Scarless Healing Faq

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 ECM’s & 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. FAQ’s ..................................................................................................................................................... 103
9. Current & previous pdfs of thread material, pre-amendments ........................................................... 104
9.1 Tom_Masons Original introduction: ............................................................................................... 104
10. Template Letter Headings and Bodies ................................................................................................ 105
Works Cited ............................................................................................................................................... 106
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
people’s 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 over
time.
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.
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 ECM’s (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 any
tissue if you have fibrosis to paraphrase Atala 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.
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 educational
purposes:
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.
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.

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 then
block 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 can’t 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 don’t 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
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 the immune system to 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
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
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)

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.
"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.
http://news.bbc.co.uk/1/hi/sci/tech/4888080.stm
Humans ‘to grow replacement body parts

Blastemas 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 mouse
and 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
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 it’s within the foreseeable future...five to ten years. – Geoff Sussman, Founder and
Director of the Wound Education & Research Group,
Monash University”
“Biologically it should 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

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’

her group had discovered the genetic characteristics that produce “good-as-new tissue”
regeneration
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 critical
window 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 not
denatured, 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.
**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
2 Technical Processes And Factors That Can Be Used in Scar
Free 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, inhibiting
inflammation, 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.
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
2.2 Inhibiting Fibrosis
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.
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
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
A small proteoglycan, 90-140 kD, of the extracellular matrix, so called because it decorates
collagen fibres.
The core protein has a mass of approximately 42 kD and is very similar to the core protein of
biglycan and fibromodulin. All three have highly conserved sequences containing 10 internal
homologous repeats of approximately 25 amino acids with leucine rich motifs.
Decorin has one glycosaminoglycan chain, either chondroitin sulphate or dermatan sulphate
and N linked oligosaccharides.
This entry appears with permission from the Dictionary 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 I’m 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-β, and whilst inhibiting TGF-B it
increases the expression of key MMPs that break down the ECM. (23) Evidence shows that
decorin is required for 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-β) family bind to the core
protein of the decorin proteoglycan. TGF-β 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-β is also chemotactic for macrophages and neutrophils, which
prolongs the inflammatory response and contributes to scarring. When TGF-β 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-β. Proteoglycans such as syndecan protect elastase from the
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 or
biglycan
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-β
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 ÈVERY 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
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 get
at 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 ECM’s 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 tissues
the 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 due
to 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
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 injury

Decorin 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 Children’s Hospital of Pittsburgh have found that
treating distressed muscles with a protein called decorin prevents scar tissue formation and
improves 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 muscle
healing 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
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
Patients
Decorin 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, 2008-05-7
http://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 more
raised 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
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
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
Protocol
This material has a strong inhibitory effect on fibroblast proliferation, and clearly suppresses it
in skin except after the first 5–6 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-β-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 TGFβ in the wound bed. In contrast, the wound bed of adult tissue is heavily
deposited with TGF-β 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.
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,
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.
(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-β1

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 of connective tissue, binds to type I collagen fibrils, (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-β1 during cell proliferation and differentiationDecorin and
transforming growth factor-β1 in satellite cells
Decorin, 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 1
collagen. (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.
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 deeper
layers 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
Decorin is 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 and
dermal 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)
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 that
decorin 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) (Embryo’s do not have fibrin clots)
Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by
adult microglia in vitro
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.
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 classes
of 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 µg/ml) of extract. Small but positive effects were also seen on
procollagen I synthesis, as compared to the control. The 1.0 µg/ml sample was also
comparatively tested with the retinoic acid (1µm), 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
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 without
Eupolin, 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
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 matrix
assembly and cell adhesion activity of laminin-511 (also known as laminin 10). (49) ECM’s
protein laminin 511 has been shown to grow hair follicles. (50)
The β3 chain short arm of laminin-332 (laminin-5) induces matrix assembly and cell adhesion
activity of laminin-511 (laminin-10)
Laminin-511: Hair Growth Molecule Discovered by Stanford Researchers

http://www.hairlossfight.com/news_interviews/laminin-511.php
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
2.3.1 ECM Antibacterial Profile
Extracellular matrix has an impressive antibacterial profile (52)
similar to that of the embryonic stage and as such it does not need a sterilization process.
It is of note there are even separate products based on ECM that are tweaked and designed by
acid digestion of the ECM scaffolds, to tackle bacteria like clinical strains of Staphylococcus
aureus and Escherichia coli. Such is the antibacterial property of ECM. (53)
Antibacterial Activity within Degradation Products of Biological Scaffolds Composed of

Extracellular Matrix
http://www.liebertonline.com/doi/abs/10.1089/ten.2006.12.2949?cookieSet=1&journalCode=t
en
2.4 Inhibiting Inflammation
In the in our unwounded adult skin that regenerates and in the embryo there is a lack of
inflammation; and scarring is said to be related to the inflammation response.
2.4.1 Fetuin
Fetuin was once thought by Dennis as being an inhibitor of regeneration that reduces
deposition of ECM. However, Kimble et al found this was not so. (54)
(WO/2006/069417) A METHOD OF TREATMENT

Thus, it appears that fetuin would be expected to promote epithelial cell growth, decrease wound healing, stimulate an immune
response and reduce the deposition of extracellular matrix. Accordingly, Dennis teaches away from using fetuin in wound
healing.
[0015] There is clearly a need for greater understanding of dermal injuries and for methods and compositions for their
treatment.
http://www.wipo.int/pctdb/en/wo.jsp?wo=2006069417&IA=AU2005001965&DISPLAY=DESC
Data points to Fetuin as an inhibitor of the inflammation response, it mops up dead cells,
promotes wound closure and is a factor that is found abundantly in the early embryonic
gestation stage. (55) (56) As of 2007 it is being investigated in childhood burns. at the Royal
Children’s Hospital, Brisbane, Queensland, Australia. (2)
The Royal Children’s Hospital Foundation, July 2005, page 3

Breakthrough in burns research – one step closer to scarless healing
Data suggests that Fetuin is an ideal protein to help skin heal with minimal scarring as it inhibits
large amounts of inflammation and helps the immune system mop up dead cells.
http://www.workingwonders.com.au/download.cfm?DownloadFile=2B7890C8-F1F6-5DEA-
B1971EFF6FD7ABD1
Fetuin-A: a major fetal serum protein that promotes "wound closure" and scarless healing,
2007 Oct 25
http://www.ncbi.nlm.nih.gov/pubmed/17960182
Fetal protein holds key, 2005-10-08

”The first protein identified as being present in the fetus but largely absent in the lamb, was
fetuin.”
“human trials have been pencilled in to start in 2007.”
http://www.news.com.au/couriermail/story/0,23739,16844871-3102,00.html
There are high levels of fetuin in fetal tissues (56)
Fetuin-A: A Major Fetal Serum Protein that Promotes "Wound Closure" and Scarless Healing
In agreement with the 2D-PAGE analysis, fetal skin expresses much higher levels of fetuin-A
than postnatal skin (Figure 1f and n). Interestingly, in F81–94 day fetal skin, the highest level of
fetuin-A expression was found in keratinocytes of the epidermal basal layer (Figure 1f), which
also express high levels of keratin 14 (Figure 1i). Fetuin A is particularly prominent at sites where
basal keratinocytes are reorganizing to form hair follicle placodes. However, from F101 day
onward basal-layer expression of fetuin-A is lost, and by day F140 only low levels of fetuin-A are
observed in the bulb region of hair follicles and outer root sheaths of hair follicles (data not
shown). Fetuin-A is also found at high levels in the dermis during fetal development (F81–140
days) and particularly in fibroblasts under and adjacent to the developing placode (dermal
condensate and fibrous sheath of hair follicle).
Unlike human and rodent
Fetuin binds strongly to TGF-βl and TGF-β2 and weakly to TGF-β3 and Fetuin binds strongly to
bone morphogenic proteins BMP-2, 4 & 6 (54)
(WO/2006/069417) A METHOD OF TREATMENT

with three N-linked and three O-linked oligosaccharide chains. Fetuin has been reported to
interact with a large number of different polypeptides and cells. It appears to regulate
inflammatory responses and particularly the innate immune system responses. Fetuin binds
strongly to TGF-βl and TGF-β2 and weakly to TGF-β3. Fetuin binds strongly to bone morphogenic
proteins BMP-2, 4 & 6 (Demetriou M. et al, 1996, J. Biol. Chem., 271(22):12755-12761; Szweras
M. et al., 2002, J. Biol. Chem., 277(22):19991-19997). Fetuin also modifies macrophage
responses, opsonizes apoptotic cells and reduces inflammatory responses (Wang H. et al, 1998,
Proc. Natl. Acad. Sci. USA, 95(24): 14429-14434).
Fetuin seems to also have other uses, maybe in fighting liver fibrosis by modifying the effects of
TGFβ and PDGF, two major growth factors in fibrosis. (57)
Effect of fetuin, a TGFβ antagonist and pentoxifylline, a cytokine antagonist on hepatic

stellate cell function and fibrotic parameters in fibrosis
Our results suggest that fetuin may be beneficial in hepatic fibrosis and suggest that
combination of fetuin and pentoxifylline may target the two key events in hepatic fibrosis by
modifying the effects of TGFβ and PDGF, the two major growth factors in fibrosis.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4P37JN3-
1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1
&_urlVersion=0&_userid=10&md5=d216163061a4d3480725218d40a7407e
2.4.2 ECM in Inhibiting Inflammation
Acellular Extracellular Matrix (ECM), that is not denatured (cross-linked), when applied early
enough, before the scar healing response, inhibits the inflammation response whilst
regenerating what local tissue is nearest to it. This is because this ECM is acellular, which means
that the markers that cause an adverse immune response are removed, allowing an adoptive
response to the ECM. (58) Which enables the ECM bioscaffold to be degraded by MMP’s,
absorbed by the body tissue to be replaced by the host tissue. Completely reducing the
possibility of a chronic inflammatory response by the host against a foreign material. (59) There
is not known one case of the SIS-ECM being rejected in thousands of cases. (60)
Why isn’t the ACell Vet™ bioscaffold rejected by the host?

