Jordana Lenon: Happy
Stem Cell Awareness Day, everyone, and thank you so much for coming.
Thank you Tom Zinnen with Wednesday Nite at the Lab and Biotech for the nice
just jump right in and introduce introduction, and I'm going to
our speaker for this evening. We're very pleased to have our new associate director for the
UW-Madison Stem Cell and
and tissue engineering. RegAnd Bill is an associater, Dr. William Murphy, here to speak to you about stem cells
rehab, and he is also director professor of biomedical engineering, orthopedics and
Bill earned his PhD in of the bio inspired materials lab in the Wisconsin Institutes for Biomedical Research.
biomedical engineering from the University of Michigan and did a postdoc in chemistry at the
University of Chicago.
And he will tell you much more about what he's doing and his lab, and so I'm very pleased to
introduce Bill Murphy.
Thank you. [APPLAUSE]
William Murphy: Thanks, Jordana, and thanks to all of you for being here. It's a real pleasure to have a
chance to tell you a little bit about stem cell research going
on here at Wisconsin which has been termed the birth place of
stem cell research, and I'll try
and describe why that is. And let me also thank Tom Zinnen and Jordana Lenon for putting
this together.
And this looks like it's going to be a terrific event. Really well attended.
It's nice that there's so much
my background is really in excitement surrounding this topic area. As Jordana mentioned,
bioengineering, and my focused background has been in
So I'm not a stem cell development of biomaterials.
biologist, although we do apply biomaterials to stem cell type applications.
And applications in what
there's a lot of different we call tissue engineering. Because this is a cross-disciplinary field and
moving parts to it, I'll spend a good bit of the talk today
What do we mean by a stem cell? What do we mean by tissue engineering? defining terms.
And what are some of the What is regenerative medicine?
advances being made here at Wisconsin over the past year and more broadly over the past
couple of decades.
So I'll go through a series of things, and then I'm told that
to have some Q&A as well. So I look forward to fielding your questions and talking more after the talk during the labd
portion of the session. So without further ado, I'll
Just to give you an idea of what share some of the discoveries now from Wisconsin.
I'm going to cover, there are a few basic questions that I'll go through.
The first is, what are stem cells and where do they come
of stem cells and sources as from? There are a few different types
well. What are the different stem cell types?
How did this all get started? What's the history
stem cells and regenerative medicine technology? of the stem cell field? What are some applications of
And then there will be time, as I mentioned, for Q&A at the end. And what is what we term tissue engineering?
termed blank slate cells because So what are stem cells? Embryonic stem cells have been
generate all of the 220 different cell types that are in cell types in the body, which means that essentially they can
mature dividing cells, which the adult organism. Many of these cells turn into
are cells that divide as we grow and grow as we age. Others become tissue specific or
adult stem cells which form an
talking about organs that turn internal repair system. What that means is when we have tissue damage and if we're
over quickly, like the blood or the intestine, there are resident stem cells that are
capable of mobilizing quickly and generating new tissues. Those are what are termed adult derived stem cells.
Where do they come from?
So adult stem cells for research some clinical uses come from
And that is a list that's expanding rapidly. many organs and tissue.
cells present in most adult tissues and organs that do a It's becoming more and more clear that there are adult stem
Human embryonic stem cells for variety of different sorts of jobs.
fertilized in the lab during in vitro fertilization, and they don't come from aborted fetuses. seven-day old embryos that are
misconception. So this is a common
These cells don't come from aborted fetuses. In vitro fertilization clinic
patients often have several embryos fertilized and frozen for later implantation in case
less than 5% of those frozen pregnancy is unsuccessful, and
embryos are discarded and no embryos are donated for research. After three years, most frozen
longer viable for implantation. So that's sort of the source for the embryonic stem cells that
are used in research
applications. This, just to give you an idea of what this looks like, is a
fertilized embryo.
So this is an early embryo termed a blastocyst.
fertilization clinic. And what you're seeing here is This is from an in vitro
sort of this hollow ball of cells. what's called the trophoblast layer on the outside, so it's
And inside of that hollow ball of cells--
I'll stay in the lighting here, inside of that hollow ball
So you can see it pointed in of cells is what's termed the inner cell mass.
isolated. So that's what represents human embryonic stem cells, and that's embryonic stem cells are
will ultimately become the adult the portion of the embryo that
human organism. The trophoblast layer on the outside here is what would
become the placenta in vivo during the development of the organism. So as I mentioned, there are a
few different stem cell types.
