Vitreous substitutes

1. VITREOUS
SUBSTITUTES
DR PAVANKUMAR NAIK

2. Anatomy of vitreous1
• Gelatinous structure that
fills the space between lens
and retina
• Non homogenous
• Vitreous cortex
• Vitreous base
• Vitreo retinal interface

3. • 99% water (vol-4ml)
• Proteins 200 to 1400 mg/ml
• Collagens-II(60-75%) ,IX,VI
300 ug/ml
• GAGs-hyaluronic acid, 65-
400 mg/ml chondroitin
sulfate, heparan sulfate
• Ascorbic acid
• Amino acids
• Fatty acids
• Cells –hyalocytes, fibrocytes,
macrophages

4. When to substitute?
• > 2 ml vitreous removed
• Major vitreo retinal surgeries

5. Ideal Vitreous Substitute3
Form
ManipulatableFunction

6. • VISCOELASTIC
• ALLOW MOVEMENT OF IONS AND ELECTROLYTES
• OPTICALLY CLEAR
• ONE TIME IMPLANTATION
• SELF RENEWABLE
• NON TOXIC, BIOCOMPATIBLE, NON
BIODEGRADABLE
• READILY AVAILABLE, REASONABLE COST AND
STORAGE

7. Classification2
Classification Example
Aqueous miscible
Low viscosity Balanced salt solution
High viscosity Chondroitin sulfate
Viscoelastic Hyaluronic acid, hydroxymethylcellulose
Aqueous immiscible Gases
Air, sulfur hexafluoride (SF6),
perfluoropropane (C3F8)
Liquids
Lighter than aqueous Silicone oil
Heavier than aqueous Perfluorocarbon liquids, Semiflourinated
alkanes,
Fluorinated silicone oil

8. Experimental Vitreous substitutes4
a) Polymers
• Hydrogels
• Smart hydrogels
• Thermosetting gels
b) Implants
c) Cell culture

9. Intra-Ocular
Gases2,3,9

10. • 1911 by Ohm.
• Rosengren used intravitreal air injection with drainage of
subretinal fluid and diathermy
• 1973, Norton used sulfur hexafluoride (SF6) gas for a longer
tamponade >air used for difficult retinal detachments,
particularly giant tears.
• Lincoff and associates then developed several perfluorocarbon
gases

11. Non
Expanding
AIR
XENON
Expanding
SF6
PFC

12. • SURFACE TENSION
• BUOYANCY
• SOLUBILITY
• BIOCOMPATIBILITY

13. • Surface tension –
between gas bubbles
and surrounding fluids
critical physical
property
of the gases in retinal
reattachment
• Electrostatic attractive
forces -van der Waals
forces -weaker and
longer range

14. • Buoyancy-ability to float
• Due to large difference in
specific gravity of fluid
and gas
• superior tear tamponaded
with a large air bubble
• Displaces fluid inferiorly
and away from the tear
• Flattens against the wall
of the eye.

15. • Buoyancy directs the
effectiveness of the
tamponade, gases -upward
gravitational direction.
• Large bubbles and face-
down positioning are
required to tamponade
inferior retinal breaks
apposition of the gas bubble against the
posterior pole and macula during face
down positioning.

16. • Solubility of a gas in the aqueous medium :
determining the reabsorption rate of a gas bubble
from the vitreous cavity
• If less soluble than nitrogen, expansion of the bubble
can occur

17. Biocompatibility
• SF6 and the perfluorocarbon gases have a purity of
99.8%
• Pure gases -chemically nonreactive, colorless,
odorless, and nontoxic
• SF6 may -0.3 ppm of hydrogen fluoride. regarded as
the most toxic contaminant found in SF6.

18. • When bubble is large enough , covers the back of the lens, a
cataract develops unless the patient is positioned so that a
layer of fluid covers the posterior surface of the lens
• On contact with corneal endothelium -causes increased
inflammation, >SF6 than perfluoropropane
• Persistent corneal edema and retro- corneal membrane -
interference with nutrition of the endothelium rather than to a
specific toxic effect

19. Gas Dynamics

20. • Bubble Expansion-gas from surrounding fluid
enter the bubble
• Equilibrium with N2: partial pressures of both
compartments equilibrate: o2/co2 diffuse rapidly, N2
slowly, maximum in 6-8 hours
• Bubble dissolution: as gases diffuse out bubble
decreases in size

21. Role of Gas bubble
• Bubble larger than the break-surface tension of gas prevents it
from passing through the retinal break
• Gas bubble apposed to the posterior end of break
• Passage of fluid from the vitreous to SRF blocked
• SRF absorbed into RPE and choroid

