Scientists at the Columbia School of Engineering and Applied Science say they have successfully grown fully functional human cartilage in vitro from human stem cells derived from bone marrow tissue. Their study (“Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation”) is published in the early online edition of Proceedings of the National Academy of Science.
“We’ve been able—for the first time—to generate fully functional human cartilage from mesenchymal stem cells by mimicking in vitro the developmental process of mesenchymal condensation,” says Gordana Vunjak-Novakovic, Ph.D., who led the study and is the Mikati Foundation Professor of Biomedical Engineering at Columbia Engineering and professor of medical sciences. “This could have clinical impact, as this cartilage can be used to repair a cartilage defect, or in combination with bone in a composite graft grown in lab for more complex tissue reconstruction.”
Many groups have studied cartilage as an apparently simple tissue: one single cell type, no blood vessels or nerves, a tissue built for bearing loads while protecting bone ends in the joints. While there has been great success in engineering pieces of cartilage using young animal cells, no one has, until now, been able to reproduce these results using adult human stem cells from bone marrow or fat, the most practical stem cell source. Dr. Vunjak-Novakovic's team succeeded in growing cartilage with physiologic architecture and strength by radically changing the tissue-engineering approach.
The general approach to cartilage tissue engineering has been to place cells into a hydrogel and culture them in the presence of nutrients and growth factors, with sometimes also mechanical loading. But using this technique with adult human stem cells has invariably produced mechanically weak cartilage. So Dr. Vunjak-Novakovic and her team, who have had a longstanding interest in skeletal tissue engineering, wondered if a method resembling the normal development of the skeleton could lead to a higher quality of cartilage.
“We discovered that the condensed mesenchymal cell bodies (CMBs) formed in vitro set an outer boundary after 5 d[ays] of culture, as indicated by the expression of mesenchymal condensation genes and deposition of tenascin. Before setting of boundaries, the CMBs could be fused into homogenous cellular aggregates giving rise to well-differentiated and mechanically functional cartilage,” wrote the investigators. “We used the mesenchymal condensation and fusion of CMBs to grow centimeter-sized, anatomically shaped pieces of human articular cartilage over 5 wk of culture. For the first time to our knowledge biomechanical properties of cartilage derived from human mesenchymal cells were comparable to native cartilage, with the Young’s modulus of >800 kPa and equilibrium friction coeffcient of <0.3. We also demonstrate that CMBs have capability to form mechanically strong cartilage–cartilage interface in an in vitro cartilage defect model. The CMBs, which acted as ‘lego-like’ blocks of neocartilage, were capable of assembling into human cartilage with physiologic-like structure and mechanical properties.”
“Our whole approach to tissue engineering is biomimetic in nature, which means that our engineering designs are defined by biological principles,” explains Dr. Vunjak-Novakovic notes. “This approach has been effective in improving the quality of many engineered tissues—from bone to heart. Still, we were really surprised to see that our cartilage, grown by mimicking some aspects of biological development, was as strong as ‘normal’ human cartilage.”
The team plans next to test whether the engineered cartilage tissue maintains its structure and long-term function when implanted into a defect.
“This is a very exciting time for tissue engineers,” she continues. “Stem cells are transforming the future of medicine, offering ways to overcome some of the human body's fundamental limitations. We bioengineers are now working with stem cell scientists and clinicians to develop technologies that will make this dream possible. This project is a wonderful example that we need to ‘think as a cell’ to find out how exactly to coax the cells into making a functional human tissue of a specific kind.”