The ACell Vet™ bioscaffold is acellular. That means that the cell markers that might cause an
adverse immune response are removed. What remains is an acellular matrix that appears to
provide signals to the host immune system that stimulates an adaptive or accommodative
response. This is ideal for both wound healing and three-dimensional growth of various cell
types.
http://www.acell.com/vetfaq.php
The Science of Tissue Engineering

Completely resorbable… This eliminates the possibility of a chronic host inflammatory response
against a permanently implanted foreign material.
http://www.acell.com/edu_science.php
Material from pig intestine is remedy for deep sores, incontinence

"We know of no cases of rejection in either humans or animals."
http://www.purdue.edu/UNS/html4ever/0002.Badylak.SIS.html
2.5 Growth Factors
Growth Factors TGF-β 1, 2, and 3 are said to play a role in scar free healing. Inhibiting or
reducing TGF-β 1, and 2 expression and increasing TGF-β 3 is said to make wound healing more
of a regenerative response than a scarring response. (5)
Scar-free healing: from embryonic mechanisms to adult therapeutic intervention 2004-04-20

As with all scar free healing pathways, timing is of the essence with implantation of
technologies that inhibit TGF-β 1, 2 and increase TGF-β 3; with the first 48hours of wounding
said to be a critical period of the regeneration pathway. (5)
Scar-free healing: from embryonic mechanisms to adult therapeutic intervention, p 4,

we have shown that early application, at the time of or shortly after (within 48 hours)
wounding, produces the best results
Juvista is a product based on TFGB3. (5)
Juvista is a product based on wound that heal with primary intention (cite needed). It can also
be used on wounds healing with secondary intention.
2.6 Stem Cells
The bodies master cells stem cells give rise to all tissues, organs and blood. It has been known
stem cells play a part in scar free healing. Embyronic stem cells being the most potent and
multipurpose.
In 2008 Japanese researchers found a way to regenerate potent stem cells from normal cells.
(61) These cells are said to be similar to embryonic cells which are said to be the most powerful
kind of stem cells. (61)
New method generates stem cells safely from mice, 2008-10-9

http://www.reuters.com/article/scienceNews/idUSTRE4988U120081009
In March 2009, scientists found a way to create embryonic stem cells from skin. (62) (63)
PiggyBac Lets Science Turn Skin to Stem Cells With Less Danger
March 1 (Bloomberg) -- A lab trick dubbed “piggyBac” enabled researchers to transform the skin
of mice and humans into stem cells without the cancer risk that hampered the original
breakthrough from a Japanese scientist, a study found.
The technique builds on the advance of Shinya Yamanaka, who electrified scientists in 2006 by
reprogramming ordinary skin cells into stem cells capable of growing heart, brain and other
tissues. Yamanaka and others kept refining the process, with each new method improving on
the last.
http://www.bloomberg.com/apps/news?pid=20601124&sid=auDr495yHivg&refer=home
Breakthrough by British scientists could see stem cells made from human skin - NOT embryos
http://www.dailymail.co.uk/sciencetech/article-1158311/Breakthrough-British-scientists-stem-
cells-human-skin--NOT-embryos.html
As well as skin a source for stem cells is our own fat. (64)
Talks Alan Russell: Why can't we grow new body parts?

Video: 15:24 – 15:54
http://www.ted.com/index.php/talks/alan_russell_on_regenerating_our_bodies.html
A spray gun application can spray stem cells.
In 2006 the paper ‘Sprayed Cultured Epithelial Autografts for Deep Dermal
Burns of the Face and Neck,’ brought forward another visual of scar free healing. (65)
Sprayed Cultured Epithelial Autografts for Deep Dermal

Burns of the Face and Neck
Our data show that enzymatic and careful surgical debridement and consecutive application of
CEA suspensions using a spray technique results in excellent cosmetic outcomes
Our data show that enzymatic and careful surgical debridement and consecutive application of
CEA suspensions using a spray technique results in excellent cosmetic outcomes (Fig. 2)
compared with our experiences with any other method. The follow-up in our series is still short.
Taking into consideration that burn scars generally improve over time, it can be expected that
the longer-term results will be even better. Our data are still of preliminary character since the
study was performed without a control group. However, we refuse to perform a prospective
randomized study with groups in which traditional skin grafting and/or wound healing are still
applied for the therapy for deep dermal burns due to the excellent results in our study.
http://www.annalsplasticsurgery.com/pt/re/annps/abstract.00000637-200701000-
00013.htm;jsessionid=JVQfS6lcgshRnzTv61XTplTVTrVLSh2kLgpcbh0j5TP2vSpK82hv!-
2118404334!181195629!8091!-1
http://www.acne.org/messageboard/post-a17028-ovidweb.pdf.html
2.6.1 ECM’s & Stem Cell
A relative to stem cell therapy, working just as well, ECM, that is not denatured, is a framework
that attracts the animals own circulating stem cells from bone marrow to populate the ECM, to
remodel the host tissue type, (66) instead of scar tissue. (52) (6)
Histogen Wnt Cell Regeneration

3/5/09
1:42-2:27
http://www.sandiego6.com/mediacenter/local.aspx?articleID=586361
A-Cell Therapy Offers Renewed Hope For Horses Incurring Tendon And Ligament Injuries
2005-06-24
“The mixture acts as a framework for the horse’s own circulating stem cells to populate the site
and become appropriate, functional tissue as the area heals, rather than scar tissue,” added
Mitchell.
Like its close relative stem cell therapy, A-cell therapy has...
this process works just as well...
In addition to having all the attending growth factors and inhibitors, another benefit of the ACell
product is its ability to attract the body’s own stem cells to an area of healing, so they can make
the proper tissues. So you’re getting the stem cell treatment without having to put the stem
cells in.

Pig-extracted extracellular matrix is already used by veterinarians to help horses repair torn
ligaments. In people, it's used to treat ulcers, closing a hole in the tissue that lines the stomach.
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 the immune system to 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.
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.
2.6.2 Progenitor Cells/Stem Cells
Non-crosslinked (to reiterate: not denatured) ECM recruits progenitor cells (67) (66)
Extracellular Matrix Heals Tendon Injuries with Progenitor Cells in Vivo

The entire healing process is transformed to one that is similar to embryonic tissue
development.
http://www.acell.com/pdf/tendonbrochurev16gedits.pdf
Histogen Wnt Cell Regeneration

3/5/09
http://www.sandiego6.com/mediacenter/local.aspx?articleID=586361
Like stem cells, progenitor cells have a capacity to differentiate into a specific type of cell. (68)
progenitor cell
<cell biology> In development a parent cell that gives rise to a distinct cell lineage by a series of
cell divisions.
11 March 2008
http://cancerweb.ncl.ac.uk/cgi-bin/omd?progenitor+cell
In contrast to stem cells, however, they are more specific than stem cells: they are pushed to
differentiate into their "target" cell.
The terms "progenitor cell" and "stem cell" are sometimes equated. (69)
Dorland's Medical Dictionary 2007

progenitor cell stem cell.
http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/d
orlands/dorland/nine/100009804.htm
A wiki link, note the piece in not yet cited:

