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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

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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)

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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

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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

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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

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Lidosite Lidocaïne

patch

(Vyteris)

Iontopatch

Dexamethasone

(Teikoku Pharma)

Ionsys Fentanyl

patch

(Incline

therapeutics)

Eyegate Transscleral

device

(Eyegate Pharma)

Phase III

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Riboflavin: a perfect candidate

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Small Molecular weight (456)

Negatively charged at physiological pH

High Solubility in water

Proof-of-concept devices

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- 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

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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