In the song "Dem Bones," the thigh and shin bones are connected to the knee bone, and as with all other skeletal connections, the whole wondrous system is identified as "the work of the Lord." But even divine handiwork breaks or decays, and that's where biomedical engineer Steve Goldstein and orthopedic surgeon Larry Matthews step in, not as substitute deities but heavenly helpers, making artificial joints, improving new bone-like "glues" that help bones mend, and genetically engineering new tissue systems that stimulate bone cells to replace broken or weakened bone with fresh and strong bone.
In the U-M Orthopedic Research Laboratory (ORL) in the basement of the 400 N. Ingalls Building, Goldstein and Matthews are showing visitors the results of their 10-year collaborative project, the Instacone artificial knee. The Instacone is a testament to Goldstein's and Matthew's efforts, as Goldstein puts it, "to think like bone, and ask ourselves what forces turn bone on."
"Think of a bridge," Goldstein says, "in which little pieces of the structure are constantly falling off and need to be replaced quickly and effectively to keep the bridge standing and functioning during the whole process-this is what our skeletal system goes through.
"Now imagine that the repair process of a bridge is undertaken not by engineers and workers but by the bridge material itself. That is what bone does. Bone senses how it's being used and maintains a dynamic balance."
Bone's constant remodeling of itself involves complex mechanisms using special cells that suck up aging bone, and other special cells that lay down fresh bone. If bone is underused, as happens when astronauts travel in space, or even when a broken limb is in a cast, it thins and weakens. On the other hand, an overloaded bone thickens, strengthening the stressed area, as can be seen in the greater mass of a tennis player's dominant arm.
"If bone fractures under a load it can't take," Goldstein says, "it starts to heal. Nature can handle most repairs, but when a healer intervenes to help make sure the healing is straight and firm, both engineering and biology must be applied." Until our era, most improvements in orthopedic care derived from progress in engineering-better braces and casts, the invention 60 years ago of pins and screws that can stabilize fractures, and the development almost 40 years ago of artificial joints like the Instacone.
Each year, about 150,000 Americans receive surgical replacements of their knees. They usually need artificial joints because age or other metabolic factors, such as disease or injury, compromise bone's ability to lay down enough new bone to enable the entire bone to hold up under normal stress.
The Knees Have It
"The cartilage that forms the load-bearing surfaces of bones at the joints is lubricated with synovial fluid," Goldstein explains. "The joints so formed have spectacular properties; their coefficient of friction is lower than that of any man-made contact bearing-more slippery even than steel on ice. But this tissue heals poorly, and injuries and age weaken it and decrease the lubrication. If it deteriorates too far, bone winds up rubbing on bone." This is the condition that often requires replacement of the knee with an artificial joint and bearing surface.
While most artificial joints provide relief and support, their components loosen and break down much more quickly than natural bone does, usually after 10 to 15 years, Goldstein says, "although some last much less long, and some a bit more; this limited effectiveness makes it a form of treatment that we don't like to have to use on younger patients."
In the last 10 years, as more was learned about the biology of bone, physicians and engineers have increasingly begun to look for biological healing factors that could enhance, and perhaps one day replace, traditional therapy. "So far, most of the breakthroughs have been a mix of ways to stimulate biological factors through the use of engineering methods," Goldstein reports.
About nine years ago, Goldstein and Matthews decided to see if altering the shape of an artificial knee's interface surface could stimulate bone's natural tendency to grow and strengthen, and thus create a tighter attachment between man-made materials and bone. After testing many shapes they found that a cone-shaped, porous titanium cleat stimulated the natural bone remodeling process.
Exactly why bone likes this shape has not been determined, Goldstein says, but he thinks it is related to the fact that "bone encounters a whole spectrum of different forces and stresses along the whole surface of the cone," with stress high at the tip and tapering to a low point at the base.
Once the patient's tibial surface is prepared, reverse cone-shaped holes are drilled into the bone; the holes are very slightly smaller than the 16 cones. All are drilled in about 90 seconds, and the implant with its extending cleats is hammered into position. Over the next six to 12 months, bone decides where it would like to grow into and around the implant. Most artificial joints are held by a bone cement called methylcrylate, which is not an adhesive, but more like wood filler or grout. "It polymerizes and hardens once in place, but doesn't have ideal mechanical properties and is considered to be a possible weak link in the therapy," Goldstein says.
