gels
Re iew
Biomedical Applica ion, Pa en Reposi o y, Clinical T ial and
Regula o y Upda es on Hyd ogel: An Ex ensi e Re iew
S adhanjali Mohapa a 1,†, Mohd. Aami Mi za 1,† , Ayah Rebhi Hilles 2, Foziyah Zaki 3,
And eia Cas o Gomes 4,5 , Mohammad Ja ed Ansa i 6, Zeena Iqbal 1,* and Syed Mahmood 7,8,*


Ci a ion: Mohapa a, S.; Mi za, M.A.;
Hilles, A.R.; Zaki , F.; Gomes, A.C.;
Ansa i, M.J.; Iqbal, Z.; Mahmood, S.
Biomedical Applica ion, Pa en
Reposi o y, Clinical T ial and
Regula o y Upda es on Hyd ogel: An
Ex ensi e Re iew. Gels 2021,7, 207.
h ps://doi.o g/10.3390/gels7040207
Academic Edi o s: Esmaiel Jabba i
and Mohsen Akba i
Recei ed: 5 Sep embe 2021
Accep ed: 8 No embe 2021
Published: 12 No embe 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
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dis ibu ed unde he e ms and
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A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
1Depa men o Pha maceu ics, School o Pha maceu ics Educa ion and Resea ch (SPER), Jamia Hamda d,
New Delhi 110062, India; [email p o ec ed] (S.M.); [email p o ec ed] (M.A.M.)
2
In e na ional Ins i u e o Halal Resea ch and T aining (INHART), In e na ional Islamic Uni e si y Malaysia,
Kuala Lumpu 53100, Malaysia; [email p o ec ed]
3Depa men o Pha maceu ics, School o Pha maceu ical Sciences, Delhi Pha maceu ical Sciences and
Resea ch Uni e si y, New Delhi 110017, India; [email p o ec ed]
4Cen e o Molecula and En i onmen al Biology (CBMA), Uni e sidade do Minho, Campus de Gual a ,
4710-057 B aga, Po ugal; [email p o ec ed]
5
Ins i u e o Science and Inno a ion o Bio-Sus ainabili y (IB-S), Uni e sidade do Minho, Campus de Gual a ,
4710-057 B aga, Po ugal
6Depa men o Pha maceu ics, College o Pha macy, P ince Sa am Bin Abdulaziz Uni e si y,
Alkha j 11942, Saudi A abia; [email p o ec ed]
7Depa men o Pha maceu ical Technology, Facul y o Pha macy, Uni e si i Malaya,
Kuala Lumpu 50603, Malaysia
8Cen e o Na u al P oduc s Resea ch and D ug Disco e y (CENAR), Uni e si i Malaya,
Kuala Lumpu 50603, Malaysia
*Co espondence: [email p o ec ed] (Z.I.); [email p o ec ed] (S.M.)
† Au ho s sha e equal con ibu ion.
Abs ac :
Hyd ogels a e known o hei leading ole in bioma e ial sys ems in ol ing pha maceu i-
cals ha ascina e ma e ial scien is s o wo k on he wide a ie y o biomedical applica ions. The
physical and mechanical p ope ies o hyd ogels, along wi h hei biodeg adabili y and biocompa i-
bili y cha ac e is ics, ha e made hem an a ac i e and lexible ool wi h a ious applica ions such
as imaging, diagnosis and ea men . The wa e -che ishing na u e o hyd ogels and hei capaci y
o swell—con ingen upon a ew ecological signals o he simple p esence o wa e —is allu ing
o d ug con eyance applica ions. Cu en ly, he e a e se e al p oblems ela ing o d ug deli e y,
o which hyd ogel may p o ide a possible solu ion. Hence, i is pe inen o colla e upda es on
hyd ogels pe aining o biomedical applica ions. The p ima y objec i e o his e iew a icle is o
ga ne in o ma ion ega ding classi ica ion, p ope ies, me hods o p epa a ions, and o he polyme s
used wi h pa icula emphasis on injec able hyd ogels. This e iew also co e s he egula o y and
o he comme ce speci ic in o ma ion. Fu he , i enlis s se e al pa en s and clinical ials o hyd o-
gels wi h ela ed indica ions and o e s a consolida ed esou ce o all ace s associa ed wi h he
biomedical hyd ogels.
Keywo ds: hyd ogel; bioma e ial; pa en s; injec able; egula o y; d ug deli e y
1. In oduc ion
Hyd ogels a e polyme ic ma ices ha ing a h ee-dimensional con igu a ion ha
abso b wa e and unde go swelling bu do no dissol e (sho e m) and acili a e he
con olled d ug- elease in o ou body [
1
]. The high he modynamic a ini y o his class
o ma e ials owa ds he sol en is con ibu ed owa ds i s swelling p ope y. They bea
a physical esemblance o li ing issues because o hei signi ican wa e con en and
consis ency. The e is also a unique ype o hyd ogel, called as in elligen gels o sma
gels. They can pe cei e he s imuli and espond by exhibi ing changes in hei physical o
chemical beha io s and subsequen elease o he en apped d ug. Hyd ogels a e widely
Gels 2021,7, 207. h ps://doi.o g/10.3390/gels7040207 h ps://www.mdpi.com/jou nal/gels
Gels 2021,7, 207 2 o 32
explo ed as a ool o biomedical applica ions due o hei abili y o o m c osslink unde
mild condi ions coupled wi h high e sa ili y, excellen biocompa ibili y, and pe meabili y
o oxygen, nu ien and unable ma e ial’s p ope ies.
Hyd ogels can be delega ed as a ool ha mee s he pa icula necessi ies o ocus on
he medica ion o he speci ic egion and con ol i s elease. P ope ies o a hyd ogel such
as hyd oly ic, enzyma ic and ecological play a ole o con ol he deli e y o medica ion
wi h he desi ed objec i es such as ex ending hei d ug elease p o ile, and expanding he
choice o medicamen s di e en d ug deli e y applica ions [
2
]. The hyd ophilic unc ional
g oups a ached o he polyme ic backbone o hyd ogels a e esponsible o hei a ini y
o abso b wa e . C osslinking be ween he ne wo k chains is answe able o i s esis ance
o dissolu ion [
3
]. Bo h na u al and syn he ic ma e ials can be used in he p epa a ion o
hyd ogels. Syn he ic hyd ogels ha e eplaced hei na u al coun e pa s om he las ew
decades due o hei high wa e -abso bing capaci y, long shel li e, high gel s eng h, and
be e s abili y p o ile in sha p luc ua ing empe a u es. Again, well-de ined s uc u es o
syn he ic polyme s can be modi ied o yield ailo -able unc ionali y and deg adabili y [
4
].
Hyd ogel has a long his o y o e olu ion and has been epo ed upon wi h di e se
classi ica ions. The e m hyd ogel was ini ially coined in he yea 1894 by Van Bemme-
len [
5
]. The i s -e e syn he ic hyd ogel poly(2-hyd oxye hyl me hac yla e) (pHEMA) was
syn hesized by scien is s DuPon in 1936, and he i s d ug deli e y hyd ogel Ce idil
®
o ce ical ipening was launched in 1995 [5]. Since hen, con inuous esea ch and de el-
opmen in hyd ogel has led o a o al o 329, 350 pa en s iled un il oday. Howe e , he
i s gene a ion o hyd ogels aimed a de eloping a e ac wi h high swelling and good
mechanical p ope ies wi h ela i ely simple a ionale. I comp ises chemical modi ica ions
o a monome o polyme wi h an ini ia o by in ol ing many c oss-linking p ocedu es.
In compa ison, he second gene a ion o hyd ogel can p oduce a esponse conce ning
speci ic s imuli, such as a ia ions in empe a u e, p essu e, ligh , magne ic ields, elec ical
ields, pH o concen a ion o speci ic molecules in solu ion. These speci ic s imuli can be
exploi ed o igge speci ic e en s. Howe e , he hi d gene a ion o hyd ogels ocusing on
he s udy and de elopmen o s e eo complexed ma e ials (e.g., PEG-PLA in e ac ion) [
6
,
7
]
o o med by c osslinking due o o he physical in e ac ions [
8
,
9
]. Nowadays, esea ch
ocuses on de eloping he so-called “sma hyd ogels”, polyme ic ma ices ha ing a b oad
spec um o unable p ope ies. Ne e heless, he e a e se e al di icul ies associa ed wi h
u ilizing hyd ogels such as hyd ophobici y o he ac i e ing edien s, which may c ea e
p oblems du ing medica ion con eyance du ing ea men . The wa e -che ishing poly-
me ic cen e is mos likely no an ideal si e o hold incong uen hyd ophobic medica ions.
O he hyd ogels ha e ail elas ici y, which occasionally causes ea ly a i al o he medi-
ca ion be o e landing a he objec i e si e. In ecen yea s, esea ch on hyd ogel has been
con inuously inc eased which can be e iden om he Figu e 1. Fu he , hese s a is ics
e eal a many old inc ease in he numbe o pa en publica ions ela ed o he injec able
hyd ogel as compa ed o hyd ogel om he las wo decades.
