SAN DIEGO, California—"Gene therapy using stem cells is a lot closer to clinical use in orthopaedics than most people think. These tissue engineered products could be on the market in 5 to 10 years," according to Regis O'Keefe, MD, PhD, professor of orthopaedics at the University of Rochester Medical Center, in New York State, and spokesperson for the American Academy of Orthopaedic Surgeons (AAOS). Dr. O'Keefe presented a media briefing on gene therapy and tissue engineering at the 74th Annual Meeting of the American Academy of Orthopaedic Surgeons (AAOS).

Dr. O'Keefe was joined by Johnny Huard, PhD, who is associate professor in the departments of orthopaedic surgery, molecular genetics and biochemistry, bioengineering, and pathology, and also director of the Stem Cell Research Center at Children's Hospital of Pittsburgh, in Pennsylvania. Steven A. Goldstein, PhD, professor of orthopaedic surgery at the University of Michigan Medical School in Ann Arbor, joined Drs. O'Keefe and Huard.

"Muscle cells have emerged as promising vehicles for gene therapy and tissue engineering in the musculoskeletal system," Dr. Huard said.

The goal of tissue engineering is to create living tissue to replace or repair diseased tissue, including bone, cartilage, muscle, or ligament loss, as well as to increase or promote bone formation in spinal fusions and difficult fractures. New approaches discussed at AAOS include gene therapy, use of "morphogens" such as bone morphogenetic proteins (BMPs), and development of new types of scaffolding to guide tissue growth. Dr. O'Keefe predicted a boom market for tissue-engineered repair methods as baby boomers age but expect to stay active longer and maintain a high quality of life. "A person cannot be fit from a cardiovascular and pulmonary standpoint without having a musculoskeletal system that is healthy and can support increased activity. There is a tremendous opportunity to use tissue engineering for osteoporosis, osteoarthritis, and bone repair to help keep that musculoskeletal system in good condition," he said.

Stem cells, morphogens tested for bone repair

New developments in bone repair presented at the AAOS meeting include the following:

• Lead author Matthew J. Jiminez, MD, reports a multicenter feasibility clinical trial showing that autologous bone marrow-derived stem cells, expanded ex vivo and mixed with a demineralized allograft carrier, improved bone repair when used to supplement open reduction and internal fixation in cases of previously failed fixation of tibia, femur, or humerus fractures.¹
  
• Erhan Basad, MD, et al report a 12-patient series suggesting that matrix-guided autologous chondrocyte implantation (MACI) plus autologous bone graft "may represent an alternative to successfully remodel the joint surface" of large osteochondral lesions in the knee. ²
  
• Philippe Hernigou, PhD, et al report that a "single percutaneous injection of [recombinant human BMP-2]/calcium phosphate matrix accelerated healing in open wedge osteotomy sites." The technique was tested in 6 patients who underwent high tibial osteotomy without bone grafting.³
  
• Adding BMP is not a panacea, however. Rahul Vaidya, MD, describes problems with rhBMP-2 when used with anterior cervical discectomy and fusion." Despite providing consistently good fusion rates, we have abandoned using rhBMP-2 and PEEK [polyetheretherketone] cages for anterior cervical fusion, due to side effects, high cost, and the availability of a suitable alternative," Dr. Vaidyo reports.⁴
  
• Dr. Sethi's group reports problems with rhBMP-2 in PEEK cages for transforaminal lumbar interbody fusion (TLIF). Nine of 50 TLIF patients required reoperation. "BMP initially produces a marked resorptive response. This causes surgical cages which are initially placed with solid bone apposition more likely to migrate, causing neurologic sequelae. Excessive bone formation in the spinal canal may also lead to neurological symptoms in TLIFs," the investigators say.⁵

Soft tissue repair also expected to benefit

Similar new work provided encouraging glimpses into the future of tendon and ligament repair.

