One hundred times less BMP-2 required for fusion using glycopeptide nanostructures

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Northwestern University (Evanston, USA) scientists have designed a sugar-coated bioactive nanomaterial—sulfated glycopeptide nanostructures—that could prove to offer a new gold standard for bone regeneration.

“Regenerative medicine can improve quality of life by offering less invasive and more successful approaches to promoting bone growth,” says Samuel I Stupp, who developed the new nanomaterial. “Our method is very flexible and could be adapted for the regeneration of other tissues, including muscle, tendons and cartilage.”

Stupp is director of Northwestern’s Simpson Querrey Institute for BioNanotechnology and the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at the university. The findings were published in Nature Nanotechnology.

For the interdisciplinary study, Stupp collaborated with Wellington K Hsu, associate professor of orthopaedic surgery, and Erin LK Hsu, research assistant professor of orthopaedic surgery, both at Northwestern University Feinberg School of Medicine. The husband-and-wife team is working to improve clinically employed methods of bone regeneration.

In the new nanomaterial, sugars are displayed in a scaffold built from self-assembling molecules known as peptide amphiphiles, first developed by Stupp 15 years ago. These molecules found on the surface of the nanomaterial provide its regenerative power.

The researchers studied in vivo the effect of the “sugar-coated” nanomaterial on the activity of bone morphogenetic protein 2 (BMP-2), compared with sulphated polysaccharide heparin. The nanomaterial was delivered to the spine using a collagen sponge. “We focused on bone regeneration to demonstrate the power of the sugar nanostructure to provide a big signaling boost,” Stupp says.

Authors found that the amount of BMP-2 needed for a successful spinal fusion was reduced to a fraction. “The glycopeptide nanostructures amplified signalling BMP-2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than that required in the animal model,” the researchers wrote.

Stupp’s biodegradable nanomaterial functions as an artificial extracellular matrix, which mimics what cells in the body usually interact with in their surroundings. BMP-2 activates certain types of stem cells and signals them to become bone cells. The Northwestern matrix, which consists of tiny nanoscale filaments, binds the protein by molecular design in the way that natural sugars bind it naturally and then slowly releases it when needed, instead of in one early burst, which can contribute to side effects.

While studied in an animal fusion model, the method for promoting new bone growth could translate readily to humans, the researchers say. Many other procedures, too, could benefit from the nanomaterial, ranging from repair of bone trauma to treatment of bone cancer to bone growth for dental implants.

To create the nanostructures, the research team synthesized a specific type of sugar that closely resembles those used by nature to activate BMP-2 when cell signalling is necessary for bone growth. Rapidly moving flexible sugar molecules displayed on the surface of the nanostructures “grab” the protein in a specific spot that is precisely the same one used in biological systems when it is time to deploy the signal. This potentiates the bone-growing signals to a surprising level that surpasses even the naturally occurring sugar polymers in our bodies.

Sulfated polysaccharides have super-complex structures impossible to synthesise at the present time with chemical techniques. Hundreds of proteins in biological systems are known to have specific domains to bind these sugar polymers in order to activate signals. Such proteins include those involved in the growth of blood vessels, cell recruitment and cell proliferation, all very important biologically in tissue regeneration. Therefore, the approach of the Northwestern team could potentially be extended to other regenerative targets.

“There is a real need for a clinically efficacious, safe and cost-effective way to form bone,” says W Hsu. “The success of this nanomaterial makes me excited that every spine surgeon may one day subscribe to this method for bone graft. Right now, if you poll an audience of spine surgeons, you will get 15 to 20 different answers on what they use for bone graft. We need to standardize choice and improve patient outcomes.”

The Northwestern research team plans to seek approval from the US Food and Drug Administration (FDA) to launch a clinical trial studying the nanomaterial for bone regeneration in humans.

“We surgeons are looking for optimal carriers for growth factors and cells,” W Hsu says. “With its numerous binding sites, the long filaments of this new nanomaterial is more successful than existing carriers in releasing the growth factor when the body is ready. Timing is critical for success in bone regeneration.”

“With small design changes, the method could be used with other growth factors for the regeneration of all kinds of tissues,” Stupp says. “One day, we may be able to fully do away with the use of growth factors made by recombinant biotechnology and instead empower the natural ones in our bodies.”

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