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Thread: Spinal Cord Injury Site "Scar Tissue"

  1. #11
    They certainly are! Thanks, GRAMMY.

  2. #12
    From what I was told and looking at my last MRI, my cord wasn't severed leaving me an incomplete C5/6. The MRI makes my cord look like an hour-glass. Leading me to believe that if the surrounding tissue, whatever it may be, was removed, that it may allow regneration of cord cells. It just seems to me that "clearing the path" may allow regeneration. mark

  3. #13
    Quote Originally Posted by 4tun8 View Post
    From what I was told and looking at my last MRI, my cord wasn't severed leaving me an incomplete C5/6. The MRI makes my cord look like an hour-glass. Leading me to believe that if the surrounding tissue, whatever it may be, was removed, that it may allow regneration of cord cells. It just seems to me that "clearing the path" may allow regeneration. mark
    4tun8, what you are suggesting is precisely what I believe should not be done. There is *no* evidence that removing "scar" improves regeneration. Many studies have tried to remove scar and, to my knowledged, none have resulted in regeneration of the spinal cord.

    Chondroitin-6-sulfate proteoglycan (CSPG) is an extracellular matrix material. This material is made by glial cells when they try to wall off what they believe is peripheral tissues from the spinal cord (and brain). CSPG will stop axonal growth but CSPG is not "scar". It is just extracellular material.

    A bacterial enzyme called chondroitinase ABC will break down CSPG. Over 100 papers have been published showing that chondroitinase will break down CSPG and allow axons to grow in the spinal cord and the central nervous system.

    Physical removal of the spinal cord produces scar. To cut a piece of the spinal cord out is to allow fibroblasts into the spinal cord. To put a piece of nasal mucosa into the spinal cord is to put fibroblasts into the spinal cord. It creates more gliosis and true scar where there may not have been before.

    Nobody has ever removed a piece of the spinal cord without more gliosis forming in the surrounding cord. This concept of removing a piece of the spinal cord in order to allow axons to grow across is, in my opinion, wrong thinking and the main reason why I am speaking out against it.

    One way to get rid of CSPG is to inject chondroitinase into the spinal cord. Many laboratories have shown that chondroitinase will break down CSPG in the spinal cord and allow functional regeneration to occur in the spinal cord [1].

    Another way is use of Decorin to prevent gliosis and CSPG accumulation, including matrix deposition, formation of an accessory glial limiting membrane, and inflammation after incisional wounds of the spinal cord [2] and stimulate regeneration in the spinal cord [3].

    Many regenerative therapies of the spinal cord, including anti-nogo antibody [4], cethrin, olfactory ensheathing cell transplants, PTEN knockout, etc, all have regenerated the spinal cord without removing glial scar. So, removing scar is neither necessary nor sufficient for spinal cord regeneration.

    Wise.

    1. http://www.ncbi.nlm.nih.gov/pubmed/18373483
    2. http://www.ncbi.nlm.nih.gov/pubmed/10506521
    3. http://www.nature.com/nature/journal...s/416636a.html
    4. http://www.ncbi.nlm.nih.gov/pubmed/16173073

  4. #14
    Dr. Young, are these therapys still in the lab, or have they been advanced to human trials?

  5. #15
    Wise, I have to say after the symposium in Brescia I am even more confused by the varying opinions on whether it is common for a traumatic injury to have a scar containing fibrotic tissue.

    In Brescia, Harry Goldsmith, Carlos Lima and even Alok Sharma all claimed that every traumatic chronic lesion they have seen on the operating table has an element of fibrosis. Harry and Carlos, as we know, believe "cleaning" the lesion to remove the fibrosis is important for chronic treatments whereas Alok stressed that this is not something we should do as there is a risk to remaining healthy tissue in the cord.

    I think this is a topic that needs to be discussed at length in a workshop type of setting by a range of experts in the field.

  6. #16
    Wise, you've spoken about scar tissue or formation at great lengths and explained it in a manner that makes sense. The question that I have is that so many of the researchers working on therapies claim that scar tissue formation is a porblem. Geron's trial, I believe , to be applied within 14vdays, is to negate scar formation. You've mentioned ways of dissolving or breakdown of CSPG. My question would be ; is there a timelimit for this to occurr. In other words does this have to occurr in the first few weeks after injury or can this be done at any time? Thanks for your explanations Wise.

    keeping on

  7. #17
    Bumped as it got buried.....

