Tissue Repair Techniques of the Future: Options for Articular Cartilage Injury

Vladimir Bobic, MD

Disclosures

Medscape Orthopaedics & Sports Medicine eJourn. 2000;4(1) 

In This Article

Techvest Conference Summary

Techvest, LLC's first annual conference on Tissue Repair, Replacement and Regeneration was held October 27-28, 1999 in New York, NY, and featured 50 presenting companies and eight lectures by leading figures in tissue engineering and medical practice. This meeting for investors and industry covered the latest developments in this rapidly changing field.

Techvest, LLC, is an investment research, consulting and investment banking firm specializing in the healthcare sector. The meeting was organized and run by Michael Ehrenreich, Techvest, LLC's founder, president and director of research. Mr. Ehrenreich focuses on the biotechnology and biomedical sectors and writes technology overviews on many biomedical topics, including tissue engineering. He has written a report on articular cartilage repair entitled "Articular Cartilage Repair: Tissue Engineering's Killer Application?"

In 1995, 680,000 knee arthroscopies were performed in the US. A survey conducted by Curl and colleagues of 31,516 knee arthroscopies revealed that chondral lesions were present in 63%, with an average of 2.7 hyaline cartilage lesions per knee. Techvest's estimate is that 427,800 arthroscopies are performed on people with hyaline cartilage lesions present. Based on these estimates, a technology superior to microfracture or mosaicplasty in achieving hyaline cartilage repair has a potential market of $300 million to $1 billion in the US alone.

Microscopic appearance of normal blue stained hyaline articular cartilage.

Following Mr. Ehrenreich's opening remarks, Professor Robert Nerem, PhD, Director of Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, described the Georgia Tech/Emory Center for the Engineering of Living Tissues. The strategy of this center is to focus on three major thrusts. The first one is cell technology, which includes cell sourcing and the manipulation of cells in order to obtain the desired functional characteristics. The second is construct technology, where the cells are organized into three-dimensional structures that mimic native tissue in both architecture and function. The third thrust focuses on the technology necessary for integration into the living system. The future attention of the tissue-engineering community will turn to the vital organs with the potential of confronting the crisis in transplantation.

Michael J. Lysaght, PhD, Associate Professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown University, and President of the Rhode Island Center for Cellular Medicine, gave a talk on the business of tissue engineering and cellular medicine. The annual growth rate in the field of tissue engineering between 1994 and 1997 averaged 21%. Ten of the forty firms were public as of 1998 with a combined net capital value of $1.7 billion according to Dr. Lysaght. Government funding plays only a minor role in the development of the tissue engineering: At least 90% of resources flowing to tissue engineering originated in the private sector. This is also a US-driven field; 90% of the companies are US-based. This field is subject to rapid growth, from $246 million in 1995 to $504 million in 1999, with 40 registered companies. Some products, such as living skin equivalents, have advanced more rapidly than others; this was the first FDA-approved tissue-engineered device.

Professor Michael V. Sefton, PhD of the Institute of Biomaterials and Biomedical Engineering at the University of Toronto in Canada, gave a presentation on The Life Initiative, a multicenter collaboration to address the vital organ shortage. The Life Initiative began in Toronto on June 2, 1998 with the goal of using tissue engineering to create an essentially unlimited supply of vital organs for transplantation. The medical capacity to treat disease is frustrated by the limited availability of donated organs. There are 150,000 patients worldwide waiting for a transplant and the demand is growing at a rate of 15% per year. If there were no waiting lists and an unlimited supply of organs, many more would benefit from a transplant, according to Dr. Sefton.

With an unlimited supply of vital organs, replacing a damaged or failed organ would be similar to "changing a part in one's car," said Dr. Sefton. One approach would be to grow human heart muscle cells outside the body, in a scaffold made of degradable material in the shape of the heart. The resulting heart muscle, together with prepared valves and other components, would be assembled into the final product. The organs would be stored until needed by the surgeon. Donor waiting lists would become a relic of the past. The Life Initiative is an international collaboration of scientists, engineers, and clinicians whose goal is to achieve this vision within 10 years.

