Scarless Healing Faq

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Table of Contents

Summary of the thread ................................................................................................................................. 3

Summary 1 ................................................................................................................................................ 4

Scar Free Healing Thread Introduction 1.0 ................................................................................................... 6

1. Informed Education .................................................................................................................................. 7

1.1 Scarring and Regenerative Pathway ................................................................................................... 8

2 Technical Processes And Factors That Can Be Used in Scar Free Healing in Adult Tissues ..................... 16

2.1 Removal of Scar Tissue...................................................................................................................... 17

2.2 Inhibiting Fibrosis .............................................................................................................................. 18

2.2.1 ECM in Inhibiting Fibrosis ........................................................................................................... 19

2.2.2 Oligo ........................................................................................................................................... 20

2.2.3 Decorin Inhibiting Fibrosis ......................................................................................................... 21

2.3 Antibacterial Factor in Scar Free Healing Concept ........................................................................... 34

2.3.1 ECM Antibacterial Profile ........................................................................................................... 35

2.4 Inhibiting Inflammation .................................................................................................................... 36

2.4.1 Fetuin ......................................................................................................................................... 37

2.4.2 ECM in Inhibiting Inflammation ................................................................................................. 40

2.5 Growth Factors ................................................................................................................................. 41

2.6 Stem Cells .......................................................................................................................................... 42

2.6.1 ECMs & Stem Cell ...................................................................................................................... 44

2.6.2 Progenitor Cells/Stem Cells ........................................................................................................ 45

2.7 Extracellular Matrix ........................................................................................................................... 47

2.7.1 Hindsight View With Regards To A Fibrin Contaminated UBM ECM ......................................... 65

3. Various Predictions ................................................................................................................................. 93

4. Advancements (Please Read) .................................................................................................................. 95

5. Anticipation ........................................................................................................................................... 100

6. External links ......................................................................................................................................... 101

7. Linked threads ....................................................................................................................................... 102

8. FAQs ..................................................................................................................................................... 103

9. Current & previous pdfs of thread material, pre-amendments ........................................................... 104

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9.1 Tom_Masons Original introduction: ............................................................................................... 104

10. Template Letter Headings and Bodies ................................................................................................ 105

Works Cited ............................................................................................................................................... 106

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Summary of the thread

The summary is not yet consensus, and makes no claims to be consensus of acne.org, and no

editor claims to be an authority on this subject. There are other summaries. Spaces are always

there for other summaries for posters to write as to how they see it.

The summary here is a logically strong summary and validated by cited sources in this fact file.

(Please note: being valid does not say it is the truth. However the first summary that is cited

below, is a strong as you can get and shows it is certainly here and every angle has been

covered, the odds on it not being here must be one against a one with many zeros when you

connect. A lot of people may agree the first summary is very close to 100%. And it is other

peoples interests to come on to the board and prove it is not here if they want it gone). There is

a chance for you to write your summary as to how you see it.

Over time who knows we may have a consensus summary, as well as personal summaries,

trying to use sourced logic. Try to use cites and maybe we can reach consensus, slowly overtime.

Note this is not advice, this is cited/non cited information on scar free healing, if you need

advice seek a professional. And hope this professional is informed; there are professionals who

are more informed than the next and so on.

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Summary 1

This thread is a discussion about the scar free healing concept. Scar free healing that for many,

will soon end disfigurement with regards to fibrosis of the fibrils.

Over the last ten year there have been claims and predictions ranging from 2007 to 2012 when

scar free healing of the fibrils will be here. (1) And over this time there have been massive

advancements...

In this thread we have seen that a lot of progress has been made, we have seen and discussed

the logic of various materials and factors, we have seen there are now applications that inhibit

inflammation and fibrosis; we have seen animals using ECM regenerate skin and hair without

strictly following a course of treatment; we have briefly hit on a component in ECM called

decorin that completely inhibits scarring, reduces wound contraction, keeps the ECM fibrils in a

normal slender woven elastin state which enables tissues to freely crawl up the ECM without

being blocked by over expression of collagen on the fibrils and we understand our tissues have

been regenerating with these slender fibrils through evolution; in 1999 scar free healing

concept was first achieved and proven when a bladder (a simple tissue like skin, Badylak, Atala

et al) regenerated (note: you can NOT have any regeneration with any fibrosis,Atala); in 2007 a

denatured 1st generation SIS ECM, denatured by a metal rim, regenerated heart tissue 95%,

bringing a further taster about the next generation ECMs (UBM-ECM) potential with our softer

tissues, considering our scarring process is the same in all our tissues. (there is a newer version

in development without the metal rim which will enable 100% resoring in the heart); We have

looked at stem cells; We have seen complete scar free healing; and in 2008 we were shown

science had announced that the genetic factors involved in perfect regeneration are

understood and can be manipulated (Heber-Katz) (note, again: you can not regenerate anytissue if you have fibrosis to paraphraseAtala law) meaning as well as having the mammal

materials to bring scar free healing we understand the micro processes of these materials In

this thread we have seen Scar free healing has been achieved and is completely understood, and

is now even understood at a micro level.

The reason for this introduction is to show new users, by cites, scar free healing, please read on

and make your own mind up.

Summary 2,

yet to be written

Summary 3,

yet to be written and so on.

Consensus summary,

yet to be written.

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Regarding all the text outside the quote boxes, below, it is free, you are free to copy, edit and do what you want;

Permission is granted to copy, distribute and/or modify this document under the terms of the GNU Free Documentation License, Version 1.2 or

any later version published by the Free Software Foundation; with no Invariant Sections, no Front-Cover Texts, and no Back-Cover Texts. A copy

of the license is included in the section entitled"GNU Free Documentation License

The quoted boxes are quotes and links used as citations from intellectual property, they can be used without modification for cited educationalpurposes:

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Scar Free Healing Thread Introduction 1.0

Scar Free Healing was once described as a concept were you bring the healing response to

perfect regeneration, a process once described as the Holy Grail. (2)

Fetal protein holds key

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

http://www.news.com.au/couriermail/story/0,23739,16844871-3102,00.html

Before it come about, perfect regeneration and scar free healing was once described as a

simple problem that would release the torture of disfigurement and mobility that involves

scarring of tissues.

