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Total thickness of cornea
Tissue type of corneal epithelium
Stratified squamous, non-keratinized epithelial tissue (5-7 cell layers thick)
Functions of corneal epith
- 1. barrier to pathogens
- 2. excess uptake of fluid from tears
- 3. UV filter
- 4. surface for tear film distribution
- 5. Transmission of O2, CO2 and metabolites**
- 6. optical refractive surface (with tear film)
What percentage of refractive power comes from the cornea?
Cell layers of K epith
- 1. Basal Layer
- 2. Wing Cells
- 3. Squamous cell layers
What does basal layer of K epith arise from?
limbal stem cells
Cell shape of K epith basal layer
more columnar than cuboidal (shape depends on source of info)
Basal layer of K Epith
- 1. highly mitotic (many mitochondria)
- 2. Produce basal lamina (40-60 nm thick)
- -thinner than bowman's
How do cells attach to basal lamina
Describe devision of basal cells
divide from stem cells (at limbus) and migrate inwardly
Basal lamina contains
- type 7 and 4 collagen and cell adhesion molec (CAMs)
- involved in gross adhesion of basal cells to the basal lamina
- 1. laminin and heparin sulfate
- 2. integrins
- 3. fibronectin
Which corneal dystrophy does not occur early in life?
Fuchs endothelial dystrophy (bw ages 40-50)
Hereditary K dystrophy that is a disorder of basal epith cells
Meesman's K dystrophy
(non-progressive, fine dot-like glycogen containing opacities)
Epithelial basement membrane disease characterized by bilateral cysts, dots or lines
Epithelial basement membrane dystrophy (EBMD)
- 1. most common cause of recurrent K erosion
- 2. look for negative staining
- 3. fibrillin material accumulates bw basal lamina and bowman's causing and incr in thickness
Wing cells make up how many layers of K epith and what begins here
1-3 layers; apoptosis (no mitosis happens here)
What makes up most superficial 2 layers of epith?
Squamous cell layers
What happens in the squamous cell layers of epith?
cells are starting to degenerate, loosing their RNA and chromatin
What does most superficial layer of the squamous epith have between the cells?
Zonula occludens; makes layer a semi-permeable membrane
In the squamous cell layer why do some epith cells appear light?
Light cells: are younger, smaller cells, that appear light due to their high level of microvilli
How are K epith cells joined together?
Junctions that are found throughout the epith layers are...
- Desmosomes (structural, cadherins)
- gap junction (common in basal cell layer)
Junctions that are only located in the most superficial, squamous layer of epith
How long does it take to haea new renewed corneal epith
~7-10 day (continues cycle)
How do K basal cells migrate on the cornea?
Vortex patten, curved (Y-axis of centripetal migration)
When medications/metabolic conditions have evident pattern of corneal migration...
- Whorl keratopathy (medications: amiodarone or choloroquine)
- Fabry's dx (metabolic)
How do basal cells divide
- mitotically, producing wing cells
- ( migrate superficially as more wing cells are produced, becoming squamous cells, X-axis of prolif)
- become less cuboidal and more squamous as move superficially
When does apoptosis begin
in wing cell layer, ending just before squamous cell desquamation into the tear filn (Z-axis cell loss)
- X=from deep to superficial
- Y=limbus to center
- Z= superficial to tear film
How is K epith renewal mediated
- May be mediated by the sympathetic nervous system, likely has a feedback control loop mechanis
- (intense pain signal may speed up the regeneration process)
- o The amount of drug instilled into
- the ocular surface
- o The active concentration of a drug
- is ½ that in the drop, as only about ½ gets to the site
- Higher concentration = more of the drug to get to its destination
Water and lipid solubility
o Lipid soluble drugs perfuse through
- the epithelium more easily
- o Water soluble drugs perfuse through
- the stroma more easily
Epithelial integrity / permeability
specific drugs that break down the epithelial junctions = increased permeability
- o Many drugs have a detergent or
- surfactant to increase permeability
Duration of contact / rate of elimination / blink
- By mode of drug instillation (ung or
- Closing eyes or punctal occlusion
- can increase duration of contact
kinetics / ionization in cul-de-sac
- Stability of drug affected by pH,
- temperature, chemistry of drug
of Zonula Occludens
- Tight junctions provide a natural
- barrier, however ions may pass intercellulaly
Epithelial cells are permeable to lipophilic molecules
- Lipophilic aka: hydrophobic, fat
- soluble molecules, non-polar
- o Nonionic molecules permeate
- epithelial cells
- o Ions have low diffusion permeability;
Stroma is permeable to...