Properties of Progenitor Cells
Most progenitors are described as unipotent or multipotent. In this point of view, they may be
compared to adult stem cells. But progenitors are said to be in a farther stage of cell
differentiation. They are in the “center” between stem cells and fully differentiated cell. The kind
of potency they have, depends on the type of their "parent" stem cell and also on their niche.
Like stem cells, mostly, they are formed and transported in a colony, with the right conditions
for them to grow and differentiate into their target tissues. In contrast, some progenitor cells
were found during research, and were isolated. After their marker was found, it was proven that
these progenitor could move through the body and migrate towards the tissue where they are
needed. Lots of properties are shared by adult stem cells and progenitor cells. But still,
controversy remains because Embryonic stem cells are true stem cells in that they are
pluripotent and show unlimited capacity for self-renewal. In contrast, many cells termed adult
stem cells would be better defined as progenitor cells, as their capacities for unlimited self
renewal and plasticity have not been comprehensively demonstrated.
Progenitor cells are only found in adult organisms, they act as a repair system for the body. They
replenish special cells, but also maintain the blood, skin and intestinal tissues.
http://en.wikipedia.org/w/index.php?title=Progenitor_cell&oldid=249353178
2.7 Extracellular Matrix
ECM turnover is responsible for unscarred skin. The micro mechanized factors in extracellular
matrix and many of its components for instance, decorin, hyaluronic acid, and wnt proteins
have been extensively studied.
Regeneration happens every day in our unwounded tissues and embryonic tissues, and is a
process involving degrading extracellular matrix and intercellular tissues that crawl up the fresh
matrix that replaces the degraded ECM. With man studying ECM it has become clear our
intercellular tissues are clever and use ECM every day to regenerate (paraphrasing Ryan et al).
Badylak et al have noted the ECM has signals that organizes the intercellular tissues by turing
on and off factors, signaling the need for appropriate intercellular factors and stem cells at
precise times in the remodelling of tissues.
What is plainly clear is, regeneration cannot happen without non-denatured ECM as our
intercellular tissues would not have an adaptable framework to work on in order to remodel; In
wounds the ECM can be inserted and, also, our bodies can be encouraged to make it (hypoxic
cultures); The mammalian body manages ECM everyday to enable intercellular tissues to crawl
through pores unhindered; Our intercellular tissues have used this external scaffold to
regenerate since evolution began; When the mammalian body manages ECM wrong and the
ECM is denatured by excess collagen, or when denatured ECM is externally applied to wounded
tissue, fibrotic (over expressed collagen) fibers in the ECM, hence fibrotic tissue is the end
result; Fibrotic tissue means no regeneration is possible Atala law; With non-denatured ECM
externally applied we have had simple tissues completely regenerated; with decorin we have
seen fibrosis (excess collagen on the ECM fibers) completely controlled in simple tissues,
enabling a free ride for our intercellular tissues to crawl up the ECM with its inbuilt normal
woven scaffold reference to do its job; fibrosis is a process of over expression of collagen hence
engorgement of the ECM woven pores hindering remodelling…
It is known that in wounds in the adult, fibroblast over produce collagen forming a scar (recap:
an over expression of collagen). And that a scar blocks any future intercellular development in
that area. (6)

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 the immune system to 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.
ECM protein decorin has a strong inhibitory effect on fibroblast proliferation, and clearly
suppresses and regulates it in the skin except in the first 5-6 days of wounding if a new ECM
scaffold material is required to fill the void. (28)
Recovery of the Decorin-Enriched Fraction, Extract (D), From Human Skin: An Accelerated
Protocol
This material has a strong inhibitory effect on fibroblast proliferation, and clearly suppresses it
in skin except after the first 5–6 days of wounding when new scaffold material is required. 2004-
09-30
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=555769
Decorin is essential for non denatured ECM.
Excitingly and reiterating: ‘Scar free healing,’ ECM’s decorin, at 100nM and 200nM, has
completely controlled keloid fibroblast proliferation (30) (Hence it has completely stopped
scarring giving a platform for normal tissues to stabilize and continue regenerating through the
ECM without the scar wall which stops regeneration). (Metaphor, imagine a scaffold on a
building, for some bizarre reason imagine the scaffold bulging so much you cant climb through
the scaffold, and the bricks cant now be laid for the remodelling. To combat this swelling,
decorin stops this collagen expansion on the ECM scaffold material, this in turn enables the
intercellular tissues to regenerate and remodel through the micro scaffold pores, in turn
denying fibrosis.)

In non-denatured ECM, through the fact it can completely inhibit scarring, it seems obvious
decorin is the factor that stops fibrosis from spoiling the ECM, which allows our tissues to crawl
up and decorate the scaffold to regenerate without any fibrotic encapsulation.
It is of note that Alloderm® ECM retains decorin (70) (71)
Advances in Tissue Banking

Qualitative assessment of the matrix also reveals that the important glycosaminoglycans,
hyaluronic acid, chrondrotin sulphate, and decorin, are retained following the AlloDerm®
process.
http://books.google.com/books?id=JaJdPtnAE5AC&pg=PA175&dq=decorin+alloderm
US Patent 6933326 - Particulate acellular tissue matrix
A reported benefit of AlloDerm® is that it maintains the structure and biochemistry of the tissue
matrix, promoting normal tissue regeneration. Studies have indicated that AlloDerm® retains
decorin, hyaluronic acid, chondroitin sulfates, nidogen, growth factors and other biochemical
proteins present in normal soft tissues.
http://www.patentstorm.us/patents/6933326/description.html
Work by Zhang, Zhi; Li, Xiao-Jian; Liu, Yan et al (30) has established that decorin can completely
inhibit fibrosis (scar/excess collagen/cicatrices etc) (30) leaving a quality scaffold without
densely populated fibrils, for the intercellular tissues to crawl through. The logical question
here is: does Alloderm retain enough decorin to stop collagen over expression which in turn
would allow our intercellular tissues to grow through the ECM to enable complete scar free
healing?
(For more on decorin please go to page 21)
ECM has completely regenerated simple tissues to site specific states (skin, bladder, tendon)
and in the next few years will bring advancements in our harder tissues, like bone, heart, liver,
pancreas etc. Our body is made up of 30% extracellular matrix.
And to reiterate all scarring has a problem with ECM production.
ECM is a material that can be sourced from many places (usually from pigs due to access and
the pigs close genetic relationship with primates), that allows the skin and every tissue to
regenerate to the local tissue state and it removes the scarring process.
Inserting ECM into wounds, the wound has to heal with secondary intention; sometimes with
the ECM material lightly tacked.
Earlier ECM’s had chemical additives added to them, which denatured, producing an excess
collagen production problem and hence fibrotic encapsulation or complete rejection of the
material by the body. It has been found all our body tissues need is an ECM, hence a simple
scaffold that has no additives added. If it has this quality it can regenerate 100%.
People assume that the ECM solely does the job but this is not so. Basically an ECM, without
being denatured (spoilt by chemical processes or handling, bringing over expression of collagen
or rejection, ruined by inappropriate protocol), carries factors and stem cells and gives a
platform for our tissues to regenerate completely Badylak et al. (18) Paraphrasing Ryan, (72)
our tissues are very smart and have been regenerating on this scaffold through thousands and
thousands of years. Our clever tissues have consistently grew through tiny holes in the un-spoilt
simple fibril scaffold system, in the same way a vine snakes its way up a trellis. (17) And if these
holes are blocked and glued together you would get a fibrotic response, just like a blocked pore
in acne, if they are unblocked you get regeneration and you can regenerate site specific skin,
bladder, tendon, bone etc.
Rebuilding the Troops

For wounded soldiers, the military's Institute of Regenerative Medicine offers dramatic new
ways to heal
Normally, when a person loses a limb, scar tissue forms over the wound, leaving a permanent
stub. The pig powder contains signaling molecules that attract cells and proteins known as
growth factors and override the scarring process, telling the cells to grow instead. (Badylak
settled on pigs because their molecules are similar to those found in humans and easy to
obtain.) Alan Russell.
http://www.popsci.com/military-aviation-space/article/2008-06/rebuilding-troops?page=

The tissue grows through tiny holes in the scaffold, in the same way a vine snakes its way up a
trellis.
"Previous attempts to find better ways of encouraging skin cell growth have used chemical
additives and other elaborate techniques to produce scaffolds, but their success has been
limited," said Tony Ryan, a professor in the university's department of chemistry, in a news
release. "We've found that skin cells are actually very 'smart.' It's in their DNA to sort
themselves into the right arrangement. They just need a comparatively uncomplicated
scaffold (and each other) to help them grow in a safe, natural way."
Described as Mother Nature's scaffold for wound healing. (60)

The same thing as the constant forming blastema found on the severed tail of a salamander (6)
(9)

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
this powder on.
Extracellular matrix, that is not denatured, is known to provide signals controlling cell shape,
migration, proliferation, differentiation, morphogenesis, and survival. (73)
Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular
matrix molecules
Extracellular matrix (ECM) is known to provide signals controlling cell shape, migration,
proliferation, differentiation, morphogenesis, and survival.
And external application of ECM has changed the way we would normally respond to injury.
(74)
Dr. Steven Badylak: The cellular matrix is in us

11:55 we changed the way we would normally respond to injury
http://www.poptech.org/blog/index.php/2008/12/18/dr-steven-badylak-the-cellular-matrix-is-
in-us/
All ECM material is universal; the same in animals, mammals (74) (75) (6) and reptiles and when
acellular and transplanted into any tissue it does not get rejected. (75)

08:41 Information highway between cells, it tells cells you should divide, you should go here… It
is in us as mammals…
in-us/
Veterinary Spotlight, p 2
In a nutshell, this material is harvested in such a way that all the genetic constructs are
removed, so there is no rejection phenomenon," explained Jeff Wood, D.V.M., who owns and
operates Northside Veterinary Hospital in Hillsdale, Michigan. Wood, who is on the veterinary
advisory board of ACell, has used the pig bladder tissue to promote regrowth in a variety of
species. "Even though this is pig tissue, you can use it in people, dogs, cats, horses, kangaroos,
reindeer, and other species.
http://www.acell.com/pdf/ThoroughbredTime111703.pdf

