The aphorism, "Use it or lose it," applies nowhere better than to bone. If you are a regular tennis player, the bone in your racket arm will increase. If you spend six "weightless" months in Space, as record-setting astronaut Shannon Lucid did recently, your "lazy" bones will lose mineral. Indeed, weight-bearing exercise is recommended to women as they age to ward off osteoporosis. External forces working on the bone help direct the constant reshaping that bones undergo.

University of Michigan biomedical engineer Steven Goldstein has spent the last fifteen years trying to understand what role mechanical forces play in the creation and maintenance of normal bone. Further, he has been applying that knowledge to counteract problems that arise when bone fails to develop properly, doesn't heal after fractures, or becomes brittle with age.

"Bone responds in specialized ways to damage, repair, and adaptation. Associated with that process are myriad clinical problems from fractures, arthritis, inherited disorders, and growth and development problems," Goldstein points out.

Goldstein says he strives to understand bone not only as a biological entity, but as a structure and a material. "Once you consider structure, you automatically bring in engineering-dimensionality, precise measurement, and characterization," he adds. While other scientists may ask how bone functions biologically, "we ask why it works that way, and how you make it work that way," he says.

Biologists have long understood that bone is a tissue capable of self-renewal. It is composed of widely-spaced cells embedded in a surrounding matrix material that is filled with collagen fibers and solidified by calcium compounds. Cells called osteoclasts are constantly dissolving the calcium compounds, making the calcium available to the body. "Craters" left into the bone by the bone-dissolving cells are promptly filled by osteoblasts, which build up the bone. Maintenance of normal bone depends on the fine balance between the bone building and bone dissolving cells. Mechanical forces seem to be critical to keeping this process in balance and orchestrate adaptation of bone through this reshaping process.

Goldstein's particular interest is in the role of mechanical forces on bone's overall shape, the organization the internal architecture of the bone, and the mechanisms by which the mechanical forces are "translated" through cellular biology into this microscopic architecture. With insights gained from his biomedical engineering studies, he works to find solutions to a host of medical problems.

"If we are going to make progress on the clinical front-whether we create a device or substrate for a worn-out joint, compensate for a genetic defect, or speed the healing of fractures-we need to better understand the structural, material, and biologic aspects of bone."

The Orthopaedic Laboratory that Goldstein heads is part of the section of Orthopaedic Surgery. There are nearly 100 projects underway, involving more than 60 people, including a talented group of clinical and basic science faculty, says Goldstein.

The laboratory has been responsible for developing some unique experimental models, using animals and human cadavers. In a pioneering analytic effort the laboratory is developing sophisticated computer modeling of bones and their responses to mechanical stresses, based on experimental results. On the patient care side, the laboratory has been involved in inventing surgical instruments and artificial joints.

Always, the laboratory strives to keep in mind the clinical problems to which its more fundamental studies may some day be applied, Goldstein says, naming joint replacement, osteoporosis, limb lengthening, limb development, and fracture repair as particular targets.

An example is a replacement knee that Goldstein developed with UM orthopaedic surgeon Larry Matthews. Called Instacone^TM, the knee is now in clinical trials at the UM. It is based on a common titanium knee replacement joint already in use. Normally, the replacement joint is anchored to the leg bones using acrylic cement, but the cement tends to fail after a decade or so.

Matthews and Goldstein have altered the ends of the prosthesis where it attaches to the leg bones. They've created a porous lattice that makes a framework for the growth of new bone into the prosthesis. The Instaconeª surface marshals the body's own bone growth to anchor the prosthesis in place. As the patient heals, new bone eventually grows into the holes in the prosthesis, and it is hoped, will provide a permanent anchor. The bone attachment could continually renew itself, just as all bone does, explains Goldstein.

The device is named for the cone-shaped projections on the attachments ends that are hammered into the leg bones, providing the initial stability of the device. Both the lattice design and the cone shapes were derived from research on how mechanical forces interact with bone, and the ways in which these forces direct bone growth. The objective is to nudge new bone growth toward a very stable configuration. If mechanical stresses where the bone meets the prosthesis are too light, the bone fails to maintain itself. If the stresses are too great, the bone is crushed.

Research is now underway to test whether, as it was designed to be, the new prosthesis is more secure and long lasting than knee replacements held in place by cements.

Meanwhile Goldstein's continues his fundamental studies of bone, the effect on bone architecture when implants of various designs are used, and responses to forces. The general hypothesis that guides his work is that bone forms and remodels in ways that optimize its structure for its functions. Mechanical strains on the bone are critical to this process.

One experiment that he and his colleagues devised reveals how the microstructure of the bone responds to specific mechanical loads. A tiny titanium chamber, about the size of a pencil eraser, is surgically placed within the femur of a dog. The dog recovers from the surgery in a day or two, and bone tissue grows into the chamber. That bone can be removed, and more bone will grow to fill the chamber.

Because the small chamber is isolated within the femur, the bone can be grown in the absence of any mechanical force. Alternatively, the growing bone can be subjected to mechanical force, which is applied by a small hydraulically operated plunger in the chamber. After a few weeks, the plugs of bone tissue are removed from the chamber and analyzed. Goldstein can compare tissues grown under varying applications of forces. He can alter the rate at which the load is applied, the amount of load added, and the frequency with which the load is applied.

Goldstein analyzes the bone using a unique tool housed at the UM called a microCT scanner. An X-ray based system with much finer resolution than the typical hospital scanner, it is used to analyze microscopically fine structures in three dimensions. MicroCT images reveal striking differences among the bone tissues grown under different mechanical loads. The no-load bone has widely spaced cells and few bony spicules. The load-grown bone is much denser.

