accident can send your vehicle to the junkyard way before its time.

The same is true of your body—as it ages, wear and tear sets in. Parts do not work as well as they used to, and sometimes they stop working altogether. Often, tissues are not constructed properly from the very start, at birth. And a heavy trauma or devastating disease can damage some organs so badly that it’s impossible to stay alive without replacing them.

However, unlike car parts, components for the human body are not being churned out by the thousands at some factory in Detroit. Hearts, livers, cartilage, and bone are not stockpiled on shelves, getting dusty while waiting to be implanted in the next lucky recipient. And corneas and blood vessels cannot be shipped on demand to your trusty surgeon if he or she needs to swap a bad part for a good one.

Not yet, at least.

But in the near future, this seemingly impossible picture could become a reality—thanks to the burgeoning field of tissue engineering, a multidisciplinary science that aims to regenerate natural tissues and create new ones using cells, biomaterials, biotechnology, and clinical medicine (1). Its main goal is to provide new human tissues or acellular vehicles that can induce regeneration of existing tissue by delivering drugs or genetically engineered cells. Tissues created by these methods might be the patient’s own genetically, or they could be composed of cells from another donor. They might be swapped for diseased or damaged tissues in the body, but they also could be studied outside the body as models for drug delivery.

Scientists in the field have had numerous successes, some of which have led to products now on the market, including several types of replacement skin and a cartilage substitute. But future successes depend on overcoming several obstacles, including preventing immune reactions against synthetic and biological components introduced into the body. Vasculature also must be induced to grow into tissues so they will be supplied with blood.

Overcoming these difficulties could lead to untold benefits for humankind—repositories of healthy organs and tissues always available for those in need.

A storehouse of spares
Unlike replacement parts for even the rarest vehicle, most human parts are virtually impossible, as yet, to replace when they are damaged. According to a study performed in 1993 by tissue engineers Joseph Vacanti (Children’s Hospital, Boston) and Robert Langer (Massachusetts Institute of Technology), 8 million surgeries are performed annually in the United States to treat tissue loss and organ failure. Yet every year, 4000 people die while waiting for an organ transplant, and at least 100,000 die without even qualifying for the waiting list. More than $400 billion is spent each year in the United States on patients suffering from organ failure or tissue loss, accounting for almost half the national health care bill (2).

Clinicians have conventionally used three different approaches to treat patients with diseased or damaged tissue. The first, called autografting, involves removing a patient’s own tissue and transplanting it elsewhere in the body. Doctors use autografting for coronary bypass operations, in which a saphenous vein from the leg is grafted onto a blood vessel in the heart, and in skin grafts for burn victims, among other uses. Autografting is an excellent way of avoiding immune system reactions—no foreign tissue is used—but it entails the difficulty of creating a wound elsewhere in the body.

The second approach, called allografting, involves harvesting tissues or organs from a donor, either a cadaver or a living donor, for transplant into the patient. A wide array of organs can be moved from one person to another, including the liver, kidneys, heart, and lungs. But because these tissues are foreign, they inevitably evoke a hazardous response from the patient’s immune system, and sometimes graft-versus-host rejection is also a problem. To avoid tissue rejection, people with allografted tissue must take immune-suppressing medication for the rest of their lives. (See also Targeted T-cell Destruction.)

The third option is to create a completely synthetic replacement for the bad organ or tissue. Doctors have had varying success with artificial heart valves, hips, knees, and breast implants, to mention the most common replacements. But these stand-ins do not behave identically to true tissues and organs—they cannot grow or change in response to biological stressors.

“There are many more diseased parts than there are replacements available,” said Dan Dimitrijevich, director of the laboratory for cell and tissue engineering at the University of North Texas Health Science Center in Fort Worth. “Most of the time, the replacements are not from optimal organisms, obviously; otherwise they wouldn’t die. There are very few accidents, really, when you come to think of how much tissue you need to take care of a number of problems.”

Just a patch
Amateur mechanics can fix many things with a roll of duct tape. Similarly, clinicians seeking to replace damaged tissue know that sometimes a patch is all you need. Research on the use of engineered tissue to patch up heart muscle, liver, and bone has been promising. But the tissue that has been patched with the most success is skin.

As early as 1979, Eugene Bell, professor emeritus of biology at the Massachusetts Institute of Technology and the founder of the tissue-engineering company Organogenesis, figured out how to grow skin in his laboratory (3). Today, many skin replacement products are available on the market. Not only do they provide protection while a patient’s skin grows back, but they are able to substantially boost the natural skin’s capacity to grow back on its own.

Having earned FDA approval in 1998, the leading tissue-engineered skin product is Apligraf, produced by Organogenesis and distributed by Novartis Pharmaceuticals. According to Vincent Li, a tissue engineering expert and director of the angiogenesis and wound-healing clinic at Brigham and Women’s Hospital in Boston, Apligraf is a living skin equivalent. It looks like skin and behaves like skin because, simply, it is skin.

Apligraf has a dermis and an epidermis, and it is derived from human skin removed during infants’ circumcisions. “Most people just throw [the foreskins] into the garbage,” said Li. “Well, it turns out that a small, postage-stamp-size piece of foreskin is enough to actually expand out to seven football fields worth of skin.” Infant foreskin is an ideal germinating material for creating replacement skin, he added, because it is some of the healthiest skin around: “It hasn’t had any type of exposure, it’s brand new, and it hasn’t gone through the types of cell divisions that will actually cause skin to age.”

Growing a spare
But sometimes duct tape just will not do the job, and a whole new part is needed to get an automobile—or a human—up and running. Some tissue engineering scientists are focusing on making entire organs from scratch in a laboratory.