• Animal studies suggest that tendon-to-bone healing might be improved by applying BMP-13 gene transferred human mesenchymal stem cells at the tendon-bone interface (Zhu et al),⁶ that recombinant human growth/differentiation factor-5 (rhGDF-5) can increase colagen synthesis, orientation, and tensile strength, thereby enhancing tendon healing (Starnes et al),⁷and that an injection of adenovirus expressing BMP-14 into damaged Achilles tendons can accelerate healing more than simple administration of the recombinant protein (Bolt et al).⁸
  
• Rotator cuff tendon tears remain a difficult problem, but animal studies suggest that they might be helped by mesenchymal stem cells suspended in fibrin glue and applied to the healing tendon-bond junction, and also that they might be used for therapeutic gene delivery (Dagher et al).⁹ Related work showed that a new cell-polymer construct of tendon cells transduced with insulin growth factor-1 (IGF-1) improved the mechanical properties of the repair site compared with suture repair alone, and "demonstrates the efficacy of a new type of bioactive implant for repair of rotator cuff injuries" (Dines et al).¹⁰

Tissue engineers help fill bone defect

Tissue engineering approaches to treatment of bone defects is being tested in clinical use by several groups. One interesting approach by Ketterl at al involves the use of a collagen-based osteoinductive scaffold with various growth factors including VDGF, TGF-1, TGF-2, IGF-1, BMP-2, BMP-3, and BMP-7. In patients with indications of infection, the bone void filler also contained antibiotics. The new method was tested in 44 men and 49 women with indications including spondylodiscitis (24), defect after osteitis (23), segment transfer (3), septic change of hip prosthesis (6), septic change of total knee arthroplasty (2), comminuted fracture (13), delayed fracture healing (8), pseudarthrosis (8), and other implant changes (6). Treatment resulted in complete bone regeneration and osseous bridging in 81 patients (87%) and partial bridging in an additional 10 patients (11%). "The results of this study suggest that Type-I collagen based osteoinductive material is effective in treating complicated aseptic and septic bone defects," the researchers include.¹¹

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References

1. Jimenez MJ, Lyon T, Balazsy J, et al. Early results of somatic stem cells for recalcitrant nonunions. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract SE62.
2. Basad E, Bachmann G, Sturz H, et al. Treatment of large osteochondral lesions in the knee with MACI and autologous bone grafting. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego,CA. Abstract P427.
3. Hernigou P, Poignard A, Valentin A. Rhbmp-2/calcium phosphate matrix accelerates open-wedge tibial osteotomy-site healing in gonarthrosis. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P112.
4. Vaidya R, Carp J, Sethi A, et al. Anterior cervical discectomy and fusion using recombinant human bone morphogenetic protein-2. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P386.
5. Sethi A, Craig JC, Bartol S, et al. Complications in the use of rhBMP-2 in PEEK cages for interbody spinal fusions. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P446.
6. Zhu W, Hanke L, Ying L, et al. Effect of BMP-13 gene transferred human mesenchymal stem cells on tendon to bone healing. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P439.
7. Starnes T, Huang D, Kesturu G, et al. Potentiation of tendon repair and regeneration. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P371.
8. Bolt P, Clerk AN, Luu HH, et al. BMP 14 gene therapy effectively increases tendon tensile strength in a rat model of Achilles tendon injury. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P562.
9. Dagher E, Hanke L, Ehteshami JR, et al. Effect of mesenchymal stem cells on tendon to bone healing in a rat model of rotator cuff repair. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract 490.
10. Dines J, Uggen C, Razzano P, et al. The effect of a novel gene therapy-tissue engineering scaffold on chronic rotator cuff tendon healing in an animal model. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P558.
11. Ketterl R, Seyler TM, Mont MA. Treatment of bone defects using a collagen based osteoinductive scaffold. Presented at: American Academy of Orthopaedic Surgeons 74th Annual Meeting; February 14-18, 2007; San Diego, CA. Abstract P510.