Scarless Healing

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I'm just plinking around this morning and have already read about 23 scientific papers! Thank God I have good eyes!

Here are some of my random findings:

On Fetuin: A disease marker for risk assessment of cardiovascular calcification

Fetuin (AHSG, or Fetuin-A) has the highest capacity in inhibiting soft tissue calcification among all other molecules in the circulation. It is the most important and major calcification regulating protein in the circulation.

http://www.fetuin.com/

I think this is really interesting. I read a book a while back called, "The Calcium Bomb" which turned out to be more of a marketing tool for the author who at the end essentially wanted people to sign up to buy his supplements and antibiotics. HOWEVER, in this book the author proposed that virtually all disease processes start with inflammation and that calcium gets deposited in the body's attempt to neutralise that inflammation...sounds like scarring to me. So, maybe using Fetuin is the key to catabolizing scar tissue which would then allow regeneration.

Another interesting tidbit:

http://ajp.amjpathol.org/cgi/content/full/157/2/423

Fetal repair is fundamentally different from adult repair. Adult skin wounds heal by scar formation, whereas fetal skin wounds heal by regeneration with restoration of normal skin architecture. This transition from scarless fetal repair to adult-type healing with scar occurs at specific times during gestation. The mechanism for scarless fetal repair is unknown, but it does not require systemic factors such as the fetal immune system, fetal serum, or amniotic fluid. Isolated human fetal skin transplanted into adult athymic mice can heal without scar. Thus the capability for scarless repair is inherent to fetal skin itself.

Isn't that fascinating?! So, since the fetus is able to regenerate and would regenerate its graft, what harm would it do to harvest the tissue and then propogate the cells in a lab for transplantation onto scarred skin? I would guess the fetus would need to be a tissue match or the risk for rejection would be raised, but I still think this this is very interesting.

A bit of a roadblock in the research is that so many articles use the term TGF generically when we know the various forms of TGF have vastly differing actions. Also, some articles refer to Fetuin as a form of TGF??? Drives me nuts!

Neca, I read up on DermaLastyl, and in the article it said that the main ingredient that the doctor used DID make the wounds heal without scarring. I know DermaLastyl is a diluted formulation but I might go ahead and order it just to try it. Probably won't hurt!


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GREAT POSTS EVERYONE, THANKS FOR THE EXCELLENT RESEARCH AND ARTICLES!!!

Thanks for posting this Kirk. A couple of months ago I was in contact with Dr. Fiona Wood in Australia and was asking about a new product they are working on called ReCell with is being used as a scar and vitiligo treatment. ReCell is a single use spray on skin treatment to reepithialize skin after a burn or cosmetic dermabrasion. Dr. Wood is renowned for her work with burn victims. I don’t remember specifically reading about fetuin, but it sounds promising. My understanding is that for those of us with existing scars what will be needed is something to eliminate all the existing scar tissue before regeneration can occur. I’ll look into it further. It is truly of note that they are using it on burns where one can assume dermal tissue has been lost. That is the real test as it pertains to those of us with indented acne scars where tissue is missing. Link to ReCell: http://www.recell.info/

Yes I definintely agree Anna, ReCell does look promising; I've had a quick look through the PDF comparison photos presented on their case studies page at http://www.recell.info/pa_casestudies.asp and the results do look reasonably good. However, this form of treatment is clearly aiming to improve scars and healing rather than remove scar tissue altogether. The most effective results are likely to be amongst 'fresh' burn patients since no scar tissue will have been deposited over the wound if the ReCell treatment is applied within a few hours of injury. Thus, ReCell can enter the wound free from scar tissue obstacles and penetrate the wound directly. However, despite this, the treatment does not prevent scar tissue formation so the success of the treatment will depend on how the wounded skin reacts to the ReCell's keratinocytes. Moreover, I'm not sure whether ReCell would be affective at all if provided in tattoo mode as it would not evenly penetrate the scar tissue. Dermabrading the scar tissue prior to treatment helps evenly remove layers of scar tissue (leaving only a thin layer of rooted scar tissue) enabling the application of ReCell to be more affective. Moreover, the tattoo mode may be a little too intrusive causing even more scar tissue to form as it is penetrated deep down. This is why I think if you look at the hypertrophic scar before/after photo on ReCell's site it looks less visible and flatter as the scar tissue has been sanded down.

ReCell could be a bit hit or miss, but it is definitely worth pursuing and researching more. Maybe if this was combined with Juvista/Juvidex then wounds could heal almost perfectly.

Oh, this is an interesting paper related to reducing excess TGF B1 for cancer patients who exhibit high levels of TGF B1. They use drugs and supplements with Papain (active enzyme in Paypaya) to reduce the high TGF B1 levels. Another piece of the puzzle maybe?

http://www.osteosarcomasupport.org/Integra...nzymes_2001.pdf

Thanks for that link, very intriguing paper. What we would need to know is whether these drugs+supplements (given to cancer patients) will also work with the same efficacy levels during the stages of wound healing. Effectively, what I am trying to say is whether these substances are able to prevent TGF1+2 from forming when the skin is seriously wounded and goes into scar tissue formation mode? The healing process which produces scar tissue may override those drugs/supplements. Nevertheless, I will definitely look more into Papain and its effects on TGF1.

Isolated human fetal skin transplanted into adult athymic mice can heal without scar. Thus the capability for scarless repair is inherent to fetal skin itself.

Isn't that fascinating?! So, since the fetus is able to regenerate and would regenerate its graft, what harm would it do to harvest the tissue and then propogate the cells in a lab for transplantation onto scarred skin? I would guess the fetus would need to be a tissue match or the risk for rejection would be raised, but I still think this this is very interesting.

I think that's incredible and am very surprised that the adult mice do not reject the skin transplant? A skin biopsy, I would have assumed, is taken from the same person as the wound that it is about to treatment due to the fact that rejection is less likely to occur. I would also assume thus that if a skin biopsy is taken from a human being and used to treat a wound on another human being, then acceptance is much less likely but not impossible due to anti-rejection drugs. Thus, maybe the mice were given anti-rejection drugs.