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1. Informed Education

There is information out there, but also misinformation. There is a need to educate about the

advancement scar free healing and how it is here. (3)

A Scarless Future: The Wound Care Update Paper 2006, pdf - P. 3

Experts remain optimistic about the future of the category, predicting a world without scars.

Research and education will be critical to the advancement of wound care practices.

Note: the above paper is now off line.

With this there is also a need to scientifically and logically think.

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1.1 Scarring and Regenerative Pathway

In healing, without intervention an adult wound, scars. A scar is collagen over expression that

blocks off regeneration. (4) In adult tissues there is a race between scarring and regeneration to

which scarring usually wins by over expressing collagen on the fibrils, these dense fibrils thenblock the pathways for regeneration In regeneration the fibrils in our tissues should be

slender.

The scarring response amongst our softer tissues is said similar in all tissues of the body. (5) (6)

And all our tissues have the ability to regenerate in them. With the bladder and skin being

simpler tissues man has already regenerated. This gives hope for more complex tissues and

digits which will come after.

To regenerate tissue it is noted you have to eliminate the scar, (4) as in tissue engineering,

everything goes back to scar tissue formation. (4) You cant regenerate tissue if you get a

fibrotic response. Scar tissue stops the intercellular tissues regenerating. (4) (6)

(and the scar free healing concept was officially proven in 1999, (4) be it under the radar, with a

bladder (4) (a simple tissue like skin badylak et al) which was perfectly regenerated with

ECM!!!)

Take note of the Atala law: It all leads back to the scar. Eliminate the scar and you can

regenerate tissue, even digits and complex organs. You dont eliminate the scar you cannot

regenerate tissue. (4) If you remove the scar you can regenerate simple tissues and move onto

regenerating organs and limbs

Scar-free healing: from embryonic mechanisms to adult therapeutic intervention." (2004-

04-20), p. 2.

glomerulonephritis, pulmonary fibrosis, etc., which share many of the cellular and molecular

mechanisms common to scarring.

http://www.renovo.com/documents/radF37FC.pdf

Profile: Anthony Atala - Nature Biotechnology

"In tissue engineering," Atala says, "everything goes back to scar formation."

Google search, Atala goes back to scar

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http://www.nature.com/nbt/journal/v24/n11/full/nbt1106-1311.html

As you can see above scar free regeneration concept was done in 1999 under the radar.

Humans can regrow fingers?It employs an entirely different process than the typical mammalian healing mechanism. Let's take the case of a

person who loses the tip of a finger. When the finger is severed, the cells die, and their contents seep into the

surrounding tissue. This alerts theimmune systemto a problem. The immune system's response to cell death is

inflammation and scar tissue. The formation of scar tissue prevents any future cellular development in the area.

That's why scars last -- cells are prevented from doing a repair job on that skin.

http://health.howstuffworks.com/extracellular-matrix.htm

As well as scar free healing in non wounded tissues, it has been cited many times scar free

healing occurs in the embryonic stage of all mammals, animals and reptiles. This stage is called

the gestation period, and this critical scar free healing period ranges from the first one third or

first half of pregnancy in mammals. It is in the first three month of pregnancy in humans. (7)

Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. (2004-04-

20), p. 2.

Skin wounds on early mammalian embryos heal perfectly with no signs of scarring and

complete restitution of the normal skin architecture

http://www.renovo.com/documents/radF37FC.pdf

It has been cited that regeneration of injured tissue happens in some body parts like the liver

and mouth. And it was noted that the small tubular intestine of a dog, when transplanted to

replace a dogs heart aorta, completely reabsorbed and morphed into the host aorta tissue. (8)

A Doctor, a Pig, and a Magical Pixie Dust That Could Regrow Fingers

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the new part of the aorta, he discovered that the intestine had not become simply a tube to pass

blood through but had literally morphed into an aorta. And no scar tissue had formed.

http://www.esquire.com/features/esquire-100/pigfinger1007

The Axolotl Urodele amphibian came to attention, this Salamander has mastered the ability to

repair and replace most of their tissues following damage. (9) It is cited that the salamander can

regenerate wounds and limbs by forming blastemas, (10) and it was found by Ellen Heber-Katz

that the Murphy Roths Large mouse (MLR) heals without scarring on certain regions its wild

field compatriot does not. (11) It is of note that the MLR mouse has shown signs of blastema

(ECM) formation in lost limbs too. And blastemas are found extensively in the human fetus but

are less prone after birth in wounded tissue. (12)

Humans can regrow fingers?But when extracellular matrix is applied to a wound, it doesn't trigger an immune response. Instead, when it begins

to break down into surrounding tissue, it causes the cells in that tissue to start repairing the damage the way they

would in a developing fetus (or a salamander that loses a limb) -- they divide and rebuild, creating new, normal

tissue, not scar tissue.

http://health.howstuffworks.com/extracellular-matrix.htm

"Researchers Work Toward Regenerating Lost Extremities",

""You pull a tail off a salamander, and it regrows," Wolf said. "The end of the tail forms what is

called a blastema, and that blastema elongates. We think that's what happens when we put

this powder on."

http://www.infozine.com/news/stories/op/storiesView/sid/30243/

"Mouse sheds light on regeneration",

"So we did it again, and we watched them, and there it was - the holes had closed up.

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http://news.bbc.co.uk/1/hi/sci/tech/4888080.stm

Humans to grow replacement body partsBlastemas are found in human foetuses but disappear after birth. Regenerative medicine would

allow a genetic trigger to be applied to tissue to prompt cells to grow into the required parts.

http://www.timesonline.co.uk/tol/news/uk/science/article3867838.ece

Research has focused on the Embryonic stage, liver, mouth, the salamander, the MLR mouseand ECM with the intestinal submucosa, liver, and latterly the uninary bladder. And has

developed key insights, bringing predictions of scar free healing over the last ten year; with

experts also claiming to have seen scar free healing in 2002. (1) A case in point in 2007 using an

earlier ECM with a metal rim that was also denatured, achieved a 95% average regeneration of

our more complex tissues (13) (what happens in the heart would easily happen in simple

tissues), the only thing that was left was the metal ring and the ECM morphed into tissue, a

newer version that promises 100% healing without the metal rim is being developed; between

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years 2003 and 2005 complete scar free healing was shown with Alloderm; (14) and in 2008

Heber-Katz, the scientist who in 2006 announced digit regeneration would be here within five

year, announced the genetic characteristics of perfect regeneration had been achieved and

manipulated (15) meaning every angle is now covered. And in figure x you can see an example

of perfect regeneration of a melanoma patient using a denatured ECM called apligraf.

