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November 26, 2001

Scientists Design Molecules That Mimic Nanostructure of Bone

EVANSTON, Ill. — Scientists at Northwestern University have become the first to design molecules that could lead to a breakthrough in bone repair. The designer molecules hold promise for the development of a bonelike material to be used for bone fractures or in the treatment of bone cancer patients and have implications for the regeneration of other tissues and organs.

Scheme showing the relationship between peptide-amphiphile fibers (silver) and hydroxyapatite crystals (blue) in the mineralized bundle. (Credit: Science)

"Recreating natural bone structure at the nanoscale level — the first level of bone structural hierarchy — is what we set out to do with our experiments, and we succeeded," said Northwestern postdoctoral fellow Jeffrey D. Hartgerink, the lead author of a paper reporting these results, which was published in the Nov. 23 issue of the journal Science.

The molecules self-assemble into a three-dimensional structure that mimics the key features of human bone at the nanoscale level, including the collagen nanofibers that promote mineralization and the mineral nanocrystals. Collagen — the most abundant protein in the human body — is found in most human tissues, including the heart, eye, blood vessels, skin, cartilage and bone, and gives these tissues their structural strength.

When the synthetic nanofibers form they make a gel that could be used as a sort of glue in bone fractures or in creating a scaffold for other tissues to regenerate. Because of its chemical structure, the nanofiber gel would encourage attachment of natural bone cells, helping to patch the fracture. The gel also could be used to improve implants or hip and other joint replacements.

The findings also map out a path for the creation of many other materials by self-assembly and spontaneous mineralization that take advantage of an inorganic material growing on an organic material (known as a composite) and which could be useful in electronics, photonics, magnetics and catalysis.

"Regenerative medicine is a big frontier," said Samuel I. Stupp, Board of Trustees Professor of Materials Science and Engineering and of Chemistry, who led the study. "Ideally we want the body to heal itself, in this case to repair bone by encouraging mineralized material to grow on a fibrous scaffold that the body would interpret as natural.

"This work also is an important step in creating an organic scaffold or matrix that can provide cells with the right information to differentiate themselves — into bone cells, neurons or pancreatic cells. This last example is, of course, important in the treatment of diabetes. Cells in any tissue live in an extracellular matrix from which they take their cues. The matrix is like a road map, made up mostly of chemical signals. We’ve mimicked this for bone, but we have offered a strategy that would work for other tissues of the human body, or to create materials inspired by bone that could be useful in electronics or photonics."

In the study reported in Science, the researchers created self-assembled nanofibers that resemble the collagen fibrils of real bone in shape and size. (A nanofiber, which measures about 8 nanometers in diameter, is 10,000 times smaller than the width of a human hair.) When the nanofibers were exposed to solutions containing calcium and phosphate ions, the fibers became covered with hydroxyapatite crystals. These thin, rectangular mineral wafers grew on the nanofibers in a direction parallel to the fiber’s length — just like the hydroxyapatite crystal growth on collagen in the formation of real bone.

The assembly of the nanofibers themselves can be easily reversed by changing the pH level of the fibers’ environment. The fibers also can be polymerized or cross-linked by oxidation to give them additional strength, a process that also can be reversed. The versatility of the nanofiber system alone offers the possibility of using the organic fibers as cargo carriers, possibly for drug delivery to a specific point in the body. Natural enzymes found in the body can disassemble the fibers so that their cargo can be released.

"The unique quality of Professor Stupp and his group is the ability to fabricate novel and imaginative macromolecules that self-assemble into new materials," said Lia Addadi, professor of structural biology at the Weizmann Institute of Science in Israel. "Their creativity has now resulted in the synthesis of a new framework molecule that offers almost unlimited opportunities to investigate aspects of the nanoscale microenvironment involved in biological mineralization. This is a major achievement."

To recreate bone’s nanostructure in the laboratory, Stupp and his team designed a cone-shaped molecule, called a peptide-amphiphile, that is bulkier and water-loving on one end (a peptide) and slimmer and water-phobic on the other (an alkyl group). When in water at low pH, the molecules assemble themselves like spokes on a wheel, with the hydrophobic greasy tail directed to the center, leaving the peptide to face the exterior aqueous environment. This basic structure is repeated so that a long nanofiber is formed, like an insulated copper wire where the insulation is the peptide and the wire the alkyl group. The synthetic fibers orient the growth of the hydroxyapatite crystals so that they mimic the structure found in natural bone.

"Nature uses organic and inorganic materials to build systems with certain properties, such as strong bones," said Stupp, who also is director of Northwestern’s Institute for Bioengineering and Nanoscience in Advanced Medicine. "Our system of self-assembly is modeled on nature."

The researchers engineered their peptide structure to attract bone cells, but the chemistry of the peptide is customizable, said Stupp, and can be changed to attract different cells to the fibrous scaffold, such as neurons, cartilage, muscle, liver and pancreas cells.

"These fibers are cell-friendly," said Stupp. "Cells like to grow on them." This property could lead to the use of the nanofibers in tissue engineering.

Stupp presented the findings from the Science paper Nov. 26 at the Materials Research Society’s fall meeting in Boston.

The third author on the paper is Elia Beniash, a postdoctoral research associate in Stupp’s group at Northwestern. The research was supported by the Department of Energy, the National Science Foundation and the Air Force Office of Scientific Research.