Tissue & Genetic Engineering for the Treatment of Arthritic Diseases

Venue: Marriott Hotel

Location: Providence, Rhode Island, United States

Event Date/Time: Oct 04, 2001 End Date/Time: Oct 05, 2001
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Thursday, October 4, 2001

8:30 Registration, Poster/Exhibit Set-Up, Coffee and Pastries
9:30 Chairperson's Opening Remarks
Michael Sittinger, Associate Professor, Laboratory for Experimental Rheumatology and Tissue Engineering, Medical Faculty Charite Berlin, Germany

9:35 Strategies in Cell-Based Technologies- Cell Orientation Guided in Design by Scaffold vs. Cell-Cell Interaction and Matrix Production Directing Tissue Fabrication
Timothey Ganey, Ph.D., Co.don Tissue Engineering, Inc.
Cell-based technologies offer the opportunity to direct phenotypic identity for specific and localized treatment. Although all tissues optimize a structure that reduces strain, individual morphology of the tissues reflects different strategies to attain this condition. Chondrocytes, osteoblasts, disc chondrocytes, and endothelial cells have been successfully used in cell-based repairs. Chondrocytes respond to variations in dynamic forces to optimize a matrix that neutralizes strain, in essence structuring water by electrochemical interaction to dissipate compressive forces of loading. The matrix-rich adult morphology emerges from a highly cellular embryonic and immature morphotype that is modeled to individual loading demands.
Separately, cell-based treatments such as endothelialized heart valves require a morpholog from the outset of implantation that carries functional capacity. Based on the immediate needs, a hybrid strategy offers an option where endothelial cells on a biodegradable scaffold can provide a functional, yet biologic solution to a medical problem.
While optimal cell environment is directed at a common final goal, the course in attaining tissue specificity must take into account progressive changes that accent the functional development.

10:10 Articular Cartilage Grafts
Barbara Huibregtse, Senior Scientist, Genzyme
This talk will cover development of a second generation product of Carticel TM (Autologous Chondrocyte Implantation).

10:45 Mesenchymal Stem Cell Therapy in Joint Disease
Frank Barry, Director, Arthritis Research, Osiris Therapeutics Inc.
Mesenchymal stem cells (MSCs) isolated from bone marrow have the capacity to differentiate into several mesenchymal tissues, including bone, cartilage and adipose tissue. Data will be presented showing that delivery of cells to joints with meniscal injury inhibits progressive changes associated with osteoarthritis and therapeutic strategies in joint disease will be discussed.

11:20 Refreshment Break and Poster/Exhibit Viewing

11:50 Optimizing Tissue Engineering for Cartilage
Barbara D. Boyan, Professor and Director of Orthopedic Research, University of Texas Health Sciences 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.

12:25 Biomimetic surfaces to control cell adhesion and promote bone formation in vitro
Andrés J. García, Ph.D., Assistant Professor, Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA
Cell adhesion to extracellular matrices through integrin receptors anchors cells and triggers signals that direct cell proliferation and differentiation. We are pursuing two biomolecular strategies for engineering surfaces to control integrin binding in order to direct bone cell function and in vitro matrix mineralization. These approaches provide a basis to the rational design of robust biospecific surfaces that tailor adhesive interactions and elicit specific cellular responses.

1:00 Luncheon, Hosted by The Knowledge Foundation

2:30 Cartilage Tissue Engineering and the Role of Mechanical Forces
Alan J. Grodzinsky, Director, MIT Center for Biomedical Engineering, Professor of Electrical, Mechanical and Bio-Engineering, MIT
Certain amino acid sequences of alternating hydrophobic and hydrophilic side groups form beta sheets in water that subsequently self-assemble into a stable gel in electrolyte solutions. Such peptide gels may have significant advantages for cartilage tissue engineering. Chondrocyte encapsulation, culture, and the time evolution of matrix deposition and biomechanical properties are desribed. The potential role of mechanical forces in cell-construct optimization is discussed.

3:05 Scaffolds for Cartilage Tissue Engineering
Jens Riesle, PhD, Senior Research Scientist, IsoTis NV, Bilthoven, The Netherlands
Our approach adopts a porous polymer scaffold with similar mechanical properties to native articular cartilage, which acts as a 3D carrier for seeding autologous chondrocytes and subsequent in vitro tissue culture. The presentation will cover 1) mechanical and protein release properties of various scaffolds and 2) cartilaginous tissue formation within the 3D carrier.

