Research

The arthroplasty group has developed a total joint replacement registry to study their patients on a prospective basis. The faculty (Nathanael Heckmann, MD, Jay Lieberman, MD, Donald Longjohn, MD, Daniel Oakes, MD) are keenly interested in improving outcomes for total joint arthroplasty patients and to use advanced technology to achieve this goal. Major areas of research interest include:

• Outcomes and complications associated with dual mobility prosthesis
• The influence of spinopelvic mobility on dislocations after THA
• Prosthetic selection and the influence on dislocation after THA
• Improving outcomes associated with total knee and hip arthroplasty
• Use large administrative database to improve outcomes and decrease complications associated with total hip and knee arthroplasty

Other areas of research include:

Dr.Nathanael Heckmann’s research focuses on outcomes following primary and revision total hip and total knee arthroplasty. In particular, his research focuses on understanding the interrelationship between degenerative diseases of the spine and hip as well as improving outcomes following the surgical treatment of infected hip and knee replacements.

Dr. Jay Lieberman’s clinical research is focused on improving outcomes after total hip and knee arthroplasty and with a special emphasis on osteonecrosis of the hip and venous thromboembolism prophylaxis following joint replacement surgery. He is also a pioneer in the development of regional gene therapy strategies to enhance bone repair for complex fractures and revision total joint arthroplasty patients. Dr. Lieberman has published more than 250 peer reviewed studies and reviews.

Dr.Daniel Oakes has a particular interest in complex and revision hip and knee arthroplasty. His research is focused on the augmentation of large cavitary osseous defects in revision hip arthroplasty patients. He is also interested in robotic-assisted knee replacement surgery and understanding how these novel technologies may improve future patient outcomes.

Dr. Gary and Dr. Patterson will leverage the strengths of Keck Medicine of USC and Los Angeles General Medical Center in addition to their collaboration with the Major Extremity Trauma and Rehabilitation Consortium (METRC) to generate high-level published evidence that guides the optimal care of injured patients.

Joshua L. Gary, MD focuses his clinical research on surgical treatments and techniques to improve patient outcomes after pelvic, acetabulum, and extremity trauma.  His award winning research includes multiple “Highlight Papers” from the Annual Meeting of the Orthopaedic Trauma Association, numerous publications and presentations at national and international meetings.  He has been instrumental in running federally funded multicenter clinical trials for more than a decade to elevate the quality of research in orthopaedic trauma.  He serves on the Executive and Publications Committees within the Major Extremity Trauma and Rehabilitation Consortium (METRC) and is the Principle Investigator of the EMS-BinD study, a $4 million award from the U.S. Department of Defense to evaluate the effect of pelvic binders on shock for pelvic ring disruptions.

Joseph T. Patterson, MD focuses his clinical research on leveraging technology to level disparities and improve outcomes after pelvic and limb trauma. He is translating personal device technology to improve access to fracture care and aftercare. He is adapting 3D navigation and modeling tools to improve the safety of pelvis fracture surgery and limb deformity correction. He uses large administrative databases to analyze patients with orthopaedic problems after trauma.

The division of Hand, Upper Extremity, and Microvascular surgery is actively engaged in multiple areas of research to continue to improve patient care. Investigators include Milan Stevanovic, MD, PhD, MD, and Luke Nicholson, MD. Topics of ongoing research include:

• Vascularity and viability of free functional tissue transfer in complex microvascular reconstructive surgery
• Use of wide awake, local-only anesthesia in upper extremity surgery
• Patient reported outcomes following operative management of distal radius fractures with an emphasis on decreasing the time to recovery following surgery
• Virtual patient care and optimizing physician-patient communication
• Vascularity of peripheral nerves in the setting of peripheral nerve compression
• Biomechanical evaluation of scaphoid nonunion fixation constructs
• Wrist-spanning fixation in the management of radiocarpal fracture dislocations

The Spine clinical research team includes  Ram Alluri, MD, Jeffrey C. Wang, MD, Raymond Hah, MD, Gene Tekmyster, DO, and Christopher Ornelas, MD..

The Spine Center research focuses on establishing innovative approaches for the treatment of spinal disorders including minimally invasive surgeries, complex deformities, disc replacement and non-surgical approaches.