The extract, called extracellular matrix, lays the framework that cells use to generate any given
body part. It's like a cellular scaffolding, and all animals have it. It holds the signals that direct
cells to divide, differentiate and build themselves into a specific form.
Extracellular matrix is a component of body tissue that functions outside of the body's cells (thus
the "extracellular" designation). It's made up mostly of collagen, a type of protein. So
extracellular matrix extracted from the bladder of a pig does not actually have any of the pig's
cells in it.
Any ECM material that is Acelluar means the cell markers that might cause an adverse immune
response are removed. (58)

adverse immune response are removed.
It is not just suited to wound care it can treat a broad range of human and animal conditions.
(76)
Summary
not limited to one market segment (e.g., wound care), but instead can serve as a core
technology for treatments across a broad range of human medical conditions.
http://www.acell.com/med.php
ECM that is not denatured can be applied to regenerate soft tissues and hard tissues,
remodeling their exact local state without scarring. (6) (60)


You could say ECM is a overall application that you apply to tissue (meaning all the complex
micro and nano mechanized intercellular processes on application are controlled by tissue using
the ECM). And though people are trying to micro analyze, synthesize and artificially replicate
mechanized components in scar free healing from the ECM and the intercellular tissue
reactions, under the microscope ECM encompasses, triggers, different proteins, in a ratio and it
is a three dimensional matrix that is virtually impossible to recreate in a lab. (58)
What is the structure of the ACell Vet™ bioscaffold?

An ECM template that is not denatured brings many factors timed precisely in to the wound to
encourage the key regeneration pathway of the host tissue, bringing in and switching on and
off growth factors, stem cells, cells and factors coming our bone marrow (74) (75)
Veterinary Spotlight
Wood explained that the scaffold in the membrane contains growth factors, which stimulate the
body to bring in a type of cell similar to stem cells. "These are cells that we all have in our bone
marrow that have the ability of turning into anything," he said. "It’s just that we don’t know
how to get them out of the bone marrow and out of the circulatory system and into…
http://www.acell.com/pdf/ThoroughbredTime111703.pdf
08:41 Information highway between cells, it tells cells you should divide, you should go here… It
is in us as mammals…
in-us/
in order to match the new tissue to the local-host tissue.
As non-denatured ECM regenerates what tissue is the host-local to regeneration, the timing of
the application of non-denatured ECM is needed before the scarring response; so the non-
denatured ECM can regenerate the preferred tissue, over scar tissue. ECM also starts the
process of regeneration (77)
Medicine's Cutting Edge: Re-Growing Organs

The Future Is Here: Regenerative Powder, Ink Jet Heart Cells And Custom-Made Body Parts
Video: 1:21, it tells the body to start that process
http://www.cbsnews.com/stories/2008/03/22/sunday/main3960219.shtml
ECM blastema is found profusely in embryo, (60)
Fundamentally Altering the Way the Body Responds to Injury

the body is stimulated (i.e., induced) to deposit organized tissues reminiscent of the
phenomenon that occurs during fetal development.
http://www.acell.com/edu_science.php
and applying ECM brings a wound to the embryonic state. Where on site, the body is induced to
deposit organized tissues in a similar way that occurs during tissue growth in the early
embryonic trimester. (67)
Extracellular Matrix Heals Tendon Injuries with Progenitor Cells in Vivo

The entire healing process is transformed to one that is similar to embryonic tissue
development.
http://www.acell.com/pdf/tendonbrochurev16gedits.pdf
Where it is covered with hyaluronic acid to maintain its moisture. (78)
Journal Of Wound Care

Volume 11. Number 2
February 2002
Mast et al.,18 however, found that the extracellular matrix of foetal wounds is rich in hyaluronic acid
http://www.pilonidal.org/pdfs/honey_wound.pdf
It is of note that hyaluronic acid inhibits excessive scarring by inhibiting platelet aggregation
and release of platelet-derived growth factors and other cytokines, (79)
Olutoye OO, Barone EJ, Yager DR, et al. Hyaluronic acid inhibits fetal platelet function:
implications in scarless healing. J Pediatr Surg 1997; 32: 1037-40
Hyaluronic acid a major component of the Extracellular matrix is involved directly in

angiogenesis and the regulation of cellular functions and in secondary healing wounds. HA also
considerably aids the healing process in secondary healing wounds (ECM application is
secondary healing), as documented by the acceleration of wound closure. (80)
Low molecular weight hyaluronic acid induces angiogenesis and modulation of the cellular
infiltrate in primary and secondary healing wounds
The morphometrical analysis of angiogenesis demonstrated a larger quantity of microvessels in
HA-treated lesions than in controls and the differences were statistically significant. These
effects were evident both in primary and in secondary healing wounds. However, no favourable
effect on the wound healing time was evident in primary healing treated wounds, whereas in
secondary healing wounds the HA effects considerably aided the healing process, as
documented by the acceleration of wound closure.
Hyaluronic acid, a natural sugar, absorbs 3000 times its weight in water. (78) It is said ECM
needs to be moist, is this, low weight hyaluronic acid, the best logically elegant solution to
keeping an ECM wound moist?
There are different sources of Extracellular matrices, like small intestinal submucosa (SIS), L-
ECM from the liver, urinary bladder matrix (UBM), and nanoscaffold all being a handful of
examples.
Again a problem with ECM is it can be denatured which may alter the integrity of the ECM’s
composition and structure, such that the mechanical and material properties are adversely
affected and cross linked. Denaturing (corruption) of the material brings a response similar to a
fibrotic response or an encapsulation response.
(As well as Acne, and other scarring, it is of note that Epidermolysis Bullosa, is a disease were
the ECM can not function properly; a disease were you get fibrosis in your skin tissues and
sparse hair follicle growth. Perhaps a denatured ECM patch could share various scale
similarities with Epidermolysis Bullosa?)
In the past ECM used to have man made additives added which altered the intergrity of the
material (denature). (17)

"Previous attempts to find better ways of encouraging skin cell growth have used chemical
themselves into the right arrangement. They just need a comparatively uncomplicated scaffold
(and each other) to help them grow in a safe, natural way."
Things that can denature and corrupt it are the handling of the materials, by the breakage of
the packaging allowing oxidisation, exposing to high temperatures, exposing to ultra violet light,
inappropriate treatment protocols. Exposure to foreign materials, like cat gut suture, chemicals
or other may make the material ineffective. Solutions like Alcohol and any alcohol based
solution; Detergents and soaps; Iodine containing products; Any product with silver nitrate;
Hydrogen peroxide. Dakin’s Soin (bleach) Chlorine; Cortisone based products (e.g. topical ant-
inflammatory mediations). And it is noted direct contact between antibiotics like amino
glycosides and products that contain sulfa, should not happen. (58) In fact there should not be
any need for additional antibiotics unless gross contamination and infection are present.
When does the ACell Vet™ product not work?

Treatment with glutaraldehyde causes cross linking of the protein material. Cross linking alters
the material such that it is resorbed slowly or nor resorbed at all, inciting a cascade pathway
that resembles the excess collagen (scar) formation pathway. Methods of treating the material
with carbodiimide, dehydrothermal and photooxidation can also cause cross linking of the
fibrils. (81)
Tissue regenerative compositions for cardiac applications, method of making, and method of
use thereof
http://www.pharmcast.com/Patents/Yr2003/Jun2003/061703/6579538_Tissue061703.htm
Sterilization processes, crosslink and denature to different degrees. Data suggests, ECM needs
to be handled specifically.
ECM’s bacterial control effect eludes that ECM does not need harmful sterilization processes.
(52) Being the infection risk of the powder is harmless. Also there has not been one noted
incidence of rejection with any ECM material (60) of which Acellular ECM has no cell markers
which may trigger an immune response. (58)
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
this powder on.


adverse immune response are removed. What remains is an acellular matrix that appears to
provide signals to the host immune system that stimulates an adaptive or accommodative
response. This is ideal for both wound healing and three-dimensional growth of various cell
types.
ECM is deposited and is central to regeneration to the animal, mammal and animal body, and in
the first third to first half of the gestation period it is used exponentially by the extraordinary
expanding stressed tissues of the developing embryo, that do not scar. ECM is the factor that
allows expanding tissues to expand without scarring.
ECM has completely regenerated a female sex organ, skin, bladders, fingertips, nerves, bone,
tendon. (17)

It must be noted that all ECM is the same in every mammal. But if you want to bring the
argument that animals are animals and are different to the human-animal. Then the pig is more
closely related to the Human animal (17) than most other animals that have had complete
regeneration. And SIS-ECM has brought outstanding results in Humans and other mammals:
Resolving persistent, open sores. Sores that would not go away for years, healed in weeks; (60)
Degloving, were the skin on legs is torn off in accidents which usually results in amputation. The
skin grew back, which was unusual in itself but also hair grew back; (60) Eye injuries, animals
who suffered from eye injuries severe enough to have caused blindness healed when ECM was
placed over the injury; (60) Women treated for urinary incontinence, all regained urinary
control within a week of surgery; (60) In the past ECM has also been used to make repairs to
internal organs, such as the kidneys that otherwise would have been impossible. (60)

It is of note that an earlier generation of ‘denatured’ ECM with a metal rim, regenerated local
Heart tissue to 95%. (13), and it is of note that a device is being developed without the metal
rim that will allow 100% regeneration. (13)

metal framework remains. An entirely absorbable implant is currently under development.
Reaffirming at the use of ECM for all our softer tissues.

