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Mouse cells grow inside a nanofiber- based scaffold developed by researchers at Northwestern University. The scaffold contains a high density of IKVAV, a bioactive sequence of five amino acids derived from the extracellular protein laminin. Although these cells are capable of transforming into several cell types, when encapsulated in this self- assembling matrix, most of them become neurons, shown in green. Cell nuclei are shown in blue. The ability to control cell differentiation is of interest in treatment of spinal cord injury because it may be possible to use the scaffolding to inhibit formation of non-neuronal cells that form scar tissue and prevent healing. Image courtesy of Dr. Samuel I. Stupp, Northwestern University.

Microscopic Scaffolds May Help Regenerate Cells: June 10, 2005

To jumpstart cell regeneration, researchers are combining biology and nanotechnology to form innovative scaffolding that transports molecular signals or DNA directly to failing cells. The scaffold is an artificial, three-dimensional matrix that is transient and compatible with the environment surrounding cells. As long as it “lives” in the body, the scaffold provides signals that alter cellular behavior, says Dr. Samuel I. Stupp, director of the Institute for BioNanotechnology in Medicine at Northwestern University's Chicago campus.

Dr. Stupp and his colleagues are developing two major types of scaffolds. The first uses nanofibers that are 10,000 times thinner than a human hair. They can be formed with a specific sequence of amino acids to promote cell growth. The second consists of a microporous polymer that carries genes to change the proteins that regulate cellular development. Eventually, the investigators may create scaffolds that help to regenerate damaged neurons, restore the junctions between nerve fibers lost in paralysis, or stimulate pancreatic progenitor cells to produce insulin.

Nanofiber Scaffold

The nanofiber scaffold combines self-assembly (capacity to transform from liquid to gel on contact with tissues) with a chemical structure that researchers tailor to present a wide variety of signals to cells. The self-assembling nature of the scaffolds would make it easy to deliver it clinically to patients. Also, unlike animal-derived scaffold materials, such as collagen, the synthetic nature of the scaffold makes it safer to use in humans, Dr. Stupp says.

By acting on progenitor cells, the nanofiber scaffold has been able to direct the “fate” of brain-derived cells, Dr. Stupp says. Neural progenitor cells are not differentiated, meaning they have not yet selected to be a specific type of cell within a tissue. When researchers combined the scaffolds with amino acids that promote neurite extension in neurons, they , discovered they could trigger the selective growth of neurons as opposed to other types of cells in the nervous system. “This is important because the synthetic scaffold alone was able to very clearly mediate the differentiation of cells,” Dr. Stupp says.

The nanofiber scaffold may also help prevent neural progenitor cells from choosing a destructive fate by becoming glial cells or astrocytes. After a spinal cord injury, astrocytes or glial cells form a scar that prevents repair of neural tissue. In experiments on animals with spinal cord injuries, Dr. Stupp and neurologist Dr. John Kessler observed increased movement of limbs following injection of a scaffold. “We know there has been some functional recovery in the animals, but we don't know what's behind it,” Dr. Stupp says. “We speculate that it has something to do with preventing the glial scar, but that has not been demonstrated yet.”

Polymer Scaffold

The second type of scaffold, made of a microporous polymer, is being investigated by chemical engineer Lonnie Shea and endocrinologist Dr. William Lowe. This scaffold has shown promise in animal studies as an alternative to pancreatic cell transplantation in treating diabetes. “Shea and Lowe have compared the method of scaffolding and the standard method of transplantation and found that, in some models, the scaffold can cure a higher percentage of animals in a shorter period of time,” Dr. Stupp says.

Strengthening the Scaffolds

The team is now taking its research to a higher level, designing the scaffolds to deliver growth factors according to a particular time schedule. “Growth factors play a key role in the way cells differentiate and elaborate tissue, but those growth factors are exposed to cells in very specific sequences in time. We want to mimic these processes of developmental biology and adapt them to a regeneration scaffold to produce a sort of built-in program in the scaffold,” Dr. Stupp says.

“What we are trying to do is recreate all the signals that tissues get in normal biological development,” says Dr. Stupp. “Scientists are making progress in understanding what those signals are, but the signals are very complicated.” For example, to function properly, a specific type of neuron may need signals from 10 different proteins within a specific time period. “We take that information and somehow recreate it synthetically in a molecularly designed scaffold that is able to trigger the complex processes of biology,” says Dr. Stupp. “This pushes chemistry and materials science to the limit.” Dr. Stupp's research on regenerative scaffolding is supported by the National Institute of Biomedical Imaging and Bioengineering. Additional funding is provided by the National Institute of Neurological Disorders and Stroke, the National Science Foundation, and the U.S. Department of Energy.

References:

Behanna HA, et al., Coassembly of amphiphiles with opposite polarity into nanofibers. Journal of the American Chemical Society 127:1193-1200, 2005.

Bull SR, et al., Self-assembled peptide amphiphile nanofibers conjugated to MRI contrast agents. Nanotechnology Letters 5:1-4, 2005.

Silva GA, et al., Selective differentiation of neural progenitor cells by high epitope density. Science 303:1352-1355, 2004.