Ongoing research studies include:

• Multi-disciplinary research projects include single center and multi-center studies and the evaluation of data from multiple insurance databases.
• The use of Kinematic MRI allows investigators to evaluate degenerative changes that are only visible with loading and bending of the spine. This allows the assessment of the spine in neutral, flexion and extension positions.
• Research on costs of spine treatments and quality of care improvement
• The utilization of predictive analytics assessing the influence of modifiable risk factors on the outcomes of spine surgery.

At USC, we believe that the world-class care is not only driven by clinical excellence, but also by a commitment to furthering our understanding of musculoskeletal disease. Our sports medicine surgeons work closely with a multidisciplinary research team to develop novel approaches for the treatment and prevention of common sports-related injuries. This work includes:

• The prospective study of the outcomes of shoulder, hip, elbow and knee surgery procedures
• Clinical trials to investigate cutting edge treatments for sports medicine injuries and osteoarthritis
• Biomechanical studies to model the effects of surgery on joint function
• Basic science studies focused investigating the basic cellular mechanisms of tissue healing and developing treatments for muscle and cartilage injury

Specific areas of research include:

Seth Gamradt, MD, an expert in shoulder, knee and elbow surgery studies the effects of specific injuries and surgical intervention on the collegiate athlete’s ability to return to play.

George F. “Rick” Hatch, MD, works to find new ways to prepare a patient’s body for the severe stress of surgery and improve recovery. He is leading a clinical trial to use nutritional and testosterone supplementation to create an environment that promotes healing after surgeries such as ACL reconstruction of the knee. Dr. Hatch is an expert in treating complex knee and shoulder injuries, with a specific interest in the study and treatment of multiligamentous knee injuries (or knee dislocations) and severe cartilage injuries. He studies the optimal techniques for reconstructing complex knee and shoulder injuries in order to restore strength and function as well as prevent reinjury.

Reza Omid, MD, is an expert in treating all shoulder and elbow conditions and is currently working to improve treatment options. He is currently developing new surgical techniques for irreparable rotator cuff tears by investigating variations of tendon transfers around the shoulder, as well as the development of a novel vascularized option to supplement current reconstructive procedures.

Frank Petrigliano, MD, a shoulder, knee and elbow specialist oversees a basic science lab that is focused on the study of muscle atrophy and degeneration following large rotator cuff tears.  Following rotator cuff repair, muscle atrophy and fibrosis may result in persistent weakness and increase the risk of repair failure. Consequently, his team is studying cutting-edge approaches to improve rotator cuff function via the delivery of stem cells that are specialized to restore muscle after chronic injury. Dr. Petrigliano also works in close collaboration with Dr. Denis Evseenko at USC developing small molecule and stem cell-based therapies to treat osteoarthritis. The goal of their work is to provide novel treatments that improve function and decrease the risk of arthritis after knee and shoulder injury.

Alex Weber, MD, a shoulder, hip, knee and elbow expert is working with researchers in kinesiology to study the biomechanical effects of femoroacetabular hip impingement on lower extremity kinematics before and after hip arthroscopy.  Dr. Weber also has an interest in the prospective outcomes of shoulder, hip and knee surgery.

Collectively, our team of sports medicine physicians and researchers are advancing novel therapeutics and surgical techniques to improve the care of patients of all ages with athletic injuries.  Our goal is to return our patients to their active lifestyles by applying state-of-the art technology developed right here at USC.

Discovering novel treatments using a wide range of research techniques From stem cell biology to genomics, the researchers in the Department of Orthopaedic Surgery conduct scientific inquiries that pave the way to major breakthroughs in musculoskeletal treatments.

As a clinical department, our goal is to develop novel therapies to enhance the care of our patients. We have a special interest in using stem cells to treat disorders of the cartilage, bone, muscle, and tendons.

Denis Evseenko, MD, PhD, bridges studies of early embryogenesis and stem cell biology to clinically relevant application of stem cell and small-molecule-based therapies. Current work addresses an unsolved question in the skeletal biology: What are the cellular and molecular components of the “niche” required for the long-term maintenance of cartilage-committed progenitors capable of differentiation into articular chondrocytes?

Recently, his research group defined the developmental progression through which primordial mesenchymal cells commit to the chondrocyte lineage in vivo. Based on these findings, his research group now focuses on developing novel translational pluripotent stem cell and small-molecule-based approaches for articular cartilage and bone regeneration. His laboratory is actively using pre-clinical in vivo models of cartilage and bone injury and repair. Visit the Evseenko Lab website. More specific information regarding current studies of note follows.

