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Paper 8, Engineering for the Life Sciences
Engineering Applied to the Living World: The Eye
Timing: Weeks 1-4 Easter term, 2pm-3pm on Mondays,
Tuesdays, Thursdays & Fridays
Structure: 14 lectures + 2 examples classes (18, 22 May)
The aims of the course are to enable students to appreciate
the vast potential for the application of engineering
principles in biology and medicine,
Paper 8, Engineering for the Life Sciences
Engineering Applied to the Living World: The Eye
Timing: Weeks 1-4 Easter term, 2pm-3pm on Mondays,
Tuesdays, Thursdays & Fridays
Structure: 14 lectures + 2 examples classes (18, 22 May)
The aims of the course are to enable students to appreciate
the vast potential for the application of engineering
principles in biology and medicine, and learn about four
specific application areas in which Part I engineering
principles can be applied to:
•  study the structure and function of the eye.
•  the design of ocular prostheses.
•  medical imaging of the components of the eye.
•  gain insight into visual processing and optimality in eye
design
4 Lectures M. Oyen (mlo29)
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
–  Eye tissue biomechanics
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
Overview
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
–  Eye tissue biomechanics
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
Of what are natural things made, from a materials perspective?
Eukarya
Animals
epithelium
muscle
tissue
connective
tissue
Plants
nervous
tissue
cells
nucleic acids
lipids
Domain
Kingdom
epidermis
ground
tissue
vascular
tissue
ECM
proteins
Tissue
Tissue
Components
sugars
biominerals
Molecular
Building
Blocks
Tissues = Cells + ECM
•  In biology, extracellular matrix (ECM) is any
material part of a tissue that is not part of any cell.
•  Extracellular matrix dominance is the defining
feature of connective tissue.
epithelial, muscle, and nervous tissue
connective tissue
Tissues = Cells + ECM
•  In biology, extracellular matrix (ECM) is any
material part of a tissue that is not part of any cell.
•  Extracellular matrix dominance is the defining
feature of connective tissue.
•  Most connective tissues are:
–  Involved in structure and support.
–  Characterized largely by the traits of non-living tissue.
–  Examples: bone, cartilage, ligaments and tendons
epithelial, muscle, and nervous tissue
connective tissue
Of what are natural things made, from a materials perspective?
Eukarya
Animals
epithelium
muscle
tissue
connective
tissue
Plants
nervous
tissue
cells
nucleic acids
lipids
Domain
Kingdom
epidermis
ground
tissue
vascular
tissue
ECM
proteins
Tissue
Tissue
Components
sugars
biominerals
Molecular
Building
Blocks
Macromolecules
sugars
proteins
Cells vs ECM Molecule Sizes
Connective Tissue
•  Cells, proteins, sugars
ECM: Proteins and sugars
Collagen
Y
X
Gly
Hyp
often
Pro
Gly
Gly = glycine
Pro = proline
Hyp = hydroxyproline, a modified form of proline found only in collagen!
Collagen
The collagen molecule is a triple helix
This can be three identical chains: (α1)3
Commonly two and one: (α1)2(α2)1
Collagen
http://www.youtube.com/watch?v=NK2VKpVyk2s&feature=related
Collagen
Cross-linking within a
triple helix
Cross-linking between
triple helices
Collagen Types
Fibrils and Self-Assembly
Typical fibril size 50 nm
Graham et al. 2000 (Kadler group)
Collagen
Julian Voss-Andreae's sculpture Unraveling Collagen (2005), stainless steel.
Overview
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
–  Eye tissue biomechanics
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
Eye Anatomy
Eye Anatomy
http://www.jirehdesign.com/eyeanimations/visionEyeAnatomy.htm
Tissues in The Eye
The connective tissue sclera is continuous with the cornea.
The cornea is transparent while the sclera is white (thus the
term the “white of the eye”).
http://www.youtube.com/watch?v=gvozcv8pS3c&feature=related
Tissues in The Eye
The crystalline lens sits behind the iris.
The overall “eyeball” is called the “globe”.
