REVIEW
www.mbs-jou nal.de
Cu en Si ua ion and Challenges in Vi eous Subs i u es
C is ina Mondelo-Ga cía, En ique Bandín-Vila , Lau a Ga cía-Quin anilla,
Ana Cas o-Balado, E a M. del Amo, Ma ía Gil-Ma ínez, Ma ía José Blanco-Teijei o,
Miguel González-Ba cia, I ene Za a-Fe o, Anxo Fe nández-Fe ei o,*
and F ancisco J. O e o-Espina *
Vi eo- e inal diso de s cons i u e a significan po ion o ea able ocula
diseases. These pa hologies o en equi e i eo- e inal su ge y and, as a
consequence, he use o i eous subs i u es. Nowadays, he i eous
subs i u es ha a e used in clinical p ac ice a e mainly di ided in o gases (ai ,
SF6,C
2F6,C
3F8) and liquids (pe fluo oca bon liquids, silicone oils, and hea y
silicone oils). The e a e specific ad an ages and d awbacks o each o hese,
which de e mine hei clinical indica ions. Howe e , de eloping he ideal
bioma e ial o i eous subs i u ion con inues o be one o he mos
impo an challenges in oph halmology, and a mul idisciplina y app oach is
equi ed. In his sense, ecen esea ch has ocused on he de elopmen o
biocompa ible, biodeg adable, and injec able hyd ogels (na u al, syn he ic,
and sma ), which also ac as medium and long- e m in e nal amponade
agen s. This comp ehensi e e iew aims o co e he main cha ac e is ics and
indica ions o use o he ex ensi e ange o i eous subs i u es ha a e
cu en ly used in clinical p ac ice, be o e going on o desc ibe he hyd ogels
ha ha e been de eloped ecen ly and which ha e eme ged as p omising
bioma e ials o i eous subs i u ion.
C. Mondelo-Ga cía, E. Bandín-Vila , L. Ga cía-Quin anilla,
A. Cas o-Balado, M. González-Ba cia, I. Za a-Fe o,
A. Fe nández-Fe ei o
Pha macy Depa men
Uni e si y Clinical Hospi al o San iago de Compos ela (SERGAS)
San iago de Compos ela 15706, Spain
E-mail: [email p o ec ed]
C. Mondelo-Ga cía, E. Bandín-Vila , L. Ga cía-Quin anilla,
A. Cas o-Balado, M. González-Ba cia, I. Za a-Fe o,
A. Fe nández-Fe ei o
Pha macology G oup
Heal h Resea ch Ins i u e o San iago de Compos ela (FIDIS)
San iago de Compos ela 15706, Spain
The ORCID iden ifica ion numbe (s) o he au ho (s) o his a icle
can be ound unde h ps://doi.o g/10.1002/mabi.202100066
© 2021 The Au ho s. Mac omolecula Bioscience published by
Wiley-VCH GmbH. This is an open access a icle unde he e ms o he
C ea i e Commons A ibu ion-NonComme cial License, which pe mi s
use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal
wo k is p ope ly ci ed and is no used o comme cial pu poses.
DOI: 10.1002/mabi.202100066
1. In oduc ion
The i eous humou is a anspa en gel
p esen be ween he lens and he e ina. I
has a olume o a ound 4 mL and occupies
80% o he eye olume.[1,2] I weighs a ound
4 g and con ains app oxima ely 99% wa e ,
only adhe ing o ocula s uc u es in he ol-
lowing pa s: he macula, he op ic ne e
disc, and he an e io bo de o he a ea su -
ounding he e ina.[2]
Vi eo- e inal diso de s cons i u e a sig-
nifican po ion o ea able ocula dis-
eases. The i eous humou o en becomes
dys unc ional due o opacifica ion, lique-
ac ion o physical collapse, as a esul
o inflamma o y diseases, de elopmen al
abno mali ies, i eous hemo hage, u-
mo s, diabe es, o degene a i e p ocesses.
In addi ion, i eous damage can also
be caused by in aocula o eign bodies
o auma.[3] The i eous humou de-
e mines he cla i y o ision meaning
E. M. del Amo
School o Pha macy, Facul y o Heal h Sciences
Uni e si y o Eas e n Finland
Kuopio 70211, Finland
M. Gil-Ma ínez, M. J. Blanco-Teijei o
Oph halmology Depa men
Uni e si y Clinical Hospi al o San iago de Compos ela (SERGAS)
San iago de Compos ela 15706, Spain
F. J. O e o-Espina
Depa men o Pha macology, Pha macy and Pha maceu ical Technology,
Facul y o Pha macy
Uni e si y o San iago de Compos ela (USC)
San iago de Compos ela 15782, Spain
E-mail: [email p o ec ed]
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he e o e ha , i no ea ed p ope ly, hese diso de s can cause
blindness. Vi eous subs i u es a e c ucial adjunc s du ing i eo-
e inal (VR) su ge y o e inal diseases.[2,4,5]
Nowadays, he mos common agen s ha a e used as i e-
ous subs i u es in clinical p ac ice boas ce ain ad an ages, in-
cluding chemical ine ness and op ical cla i y, none heless, he e
a e also many limi a ions o hei use.[2] In his sense, he de-
elopmen and cha ac e iza ion o new i eous subs i u es ha e
played an impo an ole in i eo- e inal su ge y. Despi e he ac
ha conside able effo s ha e been made in de eloping new bio-
ma e ials o i eous subs i u ion in sea ch o he pe ec al e -
na i e ha is able o o e come he disad an ages p esen ed by he
cu en ly a ailable subs ances, u he esea ch mus be pe -
o med. In his ega d, de eloping he ideal bioma e ial o i -
eous subs i u ion con inues o be one o he mos significan
challenges in oph halmology. Gi en he complexi y o his ma -
e , a mul idisciplina y app oach, which in ol es oph halmic su -
geons, pha macis s, chemis s, and expe s in bioma e ials will be
necessa y i we wan o o e come his p oblem.
Ou aim is o discuss he main cha ac e is ics and applica ions
o he wide a ie y o i eous subs i u es ha a e cu en ly used
in clinical p ac ice, be o e going on o add ess he de elopmen
o new hyd ogels ha ha e been p esen ed as p omising al e na-
i es o he op imiza ion o i eous subs i u ion.
