Transcript Slide 1

Effect of
Chondroitin Sulfate – Sodium Hyaluronate
Interactions
on the Cohesion – Dispersion Behavior of
Ophthalmic Viscosurgical Devices
Masoud Jafari, PhD
Alcon Research Ltd, Fort Worth, Texas, USA
and
Steve A. Arshinoff, MD
Humber River Regional Hospital & University of Toronto, Toronto, Canada
Financial Disclosures: Dr. Jafari is an employee of Alcon Research, Ltd.
Dr. Arshinoff is a paid consultant to Carl Zeiss Meditech and to Alcon Research, Ltd.
This poster is presented as an educational piece and not to promote any specific product(s).
Background and Purpose
The physical properties of an ophthalmic
viscosurgical device (OVD) directly correlate with
its performance during surgical procedures.*
We investigated the effect of varying concentrations and
molecular weights of chondroitin sulfate (CS) and hyaluronate
(HA) in the performance of OVDs, including:
– Effect on the Cohesion–Dispersion Index (CDI)
– Assessing the result of the modified CDI
on retention and removal properties of the OVD.
* Arshinoff S. "Ophthalmic Viscosurgical Devices.”
In Cataract and Refractive Surgery. Springer Berlin Heidelberg. 2005:37-62.
Materials and Methods


Materials
– Hyaluronate of various molecular weights, produced by bacterial fermentation,
were obtained from Genzyme Corp (Cambridge, MA) and
Lifecore Biomedical, LLC (Chaska, MN)
– Chondroitin Sulfate of various molecular weights, isolated from shark cartilage,
were obtained from SK Kaken Co (Tokyo, Japan)
Methods
– Viscosity & Elasticity were tested using a stress-controlled rheometer with a
cone-on-plate system (Malvern Instruments Ltd, Worcestershire, UK)
– Cohesion–Dispersion Index (CDI) was tested by dynamic aspiration as
previously described*
– In Vivo Performance was determined by a structured questionnaire† of
1 surgeon‡ after performance of 4 complete cataract surgeries in rabbit eyes
• LEGACY® Series 20000® instrumentation (Alcon Laboratories Inc, Fort Worth, TX),
ultrasound power of 60%, vacuum level of 300 mmHg, flow rate of 40 ml/min
• A 1.0 mm incision was made at the superior limbus in the left eye, and the OVD was
injected to completely fill the anterior chamber.
• A 3.0 mm incision was made at the nasal limbus and a phaco needle (1.1 mm ABS ®
tip, 30 degrees flared) was inserted into the anterior chamber with the tip positioned
just anterior to the lens capsule at the center of the pupil
* Poyer JF, Chan KY, Arshinoff SA. Quantitative method to determine the cohesion of viscoelastic agents by
dynamic aspiration. J Cataract Refract Surg 1998:24;1130–1135.
† The questionnaire was prospectively structured but was not a validated instrument.
‡ The authors thank Stephen S. Lane, MD, for his contribution in this work.
Variables that Affect OVD Performance
HA:CS
Ratio
Concentration of HA
Hyaluronate
(HA)
Molecular
Weight
of HA
Concentration of CS
Chondroitin
Sulfate (CS)
Polymer
interaction
Molecular
Weight
of CS
This complex relationship results in specific OVD properties
 These variables can be manipulated in order to design an OVD
with desired properties, including
1. anterior chamber maintenance (easy working space and clarity)
2. prolonged retention (endothelial protection) or ease of removal
3. some combination of #1 and #2, depending upon fluid turbulence
(viscoadaptives), or other parameters of surgery (eg, energy input)