Hyd ogel con olled medica ion deli e s he ac i e cons i uen by u ilizing amewo k
gadge s ha pe mi di usion o medica ion and discha ge h ough a c oss-sec ion (po es)
ha a e loaded up wi h wa e . In he supply deli e y amewo k, he hyd ogel ilm is
co e ed on a medica ion con aining cen e , c ea ing sec ions, cases and ci cles o ha ing a
high medica ion ocus on he ocal poin o he amewo k o encou age a s eady medica ion
discha ge a e. While he supply deli e y amewo k p oduces ime- ee and consis en
medica ion discha ge using he mac omolecula la ice. La ice deli e y is ime-subo dina e
medica ion discha ge in which he unde lying deli e y a e is ela i e o he squa e base o
ime ins ead o being s eady. The d ugs a e dispe sed in a polyme , and when hey come
in o con ac wi h wa e o bio- luid hey will begin o swell. Du ing swelling, i will expand,
which will ease he sp ead o he d ug along wi h he elaxa ion o he polyme chain
ha suppo s ime-independen and cons an d ug elease kine ics. The ac i e ing edien
di uses om he dispe sed d ug ha ing a highe concen a ion wi hin he hyd ogel o
i s su ounding en i onmen wi h lowe concen a ion due o he concen a ion g adien .
Gels 2021,7, 207 3 o 32
This me hod combines bo h he p ocesses o di usion and swelling o enabling d ug
elease [10].
1
Figu e 1.
His og am ep esen ing he published pa en s ela ed wi h he hyd ogels (
A
); and injec able
hyd ogels (B).
The ollowing ma hema ical model can explain he p ocess o swelling o a hyd ogel
ma ix:
dc/d = ∆D( )∆c−∆(cu) (1)
whe e, dc/d = change in concen a ion wi h ime,
c = concen a ion o d ug in he hyd ogel
D( ) = di usion coe icien
∆c = concen a ion g adien
u = swelling capaci y o he hyd ogel.
Gels 2021,7, 207 4 o 32
The di usion p ocess is go e ned by Fick’s law o di usion which s a es ha di usion
occu s om a egion o high concen a ion o he low concen a ion:
dc/d = χd2c/dx2 (2)
whe e χ= di usi i y,
= ime
x = dimension (in leng h)
Hyd ogels signi ican ly imp o e he emedial esul o medica ion con eyance and
ha e disco e ed gigan ic clinical use. The wo ldly and h ee-dimensional con eyance o
mac omolecula medica ions ha e ex ao dina ily imp o ed h ough hyd ogel used o
d ug deli e y [
2
]. E en hough medica ion con eyance u ilizing hyd ogels has no been
libe a ed om di icul ies, consis en upg ades a e being made o dis inguish he hyd ogel
con igu a ion mos app op ia e o explici medica ion deli e y pu poses. Howe e , hy-
d ogels ha e ecen ly d awn g ea a en ion o use in a di e si ied biomedical ield o
a ious applica ions such as he sus ained elease o ac i e medicamen s, cell he apeu ics,
cosme ics use, issue egene a ion and wound healing, e c. The ollowing igu e, Figu e 2,
illus a es he applica ion o a ious hyd ogels used in di e en body pa s o humans.
Gels 2021, 7, x FOR PEER REVIEW 5 o 36
Figu e 2. Applica ions o hyd ogels in di e en human body pa s.
This e iew b ings oge he di e en aspec s o he hyd ogel, such as classi ica ion,
p ope ies, p epa a ion me hods, he polyme used, and applica ions in he biomedical
ield. I speci ically elabo a es he injec able hyd ogels enlis ing hei o mula ions o mi -
iga ing diseases. Fu he , i emphasizes on he egula o y aspec s o comme cial hyd ogel
highligh ing he in o ma ion ela ed o ce ain ing edien s. Addi ionally, i encompasses
se e al pa en s, clinical ials and exis ing comme cial hyd ogel p oduc s wi h ela ed in-
dica ions. This e iew may ac as a esou ce o he hyd ogel sys em conce ning he bio-
medical a ea co e ing all he essen ial aspec s and may pa e he way o conduc u u e
esea ch in his pa icula ield.
2. Classi ica ion o Hyd ogel-Based Sys em
The e a e se e al opinions ound in he li e a u e conce ning he classi ica ion o hy-
d ogel. They may be classi ied on he basis o he sou ce om which hey a e ob ained,
physical p ope ies, s uc u es, c osslinking p esen , he ionic cha ge on bound g oups,
p epa a ion me hods and s imuli gi en o p oduce a speci ic esponse. Based on he
abo e, he classi ica ion o he hyd ogels a e shown in Figu e 3.
Figu e 2. Applica ions o hyd ogels in di e en human body pa s.
Gels 2021,7, 207 5 o 32
This e iew b ings oge he di e en aspec s o he hyd ogel, such as classi ica ion,
p ope ies, p epa a ion me hods, he polyme used, and applica ions in he biomedical
ield. I speci ically elabo a es he injec able hyd ogels enlis ing hei o mula ions o mi i-
ga ing diseases. Fu he , i emphasizes on he egula o y aspec s o comme cial hyd ogel
highligh ing he in o ma ion ela ed o ce ain ing edien s. Addi ionally, i encompasses
se e al pa en s, clinical ials and exis ing comme cial hyd ogel p oduc s wi h ela ed
indica ions. This e iew may ac as a esou ce o he hyd ogel sys em conce ning he
biomedical a ea co e ing all he essen ial aspec s and may pa e he way o conduc u u e
esea ch in his pa icula ield.
2. Classi ica ion o Hyd ogel-Based Sys em
The e a e se e al opinions ound in he li e a u e conce ning he classi ica ion o
hyd ogel. They may be classi ied on he basis o he sou ce om which hey a e ob ained,
physical p ope ies, s uc u es, c osslinking p esen , he ionic cha ge on bound g oups,
p epa a ion me hods and s imuli gi en o p oduce a speci ic esponse. Based on he abo e,
he classi ica ion o he hyd ogels a e shown in Figu e 3.
Figu e 3. Classi ica ion o hyd ogel-based sys ems.
3. Polyme s Used o Fab ica ing Hyd ogel
Na u al polyme s a e usually composed o componen s o p o eins and ex acellula
ma ix o de i a i es o na u al ma e ials such as algina e, chi osan and skill ibe s which
makes hem inhe en ly bioac i e, biodeg adable, biocompa ible, non oxic and p omo e
many cellula unc ions o di e en biomedical applica ions. The wo d awbacks associ-
a ed wi h na u al hyd ogels a e ha hey ha e poo mechanical p ope ies. Addi ionally, i
is unclea abou he co ela ion be ween he mechanical p ope ies and polyme iza ion o
gela ion condi ions. Fu he , hey o e di icul y in being manipula ed as hey ha e a high
ba ch a ia ion ha may lead o poo ep oducibili y. In con as , syn he ic hyd ogels a e
mo e ep oducible, al hough hei inal s uc u e can also depend on polyme iza ion condi-
ions, demanding igo ous con ol o he p epa a ion p o ocol. So, i can be concluded ha
syn he ic hyd ogels o e mo e lexibili y o al e ing chemical composi ion and mechani-
cal p ope ies han na u al coun e pa s and a e mo e p e alen . A ew commonly used
na u al and syn he ic polyme s o hyd ogels a e enlis ed in he ollowing Table 1[11,12].

Gels 2021,7, 207 6 o 32
Table 1. Polyme s commonly used in a ious hyd ogel o mula ions.
Na u al Polyme Syn he ic Polyme Hyb id Polyme
Hyalu onic acid PEG-PLA-PEG P (PEG-co-pep ides)
Pec in PEG-PLGA-PEG P-(HPMA-g-pep ide)
Alginic acid PEG-PCL-PEG P (PLGA-co-se ine)
Ca ageenan PLA-PEG-PLA Algina e-g-(PEO-PPO-PEO)
Chond oi in sulpha e PHB HA-g-NIPAAm
Dex in sulpha e P (PEG/PBO e eph hala e) Collagen-n-ac yl a e
Chi osan Polyu e hane Algina e-ac yl a e
Polylysine Polyimide
Collagen (and gela ine) Poly inylpy olidone
Ca boxy me hylchi in Poly inyl alcohol
Fib in and silk ib oin Polyac yla e
Dex in Poly hene oxide
Pullulan Polyme hac yla e
Aga ose
Elas in
Glycosaminoglycans
Decellula ized Hyd ogels
4. P ope ies o Hyd ogel
I is impe a i e o ha e a basic unde s anding o he gel p ope ies so ha a sui able
gel deli e y sys em can be designed. The in e ac ions be ween he gel and he solu e
molecules can be be e unde s ood a e s udying he ollowing p ope ies.
4.1. Swelling
Hyd ogels a e c osslinked mac omolecula polyme ic ne wo ks ha can swell in a
liquid medium. The swelled polyme ac s as a il e which allows pa ial di usion o
solu e molecules. The polyme ne wo k is able o e ain he sol en by o ming a gel and
will no dissol e i c osslinked. The p esence o a hyd ophilic unc ional g oup a ached
o he backbone and he di e ence in he osmo ic p essu e be ween he gel phase and
he sol en phase is esponsible o wa e abso p ion by he hyd ogel. In hyd ogel, he
p esence o wa e de e mines he o e all pe mea ion o nu ien s in and ou om he
gel. The mo esponsi e hyd ogels a e one o he o he ca ego ies o hyd ogels ha ing
high biomedical in e es . A oom empe a u e hese appea as luid bu con e in o
iscous gel as hey ge exposed o he body empe a u e, which leng hens hei s aying
ime, hence p olonging hei elease a e. They ha e he abili y o unde go phase ansi ion
o swell/deswell a ambien al e a ion o empe a u e. Concen a e solu ion o poloxame
wi h wa e is one good example o he mo e e sible gel widely used o issue enginee ing
applica ions nowadays [
13
,
14
]. Fu he , he a e and deg ee o swelling, con ols he elease
pa e ns o d ugs and sol en s om hyd ogel polyme ic ne wo ks.