    Quote Originally Posted by Fly_Pelican_Fly View Post
    Wise, I have to say after the symposium in Brescia I am even more confused by the varying opinions on whether it is common for a traumatic injury to have a scar containing fibrotic tissue.

    In Brescia, Harry Goldsmith, Carlos Lima and even Alok Sharma all claimed that every traumatic chronic lesion they have seen on the operating table has an element of fibrosis. Harry and Carlos, as we know, believe "cleaning" the lesion to remove the fibrosis is important for chronic treatments whereas Alok stressed that this is not something we should do as there is a risk to remaining healthy tissue in the cord.

    I think this is a topic that needs to be discussed at length in a workshop type of setting by a range of experts in the field.

  8. #18
    I realize that I may be a loner amongst scientists when it comes to the use of the word "scar" referring to the aftermath of spinal cord injury. Over the years, I have spoken up at multiple meetings, questioning speakers who use the word "scar" or "glial scar" with respect to spinal cord injury. I didn't use to be militant on this subject until I saw a talk given by Carlos Lima in 2003. He was presenting his work that transplanted olfactory mucosal into the spinal cord of patients and he said that the surgical team removed a "block" of scar tissue from the spinal cord so that they could stuff nasal mucosa into the hole. He showed pictures of the removed tissues and there were axons in the tissue.

    There is no rational or evidential basis for removing scar tissue from the spinal cord. It is not rational to remove "scar" because the act of removing scar will simply create more scar. There is no evidence that a majority of people with spinal cord injury have a "scar". This is where the discussion usually breaks down. What people are calling "scar" is simply accumulation of glial cells, i.e. astrocytes that grow at injury sites. This is properly called gliosis. To me, the word scar refers to a collagenous tissue formed by fibroblasts, skin cells, that knit damaged tissues together. Fibroblasts are present in most parts of the body. Fibrous and collagenous scars form when we cut skin, liver, heart, lung, and many other organs because these organs have fibroblasts that invade into the injury scar and form scars.

    It is true that if you cut the spinal cord and do not close the dura, fibroblasts do invade into the spinal cord and a fibrous scar may form, lined on the CNS side by astrocytes. However, the vast majority of spinal cord injuries do not involve any penetration of the spinal cord. Displaced bone or disc compresses or contuses the spinal cord, usually without penetrating the dura, a very tough membrane that surrounds and protects the spinal cord. While some fibroblasts are present in the arachnoid membranes outside the spinal cord, fibroblasts are usually excluded from the spinal cord. A contused spinal cord seldom has any collagen within the injury site.

    The vast majority of spinal cord injuries do not involve a penetrating wound of the spinal cord. Normally, no fibroblast resides in the spinal cord and they are carefully excluded by astrocytes, whose job it is to wall off the central nervous system including the spinal cord from peripheral tissues. Astrocytes are responsible for creating the blood brain barrier and line all boundaries between the central nervous system and peripheral tissues. Gliosis is part of the natural repair of the injured spinal cord. In fact, many studies have shown that if you stop gliosis, it is damaging to the spinal cord and the blood brain barrier does not reform.

    Investigators who injure the spinal cord by using a knife, scissors, vibrating probes, or laser beams to cut the spinal cord may of course see a scar at the injury site. At least one study [1] has shown that if the investigator carefully sewed the dura close and prevented invasion of fibroblasts into the injury site, there is no scar formation. I don't question the presence of scar tissues in such injury models. However, if the spinal cord is injured by compression, contusion, or ischemia, there is seldom any collagenous scar tissue in the spinal cord. Stephen Davies uses hemisection or transection model of spinal cord ijnjury, where he cuts the spinal cord. Of course he thinks that scar is important because his model has scar.

    There is also an open question whether "scar" tissues prevent axonal regeneration. For example, in recent studies by Kai Liu, et al. [2] showing rivers of corticospinal tract axons growing across a cut injury site after reducing PTEN expression, he made no attempt to remove the scar tissues and yet many axons regenerated across the injury site. Scientists such as Martin Schwab did not remove scar when he used Nogo blockers to stimulate regeneration [3]. Likewise, scientists who used chondroitinase to enhance regeneration the spinal cord did not remove "scar". For example, Yick, et al. [4] was able to regenerate 40% of the rubrospinal tract in rat spinal cord with chondroitinase and lithium.

