The Lawrence J. Ellison Musculoskeletal Research Center

Department of Orthopaedic SurgeryUniversity of California, Davis School of Medicine

Research Symposium 2010

October 15, 2010

Innovative and promising discoveries in Molecular and Biomechanical research

The Lawrence J. Ellison Musculoskeletal Research Center

morphogen signaling in bone and cartilage

Research Sponsors

AO North America

AO Resident Research Grant Program

Artimplant

Biomet Orthopaedics, Incorporated

Dr. Michael W. Chapman and Mrs. Elizabeth C. Chapman

Depuy Acromed, Inc.

Dr. Denny Dickenson and Mrs. Jeanene Dickenson

Mr. Lawrence J. Ellison

Glaxo Smith Kline

Koret Foundation

David and Doris Linn

Medtronic, Inc

National Institutes of Health

OMeGA Medical Grants Association

Orthopaedic Research and Education Foundation

Orthopaedic Trauma Association

Paul R. Lipscomb Sr. Fund

Procter & Gamble Pharmaceuticals

Shriners Hospital for Children

Smith & Nephew, PLC

Stryker Howmedica Osteonics

Synthes Corporation

Ben Trainer

UC Davis Biology Undergraduate Scholars Program

UC Davis Faculty Research Grant Program

UC Davis Health System Research Awards

Innovative and promising discoveries in Molecular and Biomechanical research

Research Symposium 2010

The Lawrence J. Ellison Musculoskeletal Research Center

Department of Orthopaedic SurgeryUniversity of California, Davis School of Medicine

4635 2nd Ave, Research Building 1Sacramento, CA 95817

Main: Phone 916-734-3311, Fax 916-734-5750www.ucdmc.ucdavis.edu/orthopaedics/education/

Established when the department was founded in 1969, the Orthopaedic Research Laboratories became the Lawrence J. Ellison Musculoskeletal Research Center in 1997,

made possible through a generous gift by Lawrence J. Ellison, president and chief executive officer of Oracle Corporation, to help develop a world-class research center

in skeletal molecular biology.

The laboratories provide a facility where faculty, residents, fellows, medical students, graduate and undergraduate students and visiting scholars can conduct broadly

interdisciplinary research in tissue and cellular biomechanics, regeneration and repair.

David Mooney, PhDRobert B. Pinkas Family Professor of BioengineeringHarvard School of Engineering and Applied Sciences

Dr. Mooney is a Core Faculty Member of the Wyss Institute for Biologically Inspired Engineering. His laboratory is focused on the design and synthesis of microenvironments, or niches, that regulate the fate of either transplanted cell populations or cells already resident in tissues.

Distinguished Guest Speaker

These polymeric systems mimic the native extracellular matrix in their spatiotemporal control of information presentation to cells, and may find special utility in controlling stem cell populations. The application of these systems include the regeneration of damaged or diseased tissues (tissue engineering), or the targeted destruction of undesirable tissue masses in the body.

Dr. Mooney was previously a faculty member at the University of Michigan, and his education and training is from the University of Wisconsin, the Massachusetts Institute of Technology, and Harvard Medical School. He is a fellow of the American Institute of the Medical and Biological Engineering, an NIH MERIT awardee, and has received the NSF CAREER award, the Society for Biomaterials Clemson Award, and the IADR Distinguished Scientist Award. His inventions have been licensed by ten companies for development and he is active on industrial scientific advisory boards.

Title of Presentation“Programming Cells in Situ with Polymers”

7:30 AM

8:00 AM

8:05 AM

9:00 AM

9:30 AM

9:50 AM

10:10 AM

Continental Breakfast

WELCOME: Paul DiCesare, MD, Professor and Chair

KEYNOTE SPEAKER - David Mooney, PhD“Programming Cells in Situ with Polymers”

A. Hari Reddi, PhD, Distinguished Professor, Lawrence J. Ellison Chair of Molecular Biology“Morphogens and Regenerative Medicine”

Dominik Haudenschild, PhD, Assistant Professor, Orthopaedics Research Lab“COMP is a Scaffold for TGF-ß1 Family Growth Factors”

Sunny Kim, PhD, Assistant Professor, Orthopaedics Clinical Outcomes Research“Operative Risk of Staged Bilateral Knee Replacement is Under-Estimated in Retrospective Studies”

Jasper Yik, PhD, Adjunct Professor, Orthopaedics Research Lab“From Stem Cells to Chondrocytes and Chondrosarcomas: Involvement of the Oncogene LRF”

BREAK (refreshments provided)

J. Kent Leach, PhD, Assistant Professor, Biomedical Engineering“Engineering of Synthetic and Natural Substrates to Modulate Bone Formation”

Derek Amanatullah, MD, Research Resident“Articular Chondrocytes and Bone Marrow Derived Stem Cells During Dynamic Compression”

Michael Hardisty, PhD Candidate“Material Level Post-Yield Behavior of Trabecular Bone Affects Apparent Toughness”

Crystal Tjhia, PhD Candidate“Bone Quality of Patients with Severely Suppressed Bone Turnover (SSBT)”

Adjournment

10:30 AM

10:50 AM

11:10 AM

11:30 AM

11:50 AM

12:10 PM

Presenters

The Lawrence J. Ellison Musculoskeletal Research Center

As people live longer, virtually everyone, given enough time, will face painful and debilitating bone diseases, such as osteoporosis, arthritis and other arthropathologies.

For the nation’s 77 million baby boomers who are just turning 60 years old, their demand for mobility and flexibility will move medical treatments and research to meet these needs to the forefront in an unprecedented way. Indeed, longitudinal studies confirm that maintaining an active and healthy quality of life is a significant requirement of the aging baby-boomer population group. As such, it is the primary challenge facing orthopaedic medicine today.

The Lawrence J. Ellison Musculoskeletal Research Center at UC Davis is a world-class research center well positioned to address the quality of life concerns through its collaborative research into tissue and cellular biomechanics, regeneration and repair - thanks to the generous support of Larry Ellison, who endowed the Lawrence J. Ellison, the Doris Linn Ellison and the David Linn Chairs.

Over the past 10 years that UC Davis has benefited from Ellison’s contributions, the Lawrence J. Ellison Musculoskeletal Research Center has conducted research, trained new scientists, recruited a very talented research team and provided the resources needed to advance bone health. Specifically, these endowments have enabled UC Davis to:

Recruit top researchers, including internationally renowned skeletal molecular biologist A. • Hari Reddi from John Hopkins School of Medicine and biomechanical engineer and researcher David P. Fyhrie. The laboratory staff includes seven basic science faculty, administrative staff, two technicians and typically a dozen postgraduate researchers: fellows, residents, visiting scholars, medical students and graduate studentsTrain and assist some 50 postdoctoral candidates and fellows in the development of their research • careers while advancing research at UC DavisAugment an 8,000 square-foot research facility that includes a machine ship, a materials • testing laboratory, cell and molecular biology laboratory, histology laboratory, tissue culture facilities, microscopy laboratory and a microsurgery suite. A new mechanobiology laboratory will soon be availableConduct dozens of research projects that would not have qualified for government funding • due to the “unknown science” involvedPublish nearly 100 research papers in more than 65 journals, magazines and books• Secure $10 million in additional research funding for projects benefiting from endowment • funding

The impact of injuries and diseases on bones and jointsMusculoskeletal conditions are the number one reason that patients visit doctors•In the US, musculoskeletal conditions cost society up to $254 billion per year in medical care and lost productivity•About one third of all American report that they have some form of arthritis•Half of all women and one out of every eight men older that age 50 will have osteoporosis-related fractures in their •lifetimeUp to 15 million people are injured or disabled each year in road accidents•

Researcher Huan Li assays markers ofstem cell chondrogenesis

bone changes to be porous and more brittle. A similar process occurs in cartilage, ligament and tendon, where the mechanical properties of the tissue degrade causing an increase of injuries with age. Our goal is to measure and determine the causes ofmechanical property changes and to help prevent or repair those changes.

our projects

Crystal Tjhia (Ph.D. candidate): The effects of age and bisphosphonate treatment on the mechanical properties of human bone tissue. Crystal uses nanoindentation, electron microscopy, finite element analysis and other methods to measure the changes of mechanical properties of the cancellous bone of human subjects who have osteoporosis or who are without disease. Changes in the mechanical properties of cancellous bone directly cause some osteoporoticfractures. Collaborators: E Lavernia, J Shoenung, SM Stover.

