Bioimaging
Mixed Conduc i e, Injec able, and Fluo escen Sup amolecula
Eu ec ogel Composi es
Mi yam C iado-Gonzalez,* Nu ia Aleg e , Alejand o M. F aca oli, Daniele Man ione,
G ego io Guzmán-González, Ra ael Del Olmo, Ken a o Tashi o, Liliana C. Tomé,
Ma ias L. Picchio,* and Da id Mece eyes*
Abs ac : Eu ec ogels a e an eme ging amily o so
ionic ma e ials al e na i e o ionic liquid gels and
o ganogels, o e ing esh pe spec i es o designing
unc ional dynamic pla o ms in wa e - ee en i on-
men s. He ein, he i s example o mixed ionic and
elec onic conduc ing sup amolecula eu ec ogel compo-
si es is epo ed. A luo escen glu amic acid-de i ed
low-molecula -weigh gela o (LMWG) was ound o
sel -assemble in o nano ib illa ne wo ks in deep eu ec-
ic sol en s (DES)/poly(3,4-e hylenedioxy hiophene)
(PEDOT): chond oi in sul a e dispe sions. These dy-
namic ma e ials displayed excellen injec abili y and
sel -healing p ope ies, high ionic conduc i i y (up o
102Scm1), good biocompa ibili y, and luo escence
imaging abili y. This se o ea u es u ns he mixed
conduc ing sup amolecula eu ec ogels in o p omising
adap i e ma e ials o bioimaging and elec os imula ion
applica ions.
Deep eu ec ic sol en s (DES) a e an eme ging class o
compounds ea u ed by an abno mal dep ession o hei
eu ec ic poin empe a u e compa ed o an ideal liquid
mix u e.[1] This nega i e de ia ion om he ideali y is o en
associa ed wi h s ong hyd ogen bonding in e ac ions be-
ween he mix u e componen s, commonly de ined as hyd o-
gen bond accep o (HBA) and hyd ogen bond dono
(HBD).[2] Since hei disco e y in 2003 by Abbo and co-
wo ke s,[3] DES ha e ecei ed inc eased a en ion as hey
a e a o able al e na i es o eplace ionic liquids (ILs) and
a e ac i ely being explo ed o a my iad o applica ions.[4]
Simila o ILs, many DES show low apo p essu e, high
ionic conduc i i y, and b oad liquid ange, bu hey bene i
om easie p epa a ion, low cos , non- oxici y, and
biodeg adabili y.[5] The immobiliza ion o hese in iguing
sol en s wi hin polyme sca olds leads o an inno a i e
amily o so ionic ma e ials called eu ec ogels ha ha e
e y ecen ly s epped in o he spo ligh .[6]
Eu ec ogels a e commonly designed om c oss-linked[7]
o en angled[8] polyme s, bu can also be p epa ed om low-
molecula -weigh gela o s (LMWGs), esul ing in sel -
assembled ne wo ks d i en by sup amolecula in e ac ions.
In 2019, Smi h e al. pionee ed he de elopmen o
sup amolecula eu ec ogels disco e ing ha 1,3:2,4-dibenzy-
lidene-d-so bi ol (DBS), a low-cos comme cial LMWG,
could sel -assemble in a DES based on choline chlo ide
(ChCl) and alcohols/u ea.[9] Only ew examples o
sup amolecula eu ec ogels ha e ecen ly ollowed up his
landma k wo k, explo ing a ious LMWGs such as
[*] D . M. C iado-Gonzalez, D . D. Man ione, D . G. Guzmán-González,
D . R. Del Olmo, D . M. L. Picchio, P o . D. Mece eyes
POLYMAT Uni e si y o he Basque Coun y UPV/EHU,
Joxe Ma i Ko a Cen e , A da. Tolosa 72, 20018 Donos ia-San
Sebas ián (Spain)
E-mail: [email p o ec ed]
[email p o ec ed].a
[email p o ec ed]
D . N. Aleg e
Cen e o Coope a i e Resea ch in Bioma e ials (CIC bioma-
GUNE), Basque Resea ch and Technology Alliance (BRTA)
Paseo de Mi amón 194, 20014 Donos ia-San Sebas ián (Spain)
D . A. M. F aca oli
Ins i u o de In es igaciones en Físicoquímica de Có doba, INFIQC-
CONICET, Facul ad de Ciencias Químicas, Uni e sidad Nacional de
Có doba
Ciudad Uni e si a ia, X5000HUA Có doba (A gen ina)
D . D. Man ione, D . K. Tashi o
In e na ional Cen e o Ma e ials Nanoa chi ec onics (WPI-
MANA), Na ional Ins i u e o Ma e ials Science
1-1 Namiki, 305-0044 Tsukuba (Japan)
D . L. C. Tomé
LAQV-REQUIMTE, Depa men O Chemis y, NOVA School O
Science And Technology, FCT NOVA, Uni e sidade NOVA de
Lisboa
2829-516 Capa ica (Po ugal)
D . M. L. Picchio
Ins i u o de Desa ollo Tecnológico pa a la Indus ia Química
(INTEC), CONICET
Güemes 3450, 3000 San a Fe (A gen ina)
P o . D. Mece eyes
Ike basque, Basque Founda ion o Science
48013 Bilbao (Spain)
© 2023 The Au ho s. Angewand e Chemie In e na ional Edi ion
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 Non-Comme cial
NoDe i s License, which pe mi s use and dis ibu ion in any med-
ium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-
comme cial and no modi ica ions o adap a ions a e made.