Goldstein is also trying to determine how the mechanical forces act to alter growth. Among the questions are what bone-growth factors are stimulated at the growth site, how rapidly they act, when in the course of growth they appear, and what cells are involved.

Controlling Bone Growth

The biological, mechanical, and material properties of bone are all highlighted in another lab research focus: distraction osteogenesis. While it is best known as the limb-lengthening procedure, distraction osteogenesis has been applied to reshaping malformed bones, fracture repair, jaw repairs from periodontal disease, and other medical problems. Many questions remain about how it works, and how to make it work optimally.

The UM Orthopaedics Laboratory is undertaking a full scope of investigations from fundamental studies of the rate at which bone forms under various conditions, to mechanical engineering studies of the equipment used in the procedure, to clinical studies of the best way to make the procedure work for patients.

In the clinical procedure, thin wires are threaded through the patient's bone and attached to a metal frame that encases the outside of the limb, called a fixator. Then through a tiny incision, the hard outside layer of bone is sliced around, rather like girdling a tree by slashing through the bark for the circumference of the trunk. The interior of the bone is left unharmed. Several times a day the patient gives the nuts on the frame a turn, "stretching" the gap in the bone about a millimeter wider each day. If all goes well, over a few weeks the gap is filled by new bone. The frame applies the right amount of pressure and maintains the proper alignment to help create new bone to fill the gap.

Led by Goldstein and orthopaedic surgeon James Goulet, the laboratory is trying to determine the optimal forces needed to create high quality bone. "Limb lengthening creates a large volume of new bone. Bone shows particular patterns of cell growth and we want to know what makes bone go through that pattern. The pattern is affected by local mechanical stresses," Goldstein explains. The researchers are learning how the mechanical forces "translate" into the biochemical machinery that drives bone production.

"Once we understand the process, we can use it specifically in limb lengthening to make more bone, more rapidly, but it will have very broad applications."

Hitching Up Your Genes

In part, bone-formation depends on growth factors-body-generated proteins that initiate and regulate the bone growth. At the UM, pathology professor Jeff Bonadio has isolated some genes-specific stretches of DNA-that code for some of these proteins.

He has teamed up with Goldstein to use this DNA directly to treat fractures that don't heal properly. Americans suffer some 6 million fractures each year; about 1 million require surgery, and 250,000 of them fail to mend well. Often, these fractures require several operations and bone grafts. These injuries are responsible for $1 billion in medical treatment costs.

As the body tries to mend a fracture, its healing abilities are marshalled in a precise pattern. First, immune system cells flood the site to "clean up" the wound, taking away blood, dead cells, and debris. A few days later, a fibrous tissue fills the wound. Then progenitor bone cells drawn to the injury site from nearby tissues start to replace the fiber with good bone. Genes for bone growth factors "switch on," directing the cells to produce proteins that stimulate and regulate the creation of new bone. In those fractures that fail to heal-often shattering injuries where the fractured bone fragments cannot be joined tightly back together-the fibrous material is replaced by scar tissue instead of good bone.

The UM researchers are now trying to give the natural healing sequence a boost in the direction of bone growth rather than scar tissue formation. Bonadio and Goldstein have been joined by Robert Levy, a UM pediatric cardiologist. Levy, who is also a professor of pharmaceutics, has developed materials that release medical compounds over time.

The team has fashioned a novel system for delivering the DNA for bone growth factors to the wound sites. Instead of using one of the usual gene-therapy vectors, such as viruses, the researchers combine the DNA with a delivery matrix that promotes migration of the cells into the implant where they encounter the DNA. Transference of the genes into the bone repair cells turns them into temporary "pharmaceutical factories" that pump out these bone-stimulating factors.

It is hoped that this boost will lead to better healing. In tests that Goldstein and Bonadio have conducted in rats and dogs, it worked like a charm. In animals that received the DNA, the fractures healed; fractures treated the same way but without the DNA, failed to mend.

The researchers are conducting studies to see that the DNA remains at the wound site, rather disrupting other genes or stimulating bone growth in the wrong places. The researchers consider it unlikely that the DNA would wander far since the body breaks it down readily.

Also, the researchers are testing the bone that is created at these sites to see how well it compares to bone grown without the growth-factor "booster."

If the DNA delivery system works out as hoped, it could be used to promote the growth of many other tissues, including ligaments, muscles, and blood vessels, and it would be applied to many other medical problems, says Goldstein.

To refine the system and market the new technology, Bonadio, Goldstein, and Levy have formed a company with the University of Michigan, called Matrigen. Matrigen, in turn, funds some research through the team's laboratories.

Goldstein says his main contribution to the project stems from his engineering perspective. From the science side, a biologist might report, "I've discovered a gene that makes bone grow." Discovery is the objective. Perhaps it would be followed by the steps needed to make it into a potential therapy, or perhaps it would languish in the scientific literature.

The team engineering approach, Goldstein says, is to focus on solving a problem. "Here is the problem: wounds aren't healing. What is it that is needed? A gene that makes bone grow. How can the gene be delivered in a more specific way?"

The engineer thinks about problems "structurally, systematically, and quantitatively," says Goldstein. As research in the Orthopaedics Laboratory has increasingly involved biological aspects of bone, Goldstein continues to apply the engineering perspective. "In the Orthopaedics Laboratory, we try in all our research, to move from the very basic through the very clinical, and never have a break in that bridge."