I just described human embryonic stem cells that are isolated
in vitro fertilization clinics. There are a couple different from embryos that are taken from
types of pluripotent stem cells, though.
Pluripotent stem cells are the
cells that are capable of differentiated or forming all of the cell types that are present
in the body.
Multipotent stem cells are stem cells that are more limited. And these are the adult derived
stem cells. Adult derived stem cells can
tissue types in the adult organism. So pluripotent stem cells, I tissue types but not all of the
there are also now genetically mentioned embryonic stem cells,
reprogrammed mature cells termed induced pluripotent stem cells. And I'll get into this discovery
a little bit later. But in each case, pluripotent stem cells have the potential to
types. become any of the 220 human cell
They can divide and survive indefinitely in culture. And they maintain their
developmental potential over
types that are taken from humans, ultimately will stop This is really important. Most cell types, adult cell
dividing in culture, and they'll lose their ability to form
tissues.
These kinds of cells are very unique in their ability to divide indefinitely and their
ability to differentiate into all tissue types in the body. Multipotent stem cells are more tissue specific.
And these are also known as adult stem cells. These come from a variety of
marrow, fetal tissue, umbilical cord, blood, skin, muscle, fat different tissue types, bone
types in the body. and other sources, and they can become some but not all cell
These are stem cells that can form all of the mature cell dtypes that are present in thed blood, but they're generally
thought to be restricted, to a
large extent, to the blood system. So you're not going to see blood
derived stem cells commonly forming neural tissue, muscle tissue, fat tissue, bone tissue.
forming blood tissue. So those are the general types You're going to see these
of stem cells. And this goes into a bit more
detail on how the different cell
types are generated, particularly the pluripotent
sometimes termed master stem stem cell types, which are also
cells because they can differentiate into all tissue types.
So in the case of induced pluripotent stem cells at the top, or IPS cells, skin samples can be taken from a patient and
grown in culture. Those skin cells can then be, so
four genes are then introduced into those skin cells.
Those four genes reprogram those
about four weeks in culture, and cells to form induced pluripotent stem cells. These can be observed after
neural cells, hematopoietic cells, cardiomyocytes, which are differentiated into lots of different cell types shown here,
heart muscle cells, renal cells, hepatocytes, which are liver
cells.
seeing embryonic stem cells, So a variety of different directions. On the bottom side here you're
which, as I mentioned, come from the inner cell mass of the
Stem cells can be isolated from there, grown in culture and differentiated down the same blastocyst.
mentioned for the IPS cells. sorts of lineages that I
where they come from. So how did this get started and gwhat is the history of the pluripotent stem cells are and
Mouse embryonic stem cells were isolated initially in 1981 and field?
set the stage for generating genetically engineered mice.
So this was really an important discovery.
mouse embryonic stem cells in 1981 and the initial isolation There was quite a lot of time lapse between the discovery of
indicates what some of the of primate embryonic stem cells in 1995 and 1996, which really
challenges are here. It's not simple to isolate these
major discovery to extend from kinds of cells and really a
the mouse to the monkey stem cells.
group here at Wisconsin isolated In this case, Jamie Thomson's
rhesus and marmoset embryonic stem cells in a series of discoveries in the mid-1990s.
That really set the stage for a major discovery in the late 1990s, 1998, in a paper in the
team from Wisconsin demonstrated journal Science Jamie Thomson's
isolation of the first human embryonic stem cells from in vitro fertilization embryos.
