3rd International Conference on TISSUE & GENETIC ENGINEERING for the Treatment of Arthritic Diseases

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Overview

October 9:
Special half day pre-conference workshop on
Polymeric Biomaterials for Medical Applications

Main Conference:

The design and development of cartilage, scaffolds and stem cell based therapies are key issues for the treatment of arthritic diseases. In order to make significant progress, numerous questions remain to be answered such as:

- How can cartilage constructs be developed, modulated and enhanced?
- How important are their biomechanical properties?
- Are there alternatives for using differentiated chondrocytes?
- What effect do engineered biomaterials have on immune responses of the host?

Our international panel of experts will discuss the latest developments on these and more topics in sessions on:

- Cartilage and Scaffolds
- Biomaterials and Biomechanics
- Gene Engineering and Immunology
- Chondrocytes

Find out what the major players in Tissue Engineering research for Arthritic Diseases are working on! Examine the program inside and register early to reserve your place!

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Agenda

Pre Conference Workshop - Wednesday, October 9, 2002

12:30 Registration, Coffee and Refreshments

1:00 Chairperson,s Keynote:
Adopting Combinatorial and High-Throughput Approaches to Measurements at the Bio-Material Interface
Eric J. Amis, Ph.D., Chief, Polymers Division, National Institute of Standards and Technology

New medical products face a rigorous regulatory process and future advances in tissue engineered medical products could be severely undermined if the cost, time, and complexity of the process grows. This becomes even more severe if the process creates competitive disadvantages in the marketplace for some products where there is no clear scientific basis. NIST is working with academic and government collaborators to help provide a rigorous scientific foundation for the testing and evaluation of biomaterials for tissue engineering products. One approach we are pioneering is the application of high-throughput or combinatorial measurement methods.

1:30 Standards and Guidelines for Biopolymers in Tissue Engineered Medical Products
Michael Dornish, Vice President, Research & Development, FMC BioPolymer AS, Norway

The American Society for Testing and Materials (ASTM) through Committee F04 Tissue Engineered Medical Products (TEMPS) is making a concerted effort to establish standards and guidelines for the entire field of tissue engineered medical products. Safety, consistency and functionality of biomaterials used as matrices, scaffolds and immobilizing agents in TEMPS are a concern. As examples, the guidelines for alginate and chitosan will be discussed.

2:10 Bioresorbable Hydrogels for Medical Therapies
Arthur J. Coury, Ph.D., Genzyme Corporation

Bioresorbable hydrogels are attaining prominence in medical devices and drug delivery systems for topical and implant applications. Current products include surgical sealants, tissue adhesives, anti-adhesion barriers and skin regeneration scaffolds. In general, highly-hydrated hydrogels devoid of peptide adhesion sequences do not permit efficient cell attachment, but they can support cell motility and mitosis at tissue interfaces. When hydrophobically-modified however, such hydrogels can promote effective cell attachment and serve as tissue regeneration scaffolds. In either case, effective healing and tissue regeneration can be enhanced during hydrogel resorption.

2: 50 Refreshment Break

3:30 Biomimetic Apatite Coated Polyactive¨ as Bone Implant
Chang Du, Ph.D., IsoTis NV, Bilthoven, Biomaterials Research Group, Leiden University, The Netherlands

We developed a simple incubation method to obtain bone-like apatite coating on flexible and biodegradable Polyactive¨ 1000PEGT70PBT30. This talk presents investigations on the characterization of the coating, the interface structure, and the adhesion property of the coating on the substrate. Bone growth on biomimetic apatite coated porous polymer was investigated after implantation in rabbit femurs.

4: 10 The Evolution of Allograft Matrices for Bone Growth
James L. Russell, Ph.D., Executive Vice President and Chief Scientific Officer, Osteotech, Inc.

Having a biocompatible graft material that can support, if not enhance repair, and be replaced by host bone represent key goals for all bone graft substitutes. A variety of processing technologies are now being combined to generate free-standing graft forms combined with different carriers and molded into shapes for both weight bearing and non-weight-bearing applications. These graft forms have evolved to formulations tailored to specific procedures that rival the performance of autograft.

4:50 Discussion
5:15 End of Workshop

Thursday, October 10, 2002

Cartilage and Scaffolds

Integration of engineered cartilage with host tissues has been used as a "gold standard" of successful joint repair. This talk will review two recent studies: integration of engineered and native cartilage studied in bioreactors as a function of the developmental stage of the engineered tissue, and the use of composites based on engineered cartilage to repair large osteochondral defects in adult rabbits.