3:40 Refreshment Break

4:00 Cell-scaffold Based Tissue Engineering for Cartilage
Anthony Ratcliffe, Ph.D., Vice President, Research, Advanced Tissue Sciences
The technology of seeding cells onto a biodegradable scaffold followed by tissue growth in vitro, has been shown to be successful in developing cartilage, and this tissue has been successful in repairing osteochondral defects in small animals. Recently significant improvements have been made to the tissue engineering of cartilage. Enhancement of the scaffold using 3-D printing technology has provided a new product design that can be easily delivered and fixed within an articular defect site. Growth of the constructs in bioreactors that can provide mechanical loading generates constructs with mechanical properties approaching those of native cartilage. These new approaches now offer the potential to generate tissue engineered constructs for a wide range of articular applications.

4:35 An Instrument for Measuring Cartilage Stiffness
Gabriele G. Niederauer, Ph.D., Director of Research and Development, OsteoBiologics, Inc.
OVERVIEW: The in vivo assessment of the quality of cartilage is a critical tool to determine how to clinically treat damaged cartilage. Utilizing non-destructive indentation, a hand-held instrument (ACTAEON(tm) Probe) can be used to rapidly measure the stiffness of articular cartilage, which can then be correlated to cartilage condition. This information can be of significant value to the clinician in detecting degenerative cartilage in human joints.
* Use of rapid indentation to measure the stiffness of cartilage
* Correlation of ACTAEON(tm) Probe stiffness measurements to other methods of characterizing cartilage
* Clinical testing of the device and its relationship to qualitative grading

5:15 End of Day One

Friday, October 5, 2001
8:30 Coffee and Pastries, Exhibit/Poster Viewing

9:00Chairperson's Opening Remarks
Timothey Ganey, Ph.D., Co.don Tissue Engineering

9:05 Immunological Approaches to in vivo Stabilization and Protection of Engineered Cartilage Transplants
Michael Sittinger, Associate Professor, Laboratory for Experimental Rheumatology and Tissue Engineering, Medical Faculty Charite Berlin, Germany
Following after in vitro studies on differentiation and extracellular matrix formation of engineered cartilage, different in vivo models contribute substantial insights leading to innovative clinical tissue engineering applications. Maintenance of tissue dimensions as well behavior and degradation of different components are frequently first evaluated in the nude mouse model. More advanced studies in immuno-competent animal models usually require entirely autologous procedures. Besides autologous cells, for long-term survival and stability of tissue engineered cartilage also other conditions such as scaffolds, cell embedding components or the maturity of engineered tissues appear to influence immunological reactions affecting the transplant. Thus, additional immunological approaches are suggested to stabilize or protect cartilage transplants in vivo. Such procedures may significantly expand clinical indications for cartilage tissue engineering in the future.

9:40 Interconnections Between Inflammatory and Immune Reponses in Tissue Engineering
Julia E. Babensee, Assistant Professor, Georgia Institute of Technology
The host response to a tissue engineered construct greatly impacts device function. Studies are focused on assessing the role of the biomaterial component as an adjuvant in the immune response towards antigens originating from the device and the underlying cellular mechanisms. Understanding the interconnections between an inflammatory response to a material and an immune response towards associated antigens is pivotal to controlling and designing well-integrated, physiologically functional devices.

10:15 Immune Responses to Allogeneic Mesenchymal Stem Cells
Kevin R. McIntosh, Assistant Director of Immunology, Osiris Therapeutics, Inc.
Mesenchymal Stem Cells (MSCs) are rare cells found primarily in bone marrow that can be expanded in tissue culture. These cells have the capacity to differentiate into a variety of tissue types including bone, cartilage, tendon, fat, and muscle. The exploitation of these cells for tissue repair would be most easily accomplished using MSCs derived from a "universal donor". We have investigated immunological responses to allogeneic MSCs and found that MSCs do not induce proliferation of allogeneic T cells in vitro. Lack of response can be attributed to low inherent immunogenicity of MSCs and the suppressive activity that these cells exhibit for alloreactive T cell responses. These results suggest that MSCs would not be rejected after transplantation to allogeneic recipients. Recent results in a variety of animal models have verified the accuracy of this prediction.

