Choosing the appropriate preclinical model when taking an idea from bench to bedside means the difference between success and failure of bringing an idea to market in research. Utilizing the correct animal model is not easy and many of us fall into similar traps in that we use the model that we are familiar with, or that is financially viable but not entirely applicable. Often, we learn best from experiences of others that have had wonderful successes and even more impactful, epic failures.
Three teams of investigators (each a basic scientist and a clinician) have brought an idea from bench (in vitro) to bedside (in vivo) successfully using preclinical models. These teams will highlight the lessons learned along the way including:
How the appropriate animal models were chosen
How proper numbers of animals were decided upon and their valuable insights if they “had to do it all over again.”
Attendees will have the opportunity submit questions and be part of the interactive conversation. Ample discussion time is planned for each segment of the workshop.
This program is geared towards investigators at all career stages with a focus on students, post-graduate trainees, early career, and industry attendees. Researchers who are active in translational applications of computational modeling and simulation (CM&S), or who collaborate with and use models from such researchers.
Bioenergetics is a key determinant of cell fate and function. The way by which cells utilize different fuels and produce energy influences multiple signaling mechanisms and the epigenetic milieu. Unlike cells of many other tissues, the metabolic needs and preferences of bone and cartilage cells are not fully understood and many questions remain to be answered in this controversial field of study. The goal of this workshop is to educate the participants on current research investigating different metabolic/bioenergetic pathways and systems in the context of cartilage and bone biology. In addition to learning about new research findings in the field, presenters will also provide some important historical background information on the bioenergetic system of interest and why they pursued this line of research in cartilage or bone. Another goal is to organize the presentation platform for emerging research from junior and mid-career investigators in the area of bioenergetics in skeletal tissues as well as stimulate new ideas and enhance future collaborations in the field.
Chondrocyte Metabolism: When Life Gives You Lemons
Mitchell Coleman, PhD
University of Iowa
Glucose Metabolism in Articular Cartilage Homeostasis
Jie Shen, PhD
Targeting Mitochondrial Mechanobiologic Pathways in Orthopedic Soft Tissue Injury and Disease
Michelle Delco, DVM, PhD,
Make No Bones About It: Bone Metabolism is Complex
Roman Eliseev, MD, PhD
University of Rochester
Mitochondrial Stress Signaling in Osteoblasts
Anyonya Guntur, PhD
Maine Medical Center
Interrogating Amino Acid Metabolism in Osteoblasts: A New Role for Proline in Bioenergetics
Courtney Karner, PhD
University of Texas Southwestern Medical Center
Single-cell RNA sequencing (scRNA-seq) is now the most sought-after technique in musculoskeletal research laboratories all over the world. This technique was first reported in 2009 that studies the gene expression profile of a single mouse blastomere. The field of single cell transcriptomics analysis really took off after 2017, when 10x Genomics announced their platform, Chromium Controller, that is capable of analyzing ten thousands cells simultaneously at an affordable price. At such a large scale, scRNA-seq has the power to interrogate rare cell types, elucidate transitional states, delineate relationships among subpopulations, and predict the course of differentiation or reprogramming. Over the past decade, the application of scRNA-seq in both biological and clinical research has been immensely valuable, providing unexpected insights on the heterogeneity and functional specialization of tissues that previous techniques are unable to examine. These investigative possibilities have broad implications for medical advancement through the identification of novel targets for therapeutic intervention. To date, more than 40 articles have reported using this new technique to investigate the heterogeneity of musculoskeletal tissues and this number is exponentially growing over the time. More and more laboratories around the world are learning and adopting this technique for revolving their research questions. However, it is technically challenging to optimize cell isolation methods and computational demanding to properly interpret the sequencing data. For this workshop, we selected three ORS members as speakers, all of them having already applied this advanced technique to their own musculoskeletal research. These speakers come from different universities with different research programs, but all have published impactful articles in the past two years elucidating the heterogeneity of musculoskeletal tissues and developing new approaches/treatments for musculoskeletal disorders. Current scRNA-seq technique cannot extract the cell location information, thus misses an opportunity of investigating cell environment. Spatial transcriptomics represents the next frontier for advances in this field, and is now being vigorously pursued in many bioinformatics laboratories to analyze single cell gene expression profiles using histology sections. First proposed in 2015, MERFISH has evolved into an imaging method capable of simultaneously measuring the copy number and spatial distribution of hundreds to thousands of RNA species in single cells. For this workshop, we invite a non-ORS speaker who has published several articles since 2016 establishing the foundation of MERFISH method for spatial transcriptomic. Taken together, this workshop aims to present the most recent discoveries in the musculoskeletal field based on scRNA-seq approaches, to educate the audience about how to apply this advanced technique to their own research, and to introduce the next generation of single cell spatial transcriptomics approach. The target audience includes all basic scientists and clinic scientists who want to apply scRNA-seq approaches to their research.