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guanosine,[10] halogena ed DBS,[11] d-gluconic ace al,[12] and
bisgluconamide de i a i es.[13] Su p isingly, al hough scien-
i ic e o s ha e been de o ed o de eloping pu ely ionic-
conduc ing sys ems, mixed ionic-elec onic conduc ing
sup amolecula eu ec ogel composi es ha e no been consid-
e ed un il now. In his ein, o ganic mixed ionic-elec onic
conduc o s (OMIECs), like poly(3,4-e hylenedioxy hio-
phene) (PEDOT) wi h enhanced cha ge s o age and
coupled anspo p ope ies could expand he applicabili y
o hese deep eu ec ic so ionic ma e ials.[14] Fo ins ance,
OMIECs open he ga e o elec os imula ion o biosensing,
and consequen ly, mixed conduc ing sup amolecula eu ec-
ogels could ind new ou es in issue egene a ion, accel-
e a ed wound healing, and ion opho e ic ocula d ug
deli e y, among o he s.[15]
Since hyd ogen-bonding in e ac ions a e inhe en ly
p esen in mos DES, he sup amolecula assembly o
classical LMWGs is no always gi en. He ein a new
phenan h oline-modi ied glu amic acid de i a i e was iden-
i ied as a eu ec ogela o in he p esence o di e en choline
chlo ide (ChCl)-based DES and combined wi h
PEDOT:Chond oi in sul a e (ChS). These speci ic DES
we e chosen as hey ha e been shown o be biocompa ible
and non-cy o oxic,[16] and ha e a s ong dissolu ion powe
o hyd ophobic d ugs.[17] In his ega d, wi h a iew owa d
biomedical applica ions, we decided o use ChS polysaccha -
ide o PEDOT s abiliza ion as i has p o en o p omo e
chond ogenic di e en ia ion and e-epi helializa ion.[18]
Mo eo e , o he bes o ou knowledge, he e a e no
compa a i e s udies be ween sup amolecula eu ec ogels
and hei ionic liquid gels o iongels coun e pa s. Thus, we
also p o ide help ul insigh s in o his ma e by compa ing
ChCl-based DES wi h cholinium-de i ed ILs.
Fi s ly, he abili y o new phenan h oline-modi ied
glu amic acid LMWG (Figu e S1) o jelli y DES was
in es iga ed. The sup amolecula eu ec ogels we e o med
by ho dissolu ion o he LMWG in he DES, ollowed by a
cooling s ep a oom empe a u e o igge he gela ion
p ocess (Scheme 1a). Di e en DES, based on ChCl and
h ee HBDs, namely glyce ol (Gly=G), lac ic acid
(LacAc=L), and glycolic acid (GlyAc=GA), we e es ed
(Figu e 1a). In e ed ial es s show he eu ec ogel o ma-
ion in he case o eGelGand eGelGA, bu no o eGelL. The
use o acidic DES esul ed in o ange gels, p obably because
o he phenan h oline g oup p o ona ion. The FTIR spec-
um o he LMGW shows cha ac e is ic peaks a 1721,
1694, 1660 (C=Oνo Boc,Fmoc, and glu amic acid esidue),
1553 ( ing skele on), 1157 (CHδip), and 739 cm1(C=Cδ)
(Figu e S2). A e gel o ma ion, he main peaks o he
LMWG a e e idenced wi hou signi ican signal shi s.