10:50 Refreshment Break and Poster/ Exhibit Viewing

11:20 Gene Therapy for Cartilage Healing
Steven C. Ghivizzani, Ph.D., Assistant Professor, Center for Molecular Orthopaedics, Harvard Medical School, Boston
Through the in vitro transfer of genes encoding certain growth factors we have found it possible to stimulate chondrogenesis of bone marrow stem cells as well as increase the synthesis and deposition of extracellular matrix components by chondrocytes. In contrast to ex vivo tissue engineering, we have been developing methods for transferring exogenous genes directly to cells surrounding and infiltrating osteochondral defects. Vectors suitable for gene delivery in vivo are absorbed into a biologically compatible matrix and implanted directly into freshly generated osteochondral lesions. Afterward, the transgene products are expressed for several weeks. This method is currently being evaluated for its effectiveness in repairing osteochondral defects following the delivery of chondrogenic genes such as TGF-?, BMP-2 and IGF-1.
In collaboration with: Thomas Oligino2, Elvire Gouze1, Glyn Palmer1, Paul Robbins2 and Christopher Evans1, 1Center for Molecular Orthopaedics, Harvard Medical School, Boston, 2Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh PA

11: 55 Targeted Gene Delivery for the Repair of Orthopedic Tissues
Ronda Schreiber, Ph.D., Senior Manager, Hard Tissue Repair, Selective Genetics, Inc.
Induction of tissue repair by selective targeting of therapeutic genes to the injured site is advantageous to protein based treatments, since there is the potential to control the duration of transgene protein expression as required for the specific clinical application. We have demonstrated the repair of long bone defects using our gene activated matrix (GAM) technology. Using naked plasmid DNA encoding human parathyroid hormone (hPTH 1-34) delivered on a collagen matrix, we have established the safety and efficacy of this plasmid based GAM for the repair of long bone defects.

12:30 Lunch on Your Own

2:00 Combined Tissue Engineering/ Gene Therapy Strategies for Repair of the Musculoskeletal System
Daniel Grande, Director, Orthopaedic Research Laboratory, Dept. of Orthopaedic Surgery, North Shore/ LI Jewish Health System, Manhasset NY
The successful repair of damaged articular and meniscal cartilage remains one of the most difficult challenges in orthopaedic surgery. In vitro cultured tissue constructs have been assembled which can deliver cells transduced with genes important in directing chondrogenesis during development. We will demonstrate the results using this strategy in healing articular cartilage and meniscal defects.

2:35 Molecular and cellular basis of rheumatoid joint destruction - gene transfer to identify novel therapeutic strategies
Steffen Gay, MD, Director, WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Department of Rheumatology, University Hospital, Zurich, Switzerland
In rheumatoid arthritis, synovial cells are activated, attach to cartilage and bone, release several sets of matrix-degrading proteinases (MMPs and MT-MMPs), cysteine proteinases (cathepsins B, L and K) as well as serine proteinases to invade the articular structures. To identify the most relevant factors mediating joint destruction we use the SCID mouse model and ex vivo gene transfer of protective genes, anti-sense sequences and ribozymes.

3:10 Human Type II IL-1? Decoy Receptor: Potential of Gene Therapy in Arthritis
Ashok R. Amin, Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003 and New York University Medical Center, New York, NY 10016
Interleukin 1 (IL-1) which is synthesized by chondrocytes, and acts within cartilage in an autocrine/paracrine fashion, plays a pivotal role in the pathophysiology of arthritis. Human arthritis-affected cartilage (but not normal cartilage) showed upregulation of IL-1? mRNA and protein in ex vivo conditions. mRNA for IL-1ra and IL-1RII could not be detected in human OA-affected cartilage by expression array. Reconstitution of IL-1RII (by gene therapy approach) in chondrocytes, synovial cells and epithelial cells immunizes and reverts the insults of IL-1?. Membrane bound IL-1RII is more effective than soluble IL-1RII, which is more effective than IL-1RI with respect to IL-1 neutralizing activity. The mechanism of action of IL-1RII in IL-1RII+ and IL-1RII- cells will be discussed.

3:45 End of Conference