Engineering nerve jumper cables for spinal cord repair in animal model

Technique holds promise for spinal cord repair in humans



Development of a nervous tissue construct for transplantation. Top panel: Neurons are plated on two membranes and a neural network (black) is formed. Bottom two panels: Movement of a block attached to one membrane (yellow) via a computer controlled microstepper motor system divides the culture and progressively separates the halves. As the microstepper motor moves the top membrane, the portion of the axonal bundles crossing between the top and bottom membranes is extended inducing stretch growth of the axon bundles. These cultures are then embedded in collagen and rolled into a tube that facilitates removal from the device. This construct is then transplanted to bridge spinal cord lesions. (Credit: Douglas H. Smith, MD, University of Pennsylvania School of Medicine)
Click here for a high resolution photograph.

Researchers at the University of Pennsylvania School of Medicine have created – in a rodent model – a completely new way to engineer nerve structures, or constructs, in culture. This proof-of-principle research has implications for eventually becoming a new method to repair spinal cord injury in humans. The work appears in the latest issue of Tissue Engineering.

"We have created a three-dimensional neural network, a mini nervous system in culture, which can be transplanted en masse," explains senior author Douglas H. Smith, MD, Professor, Department of Neurosurgery and Director of the Center for Brain Injury and Repair at Penn. Previously, Smith's group showed that they could grow axons by placing neurons from rat dorsal root ganglia (clusters of nerves just outside the spinal cord) on nutrient-filled plastic plates. Axons sprouted from the neurons on each plate and connected with neurons on the other plate. The plates were then slowly pulled apart over a series of days, aided by a precise computer-controlled motor system.

In this study, the neurons were elongated to 10mm over seven days – after which they were embedded in a collagen matrix (with growth factors), rolled into a form resembling a jelly roll, and then implanted into a rat model of spinal cord injury.

"That creates what we call a nervous-tissue construct," says Smith. "We have designed a geometrical arrangement that looks similar to the longitudinal arrangement that the spinal cord had before it was damaged. The long bundles of axons span two populations of neurons, and these neuron constructs can grow axons in two directions – toward each other and into the host spinal cord at each side. That way they can integrate and connect the 'cables' to the host tissue in order to bridge a spinal cord lesion."

After the four-week study period, the researchers found that the geometry of the construct was maintained and that the neurons at both ends and all the axons spanning these neurons survived transplantation. More importantly, the axons at the ends of the construct adjacent to the host tissue did extend through the collagen barrier, penetrating into the host tissue. Future studies will measure neuronal electrical conductivity across the newly engineered bridge and restoration of motor activity.

"The really great news – and there's still much work to be done – is that the construct survives and also integrates with host tissue," says Smith. "We find this very promising. In particular, this new technique provides a means to bridge even very long spinal lesions that are common in humans with spinal cord injury. Now we have to test whether the transplanted constructs convey a signal all the way through, and we're developing and testing a new animal model to allow us to test whether this new technique improves function."

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Study co-authors are Akira Iwata, Kevin D. Browne, Bryan J. Pfister, all from Penn; and John A. Gruner, from Cephalon Inc., West Chester, PA. The research was funded by the National Institutes of Health and the Sharpe Trust.

This release and related images can be found at http://www.uphs.upenn.edu/news/

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

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