Barbara I'm not sure where you got
to said they really need to cheer.

I mean she has a chair but
it's not one she considered him.

Shannon.

Barbara you all.

Shannon one of the chairs now for salmon.

OK Well we welcome everyone.

It's a pleasure to have everyone here
on a Friday afternoon a beautiful day.

I realize there's all kinds
of things you could be doing.

Most importantly back in the laboratory
working until nine ten o'clock

this evening but
we're glad that you are here for

this seminar it's very special
to have Dr J. have a kani here.

Jay and I been around the block several
times he was one of our he was a keynote

speaker at our first Hilton Head workshop
in one nine hundred ninety seven and

we'd been remiss to not get him back since
them have a kani originally from Nebraska

undergraduate Creighton University
Medical School University in Nebraska.

Somehow he made his way to Harvard and I
guess to some extent your life hasn't been

the same sense and
obviously very accomplished.

He's professor of surgery at Harvard
mistresses General Hospital.

He few years ago was elected to
the Institute of Medicine of

the National Academy of Sciences but
in the world of tissue engineering.

I guess what I would say about
David Conti is he's bigger than life.

He was there pioneering it.

At a time when a lot of people were who
poing what this was all going to be.

He continues to do great work and
I think it's wonderful to have him here.

And as you indicate in this title.

To provide a surgeon's perspective.

So Jay and
I want to take any more you time.

Welcome to Georgia Tech to Atlanta and
to our Georgia Tech Emory Center.

Thank you very much Bob.

I'm delighted to be here Bob said
our right we've been friends for

a very long time and I'm now delighted
to have been invited down here and

have the opportunity to not only see the
facility but also to have a chance to meet

hopefully many of you and
learn exactly what's going on here.

Now I'm a little unusual for

this campus because I am a clinical
surgeon and from the beginning.

That's sort of how I became involved.

So I put this talk together.

Mostly with the students in mind and
with that in mind and.

Bob also said it right.

It's a beautiful day out.

I should have you out here by ten.

And the other funny thing was
not to be as long as you're well

on some of those start shortly and long
but I promise you that won't happen today.

So what I'll do is take you through
this more as a personal journey.

And then I'm sure we'll have time for
questions.

After I give the talk so.

Let's see how we do with this thing.

So I don't.

I don't really want to stand in from
the podium so we'll see if we can do so

as I actually came to the Massachusetts
General Hospital a surgical intern

in one thousand nine hundred seventy four.

That's thirty one years ago.

And there's a culture at the M.G.H.
but it's a little different than this.

This is a very good hospital and

in every very good
hospital in the country.

OK Janelle Lee There is a patient
who has a terrible problem.

And in a very good place.

The answer is I am sorry but there's
nothing more that than that we can do.

And that's perfectly good
in a very good hospital.

But when you're in an academic center.

Then somebody could say I have an idea
that might help with this bad problem.

So in that circumstance.

You need to be in a very special place.

So a place like I am like Emory so

clinical people who want
to go beyond this to this.

This is a common route
to have that happen.

And we're very lucky as you
are here because if we start

with the terrible clinical problem then
we can draw upon our resources and

our friends and in the case of Mass
General which is part of Harvard we can

draw on MIT the Draper laboratories this
entity that was started at the general

almost eight years ago called the Center
for the integration of medicine and

innovative technologies but
all of these organization.

Ans.

Create young interested people like you.

That can come together to get
back to this terrible problem.

Now a spinoff is

like Dr Nerem you can become
a professor starting with the problem.

You can write grants get
them you can build buildings

write papers give lectures.

But that really isn't the central
element of what we're doing.

The central element is this
therefore to complete the loop.

All of this should result in this
which gets back to the patient.

So again from a doctor's point of view the
loop is very important to return to and

in that loop is the obligatory
involvement of industry

because if you go into any hospital any
bed space any I.C.U. any operating room

every tool we use to take care of
a patient has gone through this route.

So we as academics cannot
complete the loop alone.

That's a very important concept.

I think as we evolve our going to solve
the problem we should always have

in mind that the solution ought
to be a practical solution and

that somebody should become interested
in it so that they can have their

shareholders make money for the purposes
of getting this back to the patient.

That's not a bad thing.

There are places where that's perceived
as bad Harvard is one of those places.

So there has to be a cultural shift

because we want to get back to
the patient and I think that.

It's a very important thing.

So this is the paradigm into which
my work in tissue engineering.

Began and has evolved so what does that
mean in practical terms for me will do.

This is the kind of patient in
this is one of my patients that I

became interested in this
little girl has a progressive

disease that she was born with that
destroys first her bile ducks.

Then her liver.

And then kills her.