Matthew Soicher (Ph.D. candidate): Replacing lost bone material using a tissue engineered replacement. Matthew is determining the best method to demineralize and remove cellular debris from cortical bone tissue and then to remineralize the tissue with embedded growth factors. The goal is to build a cortical bone replacement that is sterile, strong, tough, osteogenic and which can be shaped before mineralization. Collaborators: JK Leach

Tissue Biomechanics Laboratory

David P. Fyhrie, PhD, David Linn Chair of OrthopaedicSurgery, was educated at Gonzaga and Stanford University and he worked at Henry Ford Hospital for sixteen years before joining UC Davis in 2004. His research work is to understand and prevent the age related mechanical changes in bone and cartilage that cause osteoporosis and are associated with osteoarthritis and many other orthopaedic diseases.

Mechanical loading to bone and cartilage causes nonlinear viscoelastic deformation. The deformation stimulates cells to release growth factors, causes fluid flow, causes

Michael Hardisty (Ph.D. candidate): Hydrogen bonding between collagen molecules and their role in toughening of bone. Bone is a composite material of collagen and mineral. Michael is using the surface force apparatus and finite element analysis to determine whether hydrogen bonding is a primary toughening mechanism of bone collagen. The loss of toughening is believed to be a primary cause of osteoporotic fracture. Michael’s and Crystal’s projects are related—he is building a model of bone aging and she is directly testing aged and diseased human tissue. Collaborators: T Kuhl, SM Stover.

Regenerative medicine and surgery are emerging areas of medicine that are based on design and development of spare parts for the human body; our focus being regeneration for the musculoskeletal system to restore function to tissue diseased or damaged from cancer, trauma and arthritis. Regenerative medicine is based on principles of molecular developmental biology and is governed by basic biomechanics and bioengineering. The three key elements of regenerative medicine and tissue engineering are morphogenetic signals, stem cells and scaffolds of extracellular matrix. Regeneration recapitulates embryonic development and morphogenesis.

Tissue engineering and regeneration of bone and articular cartilage are the top priorities in the research conducted at

A. Hari Reddi, PhD

cell shape and cytoskeletal morphology. In recent years, the lab has identified stem and progenitor cells in articular cartilage, muscle, and synovial tissues. Building upon this work, we are exploring the differentiation of embryonic and adult stem cells for articular cartilage and bone repair.

Dr. Reddi is the recipient of the Marshall R. Urist Award for Excellence in Regeneration Research, Orthopaedic Research Society; the NIH Directors Award; the Kappa Delta Award of the American Academy of Orthopaedic Surgeons; and the Nicolas Andry Award of the Association of Bone and Joint

Graduate Student Stephanie Chan in dissection lab

the Ellison Center. This is being addressed through multiple biological and biomechanical approaches. Superficial zone protein is producedby the top layer or articular cartilage and serves as a boundary lubricant, reducing friction. One segment of the lab is analyzing the relationship between friction and wear of articular cartilage due to changes in mechanical loading, SZP expression and the greater biomechanical environment. Previous work by this lab has shown that SZP is produced by loading-bearing regions of articular cartilage. We continue to

regeneration Laboratory

A. Hari Reddi, PhD, Distinguished Professor and Lawrence J. Ellison Chair of Musculoskeletal Molecular Biology, directs the Regeneration Laboratory.

Graduate Student Sean McNary preparing a Western blot

Visiting Post Doc Scholar, Atsuyuki Inui, MD,

concentrating proteins

study the biomechanical regulation of SZP by examining its expression in response to a variety of mechanical loading regimes. The mechanotransduction of SZP is also beingstudied at the cellular level, in relation to

Surgeons. He is the founder of the International Conference on Bone Morphogenetic Proteins (BMPs) and he chaired the conference in 1994, 1997, 2000, 2002 and 2008. Dr. Reddi has published over 330 papers.

The research conducted in the Musculoskeltal Regeneration Laboratory is a tripartite collaboration between Dr. Reddi, Dr. Paul Di Cesare and Dr. Kyriacos Athanasiou, Chairman, Department of Biomedical Engineering, College of Engineering, UC Davis.

Dr. Di Cesare’s research laboratory focuses on the mechanisms of cartilage degradation during the progression of osteoarthritis. We approach this from several angles. We have identified a protein, cartilage oligomeric matrix protein (COMP) that is an abundant non-collagenous component of cartilage. We use COMP as a model of the state of cartilage health. We have identified two enzymes that can specifically degrade COMP (ADAMTS7 and ADAMTS12), and we are studying the conditions in which these enzymes become activated, to get an idea of when cartilage matrix degradation occurs. We study the fragments of COMP created by these enzymes to use as markers of matrix degradation that can be prognostic or diagnostic of disease. We have identified that COMP is increased by mechanical stimulus simulating normal walking forces, and we are using this to

Clinical and Surgical Research Laboratories

Paul E. Di Cesare, MDMichael W. Chapman

Endowed Chairstudy the pathways and transcription factors responsible for enhancing cartilage matrix synthesis.

Basic research projects in our lab include the use of molecular and cellular biology approaches to study the mechanisms for chondrocyte differentiation from stem cells. Specifically, we are interested in studyingthe inter-relationship between positive and negative transcription factors in regulating the expression of cartilage matrix genes, and their effects on chondrogenesis and skeletal development. We are also using conventional biochemical approaches such as affinity chromatography to identify novel proteins important for regulating chondrogenesis from stem cells. Dominik Haudenschild, PhD

Assistant Professor

Jasper Yik, PhDAdjunct Professor

Eunmee Hong, PhD, Post-Doctoral Fellow: ADAMTS-12 expression in chondrogenesis and osteoarthritis. Expression of ADAMTS-12 metalloproteinase increases during chondrogenesis as cells progress towards hypertrophy, and elevated ADAMTS-12 correlates with cartilage degradation and the progression of arthritis. Eunmee used bioinformatics and molecular biology to analyze the ADAMTS-12 promoter, and discovered that ADAMTS-12 expression is controlled by the c-Maf transcription factor during chondrogenesis.

Huan Li, Junior Specialist: Control of gene expression during chondrogenesis. Huan used molecular and cell biology approaches to identify that cartilage oligomeric matrix progein (COMP) is an early marker of chondrogenesis. COMP expression precedes the expression of type II collagen by several days during the chondrogenesis of adult human bone marrow-derived stem cells. Expression analysis indicated that COMP is a primary response gene targeted by transforming growth factor ß1 (TGF-ß1) in this context.

Jeffrey Lu, M.Eng, PhD Student: Effect of mechanical stress on gene expression in Articular chondrocytes and bone marrow derived stem cells. Jeff is building a bioreactorfor application of multi-axial translational and rotational stresses on human cell-seeded alginate gels to simulate physiological forces experienced by articular cartilage. Resulting cellular responses invoked by a mechanoresponsive DNA element within a gene promoter is our target to identify. Target genes of mechanotransduction pathways include extracellular matrix genes. Cartilage Oligomeric Matrix Protein (COMP), or Superficial Zone Protein (SZP).

Kaylene Snow, Intern/Volunteer: Characterization of anti-COMP epitope recognition sites. Kaylene used deletion mutagenesis and recombinant mammalian protein expression to create recombinant truncated human COMP protein in 293T cell cultures. These recombinant proteins were used to map a battery of 20 anti-COMP monocional antibodies to specific domains within COMP, to support ongoing work in using COMP as a biomarker of osteoarthritis.

Derek Amanatullah, MD, 3rd Year Resident: Mechanical Loading of Cells in Arthritis Progression. Derek worked closely with Dr. Dominik Haudenschild to build mechanical loading systems to stimulate living cartilage cells. Their goal is to discover the cellular mechanisms that make cartilage cells sensitive to mechanical loading and to determine how mechanical loading of cells contributes to the progression of arthritis.