It makes me think...wouldn't it all be so easy if samples of our human skin was taken when we were all fetus' and then stored for potential future use? It would provide a perfect match.

Neca, I read up on DermaLastyl, and in the article it said that the main ingredient that the doctor used DID make the wounds heal without scarring. I know DermaLastyl is a diluted formulation but I might go ahead and order it just to try it. Probably won't hurt!

You could give it a go if ya want to Anna but I wouldn't get hopes up too much. Since its primarily an anti-ageing cream, the amount of anti-scarring ingredients is likely to be minimal. If it doesn't cost too much or if you are able to get a sample then it might be worth a try. But if they are charging $300 or something then I wouldn't really bother. I just hope some venture capitalist risks his money into Elastin's creator so he can go forth and produce a fully concentrated and potent form of the substance in the hope that it reduces scarring.

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Neca, all I have found is what is on the internet, entrez pubmed etc. and some article titbits that excited me when I read them. As you know though, these headlines and titbits can be misleading. So most of what I've seen and read on fetuin you will be able to see for yourself on the internet. Just type in Fetuin and Kimble in google.

Though I do have a document, that I documented on word on the 21st October 2005 (like I do with every article and PDF file I see that could have something to do with scarless healing, and I'd advise everyone who reads this thread to do the same) called 'fetal protein holds key,' by Bernadette Condren that has been took down from the newspaper website (thus I'm unsure about what rights I have to post it on this forum publically), you can only get this document now via payment etc. This document was the first article that originally excited me about this protein. I just sense through what I've read then, along with how now they only release tiny bits of info, along with the scarlessfuture PDF that they have something big and something significant is in the pipeline. (Note: I can also see on the other hand I might have been driven by hype, like the hype for other bits of progress I've read about on the web etc.),

However I did about a year ago read some information in scientific medical jargon, that was what I thought was about fetuin suppressing TGFB1 or something? I just wish I wasn't a layman. Perhaps you could look into that, as I assume you know your medical jargon?

Hey Kirk, great post; I will definitely try and track down that Bernadette Condren document that you mention. I'm sure there is a way around having to pay for that article as it's surely referenced in other places as well that provides a brief synopsis of it. If Fetuin does in fact inhibit TGFb1 then it will definitely be something to look into further. The only issue surrounding Fetuin is that the research into explaining Fetuin's role in reducing/preventing scar tissue is not very advanced. Therefore, I think we might have to wait a few years longer until something definitive pops out. But it will definitely be interesting to see what Doc. Kimble has to say if Anna manages to flatter him enough ;) ..lol!

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In Sydney last sunday one of the major papers had a 2 page spread on scarring in one of its sections talking about current methods of treatment and also "scarless future" being developed by Australian scientists. I believe Aus will probably come out with the treatment first due to amazing R&D going on here and the doctors (for those who dont know an Australian scientist was the one who created the cervical cancer vaccine) makes me swell with pride :razz:

So seems scarring is finally getting major attention.

Hey Tom, I know it's a long shot but is there any chance you still have that article or are able to scan and post that article or provide a link if it has also been posted online or just briefly describe any of the techniques it mentioned? Did it include the same things we have been talking about on here? I am sooo so happy that scarring is getting increased publicity. We are definitely well on our way along the yellow-brick road to a clear skin future...let's really hope the journey isn't too long though.

http://news.bbc.co.uk/2/hi/health/4330906.stmI'm not sure if its just the journalist mixing up the regeneration parts with the scarring research or what but it stated later that there was the 1000 patients trialling new scarring therapies. Neca and Anna im very curious to see what do you guys think of this?

That's an excellent article Tom and thanks for posting it. I can't add much that Anna hasn't already outlined in her excellent post regarding the article, which covered virtually all the bases. You are right, the journo didn't really present the article clearly enough. I think scarring therapies are definitely well advanced now and the potential for finding a real solution is not a long way off, but when we are talking about organ regeneration then it is almost entirely a different ball park. I would say it's probably another 10-15 years away in terms of military research, however I doubt the regeneration of all the organs of the body will be as easy as the other....so who really knows.

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I forgot to also mention that I will also update you guys on whether I am able to source some Mannose-6-Phosphate (anti TGFb1+2) and some TGFb3 soon. I'm looking into our various options and hopefully will be able to get hold of some samples to test on my ever present scars.

I'm also looking into whether fresh Aloe Vera leaf (which contains Mannose-6-Phosphate) can effectively reduce/remove scarring and how concentrated the leaf is regarding M-6-P. Maybe injecting it intradermally after needling could reducing scarring. The only problem would be whether the aloe vera gel from a fresh tree would be 'clean' enough??

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Anna thanks for clearing up that article and thanks Neca for your input also. Unfortunately Neca no i don't still have the paper to scan in, i can remember the gist of it though. Basically it was talking about current scar treatment methods eg peels, fraxel, excision and so on which as we know do not get rid of scars but i suppose they needed some filler material, the interesting part of the article was the last 2 paragraphs talking about the Monash University paper which i saw a link to here somewhere discussing the idea of a scarless future within 4 years. It didn't go into detail only that they were working on it, it definately is a good sign i agree.

Must be off as early morning start at work tomorrow.

Wishing you all the Best!!!

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Hey Kirk, great post; I will definitely try and track down that Bernadette Condren document that you mention. I'm sure there is a way around having to pay for that article as it's surely referenced in other places as well that provides a brief synopsis of it. If Fetuin does in fact inhibit TGFb1 then it will definitely be something to look into further. The only issue surrounding Fetuin is that the research into explaining Fetuin's role in reducing/preventing scar tissue is not very advanced. Therefore, I think we might have to wait a few years longer until something definitive pops out. But it will definitely be interesting to see what Doc. Kimble has to say if Anna manages to flatter him enough ;) ..lol!

