08/12/97 - 02:20 AM ET - Click reload often for latest version
When Isis recovered the mutilated remains of her husband, Osiris, she had at her disposal the powers of Egyptian gods to regenerate the body.
Alas, mortal humans must rely on science to regrow themselves.
But so far, so good.
Experts predict that within the next five to 10 years, people will routinely have blown-out tendons and cartilages regrown and bone loss restored for everything from cancer surgery to periodontal disease. Burn victims already benefit from patches of laboratory-grown skin, and studies are well under way for bioengineering nerves, blood vessels, organs, retinal cells, blood and bone marrow.
This week, a hundred or so researchers involved in these endeavors are gathered at Rice University, Houston, to discuss their strategies at an Advances in Tissue Engineering meeting. Almost 30 of them are presenting findings on subjects such as The Use of Mesenchymal Stem Cells in Tissue Engineering, Cell Adhesion and Adhesive Receptors, Extracellular Matrix Structure and Function, Cell Migration and Polymer Scaffolds.
Lucky Isis. Without any magic, scientists had to start from scratch.
They had to come up with primordial cells from mortal blood that they could grow in a petri dish and then morph into different types of tissues.
At the same time, they had to create biodegradable polymers and collagen scaffolds and porous calcium salt materials to give cells a structure to grow on. They had to find something sticky and pleasing to put on the surfaces of the materials to make specific cells want to grow there and to keep uninvited ones out.
Getting cells in place
Of key importance, too, they had to figure out how cells communicate with and respond to their environments, and how they get around.
Now they are accomplishing all these things and are poised to begin growing human bone, tendon and cartilage as one of the first milestones toward the goal of engineering all of the body's tissues.
"The field of cellular and tissue engineering is one in which everything is coming together," says Larry McIntire, director of the Institute of Biosciences and Bioengineering at Rice. "The science is coming along amazingly fast, the materials are coming along and cross-disciplinary research teams are beginning to be put in place now."
Arnold Caplan, director of the Skeletal Research Center, Case Western Reserve University, Cleveland, is among those at the forefront of engineering bone, tendon and cartilage.
"The reason you are alive," Caplan explains, "is that your body is constantly and continuously regenerating tissues. That means that cells are dropping dead and new cells are taking their place."
The simplest example of this is the blood cell. It lives for 60 to 90 days and then dies. Primordial cells in the bone marrow, called hematopoietic stem cells, make new blood cells and usher them into the bloodstream as replacements.
But there is a second, rarer type, called the mesenchymal stem cell, with a much more diverse job description. This cell has the impressive ability to give rise to bone, cartilage, tendon, teeth, fat and skin. It also is responsible for the scaffolding or connective tissue in the bone marrow, called stroma. As cells in these tissues die, the mesenchymal stem cell receives a series of cues and is mobilized to wherever it is needed and differentiates into the specific tissue that has called it to action.
Cell count drops
In a newborn, mesenchymal stem cells account for 1 in every 10,000 cells in the bone marrow. But the number declines dramatically with age to 1 in 100,000 cells in teen-agers to 1 in 400,000 cells by age 50 to 1 in 2 million cells at age 80. The decline of the cells is certainly linked to the decline in the ability of our bodies to regenerate naturally.
Mesenchymal stem cells have the power of Isis; they are, in a very real sense, our natural fountain of youth. And their ability to differentiate into so many types of tissues makes them ideal for tissue engineering.
"There is a need for tissues for the functional replacement of almost every type in the body," McIntire says. "Now there are tremendous advances . . . that allow to us think about it. People have talked about this in science fiction, but this is not science fiction anymore."
Caplan's team has developed a way to extract mesenchymal stem cells from bone marrow and grow them in the laboratory. "Now we can have buckets of a patient's own mesenchymal stem cells," he says. "The challenge is to figure out how to put the cells back into the body to regenerate tissues that the body couldn't possibly regenerate itself."
Among the first beneficiaries of bone tissue engineering will be cancer patients who have had large bone tumors removed, leaving gaps that cannot be repaired, and accident victims who have suffered crushing fractures. A number of labs, including Caplan's, are working with animals to prepare for such human trials.