2. Composi ion and Func ions o he Vi eous
The i eous is a gela inous s uc u e ha is composed o 98%
wa e .[3,4] I p o ec s he adjacen s uc u es and issues om au-
mas, as well as pe mi ing he ci cula ion o nu ien s and so-
lu es, and con olling he oxygen ension wi hin he eye. I helps
o main ain he shape o he ocula globe, as well as keeping he
c ys alline lens and he e ina in hei place.[3,6] The main compo-
nen s o he i eous humou , as well as he majo cha ac e is ics
o he a o emen ioned componen s a e ou lined below.
2.1. P o eins
P o eins ep esen a small pe cen age o he o e all con en o
he i eous componen s. The majo i y o he soluble p o eins
a e albumin (40%), wi h he o he impo an componen s includ-
ing immunoglobulins and i on-binding p o eins such as ans-
e in, which helps o educe i on oxici y in he case o small
hemo hages.[1,6,7] Wi h ega ds o insoluble p o eins, collagens
a e he mos abundan . The e a e diffe en ypes o p o eins
which play a majo ole in he i eous s uc u e.[4,8]
2.2. Glycosaminoglycans (GAGs)
GAGs, which a e ex acellula polysaccha ides a e a key compo-
nen o he i eous s uc u e, and hese a e mainly di ided in o
h ee ypes—hyalu onic acid, hepa an sul a e, and chond oi in
sul a e.[1]
2.2.1. Hyalu onic Acid (HA)
HA is a majo componen o he i eous, o ming 3D s uc u es
wi h collagen. The ac ha i does no con ain sul a e makes
i dis inguishable om he o he GAGs, and his also means
ha i does no a ach o p o eins o o m a p o eoglycan.[1] The
highes concen a ions o hyalu onan molecules a e ound in
he pos e io i eous co ex.[6,9–11] The HA p epa a ions consis
o molecules wi h g ea e a iabili y in e ms o hyd odynamic
size, and hese a e a ele an componen in de e mining i e-
ous iscosi y.[12]
2.2.2. Chond oi in Sul a e (CS)
CS is a sul a ed GAG, which consis s o a chain o al e na ing sug-
a s (N-ace ylgalac osamine and glucu onic acid). I cons i u es a
majo componen o he ex acellula ma ix and is also p esen
in he i eous, appea ing in he o m o he p o eoglycans e si-
can and ype IX collagen.[4,11] CS is used o p ese e he in eg i y
o he i eous and p o ide esis ance agains comp ession.[1]
2.2.3. Hepa an Sul a e (HS)
HS is a enewable p o eoglycan, which ensu es ha he e is ad-
equa e spacing be ween he collagen fib ils, none heless, small
amoun s o HS a e p esen in he i eous.[13] I also enhances
he egula ion o angiogenesis and blood coagula ion, as well as
main aining i eo- e inal adhesion.[4]
2.3. Glucose, Lac ic Acid, and An ioxidan s
Due o he impo an ole ha he i eous plays in he cellu-
la me abolism o ocula issues, i s componen s include se e al
subs ances ha ac as sub ac s o me abolism, such as glucose
and lac ic acid, which a e necessa y o suppo he me abolism
in he su ounding issues.[4,6] In addi ion, he i eous ac s as a
ese oi o glucose o he cilia y body.[14]
On he o he hand, asco bic acid is a c ucial an ioxidan
o lens and e inal me abolism, in pa icula i is used as a
me abolic buffe in po assium homeos asis. Fu he mo e, i may
also inhibi neo ascula iza ion and inc ease he p oli e a ion o
hyalocy es.[15–17]
2.4. Cells and Enzymes
The e a e h ee ypes o cells ha a e ound in he i eous
body: hyalocy es, fib ocy es/fib oblas s, and mac ophages.[6,18,19]
The main unc ions o hese cells a e ela ed o he c ea ion,
egula ion, and deg ada ion o he i eous ma ix. Se e al en-
zymes ha e been isola ed, which include hyalu onidase, se ine
p o eases, and enin-angio ensin-con e ing enzyme.[20–22]
3. Vi eous Subs i u es in Clinical P ac ice
Vi eous subs i u es mus ha e physical and biological p op-
e ies ha make hem sui able o use in clinical p ac ice. In
e ms o hei physical p ope ies, ideal i eous subs i u es will
be hyd ophilic and insoluble in wa e , easy o manipula e du -
ing su ge y, clea and anspa en o acili a e isualiza ion, and
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Figu e 1. Gas injec ion in pneummo e inopexy. A) Example o a supe io
de achmen and injec ion wi h he pa ien lying in he supine posi ion
( ace-up). B) The pa ien is placed in an up igh posi ion and he bubble
amponades he b eak. C ea ed wi h BioRende .com.
hey will also ha e a e ac i e index ha is simila o he hu-
man i eous. In addi ion, hese mus emain s able when in-
jec ed h ough a small sy inge, as well as ensu ing adequa e
su ace ension in he a emp o seal he e inal b eak.[2,23] On
he o he hand, and in e ms o hei biological p ope ies, he
ideal i eous subs i u es will be biodeg adable and biocompa i-
ble, biologically and chemically ine , and hey will no block he
aqueous d ainage. Fu he mo e, hey mus be non oxic o e inal
issues.[6,23]
An ideal i eous subs i u e does no ye exis ; all o hem o -
e ad an ages and d awbacks, which may o may no make hem
sui able depending on he clinical si ua ion. Those cu en ly used
in clinical p ac ice a e di ided in o diffe en ca ego ies based
on diffe en p ope ies. Specifically, hese a e di ided in o gases
(ai , SF6,C
3F8,andC
2F6) and liquids (sal solu ion, silicon oils
(SO), pe fluo oca bon liquids, and semi fluo ina ed alkanes). The
cha ac e is ics o each indi idual g oup, as well as hei clin-
ical indica ions ha e been ou lined in de ail in he ollowing
sec ions.
