Medicine: Making Bones About It
The splints, casts and, more recently, metal, ceramic and titanium implants used to align broken bones while they heal are better suited to repairing engines than living bodies, say orthopedic surgeons at the Hadassah–Hebrew University Medical Center at Ein Kerem.
They point to research into bone-building technologies suggesting that broken bones may be among the first ailments to benefit from biological therapies initially from stem cells and perhaps ultimately from gene therapy.
“Fractures are very common and impact badly on quality of life,” says Dr. Meir “Iri” Liebergall, head of Hadassah’s Orthopedic Surgery Department. Thousands of patients stream into his department each year with their bones cracked, snapped or splintered by falls and mishaps at home or at work, by road accidents or by the violence of terror and war.
At hadassah, we perform up to 3,000 surgical procedures a year to help heal these painful and disabling injuries,” Dr. Liebergall notes. “Current methods of fracture repair are, however, imperfect. Healing is usually slow. The tibia, or shinbone, for example, the second longest bone in the human body, takes three to six months to knit together, while the patient is immobilized or hobbles on crutches. Even more troubling are the 10 to 15 percent of all fractures that don’t heal well or don’t heal at all, resulting in long-term disability for thousands.”
Hadassah’s orthopedic surgeons and researchers, like their colleagues around the world, are working to improve and to speed the healing of fractured bones. “Today, our emphasis is on a biological rather than a mechanical approach,” says Dr. Liebergall.
Mechanical intervention is the time-honored way. Bone is rigid. Fracture disturbs its rigidity, and so the fracture is stabilized to promote healing. The most common form of stabilization is from the outside in the form of splints or plaster casts, but many kinds of implants to hold broken bones together have also been developed.
“The mechanical approach is being constantly improved,” he explains. “But however much it is improved, it can never do more than hold broken bones in place while nature heals at its own pace. What we are looking to do is increase the speed at which new bone grows, and so shorten the healing process.”
This will alleviate two situations that are clinically very different. One is the simple fracture. Accelerating bone growth will shorten the time it takes for the two snapped ends of bone to unite firmly together. “If the average healing time for a broken tibia is three to six months, we’re looking at how we can ensure it will be three months rather than six,” says Dr. Liebergall. “And if we can bring it to three months, why not three weeks?”
The other type of skeletal injury is that of bones crushed or shattered in high-impact injuries—for example, on roads or by explosives—where there is significant loss of bone tissue. Excessive bone loss can mean that a fracture never fully heals or, if it does heal, may leave the injured leg or arm shorter than its pair. It can even result in amputation. Promoting bone growth to replace destroyed tissue will enable full recovery in these patients.
It is here that orthopedics switches its traditional focus from mechanical to biological healing. “What we’re trying to do today is help create new bone tissue to bridge damaged bone fragments,” says Dr. Liebergall.
Strictly speaking, the biological approach was in use as long ago as the 1930s, when surgeons began using undamaged bone from another part of the body as replacements. Orthopedic surgeons still use this method; they harvest bone—usually from the patient’s pelvis—and graft it onto the fracture site.
The technique has, however, several major disadvantages: It requires at least two open surgical procedures and is therefore hard on the patient. In addition, healing is slow and the results are not always good.
“Modern orthopedics is trying to develop a technology that grafts not bones but cells,” says Dr. Liebergall. “Cells are the cornerstones of any healing process. If we bring to fracture sites large numbers of infant cells that will grow into bone cells, or osteoblasts, they’ll build new bone tissue where it’s needed, shorten the healing process and spare patients the two trips to the operating room required for harvesting and grafting of bone.”
New cells are born and nurtured in bone marrow. Researchers at Hadassah and a number of other medical centers worldwide are injecting healthy bone marrow into fracture sites to help hard-to-heal breaks mend.
“We’ve injected fracture sites with bone marrow in hundreds of patients during the past five to six years, with good results,” says Dr. Liebergall. “This has led us to favor an aggressive approach to all fractures with a reputation for delayed healing or for nonunion. We administer bone marrow injection as early as possible to prevent complications and delay.”
Although results have been encouraging, the technique can be further improved. “Not every part of the marrow is needed for healing,” he explains. “More than that: It remains a hard treatment for the patient because whole bone marrow must be extracted from the pelvis.”
The hadassah team has thus turned its focus to stem cells, the building blocks for all human tissue that are produced in the bone marrow.
“The importance of stem cells is well known,” says Dr. Liebergall. “What we sought to do was find a way to isolate from the patient’s bone marrow those stem cells that will grow into bone cells.”
The technology targets a type of stem cell (mesenchymal stem cells or MSC) that is found in human bone marrow in small quantities. MSC are primordial cells, able to reproduce and specialize into cells that regenerate tissues of the musculoskeletal system.
This made-in-Hadassah technology, as yet practiced nowhere else, is now beginning clinical trials. “Twenty-four young adults, most of them road accident victims with fractures that are at high risk for healing poorly”—either because of the break’s location, infection or devascularization of the bone—“will volunteer for the study,” says Dr. Liebergall. “All will have their fractures set, as usual, in our operating rooms.
“But after that,” he continues, “we will divide them into two groups. One will be sent home to heal, serving as a control group. In the other, we will harvest bone marrow, which will be taken to our lab where scientists will use our new technique to isolate the MSC and spike them with material that stimulates bone formation. Then we’ll inject this bone-healing package into the fracture sites, guided by X-ray fluoroscopy.”
Dr. Liebergall and his team believe that this trial will demonstrate the validity of the new technique. “We expect to show that injecting MSC into the fracture site is an answer for fractures that heal imperfectly and for those that heal slowly,” he says.
If their expectations are borne out, the Hadassah team sees MSC injections becoming routine.
“Bone repair is an ideal candidate for stem cell therapy because it enhances a natural repair process,” says Dr. Liebergall. “Harnessing the healing potential of stem cells will benefit patients of all ages, whether their need is joint replacement, spinal fusion or repair of the ravages of war and terror. With this new technique, we expect morbidity for patients to be minimal and gain in healing maximal.”