9:40 Potential of Human Autologous Engineered in vitro Tissues
Jeanette Libera, co.don Research Center, Germany

Several autologous cell-based therapies for in vivo tissue reconstruction and generation like ACT, AOT and ADCT are successfully integrated in clinical use. Our further challenge in tissue engineering is the in vitro generation of human tissues under strictly autologous conditions. We established a novel autologous 3D cell culture system where typical features of in vivo tissues, focused on cartilage tissues, were found. By meeting all important standards for in vitro engineered tissues clinical application is given.

10:15 Cell-scaffold Based Tissue Engineering of Cartilage for Articular Repair
Anthony Ratcliffe, Ph.D., Advanced Tissue Sciences

The technology of seeding cells onto a biocompatible scaffold, followed by growth in culture, has been shown to form cartilage in vitro. The growth of the cartilage constructs can be modulated and enhanced using specially designed bioreactors, and scaffold design has been enhanced using Theriform 3-D printing technology. In vivo feasibility studies have shown that these constructs can repair osteochondral defects.

10:50 Refreshment Break and Poster/ Exhibit Viewing

11:20 Cell Therapy in Cartilage Repair
Barbara Huibregtse, Senior Scientist, Genzyme

Provides a review of current cell therapy, and new developments, including improvements to the current treatment and development of a second generation product.

11:55 Three-Dimensional Imaging of Tissue Development in Polymeric Scaffolds
Newell R. Washburn, Research Chemist, Polymers Division, National Institute of Standards and Technology

Confocal optical coherence tomography and magnetic resonance imaging are techniques that are capable of giving chemically-specific structural information. This talk will present our work in adapting these imaging tools for the study of tissue development in polymeric scaffolds. Particular emphasis is placed on quantitative image analysis and examples of work done on hard polymer scaffolds as well as hydrogels will be discussed. The hydrogel to modulate chondrocyte function in different regions of constructs.

12:30 Novel Strategies and Models for Cartilage Repair
Daniel Grande, Director, Orthopaedic Research Laboratory, Dept. of Orthopaedic Surgery, North Shore/ LI Jewish Health System

New methods for inducing cartilage repair including novel peptides and new gene/ tissue engineering strategies will be introduced. Optimizing animal models that can best be used to test cartilage repair will also be discussed.

1:05 Luncheon, Sponsored by The Knowledge Foundation

2:25 Chairperson's Remarks
Paul Ducheyne, Gentis Inc.; Center for Bioactive Materials and Tissue Engineering, Dept. of Bioengineering, University of Pennsylvania and Dept. of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia

Biomaterials and Biomechanics

Articular cartilage has properties that vary markedly during growth as well as with depth from the articular surface. These variations in biological and biomechanical properties appear important for the normal function of articular cartilage. The superficial zone of cartilage, in particular, has specialized load-bearing and low-friction qualities. The biomimetic approach of recapitulating key biological and biomechanical features of the normal architecture of articular cartilage during development and growth may be particularly useful in tissue engineering. Issues to be discussed are, the 3-D architecture of human articular cartilage, a biomechanical "blueprint" of developing and mature human articular cartilage, the biochemical basis of cartilage biomechanical properties, the specialized role of the superficial zone of articular cartilage, tissue engineering of cartilage with functional stratification.

3:35 Hydrogels in Cartilage Tissue Engineering
Jennifer H. Elisseeff, Ph.D., Dept. of Biomedical Engineering, Johns Hopkins University

Our laboratory is investigating the use of photopolymerizing poly(ethylene glycol)-based hydrogels for cartilage tissue engineering. Primary bovine chondrocytes and goat mesenchymal stem cells have been encapsulated in hydrogels and cartilage specific proteoglycan and collagen were produced. Photopolymerization provides the advantage of spatial and temporal control over gel formation. Using this controllable photopolymerization process, multilayered composite hydrogels were created in order to build a scaffold for engineering cartilage with a superficial, middle, and deep layer to better mimic native cartilage. Furthermore, extracellular matrix molecules were incorporated into the hydrogel to modulate chondrocyte function in different regions of constructs.

4:10 Refreshment Break and Poster Viewing

4:40 Tissue Engineered Ligaments
David Kaplan, Ph.D., Dept.of Chemical & Biological Engineering: Bioengineering Center, Tufts University

One of the key issues in engineering functional tissues for clinical use is the utilization of mechanical forces in directing cell differentiation and tissue assembly. We recently engineered ligaments starting from human bone marrow derived cells, biomaterial scaffolds and bioreactors with physiologically relevant mechanical stimulation in situ. This same approach can be extended to functional tissue engineering of cartilage.