3.1. Gases
Ohm was he fi s o desc ibe in aocula gas use in 1911.[24] Se -
e al indica ions o i s use we e desc ibed, wi h he fi s o hese
being i s use as an in e nal amponade.[25] I also p o es use ul in
un olding and olding he e ina, as well as in imp o ing i s pos -
ope a i e isualiza ion and eplacing he globe olume o p e-
en fluid mo emen in o e inal b eaks. Gas is also used in se -
e al echniques: pneummo e inopexy (Figu e 1); he pa s plana
i ec omy o e inal de achmen (RD), wi h and wi hou scle-
al buckle, o fla en he e ina; sub e inal blood displacemen in
macula hemo hages; and pos i ec omy liquid–gas exchange
in p e iously i ec omized eyes.[26]
Pos ope a i e ca e is e y impo an in hese pa ien s. P one
( ace-down) posi ioning mus commence as soon as possible
a e he i ec omy p ocedu e has been pe o med. This is
c ucial in p e en ing any shi o he ea ached e ina. Mo eo e ,
i dec eases he con ac be ween he pos e io su ace o he lens
wi h he gas bubble in phakic pa ien s ( he bubble is si ua ed
owa ds he e ina); he e o e, educing he isk o ca a ac
o ma ion. Posi ioning may also a y depending on he loca ion
o he e inal b eak, usually lying on he opposi e side o he
b eak.
The mos widely used in aocula gases a e sul u hexafluo ide
(SF6) and pe fluo op opane (C3F8). These a e non oxic and ine
gases ha a e insoluble in he aqueous humou , and hey boas
a lowe wa e solubili y han ni ogen he e o e allowing hem o
expand.[27] The decision as o which one o hese gases is o be
used will be based on he amponade du a ion and he su geon’s
p e e ences, aking in o conside a ion he ype and loca ion o he
e inal b eak.[28]
I is gene ally accep ed ha SF6can be used in uncomplica ed
p ima y RD. Howe e , i a final amponade ac ion is necessa y,
based on he esul s om “The Silicone S udy”, in which he
esul s in pa ien s wi h RD and p oli e a i e i eo e inopa hy
(PVR), he pa s plana i ec omy wi h ei he C3F8gas o SO am-
ponades we e a o able.[29] Howe e , he clea ad an age o using
gases is ha i is no necessa y o emo e hem.
The e a e h ee s ages in he abso p ion o he in aocula gas:
expansion o he gas when injec ed, ni ogen equilib ium, and
dissolu ion.[30] Gases may be abso bed by diffusion ac oss he
e ina in o he blood s eam, o hey may be dissol ed in o he
aqueous humou , and emo ed h ough he an e io chambe .[31]
The abso p ion o hese gases demons a es fi s -o de pha ma-
cokine ics, wi h small olumes las ing in he in aocula ca i y
o days o weeks depending on he gas used.[30]
Knowledge o he kine ics o hese gases, as de ailed in Table 1,
comes mos ly om animal models and small s udies in which
indi ec measu emen s ha e been aken in humans.[30–35] These
s udies may no be ep esen a i e o cu en p ac ice, especially
wi h ega ds o he du a ion o he ai bubble in he pos e io
chambe o he eye, which is pe cei ed o be longe in clinical
se ings han in heo e ical ones.[36,37] The hal -li e o in aocula
gases is sho e in aphakic eyes han in phakic eyes, due o he in-
c eased con ec ion in he i eous ca i y.[38] Following he i ec-
omy p ocedu e, con ec ion cu en s appea in he aphakic eye,
which accele a e he abso p ion a e. In phakic eyes wi h no mal
i eous, he e a e much ewe con ec ion cu en s; he e o e,
he expansion and abso p ion o long-ac ing gases is slowe .[30]
3.1.1. Ai
Room ai amponade applied using non-expansible gas begins
o sh ink immedia ely a e injec ion as i dissol es in he
i eous.[28] This offe s an ad an age o e o he long-las ing gases
as i equi es sho e p one posi ioning, allowing o a as e e-
co e y o ision and less ad e se effec s.[41]
The hal -li e o a oom ai amponade was 1.6 d in phakic
eyes[30] wi h a longe i y o 5 d, bu ecen clinical imp essions
ha e sugges ed ha ai emains in he i eous ca i y o a longe
pe iod o ime. In a ecen e ospec i e coho s udy, a hal -li e
o 3.3 d wi h a longe i y o 11.4 d was de e mined.[37]
3.1.2. O he Gases: SF6,C
2F6,C
3F8
Sul u hexafluo ide (SF6) and pe fluo op opane (C3F8) a e he
mos commonly used in aocula gases in clinical p ac ice, com-
pa ed o hexafluo oe hane (C2F6) which is much less equen ly
used.[36]
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Table 1. Pha macokine ics o in aocula gases.
Gases Nonexpansile
concen a ion
Du a ion o maximal
expanded olume [h]
Hal -li e
[d]
Du a ion o ai bubble
[d]
Indica ions
Rabbi s Humans Rabbi s Humans Animals Humans
Ai – Nonexpansible – 1.6a)
0.9b)
5–6 10.7–
11.4c)
- Simple cases in which a sho du a ion is
equi ed
SF6(sul u ic
hexafluo ide)
20% 24–48 21 – 2.6a)
2.4b)
8–11 18a),c) - RD (Re inal de achmen ) wi h supe io b eaks
- RD wi h in e io b eaks
- Fla RD in he case o
me iculous i eous
dissec ion.
- Following macula hole
su ge y
C2F6(hexafluo oe hane) 16% 72 27 2 – 16 34.5a),c) No app o ed by FDA
C3F8(pe fluo op opane) 12% 72–96 30 6 5.7a)
4.5b)
4.3c)
28 67.7a),c) - RD and mul iple b eaks
- RD wi h supe io gian ea
- RD wi h p oli e a i e i eo e inopa hy (PVR)
- Failed p io RD su ge y
- Pe sis en sub e inal fluid
- Following macula hole
su ge y
- Pneuma ic displacemen o sub e inal blood clo
Re . [28] [33,39] [36] [31] [30] [32,34] [36,37,40] [25]
a) Re e ing o phakic eyes; b) Re e ing o aphakic eyes; c) Re e ing o pseudo-phakic eyes.
Gi en ha hese gases boas a lowe wa e solubili y han ni-
ogen, hey end o expand o a leas wice he olume o he gas
injec ed, as a esul , nonexpansile o minimally expansile mix-
u e o gas is p e e able in o de o p e en ad e se effec s such
as in aocula p essu e ele a ion (IOP).[28]
Wa e solubili y a ies depending on he ca bon chain leng h.
