>> [Slide 1 L5.2] Welcome back, I'm professor Rickus.
In this lecture, we're going to be talking about the cell device biointerface.
[Slide 2] So, first we're going to talk a little bit about the importance of this interface
in biohybrid devices.
Our discussion today is going to focus primarily on mammalian cells, and
we'll return to bacteria and
other prokaryotes later when we talk more broadly about cell device integration.
So we'll talk about the relationship of the cell device biointerface
to biocompatibility.
We'll talk about how cells interact with surfaces, and
the effect of different service properties on cell adhesion and cell function.
We'll highlight the difference between 2D integration and 3D integration, and
talk about some of the differences between an In Vitro device and an In Vivo device.
And that discussion will take us into the tissue device response for
implanted devices.
[Slide 3] So first, thinking about the importance of the cell device interface for
biohybrid devices.
In previous lecture, we talked about this ray biohybrid robot
that had living cardiac myocyte cells that formed, essentially,
an artificial muscle in this metal and
polymer based robot system that could swim via light controlled.
So in this case, as well as also imagine if we had an electrode array, and
we wanted to interface that array with some cell.
In these cases, right, the cells must adhere, survive, and
function within this artificial environment.
And this really comes down to this cell device interface as this first
line of action, where this adherence that affects survival and function happens.
[Slide 4] OK. So what's the relationship? You may have heard of this word, biocompatability.
So, here's a definition of biocompatability that I favor.
So biocompatability, we'll say, is something is biocompatible,
a biological performance in a specific application,
that is judged suitable to that situation.
Now that seems somewhat vague and perhaps unsatisfactory to you,
but let me tell you why I like this definition.
If someone tells you that something is biocompatible,
blanket biocompatible, don't believe them.
There's no such thing.
Biocompatibility describes a two-way interaction between the host, that is our
living cells that we're interested in, and the material or device, okay?
And so the performance of both the cells, and the material and device,
what we measure as important function or
performance, is situation dependent. Right?
And there is always a two-way interaction between these things.
So there is a host response, in other words, do the cells function
the way we want them to when they're integrated with the device?
And there's always the device response.
Does the device function when integrated with the cells?
So notice what's not in this definition.
There's nothing about being inert or no interaction,
because that almost nearly never occurs.
There's almost always some interaction.
And the question is, is it an interaction that we want, and
is beneficial to our biohybrid device?
[Slide 5] OK. So
let's talk about these interactions a little bit more specifically.
How do mammalian cells attach to a surface?
So here in the top, we have sort of a zoomed out view,
thinking about the cell, and the surface of our device that it's interacting with.
And if we focus in on this junction area now, and
think about whats really happening.
So here we've got a zoom in of the cell membrane.
And remember cell membranes have proteins
that are embedded in these membranes that act as their receptors.
And they really relay information from the outside of the cell to
the inside of the cell, both through cytoskeletal components, and
through soluble signalling.
So, how does the cell really attach to the surface?
Well there are extracellular proteins often produced by the cells themselves,
that are laid down.
And it's these extracellular proteins that act as adapters.
They bind to receptors on the cell membrane.
And they adhere and interact with the surface.
[Slide 6] So, in this way, thinking a little bit more directly about the cell device
interface, we can see that the mechanical property.
Or, excuse me.
The physical, chemical, mechanical properties, and biological properties of
our device surface influence our cell function downstream
by interacting with extracellular proteins that interact with receptors on the cell.
That relay that information to the intracellular part of the cell,
including the cytoskeleton and other components of signaling networks that can
ultimately affect gene expression, and the phenotype, or function of ourselves.
So there's two key points here.
One, that the surface properties of our device influence directly
the cell adhesion survival and function.
And that the device is really directly coupled to the cell's
intracellular signalling, via protein interactions at the interface.
[Slide 7] So now this gives us a framework to dig in a little bit more deeply, and
we can think about how do surface properties affect cell attachment?
Well, one of the most basic surface properties, is the hydrophobicity or
hydrophilicity of the cell surface.
And this will affect both directly, the protein adhesion,
including those proteins that cells use to attach to, to adhere.
And we can also think about it from a more zoomed out view.
And how those cells will, how they will spread out and
lay down on the surface in a hydrophilic state, versus a hydrophobic state.