Gail K. Naughton, PhD, President and Chief Operating Officer of Advanced Tissue Sciences, Inc. (ATIS), presented an overview of this tissue-engineering company, which uses its proprietary core technology to develop and manufacture human-based tissue products for tissue repair and transplantation. The company has two joint ventures with Smith & Nephew. The first involves the application of Advanced Tissue Sciences' tissue-engineering technology for skin wounds, and includes Dermagraft for the treatment of diabetic foot ulcers and TransCyte for the temporary covering of second- and third-degree burns. Future development is focused on venous ulcers, pressure ulcers, burns, and other nonaesthetic wound care treatments. The second joint venture is developing tissue-engineered articular cartilage (NeoCyte), initially focusing on the repair of cartilage in knee joints. The ATIS tissue-engineering technology in the field of cartilage repair was subsequently placed into a joint venture with Smith & Nephew.

The ATIS approach is to seed chondrocytes onto a synthetic matrix that can then be molded into a cartilage defect. The cartilage can either be grown in vitro and then implanted or generated in vivo by implantation of the cell-polymer construct. In either case, the synthetic scaffold would, over time, be resorbed and replaced with hyaline-like cartilage. Dr. Naughton projected that tissue-engineered cartilage, following launch in 2005, can achieve US revenues of approximately $65 million in 2006.

Vladimir Bobic, MD, Consultant Orthopaedic Knee Surgeon, from The Royal Liverpool University Hospitals Liverpool and The Grosvenor Nuffield Hospital, Chester, UK, gave a talk on "the current status of the articular cartilage repair, from the practicing orthopaedic surgeon's view."

Restoring a damaged articular surface is a multidisciplinary challenge that has generated tremendous interest among research scientists, clinicians, and patients. Many new articular cartilage repair techniques have emerged in the past four to six years, most of which appear to be very promising. Current treatments can be divided into four basic categories: those that stimulate the bone marrow to form a repair tissue, transplantation of osteochondral autografts or allografts, implantation or transplantation of cultured autologous chondrocytes, and the use of resorbable scaffolding with or without cells. However, most cartilage repair techniques have not proved entirely successful yet and fail to provide durable hyaline articular cartilage.

Arthroscopic photograph of microfracture technique (bone marrow-stimulating technique) with arthroscopic awl, applied to the cartilage defect in the medial femoral condyle.

Current state of the art of articular cartilage repair is the result of the increased awareness of the significance of articular cartilage damage and the explosive interest in, intense research into, and rapid development of clinical applications. The final product is still in its infancy and far from being finished, but it is this systemic and rapid sequential progression that will lead to future developments according to Dr. Bobic. At this rapid pace, further advances in articular cartilage research, leading to clinical application with a reliable long-term outcome, are not far away. The question is not whether we will get there, but when.

Osteochondral autograft transfer: appearance of the graft used to repair focal defect of the medial femoral condyle, one year after transplantation. (Craig Morgan, MD)

Carl. H. Winnebald, President and Chief Executive Officer of OsteoBiologics, Inc. (OBI), gave a talk on clinical application of cartilage regeneration. OBI researches, develops, and manufactures bioabsorbable, tissue-engineered, PLA/PGA polymer scaffolds (IMMIX) for the repair and replacement of articular cartilage. OBI is developing a biphasic polymer for the resurfacing of osteochondral defects. It is comprised of PLA/PGA copolymer as the base material and includes PGA fibers, Bioglass (a 45S5-type glass), and calcium sulfate as additives to vary stiffness. The implant consists of a bone phase, a cartilage phase, and a thin solid film surface. In clinical application, this implant would be press-fit into an osteochondral defect. Over a period of 6 to 9 months, the implant would be infiltrated by cells and remodelled into cartilage, hopefully of a hyaline nature. The IMMIX-CB can also support cell growth and may be a potential carrier for cell-based therapies. OBI is also working on a PLA/PGA polymer that can be used to resurface full-thickness defects. IMMIX-CB may enter the clinic in the US in 2000.