Tissues in The
Eye
The cornea contributes
the majority (2/3) of the
eye’s focussing power
but is fixed focus. The
crystalline lens sits
behind the iris and
contributes the
remainder (1/3) of the
eye’s focussing power.
Tissues in The Eye: Cornea
Cells
Collagen and some sugars
Cells
In humans, the cornea has a diameter of about 11.5 mm and a thickness
of 0.5–0.6 mm in the center and 0.6–0.8 mm at the periphery.
NB there is no blood supply to the cornea!
Anatomy of cornea
Epithelium
(50 µm)
A cornea has 3 main parts.
•  Stroma has 90% of total thickness and
contributes to its toughness & transparency
•  Collagen fibers + sugar-protein + water
Stroma
(500 µm)
Collagen fibres
(30 nm)
Endothelium
(5 µm)
Sugar-protein
ground substance
Cornea:
OF COLLAGEN FIDRILS IN THE HUMAN CORNEA AND 5CLERA / Komoi and Ushiki
2247
cornea
d are
within
,OOO),
Real collagenintertwined
fibrilsin aninirregular
cross-section
(TEM)
manner. Those in the pos-
ed of successively stacked
enfibrils(Figs. 7, 8). These
terior region (Fig. 8) were piled up almost parallel to
the corneal surface. When specimens were sectioned
Corneal Collagen
Collagen fibres
(30 nm)
Sugar-protein
ground substance
Corneal collagen is crystalline
•  The collagen fibril diameter is
nearly constant
•  The collagen fibril spacing is
regular (and nearly perfect)
Corneal collagen crystallinity is crucial both mechanically and
optically:
•  The biaxially aligned collagen adds stiffness to resist the
intraocular pressure (IOP)
•  The regularity of collagen size and spacing results in optical
transparency. Corneal index of refraction n = 1.376
Tissues in The Eye
Both the cornea and the sclera are made up of collagen
and the difference between the two is in the regularity or
irregularity of the collagen fibrils.
2254
Cornea:
OF COLLAGEN FIDRILS IN THE HUMAN CORNEA AND 5CLERA / Komoi and Ushiki
2247
cornea
d are
within
,OOO),
Collagen fibrils
in cross-section
intertwined
in an irregular manner. Those in the posterior region (Fig. 8) were piled up almost parallel to
(side view). the corneal surface. When specimens were sectioned
ed of successively stacked
enfibrils(Figs. 7, 8). These
Sclera:
INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / July 1
F
TEM
ing
emp
bun
(X6
Side view
Cornea:
2252
INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / J u l y 1991
Vol. 32
Fig. 9. Higher magnification of the lamellar surface of the cornea. Collagen fibrils of each bundle are arranged in the
same direction. Small bundles (arrows)
extended between lamellae. Fine netlike
patterns are observed on the lamellar
surface (arrowheads) (X6200).
= Top view
Collagen fibrils in SEM (Top view).
The spatial relationship of adjacent lamellae also is
considered to be an important factor for the corneal
transparency. Our study showed that the arrangement
of the stromal lamellae is more complicated than ex-
Cornea:
2252
INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / J u l y 1991
Sclera:
fore, we consider that stacked lamellae, as a whole,
optically act as a single uniform sheet, causing no
significant reflections at the surface of individual
lamellae.
Vol. 32
Fig. 9. Higher magnification of the laFig. 16. A tangential view of the colla-mellar surface of the cornea. Collagen figen bundles in the sclera. Collagen fibril:brils of each bundle are arranged in the
run in a wavy fashion and interminglesame direction. Small bundles (arrows)
within individual bundles. Note thtextended between lamellae. Fine netlike
loose networks of collagen fibrils arouncpatterns are observed on the lamellar
the bundles (arrows) (X2700).
surface (arrowheads) (X6200).
Collagen fibrils in SEM.
Alignment of Corneal Collagen Fibrils
This simple basket-weave structure is for the central region of the cornea.
On the periphery, collagen fibrils are directed towards muscle attachments.
Alignment of Corneal Collagen Fibrils
NB The eyes are slightly different but mirror images.