22. • Sp gravity of gas lower than water
• Buoyant forces push retina against RPE (max at apex ) 10x >
silicone oil)
• Head position till chorio- retinal adhesion
Advantages:
• When visualisation of retina is difficult-optical window
• Allows fluid gas exchange
• Mechanical barrier-cellular elements & growth factors
“compartmentalisation”

23. 0.3-0.5ml injected
rapidly into the eye to
avoid “fish egg bubble
“formation

24. Factors affecting dissolution
• Vitreous currents
• Surface area of bubble
• Gas solubility in fluid
• Diffusion coefficient of gas
• Partial pressures
• Ocular blood flow

26. CHANGES IN THE VITREOUS
• In a non vitrectomised eye: collagen condensed and
compacted behind lens and at optic nerve head
• Hyaluronic acid expressed from vitreous space
• Lamellae - concave margins and rolled edges
• ? Formation of pre retinal membranes complicating
retinal detachment

27. Choice of Gas
Condition Xenon Air SF6 C2F6 C3F8
RD 2 1 1 2 --
PDR -- 1 1 2 --
RD+mac
hole
-- 2 1 -- 2
GRT -- 1 1 -- 2
PVR -- -- -- -- 1
Trauma -- 2 1 1 2
1-mc used 2-
selected cases

28. • Inj using 30 g , 13 mm needle
• Injected immediately

29. • Head position during air fluid exchange

30. Complications of gas use
• Cataract or corneal opacity
-Face-down or lateral positioning is necessary to
prevent continuous contact of the gas bubble with the
cornea and lens
• Glaucoma
-large bubble
-if the patient remains supine, fluid from the ciliary
body fills the posterior segment & air bubble blocks
fluid egress through the trabecular meshwork
-Medium size -peripheral anterior synechiae with total
angle closure

31. • Central Retinal Artery Occlusion
-Overfilling of the eye with expansile gas
• Laser treatment -undesirable burns
-Reflections of internal fluid–air and air–fluid surfaces.
-Avoid treatment through a gas–fluid or fluid–gas
interface
-Perpendicular to the interface: intensity of a reflected
beam increases as the angle of incidence decreases. -A
divergent beam should be used
• Endophthalmitis

32. • Subretinal gas
• New tears -7% to 23% of patients treated with
pneumatic retinopexy
• Dislocated intraocular lens implant
Gas injection into
vitreous base accidentally
A. Donut sign when gas
encircles the lens
posteriorly.
B. B. Sausage sign when
gas partially encircles
the lens posteriorly.
In both cases the gas
bubble is immobile

33. Perfluoro-
carbons2,10

34. • Fluorine and carbon atoms - most biologically inert in the eye
• Surface tension of approximately 14 to 16 dynes/cm measured
against air –comparable to silicone oil
• Most remarkable property of the perfluorocarbon liquids is the
specific gravity, which is higher than that of water.
• specific gravities range from 1.7 to 2.03

35. • Enables the fluid to settle posteriorly, opening folds in the
retina while expressing subretinal fluid anteriorly through pre-
existing retinal breaks
• Perfluorodecalin & perfluorophenanthrene -high transparency
to light in the visible spectrum
• No obstacle to laser photocoagulation
• Perfluorooctylbromide is radiopaque, and it has potential
application as a contrast agent

36. Biocompatibility
• Inferior corneal endothelial loss with subsequent corneal opacity and
thickening
• Dispersion and droplet formation will develop
• Gial cell proliferation and retinal disorganization -1 month.
• 3 months-preretinal membranes, gliosis, and retinal disorganization
• 6 months, retinal detachments
• Perfluorotributylamine -a “moth-eaten appearance,” - irregularly
shaped defects in the outer segment discs in both the superior and
the inferior retina after 2 days
• Combined use of silicone oil and perfluoropolyether has shown a
tendency to reduce the emulsification PFC

37. 5 main indications:
• Giant retinal tears
• Detachments with complicated PVR
• Traumatic retinal detachments
• Removal of posterior lens fragments and posteriorly dislocated
intraocular lenses
• Macular rotation with a 360-degree retinotomy
• +ROP

38. • PVR: tamponade effect to
open up funnel detachment
exposing any areas of
residual membranes
• Giant retinal tears:
unfolding and displacement
of SRF and blood

39. • PPV removal of anterior
vitreous base
• Crystalline lens floated
anteriorly over ONH
• SRF displaced through
the break
• Posterior retina flattened
• Dislocated lens removed
with fragmatome/vit
cutter

40. DISADVANTAGES
• irreversible cell damage
• Disorganization of retinal
cell growth pattern, loss of
neurites
ADVANTAGES
• Specific gravity of PFCLs -
effective for the intraoperative
repair of complex retinal tears
• Anterior and posterior segment
complications are uncommon
• Low viscosity of PFCLs allow
for tissue manipulation,
injection, and removal

