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Monday,
September 11, 2000
7:30 Registration, Poster
Set-up, Coffee and Danish
Chondrocyte Metabolism
8:30 Chairperson’s Opening
Remarks
Michael Sittinger, Associate Professor, German Rheumatism Research
Center, Berlin and Medical Faculty Charite Berlin, Experimental Rheumatology
and Tissue Engineering, Berlin, Germany
8:35 Therapeutic Targets
for the Control of Cartilage Damage in Arthritis
A. Robin Poole, Ph.D., D.Sc, Director, Joint Diseases Laboratory,
Shriners Hospitals for Children, Canadian Hospital; Professor, McGill
University, Montreal; Associate Program Director of the Canadian Arthritis
Network
The presentation will identify new opportunities for the regulation
of cartilage turnover in arthritis, dealing with cytokines, collagen
and proteoglycan turnover and cell-matrix interactions.
9:10 Role of Growth Factors
in Cartilage Repair
Wim B. van den Berg, Ph.D., Prof. of Exp. Rheumatology, Nijmegen,
The Netherlands
Growth factors such as IGF-1, TGFb and the morphogenetic proteins are
major stimuli for cartilage matrix synthesis. TGFb is a potent regulator
of cartilage proteoglycan loss, inhibiting IL-1 driven catabolic effects
and showing superior counteraction of IL-1. On the other hand TGFb induces
chondrogenic outgrowth from periosteal layers, with a risk of induction
of osteophytes. Its application in promoting cartilage repair and tissue
engineering asks for careful targeting.
9:45 Optimizing Tissue
Engineering for Cartilage: What In Vitro Tests Can Tell Us about In
Vivo Behavior
Barbara D. Boyan, Ph.D., Professor and Director of Orthopaedic Research,
Director of the Center for the Enhancement of the Biology/Biomaterials
Interface, University of Texas Health Science Center at San Antonio
Development of cartilage replacement, repair, and regeneration materials
is confounded by the need for long-term animal studies to ensure even
incremental improvement over current therapy. We have developed pre-screening
strategies to limit the size and scope of large animal trials. One concern
has been the differences in phenotypic expression of chondrocytes in
vitro and in vivo. Data will be presented showing an analysis of chondrocyte
response to growth factors and scaffold design in vitro, and in a nude
mouse model. Results will be compared to the behavior of the scaffold
in a large animal goat model.
10:20 Refreshment Break
& Poster Viewing
Biomechanical Regulations
10:45 The Biomechanical
Environment of the Chondrocyte as a Mediator of Inflammation in Arthritis
Farshid Guilak, Ph.D., Assistant Professor and Director of Orthopaedic
Research, Duke University Medical Center
Mechanical factors play an important role in the health of diarthrodial
joints. Our studies have focused on characterizing the stress-strain
environment of chondrocytes in articular cartilage and determining the
influence of mechanical factors on chondrocyte inflammatory response.
Our findings indicate that mechanical stress has a strong influence
on the production of inflammatory mediators such as nitric oxide and
prostaglandins.
11:20 Effect of Mechanical
Loads on Articular Cartilage Function and Damage
Peter A. Torzilli, Ph.D., Senior Scientist, Laboratory for Soft Tissue
Research, Research Division, Hospital for Special Surgery, New York
Under normal physiological conditions, articular cartilage must function
under a wide range of mechanical loading conditions, including static,
repetitive and impact forces. However, when the loading environment
becomes excessive or abnormal, the cartilage can become damaged, leading
to degenerative processes and arthritis. Damage can occur at both the
cellular level and structural level. Tissue engineered replacements
will have to withstand these mechanical conditions, and as such will
have to be designed accordingly, at least on a short-term basis.
11:55 Biomechanical Regulation
and Physical Diagnostics of Chondrocyte Behavior in Cartilage and Tissue
Engineered Constructs
Alan J. Grodzinsky, Director, MIT Center for Biomedical Engineering;
Professor of Electrical, Mechanical, and Bioengineering, Departments
of Electrical and Mechanical Engineering, and Division of Bioengineering
and Environmental Health, Massachusetts Institute of Technology
Recent results have shown that mechanical shear and compression can
regulate chondrocyte biosynthesis and gene expression. Thus, specific
physiological loading regimens can alter the molecular structure of
matrix molecules such as aggrecan, and thereby affect the biomechanical
function and potential for success of neocartilage constructs. An assessment
of in situ physical properties of engineered constructs is therefore
very important; new approaches to non-destructive cartilage physical
diagnostics will be described.