Here is a brief description of a study on the Kappa opioid receptor agonist as a potential joint protective therapy in osteoarthritis telling what it is and why it is significant.

The medication activates the kappa opioid receptor (KOR), which binds to opioid-like compounds in the central and peripheral nervous systems to alleviate pain, resulting in targeted pain relief with a reduced risk of addiction. Previous research shows that some opioids that selectively activate only KORs relieve pain locally at the site of injury without crossing the blood brain barrier and inducing substance dependency, whereas commonly prescribed opioids that target other receptors in the brain are more addictive. In this study, lead author Alexander Weber, MD, sports medicine physician and orthopaedic surgeon with Keck Medicine, and corresponding author Denis Evseenko, MD, PhD, vice chair for research and associate professor of orthopaedic surgery at the Keck School of Medicine of USC, locally administered a kappa opioid into arthritic rodent knees and measured the progression of the disease in their joints. The researchers confirmed that the medication effectively alleviated pain, however findings also suggest that the medication prevented the loss of cartilage, the connective tissue between the joins that pads bones, and slowed the progression of osteoarthritis. Arthritis affects nearly a quarter of adults in the United States, many of whom take addictive opioids to manage their pain. The implications of this study may someday alter how we provide orthopaedic care to significantly reduce the number of patients experiencing long-term pain and addiction.

More can be seen at the HSC News site.

Another study of interest concerns the Pluripotent stem cell-based bioimplants for restoration of articular cartilage.

Articular cartilage injury and the lack of cartilage regeneration often lead to osteoarthritis, characterized by the degradation of joints, including articular cartilage and subchondral bone. Current treatments for cartilage lesions, cartilage degeneration and arthritis are mostly palliative, with most efforts focused on reducing inflammation and pain. Drugs like ibuprofen reduce pain and inflammation, but they do not induce regeneration of tissue. Stem cell therapies are designed to regenerate the tissues, to restore them to as close to normal as possible. After years of painstaking research funded by the California Institute of Regenerative Medicine (CIRM), USC team led by Drs Evseenko MD., PhD and Frank Petrigliano MD, have pioneered a stem cell therapy for what are called focal cartilage lesions.

The team has developed a patch infused with stem cells with strong reparative potential and ability to integrate and rebuild damaged joint tissues by providing new supply of juvenile cartilage cells naturally lacking in adults. This biomimetic stem cell patches called Plurocart are nearing the clinical trial stage. Therapeutic intervention at the early stage, when the lesion is contained and most of the joint tissues are healthy, is likely to delay the onset of osteoarthritis and perhaps completely eliminate the need for total joint replacement. Surgeons place the patch on a lesion where the stem cells are intended to create new cartilage cells. The team has successfully presented this new therapy to the FDA and has recently entered a partnership with GMP facility to manufacture clinical grade implants for first in man clinical trial.

More information about the Evseenko lab is available at HSC News.

Thomas Lozito, PhD, joined our department on Feb. 1, 2019. Lizards are the closest relatives of mammals that exhibit the amazing ability to regrow amputated tails. In doing so, lizards regenerate several tissues including cartilage, peripheral nerves, spinal cords, muscle and skin. The Lozito Lab examines wound healing in lizards and mice — including commonalities, differences, and the underlying causes of varying outcomes — for the purpose of improving human regeneration. Visit the Lozito lab site at: https://lozitolab.usc.edu/.