- to hydrophilic molecules because there is so much
- water in the stroma
- Since it is only 1 cell layer thick,
- this will not limit permeability
- o Determined by molecule size, as
- junctional gaps, and macula Occludens allow ions and non-ions to pass
Action of detergents
- Detergents are surfactants that kill
- bacteria by breaking down lipid membranes and junctions
Examples of detergents
BAK, Chlorohexidene, EDTA
break down junctions and cause sloughing off of outer cells; inhibit wound healing, break down lipids and cell to cell junctions; cell membr
Benzalkonium Chloride (BAK) 0.01%
- - Causes an immediate increased
- permeability to NaFl by breaking down junctions
- § Inhibits healing, so prolonged
- contact is not indicated
- · Repeated use of 0.02% may cause
- irreversible corneal damage
- § Bacteriostatic: breaks down cell
- junctions and lipid bilayers
- § Commonly used in the best hand sanitizers
§ Similar to BAK, but weaker
- § Bactericidal; static: disrupts
- § Also breaks down cell-to-cell
- junctions but does this by chelating metal ions
- § Chelates calcium which makes
- bacteria unable to survive
- · The calcium is also required for
- maintenance of tight junctions
- · Chelation is where a molecule binds
- a metal ion so that it becomes unusable to other functions; sequestering
Increased pH favors:
Increased pH decreases:
Toleration of pH ranges
- - Tear pH of 7.3-7.7 is within the
- comfort zone
- § Tear pH of <6.6 and >7.8 will
- cause discomfort
- § Tear pH of <6.5 and >8.5
- indicates that endothelial damage is possible
- 1. Biphasic (stimuli sensitive)--see notes
- 2 . Small molecules
- 3. Increased contact time with cornea
- 4. Vehicle with surfactant / detergent
- to break up epithelial integrity
· The average drop is 50uL
- · The cul-de-sac holds 20-30uL
- · The volume of tear file is 7-9uL
- · Excess drops will run over (50uL)
- · Quick dilution with reflex tearing
- · Inflamed / infected eye – increased
- protein in tears will bind to drug and decrease bioavailability of the drug
How does a CL affect K epith?
long term EW can thin epith by up to 5.6%
What provides structural strength to the K?
Corneal stroma accounts for how much of K thickness
What percentage of stroma is water
what makes up stromal dry weight?
- 68% is
- collagen, 9% is proteoglycans, 10% is keratocyts, and the remainder is
- random ions, salts, and glycoproteins
How is collagen organized in k stroma?
- organized in lamellae
- (perpendicular, stacked, oblique), as regular dense connective tissue
What are Keratocytes and what are their function?
- modified fibroblasts
- · Production and organization of collagen and proteoglycans
- · Turnover of the extracellular matrix, which takes 12 months or more
- o Matrix metalloproteinase, MMP, are
- enzymes produced by keratocytes to degrade the extracellular material so that
- it can be renewed
- · Communication throughout the cornea
- via keratocyte-to-keratocyte gap junctions
- · Provision of energy
- · Tethering of neighboring lamellae
- · Stromal wound healing
Where are keratocytes found?
bw the collagenous lamellae of the stroma
Why are keratocytes transparent
- When developing, they are very active and have many organelles, but once the stroma is mature, they have
- lost most of their organelles and are fairly transparent and less active.
- -There are also enzymes (ALDH1 and TKT) and crystalline that helps keep them transparent. When there is a wound, keratocytes mobilize to heal it and stop production
- of these enzymes and are therefore not transparent during healing.
- They are also extremely flat and a very small percentage of stroma.
What are flat cells with extensive processes that interconnect via gap junctions?
- They can extend up to 100um and don’t have many organelles in their processes; organelles in the processes are within nodules
What is a water insoluble structural protien, common throughout the body and eye?
Functions of collagen
- 1. structural support
- 2. an anchor for overlying epithelial tissues, & basal lamina
- 3. bed for wound repair
- 4. In the cornea, its arrangement aids
- corneal transparency
is collagen hydrophilic or phobic?