It was an interesting article, you should try and track it down. ;)

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Secret Squirrel Reporting with article by Bernadette Condren, you will have to beat me for me to give up my sources and even then I won't:

Fetal protein holds key

In a world first, Brisbane scientists have found the key to scarless healing. Bernadette Condren reports

08oct05

CHILDHOOD burns are among the most horrific and most preventable accidents.

A pot pulled from a stove, a hand on an open barbecue, a steaming cup dragged from a benchtop – scarring can be for life.

Minor burns that heal within two weeks heal without leaving a scar.

More severe burns, known as partial-depth burns, can take years of treatment, exacting a toll on the child and its family so immense that it is life-changing.

Roy Kimble is a quiet Scotsman with a great passion. He wants to create a treatment that will minimise, even eradicate, scarring from burns wounds.

And he's close. Very, very close.

In a world first, Dr Kimble and his team of scientists at Brisbane's Royal Children's Hospital have found that a protein called fetuin is a major player in the scarless treatment of burn wounds.

Those who will benefit from Dr Kimble's research are not only children, but also adults who have severe burns, such as those sustained during the Bali bombings.

Experts have known for many years that babies who have surgery while still in the uterus, and babies born very prematurely and who have surgery, heal without scars.

This was the scrap of information Dr Kimble and his team began with when their research project started in 2000.

"We asked: 'OK, a fetus can heal an incisional wound without scarring, but can it heal a burn without scarring?' " Dr Kimble recalled. "That was the first thing we set out to prove."

And they did.

In another world first, the Royal Children's Hospital Burns Research Group – which is funded by the hospital's foundation – used fetuses in sheep to prove the theory.

The quest for the holy grail of scarless healing had truly begun.

They set out to establish which proteins differed between the skin of a lamb in the womb and the skin of a lamb after birth. The first protein identified as being present in the fetus but largely absent in the lamb, was fetuin.

Fetuin has been pretty much ignored by the scientific community since it was discovered almost 70 years ago, but its days of obscurity are over. After identifying fetuin as a major player in scarless healing, the team in the burns lab created an artificial wound.

They grew a cell culture, scored it to create a gap in the cells then watched it to determine how long it took for the cells to close the gap. They repeated the process, adding fetuin to the next culture they grew.

Again they timed how long it took for the gap to close. The difference was significant – significant enough for Dr Kimble to patent the protein.

"Nothing closes a wound like fetuin does, so we know it has some very important qualities," Dr Kimble said.

At the University of Queensland's St Lucia campus there is a pig that hundreds of thousands of parents around the world will never know about but when they thank God that the hot cup of coffee their toddler has tipped on his or her head can be treated in such a way that there will be no scarring, it's the pig they should be thanking.

"We're in the middle of testing fetuin on our burns model," Dr Kimble said.

"We've recreated the deep thermal partial-thickness burn that you see in a child, which will heal on its own but will take more than two weeks to heal and always heals with scarring. We're currently testing fetuin on our animal model to see whether it will make wounds heal faster and with less scar tissue."

This trial is going so well that human trials have been pencilled in to start in 2007.

Current treatment for burns include patients having to wear pressure garments to prevent scar tissue from building up. Sheets of silicon are put over the wound before the garments are put on.

They have to be worn 24 hours a day and in the uncomfortable heat of Queensland's long summers.

If the scar is over a joint, the child will develop a contracture requiring surgery until they stop growing. Even then, they may not develop the full range of movement in the joint because scar tissue does not grow like normal skin.

"If we can use fetuin to reduce scarring, a lot of that is not going to be necessary," Dr Kimble said. "If you can get a wound to heal nice and fast at the beginning, you don't need all the pressure garments, silicon and repeated surgeries."

Fetuin would be applied as a topical cream and would provide a salve not only for the patient but also for parents.

"Because the vast majority of burns in kids are household accidents that are totally preventable, the parents feel very guilty and will probably feel guilty for the rest of their lives," Dr Kimble said.

As head of the burns unit, Dr Kimble shakes his head in despair because, he says, 99 per cent of the burns he sees are preventable.

"I do the research just to make things better," he said. "But if it can be prevented from happening in the first place – that's the best."


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Here is a link to the patent for the Fetuin product Professor Kimble is involved with. It is LONG and you have to go through the tabs to get the details. I'll read it in greater detail this weekend. Mainly, I'm looking for something that gives a glimmer of hope for treating existing scarring.

http://www.wipo.int/pctdb/en/ia.jsp?LANGUA...;DISPLAY=STATUS


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Wow anna awesome work on the info, still in the process of reading through it all. From what i can gather about treating existing scarring wouldn't they merely create a wound on your scars and then proceed in treating it in the same way which they treat the initial burns? Just a thought. Haha by the way when i read

"Fetuin has been pretty much ignored by the scientific community since it was discovered almost 70 years ago, but its days of obscurity are over. After identifying fetuin as a major player in scarless healing, the team in the burns lab created an artificial wound". I could feel a rise in my blood pressure, similar for anyone else?

Looking forward to reading the rest of it

Have a good one all

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Thanks Tom!

The more I read the more interesting it gets. The whole world of TGF and its variations is fascinating. In reading some of the literature it seems that TGF B1 is lowest at the fetal stage goes to its highest level during puberty and goes back to almost a fetal state in the 90's, something to look forward to??? Could it be implicated in causing acne itself? Will our scars go away at age 90? Is it necessary for cognition?

Fetuses and really old people have a few things in common such as lack of muscle control and inability to form memories, therefore could treatment with TGF B1 treat senile dementia...bad for scarring but good for the memory? All just stuff I'm thinking about.

I think that for Fetuin to work, first any minute remnant of scar tissue has to be removed. If Fetuin will do that by itself and then simply allow regeneration, that would be a miracle. I don't know if there is any way to disclose what is scar tissue and what isn't at a microscopic level. I have read about something called Von Giesen stain (sp?) which discloses fibronectic by staining it blue, but I don't know if that would be enough. Even if you could remove all scar tissue that you see, would that be enough? What about the scar tissue at the microscopic level?