Tissues in The Eye:
Crystalline Lens
The cornea and sclera are typical soft connective tissues in the body. In
contrast, the crystalline lens is extremely unusual in its composition and
structure.
Basic lens structure:
The lens is about 10 mm in
diameter and 3.5-5 mm thick
at its center.
Tissues in The Eye:
Crystalline Lens
The lens capsule is typical connective tissue with collagens and sugars.
It varies in thickness. Directly beneath the capsule is a layer of epithelial
cells. These cells are a source of new lens fibers.
Front
Back
o
t
Tissues in The Eye:
Crystalline Lens
The lens capsule is typical connective tissue with collagens and sugars.
It varies in thickness. Directly beneath the capsule is a layer of epithelial
cells. These cells are a source of new lens fibers.
Zonular fibres close to the capsule
Capsule
Epithelium (transition zone)
Lens fibres
Front
Back
[
]
o
t
Crystalline Lens
The bulk of the lens, the cortex (newer fibers) and the nucleus (older
fibers), is cellular. These specialized cells are the “lens fibers” and they
are vastly elongated lens epithelial cells that have lost most of the
normal cell contents (nucleus and organelles). The lens is also 30%
protein by mass and the proteins are the very unusual “crystallins”.
Zonular fibres close to the capsule
Capsule
Epithelium (transition zone)
Lens fibres
[
]
As with the cornea, a large degree
of organization is found in the lens
and this gives rise to its optical
transparency (in a manner that is
actually not understood very well).
The overall layered structure of the
lens fibers is often compared to the
layers of an onion. Also in common
there are no lens blood vessels.
Lens Accommodation
•  “Amplitude of accommodation” is the max amount that the
lens can accommodate in diopters (D), equal to the
reciprocal of the focal length measured in metres.
Lens Accommodation
•  The transparent, biconvex lens structure changes shape
to change focus. (remember, this controls 1/3 of total
focus)
•  Lens curvature is controlled by ciliary muscles
–  By changing curvature, one can focus the eye on
objects at different distances.
–  This process is called accommodation.
–  The lens continually grows
throughout life, laying new cells
over the old cells = stiffening
–  The lens gradually loses
accommodation ability with age
Aqueous and Vitreous Humor
The aqueous humor sits in front of the lens and the
vitreous humor fills the large part of the globe.
Aqueous and Vitreous Humor
A
V
The aqueous and vitreous
humors are gels. They consist of
proteins and sugars and have
very large water contents
compared to other soft tissues
(98-99% water in VH vs 75% in
cornea).
The aqueous humor is a a more water-like gel.
The vitreous humor is a more solid, gelatinous gel with a loose
type II collagen network (recall cornea is type I collagen).
Intraocular Pressure
The cornea maintains its shape via the pressurized fluid
inside the globe.
Normal Intraocular Pressure (IOP) is 15.5 mmHg
with a range 10-20 mmHg (1 mmHg = 133 Pa)
Intraocular Pressure
h
pR
σ=
2h
p
R
€
The stress σ in the corneal wall can be approximated via
the Laplace Law for a bubble.
p = internal fluid pressure (IOP)
R = globe radius
h = corneal thickness
Summary 1a
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
• 
• 
• 
• 
• 
Tissues are made of cells + extracellular matrix (ECM)
Connective tissues are mostly ECM
Soft tissue ECM is water, proteins and sugars
Collagen is the most important structural protein
Collagen self-assembles from a base unit of the triple
helix, into quarter-staggered arrays forming fibrils
Summary 1b
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
•  Cornea (2/3 of focal power)
–  Stroma versus cell layers; collagen in sugar-water ground substance
–  Stromal collagen fibril orientation 0 ± 90° at central cornea
–  Stromal collagen fibril spacing extremely regular (required for
transparency)
–  Differences between cornea and sclera
•  Crystalline lens (1/3 of focal power)
–  Capsule, cortex (anterior and posterior) and nucleus
–  Specially adapted cells (lens fibers) and proteins (crystallins)
–  Complicated onion-like layered structure
•  Vitreous, Aqueous Humors and IOP
Overview
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
–  Eye tissue biomechanics
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
Tissue Biomechanics
•  Concerned with baseline structure - (composition) properties relations
•  Continuum mechanics approaches based on classical
elasticity incorporate the “special features” of the
mechanical behavior of biological tissues
1.  Nonlinear elasticity
2.  Anisotropy
3.  Time-dependent mechanical responses
Tissue Biomechanics 1. Nonlinear Elasticity
•  Recall typical metal stress-strain response…
Tissue Biomechanics 1. Nonlinear Elasticity
•  Recall typical metal stress-strain response and contrast it
with the typical response for a soft biological tissue:
Tissue Biomechanics 1. Nonlinear Elasticity
•  This shape results from the reorientation and sequential
“recruitment” of collagen fibrils.
