Advances in Bone Regeneration

Recent orthopedic discoveries have led to advances in understanding mechanisms of bone regeneration and are rapidly being translated into clinical applications that improve musculoskeletal patient care across a spectrum of bone disorders.

At Mayo Clinic, a tradition of multidisciplinary collaborative research has created highly productive lines of inquiry related to bone regeneration. Recent highlights include

• Exploration of the molecular mechanisms such as signaling pathways of bone growth and resorption
• Design of bone-regenerating scaffolding to cue bone growth
• Design of an automated imaging system to calculate bone strength
• Development of bone and nerve regeneration techniques to treat war-wounded patients

Waves of Innovation
Michael J. Yaszemski, M.D., Ph.D., views advances in bone regeneration as waves of innovation occurring on multiple fronts. Dr. Yaszemski is head of the Tissue Engineering and Biomaterials Laboratory at Mayo Clinic in Rochester, Minnesota. The Tissue Engineering Laboratory's biomaterials area provides synthesis, characterization, processing, and tissue-engineering application of novel polymeric and composite biomaterials. These biomaterials are used as drug delivery vehicles or temporary scaffolds in 3 main areas: bone, cartilage, and nerve tissue engineering.

Figure 1. Dorsal Root Ganglion Explant

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"We are able to use more strategies for restoring structural and mechanical function of bone than ever before, which means providing more patients with excellent outcomes than ever before," Dr. Yaszemski explains. "Bone usually heals itself pretty well—but there are times it doesn't do this. When that happens, we need to integrate biology and engineering to coax the bone to heal, which is why the multidisciplinary team is so important."

For example, a complex tumor resection for bone cancer involving the pelvis may require removal of bone that leaves a gap of 7 inches. "That big gap won't fill with bone. A large defect may not follow the usual rules of healing and leaves a part of the skeleton structurally incompetent," Dr. Yaszemski explains. In these patients, surgeons restore the structural function with an allograft, usually from a cadaver. "But this dead bone takes longer to fill the defect and is not as robust as the patient's own bone."

To have a long-lasting positive effect in the patient's skeleton, the bone must heal. Jennifer J. Westendorf, Ph.D., a molecular biologist in the Department of Orthopedic Surgery, studies signaling molecules that cue and direct bone healing. "Once bone gets the signal to regenerate, the natural growth mechanism takes over. Working as a team, we can create conditions that optimize bone regeneration," explains Dr. Westendorf.

Cell Signaling to Increase Bone
Managing osteoporosis by stimulating new bone formation and improving the healing of fractures are related problems that Dr. Westendorf's research team is addressing. The team focuses on understanding the complex interactions of key proteins, signaling pathways, and cell types involved in bone tissue remodeling dynamics.

"Osteoclast-mediated bone resorption and bone replacement through osteoblastmediated bone formation are tightly coupled. The compounds we're looking at in vivo as possible therapeutic agents alter the balance of osteoblasts and osteoclasts," says Dr. Westendorf. "They suggest that the development of agents that target more than 1 cell type could have important implications for clinical treatment of osteoporosis. These same signaling pathways might also be modulated to accelerate healing of fractures and to treat the 5% to 10% of fractures that fail to heal satisfactorily."

Bone Regeneration Scaffolding
Connective tissue cells are contact dependent. For bone cells to make bone, they have to encounter a surface and secrete material that becomes mineralized and then ossifies into bone. By implanting a scaffold, bone regeneration is prompted by mimicking conditions in nature that favor bone growth. The scaffold creates the necessary contact points that cue cells to grow (Figure 2).

Figure 2. Cueing Bone Growth

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Within the next 5 years, Drs. Yaszemski and Westendorf hope to refine the bone regeneration scaffolding for clinical use with humans. They are working to expand the scaffold function for human therapy as a drug delivery vehicle, in addition to a mechanical support to initiate bone growth. Results from animal studies testing incorporation of bone morphogenic protein 2 (BMP2) into various bone tissue–engineered composites are encouraging in terms of bone growth and sustained bioactivity. "Once the scaffolding is available, clinicians can embed it with drugs or signaling molecules to guide growth and influence treatment," Dr. Yaszemski says. For example, in patients with cancer, scaffolds can be used both to fill criticalsized defects so holes caused by aggressive resections close and to deliver chemotherapeutic agents to fight residual cancer cells. If infection is a threat, the scaffolding can be loaded with antibiotics for sustained release. The Mayo team envisions creating a scaffold that automatically recognizes and responds to skeletal contact and then delivers the necessary molecules to optimize therapy.

Automatically Calculating Bone Strength
Another bone regeneration project analyzes the degree of mineralization of bones, as quantified by CT scans, in order to calculate load-bearing strength of the vertebrae. Dr. Yaszemski is collaborating with Mayo Clinic imaging specialists to automate an existing algorithm to provide rapid results. "For this process to be useful for patients, it has to be automated—it's too time-consuming now," says Dr. Yaszemski. "When we achieve this, we'll have a useful tool to quantitatively assess the strength of bones."

The tool would calculate vertebral load-bearing capacity. Rapid results could be helpful for diagnosis of osteoporosis, for assessing its progression in a series of time measurements, or to determine the effectiveness of a particular treatment when strength is calculated at baseline and after treatment through sequential imaging studies. Explains Dr. Westendorf: "If a patient has a hole in a bone, Mayo clinicians can work together to fix it. For example, we can make a polymer and fill it with cells and modify the cells for maximum benefit—then analyze our work with this imaging program to see how effective the treatment has been."

Combined with Mayo's epidemiologic database of CT scans containing bone strength information, data from its new program to calculate bone strength may be used to help set quantitative norms for bone strength. Dr. Yaszemski envisions this tool helping to identify patients at risk of developing osteoporosis— and treating them before the condition is problematic. "We prefer to prevent rather than treat, and we may be able to do that with this tool by identifying patients early on, before they develop insufficiency fractures, and then treating them to prevent osteoporosis," he says.

Biodegradable Scaffolding for War-Related Injuries
The Armed Forces Institute of Regenerative Medicine (AFIRM) consortium was created and funded by the US Army Medical Research and Materiel Command, in conjunction with the Office of Naval Research and the National Institutes of Health. In the new consortium, to which Mayo Clinic orthopedics belongs, AFIRM will use regenerative medicine techniques to help develop new products and therapies to repair battlefield injuries. This innovative approach uses cell therapy, including stem cells, tissue and biomedical engineering, and transplants.

Mayo Clinic's involvement focuses on bone and nerve regeneration and is led by Dr. Yaszemski, who also is a brigadier general in the US Air Force Reserve. He has cared for patients in Iraq, as deputy commander of the Air Force Theater Hospital in Balad. "The opportunity to collaborate at this level to meet the medical and surgical needs of our injured service members is a privilege, and we are proud to contribute in whatever way we can," Dr. Yaszemski says.

Mayo Clinic's biodegradable scaffolding has a promising application in AFIRM efforts for improving healing of peripheral nerve injuries. Dr. Yaszemski explains: "We've designed the scaffold with a channel down the middle for loading with Schwann cells and for adding signaling molecules that diffuse outward to modulate growth. It provides an efficient, durable solution for regenerating bone tissue." Because the scaffolding is composed of natural body materials, it eventually converts to ordinary metabolic products over time and does not require complex aftercare.