Dr. Kim’s research is focused on the epidemiology, health outcomes, and health economics of chronic conditions, particularly diabetes and osteoarthritis. Her outcome research interests include instrument development/validation of patient reported outcomes (PROs) with special emphasis on the health related quality of life measurements. More recently, she and her colleagues investigated the burden of knee arthroscopy in the nation. As the population ages and as the obesity epidemic continues. The health care community should be prepared for the upcoming demand of orthopaedic surgical loads and its economic burden on government and private insurance systems.

Our Spine Research Group merges cutting edge technology with medicine in major research areas, including stem cells for bone regeneration, biology of spinal fusion, and characterization of disc degeneration. We are investigating the interplay of BMP antagonists during spinal fusion in an animal model of posterolateral lumbar fusion and have discovered the reciprocal interaction between bone grafts and the local microenvironment. We are developing and validating an innovative stem cell strategy to improve fusion efficiency.Munish Gupta, MD

Professor and ChiefRolando Roberto, MD

Assistant ProfessorEric Klineberg, MDAssistant Professor

In addition, we are studying new MRI imaging technologies for characterization of biomechanical and biochemicalproperties of lumbar disc degeneration. In the past year, this work has resulted in three meeting abstracts, and we have two manuscripts in publication. In addition, our lab has recently been awarded the AO Spine Hansjorg Wyss Start Up Grant to study the Effects of Noggin-targeted RNA Interference on BMP-2 Induced Spinal Fusion.

Our laboratory has also placed a great focus on motion preservation technologies and stabilization of spinal disorders. We have developed synergistic relations with the UC Davis Biomedical Engineering graduategroup and have been the recipients of several research grants from both corporate sources and from not-for-profit organizations. Additionally, we are collaborating with investigators from Oregon Health Sciences University on upper cervical kinematics and stabilization of the C1-C2 articulation without obliteration of rotation. Finally, we have worked in a collaborative fashion with Reduction Technologies, Inc., on the design and implantation of motion preserving scoliosis correction implants. As spinal motion is crucial to function, we are dedicated to pursue stabilization of spinal pathologies without reduction of motion.

Dr. Christiansen’s lab focuses on the adaptation of bone to the mechanical loading environment, and the investigation of non-pharmacologic therapies for treating musculoskeletal pathologies such as osteoporosis. We are developing and characterizing animal models of post-injury osteoarthritis and models of age-related degeneration of peripheral nerves affecting the maintenance of bone mass. We utilize multidisciplinary methods to assess skeletal responses in our studies, including micro-computed tomography (microCT), gene expression by real-time PCR and microarray analysis, dynamic and static histomorphometry, and mechanical testing.

Sunny Kim, PhDAssistant Professor

Blaine Christiansen, PhDAssistant Professor

Clinical and Surgical Research Laboratories

Clinical and Surgical Research Laboratories

Dr. Athanasiou’s research focus is on finding clinically acceptable solutions to treat cartilage injury and diseases and in elucidating how mechanical forces induce cartilage metabolism from the single cell to the tissue level. Long-term cartilage and fibrocartilage regeneration continues to be elusive in musculoskeletal medicine, particularly since these tissues are unable to heal themselves in a way that would allow them to functionally persist within their naturally strenuous and biomechanically difficult environments. It has become clear that exogenous intervention is required for these tissues, and an engineered product may fill the void. On the tissue level, processes have been developed by the Athanasiou Laboratory whereby differentiated cells from both cartilage and fibrocartilage self-assemble to form neocartilage possessing functional properties on par with native tissue. These functional properties are then improved using anabolic, catabolic, and mechanical stimuli. Thresholds of mechanical stimuli that precipitate in metabolic changes have also been determined on the single cell level. Skin-derived cells, in addition to mesenchymal and embryonic stem cells, are under examination for their utility in regenerating or repairing articular cartilage and fibrocartilages of the knee and the temporomandibular joints. Dr. Athanasiou is the Distinquished Professor of Biomedical Engineering and Orthopaedic Surgery and Chair of the Department of Biomedical Engineering.

Gina MacBarb (PhD Candidate)Comparison of Stem Cell Sources in Cartilage Tissue Engineering for the Equine Athlete: Gina is comparing the chondrogenic potentials of four different sources of equine mesenchymal stem cells. The four sources include bone marrow, adipose, cord blood, and cord tissue derived equine mesenchymal stem cells. Using the Athanasiou Laboratory’s previously established self-assembly method, tissue engineered cartilage constructs will be created using the most promising of the four cell sources. Collaborators: C Yellowley, LD Galuppo, GL Ferraro

Pasha Hadidi (PhD Candidate)Chemical and Mechanical Stimulation of Knee Meniscus Cartilage: The knee meniscus is a piece of cartilage important for load transmission and joint stability. Recent studies have suggested several methods for producing significantly enhanced meniscus tissue grown in the lab. Mechanical testing of cultured constructs has shown hydrostatic pressure stimulation and TGF-β1 growth factor application to lead to beneficial effects on bulk tissue properties. Pasha’s current studies deal with looking for synergistic effects in these stimuli and optimizing them, by manipulating their temporal application, for multiple treatments.

Sriram Eleswarapu (M.D./Ph.D. candidate)Modulating chondrocyte phenotype and immunogenicity in native and tissue engineered articular cartilage: Sriram’s work focuses on probing the gene expression and mechanical properties of single articular chondrocytes, alone and in the presence of growth factors. Scaling up from single cells to the tissue level, Sriram is also working on characterizing the developing proteome of tissue engineered articular cartilage constructs and addressing translational challenges in immunogenicity. Collaborators: L. Griffiths

Kyriacos A. Athanasiou, PhD

This fellowship is a unique and extremely important program, which trains one of our outstanding residents each year for a career in academic orthopaedic surgery.

The Dickenson Fellowship allows this resident to work on a research project for a year with our world-recognized research clinicians, molecular biologists and engineers. This prepares the resident for a career in translational research where they will work with basic science research to transition novel treatments for disorders of the musculoskeletal system from the laboratory into the clinic for patient care.

Last year’s fellow was Dr. Derek Amanatullah, who worked closely with Dr. Dominik Haudenschild to build mechanical loading systems to stimulate living cartilage cells. Their goal is to discover the cellular mechanisms that make cartilage cells sensitive to mechanical loading and to determine how mechanical loading of cells contributes to the progression of arthritis.

This year’s fellow is Dr. Joel Williams, who has been working closely with Dr. Lee to improve the healing of long bone segmental defects. Using a novel fixation device in a rat model, our goal is to better understand the role of mechanical environment in healing these defects.

Dr. Lee’s lab focuses on a variety of research areas pertaining to fracture healing, including animal models of fracture nonunion, mesenchymal stem cell applications for fracture repair, and biomechanical evaluations of fracture implants. Our lab has optimized a rat model for atrophic nonunions and has performed evaluations of mesenchymal stem cells in the prevention of atrophic nonunions. We are initiating studies of critical size defect repair in small and medium size animal models utilizing biocompatible scaffolds with stem cells and growth factors. All of our bone regeneration experiments are focused on translational applications and we have initiated work on autologous stem cell concen-tration and delivery for fracture nonunions. In addition, we have performed numerous cadaveric and composite bone model biomechanical analyses of fracture implants and are working toward the development of clinically relevant cyclic loading protocols.

Mark Lee, MDAssociate Professor

Professor Szabo’s research focus, both clinically and in the laboratory, is on nerve compression syndromes. A major emphasis on his laboratory efforts was focused on examining the effects of compression on the tibial nerve on a rat model. His specific aim had been to characterize the response of peripheral nerves to intermittent compression with a goal of understanding the role of repetitive motion, as seen in cumulative trauma, in the pathophysiology of nerve compression. In the laboratory, he developed an animal model to study end-to-side nerve regeneration and repair. Professor Szabo’s second research focus is in biomechanics of fracture fixation, specifically with determining the role of locking, non-locking and hybrid fixation in the hand. Professor Szabo also has a strong interest in clinical research design and outcome studies that can contribute to the foundation of evidence-based medicine.