The longe he ca bon chain, he lowe he solubili y in wa e ;
he e o e, esul ing in a longe in aocula longe i y:[42] A mix-
u e o 10% C3F8had a hal -li e o 5.7 d in phakic and 4.3 d in
pseudophakic eyes.[30] A mix u e o 20% SF6had a hal -li e o 2.8
d in phakic eyes. The hal -li e o C2F6was no measu ed; how-
e e , a longe i y o 34 d was de e mined in he i eous ca i y.[36]
Ce ain pos ope a i e complica ions ha e been epo ed
ollowing he use o in aocula gas, howe e , mos o hese
can be p e en ed by aking g ea e ca e when unde aking he
su gical p ocedu e. Fo example, gas could go unde he e ina
al hough his is p e en able, o gas could become en apped a
he injec ion si e.
One o he mos equen complica ions is he o ma ion
o ca a ac s due o he gas coming in o con ac wi h he c ys-
alline lens.[43] Raised in aocula p essu e may occu , bu his
ends o happen on he fi s pos ope a i e day, and i s cause has
been a ibu ed o he expansion o he bubble o o an o e -
filled eye. On he con a y, hypo ony may occu i he e is any
gas leakage om he scle o omies. O he complica ions include
he p esence o gas in he an e io chambe , seconda y co neal
decompensa ion,[44] which is mo e equen in aphakic pa ien s,
and non-in ac pos e io capsule. In pseudophakic pa ien s, in-
aocula lens cap u e may occu due o i being pushed o wa d
in o he an e io chambe .[45,46]
3.2. Liquids
Diffe en liquid i eous subs i u es a e used in clinical p ac ice.
The main g oups and hei majo cha ac e is ics a e depic ed in
Table 2.
3.2.1. Sal Solu ions
Sal solu ions ha e simila cha ac e is ics o aqueous humou in
e ms o hei densi y, e ac i e index and anspa ency.[3] In he
clinical se ing, hese a e used on a empo a y basis du ing he
exchange wi h ai o liquids as hei low su ace ension means
ha hese do no ha e amponade p ope ies.[4]
3.2.2. Silicon Oil
Silicon oil (SO) is a polyme ized siloxane wi h o ganic side
chains. I belongs o he class o syn he ic o ganosilicon com-
pounds and is a epe i ion o he –[R2Si–O]– g oup in which R is
he o ganic side chain.[47] Specifically, SOs used as i eous sub-
s i u es a e polyme s o polydime hylsiloxane (PDMS).
In con as o silicone ubbe , polyme chains a e sho e , and
gi en he lack o chemical c oss-linking be ween hem, hese
p esen in a liquid o m. They a e hyd ophobic subs ances wi h
a specific g a i y, which is sligh ly lowe han wa e , and a e-
ac i e index ha is highe han ha o he i eous.[48] These
a e a ailable in diffe en iscosi ies, which is measu ed in cen is-
okes (cS ), and which anges om 1000 o 5000 cS in clinical
p ac ice.
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Table 2. Physical p ope ies o liquid i eous subs i u es and clinical indica ions.
P oduc Specific g a i y
[g cm−3]
Viscosi y [cS ] Re ac i e index Indica ions
A. SALT SOLUTIONS
BSS 1 Tempo a y eplacemen du ing ai /oil exchange
B. SILICON OILS
SO 1000 cS 0.97 1000 1.4 Complex RD associa ed wi h PVR
Gian ea , RD wi h PVR
T auma ic RD wi h PVR
Recu en RD wi h b eaks in ol ing he lowe quad an s
RD associa ed wi h se e e p oli e a i e diabe ic e inopa hy
RD associa ed wi h macula hole in pa hologic myopia
Pedia ic RD
RD associa ed wi h i al e ini is
Pos auma ic endoph halmi is
SO 2000 cS 0.97 2000 1.4
SO 5000 cS 0.97 5000 1.4
C. PERFLUOROCARBON LIQUIDS
Pe fluo ooc ane (C8F18) 1.76 0.69 1.27 P ima y Rhegma ogenous RD
Complica ed RD wi h PVR
Gian ea RD wi h PVR
RD associa ed wi h disc coloboma, Disloca ed lens, Sup acho oidal
hemo hage
Pe fluo odecalin (C10F18) 1.94 2.7 1.33
Pe fluo ope hyd ophenan h ene (C14F24) 2.03 8.03 1.31
Oc afluo op opane (C3F8) 1.6 0.465 1.22
i .SEMIFLUORINATED ALKANES
Pe fluo ohexyloc ane (F6H8) 1.35 3.44 1.387
D. SFA-SO combina ions
(a) Double fillings
(b) Hea y Silicon Oils
Densi on-68 1.06 1387 1.39 RD associa ed wi h in e io ea s and PVR
Oxane HD 1.02 3300 1.4
HWS 46–3000 1.12 2903 1.37
Since he 1960s, SO ha e been used as sho and long- e m i -
eous subs i u es because o hei anspa ency, low su ace en-
sion, buoyancy, and low oxici y. The ole o SO in clinical p ac ice
was defined by “The Silicone S udy”,[49,50] a mul icen e p ospec-
i e andomized clinical ial ha compa ed he effec o SO o
long-ac ing in aocula gases (SF6and C3F8) in he managemen
o complex RDs associa ed wi h se e e PVR. Globally, SO was
demons a ed o be mo e effec i e han SF6, and equally as e -
ec i e as C3F8in ea aching he e ina.[49] In addi ion, SO and
C3F8p oduced e y simila esul s in e ms o he imp o emen
o isual unc ion and he low complica ion a es. Fu he mo e,
he oph halmologis ‘s p e e ence o he need o he pa ien o
ake a fligh soon a e he in e en ion could be easons o
using SO.[1]
The use o SO in gian ea s wi hou PVR is s ill being deba ed.
