M. Stoddart (Davos Platz, CH)

AO Research Institute Regenerative Orthopaedics
Dr. Martin Stoddart has been working at the AO Research Institute since 2005. In 2020 he become Program Leader for the Regenerative Orthopaedics program; where he also runs the Progenitor Cell Biology & Mechanoregulation Focus Area. He completed his bachelor studies in Biology at the University of Aberystwyth in 1995. He then spent a year in Davos at ARI where he completed his M.Phil in Cartilage Biology. Between 1996-2000 he carried out his doctoral thesis at the University of Nottingham in the field of Cancer Angiogenesis. He then returned to Switzerland to work in the Laboratory for experimental cartilage research in Zürich; initially as Post-Doc and between 2003-2005 as Group Head. During that time; he also took a 6 month sabbatical at the Centre for Molecular Orthopeadics; Harvard Medical School; Brigham and Womens Hospital; Boston; to learn viral gene transfer techniques. In 2005 he returned to ARI. He is an Honorary Professor at the Medical Faculty of Albert-Ludwigs University; Freiburg; Germany and at the Institute for Science and Technology in Medicine; University of Keele; United Kingdom. He is a fellow member of the ICRS and a Fellow of the Royal Society of Biology (FRSB). His main focus is the use of autologous stem cells and gene transfer for the repair of musculoskeletal tissues using a cell therapy approach. To this aim he investigates novel cell identification and isolation methods. His research interests include the mechano-regulation of stem cell fate; in particular chondrogenic differentiation. He is also interested in the mechanisms by which stem cells direct cell fate and interact with endogenous cells to effect a repair. He is the author of over 110 scientific papers and book chapters and is the editor of two books. He is deputy co-chair of the ICRS Basic Science committee and the Chair LearnORS. He is an Associate Editor for Frontiers in Bioengineering and Biotechnology and BioMed Research International Orthopedics. He is a Scientific Editor for eCM Journal and an organiser of the yearly eCM Conference.

Presenter Of 1 Presentation

Extended Abstract (for invited Faculty only) Cartilage /Cell Transplantation

19.3.1 - Cell Therapy for Cartilage Repair-Modelling - Increasing Complexity of Cartilage Models

Presentation Topic
Cartilage /Cell Transplantation
Date
14.04.2022
Lecture Time
16:00 - 16:15
Room
Potsdam 3
Session Type
Special Session

Abstract

Introduction

Articulating cartilage experiences a multitude of biophysical cues. Due to its primary function in distributing load with near frictionless articulation, it is clear that a major stimulus for cartilage homeostasis and regeneration is the mechanical load it experiences on a daily basis. While these effects are taken into account when performing in vivo studies, in vivo studies are still largely performed under static conditions.

Content

We and others have shown that mechanical load can greatly influence chondroprogenitor and chondrocyte phenotype, generally beneficially, with factors such as TGF and nitric oxide being implicated. Taken together there is an increased need to implement mechanical stimulation during in vitro studies and to further understand the relative role of the specific load applied. This requires an increasing complexity of in vitro culture models, with the ultimate aim to recreate the articulating joint as accurately as possible. Building on previous studies that demonstrated the mechanical activation of endogenous TGFβ, and subsequent chondrogenesis of human bone marrow derived MSCs (1, 2), we have been further increasing the complexity of our in vitro/ ex vivo models. For example, the addition of high molecular weight hyaluronic acid, a component of synovial fluid, culture medium leads to reduced hypertrophy and increased glycosaminoglycan deposition (3). In addition, combining osteochondral defect models where viable cartilage and bone tissue can provide soluble cross talk, and a potential cell source, with an implanted therapeutic provides a multicellular environment more representative of the in vivo situation.

We have for many years utilized a complex multiaxial load bioreactor capable of applying tightly regulated compression and shear loading protocols. While being able to apply multiple stimuli, selecting the stimuli for the vast number possible is a major challenge. Utilization of a design of experiment (DoE) approach can allow for a rapid screening of multiple factors, and their interactions, allowing for a smaller number to be selected for longer term studies. Design of higher throughput, multiwell multiaxial load bioreactors further increases the possibility to test multiple conditions or materials simultaneously opening more opportunities for in vitro screening. In vitro models have the major advantage that human cells from skeletally mature adults can be used, thus providing more clinically relevant data.

Improved understanding of the underlying mechanism of mechanically induced chondrogenesis can also assist with designing better protocols and streamlining biomaterial testing. Latent TGFβ can be mechanically activated and investigating the ability of cell free materials to activate TGFβ under mechanical load provides an insight to their performance under kinematic loading conditions (4).

The ultimate aim of all of these endeavors is to identify promising materials and therapies during in vitro/ ex vivo studies, therefore reducing the numbers or candidates that are finally tested using in vivo studies. This 3R approach can improve the opportunities for success while leading to more ethically acceptable development pathways.

References

1. Gardner OFW, Fahy N, Alini M, Stoddart MJ. Joint mimicking mechanical load activates TGFbeta1 in fibrin-poly(ester-urethane) scaffolds seeded with mesenchymal stem cells. Journal of tissue engineering and regenerative medicine. 2017;11(9):2663-6.

2. Li Z, Kupcsik L, Yao SJ, Alini M, Stoddart MJ. Mechanical Load Modulates Chondrogenesis of Human Mesenchymal Stem Cells through the TGF-beta Pathway. J Cell Mol Med. 2010;14(6A):1338-46.

3. Monaco G, El Haj AJ, Alini M, Stoddart MJ. Sodium hyaluronate supplemented culture medium combined with joint-simulating mechanical loading improves chondrogenic differentiation of human mesenchymal stem cells. Eur Cell Mater. 2021;41:616-32.

4. Behrendt P, Ladner Y, Stoddart MJ, Lippross S, Alini M, Eglin D, et al. Articular Joint-Simulating Mechanical Load Activates Endogenous TGF-beta in a Highly Cellularized Bioadhesive Hydrogel for Cartilage Repair. Am J Sports Med. 2020;48(1):210-21.

Acknowledgments

This work was funded by the Swiss National Science Foundation (31003A_179438) and the AO Foundation.

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Moderator Of 2 Sessions

Bellevue Special Session
Session Type
Special Session
Date
13.04.2022
Time
14:45 - 15:45
Room
Bellevue
Session Description
Worldwide experts discuss the role of the genome in cartilage degeneration, the implication of the mitochondria in osteoarthritis, and the identification of novel markers of cartilage injuries by omics.
Session Learning Objective
  1. Participants will acquire the latest knowledge on the implication of novel cartilage disease processes and markers using genome, omics, and system biology analyses.
CME Evaluation
Potsdam 1 Special Session
Session Type
Special Session
Date
15.04.2022
Time
12:30 - 13:30
Room
Potsdam 1
Session Description
Worldwide experts present the utility of innovative materials and techniques (3D bioprinting) for cartilage tissue engineering approaches, including strategies based on cell and factor delivery.
Session Learning Objective
  1. Participants will have access to critical information on the most up-to-date procedures of tissue engineering in the view of cartilage repair.
CME Evaluation