And before about the mid
one nine hundred seventy S.

roughly ninety percent of kids born
with this particular problem died.

So there weren't any medicines and

there weren't any operations before
the mid seventy's that were successful and

so we would say I'm sorry there's nothing
more we can do but by the mid one nine

hundred seventy S. there were some
surgical techniques that evolved and

I became involved as a young
surgeon with if the reconstructive

operation failed then we were able to
remove the diseased Oregon the liver.

And replace it with somebody else's liver
and that's an organ transplant and here

I am in almost exactly this amount this
date in one thousand nine hundred four.

It was Patriots Day.

So these urgent terrible operations
always occur on a holiday.

Or a personal important day or or
a Christian holiday because I'm Christian.

So this occurred on Patriots Day
which is the day that we sell it.

We have the Boston Marathon but it's
actually the shot heard around the world

Lexington and Concord it's a very
important day in New England.

So here we were in one thousand nine
hundred four doing the first successful

liver transplant in
a child in New England and

as a young surgeon that was a fairly
stressful circumstance to be doing

the first and there were a few times
it's a very complex operation where

we were a little bit not certain
of where we were and what we.

Were doing but
the radio kept saying we were doing great.

We had the radio on and
they said we were doing great.

So that gave us confidence in any

event that operation in one thousand
nine hundred four was successful.

It was an infant a fifteen month old
child with the disease I showed you

there was a fair amount of press and
here he is twenty years later.

So again I show you this because
again from a clinician's

perspective that thing that drives
us is the potential for success.

So many people ask me how can you take
care of these terribly ill patients.

Isn't it depressing and
the answer is it would be depressing.

If we were never successful but
the truth is we are and

this is an example of turning a disease
with a ninety percent fatality into

a success of about ninety percent at ten
years using the tools that we have today.

So it's a very good thing and you can
see here that he's healthy and happy.

In fact he's married and

is doing quite well because another little
girl who was similar to the first little

child I showed you here she is several
years after her transplant as a newborn.

But this is what she looked like and
again I show you these

pictures not to shock you but to have
you understand from a clinician's X..

Perspective why you're driven
to try to find new solutions.

So this girl is this girl and
when we were taking care of her again.

Remember it's just one tissue
that isn't working right.

But it's a vital to shew the liver and

in any vital organ failure especially
in kids they can do very well and

compensate with the enormous reserve
until about ninety percent of that war.

Function is failing.

And the final ten percent
is a horror beyond belief.

So we put her on a waiting list as soon
as we knew she had the problem and

she waited and waited and waited and

I took this photograph when she was still
an outpatient living with her family.

We were doing everything we
could to support her nutrition.

But again since it's a vital organ
all the systems begin to fail and

you can see that clearly here.

We ended up finding an organ for
her from the West Coast

because she was in an intensive care unit
on life support and that finally got

us high enough on the list that
we were able to get her an organ.

So again putting my clinical had on
I'll just quickly take you through this.

So now I've been involved with
this one kind of patient care.

One kind of surgery now for
about twenty years.

And transplant patients I'm very proud
to say began in the Harvard hospitals.

This is a painting the now hangs
in the Count way a library

that demonstrates the world's
first successful human transplant

which was done at the Brigham hospital
in one nine hundred fifty four and

this is Dr Murray who's one of my
teachers transplanting a kidney

from a twin brother who was being
operated on here and identical twin so

genetically identical his kidney
one of his kidneys into his

dying brother and that was successful and
from a chief's point of view.

Bob there's something
very interesting here.

He was a young surgeon who did all
the research to lead to this operation and

the chairman or the chief is carrying
the organ from one room to the other.

That's Dr Francis more so

when you become senior enough
to become a chief part of the.

Recruitment is to find somebody who
is extraordinarily generous and

who can take pride in the students
that he's training and

certainly Dr Moore
exemplifies that here and

I think that that's a wonderful
depiction of how it really happened and

as many of you may know Dr Murray went
on to win the Nobel Prize in Medicine

in one nine hundred ninety for
his contributions in transplant patients.

OK again.

Here's the operating room.

This is a bad liver.

OK this is in stage right
before we're taking it out.

Here's a good liver.

You can see the ice here.

And again one tissue one two issue
set of functions and so we need

to replace anough of that tissue in
this circumstance it's the entire organ.

And it must work immediately.

And here it is after We've implanted it.

And we've actually as you know
sewn in the blood vessels so

that we release the clamps there's
a media perfusion of oxygenated blood

throughout the organ so
that there can be immediate function.

This was actually the first Canadian child
that had a successful liver transplant

as was nine hundred eighty five.

And I show this slide
to give you all a sense

of just how difficult it is to not
only get through the surgery but

to take care of the patients and
every monitor that's been invented.

