The Status of Vitreous Substitutes
TORSTEN W. WIEGAND, MD, PHD, & CAROLINE R. BAUMAL, MD
Current and Future
vitreous substitutes have been in use for almost a century, the advent of modern
vitrectomy techniques pioneered by Machemer in the 1970s produced a tremendous increase
in demand for intraoperative and long-term artificial vitreous replacements. Advances
in vitreoretinal surgical techniques, instrumentation, and vitreous substitutes
have improved anatomic and functional success rates greatly over the past few decades.
Vitreoretinal surgeons now
have an array of agents available that are optimized for specific tasks. The three
most common types of vitreous substitutes available in North America are intraocular
gas, silicone oil, and perfluorocarbon liquid. In this article, the properties,
indications, and complications associated with each group of vitreous substitutes
One of the earliest descriptions
of vitreous substitutes dates to 1911 when Ohm treated retinal detachment with injection
of sterile air into the vitreous cavity.1 However, it was Rosengren who
established the concept of internal gas tamponade in 1938.2 Due to the
high surface tension of the gas bubble, an effective seal of the retinal break can
be established, allowing the retinal pigment epithelium (RPE) to pump the subretinal
fluid into the choroids and re-establish the natural retinal architecture.3
The buoyancy of the bubble helps to push the retina against the scleral wall while
the surface tension prevents breakup of the bubble and entering of the subretinal
space. For this tamponade to be effective with low-volume gas fills, such as those
used during pneumatic retinopexy, the patient needs to be positioned so that the
retinal break is located at the apex of the eye.
The role of intraocular gases broadened
with expansile gases as investigated by Lincoff.4 The most commonly used
gases are sulfur hexafluoride (SF6, Figure 1a) and perfluoropropane (C3F8,
Figure 1b). These gases are colorless, odorless, heavier than air, and nontoxic
to the human eye. During the life cycle of the intraocular gas bubble, three
can be distinguished: expansion, equilibrium, and dissolution.5,6 The
initial expansion is based on the net uptake of nitrogen, oxygen, carbon dioxide,
and water vapor from the
surrounding vitreous into the bubble. In the equilibrium
phase, loss of gas is balanced by continued uptake of nitrogen. During dissolution,
a net exit of all gaseous components leads to a gradual disappearance of the bubble.
These intraocular bubble dynamics depend on various factors, including initial gas
concentration, initial gas volume, axial length, phakic status of the eye, and history
of prior vitrectomy. But on average, a bubble of pure SF6 expands about
2 times within 24 to 48 hours with a duration of 1 to 2 weeks.5 A pure
C3F8 bubble expands about 4 times within 72 to 96 hours and
lasts 6 to 8 weeks until dissolution.6-8 The physical properties and
bubble dynamics are summarized in Table 1.
Intraocular gases are used in clinical
and operative settings. Pneumatic retinopexy is an option for repair of rhegmatogenous
retinal detachment9 and involves injection of 0.4 to 0.6
mL of pure SF6.
Intraocular gas may also be used in a procedure coined "pneumatic buckle" as an
adjunct in a scleral buckle procedure to tamponade a break. After vitrectomy for
retinal detachments, a nonexpansile long-term gas fill of C3F8
allows the formation of chorioretinal adhesions while minimizing the positioning
requirements for the patient. For macular hole surgery with epiretinal membrane
peel, SF6 is used for initial procedures and the longer acting C3F8
in repeat attempts of closure. For cases of tractional retinal tears in diabetic
retinopathy and proliferative vitreoretinopathy (PVR) repair, the longer-chained
perfluorocarbon gases C2F6 or C3F8 are
the common choices, unless the severity requires use of silicone oil.
When preparing the gas for injection,
using a filter (0.22 μm, Millipore, Billerica, Mass) is recommended to sterilize
the gas, although there have not been demonstrated reports of intraocular infection
secondary to omitting this step. Flushing the syringe several times with the gas
is recommended to avoid dilution of the desired concentration with residual air.
The gas should not be left in the syringe for a prolonged period of time prior to
injection, as diffusion will alter the effective gas concentration.10
The most common postoperative complication
after fluid-gas exchange with expansile gases is elevation of the intraocular pressure
(IOP), with up to 60% of patients experiencing a measurable pressure spike.11,12
Predisposing factors for IOP elevation include pre-existing glaucoma, anterior synechiae,
and compromise of the outflow angle by pigment, hemorrhage, or neovascularization.
