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Thread: Living Jumper Cables: Lab-Grown Nerves Promote Nerve Regeneration After Injury

  1. #1

    Living Jumper Cables: Lab-Grown Nerves Promote Nerve Regeneration After Injury

    http://www.uphs.upenn.edu/news/News_...eneration.html
    MARCH 19, 2009

    Living Jumper Cables: Lab-Grown Nerves Promote Nerve Regeneration After Injury, Penn Study Finds

    PHILADELPHIA – Researchers at the University of Pennsylvania School of Medicine have engineered transplantable living nerve tissue that encourages and guides regeneration in an animal model. Results were published this month in Tissue Engineering.

    About 300,000 Americans suffer peripheral nerve injuries every year, in many cases resulting in permanent loss of motor function, sensory function, or both. These injuries are a common consequence of trauma or surgery, but there are insufficient means for repair, according to neurosurgeons. In particular, surgeons need improved methods to coax nerve fibers known as axons to regrow across major nerve injuries to reconnect healthy targets, for instance muscle or skin.

    “We have created a three-dimensional neural network, a living conduit in culture, which can be transplanted en masse to an injury site,” explains senior author Douglas H. Smith, MD, Professor, Department of Neurosurgery and Director of the Center for Brain Injury and Repair at Penn. Smith and colleagues have successfully grown, transplanted, and integrated axon bundles that act as ‘jumper cables’ to the host tissue in order to bridge a damaged section of nerve.

    Previously, Smith and colleagues have “stretch-grown” 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.

    These nerves were elongated to over 1 cm over seven days, after which they were embedded in a protein matrix (with growth factors), rolled into a tube, and then implanted to bridge a section of nerve that was removed in a rat.

    “That creates what we call a ‘nervous-tissue construct’,” says Smith. “We have designed a cylinder that looks similar to the longitudinal arrangement of the nerve axon bundles before it was damaged. The long bundles of axons span two populations of neurons, and these neurons can have axons growing in two directions - toward each other and into the host tissue at each side."

    The constructs were transplanted to bridge an excised segment of the sciatic nerve in rats. Up to 16 weeks post-transplantation, the constructs still had their pre-transplant shape, with surviving transplanted neurons at the extremities of the constructs spanned by tracts of axons.

    Remarkably, the host axons appeared to use the transplanted axons as a living scaffold to regenerate across the injury. The authors found host and graft axons intertwined throughout the transplant region, suggesting a new form of axon-mediated axonal regeneration. “Regenerating axons grew across the transplant bridge and became totally intertwined with the transplanted axons,” says Smith

    Axons throughout the transplant region showed extensive myelination, the fatty layer surrounding axons. What’s more, graft neurons had extended axons beyond the margins of the transplanted region, penetrating deep into the host nerve. Remarkably, the constructs survived and integrated without the use of immunosuppressive drugs, challenging the conventional wisdom regarding immune tolerance in the peripheral nervous system.

    The researchers suspect that the living nerve-tissue construct encourages the survival of the supporting cells left in the nerve sheath away from the injury site. These are cells that further guide regeneration and provide the overall structure of the nerve.

    “This may be a new way to promote nerve regeneration where it may not have been possible before,” says co-first author D. Kacy Cullen, PhD, a post doctoral fellow in the Smith lab. “It’s a race against time - if nerve regeneration happens too slowly, as may be the case for major injuries, the support cells in the extremities can degenerate, blunting complete repair. Because our living axonal constructs actually grow into the host nerve sheath, they may ‘babysit’ these support cells to give the host more time to regenerate.”
    more...

  2. #2
    I dislike the use of the words "jumper cables" because they encourage an already prevalent misconception amongst people that nerves work like wires. They do not. Wise.

  3. #3
    Quote Originally Posted by Wise Young View Post
    I dislike the use of the words "jumper cables" because they encourage an already prevalent misconception amongst people that nerves work like wires. They do not. Wise.
    Wise,
    Is there an analogy that would be better suited?

