WSU nanofiber research to defeat tumors

Imagine a condition in which growths suddenly appear anywhere a nerve runs in your body. The tumors may not be cancerous, but they push on otherwise healthy tissues. If they're on your skin, they're disfiguring and unsightly; if they're next to your spinal cord, sciatic nerve, or a vital organ, they can be debilitating or deadly.

That's Type 1 Neurofibromatosis (NF1), a genetically inherited condition, and to date there's no cure for it, no preventative medicine against it, and not even a good understanding of exactly how and why the tumors form along nerves. The condition affects 1 of every 3,500 people.

Harini Sundararaghavan thinks nanofibers may soon help answer the NF1 tumor formation question. In the far future, nanotech neurofibers may even help repair some of damage done by such tumors or other injuries. An assistant professor in Wayne State's biomedical engineering program, Sundararaghavan has just received a $665,000 grant from the U.S. Department of Defense (DoD) for a new kind of model for an in vitro study of neurofibroma formation.

Her work is focused on fabricating nanofibers spun from hyaluronic acid, a naturally occurring polymer, to control cell behavior. Creation of such fibers was the concentration of postdoctoral work she did at the University of Pennsylvania before coming to Wayne State in autumn of 2011. The fibers are tiny enough that they can be used to mimic the fibrous scaffold of a human nerve pathway.

While giving a seminar at the Wayne State School of Pharmacology, shortly after arriving on campus, Sundararaghavan met Raymond R. Mattingly, professor at the University School of Medicine's Department of Pharmacology, whose focus has been on creation of in vitro neurofibroma tumor models. Together, the two realized that a three-dimensional model that included not just the tumor but also the peripheral nerve structures that it grows on could provide valuable insights and allow researchers to examine how various drugs might affect tumor growth.

"Initially we were talking about using some of the materials to make better scaffolds for the in vitro tumor development, but when we looked at it more we realized maybe the fibers themselves are the key component. Maybe the fibers could mimic neurites," says Sundararaghavan.

Neurons naturally form in a particular alignment with one another, and tumors seem to form around the aligned components. "It could be because of the physical cue of that aligned fiber, something about the physical structure, or it could be a chemical cue. We are designing fibers that can actually release these chemical cues," she says of their preliminary research.

Ordinarily, synthetic material made for 3D culture models is gelatin-like and lacks the fibrous base that characterizes natural biological tissue structures. By creating a mimic set of peripheral nerve fibers, the investigators may be able to nail down the growth mechanism used by neurofibromas. "Once we know why the tumor forms, we may be able to get rid of it or discourage the tumor forming," Sundararaghavan says.

What's more, the nanofibrous structure can be used to direct particular nerve pathway development. Like the natural nerve pathway, the fibers promote the development of myelin that sheathes and protects the nerve, allowing nerve signals to flow uninterrupted. Electrospun nanofibers may eventually allow new neural pathways to be created that bypass damaged or diseased areas of the body. "In vitro we see that the neurons follow the fibers, so that could be a really good way to direct neurons," says Sundararaghavan. Though not part of the current DoD study, this feature could be important in work to develop spinal cord repair mechanisms in particular.

Preliminary research undertaken using an internal grant from the Office of the Vice President for Research has shown that endothelial cells can form vessel-like structures along the nanofibers; that portion of the larger study will involve cooperation with the WSU School of Medicine to culture a pool of patient-derived cells. The next portion of the DoD-funded study will be to make motor neurons from embryonic stem cells for use in the models.

With those structures in place and models made, drug testing of the 3D in vitro tumor and nerve models can begin to try to isolate substances that battle the tumors. If the tumor formation mechanism is discovered and an effective chemical family is identified to control neurofibromas, a clinical trial could eventually yield the first effective treatment for the genetic condition.

In addition to Sundararaghavan, the principal investigator, and Mattingly, the co-principal investigator, the DoD grant team includes Douglas Ruden, Ph.D., an expert in human embryonic stem cells and professor of obstetrics and gynecology at the Institute of Environmental Health Sciences, and clinician William Kupsky, M.D., professor of pathology at Wayne State.

The DoD-funded project is expected to take three years and follow-up from its results even longer. It's a lengthy path, but Sundararaghavan is excited to begin.