In his sense, good ana omic success has been epo ed wi h SO
and gases. Gene ally speaking, SO is he mos used agen in
Eu ope, while in he Uni ed S a es some oph halmologis s s ill
ha e a p e e ence o in aocula gas.[51]
SO amponade ends o be adminis e ed a he p ima y i -
ec omy o ac ion RD associa ed wi h se e e p oli e a i e di-
abe ic e inopa hy.[52] Howe e , o da e, no clinical ials ha e
adequa ely e alua ed i s efficacy in his use. In addi ion, wi h
ega ds o he ea men o RDs in i al e ini is, SO offe s
long- e m in e nal amponade, he e o e dec easing he isk o
e-de achmen .[53,54]
Rega ding he pedia ic popula ion, he main indica ions o
he use o SO amponade a e RDs associa ed wi h e inopa hy
o p ema u i y, auma, congeni al anomaly, and myopia. In he
case o se e e auma isms, SO in e nal amponade may help o
fla en he e ina and p e en hemo hage, which would inc ease
he isk o PVR.[55]
Finally, i has been a gued ha SOs ha e ce ain an imic obial
ac i i y, which is why hey a e usually used as a amponade in
pos auma ic endoph halmi is cases.[56]
Wi h ega ds o he disad an ages o SOs, hese include he
need o op ical adjus men s o be made due o he diffe en e-
ac i e index when compa ed o he na u al i eous body, and
he less effec i e na u e o he use o he amponade in ea ing
in e io e ina b eaks due o i s low specific g a i y.[57,58]
Fu he mo e, se ious complica ions such as e inal oxici y,[59]
op ical neu opa hy,[60] o glaucoma [61] ha e been epo ed wi h
he use o SO, some o which a e ela ed o he emulsifica ion
o SO, especially in long- e m use. This emulsifica ion leads
he o iginal SO bubble o b eak down in o smalle d ople s,
esul ing in e inal inflamma ion by inducing a mac ophagic
esponse.[62]
SOs mus be emo ed as soon as hey ha e ulfilled hei
pu pose, and when i is es ablished ha u he e en ion could
inc ease he isk o complica ions (Figu e 2). This emo al is
gene ally ecommended wi hin a six-mon h pe iod a e he
in e en ion.
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Figu e 2. Silicone oil (SO) emo al h ough ac i e suc ion wi h machine
assis ance. C ea ed wi h BioRende .com.
3.2.3. Pe fluo oca bon Liquids
Pe fluo oca bon liquids (PFCLs) a e fluo ine-subs i u ed hyd o-
ca bons, which a e clea , colo less and odo less liquids. These
syn he ic compounds a e cha ac e ized by a high specific g a -
i y, be ween 1.7 and 2.1 g cm−3, wice as high as wa e , and
hei e ac i e index is simila o ha o he i eous humou .[63]
They a e insoluble in wa e and poo ly soluble in SOs. The mos
commonly used PFCLs in clinical p ac ice a e pe fluo odecalin
(C10F18), pe fluo ope hyd ophenan h ene (C14F24), pe fluo ooc-
ane (C8F18 and oc afluo op opane (C3F8).[4] His o ically, hese
we e fi s in es iga ed as blood subs i u es due o hei ex en-
si e capaci y o anspo ing and eleasing oxygen and ca bon
dioxide.[64]
In he clinical se ing, he use o PFCLs has imp o ed he i-
sual ou comes and he ana omic success a e in PVR su gical
p ocedu es.[65–68] PFCLs p o ide he bes cu en ly a ailable in e -
nal amponade du ing memb ane dissec ion. Simila ly, he use
o PFCLs in ea ing gian - ea RD has imp o ed he ana omic
success a e by o e 90%.[66] The PFCLs allow o he eposi ion-
ing o he olded flap, enabling di ec PFCL-SO exchange in o de
o p e en he pos e io flap om slipping.
PFCLs also offe se e al ad an ages in he ea men o au-
ma ic RD, including he s abiliza ion o he e ina du ing he
i ec omy p ocedu e, he displacemen o p e e inal, sub e inal,
and sup acho oidal blood, he elimina ion o inca ce a ed i e-
ous o e ina, and he main enance o a anspa en medium o
isualiza ion du ing su ge y.[69]
The use o PFCLs in o he oph halmic pa hologies has al eady
been p o ed, o example in cases o RD associa ed wi h diabe ic
e inopa hy,[70] de achmen associa ed wi h disc coloboma,[71] de-
achmen om e inopa hy o p ema u i y,[72] i ec omy o en-
doph halmi is, displacemen o submacula hemo hage du ing
su gical d ainage, and he excision o sub e inal memb anes.[73]
Figu e 3. Pe fluo oca bon liquid (PFCL) – silicone oil (SO) exchange. SO
is filled p og essi ely supe io ly, while PFCL is ex uded h ough he flu e
needle placed wi hin he PFCL bubble. C ea ed wi h BioRende .com.
Wi h ega ds o he sa e y o PFCLs, in ecen yea s, se e al
cases o e ino oxici y caused by pe fluo ooc ane ha e been e-
po ed wo ldwide. In his ega d, i is necessa y o s ic p o o-
cols o be es ablished o de e mine he cy o oxici y o in aocula
medical de ices in o de o ensu e he adequa e quali y o hese
p oduc s.[74] Nowadays, hei use is limi ed o he in aope a i e
se ing because o hei long- e m oxici y, and as a esul hey
ha e been exchanged wi h SO (Figu e 3) o ano he long- e m
i eous subs i u es.[75–77]
3.2.4. Semifluo ina ed Alkanes
Semifluo ina ed alkanes (SFAs) we e iden ified in he 2000 s
as an al e na i e o PFCLs gi en he p esump ion ha he la -
e could cause e inal oxici y due o hei high specific densi y.
Mo eo e , SFAs main ain p ope ies such as ine ness, biocom-
pa ibili y, in e ace ensions, e c., con aining bo h pe fluo oca -
bon and hyd oca bon segmen s. They ha e lowe densi ies com-
pa ed o PFCLs, anging om 1.1 o 1.7 g cm−3, and hey a e
soluble in PFCLs, hyd oca bons and SO. They also ha e e y low
su ace and in e ace ensions.[76]
The sho e he pe fluo oalkyl chains and/o he longe he
alkyl chain, he mo e oxic he semifluo ina ed alkanes a e. Im-
pu i ies con aining –CHF g oups mus also be aken in o ac-
coun , gi en ha hyd ogen fluo ide g oups can be elimina ed in
he p esence o nucleophilic bases, esul ing in oxic alkenes.[76]
SFAs we e ini ially used as SO sol en , and la e as em-
po a y endo amponades when i was obse ed ha SO was
ineffec i e.[78] The mos common p oblems ela ed o he use o
SFAs a e ca a ac s and emulsifica ion. Nowadays, SFAs end o
be mixed wi h SO.