5:15 Recombinant Human Collagens for Tissue Engineering Applications
Robert C. Spiro, Ph.D., Director, Tissue Engineering, FibroGen, Inc.

The development and commercialization of recombinant forms of human collagens will have a significant impact on clinical approaches to tissue repair and regeneration. Until now, the clinical utility of collagen has been limited, for the most part, to the use of Type I collagen isolated from animal sources such as bovine, porcine and equine hides, bones and tendons. The application of genetic engineering and recombinant protein expression technology for the commercial production of recombinant human collagens now opens up the possibility to utilize additional collagen family members in the design of new tissue engineering scaffolds. The multigene technology approach to be described here expresses the structural chains of collagen and the enzyme machinery necessary to thermally stabilize the mature protein in host systems (yeast) that are well adapted for commercial scale processes. The availability of pure, non-animal-derived forms of collagen family members will allow the custom fabrication and application of matrices that match recipient tissues at the levels of primary protein sequence and tissue-specific matrix composition and architecture. This presentation will highlight the utility of recombinant human collagen-based biomaterials for tissue engineering applications.

5:50 Tissue Engineering of the Intervertebral Disc
Paul Ducheyne*

Surface modified bioactive glass templates which are resorbable and porous are unique in that they stimulate nucleus pulposus cells in vitro. This suggests that glass-cell hybrids may provide an exciting novel approach to repairing and regenerating diseased intervertebral discs. In cultures, an apatite layer forms on the bioactive glass surface which functions as an attachment substratum by binding fibronectin and other serum molecules. The cells express the surface glycoprotein CD-44 which binds to hyaluronic acid, which in turn can bind to fibronectin. This then leads to cell attachment and proliferation of nucleus pulposus cells, as was experimentally confirmed. *In collaboration with Q. Qiu, I. Shapiro

6:30 End of Day One.

Friday, October 11, 2002

Chondrocytes

9:05 BMPs, Chondrogenesis and Cartilage Repair
Manas K. Majumdar, Dept. of Musculoskeletal Sciences, Wyeth Research

Bone morphogenetic proteins (BMPs) are growth and differentiation factors which play a major role in connective tissue morphogenesis. Interaction of BMPs with human multipotential mesenchymal cells have been evaluated to better understand the role of these factors. Role of IL-11 in chondrogenesis and its interaction with BMPs have been evaluated. The results from these studies will be helpful in understanding cartilage repair.

9:40 Engineering Cartilage Tissue Using Human Dermal Fibroblasts
Steven B. Nicoll, Ph.D., Assistant Professor, Depts. of Bioengineering and Orthopaedic Surgery, University of Pennsylvania, Philadelphia

Current approaches to engineer articular cartilage often rely upon the use of differentiated chondrocytes which are of limited supply and require harvesting by invasive surgical procedures. Here we describe an alternate method of producing cartilage tissue using human dermal fibroblasts. The cells are exposed to specific epigenetic modulators, including biochemical and mechanical stimuli, which induce chondrogenic differentiation in both 2-D and 3-D culture environments. Such dermal fibroblast-derived chondrocytes may have application in the repair of articular cartilage lesions.

10:15 Refreshment Break and Poster/ Exhibit Viewing

10:45 Clinical Aspects of Autologous Chondrocyte Implantation on a Resorbable 3-D Matrix
Christoph Erggelet M.D. Ph.D., Dept. for Orthopedic Surgery and Traumatology, University of Freiburg

Autologous chondrocyte implantation is an established option for the treatment of full thickness cartilage defects of the knee. In further development of the technique originally described we transplant autologous chondrocytes on a resorbable polymer fleece to standardize cell distribution and improve operative handling. Transosseous anchoring assures high initial stability of the implant. Tibial defects can be addressed. The arthroscopic implantation of autologous chondrocytes is possible and eliminates a substantial amount of the side effects known to occur after open ACI procedures.

11:20 Human Adipose-Derived Adult Stem Cells - Potential Applications
Jeffrey M. Gimble, M.D., Ph.D., Artecel Sciences, Inc.

Artecel Sciences has developed proprietary technology for the isolation, expansion and differentiation of human adipose-derived adult stem (ADAS) cells. Proof of principle studies have demonstrated that ADAS cells can differentially express phenotypic markers of adipocytes, chondrocytes, and/or osteoblasts and will support the proliferation and differentiation of hematopoietic stem cells. Artecel is conducting pre-clinical safety studies to further develop ADAS cell therapeutic products.

11:55 Chondrocyte Genomics: Implications for Disease Modification and Repair in Cartilage Injury and OA
K. Wayne Marshall, M.D., Ph.D., FRCSC, President and CEO, ChondroGene, Inc.

