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Posts tagged ‘Nerve Regeneration’

I grew up watching Lee Majors in the 1970’s TV show “The Six Million Dollar Man”, about an injured former astronaut whose bionic implants allowed him to do superhuman feats.

That was fiction, but it is becoming closer to reality as a result of new research into how artificial limbs can integrate with human tissues. This work on neural-electrical interfaces may ultimately allow someone to control a prosthesis as you would a normal limb, i.e. by nerve impulses that travel from the brain.

The promise of “functional integration” between the human nervous system and an electro-mechanical device is the greater control this would give amputees and potential for sensory feedback.

The laboratory of D. Kacy Cullen, Ph.D, assistant professor in the Department of Neurosurgery, Center for Brain Injury & Repair at the University of Pennsylvania, Perelman School of Medicine is actively working in this area. I had the pleasure to hear Dr Cullen talk about his research at Health Journalism 2011 earlier this year. I previously wrote on this blog about his research on nanomaterials that change color with blast impact.

Source: D Kacy Cullen PhD, University of Pennsylvania

In his presentation to the Association of Health Care Journalists he described some of the neural tissue engineering work in his laboratory. This research has shown the ability to integrate axons in the peripheral nervous system (PNS) with an array of electrodes embedded in a living collagen matrix.

In essence this is the development of a nerve tissue/electrical interface that potentially allows the integration of man and machine.

Nervous System Integration

Key to success has been the development of a living, 3-D scaffold where this integration between nerve and electrodes can take place. Nerve axons in the peripheral nervous system require a living target for innervation. This has involved designing and engineering a 3-D living cellular matrix/scaffold that will work within a living body (to date the research has been on animal models).

Not only is Cullen and his laboratory looking at machine/nerve interfaces, but they have also developed techniques that may allow nerves to be repaired.  They have shown that nerves can be elongated or stretched using novel tissue engineering techniques.

The resulting axonal constructs via stretch-growth have been transplanted into rats and used to bridge an excised segment of sciatic nerve.  What was subsequently seen was an interwining plexus of host and graft axons, suggesting axonal regeneration across the lesion.

While still early stage, and not yet tested in humans, this research has tremendous potential for those paralysed due to traumatic nerve damage in the future.

Moving forward, the Penn researchers aim to develop an application for CNS tissue repair that can be delivered to the brain or spinal cord via stereotactic microinjection. This is minimally invasive surgery that allows delivery of cells to a precise location using 3D co-ordinates.

According to research published in Critical Reviews™ in Biomedical Engineering they plan to use micro-engineered hydrogel conduits, several centimeters long and the width of three hairs. These hydrogels will contain living axonal tracts that will then hopefully reconnect damaged nerves, and provide a platform or path for regeneration.

Many challenges still remain to be worked out for the tissue engineered neural constructs such as issues relating to inflammation and immune tolerance.

The research also needs to move from animals to humans, and be shown to be safe. The long-term functional outcome is also unknown.  It is far too early to think of this as a treatment option.

However, advances in neural tissue engineering, neuroregeneration and neuro-prosthetics do offer a lot of promise and hope to the many patients who suffer from spinal cord injuries or loss of a limb.

In a short blog post, I have not been able to do full justice to the innovative research or fully describe the techniques and methodology.  More information on the fascinating work being done at Penn, along with details of the associated scientific publications, can be found on the web page of the Cullen Laboratory: Neural Engineering in Neurotrauma.

ResearchBlogging.orgD. Kacy Cullen, John A. Wolf, Douglas H. Smith, & Bryan J. Pfister (2011). Neural Tissue Engineering for Neuroregeneration and Biohybridized Interface Microsystems In vivo (Part 2) Crit Rev Biomed Eng., 39 (3), 243-262

Taxanes are a class of drug that are used in breast, lung and ovarian cancer chemotherapy to disrupt the function of microtubules that are essential to cell division. They include paclitaxel (Taxol®) and docetaxel (Taxotere®).

Paclitaxel is also used to prevent the narrowing (restenosis) that occurs with coronary artery stents that are used to open blocked coronary arteries. Drug coated stents (a.k.a. “drug-eluting stents) reduce scar tissue.

Research published in the February 18, 2011 edition of Science, by Farida Hellal and colleagues has now shown that treatment with paclitaxel reduces the scarring associated with spinal cord injury (SCI) and promotes nerve regeneration.

The paper in Science is well worth reading and takes the reader through a logical thought process as the researchers tested their hypothesis that paclitaxel might stabilize microtubules around the site of SCI.

One of the cellular events that occurs after SCI is the activation of transforming growth factor-ß signaling (TGF-ß).

Increased TGF-ß leads to fibrosis or scarring.  TGF-ß acts on Smad2 to bind to microtubules through kinesin-1.  Hellal and colleagues asked if treatment with paclitaxel would impair Smad-dependent TGF-ß signaling? The answer from their elegant series of experiments is that yes it does.

Not only that, but TGF-ß also regulates the axon growth inhibitor, chondroitin sulfate proteoglycans (CSPGs).  The researchers asked whether pacllitaxel decreased CSPGs after SCI?  They found that cultured meningeal cells and astrocytes treated with 10 nM paclitaxel showed a 35% and 32% decrease of glycosaminoglycan (GAG) levels.

The next logical question is whether the reduction of scar formation by paclitaxel results in any benefits for new nerve formation? The regeneration of dorsal root ganglions (DRG) were evaluated.  In what to me was a finding of great significance, the researchers found (references to figures omitted) that:

“Taxol-treated animals had regenerative fibers growing along the edge of the lesion cavity into the injury site and beyond. The longest axons per animal grew 1199 T 250 mm in the Taxol-treated group versus 176 T 225 mm in the vehicle-treated an- imals (n = 13 animals per group; P = 0.002; two- tailed t-test). The Taxol-treated lesion site thus becomes favorable for regeneration of growth-competent axons.”

The final part of this research asked whether treatment with paclitaxel led to any functional improvement after the test animals received a spinal cord injury? They found that those rats that received paclitaxel after injury, had greater improvement in their locomotor function.   The conclusion being that “Taxol-induced functional recovery correlates with its axon growth–inducing effect.”

The results from any animal study must be viewed with caution, since they don’t necessarily translate to humans.  However, this animal research, if supported by data from human clinical trials, suggests that treatment with taxanes may be of benefit to those with spinal cord injuries.

Given the debilitating effect of any spinal cord injury, this is an important finding.


ResearchBlogging.orgHellal, F., Hurtado, A., Ruschel, J., Flynn, K., Laskowski, C., Umlauf, M., Kapitein, L., Strikis, D., Lemmon, V., Bixby, J., Hoogenraad, C., & Bradke, F. (2011). Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration After Spinal Cord Injury Science, 331 (6019), 928-931 DOI: 10.1126/science.1201148

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