Mentors for the Musculoskeletal Training Grant

Ed M. Greenfield, PhD (Director)

Dr. Greenfield’s research examines cellular mechanisms that regulate bone turnover in response to hormones, cytokines, orthopaedic wear particles, bacterial endotoxin and osteosarcoma. His laboratory studies signal transduction, regulation of gene expression and differentiation of osteoclasts and osteoblasts.

These studies use cell cultures as well as in vivo mouse models. The roles of specific molecules are studied using a variety of techniques, including gene knock out, gene knock down (siRNA and antisense) and neutralizing antibodies. These studies have important implications for regulation of bone turnover in various diseases, including osteoporosis, loosening of orthopaedic implants and tumors.

Specific areas of current research include: the role of bacteria in "aseptic loosening" of orthopaedic implants, regulation of parathyroid hormone signaling by Protein Kinase Inhibitor, regulation of bone turnover by the gp130 family of cytokines and mechanisms responsible for tumorigenesis and metastasis in osteosarcoma. Trainees can participate in all aspects of these projects and obtain diverse training in many aspects of modern bone cell biology.

Ozan Akkus, PhD

The focus of the Akkus lab is on musculoskeletal biomaterials and mechanobiology. In the biomaterials realm, the lab has developed an electrochemical fabrication method for the generation of a strong and dense collagenous tissue analog called electrochemically aligned collagen (ELAC). ELAC’s strength approximates that of tendon/ligament, and emerging results indicate that ELAC supports the differentiation of mesenchymal stem cells to tenocytic lineage. The trajectory of this project into the future includes the development of transplant-ready constructs based on ELAC which will encompass bony ends to promote osteogenic and tenogenic differentiation on the same platform. In the mechanobiology realm, the lab has been breaking ground in understanding the role of VEGF in osteogenesis by studying 3D cultures of ossifying bone marrow explants. The Akkus lab is highly interdisciplinary in nature and trainees with biological, biomedical and engineering backgrounds are sought to participate in these research activities.

Eben Alsberg, PhD

Dr. Alsberg’s laboratory focuses on engineering functional biologic replacements to repair damaged tissues. One of the primary thrusts is on regeneration of musculoskeletal tissues. Complex signals that are implicated in musculoskeletal morphogenesis, repair and homeostasis are used as a template for the development of biomaterials for tissue regeneration. Through the temporal and spatial presentation of bioactive factors, mechanical forces and biomaterial physical and biochemical properties, microenvironments are created that regulate cell gene expression and new tissue formation.

Some areas of active investigation include controlling stem cell differentiation, delivering bioactive factors sequentially, developing spatially patterned constructs, understanding cell-cell interactions and determining mechanical influences on cell function. Trainees can be involved in all parts of these investigations (e.g., biomaterials design, fabrication, and characterization, cell and molecular biology, in vitro and in vivo model systems, etc) to acquire strong research experience in musculoskeletal biomaterials development and tissue engineering.

Radhika P. Atit, PhD.

Kath Bogie, DPhil

Dr. Bogie’s research interests include wound treatment and prevention, biomechanics of wheelchairs and seating for people with limited mobility. Her research program encompasses both basic science studies to develop improved methods for the use of surface electrical stimulation in wound treatment and clinical studies to evaluate an implanted stimulation system to prevent pressure ulcers in wheelchair users.

A primary goal of her research in the area of wound treatment is to develop a rational methodology for the treatment of wounds using electrical stimulation. The initial application would be in the field of chronic wounds, such as pressure ulcers. This technique has been used by therapists clinically, but results have been rather hit and miss – mostly because nobody has established the underlying mechanism, i.e. what is going on in the stimulated wound to enhance healing. The range of treatment and stimulation paradigms that has been used is huge. They are currently working on both in vivo and animal studies in this area. In the area of pressure ulcer prevention, Dr Bogie’s group is evaluating the safety and efficacy of novel implanted mini-stimulation devices, which have the potential to provide long-term improvement of tissue health. This study involves preclinical testing of the system prior to a pilot clinical trial.

Kathleen A. Derwin, PhD

Steven J. Eppell, PhD:

Native type I collagen fibril gels will be self-assembled and mineralized under in vitro conditions. The resulting gels will be doped with bioactive agents and pressed into shapes capable of load bearing. These samples will be analyzed physico-chemically, using in vitro cell assays, and using critical-sized-defect small-animal models.

In a separate project, isolated collagen fibrils (both from sea cucumbers and from reconstituted gels) will be mechanically analyzed using a microelectromechanical system we have developed for this purpose. Strength and modulus of the individual submicron diameter fibrils will be measured. In a related project, the location of mineral within collagen fibrils will be measured using both atomic force microscopy and near field scanning optical microscopy.

Trainees will participate in all facets of these projects, including sample preparation and analysis, cell and animal experimentation, journal article preparation and collaboration with surgeons currently working on the projects as well as with industrial partners.

Ahmet Erdemir, PhD

Zhenghong Lee, PhD:

Specific imaging modalities such as CT or SPECT, or PET allow Dr. Lee to study the subject repeatedly, non-invasively, and quantitatively. Among these imaging modalities, CT stands out as a well-developed tool for use in bone studies. Specialized measurements of bone parameters or characterizations can be made from the acquired CT image data. SPECT, PET, and Bioluminescent Imaging (BLI) can be used to trace infused cells’ (including stem cells) distribution, dynamics, and differentiation, and to measure gene expression, protein-protein interactions, and signaling pathways.