‘Another example of scar free healing’, A visual example of an earlier similar ECM-type
regeneration with a denatured product called APLIGRAF is
CASE STUDY2
Healing acute excisional wounds from Mohs Micrographic Surgery:
http://www.biomed.metu.edu.tr/courses/term_papers/artificial%20skin_cinar.htm
Images of the patient:
http://www.biomed.metu.edu.tr/courses/term_papers/artificial%20skin_cinar_files/image061.
gif,
gif and
gif
As you can see, perfect regeneration of the defect with a simple ECM type material. You can
see the ECM material, has been 99.9% successful in controlling the cell shape, migration,
differentiation, morphogenesis in a time window bringing about local tissue, which usually a
denatured ECM, which would usually bring a fibrosis response, can not do. For some reason the
material this person was given was not denatured, and the fibrils stayed slender and the
intercellular cells were allowed to migrate with no scar wall in the fibrils blocking progress.
Documentary video involving ECM

Powder Mends Severed Finger
http://www.cbsnews.com/video/watch/?id=3805429n
Here is the result of an earlier ECM, Alloderm that has visually completely regenerated knuckle
skin 100%
http://www.eplasty.com/article_images/eplasty08e33_fig1.gif
=15
In 1996, 1997 it was reported Alloderm got excellent results in burns (26)
Alloderm is reported to induce the regeneration of dermis with the normal orientation of
collagen and elastin fibrils instead of the cross-linked collagen and lack of elastin seen in scar
tissue (Wainwright et al., 1995) The fibroblasts that repopulate the Alloderm lack the
myofibroblastic phenotype of granulation tissue and the grafts exhibit minimal contraction. The
basement membrane of the dermis interacts with overlying keratinocytes to induce the
formation of hemidesmosomes and Type VII collagen anchoring fibrils. Alloderm has been
evaluated clinically for burns and is reported to provide good to excellent cosmetic appearance
and functional performance (Wainwright et al., 1996: Lattari et al., 1997: Sheridan and
Choucair. 1997)
http://books.google.com/books?id=3Ue5oF3INKsC&pg=PA73&lpg=PA73&dq=badylak+decorin
&source=web&ots=Zfej2sWyw1&sig=UGvEh98dPmI-Q6wRDAmWWC-
zwZg&hl=en&ei=RquSSfPNIZWn-gb0yqiJCw&sa=X&oi=book_result&resnum=4&ct=result
Here is a result involving a diabetic ulcer that had not healed for some time:
Talks Alan Russell: Why can't we grow new body parts?
10::30 – 11:50
2.7.1 Hindsight View With Regards To A Fibrin Contaminated UBM ECM
Acell ECM like all ECM does not need clinical trials, it is approved, but it can have
demonstrations to the public which can alter the public’s perception and expectancy.
October 31
On October 31, 2008, Dr Robert Jones, a hair surgeon done his first demonstration with Acell,
the patient had a strip scar revised and Acell applied and tacked in between the skin flaps
enabling a kind of secondary closure. He followed the protocol given to him by the
manufacturers.
In hindsight it looks like the demonstration was not successful as the fibrin scab in the material
showed something denatured the material. Fibrin is known to transform the ECM to scar, it
makes makes the fibrils more dense, they expand with excess collagen, lose the elastin property
and it is harder for the intercellular tissues to crawl up the ECM, this brings fibrotic
encapsulation.
Dr. Jones' Hair Transplant Center Blog

Acell
http://www.drrobertjones.com/acell.html
Friday, October 31, 2008, Scar treatment with Acell

http://www.drrobertjones.com/2008/10/scar-treatment-with-acell.html
First pre revision image
http://www.drrobertjones.com/uploaded_images/acell1-727475.jpg
Second pre revision image

Below you can see the ECM applied with the wound held together by with 5-0 gut.
Second post operation image below.

Nov 4
The first follow up images were put up on the blog on Novemer 4 2008. The wound had
scabbed over.
Tuesday, November 4, 2008

Brief surgical history of patient, first post-op photos
http://www.drrobertjones.com/2008/11/brief-surgical-history-of-patient-first.html
Image 1, Nov 4.
http://www.drrobertjones.com/uploaded_images/Daves-019-640-724264.jpg
Second image, Nov 4 2008
Third image, Nov 4

Wounds must be kept moist. (1) Worryingly with the above images the ECM had scabbed over.
Scabbing is a sign of a dry wound and scabbing means the epithelial cells must travel further
(i.e intercellular cells must travel further) to repair the wound site. (1)
The proper treatment of wounds and ways to minimize scarring, 2003, P. 16, pdf
Wound left uncovered to dry out
Dermis dries out and forms scab/crust that impedes epithelial cell migration
Epithelial cells must travel further to repair wound site
Scabs fall off causing scarring or reinjury
Fibrin is a clotting factor in scabs, (82) and if plasmin (plasmin is a fibrinolytic enzyme, (20) see
page 17) is not available, it is a player in scar tissue, (83) fibrin is also involved in inflammation.
(84) Fibrin clots are not found in the embryo. Will the fibrin bring about a fibrotic or
encapsulation like result? Maybe by blocking up micro pores in ECM forcing over production of
collagen? Fibrin is known to transform extracellular matrix to bring fibrosis (84) (85)
(scars/excess collagen/cicatrices etc.). (83)
Scar Formation
http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2007/392/tw226
Enzymes For Fibrin Control

excess fibrin has been found to be responsible for scar tissue, thrombus formation and
inflammation and its associated pain.
http://www.taoofherbs.com/articles/88/NeprinolEnzyme.htm
Peyronie’s Disease
This leads to fibrin accumulation and exacerbation of fibrosis
http://books.google.com/books?id=fLlNmRPzaEEC&pg=PA22&lpg=PA22&dq=fibrin+ecm+fibroti
c&source=web&ots=bFDjq5jW-
n&sig=1vZWDyFV3862TMktOrGyaLA88EM&hl=en&sa=X&oi=book_result&resnum=4&ct=result
Why Do Wounds Form Scabs?

a new substance called fibrin starts to build a web over the wound.
http://www.wisegeek.com/why-do-wounds-form-scabs.htm
A regenerative response would control the bleeding, (74) which it doesn’t look like this has
happened here.

06:27 A regenerative approach would be… control the blood flow…
in-us/
This was a sign the ECM was denatured or had been denatured. (1) (81) To recap, a denatured
response brings a fibrotic or encapsulation response which hits the cell shape, migration,
proliferation, differentiation, morphogenesis, (81) non-denatured ECM controls cell shape,
migration, proliferation, differentiation, morphogenesis etc. (73) Denaturing (cross-linking)
means the ECM loses the fibril elastin and is having a harder time being resorbed. (81) The
scabbing is blocking the intercellular tissues, the scabbing eludes the intercellular tissues are
finding it hard to crawl up the ECM. (1)
Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular
matrix molecules
Extracellular matrix (ECM) is known to provide signals controlling cell shape, migration,
proliferation, differentiation, morphogenesis, and survival.
United States Patent: 6,579,538

that causes cross linking of the protein material, but this treatment substantially alters the
material such that it is slowly resorbed or not resorbed at all and incites a different type of host
remodeling which more closely resembles scar tissue formation or encapsulation rather than
constructive remodeling.
Out of interest with regards to the scab term, the healing response ‘without’ ECM applied and
‘with’ applied ECM is conveyed here in layman terms. He almost eerily hints and warns about
fibrin scabbing bringing scar wall that closes the wound:
Powder Mends Severed Finger

From my understanding basically the human body forms a scab (fibrin), which then turns into a
scar and a scar is like a brick wall, it stops the whole process. What this material (ECM) does is it
keeps the wound open. You must also allow the enzymes (fibrinolytic enzymes etc.) that the
wound creates to do the healing, you cant use any antibiotics otherwise it kills the system
(denaturing). And by keeping the wound open (secondary intention) the body starts
regenerating itself. All this material is doing is keeping the wound from going to a scar tissue.
1:30-2:08
February 8, 2008
http://www.cbsnews.com/video/watch/?id=3805429n
It is seemingly obvious the ECM lacks the retention of the ECM component decorin, which
controls any fibrin response and allows our tissues to crawl up the ECM, and has probably been
denatured. (It is of note that decorin at concentrations of 100 nM and 200 nM can inhibit
scarring completely. (30) Keeping the elastin fibrils slender enabling migration)
Nov 7
November 7 2008, scabbing still apparent, sutures still in.
According to Acell the ECM should not scab.
The scabbing has clearly denatured the ECM, or it is a sign the ECM inserted was denatured. It is
a sign the intercellular tissues are finding it hard to weave through the ECM and that the wound
has not been kept moist. (1) It is a sign the ECM is making hard work of degrading.
The only logical thing to expect in this scenario is fibrotic tissue encapsulation blocking up the
pores in the ECM, completely hindering any intercellular tissues the chance to remodel.