- Since collagen is hydrophobic, this
- prevents most interactions between molecules, with crosslinking being the
- · The collagen is staggered
- which gives a banded appearance due to the gaps
- o This occurs every 64um
Corneal collagen is Type?
mainly 1 , some types 5, 6, 7
Refractive index of collagen
- -organizes into lamellae, of which
- there are 200 to 250 arranged parallel to one another in the stroma
- -highly organized
- -Each lamella is 2um thick, and runs from limbus to limbus
-At the limbus, the lamellae turn toform a 1.5-2.0mm wide annulus running circularly around the limbus; this functions to maintain tension on the central cornea, controlling corneal curvature
- - Lamellar structure of the stroma makes
- a partial corneal transplants possible
Loss of lamellae over time, Thinning disorder of cornea
Collagen in stroma V sclera:
- -Size: Stroma – 30nm diameter fibrils
- (22-32nm); Sclera - ~120nm diameter fibrils (variable)
-Arrangement: Stroma – form into parallel lamellae (sheets), very regular; Sclera – interwoven connections of various sized fibrils, makes sclera stronger than stroma
- -Spacing: Stroma – 42-44nm between
- fibrils; Sclera – variable spacing, larger than cornea
This provides volume to the stroma
- water-soluble glycoproteins that are composed of a single
- protein core or chain, with glycosaminoglycan (GAG) side chains
GAGs of corneal proteoglycans are?
sulfated; negatively charges the proteoglycan
sulfating corneal proteoglycans does what?
- causing attraction of water and repulsion of nearby
- collagen fibrils, accounting for the interfibrillary distance in the stroma
Proteoglycans found posteriorly and centrally in the stroma
Tpyes of KS proteoglycans
- 1. Lumican, the most common, which regulates collagen fibril diameter and spacing; it also regulates production of collagen by inhibiting fibrillogenesis
- · Essential for maintaining corneal
- 2. Keratocan is found almost exclusively in the cornea
Which proteoglycans are found
found more anteriorly and peripherally in the stroma
- CD and DS proteoglycans
- -They tend to be more negativelycharged than KS proteoglycans, so the interfibrillary distance is larger in the
- -Decorin is a
- CD/DS proteoglycan found in the cornea that is also involved in inhibition of fibrillogenesis
Which proteoglycans occur more frequently during scarring
CD and DS proteoglycans
Proteoglycan content in sclera vs stroma
- -Increase of CD in stroma
- -Increase of DS in stroma
-Decrease of KS (or none) in stroma
Sclera vs stroma, which has more water content
Sclera vs stroma?
has larger fibrils, more widely spaced and poorly organized
3 most common inherited stromal dystrophies
- 1. lattice
- 2. granular
- 3. macular
Most anterior 10um of the stroma
Bowman's layer (not a membrane)
Where does bowman's
layer come from?
Comes from modified fibroblasts that are part ofthe first mesenchymal wave
What type of
collagen does Bowman's layer have?
◦ types 3, 5, 6, and 7 are more common in Bowman’s◦ -It does not have as much Type 1 collagen as therest of the stroma
What K dystrophy is specific to bowman's layer?
What is Bowman's
layer composed of?
- ◦ It is composed of interweaving(non-parallel)collagen fibrils that are attached to fibrils in the anterior◦ stroma◦
- o The interweaving is irregular andthe fibrils haverandom termination◦
- o This organization gives the layer toughness(tougher than the rest of stroma)
Does Bowman's layer contain keratocytes? Is it acellular or cellular layer?
An Algar brush automatically stops at what layer?
How can corneal transparency be lost?
- Altered structure
- Altered refractive index
- Energy transfer
- Produces heat
- Produces altered frequency
- Produces broken bonds (photopigment)
- Destructive interference
Goldman and Benedek's theory
A simple (single layer) epithelial tissue of
regularly arranged polygonal (mostly
This layer is leaky, allowing diffusion from aqueous into the stroma and pumps material out
Thickness of endothelium
4-6um thick from base to apex
Cell shape of endothelial cells
- polygonal; 70-75% are hexagonal which is preferential as it is thermodynamically very stable and
- strong (think benzene rings!)
Diameter of K endoth
How many endothelial cells are in young cornea and what happens with age?