And this work showed the first
example of isolating these cells from an embryo, being able to culture these cells over very
long periods of time in vitro,
allowing them to expand what was termed indefinitely.
indefinitely. And they were capable of forming So these cells could grow
tissues along all of the different germ layers of an
embryo. So, for example, they could generate cells derived from the ectoderm, the endoderm and the
mesoderm. I'm not going to get into detail
in terms of what those developmental origins mean, but
effectively what that means is
that ultimately these cells were capable of generating all of the
the adult. cell types that are present in
One of the maybe less anticipated consequences of the initial isolation of human popular press.
they really ultimately gave birth to what are called induced embryonic stem cells is that
decade later, a few different groups were able it generate pluripotent stem cells. Some years later, almost a
cells, specifically skin pluripotent stem cells from adult cells, from adult derived
fibroblasts. And this was done by Jamie
that was published, again, in the journal Science in 2007, by Shinya Yamanaka's group in Japan Thomson's group here, in a paper
So this was a discovery that was and by a third group as well.
quite a lot of interest in made concurrently by multiple groups. And you can see that there was
trying to generate these cells. What these cells really open the door to is the ability to
generate pluripotent stem cells that are patient specific.
So the possibility of taking a cell type from a patient,
transforming that cell in culture into a pluripotent cell which can then generate any specific cell type.
So you can imagine that there are lots of potential consequences of this that are positive.
So what have we done with induced pluripotent stem cells
and human embryonic stem cells over the last few years at
Wisconsin?
There's quite a lot of exciting research that's come out of this area, and I want to feature just
a few things that I think might be of interest to the audience
cardiomyocytes. These are the muscle cells in the heart. The first relates to
disease, cardiomyocytes oftentimes going awry or are And in conditions such as heart
scarring that is present in the heart. missing because of defects that are present in the heart or
cardiomyocytes that are replace diseased or damaged cardiomyocytes in the body and interest in generating adult
cardiomyocytes that can be used to screen for drugs, that can be also for generating
used against heart disease, to screen for toxins that could
potentially influence cardiomyocytes in the heart,
etc. So there's a great deal of
interest in these cells.
If one starts with induced pluripotent stem cells and
right sets of conditions, it's cultures them under just the
possible to generate cells that will beat like cardiomyocytes, like heart cells, in the lab.
And that's what's being shown here. So if you look on the left, what
this is a real-time movie of I'm going to show is a movie and
sitting in a culture dish, just cin a petri dish. What you're seeing initially is a big bed of cells that's
So these cells started out as dermal fibroblasts, skin cells. AnThey were reprogrammed intoll pluripotent cells, and then.
under just the right conditions were induced to differentiate into cardiomyocytes, which
culture. you're seeing beating in
And this is done by Tim Kamp's lab.
Cell and Regenerative Medicine Tim is the director of our Stem
stem cells. A second example of this comes world leader in cardiomyocyte development differentiation from
from Igor Slukvin's lab. Again, here at Wisconsin.
What Igor has been able to do is, starting with human embryonic stem cells, identify
conditions in culture to induce these cells to differentiate just the right sets of
particular, are red blood cells. into blood cells. And what you're seeing here, in
So this is quite important potentially because everybody is
shortages, the need for blood. familiar with the possibility of
If one were able to generate a continuous source of blood
cells, there's a great deal of derived cells like red blood
potential clinical potential. Another example comes from Su Chun Zhang's group here at
Wisconsin, again, over in the Waisman Center which is on the
hospital campus. Su Chun is working on neural
development mechanisms, understanding how the brain develops, how the spinal cord develops, and has a particular
interest in early stages of neural development. What you're seeing here are cells that were derived from
human embryonic stem cells and
then under just the right sets of conditions induced to
So you see in this culture differentiate into neural cells.
fibers of neural tissue that are extending from one spot in the
And these are stained for proteins that are particularly culture to another.
green. prevalent in neural tissue like the NF in red and the GFAP in
So essentially these are neural proteins that are being stained. So this demonstrates the ability
to form neural tissue from
think represents, in some ways, where the field is going is embryonic stem cells represent important about this work that I
development. the earliest stage of
What that means is if we understand how the embryo develops into the spinal cord,
for example, what are the time
scales, what are the signals that those cells are exposed to while they form neural tissue,
we can try to recreate that in
embryonic stem cell culture to form neurons. So in some sense we're mimicking
development.
We're mimicking the way tissues develop in order to create adult cells that can be used for
therapeutic purposes or drug
screening or toxin screening. And what Su Chun in this study that was so unique is that he
mimicked some of the timing associated with neural
development in order to get very efficient differentiation of
these cells down the neural lineage.
