Molly Stevens: A new way to grow bone

As humans, it's in our nature

to want to improve our health and minimize our suffering.

Whatever life throws at us,

whether it's cancer, diabetes, heart disease,

or even broken bones, we want to try and get better.

Now I'm head of a biomaterials lab,

and I'm really fascinated by the way that humans

have used materials in really creative ways

in the body over time.

Take, for example, this beautiful blue nacre shell.

This was actually used by the Mayans

as an artificial tooth replacement.

We're not quite sure why they did it.

It's hard. It's durable.

But it also had other very nice properties.

In fact, when they put it into the jawbone,

it could integrate into the jaw,

and we know now with very sophisticated

imaging technologies

that part of that integration comes from the fact

that this material is designed

in a very specific way, has a beautiful chemistry,

has a beautiful architecture.

And I think in many ways we can sort of think

of the use of the blue nacre shell and the Mayans

as the first real application

of the bluetooth technology.

(Laughter)

But if we move on and think throughout history

how people have used different materials in the body,

very often it's been physicians

that have been quite creative.

They've taken things off the shelf.

One of my favorite examples

is that of Sir Harold Ridley,

who was a famous ophthalmologist,

or at least became a famous ophthalmologist.

And during World War II, what he would see

would be pilots coming back from their missions,

and he noticed that within their eyes

they had shards of small bits of material

lodged within the eye,

but the very interesting thing about it

was that material, actually, wasn't causing

any inflammatory response.

So he looked into this, and he figured out

that actually that material was little shards of plastic

that were coming from the canopy of the Spitfires.

And this led him to propose that material

as a new material for intraocular lenses.

It's called PMMA, and it's now used

in millions of people every year

and helps in preventing cataracts.

And that example, I think, is a really nice one,

because it helps remind us that in the early days,

people often chose materials

because they were bioinert.

Their very purpose was to perform a mechanical function.

You'd put them in the body

and you wouldn't get an adverse response.

And what I want to show you is that

in regenerative medicine,

we've really shifted away from that idea

of taking a bioinert material.

We're actually actively looking for materials

that will be bioactive, that will interact with the body,

and that furthermore we can put in the body,

they'll have their function,

and then they'll dissolve away over time.

If we look at this schematic,

this is showing you what we think of

as the typical tissue-engineering approach.

We have cells there, typically from the patient.

We can put those onto a material,

and we can make that material very complex if we want to,

and we can then grow that up in the lab

or we can put it straight back into the patient.

And this is an approach that's used all over the world,

including in our lab.

But one of the things that's really important

when we're thinking about stem cells

is that obviously stem cells can be many different things,

and they want to be many different things,

and so we want to make sure that the environment

we put them into has enough information

so that they can become the right sort

of specialist tissue.

And if we think about the different types of tissues

that people are looking at regenerating

all over the world, in all the different labs in the world,

there's pretty much every tissue you can think of.

And actually, the structure of those tissues

is quite different, and it's going to really depend

on whether your patient has any underlying disease,

other conditions, in terms of how

you're going to regenerate your tissue,

and you're going to need to think about the materials

you're going to use really carefully,

their biochemistry, their mechanics,

and many other properties as well.

Our tissues all have very different abilities to regenerate,

and here we see poor Prometheus,

who made a rather tricky career choice

and was punished by the Greek gods.

He was tied to a rock, and an eagle would come

every day to eat his liver.

But of course his liver would regenerate every day,

and so day after day he was punished

for eternity by the gods.

And liver will regenerate in this very nice way,

but actually if we think of other tissues,

like cartilage, for example,

even the simplest nick and you're going to find it

really difficult to regenerate your cartilage.

So it's going to be very different from tissue to tissue.

Now, bone is somewhere in between,

and this is one of the tissues that we work on a lot in our lab.

And bone is actually quite good at repairing.

It has to be. We've probably all had fractures

at some point or other.

And one of the ways that you can think

about repairing your fracture

is this procedure here, called an iliac crest harvest.

And what the surgeon might do

is take some bone from your iliac crest,

which is just here,

and then transplant that somewhere else in the body.

And it actually works really well,

because it's your own bone,

and it's well vascularized,

which means it's got a really good blood supply.

But the problem is, there's only so much you can take,

and also when you do that operation,

your patients might actually have significant pain

in that defect site even two years after the operation.

So what we were thinking is,

there's a tremendous need for bone repair, of course,

but this iliac crest-type approach

really has a lot of limitations to it,

and could we perhaps recreate

the generation of bone within the body

on demand and then be able to transplant it

without these very, very painful aftereffects

that you would have with the iliac crest harvest?

And so this is what we did, and the way we did it

was by coming back to this typical tissue-engineering approach

but actually thinking about it rather differently.

And we simplified it a lot,

so we got rid of a lot of these steps.

We got rid of the need to harvest cells from the patient,

we got rid of the need to put in really fancy chemistries,

and we got rid of the need

to culture these scaffolds in the lab.

And what we really focused on

was our material system and making it quite simple,

but because we used it in a really clever way,

we were able to generate enormous amounts of bone

using this approach.

So we were using the body

as really the catalyst to help us

to make lots of new bone.

And it's an approach that we call

the in vivo bioreactor, and we were able to make

enormous amounts of bone using this approach.

And I'll talk you through this.

So what we do is,

in humans, we all have a layer of stem cells

on the outside of our long bones.

That layer is called the periosteum.

And that layer is actually normally

very, very tightly bound to the underlying bone,

and it's got stem cells in it.

Those stem cells are really important

in the embryo when it develops,

and they also sort of wake up if you have a fracture

to help you with repairing the bone.

So we take that periosteum layer

and we developed a way to inject underneath it

a liquid that then, within 30 seconds,

would turn into quite a rigid gel

and can actually lift the periosteum away from the bone.