A Scarless Future: The Wound Care Update Paper 2006, P. 5, pdf

Professor Kimble believes may be a reality within the next four years.

The proper treatment of wounds and ways to minimize scarring, 2003, P. 25, pdf

I can show you scarless healing... Dr Peter Maitz, Director of Burns Unit, Concord Hospital

I think its within the foreseeable future...five to ten years. Geoff Sussman, Founder and

Director of the Wound Education & Research Group,

Monash University

Biologically itshould be feasible to have tissue heal perfectly. Professor John Harris, Head of

Department of Surgery, Sydney University

First Ever Implantation of Bioabsorbable Biostar Device at DHZB

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The almost transparent collagen matrix consists of medically purified pig intestine, which is

broken down by the scavenger cells (macrophages) of the immune system. After about 1 year

the collagen has been almost completely (90-95%) replaced by normal body tissue: only the tiny

metal framework remains. An entirely absorbable implant is currently under development.,

DHZB NEWS, December 2007

http://www.dhzb.de/international_services/dhzb_aktuell/detail/ansicht/pressedetail/290/

The Use of Acellular Dermal Matrix for Coverage of Exposed Joint and Extensor Mechanism in

Thermally Injured Patients With Few Options

http://www.eplasty.com/article_images/eplasty08e33_fig1.gif

http://www.eplasty.com/index.php?option=com_content&task=view&id=213&Itemid=36&sect

=15

Humans to grow replacement body parts

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her group had discovered the genetic characteristics that produce good-as-new tissue

regeneration

http://www.timesonline.co.uk/tol/news/uk/science/article3867838.ece

the key to changing the scarring response in wounded tissue, to regeneration, involves getting

the body to sense it is not injured and does not need excess collagen. Our unwounded tissues

and embryonic tissues proved to man this would lie in the course of the wound healing, early

timing, inhibition of the inflammation response, and the availability of available factors, given at

the time of wounding for the regeneration pathway instead of the scarring cascade pathway. To

reiterate the wound needs to understand it is not injured and it has to regenerate like it does

non wounded. These early insights brought forward that early intervention around the initial

time of wounding can alter the scarring response, with the early window being a criticalwindow for a scarring pathway to a regeneration pathway. (16)

The proper treatment of wounds and ways to minimize scarring, pdf - P. 6

The time taken to heal a wound is directly related to how that wound will scar the best time

to treat a scar is during the initial phases of wound healing.

There are said to be a number of processes and factors said to be involved in the non wounded

tissue and the embryonic stage and tissue engineering that brings scar free healing that can be

manipulated in wounded adult tissues to bring about scar free healing. These factors are micro

factors involved in ECM and components of ECM like decorin, hyaluronic acid etc.:

*Growth Factors for pathways

*Inhibiting fibrosis

*Inhibiting Inflammation

*Stem Cells

*Timing, immediate implantation of factors at wounding by appointment is preferred.

**Extracellular matrix, the material matrix, that is not denatured and thus has slender fibrils,

regenerates all local tissues, and controls timing of factors, brings in stem cells, if notdenatured, it resorbs, inhibits fibrosis, it inhibits inflammation. It controls morphology and cell

shape, differentiation. On the other hand, if denatured it finds it harder to resorb and attracting

collagen over expression in the fibrils which brings a fibrotic response or an encapsulation

fibrous response which blocks of intercellular signaling. The denaturing of ECM affects the

fibrosis/regeneration balance.

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**Decorin a component of ECM has completely inhibited scarring in tissues keeping the fibrils

slender.

It is known our tissues are clever they have been regenerating for thousands of years, and all

our intercellular tissues need is slender fibrils in the degradable scaffold (ECM). (17)

U.S. military can regrow human limbs, organs

American military researchers say they have unlocked the secret to regrowing limbs and

recreating organs in humans who have sustained major injuries.

'Nanoscaffolding' has succesfully regrown fingertips and organs on test subjects

Friday, November 07, 2008

http://www.canada.com/topics/news/story.html?id=6864c9e0-cfcc-4cf6-b373-6d4cbabe6cd3

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2 Technical Processes And Factors That Can Be Used in ScarFree Healing in Adult Tissues

There is an understanding, that regeneration cannot happen without scar free healing and scar

free healing involves early application of factors to a wound, inhibiting fibrosis, inhibitinginflammation, inducing stem cells anything encouraging the regenerative pathway, similar to

the early embryonic stage and salamander limb regeneration, or our unwounded adult tissue

state; hence doing all the micro processes of the non denatured ECM.

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2.1 Removal of Scar Tissue

Removing scar tissue. Wounding by appointment. To remove a scar you have two techniques, a

scar revision or, have the scar dissolved with an enzyme, that attacks scarring to make a fresh

wound were the factors can be allowed to remodel without the fibrotic fibers (scarring/collagen

over expression etc.) blocking up the micro pores. (18)

Rebuilding the Troops

researchers have developed an enzyme that eats away scar tissue so they can dust the healthy

cells below.

http://www.popsci.com/military-aviation-space/article/2008-06/rebuilding-troops?page=

It is of note that lack of fibrinolytic enzymes brings fibrosis of tissues. (19)

Anti Fibrosis (Scar Tissue removal)

Fibrinolytic enzymes eat scar tissue and fibrosis

we make a finite amount of enzymes in a lifetime and we use up a good deal of them by the

time we reach our 40's Cystic Fibrosis patients who have virtually no enzyme production to

speak of, even as children usually don't make it past their 20's before they die of the restriction

and shrinkage in the lungs from the formation of fibrosis or scar tissue.

http://www.enzymus.com/scar_tissue_buildup

It is also of note that plasmin is a fibrinolytic enzyme our own body naturally makes. (20)

Eat Natto and Care for Your Cardiovascular System Naturally

The body naturally produces its own fibrinolytic enzyme, called plasmin.

http://www.naturalnews.com/025684.html

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2.2 Inhibiting Fibrosis

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2.2.1 ECM in Inhibiting Fibrosis

Non-denatured ECM, which has decorin, hyaluronic acid, when applied to a fresh wound in the

early stages, going by it regenerates local host tissues, inhibits the fibrosis response. They key is

an early application to a fresh wound without a scar wall.