Howe e , he ela i e in ensi y o he CHδip and C=Cδ
peaks changed in he eu ec ogel, sugges ing ha π–π
in e ac ions play an essen ial ole in gel o ma ion. The
s uc u al o ganiza ion o he eu ec ogel eGelG3 was u he
in es iga ed by ci cula dich oism (CD) (Figu e S3). The
CD spec um o eGelG3 shows a posi i e band a 196 nm
and a s ong nega i e band a 221 nm, which is he signa u e
o β-shee s uc u es.[19] Besides, he maxima a 251 nm is
cha ac e is ic o s acking in e ac ion o he a oma ic uni s o
he LMWG, and he nega i e bands a 271 and 308 nm a e
a ibu ed o he o se ace- o- ace s acking o he Fmoc
moie ies and he luo enyl abso p ion, espec i ely.[20] The
iscoelas ic p ope ies o he eu ec ogels, pa icula ly he
elas ic modulus (G’) and loss modulus (G’’), we e measu ed
by dynamic oscilla o y heology. S ain sweeps allow us o
de e mine he linea iscoelas ic egime (LVR) up o 3%
s ain and he o al gel o sol ansi ion (G’’>G’) om 40%
s ain. A 1% s ain, in he LVR zone, G’(�104Pa) is
highe han G’’ (�103Pa), which is he condi ion o he gel
s a e and keeps s able in he whole equency ange
(Figu e S4). Injec able and sel -healable gels a e ac i ely
sea ched o minimally in asi e ea men s in
biomedicine.[21] Thus, hese p ope ies we e s udied by
dynamic s ep s ain es s (Figu e 1b). A low s ains (�=
1%), G’is highe han G’’ o bo h o med eu ec ogels,
eGelG3 (G’=350 Pa>G’’=90 Pa), and eGelGA3 (G’=
1500 Pa>G’’=180 Pa), p o ing he gel s a e be o e injec-
ion. Then, he samples we e subjec ed o high s ains (�=
1000%) du ing sho imes (180 s), mimicking he pass o
he gel h ough he needle, aking place a gel o sol
ansi ion (G’’>G’). Subsequen ly, by ceasing o apply g ea
e o s and applying low s ains (�=1%) again, his
beha io was e e sed in he case o eGelG3 eu ec ogels
(G’=120 Pa>G’’=40 Pa), p o ing he eco e y o he gel
s a e a e injec ion, whe eas eGelGA3 eu ec ogels ba ely
eco e ed he gel s a e (G’=40 Pa�G’’=25 Pa), exhibi ing
modulus a om he ini ial alues. These esul s show ha
only he eGelG3 eu ec ogels possessed sel -healing and
injec abili y p ope ies, and hus, he eGelG3 we e selec ed
o u he expe imen s. No e ha simila elas ic moduli
ha e been ound o xan ham gum eu ec ogels o med in
Gly/ChCl DES.[22]
Scheme 1. (a) Single ionic conduc i e eu ec ogel o med by he
sup amolecula in e ac ion o a glu amic acid-de i ed LMWG and a
DES. (b) Hyb id mixed ionic/elec onic conduc i e eu ec ogel compo-
si e o med by he sup amolecula in e ac ion o LMWG, DES, and
PEDOT:ChS.
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Once he abili y o he glu amic acid-de i ed gela o o
o m sup amolecula ne wo ks in DES was con i med, he
compa ison o eu ec ogels s. iongels was add essed. The
iongels we e p epa ed by he ho dissolu ion o he LMWG
in cholinium lac a e (ChLac) and cholinium glycola e
(ChGly) ILs (Figu e S5–S6) and subsequen cooling (Fig-
u e 1c). The heological es s show ha bo h he iongels
ha e sel -healing p ope ies wi h he eco e y o he gel
s a e a e he low-high-low s ain cycle, iGelGA3 (G’=
60 Pa>G’’=30 Pa), and iGelL3 (G’=360 Pa>G’’=300 Pa)
(Figu e 1d). Mo eo e , we ound ha using DES ga e gels
wi h enhanced mechanical p ope ies, showing highe G’
alues han he gel ma e ials p epa ed wi h ILs (Figu e S7).
Besides, he ionic conduc i i y (σi) was de e mined by
elec ochemical impedance spec oscopy om 23 o 85°C
(Figu e 2a). The eGelG3 eu ec ogels ha e highe ionic
conduc i i y (σi=102Scm1) han ha o iGelL3 iongels
(σi=103Scm1), wi h a ypical linea dependence o σiwi h
he empe a u e as a consequence o he a o ed ca ie
mobili y. The highe ionic conduc i i y o eGelG3 is p ob-
ably due o he signi ica i ely lowe iscosi y o Gly/ChCl
DES compa ed wi h [Ch][Lac] ionic liquid, a o ing he
ionic mobili y. These σi alues a e in ag eemen wi h
p e ious wo ks ela ed o eu ec ogels o med by a glyce ol-
based DES wi h polyme s, i.e., gela in, polyac ylic acid
(PAA),[8a,23] o o he LMWGs such as DBS.[9]
Conside ing he supe io mechanical and ionic conduc-
i e p ope ies o he p epa ed eu ec ogels, he eGelGwas
u he s udied in de ail. The eu ec ogel exhibi ed a ib illa y
mo phology wi h ibe diame e s lowe han 50 nm, as
obse ed by ansmission elec on mic oscopy (TEM) (Fig-
u e 2b). The in luence o he LMWG concen a ion on he
eu ec ogel mechanical p ope ies was analyzed by heology.