Patients should be screened for these factors and the concentration, amount, and
choice of gas should be modified accordingly. In the majority of eyes, temporary
IOP control with antiglaucoma agents is sufficient. If the gas bubble expands to
such a degree that the lens iris diaphragm is pushed forward, resulting in pupillary
block and angle-closure glaucoma that is not controllable with medications, gas
aspiration from the posterior compartment by pars plana approach may be indicated.13
Acute IOP increase can occur under
special circumstances with overexpansion of the gas bubble. Nitrous oxide is a highly
water-soluble inhalation agent that may be used during general anesthesia and will
rapidly diffuse into an intraocular gas bubble. Patients with intraocular gas should
be provided with an identification bracelet to alert medical personnel if subsequent
anesthesia needs to be administered. During eye surgery nitrous oxide must be discontinued
20 minutes prior to intraocular gas injection to allow clearance of the nitrous
oxide from the bloodstream and tissues.14
Air travel with intraocular gas
is unsafe because the cabin pressure in airliners is reduced during flight. This
leads to initial expansion of the intraocular gas bubble and subsequent increased
trans-scleral pressure manifested as pain and decreased vision. Should a patient
experience this situation the pilot needs to lower the plane to allow normalization
of the cabin pressure. Experimental studies and clinical observations indicate that
0.6 to 1.0 mL of residual gas are safe for air travel.15-17
Prolonged contact of the intraocular
gas with the lens can lead to gas-induced cataracts, presenting typically as feathery
posterior subcapsular lens opacifications. These lens changes can be reversible
if the patient is positioned to break the gas lens contact, but some of these patients
will retain permanent lens changes.18
In aphakic eyes, contact of gas
with the corneal endothelium can lead to decompensation and stromal edema by limiting
diffusion of nutrients from the anterior chamber fluid to the corneal endothelial
layer.19 To limit these anterior segment complications, patients with
intraocular gas need to be reminded not to sleep in a supine position.
The use of silicone oil as
a long-acting vitreous substitute was pioneered by Cibis20 in 1962 prior
to development of pars plana vitrectomy. Due to the high level of contaminations
in these early silicone oil preparations, the high complication rate resulted in
near abandonment of this approach. Only after development of vitrectomy techniques
and with availability of higher purification oils has this approach found widespread
acceptance.21-23 To date a transatlantic gradient exists, with European
vitreoretinal surgeons appearing to rely on silicone oil more than their North American
colleagues. The most commonly used silicone oil preparations contain trimethylsiloxyl-terminated
polydimethyl siloxane (Figure 2), but standards have yet to be established and batch
variation may exist.
Silicone oil is transparent and
has a refractive index of 1.404. This is slightly higher than that of vitreous gel
and thus induces a mild hyperopic shift in phakic patients. However, in an aphakic
eye, the steep anterior curvature of the silicone oil fill causes an increase in
refractive power and lessens aphakic hyperopia.24 Compared to a gas fill
that allows little useful vision until the meniscus clears the visual axis, a postsurgical
eye with oil has a shortened visual rehabilitation time, which is important to consider
in monocular patients.
At a specific gravity of 0.97,
silicone oil is slightly lighter than water and a silicone globule will float on
a residual aqueous base inside the eye. The resulting buoyant force is only one-thirtieth
of that contained within a corresponding gas bubble.25 Because silicone
oil is not miscible with the aqueous phase, the resulting interface develops surface
tension, but at 20 to 40 mN/m this tension is one-half to one-third of a gas bubble's
surface tension. In combination, these 2 forces are sufficient to postsurgically
support the reattached, tension-free retina, but residual or recurrent radial traction,
especially in the inferior half of the retina, can lead to re-detachment under oil.26
This is important to consider in cases of PVR, when pathology tends to be concentrated
inferiorly or can recur in this location.27,28 Table 2 summarizes the
physical properties of common silicone oils.