41. SemiFluorinated
Alkanes2

42. • Semifluorinated alkanes (SFAs),or partially fluorinated
alkanes (PFAs) or FA -first internal tamponade agents - used
beyond the intraoperative setting
• Low sp. gravity of SFA< PFCLs:so produce less retinal
damage
• Esp used for macular rotation surgery -press down on the
retina less , allowing rotation of the unfolded macular without
mechanical damage
• Using F6H8 and OL62 HV oligomers increases viscosity and
decreases droplet formation
• Ex: Perfluorohexyloctane(F6H8/O68),
Perfluorohexylethane(F6H2/O62)
• Complications: Glaucoma-Superior PI, Cataract ,Droplet
formation & dispersion

43. Silicone Oil2,10

44. • Silicone oil chains - helix
with six silicium units per
turn.
• Pure 1,000-centistoke oil -
helix of 63 turns and a
5,000-centistoke oil a
helix of approximately
100 turns
• Interdigitation of the helix
& increasing molecular
weight -viscosity
linear chain coils into a helix,
composed of 6 (Si-O) units per turn.
For a molecular weight of 28,000
(1,000 centistokes), the helix will
have 63 turns in average

45. • Buoyancy:
• Difference in specific gravity of aqueous humor, vitreous and
hydrophobic polymer accounts for buoyancy
• Force is spread over an area max at apex and decreases to zero
at horizontal interface
• Directs the tamponade of the immiscible silicone oil upward.

46. Refractive state of the eye
• Higher refractive index compared to vitreous
• Refractive shift depends on lens status
• Phakic eye-oil forms a concave surface behind lens
Acts as a minus lens-making eye hyperopic-8D hyperopia
• Aphakic eye-convex surface as it bulges through pupillary
aperture-plus lens-myopic
Varies with pupillary aperture size-from +12.5 to +5.6D
• Contact lens –to minimise the anisoconia
• IOL-plano posterior surface preferred

48. Indications for silicone oil

49. B. Severe Proliferative Diabetic Retinopathy
• Silicone oil: decreased post op hemorrhage
• Rapid recovery
• Especially in patients with anterior segment
neovascularisation/anterior hyaloid proliferation
• Acts by impending movement of vasoproliferative factors
from posterior segment to anterior segment
• PDR with rhegmatogenous RD involving the macula
C. Macular Hole
• RD due to macular hole
• Idiopathic/Traumatic macular hole

50. D. Giant Retinal Tears
• Unfolding the tear
• Long term tamponade
E. Chronic uveitis with profound hypotony
F. Infectious retinitis
• RRD in CMV retinitis
• Gancyclovir implants with silicone tamponade
F. Endophthalmitis
• Increase concentration of intravitreal antibioticcs
• Antibacterial properties of silicone oil
• Stabilise atrophic retina

51. Complications of Silicone
Oil
• Cataract,
• Glaucoma,
• Keratopathy
• Absorption of silicone oil by silicone intraocular lenses,
• Migration of silicone oil into the optic nerve and rarely into the
brain, and
• Emulsification.
• Retinopathy
• Recurrent retinal detachments

53. Emulsification of Silicone
Oils
• Smaller silicone oil droplets at the interface of oil droplet and intra
ocular fluids
• Factors promoting emulsification:
-Difference in density of two liquids
-Lower viscosity
-Decrease in interfacial tension
-Adsorption of surface active agents
-Ocular saccadic motion
(micro current in and outside the bubble)
1%-1month, 11%-3 months ,85% 6 months, 100%- 1 year 8

54. Stages of Emulsification

55. • Choice of IOL: heparin coated PMMA/ regular PMMA
• Silicone oil acts as a foreign substance and not reabsorbed by
the eye
• On removal-retinal redetachment 3-33%
• Indications for removal:
-Glaucoma
-Keratopathy
-reasonable chance that retina will remain attached
(followed by infusion of BSS / Air –fluid exchange)

57. • Disadvantages
• can pass through retinal
breaks under traction
• Requires optical
adjustments
• tamponade of the inferior
retina is difficult
• Emulsification
• Complications
• Sticky silicone oil
o Advantages
• high surface tension, ease of
removal, low toxicity, and
transparency.
• tamponade effect on the
superior retina
• airplane or high elevation
travel is planned
• post-operative positioning is
difficult

58. • Combinations
“Double Fill”
• Double fill (DF) is a combination of SO and SFAs,
• light SO support the superior retina ,heavier SFA supports the
inferior retina,
• Tamponade agent and reduces dispersion
“Heavy Silicone Oil”
• SO and a PFA mixed in such a way as to create a homogenous
solution.
• More viscous, more stable
• Complex retinal detachments involving inferior proliferative
vitreoretinopathy
• HSO can be challenging to remove-heavier than water