Caplan's lab has shown that mesenchymal stem cells will transform into normal bone when exposed to bone cells in an animal. The trick is developing the best vehicle for humans to get the mesenchymal cells to the job site.
Where Caplan and his colleagues have excelled at getting the stem cells needed for the job, Tony Mikos and his team at Rice University are leading the way with the development of scaffolding upon which new bone can be grown.
"We are fabricating a highly porous polymer material, as porous as a sponge, that can accommodate a large number of cells that touch, grow and function," Mikos says. "The material provides the surface for the cells to grow on, and then eventually it is degraded."
Biodegradable supports are the most desirable because the new tissue will develop its own supportive matrix in time. Mikos' lab has designed materials that will dissolve at the same rate as the bone growth, so that by the time cells have matured the polymer has disappeared.
Getting bones to grow
Facial bones, such as a jaw removed for cancer, are of particular interest to Mikos and surgeon Michael Miller of the M.D. Anderson Cancer Center in Houston.
The current practice is to take bone from the hip or ribs and manufacture it into a new jaw. Engineering bone offers a much better alternative.
"The challenge is to form new bone in vivo," or in the body, Mikos says.
Bone growth poses a challenge because it requires a blood supply. Mikos' group has learned to to grow bone in vivo on a sheep by using its rib as a platform and an artery to feed the implanted cells. "That has great promise for reconstructive surgery," Mikos says.
For tendons and cartilage, Caplan and his team place mesenchymal cells into a collagen gelatin-like material. For cartilage, the cells are placed in a cube and then inserted into the damaged area. Animal studies show that holes cut into a knee cap and filled with the gel heal normally and completely. That is significant, considering cartilage does not grow back on it own.
For tendons, biodegradable surgical sutures are placed in a pencil-shaped mold where the cells essentially suck the water out of the gel, stick to each other and form tight bonds around the suture. When these are sewn onto a severed tendon, they grow into new tendons.
Importance of basics
All of this is possible because of decades of basic research on cell communication and migration, says Kyriacos Zygourakis of Rice University.
"Migration becomes important from the moment of conception," Zygourakis says. "As the cells divide and differentiate in a developing embryo, they need to move to specific places to make nerves and heart tissue and lungs and skin. Early development is a very active period when cell migration is the name of the game."
Knowledge gained from developmental research and studies of cancer metastasis, where cancer cells learn to spread to different tissues of the body, provides tremendous insight for tissue engineers who must get their cells not only to multiply but also to move and make room for new cells as they colonize.
Cells communicate chemically with each other and respond to chemical cues from their environment. The cues important to tissue engineers are those that tell cells to divide, migrate and differentiate into tissue, Zygourakis says.
Natural substances called growth factors contain cues for getting cells to multiply and to migrate. Substances called adhesive peptides hold the cues to encourage cells to stick to and colonize the scaffolding materials that are used to deliver the cells.
"Suppose you want the cells to grow in a certain area," Zygourakis says. "You create an area by adding adhesive peptides that the cells like and the cells will move fast and colonize that area."
It also is important to keep cells out. A goal of research on dental implants is to create new surfaces on the implants that will encourage bone cells to bind to it, but keep fibroblast cells away. Fibroblasts create fibrous tissue that interferes with the implants. The strategy is to place peptides that have no cues or signals for fibroblasts on the implant surface.
"The general goal is to engineer surfaces that will keep certain cells out while allowing other cells to come and grow," Zygourakis. "With the right peptides, the possibilities are endless."
Putting it together
After the scaffold and cell colony are transplanted into the body, say into a knee, the native cartilage sends signals that tell the stem cell population to transform itself into cartilage. The same cells placed in bone will receive signals from those cells and become bone. The same should hold true for any environment in which stem cells can be placed.
With advances in cells and materials and increasing knowledge of how to make them work together, science will achieve the ability to regenerate much of what ails our worn-out bodies.
"There are really no bounds to what we think we can eventually grow," says tissue engineering pioneer Gail Naughton of Advanced Tissue Sciences Inc. "We will redefine transplantation as it's done right now. What unites all tissue engineers now is the belief that we will be able re-create any tissue or organ."
By Tim Friend, USA TODAY