Friday November 7, one week post op.
http://www.drrobertjones.com/2008/11/friday-november-7-one-week-post-op.html
Nov 7 Image 1
Nov 7, Image 2
Nov 7, Image 3
Nov 7, Image 4
Nov 18
November 18, 2008
The ECM wound is two weeks and the fibrin scab was rubbed off to remove fibrin.
However at this juncture the wound has had weeks of healing with fibrin blocking off the
healing system, blocking intercellular cells from migrating.
And as you can see in hindsight as you look down the pictures, fibrotic encapsulation like
response was the end result. The body responded with a little collagen overexpression
(scarring), which blocked off the pores to migrating intercellular cells. Any new tissues were
not be able to grow through the pores and micro holes and the ECM was not be able to be
degraded with MMP’s. There was not much opportunity for site specific tissue.
Knowing ECM that is not denatured regenerates what tissue is local, the fact it regenerates hair
in other mammals (60) less related to the pig than the primate, Dr Robert Jones was rightly still
positive about hair growth.

Not only did all of the skin grow back, which is unusual in itself, but the hair grew back as well.
However in hindsight you can see the material was spoiled by fibrin, bringing about collagen
over expression blocking up the pores site specific tissue would use.
He talks about results in the coming months were the scaffold is resorbed and degraded into
the surrounding tissues. He also stresses on the importance of being patient in this
demonstration. And says if this one fails he will do other demonstrations with a different
protocol.
Tuesday, November 18, 2008

Nov. 18, two weeks post-op
http://www.drrobertjones.com/2008/11/nov-18-two-weeks-post-op.html
Nov 18 Image 1
Nov 24
November 24, 2008
The wound looked like it was having trouble healing again, the fibrin scab and the dryness was
again of concern. The wound was clearly not moist enough, and logically, through the fibrin
scab the wound probably lacked retention of decorin, which expresses plasmin which inhibits
fibrin. In the womb ECM is surrounded my hyaluronic acid to maintain its moisture, and it is
said that the wound must remain moist in protocol.
It has also been said that this ECM here had a problem with angiogenesis (blood vessel
formation). Low weight hyaluronic acid is known to provide more micro vessels in secondary
wounds. (80)
Low molecular weight hyaluronic acid induces angiogenesis and modulation of the cellular
infiltrate in primary and secondary healing wounds
The morphometrical analysis of angiogenesis demonstrated a larger quantity of microvessels in
HA-treated lesions than in controls and the differences were statistically significant. These
effects were evident both in primary and in secondary healing wounds. However, no favourable
effect on the wound healing time was evident in primary healing treated wounds, whereas in
secondary healing wounds the HA effects considerably aided the healing process, as
documented by the acceleration of wound closure.
It is of not that Hyaluronic acid is produced when hepatocyte growth factor (HGF) is injected into
previously injured vocal folds. This injection suppresses excess collagen production (scarring).
(86) Is the activation of HA the reason?
The Application of Tissue Engineering Procedures to Repair the Larynx

They found that the hepatocyte growth factor—the regulation factor of the triad—when
injected into the previously injured vocal folds stimulated the fibroblasts of the lamina propria to
produce hyaluronic acid while suppressing the collagen production, a major constituent of the
scar.
http://jslhr.asha.org/cgi/content/full/49/1/194
Another thing, does the HA act as a safe guard and carrier for decorin???
It is also of note that HA has been suggested as a carrier of decorin. (29)
Is hyaluronic acid an elegant solution for keeping the wound moist and retaining decorin? It
seems it is.
Monday, November 24, 2008

New Photo
http://www.drrobertjones.com/2008/11/new-photo.html
Nov 24, Image 1
Dec 1
Images were put forward on December 1, 2008, as you can see like the previous images on the
24th, it looks scabbed and yet the wound is not new and had been cleaned of scabbing
previously prior to the 18th. It is clear here in hindsight intercellular cells will have had
problems migrating and that collagen was to be over expressed creating encapsulation blocking
up the migratory pores.
Monday, December 1, 2008

http://www.drrobertjones.com/acell.html
Image 1, Dec 1
http://www.drrobertjones.com/uploaded_images/Daves-069-712375.jpg
Image 2, Dec 1, 2008

Also if you look on the right of images on Dec 1 (above), you can see the right of the wound
looks like it is making hard work of the ECM (It does not look like it is resorbing well). To recap,
paraphrasing Spievack’s patent, this is a sign of a denatured material as this will cause scar that
will affect cell shape, migration, proliferation, differentiation, morphogenesis hence bringing
about a fibrotic and encapsulation response instead of a regenerative response. (81)
Tissue regenerative compositions for cardiac applications, method of making, and method of
use thereof
that causes cross linking of the protein material, but this treatment substantially alters the
material such that it is slowly resorbed or not resorbed at all and incites a different type of host
remodeling which more closely resembles scar tissue formation or encapsulation rather than
constructive remodeling.
Dec 11
The right hand side, like it did on Dec 1, still looks like it is not being resorbed, check out image
3. And regarding the whole of the wound that is now not scabbed and though this is a midway
point of the ECM degrading, the wound looked like collagen had over expressed massively by
the way the wound looked lumpy.
Thursday, December 11, 2008

Six Weeks Later
http://www.drrobertjones.com/2008/12/six-weeks-later.html
Dec 11, Image 1
http://www.drrobertjones.com/uploaded_images/untitled-788547.jpg
Dec 11, Image 2

http://www.drrobertjones.com/uploaded_images/untitled2-709530.jpg
Dec 11, Image 3
http://www.drrobertjones.com/uploaded_images/untitled3-730211.jpg
As well as having a scab that shows contamination with fibrin through the lack of plasmin
activation... The previous pictures on December the 11th seemed to make the ECM remodeling
look like it failed with regards to cell shape, it seemed uneven.
Dec 19
The newer picture on the December 19th was a surprise, the wound did not look uneven like
collagen had over expressed too much and looks excitingly flat like the surrounding tissue, the
wound seemed to be losing redness. The left hand side of the wound looks like it is on it way to
complete regeneration, by the look of its flatness and its pale pink color
By the fibrin over expression earlier on in the healing, it is logic to propose that this ECM was
denatured and in the dry wound lacked any retention of decorin, decorin which would have
denied any fibrin over expression with plasmin expression (41) and collagen over expression in
the fibrils (scar). (30)
However in retrospect as time went by Jones himself even called the wound a scar which shows
collagen was continuing to be over expressed from this point.
Would a belated application here of Decorin have helped the wound, by denying any further
fibril expansion, thus helping what elastin properties are left and helped regeneration by
leaving passages for the intercellular cells to migrate. (More on decorin see page 21)
It is known decorin is the factor that stops collagen from being over expressed, (30) it is the
factor that says do not scar. (30) It is the factor that decorates and stops the ECM from being
dense with to much collagen, (30) which enables the micro pores to remain open so the
intercellular tissues can crawl up the ECM.
There is logic that says it would. (30) The wound itself looks like it does not need any more
collagen expression expanding the fibrils, blocking the pores; in the ECM the flatness is good;
Fibroblasts proliferate creating excess collagen in wound healing, decorin at 100 to 200nM
brings cell growth arrest with no apoptosis. (30) This means decorin here would have insured
the wound stayed flat and no more fibrotic tissue could emerge over the coming weeks and
months.
The logic says decorin injected into the wound and retained with HA would have stopped
fibroblasts creating excess collagen it would have partially rescused regeneration of a wound
already spoilt. And though at this stage it was probably to late for perfect regeneration, as the
ECM had spoiled earlier, a boost application of decorin, maybe in the deep tissues and dermis,
could have stopped anymore over expression of collagen, (30) helped with the flatness, and
helped get intercellular tissues in to grow through any paths that remain, especially on the left
hand side.
The dry ECM here lacked decorin retention, so would an injection of decorin have boosted a
result here?
And would Eupolin ointment have helped here. Eupolin ointment expresses decorin in wounds,
(45) it reduces contraction. (47)
Eupolin along with HA to carry the decorin?
Eupolin also strongly enhanced Laminin 5 in the ECM (48). Laminin 5 induces cell adhesion
activity of Laminin-511. (49) Laminin 511that has been shown to grow hair follicles. (50)
Friday, December 19, 2008

Close up
http://www.drrobertjones.com/uploaded_images/Daves-087_2-796403.jpg
January 7, 2009
The two photos here are provided by the patient and they are blurry, they focus more on the
hair than the wound, but still, they don’t look good and it is fair to say, with the ECM earlier
having a scab that the fibers in the ECM are probably producing excess collagen bundles (hence
scarring) which would block up pathways for the intercellular tissue to crawl up, creating
encapsulation.
It also looks like the wound is lumpy, a sign of excess collagen bundles being produced in the
fibrils. Jones, is also now calling this wound a scar.
It is logical to expect that hyaluronic acid would have prevented this by retaining the decorin
and keeping the wound moist.
Close up 10 weeks
http://www.drrobertjones.com/uploaded_images/Daves-099_2-729549.jpg
10 weeks post op
These photos were just provided by the patient. They were taken yesterday.
At this point it is still difficult to see any growth in the scar, although it looks much better than it did pre op, New
grow would not be expected until about 12 weeks post op.
The protocol for this procedure was provided by the company that supplies the Acell product. Hopefully we will see
new growth over the next few weeks from the scar area.
Dr. Robert Jones