So this isn't the first time that one has seen neural cells
come from human embryonic stem
cells, but arguably it's the first time it was done with a level of efficiency like this.
So really an impressive sort of mimicry of tissue development.
the applications of these cells, Okay, so just very briefly to review before I get into some of
I just want to mention again, so adult stem cells have been
I'll get into a little bit of the adult stem cell work that's going on here at Wisconsin in a studied for mobit.han 60 years.
Mouse embryonic stem cells were first isolated in 1981. That ultimately led to the
non-human primate embryonic stem discovery in the mid-1990s of
cells in Jamie Thomson's group. Jamie Thomson's group followed that up with what was really the
big discovery of human embryonic
And then human induced stem cells in 1998 which is what's made Wisconsin the birth place of stem cells.
pluripotent stem cells were also first generated in 2007 by Jamie
other groups. So you with see that there's Thomson's group as well as two
clearly some level of bias because I'm here at Wisconsin
and here all here in Madison. [LAUGHTER]
However, it's very difficult to describe the history
of stem cell research without sounding like we're bragging about what we do at
Jamie's lab really was the birth Wisconsin.
pioneering in the area. pOkay, so adult derived stemm cells and acells.f the work that's followed here has by
different types of adult derived As I mentioned, there a lots of
Bone marrow transplants are a very good example of a stem cell familiar with bone marrow transplants.
cells that are present in bone transplant. There are blood derived stem
marrow transplants that can repopulate the blood system of a patient.
One of the stem cell types
These are stem cells that can thadifferentiate into lots of a lot of attention are what are termed mesenchymal stem cells.
cells, in some cases cardiac different connective tissue cells like bone cells, cartilage
in the tendon, and adipose myocytes, muscle cells, stromal cells that are present in the marrow, cells that are present
cells, fat cells. Arguably, we don't need more fat cells particularly, given the
obesity epidemic and the ready
availability of brats and cheese curds here in Wisconsin in particular.
[LAUGHTER]
However, there are reasons why one might want to generate
So these cells are capable of going down many lineages, not all lineages. So this is where they're limited
when compared to embryonic stem cells.
potentially quite interesting and important because they can However, for clinical applications, these are
be isolated in the operating room and placed back into the
same patient, transplanted into the same patient. So there are now systems that can be used today essentially
process bone marrow to process
liposuction fat in the operating room to isolate populations of
add them back to a patient. So some of this you'll see in the popular press when you see mesenchymal stem cells and then
get a procedure done with stem an athlete flying to Europe to
cells. They're not having embryonic
tendons. stem cells injected into their
cases is that they're having That's not happening, to my knowledge, in Europe. What's happening instead in many
procedures done that involve isolating stem cells from their marrow or from their fat tissue
and then injected into a defect site or a healing tissue. And there aren't really clear sets of evidence that those
kinds of therapies are very effective but that's lots of
but they're not really gaining anecdotal evidence. So these things are being done,
of what can be done with this wtype of cell.. And I'll talk a little bit more later about maybe more generally
what's being done with this type
of cell. But this is an example from Wan-Ju Li's lab.
Wan-Ju Li is in orthopedics and rehabilitation in biomedical
starting with scaffolds of engineering at Wisconsin. And what Wan-Ju is doing is
materials and then he cultures polymers that degrade, so these are biodegradable materials, he adds stem cells on to those
the materials that are cell laden in a bioreactor. What I mean by bioreactor is
that environment is set up to create an environment that
In a normal environment these cells might grow, but they're not likely to differentiate into these cells.
They're likely to form maybe a specific tissue.
multiple different tissue types. But Wan-Ju has identified just
get these cells to different ate the right sets of conditions to
into chondrocytes, which a cartilage forming cells, and
over time, it's biodegradable, then since the material degrades
left with is what's termed it gets replaced by cartilage tissue. And then ultimately what you're
engineered cartilage. So on the top right here you see chunks of engineered cartilage
that have been generated in the lab.