12:30 Biomechanics and
Articular Cartilage Tissue Engineering
Robert Sah, M.D., Sc.D., Associate Professor of Bioengineering, Department
of Bioengineering, University of California San Diego
The treatment of cartilage defects through tissue engineering approaches
can be conceptualized as two related processes: (1) filling of the bulk
of the defect with tissue that becomes normal articular cartilage, and
(2) integration of the repair tissue with the surrounding host tissue.
Each of these processes may involve cell adhesion, proliferation, and
matrix remodeling. The occurrence of these processes, and their regulation
by biomechanical forces, in current and novel cartilage tissue engineering
methods will be discussed.
1:05 Lunch, sponsored
by The Knowledge Foundation, Inc.
Materials and Templates
2:15 Engineered Type I
Collagen-Based Template for Meniscus Regeneration
Shu-Tung Li, Ph.D., President, Collagen Matrix, Inc.; Sr. VP of Research,
ReGen Biologics, Inc.
Crescent shaped fibrocartilage of the knee joint, menisci, serve important
biomechanical functions of the knee. Animal and human studies have shown
that removal of the menisci typically results in subsequent degenerative
arthritis. Since there is no adequate substitute for the meniscal tissue,
removal of the irreparably damaged tissue is still the preferred clinical
treatment. A type I collagen based template has been designed and engineered
to support and guide meniscus regeneration. Animal and human studies
demonstrated the safety and effectiveness of this template. Future studies
will involve the design and engineer of bioactive matrices to accelerate
the regeneration and maturation process.
2:50 Chemical Acylation
of Type II Collagen Suppresses Induction of Polyarthritis in Animal
Models
Dale P. DeVore, Ph.D.,* Chief Scientific Officer and Senior Vice
President of R&D, Collagenesis, Inc.
Immunological hypersensitivity to Type II collagen, the major structural
component of articular cartilage, has been associated with the systemic
nature and chronicity occurring in rheumatoid arthritis. Purified type
II collagen has been used to induce polyarthritis in animal models resulting
in high levels of cellular and humoral immunity and lesions resembling
those observed in humans. If purified Type II collagen is chemically
acylated prior to immunization of animals, antibody titers to Type II
collagen are reduced to control levels and clinical symptoms of arthritis
do not develop. Localized treatment of eroding articular cartilage surfaces
may reduce immunological hypersensitivity associated with Type II collagen.
Contributing Author: Braden P. DeVore, President, Xium LLC
3:25 Cartilage Tissue
Engineering
Jennifer Elisseeff, Ph.D., Pharmacology Research Associate Fellow,
Craniofacial Developmental Biology and Regeneration Branch, NIDCR, NIH
Tissue engineering has developed as a potential method to replace cartilage.
Cartilage tissue engineering requires a multidisciplinary approach including
biomaterials, cell and developmental biology. A wide variety of solid
and gel biomaterials are used for cartilage engineering. A novel method
for the minimally invasive implantation of hydrogels has been developed
using light and photopolymerization. Articular cartilage is comprised
of a heterogenous population of chondrocytes. Understanding and controlling
the biological responses of these chondrocytes to tissue engineering
scaffolds is critical to the development of a tissue-engineered cartilage
comparable to native human cartilage. Paradigms of cartilage developmental
biology and their potential application to cartilage tissue engineered,
will be discussed.
4:00 Refreshment Break
& Poster Viewing
4:25 Intercellular Matrix
Therapy in Arthritic Diseases
Endre A. Balazs, MD, Chief Executive Officer, Chief Scientific Officer,
Biomatrix, Inc.
Hyaluronan and its derivatives have been widely used for the treatment
of arthritis. Elastoviscous solutions and viscoelastic gels made from
hyaluronan and hylans act as analgesics and control hyaluronan synthesis
in the joint. Hylans, used as elastoviscous supplements (viscosupplementation)
of pathological, low viscosity, synovial fluid, decrease the sensitivity
of nociceptor pain receptors in the joint and restore normal hyaluronan
synthesis in the joint.