•  As fibers rotate, there can be deformation with no force
•  As the fibers reorient, they can then support force
•  We assume each collagen fibril acts as an elastic spring
Tissue Biomechanics 1. Nonlinear Elasticity
Reminders from Basic Mechanics
From strength of materials
σ = Eε
F
δ
=E
A
L
€
€
F
F
€
F = kδ
EA
k=
L
Reminders from Basic Mechanics
Springs in series
F = F1 = F2
δ = δ1 + δ 2
€
Springs in parallel
δ = δ1 = δ 2
F = F1 + F2
Reminders from Basic Mechanics
Springs in series
F = F1 = F2
δ = δ1 + δ2
€
Springs in parallel
δ = δ1 = δ2
F = F1 + F2
F = kδ = k1δ1 + k2δ2
kδ = k1δ + k 2δ
k = k1 + k 2
Reminders from Basic Mechanics
Springs in series
F = F1 = F2
δ = δ1 + δ2
€
1 1 1
= +
k k1 k 2
Springs in parallel
δ = δ1 = δ2
F = F1 + F2
F = kδ = k1δ1 + k2δ2
kδ = k1δ + k 2δ
k = k1 + k 2
Elastic Recruitment
E
E
E
E
E
The maximum effective stiffness (kmax) or modulus (Emax) is the sum of the
stiffnesses of all parallel springs, Emax= n E.
Tissue Biomechanics 2. Anisotropy
•  Because the
collagen fibrils are
not randomly
oriented in 3D, soft
tissues are
anisotropic like
other composite
materials.
•  (IA Materials,
composite bounds
as in Data Book)
Volume Fraction Stiff Phase, Vf
Soft Tissue Anisotropy
Tissue Biomechanics 3. Time-Dependence
Two Mechanisms:
1. These are organic
materials, like polymers,
so there is bulk
viscoelasticity
2. These are hydrated
materials, so there is
poroelasticity, where
time-dependent
deformation results from
fluid flow.
Soft Tissue Viscoelasticity
Soft Tissue Viscoelasticity
Soft Tissue Viscoelasticity
εS = ε D = ε
σS + σ D = σ
Soft Tissue Viscoelasticity
εS = ε D = ε
σS + σ D = σ
EεS + ηε˙D = σ
Eε + ηε˙ = σ
τ = η/E
Soft Tissue Viscoelasticity
εS = ε D = ε
σS + σ D = σ
EεS + ηε˙D = σ
Eε + ηε˙ = σ
τ = η/E
Limitation:
No instantaneous elastic response
(no ‘free’ spring): cannot respond to a
step change in strain
Solution:
Soft Tissue Viscoelasticity
σ (G1 + G2 ) + σ˙η = G1G2ε + G1ηε˙
€
G1
G(t) =
G2 + G1 exp(−t /τ )}
{
G1 + G2
η
Instantaneous modulus
where τ =
G(0) = G1
G1 + G2
Equilibrium modulus
G(∞) = G1G2 (G1 + G2)-1
Viscoelastic Extent
Viscoelastic Recruitment
Viscoelastic Recruitment
Poroelasticity
→ Hydrated biological tissues exhibit time-dependent
mechanical behavior in part due to the flow of fluid through a
porous elastic or viscoelastic “solid” network.
t = 0
t > 0
t >> 0
Poroelastic (Biphasic)
E(∞)
<< 1
E(0)
Fluid-like (80% water!)