So these are all done in the lab, can be taken off of a shelf
and be placed into a cartilage
defect in the body. What Wan-Ju has done recently is formed defects in large animal
models, this is in a pig model, but what he's been able to do is
diameter in the femoral condyle and then replace them with this formengineered cartilage andare about eight millimeters in
cartilage becomes fully integrated into the recipient and ends up becoming functional. determine whether or not the
right there is fully repaired cartilage. And what you see on the bottom
So you see this smooth surface that's typical of cartilage in
the joint and really nicely integrated with the native
The suggestion is that if one has severe osteoarthritis or a tissue. So this is really promising.
cartilage lesion, that's the possibility of taking cartilage
from a shelf and placing it into
a defect site. And you can imagine how this
orthopedic tissues like bone might be applied to other
So one just quick description of tissue, like tendon, like ligament. Okay.
but I just want to describe them a few things that have happened this year, and I'm not going to get into detail on any of these
because some in the audience might be interested in following
There have been a few really up on this kind of information.
high profile papers published from folks at Wisconsin this year in the stem cell area.
The first at the top here is a
new method for culturing pluripotent stem cells. It turns out that under most
sets of culture conditions for
these cells, the cells have to be exposed to animal products,
in order to grow properly in culture. So there are groups on campus and elsewhere that are trying to
identify animal free
environments that will allow for expansion of these cells so that
cells don't get exposed to in clinical applications the
animal products. The challenge with getting
that the cells then bear the exposed to animal products is
potential of presenting animal antigens when transplanted back into a patient and that has
immune consequences.
So Laura Kiessling's group in chemistry here really used the clever approach to expose stem
cells to surfaces that contain
the right kind of surface environment to promote growth of these cell populations.
So the cells will grow in culture and they'll stay
undifferentiated, they'll stay stem cells.
So that's really exciting because the surfaces are
synthetic. They're all man made.
There's no animal products that are used in that kind of culture
environment. The second piece here is genetic
correction of induced pluripotent stem cells from a patient with gyrate atrophy in
So Jamie Thomson's group and this advanced hope for therapy.
how diseases might be manipulated, might ultimately be essentially have been using IPS technology to try to understand
cured by making changes to the genetic code of the cell.
So in that case it was a genetic
correction. But this is something that could be done with a variety of
different disease states. This specifically was done with gyrate atrophy. The last piece here, human
induced pluripotent stem cells
beginning to form into a structure like a retina in a
Gamm's laboratory. dish, this also comes from David
What you see is really remarkable. It's difficult to form retinal
tissue in a dish, but the possibility of doing so using stem cells is really quite
the retina are highly specialized and they're difficult to grow outside of the exciting because the cells in
need for another source of cells body which means that there's a
to generate retinal tissue. So those are a few breakthroughs just from this year at
Wisconsin, and it's not unlikely
that next year will bring similar levels of breakthrough that we'll be able to talk about
again.
Okay, so I mentioned earlier what sorts of applications are
cells and with adult derived possible with embryonic stem
stem cells, but I think really there are a few categories. And one of the categories that
generates the most excitement is
what's termed regenerative medicine, the ability to replace
functional tissue that's derived lost or damaged tissue with
from stem cells. So because stem cells are ultimately capable of making
tissue, they may be able to make
tissue for therapeutic purposes. This also is arguably the hardest application of stem
cells to address because of barriers related to regulatory
of these kinds of therapies. hurdles, FDA for example, and business hurdles related to cost
So there are a lot of challenges but there's quite a lot being done as well.
So regenerative medicine is a field where lots of different researchers are trying to generate, regenerate tissues in
the body using stem cell related
techniques. So it's a new and emerging field, explores stem cells and
derivatives of stem cells to
repair damaged or degenerated tissues and can now start to exploit endogenous mechanisms of
tissue repair and regeneration. What I mean by that is this sort
of general concept of taking stem cells from a patient,
manipulating them in culture, putting them in a bioreactor and
injecting them back into the patient might be the most
complex type of method that we
can use. Something that might be much
mobilizing native stem cells to generate new tissues because more simple is the idea of
So there are lots of techniques along those lines as well. there are some that are already present in the organism.