500,000, decrease 0.6% per year
Newborn cornea has a cell density=
Adult cornea has a cell densit=
(Remember cell density = cell/area)
2500 to 3500cells/mm2
Minimum cell density to maintain normal endothelial function is ?
What do you need to look at besides cell density to determine endothelial health?
- Variation of cell size and # of hexagonal cells
- -Specular microscopy (looks at the reflected light and allows measurement of cell size and number)
2 stress indicators of endothelium:
1. CV of normal endothelium is approximately 0.25 and any increase in this value indicates a more variable cell area, acondition called polymegathism
2. In a healthy young cornea, 70-80% ofendothelial cells are hexagonal at their apices and a reduction in thispercentage indicates that endothelial cells are losing their shape, a conditioncalled pleomorphism
Describe organelles of K endoth
- have large nucleus, many mitochondrion (very active), many ER and Golgi (produces a
- lot of protein)
What happens when endoth cell dies
Amitotic: cell not replaced, but cells spread out and cover that area
Why is endoth tissue is amitotic?
- § Less energy is required (can use for running
- § Less chance of mutations
- § Would slough off endothelial cells like the
- epithelial cells do and where would they go?
Factors that cause alterations, both polymegathism and pleomorphism, in the K endothelial mosaic:
- 1. Age
- 2. Surgery (see details in notes)
- 3. Keratoconus
- 4. DM
- 5. Ocular HTN (causes a decr in cell density)
- 6. CL use
Lateral linkage of endothelial cells is via ...
interdigitations,Macula Occludens, and gap junctions
How many Na+ to K is moved by na/k/atpase pumps?
3 Na+ for every K+
Besides Na and K what is also transported thru endoth pumps?
- Hydrogen, bicarbonate, and water are also
- o Water follows along with the sodium, helping the corneal stroma to retain its dehydrated state
What is the basal lamina of the Endoth?
Thickness of Descemet's at birth
What is the anterior banded layer?
- at birth, This
- portion of Descemet’s is composed of collagen types 4 and 8, and remains distinct throughout life as the anterior
- banded layer
As a person ages, the endothelial cells continually
add new material (at a rate of 1-2 um/decade; increases in width) to the
posterior surface of Descemet’s, which forms the
posterior un-banded layer
thickness of entire Descemet's as an adult
Descemet’s is connected to stroma how?
- anteriorly to the stroma via collagen fibrils that run between thelayers
- § Posteriorly, it connects to the endothelial
- cells via Fibronectin adhesion, NOT
What is a normal finding in peripheral endothelium
- Hassal-Henle bodies
- § Small white hyaline outgrowths on Descemet’s membrane, on the inside surface of the
- cornea in its periphery; normal aging change
- § CL patients may present with them sooner than
Name 5 disorders of Descemet's membrane
- 1. Guttata
- 2. Fuch's dystrophy
- 3. Posterior polymorphous dystrophy
- 4. Descemetocele
- 5. Descemet's rupture
What happens as corneal hydration increases
- interfibrillary distance increases, thickness
- increases, and light scatter increases (the only factor that affects thickness is hydration)
- stromal hydration increases linearly with stromal thickness
What is normal hydration of the cornea
Factors that support an increase in hydration:
- · Tendency of stroma to imbibe water (take inwater) and swell
- Structural capacity for swelling, based uponits extracellular natureo Sincethere are lots of fibers etc. (not completely cellular); there is space for itto swell·
- IOP forces water from aqueous into the stroma (bulk flow)·
- Homeostatic characteristic of stromao Waterheld into place due to the negative charge of GAG’s
Factors that support a decrease in hydration
- 1. Structural limits on swelling·
- 2. Action of pumps·
- 3. Tear film osmolarity has a slight effecto As thetear film evaporates, water is evaporating, and solutes are left behind à tear film is hypertonic and fluid leavesstroma to make the tear film isotonic again·
- 4. Cell-to-cell barriers and junctions
Swelling pressure is equal to ?
the force necessary to prevent swelling at a given level of hydration
What is equilibium point of swelling pressure?
If you increase thickness/hydration what happens to swelling pressure?
- (inverse relationship)
What is a measure
of hydration and can be thought of as the pressure that results from stromal water uptake or the pressure from just being more full (pushback pressure)?