Is brought to the bedside this little
bag actually monitors biol output and

then these are drains because
it's a big operation and

there can be a lot of bleeding.

Not only during the operation but
after the operation and

again this photograph was taken
in one thousand nine hundred five

The surprise is it's not much
different in the year two thousand and

five areas after the surgery
curious that is.

First Communion.

Here he is playing hockey and
here he is with his little brother.

So again the success is what drives us

to seek solutions in which there
are currently no good solutions.

This little guy was sent up from
New York and you see here a bag

in this bag was trying to drain vial from
a previous reconstructive operation.

It did not work and this baby was dying
and in order to get him an organ.

We did something that we had
never done before which is

it was a mortal sin in this era I can
say that because the pope has died.

You cannot you cannot cross blood groups.

So we all are either an A a B.
or no and there are and

there are certain combinations which will
work but other combinations which will

absolutely be recognised by your body and
you'll have an intense acute reaction.

Well we crossed blood
groups in this child.

He was an blood group A and
we put a blood group B.

liver into it because we had a little
insight into the biology and

the antibodies that circulate in our blood
stream against the other blood types

actually evolve over time and so we had
measured the antibodies in this child and

we now know that age two and
under you can actually do this

safely with the strategy of what we
call plasmapheresis So in any of it.

He was our first this was about
one thousand nine hundred seven.

And here he is and so
again another example of

persistence creativity with
the tools we have what can we do.

And as you know the organ shortage has
been an ongoing issue that I'll get to but

a surgical solution is the following.

That anatomically the liver has

discrete anatomic units that
contain a complete blood supply.

I and a complete biliary tract so

that if we're very careful in delineating
these into Second these we can actually

take a piece of a bigger liver and
put it into a smaller patient.

And that was the first step with taking

with toward solving the organ
shortage create creatively.

So then one could imagine that not
only could you take one piece and

and not throw away the rest but
divided in such a way that part could

go into a bigger patient and the smaller
part could go into a smaller patient and

that's called split liver transplant
patient and here's an example of a piece.

This is the smallest
piece that you can do.

Anatomically It's called
the left lateral segment and

you can see all the various
connections here.

Here's the portal vein all the blood from
the intestine going to the liver and

the outflow of the a paddock
vein back up to the heart.

Here's the arterial inflow and
here's the bile duct output.

This is a little baby
in the newborn period.

You can see the big incision here.

This is the opposite of
minimally invasive surgery.

This is maximally invasive surgery but

maybe someday with tissue engineering
we can turn it into minimally invasive.

Here's that piece of liver after
we've individually stitched the raw

surface where we've cut through the liver.

And here's that child some
many years after that first

operation this little girl was
the first one on the East Coast.

They got a piece of liver from a living
donor in this case it was her father and

this was one nine hundred ninety two.

And here she is after that operation and
here she is more recently.

And I'll tell you one last
sort of anecdotal story

from the operating room before
we get into the science.

So this is a newborn baby and
you can see he's very.

Sick and he was sent up from
Hasbro Children's in Rhode Island with his

heart not working his lungs not
working his kidneys not working and

his liver not working his brain seemed
to work and his intestine nobody knew.

OK so you're sent out because we have
a machine at our children's hospital

at Mass General.

It's called ECMO extra cup
Oriel membrane oxygenation and

it's a form of cardio pulmonary
support but for newborns

you can actually totally support the heart
and lungs in the I.C.U. for up to a month.

So we put him on that machine for
three weeks and

during that three week interval
heart return function his lungs

return function his kidneys return
function but his liver remained dead.

So at that period of time we entertained
with the family the possibility of

doing a transplant to make
a very long story short.

There had been no previous case
of this that had been reported or

that anybody knew of so

we generously quoted about a twenty
percent chance of success to the family.

We ended up doing what what is
termed a split liver transplant.

Here you can sort of see it where we're
dividing the liver almost down the middle

and this piece smaller piece
went into that child and

here he is some two years later.

So the part of me that Bob doesn't
see talked about very well or

often is the clinical piece
which is really what has driven

our work that I'll now go through so
to make it summarize

just this one kind of patient care
liver transplant patient and children.

The bottom line is now after twenty years.

Two thirds of all of those
kids are still alive and

virtually all of those kids
that are alive are well.

So again the success.

The hint of six.

SAS drives us to make it better and

this is the problem that has driven us in
all of our work in tissue engineering.

This is four years after we began
our work until to engineering and

the organ shortage was
described as awful and

acute nineteen thousand
patients in the United States.

Now all these years later it's
up to eighty eight thousand.

So the drive to actually get
this done complete the loop and

solve the organ shortage is
really very very pressing.

