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.
Interviews and Articles - Dr. Karen Hasty
Karen Hasty, PhD, George Thomas Wilhelm Endowed Professor
Researcher relished days spent chasing answers about arthritis.
What Karen Hasty knows about arthritis could fill not just a book but a small library of books. The problem, Dr. Hasty says, is that for everything she knows about arthritis, there's far more that she doesn't.
"That is what it's like to be a research scientist," said Hasty, chief researcher for the UT-Campbell Clinic Department of Orthopaedic Surgery. "Every answer raises another question. It's not frustrating, it's fascinating. I've been doing research for 30 years, and I still think it's a wonderful way to spend your life."
Since Hasty is accustomed to questions, we asked some about her work and the scientific research profession. Here are her answers:
What are some of the questions you are studying in regard to arthritis?
"My work is concerned primarily with understanding what is happening on the cellular level as arthritis develops. We have been using a machine in the lab to put physical stresses on cartilage and asking, how does mechanical stress affect cellular behavior? We ask, how do young cartilage cells respond to those stresses in comparison with old cartilage cells? We're looking at the effects of certain growth factors. We want to prevent the breakdown of cartilage early in the disease and develop the possibility of cartilage regeneration, if it has broken down. Those are just a few; there are a lot more."
What has changed most during the three decades you've been a scientific researcher?
"Scientific advances and new technology developed over the course of my career have been just phenomenal. We now know the sequence of every gene in the human body, and you can buy 20,000-plus genes on a microchip to study in the lab. This year our department was able to purchase a MicroCT, an amazing machine that will let us label cells, inject them, and watch where they go. There are more than I can mention, but I feel like we're just at the beginning of a great era for scientific discovery."
"Another big change is that research science today is more multi-disciplinary. You can't be just a chemist, or a molecular biologist, or a bioengineer. You've really got to encompass all those fields. The questions we're asking are more complex, and you can't know everything, so you work with other scientists who are specialists in the other areas. We used to work in boxes; now we are putting the boxes together in a systems approach."
How does that apply to your research on arthritis?
"I started out as a cell biologist, growing cells in a Petri dish. Then the research I became involved in required that I evolve into a biochemist, then a molecular biologist. Now what I am doing means I have to pick up some parts of the orthopaedic approach as well as tissue engineering. I do not know all these fields as well as someone who is a specialist. I really think the era of the individual scientist is over. The breakthroughs are beginning to come from larger, interdisciplinary groups."
What's the most interesting project you've ever worked on?
"What I'm working on right now. It's always that way – my current project absorbs me; the next experiment is the most exciting. I can't believe I get paid to do something I love so much."
Interview taken from the Campbell Foundation Momentum.
Karen Hasty, PhD, George Thomas Wilhelm Endowed Professor
Cartilage Research Offers Hope for Halting Damage Earlier
How do you make new cartilage more like old cartilage, so the two are compatible and work together to restore function in a damaged joint?
That's one of the questions facing two scientist conducting research supported by the Campbell Foundation in the promising field of cartilage regeneration and repair.
Dr. Karen Hasty is the George Thomas Wilhelm Professor in Orthopaedics and chief research for the UT-Campbell Clinic Department of Orthopaedic Surgery. Dr. Jinsong Huang is an instructor in the Department. The two scientists are studying ways to make the body bind to new cartilage cells generated in the laboratory, then inserted where cartilage has been damaged.
"Our research focuses on cartilage integration," Dr. Hasty said. "We want to learn how to make the cartilage tissue that we implant more like the original, and smoothly join the two together. If the two don't fit correctly, the new cartilage will loosen and deteriorate."
Repeated use or trauma to a joint can result in damage to cartilage, the slick, water-rich tissue located between bones that permits smooth movement of joints. Cartilage does not regenerate in the body. Over time, damaged cartilage is lost, causing pain, osteoarthritis, and limited function in affected joints.
Tissue engineers have become adept at growing new cartilage cells in the laboratory. Surgeons can then clear away damaged tissue and insert the new cells, Dr. Huang said. Problems can arise, however, when the newly generated cartilage that is inserted must integrate with existing cartilage in the joint.
"We are working on ways to make the two more compatible," Dr. Huang said. "For example, new cartilage is slick, so we are using enzymes to roughen the surface of old cartilage and make it more adherent. Once the cartilage is rough, we are experimenting with a "Bio-Glue" made from collagen molecules mixed with cartilage cells, which gives us a living interface between the two types of cartilage."
Dr. Fred Azar, a Campbell Clinic surgeon specializing in Sports Medicine, has performed several types of cartilage restoration procedures.
"Cartilage repair offers hope for the future, especially in dealing with osteoarthritis," Dr. Hasty said. "Osteoarthritis often means the cartilage is gone, and there's only bone on bone."
From the Campbell Foundation Momentum.
Research studies focus on using body's own cells to repair damaged discs...
At some point in their lives, eight out of ten adult Americans will experience low back pain. In approximately one-third of those cases, the pain will be due to degeneration of the intervertebral disc, the tissue that separates the vertebra in the spine.
Surgical solutions can help relieve the pain and other symptoms of disc degeneration. Now Campbell Foundation-supported researchers are looking at solutions from a different angle.
Dr. Karen Hasty leads a research team that is studying ways to repair the disc itself, correcting the defect rather than treating the resulting problems. Dr. Hasty is the George Thomas Wilhelm Professor of Orthopaedics and chief researcher for the UT-Campbell Clinic Department of Orthopaedic Surgery.
The intervertebral disc consists of a central water-filled nucleus surrounded by a tough, fibrous ring of cartilage. Over time, the central nucleus can lose fluid, so the disc is less effective as a cushion between the vertebra.
"We are conducting several research projects in which we are growing intervertebral disc replacement tissue in culture in the lab," Dr. Hasty said. "We are looking at ways to repair the nucleus using collagen, plasma and other components that encourage regeneration."
Dr. Richard Smith, a basic scientist who is an Assistant Professor of Orthopaedic Surgery, is studying what happens when certain growth factors are inserted into a damaged disc. Dr. Hongsik Cho, a biomedical engineer in the Department of Orthopaedic Surgery at UT, has been engineering an intervertebral disc in the laboratory, experimenting with ways to culture the cells in order to make them proliferate and create the water-filled network needed.
"There could come a day when, if an MRI reveals degeneration in one of your disc, a surgeon could take some bone marrow from your hip, process that, add collagen, take some of your platelets, put them into the mix, inject that into your disc-and your disc will begin to regenerate itself," Hasty said.
When does Hasty expect that day to come? "As always, the more resources that go into the research, the faster it will go," Hasty said.
The biologics approach encourages replacing human parts with natural parts instead of metal or substances.
Dr. Karen Hasty
"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, 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.