Basic Science

New, collaborative Approaches in Orthopaedic Research Give Hope to a Myriad of Patients Infinite applications. Limitless possibilities. The University of Tennessee-Campbell Clinic Department of Orthopaedic Surgery is poised at the threshold of new treatments and preventive medicine due to pioneering research supported by Campbell Foundation. Key collaborations in research are propelling the department forward.

"We have scientist, bioengineers, and clinicians working side by side accelerating the 'bench to bedside' approach" said Karen Hasty, PhD, chief researcher for the department and George Thomas Wilhelm, MD Endowed Professor in Orthopaedics.

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"The clinician evaluates an orthopaedic problem in the context of his individual patient with respect to age, health status, and available therapies. The cell biologist focuses on the same problem as a malfunction of cellular interactions. A biomedical engineer might consider this problem as a defect in the skeletal structure and investigate mechanical failure of the skeletal structure as well as replacement biomaterials. "What is the correct approach? All of the above! The relationship between these investigators represents the "3-D" view that is vital for developing innovative therapies.

Dr. S. Terry Canale, President, Campbell Foundation, and recently appointed Chair of the UT-Campbell Clinic Department of Orthopaedics, is enthusiastic about this collaboration of basic scientists and clinicians. "We are on the verge of the orthopaedic scientist being able to isolate specialized living cells in the test tube, multiply them in culture, and ultimately create living, structural body parts such as knees and hip joints that can then be implanted into the human body by orthopaedic surgeons." Dr. Hasty adds, "Every year, there is new information and new technology, enabling us to examine questions we couldn't explore before."

Large-scale studies usually require funding from large institutions such as the National Institutes of Health (NIH). Corporate partnerships also provide resources for larger research projects, but that is not enough. These organizations will not fund untested hypotheses, so Campbell Foundation helps fill this critical gap. "The Foundation provides seed money for pilot studies to extract preliminary data, backing up proposals for larger grants. A surgical resident and surgeon at the bedside may propose an alternate method of treatment, but how do you test this? Patients need conservative, tested therapies. Pilot studies allow us to test the feasibility of new ideas and pave the way for acquiring research grants to conduct large scale testing," Hasty said. The department currently collaborates with businesses such as Medtronic Sofamor Danek, Smith & Nephew, and Wright Medical Technology. An example of just one of these projects is a study of a Smith & Nephew product called Jax, a bone graft substitute. Scientist Richard Smith, PhD is working closely with the company on this project, the results of which have just been accepted for presentation at the National Orthopaedic Research Society meeting. The breadth of orthopaedic research projects in the Department of Orthopaedics can also benefit other fields of medicine from neurology to tissue engineering to oncology. Growing and reimplanting an individual's own stem cells to regenerate tissue is the goal of one study, "The Use of Mesenchymal Stem Cells for Repairing Growth Plate Defects." Everyone has mesenchymal stem cells (MSCs) in his or her bone marrow that function to aid healing of damaged tissues. However, they are normally present in very small numbers. Harvesting MSCs, growing them in culture to large numbers, and reimplanting them where needed - a field know as tissue engineering - could have limitless applications.

Principles learned in this study could benefit many other disciplines. For example, neurology could use tenets of tissue engineering to replace diseased dopamine cells in the brains of Parkinson's Disease patients. And Dr. Robert Heck, orthopaedic oncologist with Campbell Clinic, already has direct applications in mind for regenerating bone tissue in pediatric cancer patients at St. Jude.

Another project is a melding of the basic science of growing tissue in culture with the clinical application of surgically implanting this tissue. "Growing Chondrocytes in Culture for Tissue Transplantation" is a collaborative study of the Department of Orthopaedics with Jae Rho, PhD and Kwidoek Park, PhD, of the University of Memphis, and Frederick Azar, MD of Campbell Clinic. They are growing cartilage cells in culture for transplantation into cartilage defects in pigs and will also examine the role of mechanical stress on cartilage degeneration.

"Cartilage is a tissue that requires mechanical stress to be healthy, but clearly, wear and tear play a major role in joint degeneration. So, what are the critical elements that shift the balance? What role does aging play in this shift?" Dr. Hasty said.

Understanding why cartilage breaks down in osteoarthritis and autoimmune diseases such as rheumatoid arthritis is the chief research area of Dr. Hasty in the Department of Orthopaedics. This research involves identifying the enzymes that break down cartilage, understanding how they work and finding what causes their production or inhibits them. Funded by the VA and NIH grants, this study was the subject for the Department of Orthopaedics' presentation at the American College of Rheumatology.

A recent study by the Centers for Disease Control and Prevention asserts that arthritis now affects one in three adults in the United States. This would account for 69.9 million arthritis sufferers.

"We are an aging population in this country. The collaborative work we are doing now has the potential to help older people heal faster and live longer, more active lives," says Dr. Hasty.

Current research projects and sheer momentum in the Department of Orthopaedic Surgery offer great hope to patients of all ages suffering from a broad spectrum of maladies - from bone cancer to congenital musculoskeletal disorders, from arthritis to Parkinson's Disease, from diseases of aging to sports injuries, just to name a few. The collaborative team approach of the researchers puts these findings on the fast track to help all of our patients much sooner. "I really believe in this," said Dr. Hasty. "These partnerships are the wave of the future."

Research to Lengthen Life of Joint Implants

Committed to optimizing quality of life for all current and future joint replacement patients, Campbell researchers are involved in breakthrough research on joint implant loosening. An estimated 15 percent of all replacement patients will need revision surgery at some point due to loosening. With funding from Smith & Nephew, Inc., the University of Tennessee-Campbell Clinic Department of Orthopaedic Surgery is working to find the cause of osteolysis, a resorption of bone around implants, wearing bone away until the implant loosens enough to fail. Of patients needing revision surgery, 40 percent are caused by osteolysis. Applications of research findings are aimed at lengthening the life of implants and lessening the need for later revision surgery. "Revision is very hard on the patients," said Richard A. Smith, PhD, the project's principal investigator and Assistant Professor in the Department of Orthopaedic Surgery. "There is less bone to work with than in the primary replacement, and the lifespan of the revised hip is much shorter than with the first surgery." Smith, in orthopaedic research for over 17 years, explained previous research has linked joint implant loosening to wear debris generated by the implant. The studies beg more questions. "In biology, each question answered brings a whole new set of questions," said Smith. "The questions of wear particles and their role is not answered. We are trying to understand the biological mechanisms involved in osteolysis; Does it have anything to do with materials used in the hip replacement? Is is exacerbated by drugs the patient takes to combat their disease? It gets pretty complicated, but we're getting closer," Smith said.

Dr. Karen Hasty and Christy Patterson, Technical Director, have isolated a collagenase gene that breaks down cartilage in rheumatoid and osteoarthritis. Studies are now being done to block the action of this enzyme.

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