There are a number of barriers that are inhibiting the development of disease-modifying therapies for cartilage injury and OA. These barriers include:
- a lack of biologic markers;
- a shortage of therapeutic targets; and
- limited understanding of developmental, homeostatic, anabolic and catabolic chondrocyte pathways.

Chondrocyte genomics has the potential to overcome these barriers by enabling development of a comprehensive understanding of chondrocyte biology and pathophysiology at the molecular level.

12:30 Lunch On Your Own

1:40 Chairperson's Remarks
Michael Sittinger, Associate Professor, Laboratory for Experimental Rheumatology and Tissue Engineering, Medical Faculty Charite Berlin, Germany

Genetic Engineering/ Immunology

In a tissue engineered device, implanted cells or proteins combined with a biomaterial can serve as a source of antigens such as foreign proteins secreted by the cells including the therapeutic agent, cell surface molecules, or cell components released upon cell death. An immune response to such antigens would sensitize the host, leading to immune and inflammatory responses that could directly affect transplanted cell viability and device function. We have demonstrated that the polymeric biomaterial component acts as a moderate adjuvant in the immune response to model shed antigen co-delivered with the polymer. We are examining the effect of biomaterial contact on the maturation of dendritic cells, the key initiators of immune responses, as one possible explanation for this observed adjuvant effect of biomaterials. Furthermore, we envision a biomaterial-centered approach for controlling DC phenotype, key mediators of immunopathogenic responses in rheumatoid arthritis (RA), that will lead to design of biomaterials for robust TE devices suitable for the amelioration of RA.

2:20 Development of a Novel Therapeutic Protein to Treat Arthritic Diseases
J. Joseph Kim, Ph.D., President and CEO, Viral Genomix, Inc.

Rheumatoid arthritis (RA) is an autoimmune disease that affects the entire body, and is the most common form of arthritis. RA is characterized by the inflammation of the membrane lining the joint, which causes pain, stiffness, warmth, redness and swelling. The inflamed joint lining, the synovium, can invade and damage bone and cartilage. Inflammatory cells release cytokines and enzymes that may digest bone and cartilage.
A novel therapeutic protein (Vpr) has been developed to potentially treat RA as well other inflammatory diseases. Vpr exhibits many therapeutically relevant properties related to macrophage and T cell biology. Vpr suppresses T cell activation and cytokine elaboration. Importantly, it suppresses proinflammatory cytokine (including TNF-a, Il-1, and IL-6) and chemokine production. This activity is at least in part targeted at inhibiting NF-kB. Up-to-date data on the pre-clinical development of this product will be addressed.

2:25 Refreshment Break and Poster / Exhibit Viewing

3:00 Gene Therapy and New Proteins for the Treatment of Spinal Disorders
Peter Wehling, M.D., Director, Praxis u. Klinik f. Orthopaedie u. Neurochirurgie Duesseldorf, Associate Professor,University of Duesseldorf; CEO Orthogen AG, Germany

The talk describes the actual status of the clinical application of new proteins e.g. IL-1ra, PDGF, IGF and others for the treatment of spinal conditions as radiculopathy, disc degeneration and disc prolapse. The author, who performs a clinical gene therapy trial in Europe against RA, also gives an overview on the preclinical status of the treatment of spinal conditions by gene therapy (GT). A target specific long lasting delivery of proteins is feasible by local GT.

3:35 Therapeutic Potential of Genetically Engineered Mesenchymal Stem Cells
Padmavathy Vanguri, Ph.D., Senior Manager, Gene Delivery, Osiris Therapeutics Inc.

Mesenchymal stem cells (MSCs) are multipotent stem cells that contribute to the regeneration of various mesenchymal tissues. MSCs can be efficiently transduced with retroviral vectors to express high levels of transgene and continue to retain their ability to differentiate in vitro and in vivo. MSCs have low immunogenicity and suppress alloreactive T cell responses. Thus MSCs have potential clinical utility as cellular vehicles for systemic or tissue-specific delivery of therapeutic genes as well as in tissue engineering.

4:15 End of Conference

Call for Posters

Call for Posters
Industry and academic scientists are encouraged to submit poster titles for this event. One-page abstracts (8 1/2” x 11” with 1-inch margins) must be submitted no later than September 18, 2002 for inclusion in conference documentation. Additional poster submissions will be accepted until October 4, 2002 but may not be included in conference documentation.

Please email poster abstracts to: meder@knowledgefoundation.com

Size of Posterboard: 3x4 feet (90 x 120 cm)

Note: If you are submitting a poster, you MUST be registered and paid in advance to ensure that a posterboard is reserved for you.

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