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3.2.5. Silicon Oils and Semifluo ina ed Alkanes Combina ion
The combined use o SO and SFAs amponade agen s has been
widely s udied, wi h he idea o b inging oge he he high is-
cosi y o SO and he high specific g a i y o SFAs. This mix u e
gene a es i eous subs i u es ha boas good amponade p op-
e ies and minimal emulsifica ion.[79]
Depending on he p opo ion o SO and SFAs included in he
mix u e, i is possible o ob ain homogeneous solu ions (hea y
silicone oils) o sepa a ed solu ions (double fillings).[80]
Hea y silicone oils—Hea y silicone oils (HSO) a e homoge-
neous solu ions ha a e hea ie han wa e and ha a e o med
by combining SO and SFAs. In clinical p ac ice, hese a e used
o ea ing complica ed RDs, especially hose which in ol e in-
e io PVR. The e a e h ee p e ab ica ed HSOs cu en ly on he
ma ke : Densi on 68, Oxane HD, and HWS 46–3000.
Densi on 68 (Fluo on Co, Ulm, Ge many) is a mix u e
o 30.5% SFA F6H8(pe fluo ohexyloc ane) wi h 69.5% SO,
5000 cS .[78] By adding SO, he iscosi y o F6H8inc eases om
2.5 o almos 1400 mPa s, educing i s dispe sion endency, which
is belie ed o cause he p oblems de i ed om he long- e m use
o F6H8. I has a specific g a i y o 1.06 g cm−3and a e ac i e
index o 1.387.
Oxane HD (Bausch & Lomb, Toulouse, F ance) is a mix u e o
88.1% Oxane 5700, a 5000 mPa s SO, wi h 11.9% RMN3, a pa -
ially fluo ina ed olefin. I has a sligh ly supe io specific g a -
i y and e ac i e index han wa e , 1.02 g cm−3and 1.4, espec-
i ely. I is he mos iscous, 3800 mPa s, and leas hea y HSO o
he h ee p oduc s. Because o i s lowe specific g a i y, sligh ly
highe e-de achmen a es we e ound when using his HSO.[81]
The las comme cialized HSO is called HWS 46–3000, which
is a mix u e o 45% ul apu ified SO 100 000 ( iscosi y 97 100
mPa s and specific g a i y 0.977 g cm−3) and 55% pe fluo obu yl-
hexane (F4H6) a semifluo ina ed alkane ( iscosi y 1.28 mPa s and
specific g a i y o 1.254 g cm−3). The esul ing solu ion (specific
g a i y o 1.105 g cm−3and a iscosi y o 3109 mPa s) is homo-
geneous and s able in he p esence o wa e , ai o PFCLs. I is
he hea ies and mos iscous mix u e o he h ee. In he pilo
s udy by Rizzo e al., high success and low complica ion a es
we e achie ed when HWS 46–3000 was used as a long- e m am-
ponade (1–3 mon hs), e en hough, due o i s highe iscosi y,
handling his subs ance may be mo e difficul , e.g., when emo -
ing i .[75]
Densi on 68, Oxane and HWS 46–3000 ha e shown p omising
esul s in he ea men o RDs associa ed wi h in e io ea s.[82]
Howe e , in a p ospec i e, mul icen e ed, andomized con olled
ial (HSO S udy) ha compa ed he effec o hea y amponade
(Densi on 68) and con en ional SO in eyes wi h in e io and pos-
e io PVR g ade C o abo e, esea che s concluded ha he e
we e no significan benefi s o using hea y amponade ins ead o
con en ional SOs in hese cases.[29]
Double fillings—Double fillings a e he e ogeneous solu ions
in which he SFA sinks and he SO floa s due o i s specific
g a i y, meaning ha hey a e able o p o ide supe io and in e-
io amponades simul aneously. The mos commonly used SFA
is pe fluo ohexyloc ane (F6H8). The amoun o F6H8is much
g ea e han he amoun ha can be dissol ed by SO; he e o e,
he op pa o he bubble consis s o SO sa u a ed wi h dissol ed
F6H8, whe eas he bo om pa o he bubble is pu e F6H8.The
Table 3. Ad an ages and limi a ions o he i eous subs i u es used in
clinical p ac ice.
Ad an ages Limi a ions
Gases - No need o emo al
- Non- oxic
-Ine
- Expansile
- P one posi ioning a e i ec omy
- Expansile gases can p oduce
in aocula p essu e ele a ion (IOP)
Silicone Oils - T anspa ency
- Low su ace ension
- Long- e m in e nal
amponade
- Low oxici y
- Mus be emo ed wi hin a 6-mon h
pe iod
- Op ical adjus men s may be
equi ed
- Less effec i e amponade o he
in e io e ina due o i s low specific
g a i y
Pe fluo oca bon
liquids
- Clea , colo less and
odo less
- Simila e ac i e
index o i eous
humou
- S abiliza ion o he
e ina du ing
i ec omy
- Limi ed o in aope a i e se ing
- Long- e m oxici y
- Mus be eplacedwi hSO
Semifluo ina ed
alkanes
- Less e ino oxici y
han PFCLs due o i s
lowe specific densi y
-SolubleinPFCLsand
SOs.
- Emulsifica ion
- Ca a ac s
Hea y Silicone
Oils
- Good anspa ency,
high densi y and
iscosi y
- Good amponade
p ope ies
- Less endency o
dispe se
- Difficul o handle due o i s iscosi y
- Mus be emo ed wi hin a 2-mon h
pe iod.
mos commonly epo ed combina ion is F6H8mixed wi h 1000
cS SO in a 3:7 p opo ion.[83,84] A combined in e nal amponade
o F6H8and SO may be use ul o ea ing complica ed RD wi h
b eaks in ol ing he e ina’s lowe quad an s.[85]
In o de o cla i y all o he ad an ages and limi a ions o he
i eous subs i u es ha a e cu en ly used in clinical p ac ice,
hese cha ac e is ics ha e been included in Table 3.