Now at least our work didn't.

I'm sure here you have an idea and
it's a straight line to the to Homebase

that isn't really how our work evolved and
in fact when we began

this picture is from one nine hundred
eighty five and this is a mouse and

this clamp is on the liver after
removing part of the liver but

we were removing it to grow
the liver cells to grow a new liver

the first idea that I had was
when you cut across the liver.

You can imagine all those bile docs and
all those blood vessels losing.

That was a big problem especially
in one thousand nine hundred five.

So I thought you know one
of my very closest friends

is Professor Robert Langer.

And I thought wouldn't it be nice
if you could paint on a plastic

have it harden instantly and then be like
Plexiglas here in seal this raw surface.

So I went to Bob and I said Do you have
any stuff like this and could it go away.

Could it be temporary and go away so that
we'd end up with a healed surface with no

foreign body so it wouldn't get infected
and he said Sure we can do that and

he assigned one of his post-doctoral
fellows to the project.

Avi dome who is now in Israel and

he worked up a few concoctions from my
point of view was a few concoctions.

And so I would paint these
things on they would dry and

then we'd let it heal and
I'd look at it under the microscope and.

This actually was very successful and

there was very good healing
minimal inflammation.

But as I looked at hundreds of these
sections it occurred to me that the liver

cells looked so healthy that maybe we
could use these polymers as a delivery

pallet to deliver a pad ascites back
a form of cell transplantation.

So really that first inclination to
produce something to deliver a patent

sites really was trying
to solve the problem

in an incremental way
using liver reception.

And as people know that turned out to
be a pretty successful approach so

much so that we never wrote
up that last set of studies.

If it remains so if anybody here is
interested in right now up a nice little

paper on how to heal the liver using
polymers there is some preliminary work.

And it's now about twenty years old.

So this is one of the first wafers that we
designed it's about the size of a dime and

this is made out of a degradable poly and
hydride and

we load this with a pad of sites and
then implanted in the omentum.

But what's interesting
is this is not a foam.

It's not a fiber base material I'll get
to that but when I look back at all this

this little branching structure was not
there to increase surface area but it

was actually there to try to cue the a pad
of sites to begin this form by all docs.

So even as early as one nine
hundred eighty five eighty six

we are trying to think through how
to start signaling those cells to do

what we'd like them to do
to not only put a little.

Lump of liver there but
try to form bio docs and

again that's probably everybody in
this room knows the central issue.

You in terms of design of the systems.

If what you want is a big enough
piece of tissue is this fundamental

problem that as the mass
of cells is larger and

larger the surface area where
the exchange of oxygen and

nutrition occurs only increases
as the square of the radius.

But the volume of cells that
needs the mass transfer increases

is the Q So every design in
the field of tissue engineering

must try to match the surface area to
volume for effective mass transfer and

there are a number of strategies to
try to do it but you can't avoid this.

So whether you start with two
stem cells and have them grow

a mass of tissue and grow the blood
vessels as they grow the mass of tissue or

whether you try to implant
a very large structure.

You have to deal with this problem.

And our solution in one thousand nine
hundred six was really based on nature

solution for multicellular systems
which is the volume is broken up

through these fractal based
branching systems and

that way you have an effective increase
in surface area as the volume increases.

So based on this and this you see
is a vascular cast of the human

lung demonstrating that
this is nature's solution

through all systems that are multicellular
in the plant world the animal world.

The human world and
in fact all communication

between all systems is sort of these
of these fractal branching patterns.

So this is from one nine hundred eighty
six and it's a little graft of hepatocytes

and when we started doing this we actually
had very early success and in fact even

in these early graphs you can see on a pad
a side undergoing my ptosis here and

another one here in the very earliest
beginnings of a Billy or a system.

This is from one thousand nine hundred six
and it's a little cyst that started as

little minced pieces of fetal intestine
and again showing success very early on.

So our first paper was actually in
my specialty in pediatric surgery

and this led to then our general
approach myself with Professor Langer

with combining these synthetic degradable
systems that were suitably configured for

mass transfer with
the appropriate cell type.

Implantation vascular in
growth a range of Genesis and

then formation of a permanent tissue.

If we were really good at
it we got good tissue.

If we were bad at it we got scar tissue.

So the trick to get all this became how do
you do this in the best possible way using

all the tools of tissue engineering and
again just for the historical record for

all of the young people when
ever you start down a new road.

You're not universally embraced.

And so
this is roughly ten years into our work.

Eugene Bell who's really one of
the pioneers of the field and

he wrote this in this journal.

I think it's fatuous to think that one can
take a plastic material off the shelf and

so on and so forth.

So when I saw that he had actually.