Thomas Lozito, PhD, is attempting to answer the question “Why can’t mice regenerate tails like lizards?”. From lizard species capable of spontaneously regrowing amputated tails to mammals that favor scarring over new tissue growth, amniotes include a diverse range of regenerative potentials. The Lozito Lab seeks to determine the cellular and molecular determinants of this diversity in tail amputation regenerative capacities with the goal of improving an organism’s natural wound healing abilities. Our ten-year-goal is to create a mouse capable of spontaneously regrowing an amputated tail like a lizard. We have established research colonies of specialized lizard species exhibiting a gradient of regenerative capabilities, as well as tools for manipulating these capabilities in vivo. Some of these lizard species complete the full tail regrowth program, while other species fail to reach specific milestones along the process. The vision for our research program involves using these select lizard species as “stepping stones” for bridging the gap in wound healing capabilities between non-regenerative mice and fully regenerative lizards. If we can sequentially manipulate the mouse to match the healing processes achieved by the next most similar lizard species along the gradient, the anticipated result will be a mouse line with full regenerative capabilities. For example, one of the earliest milestones in tail regeneration involves activation of specific populations of spinal cord neural stem cells (NSCs). NSC activity varies greatly among amniotes, and regenerative species exhibit a cell state not achieved by non-regenerative species. During another milestone, regenerative lizard species reprogram their own connective tissue stem cells known as blastema cells capable of differentiating into new tail tissues. Non-regenerative species do not achieve sufficient reprogramming depth, resulting in poor-quality cells with hindered differentiation capacities that favor scar formation. We believe that differences in NSC and blastema cell signaling account for divergent regenerative abilities among species, and “correcting” these differences will enhance tail regrowth in non-regenerative organisms. The overall goals of this research are to identify the specific signaling activities responsible for inducing tissue regeneration, and influence these regenerative signals to improve amputation healing in naturally non-regenerative organisms. The successful completion of this research program will answer several long-standing questions central to the field of regeneration and enhance our understanding of differentiation processes involved in adult amniote regeneration. The principles and experience gained from completing such a milestone can contribute to the knowledge base for improving the healing abilities of non-regenerative organisms, including humans.

Albert E. Almada, PhD is investigating one of the greatest mysteries in muscle regenerative biology—how stem cells rebuild functional muscle tissue after traumatic injury. His multidisciplinary team integrates state-of-the-art experimental and bioinformatic approaches to study this biological phenomenon at the molecular, cellular, and organ level in various animal models and in humans.

Recently, Dr. Almada discovered a new “Super-Healing” gene regulatory program, and he is exploring the biology and therapeutic potential of these pro-regenerative molecules in pre-clinical mouse models. Dr. Almada’s long-term goal is to translate his basic science discoveries into effective stem cell-based therapies that restore muscle function to injured athletes, wounded soldiers, the elderly, and patients suffering from degenerative muscular pathologies. Visit Dr. Almada’s Lab site.

Jay R. Lieberman, MD, is a pioneer in the development of regional gene therapy to enhance bone repair. A number of difficult bone repair scenarios exist for which no consistently satisfactory solution is available, including: fracture nonunion, acute fractures with extensive bone loss, revision total joint arthroplasty and pseudarthrosis of the spine.

Traditionally, autologous bone graft has been the gold standard but, with a limited supply of this bone, concerns remain regarding the morbidity associated with graft harvest. Recombinant bone morphogenetic proteins (BMPs) are FDA-approved for use in spinal fusion and treatment of fresh tibial fractures. However, BMPs have had mixed success in humans and are associated with side effects including soft tissue edema and heterotopic ossification.

Orthopaedic surgeons have long sought alternative tissue engineering strategies to enhance bone repair. Lieberman aims to develop regional gene therapy using transduced bone marrow cells as a comprehensive tissue-engineering strategy to enhance bone repair. The Lieberman laboratory was the first to successfully heal a critical-sized femoral defect using bone marrow cells genetically manipulated to overexpress BMP. Recently, his group developed a “same day” gene therapy strategy to facilitate clinical adaption of this regimen. Bone marrow cells were transduced with a lentiviral vector containing the cDNA for BMP-2 and successfully healed a large bone defect. The laboratory is now assessing the biologic potential of genetically manipulated human bone marrow cells and adipose-derived stem cells in order to move this research closer to the clinic.

Low back and neck pain are leading causes of disability worldwide. The primary focus of Jeffrey C. Wang MD is understanding the biology and mechanisms of various spine pathologies using basic science models and clinical research. In vitro and in vivo studies include projects on spinal fusion and bone formation, and intervertebral disc degeneration. Osteobiologics are one of the key interests, they serve as a framework to reinforce and support bone growth after spine fusion. Our studies utilize animal models of lumbar posterior fusion to analyze various graft materials, assess bone remodeling and compare what components (stem cells vs. growth factors) drive bone formation. Clinical questions are intertwined with both our animal and in vitro models. Certain clinical aspects such as risk factors (e.g. nicotine) are implemented in our cell models to better understand the changes in molecular mechanisms of bone formation.

We apply our expertise in the field of tissue engineering, biomarkers and mechanobiology to look at the potential of matrix markers, and stem cells to drive disc regeneration. Our animal models of disc degeneration use minimally invasive methods to create degenerative cascades and test different molecules as promotors of regeneration. Close interactions within the Department of Orthopaedic Surgery, as well as with other research centers and spine societies, enable extensive collaboration on a range of projects.