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2.2.2 Oligo

Oligo decoys (small sugar chains) are natural therapeutics for inhibition of tissue fibrosis. (21)

TGF-beta-induced fibrosis and SMAD signaling: oligo decoys as natural therapeutics for

inhibition of tissue fibrosis and scarring,2007 Sep-Oct

http://www.ncbi.nlm.nih.gov/pubmed/17727468?ordinalpos=4&itool=EntrezSystem2.PEntrez.

Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

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2.2.3 Decorin Inhibiting Fibrosis

Decorin gets its name from the fact it decorates collagen fibrils (22) (fibrils are fibres these

fibres have more fibres within the fibres).

Decorin

Asmallproteoglycan, 90-140kD, of theextracellular matrix, so called because it decorates

collagenfibres.

Thecoreproteinhas amassof approximately 42kDand is verysimilarto the core protein of

biglycanandfibromodulin. All three have highlyconserved sequencescontaining 10internal

homologousrepeats of approximately 25amino acidswithleucinerichmotifs.

Decorin has oneglycosaminoglycanchain, eitherchondroitin sulphateordermatan sulphate

and Nlinkedoligosaccharides.

This entry appears with permission from theDictionary of Cell and Molecular Biology

(11 Mar 2008)

http://www.mondofacto.com/facts/dictionary?decorin

Like ECM, and hyaluronic acid, decorin (a component of ECM) has been studied and a lot of

products are being designed on its micro mechanisms of action.

In wounds it is known there is a race between scarring and regeneration. Decorin stops scarring

by keeping the fibrils slender. Decorin plays a part in non denatured ECM healing. (Question,

would decorin salvage slightly denatured ECM?). It is the factor that tells the ECM Im not

injured, do not scar, and let the ECM be normally woven without the over expression of collagen

on the fibers. Decorin completely hinders the scarring response which enables intercellular

tissues to crawl up the ECM to win the race.

Decorin is a normal human protein, and naturally occurring extracellular matrix protein, a

proteoglycan that has a regulatory effect mechanism over TGF-, and whilst inhibiting TGF-B it

increases the expression of key MMPs that break down the ECM. (23) Evidence shows that

decorin is requiredfor the proper assembly of collagenous matrices

Extracellular matrix: review of its roles in acute and chronic wounds

Proteoglycans can also bind chemokine molecules on the surface of endothelial cells, prolonging

the inflammatory response. Although growth factors typically bind to the GAG chains of

proteoglycans, members of the transforming growth factor beta (TGF-) family bind to the core

protein of the decorin proteoglycan. TGF- directly increases scar formation by increasing the

expression of collagen, fibronectin and lysyl oxidase while reducing the expression of MMPs,

which break down the ECM. TGF- is also chemotactic for macrophages and neutrophils, which

prolongs the inflammatory response and contributes to scarring. When TGF- is bound by the

core protein of decorin it is not able to interact with its normal receptor protein on target cells,

which inhibits the activity of TGF-. Proteoglycans such as syndecan protect elastase from the

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inhibition by alpha-1 proteinase inhibitor, suggesting that they modify the proteolytic

environment of wounds.

http://www.worldwidewounds.com/2005/august/Schultz/Extrace-Matric-Acute-Chronic-

Wounds.html

United States Patent 6509314 - Methods of preventing or reducing scarring with decorin orbiglycan

The advantage of using decorin or a functional equivalent in the methods of the present

invention is that it is a normal human protein and is believed to be involved in the natural TGF-

regulatory pathway. Thus, decorin can be used to prevent or reduce dermal scarring resulting

from burn injuries, other invasive skin injuries, and cosmetic or reconstructive surgery.

Decorin-treated wounds have been found to exhibit essentially no detectable scarring compared

to control wounds not treated with decorin.

http://www.freepatentsonline.com/6509314.html

It has been known since 1992 that decorin causes wound repair in every tissue. (24)

PROTEIN HELPS REPAIR `EVERY TISSUE,' MAY...

``This protein causes wound repair in every tissue,'' he said.THE SALT LAKE TRIBUNE SLTribune , 1992-11-26

http://nl.newsbank.com/nl-

search/we/Archives?p_product=SLTB&p_theme=sltb&p_action=search&p_maxdocs=200&p_to

pdoc=1&p_text_direct-0=10114883EC896EBC&p_field_direct-

0=document_id&p_perpage=10&p_sort=YMD_date:D&s_trackval=GooglePM

In a normal wound healing response, were extracellular matrix is not externally applied,

contraction of wounds is a factor that brings fibrosis. (25)

New mechanical insights into wound healing and scar tissue formation

When we are injured, the body launches a complex rescue operation. Specialized cells called

fibroblasts lurking just beneath the surface of the skin jump into action, enter the provisional

wound matrix (the clot) and start secreting collagen to close the wound as fast as possible. This

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matrix is initially soft and loaded with growth factors. The fibroblasts "crawl" around the matrix,

pulling and reorganizing the fibers. The matrix grows stiffer, and at a certain point, the

fibroblasts stop migrating and, like Popeye, change into powerful contractile cells, anchoring

themselves to the matrix and pulling the edges of the wound together.

