I am a biomedical engineer that means I
was trained as an engineer focusing on
applications in the healthcare sector
and for us biomedical engineers the Holy
Grail is developing technologies that
will have an impact on patients lives as
a researcher I've been fortunate enough
to be in close contact with the patients
that we're working for so I would like
to start by telling the story of one of
these patients let's call her Rose when
Rose was born she had a curvy leg
nothing special a lot of babies have
curvy legs but in Rosa's case her leg
kept on getting more and more curvy and
at some point four months after she was
born
it broke she didn't fall she didn't kick
it just snapped and it did not heal
months went by nothing happened in 95%
of the cases fractures in your bones
will heal with just only a cast or a
fixation but that did not happen for
Rose and that was because she had a
genetic defect in the cells at the
location where her bone fractured those
cells formed weak bone which was which
explained the curviness of her bone and
that genetic defect made sure that the
bone could not heal properly now when
she was four years old she was finally
big enough to have more invasive
treatments but still nothing worked
and again years went by and at some
point when she was nine years old she
and her parents had had enough without
an immediate outlook on new therapies
they decided to go for an amputation now
many of you or all of you have known
multiple people that at some point in
their lives have broken a bone fewer of
you know people where this fracture
process or where this healing process
did not occur smoothly and far fewer of
you I'm sure
no of cases were a broken bone having
received the best possible medical care
that we have available today resulted in
an amputation not what Rose needed and
what is not available today is a
biological spare part was for the bad
tissue to be removed completely and to
be replaced by a living implant not an
implant made of plastic or metal that
doesn't grow as she would grow that had
to be replaced after 20 years but an
implant that would fully and
functionally integrate in her body so
today I want to take you on a journey of
how to make such a living implant and I
will do that by focusing on the five key
words that you see behind me and I'll
start with the why why are we doing this
why do we want to make these living
implants is that just for Rose and and
the 500 other patients like her in
Europe which have a similar genetic
defect well absolutely not in the
Western world alone there are hundreds
of thousands of patients that are
waiting for a biological spare part and
a golden standard treatment nowadays is
organ transplantation and as you see the
amount of people waiting for a
biological spare part is increasing
every year and even though the amount of
human donors is increasing and every
donor can donate multiple organs it's
still very unlikely that we will be able
to help all the patients on the waiting
list so the concept of tissue
engineering was born as a part of the
answer to this unmet medical need to
develop these living implants and tissue
engineering is a field where we combine
insights from biomedical sciences and
engineering sciences to create these
implants so what is it that we want to
make what is this living implant well if
you want to make something and you don't
really know what to make then you look
around for examples and in our case the
example is obvious there is a tissue
engineer par excellence and that is
Mother Nature
who has had millions of years to develop
living tissues so how
we copying mother nature's well there's
or trying to copy mother nature there
are two ways that we can do that well
the first way is that we look at what
our tissues and our organs look like in
our bodies and if we stay with the bone
example you see that bone tissue is a
composite material it has a mineral part
which gives bone its strength and it has
a fibrous part which gives bones its
resilience and this tissue on the
outside of our bones is a very dense
compact tissue but on the inside of our
long bones at the ends you see it has a
kind of sponge like structure and it is
this combination of a sponge-like
structure together with the composite
material that is sought after as a
biomaterial that is clinically used
nowadays in orthopedics and dentistry
unfortunately the results with these
type of materials are not exactly what
we would like them to be they're very
variable and why could that be well if
you think about how these tissues are
formed this structure does not happen
overnight this tissue is formed by cells
that interact with their environment
with each other to create a process at
the end of which you will get a
structure like that so another way in
which we can try to copy nature is by
trying to copy the process of forming a
tissue the developmental process of
making such a tissue so what does that
look like for bone it first starts with
cells that are coming together and form
a tight group a condensation and in this
group the cells will start specializing
in the case of bone they will start
turning into cells that will form
cartilage and this cartilage tissue will
be like an intermediate structure a
template in which over time you will see
some cells starting to mature starting
to specialize and as the bone grows you
will see or as the template grows you
will see that it in the middle and at
the ends of the bone you'll get bone
formation now the two red zones that you
see here are the places where the
cartlidge template keeps on being
present and that is what we call the
growth plate the growth plate you all
know it it is the the source or the the
the motor of most of the bone formation
after we're born so if we want to make
this growth plate like structure how do
we do that
as with any building project the first
thing you do is gather your building
blocks and the building blocks to create
a living implant are your cells growth
factors and a biomaterial for the cells
we want to use stem cells stem cells are
cells that you can find in all the
tissues of your body and that are able
or capable of specializing in too many
tissue forming cells so for the bones we
find these stem cells in the bone marrow
and in the soft tissue that surrounds
our bones and we're lucky because those
places are relatively easy accessible so
we can take these cells and we can take
them to the lab and we can draw them
until we have enough cells to form a
living implant now the way we grow them
if we want to grow them in the
laboratory we need to give them
incentives we need to give them
instructions of whether to multiply or