Stuart M. Essig, President and Chief Executive Officer of Integra LifeSciences Holdings Company, introduced Integra LifeSciences. Integra LifeSciences, founded in 1989, has a number of projects underway to develop products that support the regeneration of bone, cartilage, and connective tissue. Collaborative projects include those being undertaken with DePuy, a Johnson & Johnson company; Genetics Institute, Inc., a subsidiary of American Home Products Corporation; Sofamor/Danek Group, Inc., a subsidiary of Medtronic, Inc.; Bionx Implants, Inc., the Linvatec division of CONMED Corporation; and the National Institute for Standards and Technology.

Peptides are small synthetic chains of amino acids that are designed to perform specific functions on cells. Using patented technology from Integra's Corporate Research Center in San Diego, Calif, peptides can be engineered to mimic very large natural matrix proteins that are found within tissues of the body. Peptides bind integrin receptors that are found on the surface of nearly all cells in the body.

There are more than 20 such integrin types within this family of cell receptors. Integrins control cell attachment, growth, migration, and differentiation. Cells present within tissues rely on specific integrin types during tissue regeneration. Small synthetic peptides can be designed to interact selectively with certain integrins to achieve differing outcomes by enhancing the interaction between cells and matrix.

When used in combination with a collagen scaffold, these peptides signal through integrins, adopt cell-matrix functions, and promote the formation of new tissue by guiding the attachment and growth of cells. Accordingly, in a tissue such as cartilage that inherently lacks the ability to repair itself when damaged, the introduction of a peptide-enhanced collagen matrix that is able to actively guide the recognition of normal cartilage represents a unique, simple approach to the treatment of injured cartilage.

Integra and its corporate partner DePuy are developing an alternative single-step regenerative product for cartilage repair that regenerates tissue using the cells within the patient's body. It is composed of a specifically engineered collagen-based scaffold (matrix) combined with Integra's unique peptide technology. With this new off-the-shelf, single-step procedure, the surgeon would be able to place the Integra matrix into the damaged cartilage defect and allow the body to heal over time, with less risk and patient discomfort that is associated with current procedures.

Rory Riggs, President of Biomatrix, Inc., described his company's development and manufacture of viscoelastic products made from proprietary biological polymers called hylans. The company's lead product, Synvisc, is a nondrug therapeutic used to provide pain relief for those who suffer from osteoarthritic knee pain. Synvisc is a solution of hylans (hyaluronan derivatives, molecular weight of about 6 x 106 daltons) in a prefilled 2-mL syringe. The manufacturer recommends Synvisc for a 3-week course (repeatable once within 6 months, with at least 4 weeks between courses). It has been suggested that hylans may produce a longer-lasting effect by stimulating endogenous hyaluronan synthesis and reducing inflammation.

J. Melville Engle, President and Chief Executive Officer of Anika Therapeutics, Inc, gave an overview of the company and its products. Founded in 1993, Anika Therapeutics develops and manufactures therapeutic products based on hyaluronic acid (HA) for the repair, protection, and healing of bone, cartilage, and soft tissue. HA is a naturally occurring, biocompatible polymer found throughout the body and enhances joint function and coats, protects, cushions, and lubricates soft tissues. Anika has developed proprietary manufacturing techniques for extracting and purifying HA from connective tissue found in rooster combs. Anika's leading product, ORTHOVISC, is an injectable treatment for osteoarthritis pain. ORTHOVISC is a naturally derived, highly purified form of HA designed to emulate the viscoelastic and cushioning properties of natural HA found in the synovial fluid of healthy joints. ORTHOVISC is administered by three intra-articular injections over a 2-week period and relieves pain for an extended period of time. Engle projected that worldwide sales of HA products for the treatment of osteoarthritis currently total $500 million, and there is a potential market of $1 billion.

