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March 3, 2014
Researchers developed a 3-D scaffold that guides the development of stem cells into specialized cartilage-producing cells. The approach could allow for the creation of orthopedic implants to replace cartilage, bone, and other tissues.
Cartilage is the slippery tissue that covers the ends of bones in a joint. In osteoarthritis (the most common type of arthritis), cartilage breaks down and wears away. Replacing cartilage in this and other situations has been a major goal in tissue engineering.
Cartilage contains water, collagen, proteoglycans, and chondrocytes. Collagens are fibrous proteins that serve as the building blocks of skin, tendon, bone, and other connective tissues. Proteoglycans, made of proteins and sugars, form strands that interweave with collagens to form a mesh-like structure. This structure, called an extracellular matrix, allows cartilage to flex and absorb shock. Chondrocytes, cells found throughout cartilage, produce and maintain the structure.
Creating replacements for musculoskeletal tissues is challenging. Stem cells have required extensive treatment in the lab with growth factors in order to develop (or differentiate) into suitable specialized cells. These cells then need to be placed into an appropriate 3-D structure. A team led by Drs. Farshid Guilak and Charles Gersbach at Duke University set out to create an artificial scaffold that could direct stem cells within to differentiate and form extracellular matrix. Their work was supported in part by NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Aging (NIA), and an NIH Director’s New Innovator Award.
The team used human mesenchymal stem cells, which are found in adult bone marrow. These cells can differentiate into different types of musculoskeletal cells. The scientists coated a 3-D woven scaffold with a compound that can secure viruses to a surface but still allow them to transfer genes into target cells. Lentiviruses were chosen to deliver the TGF-β3 (transforming growth factor β3) gene into the cells. TGF-β3 drives stem cells to become chondrocytes. After the viruses were attached to the structure, it was seeded with human mesenchymal stem cells and incubated in culture media.
Cells within the artificial scaffold successfully differentiated into chondrocytes within 2 weeks. Without any extra prompting, the cells created a cartilage-like extracellular matrix within 4 weeks. The results appeared online on February 18, 2014, in the Proceedings of the National Academy of Sciences.
“One of the advantages of our method is getting rid of the growth factor delivery, which is expensive and unstable, and replacing it with scaffolding functionalized with the viral gene carrier,” Gersbach says. “The virus-laden scaffolding could be mass-produced and just sitting in a clinic ready to go. We hope this gets us one step closer to a translatable product.”
This approach could allow for implants that restore function to a joint immediately and drive development of a mature, viable tissue replacement. The technique could also be applied to other kinds of tissues using other stem cells—or even a patient’s own cells. However, further refinement will be needed before it could safely be used in the clinic.
—by Harrison Wein, Ph.D.
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Reference: Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Brunger JM, Huynh NP, Guenther CM, Perez-Pinera P, Moutos FT, Sanchez-Adams J, Gersbach CA, Guilak F. Proc Natl Acad Sci U S A. 2014 Feb 18. [Epub ahead of print]. PMID: 24550481.
Funding: NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Aging (NIA), an NIH Director’s New Innovator Award, and National Cancer Institute (NCI); National Science Foundation; Collaborative Research Center; AO Foundation, Davos, Switzerland; Nancy Taylor Foundation for Chronic Diseases; and the Arthritis Foundation.