Robert Szabo, MD, MPHProfessor

The Denny and Jeanene Dickenson Orthopaedic Resident Research Fellowship

Clinical and Surgical Research Laboratories

A B S T R A C T S

COMP IS A SCAFFOLD FOR TGF-ß1 FAMILY GROWTH FACTORSDominik Haudenschild,PhD; Eunmee Hong, PhD; Jasper Yik, PhD; Brett Chromy, PhD;

and Paul DiCesare, MD

The Transforming Growth Factor beta (TGF-ß1) family is a group ofpotent growth factors that increase chondrogenesis both in stem cells and in de-differentiated chondrocytes. The chondrogenic effects of TGF-ß are widely used for tissue engineering of cartilaginous constructs. TGF-ß activity is tightly regulated by many extracellular factors that control its bioavailability, most often through interfering with the binding of TGF-ß1 to its receptors. Cartilage Oligomeric Matrix Protein (COMP) is an important cartilage protein that is essential for the structural integrity of the cartilage extracellular matrix. COMP interacts with collagens (Types II and IX), proteoglycans (aggrecan), and non-collagenous matrix proteins (matrillin). Each COMP monomer consists of 4 EGF repeats, 8 thrombospondin type-3 repeats, and a thrombospondin C-terminal domain. Five COMP monomers are disulfide-bonded to form mature pentameric COMP. The repeated modular structure of COMP is critically important for its function to ‘bridge’ and assemble multiple extracellular matrix components: for example, the COMP pentamer (but not monomeric OMP) simultaneously binds several free collagen molecules to accelerate collagen fibrillogenesis. In addition, COMP can also ‘bridge’ extracellular matrix components to the cell surface via an integrin-binding RGD sequence and interactions with the thrombospondin receptor CD47. Overexpression of COMP promotes mesenchymal hondrogenesis through an as-yet unknown mechanism.

We demonstrate for the first time a direct interaction between COMP and a growth factor, namely TGF-ß1. There are at least 2 TGF-ß1 binding sites on each COMP peptide, therefore the COMP pentameric molecule can potentially bind at least 10 TGF-ß1 molecules. This exciting result suggests that a new function for matrix-bound COMP is to increase the local concentration of TGF-ß1 and slow its diffusion out of cartilage. We are currently investigating whether the presentation of multiple TGF-ß1 molecules on a COMP scaffold elicits a more potent cellular response than unbound TGF-ß1, with a focus on the chondrogenic effects on stem cells.

POLYMERS TO PROGRAM CELLS IN SITUDavid Mooney, PhD

There are hundreds of clinical trials of cell therapy currently underway, but simple cell infusions lead to large-scale cell death, little control over cell fate, and a typically poor clinical outcome. We propose a new approach, in which material systems are first used either as cell carriers or attractors of host cell populations, and in either case the material then programs the cells in vivo and ultimately disperses the cells. Key features of these material systems include the ability to create gradients of chemotactic molecules to recruit and/or disperse cells, and immobilization of signals that regulate cell activation/differentiation of cells in contact with the material. The potential utility of this approach will be demonstrated with examples from regenerative medicine and cancer immunotherapy.

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ENGINEERING OF SYNTHETIC AND NATURAL SUBSTRATES TO MODULATE BONE FORMATION

J Kent Leach, PhDThe development of synthetic materials and extracellular matrices capable of directing cell behavior has been an overriding goal in the field of biomaterials science, tissue engineering, and bone repair for more than four decades. By working at the intersection of biomaterials science and cellular interactions, our primary goal is to develop instructive biomaterials that predictably result in specific cell functions including accelerated bone formation, maintenance of stemness for associated stem and progenitor cells, or slowed ossification. In this presentation, I will discuss some of our recent work in engineering and applying natural and synthetic matrices for use as deployment vehicles for cell-based therapies, platforms for cell culture, and underlying substrates to modulate cell phenotype, all with an eye toward bone engineering and regeneration.

FROM STEM CELLS TO CHONDROCYTES AND CHONDROSARCOMAS:INVOLVEMENT OF THE ONCOGENE LRF

Jasper Yik, PhD, Huan Li, PhD, Dominik Haudenschild, PhD, Paul DiCesare, MD, FACSThe Leukemia/Lymphoma-Related Factor (LRF) is an oncogene capable of inhibiting the activity of the tumor suppressor p53. Overexpression of LRF in B and T progenitor cells can lead to leukemia in mice. Here we report that overexpression of LRF in messenchymal stem cells (MCS) effectively blocks chondrogenic differentiation of MSC in pellet culture, indicating that LRF is a novel inhibitor of chondrogenesis. In support of this, the expression of endogenous LRF protein is down-regulated during chondrogenesis in a time-dependent manner that correlates with the concomitant increased in cartilage markers expression. The inhibitory effect of LRF on chrondrogenesis is due to its ability to enhance the rate of MSC proliferation and to facilitate cell cycle progression. Therefore, uncontrolled proliferation will be detrimental to the developing chondrocytes as the deposition of cartilage extracellular matrix will severely limit the available space for cell division. Due to its oncogenic properties, LRF is found aberrantly expressed in a variety of malignant cancers. In a tissue microarray analysis of various chondrosarcoma specimens, we discover that high LRF expression is associated with high grade chondrosarcomas. Whereas in low grade chondrosarcomas, LRF expressed ranges from completely undetectable to a mixture of negative and slight positive cells. These results indicate the potential use of LRF as a therapeutic target for advanced chondrosarcomas. LRF may also have the potential as a diagnostic marker to distinguish low grade chondrosarcomas from benign chondromas, which are often difficult to definitively diagnose.

OPERATIVE RISK OF STAGED BILATERAL KNEE REPLACEMENT IS UNDER-ESTIMATED IN RETROSPECTIVE STUDIES

Sunny Kim, PhD, John Meehan, MD, Richard White, MD, FACP To find a safer surgical option, a number of studies have compared post-operative complications after Bilateral Total Knee Arthroplasty (BTKA) versus Staged Total Knee Arthroplasty (STKA) by contrasting post-operative complications collected retrospectively. However, we believe that a comparison based on retrospective studies could be biased. The purpose of this study was to demonstrate the misclassification bias associated with a retrospective study in comparing operative outcomes. Our analysis indicates that any conclusions based simply on retrospective analysis of subjects who successfully completed STKA is biased because it includes only cases that recovered after the first operation, rather than all of the patients that had planned STKA. In the absence of a prospective study to date, published studies should be interpreted with caution.

MONITORING GENE EXPRESSION IN ARTICULAR CHONDROCYTES AND BONE MARROW DERIVED STEM CELLS DURING DYNAMIC COMPRESSION

Derek Amanatullah, MD, Paul Di Cesare, MD, Dominik Haudenschild, PhD

Expression of chondrocyte-specific genes is regulated by mechanical force. However, despite the progress in identifying the signal transduction cascades that activate expression of mechanoresponsive genes, little is known about the transcription factors that activate transcription of mechanoresponsive genes. Adapting traditional promoter analysis, performed mainly on monolayer cultures of immortalized cell lines, to the study the mechanoresponse of primary chondrocytes in three-dimensional culture systems has proven difficult. As a result, the DNA elements that confer mechanoresponsiveness within a cartilage gene promoter have yet to be identified. We have established an experimental system to identify the DNA elements and transcription factors that mediate the mechanoresponse of a promoter upon compression of primary human chondrocytes and stem cells in a three-dimensional culture system. Our secreted luciferase reporter system has identified the proximal 3 kb of the human COMP promoter as sufficient to mediate a mechanoresponse in human articular chondrocytes and stem cells at the RNA and protein level. This information is critical to understanding how mechanical force regulates the transcriptional activation of cartilage genes in three-dimensional culture and will eventually clarify the role of joint loading in cartilage homeostasis and pathology.

MATERIAL LEVEL POST-YIELD BEHAVIOR OF TRABECULAR BONE AFFECTS APPARENT TOUGHNESS

Michael R. Hardisty, Sue Stover, David P. Fyhrie, PhD

Introduction: With increasing average population age, the occurrence of fracture has the potential to adversely affect a patient’s quality of life. This investigation focuses on the energy required to degrade the apparent material (cm) properties of cancellous bone as a function of intrinsic (hard tissue) post-yield material (µm) properties. The greater the mechanical energy input the lower the likelihood of pathologic fracture.