E(∞)
= 0.92
E(0)
Solid-like
Poroelastic (Biphasic) Theory
•  Simplest form: linear poroelastic theory
–  Solid phase is linearly elastic and isotropic (E, ν)
–  All time-dependence is due to flow of fluid through the
porous matrix
–  Effective pore size is typically estimated at nanometre
scale
–  Poroelasticity has three additional material parameters
related to the flow and fluid-solid interactions for a total
of 5 constants (E, ν, α, β, κ)
–  α, β, dimensionless and often taken as unity
Poroelastic (Biphasic) Theory
•  Darcy’s Law
κA(Δp)
Q=
h
•  κ = hydraulic permeability [units m4 (Ns)-1]
•  Q = rate of volume discharge across an area, A
•  Δp = pressure gradient applied across specimen with
€ thickness h
Poroelastic (Biphasic) Theory
•  Time constant
h2
τ=
Eκ
•  Intrinsic permeability
k = ηκ
•  η = fluid viscosity (1 mPa s for water)
2 and gives an estimate of the intrinsic pore
• 
k
has
units
of
m
€
size
•  h = specimen height€
(thickness)
•  Pore sizes can be too small to see (nm) but can be
measured mechanically
Intrinsic permeability
Various analytical and computational models exist for relating permeability (k) to
microstructure (fiber size, a, and solid fraction, φ): k = a 2 f (φ )
Langmuir
Happel
Jackson & James
1 $
3
φ2 '
f (φ ) =
&−ln(φ ) − + 2φ − )
2
2(
€ 4φ %
1 $
φ 2 −1 '
f (φ ) =
&−ln(φ ) + 2 )
8φ %
φ +1 (
* 1 -'
3 $
f (φ ) =
/)
&−ln(φ ) − 0.931+ O,
20φ %
+ ln(φ ) .(
Jackson and James, Canadian J. Chem. Eng. 64 (1986) 364-74.
Intrinsic Permeability Scaling Laws
Langmuir
Happel
Jackson & James
Mechanical Testing of Cornea
Test parameters:
Force, displacement, time
Test parameters:
Pressure, shape, time
Geometry:
Width, length, thickness
Geometry:
Radius, thickness
Excision of strip for tensile testing
Ends are
attached to
tensile
grips
Strip Extensometry Test Set-up
Thickness variation in strips
Corneal strip extension tests
•  There is clear evidence of the nonlinearity of response
•  Rupture occurs atan axial force of between 23 and 26 N.
•  Behaviour beyond 16 N (not shown) remains approximately
linear at the maximum stiffness until rupture.
How to mechanically test corneal tissue?
•  Strip extensometry (tensile) test
–  Dissect strip of corneal tissue
–  Inherent challenges:
•  Strip is from spherical surface – centerline is
longer than along sides
•  Flattening of curved specimen
– Initial compressive and tensile strains
– Compressive stresses cause reduced tensile
stresses under external tensile loading
•  Corneal thickness increases with distance from
center
Corneal Inflation Test Set-up
Last Revised on: 5/2/12
MCEN 4134 / 5228 Biomechanics
85
Corneal Inflation Tests
•  Long phase of linear behaviour followed by gradual
stiffening at ~15–30 mmHg
Comparing strip extension and inflation test results
• 
On average, the strip tests
overestimate the material
stiffness by about 32%
compared with the inflation
test procedure.