    While I don't disagree with you, I find myself using that analogy because axons (copper wire) are myelinated by insulating by schwann cells (similar to a copper wire being insulated by a rubber shealth). Axons conduct an electro-chemical transmission to its target destination, not unlike an electrical wire does from its power source (brain) to its target like a lamp or motor (skin or muscle).

    Just curious because I can't think of a closer analogy that the average layman (me) could wrap their heads around.

    I know you spend more than enough time teaching, so if someone else has got an answer, please cough it up.

    Thanks,
    Chris

  4. #4
    Quote Originally Posted by cljanney View Post
    Wise,
    Is there an analogy that would be better suited?

    While I don't disagree with you, I find myself using that analogy because axons (copper wire) are myelinated by insulating by schwann cells (similar to a copper wire being insulated by a rubber shealth). Axons conduct an electro-chemical transmission to its target destination, not unlike an electrical wire does from its power source (brain) to its target like a lamp or motor (skin or muscle).

    Just curious because I can't think of a closer analogy that the average layman (me) could wrap their heads around.

    I know you spend more than enough time teaching, so if someone else has got an answer, please cough it up.

    Thanks,
    Chris
    Chris,

    A nerve fiber or axon is a living extension of a neuron. The axons carry signals that are mediated by ions (sodium and potassium) that go in and out of the axons, causing a travelling wave of ionic fluxes (called an action potential) that go down the axon to its tip which contacts another neuron. When the action potential arrives at the tip, it allows calcium ions into the tip and releases neurotransmitters that excite or inhibit the neuron that it contacts. Myelin wraps around segments of the axon. To speed up the conduction of signals in an axon, the action potentials occur only between the places where the myelin segments wrap around the axon. These in-between places are called nodes. An action potential in one node causes the next node to activate. A myelinated axon can conduct between 1-100 meters per second, depending on the diameter of the axon (see below).

    Let me summarize the differences between a wire and an axon:
    1. Cutting an axon causes the part of the axon that is not connected to the neuron to die. The part that is still connected to the neuron may die back a short distance and will generally live. Regeneration is to regrow the axon back to its original or similar target. In contrast, when you cut a wire, both side of the cut survives. To make the wire conduct again, you just contact the two wires to each other.
    2. An myelinated axon conducts by allowing action potentials to jump from node to node. An action potential in one node causes a voltage shift in the next node, opening up sodium channels and causing an action potential in that node. The action potential jumps from node to node, called saltatory conduction. The speed of action potential conduction depends on axial resistance and capacitance of the axon between the nodes. The higher the resistance and capacitance, the lower the conduction velocity. The general rule is that the rate of conduction in meters per second is approximately equal to 6 times the diameter of the axon in micrometers. In contrast, a wire conducts almost instantaneously.
    3. Cutting an axon will cause the part of the axon not connected to the neuron to die. The part that is connected to the neuron generally dies back a short distance and then will grow back the edge of the injury site.


    I will finish this at a later time.

    Wise.

  5. #5

    Opinion on the Study Dr. Young?

    Apart from the misleading/poor analogy what do you think of the study. Do you think that it will eventually make its way to being beneficial for SCI cure/improved function?

  6. #6
    Quote Originally Posted by P. J. View Post
    Apart from the misleading/poor analogy what do you think of the study. Do you think that it will eventually make its way to being beneficial for SCI cure/improved function?
    PJ,

    This is essentially a bridging material for peripheral nerve axonal growth. Nearly a decade ago, Doug Smith found that he could get axons to grow faster if he mechanically stretched them. In this particular situation, he grew axons from a rat into a bundle and then stretched the bundle slowly to speed up axonal growth, until the bundle was 1 cm long. Then, he and his colleages embedded the bundle of axons a protein matrix, wrapped the bundle in a material to form a tube, and then used the tube to bridge a segment of the peripheral nerve.