59. Experimental
substitutes 3

60. vitreous molecular
structure
filling function,
to control
elasticity
pressure of the
eye
chemical and
physiological
properties
diffusion of
metabolites
and gases
Perfusion of
drugs
Interact with
intraocular
structures

61. A Natural Polymers
• Hyaluronic acid (HA) and collagen,
B Hydrogels “swell gels”
• hydrophilic polymers that form a gel network when cross-
linked & swell by absorbing several times their own weight in
water
• molecules as tamponades is coupled with the active action as
drug releasers or exchangers

62. • investigated include poly(vinyl alcohol),poly(1-vinyl-2-
pyrrolidone), poly(acrylamide), copoly(acrylamide), polyvinyl
alcohol methacrylate, poly(glyceryl methacrylate), poly(2-
hydroxythylacrylate), and poly(methyl-2-acrylamido-2-
methoxyacetate).

63. C. Transplants & Implants
• Transplant vitreal tissue
• Correctly stored, the vitreous body :maintain its structure
and also its enzymatic properties
• Low inflammatory reaction and interesting surgical
results on 40% of patients.
• Cataract, glaucoma, and more severe adverse events until
ocular atrophy
.

64. Implants
• artificial capsular bodies,
• silicone rubber elastomer and filled with a saline solution,
• silicone oil, controlled using a valve system
• FCVB
• Good mechanical, optical, and biocompatible properties
• PVA filling model
• X. Lin, J. Ge, Q. Gao et al., “Evaluation of the flexibility,
efficacy,and safety of a foldable capsular vitreous body in the
treatment of severe retinal detachment,” Investigative
Ophthalmology &Visual Science, vol. 52, no. 1, pp. 374–381, 2011.

65. Future??
A. VITREOUS SUBSTITUTES AS A DRUG DELIVERY
MEDIUM
• A proper vitreous substitute used as a long-term (>3
months) drug delivery system to reduce or eliminate the
need for multiple intra-vitreal injections
• Hydrogels may be a promising biomaterial for fragile
protein drug delivery
B. CELL CULTURE/GENE THERAPY: CAN WE GROW
VITREOUS?

66. REFERENCES
1. SURVEY OF OPHTHALMOLOGY VOLUME 56 NUMBER 4 JULY–AUGUST 2011
Vitreous Substitutes: A Comprehensive Review Teri T. Kleinberg, MS, MD,1 Radouil T.
Tzekov, MD, PhD,1 Linda Stein, MS,1 Nathan Ravi, MD, PhD,2 and Shalesh Kaushal,
MD, PhD1
2. Duanes Ophthalmology Volume 6 ,Chapter 54 Vitreous Substitutes MARK E.
HAMMER
3.Hindawi Publishing Corporation BioMed Research InternationalVolume 2014,
Article ID 351804, 12 pagesReview Article Vitreous Substitutes: The Present and the
Future Simone Donati,1 Simona Maria Caprani,1 Giulia Airaghi,1 Riccardo
Vinciguerra,1 Luigi Bartalena,2 Francesco Testa,3 Cesare Mariotti,4 Giovanni Porta,5
Francesca Simonelli,3 and Claudio Azzolini1
4.Intraocular gas in vitreoretinal Surgery Shaheeda Mohamed, FRCS, Timothy Y. Y.
Lai, MD, FRCS
5.Department of Ophthalmology & Visual Sciences, The Chinese University of Hong
Kong, Hong Kong

67. 5.Department of Ophthalmology & Visual Sciences, The Chinese University of
Hong Kong, Hong Kong
6.Swartz M, Anderson DR: Use of Healon in posterior segment surgery. J Ocul Ther
Surg , January-February, pp 26–28, 1984
7.Poole TA, Sudarsky RD: Suprachoroidal implantation for the treatment of retinal
detachment. Ophthalmology 93:1408, 1986
8.Stenkula S, Ivert L, Gislason I, et al: The use of sodiumhyaluronate (Healon) in the
treatment of retinal detachment. Ophthalmic Surg 12:435, 1981
9.Stenkula S: Sodium hyaluronate as a vitreous substitute and intravitreal surgical
tool. In Rosen ES (ed): Viscoelastic Materials: Basic Science and Clinical
Applications, pp 157–160. New York, Pergamon Press, 1989

68. 10.Stephen J Ryan –Retina 4 th edition volume 3
11.Lincoff H, Mardirossian J, Lincoff A, et al: Intravitreal longevity of three
perfluorocarbon gases. Arch Ophthalmol 98:1610, 1980
12.Silicone Study Group: Vitrectomy with silicone oil or perfluoropropane gas in eyes
with severe proliferative vitreoretinopathy: Results of a randomized clinical trial: Report
2 Arch Ophthalmol 110:780, 1992