The research reported today reveals for the first time that a mechanical mechanism is crucial for

this switch from migrating to contractile cells. To make this change, the fibroblasts need to getat their "spinach" -- the growth factor sitting in the matrix which, once liberated, stimulates the

production of smooth-muscle proteins. Previously, researchers postulated that the fibroblasts

did this by digesting the matrix. But EPFL scientist Boris Hinz, doctoral student Pierre-Jean Wipff

and their colleagues have discovered that the cells unlock the growth factor via a purely

mechanical process. With experiments using novel cell culture substrates of varying rigidity, they

found that at a certain point, the matrix is sufficiently rigid that cell-exerted force allows the

growth factor to pop out, like candy from a wrapper. Once the growth factor is available, the

fibroblast expresses the contractile proteins, sticks more firmly to the matrix and starts to

contract, pulling the matrix tightly together. In the process it liberates yet more growth factor

that in turn stimulates other fibroblasts to become contractile. The mechanical nature of the

switch ensures that the contraction only develops when the matrix is "ready."

Although this process will heal a wound quickly, if left unchecked, it can also lead to a buildup of

fibrous tissue.

http://www.eurekalert.org/pub_releases/2007-12/epfd-nmi121707.php

http://www.eurekalert.org/multimedia/pub/6269.php?from=106535

It is of note: non denatured ECMs Decorin is a solution to contraction and fibroblast

proliferation. Fibroblast proliferation that brings about more parallel collagen bundles (scar

tissue/fibrosis/cicatrices.), to attach to the woven ECM which denies the intercellular tissuesthe scaffold micro pores it needs

Decorin, that is almost absent in adult injury but present in non injured skin and embryonic

skin, that inhibits fibroblast proliferation, is also important in reducing wound contraction. (26)

Regenerative Biology and Medicine

Collagen-GAG mixtures are often used as templates, and it has been found that GAG component

is critical for the activity of the template in inhibiting contraction and promoting regeneration

(Shafritz et al., 1994). Chondroitin-6-sulfate is the commonly used GAG, but dermatan sulfate or

decorin were more effective in reducing contraction and promoting regeneration, perhaps dueto their ability to neutralize TGF-B and mitigate the inflammatory response. One of the best

results, on full-thickness porcine wounds, was obtained with a type 1 collagen/elastin mixture

(Devries et al., 1994)

http://books.google.com/books?id=3Ue5oF3INKsC&pg=PA73&dq=reducing+contraction+decori

n

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Decorin, which inhibits TGFB1 and regulates TGFB1 has been described as a power house in

inhibiting fibrosis. (27)

On internal tissues it would be impractical to apply many micro mechanized products based on

the micro mechanisms of decorin, so decorin has been used as a sole product for other

essential internal tissues. (27)

Using decorin, an anti-fibrosis agent, to improve muscle recovery after injuryDecorin appears to be a powerhouse

Decorin has been shown to inhibit fibrosis in the kidney, liver, and lung, so why - the Pennsylvania scientists

reasoned - would it not also stop fibers from taking over muscle tissue?

sportsinjurybulletin.com

http://www.sportsinjurybulletin.com/archive/decorin.htm

It is widely known the scarring response in all our tissues is the same. (5) (6) And decorin has

been used successfully in our tissues like skin, (28) (29)(30) the kidney, (27) liver (27) and lung,

(27) spinal cord, (31) then on to organs like muscle, (32) (33)basically every tissue in the body

that scars.

Protein Pushes Damaged Muscle Toward Repair

Researchers at the University of Pittsburgh and Childrens Hospital of Pittsburgh have found that

treating distressed muscles with a protein called decorin prevents scar tissue formation andimproves regeneration and repair.

mda.org

http://www.mda.org/research/070912musclerepair.html

Tissue Engineering and Artificial Organs

By Joseph D. Bronzino

As described above, our recent data shows that TGF-B1 plays a central role in skeletal muscle

fibrosis and that the use of antifibrotic agents (e.g., decorin, suramin, yIFN, and relaxin) to

inactivate this molecule can reduce muscle fibrosis and consequently improve muscle healing to

near-complete recovery levels. We believe that the ultimate approach to improving musclehealing after sports-related muscle injuries may involve the transplantation of muscle cells

genetically engineered to express antifibrotic agents in order to block scar tissue formation

while promoting muscle regeneration.

http://books.google.com/books?id=Seresoz8QdIC&pg=PT812&dq=decorin+antifibrotic+agents

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Internally in the spinal cord, man made recombinant grade decorin suppresses the fibrotic

response 90% and allowed the intracellular nerve fibers to crawl up the scaffold in just 4 days.

(31)

CU Doctors Reveal Spinal Cord Technology - Researchers Bring New Hope To Paralyzed

PatientsDecorin is a naturally occurring molecule in the spinal cord that suppresses scar formation. We

were able to make pharmaceutical grade Decorin and infuse it into spinal cord injury rats and

suppress the scar by up to 90 percent, which allowed the nerve fibers to cross the injury in just 4

days,"

thedenverchannel.com, 2008-05-7http://www.thedenverchannel.com/health/16164126/detail.html

It is known that fibroblast proliferation can regenerate tissue or over produce collagen in the

fibrils to form scars, hence densely populated poorly woven collagen fibers that intercellular

tissues cannot grow through. (34)

What are scars?

A scar is a mark left in the skin by the healing of a wound or surgical incision in which the

normal functional tissue (skin) is replaced by connective tissue (scar). Keloids are excessive

accumulations of scar tissue beyond what is normally seen in most people. Keloids are moreraised and thickened masses of connective tissue than scars.

What cause the scar?

After a large, deep wound has occurred to the skin, whether by accident or due to surgery, both

skin cells and connective tissue cells (fibroblasts) begin multiplying to repair the damage. The

fibroblasts form a framework upon which the skin cells can migrate and fill in the wound. It is

the balance between the rate of replication of fibroblasts versus skin cells that is important here.

If the skin cells do not replicate fast enough and the fibroblasts replicate too quickly, the result is

a dense network of fibroblasts. This dense network of fibroblasts is not easily penetrated by the

skin cells, so the skin cells have a hard time replacing the fibroblasts. What results is a dense

network of fibroblasts, in other words a scar! If the skin cells replicate quickly and keep up with

the fibroblasts, then little scar tissue is formed and the skin has a more normal appearance after

the wound has healed. This is why scars do not occur as often in younger people as in older

people because the skin cells in younger people replicate more quickly and fill in the wound with

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normal skin tissue versus too many fibroblasts.

http://www.nomorescar.com/

It is also of note that fibroblasts in a hypoxic culture have been used to create an ECM in the

lab:

Human ECM for Devices and Therapeutics

Fibroblasts (blue DAPI stain) cultured on bead-like sphere structures produce embryonic ECM.