So this is a figure that was taken from an article from 1998
in the journal Business Week, and the name of the article was "Biotech Bodies." And I like to describe this
because it's incredibly optimistic. This paper was from almost
was on the horizon at the time. There was this new era of regenerative medicine right 1around the corner, and it wast
going to be no time, if you read
valves right off the shelf and the article, it was going to be no time until we'd be taken bone, skin, pancreas, heart
placing them into a patient. Well, it turns out that because of lots of different hurdles,
including not just scientific hurdles, but as I mentioned,
regulatory hurdles, cost hurdles, each of these tissue
types has been really difficult to generate and our regenerative
medicine techniques, at least in terms of therapeutic
regenerative medicine, have really been slowed and really a tremendous challenge to put forth.
So there's still quite a lot for
us to be doing on the academic side, understanding how we can
can do to help these cells to generate new tissues. But I just want to describe this leverage these cells and what we
tale. The concepts that I described today are really quite as sort of maybe a cautionary
close, I think, but I'm not ready to say that we're going to challenging, and we're getting
be taking these kinds of tissues off the shelf in the near term.
What I do think is coming on the
And this is the cartoonish horizon relatively quickly is this field that's termed tissue engineering.
from a patient, isolates those representation of the general tissue engineering concept. The idea is one takes stem cells
cells, maybe places them into a bioreactor, seeds those cells on to what's termed a scaffold, the
scaffold has properties and functions that are similar to a scaffolding in a building,
to generate the building over time, ultimately forming a new provides the shell for the cells
patient. tissue or a neo-tissue that can be implanted back into that
And the scaffold, in particular, has been an area of constant
was initially formulated in the mid-1990s. interest in this field since it
biodegradable. The idea here is one has to generate a scaffold that's
It has to go away over time and allow for formation of a new tissue.
It has to be biocompatible which
strong. In skin, not so strong but it has to be quite elastic. In bone it has to be very
tissue types have different requirements. It also has to include what are Yotermed inductive factors.nt
These are environments that promote formation of a
scaffold to form bone, they typically have to be exposed to an environment that encourages If you want these cells in a
Okay? So relatively simple but bone to grow.
literally every one of the arrows in this graph is an
active area of study with multiple research groups
in this field. nationwide and worldwide. So there's quite a lot going on
And the history of this field has primarily been combining mature cell types and material
carriers. What I mean by this is for
example, there's a company called Organogenesis that's been
trying to generate skin substitutes in the simplest way you can imagine, taking cells that are known to form skin
tissue, placing them into a scaffold that degrades and
form skin tissue. There's a company called Genzyme allowing these cells to effectively do what they do:
that's been generating approaches for cartilage
regeneration where they're
isolating autologous chondrocytes, that means
patient, and they're injecting cartilage forming cells from a
them into that patient for therapeutic purposes. So they're taking them out,
expanding them, putting them
right back into the patient. And then the last piece here, there are areas where
researchers, in particular Tony Atala's group at Wake Forest
There's a company called Tengion University, has been generating bladder tissue.
that's commercializing these kinds of concepts.
muscle cells and urothelial cells from the bladder, seed Where the idea is to take smooth
them on a construct, and again sort of allow them to do what
they do: form new tissues.
One is each of these tissue types is either relatively thin or it's poorly vascularized. important ways.
It's difficult to generate And there's a reason for that.
highly vascularized large chunks of tissue.
cardiovascular tissue that need a lot of blood vessels to supply So tissues like bone and
In addition to that, these are a large tissue are difficult to generate.
tissues that contain one primary cell type generating the tissue,
way. and most tissues don't work that
more than that if you sort of Texpand, depending on how you different functional cell types in the liver and there's many
define what is an individual cell type.
So most tissue types and organ
types have many different cell types present in this.
has led a lot of investigators So as you might imagine, this
to move from adult derived specialized cell types to stem
general concept. cell types but using the same
The idea of taking cells, seeding them on to a construct and allowing them to form new
tissues and really encouraging
them to form specific new tissues. So the way the field is going
really is toward combining stem cell types and materials with the goal of allowing the
stem cells to form the new materials to degrade and the
tissues that are functional. So these are just a few examples.
Embryonic stem cells in sponges that degrade. Mesenchymal stem cells in hydrogels that degrade.
