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Corneal Collagen Crosslinking
New Techniques and Biomechanics
Paolo Vinciguerra MD, Edoardo Stagni MD,
William Dupps MD PhD, Cynthia Roberts PhD,
Karolinne Maia Rocha MD PhD, George O. Waring IV MD
Course Director:
R. Doyle Stulting MD, PhD
September 17, 2011
XXIX European Society of Cataract and Refractive Surgery
Vienna, Austria
Financial Disclosures
Some authors have financial interest
in the material presented
Corneal Collagen Cross-Linking
Treatment
Riboflavin 0.1% drops
– Pretreat x 20 min
– Q 5 min during irradiation
UVA Light irradiation
– 365 nm
– 0.3 mW/cm2
– 30 minutes
Ricrolin®
Riboflavin
VEGA Cross-Linker
Initial Concept
Slide courtesy Prof. Theo Seiler
History: UVA + Riboflavin
Studied since 1994 in Europe– University of Dresden
• Prof. Theo Seiler
• Eberhard Spoerl
• Gregory Wollensak
– Looking for ways to increase cross-links in corneal stroma
First clinical use in 1998
Keratoconus Corneal Collagen Structure
Corneal collagen fibrils
– Posterior displacement of
lamellae
– Lack orthogonal uniformity
– Uneven distribution
– Areas of vertical elongation
Slippage of corneal fibrils
– Corneal remodeling
– Thinning at apex of cone
Normal corneal surface
Keratoconus corneal surfacePhoto courtesy CA Eksteen, www.eyesite.co.za
2
Epithelial Thickness in Keratoectasia
* **
* *
* p < 0.05
Design Specifications
Riboflavin– Absorption peak 365 nm to
370 nm– Concentration 0.1%
UVA toxicity depends on how deeply radiation penetrates the eye– Determined by:
• Wavelength
• Intensity• Duration of Exposure
• Frequency of Exposure
UVA + Photosensitizer– Absorption coefficient
maximizes absorption in cornea
– Minimize threshold for endothelial cell toxicity
0
1
2
3
4
5
300 350 400 450 500 550
Riboflavin biphasic
absorption peak
Riboflavin
Vitamin B2 Water Soluble Vitamin
– Non-toxic
Normal function– Catalyzes oxidation-reduction reactions
Cross-linking function– Increases absorption of UVA irradiation
– Photosensitizer for production of reactive oxygen molecules (singlet oxygen)
UVA Corneal Absorption in
Presence of Riboflavin
Stress-Strain Measurements
0
1
2
0 2 4 6 8 10 12
Strain in %
Str
es
s in
10
5 P
a
porcine corneas
crosslinked
untreated
(Spoerl/Seiler:Exp Eye Res, 1998)
Increased Resistance Against
Enzymes
0
2
4
6
8
10
0 2 4 6 8 10 12 14
Time in days
co
rne
al d
iam
ete
r in
mm
collagenase digestion in dependance on time
2 mW/cm² 3 mW/cm²1 mW/cm²control group
(Spoerl,Wollensak,Seiler: Current Eye Res. 2004)
3
Increased Collagen Fiber Diameter
12,2 %
4,6 %
(Wollensak,Spoerl,Seiler: Cornea 2004)
Intact Epithelium Prevents
Riboflavin Absorption
EPI Intact
EPI Removed
Riboflavin Q1 x 10
Asota, Fant, Edelhauser, and Stulting, unpublished
Str
om
a
US Clinical Trial on Ricrolin
CXL
12 sites currently enrolling
Early data (stay tuned)
Trans-epithelial CXL
• Operating Room not necesary
• Corneal thickness < 400 µ
• Easier technique
• Pre treatment VA maintenance
• Better patient compliance (children)
• No post-treatment pain
• No complications derived from
disepithelization
4
Ricrolin TE (SOOFT, Italia)
Riboflavin
Dextran T500
Bio-Enhancer
Photo-enhancer
Trometamol
Trometamol (Tris -(hydroxymethyl)aminomethane)
Inert aminoalcohol with low toxicity
Commonly used in cosmetics and other drugs as
buffer
Buffer action mitigates carbon dioxide and others
acids
It’s present cosmetics and drugs
Low toxicity
– in literature, is reported only one case regarding a
periorbital dermatitis
Nahas G G, Sutin K M, Fermon C et al. Guidelines for the treatment of acidaemia with THAM.
Drugs 1998: 55: 191–224.
(Cover et al., Microbios, 68 1991)
Trometamol
• Increases efficacy (Abdelkader H et al., AAPS SciTech.,
• Decrease toxicity (U.S. Pharmacopoeia, Vol. XXII)
• Improve liposolubillty(Valles et al., Me6)
• Combined with EDTA allow the transit
through the tight-junctions
Evaluation of Ricrolin TE
Stagni E. Caporossi
Inclusion Criteria
• 50 patient
• Age: 12 to 42 years
• Progressive Keratoconus II-III° Amsler–
Krumeich
• Treated worst eye (larger corneal curvature
and thinner pachymetry)
• Contralateral eye used as control
• Mean corneal thickness: 412,9 micron
Materials and Methods
Follow up: T0, 7, 15 days, 1, 3, 6, 9,12, 18 months
VA measured with LogMar ETDRS tables
Used instruments:– Digital Slit lamp
– Ultrasound and optic pachimetry
– Corneal topography and aberrometry
– Corneal OCT
– Corneal endothelial count
– Corneal confocal microscopy
5
TechniqueRicrolin MUST BE preserved at 4-8°C during the treatment
p
6
Stroma 250 µ
treated with CXL TE
Stroma 250 µ
control
Stroma 250 µ
treated with CXL
Confocal microscopy
Control endothelium
Confocal microscopy
CXL TE endothelium
statistically not significant (p< 0.5)
CXL
Pre: 2427 ± 236.4
Post: 2387 ± 361.0
Controls
Pre: 2523 ± 198.2
Post: 2474 ± 241.0
Corneal endothelial count (cell/mm2)
Results TE CXL Summary
• Better compliance of patients (possibility to treat
patients under 15 years and “complicated patients”)
• No post-treatment pain
• Age over 35 y.o.
• Corneal thickness < 400 micron
• Manteinance of pre-treatment visual acuity
• Cooperate with traditional CCL (possibility to use both
techniques in the same patient)
Iontophoretic Delivery of
Riboflavin
Applications
36
Lidosite Lidocaïne
patch
(Vyteris)
Iontopatch
Dexamethasone
(Teikoku Pharma)
Ionsys Fentanyl
patch
(Incline
therapeutics)
Eyegate Transscleral
device
(Eyegate Pharma)
Phase III
7
Riboflavin: a perfect candidate
37
Small Molecular weight (456)
Negatively charged at physiological pH
High Solubility in water
Proof-of-concept devices
38
- Surface 0.8 cm2
- Riboflavin volume
0.35 ml
- Stainless steel
electrode
- Current controlled generator
- 0,25 – 2,5 mA current range
- 0,5 – 5 min time range
Corneal Riboflavin content
39
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5min iontophoresis 0.9% NaCl solution
15min Passive Riboflavin 3min Iontophoresis Riboflavin
5min Iontophoresis Riboflavin
Mean Concentration of riboflavin (ng/g of cornea)
What does the future hold for
Crosslinking?
Increased wattage decreased treatment time
Iontophoretic delivery system
Combination therapy
– Rings
– Thermal keratoplasty– Topography guided PRK with crosslinking
Neurolinking
Prophylactic CXL combined with excimer surgery in boarderline patients
Biomechanically modulated vision correction
Scleral crosslinking
Thank You
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