    It is a nice idea and much needed for surgeons to repair peripheral nerves. At the present, if the peripheral nerve is not long enough to anastomose (i.e. connected the two ends together) the most commonly used bridge is another peripheral nerve. If this works, this means that another peripheral nerve does not need to be sacrificed for the repair.

    It would be nice to see a comparison between this bridge and an actual peripheral nerve graft. I have yet to see any artificial bridging material that is as good or better than a peripheral nerve graft. In most bridges, the regrowing axons completely avoid the sides of the bridge and simply grow in a fasciculated bundle in the center of the tube.

    I also wonder where the neurons that contributed the axons to the bridge are. Do they cut the axons on each side of the bundle or leave the neurons there? It seems to me that they must have left the neurons in or else the cut axons would not be there more than a few days later.

    Wise.

  7. #7

    Thanks!

    Thank you Dr. Young for your quick response. The questions that you raise are very interesting.

  8. #8
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    Is the bigger or underlying question here "can this be done within the spinal cord?" or can anything be learned by what they are doing in peripheral nerve regeneration and apply it to SCI?

    Dr. Young you mentioned this type of work was done 10 years ago, that's what bothers me about research, discoveries are made, they never move along and then someone redoes it years later. Nerve rerouting has been done for almost 100 years from what I have read and still today it's hard to find a standardized nerve rerouting proceedure readily avalible for say bladder control.

    I have been doing some reading about nerve rerouting and the work that Dr. John Martin at Columbia University has done where he has rerouted a periphreal nerve from above the injury site in an SCI rat and fused it directly back into the spinal cord below the injury and showed that there was a functional connection, a true "Jumper Cable". I am wondering why this has not been explored before or maybe it has and I have just not found those studies yet.

    It seems to me that something like that type of proceedure would be much quicker to research and easier to get approved than say stem cells or developing a new drug.

  9. #9
    Quote Originally Posted by rjames View Post
    Is the bigger or underlying question here "can this be done within the spinal cord?" or can anything be learned by what they are doing in peripheral nerve regeneration and apply it to SCI?

    Dr. Young you mentioned this type of work was done 10 years ago, that's what bothers me about research, discoveries are made, they never move along and then someone redoes it years later. Nerve rerouting has been done for almost 100 years from what I have read and still today it's hard to find a standardized nerve rerouting proceedure readily avalible for say bladder control.

    I have been doing some reading about nerve rerouting and the work that Dr. John Martin at Columbia University has done where he has rerouted a periphreal nerve from above the injury site in an SCI rat and fused it directly back into the spinal cord below the injury and showed that there was a functional connection, a true "Jumper Cable". I am wondering why this has not been explored before or maybe it has and I have just not found those studies yet.

    It seems to me that something like that type of proceedure would be much quicker to research and easier to get approved than say stem cells or developing a new drug.
    rjames,

    It is not difficult to follow the research that is being done. For example, if you are interested, all you have to do is to go to Google Scholar and do a search for John Martin's work. He has gone a long long ways since the early reports that peripheral nerves could be used as an external bridge between the spinal cord above and below the injury site. I recently heard him give a talk in Brescia and I was impressed by how much he has been able to show and a lot of it was unexpected.

    First, Martin has demonstrated that axons from above the injury site will grow into the bridge and enter the spinal cord, innervating neurons below. Many scientists thought that this was impossible and the person who first gave me that impression with Albert Aguayo who had done similar studies in 1981 and reported that the axons would grow beautifully in the peripheral nerve but would not reenter into the spinal cord. What Martin did was to show that many axons will grow into the spinal cord. Actually Aguayo was sitting in the audience and I asked him publicly whether Martin has shown that his original work was incorrect. Aguayo pointed out that his work focussed on the corticospinal tract and that they had found that other axons would grow into the spinal cord. In any case, that was over 25 years ago and I believe that Martin has seriously challenged the dogma that axons can grow only in the periphery and not in the spinal cord.