[Slide 8] Another very important property of the surface, are the mechanical properties.
One of those properties that's been looked at extensively, is elasticity.
The elasticity of that matrix.
Essentially, you can think about how stiff, or how elastic that material is,
that the cells are attaching to.
And here's some data from some now classic experiments, that demonstrated,
that even the stem cell lineage commitment.
So in other words, what type of cell a stem cell turns into.
Right, for these mesenchymal stem cells, can be driven by mechanical properties.
So these same cells in the same environment, varying only the stiffness of
the substrate, you can induce these cells to differentiate into brain-like
neural cells, if they're on very soft materials, right?
And as that material gets more stiff,
then you can induce them to differentiate into muscle.
Or at the most stiff material,
you can induce them to differentiate into bone-like cells, right?
So this is, as I said, a classic example, and
a dramatic one, that shows how the mechanical properties of the surface
can dramatically influence cell fate and their function.
[Slide 9] So another property that can be very important, is the typography.
Particularly at the nano, and the micro scale.
Remember these proteins that are adhering?
Proteins adhere really, they're living in the nanoscale, right?
And cells are microscale structures.
So here we have two materials.
These are silica based materials produced in my lab.
They are identical chemically, in every way.
They've only be processed differently, in order to change their surface topography.
And so here we see atomic force microscope image, of these two materials.
One that's very rough on the nano scale.
And notice these axes even, are different.
So this axes here is about 150 nanometers.
Whereas this, you can see this material is very, very smooth,
sub 30 nanometer surface features on this material.
And just by changing the surface topography,
we can dramatically affect how neural cells attach to this surface.
So on the nanoscale rough material,
we see almost no neural attachment to these surfaces.
While the same material of identical chemistry,
now that's much smoother on this size scale,
we can get very strong and nice neural cell attachment to these surfaces.
[Slide 10] So, I put this figure up just to show you and
sort of put in your mind, the complexity of this interplay.
Again, we're looking at from this surface or scaffold.
Interacting through these protein layers with the cell,
versus multiple different types of receptors and
adhesion molecules, coupling in to both the cytoskeletal elements,
as well as the complex signaling network of the cell.
And as well, interacting with the soluble and interstitial volume and space,
and the signaling that's happening in here, as well any other physical inputs,
such as pressure and sheer force from, for example, fluid flow.
So all of these things are interacting to influence how those cells adhere,
survive, and function.
[Slide 11] Okay, so we've mostly been talking about cell
biointerface in a two-dimensional context.
But quite often, we're also looking at cells in a three-dimensional context.
And so I put up this cartoon here that I made,
as sort of articulate these two things.
One looking at this cell attaching to a planar surface.
versus cells that may be within a matrix, artificial,
that may be integrated into a device.
And you can see how they're interacting with, and
adhering to the artificial components can be very different.
[Slide 12] So in a two-dimensional, we typically get a very flattened cell shape.
And actually an abnormal distribution of these receptor adhesion ligand complexes.
So there's often this forced polarity and
abnormal morphology, in this, sort of planar orientation.
And cells are very dramatically,
again, you can see how their morphology even changes.
Again, as we vary stiffness as we looked at before.
So now you're sort of seeing the attachment points, and
how the cells sort of spread out and have these different morphological shapes.
Which, you can imagine has a direct impact on the signaling and
how they're functioning, and what's happening internally to the cells.
[Slide 13] Whereas 3D is generally considered a bit more of a native environment.
This is how cells typically live, in a three-dimensional sort of environment.
And so they often have a more natural distribution
of adhesive sites with the material that they're interacting with, and
less of a forced polarization state that can influence cell fate.
And in many ways, this sort of cell fate and function, in most of the ways that
you can measure, is often different for the same cell, if you are to
interface it in a three-dimensional environment, versus a 2D environment.
Now, for the sake of devices, there are different types of
three-dimensional materials that we often use, to house cells in devices.
They can be synthetic, such as a peg based system.
It can be natural and non native, such as alginate polymers.
And they can be natural and native, such as collagen and
laminin types that we would often see, mammalian cells for example,
surrounded in the body, and in natural organisms, okay?
[Slide 14] So, cells can actively remodel and shape their 3D environments.