Figu e 2c shows an inc ease o G’wi h he LMWG
concen a ion, om 350 Pa o 3% LMWG o 2150 Pa o
5% LMWG. The yield s ain is no signi ican ly a ec ed by
he LMWG concen a ion showing a gel- o-sol ansi ion
om 20% s ain in all cases (Figu e S8). Ne e heless, he
sel -healing p ope ies a e ad e sely a ec ed (Figu e 2d)
wi h lowe G’ eco e y wi h espec o he ini ial G’ alues
as he LMWG concen a ion inc eases.
The mixed ionic/elec onic sup amolecula eu ec ogel
composi es we e p epa ed by adding a conduc ing polyme
PEDOT:ChS o he selec ed LMWG+DES mix u e du ing
he hea ing s ep, o be hen cooled down un il oom
empe a u e o igge he gela ion p ocess (Scheme 1b).
Figu e 1. (a) Eu ec ogels o med by he sup amolecula in e ac ions o di e en choline chlo ide based DES wi h a glu amic acid-de i ed LMWG,
wi h hei co esponding in e ed ial es pic u es. [LMWG]=3% w/ . (b) Dynamic s ep-s ain ampli ude es s o he eu ec ogels, eGelG3 and
eGelGA3. (c) Iongels o med by he sup amolecula in e ac ions o cholinium-based ionic liquids and he LMWG, wi h hei co esponding in e ed
ial es pic u es. [LMWG]=3% w/ . (d) Dynamic s ep-s ain ampli ude es s o he iongels, iGelL3 and iGelGA3.
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The p esence o PEDOT:ChS did no a ec he gela ion
kine ic as de e mined by he in e ed ube es s, which show
he eu ec ogel composi e o ma ion in he p esence o
PEDOT:ChS, and whose mo phology was u he isualized
by TEM (Figu e 3a). In ha case, apa om he cha ac e -
is ic ibe s o he LMWG sel -assembly in he DES,
PEDOT:ChS agg ega es a e also dis inguished and homo-
geneously dis ibu ed along he whole eu ec ogel composi e
ne wo k. As con ols (Figu e S9), he TEM pic u e o he
DES solu ion does no show any s uc u al con o ma ion,
while he PEDOT:ChS dispe sion p esen s he same
mo phology as agg ega es obse ed in Figu e 3a and Fig-
u e S10, con i ming he success ul inco po a ion o he
elec onic componen PEDOT:ChS in he eu ec ogel. FTIR
spec um o PEDOT:ChS display ypical peaks a 1515
(skele al ib a ions), 1314 (ROSO3νas), 1185 (ROSO3
νsy), 1048 (COCνas), 974 (CHδoop), and 825 cm1
(SOν) (Figu e S2). Howe e , hese ib a ional modes we e
ha d o iden i y in eGelG3/CP as hey o e lap wi h he
in ense peaks o he DES. An inc ease o he PEDOT:ChS
concen a ion in he eu ec ogel composi es, om 2 o
5% w/ , p oduces an inc ease o he elas ic modulus, om
1300 o 7400 Pa o eGelG3, and om 2100 o 4000 Pa o
eGelG4 (Figu e 3b and Figu e S11). Conce ning he in lu-
ence o PEDOT:ChS concen a ion on he sel -healing
p ope ies, eGelG3/CP2 eu ec ogel composi es p esen be e
G’ eco e y alues han eGelG3/CP5 (Figu e 3c and Fig-
u e S12), possibly because o highe concen a ion o
PEDOT:ChS agg ega es impac he c osslinking densi y o
he sup amolecula ne wo k, making he esul ing ma e ials
mo e b i le. This e ec has also been ound in blends o
PEDOT:PSS (polys y ene sul ona e, PSS) wi h wa e bo ne
polyu e hane (WPU),[24] and wi h a inyl esin con aining
poly(e hylene glycol) diac yla e (PEGDA),[25] which bo h
ypes o ma e ials exhibi ed a conside able educ ion o he
elonga ion a b eak wi h he PEDOT:PSS loading. The
e ec o he empe a u e on he iscoelas ic p ope ies was
also s udied (Figu e S13), and he esul s demons a e ha
he e is no any impac on G’ alues when he empe a u e
changes om oom empe a u e (20°C) o ex eme body