    Second, most of the studies show remarkable axonal ingrowth but they do not seem to improve function by all that much. Much of Martin's work, for example, involve hemisections or partial cuts of the spinal cord and the functional improvement was not that impressive at the beginning. However, he has now made very substantial improvements in assessing behavior and he has now some data indicating that there is functional improvement associated with the reconnections. One of the main questions that has not been answered is the extent to which training and exercise may be a major part of the motor recovery, while morpholigical reconnection may be occurring, the connections may not translate into functional improvement. We always assume that just getting axons down there would be sufficient. It is often not.

    Third, Martin has spent much of his time demonstrating how the axons get into the spinal cord and what they connect to. You see, his model allows study of how axons decide what to do when they grow into the spinal cord. So little is known about this. So, he is doing what a good basic scientist should be doing. He is also giving talks at clinical meetings to get clinical surgeons excited and interested in the results, and possibly to try. A lot of questions remain unanswered. For example, what this the best place to insert the nerve... down around L2 (where the central pattern generator is)? The axons grow only a short distance into the spinal cord. The lack of long distance sensory axonal growth in the spinal cord also limits the amount of sensory recovery. The details are really critical to clinical application.

    Finally, I want to point out that Martin himself will not be doing surgery on patients. There is much confusion about what a scientist does and a clinician does. The surgery has to be done by a neurosurgeon. The block is at the translation step. Part of the problem that you refer to is not a problem with scientists not doing their work. The problem is that there is no method of translating basic science into clinical practice. There are too few neurosurgeons who are committed, who keep up with the research, and who are willing to spend the time and risk to move such techniques into the clinic. At least in the United States, there is almost no incentive for a neurosurgeon to do anything new and a lot of disincentives for the neurosurgeons to do anything risky. I am spending a lot of time bring individual surgeons and rehabilitation doctors to China, for example, to show them. Many won't believe until they see with their own eyes.

    A lot of this should change as we get more clinical trials going in the United States. We have had so few clinical trials in the United States over the past decade that doctors get use to practicing without clinical trials. In short, we have just created another generation of doctors who are not used to spinal cord injury clinical trials.

    Wise.

  10. #10
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    Quote Originally Posted by Wise Young View Post
    rjames,


    Finally, I want to point out that Martin himself will not be doing surgery on patients. There is much confusion about what a scientist does and a clinician does. The surgery has to be done by a neurosurgeon. The block is at the translation step. Part of the problem that you refer to is not a problem with scientists not doing their work. The problem is that there is no method of translating basic science into clinical practice. There are too few neurosurgeons who are committed, who keep up with the research, and who are willing to spend the time and risk to move such techniques into the clinic. At least in the United States, there is almost no incentive for a neurosurgeon to do anything new and a lot of disincentives for the neurosurgeons to do anything risky. I am spending a lot of time bring individual surgeons and rehabilitation doctors to China, for example, to show them. Many won't believe until they see with their own eyes.

    A lot of this should change as we get more clinical trials going in the United States. We have had so few clinical trials in the United States over the past decade that doctors get use to practicing without clinical trials. In short, we have just created another generation of doctors who are not used to spinal cord injury clinical trials.

    Wise.
    Dr, Young, thank you for the comprehensive reply to my question and the tip about the "Google Scholar" search I have just been using the standard google search method.

    You really hit the nail on the head about the translational research issue, I never really understood beyond the scarcity of funding why good solid research projects never seem to move beyond the lab. I hope this changes soon otherwise all the great research going on will never see the light of day. Thank you for your efforts with regards to trying to change this by taking clinicians to China to see what's possible.

    I actually contacted Dr. Martin a few weeks ago about his work and his future plans, he mentioned he was going to move it to larger animals but had no specific time line to do so. I started thinking about what some of the top nerve rerouting clinical specialists would think of this method so I did a search, came up with a list of names and contacted one of them in Europe, he felt that it probably would not lead to much success. I think he is the type you were referring to, not intrested in taking the time or the risk to look into it. Do you know of anyone in china that is doing anything like this? Dr. Zhang or Dr. Xiao?

    Thanks again for your time,
    Rick

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