January 28, 2009
This image has a much better focus than the two uploaded on the 7 th. And when you compare it
with the picture on Dec 19, you can see by the redness that fibroblasts have probably
proliferated more in the ECM in turn over expressing collagen on the fibrils. And though the
wound looks flat, it doesn’t look as flat as the images on the Dec 19. It looks like it is over time
maybe developing a lumpy texture in parts, especially on the right. This suspicion is
strengthened when Jones, who examined it at first hand, calls it scar.
It is clear here decorin retained with the carrier HA would have stopped collagen over
expression in the fibrils.
The scar wall here also strongly suggests any hair growth will not happen as hair growth in
fibrous tissue is either sparse on nonexistent; also the intercellular tissues would not be able to
grow through the fibrils which have over expressed collagen.
12 weeks post-op
http://www.drrobertjones.com/uploaded_images/acelljan28th-741310.jpg
At this point I would expect to see some growth through the scar.
The acell was used following exact directions from the company.
If I see no growth over the next month, I will consult with representative from Acell again and
consider trying another patient.
Next update in a few weeks,
Dr. Jones
It is of note that an earlier ECM called alloderm, which retains Hyaluronic acid and decorin, (70)
(71) got complete scar free healing in human dermal tissue. (14)
In a non wounded state, where our body has no fibrin being secreted, it is of note that when
our body creates ECM at this unwounded time, or embryonic time, the ECM is not denatured
and the tissues can regenerate with no fibrosis. Histogen® has created a product that creates
non denatured ECM in our tissues, and when injected into the scalp it creates hair. The culture
when injected influences the body to create ECM, the unwounded body usually does not create
denatured ECM, only non-denatured which enables intercellular tissues to create site specific
tissue.
3. Various Predictions
In the Australian panel interviews, 2002, Sussman, when interviewed announced the prospect
of scar free healing was good, and would probably be here is 5 to 10 year. (13) Maitz
announced he had already seen examples. (13) And Professor Harris said it is feasible for scars
to heal perfectly. (13)
In 2006, Australian panel interviews, Kimble announced that it would be here within 4year. (3)
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 it’s within the foreseeable future...five to ten years. – Geoff Sussman, Founder and
Director of the Wound Education & Research Group,
Monash University”
“Biologically it should be feasible to have tissue heal perfectly. – Professor John Harris, Head of
Department of Surgery, Sydney University”
A Scarless Future: The Wound Care Update Paper 2006, P. 5, pdf –

“Professor Kimble believes may be a reality within the next four years.”
In 2006 Heber-Katz announced that harder tissues like digits would be regenerated in five
years, whole limbs not long after and we would expect this. (87)
Ellen Heber-Katz forecasts the future

http://www.newscientist.com/article/mg19225780.095-ellen-heberkatz-forecasts-the-
future.html
4. Advancements (Please Read)
In 1996, 1997 it was reported Alloderm ECM got excellent results in burns (26)
Alloderm is reported to induce the regeneration of dermis with the normal orientation of
collagen and elastin fibrils instead of the cross-linked collagen and lack of elastin seen in scar
tissue (Wainwright et al., 1995) The fibroblasts that repopulate the Alloderm lack the
myofibroblastic phenotype of granulation tissue and the grafts exhibit minimal contraction. The
basement membrane of the dermis interacts with overlying keratinocytes to induce the
formation of hemidesmosomes and Type VII collagen anchoring fibrils. Alloderm has been
evaluated clinically for burns and is reported to provide good to excellent cosmetic appearance
and functional performance (Wainwright et al., 1996: Lattari et al., 1997: Sheridan and
Choucair. 1997)
http://books.google.com/books?id=3Ue5oF3INKsC&pg=PA73&dq=reducing+contraction+decori
n
It is known our tissues are always regenerating, and to get regeneration of a tissue you have to
stop fibrosis. (4) Hence to prove regeneration would also show the concept of scar free healing.
In 1999, the concept of scar free healing was official proven on a simple tissue when, using
ECM, bladders were regenerated. (4)
Profile: Anthony Atala - Nature Biotechnology

"In tissue engineering," Atala says, "everything goes back to scar formation."
Google search, Atala goes back to scar
http://www.nature.com/nbt/journal/v24/n11/full/nbt1106-1311.html
2003-2005, Alloderm visually demonstrated scar free healing via the knuckles of a burned to
the bone hand, as you can see it completely controlling cell shape, migration, proliferation,
differentiation, morphogenesis, and survival of a simple tissue. (14)
=15
In 1992 an ECM protein called decorin was reported to cause repair in every tissue. (24)
PROTEIN HELPS REPAIR ÈVERY 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-
0=document_id&p_perpage=10&p_sort=YMD_date:D&s_trackval=GooglePM
It is clearly understood that scarring occurs due to collagen over expression which dense up the
collagen fibers in ECM which blocks pathways. In 2006 it was officially announced in a
publication that this ECM protein can completely inhibit scarring by inhibiting collagen over
expression. (30) Allowing our intercellular tissues to grow through the ECM just like what
happens scar free healing.

In 2006, Professor Tony Ryan, a researcher of ECM, announced complete scar free skin healing
in dermal tissues using a man made scaffold (72) that is designed on ECM.
Scaffold surgery
Before being placed on the wound, via a biopsy, the patient's skin cells are introduced and
attach themselves to the scaffold, multiplying until they eventually grow over it. This is then
placed over the wound and after six to eight weeks the scaffold dissolves, leaving the skin cells
behind.
http://www.theengineer.co.uk/Articles/295184/Scaffold%20surgery.htm
In 2007, using ECM NMT Medical Inc. brought out an ECM product with a metal rim, that
regenerates heart tissue to 95% of its local softer tissue environment, the ECM they used was
derived from the intestine of the pig (SIS), said to be a first generation ECM. It was denatured
by the metal rim. Checked after about one year only the metal rim remains as the ECM material
has been completely absorbed by the body. This is exciting for our more softer simpler tissues
(skin, bladder), using the fact that ECM is absorbed, and degraded were the host local tissue
takes its place. They are in the process of development without a metal rim. (13)

metal framework remains. An entirely absorbable implant is currently under development.
2008, every angle in scar free Healing is now covered. Ellen Heber-Katz, the scientist who
earlier discovered the MLR mouse regeneration response, (11)
Mouse sheds light on regeneration

http://news.bbc.co.uk/1/hi/sci/tech/4888080.stm
under the radar, announced that she has found and can manipulate the complete genetic micro
characteristics that produce as good-as-new tissue. (12) (To reiterate, it is of note that you can
not have any regeneration if you have fibrosis Atala law. (4) So we now also know the micro
processes of scar free healing as well as the macro). Comprehensively proving every angle has
been covered and understood and manipulated in scar free healing to get complete scar free,
site specific tissue.
Humans ‘to grow replacement body parts’

And in November of this same year the US army announced regeneration of tissues is very
advanced, planning announcements at the 26th Science conference, in December. (17) Claiming
complete regeneration and that the ‘nanoscaffold’ can regrow many tissues and has already
been used to regrow a bladder (Atala et al, 1999) a simple tissue like skin, uterous, sexual
organs. (17) Asserting the scaffold helps the body regrow tissue much the same way a
salamander regrows a tail and their aim is to go into complex tissues like the heart. (17) Also
showing that there are denatured versions around chemical additives and that the material can
be denatured. (17)
U.S. military can regrow human limbs, organs - 'Nanoscaffolding' has succesfully regrown
fingertips and organs on test subjects Vito Pilieci. 2008-11-07
“The military plans to announce the breakthrough at the 26th Army Science Conference - which
attracts more than 1,600 international military scientists - in Florida next month.”
“By using nanoscaffolding, the military was able to regrow the man's fingertip, restoring
everything he had lost, much like some amphibians can regrow a leg or tail.”
“Parmentola said the military has been able to regrow "whole bladders" in people who have had
bladder damage. The technology has also been used to repair the wall of a woman's uterus.”
“"There is one example of a young girl who . . . was born without a sex organ, and that was
regrown," he said.”
“The U.S. military has set up two research institutes to continue testing different ways
nanoscaffolding can repair major injuries in humans. Parmentola said the institutes are
researching cellular regeneration in lizards to further their understanding of how nano-
scaffolding can help humans.”
“Researchers attached a person's skin cells to a nanoscaffold, and the cells grew over it. The
skin-covered scaffold was then placed over the wound, where it bonded with the patient's body.
The scaffold then dissolved.”
“"Previous attempts to find better ways of encouraging skin cell growth have used chemical
themselves into the right arrangement. They just need a comparatively uncomplicated scaffold
(and each other) to help them grow in a safe, natural way."”
Scar free healing is here and is understood.

