Next Generation: Neuronal Monkey Bars

Three-dimensional scaffolds for growing and guiding neurons are getting smaller and more tailored in design.

By | September 23, 2011

Primary rat hippocampal cells grow along a scaffold.IMAGE COURTESY OF JENNIFER N. HANSON SHEPHERD, SARA T. PARKER, ROBERT F. SHEPHERD, MARTHA GILLETTE, JENNIFER A. LEWIS, AND RALPH G. NUZZO.

THE DEVICE: Using a laser aimed at a polymer called polylactide, researchers have been able to fabricate a 3-D scaffold that's biodegradable, biocompatible, and on a scale that neurons can wrap their arms around. The scaffolds can provide a frame for studying neuronal regeneration in vitro or for repairing lacerated peripheral nerves in vivo.

In one design, Frederik Claeyssens at the University of Sheffield and his colleagues created a scaffold resembling a set of monkey bars with gaps between the rungs of 10 to 20 micrometers. They found that neurons attached to the bars and extended neurites along them, according to the report published this week in Biofabrication.

The laser works by “writing” a structure into a material. In this case, the material hardens when the four arms of the polylactide are crosslinked by photocuring from the laser. The excess material that has not been hardened is washed away, leaving the 3-D structure behind.

PolyHEMA scaffold constructed by direct write assembly.
PolyHEMA scaffold constructed by direct write assembly.
IMAGE COURTESY OF JENNIFER N. HANSON SHEPERD, SARA T. PARKER ROBERT F. SHEPERD, MARTHA GILLETTE, JENNIFER A. LEWIS,  AND RALPH G. NUZZO.

“The user has complete control. Whatever pattern you put in is written by the laser,” Claeyssens told The Scientist. In a beautiful demonstration, Claeyssens's team was able to build scaffolds resembling the spiral of a snail's shell.

In an earlier construction of a similar scaffold, Jennifer Lewis at the University of Illinois and her colleagues built a 3-D grid out of a hydrogel called polyHEMA, a non-biodegradable material used in contact lenses. Lewis's technique, called direct write assembly, deposited the material through a tiny nozzle and then hardened it using UV light. She too was able to grow neurons along mesh scaffolds that had grid sizes in the tens of microns, and published her results in Advanced Functional Materials last November.

WHAT'S NEW: Tissue scaffolds with three dimensions are not new, but the ability to design them with ordered structures and on the scale appropriate for neuronal growth is an advance, said Lewis. “These are the first two examples of creating 3-D scaffolds with feature sizes that are truly in the micron-size range.”

“The finer the scaffold features can be, the more chance you have of mimicking the cells' extracellular matrix,” said Lisa Freed, a senior scientist at the Draper Laboratory in Cambridge, Massachusetts, who was not involved in these studies. Freed said her group has constructed tissue-growing material with ridges and grooves on the 10 micrometer scale, and these papers demonstrate that orderly meshes can also be developed at this size.

IMPORTANCE: Though both new techniques are biocompatible, the laser method has the added appeal that polylactide is biodegradable. Claeyssens said this opens up the opportunity for potentially using the scaffold as an implantable device that would eventually disappear, while leaving behind the newly grown tissue.

“The value of these structures is that they could be used therapeutically, and not just for in vitro diagnostics or research,” Freed told The Scientist. One possibility Claeyssens's group discusses in the paper is injecting scaffolds seeded with neurons into the central nervous system. The cells would be directed to a site of damage caused by injury or disease to repopulate and repair the nervous tissue.

Mohammad Reza Abidian, a professor in at Penn State University who did not participate in this research, is also working on developing implants for central and peripheral nerve regeneration. "In the peripheral nervous system, axons can regenerate on their own up to a couple of centimeters, however, the problem is the guidance.” Abidian is developing nanotube guides, and 3-D scaffolds could also provide mechanical guidance.

NEEDS IMPROVEMENT: Claeyssens said his group is working on developing scaffold tubes for nerve repair. “These nerve guidance conduits, there are a few on the market, but there is still a niche for biodegradable materials to fill in.”

As far as applying these structures to tissue regeneration, more work has to be done. Abidian points out that neurons need more than physical guidance, but chemical and electrical as well. This will take further research about how to control the natural environment mediating neural development.

While the advantage of Claeyssens's approach is that it uses a biodegradable compound, it's limited in that the type of material used must always be photocurable. In this way, Lewis's technique has more flexibility, because it is not limited in the method of hardening.

The other downside of the laser is that it's slow, taking 10 to 30 minutes to build a single scaffold. “Improving speed would be a very good thing,” Claeyssens said.

J.N. Hanson Shepherd, et al., 3D microperiodic hydrogel scaffolds for robust neuronal cultures,” Advanced Functional Materials, DOI: 10.1002/adfm.201001746, 2011.

V. Mellisinaki, et al., Direct Laser Writing of 3D scaffolds for neural tissue engineering applications,” Biofabrication, DOI: 10.1088/1758-5082/3/4/045005, 2011.

 

 

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