I wish I knew more!

The research continues!

Anna


We search for more answers because the ones we have found are not to our liking.


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Hey Kirk, great post; I will definitely try and track down that Bernadette Condren document that you mention. I'm sure there is a way around having to pay for that article as it's surely referenced in other places as well that provides a brief synopsis of it. If Fetuin does in fact inhibit TGFb1 then it will definitely be something to look into further. The only issue surrounding Fetuin is that the research into explaining Fetuin's role in reducing/preventing scar tissue is not very advanced. Therefore, I think we might have to wait a few years longer until something definitive pops out. But it will definitely be interesting to see what Doc. Kimble has to say if Anna manages to flatter him enough ;) ..lol!

It was an interesting article, you should try and track it down. ;)

LOL! Seems like you and Anna have your detective caps on at the same time ;) Great tracking down guys, that's an excellent article. Is there a link for it anywhere as google is not being my friend :(

Here is a link to the patent for the Fetuin product Professor Kimble is involved with. It is LONG and you have to go through the tabs to get the details. I'll read it in greater detail this weekend. Mainly, I'm looking for something that gives a glimmer of hope for treating existing scarring.

http://www.wipo.int/pctdb/en/ia.jsp?LANGUA...;DISPLAY=STATUS

Great find Anna, the very fact that Fetuin is being patented suggests that it could become an extremely important substance in the anti-scarring world.

I've briefly skimmed through the document; it's interesting to note that they reference Ferguson (of Renovo) and actually question whether using TGFb3 by itself actually provides scarless healing:

A review article by Ferguson et al (Phil. Trans. R. Soc. Lond. B (2004) 359, 839-850) discusses the use of neutralizing antibodies to PDGF, TGF-βl or TGF-β2 generally to enhance wound healing in the case of incisional or excisional wounds but not burn wounds. The authors suggest that TGF-β3 is critically important for stimulating fibroblast migration into a healing wound and reduced scarring. They suggest that all isoforms of TGF-β cause fibroblast proliferation indicating that this activity is not required for wound healing. This approach is based on the observation that fetal wounds heal without a scar and are associated with low levels of TGF-βl and TGF-β2 and high levels of TGF-β3. Burn wounds are not discussed in any detail although they are merely cited as an example of a traumatic injury requiring rapid attention (page 843, first full paragraph). However, other studies suggest that exogenous TGF-βs stimulate re-epithelialization and granulation tissue formation consistent with their endogenous role (Werner et al, supra) and thus the roles and effects of TGF-βs are by no means clear. In particular, it is unclear as to whether TGF-β modulation by itself provides the proposed panacea for dermal injury.

It also indicates that Fetuin may be more effective than JuviDEX when treating wounds:

Further, fetuin was shown to be markedly more effective than either thyroglobulin or a TGF-βl inhibitor in enhancing healing of dermal injury and in promoting wound closure and healing.

Under the claims tab, it doesn't make any direct link between Fetuin and healing scarred tissue. Instead it refers to treating burns and using Fetuin as a wound healing agent along side other growth factors. Surely if they include TGFb3 and TGF1+2 inhibitors with Fetuin then it would directly become an extremely potent anti-scar treatment:

27. The kit of claim 25, further comprising an ancillary wound healing agent.

28. The kit of claim 27, wherein the ancillary wound healing agent is selected from cytolines, keratinocyte growth factors, platelet-derived growth factors, fibroblast growth factors, epidermal growth factors, neu differentiation factor, insulin-like growth factors and agents that modulate transforming growth factors.

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I think that for Fetuin to work, first any minute remnant of scar tissue has to be removed. If Fetuin will do that by itself and then simply allow regeneration, that would be a miracle. I don't know if there is any way to disclose what is scar tissue and what isn't at a microscopic level. I have read about something called Von Giesen stain (sp?) which discloses fibronectic by staining it blue, but I don't know if that would be enough. Even if you could remove all scar tissue that you see, would that be enough? What about the scar tissue at the microscopic level?

Anna, I'm not sure whether Fetuin's modus operandi is really in fact to remove scar tissue. I think it's main mode of action is to prevent the scar tissue forming in the first place hence the reason why they intend to use it to treat burns patients. If Fetuin is applied immediately post burn impact then it will be able to inhibit the scar tissue from forming (in theory). However, if you apply Fetuin to scars like the ones you and me have on our faces then I don't think it will do much. The scar tissue would first need to be excised, just like the procedure for Juvista/Juvidex.

Yes you can differentiate between scar tissue and normal skin tissue at a microscopic level. Scar tissue is much more fibrotic with tightly woven strands holding the tissue close together. I remember Renovo performed a before and after picture analysis during one of their presentations showing someone's scar in its natural state and then in its state post-Juvista treatment at microscopic levels. You could clearly see where the scar tissue was situated. I don't think we really need to worry about scar tissue at a microscopic level though. What we are more concerned about is removing the scar tissue so that it is not visible at eyesight level. Whatever scar tissue is left remaining at microscopic level will be consumed by the body over time.

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Intercytex prepares to launch their new product Vavelta in late 2007

Intercytex Group plc, the cell therapy company focused on aesthetic medicine and tissue repair, announces that it has introduced VAVELTA, its facial rejuvenation product.

VAVELTA is on track for launch in the second half of 2007 and will be launched initially with a selected group of physicians who have significant experience in the use of cell therapy for facial rejuvenation. It is expected that the first VAVELTA practitioners will be announced shortly. VAVELTA incorporates the same cells, allogeneic human fibroblasts, as used in two other Intercytex products in development - ICX-SKN (skin graft replacement) and ICX-PRO (chronic wound healing).

http://www.intercytex.com/icx/products/aesthetic/icxrhy/

http://www.vavelta.com/vavelta

Intercytex's FOUR product pipeline

1* ICX-RHY - Vavelta= a facial rejuvenation product to be launched in the second half of 2007

http://www.intercytex.com/icx/services/dow...x-rhy_0106_.pdf

http://www.intercytex.com/icx/services/dow..._rhy_june07.pdf

For the treatment of wrinkles, is currently in a Phase II trials in the UK and product launch is expected end of 2007.