Resea che s use se e al me hods o de e mine he ela i e ee and bound wa e
con en s wi h espec o o al wa e con en . I indica es he swelling p ope y o he
hyd ogel. Some o he common echniques used o ou ine in es iga ion o wa e con en
in hyd ogels a e: small molecula p obes, DSC and p o on NMR. Addi ionally, e alua ion
o swelling p ope ies o he hyd ogel se es as a measu e o many o hei p ope ies
such as mechanical p ope ies, deg ee o c osslinking, a e o deg ada ion and many
mo e. E alua ion o he swelling and swollen s a e s abili y may help dis inguish be ween
c osslinked gels and he non-c osslinked o iginal polyme [15,16].
4.2. Mechanical P ope ies
Gene ally, he mechanical p ope y o hyd ogel is linked o hei wa e con en s and
c oss linking densi y. The s i ness o he gel can be inc eased by inc easing he deg ee o
c osslinking o can be dec eased by hea ing he ma e ial. An ideal hyd ogel should be
mechanically obus wi h apid di usion and esponse a e. The mechanical p ope ies can
Gels 2021,7, 207 7 o 32
be changed by a wide ange o a iables and causes, so i should be analyzed based on he
aim o he s udy, ypes o ma e ial and he condi ion, e c. The mechanical p ope ies o he
hyd ogel can be de e mined by ex u e p o ile analyze o a heome e by calcula ing young
modulus, Poisson modulus, s o age and loss moduli, e c. Cu en ly, mo e e o s ha e been
made o cons uc hyd ogels wi h subs an ial mechanical pe o mance. Double-ne wo k,
opological, nanocomposi e, mac omolecula mic osphe e composi e and sup amolecula
hyd ogels a e among he success ul s a egies o ab ica ing high-s eng h hyd ogel. These
a e p omising mul i unc ional ma e ials ha ing su icien and obus mechanical p ope ies
ha can be used success ully as issue enginee ing sca olds. The deg ee o s i ness o
he hyd ogel is de e mined based on i s applica ion a ea, i.e., whe e i has o be applied.
Fo example, o seed os eoblas cells, a mo e igid ma e ial is equi ed han o cul u ing
adipocy es [
17
]. Howe e , ma e ials cha ac e iza ion, ensile and comp essi e es s a e
basic me hods o mechanical pe o mance e alua ion [18,19].
4.3. Po osi y and Pe mea ion
This is ano he impo an p ope y ha can simply indica e he p esence o a oid
ca i y inside he bulk. The e may exis smalle po es wi hin he ne wo k o may be
o med in hyd ogels du ing syn hesis (by phase sepa a ion). I is bene icial o con ol he
po osi y o se e al applica ions, such as he unable elease o mac omolecules, op imal cell
mig a ion in hyd ogel-based sca olds, e c. I has been ound ha po osi y is a signi ican
ac o ha in luences he swelling and d ug elease beha io o he hyd ogels [
20
]. The
p esence o a po ous s uc u e imp o es he d ug elease while non-po ous hyd ogels led
o a e y slow elease. Addi ionally, he p esence o po es can help in sus ain elease d ugs
o p olonged pe iods o ime [21].
Po osi y can be assessed by heo e ical me hods, such as liquid displacemen me hod,
A chimedes me hod, e c., wi h he use o op ical and elec onic mic oscopy. Some o he
me hods such as gas pycnome e me hod, gas adso p ion, capilla y low po osi y ha e
also been epo ed. One o he o he impo an assays is X- ay mic o omog aphy [
22
].
Mic oscopy is ano he echnique ha can be used in assays in ol ing hyd ogels by which
su ace mo phology and opog aphy can be assessed. I in ol es he use o op ical mi-
c oscope, scanning elec on mic oscope (SEM), ansmission elec on mic oscope (TEM),
unnelling mic oscope, a omic o ce mic oscopy (AFM) [
23
]. Addi ionally, he mopo ome-
y helps o de e mine po e size based on mel ing o c ys alliza ion poin o wa e molecules
con ined in o he po es o hyd ogels. I has ad an ages o e o he echniques, as i analyzes
he sample in d ied s a e [
24
–
26
]. I is based on analyzing he he modynamic beha io o
wa e ela ing o i s in e ac ion wi h polyme s and p o ide a ange o po e sizes in nano
scale [27].
4.4. C osslinking
Al hough c osslinking is no a basic p ope y o hyd ogels, i a ec s all he o he
ma e ial p ope ies. I has some impo an cha ac e is ics, as i makes he hyd ogel mechan-
ically s ong, and hea and e osion esis an . I may in luence he heological pa ame e s,
hyd a ion and di usion h ough skin [
28
]. The deg ee o c osslinking can be in e connec ed
o e e y cha ac e is ic o a hyd ogel, howe e he na u e o c osslinking can a y a lo . The
hyd ogel’s ne wo k can be ob ained in many di e en ways such as physical c osslinking
(by complex coace a ion o ionic in e ac ion), chemical c osslinking ia c osslinke o
by adia ion c osslinking. By egula ing he deg ee o c osslinking, we can con ol he
p ope y o he ma e ial and can op imize i o nume ous applica ions om he same
o iginal polyme [
29
,
30
]. Howe e , he e a e se e al disad an ages such as ela i ely
in lexibili y in hei p ocessing p ope ies as hey a e insoluble and in usible [31].
5. Me hod o P epa a ion
Usually, hyd ogels a e p epa ed om hyd ophilic monome s, bu some imes hy-
d ophobic monome s a e also used o achie e ce ain desi able a ibu es. Syn he ic
Gels 2021,7, 207 8 o 32
polyme s a e hyd ophobic and used o p o ide mechanical s eng h and du abili y o
he hyd ogels. The main componen s o ab ica e hyd ogels a e monome , c oss linke
and ini ia o , along wi h wa e ha ac s as diluen o egula e he hea o he eac ion.
C osslinking eac ions in hyd ogel can occu ia di e en me hods, such as u ilizing eac-
ion and ionizing adia ion o p oduce ee adicals ha ecombine, c ea ing c oss-links,
en anglemen s, elec os a ics, and c ys alline o ma ion.
Hyd ogels a e de i ed om pola monome s and unde go c osslinking eac ions by
linking polyme chains o o m ne wo ks. Such al e a ions can imp o e he mechanical
p ope ies and iscoelas ici y o nume ous biomedical applica ions in he pha maceu ical
ields. The gene al me hods o p oduce physical and chemical gels a e summa ized
in Figu e 4[32].
Gels 2021, 7, x FOR PEER REVIEW 9 o 36
p ope ies and iscoelas ici y o nume ous biomedical applica ions in he pha maceu i-
cal ields. The gene al me hods o p oduce physical and chemical gels a e summa ized in
Figu e 4 [32].
Figu e 4. Di e en me hods o p epa a ion o hyd ogel.
6. Applica ions o Hyd ogel
Due o i s e sa ili y and lexibili y, hyd ogel possesses di e si ied applica ions such
as biomedical, ag icul u e, sani a y diape s, dyes emo al, hea y me al ions emo al, bi-
osenso s, pH-senso s, and supe -capaci o s, e c. [33]. The ollowing sec ion includes bio-
medical applica ions o hyd ogels in a eas o cosme ic echnology, wound healing, con ac
lenses, d ug deli e y, and issue enginee ing, e c. [12,34]. Figu e 5 men ions he biomedi-
cal applica ions o hyd ogel. Fu he , his sec ion includes a lis o pa en s and clinical
ials (Tables 2 and 3) ela ed o a ious hyd ogel o mula ions, which gi e an idea abou
he cu en esea ch conduc ed in his a ea.
Table 2. Lis o Pa en o a ious hyd ogel o mula ion.
S. No.
Pa en No./Coun y
Ti le
Disease/P oblem
De ails
1
US10799696B2
Uni ed S a es
Polyme o mula ions
o nasolac imal s im-
ula ion
D y eye
The hyd ogel o mula ion (p epa ed by a UV
c osslinking p ocess) pe mi s elec ical s imula-
ion o he lac imal gland, nasal o sinus issue o
↑ p oduc ion o ea and o ea d y eye
2
US20200085733A1
Uni ed S a es
Hypo onic hyd ogel
o mula ions o en-
hanced anspo o
ac i e agen s a mu-
cosal su aces
Adminis e ed in o agina
o colo ec um o diag-
nos ic, p ophylac ic and
he apeu ic pu pose
An aqueous polyme ic hyd ogel (poloxame s)
used as a ba ie by o ming plug and/o used
o he deli e y o a mucosal/epi helial su ace
o he apeu ic, p e en i e, diagnos ic o
nu aceu ical pu pose
3
US20200114010A1
Uni ed S a es
P
Non-injec able hyd o-
gel o mula ions o
sma elease
The o mula ion con ains
an i-in lamma o ies, an i-
in ec i es, o o he he a-
peu ic, p ophylac ic, o
diagnos ic agen s ha can
be adminis e ed o ally o
p oduce desi e ac ion
A non-injec able o mula ion/ o mula ion o in-
s illa ion, wi h sel -assembling hyd ogels de-
signed o gela o s, in he o m o capsules, ab-
le s, o al suspensions, ec al o aginal supposi-
o ies, enemas, and inse s
Figu e 4. Di e en me hods o p epa a ion o hyd ogel.