• 
Mathematically account for:
(1)  Standard approach
31% (2)  Consider length variation
17% (3)  Consider flattening of initial
curvature
5% (4)  Consider thickness variation
% difference from (1)
Mechanical Testing of Cornea
Pros:
Simple and fast to execute, analyze
Can obtain some anisotropy information
Pros:
More physiological
3D information
Cons:
Uniaxial deformation does not reflect
cornea biaxial loading in vivo
Cons:
Difficult to execute
Requires models to interpret
Summary 2
•  The Normal Eye
–  Eye tissue biomechanics
•  Nonlinearity
–  Spring recruitment models Emax
•  Anisotropy
–  Composite bounds Eupper and Elower
•  Time-dependent deformation: viscoelasticity
–  Spring-dashpot models G(0) and G(∞)
•  Time-dependent deformation: poroelasticity
–  k = a2 f (Φ)
•  Uniaxial and biaxial mechanical testing of cornea
Overview
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
–  Eye tissue biomechanics
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
Lens Accommodation
muscles
Myopia, Hyperopia, Presbyopia
Myopia = nearsightedness, an inability to view distant
objects in focus; this is corrected with concave lenses
Myopia, Hyperopia, Presbyopia
Hyperopia and Presbyopia = farsightedness, an inability to
view close-up objects in focus; this is corrected with
convex lenses
Myopia, Hyperopia, Presbyopia
Myopia and Hyperopia are genetic but Presbyopia is part of
the aging process and happens to nearly everyone.
The near point is the closest object that can be brought into
focus naturally. This ranges from a few cm in children to
an arm’s length in advancing middle age to beyond an
arm’s length in old age
Lens Biomechanics
There appears to be no protein turnover in the nucleus throughout lifespan.
–  The lens is thus prone to age related changes.
–  Lens stiffening with age inhibits accommodation.
Mechanical Testing of Lens
• 
• 
• 
• 
• 
Indentation testing of lens
across the surface
Tested 8 points across lens
Three rows when possible
1mm spacing
Calculate Shear Modulus, G
(Pa), from:
where:
P = total load (N)
R = indentor radius (m)
d = maximal depth of penetration (m)
ν = Poisson’s ratio
Stiffness profile across young and old lens
YOUNG HUMAN LENS
OLD HUMAN LENS
Observe the difference in magnitude of G !!!
Stiffness changes with age
Nucleus (interior) and
cortex (exterior) of lens
both become
substantially stiffer with
increasing age.
(again note Log scale!)
Lens Geometry Changes with Age
The lens becomes larger
with age, in addition to
becoming stiffer.
LASIK Surgery
Laser-Assisted In Situ Keratomileusis
Recall that 2/3 of the eye’s focussing power comes via the
cornea. LASIK is used to re-shape the cornea to restore
vision.
•  The cornea is opened in a “flap” to expose the stroma
•  A laser is used to vaporize regions of the corneal stroma
•  The flap is closed and naturally re-adheres (no sutures
are required)
This is a cornea-based fix to a lens- (accommodation) based
problem.
LASIK patients cannot be cornea donors.
http://catalog.nucleusinc.com/generateexhibit.php?ID=32886&ExhibitKeywordsRaw=&TL=&A=2
Contact Lenses
The idea started percolating through the medical and
scientific community in the first half of the 20th century
Types of lenses (Elastic modulus):
•  Glass 1880s-1930s (70 GPa)
•  PMMA 1930s-80s (4 GPa)
“rigid”
•  Silicone acrylates (gas permeable) 1980s-90s (~GPa)
•  Silicone rubbers1960s (1-10 MPa)
•  Hydrogels 1970s-present (kPa-MPa)
Cornea elastic modulus: 1-15 MPa depending on location,
orientation
Advances in contact lens materials technology have made
them increasingly cheap and disposable over the years.
€
Hydrogel Contact Lenses
A hydrogel is a water-swollen polymer network, that can be up
to 99% water by volume
(recall the cornea is approximately 75% water)
A hydrogel’s properties are largely defined by the volume
fractions of polymer and water within the material, as
defined by a swelling ratio, Q, which is in turn related to the
most important gel physical characteristic, the mesh size ξ
Vswollen
Q=
Vdry
€
ξ ∝ Q1/ 3
Determinants of Swelling Ratio
Determinants of the swelling behavior:
l  type and concentration of monomers (nature of the
hydrogel polymer network)
l  cross-link density
l  temperature, pH during network formation
l  ionic strength of fluid (salts)
Swelling (Q) a.k.a. mesh size (ξ) determines the
mechanical stiffness, strength and permeability
Bottom line: Hydrogels demonstrate a trade-off between
relatively poor mechanical properties and excellent
biocompatibility, in both cases due to the large water
content!