2* ICX-PRO= designed to stimulate active repair in chronic wounds:

http://www.intercytex.com/icx/services/dow...cx-pro_0106.pdf

Their lead product for the treatment of leg ulcers, currently in a multi-centre Phase III trial in the US, UK and Canada, having successfully completed a Phase IIb trial for venous leg ulcers in 2005. The results of the Phase II trial indicated good efficacy and beneficial performance characteristics. The Phase III trial is expected to be completed in the first half of 2007.

3* ICX-SKN= being developed as a durable and robust skin replacement - recently completed a Phase I trial

http://www.intercytex.com/icx/services/dow...cx-skn_0106.pdf

In development as a living skin substitute, is expected to commence a Phase I trial in the second half of 2006.

http://news.bbc.co.uk/2/hi/health/6236282.stm I've previously posted about this product

4* ICX-TRC= a hair regeneration product - in a Phase II trial

http://www.intercytex.com/icx/services/dow...cx-trc_0106.pdf

For hair regeneration in male-pattern baldness, has completed a Phase I safety trial and applications are being prepared to commence a Phase II efficacy trial in mid-2006.

All Intercytex' products are derived from unmodified human cells.

==========================================

So, although Vavelta is not directly intended to treat scars, but rather wrinkles, it shows that Intercytex are slowly rolling out their pipeline of products and hopefully ICX-SKN is not too far away and will show great results for wound healing and scar-free healing. Moreover, as Vavelta is supposed to smooth out skin it actually might work as a temporary solution for depressed scarring.

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What is New in Wound Healing?

March 2004

Despite being a few years old, this article is great at illustrating the various factors that are encountered during wound healing. It basically indicates that wound healing is multi-factoral and thus I believe provides further evidence that Renovo should have combined both Juvista and Juvidex into a single product rather than two different ones. As a result, when I obtain the TGFb3, I will make sure I also use Mannose-6-Phosphate to inhibit the TGF1+2 at the same time to greatly increase positive chances.

http://journals.tubitak.gov.tr/medical/iss...-3-1-0403-2.pdf

Abstract

Wound biology is complex. Wounds which were until recently seen only as defects in tissues are now increasingly interpreted in cellular and molecular terms. Growth factors, cytokines, proteases and adhesion molecules which participate in wound healing are discussed in this article. From a clinical perspective, conceptual shifts of importance, including moist wound healing, wound bed preparation and wound assessment, are presented. The frontiers of therapeutics employed in wound healing continue to advance with an increasing array of modalities joining the ranks at a regular pace. A range of currently available as well as evolving therapiesÐ physical (topical negative pressure therapy, warming, electrical stimulation), biological (larva therapy, skin substitutes, stem cell therapy, growth factors, gene therapy) and of a miscellaneous variety (hyperbaric oxygen, dressings)Ð are appraised.

Important excerpts from the article:

Wound healing is a collaborative process involving a variety of cells and matrix components which need tointeract continually towards a common goal. Growth factors, cytokines, proteases and adhesion molecules, which are discussed here, are but a few examples of substances by which cells conduct a molecular talk and engage in interactive cascades. Normal wound healing is heavily dependent on a plethora of growth factors and cytokines which variably interact with cells and the matrix at different stages. Use of growth factors topically to augment wound healing, although a very intuitive prospect, is fraught with difficulties for the following reasons:

* The multitude of factors involved

* Problems in matching the spatial and temporal profile found in wounds

* Rapid degradation in the wound by proteases

* Lack of a vehicle for sustained release

* Cost

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Secret Squirrel Reporting with article by Bernadette Condren, you will have to beat me for me to give up my sources and even then I won't:

Fetal protein holds key

In a world first, Brisbane scientists have found the key to scarless healing. Bernadette Condren reports

08oct05

CHILDHOOD burns are among the most horrific and most preventable accidents.

A pot pulled from a stove, a hand on an open barbecue, a steaming cup dragged from a benchtop â€â€œ scarring can be for life.

Minor burns that heal within two weeks heal without leaving a scar.

More severe burns, known as partial-depth burns, can take years of treatment, exacting a toll on the child and its family so immense that it is life-changing.

Roy Kimble is a quiet Scotsman with a great passion. He wants to create a treatment that will minimise, even eradicate, scarring from burns wounds.

And he's close. Very, very close.

In a world first, Dr Kimble and his team of scientists at Brisbane's Royal Children's Hospital have found that a protein called fetuin is a major player in the scarless treatment of burn wounds.

Those who will benefit from Dr Kimble's research are not only children, but also adults who have severe burns, such as those sustained during the Bali bombings.

Experts have known for many years that babies who have surgery while still in the uterus, and babies born very prematurely and who have surgery, heal without scars.

This was the scrap of information Dr Kimble and his team began with when their research project started in 2000.

"We asked: 'OK, a fetus can heal an incisional wound without scarring, but can it heal a burn without scarring?' " Dr Kimble recalled. "That was the first thing we set out to prove."

And they did.

In another world first, the Royal Children's Hospital Burns Research Group â€â€œ which is funded by the hospital's foundation â€â€œ used fetuses in sheep to prove the theory.

The quest for the holy grail of scarless healing had truly begun.

They set out to establish which proteins differed between the skin of a lamb in the womb and the skin of a lamb after birth. The first protein identified as being present in the fetus but largely absent in the lamb, was fetuin.

Fetuin has been pretty much ignored by the scientific community since it was discovered almost 70 years ago, but its days of obscurity are over. After identifying fetuin as a major player in scarless healing, the team in the burns lab created an artificial wound.