Methods: To investigate the importance of material level post-yield properties on the apparent level behavior of trabecular bone, voxel based finite element analysis was used. Trabecular bone core geometries were obtained from µCT (50µm/voxel) scans of cadaveric T12 vertebrae. Isotropic and initially homogenous material properties were used for all elements. The elastic modulus (E) of individual elements (50µm) was reduced with a secant rule relying on strain based damage criteria. Models were run with different damaging rules. Resistance to fracture was assessed by calculating the input mechanical energy and the apparent yield strength (σay).

Results: Post-yield intrinsic (material) properties had a profound effect on the apparent level mechanical response. This was clear from two observations, 1) material level yielding and failure (ε>εdamaage) occurred to some degrees before apparent yield, and 2) σay (varied strongly, 1200%) and the mechanical energy input varied (strongly, 400%) with changes in material level post-yield behavior.

Conclusion: This damaging model provides a means to determine how changes in post-yield tissue properties determine the apparent behavior of bone. Collagen may affect post-yield mechanical behavior leading to large changes in apparent strength. The model reproduced apparent level behaviors (softening after peak load, micro-damage accumulation before apparent yield, unload softening) not previously modeled.

BONE QUALITY OF PATIENTS WITH SEVERELY SUPPRESSED BONE TURNOVER (SSBT)

Crystal Tjhia, Clarita Odvina, D. Sudhaker Rao, Susan Stover, Xiang Wang, David Fyhrie, PhD

Bisphosphonates are commonly prescribed drugs for the treatment of osteoporosis, a condition of increased fracture risk. Long-term bisphosphonate use be associated with suppressed bone turnover and atypical fractures in the shafts of femurs, tibias, and other long bones. It is currently unclear whether these fractures are associated with changed bone quality. We hypothesized that osteoporotic patients with severely suppressed bone turnover, or SSBT, and long-term bisphosphonate treatment, have decreased bone quality associated with changes in tissue-level mechanical properties and mineralization densities of the bone.

Nanomechanical properties and mineralization densities were measured from iliac crest biopsies taken from SSBT patients, non-drug-treated osteoporotic patients, young normal subjects, and old normal subjects. Trabecular bone elastic modulus and hardness were higher is SSBT patients compared to normal subjects and osteoporotic patients. SSBT trabecular bone also had higher mean mineral content that osteoporotic patients and old normal subjects but not your normal subjects. Cortical bone nano-mechanicalproperties were not different among the four groups.

We conclude that the presence of SSBT in osteoporotic patients treated with bisphosphonates alters trabecular bone quality by increasing hardness and elastic modulus, and by increasing mean mineral density. We suggest that SSBT trabecular bone property differences are due to aging of bone tissue from reduced turnover.

Selected Publications from the Ellison Laboratory for the Last Year

2010 Cheung I, Amanatullah DF, Di Cesare PE, Wound Complications in Hip Arthoplasty - Treatment and Prevention. Surgery of the Hip, DJ Berry and JR Lieberman, editors, Elsevier, New York, NY **IN PRESS**

2010 James MA, Amanatullah DF. Upper Limb Transverse Deficiency. Pediatric Orthopaedic Knowledge Update 4. **IN PRESS**

2010 Amanatullah DF. Surgical Intern Survival Guide. Einstein Journal of Biology and Medicine. **IN PRESS**

2010 Amanatullah DF, Cheung Y, Di Cesare PE. Hip Resurfacing Arthroplasty: A Review of the Evidence for Surgical Technique, Outcome, and Complications. Orthop Clin N Am, 41(2010): 263-272.

2010 Kong L, Tian Q, Guo F, Mucignat MT, Perris R, Sercu S, Merregaert J, Di Cesare PE, Liu CJ. Interaction between cartilage oligomeric matrix protein and extracellular matrix protein 1 mediates endochondral bone growth. Matrix Biol., Feb. 4.

2010 Neu CP, Reddi AH, Komvopoulos K, Schmid TM, Di Cesare PE. Friction Coefficient and Superficial Zone Protein is Increased in Patients with Late-stage Osteoarthritis. Arthritis Rheum, 2010(May 24): Epub ahead of print.

2010 Di Cesare PE. Current Treatment Options for Osteonecrosis of the Femoral Head. Am J Orthop. ** IN PRESS **

2010 Amanatullah DF, Landa J, Strauss E, Garino J, Kim S, Di Cesare PE. Comparison of Surgical Outcomes and Implant Wear between Ceramic-on-Ceramic and Ceramicon-Polyethylene Articulations in Total Hip Arthroplasty. J Arthroplasty. ** IN PRESS **

2010 Motaung SCKM, Di Cesare PE, Reddi AH. Differential Response of Cartilage Oligomeric Matrix Protein (COMP) to morphogens of Bone Morphogenetic Protein/Transforming growth factor-beta family in the surface, middle and deep zones of Articular Cartilage. J Tissue Engineering and Regenerative Medicine. ** IN PRESS **

2010 Di Cesare PE, Cheung Y: Chapter 106: Wound Complications, Della Valle CJ,Berry D, Lieberman JR, (ed), Berry’s Surgery of the Hip, Elsevier. ** IN PRESS **

2010 Giza E, Annahita K, Sarcon MS & Kreulen C. Case Report: Tibiotalar Nonunion Corrected by Hindfoot Arthrodesis. Foot & Ankle Specialist, 3(2): 76-79.

2010 Panchbhavi VK, Aronow MS, DiGiovanni BF, Giza E, Grimes JS, Harris TG, Roberts MM & Straus B. Foot and Ankle Experience in Orthopedic Residency: An Update. Foot & Ankle International, 31(1): 10-13.

2010 Giza E, Sullivan M, Ocel D, Lundeen G, Mitchell M, Frizzell L. First metatarsophalangeal hemiarthroplasty for hallux rigidus. Int Orthop.

2010 Khan SN, Lee MA, Gupta MC. Preface. Evidence-based medicine in orthopedic surgery. Orthop Clin North Am, 41(2): xiii.

2010 Lo EY, Eastman J, Tseng S, Lee MA, Yoo BJ. Neurovascular risks of anteroinferior clavicular plating.Orthopedics, 33(1): 21.

2010 Hak DJ, Lee MA & Gotham DR. Influence of prior fasciotomy on infection following open reduction and internal fixation of tibial plateau fractures. (MS# 15297) The Journal of Trauma. ** IN PRESS **

2010 Eastman JG, Tseng SS, Lee MA & Yoo BJ. Injury to intraarticular structures of the knee during retropatellar intramedullary nailing of tibia fractures (MS# JOT2666). Journal of Orthopaedic Trauma. ** IN PRESS **

2010 Eastman JG, Tseng SS, Lo E, Li CS, Yoo BJ & Lee MA. Retropatellar technique for intramedullary nailing of proximal tibia fractures: A cadaveric assessment (MS# JOT2362R1). Journal of Orthopaedic Trauma. ** IN PRESS **

2010 Cardoso R, Szabo RM. “Wrist Anatomy and Surgical Approaches”. Hand Clinics, 26(1): 1-19.

2010 Szabo RM. “Perioperative Antibiotics for Carpal Tunnel Surgery”. Journal of Hand Surgery, 35(1): 122-124.

2010 de Roode CP, James MA, McCarroll HR. Abductor Digit Minimi Opponensplasty: Technique, modifications, and measurement of opposition. Tech Hand Up Extrem Surg, 14(1): 51-3.

2010 McCarroll HR, James MA, Newmeyer WL, Manske PR. Madelung’s Deformity: Diagnostic thresholds of radio-graphic measurements. J Hand Surg Am, 35(5): 807-12.

2010 McCarroll HR, James MA. Very distal radial osteotomy for Madelung’s Deformity. Tech Hand Up Extrem Surg, 14(2): 85-93.

2010 James MA. Unilateral Upper Extremity Transverse Deficiencies: Prosthetic Use and Function. Journal of Pediatric Orthopaedics, 30(March): S40-S44.

2010 de Roode CP, James MA, Van Heest AE. Tendon transfers and releases for the forearm, wrist, and hand in spastic hemiplegic cerebral palsy. Tech Hand Up Extrem Surg, 14(2): 129-34.