empe a u e condi ions (42°C). Impo an ly, he p esence o
PEDOT:ChS a o ds elec onic conduc i i y (σe) o he
eu ec ogel composi es ha inc eases wi h he PEDOT:ChS
loading, as measu ed by di ec cu en (DC) pola iza ion
(Figu e S14). The con ol eu ec ogel eGelG3 wi hou
PEDOT deli e ed a negligible cu en , whe eas composi e
eu ec ogels eGelG3/CP2 and eGelG3/CP5 eached cu en s
o 0.06 mA and 0.82 mA, espec i ely, a e 1 h. Conside ing
he Ohm’s law and he geome ic pa ame e s, hese alues
we e ansla ed in elec onic conduc i i y: σe=0 o eGelG3,
σe=1.6·105Scm1 o eGelG3/CP2, and σe=2.1·104Scm1
o eGelG3/CP5. This e ec can be explained by he ac ha
eGelG3/CP5 possesses a highe pe cola ion pa h which gi es
ise o an e icien hopping be ween π–π s acked chains and
highe elec onic conduc i i y han eGelG3/CP2 ha could
achie e a pe cola ion h eshold dec easing he elec onic
conduc i i y.[26] On he o he hand, he ionic conduc i i y
(Figu e 3d) emains una ec ed (σi=102Scm1), and mixed
ionic/elec onic eu ec ogel composi es p esen he ypical σi
linea dependence wi h he empe a u e as in he case o
simple ion conduc i e eu ec ogels. No e ha al hough
PEDOT is a mixed conduc o , a negligible con ibu ion o
he o e all ionic conduc i i y is obse ed, p obably because
Figu e 2. (a) Ionic conduc i i y o he eu ec ogel eGelG3 and he iongel
iGelL3 a di e en empe a u es. (b) TEM image o he eu ec ogel
eGelG3. The inse shows he eu ec ogel’ isual appea ance. (c) S o age
modulus (G’) and loss modulus (G’’) as a unc ion o he equency o
he eu ec ogels eGelG3, eGelG4 and eGelG5. (d) Dynamic s ep-s ain
ampli ude es s o eGelG4 and eGelG5 eu ec ogels.
Figu e 3. (a) TEM image o he eu ec ogel composi e eGelG3/CP2. The
inse shows he eu ec ogel’ isual appea ance. (b) S o age modulus
(G’) and loss modulus (G’’) as a unc ion o he equency o he mixed
ionic/conduc i e eu ec ogel composi es eGelG3/CP2, eGelG3/CP5,
eGelG4/CP2 and eGelG4/CP5. (c) Dynamic s ep-s ain ampli ude es s,
and (d) Ionic conduc i i y a di e en empe a u es o he eu ec ogel
composi es, eGelG3/CP2 and eGelG3/CP5.
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o i s low concen a ion in he eu ec ogel composi e
compa ed wi h he eu ec ic ca ie .
In e es ingly, he Fmoc and phenan h oline g oups in
he LMGW endow he eu ec ogels wi h in insic
luo escence, which is e y use ul o bioimaging (Fig-
u e 4a). Bo h kinds o eu ec ogels, single ionic conduc i e
and mixed ionic/elec onic conduc i e gels, display simila
luo escence spec a wi h maximum emission peaks in he
blue egion a 408 and 435 nm, meaning ha he LMWG
luo escence is no a ec ed by he inco po a ion o
PEDOT:ChS wi hin he eu ec ogel ne wo k. P e iously o
s udy biocompa ibili y, he eu ec ogels’s abili y in physio-
logical mimicking condi ions (Phospha e bu e ed saline
(PBS) a pH 7.4 and 37°C) was es ed (Figu e S15). In he
case o single ionic conduc i e eu ec ogels (eGelG3), a
pa ial disagg ega ion o he gel s uc u e is obse ed a e
48 h, while he mixed ionic/elec onic conduc i e eu ec ogel
composi es (eGelG3/CP2) emains s able, a leas , up o 72 h.
The sup amolecula H-bonding in e ac ions be ween he
LMWG and he DES can be b oken in p esence o an ionic
media such as PBS, which can in e ac elec os a ically wi h
he DES leading o a pa ial disassembly o he eu ec ogel.