    Some scientist say that astrocytes secrete chondroitin-6-sulfate proteoglycan (CSPG) which stops axonal growth. While it is true that CSPG does stop axonal growth, CSPG is not "scar". It is a glycoprotein that is present in the extracellular space. While CSPG does stop axonal growth, this is its purpose, i.e. it is present at the edges of the nervous system and its "job" is to channel axons so that they grow within the central nervous system and do not sprout like hair from the surface of the brain and spinal cord. One can have astrocytes without CSPG. In fact, Stephen Davies himself showed that certain types of astrocytes are beneficial for axonal regeneration in spinal cord injury.

    Some people may dismiss my argument as just semantics. I would agree with them if I have not seen so many patients with spinal cord injury coming to me and to this web site saying that "scar" has to be removed from the spinal cord before regeneration can occur. I would agree if there were not people like Carlos Lima whose surgical team actually cut out "scar" from the spinal cord. I would agree if the word "scar" were not used so indiscriminately as to refer to any kind of gliosis, including a company that actually set as its therapeutic goal the elimination of gliosis from spinal cord injury. So, it is not just semantics. Based on the false premise that glia cells block regeneration, surgeons are removing "scar" from human spinal cords. Patients are demanding it. Companies are trying to find ways of removing "scar". So, it is wrong and bad for patients for this term to be floating around. It gives the wrong impression.

    There is one other reason why the use of the word "scar" is inappropriate when applied to gliosis in the spinal cord. There are true fibrous scars that develop in spinal cord injury. For example, as pointed out, when the spinal cord is cut and the dura is not repaired, fibroblasts do move into the spinal cord and form collagenous scars that are walled off by glial cells. Likewise, fibrous adhesions do develop between the spinal cord/roots with surrounding tissues. Removal of these adhesions or untethering the spinal cord is an important surgical procedure that can help restore function. The word scar should be reserved for such fibrous attachments and true scars instead of being meaninglessly applied to gliosis in the spinal cord.

    Scientists should not be using the term "scar" so cavalierly. Words have power to mislead and this is one of those words that have actually led to harmful clinical practices and misleading concepts of spinal cord injury. It scares me every time I see somebody ask a question in the Cure forum about having their "scar" cut out from their spinal cord. Until somebody has better evidence that "scar" is preventing regeneration and that cutting scar out from the spinal cord is doing anything to improve function, I feel the necessity to speak out strongly against the use of the word scar to refer to gliosis in the spinal cord.

    Wise.

    1. Seitz A, Aglow E and Heber-Katz E (2002). Recovery from spinal cord injury: a new transection model in the C57Bl/6 mouse. J Neurosci Res 67: 337-45. The Wistar Institute, Philadelphia, Pennsylvania 19104, USA. Spinal cord transections in mammalian animal models lead to loss of motor function. In this study, we show that functional recovery from complete transection of the adult mouse spinal cord can in fact occur without any intervention if dural injury along with displacement of the ends of the cut cord and fibroblastic infiltration is minimized. Underlying this function is the expression of GAP-43 in axonal growth cones, axonal extension and bridging of the injury site indicated by biocytin retrograde tracing and neuronal remodeling of both the white matter and the gray matter. Such studies suggest a new murine model for the study of spinal cord regeneration.

    2. Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B and He Z (2010). PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 13: 1075-81. F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

    3. von Meyenburg J, Brosamle C, Metz GA and Schwab ME (1998). Regeneration and sprouting of chronically injured corticospinal tract fibers in adult rats promoted by NT-3 and the mAb IN-1, which neutralizes myelin-associated neurite growth inhibitors. Exp Neurol 154: 583-94. Brain Research Institute, University of Zurich and Swiss Federal Institute of Technology, Zurich, Switzerland. Myelin-associated inhibitors of neurite growth play an important role in the regenerative failure after injury in the adult mammalian CNS. The application of the mAb IN-1, which efficiently neutralizes the NI-250/35 inhibitory proteins, alone or in combination with neurotrophin-3 (NT-3), has been shown to promote axonal regeneration when applied in acute injury models. To test whether IN-1 application can induce axonal growth also in a chronic injury model, we treated rats with IN-1 and NT-3 starting 2 or 8 weeks after injury. Rats underwent bilateral dorsal hemisection of the spinal cord at the age of 5-6 weeks. Regeneration of corticospinal (CST) fibers into the caudal spinal cord was observed in three of eight of those animals with a 2-week delay between lesion and treatment. CST fibers regenerated for 2-11.4 mm. In the control group sprouting occurred rostral to the lesion but no long-distance regeneration occurred. In animals where treatment started at 8 weeks after injury the longest fibers observed grew up to 2 mm into the caudal spinal cord. The results show that transected corticospinal axons retain the ability to regenerate at least for a few weeks after injury. Functional analysis of these animals showed a slight improvement of functional recovery.