ORTHOVISC is currently in a Phase III clinical trial with orthopaedic surgeons and rheumatologists in the US and Canada, and the study is expected to be completed by mid-2000. Zimmer, Inc. (a subsidiary of Bristol-Myers Squibb), has licensed ORTHOVISC distribution rights for most of the world.

Dr. Alessandra Pavesio, Director of Research & Development for Fidia Advanced Biopolymers (FAB), spoke about hyaluronan-based scaffolds in tissue engineering. Hyaluronan (HA) derivatives represent a novel alternative to currently available resorbable biomaterials. As a naturally occurring extracellular matrix (ECM) molecule, HA, a high-molecular-weight glycosaminoglycan, offers the advantages of being recognized by cell receptors interacting with other ECM molecules and being metabolized by intrinsic cellular pathways. Esterification and cross-linking have been employed to produce novel biopolymers with increased longevity in vivo, cell-receptor interactivity, and processability into stable three-dimensional configurations. Keratinocytes, fibroblasts, chondrocytes, mesenchymal stem cells, endothelial cells, hepatocytes, urethral cells, and nerve cells have proven to efficiently proliferate on FAB's proprietary three-dimensional scaffolds. Entirely biodegradable, based on a ubiquitous molecule such as HA, these scaffolds represent the most advanced and user-friendly enabling technology for tissue engineering currently available in clinical practice. FAB has had three of its proprietary scaffolds approved by the European Community, an ISO-accredited tissue culture laboratory, and two tissue-engineered products launched.

William A. Haseltine, Chairman and Chief Executive Officer of Human Genome Sciences, gave a talk entitled "Genomics: A Systematic Approach to Regenerative Medicine." Genomics, the study of all genes of an organism, has opened up a new window of opportunity for medicine. Human Genome Sciences has isolated a virtually complete set of human genes in their most usable form -- DNA copies of the messenger RNA that can be used to make functional proteins. One of the most interesting sets of human proteins is the genes that are part of the signalling apparatus that specifies proteins that transmit and receive information passed between organs, tissues, and cells. These signals control embryonic and fetal development, growth and maturation, adult size and shape, the ordered replacement of normal organs and tissues, repair of injury, and response to infection. Human Genome Sciences has isolated full-length cDNAs corresponding to 14,000 human proteins containing signal peptide sequences, believed to represent the majority of human signalling proteins. Each gene codes for a functioning protein. The nucleotide sequence of each is known, as is considerable information regarding the cells and tissues in which the proteins are made, as well as the chromosomal map location. Functional proteins are made from each gene. This set-up of genes and proteins has the potential to accelerate regenerative medicine and tissue-engineering efforts. Simply explained, each cell responds to sets of opposing signals that regulate growth, differentiation, activation of differential characteristics, and cell death. The ability to search for and find the signals and receptors that control cell behavior should greatly accelerate tissue-engineering studies by allowing controlled growth of cells, organs, and tissues in culture.

Richard R. Tarr, Vice President of Research & Orthobiologics at DePuy, gave a talk entitled "Orthobiologics: Ligament and Cartilage Regeneration." Tissue engineering has come of age with the commercialization of several products. At DePuy, the Restore Orthobiologic Implant has been approved as a soft tissue patch reinforcing weakened soft tissue structures. In addition, work done with Purdue University is continuing for the development of small-intestine submucosa applications for meniscal repair and regeneration, as well as for ligament and tendon repair. For articular cartilage, collaborations with Integra LifeSciences, Matrix Biotechnologies, and the Corporate Biomaterials Center of Johnson & Johnson are approaching the preclinical phase of testing various matrix scaffold materials and a patented anchorage technology.

A biodegradable, off-the-shelf cartilage repair unit has been developed at Long Island Jewish Medical Center, New Hyde Park, NY, and North Shore University Hospital in Manhasset, NY. Tests of the unit in a rabbit model have been encouraging. The unit consists of a hexagonal PLA plug designed to fit within an osteochondral defect. A ring holds the three-dimensional "gem" of PGA nonwoven felt matrix. According to Daniel A. Grande, one of the investigators, the unit generates a hyaline-like repair surface when the "gem" is treated with transforming growth factor (TGF)-beta, with no chondrocytes added.