6. Applica ions o Hyd ogel
Due o i s e sa ili y and lexibili y, hyd ogel possesses di e si ied applica ions such
as biomedical, ag icul u e, sani a y diape s, dyes emo al, hea y me al ions emo al,
biosenso s, pH-senso s, and supe -capaci o s, e c. [
33
]. The ollowing sec ion includes
biomedical applica ions o hyd ogels in a eas o cosme ic echnology, wound healing,
con ac lenses, d ug deli e y, and issue enginee ing, e c. [
12
,
34
]. Figu e 5men ions he
biomedical applica ions o hyd ogel. Fu he , his sec ion includes a lis o pa en s and
clinical ials (Tables 2and 3) ela ed o a ious hyd ogel o mula ions, which gi e an idea
abou he cu en esea ch conduc ed in his a ea.
Gels 2021,7, 207 9 o 32
Gels 2021, 7, x FOR PEER REVIEW 15 o 36
Figu e 5. Possible biomedical applica ions o hyd ogel.
6.1. Cosme ics Applica ions
Skin is he la ges o gan ha ac s as a physical and chemical ba ie and p o ec s he
body. F om he cosme ic poin o iew, skin is esponsible o ex e nal appea ance and is
usually ea ed wi h cosme ic p epa a ions. Skin condi ion depends on se e al ac o s,
among which hyd a ion o he skin is c i ical in main aining i s appea ance and ex u e
[35]. When he skin ba ie is damaged, ei he due o clima ic condi ions and pollu ion o
na u al ageing ( he gene ic ac o s and pho o-aging) i demands econdi ioning. Fo his
pu pose, a ange o mois u ize s o e-es ablish he skin p ope ies and ba ie unc ions
can be used. S a um co neum (uppe laye o he skin) can be ehyd a ed by h ee mech-
anisms such as by using humec an s, occlusi e and hyd ophilic ma ices. Nowadays, hy-
d ogel is widely exploi ed in he cosme ics indus ies due o p ope ies such as high wa e
e en ion, biocompa ibili y, elas ici y and so ness [36]. These a e mainly employed o
skin hyd a ion, w inkles, pigmen a ion, celluli e and ageing, e c. Cosme ically hese a e
mainly applied opically on skin, hai , and also used in o al ca e. Bioadhesi e hyd ogels
a e used o skinca e pu poses as hey ha e ad an ages, such as long esidence imes on
he si e o applica ion which ul ima ely educes adminis a ion equency. Ac yla e-based
hyd ogel, due o i s supe abso ben p ope ies, is highly exploi ed o p epa e hygiene
p oduc s ha can abso b luids and keep mois u e away om he skin, p e en ing diape
ash, p omo ing hygiene, and p o iding com o .
6.2. Wound D essings
Human skin has a unique po en ial o sel - egene a ion, owing o his, skin de ec s
can heal spon aneously bu i he de ec is measu ing mo e han a ce ain diame e , hen
i equi es skin ansplan a ion. Mo eo e , he wound healing p ocess is impai ed in some
pa ien s due o a ious condi ions ha lead o ch onic wounds, which ul ima ely esul in
d as ic condi ions o e en mo ali y [37]. Hyd ogels a e he mos p omising app oach in
wound healing amongs a ious wound d essings polyme ic ma e ials such as gauzes,
Figu e 5. Possible biomedical applica ions o hyd ogel.
Table 2. Lis o Pa en o a ious hyd ogel o mula ion.
S. No. Pa en No./Coun y Ti le Disease/P oblem De ails
1US10799696B2
Uni ed S a es
Polyme o mula ions
o nasolac imal
s imula ion
D y eye
The hyd ogel o mula ion (p epa ed by
a UV c osslinking p ocess) pe mi s
elec ical s imula ion o he lac imal
gland, nasal o sinus issue o ↑
p oduc ion o ea and o ea d y eye
2US20200085733A1
Uni ed S a es
Hypo onic hyd ogel
o mula ions o
enhanced anspo o
ac i e agen s a
mucosal su aces
Adminis e ed in o
agina o colo ec um
o diagnos ic,
p ophylac ic and
he apeu ic pu pose
An aqueous polyme ic hyd ogel
(poloxame s) used as a ba ie by
o ming plug and/o used o he
deli e y o a mucosal/epi helial su ace
o he apeu ic, p e en i e, diagnos ic
o nu aceu ical pu pose
3US20200114010A1
Uni ed S a es
Non-injec able
hyd ogel o mula ions
o sma elease
The o mula ion
con ains an i-
in lamma o ies,
an i-in ec i es, o
o he he apeu ic,
p ophylac ic, o
diagnos ic agen s ha
can be adminis e ed
o ally o p oduce
desi e ac ion
A non-injec able
o mula ion/ o mula ion o ins illa ion,
wi h sel -assembling hyd ogels
designed o gela o s, in he o m o
capsules, able s, o al suspensions,
ec al o aginal supposi o ies, enemas,
and inse s
4US20180023049A1
Uni ed S a es
Syn he ic pep ide
hyd ogel o mula ions
o use as
ex acellula ma ix
Cell cul u e
expe imen a ion
Syn he ic pep ide hyd ogel solu ions
ha ing a pH le el o abou 3.5/< and
ha ing a onici y wi hin an iso onic
osmolali y ange
5US20200360281A1
Uni ed S a es
A he mo- esponsi e
hyd ogel o
in e umo al
adminis a ion as a
ea men in solid
umo cance s
In a umo al ea men
o solid cance
Injec able he mo- esponsi e hyd ogel
o ming a chi osan and genipin
in e pene a ing sca old by c osslinking
can e ec i ely inco po a e
chemo he apeu ic d ugs wi hou any
loss o he mo- esponsi eness
Gels 2021,7, 207 16 o 32
inc eased ea men cos s; hus, limi ing hei clinical uses. Injec able hyd ogels can o e -
come such disad an ages in biomedical applica ions wi h minimal in asi eness in o a ge
si es. These hyd ogels can be exploi ed as a p omising and e icacious ma e ial sys em o
many applica ions in he medical ield, such as ea men o cance s, in lamma o y and
in ec ious diseases; deli e y o d ugs, cells, and bioac i e molecules and applica ions in he
epai and egene a ion o issues such as skin, muscles, bone and ca ilage [
48
].
Table 4
enlis s a ious injec able hyd ogels wi h biomedical applica ions.
Injec able hyd ogels in ol e he sol–gel ansi ion p oduced by c oss-linking. Fo
solu ions o a polyme /monome wi h he apeu ic agen s ha ha e low iscosi y when
adminis a ed o a desi ed si e in he body, a hyd ogel loaded wi h a he apeu ic agen
can be o med by c osslinking eac ion ha has a compa a i ely highe iscosi y, called
a gel s a e. The polyme s in he hyd ogel o m a c oss-link by chemical o physical
in e ac ions which a e esponsible o phase ansi ion om solu ion o gel s a e. The sol-
gel phase ansi ion is sensi i e o changes in pH, empe a u e, ligh , enzymes, ul asounds,
e c. [
49
–
51
]. Physical c osslinking occu s due o elec os a ic ionic and hyd ogen bond
in e ac ions,
π
-in e ac ions, hyd ophobic in e ac ions, Van de Waals o ces, e c. In con as ,
chemical c osslinking occu s due o Schi base eac ions, Diels-Alde eac ions, pho o
polyme iza ions, Michael addi ions, enzyme-media ions, e c.
Recen ly, he deli e y o chemo he apeu ics in he o m o injec able hyd ogels became
a p omising al e na i e o cance / umo managemen wi h biocompa ibili y, enhanced
d ug loading, p olonged and con olled d ug elease, wi h explici s imuli sensi i i y.
Injec able hyd ogel can be used as a lexible ool o each some a eas ha canno be
easily ouched by su ge y. Fu he mo e, hyd ogel can be used as a pla o m o issue
epai ( issue enginee ing [
52
–
54
]) and p e en pos ope a i e umo ecu ence. Injec able
biodeg adable hyd ogels ha can o m gels in si u ha e been widely u ilized o biomedical
applica ions. Addi ionally, hese hyd ogels can be bio unc ionalized by a ge ing moie ies
ha ha e an a ini y o o e exp essed and/o unique umo cell ma ke s o a ge ed d ug
deli e y applica ions [55].
Hyd ogels ha e been used as a subs i u e o con en ional cance he apy, which is
equen ly associa ed wi h a ious ac o s such as unwan ed oxici y o no mal issues,
gigan ic issue loss, and unan icipa ed ecu ence du ing o a e he ea men . Localized
d ug deli e y echniques (such as hyd ogels [
56
], liposomes, nano/mic opa icles
[57–59]
,
micelles
[8,60]
o e localized sus ained elease o he chemo he apeu ic. I esul s in
inc eased e icacy o he ea men wi h minimal issue oxici y by ci cum en ing sys emic
ci cula ion o he chemo he apeu ic agen s. They u he acili a e high d ug loading,
imp o e solubili y, and sus ain d ug elease a he desi e ea men loca ion. Se e al
sys ems ha e been explo ed o his pu pose. The ollowing Figu e 6depic s an o e iew
o injec able hyd ogel.
Table 4. Lis o a ious injec able hyd ogels ha ing biomedical applica ions.