Part 1: Varying the Concentration of Chondroitin Sulfate
A. Effect on the Cohesion–Dispersion Index (CDI)
Higher concentration of
chondroitin sulfate (CS)
yielded
100
Cohesion-Dispersion Index
When hyaluronate of constant
molecular weight (2.2 MDa) and
constant concentration (1.65%) was
mixed with varying concentrations of
chondroitin sulfate with a fixed
molecular weight:
80
60
40
20
Lower Cohesion–Dispersion Index
(i.e. more dispersive behavior)
Further studies are warranted to confirm this
effect on broader ranges of hyaluronate
molecular weight and concentration.
0
0
1
2
3
Concentration of CS, %
4
Part 1: Varying the Concentration of Chondroitin Sulfate*
B. Effect on the Surgical Performance of OVDs
Ease of removal
10
80
8
60
6
40
4
20
0
2
0% CS
1% CS
2% CS
4% CS
10 = Most (retention, ease)
OVD Performance Score
(Bar Chart)
Cohesion - Dispersion Index
(Line Graph)
Retention during phaco
0
0 = Least (retention, ease)
Concentration of Chondroitin Sulfate, %

As the concentration of chondroitin sulfate increased,*
–
OVD retention during phacoemulsification increased
–
ease of OVD removal decreased
–
the Cohesion–Dispersion Index decreased

These observations are similar to properties indicated by laboratory data on CDI (previous slide) and
to known clinical experience with various OVDs in human surgery†

A lower CDI yielded better retention of the OVD during phacoemulsification,
which may relate to better protection of endothelial cells
* While hyaluronate was held constant at MW = 2.2 MDa, concentration = 1.6%
† Pandey S, et al. Update on ophthalmic viscosurgical devices. In: Phacoemulsification. Taylor & Francis; 2004:179-95.
Part 1: Varying the Concentration of Chondroitin Sulfate
Summary: Effects on OVD Performance
Increasing the concentration of chondroitin sulfate yielded a lower
Cohesion-Dispersion Index (CDI) – meaning, a more dispersive OVD
Advantages
Longer retention of OVD
during phacoemulsification
Disadvantages
Longer duration of
irrigation/aspiration needed for
removal
These properties can be balanced by
• Choosing the optimal concentration of chondroitin sulfate
(as discussed in previous section)
• Adding hyaluronate (as discussed in next section)
Part 2: Varying Hyaluronate MW and Concentration
A. Effect on Cohesion–Dispersion Index (CDI)
Changing the
molecular weight of
hyaluronate (ranging
from 0.75 to 2.75 MDa)
had no effect on CDI
100
80
CDI

60
40
20
0
0.5
1
1.5
2
2.5
3
Molecular Weight of Hyaluronate, MDa

Changing the
concentration of
hyaluronate (ranging
from 1.6 to 1.8%) had
no effect on the CDI.
Note: larger changes in MW or
concentration would likely have
effected CDI (see next slide)
100
80
CDI

60
40
20
0
1.55
1.6
1.65
1.7
1.75
1.8
Concentration of Hyaluronate, %
To investigate effects of hyaluronate,
chondroitin sulfate was held constant at MW = 25 KDa; concentration = 4%
1.85
Part 2: Varying Hyaluronate MW and Concentration
B. CDI with a Broader MW Range of Hyaluronate
As shown previously by Arshinoff et al,* hyaluronate concentration and molecular
weight do affect CDI when a broader range of molecular weight is considered:
Cohesion Dispersion Index
Lower CDI =
Better retention during phaco
80
Legend of OVDs,§ ordered by MW:
Fluid
60
VISCOAT® OVD: HA = 3%, 0.5 MDa†
Solid
DISCOVISC® OVD: HA = 1.7%, 1.7 MDa†
40
PROVISC® OVD: HA = 1%, 2.4 MDa
HEALON® OVD : HA = 1%, 3.8 MDa
20
HEALON5® OVD: HA = 2.3%, 4 MDa
HEALON GV® OVD : HA = 1.4%, 5 MDa
0
1
2
3
4
5
iVISC Phaco® OVD : HA = 2.5%, 7.9 MDa‡
Log Zero Shear Viscosity (V0) (PaS)
*Arshinoff SA, et al. “OVD Use Enhanced by Cohesion Data.” ASCRS, San Francisco, Mar 18 – 23, 2006
§All trademarks are the property of their respective owners
†These OVDs also contain chondroitin sulfate
‡This OVD is sold in Canada as iVisc Phaco® OVD and in other countries as MicroVisc Phaco® OVD or BD Multivisc® OVD
Part 2: Varying Hyaluronate Molecular Weight
C. Effect on the Surgical Performance of OVDs
Clarity
7
10
6
8
5
4
6
3
4
2
2
1
0
0
0.8
1.6
1.7
1.8
2.2
10 = Most (depth, clarity)
OVD Performance Score
(Bar Chart)
Zero Shear Viscosity, kPa.s
(Line Graph)
Anterior chamber depth maintenance
0 = Least (depth, clarity)
2.8
Molecular Weight of Hyaluronate, MDa