Creation of this material begins by using a scalable bioreactor (see Figure 2) to seed newborn

fibroblasts onto microcarriers. They are grown in suspension while being conditioned with liquid

media. Within a few days, under hypoxic culture conditions that simulate the embryonic

environment, the cells produce a dense embryonic-like extracellular matrix and secrete wnt

proteins (molecules that regulate cell-to-cell interactions in embryogenesis) and various growth

factors into the media.

http://www.devicelink.com/mddi/archive/08/05/007.html

It is of note that through many years of researching ECM a form of a hypoxic culture, involving

wnt protein, has been made into an injectable to create ECM on site.

Stem Cell Summit

Hypoxic (1-5% oxygen) and low gravity conditions stimulated cells to make embryonic matrix

http://www.histogeninc.com/downloads/stem_cell_summit.pdf

Decorin in fibroblast control: Decorin organizes ECM! It is known that in wounds fibroblast

over produce forming excess collagen, which forms a scar. (34) Decorin which to recap also

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reduces wound contraction, has a strong inhibitory effect on fibroblast over expression, and

clearly suppresses it in the skin except in the first 5-6 days of wounding when new non

denatured ECM scaffold material is required in a wound void. (28)

Decorin has an elegant regulatory relationship with ECM. (28)

Recovery of the Decorin-Enriched Fraction, Extract (D), From Human Skin: An Accelerated

ProtocolThis material has a strong inhibitory effect on fibroblast proliferation, and clearly suppresses it

in skin except after the first 56 days of wounding when new scaffold material is required. 2004-

09-30

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=555769

Decorin is the factor that tells the fibroblasts and non denatured ECM, There is no injury, do

not scar. (28) (29)(30)

Slam dunk one: Decorin treated wounds have been found to have no scarring and the tissue

resembled fetal wounds in the first two trimesters. (29)

Methods of preventing or reducing scarring with decorin or biglycan

Decorin-treated wounds have been found to exhibit essentially no detectable scarring compared

to control wounds not treated with decorin. The TGF--induced scarring process has been shown

to be unique to adults and third trimester human fetuses, but is essentially absent in fetuses

during the first two trimesters. The absence of scarring in fetal wounds has been correlated with

the absence of TGF in the wound bed. In contrast, the wound bed of adult tissue is heavily

deposited with TGF- and the fully healed wound is replaced by a reddened, furrowed scar

containing extensively fibrous, collagenous matrix. The decorin-treated wounds were

histologically normal and resembled fetal wounds in the first two trimesters.

http://www.freepatentsonline.com/6509314.html

It is of note hyaluronic acid is known to be a favourble carrier of the protein decorin (29)

Methods of preventing or reducing scarring with decorin or biglycan

In addition, the present invention further relates to a pharmaceutical composition containing

decorin or its functional equivalent and a pharmaceutically acceptable carrier useful in the

above methods. Pharmaceutically acceptable carriers include, for example, hyaluronic acid,http://www.freepatentsonline.com/6509314.html

Slam dunk 2: Excitingly decorin at concentrations of 100nM and 200nM has completely

controlled Keloid fibroblast proliferation (30) Enabling the ECM fibers to be and stay slender

hence woven correctly, without the over expression of collagen densing up the fibers which

denies the intercellular tissues passages to form.

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(Hence it has completely stopped type 1 collagen dense over expression. In fibrils it has

stopped the building up the parallel bundles of collagen fibers blocking up woven micropores in

the ECM which always leads to scarring; thus it has given a platform for normal tissues to

continue regenerating without the dense fiber scar wall on ECM which stops regeneration. It

has protected and decorated the ECM. It has completely stopped the scarring response.)

Recombinant Human Decorin Inhibits Cell Proliferation and Downregulates TGF-1

Production in Keloid Fibroblasts

VOLUME: 18 PUBLICATION DATE: Aug 01 2006

At decorin concentrations of 100 nM and 200 nM, fibroblast proliferation was completely

inhibited (P < 0.001), and the expected temporal increase in absorbance units was completely

abolished, indicating a static population (Figure 1).

http://www.woundsresearch.com/article/6067

Along with tenascin, the decorin dermal proteoglycan also directs the assembly of collagen,

This protein is a component ofconnective tissue, binds totype I collagenfibrils, (35) and an

important small proteoglycan in extracellular matrix assembly.

DCN decorin

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=16

34

Extracellular matrix proteoglycan decorin-mediated myogenic satellite cell responsiveness to

transforming growth factor-1 during cell proliferation and differentiationDecorin and

transforming growth factor-1 in satellite cellsDecorin, a small proteoglycan in the extracellular matrix

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T62-4T07XGM-

1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1

&_urlVersion=0&_userid=10&md5=d1428677762be9c48ddf810469bf771a

It has a relationship with ECM. It is of note that ECM is made predominantly of Type 1 collagen

(cite needed) which is created by fibroblast.

Type 1 collagen is a factor in scar free healing and healthy skin. (36) It is also the most abundant

collagen in the body. Fibroblasts in the adult healing scarring response over expresses Type 1collagen. (36) (Does excess collagen block up micro pores in ECM, by attaching to much of itself

to the ECM scaffold?)

On the other hand type 1 collagen when over expressed is also known to be expressed in scar

tissue. (36) Decorin, controls fibroblast proliferation keeping it at a static rate,(30) and Decorin

(that completely inhibits scar response(30)), binds to Type 1 collagen keeping regeneration

constant as needed for normal tissue.

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Skin collagen: More than meets the eye.

The most abundant types of collagen in the skin are I and III; their fibrils form the mesh largely

responsible for the skin's mechanical properties. Other types of collagen in the skin are V, VI,

and XII. They are found in much smaller amounts and appear to have a supportive role, whose

details remain unclear.http://www.smartskincare.com/skinbiology/skinbiology_collagen.html

It is known if you have a superficial wound you will be much less likely to scar than if you have a

deep dermal wound which will usually which bring a hypertrophic scar (HTS). (37) Interestingly

in deep dermal tissue after injury there is more collagen and less decorin in the deep tissues.