The Emerging Power of Single Cell Transcriptomics on Musculoskeletal Tissues Farshid Guilak, PhD
Discovering Mesenchymal Cell Hierarchy in Bone: The Power of Single Cell RNA-sequencing Ling Qin, PhD
University of Pennsylvania
Predicting Your Fate or Misfortune Using Single Cell RNA and Single Nucleotide ATAC Sequencing: Using Single Cell Genomics to Understand Heterotopic Ossification Benjamin Levi, MD
UT Southwestern Medical Center
Imaging the Transcriptome: Creating Tissue Atlases with MERFISH Jeffrey Moffitt, PhD
Harvard Medical School
Intervertebral disc is the largest vascular tissue in human body and this imposes a hypoxic state on the cells of the nucleus pulpous and annulus fibrosus. Additionally disc cells experience high mechanical loads and an hyperosmitic environment. This unique niche poses several challenge in terms of metabolic substrate availability and metabolic demands of the cells. Another interesting aspect of intervertebral disc niche is very limited cell division that occurs in disc compartments post skeletal maturity. Very recent work showed interesting contribution of key signaling molecules and metabolic pathways in maintenance of disc health as well as in models of disc degeneration. Likewise, role of cell senesce is now being explored as a possible contributor to disc degeneration. These are evolving fields and many important questions still remain unanswered. The goal of the workshop is to discuss what is known and highlight areas of investigation that require further work.
Unraveling Role of Cell Metabolism in Intervertebral Disc Health and Disease Makarand Risbud, PhD
Thomas Jefferson University
Role of Cell Senescence in Intervertebral Disc Aging and Degeneration Nam Vo, PhD
University of Pittsburgh
Senotherapeutics as a Novel Strategy to Treat Intervertebral Disc Degeneration Lisbet Haglund, PhD
The rapid development of CRISPR/Cas9 and related technologies has enabled efficient and specific genome editing. The request for workshop applications specifically mentions genome editing, highlighting the importance of this topic to our research community. While many ORS members will be familiar with the concepts of genome editing, the rapid expansion of variations and applications make this an intimidating research area for those that want to apply these tools for the first time. For example, those seeking to use editing for basic science applications would benefit from a practical tutorial on the use of ribonucleoprotein (RNP) in place of plasmid DNA, the use of deactivated Cas9 to deliver cargo to genomic locations without cutting DNA, and the manipulation of the cellular environment to enhance the rate of homology directed repair (HDR) for base pair changes. Investigators who desire to use genome editing as a therapeutic strategy will benefit from an in depth discussion on the advantages and disadvantages of different methods for delivering genome editing tools in vivo, as well as considerations with regard to the potential immune response.
