Dr. Young - If Cure Found For Acutes How Hard Will It Be To Remove Scar Tissue?

[angel7]

Dr. Young,

Is scar tissue the only obstacle in gaining recovery utilizing ESC? I read that nerve atrophy would also be a hinderence but can be reversed with extensive physical therapy. Is this correct? Is there not a drug available that can dissolve scar tissue? What else would be other hinderances for Chronic injuries?

Thanks,

Deb

[Steven Edwards]

Debbie,

A paper being presented by Tuszynski at the Society for Neuroscience meeting shows that axons can grow into bone marrow stromal cell substrates in the presence of chondroiton sulfate proteoglycan, which is expressed by the scar tissue. The results concluded that chronically injured axons can overcome the scar tissue and 'follow growth patterns observed after acute injury'.

I would post the abstract, but it says I can't. [img]/forum/images/smilies/smile.gif[/img]

-Steven
...taking it back, I'm taking it back, taking back my life

[angel7]

Thanks Steven - that gives me hope.

Deb

[Mungos]

Dr Young
So in other words what you are saying is that the scar tissue can be overcome with little difficulty? or is it still a ?? work in progress?. [img]/forum/images/smilies/rolleyes.gif[/img]

[Wise Young]

Mungos,

This work is based on two earlier studies that had been published by Tuszynski's laboratory and should be appearing soon. In one paper by Lu, et al. (2004), they reported the combination therapy with cAMP and neurotrophin (NT-3) stimulated regeneration better than NT-3 or cAMP alone.

If I remember correctly, what Tuzynski's laboratory showed was that the combination of cAMP, NT-3, and bone marrow stem cell transplants produced better regeneration than any of the treatment alones in injured spinal cords. I have been waiting for this paper to come out. It was announced in a press release earlier.

Wise.

[Javi]

I appologize for my ignorance to SCI, but I'm a fairly new quad, and learning.Anyway, my question is regarding scar tissue, what exactly is it and how does it affect an OEG transplant or any other type of spinal cord surgery.
THANKS

[NoDecafPlz]

Dr. Young,

This deals with scar tissue, therefore
it applies to chronics yes?

Any time frame specified?

J.

[Wise Young]

Javi,

There are two kinds of "scar" tissues that form in the spinal cord after an injury: astrocytic scar and fibrotic scar. Let me try to explain the difference as best as I can.

In the spinal cord (and brain), there are glial cells called astrocytes. Astrocytes are all over the brain and they line the blood vessels (capillaries), forming what is called the blood brain barrier. This is so that the brain and spinal cord can control what goes in and out.

Fibroblasts are skin cells that produce the scar in your skin when you cut yourself. They are also present in most membranes, including the dura (the tough membrane that covers the outside of the spinal cord). Normally, there are few or no fibroblasts in the brain and spinal cord. When fibroblasts get into the spinal cord, the astrocytes in the spinal cord regard these cells as foreigners and they multiply around the fibroblasts and wall them off. That is the job of astrocytes, to distinguish between what is in the central nervous system and what is outside, and to segregate them.

There are two types of injuries to the spinal cord: a closed injury and a penetrating injury. A closed injury is when the spinal cord is compressed. When the compression is rapid, it is called a contusion. A penetrating injury occurs with bullets, knives, or very severe spinal cord injuries that actually may tear the dura or the spinal cord itself.

Most spinal cord injuries are of the closed variety. In other words, there is fracture of the spinal bone and the bone presses against the spinal cord. When the spinal cord is injured with a compression or contusion, the blood vessels in the spinal cord are also damaged. There is usually bleeding. The injury mobilizes the astrocytes and they rapidly grow to wall off all the blood vessels and reform the blood brain barrier. Sometimes, a lot of astrocytes surround the injury. Some scientists have called this astrocytic or glial "scarring".