Acknowledged us and
being a kid from Nebraska.

I called my wife and I said Gee Dr Bell
and has acknowledged us in this paper but

I couldn't really remember what
fatuous meant so I looked it up and

fatuous means complacently or
in the Namely foolish or stupid.

So that I said.

I hope he's not one of our grant
reviewers and through the years.

It turned out that not only was he a
reviewer but a lot of his friends were so

as a young person you know the more
risky year the road you take.

Don't count on everybody embracing
your work but you must be persistent.

Passionate and you must have chiefs or
chairmans that will protect you and

support you.

So I'll quickly very much go
through a lot of the evolution in

our laboratories my brother Charles
who is now chief of anesthesia

at the Brigham hospital began the work in
the lab it with bone and cartilage and

here you see one of our early polymer
structures in a clinician's and

the audience would recognise that these
actually were not built at MIT and

they really were expensive because we
stole them from the operating room and

the this is just unfree suture material

made of poly guy colic acid this
particular material is called Exxon.

So we were able to raid the operating room
as long as it was the middle of the night.

And then we would fashion these add
the cells of the implant these into small

animals and here you see the progression
over time of cartilage formation

as the polymer disappears new cartilage
is formed and you all are aware of

this from early to late in culture you can
drive it all the way to complete tissue.

And then the clinical perspective.

This child has been born with
terrible cranial facial anomalies

some of which are life threatening other
of which are disfiguring but even if it's

only disfiguring as this year would
be you can imagine that would produce

such terrible psycho social implications
for not only the child but the family.

That any improvement that we can do
with these terrible anomalies would

be a great advance for the field
of plastic cranial facial surgery.

So again by a one nine
hundred eighty nine.

We were experimenting with this with the
cartilage that I had shown you previously

and here is an animal.

That has been reconfigured
in sort of a cling on way.

And here's the new cartilage
that was formed and

we learned by one nine hundred eighty nine
that we could make very specific shapes

at the appropriate number
of cells implant them and

then the shape would be well
maintained and this famous or

infamous mouse is a demonstration of that
with human cells in human shape of an ear.

It's a human ear on the back of
a mouse and it became a relative icon.

I thought it would be a terrible thing
to have this come out in the late press

my brother thought otherwise.

And it turns out I think the net
effect has been good because

it increased late awareness
that this field was emerging.

But when this was originally presented
in one thousand nine hundred four at

the American College of Surgeons Jurassic
Park had just come out so we called him.

Our regular Saurus And
here's the cartilage that has been formed.

There was a reasonable amount
of press here you see nasal

cartilage is cells on polymers
here by nine hundred ninety six

we are making composites of bone
bone joint space in between with

you know this is about six months after
implantation on the back of a mouse and

you can see good bone good
bone joint space and good.

Histology.

So where are we going with that.

Well there is this technology
called a three dimensional printer

that you all probably know more about
than I do but it's a very cool and

is very germane to the work.

So this skull started as
a three dimensional C.T.

scan of a real human and
it's been converted to digital data and

then converted through this machine
layer by layer to make this skull.

And you can imagine then if
you use of degradable polymer

make it suitably porous with the right.

Mechanical characteristics.

If you took a sample of the patient's
own bone marrow enrich to it for

the stem cells signal
them to turn to bone.

You could do a complete
surgical reconstruction

of the cranial facial
skeleton as a one step.

Definitive reconstruction.

So that's the road.

We're going down in pigs
cardiovascular I'm really going

to skip through because it's like
bringing coals to Newcastle.

But as people here know the first now.

Vascular implants are in
patients in Japan from one of our

former fellows who is a congenital heart
surgeon at Tokyo Women's Hospital and

he's now done over fifty children with
either pulmonary artery segments or

Veena K. the segments with success.

As a pediatric surgeon I also
take care of this kind of baby.

He's born with an abdominal wall
defect but then his intestine

continues to flow in amniotic fluid and
his injured and

some of these kids have what we call short
gut syndrome and the gut is a vital organ.

So could you make intestine.

We were making it by the late
one nine hundred eighty S..

Here's one of those early photographs.

Here is Rosa Choi's work with normal rat

intestine here tissue
engineering intestine here.

And here's a more recent work from
Tracy Gregg shite comparing normal

rat to engineer that's been
sewn back into the main

intestinal lumen and
now showing benefit to the animals.

After a massive small bowel resection.

My field of congenital.

Anomaly surgery children are born
with the defect in there are so.

Half a guess it's called
esophageal A trees you know

this was one hundred percent fatal before
the one nine hundred thirty S. for

lack of a simple tube but it was
an important too because of the food too.

And there are some that
are called long gap and trees.