5:00 Alginata-Recovered-Chondrocyte
Method (ARC Method) A New Approach for the Formation of Cartilaginous
Tissue In Vitro
Koichi Masuda, M.D., Associate Professor, Department of Biochemistry
and Orthopedic Surgery, Rush Medical College
We have developed a novel two-step culture method (Alginate-Recovered-Chondrocyte
method: ARC method) for the production of cartilaginous tissue in vitro.
The cartilaginous tissue thus engineered without using a resorbable
scaffold can be easily transplanted within an articular cartilage defect.
The biochemical and biomechanical properties of this tissue will be
discussed.
5:35 End of Day One
Tuesday,
September 12, 2000
8:30 Poster Viewing &
Coffee and Danish
Cell Transplantation Therapies
9:00 Chairperson’s Opening
Remarks
Steven C. Ghivizzani, Ph.D., Assistant Professor, Center for Molecular
Orthopaedics, Harvard Medical School
9:05 Autologous Chondrocyte
Implantation — Current Technique and New Developments
Barbara Huibregtse, DVM, Genzyme Corporation
A brief review of the Carticel procedure for autologous chondrocyte
implantation is given, followed by a description of new developments
in the technique. A novel method of securing the periosteal graft in
the current procedure, as well as progress in alternative methods of
autologous chondrocyte delivery will be described.
9:40 Autologous Chondrocyte
Transplantation (ACT) for Tissue Repair, Regeneration and Reconstruction
Karl-Gerd Fritsch, M.D., Ph.D.*, Co.don AG, Germany
ACT was developed first for regeneration of large focal traumatic or
degenerative (e.g. osteochondrosis dissecans) defects. The potential
for using ACT with new approaches in arthritic diseases will be discussed.
Co.Don chondrotransplant® for autologous chondrocyte transplantation
(ACT) is the first commercial provider of autologous chondrocyte transplants
for the regeneration of joint cartilage under strict autologous conditions.
The cell transplants are produced using autologous cells, autologous
serum and without using antibiotics, fungistatics, growth factors or
gene therapy. The transport logistics take place under live human organ
(LHO) conditions. The patients’ total care is organized under standardized,
quality-controlled, GMP/ ISO 9001 “all in one” conditions. The company
has developed an integrated isolator technology (ITT) as an industry
standard for the manufacturing of tissue engineering products. Under
the supervision of the federal health authorities, a 90% success rate
in good to very good regeneration and integration of the cartilage could
be confirmed in over 500 ACTs carried out with Co.Don chondrotransplant®
with biologic license approval (BLA Germany), in a 1-4 years, prospective,
comparative, multicentre study (EURACT). *Contributing Author: Olivera
Josimovic-Akasevic, M.D., Ph.D., Co.don AG, Germany
10:15 Tissue Engineering
Strategies for Cartilage Repair in Chronic Joint Diseases
Michael Sittinger, Associate Professor, German Rheumatism Research
Center, Berlin and medical faculty Charite Berlin, Experimental Rheumatology
and Tissue Engineering, Berlin, Germany
The biological reconstruction of pathologically altered articular surfaces
is a major challenge of the new millennium. The basic principle of the
different strategies focused on this objective is the implantation of
functionally active cells or growth factors using an appropriate delivery
system. Procedures for tissue construction, results of transplantations
in various animal models and novel approaches to protect repair tissues
against degeneration and chronic inflammatory reactions will be presented.
10:50 Refreshment Break
& Poster Viewing
11:15 Cell Therapy Approaches
for Cartilage Repair
Frank Barry, Ph.D.
Cell therapy provides a number of exciting opportunities for the development
of effective strategies in the regeneration of connective tissue defects,
including acute and chronic lesions in articular cartilage, as well
as large defects in bone and tendon. The repair of defects in articular
cartilage by the delivery of chondrocytes or chondroprogenitor cells
to the lesion site has been evaluated. Cells may be delivered to the
joint using a solid biomatrix or retained by other fixation methods.