Corneal Opacity
Corneal opacity is similarly a cloudy (opaque) cornea.
This is most often (but not exclusively) due to injury,
inflammation or infection, and thus sudden in onset
compared with the gradual deterioration of the lens in
cataracts.
The best current fix is a corneal transplant (increasingly difficult to find donors).
Corneal Transplants
•  There exists a need for a material to act as the corneal
stroma, to allow for re-creating the cell layers on both
surfaces to better mimic a real cornea
–  It would be a bonus if the material would “heal” into the surrounding
healthy tissue
Corneal Transplants
•  In cases of corneal opacity, transplants from donor eyes are
very successful
–  As with all transplant surgeries, there is a risk of rejection
–  There is also a significant shortage of donor corneas, waiting lists
are up to two years and likely to increase significantly since eyes
with LASIK surgery are unusable as donors
•  There have been some precedents of polymeric materials
(PMMA, in particular) used for corneal transplants,
especially in cases of a failed cornea transplant.
–  Complications include induced glaucoma, extrusion of the implant,
and inflammatory reactions
–  These tend to be very invasive procedures, not just involving the
cornea itself but invading the globe substantially
Amniotic Membrane Grafts
November 2008
•  Amniotic membrane
graft for eye surgery
•  100+ microns thick
http://www.iopinc.com/news/ambio5-launch/
Artificial cornea project: Flexicornea
Polymethylmethacrylate (PMMA)
- 
non-degrading
- 
First human use in 2009
Thickness: central 0.3 mm, skirt 1 mm.
Dr. Joachim
Storsberg
Fraunhofer institute
Cataracts
A cataract is defined as a cloudy (opaque) lens.
This is extremely common in the elderly and is a leading
cause of blindness in people of all ages in the developing
world.
Cataract Surgery
•  Artificial intraocular lenses (IOLs) are implanted after
removal of the cloudy lens (cataract) in a very common
surgery (10,000,000 IOLs implanted per year)
http://catalog.nucleusinc.com/generateexhibit.php?ID=34654&ExhibitKeywordsRaw=&TL=&A=2
Intraocular Lens Materials
•  Early intraocular lenses were PMMA (E ~ 4 GPa)
•  Modern acrylate lenses are flexible so as to be folded for the
surgical insertion; these include both hydrophobic and
hydrogel polymers. In addition to acrylates, silicone rubber
has been used. (E ~ 3 MPa)
Intraocular Lens Materials
•  Although first done in 1950, the procedure gained significant
popularity in the 1970s with improved IOL materials
•  Modern lenses are significantly lighter as well, 20 mg on
average compared with 110 mg for early PMMA lenses
•  The reduction in stiffness associated with the modern,
flexible lenses allowed for a change in surgical procedure
for a minimally-invasive approach requiring no stitches
–  Recovery is much faster
–  Outcomes are significantly approved
•  IOL materials are often doped with UV absorbing additives
to protect the retina from radiation damage
•  Historically IOLs are monofocal—accommodation is lost
Intraocular Lens Future
•  Cataracts are an enormous problem in the developing
world: it is estimated that 35 million more operations could
take place a year compared with the 10 million currently
•  Multi-focal and accommodating IOLs are currently under
development for improving on monofocal IOLs
–  A word of caution is warranted here: in many types of medical
implants, the earliest designs and simplest principles have proven
more effective than “advanced” designs
•  In the future, advanced IOLs may be used to correct vision
defects, instead of glasses, contacts, or LASIK
–  “Phakic” IOLs are like permanent contact lenses implanted between
the cornea and iris
Overview
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
–  Eye tissue biomechanics
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
Tissues = Cells + ECM
•  The living parts of tissues are the biological cells
•  Solid polymers, or even hydrogels, replace only part of a
tissue that is diseased or injured—the ECM
•  This has resulted in the frequent favoring of transplant
technology where living cells are included (heart, liver)
•  The new field of tissue engineering aims to use polymers
or hydrogels as artificial ECM and to seed this artificial
ECM with living biological cells
connective tissue
Tissue
Engineering
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Corneal
Tissue
Engineering
Tissue
Engineering
Cells
Scaffolds
Tissue Engineering
Bioreactors
Signals
Corneal
Tissue
Engineering
Tissue
Engineering
Cells
Scaffolds
Tissue Engineering
Bioreactors
Signals
Tissue
Engineering
and Scaffolds
Corneal
Tissue Engineering
Two routes to implantation:
• Implant a cell-scaffold
construct
• Grow the cell-scaffold
construct in vitro prior to
implantation
Tissue
Bioreactors
(a) Spinner flasks
(b) Rotating wall vessels
(c) Hollow fibre perfusion
(d) Direct flow perfusion
(e) Direct compression
Different benefits to each
in terms of nutrient
transfer, mechanical
stresses
Closed-loop Tissue Engineering?