    4. Yick LW, So KF, Cheung PT and Wu WT (2004). Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. J Neurotrauma 21: 932-43. Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong. After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3beta inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3beta as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.
    Last edited by Wise Young; 05-17-2011 at 10:29 AM.

  9. #19
    Senior Member Schmeky's Avatar
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    Quote Originally Posted by Young
    Over 100 papers have been published showing that chondroitinase will break down CSPG and allow axons to grow in the spinal cord and the central nervous system
    This is no way directed at you Dr. Young . . . . but over 100 papers and still no application to humans.

    Am I the only one?

  10. #20
    Quote Originally Posted by Schmeky View Post
    This is no way directed at you Dr. Young . . . . but over 100 papers and still no application to humans.

    Am I the only one?
    Schmeky,

    There are several reasons why chondroitinase has not yet gone to trial.

    First, chondroitinase is a very old compound. The composition of matter patent is held by a food company in Japan that has had little interest in licensing it. The processing patent is held by a company called Seikagaku in Japan and that company gave up of developing chondroitinase for spinal cord nearly a decade ago after having spent some money trying to develop the enzyme for soften spinal discs. The use patent for the treatment was licensed by Acorda Therapeutics, which is just beginning to make enough money to consider investing in the development of chondroitinase for spinal cord injury. Spinal cord injury is still considered a small market and most companies are not willing to get into this field without stronger patent protection and certainly not while there is still a recession and economic uncertainty.

    Second, funding for U.S. spinal cord injury research and clinical trials is at its lowest ebb in memory. The combination of the anti-terrorism priorities of this country and the recession essentially wiped out any gain of research funds that we may have had since 1995. In 2011, we are getting less funding for spinal cord injury research and clinical trials from the federal government and state government than we did a decade ago. Last year, Governor Chris Christie of New Jersey diverted funds from the $1/traffic ticket fund for spinal cord injury research and our center at Rutgers was left with a million dollar grant gap. At the Keck Center, we are now running on fumes and a skeleton staff. All efforts by the spinal cord injury community to lobby the government for more research funding essentially stopped two years ago.

    Third, the number of U.S. clinicians who are willing and able to do clinical trials for spinal cord injury therapies is likewise at an all-time low in the U.S. The last major clinical trial for spinal cord injury was by Acorda Therapeutics. We have a couple phase I/II trials and no phase III spinal cord injury therapy trial over the past decade. It has been next-to-impossible to move any therapy into phase III. The pressure on doctors and hospitals to make money and to take care of patients is greater than ever before. Few doctors are willing to give their time and resources like they did in the past. Our effort to move the Christopher & Dana Reeve Paralysis Act through Congress was abandoned before we got the funding. More clinical trials are going on overseas than in the United States.

    So, what can be done? I have been pushing as hard as I can within Acorda to urge them to invest into chondroitinase and more into spinal cord injury research. Hopefully, the fruits of that pushing will show up soon. In the meantime, we need to do other things to move things forward rather than sit around and complain. So, what else can we do?

    • The community must raise the money for its own clinical trials. As I have pointed out earlier, if 10% of the community (say 100,000 people) paid a dollar a day to support the trials in the United States, this would add up to $36.5 million per year. We are just getting this program going.
    • People must lobby Congress and state governments to fund more spinal cord injury clinical trials. For much of the last two years, such lobbying would have and did fell on deaf ears. Since the demise of bin Laden and the easing of the recession, now is the time to restart lobbying.
    • We must get a few trials going and hope that the success of these trials will attract more companies and money to get into the field. Once we have the first therapy that improves function in chronic spinal cord, many companies will want to jump on the bandwagon.

    Finally, let's work together to make all of this happen.

    Wise.
    Last edited by Wise Young; 05-17-2011 at 09:23 PM.

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