How does one go about constructing a new organ? With a little luck, lots of patience, and an engineered scaffold made of biodegradable materials.

The basic concept for a great deal of organ construction originated in 1986, when Vacanti and Langer hit upon an ingenious idea: Make a scaffold out of a biodegradable polymer matrix, and shape it to fit any space. Then seed it with cells, bathe it with growth factors, and watch it grow. The cells in the scaffold multiply and differentiate into various types—an activity not seen when cells multiply in a monolayer, as in a petri dish—and after implantation in the body, the scaffold eventually dissolves. All you’re left with is a functioning organ made of real, active tissue (2).

If cells from a donor are used to seed the matrix, then the resulting organ has the same drawbacks as a typical donor organ transplant: an immune response from the new host and, ultimately, rejection unless antirejection medication is used. But in the case of a long-spanning illness or elective surgery, the patient’s own cells could be used to seed the scaffold, resulting in an organ that is genetically the patient’s own.

But challenges abound in creating whole, living organs outside of the body. Researchers have not yet figured out how to induce angiogenesis, or the formation of blood vessels, in these constructed organs. “It’s an area that people are very aware of—the point at which we can go from ‘here is a patch of tissue’ to ‘here is an actual organ or a more complex tissue structure,’” said Tejal Desai, a professor of biomedical engineering at the University of Illinois in Chicago.

Desai’s research group and others in the field are trying to solve the problem by using several methods. These include creating conduits and topographical clues in the tissue that stimulate blood vessel formation, and seeding those areas with vascular endothelial growth factors.

Another challenge for researchers in creating large and complex organs, such as the heart or liver, is learning the intricacies of each tissue type that exists there and figuring out how they all work to make up a harmonious whole. Although researchers have been studying these organs for centuries, said Vincent Li, there is a major difference between learning how to fix a diseased organ and understanding how to build a new one. “Does it secrete something, does it digest something, does it metabolize something, and what are all the proteins and molecules involved in those processes? You have to be able to reconstruct every one of those,” said Li.

Keep wishing, cars

The stem cell connection
Four days after the union of an egg and a sperm, the rapidly progressing zygote gives rise to a blastocyst, a hollow ball of cells. Inside the ball is a cluster of cells called the inner cell mass. The cells in this mass are special—they are what scientists refer to as pluripotent stem cells. They can become almost any tissue in the body, with the right type of stimulation.

Adults also have small numbers of stem cells in various tissues of the body, although their stem cells are only multipotent. They are already partially differentiated along a particular developmental line. For example, an adult blood stem cell can become a red blood cell, a white blood cell, or a platelet. But it cannot, in most circumstances, become a liver cell.

Scientists in many research areas are excited about the potential of stem cells, both the pluripotent variety available from human embryos and the multipotent variety available from adults. The study of these cells could help us understand diseases that involve errors in cell differentiation, such as cancer or birth defects, and they could be a boon to drug development and testing. And for researchers in tissue engineering, stem cells could be the magic bullet for addressing a host of tissue propagation difficulties.

Depending on the chemical cues that scientists deliver to stem cells after they are placed on a biodegradable matrix, any organ in the body could be created. The possibilities are limitless—an unending supply of any tissue or organ could be available for study or patient treatment.

“We really have no idea how these cells react in different environments and what they’re going to do,” said Jennifer Elisseef, a biomaterials expert at Johns Hopkins University in Baltimore. “Their potential to do things is so great. Anything you do to them comes out with an interesting result.”

One thing real tissue can do—which cars cannot—is fix itself. The final goal of tissue engineering is to stimulate the body to do just that—to heal itself so further intervention is no longer necessary.

In 1965, Marshall Urist of the University of California, Los Angeles, discovered that animals injected with powdered bone formed new bony tissue at the injection site. Later, scientists found that growth factors alone, isolated from the bone, could evoke the desired response (3). Nowadays, researchers are testing numerous other growth factors to see if they can stimulate the regeneration of tissue.

According to Li, the future of tissue regeneration might rely heavily on changing the genetic makeup of engineered substitutes so that they produce additional growth factors, beyond the usual amount. A recent study performed by Dan Medaglia and Jeff Morgan of Shriners Burn Hospital in Boston showed that a skin substitute genetically engineered to synthesize and deliver keratinocyte growth factor, a thickening agent, produced new skin that was tougher and thicker than skin produced without the growth factor. Tougher skin would be better than fragile skin for wound healing.

“Scientists are saying, ‘Why don’t we just introduce extra genes, why don’t we rev up the process and see if we can get it to happen even faster?’” said Li.

This type of regeneration, as well as advances in tissue and organ creation, were unheard of a few years ago, he said. But many in the field believe that the technology they have already created is just the tip of the iceberg in terms of what they will be able to do in the future.

“We are starting to understand the biology of human processes and cellular processes down to a very fine molecular level,” said Li. “Science moves at an incredibly rapid rate. Not too long ago, people thought we would never put a man on the moon.”

References

  1. Tissue Engineering Network. www.tissueeng.net/.
  2. Artst, C. Biotech Bodies. Business Week, July 27, 1998. www.businessweek.com/1998/30/b3588001.htm.
  3. Mooney, D. J.; Mikos, A. G. Growing New Organs. Sci. Am., April 1999. www.sciam.com/1999/0499issue/0499mooney.html.

Further reading

  • Principles of Tissue Engineering; Lanza, R., Ed.; Academic Press: San Diego, 1997.


Christen L. Brownlee is an assistant editor of Modern Drug Discovery. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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