Using CRISPR to Dissect the Genetic Risk Factors for Osteoarthritis Brian Diekman, PhD
University of North Carolina at Chapel Hill
Modulating Pain with CRISPR Epigenome Editing Robby Bowles, PhD
University of Utah
Stem Cell-targeted Genome Editing Strategies to Advance Regenerative Medicine Amy Wagers, PhD
ORS International Section of Fracture Repair (ISFR), ORS Preclinical Models Sections, and British Orthopaedic Research Society (ORS Guest Nation)
Chelsea Bahney, PhD, Uma Sankar, PhD
The gap between discovery and improving human health typically requires efficacy testing in preclinical models. In this proposed workshop ISFR and the preclinical models section co-jointly organize a workshop that aims to help researchers decide which preclinical model will best address their fracture and/or bone regeneration research goals.
Animal Models on Inflammaging in Bone Georg Duda, PhD
Animal Models for Non-union and Delayed Fracture Healing After Multiple Trauma Melanie Haffner-Luntzer, PhD
Non-Unions: Matching your Model to the Clinical Scenario Hamish Simpson, DM
University of Edinburgh
To Heal or Not to Heal: The Utility of Minipigs as Bone Healing Models Melissa Kacena, PhD
Engineering Cell-based Approaches to Treat Critically Sized Bone Defects Kent Leach, PhD
University of California Davis
Clinical Studies in Companion Animals to Accelerate Translation Nicole Ehrhart, VMD
Colorado State University
Microphysiological systems (MPSs) have been proposed as new models for simulating human diseases and for screening potential drug treatments. Currently, the application of MPS in orthopaedic research is still under development. Many investigators in the musculoskeletal research field may not be familiar with this concept and technology. Therefore, the workshop aims to provide an educational opportunity to introduce the basic concepts of MPSs and their applications. The invited speakers will also give examples of how the use of MPS can further our understanding of specific aspects of musculoskeletal diseases and provide a tool for the assessment of different treatments and interventions.
The NIH Microphysiological Systems Program: In Vitro Tools for Drug Development and Precision Medicine Danilo Tagle, PhD
Integrated Human Multi-tissue Platform with Vascular Perfusion Gordana Vunjak-Novakovic, PhD
Cartilage-Bone-Synovium MPS for studies of PTOA Disease and Treatment on Earth and in Space Alan Grodzinsky, ScD
A Microphysiological System to Model Inflammation and Cell Cycle Regulation in Peritendinous Fibrovascular Scar Tissue Hani Awad, PhD
University of Rochester
Joint-on-a-chip; A Novel Platform for Mechanistic Studies and Drug Testing for Osteoarthritis and Pain Management Hang Lin, PhD
University of Pittsburgh
Many trainees who wish to continue in academia choose to pursue education as a primary responsibility or pursue faculty positions at universities that require a nominal teaching load. However, many trainees and faculty are not exposed to pedagogical training. Workshops like this one are meant to bridge that gap and provide hands-on opportunities to trainees so they may learn about career opportunities and innovative methods in education.
Students Grading Themselves? No, Really! Joe Towles, PhD
An Objective View of Learning Objectives
Laurel Kuxhaus, PhD
Getting Active: How to Shape Your Teaching Practices
Jennifer Weiser, PhD
For long time, the therapeutic benefits of antidepressants as disease modifying agents for osteoarthritis (OA) and for pain management have been anecdotal. Recently, scientific research has provided the basic foundation for the efficacy of particular anti-depressants in OA treatment, showing chondroprotective and chondroregenerative effects of the SSRI paroxetine, and demonstrating the effectiveness of the SNRI duloxetine in managing OA-associated pain. This workshop is designed to initiate discussions that engage both basic scientists and clinicians, which is of paramount importance for better understanding of the therapeutic potential of anti-depressants in managing this deliberating disease.