5. Anticipation
Despite modern media, information adoption to technologies, sometimes, can be slow. (88)
Using this fact file either by reading it, or looking at the advancements, you can see scar free
healing is clearly here.
With scar free healing being here, the rhetorical question should be asked, how much slack
should be given?
Alan Russell hints at the important necessity of expectancy for progress.
Talks Alan Russell: Why can't we grow new body parts? 19:13-19:20
6. External links
*http://www.acne.org acne.org
*http://www.workingwonders.com.au The Royal Children’s Hospital Foundation
*http://www.changingfaces.org.uk/Home changingfaces.org.uk
*http://www.burnedchildrensclub.org.uk/ burnedchildrensclub.org.uk
*http://www.childrensfireandburntrust.org.uk/ childrensfireandburnstrust.org.uk
*http://www.cleft.ie cleft.ie Cleft lip and palate association of Ireland
*http://www.limbless-association.org/ limbless-association.org
*http://www.scarinfo.org/ Scar information service
*http://www.phoenix-society.org/ The Phoenix Society for Burn Survivors
7. Linked threads
8. FAQ’s
9. Current & previous pdfs of thread material, pre-
amendments
9.1 Tom_Masons Original introduction:
Jun 7 2007, 08:55 AM

Im unsure if many people here have heard of this product but seems to be quite promising, and not like another 20 years away
either. The crux of it seems to be that after an operation, (not specifically acne scar revision) but similar, the companies lead
product juvista is injected into the wound margins and scarring is significantly reduced. They appear to have other products as
well in the pipeline for internal scarring also. If u were going to have an excision or similar this seems the way to go. Anyways
definately worth checking out!!!
http://www.renovo.com/content.asp?c_id=9
10. Template Letter Headings and Bodies
Works Cited
1. Lombard, Danielle and Dec, Agata. A Report on the Proper Treatment of Wounds and Ways
To Minimise Scarring. Australia : Weber Shandwick Australia, 2002. p. P. 27. I can show you
scarless healing... – Dr Peter Maitz, I think it‟s within the foreseeable future...five to ten years.–
Geoff Sussman, Biologically it should be feasible to have tissue heal perfectly.– Professor John
Harris,.
2. Condren, Bernadette. Fetal protein holds key. news.com.au. [Online] October 7, 2005.
[Cited: December 2, 2008.] http://www.news.com.au/couriermail/story/0,23739,16844871-
8362,00.html.
3. A Scarless Future: The Wound Care Update Paper 2006, pdf. Australia : Weber Shandwick
Australia, 2006. p. P.3, Update. 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..
4. Aschheim, K. Profile: Anthony Atala - Nature Biotechnology. nature.com. [Online] 2006. "In
tissue engineering," Atala says, "everything goes back to scar formation.".
http://www.nature.com/nbt/journal/v24/n11/full/nbt1106-1311.html.
5. Ferguson, Mark W. J. and O’Kane, Sharon. Scar-free healing: from embryonic
mechanisms. Renovo.com. [Online] April 20, 2004.
http://www.renovo.com/documents/radF37FC.pdf.
6. Layton, Julia. Humans can regrow fingers? howstuffworks.com. [Online] 2008.
http://health.howstuffworks.com/extracellular-matrix.htm.
7. Ferguson, Mark W. J. and Whitby, D. J. Scar-free healing: from embryonic mechanisms to
adult therapeutic intervention. Renovo.com. [Online] 2004. 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.
8. Rosenwald, Michael. A Doctor, a Pig, and a Magical Pixie Dust That Could Regrow Fingers.
esquire.com. [Online] September 18, 2007. 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.. http://www.esquire.com/features/esquire-100/pigfinger1007.
9. Wilson, Elaine. Researchers Work Toward Regenerating Lost Extremities. infozine.com.
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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/.
10. Layton, Julia. Humans can regrow fingers? Howstuffworks.com. [Online] 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... http://health.howstuffworks.com/extracellular-
matrix.htm.
11. Morelle, Rebecca. Mouse sheds light on regeneration. bbc.co.uk. [Online] April 11, 2006.
"So we did it again, and we watched them, and there it was - the holes had closed up..
http://news.bbc.co.uk/1/hi/sci/tech/4888080.stm.
12. Rogers, Lois. Humans „to grow replacement body parts‟. timesonline.co.uk. [Online] May 4,
2008. Blastemas 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.
13. First Ever Implantation of Bioabsorbable Biostar Device at DHZB. dhzb.de. [Online]
December 2007. 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. .
http://www.dhzb.de/international_services/dhzb_aktuell/detail/ansicht/pressedetail/290/.
14. Home Journal Article The Use of Acellular Dermal Matrix for Coverage of Exposed Joint
and Extensor Mechanism in Thermally Injured Patients With Few Options. eplasty.com. [Online]
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15. Rogers, Lois. Humans „to grow replacement body parts‟. timesonline.co.uk. [Online] May 4,
2008. had discovered the genetic characteristics that produce “good-as-new tissue”.
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16. The proper treatment of wounds and ways to minimize scarring (pdf). Australia : Weber
Shandwick Australia, 2002. p. 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. .
17. Citizen, Ottawa. 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. canada.com. [Online] November 7, 2008. Using
“nanoscaffolding,” the researchers have regrown a man‟s fingertip and the internal organs of
several test subjects.. http://www.canada.com/topics/news/story.html?id=6864c9e0-cfcc-4cf6-
b373-6d4cbabe6cd3.
18. Schupak, Amanda. Rebuilding the Troops For wounded soldiers, the military's Institute of
Regenerative Medicine offers dramatic new ways to heal. popsci.com. [Online] June 24, 2008.
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.
19. Scar Tissue Build Up: Anti Fibrosis (Scar Tissue removal). enzymus.com. [Online]
Fibrinolytic enzymes eat scar tissue and fibrosis... we make a finite amount of enzymes in a
lifetime. Cystic Fibrosis patients who have virtually no enzyme production to speak of....
http://www.enzymus.com/scar_tissue_buildup.
20. Minton, Barbara. Eat Natto and Care for Your Cardiovascular System Naturally.
naturalnews.com. [Online] February 20, 2009. http://www.naturalnews.com/025684.html.
21. Cutroneo, KR. TGF-beta-induced fibrosis and SMAD signaling: oligo decoys as natural
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Table of Contents

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

Fetal protein holds key

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

Note: the above paper is now off line.

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

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

Profile: Anthony Atala - Nature Biotechnology

Humans can regrow fingers?

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

Humans can regrow fingers?

"Researchers Work Toward Regenerating Lost Extremities",

"Mouse sheds light on regeneration",

Humans ‘to grow replacement body parts

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

First Ever Implantation of Bioabsorbable Biostar Device at DHZB

Humans ‘to grow replacement body parts’

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

*Growth Factors for pathways

U.S. military can regrow human limbs, organs

Rebuilding the Troops

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

Anti Fibrosis (Scar Tissue removal)

Eat Natto and Care for Your Cardiovascular System Naturally

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

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

It is of note: non denatured ECM’s Decorin is a solution to contraction and fibroblast

Regenerative Biology and Medicine

Using decorin, an anti-fibrosis agent, to improve muscle recovery after injury

Protein Pushes Damaged Muscle Toward Repair

Tissue Engineering and Artificial Organs

What are scars?

What cause the scar?

Human ECM for Devices and Therapeutics

Stem Cell Summit

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

Methods of preventing or reducing scarring with decorin or biglycan

Methods of preventing or reducing scarring with decorin or biglycan

Recombinant Human Decorin Inhibits Cell Proliferation and Downregulates TGF-&beta;1

Extracellular matrix proteoglycan decorin-mediated myogenic satellite cell responsiveness to

Deep dermal fibroblasts contribute to hypertrophic scarring.

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

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

New Technologies for Repairing Spinal Cord Injuries:

Plasmin Triggers Rapid Contraction and Degradation of Fibroblast-Populated Collagen

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

SKIN TREATMENT BASED ON THE USE OF CHROMOLAENA ODORATA

Retinoic acid and its receptors in limb regeneration

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

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

Upregulation of adhesion complex proteins and fibronectin by human keratinocytes treated

Upregulation of adhesion complex proteins and fibronectin by human keratinocytes treated

Laminin-511: Hair Growth Molecule Discovered by Stanford Researchers

Extracellular matrix has an impressive antibacterial profile (52)

Antibacterial Activity within Degradation Products of Biological Scaffolds Composed of

(WO/2006/069417) A METHOD OF TREATMENT

The Royal Children’s Hospital Foundation, July 2005, page 3

Fetal protein holds key, 2005-10-08

There are high levels of fetuin in fetal tissues (56)

(WO/2006/069417) A METHOD OF TREATMENT

Effect of fetuin, a TGFβ antagonist and pentoxifylline, a cytokine antagonist on hepatic

Why isn’t the ACell Vet™ bioscaffold rejected by the host?

The Science of Tissue Engineering

Material from pig intestine is remedy for deep sores, incontinence

Recombinant Human Decorin Inhibits Cell Proliferation and Downregulates TGF-β1

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