2010 Campbell AJ, Bagley A, Van Heest A, James MA. Challenges of randomized controlled surgical trials. Orthop Clin North Am, 41(2): 145-55.

2010 Szabo RM. “Dorsal Intercarpal Ligament Capsulodesis”. Master Techniques in Orthopaedic Surgery: The Wrist, 3rd Edition. Gelberman RH (Editor), Lippincott, Williams & Wilkins, Philadelphia, PA, Chapter 21, pp. 235-242.

2010 Szabo RM, Newland CC. “Ligamentous Repair for Acute Lunate and Perilunate Dislocations.” Master Techniques in Orthopaedic Surgery: The Wrist, 3rd Edition. Gelberman RH (Editor), Lippincott, Williams & Wilkins, Philadelphia, PA, Chapter 22, pp. 243-261.

2010 Szabo RM, “Sauve Kapandji Procedure.” Master Techniques in Orthopaedic Surgery: The Wrist, 3rd Edition, Gelberman RH (Editor), Lippincott, Williams & Wilkins, Philadelphia, PA, Chapter 35, pp. 399-409.

2010 Amanatullah DF, Ngann KK, Borys D, Tamurian RM. Case Report: Progression of Aggressive Metastatic Carcinosarcoma After Treatment of Epithelioid Osteosarcoma. Orthopedics, 33(6):445, June.

2010 Tamurian RM, Amanatulla D. Pelvic Osteoid Osteoma in a Skeletally Mature Female. The American Journal of Orthopedics. **IN PRESS**

2010 Leslie M, Ferguson TA, Jamali A & Wolinsky PR: Fixation of femoral head fractures. Techniques in Orthopaedics. **IN PRESS**

2010 Tejwani N, Webb L, & Wolinsky PR: Mangled extremities: Limb salvage vs amputation. American Academy of Orthopaedic Surgeons Instructional Course Lectures. Book Chapter **IN PRESS**

2010 Wolinsky PR, Dennis D, Curtiss S & Hazelwood SJ. The mechanical effect of screw number and “locked” versus “nonlocked” proximal locking bolts on intramedullary fixation of proximal third tibia fractures. Journal of Orthopaedic Trauma. **IN PRESS**

2010 Haudenschild DR, Chen J, Pang N, Lotz MK, D’Lima DD. Rho Kinase-Dependent Activation of Sox9 in Chondrocytes. Arthritis & Rheumatism, 62(1): 191-200.

2010 Haudenschild DR, Chen J, Pang N, Steklov N, Grogan SP, Lotz MK, D’Lima DD. Vimentin contributes to changes in chondrocyte stiffness in osteoarthritis. J Orthop Res.

2010 Hong E, Di Cesare PE, Haudenschild DR. Role of c-MAF in Chondrocyte Differentiation: A Review. Cartilage. ** IN PRESS **

2010 Chan SM, Neu CP, Duraine G, Komvopoulos K, Reddi AH. Atomic force microscope investigation of the boundary-lubricant layer in articular cartilage. Osteoarthritis Cartilage.

2010 Ferguson TA, Patel R, Bhandari M, Matta JM. “Fractures of the Acetabulum in Patients Aged 60 Years and Older: An Epidemiology And Radiological Study. The Journal of Bone and Joint Surgery British Edition, 92-B(2): 250-7.

2010 Lowe JA, Crist BD, Bhandari M, Ferguson TA. Optimal Treatment of Femoral Neck Fractures According to Patient Physiologic Age-An Evidence Based Review. Orthopaedic Clinics of North America, 41(2):157-66.

2010 Fritz AT, Reddy D, Meehan JP, Jamali AA. Femoral neck exostosis, a manifestation of cam/pincer combined femoroacetabular impingement. Arthroscopy, 26(1):121-27.

2010 Jamali AA, Fritz AT, Reddy D, Meehan JP. Minimally invasive bone grafting of cysts of the femoral head and Acetabulum in femoroacetabular impingement: arthroscopic technique and case presentation. Arthroscopy, 26(2):279-85.

2010 Kim S, Meehan JP, Jamali AA. Changes in Medicare diagnosis related group (DRG) system for primary and revision hip and knee replacements and their implications on hospital reimbursement. Current Orthopaedic Practice, 21(2):120-25.

2010 White RH, Meehan JP, Romano PS. Re: Does aspirin have a role in venous Thromboembolism prophylaxis in total knee arthroplasty patients? J Arthroplasty, 25(4):667-68.

2010 Kim S, Boye KS. Obesity and incremental hospital charges among patients with and without diabetes in the United States. Value in Health, 12(5): 723-29.

2010 Kim Y, Kim S, Kim H. Disenrollment from a home and community-based long-term care program to a nursing home: Ohio’s experience. International Journal of Public Policy. ** IN PRESS **

2010 Kim YM, Lee CA, Matava MJClinical Results of the Arthroscopic, Single-bundle, Trans-tibial Posterior Cruciate Ligament Reconstruction: A Systematic Review AMJSPORTS/071746

2010 Klineberg, E; Gupta M; Cervical Open Posterior Reduction of Facet Dislocation, Spine Trauma; Patel, Burger, Brown ed, Springer. July

2010 Choi, G, Klineberg E, ; Gupta M. Anterior Treatment of Thoracolumbar Burst Fractures, Spine Trauma; Patel, Burger, Brown ed, Springer. July

2010 Tang, Y, Ye, X; Klineberg, E; Curtiss, S; Maitra, S; Gupta, M; Temporal and spatial expression of BMP’s and BMP antagonists during posterolateral lumbar fusion, Spine **In Press*

2010 Macagno; O’Brien, M; Hook H; Betz, R; Lonner, B; Shah, S; Crawford, A; Letko, L; Abel, M; Flynn, J; M. Gupta; Efficacy of hemivertebra resection for congenital scoliosis (CS); A multicenter restrospective comparison of three surgical techniques. Hemivertebra resection for congenital scoliosis. Harms Study Group Book. Two Chapters. **In Press**

2010 Stein-Wexler; Ton, J; Gupta M. Rib head protrusion into the central candal in type 1 neurofibromatosis. Pediatric Radiology Journal. **In Press**

2010 Roberto, R; Klineberg, E; Complications in the Treatment of Subaxial Cervical Fractures and Dislocations. The Cervical Spine – Chapter 107 Lippincott Williams & Wilkins **In Press**

2010 Roberto, R; The Natural History of Cardiac and Pulmonary Function Decline in Patients with Duchenne Muscular Dystrophy. Spine Journal Submission F11006R1 **In Press**

2010 Roberto, R; Kinematics of Progressive Circumferential Ligament Resection (Decompression) in Conjunction With Cervical Disc Arthroplasty in a Spondylotic Spine Model. Spine Journal May

2010 Klineberg, E. Cervical Spondylotic Myelopathy: A Review of the Evidence. Orthopedic Clinics of North America, April

2010 Tang, Y, Ye, X, Klineberg, E, Curtiss, S, Maitra, S, Gupta, MC Temporal and spatial expression of BMP’s and BMP antagonists during posterolateral lumbar fusion, , Spine **In Press**

2010 Mroz, TE; Abdullah, K; Steinmetz, MP; Klineberg, E; Lieberman, IH; Radiation exposure to the surgeon during percutaneous pedicle screw placement, , J Spinal Disord Tech, **In Press**

2010 Klineberg, E; Wang, J, Butler; J, Ferrara; L, Benzel; Chapter 136 - Basic Biomechanically Relevant Anatomy, EC, Spine Surgery: Techniques, Complications, Avoidance and Management, 3rd Edition, Benzel ed., Elsevier Science Inc, Philadelphia, PA

2010 Klineberg, E, Gupta M. Cervical Open Posterior Reduction of Facet Dislocation, Spine Trauma; Patel, Burger, Brown ed, Springer. July

2010 Choi, G, Klineberg, E, Gupta M. Anterior Treatment of Thoracolumbar Burst Fractures, Spine Trauma; Patel, Burger, Brown ed, Springer. July

2010 Samandouras ed. Klineberg, E. Spinal Injuries Section, The Neurosurgeon’s Handbook, Oxford University Press. March

2010 Zochowski CG, Salgado CJ, Jamali AA. Extensive muscle necrosis and infection following treatment of a lower extremity vascular malformation with Sotradecol and absolute ethanol. Blood Coagul Fibrinolysis. 2010 Jul;21(5):480-6.