Hyd ogel Ac i e Ing edien Type o Disease In Vi o Cell Line In Vi o Model Conclusion Re e ence
The mosensi i e
chi osan-based Disul i am(DSF) Cance Human HCC cell
lines (SMMC-7721
cells) -
A no el injec able sus ained
o mula ion o an icance
d ugs aimed a he deli e y o
DSF o long- e m
cance ea men
[61]
Dual he mo-and
pH-sensi i e injec able
hyd ogels o
chi osan/(poly(N-
isop opylac ylamide-co-
i aconic acid)
Doxo ubicin B eas cance MCF-7 cells -
Cy ocompa ible and exe
no/negligible cy o oxici y on
MCF-7 cells and has he
po en ial o local he apy o
b eas cance
[62]
pH-sensi i e poly(lac ic
acid-co-glycolic
acid)-b-poly(e hylene
glycol)-b-poly(lac ic
acid-co-glycolic acid)
(PLGA-PEG-PLGA)
iblock copolyme s
He cep in B eas cance - SK-BR-3 umo
bea ing mice
G ea po en ial o p e en ing
he elapse o HER2+ b eas
umo s a e b eas -conse ing
su ge y wi h ↑ he apeu ic
e icacy, ↓side e ec s and ↑
pa ien compliance
[63]

Gels 2021,7, 207 17 o 32
Table 4. Con .
Hyd ogel Ac i e Ing edien Type o Disease In Vi o Cell Line In Vi o Model Conclusion Re e ence
pH-sensi i e injec able-
polysaccha ide-based
sel -healing hyd ogels Doxo ubicin Hepa ocellula
ca cinoma
HepG2( elease o
d ug om hyd ogel)
L929 cells
(Cy o oxici y es o
he hyd ogel)
-
Sel -healing p ope y wi h high
d ug-loading a io could
p olong hei li e ime du ing
implan a ion and p o ide he
bene i o nominally
in asi e su ge y
[64]
Dual pH- and
empe a u e- esponsi e
physically c osslinked
injec able hyd ogel
Cance Oncoly ic
adeno i uses -Human xenog a
umo models
Exhibi ed ↑and long- e m
an i umo he apeu ic e ec s in
umo models and migh ha e
po en ial o long- e m
cance ea men
[65]
No el palladium
nanoshee (Pd
NS)-based chemo-
pho o he malhyd ogel
(Pd Gel)
Palladium and
doxo ubicin Cance - Mouse
A no el an icance s a egy ha
allows he elease o
doxo ubicin mo e p ecisely,
elimina e umo mo e
e icien ly and inhibi umo
me as asis mo e pe sis en ly
[66]
ABA iblock
copolyme s o i amin
D- unc ionalized
polyca bona e and
poly(e hylene glycol),
ha is, VDm-PEG-VDm
we e syn hesized and
employed o o m
physically c osslinked
injec able hyd ogels
Be acizumab;
A as in Cance HCT116
xenog a mouse
models
Injec ion o he hyd ogel was
e ec i e o show an ime as a ic
ac i i y as ha o 4×weekly
injec ions o A as in hus ↓ he
injec ion equency and may ↑
pa ien compliance o ea
me as a ic cance
[67]
pH- esponsi e injec able
hyd ogels made o a
sup amolecula
c oss-link ne wo k
doxo ubicin Cance L929 mouse
ib oblas s -
Showed biocompa ibili y,
con olled elease p o iles and
unable p ope ies which show
a↑po en ial as a d ug- eleasing
ma e ial o localized
ea men s
[68]
T iblock Copolyme s
o Vi amin
E-Func ionalized
Polyca bona e and
Poly(e hylene glycol)
He cep in B eas cance
Human b eas
cance cell lines
(an i umo
speci ici y
and e icacy)
BT474 umo -
bea ing mice-
(biocompa ibili y
and biodeg ad-
abili y)
↑po en ial o use in
subcu aneous and sus ained
deli e y o an ibodies o ↑
he apeu ic e icacy and/o ↑
pa ien compliance as
compa ed o in a enous and
subcu aneous deli e y o
He cep in in solu ion o m
[69]
pH- esponsi e injec able
hyd ogels wi h mucosal
adhesi eness based on
chi osan-g a ed-
dihyd oca eic acid and
oxidized pullulan
Doxo ubicin Colon umo Colon umo cells
(HCT116 cells) -
Showed good d ug elease,
e ec i ely killing colon umo
cells, ideal candida es o
de elopmen o colon cance
d ug deli e y ca ie s
/mucoadhesi e d ug
deli e y sys ems
[70]
Algina e hyd ogel
sys em
Angiogenesis wi h
ascula endo helial
g ow h ac o
(VEGF)
Ca dio ascula
diseases
Human
mic o ascula
de mal endo he-
lial cells
Ac as a new gene a ion o
he apeu ic deli e y ehicle by
combining long- e m in i o
he apeu ic ad an ages wi h
minimal in asion o ea
ca dio ascula diseases
[71]
Dual- esponsi e (pH
and ROS) injec able
hyd ogels encapsula ing
d ug-loaded micelles
Amikacin,
andNap oxen Wound healing SD male a s
Possess good biocompa ibili y
wi h e icien an ibac e ial and
an i-in lamma o y ac ion, ↑ he
healing p ocess and p omising
o be applied opically agains
a ious mic obial in ec ions
[72]
Algina e–chi osan
hyd ogels
IgG model
an ibodies and Fab
an ibody agmen s
Applica ions in
d ug deli e y
and egene a-
i e medicine
- -
O e s con olled deli e y o
an ibodies and an ibody
agmen s and will be
p omising o mula ion o
se e al applica ions in d ug
deli e y and
egene a i e medicine
[73]
Dopamine-based and
polydopamine
c osslinked injec able
hyd ogels
Dopamine and
me onidazole Pa kinson’s
disease -mouse L929
ib oblas cells
Can be used as long- e m,
localized, sus ained elease
injec able sys em o dopamine
as well as an i-in lamma o y
d ugs o ea Pa kinson
[74]
Co alen ly c osslinked
composi e hyd ogel
embedded wi h
mic osphe es
So issue
enginee ing - -
Can be exploi ed as a po en ial
oppo uni y o use his
injec able composi e gel
sca old in p o ein deli e y and
so issue
enginee ing applica ions
[75]
Gels 2021,7, 207 18 o 32
Table 4. Con .
Hyd ogel Ac i e Ing edien Type o Disease In Vi o Cell Line In Vi o Model Conclusion Re e ence
Gela in-hyd oxyphenyl
p opionic acid
(G n-HPA) and
hyalu onic
acid- y amine
(HA-Ty )-based
hyd ogels
Human epide mal
g ow h ac o
(hEGF)
Oph halmic
applica ions
Hyd odynamic model, gi ing a
no malized di usion and
elease o hEGF and p o ide
he mos sui able explana ion
o he measu ed solu e
di usion coe icien
[76]
Po ous algina e gels Pep ide an igen Immuno he apies -
Nonobese
diabe ic mouse
model o ype
1 diabe es
A nonin lamma o y bioma e ial
sys em can gene a e
an igen-speci ic, ha may
enable he de elopmen o new
he apies o ea ansplan
ejec ion/au oimmune diseases
[77]
Sel -healing injec able
micelle/hyd ogel
composi es qua e nized
chi osan (QCS) solu ion
and benzaldehyde-
e mina ed poly(e hylene
oxide)-b-poly(p opylene
oxide)-b-poly(e hylene
oxide) (PEO99-b-PPO65-b-
PEO99, Plu onic®F127
(PF127)) (PF127-CHO)
solu ion
Cu cumin Wound d essing
o join s skin
wound healing
Female Kunming
mice
Sel -healing an ibac e ial
adhesi e hyd ogels wi h good
mechanical p ope y o e
signi ican p omise as d essing
ma e ials o join s skin
wound healing
[78]
Algina e-gela in
injec able hyd ogel
Oligochi osan
coa ed ce ium oxide
nanopa icles
Age- ela ed
macula
degene a ion
Human e inal
pigmen
epi hlium-19
(ARPE-19) and
umbilical
endo helium
-
Biocompa ible and ha e ↑
po en ial in p o ec ing cells
om angiogenesis, apop osis,
and p oduc ion o
p oin lamma o y cy okines
wi h con olled d ug elease
[79]
Decellula ized injec able
ca diac and skele al
muscle ex acellula
ma ix hyd ogel
-
Po en ial
sca olds
o issue
egene a ion
and/o epai
o ea ing
myoca dial
in a c ion, hea
ailu e and
pe iphe al
a e y disease
- - Tissue speci ic bioma e ial
he apies wi h
minimal in asion [80]
Polysaccha ide-based
hyd ogels(N-
ca boxye hyl chi osan
and oxidized
sodium algina e)
Neu al s em
cells deli e y Neu ological
diso de s Neu al s em cells -
Neu al s em cells
ansplan a ion and
managemen o
neu ological diseases
[81]
Non-deg adable
dend i ic polyglyce ol
sul a e (dPGS) hyd ogel
Dend i ic
polyglyce ol sul a e Os eoa h i is - -
Fo mula ion ha ing good
iscoelas ic p ope ies and has
he bene i o being much less
easily displaced om i s
injec ion si e
[82]
Conduc i e an i-oxidan
hyd ogels (N-
ca boxye hyl chi osan
and oxidized hyalu onic
acid-g a -
aniline e ame
Amoxicillin Wound d essing
C2C12
myoblas cells
(Cy ocompa ibili y)
Esche ichia coli and
S aphylococcus au-
eus (An ibac e-
ial ac i i y)
Male Kunming
mice
Ha e good an ibac e ial,
biodeg ada ion, elec oac i e
and ee adical sca enging
p ope y o e icien ly p e en
he wound in ec ion and can be
designed as an elec oac i e
injec able hyd ogel wi h
p omising applica ions
[83]
Injec able poly(e hylene
glycol) (PEG)–
gela in hyd ogel
Mu ine
adipose-de i ed
s em cells
Wound Healing
and issue
egene a ion -Mu ine wound
healing model
Signi ican ly ↑cell e en ion, ↑
angiogenesis, and ↑wound
closu e and can be used o
egula ing s em cell beha io s
in 3D cul u e, deli e ing cells
o wound healing and o he
issue egene a ion applica ions
[84]
Polyplex Micelle-Loaded
Injec able Hyd ogels Mic oRNA-29 In e e eb al
disc degene a-
ion(IDD)
Rabbi s ( he a-
peu ic e icacy
on ib osis
Inhibi ion)
Sp ague-Dawley
a s (In i o
deli e y analysis)
Success ully s op he exp ession
o ma ix me allop o einases,
p e en he ib osis p ocess and
e e se IDD in animal models
[85]
Gels 2021,7, 207 19 o 32
Table 4. Con .