Hydrogels are basically similar to gelatin. Tissue specific scaffold
So in this case one can generate material.
a scaffold that looks and acts like bone tissue and that can be
new bone. And there's quite a lot of seeded with stem cells to form
But the general direction the field is going is take these different directions that folks are heading here.
stem cells that are capable of doing lots of things, develop
scaffolds that instruct these cells to form some specific tissue type.
before we finish is describe one One thing I'd like to do just
company that I co-founded a few example oyears back.ink is an And I think it gives sort of an tecexample of not just theto a
positives but also the
challenges related to tissue engineering technologies and
going. sort of the way the field is
So cranial facial tissue engineering.
cranial facial tissue engineering for a variety of There's a lot of interest in
reasons. Not the least of which is for
blast injuries in war veterans. So a lot of the injures that are
soldiers have lost large chunks of tissue from their face, for coming back from Iraq and Afghanistan involve blasts where
example. And they might be missing an
entire mandible.
It's difficult to replace that kind of tissue and maintain function.
So you can replace it with
titanium, but that titanium doesn't maintain function over time, and the bone that's
adjacent to that titanium oftentimes will ultimately
and an inability to properly become necrotic and you'll have a series of surgeries over time
chew, facial deformities that extend from these sorts of things as well.
So there's lots of issues associated with using hardware
to try and replace these kinds of tissues.
So healing of very large defects
in the cranium is difficult. Here's another example. This is actually a cancer
resection.
So this was an osteosarcoma where the bone had to be resected and the tissues
surrounding it had to be
resected, and then you see on the right-hand side, in that diagram, a large defect.
So what does one do?
Very difficult to determine what to do to replace at that kind of
And what's often done these days a defect.
is it's replaced with a chunk of titanium and the bone is
titanium, but ultimately that patient won't regain normal function or, in many cases, normal aesthetic appearance.
So there's an interest in using autologous bone grafts. Essentially, you take a bone
and implant it into another spot graft from one spot in the body
in the body. And there are lots of procedures
Many times harvested from the hip bone or the femur and then that are done in the U.S.
developing growth factors, placed in vivo. There are also groups that are
able to replace the hardware, like titanium that's often used in current procedures, and to be So ultimately the hope is to be
techniques when compared to autologous bone graft harvesting. Because when you take bone from
one spot and place it into
another spot, oftentimes you get what's called donor site
So you get problems, pain and loss of function at the donor site. So there's a need to develop
synthetic techniques that are capable of initiating new bone
in the cranial area, in the maxillofacial area, the aesthetic requirements are quite The challenge, though, is that
Whatever is placed in this kind of a defect has to form fit quite well. It has to be quite strong
because the chewing forces are
And it also has to be porous and high. So it can't crumble under the force of chewing.
bone and the material can degraddegrade over time.t the cells that are going to come in and form new bone can form the
Michigan, the PI's name is Scott So there's a group that we've been collaborating with at
Hollister, who's been developing rapid prototyping techniques, that are oftentimes used in the
auto industry, for example, to
generate scaffolds for mandibular reconstruction and more generally for cranial
facial reconstruction.
And what you're seeing here is essentially what would amount to
lower left. This is on the left-hand side, a temporomandibular joint on the
on the lower left, left-hand side, this is a computational
design of what a scaffold could look like, and on the right,
just adjacent to it, is an actual polymer scaffold.
This is an actual plastic scaffold that degrades over time, and you can see that it's porous to allow for a new bone
to grow into the defect site. So there was a company generated
Systems, and the idea is to move from Scott's work and my work called Tissue Regeneration
from reconstruction that's commonly done with titanium to
The part that we're interested regeneration.
in is trying to promote stem cells to generate new bone in these materials.
So Scott's handling the rapid prototyping and generating the
scaffolds. scaffolds, and we're working on filling in the gaps in those
fit into the mandible, and in this case we actually have sort that yoof a Lego design. doing. GThere's two pieces that snapl
together, there's a pin that
fastens them, and then those end pieces go right into the native bone in a mandible defect.
So that scaffold can be generated to essentially any
size of defect and it can be generated on-site immediately.
So basically one can take a CT
scan of a defect site, generate a scaffold that fits, paste it in.
And one thing that we've been doing at the bottom here is isolating stem cells from bone
kinds of scaffolds so that those marrow, placing them into these
formation of new bone by these stem cells can generate new bone, and then we're creating environments that promote
cells. So the point of describing this to you is not to get you to buy
the product.