So again, this is that two-dimension, or excuse me, two directional communication,
between cells and the materials that they are surrounded in.
And here's some examples now,
we put in these different three-dimensional environments.
They can also, not only being sort of natural or non natural, or native or
non native, we can also have materials that are either degradable,
or non degradable by the cells.
And you can see that in the non degradable material,
such as alginate, or this artificially cross-linked hyaluronic acid,
another natural component of many tissues,
that in these cases the cells are fairly confined, right?
And their morphology is somewhat rounded.
And you put the same cells in a degradable, either collagen, or in this
case now, a differently cross-linked hyaluronic acid, one that is degradable.
You can see that the cells now are able to change their shape,
by degrading and manipulating the environment in which we put them in.
And that's something cells naturally do in their native environments.
[Slide 15] Okay, so we've mostly been talking about In vitro.
We've talked about 2D and 3D, but let's also talk about In vivo.
So In vitro, we're typically putting the cells onto, or into, an environment.
But In vivo, we're often integrating the device into the tissue.
And with that, often comes injury from that integration, broken capillaries,
other tissue damage, and a little bit different of a tissue response.
And so because of this acute injury, and this more complex tissue response,
because now, if we're in a whole organism, we often have an immune system and
other functioning components going on.
And so this complicates our cell device biointerface.
[Slide 16] And so one of the things that typically happens when you put a large engineered
device into the body, is what's known as the foreign body response to the implant.
And this happens over a course of time,
beginning with an initial injury or implantation.
And there's often initially, protein adhesion,
an inflammatory cell, infiltration from that entry.
And then we have a continuation from an acute to a chronic effect,
both at the material interface of our device, and within the surrounding tissue.
And again, this propagates from an acute inflammation,
into potentially chronic inflammation, and ultimately,
an encapsulation of our device with fibrous tissue.
Obviously something that we often don't want, if we want a good,
healthy integration of our cells in tissue, and our device.
[Slide 17] And so the end result of a device being put into the body,
is often this sort of encapsulation and fouling,
due to this fibrous capsule that's formed around here.
We have an image of a sensor that's been placed into the body.
And around the sensor membrane and the sensor components,
we have protein adhesion and fouling of that device,
as well as a fibrous encapsulation, that sort of forces away the cells of interest.
The natural cells and the capillaries, and
typically the systems that we want to interface in.
[Slide 18] So here's what this can look like in the brain.
Here's a reactive tissue response to a neural implant.
So in our last lecture we were talking about the brain computer interface, and
neural implants as a type of biohybrid device.
And what you see here is a very typical, after that, in this case,
an electrode was removed from the brain.
We can see the site where the electrode was.
And you can see all this fibrous tissue, and what's called the glial scar.
So this scarring around.
And so now if you look at some of the individual cell components,
we can see the resident immune cells of the brain, the microglia.
And the other glial cells, which are reactive, and
have been activated to form this glial scar around the cells.
And now most often, the cells we're interested in interfacing with for
the brain computer interface, the neurons and its axons, you can see, have now been
pushed away and are no longer near the electrode surface that's depicted here.
So this is obviously something we don't want quite often,
when we're making our biohybrid devices.
We want a healthy integration of cells and tissues with our engineered components.
[Slide 19] So there are, I think probably the two winning and probably most
promising approaches to avoiding the foreign body response, is kind of twofold.
And one, is to make our devices smaller.
The smaller we make our devices, if we can make them on the size scale of cells,
we have much less of an injury impact.
And they're much more able to mechanically match the tissue.
And that leads into our second approach.
And that is to make the devices themselves less foreign to the body.
And so this has approaches in both chemically mimicking the native cells, as
well as mechanically matching the tissue, so that there's not chronic inflammation.
And the cells in the surrounding tissue see the interacting device more as self,
and don't attack it and wall it off via this scarring and fibrous encapsulation.
[Slide 20] Okay, so coming up, we're going to move into talking about cells as sensors,
and then we'll move on to actuators and talk more about cell device integration.
And here, we'll also bring back in our bacterial friends, and the prokaryotes and
talk about their integration and devices,
as well as continuing our discussion on eukaryotic cells and mammalian cells.
And talk a bit about bioencapsulation, and
how we integrate these cells into devices in a broader sense.
So I hope to see you next time.