With very long distances
between the top and the bottom.

There's little guy presented with that.

And here he is after a surgical
reconstruction some twenty years later.

But now we now have to show engineer
a soft Agus and this again is some of

Tracy's work demonstrating engineer to
Sophos compared to native esophagus.

So I'm going to end this talk with the
same organ that I began with the liver.

So the vital organs continue to be
an enormous challenge not only for

our groups in Boston but worldwide.

It's a terrible problem
as I've demonstrated and

based on all the work that we've done and
others have done.

We've sort of boiled it down to
the following simple analysis.

Why can't we do it yet.

The answer is our answer is we can't do it
yet because we can't deliver a nuff mass.

You need a very big piece of liver
to keep somebody alive and well.

So what we've learned all the tools
of tissue engineering to date

we can get good tissue of any X.
dimension in any Y.

dimension but the Z.
axis distance from a vascular bed.

The best anybody's been able
to do is about a centimeter.

So for most tissues of the body
a centimeter is really not bad.

It's perfectly fine even bone is a hollow
tube not hollow but it's a tube and

the dimension the thickness of even
thick femurs only about a centimeter so

you can do a lot with centimeter but
that's not enough for a liver.

It's not enough for kidney or luck.

So the question is.

How do you solve that problem.

So again there are about three or
four conceptual solutions.

The solution we chose about six years ago.

Again was very simplistic.

It was if you can't wait
three to five days for

blood vessels to grow than
build the blood vessels.

If you can build the liver.

Why can't you build the blood vessels.

So that's what we decided to do and

it turns out that it's a very
simple conceptual solution.

It is a very difficult engineering and
science so Lucian.

But I'll take you through where we are and
what we've done so

the first thing you need to do
is understand the design and

then you have to figure out a way how to
duplicate the design and then test it.

So here's the design.

This is a vascular cast of the human
liver and again it looks fairly

complicated and it is but
it's based on fractal mathematics.

So Roger Cambs group at MIT Dr Mohammad
causen poor most of it has

spent the last six years developing
a very robust computational

model of vascular network
top ology Ryall A-G.

of blood flow through it and
then mass transfer across it.

So once we have those designs which we
do then we give those designs to our

colleagues at Draper's specifically Jeff
Borenstein who runs man's fabrication and

then we translate these designs
in demands based systems and

then add the living elements to them.

So the man's is ideal because

its scale is the same as
the scale of a circulation and

in it and
the end of the oil line circulation.

So here's part of the vascular
network the capillaries here is

a high sort of magnification of that.

And here is one of our channels in a man's
based device compared to the same scale.

This happens to be a.

Man's guidance system because Draper

spun out of MIT in the seventy's
during the Vietnam War and

has largely been a secret contract lab for
the Department of Defense.

So it's only within the last six years or
so

where health care has become
an agenda item at Draper labs so

translating this kind of technology
into these sorts of solutions

was the challenge and
here's the approach that we have taken.

So it's silicon based you
have a silicon wafer but

instead of an electrical circuit
etched on it like a computer chip.

We're actually no vascular circuit and
then we edge in reverse.

So that we can pour
a liquid polymer on it.

The polymer dries we peel it off the mold
and then we seal it and then we stack it.

So through a strategy of stacking like
units with communication through the Z.

axis.

If we can stack enough in layers.

Then we should be able to duplicate
a vascular circulation in Heres

a degradable polymer based
single layer of channels.

And here again demonstrates
a later generation of a circuitry

with the in the analytical solution based
on what the capillaries looked like and

here's our strategy for
liver conceptually So

here you see the stack
of the blood vessels.

But in between is the parental more
functional layer you need to get in

the liver and bile docs.

So this is the approach we've taken.

Here's the vascular side we have a semi
permeable membrane which dictates how much

communication occurs between the vascular
side and the liver biliary side and

then this by layer component
becomes the stackable unit.

So that's what we've been
working on over the last sick.

Yours.

This shows that it's not just
surgeons playing in the laboratory

that in fact there's honest
to God engineering going on.

Here's microfluidic flow through a.

This is a single channel capillary channel
the smallest dimension in this fractal set

of channels and you can see the modeling
of the viscous laminar flow through it.

This is a polymer that
has distance ability.

So again that can be modeled as
you all know better than I do and

that factored in.

So we make the models we do the experiment
we compare Aspera mental data to

the model and
it's an iterative process over time.

And again I won't go through all of this
mostly because I don't understand it

myself but this shows
the differences of predicted and

experimental with two different pressures
in these distance of all channels.

This is the model of the distribution
of pressure throughout so

that we design these things to
be physiologic with sheer stress

pressures and flows and then we test.