to start specializing and we do that by
using growth factors or hormones so once
we have our cells in the state where we
want them to be then we have to provide
some structure to form our living
implant and we can do that by
biomaterials and if we're following
development this needs to be some kind
of soft hydrogel and a hydrogel you can
think of it as a bunch of intertwined
spaghetti that together can hold a huge
amount of water and these biomaterials
we can make them smart by decorating
them as we call it with broad factors or
with nutrients that will instruct the
cells to keep on multiplying or start
forming tissue specific cells now that
we have all these building blocks how do
we put them together how do we make our
living implant well there's multiple
manual
technologies that we can use but there
is one that has been receiving quite a
lot of attention lately and that is 3d
bioprinting 3d bioprinting as a process
uses the same elements as normal
printing you start with a design in our
case we want to make a growth plate then
you have to come up with an ink in our
case that will be a bio ink which is a
mixture of the cells and the soft
hydrogel and then you have to have your
printer and I'll give the example of
what is called an extrusion bio printer
that is a bio printer that looks a lot
like a syringe where you put your
hydrogel in with your cells and then you
push it you push the hydrogel out and so
you form layer by layer your 3d
structure your 3d living implant now
this technology itself is not without
it's not perfect yet so for instance
when we push our cells through the
syringe we're exerting a lot of
mechanical forces on it we're giving
them a lot of stress and cells when you
stress them too much they can change or
they could even die so there is still
quite some development to be done in the
building blocks and your manufacturing
technologies now if we have all of that
when can we build our living implants
that we can give to our patients well
before looking into the future let's
first take a step back and look how how
the field has developed 30 years after
30-something years after it was first
established we're still describing
tissue engineering as a highly
innovative field but the focus of this
innovation has shifted quite a bit over
time in the very first phase of tissue
engineering it was the concept itself
the idea of creating a living implant
that was the innovation and as with any
new promising technology there was a
hype that was created bold claims were
made and expectations were inflated
there was a lot of money that was
invested in startup companies that would
bring all of this to the market
if we look back now people back then
didn't really have a very clear concept
of what it was that they wanted to make
as a living implant nor did they have
access to all of the building blocks and
the manufacturing technologies that I
just described
so around year 2000 most of these
startups had failed or folded and the
hype had died down but in academia
tissue engineering was still very much
alive and it kept on developing and it
became a proper scientific discipline
with its own community its own jargon
and the focus of the innovation shifted
towards the blueprint what was this
living implant that we needed to make
what was the right blueprint to follow
now the quality of the science increased
but what people were not paying a lot of
attention to was the fact that once we
would be able to make such a living
implant we had to not do this once in
the lab but we had to do this for many
patients at a large scale and so that
meant that we had to think about how to
produce it which we hadn't done until
now so that's where we are now in the
third phase where we are reiterating
these scientific developments but with a
process engineering mindset so who were
actually these innovation drivers so in
the very first phase it was the
disciplines so the different disciplines
if you had the biomaterial people that
had come up it had come up with a brand
new biomaterial well that would be used
not no-questions-asked butter that would
be the best buy material but that was
the thing that would be used in the
second phase you had the first real
tissue engineers appearing that were
able to cross the the lines between
these disciplines and bring all of these
building blocks together it in a living
implant now at that stage people were
not really thinking about the patient
the patient was almost like an
afterthought which of course is not what
it should be so now in the third phase
we are reversing these innovation
drivers we are starting from the
patient we're identifying what are the
needs of this patient and what does that
mean in terms of the requirements for
our living implants bearing in mind that
at some point we'll have to produce this
and then these requirements for the
living implant will then translate into
innovations that are needed in terms of
biological building blocks manufacturing
technologies and quality control tools
the innovation is not only at this stage
in the rnd process the innovation is
also in the business model that we'll
have to use because if you think about
living implants they're very complex and
they're very personalized much more so
than typical pharmaceuticals and if you
combine that with the low volume in
which they will have to be produced and
the complex regulatory landscapes or the
complex ways in which you can get
approval to use them in patients that
makes for a very tricky business case so
classic Pharma models cannot apply and
we'll have to think about other ways to
do that and one of the concepts that
will be important for instance is
designed to cost that means that from
the very beginning of your R&D process
you have to take along the manufacturing
cost as an independent design variable
so that once you are making your implant
you're sure that you can offer it at an
affordable cost now once we have all
that will we then be able to help the
patient and close this cycle so we
started by identifying the unmet medical
need we said we were going to address it
by making a living implant for which we
would take inspiration from the
quintessential tissue engineer that is
mother nature bearing in mind that we
had to produce this for the patient and
so when we do all that then we can
address the need of the patient so by
closing this cycle we are guaranteeing
that we will be able to design develop
and the liver functional or living
implants biological spare part that will
fully and functionally integrate and
replace the missing or the absent
tissues and organs in our body for ROS
and for all the other patients out there
thank you
[Applause]