We don't have any products. So this is not an advertisement. What it essentially describes is
one of the ways in which stem cells are being used in the very
near-term for clinical applications.
Part of the reason why this is
near-term is that that scaffold is likely to be regulated as a device, similar to the wound
dressings that are currently
used, the injectable pastes that are used to form bone.
cells in the operating room is And combining these with stem
something that can be done without additionally regulatory approval, potentially.
So depending on how it's done and whether or not the cells are
manipulated in some way. But if the cells are not
manipulated, then it's possible for the surgeon to essentially
isolate the cells, inject them on to a scaffold and place them
into a defect site. And if those cells are properly encouraged to form bone, then there's the potential for
regenerative therapies to get to
the clinic maybe more quickly than they would if these cells were grown in a scaffold in a
bioreactor for eight weeks
So this is a relatively simple outside the body. That's just much more complicated.
tissue engineering technique. This just gives you an idea of what the general approach is.
You see on the upper portion
directly into that defect, load that scaffold with stem cells Oand other molecules in the generate an implant that fits
that scaffold into a defect site. And this happens to be a defect opersite in a primate model.ant
What we've found is that new
bone will form effectively in these kinds of sites, and we get degradation of these site over a
long time, a couple of years, but it gets replaced with new bone. So quite exciting, I think, as a
potential therapeutic application.
cartoonish representation of So as I mentioned, tissue engineering, this is sort of the
what the field can be, but one can argue that the techniques I was just describing that are
maybe short circuiting some of
And all of these methods are these arrows might be a simpler route to regenerative therapies in the clinic.
potentially exciting for clinical applications.
want to summarize some facts So before I finish up, I just
about stem cells, and I know that I'm sort of beating you
part of the function of the Wednesday Nite at the Lab talks is to educate. over the head with this, but
audience that has a variety of And I know that we have an
different sort of expertise in the area. So embryonic stem cells can form
all 220 cell types in the human body. And these are a scientific gold standard for learning how all
cells, including stem cells,
work, functionally. Scientists study early embryonic stem cells to understand
reproduction and development. Human embryonic stem cells
are already widely used in drug safety and toxicity tests. successfully cultured for the first time just a few years back
And there are companies in Wisconsin that are generating
these kinds of tests. Tissue specific adult stem cells
ways. As I mentioned, they don't have hthe ability to form all cell for 40 years, albeit in limited
Tissue specific adult cell types types, all tissue types.
can do with adult stem cells. And important to note is that a lot of the debate surrounding stem cells has been one or the
other.
Why aren't we always using adult Why are we using embryonic stem cells when we have all of these adult derived stem cells?
stem cells? And then vice versa. If we can isolate embryonic stem
cells, why would we ever want to
work with adult derived cells? The embryonic stem cells are
Each of those, I think, misses more powerful.
part of the point and that is that each area of research informs the other.
Improved embryonic stem cells culture techniques have led to
better ways to grow tissue specific stem cells.
And vice versa. So there's different pieces of
the research inform one another. They're really both needed.
So human embryonic stem cell
culture led ultimately to the birth of induced pluripotent stem cells which has now become
really an important area in drug
between induced pluripotent stem screening and understanding disease mechanisms, but there are significant differences
cells and human embryonic stem cells that we're just starting
So it's important to note that to understand.
never have come from aborted these are not effectively the same cell type. Embryonic stem cells don't and
fetuses. I mentioned that that's a common
They come from five-day-old blastocysts that are grown in a petri dish. IVF procedures are privately
funded and always have been.
discoveries, but pioneering Adiscoveries have been made inI all areas of stem cell research, focus on Wisconsin's
economy. brings millions into the state
I didn't really focus on this but really it's an important note.
Stem cell research and
regenerative medicine research, more generally, is a form of economic development for the
state, and because Wisconsin is so well positioned on the scientific side and because there's a burgeoning biotech
industry in the town, there's the potential for this really to
we need things added to the state economy and the national add a lot to the state economy. And this is a time when clearly
economy. So hopefully this can be
a source of that. Okay, so I think I'll stop
there, and I'm delighted to take any questions that you might
have. [APPLAUSE]