Due to its lower surface tension,
silicone oil will slip through retinal tears more freely than intraocular gas and
it may emulsify with the formation of miniature droplets of oil over time. While
the molecular details leading to emulsification of the oil globule are not completely
understood, it is apparent that low molecular weight contamination in the silicone
oil plays a role.29 The two common silicone oils used in vitreoretinal
surgery have viscosities of 1000 cS and 5000 cS, respectively. While the surface
tensions of these oils do not differ significantly, the lower-viscosity 1000-cS
oil tends to harbor a higher level of low molecular weight contaminants and therefore
emulsifies more readily over time. With improved production and purification techniques
this problem has decreased and residual time of silicone oil inside the eye without
complications has been expanded.
Silicone oils are used when long-term
need for stabilization of the retina with internal tamponade is anticipated. The
Silicone Study Report, comparing the use of intraocular gas and silicone oil in
surgical management of PVR, concluded that silicone oil was equivalent to C3F8
but superior to SF6.30-32 Subgroup analysis showed a benefit
for oil use over gas in patients with anteriorly located PVR and patients without
prior vitrectomy who received retinotomy during surgical repair. In management of
severe diabetic tractional retinal detachment, silicone oil may have the added benefit
of suppression of future neovascularization; however, prospective trials have not
been performed. A small prospective trial of silicone oil in the management of traumatic
endophthalmitis suggests a benefit possibly due to concentration of intravitreal
antibiotic or through bactericidal properties of silicone oil.33 In cases
of endophthalmitis refractive to initial intravitreal antibiotics, this approach
should be considered. Other surgical indications for silicone oil include complicated
retinal detachment, giant retinal breaks, hypotony due to chronic uveitis, infectious
retinitis, and finally, retinal detachments where postoperative positioning would
not be possible.
Postsurgical and late complications
of intraocular silicone oil fills are common and may require removal of the oil
earlier than the desired duration. Prolonged contact of silicone oil with the posterior
capsule of the lens will inevitably induce cataract formation,34 likely
due to prevention of nutrient diffusion rather than a direct toxic effect. Some
surgeons may remove the crystalline lens during vitrectomy; however, retention of
an intact posterior capsule is desirable to keep the oil confined to the posterior
compartment. The increased use of silicone intraocular lenses (IOLs) during cataract
extraction poses a challenge for use of intraocular silicone oil when a retinal
detachment develops after cataract surgery. If the posterior capsule was violated
during surgery or an yttrium aluminum garnet (YAG) capsulotomy has been performed,
silicone oil droplets may adhere to the posterior lens surface, necessitating lens
removal.35 Thus use of a silicone IOL is not recommended in an eye that
has any predisposing risk factors for retinal detachment.
Silicone oil migration into the
anterior chamber may result in keratopathy or corneal endothelial decompensation.
Interestingly, according to the Silicone Study Report, the rate of corneal complications
is comparable to the
2-year complication rate in eyes that received a gas fill
(26% vs 28%, respectively).36 If severe corneal decompensation occurs,
ethylenediaminetetraacetic acid (EDTA) chelation can be performed to reduce band
keratopathy, or a corneal transplantation can be considered. If possible, the silicone
oil should be removed at that time, as 68% of penetrating keratoplasties fail in
Increased IOP after silicone oil
use in treatment of PVR occurs in up to 40% of patients.37,38 Emulsification
of silicone oil can directly clog the trabecular mesh, or recruitment of macrophages
and other inflammatory components can lead to open-angle glaucoma. If the silicone
globule remains intact, pupillary block with angle closure can occur when the silicone
oil occupies the pupillary sphincter and prevents aqueous fluid from passing into
the anterior chamber. An inferior peripheral iridectomy is therefore routinely created
in aphakic eyes prior to silicone oil fill. Spontaneous closure of the iridectomy
may occur postsurgically in up to one-third of patients.39
While hypotony occurs in about
one-fifth of silicone filled eyes within 3 years of surgery, this complication is
significantly less frequent than in comparable gas-filled eyes.37 Hypotony
can be managed with peeling of membranes of the ciliary body, subtenon steroid injection,
or long-term retention of the oil to prevent phthisis.
In contrast to other vitreous substitutes,
perfluorocarbon liquids have a specific density greater than water and are therefore
unique in applying gravitational force onto the dependant portion of the retina.40
These liquids had been developed as blood substitutes based on their inert nature
and ability to carry oxygen. In contrast to silicone oil, perflurocarbon liquids
have low viscosity and can be easily injected and withdrawn through standard vitrectomy
instruments. Perflurocarbon liquids are optically clear and do not absorb wavelengths
of lasers used in retinal surgery, allowing application of endolaser during tamponade
with perfluorocarbons. The commonly used agents are perfluoro-n-octane (C8F18),
perfluorodecaline (C10F18), perfluoroperhydrophenanthrene
(C14F24), and perfluorohexyloctane (C6F13C8H18).