Hyd ogel Ac i e Ing edien Type o Disease In Vi o Cell Line In Vi o Model Conclusion Re e ence
Collagen–chi osan-based
hyd ogel
Thymosin β4, (a
43-amino
acid pep ide)
Myoca dial
In a c ion Monolaye s o
BHK-21
S imula e angiogenesis and
epica dial hea cell mig a ion
can be conside ed as a ca ie o
o he nega i ely cha ged ac i e
biomolecules and hus shows
nume ous applica ions
[86]
Chi osan hyd ogel
Human
placen a-de i ed
mesenchymal s em
cell -de i ed
exosomes
Hindlimb
Ischemia - Mu ine model
Can ↑ he e en ion and s abili y
o exosomes and u he ↑ he
he apeu ic e ec s ha may
acili a e he de elopmen o
easy and e ec i e app oaches
o assessing and enhancing he
he apeu ic e ec s o s em
cell-de i ed exosomes
[87]
Sus ained elease,
he mosensi i e
polyme ic [poly(lac ic
acid-co-glycolic
acid)-poly(e hylene
glycol)-poly(lac ic
acid-co-glycolic acid)
(PLGA-PEG-
PLGA)]hyd ogel
A as in®Pos e io segmen
diso de s - Ra
A p omising candida e o
ocula d ug deli e y o
A as in® h ough
in a i eal injec ion
[88]
Ca he e -injec able
hyd ogel u ilizing a
polyme –nanopa icle
c osslinking mechanism
-Va ious
he apeu ic
applica ions Wis a a s
Biocompa ible, cell-signaling
and can be di e en ially
eleased wi h dis inc elu ion
p o iles, allowing p ecise
con ol o e d ug deli e y
[89]
Sel -healing hyd ogel
based on chond oi in
sul a e mul iple
aldehyde and
N-succinyl-chi osan
Cells encapsula ed
in he hyd ogel
Cell ca ie and
in issue
enginee ing Ra model
Shows biodeg adabili y,
p oduced ↓in lamma o y
esponse and ha ing po en ial
applica ion as a cell ca ie and
in issue enginee ing.
[90]
Physiological
empe a u e- esponsi e
con ollable
NO- eleasing edox
injec able hyd ogel
Ni ic oxide(NO) Ca dio ascula
diseases - Mice
Signi ican ly ↑ he angiogenesis
and new blood essels
o ma ion by egula ing he
sus ained elease o NO and
edox equilib ium in animal
model. I has a ↑po en ial in
p e en ing and
ea ing diseases
[91]
Gels 2021, 7, x FOR PEER REVIEW 22 o 36
Figu e 6. An o e iew o a ious aspec s o injec able hyd ogels.
6.4. Tissue Enginee ing and Regene a i e Medicine
Tissue enginee ing is a biomedical enginee ing discipline ha e e s o he p ac ice
o combining biologically ac i e molecules, cells, and sca olds in o unc ional issues. The
main objec i e o issue enginee ing is o accumula e biological subs i u es ha es o e,
epai , main ain, o imp o e inju ed issues o whole o gans. The sca old esembles he
ex acellula ma ix composed o po ous s uc u e esponsible o supply o nu ien s, cell
g ow h and was e emo al and hus aids issue egene a ion. In addi ion, he sca olds
should possess he desi ed quali y a ibu es such as biocompa ibili y, biodeg adabili y,
mechanical s eng h and he abili y o be s e ilized. These cha ac e is ics a e necessa y o
p o iding s uc u al suppo o he cell and help in he p ocess o cell g ow h and di e -
en ia ion [92].
Regene a i e medicine is a b oad ield whe e he body uses i s own sys ems, occa-
sionally wi h help o eign biological ma e ial o econs uc cells and es uc u e issues
and o gans. The e ms “ issue enginee ing” and “ egene a i e medicine” can be used in-
e changeably, as he ield ocuses on cu es ins ead o ea men s o complex, o en
ch onic diseases [34].
Al hough hese a eas cu en ly play a ela i ely small ole inpa ien ’s ea men due
o lack o ep oducibili y and high cos bu ha e a g ea e pe spec i e in he ield o d ug
de elopmen o sc een di e en medica ions. Cu en ly, hese a e used in he egene a ion
o ca diac issues, ca ilage, and bone [93]. Hyd ogels ep esen a la ge class o ma e ials
ha can unc ion as issue enginee ing o ab ica e biocompa ible and biodeg adable cell
sca olds [94,95]. P ope ies o hyd ogels such as s uc u al simila i ies o na u al ex acel-
lula ma ix, delicacy and lexibili y akin o so issue and abili y o injec easily inside he
body o o m i egula non lowing gels a e made i use ul as a sca old ma e ial in issue
enginee ing. The abili y o he hyd ogel o show elec ical conduc i i y also plays an ex-
cellen ole in issue enginee ing [96]. Lyophiliza ion, pho oli hog aphy, mic o luidic, mi-
c o molding, emulsi ica ion, sol en cas ing—leaching, gas oaming—leaching, and 3D
p in ing a e some app oaches o he p oduc ion o hyd ogel sca old [97].
Figu e 6. An o e iew o a ious aspec s o injec able hyd ogels.
Gels 2021,7, 207 20 o 32
6.4. Tissue Enginee ing and Regene a i e Medicine
Tissue enginee ing is a biomedical enginee ing discipline ha e e s o he p ac ice o
combining biologically ac i e molecules, cells, and sca olds in o unc ional issues. The
main objec i e o issue enginee ing is o accumula e biological subs i u es ha es o e,
epai , main ain, o imp o e inju ed issues o whole o gans. The sca old esembles he
ex acellula ma ix composed o po ous s uc u e esponsible o supply o nu ien s, cell
g ow h and was e emo al and hus aids issue egene a ion. In addi ion, he sca olds
should possess he desi ed quali y a ibu es such as biocompa ibili y, biodeg adabili y,
mechanical s eng h and he abili y o be s e ilized. These cha ac e is ics a e necessa y
o p o iding s uc u al suppo o he cell and help in he p ocess o cell g ow h and
di e en ia ion [92].
Regene a i e medicine is a b oad ield whe e he body uses i s own sys ems, occa-
sionally wi h help o eign biological ma e ial o econs uc cells and es uc u e issues
and o gans. The e ms “ issue enginee ing” and “ egene a i e medicine” can be used
in e changeably, as he ield ocuses on cu es ins ead o ea men s o complex, o en
ch onic diseases [34].
Al hough hese a eas cu en ly play a ela i ely small ole inpa ien ’s ea men due
o lack o ep oducibili y and high cos bu ha e a g ea e pe spec i e in he ield o d ug
de elopmen o sc een di e en medica ions. Cu en ly, hese a e used in he egene a ion
o ca diac issues, ca ilage, and bone [
93
]. Hyd ogels ep esen a la ge class o ma e ials
ha can unc ion as issue enginee ing o ab ica e biocompa ible and biodeg adable
cell sca olds [
94
,
95
]. P ope ies o hyd ogels such as s uc u al simila i ies o na u al
ex acellula ma ix, delicacy and lexibili y akin o so issue and abili y o injec easily
inside he body o o m i egula non lowing gels a e made i use ul as a sca old ma e ial
in issue enginee ing. The abili y o he hyd ogel o show elec ical conduc i i y also plays
an excellen ole in issue enginee ing [
96
]. Lyophiliza ion, pho oli hog aphy, mic o luidic,
mic o molding, emulsi ica ion, sol en cas ing—leaching, gas oaming—leaching, and 3D
p in ing a e some app oaches o he p oduc ion o hyd ogel sca old [97].
6.5. O he Applica ions
6.5.1. Hyd ogel Machines
The unique p ope ies o hyd ogels, make hem sui able candida e o ab ica ing
di e en hyd ogel machines o biomedical applica ions such as senso s, ac ua o s, op ics,
coa ings, elec onics, e c. [
98
,
99
]. The basic equi emen o his is he obus ness o he
hyd ogels in e ms o mechanical pe o mance and unc ionali y o ensu e he s able ope a-
ion o hyd ogel machines. Recen inno a ions in he design o ough hyd ogels
[100,101]
,
ough adhesion o hyd ogels o o he enginee ing ma e ials, and ad anced ab ica ion
me hods o hyd ogels [
102
] ha e made hyd ogels a p omising ma e ial candida e o he
nex -gene a ion machines [99].
6.5.2. Biosenso
A senso can be de ined as a machine o pa o i ha de ec s and esponds o signals
in he en i onmen s [
103
]. Con en ional senso s, (elec onic senso s and elec ochemi-
cal senso s) con e en i onmen al inpu s o elec ical ou pu s based on semiconduc o s
and/o me allic elec odes; whe eas, hyd ogel senso s a e based on exclusi e cha ac e -
is ics o hyd ogels, such as high wa e con en , s imuli- esponsi eness, high compliance,
and high pe meabili y o a wide ange o molecules. They can be classi ied in o wo
ypes: (a) s imuli- esponsi e hyd ogels ( ha can exhibi acco ding o en i onmen al in-
pu s)
[104,105]
; and (b) passi e hyd ogels (as ma ices o hos esponsi e subs ances such as
ee ions, nanopa icles, biomolecules, and li ing cells, e c. ha espond o en i onmen al
inpu s). Hyd ogel senso s a e becoming p ac ical ools o di e se applica ions including
poin -o -ca e de ec ion, medical diagnos ics, and en i onmen al moni o ing, e c. [105].