"While this concept of 'ingrowth fixation' has been investigated for nearly 20 years," he adds, "and is used in some clinical implants, success has been inconsistent. We believe that the major reasons that have limited this biologic fixation are related to the specific design geometry of the devices. Non-optimal designs may make it difficult to obtain initial stability of the implant immediately after surgery and provide inappropriate mechanical stresses at the implant bone interface, preventing optimal bone remodeling and ingrowth."
Dr. Matthews confides that "when I hammer the artificial knee into place, it looks strong as heck. That gives me a great feeling. We've had the Instacone in our first two patients for about a year now. It seems to be doing very well."
Goldstein says he hopes long-term tests show the Instacone is good for 30 years, because "that would make prosthetic joints a much more attractive therapy for patients in their 40s, 50s and 60s, who now face the prospect of a limited life expectancy for their artificial joints." But even if the Instacone meets his wish, it is still "only an interim solution to solving the long-term solution of joint disease."
Skeletal Repair Systems
Goldstein and other researchers suspect the long-term solution will involve "a biologically derived material to replace cartilage, or a way to induce cartilage to repair itself." This quest has carried Goldstein and his colleagues into the burgeoning field of tissue engineering.
With a $750,000 grant from the Whitaker Foundation of Washington, DC, Goldstein, co-principal investigator John Faulkner and 15 other faculty colleagues are developing research and training in the area of musculoskeletal tissue engineering. There are two main approaches in tissue engineering. One is aimed at replacing or augmenting damaged or diseased bone, tendon or muscles by stripping in a substitute tissue; the other involves biologically stimulating the growth of new, healthy bone, optimally by gene therapy.
An example of the first approach is the U-M lab's work with a mineral bone substitute that can be injected into a fracture, where it quickly hardens, stabilizing the bone and promoting rapid healing. It is especially useful in treating breaks in spongy, porous bone called trabecular bone, which forms near joints and is slower-healing than the denser bone on the shaft.
"We knew that the Norian Corporation of Cupertino, California, had developed a patented cement made of calcium phosphate, a mineral that is chemically similar to bone," Goldstein says. "The material mixes to a toothpaste consistency and hardens in about six minutes after injection at the site of fracture, where it forms calcium apatite, the main ingredient of natural bone."
The paste is so similar to bone that the cells that lay on new bone apply bone layers right on top of the material. "In time," says Goldstein, "it appears that the bone cells take the Norian away and replace it with natural bone. The material is currently under FDA clinical trials." Goldstein thinks the paste may improve treatment of fractures suffered by the elderly, improve the affixing of screws or rods to bone with poor density, and lead to an improved, biologically active grout to hold artificial joints.
Tissue of Lives
Perhaps the most spectacular new technology Goldstein and his colleagues are developing is a genetic engineering breakthrough in which they hope to use DNA, which encodes and directs the production of proteins, as a pharmaceutical.
While some tissue-engineering labs are growing the desired tissue cells on a dissolvable matrix and implanting this temporary scaffolding at the site where new tissue would replace it, Goldstein and his colleagues are working on a new therapy that would permit placement of DNA at the site. After receiving their own DNA "medicine," patients would become their own bioreactor and make the protein that the DNA codes for right at the spot of the injury.
Pathologist Jeffrey F. Bonadio, pediatrician Robert Levy and Goldstein formed a spin-off company, Matrigen, a few months ago to develop the new technology. So far, they're evaluating it to see how well it stimulates bone formation in fracture defects.
"How we deliver the genes is special," Goldstein says. "It's a time-released system governed by a delivery matrix. Say a fracture is not healing well. We'd like to inject our 'carrier matrix,' which would deliver the DNA to the site. The matrix solution solidifies in the site and stimulates the patient's own cells to produce bone.
"We're hoping our work leads to clinical trials in the near future. It's part of a broader effort in tissue-regeneration technology. If it works, it may be applicable to many other tissue and organ systems."
Farther down the research road, tissue engineering like that in the Orthopedic Laboratory may lead to "bioartificial organs" that can be developed in the lab from the patient's own cells and tissues, and then used to replace the damaged or dead organ.
"All of these developments," Goldstein says, "reflect our commitment to basic science in our lab. Our team includes basic scientists, surgeons, graduate students in bioengineering and mechanical engineering, medical students and post-doctoral fellows. We want our work to bridge from the molecular scale all the way up to the patient."
. . . October 1995