DePuy is exploring the use of TGF-beta1 in conjunction with various matrices to promote cartilage repair. Specifically, it is working with the PGA scaffolds of Matrix Biotechnologies. These PGA scaffolds are designed to be tethered to the bone using a porous PLA anchor. PGA matrices have been shown to be capable of delivering therapeutic doses of TGF-beta for up to 21 days. However, in this model, TGF-beta in a PGA matrix was not superior to PGA alone in generating repair tissue. Both groups were superior to empty controls.

Tim Surgenor, President of Genzyme Tissue Repair, gave a talk entitled "The Development of Genzyme Tissue Repair Orthopaedic Portfolio." Genzyme Tissue Repair is a division of Genzyme Corporation and develops biological products for the treatment of severe burns as well as orthopaedic injuries such as cartilage damage.

Mr. Surgenor reported on further advances of Carticel autologous cultured chondrocyte implantation for the repair of chondral defects. Carticel was introduced in 1995 and approved by the FDA in August 1997 for the repair of clinically significant, symptomatic cartilaginous defects of the femoral condyle. Since its introduction, Carticel has been used in approximately 3000 patients worldwide.

Implantation process of autologous cultured chondrocytes.Illustration published with permission of Genzyme Tissue Repair.

The results of the 1999 Cartilage Repair Registry report (including 40 patients with 3-year follow-up) indicate 85% improvement following treatment of chondral defects with Carticel, with 10% of patients with no improvement and 5% failures. Genzyme Tissue Repair initiated the Registry in 1995. Mr. Surgenor also reported on the Carticel improvement program, which involves a shorter and less invasive operative procedure and better fixation of the periosteal cover with Quick TackGenzyme Tissue Repair development programs include: Carticel II (a preformed Carticel graft), Quick Tack (tacked to attach periosteum during the Carticel procedure), photoactive tissue-welding technology (light-activated compound used to reconnect torn tissue), and TGF-beta2 (bioresorbable collagen sponge that releases TGF-beta2). Genzyme Tissue Repair is also examining the potential use of TGF-beta1 in conjunction with autologous cultured chondrocyte implantation.

Dr. Karl-Gerd Fritsch and Dr. Olivera Josimovic-Alasevic, co-CEOs of co.don AG, presented "Advances in Autologous Chondrocyte Transplantation (ACT)." co.don is an independent biopharmaceutical company, headquartered in Teltow/Berlin (Germany), involved in the development of autologous cell and tissue bioprocessing and transplantation techniques for treatment of vascular, heart, cartilage, and bone defects. co.don's clean-room and isolator technologies for cell-based products have contributed to the development of autologous somatic cell therapies. co.don is certified according to DIN EN ISO 9001 and GMP/GTP guidelines, and is licensed for clinical use of co.don chondrotransplant for cartilage repair and co.don osteotransplant for the treatment of segmental bone defects and dental disorders. Both products are regulated by the German Health Ministry/Department as biologics.

Since 1996, 400 patients with acute and chronic chondral and osteochondral defects have been treated using co.don chondrotransplant. Clinical studies with 2-year follow-up show that co.don autologous chondrocyte transplantation offers therapeutic benefits over traditional treatments of cartilage damaged by trauma or degenerative diseases. co.don also manages a portfolio of patent-pending technologies and instrumentation for performing minimally invasive surgeries. co.don's instruments for arthroscopic and endoscopic use simplify preparation of damaged tissue areas, excision and fixation of tissue patches, and facilitate cell injection and transplantation.

Professor Dr. Clemens A. Van Blitterswijk, President and Chief Executive Officer of Isotis B.V., introduced his company, which is based in The Netherlands. Its mission is to fulfill the increasing need for human tissue and organ replacement by bridging the gap between materials science, tissue engineering, and biotechnology.

Histologic appearance (low magnification) of normal distal femoral hyaline articular cartilage.

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