Increasing the molecular weight of hyaluronate:
– increased the zero shear viscosity of the OVD
– increased the maintenance of depth in the anterior chamber

Clarity seemed to peak in the mid range of MW of hyaluronate
To investigate effects of hyaluronate,
chondroitin sulfate was held constant at MW = 25 KDa; concentration = 4%

Viscosity tested for HA:CS ratios of
0.5 to 2, with molecular weights of
CS & HA fixed as on previous slides
– HA:CS ratio yielded viscosity
behavior that could be fitted by a
quadratic equation
– Minimum viscosity occurred when
HA:CS was near 1:1
Zero shear viscosity, Pa.s
Part 3: Effect of the HA:CS Ratio on CDI
400
300
200
100
0
0
0.5
1
1.5
HA:CS Ratio
CDI tested for HA:CS ratios of
0.5 to 2; little effect on CDI
100

Overall, changing HA:CS ratios
altered ZSV, but not CDI with the
molecular weights of HA & CS that
were tested
2.5
Fixed HA MW
= 2.2 MDa
Fixed polymer MW for both HA and CS;
Variable HA and CS concentration
80
CDI

2
60
40
20
0
0
0.5
1
1.5
HA:CS Ratio
2
2.5
Conclusions: Chondroitin Sulfate and Hyaluronate in OVDs


Our studies indicated that changes in HA MWs
and concentrations (within the ranges that were
tested):
– showed increasing zero shear viscosity and
increasing anterior chamber depth
maintenance with increasing molecular
weight
– had little effect on CDI
Limitations of our study, which used mid-range
MW and concentration of HA:
– We did not test very low MW hyaluronate
products, which demonstrate greater
dispersive behavior
– We did not test very high MW viscoadaptive
hyaluronate products (eg, Healon5® OVD
and iVisc Phaco® OVD), which demonstrate
unique biphasic behavior (see slide 9)



Our studies indicated that the properties of
OVDs containing HA and CS
– could be manipulated by changing HA MW
and concentration, CS concentration, and
HA:CS ratios
– could be tailored to yield an optimal
preparation for given raw materials of HA
and CS
OVDs containing HA and CS can be formulated
to yield better OVD retention and endothelial
protection during phacoemulsification, while
maintaining adequate viscosity to maintain a
deep anterior chamber
Incorporation of CS in OVDs can offer benefits in
formulation variations and use
 Only longitudinal phacoemulsification was tested; results with torsional phacoemulsification would be interesting.
 For more information, see presentation on Monday, 12-Apr-2010, at 3:32 PM in 208 (BCEC): “Role of Chondroitin SulfateHyaluronate Interactions in Viscosity of Ophthalmic Viscoelastic Devices.” Modi SS, Arshinoff SA, Jafari MR.
 These studies were carried out as exercises en route to optimizing the formulations for planned commercial OVDs, and are
presented to illustrate the rheological basis upon which CS OVDs can be optimized to achieve desired parameters for surgery.
The range of MWs and concentrations herein were insufficient for global generalizations about all OVDs.
--Thank you, MJ & SAA