4. Influence o Vi eous Subs i u ion on
Pha macokine ics o In a i eal D ugs
When he i eous is subs i u ed wi h SO, 80% o he i eous ca -
i y will be filled wi h he amponade, while he es will be eplen-
ished wi h aqueous humou and some i eous emnan s may be
p esen . In he case o ine gas subs i u es, he p opo ion ha
is o be efilled wi h he aqueous humou will inc ease as he gas
disappea s, and he ime i akes o o ally disappea will diffe de-
pending on he ype o gas (Table 1). A ificial subs i u es ha a e
cu en ly used in clinical p ac ice diffe in e ms o hei i eous
composi ion, and his may affec he pha macokine ics o in a -
i eally injec ed d ugs.[86] Mos o hese d ugs a e wa e -soluble
and will only dissol e in he i eous aqueous phase. To he bes
o ou knowledge, e y ew in a i eal pha macokine ic s udies
ha e been conduc ed on amponade animal eye models[87,88] in
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which SO was used as he i eous subs i uen . In his sense, Xu
e . al in es iga ed he be acizumab injec ion (1.25 mg/0.05 mL)
in a abbi model, obse ing ha silicone ac ed as a empo a y
depo o con olled d ug deli e y, delaying d ug dis ibu ion in o
he emaining i eous aqueous phase, whe e he d ug dissol ed,
be o e being u he dis ibu ed in o he su ounding issues.
The e o e, i is an icipa ed ha he d ug concen a ion- ime p o-
files will change be ween he na i e and filled i eous. Howe e ,
gi en he lack o in e nal con ol he in a i eal clea ance o hal -
li e diffe ences be ween SO- i eous and he con ol heal hy eye
we e no de e mined in hose s udies.[87,88] Fo e hical easons i
is no possible o pe o m hese ypes o pha macokine ic s udies
in pa ien s. Ne e heless, a ew s udies ha e e alua ed he sa e y
and efficacy o ea men e sus no- ea men in SO-filled eyes
wi h an i i als[89] o be acizumab injec ions,[90,91] obse ing pos-
i i e clinical ou comes in he ea ed pa ien s. Se e al o he case
epo s ha e shown ha he Ozu dex implan (dexame hasone
0.7 mg loaded in a biodeg adable sus ained- elease in a i eal
implan (Alle gan Inc., I ine, CA)) appea s o be ole a ed by and
beneficial o pa ien s wi h SO amponade.[92–94] Howe e , i mus
be no ed ha he epo ed clinical s udies a e based on a limi ed
numbe o pa ien s. The d ug elease om he implan will de-
pend on he phase in which said implan is loca ed, ha is o say
he aqueous phase o he SO/gas phase, as his elease will only
be possible in a medium in which he d ug can be dissol ed. In
he case o ac ing-gas amponade, he elease may also be depen-
den on he iming o he gas disappea ing. Mo eo e , he d ug
elease om he implan may be delayed in he filled-eye, and
longe d ug le els may be main ained, none heless, u he in-
es iga ions on an animal models a e equi ed.[95]
O e all, he e is s ill a lack o quan i a i e da a on he effec o
he i eous subs i uen s on in a i eal pha macokine ics. Fu -
he pha macokine ic s udies mus be conduc ed in o de o cla -
i y hei effec on he d ug concen a ions ollowing in a i eal
adminis a ion, o bo h d ug solu ions and implan s.
5. Expe imen al Vi eous Subs i u es: Hyd ogels
The e a e s ill nume ous incon eniences and limi a ions o he
use o cu en ly a ailable i eous subs i u es in clinical p ac ice.
Consequen ly, he sea ch o new bioma e ials ha can be used
o achie e he ideal i eous subs i u e s ill con inues. P e ious
esea ch a emp ed o p oduce i eous subs i u es ha boas ed
simila physiological p ope ies and molecula s uc u e o he
i eous body. The limi s o his app oach included he oxici y
o he compounds and hei incapaci y o p o ide sufficien in-
e nal amponade o i eous eplacemen su ge y.[96] In o de
o o e come hese d awbacks, ecen esea ch has ocused on de-
eloping biocompa ible, biodeg adable, and injec able hyd ogels
(na u al, syn he ic, and sma ), which will also ac as medium and
long- e m in e nal amponade agen s.[2] Hyd ogels do no ha e o
be emo ed a e a ce ain pe iod o ime, he e o e o e coming
one o he main incon eniences ela ed o his p ocedu e. In ad-
di ion, depending on he ypes o polyme s used o hei syn he-
sis, some o hei p ope ies can be op imized. Specifically, hei
iscosi y, po osi y, good mechanical s eng h, and he possibili y
o d ug encapsula ion make hese ad an ageous o hei clinical
use in pa ien s. Main hyd ogels which ha e been de eloped as i -
eous subs i u es in ecen yea s ha e been ou lined in Table 4.
5.1. Na u al Hyd ogels
The use o HA and collagen as i eous subs i u es has been e al-
ua ed due o hei g ea biocompa ibili y and gi en ha hese a e
he main componen s o he i eous. Howe e , hey ha e a poo
amponade effec and a limi ed e en ion ime in i o compa -
ing o he esul s p oduced by syn he ic and sma hyd ogels,
due o he molecules endency owa ds deg ada ion and hei low
iscosi y.[23,97]
To inc ease e en ion ime, HA has been c oss-linked h ough
UV and dihyd azide, esul ing in biocompa ible hyd ogels ha
p esen good anspa ency, iscosi y, and amponade effec
hanks o hei hyd ophilic p ope ies, none heless, hese ma e-
ials s ill p esen ela i ely sho - e m s abili y.[99,103] In addi ion,
c oss-linked hyalu ona e o mula ions and combina ions o HA
wi h o he polyme s, such as mic obial anionic polysaccha ide
gellan ha e also been es ed. Howe e , due o he ins abili y o
he physical c osslinks, hese combina ions a e no a ailable o
long- e m use.[97,98,100,101]
Aiming o imp o e his ea u e, Raia e al. syn hesized silk and
HA composi e hyd ogels by c oss-linking he y osine esidues
na i e o silk fib oin and y amine-conjuga ed HA. In his sense,
he composi e silk-HA hyd ogel e ained he a o able p ope ies
o each o he polyme s. Consequen ly, he be e con ol o he
wa e con en in he composi e ma ix exe ed by HA and he slow
p o eoly ic deg ada ion o he silk esul ed in longe s abili y and
du abili y.[125]
Addi ionally, Uesugi e al. used a na u al polyme , which was
no based on collagen o HA as a i eous subs i u e. Specifi-
cally, hey epo ed he use o PanaceaGel SPG-178 (0.1%), a sel -
assembling gel, he main componen o which is 13 amino acid
syn he ic pep ide. This gel can be injec ed h ough a 27-gauge
needle and i s e ac i e index, isible ligh ansmission a e, and
heological p ope ies a e simila o hose o human i eous. In
addi ion, hey ca ied ou a h ee-mon h in i o s udy in abbi s
in which good biocompa ibili y and no oxici y we e obse ed.[102]
Ne e heless, apid deg ada ion emains a majo p oblem o
his ype o subs i u es, as bioma e ials end o deg ade and
change hei physicomechanical p ope ies in a sho pe iod o
ime. This is a conside able d awback gi en ha he ideal i e-
ous subs i u es mus be s able o long pe iods o ime, p e e ably
o e h ee mon hs.[2,6]
5.2. Syn he ic Hyd ogels
Polyme ic hyd ogels a e he nex s ep owa ds p oducing he
ideal i eous subs i u e. These ma e ials a e ne wo ks o c oss-
linked hyd ophilic polyme chains wi h ex ensi e swelling, ab-
so bing se e al imes hei own weigh in wa e .[126,127] They ha e
a good le el o anspa ency, biocompa ibili y, and p esen is-
coelas ic p ope ies ha a e simila o he i eous body, imi a ing
i s bio unc ionali y.[128]
Poly(1- inyl-2-py olidone) (PVP) was he fi s syn he ic poly-
me o be es ed as a po en ial i eous subs i u e. The mos
commonly epo ed ad e se effec s we e i eous opacifica ion
and inflamma ion eac ion, esul ing in ea ly PVP deg ada-
ion due o phagocy osis.[129] In addi ion, 1- inyl-2-py olidone
(VP) monome was polyme ized wi h di inyl glycol (DVG) as a
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Table 4. Hyd ogels de eloped as i eous subs i u es and hei main cha ac e is ics.