2010 Bargar WL, Jamali AA, Nejad AH. Femoral anteversion in THA and its lack of correlation with native acetabular anteversion. Clin Orthop Relat Res. 2010 Feb;468(2):527-32. Epub 2009 Aug 28.

2010 Ryan JA, Jamali AA, Bargar WL. Accuracy of computer navigation for acetabular component placement in THA. Clin Orthop Relat Res. 2010 Jan;468(1):169-77. Epub 2009 Jul 24.

2010 Salgado CJ, Jamali AA, Ortiz JA, Cho JJ, Battista V, Mardini S, Chen HC, Gonzales R. Effects of hyperbaric oxygen on the replanted extremity subjected to prolonged warm ischaemia. J Plast Reconstr Aesthet Surg. 2010 Mar;63(3):532-7. Epub 2009 Mar 24.

2010 Yoo BJ, Beingessner DM, Barei DP. Stabilization of the posteromedial fragment in bicondylar tibial plateau fractures: a mechanical comparison of locking and nonlocking single and dual plating methods. J Trauma. 2010 Jul;69(1):148-55.

2010 Lo EY, Eastman J, Tseng S, Lee MA, Yoo BJ. Neurovascular risks of anteroinferior clavicular plating. Orthopedics. 2010 Jan 1;33(1):21.

2010 Neu CP, Reddi AH, Komvopoulos K, Schmid TM, Di Cesare PE. Friction coefficient and superficial zone protein are increased in patients with advanced osteoarthritis. Arthritis Rheum. 2010 May 24.

2010 Rab, G.T., Oblique Tibial Osteotomy Revisited. Journal of Children’s Orthopaedics, 4(2):169-172. **IN PRESS**

2010 Jones CN, Tuleuova N, Lee JY, Ramanculov E, Reddi AH, Zern MA, Revzin A. Cultivating hepatocytes on printed arrays of HGF and BMP7 to characterize protective effects of these growth factors during in vitro alcohol injury. Biomaterials. 2010 Aug;31(23):5936-44.

2010 Chan SM, Neu CP, Duraine G, Komvopoulos K, Reddi AH. Atomic force microscope investigation of the boundary-lubricant layer in articular cartilage. Osteoarthritis Cartilage. 2010 Jul;18(7):956-963.

2010 Rolando Roberto MD, Anto Fritz MD, Yolanda Hagar, Braden Boice M., Andrew Skalsky MD, HoSun Hwang MD, Laurel Beckett PhD, Craig McDonald MD, Munish Gupta MD. The Natural History of Cardiac and Pulmonary Function Decline in Patients with Duchennes Muscular Dystrophy, Department of Orthopedics, University of California, Davis, 2 Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, School of Medicine, Univ. of California, Davis, Department of Physical Medicine and Rehabilitation, University of California, Davis. Manuscript accepted July 2010, Spine

2010 R. F. Roberto, T. McDonald, S. Curtiss, . P. Neu, K. Kim, and F. Pennings. Kinematic Effects of Progressive Circumferential Ligament Resection (Decompression) in Conjunction with Cervical Disc Arthroplasty in a Spondylotic Spine Model, Spine 35(18): 1676-1683.

2010 Roberto R, Klineberg E. Complications In the Treatment of Subaxial Fractures and Dislocations , Cervical Spine Research Society Textbook, Chapter 106. Pending Publication 2010

2010 Boakes JL. Disorders of the Child’s Foot. In Pediatric Orthopaedics for the Primary Care. In press.

2010 Rab GT, Oblique Tibial Osteotomy Revisited. Journal of Children’s Orthopaedics, 4(2):169-172.

2010 Bouxsein, M.L., Boyd, S.K., Christiansen, B.A., Guldberg, R.E., Jepsen, K.J., Müller, R., Guidelines for assess-ment of bone microstructure in rodents using microcomputed tomography, Journal of Bone and Mineral Research, DOI: 10.1002/jbmr.141.

2010 Iyer, S., Christiansen, B.A., Roberts, B.J., Valentine, M.J., Manoharan, R., and Bouxsein, M.L., A biomechanical model for estimating loads on thoracic and lumbar vertebrae. Clinical Biomechanics, DOI: 10.1016/j.clinbiomech.2010.06.010.

2010 Samelson, E.J., Christiansen, B.A., Demissie, S., Broe, K.E., Meng, C-A, Yu, W., Cheng, X., O’Donnell, C.J., Hoffmann, U., Genant, H.K., Kiel, D.P., Bouxsein, M.L., Reliability of vertebral fracture assessment using multidetector CT lateral scout views: the Framingham osteoporosis study. Osteoporosis International, DOI: 10.1007/s00198-010-1290-6.

2010 Christiansen, B.A., Bouxsein, M.L. Methods in small animal imaging. For “Osteoporosis Research: Animal Models”, In Press.

2010 Christiansen, B.A., Bouxsein, M.L. Biomechanics of Vertebral Fractures and the Vertebral Fracture Cascade. For “Current Osteoporosis Reports - Epidemiology and Pathophysiology”, In Press.

2010 Lowe JA, Crist BD, Bhandari M, Ferguson TA. Optimal treatment of femoral neck fractures according to patient’s physiologic age: an evidence-based review. Orthop Clin North Am. Apr;41(2):157-66. Review.

2010 Genetos DC, Toupadakis CA, Raheja LF, Wong A, Papanicolaou SE, Fyhrie DP, Loots GG, Yellowley CE. Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts. J Cell Biochem. May 15;110(2):457-67.

2010 Fyhrie DP. On the Horizon from the ORS Journal of the American Academy of Orthopaedic Surgeons, 18, 1 59-59.

2010 Becerra J, Andrades JA, Guerado E, Zamora-Navas P, Lopez-Puertas JM, Reddi AH. Articular cartilage: structure and regeneration. Tissue Eng Part B Rev. 2010 Sep 14. [Epub ahead of print]

2010 Yu K, Meehan JP, Fritz A, Jamali AA. Osteochondroma of the femoral neck: a rare cause of sciatic nerve compression. Orthopedics. 2010 Aug 11;33(8). doi: 10.3928/01477447-20100625-26. PMID: 20704099

2010 Roberto RF, McDonald T, Curtiss S, Neu CP, Kim K, Pennings F. Kinematics of progressive circumferential ligament resection (decompression) in conjunction with cervical disc arthroplasty in a spondylotic spine model. Spine (Phila Pa 1976). 2010 Aug 15;35(18):1676-83. PMID: 20508554

2009 Ciarelli TE, Tjhia C, Rao DS, Qiu S, Parfitt AM, Fyhrie DP. Trabecular packet-level lamellar density patterns differ by fracture status and bone formation rate in white females. Bone. 2009 Nov;45(5):903-8. Epub 2009 Jul 14.PMID: 19615479

2009 Meehan JP, Jamali AA, Ryan JA. Pantaloon hip spica cast and constrained liner for the treatment of early total hip dislocation in a young patient with sickle cell disease. Am J Orthop (Belle Mead NJ). 2009 Dec;38(12):E184-6. PMID: 20145795

2009 Sheffler LC, Hanley C, Bagley A, Molitor F, James MA. Comparison of self-reports and parent proxy-reports of function and quality of life of children with below-the-elbow deficiency. J Bone Joint Surg Am. 2009 Dec;91(12):2852-9. PMID: 19952247

2009 Gajendran VK, Szabo RM, Myo GK, Curtiss SB. Biomechanical comparison of double-row locking plates versus single- and double-row non-locking plates in a comminuted metacarpal fracture model. J Hand Surg Am. 2009 Dec;34(10):1851-8. Epub 2009 Nov 7. PMID: 19897325

2009 Lee SY, Nakagawa T, Reddi AH. Mesenchymal progenitor cells derived from synovium and infrapatellar fat pad as a source for superficial zone cartilage tissue engineering: analysis of superficial zone protein/lubricin expression. Tissue Eng Part A. 2010 Jan;16(1):317-25. PMID: 19702511