They grew a cell culture, scored it to create a gap in the cells then watched it to determine how long it took for the cells to close the gap. They repeated the process, adding fetuin to the next culture they grew.

Again they timed how long it took for the gap to close. The difference was significant â€â€œ significant enough for Dr Kimble to patent the protein.

"Nothing closes a wound like fetuin does, so we know it has some very important qualities," Dr Kimble said.

At the University of Queensland's St Lucia campus there is a pig that hundreds of thousands of parents around the world will never know about but when they thank God that the hot cup of coffee their toddler has tipped on his or her head can be treated in such a way that there will be no scarring, it's the pig they should be thanking.

"We're in the middle of testing fetuin on our burns model," Dr Kimble said.

"We've recreated the deep thermal partial-thickness burn that you see in a child, which will heal on its own but will take more than two weeks to heal and always heals with scarring. We're currently testing fetuin on our animal model to see whether it will make wounds heal faster and with less scar tissue."

This trial is going so well that human trials have been pencilled in to start in 2007.

Current treatment for burns include patients having to wear pressure garments to prevent scar tissue from building up. Sheets of silicon are put over the wound before the garments are put on.

They have to be worn 24 hours a day and in the uncomfortable heat of Queensland's long summers.

If the scar is over a joint, the child will develop a contracture requiring surgery until they stop growing. Even then, they may not develop the full range of movement in the joint because scar tissue does not grow like normal skin.

"If we can use fetuin to reduce scarring, a lot of that is not going to be necessary," Dr Kimble said. "If you can get a wound to heal nice and fast at the beginning, you don't need all the pressure garments, silicon and repeated surgeries."

Fetuin would be applied as a topical cream and would provide a salve not only for the patient but also for parents.

"Because the vast majority of burns in kids are household accidents that are totally preventable, the parents feel very guilty and will probably feel guilty for the rest of their lives," Dr Kimble said.

As head of the burns unit, Dr Kimble shakes his head in despair because, he says, 99 per cent of the burns he sees are preventable.

"I do the research just to make things better," he said. "But if it can be prevented from happening in the first place â€â€œ that's the best."

Damn you posted it before me. It is probably the same secret source that I got the same article from.

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BTW, have any of you lot heard anything about the insulin that 'RAFT' a british charity are researching? As I'm sure they will soon be publishing their trial data.

Here are two website you could read up on. One is an archived earlier raft web page, and the other is the current RAFT website.

http://web.archive.org/web/20060416083315/...h/vascular.html

www.raft.ac.uk

Cheers and happy researching,

Kirk

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BTW, have any of you lot heard anything about the insulin that 'RAFT' a british charity are researching? As I'm sure they will soon be publishing their trial data.

Here are two website you could read up on. One is an archived earlier raft web page, and the other is the current RAFT website.

http://web.archive.org/web/20060416083315/...h/vascular.html

www.raft.ac.uk

Great post Kirk, thank you very much; this is the first time I've heard about RAFT. It's oh so great to know that there is an impartial institution out there setup to look into "The Restoration of Appearance"...God do I need a lot of that ;)!

It's so reassuring that this trust's main goal is to improve the well being of people instead of just making profit! In fact, I might make a donation to them as I'm sure they need all the support they can get :dance:.

On their main site at Raft.ac.uk, it states:

We are engaged in the complex task of developing a prototype skin scaffold that incorporates this new component. The aim is that this will lead to the development of a second-generation artificial skin that accelerates healing and reduces scarring to produce a material which improves upon those currently available, both accelerating the initial healing process and ultimately resulting in a normal skin structure.

This is very similar, if not identical, to the research that Intercytex is currently carrying out for their product> ICX-SKN (being developed as a durable and robust skin replacement). I wrote about this product a few posts up...very interesting.

On their anti-scarring approach, RAFT's site isn't entirely specific about what exactly they are planning to use to prevent scarring:

http://www.raft.ac.uk/research_burns.htm

All they really say is:

The work has helped to identify a promising anti-scarring agent that the team has now put into clinical trial and we are eagerly awaiting the results.

The team have discovered that scarless healing can take place because the response to a number of wound healing factors is not only more rapid than in ‘normal healing’ but also more short-lived. This transient response may be the reason why and could provide a new approach to our battle against scarring.

Kirk, you mention something about them researching Insulin and I tried clicking on the second link you provided but the page is unaccessible:

http://web.archive.org/web/20060416083315/...h/vascular.html

It might have something to do with the ...h not being fully typed out, can you confirm that the above link is correct as it would be great to read, thanks!

[EDIT: I got the correct link now thanks: http://web.archive.org/web/20060416083315/...h/vascular.html]

I've found an interesting research paper in the BMJ (British Medical Journal) which was presented at RAFT Institute of Plastic Surgery and dated August 1998:

http://www.pubmedcentral.nih.gov/articlere...i?artid=1113673

It makes the following valid points:

Strategies currently under investigation to provide a cultured skin substitute include the use of collagen matrices seeded with cultured fibroblasts and covered with autologous keratinocytes. Such work is likely to lead to the ultimate goal of the “off the shelf skin replacement.â€

and...

The highly visible effects of scarring have focused attention on wound healing in plastic surgery.

A sequence of growth factors and cytokines released after injury controls wound healing. In fetuses, wounds heal with a reduced inflammatory and angiogenic response and without scarring[21]. By manipulating the concentrations of transforming growth factor β (TGFβ) in wounds in adult human skin, scar formation can be reduced[22]. This has not yet been applied in regular clinical practice, but research in this area points the way towards a solution to this difficult problem.

REFERENCES:

>21.Lorenz HP, Longaker MT, Perocha LA. Scarless wound repair: a human fetal skin model. Development. 1992;114:253��“259. [PubMed]

>22.Shah M, Foreman DM, Ferguson MWJ. Neutralisation of TGFβ1 and TGFβ2 or exogenous addition of TGFβ3 to cutaneous wounds reduces scarring. J Cell Sci. 1995;108:983��“1002.