Hyd ogels Polyme con en [%] Re ac i e index Ligh ansmi ance [%] In i o s udies Re e ence
Na u al polyme s
Gellan and hyalu onic acid 1 85–95 no [97]
Me hac yla ed gellan gum 1 no [98]
Hyalu onic acid 1 1.338 abbi s [99]
Hyalu onic acid 3 1.341 abbi s [100]
Hyalu onic acid 1–2.2 1.32–1.34 abbi s [101]
Pep ide gel 0.10 1.3339 96.7 abbi s [102]
Hyalu onic acid 1 1.32–1.33 abbi s [103]
Hyalu onic acid 1 1.336 75–91 no [23]
Syn he ic polyme s
Poly inyl alcohol me hac yla e 9 no [104]
Poly inyl alcohol 7 macaques [105]
Poly inyl alcohol 4 85 no [106]
Poly(e hylene glycol) 5 1.339 abbi s [107]
Poly inyl alcohol 5 no [108]
Poly inyl alcohol 1–7 1.3361 93 abbi s [109]
Poly inyl alcohol 4 1.3420 no [110]
Ac ylic acid and ac ylamide 1.25 –1.75 no [111]
Poly N-ac yloyl glycinamide-polyca boxybe aine ac ylamide 1.60 1.3354 93.2 abbi s [112]
Sma hyd ogels
WTG-127 89.3 abbi s [113]
Poly(e hylene glycol) 25 1.353 >90 no [114]
Poly(e hylene glycol) 10 1.3325 abbi s [115]
Sul obe aine me hac ylamide and ac yloyl cys amine monome s 5 >90 abbi s [116]
Gellan and poly(me hac ylamide-co-me hac yla e) 0.65–1.29 1.3351–1.3372 87.6–94 abbi s [117]
Me hac ylic acid,
me hylac ylamide, and bisme hac yloylcys amine
1–1.4 no [118]
Poly(e hylene glycol) 0.4–0.7 abbi s [119]
Polyme hac ylamide and poly-me hac yla e 0.9–1.8 1.3345–1.3348 >95 no [120]
Hyd oxyp opyl chi osan and algina e dialdehyde 1–3 1.3348 >80 abbi s [121]
Poly(e hylene glycol), poly(p opylene glycol), and
poly(𝜖-cap olac one)
3–12 1.339–1.344 abbi s [122]
Poly(e hylene glycol) me hac yla e and poly(e hylene glycol)
diac yla e
0.75–5.7 1.3350–1.3359 >90 no [123]
Gellan and
poly(me hac ylamide-co-me hac yla e-co-
bis(me hac yloyl)cys amine)
1.3355–1.3370 >83 abbi s [124]
c oss-linking agen in o de o ob ain a anspa en hyd ogel wi h
a simila densi y and iscosi y o he i eous body.[129] Finally,
VP was also co-polyme ized wi h 2-hyd oxye hyl me hac yla e
(HEMA) using diallyl e he (DAE) as a c oss-linking agen , e-
sul ing in a clea and anspa en gel wi h mechanical p ope ies
close o hose o he i eous, howe e , he main incon enience
was ha he elas ic p ope ies we e educed o e en los when
injec ed.[130]
Polyac ylamide (PAA) has been syn hesized by he polyme -
iza ion o ac ylamide, a oxic and ca cinogenic subs ance, wi h a
disulfide c oss-linking agen . Howe e , his polyme iza ion p o-
cess highly imp o es i s biocompa ibili y. PAA p esen s good bio-
compa ibili y and long- e m s abili y, as well as offe ing a simila
iscosi y and densi y o he i eous. Wi h ega ds o ad e se eac-
ions, se e e ocula inflamma ion and i eous opacifica ion ha e
been epo ed.[131]
Poly(2-hyd oxye hylac yla e) (PHEA) p esen ed e y good
physical p ope ies; howe e , due o he eme gence o inflamma-
o y eac ions, as well as ca a ac and glaucoma his subs ance is
no longe being in es iga ed.[4,6]
All o he a o emen ioned polyme s p esen ed complica ions
ela ed o inflamma ion and oxici y. As a esul , o he polyme s
such as poly(glyce yl me hac yla e) (PGMA) and hyd oxyp opyl
me hylcellulose (HPMC) we e in es iga ed; howe e , hese did
no each he clinical s udy s age due o hei sho deg ada ion
ime.[132,133]
Mac omol. Biosci. 2021, 2100066 2100066 (9 o 15) © 2021 The Au ho s. Mac omolecula Bioscience published by Wiley-VCH GmbH