vitreous substitutes

VITREOUS SUBSTITUTE

SDR PAVANKUMAR NAIK

Anatomy of vitreous1• Gelatinous structure

that fills the space between lens and retina

• Non homogenous• Vitreous cortex• Vitreous base• Vitreo retinal interface

• 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

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

Ideal Vitreous Substitute3

Form

ManipulatableFunction

• 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

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

Experimental Vitreous substitutes4

a) Polymers• Hydrogels• Smart hydrogels• Thermosetting gelsb) Implantsc) Cell culture

Intra-Ocular Gases2,3,9

• 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

Non Expandin

g

AIR

XENON

Expanding

SF6

PFC

• SURFACE TENSION • BUOYANCY• SOLUBILITY• BIOCOMPATIBILITY

• 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

• 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.

• 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.

• 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

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.

• 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

Gas Dynamics

• 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

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

• 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”

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

Factors affecting dissolution

• Vitreous currents• Surface area of bubble• Gas solubility in fluid• Diffusion coefficient of gas• Partial pressures• Ocular blood flow

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

Choice of GasCondition Xenon Air SF6 C2F6 C3F8RD 2 1 1 2 --PDR -- 1 1 2 --RD+mac hole

-- 2 1 -- 2

GRT -- 1 1 -- 2PVR -- -- -- -- 1Trauma -- 2 1 1 2

1-mc used 2-selected cases

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

• Head position during air fluid exchange

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

• 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

• Subretinal gas • New tears -7% to 23% of patients treated

with pneumatic retinopexy• Dislocated intraocular lens implant

Gas injection into vitreous base accidentallyA. 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

Perfluoro-carbons2,10

• 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

• 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

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

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

• PVR: tamponade effect to open up funnel detachment exposing any areas of residual membranes

• Giant retinal tears: unfolding and displacement of SRF and blood

• 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

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

SemiFluorinated Alkanes2

• 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

Silicone Oil2,10

• 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

• 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.

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 lensActs as a minus lens-making eye hyperopic-8D hyperopia• Aphakic eye-convex surface as it bulges through

pupillary aperture-plus lens-myopicVaries with pupillary aperture size-from +12.5 to +5.6D• Contact lens –to minimise the anisoconia• IOL-plano posterior surface preferred

Indications for silicone oil

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

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

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

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

Stages of Emulsification

• 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)

• 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

• 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

Experimentalsubstitutes 3

vitreous molecularstructure

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

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

• 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).

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

.

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.

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?

REFERENCES1. 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

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

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