2009 Christiansen BA, Kotiya AA, Silva MJ. Constrained tibial vibration does not produce an anabolic bone response in adult mice. Bone. 2009 Oct;45(4):750-9. Epub 2009 Jul 1. PMID: 19576309

2009 Kishimoto KN, Oxford CL, Reddi AH. Stimulation of the side population fraction of ATDC5 chondroprogenitors by hypoxia. Cell Biol Int. 2009 Dec;33(12):1222-9. Epub 2009 Jun 12. PMID: 19524690

2009 Jamali AA. Digital templating and preoperative deformity analysis with standard imaging software. Clin Orthop Relat Res. 2009 Oct;467(10):2695-704. Epub 2009 May 15. PMID: 19444527

2009 Entwistle RC, Sammons SC, Bigley RF, Hazelwood SJ, Fyhrie DP, Gibeling JC, Stover SM. Material properties are related to stress fracture callus and porosity of cortical bone tissue at affected and unaffected sites. J Orthop Res. 2009 Oct;27(10):1272-9. PMID: 19382182

2009 Shea KG, Rab GT, Dufurrena M. Pathological Fracture After Migration of Cement Used to Treat Distal Femur Physeal Arrest. Journal of Pediatric Orthopaedics, 18(4): 185-1887.

2009 Walker JL, Knapp DF, Minter C, Boakes JL, Salazar JC, Sanders JO, Lubicky JP, Drvaric DM, Davids JR. Adult Outcomes Following Amputation or Lengthening for Fibular Deficiency. J Bone Joint Surg 91A(4): 797-804, 2009.

2009 Bonds CW, James MA. Posterior deltoid-to-triceps tendon transfer to restore active elbow extension in patients with tetraplegia. Tech Hand Up Extrem Surg, 13(2): 94-97.

2009 Sheffler LC, Hanley C, Bagley A, Molitor F, James MA. Comparison of self-reports and parent proxy-reports of function and quality of life of children with below-the-elbow deficiency. J Bone Joint Surg Am, 91(12): 2852-9.

2009 Bannerman P, James MA. Molecular mechanisms to improve nerve regeneration following damage to the immature peripheral nervous system. J Bone Joint Surg Am, 91 Suppl 4: 87-89.

2009 Bednar MS, James MA, Light TR. Congenital Longitudinal Deficiency. Journal of Hand Surgery, 34A: 1739-47.

2009 Satoh A, James MA, Gardiner DM. The role of nerve signaling in limb genesis and agenesis during axolotl limb regeneration. J Bone Joint Surg Am, 91 Suppl 4: 90-98.

2009 Ty JM, James MA. Failure of differentiation: Part II (Arthrogryposis, Camptodactyly, Clinodactyly, Madelung’s Deformity, Trigger Finger, and Trigger Thumb). Hand Clin, 25(2): 195-213.

Basic Science FacultyDavid Fyhrie, PhD, ProfessorA. Hari Reddi, PhD, Distinguised ProfessorKyriacos Athanasiou, PhD, Distinguished Professor and Chair of Biomedical EngineeringBlaine Christensen, PhD, Assistant ProfessorDominik Haudenschild, PhD, Assistant ProfessorSunny Kim, PhD, Assistant ProfessorJasper Yik, PhD, Adjunct Professor

Clinical FacultyRobert Allen, MD Joel Lerman, MDJennette Boakes, MD Kirk Lewis, MDPaul Di Cesare, MD Richard Marder, MDTania Ferguson, MD Debra Popejoy, MDEric Giza, MD George Rab, MDMunish Gupta, MD Rolando Roberto, MDAmir Jamali, MD Peter Salamon, MDMichelle James, MD Robert Szabo, MD, MPHEric Klineberg, MD Robert Tamurian, MDCassandra Lee, MD James Van den Bogaerde, MDMark Lee, MD Philip Wolinsky, MD

Brad Yoo, MD

Emeritus FacultyDaniel Benson, MDMichael W. Chapman, MD

StaffNancy Boyd Research Personnel

Denny and Jeanene Dickenson Resident Research FellowsJoel Williams 2010-2011Derek Amanatullah 2009-2010

P e r s o n n e l

Visiting Postdoctoral Scholars, Fellows and Junior Specialists

Matt Anderson, MS University of California, DavisEunmee Hong, PhD Purdue University, IndianaAtsuyuki Inui, MD Kobe University School of Medicine, JapanTakeshi Iwakura, MD Kobe University School of Medicine, JapanHuan Li, MS Nachang University, China

Graduate StudentsStepanie Chan Biomedical EngineeringMichael Hardisty Biomedical EngineeringEnoch Leung Biomedical EngineeringJeffrey Lu Biomedical EngineeringSean McNary Biomedical EngineeringMatthew Soicher Biomedical EngineeringCrystal Tjhia Biomedical Engineering

Medical StudentsBasic Science ProjectsJake Becker Nicolas Karvelas

Nhat To Ping WangClinical ProjectsKimberly Yu Dora Rendulic

Shihari NampermalInternKaylene Snow

Former StaffShane Curtiss, SRA IVXiaojing Ye, University of Pittsburgh

Thanks and RecognitionI would like to thank Nancy Boyd for her continued hard work and dedication to thelaboratory. Special recognition is given Nancy Boyd, Susan Lutman and Lisa Bertschinger for their contributions to organizing the 2010 Research Symposium and for creating theprogram.

There are numerous other contributors to the success of the laboratory who deservethanks, only some of whom are listed above.- David P. Fyhrie

P e r s o n n e l

Research CollaboratorsMatthew Allen, Indiana University, Dept of Anatomy & Cell Biology

Justin Barone, USDA, Environmental Quality LaboratoryDavid Burr, Indiana University, Dept of Anatomy & Cell Biology

Brett Chromy, Lawrence Livermore National Laboratory, Dept of Physical and Life Sciences Directorate

Regina Gandour-Edwards, UC Davis Pathology DepartmentJeffrey Gibeling, UC Davis, Chemical Engineering & Materials Science Dept

Robert Guldberg, Georgia Institute of Technology, Petit Institute for Bioengineering & Bioscience

David Hawkins, UC Davis Exercise Science DepartmentEnrique J. Lavernia, UC Davis Dean Engineering

Maury Hull, UC Davis Mechanical & Aeronautical Engineering DeptMohammad Ilyas, Leeds General Infirmary, United Kingdom

Thomas Jue, UC Davis Biochemistry DepartmentTony Keaveny, UC Berkeley, Dept of Mechanical Engineering

David Kohn, University of Michigan, Biological & Materials Sciences& Biomedical Engineering

Kyriakos Komvopoulos, UC Berkeley, Dept of Mechanical EngineeringHsing-Jien Kung, UC Davis Cancer Center

Clifford Les, Henry Ford Hospital, Orthopaedic Surgery DepartmentMichael Morris, University of Michigan, Department of Chemistry

Anita Oberbauer, UC Davis Animal Science DepartmentNesrin Sarigul-Klijn, UC Davis, Mechanical & Aeronautical Engineering Dept

Mitchell Schaffler, Mount Sinai Hospital, Orthopaedic Surgery DeptKurt Schulz, UC Davis Dept of Surgery and Radiological Science

Tony Siebert, UC Davis, Department of RadiologyHarlan Stockman, Sandia National Laboratories, Div of GeochemistrySusan Stover, UC Davis, Dept of Anatomy, Physiology & Cell Biology

Clifford G. Tepper, UC Davis, Biochemical & Molecular Medicine DeptSimon Turner, Colorado State University, Dept of Clinical Sciences

Deepak Vashishth, Renssellaer Polytechnic University, Biomedical Engineering DeptDonna Wheeler, Colorado State University, Mechanical & Biomedical Engineering DeptGuozhi Xiao, University of Michigan, Dept of Periodontics/Prevention & Geriatrics

Clare Yellowley, UC Davis, Dept of Anatomy, Physiology & Cell BiologyYener N. Yeni, Henry Ford Hospital, Orthopaedic Surgery DepartmentRoger Zauel, Henry Ford Hospital, Orthopaedic Surgery Department