This e ec is p e en ed when PEDOT:ChS is inco po a ed
wi hin he eu ec ogel ne wo k due o he elec os a ic
in e ac ions o he long chains o he polyme ChS wi h he
LMWG, which s abilize he eu ec ogel ne wo k becoming i
mo e esis an and p e en ing i s disin eg a ion in p esence
o PBS. In i o cell es s we e pe o med by placing he
eu ec ogels in con ac wi h iPSC cells. Rega ding he
cy o oxici y es s (Figu e 4b), he esul s show no signi ican
di e ences in he abso bance o he eu ec ogels when
compa ed o he Ma igel-coa ed well-pla e used as a con ol
(CTL). This means ha he cell su i al is no al e ed in
con ac wi h he eu ec ogels, demons a ing ha hey a e
non-cy o oxic. Besides, Figu e 4c shows a sligh inc ease in
cell iabili y in he mixed ionic/elec onic conduc i e
eu ec ogel composi es, eGelG3/CP, compa ed o ha o he
single ionic conduc i e eu ec ogel, eGelG3 (wi hou PE-
DOT:ChS in he ne wo k). This beha io can be a ibu ed
o he ac ha conduc i e ma e ials can p omo e p oli e -
a ion and di e en ia ion when esponsi e cells a e cul u ed
on op o wi hin hem.[27] In ac , he esul s ob ained by
di ec cu en (DC) pola iza ion es s showed ha bo h
eGelG3/CP2 and eGelG3/CP5 eu ec ogel composi es display
addi ional elec onic conduc i i y when compa ed o he
eGelG3, which only p esen s ionic conduc i i y. The e o e,
mixed ionic/elec onic eu ec ogel composi es, eGelG3/CP2,
and eGelG3/CP5, may p o ide an ex a elec ical s imula ion
pe se o he cells in con ac wi h hem, a o ing he chemical
exchanges and signal communica ions among he cells a he
cell memb ane-ma e ial in e ace, inducing hei
p oli e a ion.[28] This p elimina y g ow h endency is a i s
inding o mixed ionic/elec onic eu ec ogel composi e
sys ems ha needs o be explo ed in de ail, and u he
expe imen s in ol ing di e en cellula models and ex e nal
elec ical s imuli will be conduc ed in he u u e.
Finally, he p oo o concep o he de eloped eGelG3/
CP2 eu ec ogel composi es o be employed as an agen o
local and minimally in asi e bioimaging applica ions was
assessed wi h mice bodies, which we e no explici ly
sac i iced o his expe imen . The eu ec ogel composi e was
injec ed subcu aneously in a local pa o he mouse’s ea
(Figu e 4d). Then, he mouse‘s ea was i adia ed, obse ing
clea ly he luo escence ligh emi ed a he local pa o he
issue whe e he eu ec ogel composi e had been p e iously
injec ed (Figu e 4e). The employmen o he eu ec ogel in
o he body a eas, such as oden ails, was also es ed
Figu e 4. (a) Fluo escence spec a o he eu ec ogels eGelG3 and eGelG3/CP2. The inse shows a pic u e o he luo escen eu ec ogel eGelG3 when
i is i adia ed wi h a UV lamp a 354 nm. LDH assays o de e mine he (b) cy o oxici y and (c) cell iabili y o he eu ec ogels in con ac wi h iPSC
cells (mean and s anda d de ia ion om n=4). In i o injec abili y o he eu ec ogel composi es in mice a di e en a eas: (d) ea s and (e) he
localized bioimaging luo escence showed by he dashed blue ci cle, ( ) ails and (g) he localized bioimaging luo escence showed by he dashed
blue ci cle. UV exci a ion a 254 nm.
Angewand e
Chemie
Communica ions
Angew. Chem. In . Ed. 2023,62, e202301489 (5 o 7) © 2023 The Au ho s. Angewand e Chemie In e na ional Edi ion published by Wiley-VCH GmbH
15213773, 2023, 26, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/anie.202301489 by Uni e sidad Del Pais Vasco, Wiley Online Lib a y on [28/06/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
(Figu e 4 –g and Videos S1–S2), co obo a ing he localized
bioimaging p ope ies in di e en body issues.
In summa y, mixed ionic/elec onic conduc i e eu ec o-
gel composi es we e success ully o med by combining a
luo escen glu amic acid-de i ed LMWG wi h
PEDOT:ChS and ChCl-based DES. Among di e en DES
es ed, sup amolecula eu ec ogels o med wi h Gly/ChCl
DES showed he bes sel -healing and injec abili y p ope -
ies. The compa ison be ween he ChCl-based eu ec ogels
(eGel) and cholinium-based iongels (iGel) was also ackled,
e ealing he enhanced ionic conduc i i y p ope ies o he
eu ec ogels (�102Scm2) compa ed o iongels (
�103Scm3). The biological es s con i med he non-
cy o oxic p ope ies o he eu ec ogels in con ac wi h iPSC
cells. Fu he mo e, he eu ec ogel composi es we e success-
ully injec ed in subcu aneous local a eas o a s exhibi ing a
localized luo escence, which opens he way o po en ial
minimally in asi e bioimaging applica ions.
Acknowledgemen s
This wo k was suppo ed by Ma ie Sklodowska-Cu ie
Resea ch and Inno a ion S a Exchanges (RISE) unde he
g an ag eemen No 823989 “IONBIKE”. The inancial
suppo ecei ed om CONICET and ANPCyT (A gen i-
na) is also g a e ully acknowledged. M. C.-G. hanks
Emakike G an P og am o POLYMAT. L. C. T. is g a e ul
o Fundação pa a a Ciência e a Tecnologia (FCT/MCTES)
in Po ugal o he esea ch con ac unde Scien i ic
Employmen S imulus (2020.01555.CEECIND), and Asso-
cia e Labo a o y o G een Chemis y—LAQV, which is
also inanced by FCT/MCTES (UIDB/50006/2020 and
UIDP/50006/2020). D. M. hanks “Ayuda RYC2021-031668-
I inanciada po MCIN/AEI/10.13039/501100011033 y po la
Unión Eu opea Nex Gene a ionEU/PRTR”. The au ho s
hank he echnical and human suppo p o ided by SGIke
(UPV/EHU/ERDF, EU).