Gels 2021,7, 207 21 o 32
6.5.3. Ac ua o
An ac ua o can be de ined as a machine o a pa o i ha con e s o he o ms o
ene gy in o mechanical ene gy o p oduce o ces and mo ions. Con en ional ac ua o s
adap ed o mechanical sys ems usually con ain me als and ce amics, and hei ac ua ion
usually depends on ela i ely small de o ma ions o he igid ma e ials [
106
]. Whe eas
hyd ogel ac ua o s p o ide mechanical mo ions commonly d i en by ela i ely la ge
de o ma ions o he hyd ogels [
107
]. Hyd ogel ac ua o s can be di ided in o h ee ypes
such as (a) s imuli- esponsi e hyd ogels d i en by osmo ic p essu e change; (b) hyd ogels
ma ices inco po a ing ac i e elemen s (such as magne ic pa icles o ee ions) in esponse
o a ying ex e nal ields (such as magne ic o elec ic ields); and (c) hyd ogel s uc u es
wi h chambe s.
6.5.4. Coa ings
In he human body, many issues and o gans a e co e ed wi h hyd ogel coa ings,
esul ing in ex emely slippe y selec i ely pe meable su aces. Fo example, a icula
ca ilage on bones p o ides a lub ica ed su ace o smoo h join mo emen [
108
]. Simila ly,
when igid machines such as o hopedic implan s, neu al p obes, ca diac slee es, glucose
senso s, needles, ca he e s, ul asound ansduce s, and elec odes o elec oencephalo-
g am, elec omyog am, elec oca diog am, and anscu aneous elec ical ne e s imula ion
come in o di ec con ac wi h he human body, hyd ogel coa ings can po en ially p o ide a
biocompa ible in e ace wi h minimal mechanical misma ch and o eign body esponses.
In o de o coa hyd ogels on enginee ing ma e ials, including me als, ce amics, glass,
and elas ome s, adhesion needs o o m be ween he hyd ogels and enginee ing ma e-
ials. Acco ding o di e en mechanisms o hyd ogel adhesion, we classi y hyd ogel
coa ings in o ou ypes: (a) physical a ached [
109
] (b) co alen ancho ed (c) in e acially
in e pene a ed, and (d) mechanically in e locked [110] hyd ogel coa ings.
6.5.5. Op ics
Ligh and op ical echniques ha e ound pa icula impo ance in diagnosis, imaging,
su ge y, he apy, and many o he biological ypes o esea ch. Hyd ogels is an ideal
ma e ial o op ic de ices due o he abo e-discussed uniqueness, especially o hose in
close con ac wi h biological o ganisms. The e a e wo ac o s such as high anspa ency
(low ligh abso p ion and sca e ing) and high e ac i e index (low bending loss) on which
he e ec i eness o hyd ogel op ics depends. Acco ding o hei applica ions, he e a e
ou ep esen a i e ypes o hyd ogel op ics de eloped so a , including (a) oph halmic
lenses [
111
], (b) sma windows and displays, (c) op ical ibe s [
112
], and (d) bioassay
ma ices [113].
Con ac lenses a e delica e oph halmic ools ha ge di ec con ac wi h he eyes and
a e used o co ec he ision, o cosme ic use impa ing aes he ic e ec s and o deli e he
ac i e cons i uen s o oph halmic condi ions [
114
]. Biocompa ibili y and pe meabili y a e
wo key p ope ies o be conside ed du ing design besides com o , pe meable o ions o
main aining mo emen , con inuous ea ilm o clea ision, non-i i able and esis ance
o ea ilm accumula ion. Co nea needs oxygen o i s p ope unc ioning and he e o e
oxygen pe meabili y is essen ial. Oxygen pe meabili y is a e y impo an p ope y [115].
P incipally he e a e wo ypes o con ac lenses, as igid and so con ac lens.
Rigid con ac lenses a e ypically made up o polyme hyl me hac yla e polyme s
which gi es i p ope ies such as we abili y, elas ici y and du abili y bu lack o oxygen
pe meabili y. Howe e a so o hyd ogel (poly(2-hyd oxye hyl me hac yla e) c osslinked
wi h e hylene glycol dime hac yla e o silicone [
116
] ha ing p ope ies such as he abili y
o pe mea e wa e and oxygen wi h ela i ely high wa e con en and good he mal and
chemical s abili y [
117
]. They ha e he po en ial o assis in he ea men o a ious eye
diseases, which is he eason why hyd ogels a e highly exploi ed as an impo an aw
ma e ial o p epa ing con ac lenses [118].

Gels 2021,7, 207 22 o 32
6.5.6. Hyd ogel Elec onics
Due o hei simila i ies o biological issues and e sa ili y in elec ical, mechani-
cal, and bi unc ional enginee ing, hyd ogels ha e ecen ly a ac ed g owing a en ion in
bioelec onics o po en ially p o ide a seamless in e ace be ween biology and elec on-
ics. Hyd ogels a e gene ally conside ed elec ical insula o s due o he absence o mobile
cha ges o cha ge ca ie s. The elec ical conduc i i y o hyd ogels in he physiologically el-
e an condi ions is simila o ha o issue media, and much in e io o common elec onic
conduc o s such as me als, limi ing hei applica ions in elec onics [
119
]. To o e come such
limi a ion and enable he possibili y o hyd ogel elec onics o imp o ed issue-elec ode
in e aces, a ew s a egies ha e been de eloped o enhance he elec ical conduc i i y o
hyd ogels, including (a) he addi ion o ionic sal s in he hyd ogels o achie e ionically
conduc i e hyd ogels (b) inco po a ion o elec ically conduc i e mic o-and nano-ma e ials
wi hin hyd ogel ma ices o endow elec onic conduc i i y [
120
,
121
], and (c) in oduc ion
o conduc ing polyme s in o hyd ogels o enhance elec onic conduc i i y [122,123].
The Table 5depic s a ious comme cially a ailable hyd ogel p oduc s wi h hei
espec i e indica ions which gi e an idea abou he applicabili y o hyd ogel in a ious
ield and pa e he way o u u e esea ch.
Table 5. Comme cially a ailable hyd ogel p oduc .
S.No. P oduc
P oduc
Manu ac u ed
by/Ma ke ed by
Type o Hyd ogel Ac i e Componen Indica ions Re e ence
1 AquaDe m™
De maRi e
Hyd ogel shee
2-Ac ylamido-2 me hyl-1
p opane sul onic acid
sodium, P opylene Glycol,
Poly (e hylene glycol)
dime hac yla e, 2-Hyd oxy-2-
me hylp opiophenone wi h
38–55% wa e
Mino bu ns, p essu e ulce s
and adia ion issue damage
[124]
2De maSynTM Amo phous hyd ogel Acu e/ch onic pa ial and
ull hickness wounds/ulce s
ha ing minimal exuda e
3 De maGauze™ Hyd ogel imp egna ed
gauze d essing Ac yla e polyme
Acu e/ch onic pa ial and
ull hickness wounds ha ing
minimal exuda e and
wounds wi h unneling o
sinus ac s
4 De maSyn/Ag™ Wa e -based
an ibac e ial sil e
Wound gel Sil e
Venous ulce s, issue auma,
p essu e ulce s, diabe ic
ulce s, su gical incisions
The mal bu ns, e c.
5In asi e®GEL Smi h and Nephew Hyd ogel Ca boxyme hyl cellulose and
p opylene glycol
Ease gen le, e ec i e
au oly ic deb idemen o
p epa e he wound bed in all
ypes o wounds
[125]
6Sup aso b®GLohmann and
Rausche Global Hyd ogel ilm
Wa e (70%), ac ylic
polyme s based on a au a e
de i a i e, polye hylene,
phenoxye hanol, anspa en
polye hylene ca ie ilm
Used o he managemen o
he i s and second deg ee
bu ns, d y ac u es, ulce o
he lowe leg, p essu e
ulce , e c.
[126]
7Neoheal®Kikgel Hyd ogel shee
Wa e (90%),
poly inylopy olidone,
polye hylene glycol and aga ,
c osslinked by a beam
o elec ons.
Bu ns, ulce a ions, bedso es
and all ypes o skin damages
whe e humid medium
is a ou able
[127]
8Woun’D es®Collagen
Hyd ogel
Coloplas
Collagen Hyd ogel Polyme s such as ca bome
and collagen D y wounds and escha
[128]
9Pu ilon®Wa e , calcium algina e
and sodium
ca boxyme hyl cellulose
Fi s and second deg ee
bu ns, leg ulce s, p essu e
ulce s, non-in ec ed diabe ic
oo ulce s
10 Simpu i y®
Sa e n’Simple
Abso ben
hyd ogel shee s
wa e , polye hylene oxide,
poly inyl alcohol,
ac yla e, polyu e hane
Wounds wi h minimal o no
exuda e, skin bu ns and
d y scabs [129]
11 Simpu i yHyd oGel®Imp egna ed Gauze
Wound D essings
Fi s and second deg ee
bu ns, p essu e so es and
leg ulce s
Gels 2021,7, 207 23 o 32
Table 5. Con .