PET and SPECT data will be used for more quantitative measurement, but BLI will be used for screening or daily monitoring due to its high sensitivity in terms of the number of the cells it can detect and the amount of gene expressed that can be imaged. BLI requires no radioactive materials, allowing easy use in various lab settings.

Overall, these imaging techniques offer nontraditional ways to study biology, which may help trainees who are only familiar with regular bench type lab work. Depending on the nature of the research project as well as the interest and willingness of a trainee to go "outside the box", imaging-based research provides a new approach to study old and new problems. This should benefit the trainee as well as the research program as a whole.

Veronique M.A. Lefebvre, PhD

M. Edward Medof, MD, PhD

George F. Muschler, MD

P. Hunter Peckham, PhD:

Dr. Peckham’s research is in rehabilitation engineering and neural prostheses. Research focuses on functional restoration of the paralyzed extremities in individuals with spinal cord injury. Dr. Peckham has developed implantable neural prostheses that utilize electrical stimulation to control neuromuscular activation and provide control of grasp-release in individuals with tetraplegia.

This function enables individuals with central nervous system disability to regain the ability to perform essential activities of daily living. Dr. Peckham’s efforts concern the integration of rehabilitation and surgical approaches to restore functional capabilities. He is working on an advanced neuroprosthesis that employs implantable sensors for internal control and regulation of movement.

Nora G. Singer, MD

Kurt Spindler, MD

Dawn M. Taylor, PhD

Ronald J. Triolo, PhD:

Dr. Triolo’s research encompasses rehabilitation engineering, biomechanics, control of posture and balance, bipedal gait analysis, and seated ergonomics. He investigates applications of functional electrical stimulation (FES) for exercise, standing, walking, and trunk control in paralyzed patients.

Projects include:

  1. Clinical evaluation of implanted neuroprostheses for standing
  2. Automatic control of standing and seated balance
  3. Ambulation after incomplete spinal cord injury
  4. Seated posture, reach, and wheelchair function
  5. Selective neural interfaces

Basic aspects of his research focus on the biomechanics of human movement, dynamic modeling of the musculoskeletal system, and advanced control systems for regulating posture with FES. These projects have developed a three-dimensional computer model of human stance that includes the pelvis, bones, joints, and muscles of both lower extremities, as well as a realistic model of the kinematics of the spine and the moment generating capacities of the major trunk muscles.

His recent R01 focuses on the design, optimization and clinical testing of stimulating nerve cuff electrodes for fascicular selectivity in mixed peripheral nerve trunks. Dr. Triolo also directs the Case/VA Advanced Platform Technology Center which designs new assistive technologies and medical devices.

Dustin J. Tyler, PhD

Heather A. Vallier, MD

Horst A. von Recum, PhD:

Dr. von Recum’s research is in drug delivery and in tissue engineering. The drug delivery group focuses on the use of molecular interactions to control the rate of release of therapeutic molecules several orders of magnitude longer than is possible by conventional diffusion based drug delivery.

Applications of this research are in delivery of antibiotics from implants, which are bioavailable locally from weeks to months. This is particularly relevant in orthopedic applications in which implants may become colonized with bacteria up to a year after implantation.

This same technology is being investigated to reversible associate biological molecules such as attachment peptides and growth factor molecules on the surface of an implant. The tissue engineering group focuses on the directed differentiation of embryonic stem cells into endothelial cells or endothelial precursors for formation of a vascular bed.

Guang Zhou, PhD:

Dr. Zhou’s laboratory focuses on studying how transcription factors interact with each other to determine cell fate and regulate cell function during skeletogenesis and bone metastasis. Utilizing molecular, biochemical, and genetic approaches, Dr. Zhou has shown that chondrogenic transcription factor SOX9 is a strong inhibitor for osteogenic transcription factor RUNX2 during bone formation.

His laboratory is currently studying the role of SOX9 in chondrocyte hypertrophy, bone mechanical strength, bone marrow stromal cell differentiation and osteoarthritis pathogenesis using transgenic mice. His laboratory has also recently demonstrated that an evolutionarily conserved transcriptional cofactor, Jab1, plays essential roles in successive steps of skeletogenesis in vivo.

Other projects in Dr. Zhou’s lab include studying the roles of tumor suppressor genes Rb and p53 in chondrocyte and osteoblast differentiation and bone tumorigenesis using transgenic and knockout mice models. Dr. Zhou’s work will provide a better understanding of how tissue-specific and ubiquitous transcription factors interact with each other to control bone and cartilage formation.

Eventually, this work could lead to the development of therapeutic and diagnostic methods for bone diseases. Trainees can participate in all aspects of these projects and obtain comprehensive training in various aspects of bone and cartilage biology with emphasis on mouse genetics and cell biology.

Associate Mentors

Donald D. Anthony, MD, PhD
Chris A. Flask, PhD
Umut A. Gurkan, PhD
Raymond W. Liu, MD
Charles J. Malemud, PhD
Randall E. Marcus, MD
Clare M. Rimnac, PhD
Angela B. Robinson, MD, MPH

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