So it seems the future of scarless healing almost certainly lies on two main paths:

>One where synthetic skin is created and 'implanted' on the wound

>And one where the TGFs are manipulated along with Cytokines and Fetuin (presumably).

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BBC NEWS | Skin cells 'fight child cancer' | Saturday, 7 July 2007

http://news.bbc.co.uk/1/hi/health/6268840.stm

Genetically modified skin cells could be used to fight a cancer which strikes the very young, a UK study suggests.

Scientists at UCL said they were able to stimulate the immune system of mice by injecting the animals' skin cells into a neuroblastoma tumour.

Once the skin cells were genetically modified they became "little factories" producing a sort of protein which helped the immune system, said lead researcher Dr Stephen Hart. When they were injected into the tumour site, these cells apparently helped the mouse fight the cancer

Okay, this is a pretty left-of-field idea/thought that I have but it came about after having read the above article. If scientists can genetically modify skin cells to specifically and only attack tumours then surely they can pre-program skin cells to also only attack scar tissue in a way that they are almost able to consume the fibroblast structure of scars?

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Wow that looks great! Is it expensive?

supposedly it's going to be around 270 something I believe. The thing is though I don't mind saving up money to get it but hopefully it's permanent and actually produces some results. ><;; I don't want to pay for something which works for a few weeks or doesn't even work at all.

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Wow! Everyone has been so busy! Let’s get right into it~

Neca wrote:

“Anna, I'm not sure whether Fetuin's modus operandi is really in fact to remove scar tissue. “

I think you are right, in that that is the main focus, but I’m still looking for a glimmer of something that will allow regeneration without first having to go through something traumatic like excision, dermabrasion or a chemical peel. I can’t help but think that if it can prevent it scar tissue from forming it might also be able to catabolize it. This is maybe just a hope and a dream. The only thing I have seen which has shown anecdotal evidence of being able to do this is Topirimate (Topamax), but I don’t want to mess with my mind in the off chance it will help scarring. I am going to see if I can find or have formulated a topical version of Topirimate made by a compounding pharmacist. I would also love to try applying Fetuin or TGF B3 on an existing scar just to see what it would do.

Neca wroteâ€

“Yes you can differentiate between scar tissue and normal skin tissue at a microscopic level. Scar tissue is much more fibrotic with tightly woven strands holding the tissue close together. “

Again you are right, but I believe they are able to do this in their histology reports by staining the sample with the Von Giesen stain. It discloses the fibronectin and stains it blue. If there is any scar tissue left I believe it will impede regeneration. I think that scar tissue is so calcified that the body cannot easily consume it.

Neca wrote:

“* ICX-TRC= a hair regeneration product - in a Phase II trial

http://www.intercytex.com/icx/services/dow...cx-trc_0106.pdf

For hair regeneration in male-pattern baldness, has completed a Phase I safety trial and applications are being prepared to commence a Phase II efficacy trial in mid-2006.â€

This is interesting. It has long been said that if you can regenerate hair you can regenerate skin.

Neca wrote

“o, although Vavelta is not directly intended to treat scars, but rather wrinkles, it shows that Intercytex are slowly rolling out their pipeline of products and hopefully ICX-SKN is not too far away and will show great results for wound healing and scar-free healing. Moreover, as Vavelta is supposed to smooth out skin it actually might work as a temporary solution for depressed scarring.â€

I hope you are right!

Neca wrote

Important excerpts from the article:

Wound healing is a collaborative process involving a variety of cells and matrix components which need tointeract continually towards a common goal. Growth factors, cytokines, proteases and adhesion molecules, which are discussed here, are but a few examples of substances by which cells conduct a molecular talk and engage in interactive cascades. Normal wound healing is heavily dependent on a plethora of growth factors and cytokines which variably interact with cells and the matrix at different stages. Use of growth factors topically to augment wound healing, although a very intuitive prospect, is fraught with difficulties for the following reasons:

* The multitude of factors involved

* Problems in matching the spatial and temporal profile found in wounds

* Rapid degradation in the wound by proteases

* Lack of a vehicle for sustained release

* Cost

All of this is correct, but it is so frustrating in knowing that if we could just use gene therapy we could incite our cells to play conductor to have this symphony of regeneration occur naturally and perfectly as it did in the womb our troubles would be over and we wouldn’t need to do this manually. This is what DARPA is trying to do with it’s attempt to create a blastema (remember the mouse ear : ). It they can do that they will be able to regenerate not only skin but limbs. I still would love to hear what Professor Ferguson says about all of this. Especially where he was saying that skin is pretty simple!!!

Kirk wrote:

Damn you posted it before me. It is probably the same secret source that I got the same article from.

LOL : )!

Kirk wrote: BTW, have any of you lot heard anything about the insulin that 'RAFT' a british charity are researching? As I'm sure they will soon be publishing their trial data.

Here are two website you could read up on. One is an archived earlier raft web page, and the other is the current RAFT website.

http://web.archive.org/web/20060416083315/...h/vascular.html

www.raft.ac.uk

Cheers and happy researching,

Kirk

This is really interesting Kirk, and I agree it is wonderful to see an organization not involved with a big pharmaceutical company in the mix.

Neca wrote:

The team have discovered that scarless healing can take place because the response to a number of wound healing factors is not only more rapid than in ‘normal healing’ but also more short-lived. This transient response may be the reason why and could provide a new approach to our battle against scarring.

This is where things might start to get murky. I have read that diabetics with non healing wounds are actually lacking TGFB1 which we understand to be the scarring factor. When it comes to scar free healing I have come to the understanding that we want slow and perfect.