In 1987, Chang41 reported
on the use of perfluorocarbon liquids for repair of giant retinal tears, which previously
required placing the patients into a prone position during surgery. Application
of the heavier-than-water perflurocarbon liquids displaces subretinal fluid anteriorly,
and the inverted flap of the retinal tear can be flattened with minimal manipulation.
Because perfluorocarbon liquids are not used as long-term vitreous substitutes,
exchange of the perfluorocarbon liquid with air and gas or directly with silicone
oil is required. Bypassing the perfluorocarbon-air exchange and going directly to
silicone oil has the advantage of reducing the risk of retinal slippage and the
formation of folds.42 The use of perflurocarbon liquids in management
of severe PVR has improved the anatomic success rate.43 Funnel detachments
may on occasion be opened up, and epiretinal membranes and gliotic tractional bands
can be visualized and dissected with progressive perflurocarbon injection and flattening.
Posterior retinotomies may be avoided since subretinal fluid is forced anteriorly
and allowed to escape through pre-existing breaks. Other indications for the use
of perfluorocarbon liquids include repair of detachments secondary to ocular trauma,
removal of dislocated crystalline lenses, and management and displacement of suprachoroidal
Due to the low viscosity of these
liquids, long-term intraocular tolerance is limited by dispersion into microdroplets
over time, which leads to decrease in vitreous clarity, compromise of the trabecular
meshwork with subsequent IOP rise, and subretinal migration of droplets through
residual breaks. Perfluorocarbon liquids are therefore used primarily as a temporary
intraoperative vitreous substitute and long-term complications are rare. In up to
10% of surgical cases, small amounts of retained perflurocarbon liquids were identified.44
While small amounts of residuals in the vitreous are usually well tolerated, subretinal
migration of perfluorocarbon liquids can result in persistent focal retinal detachments
with possible direct toxic effects to the photoreceptor layer.45 Perfluorocarbon
liquid droplets found in the anterior chamber in aphakic patients should be removed
by small-gauge needle aspiration to prevent possible corneal endothelium toxicity.
Perflurocarbon liquids represent
the only class of heavier-than-water vitreous substitutes, but current agents cannot
safely remain in the eye for an extended time. Research efforts are therefore focusing
on long-term tamponading vitreous substitutes that can support the inferior retina.
This would reduce the need for prolonged postsurgical face-down positioning and
may increase the anatomic success rate in management of PVR by displacing proliferative
cells from the inferior quadrants of the retina. Partially fluorinated alkanes,
used either as pure liquids or in mixtures with silicone oil to create low viscosity
oils with a density greater than water, have been tested in vitro46,47
and used in vitreoretinal surgery. Initial reports appeared encouraging, but long-term
complications, including severe emulsification,48 intractable uveitis,49
and pathologic responses of the retina,50 have been reported recently.
While this novel class of heavy tamponading agents holds promise, further investigational
work is needed to address these complications. Based on the use of semifluorinated
alkanes in rabbit eyes, the persistent gravitational force on the inferior retina
alone does not appear to be deleterious.51
The intraocular vitreous body is
a highly complex macromolecular structure, and despite significant progress over
the past few decades, the ideal, universal vitreous substitute does not exist. The
array of artificial substitutes available for short- and long-term replacements
each have specific advantages and drawbacks. A thorough understanding of the properties,
indications, and potential complications of intraocular gas, silicone oil, and perflurocarbon
liquids is essential to utilize these adjuncts successfully during vitreoretinal
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Exp Ophthalmol. 2006; [Epub ahead of print].
W. Wiegand, MD, PhD, and Caroline R Baumal, MD, are both ophthalmologists at the
Vitreoretinal Department of the New England Eye Center at the Tufts University School
of Medicine in Boston. You can reach them at (617) 636-1486. Neither author has
any financial interest in any of the products mentioned here.
ALL FIGURES IN
THIS ARTICLE APPEAR COURTESY OF THE AUTHORS.
Retinal Physician, Issue: January 2007