Con lic o In e es
The au ho s decla e no con lic o in e es .
Da a A ailabili y S a emen
The da a ha suppo he indings o his s udy a e a ailable
om he co esponding au ho upon easonable eques .
Keywo ds: Bioimaging ·Deep Eu ec ic Sol en s ·Ionic
Liquids ·O ganic Mixed Ionic–Elec onic Conduc o s ·
Sup amolecula Eu ec ogels
[1] M. A. R. Ma ins, S. P. Pinho, J. A. P. Cou inho, J. Solu ion
Chem. 2019,48, 962–982.
[2] a) D. Yu, Z. Xue, T. Mu, Chem. Soc. Re . 2021,50, 8596–8638;
b) E. L. Smi h, A. P. Abbo , K. S. Ryde , Chem. Re . 2014,
114, 11060–11082.
[3] A. P. Abbo , G. Cappe , D. L. Da ies, R. K. Rasheed, V.
Tamby ajah, Chem. Commun. 2003, 70–71.
[4] a) F. M. Pe na, P. Vi ale, V. Cap ia i, Cu . Opin. G een
Sus ainable Chem. 2020,21, 27–33; b) M. L. Picchio, D.
Minud i, D. Man ione, M. C iado-Gonzalez, G. Guzmán-
González, R. Schma sow, A. J. Mülle , L. C. Tomé, R. J.
Mina i, D. Mece eyes, ACS Sus ainable Chem. Eng. 2022,10,
8135–8142.
[5] a) A. Pai a, R. C a ei o, I. A oso, M. Ma ins, R. L. Reis,
A. R. C. Dua e, ACS Sus ainable Chem. Eng. 2014,2, 1063–
1071; b) Y. Liu, J. B. F iesen, J. B. McAlpine, D. C. Lankin, S.-
N. Chen, G. F. Pauli, J. Na . P od. 2018,81, 679–690.
[6] a) J. Wang, S. Zhang, Z. Ma, L. Yan, G een Chem. 2021,2,
359–367; b) L. C. Tomé, D. Mece eyes, J. Phys. Chem. B 2020,
124, 8465–8478.
[7] G. Li, Z. Deng, M. Cai, K. Huang, M. Guo, P. Zhang, X. Hou,
Y. Zhang, Y. Wang, Y. Wang, X. Wu, C. F. Guo, npj Flexible
Elec on. 2021,5, 23.
[8] a) M. L. Picchio, A. Gallas egui, N. Casado, N. Lopez-La ea,
B. Ma chio i, I. del Agua, M. C iado-Gonzalez, D. Man ione,
R. J. Mina i, D. Mece eyes, Ad . Ma e . Technol. 2022,7,
2101680; b) H. Zhang, N. Tang, X. Yu, M.-H. Li, J. Hu, Ad .
Func . Ma e . 2022,32, 2206305.
[9] J. Ruiz-Olles, P. Sla ik, N. K. Whi elaw, D. K. Smi h, Angew.
Chem. In . Ed. 2019,58, 4173–4178.
[10] C. Gu, Y. Peng, J. Li, H. Wang, X.-Q. Xie, X. Cao, C.-S. Liu,
Angew. Chem. In . Ed. 2020,59, 18768–18773.
[11] K. Fan, L. Wang, W. Wei, F. Wen, Y. Xu, X. Zhang, X. Guan,
Chem. Eng. J. 2022,441, 136026.
[12] a) B. Zhang, H. Sun, Y. Huang, B. Zhang, F. Wang, J. Song,
Chem. Eng. J. 2021,425, 131518; b) H. Sun, B. Zhang, L. Lu,
Z. Chen, Y. Huo, W. Li, B. Zhang, J. Song, Chem. Eng. J.
2023,451, 139051.
[13] K. Wang, H. Wang, J. Li, Y. Liang, X.-Q. Xie, J. Liu, C. Gu, Y.
Zhang, G. Zhang, C.-S. Liu, Ma e . Ho iz. 2021,8, 2520–2532.
[14] a) B. D. Paulsen, K. Tyb and , E. S a inidou, J. Ri nay, Na .
Ma e . 2020,19, 13–26; b) D. Ohayon, S. Inal, Ad . Ma e .
2020,32, 2001439; c) M. ElMahmoudy, S. Inal, A. Cha ie , I.