For many years, scientists have observed axons (nerve fibers) grow towards the injury site and stop at the glial "scar" or gliosis. Early scientists thought that the glial cells provided a mechanical barrier against growth. So, much effort has been put into devising ways to prevent gliosis at the injury site and, to my knowledge, none of these treatments have really produced significant beneficial effects in spinal cord injury.

In the early 1990's, Jerry Silver and his colleagues at Case Western proposed that it was not the glial "scar" that prevented the growth but a chemical that was secreted by astrocytes that stopped axonal growth. This chemical was called chondroitin-6-sulfate-proteoglycan or CSPG. In the late 1990's, a great deal of evidence was gathered to show that a specific bacterial enzyme called chondroitinase ABC would break down CSPG and allow axons to grow through areas of gliosis. Chondroitinase is now one of the hottest regenerative therapies for brain and spinal cord.

In the other kind of damage to the spinal cord caused by a penetrating wound, i.e. a knife or bullet, the spinal cord is actually exposed to outside tissues. When this happens, fibroblasts from the surrounding tissue invade into the spinal cord. The fibroblasts produce collagen and fibronectin, two chemicals that form fibrous scar. So, spinal cords with penetrating wounds do form true fibrous scar that will mechanically block axonal growth.

Many spinal cord injury scientists injure the spinal cord by cutting it with a knife. When they do that, a fibrous scar forms. Also, many scientists when they cut the spinal cord, they do not repair the dura (the membrane covering the spinal cord) and this allows more fibroblasts to invade into the injury site. So, there is no question that there is indeed real "scar" tissues that can develop in such spinal cords.

A majority of human spinal cords, however, are either compressed or contused. They do not involve any penetrating wound into the spinal cord. In such cases, there is no need to "remove" the scar. This is one of the reasons why I am uncomfortable with the Portuguese procedure used by Dr. Lima and his colleagues. They believe that there is "scar tissue" at the injury site and then cut out part of the spinal cord to "remove scar". In my opinion, this is not necessary in a majority of the cases. This approach might be justified if the original injury was a penetrating wound but it still doesn't make sense to me because they then put nasal mucosa into the spinal cord. After they cut a chunk of the spinal cord out, ostensibly removing the scar, they stuff pieces of nasal mucosa inot the opening. Nasal mucosa contain fibroblasts and many other cells that would be recognized by astrocytes in the surrounding spinal cord as "foreign" and would be walled off by the astrocytes. So, to tell you the truth, I don't know what is happening to those spinal cords.

The method used by Dr. Huang to transplant olfactory ensheating glial cells in to the spinal cord is very different. What he does is expose the spinal cord above and below the injury site. He opens the dura and inserts a very fine needle (40 gauge, I believe) into the midline of the spinal cord, and then injects a small volume (10 microliters, I believe) of olfactory ensheathing glial (OEG) cells into the spinal cord. The OEG are isolated and grown from the olfactory bulb of aborted fetuses. These cells are known to migrate in the spinal cord and this is the reason why he injects them into the surrounding cord rather than into the injury site. This way, he does not damage any of the existing axons that may still be crossing the injury site. Note that he does the operation on some patients who have "incomplete" spinal cord injury with some preserved function. Dr. Huang does a "tight dural closure" which means that he sews the dura so that it is water-tight.

The Brisbane group (McKay-Sims) have transplanted OEG cells that were cultured from the nose of the patients. They expose the spinal cord and then inject the cells into the spinal cord. This was done in two patients and I have been anxiously awaiting the results of their trial. Because Dr. Huang uses OEG cells from fetuses and they are not genetically matched with the recipients, this means that the cells are likely to be eventually rejected by the immune system. The spinal cord rejects cells relatively slowly and one expects the cells to survive several months or perhaps even a little longer (because the cells are fetal cells and they are not supposed to be recognized and rejected as quickly as adult cells). However, the Brisbane group was using cells from the same person and therefore the cells should not be immunologically rejected. Likewise, the Portugal group are using nasal mucosa from the same patient and it should also not be rejected.