(37)

Deep dermal fibroblasts contribute to hypertrophic scarring.

Fibroblasts from the deeper layers were also found to produce more collagen, but less

collagenase by mass spectrometry and collagenase assay. Interestingly, cells from the deeperlayers also produced more of the proteoglycan, versican, but less decorin. Taken together, these

data strongly demonstrate that fibroblasts from the deeper layers of the dermis resemble HTS

fibroblasts, suggesting that the deeper layer fibroblasts may be critical in the formation of HTS.

http://www.ncbi.nlm.nih.gov/pubmed/18955978?ordinalpos=4&itool=EntrezSystem2.PEntrez.

Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Decorinis known to regulate collagen fibril (fibril means slender fiber (38)) formation in the

ECM and is important in the development of the structure of the extracellular matrix.

It is of note that the expression of decorin is decreased in photo damaged skin (39)

(WO/2000/037040) SKIN CARE COMPOSITIONS CONTAINING CIS-9, TRANS-11 LINOLEIC ACID

J. Inv. Derm., (1979), 73,79-66; Griffiths et al. N. Eng. J. med. (1993) 329,530-535). In the case of

decorin, it has been shown that mRNA expression and expression of the proteoglycan is greatly

reduced in photodamaged skin in vitro (Bernstein et al. Lab. Invest. (1995) 72,662-669). The

reduction of the levels of these skin proteins is accordingly associated with a decrease in the

tensile strength of the skin causing wrinkles and laxity.

The level of decorin in skin is associated with improved condition and appearance of skin.

Increasing the level of decorin in skin is important for controlled and correct deposition of

collagen in skin which is associated with many skin benefits such as wrinkle effacement anddermal repair of photodamaged skin.

http://www.wipo.int/pctdb/en/wo.jsp?IA=EP1999009589&DISPLAY=DESC

Decorin plays a pivotal role in tissue remodeling by acting on the balance between extracellular

matrix synthesis and degradation. (40)

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Effect of adenovirus-mediated overexpression of decorin on metalloproteinases, tissue

inhibitors of metalloproteinases and cytokines secretion by human gingival fibroblasts

These results suggest that decorin could modulate the expression of certain metalloproteinases

and their inhibitors, as well as the production of cytokines. Altogether, our data suggest thatdecorin might play a pivotal role in tissue remodeling by acting on the balance between

extracellular matrix synthesis and degradation.

http://cat.inist.fr/?aModele=afficheN&cpsidt=14958566

Decorin inhibits Fibrin(ogen) clotting. It is of note that Decorin promotes plasminogen/plasmin

expression. (41) Plasmin limits fibrin of which excess fibrin has been noted as the main player in

fibrosis and inflammation, plasmin has also been used for the past two decades as first-line

treatment of acute myocardial infarction to limit more fibrosis. (42) Wounds high in fibrin low

in plasmin scar, they transform the ECM along the fibrotic excess collagen pathway. Wounds

high in plasmin limit fibrin and remove fibrosis. (43) (Embryos do not have fibrin clots)

Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by

adult microglia in vitro

http://cat.inist.fr/?aModele=afficheN&cpsidt=17743545

New Technologies for Repairing Spinal Cord Injuries:

Suppressing scar formation and bridging injury sites.

1. Controlling scar formation with Decorin:In collaboration with Integra LifeSciences, my

research team has shown that a naturally occurring suppressor of scar formation, a molecule

called Decorin, is highly effective at suppressing the formation of both misaligned scar tissue

and the levels of axon growth inhibitors at sites of spinal cord injury. More importantly we

observed the rapid growth of sensory axons across decorin treated spinal cord injuries in just 4

days. We have also shown that decorin can induce the spinal cord to make an enzyme called

Plasmin that has the ability to break down scar tissue.

http://unite2fightparalysis.org/images/uploaded/Davies.pdf

Plasmin also aids in remodeling of ECM to tissue activating latent matric metalloproteinase.

(44)

Plasmin rapidly contracts dermal fibroblasts which are populated in type 1 collagen lattices, this

contraction favors ECM remodeling. (44)

Plasmin Triggers Rapid Contraction and Degradation of Fibroblast-Populated Collagen

Lattices

Within 16 h, fibroblast-populated collagen lattices treated with plasmin rapidly contracted from

approximately 20 mm to less than 2 mm in diameter.

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Following lattice contraction, the fibroblasts have been shown to adopt phenotypic

characteristics which favor ECM remodeling (Unemori & Werb 1986;Nakagawa et al. 1989;Grinnell 1994

).

ECM degradation is critical to tissue remodeling. This process is essential for removing damaged

tissue and provisional matrix, facilitating cell migration and guiding angiogenesis during wound

healing and tissue repair. ECM degradation during tissue remodeling is mediated by two classesof matrix-degrading proteinases: serine proteinases and matrix metalloproteinases (for reviews

seeMatrisian 1990;1992;Krane 1994;Mignatti et al. 1996). During wound healing, the serine proteinase plasminogen

activator (PA) catalyzes the conversion of the plasma protein plasminogen to plasmin. As

plasmin, a second serine proteinase, degrades several ECM components and activates latent

matrix metalloproteinases, it is frequently implicated as a key mediator in controlling connective

tissue turnover during wound healing.

http://www.nature.com/jid/journal/v114/n4/full/5600659a.html

Retinoic Acid and Linoleic acid up-regulates Decorin, (39) as does Chromolaena Odorata (45)

(WO/2000/037040) SKIN CARE COMPOSITIONS CONTAINING CIS-9, TRANS-11 LINOLEIC ACID

The results in table 6 indicate that the c9, tll isomer enriched CLA significantly upregulates the

synthesis of decorin in human dermal fibroblasts as compared to the control and as compared

to the tlO, c12 CLA and the CLA.