Uguz, G. G. Mallia as, S. Sanau , Mac omol. Ma e . Eng. 2017,
302, 1600497.
[15] S. Zhao, A. S. Meh a, M. Zhao, Cell. Mol. Li e Sci. 2020,77,
2681–2699.
[16] a) I. P. E. Macá io, H. Oli ei a, A. C. Menezes, S. P. M.
Ven u a, J. L. Pe ei a, A. M. M. Gonçal es, J. A. P. Cou inho,
F. J. M. Gonçal es, Sci. Rep. 2019,9, 3932; b) M. Pe ko ic, J. L.
Fe guson, H. Q. N. Guna a ne, R. Fe ei a, M. C. Lei ão, K. R.
Seddon, L. P. N. Rebelo, C. S. Pe ei a, G een Chem. 2010,12,
643–649.
[17] T. Jeliński, M. P zybyłek, P. Cysewski, Pha m. Res. 2019,36,
116.
[18] a) B. Co ade i, F. Ta aballi, S. Mina di, J. Van Eps, F.
Cab e a, L. W. F ancis, S. A. Gazze, M. Fe a i, B. K. Weine ,
E. Tascio i, S em Cells T ansl. Med. 2016,5, 670–682; b) M.
Concha, A. Vidal, A. Giacaman, J. Ojeda, F. Pa icic, F. A.
Oya zun-Ampue o, C. To es, M. Cab e a, I. Mo eno-Villos-
lada, S. L. O ellana, J. Biomed. Ma e . Res. Pa B 2018,106,
2464–2471.
[19] N. J. G een ield, Na . P o oc. 2006,1, 2876–2890.
[20] M. C iado-Gonzalez, D. Wagne , J. Rodon Fo es, C. Blanck,
M. Schmu z, A. Chaumon , M. Rabineau, J. B. Schleno , G.
Flei h, J. Combe , P. Schaa , L. Jie y, F. Boulmedais, Chem.
Ma e . 2020,32, 1946–1956.
[21] a) M. C iado-Gonzalez, E. Espinosa-Cano, L. Rojo, F. Boul-
medais, M. R. Aguila , R. He nández, ACS Appl. Ma e .
Angewand e
Chemie
Communica ions
Angew. Chem. In . Ed. 2023,62, e202301489 (6 o 7) © 2023 The Au ho s. Angewand e Chemie In e na ional Edi ion published by Wiley-VCH GmbH
15213773, 2023, 26, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1002/anie.202301489 by Uni e sidad Del Pais Vasco, Wiley Online Lib a y on [28/06/2023]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
In e aces 2022,14, 10068–10080; b) T. Bi man, D. Selik a ,
Ad . Func . Ma e . 2021,31, 2100628.
[22] C. Zeng, H. Zhao, Z. Wan, Q. Xiao, H. Xia, S. Guo, RSC Ad .
2020,10, 28376–28382.
[23] J. Wang, Z. Ma, Y. Wang, J. Shao, L. Yan, Mac omol. Rapid
Commun. 2021,42, 2000445.
[24] H. He, J. Ouyang, Acc. Ma e . Res. 2020,1, 146–157.
[25] N. Lopez-La ea, M. C iado-Gonzalez, A. Dominguez-Al a o,
N. Aleg e , I. d. Agua, B. Ma chio i, D. Mece eyes, ACS
Appl. Polym. Ma e . 2022,4, 6749–6759.
[26] M. Be gg en, X. C ispin, S. Fabiano, M. P. Jonsson, D. T.
Simon, E. S a inidou, K. Tyb and , I. Zozoulenko, Ad .
Ma e . 2019,31, 1805813.
[27] a) A. G. Guex, J. L. Pue ze , A. A mga h, E. Li mann, E.
S a inidou, E. P. Giannelis, G. G. Mallia as, M. M. S e ens,
Ac a Bioma e . 2017,62, 91–101; b) S. Wang, C. Sun, S. Guan,
W. Li, J. Xu, D. Ge, M. Zhuang, T. Liu, X. Ma, J. Ma e .
Chem. B 2017,5, 4774–4788.
[28] A. Dominguez-Al a o, M. C iado-Gonzalez, E. Gabi ondo, H.
Lasa-Fe nández, J. L. Olmedo-Ma ínez, N. Casado, N. Ale-
g e , A. J. Mülle , H. Sa don, A. Vallejo-Illa amendi, D.
Mece eyes, Polym. Chem. 2022,13, 109–120.
Manusc ip ecei ed: Janua y 30, 2023
Accep ed manusc ip online: May 2, 2023
Ve sion o eco d online: May 15, 2023
Angewand e
Chemie
Communica ions
Angew. Chem. In . Ed. 2023,62, e202301489 (7 o 7) © 2023 The Au ho s. Angewand e Chemie In e na ional Edi ion published by Wiley-VCH GmbH
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