So it creates, in essence, an artificial cavity

that is right next to both the bone

but also this really rich layer of stem cells.

And we go in through a pinhole incision

so that no other cells from the body can get in,

and what happens is that that artificial in vivo bioreactor cavity

can then lead to the proliferation of these stem cells,

and they can form lots of new tissue,

and then over time, you can harvest that tissue

and use it elsewhere in the body.

This is a histology slide

of what we see when we do that,

and essentially what we see

is very large amounts of bone.

So in this picture, you can see the middle of the leg,

so the bone marrow,

then you can see the original bone,

and you can see where that original bone finishes,

and just to the left of that is the new bone

that's grown within that bioreactor cavity,

and you can actually make it even larger.

And that demarcation that you can see

between the original bone and the new bone

acts as a very slight point of weakness,

so actually now the surgeon can come along,

can harvest away that new bone,

and the periosteum can grow back,

so you're left with the leg

in the same sort of state

as if you hadn't operated on it in the first place.

So it's very, very low in terms of after-pain

compared to an iliac crest harvest.

And you can grow different amounts of bone

depending on how much gel you put in there,

so it really is an on demand sort of procedure.

Now, at the time that we did this,

this received a lot of attention in the press,

because it was a really nice way

of generating new bone,

and we got many, many contacts

from different people that were interested in using this.

And I'm just going to tell you,

sometimes those contacts are very strange,

slightly unexpected,

and the very most interesting,

let me put it that way, contact that I had,

was actually from a team of American footballers

that all wanted to have double-thickness skulls

made on their head.

And so you do get these kinds of contacts,

and of course, being British

and also growing up in France,

I tend to be very blunt,

and so I had to explain to them very nicely

that in their particular case,

there probably wasn't that much in there

to protect in the first place.

(Laughter)

(Applause)

So this was our approach,

and it was simple materials,

but we thought about it carefully.

And actually we know that those cells

in the body, in the embryo, as they develop

can form a different kind of tissue, cartilage,

and so we developed a gel that was slightly different

in nature and slightly different chemistry,

put it in there, and we were able to get

100 percent cartilage instead.

And this approach works really well, I think,

for pre-planned procedures,

but it's something you do have to pre-plan.

So for other kinds of operations,

there's definitely a need for other

scaffold-based approaches.

And when you think about designing

those other scaffolds, actually,

you need a really multi-disciplinary team.

And so our team has chemists,

it has cell biologists, surgeons, physicists even,

and those people all come together

and we think really hard about designing the materials.

But we want to make them have enough information

that we can get the cells to do what we want,

but not be so complex as to make it difficult

to get to clinic.

And so one of the things we think about a lot

is really trying to understand

the structure of the tissues in the body.

And so if we think of bone,

obviously my own favorite tissue,

we zoom in, we can see,

even if you don't know anything about bone structure,

it's beautifully organized, really beautifully organized.

We've lots of blood vessels in there.

And if we zoom in again, we see that the cells

are actually surrounded by a 3D matrix

of nano-scale fibers, and they give a lot

of information to the cells.

And if we zoom in again,

actually in the case of bone, the matrix

around the cells is beautifully organized

at the nano scale, and it's a hybrid material

that's part organic, part inorganic.

And that's led to a whole field, really,

that has looked at developing materials

that have this hybrid kind of structure.

And so I'm showing here just two examples

where we've made some materials that have that sort of structure,

and you can really tailor it.

You can see here a very squishy one

and now a material that's also this hybrid sort of material

but actually has remarkable toughness,

and it's no longer brittle.

And an inorganic material would normally be really brittle,

and you wouldn't be able to have

that sort of strength and toughness in it.

One other thing I want to quickly mention is that

many of the scaffolds we make are porous, and they have to be,

because you want blood vessels to grow in there.

But the pores are actually oftentimes

much bigger than the cells,

and so even though it's 3D,

the cell might see it more as a slightly curved surface,

and that's a little bit unnatural.

And so one of the things you can think about doing

is actually making scaffolds with slightly different dimensions

that might be able to surround your cells in 3D

and give them a little bit more information.

And there's a lot of work going on in both of these areas.

Now finally, I just want to talk a little bit about

applying this sort of thing to cardiovascular disease,

because this is a really big clinical problem.

And one of the things that we know is that,

unfortunately, if you have a heart attack,

then that tissue can start to die,

and your outcome may not be very good over time.

And it would be really great, actually,

if we could stop that dead tissue

either from dying or help it to regenerate.

And there's lots and lots of stem cell trials going on worldwide,

and they use many different types of cells,

but one common theme that seems to be coming out

is that actually, very often, those cells will die

once you've implanted them.

And you can either put them into the heart

or into the blood system,

but either way, we don't seem to be able

to get quite the right number of cells

getting to the location we want them to

and being able to deliver the sort of beautiful

cell regeneration that we would like to have

to get good clinical outcomes.

And so some of the things that we're thinking of,

and many other people in the field are thinking of,

are actually developing materials for that.

But there's a difference here.

We still need chemistry, we still need mechanics,

we still need really interesting topography,

and we still need really interesting ways to surround the cells.

But now, the cells also

would probably quite like a material

that's going to be able to be conductive,

because the cells themselves will respond very well

and will actually conduct signals between themselves.

You can see them now

beating synchronously on these materials,

and that's a very, very exciting development

that's going on.

So just to wrap up, I'd like to actually say that

being able to work in this sort of field,

all of us that work in this field

that's not only super-exciting science,

but also has the potential

to impact on patients,

however big or small they are,

is really a great privilege.

And so for that, I'd like to thank all of you as well.

Thank you.

(Applause)