Pain Regulation in Osteoarthritis Beth Winkelstein, PhD
University of Pennsylvania
Antidepressants and signaling pathways: dynamic regulation of chondrocyte homeostasis Fadia Kamal, PharmD, PhD
Penn State University
Antidepressants for osteoarthritis, who and when? Robert Gallo, MD
Penn State University
International Federation of Musculoskeletal Research Societies (IFMRS)
Jonathan Gustafson, PhD
It has never been more important to make research knowledge easily accessible to the current and next generation of musculoskeletal researchers, in a way that brings together basic and clinical research and enables the application of knowledge and data in practice. Digital platforms and databases today make this both easy and imperative, insofar as digital communications have changed the way that information is accessed and shared. The HubLE online learning environment developed by the IFMRS provides a platform for primarily early career researchers and young investigators in the musculoskeletal (MSK) field to access information and resources; share knowledge and learning; and engage in discussion and dialogue with other students and professionals from across the world. Often, data and evidence which could be useful in advancing MSK research is not able to be shared effectively or in a timely manner, owing to the many, often stringent requirements which must be met ahead of publication. Consequently, information gets ”stuck” in the system, and advances in research are delayed. As well as providing an easy-to-access repository of published information, HubLE encourages innovation and dialogue from a growing and genuinely global community of primarily early career researchers, thereby helping to advance knowledge rapidly and productively. Members of the ORS are among the prime contributors and beneficiaries of this knowledge exchange, which is transforming the way our global community is sharing information and learning from each other.
We’d like to make this engaging, so please do have a look at our MSK Knowledge Portal and HubLE and come armed with any questions, ideas or suggestions if you can!
HubLE: A Learning Environment for Sharing Knowledge and Innovation Jonathan Gustafson, PhD
Building a Global Scientific Community for Early Career MSK Researchers Through Digital Networks Karl Lewis, PhD
Next Generation Digital Platforms and Portals for Advancing MSK/Orthopaedic Research Jennifer Westendorf, PhD
Recent advances in biomaterial design, coupled with an increased understanding of the cellular and molecular basis of tendon and ligament healing have resulted in a tremendous opportunity to advance clinical translation and success of biomaterials approaches to enhance healing. In this session we discuss the current state of the art for tendon/ligament biomaterial design and pre-clinical success criteria, as well as examine the translational pipeline from basic science idea to commercialization from the industry and academic perspective.
Preclinical Design Considerations Johnna Temenoff, PhD
Georgia Tech University
Translational Perspective from Industry Anthony Ratcliffe, PhD
Translational Perspective from Academia Martha Murray, MD
Boston Children’s Hospital
Speaker: David Butler, PhD University of Cincinnati
Treatment of tendon and ligament injuries continues to be challenging despite active research since the 1970’s, in part due to the inability of repaired or reconstructed tissues to meet functional demands (e.g. in vivo forces). The evolution of tendon repair and ligament replacement procedures will be highlighted, supported by the efforts of researchers to measure in vivo forces in corresponding pre-clinical models, to discover structure-function relationships for these complex structures, and to develop criteria for the selection and use of autografts and allografts to sustain expected activities of daily living (ADLs). These advances led in the early 2000’s to a new sub-discipline called Functional Tissue Engineering in which guidelines and design limits were proposed for treatments to meet and even exceed these ADLs. This presentation will survey early successes and failures, which often led to modification of constituents and design strategies. The influence of other fields (e.g., cell and developmental biology, biomaterials, and bioreactor design) on functional tissue engineering will also be briefly examined. It is hoped that this review of 5 decades of research and clinical treatment might favorably influence not only fundamental research going forward but the future clinical treatment of tendon and ligament injuries.
Interfaces occur between tissue types with differing material properties, and cell and matrix components. Age, disease, and trauma can influence interactions between interfaces. This Workshop will focus on the importance of such interfaces in the joint and how they are considered in various models. It will describe current research on interfaces between different biological tissues in both disease and sports -related injury models and question whether our models of these interactions are appropriate. Full consideration of interactions between tissues and improvement of the models used to study interfaces would develop our understanding of potential intervention strategies and regenerative therapies.
Workshop Outline Mark Wilkinson MB, ChB, PhD, FRCS
University of Sheffield
The Tendon-Bone Interface Catherine Pendegrass, PhD
University College London
Bone Nerve Interface Prof Deborah Mason, PhD
University of Cardiff
Cartilage Bone and Inter Tissue Interfaces in the Intervertebral Disc Christine Le Maitre, PhD
Sheffield Hallam University
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