I am deep into research on Fetuin, barring gene therapy it looks like the most promising thing on the horizon. I am also revisiting the Topirimate (Topamax) drug. I am wondering if it were formulated as a topical cream it could be effective without the cognitive impacts the oral version has. If you haven’t read this study there was a thread posted here some time ago. The pictures are a little iffy with the angle too, but still…http://dermatology.cdlib.org/95/original/scars/shapira.html


We search for more answers because the ones we have found are not to our liking.


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What do you lot think this text in the quotes below translates to with regards to fetuin in a fetus?

Excuse me, basically as I'm impatient and crap at reading and deciphering medical text, heh, heh, heh and thus to infuriate you lot I'll leave this up to Anna and Neca et al if they so wish to read it etc. :shifty:

A question, do the adjusting fetuin levels in fetuses correlate very close to the known time limits in fetal scarless healing with regards to various soft tissues in the fetus???

So hence do the higher levels seem to taper off in much the same patternistic way as scar free healing regeneration slowly turns to a scarring response in the fetus round about day x etc.?

Note: they didn't seem to measure the fetuin levels in skin, unless of course there is a clever medical name for skin in this text?

http://www.springerlink.com/content/w5076r527j30h285/

N. R. Saunders1, 2, A. Deal1, K. M. Dziegielewska1 , M. Reader2, S. A. Sheardown3 and K. Møllgård4

(1) Department of Physiology, University of Tasmania, GPO Box 252C, 7001 Hobart, Tasmania, Australia

(2) Clinical Neurological Sciences, University of Southampton, Southampton General Hospital, Tremona Road, SO9 4XY Southampton, UK

(3) Section of Comparative Biology, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, DuCane Road, W12 ONN London, UK

(4) Institute of Medical Anatomy, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark

Accepted: 7 September 1994

Abstract Tissue distribution and developmental expression of fetuin were studied in the sheep fetus from embryonic day (E) 30 to adult (gestational period is 150 days). The presence of fetuin was demonstrated immunocytochemically using anti-fetuin antibodies; in situ hybridisation using short anti-sense oligonucleotide probes labelled with digoxigenin was used to study the ability of the developing tissue to synthesise fetuin, and reverse transcription-polymerase chain reaction (RT-PCR) was used to estimate the level of fetuin mRNA in selected tissues. Tissue distribution of fetuin was widespread in the younger fetuses (E30 to E40). The most prominent presence due to in situ synthesis was demonstrated in the liver, central nervous system (CNS) including anterior horn cells, dorsal root ganglia and in skeletal muscle cells. Other developing tissues and organs that showed evidence of fetuin synthesis and presence of the protein included mesenchyme, kidney, adrenal, developing bone, gut, lung and heart. In the immature liver (E30â€â€œ40) there was a strong signal for fetuin mRNA in hepatocytes and also in numerous haemopoietic cells; the proportion of these latter cells that was positive for fetuin mRNA increased between E30 and E40. Only some hepatocytes and a proportion of the haemopoietic stem cells were immunoreactive for fetuin itself at E30â€â€œ40; immunoreactive hepatocytes were more frequently observed in the more mature outer regions of the developing liver. Lung and gut contained scattered fetuin-positive epithelial cells, especially at E30; a weak fetuin mRNA signal could be detected above background in many of these cells up to E40, but not at E60â€â€œE115 or in the adult. Particularly at E30 to E40, mesenchymal tissue both within organs such as the gut and lung and around forming bone and skeletal muscle contained cells that were positive for fetuin mRNA. Mesenchyme at these ages was also very strongly stained for fetuin protein, much of which may reflect fetuin in tissue extracellular spaces and be derived from the high concentration in plasma. By E80 fetuin mRNA was mainly present in the liver and the CNS; staining of the muscle tissue was becoming less pronounced. However in developing bone tissue, staining of chondrocytes for fetuin mRNA was still prominent in older (E80) fetuses; there was also fetuin protein staining of chondrocytes at the growing surfaces of bones and in bone marrow at this age. In the adult, weak immunocytochemical staining for fetuin itself was present in hepatocytes, but the mRNA signal was barely above the threshold limit of detection. Other tissues in the adult were generally negative for both fetuin mRNA and fetuin, except that fetuin could generally be detected immunocytochemically in precipitated plasma within vessels in many tissues and in their interstitial spaces. The highest levels of fetuin mRNA, as demonstrated by RT-PCR, were detected in E40 and E60 liver followed by E40 muscle. The very low level of fetuin mRNA in adult liver, evident from in situ hybridisation, was confirmed by RT-PCR (about 0.1% of that at E60). These results show that in many tissues in which fetuin could be demonstrated immunocytochemically, its presence is likely to be due to synthesis in situ. However in some instances (e.g. gut and mesenchymal tissue) fetuin probably originates predominantly by uptake from plasma or extracellular fluid. The functional significance of the presence of fetuin in different tissues during their development is considered.

--------------------------------------------------------------------------------

K. M. Dziegielewska

Phone: 002 202678

Fax: 002 202679

Cheers and happy researching,

Kirk

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You are right Kirk, they don't mention the epidermis or dermis. And, you are right in that the Fetuin levels gradually decrease just as TGF B3 does as the fetus progresses to the end of it's gestational period.

I don't want to be doing all this research either. I would be thrilled if somebody more educated than I seemed genuinely more interested in progressing toward translatable (into effective cures) research than profits, but because I don't trust that to be the case, we are left to stumble toward our own answers... AND, I think we are getting there! :dance:

All my best!

Anna


We search for more answers because the ones we have found are not to our liking.


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Another interesting tidbit. I mentioned I am looking into Topirimate (Topamax) and see that it is a sodium channel blocker, so I also looked into calcium channel blockers (since I've learned that calcification is high in scarring and we know that Fetuin is the most effective calcium inhibitor there is) and look what I found: http://www.pharmcast.com/Patents/Yr2002/Ma..._Scar030502.htm

Apparently, they are using these to stop scarring in surgeries....interesting!

Plodding on...

Anna


We search for more answers because the ones we have found are not to our liking.


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