This is only one of the later
generation of systems and

it's very interesting as we built these
we compare the orders of branching to

normal human pulmonary vasculature or
in this case right

corner an artery of the pig where there's
you can actually go to the literature and

those designs started to fall off
in terms of density as the as

the units of tubes became smaller and
smaller in the fractal order.

So Mohamed went back to the computer and

went from this sort of design to
this sort of design and was able

to get the calculated distribution much
closer in density to the normal situation.

Instead of this he ended up with this and

we haven't been able to build that yet
but we're building that now.

And if that's the case and we make these
thin enough then we're almost to tissue

density not only for
the vascular circulation.

But also for the prank almost side of it.

The functional side of it.

So where are we testing these devices and
again our labs are surgical labs so

we can go to animal models and
from day one twenty

years now we've never drifted from animals
because we want to get back into humans.

So we've always tested in animals.

I'll show you first in vitro so
these are now.

These by layer units with a semi
permeable membrane loaded on

one side with human liver cell line hep-C.

two way and
on the other side is our vascular flow.

And again my fellows tell me.

And again they recognize I'm a surgeon.

So they say it very slowly and
very simply.

They say these are liver cells.

Green is good green means they're alive.

Red is bad.

Red is dead.

So after ten days in these flow
bio reactors you see it's mostly

green green is good
the cells are alive but

as importantly not only are they alive but
they're still doing their housekeeping.

So here you see production
Farrington over time and per cell.

This is about normal for that cell line.

And very potentially very
importantly if you drip

a drug in on one side this is a doxie
Qumran and it's depicted here.

The drug goes down over
time it's metabolized but

the human P. for
fifty metabolic products go up over time.

So it isn't just degradation.

It's actual drug metabolic
activity of a human system

in a flow bio reactor so we feel that it
may be important for the drug industry

because as you all know you can make two
terrible errors developing a drug and

for a drug company either
one is really expensive.

So it costs about eight hundred million
dollars to get a drug to market and

most of that is up front
before the first human trials

in twenty five percent fail
when they go into humans.

So when they've been
studied in animals and

shown to not be toxic than a human
trial is to cite twenty five

percent show toxicity a few escape
that and then show toxicity late.

It's all over the news now.

So that's one bad error but
think about the other error.

Let's say you have a new
drug to cure cancer and

it makes our rat sick but
if you gave it to a human

it wouldn't make him sick and
it would help with the cancer.

How many of those drugs are sitting on
shelves because they made rat sick.

So if there was a way to test this
before it actually went into a human.

That's a rat was sick human a patas
sites didn't get sick you my

design some sort of tie breaking third to
test it to see whether it's worth pursuing

just simply because it didn't and
it made the rat sick so that's another non

quantifiable error that maybe a very
important error to try to correct.

This is one of those things
implanted in Iran and

this is actual femoral artery
blood flow through it.

Femoral vein back to the heart.

So we're implanting these in
animals we have documented flow in

survival out to ten days after
implantation currently so we're.

Area encouraged that not only
can we build these devices but

they actually will support blood flow and
support cells revival in an intact animal.

And I want to show you
these movies because again.

Cardiovascular tissue
engineering is huge and

important here and this is pretty cool.

So this is not a real capillary this
is a tissue engineered capillary.

But this is real blood flowing through it.

And what you see.

So this is a con focal system
that actually counts red cells.

So we actually have quantitative data
that shows the blood in through and

here's the capillary and then the outflow
but you can see here how nicely laminar

this flow is and the early results
of our quantitative is that

it actually matches the model in terms
of all the physiologic characteristics.

So to me that's very exciting.

So I'll end with where we
are currently with this.

Part of our research.

This is a stack of those by layer units
it's about a thirty five layer stack and

you can see here vascular inflow outflow
but also you can see on the other

side we can actually sample
the paddock and biliary side.

Here's a side view.

And I thought I'd show you this.

So here you see that vascular
cast I showed you earlier.

And now we've injected a dye and
taken a C.T.

scan of our vascular network
that's been stacked.

So this is thirty five layers
in the dimensions you see.

Then I'll show you this movie.

So this is now a three dimensional C.T.

scan using what's called a volumetric C.T.
that has a resolute.

Down to one hundred microns.

So as it comes around you'll be able to
see the inflow here through out here and

then you can see the even
distribution of flow throughout

the vascular elements including all
the capillaries throughout the device.

So again we're currently quantitative in
this and comparing it to the model but

from my point of view this
is now proof of principle

that we can not only make these but
we can make them in significant amounts

to get by the original problem we
started with which was dimensions.

Make things as big as we need them to be.

So currently this probably is
not completely accurate but

as of a year and
a half ago now there were about six

structures that were either of vailable
for humans or in human trials.