The success of these approaches depends upon the ability of the implanted
cells to synthesize and deposit a new matrix to bring about the regeneration
of the tissue. The phenotypic response of the implanted cells to the
local environment is therefore critical.
11:50 Mesenchymal Stem
Cells: Cell Therapy Applications
Robert Deans, Vice President Applied Research, Osiris Therapeutics
Mesenchymal Stem Cells (MSCs) are adult stem cells which reside
in bone marrow and are distinct from the hematopoietic stem cell (HSC).
MSCs can be demonstrated to differentiate along multiple mesenchymal
lineages in vitro and in vivo, including bone, muscle, fat, tendon,
cartilage, and marrow stroma. We have developed a clinical manufacturing
process for the isolation and ex vivo expansion of human MSCs. Our current
clinical studies include the use of MSCs as an infused cell product
(Allogen™) for the regeneration of stroma in allogeneic hematopoietic
transplants. In addition, we have initiated a Phase I study for the
repair of bone in a dental model (Osteocel™). Data will be presented
demonstrating the potential of the MSC as a gene delivery vehicle in
two rodent models of antigen-induced arthritis. Pre-clinical studies
in the goat will be presented, which provide evidence for the fate of
MSCs and contribution to tissue repair when injected intra-articularly
into arthritic joints.
12:25 Lunch on your own
Gene Therapy
1:45 Lipid-Mediated Gene
Transfer to Articular Chondrocytes
Stephen B. Trippel, M.D., Professor, Department of Orthopaedics,
Massachusetts General Hospital and Harvard Medical School
Damaged adult articular cartilage does not heal. One approach to this
problem is the use of genetically engineered chondrocytes to enhance
cartilage repair or to modulate the progression of cartilage degeneration.
Recent studies have shown that isolated articular chondrocytes can be
transduced with viral vectors. Non-viral gene delivery would avoid the
risks and limitations of viral methods. We have demonstrated that lipid-based
methods can be optimized to achieve a transfection efficiency of over
20% in normal adult human articular chondrocytes. In contrast, efficiency
was less than 8% in osteoarthritic human articular chondrocytes but
was over 40% in normal neonatal bovine articular chondrocytes. Transplantation
of genetically modified articular chondrocytes that express human recombinant
insulin-like growth factor I (rhIGF-1) onto articular cartilage in explant
culture have been shown to resurface the explant with neo cartilage.
These data suggest that non-viral methods could potentially serve as
a useful tool in studies of articular cartilage damage and repair.
2:20 Direct Gene Delivery
Strategies for the Treatment of Rheumatoid Arthritis
Steven C. Ghivizzani, Ph.D.*, Assistant Professor, Center for Molecular
Orthopaedics, Harvard Medical School
We have been exploring the use of direct intra-articular gene delivery
for the treatment of rheumatoid arthritis. Research has focused in two
complementary directions. The first involves determination of the therapeutic
potential of specific gene products such as vIL-10, IL-4, FasL and p53
in animal models of disease. The second, is the evaluation of available
vector systems, both viral and non-viral for their suitability as tools
for gene transfer to the joint. *Contributing Author: Christopher
H. Evans, Ph.D., Professor, Center for Molecular Orthopaedics, Harvard
Medical School
2:55 Refreshment Break
& Poster Viewing
3:20 Suppression of Arthritic
Bone Destruction by Adenovirus Vector-Mediated Gene Transfer
Sakae Tanaka, M.D., Ph.D., Department of Orthopaedic Surgery, Faculty
of Medicine, The University of Tokyo, Japan
Suppression of bone destruction is an important issue in the treatment
of rheumatoid arthritis. We demonstrate that adenovirus vector can efficiently
transduce osteoclasts as well as synoviocytes, and adenovirus-mediated
csk gene transduction suppresses activation of synoviocytes and osteoclasts
in vitro and bone destruction in rat adjuvant arthritis. This suggests
csk gene transduction is a possible therapeutic approach for arthritic
bone destruction.
3:55 Gene Therapy for
Arthritis: Targeting Cartilage versus Synovium
Vijaykumar Baragi, Senior Research Associate, Inflammation Therapeutics,
Parke-Davis
Abstract unavailable.
4:30 End of Conference
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