For scaling up the process for widespread use, many additional issues will
have to be considered including sterilization, labeling, automation
Tissue
Engineering
and Scaffolds
Corneal
Tissue Engineering
Cells
Scaffolds
Scaffolds (porous frameworks)
• Naturally-derived
Tissue Engineering
–
Collagen, collagen-GAG
• Polymeric
–
Can be biodegradable (PLGA)
• Apatite (bone, teeth replacement)
• Hydrogels
• Self-assembled or Fabricated
Bioreactors
Signals
Tissue
Engineering
and Scaffolds
Corneal
Tissue Engineering
Scaffold architecture and tunable properties
– Composition
– Porosity
– Permeability
– Isotropy or anisotropy
– Stability/resorption rate
– Ease of manufacture
– Stiffness
– Strength
– Cytocompatibility
Advantages of scaffold-based systems
– Greater initial mechanical properties
– 3D structure to grow large tissue samples
Disadvantages of scaffold-based systems
– Permanent exogenous materials or clearance of degradation byproducts
may affect performance
ScaffoldTissue
Mechanical
Design
Corneal
Engineering
Scaffold porosity involves a mechanical optimization
E porous
E solid
# " porous & 2
!%
(
$ " solid '
Esolid and relative density are the tunable initial parameters.
Scaffold transport behavior
–Ratio of Permeability to Porosity !/!
–Related to pore interconnectivity
–Tissue formation is often on surface only
Electrospinning
Static target
Gelatin solution
15kV
Needle
Syringe pump
Voltage generator
Electrospinning set-up for random fibres
Gelatin solution
Gelatin fibres
15kV
Needle
Rotating mandrel
Syringe pump
Voltage generator
Electrospinning set-up for aligned fibres
Natural collagen
Electrospinning
http://nano.mtu.edu/Electrospinning_start.html
Electrospun fibres
Natural collagen
Corneal Tissue Engineering
•  True corneal tissue engineering is still “of the future”
although research is being actively pursued across the
world due to the increasing scarcity of donor tissue
•  Current challenges include:
–  poor mechanical properties of man-made stromal
matrices
–  poor optical transparency of man-made stromal matrices
•  Tissue engineered constructs are currently
seen as an excellent mechanism for studying
corneal tissue in the laboratory, without
having an imminent clinical application
Corneal
Tissue
Engineering
Tissue
Engineering
Cells
Scaffolds
MUCH MORE IN
Tissue Engineering
MODULE 3G5: BIOMATERIALS
NOW IN MICHAELMAS
Bioreactors
Signals
Summary 3
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
•  Hydrogels
•  LASIK surgery
•  Electrospinning
That’s All, Folks!
•  The Normal Eye
–  Composition and structure of biological tissues
–  Normal eye anatomy
–  Eye tissue biomechanics
•  The Abnormal Eye
–  Cataracts
–  Corneal opacity
–  Myopia, presbyopia
•  Artificial Materials for Eye Repair
–  Contact lenses
–  Intraocular lenses
•  Tissue Engineering for Eye Repair
–  Corneal stroma transplants and TE
Examples Class 18 t h May