And I'll end with this quote
from Alan Kay Xerox PARC and

MIT many of you may know the story
that Xerox PARC in the early seventy's

late sixty's was really the innovator
of the personal computer and

that when Steve Job's went and
took his team after he had formed Apple.

That's where he got the concept of
the pulldown windows and also the mouse

actually came out of Xerox PARC and then
when Bill Gates stole it from Steve Jobs.

Steve Jobs couldn't fight it because
he stole it from Xerox PARC but

Alan Kay was one of those
people in Xerox PARC and

there's a book out called The dealers
of lightning about this whole era and

what he said was the best way to
predict the future is to invent it.

So that's really the challenge for
all of you young people and

I think the collaboration
in the center here that

Bob has created really
allows your sorts of the.

People to work with people like me so

that we can complete the loop and
actually make patients better.

So with that I'll end and
I'm happy to answer any questions.

Thank you.

Thousand.

Thank you.

Exactly right.

Because the people that
that ran Xerox Corporation

thought that they were kids in a sandbox
and it wasn't going to go anywhere.

So they killed it.

Is that is an affair.

That's high.

Yes.

Well the answer is ultimately.

What we would like is
a completely living structure.

So we plan on having the vascular piece
be completely living and the paddle

biliary peace be completely living to
date the experiments have been limited.

We have completely lined some of these
with vascular and of the illegal cells.

So we know we sort of have enough tricks
that we can cobble stone them and

have flow through them.

We also know that we can put these human
cell lines into the other side and

have them plate grow in three dimensions
and function as I've shown you

in the last month or so we've been doing
work with primary human a pat of sites and

primary wrap out of sites and we're
duplicating the work that you see here.

It's generally known that CO cultures X..

Really helped the whole picture.

So our plan is to actually extend the CO
culturing to see what the optimal

things are and actually develop a billiard
a system a true bill Yuri system.

So that's that's work yet

to be done but these are these
are what we've done so far.

Yes.

Yeah no way.

Yes So the question is do we any quite
delayed the animals and the answer is yes.

So these animals that we've done so far.

Do not have an end to feel aligning
the structures are made of P.T. amounts.

And we do have her nice the system and
we've gotten flowed to ten days.

That's the best we've done so far.

You're right that

more research.

Or are you had any.

I think it's all of the above.

I think the short answer your question
is any of those scenarios can play out.

And it completely.

Depends on the individual who the
individual works with what motivates and

drives them in the setting their area so

I would say in a collaborative setting
all the good things can happen.

And but.

Whether or not you're you know
eighty percent of your activity or

one hundred percent of your
activity is in the laboratory.

I think that the ultimate driver for

these sorts of technologies is
not the high impact Journal.

That's the root.

But again it's patient benefit in the end.

So I think these these kinds
of things are basic and

they're engineering but then they they
are intended to be translational and

to get back into into therapy.

Yes.

Yes.

So.

It's so.

Yes yes.

So the question is terrible problem cancer

liver failure is there any way that these
could be adapted in that circumstance and

I think the answer is yes and I think this
field of regenerative medicine has already

had an impact on the cancer field

because stem cells which were
not understood ten years ago and

now are more understood there are now
theories that certain forms of cancer or

all cancer may start from clonal
proliferation of stem cell populations.

So there's an immediate application but
then to have a liver assist device or

another way to deliver more effective
agents or repopulate the liver.

I think all of those
technologies are potential.

Improvements in the way we take
care of cancer patients and

I think again the tools of how to deliver
things locally and in high concentrations.

In many other ways to think about things
could come out of an institute like this.

Yeah two two phrases.

Dead animal dead graft the the so

the implants are just beginning.

And it's after all the bio
reactor work that we've done so

far but if you put these if
you implant these things and

close the incision there's really not
a good way to assaye it day to day.

So what we have to do is pick days

we actually put the animal
to sleep open it up.

Take a look and
see if there is blood flow.

So we've gotten fall off.

But the longest is ten days.

So if we come in in the morning the
animals are dead in the cage then you can

be sure of the the graft is dead and
it's clod but you can have a well.

Well a strong but you can have
an animal that's still alive and

you open them up in the graft is dead
in the blood vessels or clot it.

So we really haven't sorted out yet.

What the you know there are probably
a thousand variables that need to be

sifted through but those that's sort of
the empirical observation that we have so

far that animal that
graft clotted vessels.

So.

Yeah.

So

the.
Question is how broad

is the definition of the field.

I think at least conceptually
the way I'd think of it is how broad

are all the technologies that could be
brought to bear to help the patients and

I think it's much much broader
than that strict definition.

So I have slides which I
did not bring that really.