Finally, I want to tell you about a third kind of scar that is not actually in the spinal cord. These are adhesive scars that can from between the spinal cord, arachnoid, and dura. Because there is bleeding and inflammation at the injury site and there are fibroblasts in the dura, they often form adhesive scars. Such scars cause the spinal cord to "tether". Normally, the spinal cord slips and slides within the dura. Also, cerebrospinal fluid (CSF) flows between the spinal cord and the arachnoid membranes that cover the spinal cord. When adhesive scars develop, they prevent CSF flow. On an average day, about a liter or more of CSF flows from your brain down the spinal cord. The CSF is then absorbed by the arachnoid. However, when there is adhesive scarring between the spinal cord and surrounding arachnoid and dura, the CSF shunts into the spinal cord and can cause an enlargement of the central canal called a syringomyelic cyst or syrinx for short. When a spinal cord is tethered, movement of the spinal column causes stretching and pulling of the spinal cord. In any case, this may cause neurological loss.

There is no need to "remove scar" from the spinal cord in most cases. Even in cases of penetrating wounds (unless the spinal cord is transected), there is often parts of the spinal cord where there is no scar. By the way, much animal data support this. For example, almost all the spinal cord injury experiments that report successful regeneration with restoration of function in animals do not remove scar from the injury site. For example, the studies showing that Nogo receptor blockers or Nogo blockers regenerating the spinal cord do not remove scar in order to allow regeneration to occur.

In summary, I believe that a vast majority of people with spinal cord injury do not have fibrous scar tissues inside their spinal cord. They may form scars between the spinal cord and surrounding membranes. If there is a penetrating wound of the spinal cord, fibrous scarring may result. However, a vast majority of spinal cord injuries do not result in fibrous scar tissue formation in the spinal cord. Injury does cause glial cells in the spinal cord to grow but this is necessary for repair of blood vessels at the injury site and to restore the blood brain barrier.

So, I repeat again, it is not necessary to "overcome" scar tissue to get regeneration. In certain cases when penetrating wounds are involved, it might be helpful, but people should understand that it is not the primary obstacle to regeneration. The main obstacle to regeneration are:
• the presence of growth inhibitors in the spinal cord (Nogo, CSPG) that stop axonal growth.
• the absence of growth cues to guide axonal growth and the axons get lost.
• the long period of growth that is needed for axons to get across the injury site and grow all the way down to their original target (it may take months). Growth factors may be necessary to stimulate the axons to grow such long distances.

I hope that this is helpful and I would be glad to clarify, amplify, and re-explain...

Wise.

[QuadPro]

Wow! It's not not necessary to overcome scar tissue for regeneration. This is great news.

[Leo]

Wise, in the latest from SCS pdf in this thread here

aren't they saying poor results due to scar tissue?

"All you have to decide is what to do with the time that is given you."
Gandolf the Gray

[Susan M]

Excellent explanation, Wise.

Thank you.
Sue

[harrisa]

Dr. Young-

Awesome reading...and a question...

My injury resulted in compromised dura but intact arachnoid and a recent MRI shows a scar along the midline of the spinal cord. Might "extraspinal" fibroblasts have penetrated the intact cord to participate in this scar formation? I assumed gliosis only.

Harris

[Max]

Wise,

My spine was transected on many levels from left to right C5-6-7....

Does this mean I'm hopeless case?

Possibly scar will have to be removed in my case>..?[img]/forum/images/smilies/frown.gif[/img]

Can it be done on so many levels?

[angel7]

Thanks for the positive explanations Dr Young and everyone. Can I assume that because my dura was intake that I may not have any scarring?

Deb

[Belle]

Dr. Young,

How might your discussion of scarring be relevant to the comments by Kierstead in the article referenced in this topic? He seemed to think that the treatment he tried did not work in the longer term injured rats because of the 'scarring.' Might this be a technique that could benefit from using a cAMP/combination?

*************
AB wife of T8 complete para