Surprisingly, the data thus further indicates that the magnitude of the upregulation of decorin

synthesis in human dermal fibroblasts effected by the c9, tll isomer of conjugated linoleic acid

exceeds that of the bench-mark anti-aging dermal repair active, retinoic acid.

http://www.wipo.int/pctdb/en/wo.jsp?IA=EP1999009589&DISPLAY=DESC

SKIN TREATMENT BASED ON THE USE OF CHROMOLAENA ODORATA

The results indicate that decorin synthesis in the model is substantially up regulated by even

relatively low levels (e.g. 0.01 g/ml) of extract. Small but positive effects were also seen on

procollagen I synthesis, as compared to the control. The 1.0 g/ml sample was also

comparatively tested with the retinoic acid (1m), showing an upregulation of decorin, 138

14.0 (p = 0.035, n = 4), as determined relative to a vehicle treated control value of 100 arbitrary

units. This further indicates the magnitude of the increase of decorin synthesis in human dermal

fibroplasts effected by Chromolaena Odorata extract, compared to the effect of retinoic acid.

http://www.freepatentsonline.com/EP1367988.html

It is of note that retinoic acid receptors are expressed in the regeneration blastema. (46)

Retinoic acid and its receptors in limb regeneration

Various retinoic acid receptors are expressed in the regeneration blastema and the experiments

which have revealed functions for individual isoforms are described. These experiments reveal

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that retinoids are a crucial component of the normal, regenerating limb and demonstrate the

value of the regenerating limb as an experimental system for providing functional data on

individual retinoic acid receptors.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WX0-45K142V-

10&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=

1&_urlVersion=0&_userid=10&md5=93249ca728ea1defe693bb9ab7cb2b49

Chromolaena Odorata extract (also known as Siam weed extract), is regularly used for burns

and soft tissue treatment in Vietnam and has shown efficacy in inhibiting contraction in

hydrated collagen lattice at 50 to 200 micrograms/ml (47)

An aqueous extract of the leaves of Chromolaena odorata (formerly Eupatorium odoratum)

(Eupolin) inhibits hydrated collagen lattice contraction by normal human dermal fibroblasts.

The significant inhibition of collagen gel contraction by Eupolin extract at 50 to 200

micrograms/ml is demonstrated in various concentrations of collagen. When the extract at 50

to 150 micrograms/ml was washed out of the lattices and replaced by fresh medium withoutEupolin, the contraction of collagen by cells was resumed.

http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=4

6275

Crushed chromolaena odorata leaves, manufactured by the Vietnam National Institute of

Burns, make up a formulation called Eupolin ointment. (48)

Upregulation of adhesion complex proteins and fibronectin by human keratinocytes treated

with an aqueous extract from the leaves of Chromolaena odorata (Eupolin)

Eupolin ointment is a formulation of an extract from the leaves of Chromolaena odorata,

manufactured and provided by the Vietnam National Institute of Burns, Hanoi.

http://www.john-libbey-eurotext.fr/fr/revues/medecine/ejd/e-docs/00/01/89/FA/article.phtml

Eupolin ointment, which expresses decorin in wounds that have not had non-denatured ECM

added, strongly enhanced Laminin 5 and laminin 511 in the ECM,(48)

Upregulation of adhesion complex proteins and fibronectin by human keratinocytes treated

with an aqueous extract from the leaves of Chromolaena odorata (Eupolin)

We have shown that the expression and secretion of laminin 5 are strongly enhanced in cultured

keratinocytes by increasing amounts of Eupolin. Laminin 5 is crucial to the stability of epithelial

attachment, and has been called a "biological glue" as it increases adherence of epithelial

sheets to wound surfaces and the rate of assembly of a new basement membrane zone [9]. It is

the first extracellular matrix component to be expressed and deposited by migrating

keratinocytes during wound healing and is essential for the regulation of keratinocyte migration

and motility [17-20]. Laminin 5 induces the assembly of hemidesmosomes by cultured epithelial

cells and regulates cell adhesion by the alpha3beta1 integrin and the alpha6beta4 integrin, its

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extracellular ligand [21]. These processes are all essential to wound healing. We believe that the

enhanced secretion of laminin 5 by Eupolin is a major finding that partly explains the clinical

effectiveness of Eupolin

http://www.john-libbey-eurotext.fr/fr/revues/medecine/ejd/e-docs/00/01/89/FA/article.phtml

concerning logic, it is of note that laminin 5 (also known as laminin 332) induces matrixassembly and cell adhesion activity of laminin-511 (also known as laminin 10). (49) ECMs

protein laminin 511 has been shown to grow hair follicles. (50)

The 3 chain short arm of laminin-332 (laminin-5) induces matrix assembly and cell adhesion

activity of laminin-511 (laminin-10)

http://cat.inist.fr/?aModele=afficheN&cpsidt=18480550

Laminin-511: Hair Growth Molecule Discovered by Stanford Researchers

http://www.hairlossfight.com/news_interviews/laminin-511.php

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2.3 Antibacterial Factor in Scar Free Healing Concept

It once was said our wounds need a sterile environment to have regeneration. Which lead to

treatments like drying and chemicals and treatment that completely destroy, or hinder and

denature any factors that can be used in scar free healing. (51)

A Scarless Future: The Wound Care Update Paper 2006, pdf - Page 10

The move from dry healing to moist healing is not new anymore, and is known by most medical

practitioners. However, this is not widely known amongst the public.

And this sterilization concept is equally challenged, by the Kangeroo marsupial, where the

embryo in the pouch is repeatedly contaminated by urine and faeces.

Also it is of note that adult salamanders that regenerate lost limbs with blastema, do not have

clinically sterile environments. Suggesting the blastema has antibacterial properties. And also

proving that a sterile environment is not as central to perfect regeneration.

It is also noted ECM has its own antibacterial properties, which leave the idea of sterilization of

wounds and the healing factors redundant. (52)

A-Cell Therapy Offers Renewed Hope For Horses Incurring Tendon And Ligament Injuries, p 4

http://www.acell.com/pdf/TCOTH%20ACell%20Article.pdf

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2.3.1 ECM Antibacterial Profile

Extracellular matrix has an impressive antibacterial profile (52)

A-Cell Therapy Offers Renewed Hope For Horses Incurring Tendon And Ligament Injuries, p 4

http://www.acell.com/pdf/TCOTH%20ACell%20Article.pdf

similar to that of the embryonic stage and as such it