S.No. P oduc
P oduc
Manu ac u ed
by/Ma ke ed by
Type o Hyd ogel Ac i e Componen Indica ions Re e ence
12 P o iDe m®D . De m P o essional Hyd ocollagen ace gel Sea collagen and
hyalu onic acid
Nou ishes, hyd a es, soo hes
skin, helps o egene a e he
skin o he ace, ↑ he
elas ici y and ones
he issues
[130]
13 Ad anced géni ique
ligh pea l hyd ogel
mel ing 360 eye mask Lancome Pa is
Hyd ogel eye mask
↓ he appea ance o unde eye
bags, pu y eyes, unde eye
ci cles and eju ena e he
eye a ea
[131]
14 Ad anced géni ique
hyd ogel mel ing
shee mask Hyd ogel shee mask Wa e , glyce ine,
polyac yla e-13,
bi idus ex ac
Mois u ized ace skin, and
make i adian , smoo he ,
shiny and heal hy [132]
15 Wa e bomb
hyd ogel mask Mo ia Hyd ogel mask Sodium polyac yla e,
glyce ine, cellulose
gum, wa e
Res o e hyd a ion a a deepe
le el, soo hesand eju ena e
he skin [133]
16 Eau aSil™
Miaca e™
Silicone Hyd ogel
Con ac Lens Hyalu onic Acid and
Sodium Algina e
E ec i ely p e en
hypoxia- ela ed
complica ions (co neal
neo ascula iza ion, edness,
and co neal
epi helium-aging)
[134]
17 Con idence
Silicone Hyd ogel Con ac
Lens wi h Do Ma ix
Colou P in ing
Technology
Hyalu onic Acid and
Sodium Algina e Long las ing com o [135]
18 Cha coal Hyd ogel
unde eye mask ELF cosme ics Hyd ogel mask Cha coal Powde , G een
Tea Ex ac ,
La ende Ex ac
Unde eye skin p o ec ion
and eju ena ion [136]
19 SEVEN RX®Ma k’enno y Hyd ogel lens Bioinspi ed silicone
hyd ogel lens Sho sigh and long sigh [137,
138]
20 Gen le 59 Ma k’enno y Bio-inspi ed hyd ogel lens Sho sigh and long sigh [137]
21 Max ueHiTo ic®Max ue ision Silicone hyd ogel Hyalu onic Acid As igma ism [137]
22 ACTIVHEAL®HYDROGEL Ad anced medical
solu ion L d. Amo phous gel A p ima y wound d essing
con ains 85% wa e
D y and sloughy wounds
wi h ze o o low exuda e
such as p essu e ulce s, leg
ulce s, ca i y wounds, g a
a dono si es, pos op
su gical wounds, lace a ions
and ab asions
[139]
23 Nu-Gel®Hyd ogel wi h
Algina e Sys agenix wound
managemen Hyd ogel wi h algina e Algina e
Helps in managemen o
ch onic wounds h ough all
s ages o healing. Manage
d y, enc us ed and nec o ic,
sloughy, g anula ing
andepi helialising wounds.
[140]
24 SUPPRELIN®LA Endo Pha maceu icals,
USA Implan His elin ace a e T ea men o child en ha ing
cen al p ecocious pube y [141]
25 Ce idil®Fe ing
Pha maceu icals, Inc. Ce idil (dinop os one)
Vaginal Inse
c osslinked polye hylene
oxide/u e hane polyme ,
dinop os one
Ini ia ion and/o
con inua ion o ce ical
ma u emen in
p egnan women
[142]
26 SQZgel™ Mac oMed Con olled- elease
o al able s chi osan and
polye hylene glycol Hype ension [143]
27 Mebiol®Gel Cosmo Bio co l d The mo e e sible hyd ogel poly(N-
isop opylac ylamide) and
poly(e hylene glycol)
High anspa ency o cell
obse a ion, s em cell cul u e,
cell implan a ion,
o gan/ issue egene a ion,
d ug deli e y, and non-cell
cul u e applica ions
[144]
28 Gel in C™ Regen is
Bioma e ial L d. Pho o c osslinked hyd ogel polye hylene glycol and
human ib inogen p o ein
p ojec ed o he epa a ion
o ocal de ec s in ca ilage
and/o os eochond al de ec s [145]
29 Mebiol®Gel Cosmo Bio The mo e e sible
Hyd ogel
Poly (N-
isop opylac ylamide) and
POLY glycol e hylene
Cell implan a ion, o gan and
issue egene a ion, s em cell
cul u e, d ug deli e y, and
non-cell cul u e applica ions
[146]
30 HyS em®Hyd ogel ESI BIO Hyalu onic acid UV
ligh -con olled sys em hyalu onic acid 3D cell cul u e o issue
enginee ing pu poses and 3D
p in ing applica ions [147]
Gels 2021,7, 207 24 o 32
Table 5. Con .
S.No. P oduc
P oduc
Manu ac u ed
by/Ma ke ed by
Type o Hyd ogel Ac i e Componen Indica ions Re e ence
31 Co ning®
Pu aMa ix™
Co ning
Inco po a ed
Li e sciences Pep ide hyd ogel -
3D cell cul u e used o s em
cell p oli e a ion, umo cell
mig a ion and in asion, and
in i o analysis o
issue egene a ion
[148]
32 Biogelx™ Bioglex L d. Simple, sho
sel -assembling pep ides -
C ea e an op imal
en i onmen o he cul u e
o a a ie y o cell ypes,
deli e syn he ic ye
biologically- ele an
al e na i es o
animal-de i ed 3D ma ices
o example ma igel
and collagen
[149]
33 SpaceOAR®Bos on scien i ic Abso bable Injec able
hyd ogel -
Imaging o cance ous cells
and p o ec ing heal hy cells
om adia ion
induced damage
[150]
34 Bulkamid®Con u a
In e na ional
So injec able,
anspa en ,
hyd ophilic gel
Syn he ic polyac ylamide
and wa e S ess u ina y incon inence [151]
35 Symphony®Cyp e’s S imuli– esponsi e
hyd ogels as senso s 3D pho oli hog aphic
ins umen
Animal cell cul u e, 3D
imaging, iPSCs, ESc cell
lines, e c. [152]
36 Valleylab™ Med onic Co alen
ancho ed coa ings Chi osan-hyalu onic
acid-based hyd ogel ca he e Pos ope a i e adhesion [153]
37 Bol Bis-T is Plus Gels The mo Fishe Bioassay ma ices(gel) Polyac ylamide gels Wes e n blo ans e
and analysis [154]
38 Tadpole™ Ne ena®Hyd ogel elec ode Ionically
conduc i e hyd ogels Use in Pa o idec omy and
o ologic Su ge y
7. Regula o y Aspec s o Hyd ogel and I s Componen s
The di e si ied aw ma e ials employed o de elop hyd ogel sca olds make hei eg-
ula o y a angemen and app o al challenging. Unlike d ugs which a e b oadly classi ied,
hyd ogels a e classi ied unde he “de ices” ca ego y acco ding o Sec ion 201(g) o he
FD&C Ac . Fu he mo e, o he han a ew excep ions, mos hyd ogel-based p oduc s a e
equi ed o unde go addi ional FDA e iew o a 510(k) p e-ma ke no i ica ion submission
o ob aining legal ma ke ing igh s in he Uni ed S a es, which akes many yea s o ge
egula o y app o al. Howe e , acco ding o he new Eu opean egula ion, hyd ogels a e
conside ed as medical de ice class III, and i should be aken in o conside a ion h oughou
he en i e li ecycle o he hyd ogel, s a ing om he ma e ial and machine quali ica ion o
scale-up. Table 6enlis s some egula o y in o ma ion o hyd ogel ing edien s used o he
manu ac u ing o hyd ogels.
The commission egula ion (EU) N0 722/2012 o 8 Augus 2012, conce ning pa icula
equi emen s as ega ds he equi emen s laid down in Council Di ec i es 90/385/EEC
and 93/42/EEC. These we e conce ning ac i e implan able medical de ices and medical
de ices manu ac u ed u ilizing issues o animal o igin, has adop ed a egula ion based on:
The o iginal equi emen s, he main enance o a high le el o sa e y and heal h p o ec ion
agains he isk o ansmi ing animal spongi o m encephalopa hies. The egula ion
also conside s ha class III’s ac i e implan able medical de ices and medical de ices a e
subjec o he con o mi y assessmen p ocedu es be o e being placed on he ma ke o pu
in o se ice, demanding he adop ion o mo e de ailed speci ica ions ela ing o he isk
analysis and managemen . The egula ion es ablishes pa icula equi emen s conce ning
he placing on he ma ke and/o pu ing in o se ice o medical de ices, including ac i e
implan able medical de ices, manu ac u ed u ilizing animal issue and hei de i a i es,
o igina ing om bo ine, o ine and cap ine species, dee , elk, mink and ca s. In he case o
collagen, gela in and allow used o he manu ac u ing o medical de ices hey shall mee
a leas he equi emen s as i o human consump ion. The egula ion also es ablishes ha
Gels 2021,7, 207 25 o 32
he manu ac u e o medical de ices o his au ho ized ep esen a i e shall ca y ou he
isk analysis and isk managemen scheme be o e applying a con o mi y assessmen . The
membe s a es shall e i y ha bodies ha e up- o-da e knowledge o he medical de ices
o assess he con o mi y o hose de ices, and shall ake all necessa y s eps o ensu e ha
medical de ices a e placed on he ma ke and/o pu in o se ice only i hey comply
wi h he cu en p o isions and he pa icula equi emen s laid down in his egula ion.
Con o mi y assessmen p ocedu es o medical de ices shall include he e alua ion o
compliance o he de ices wi h he essen ial equi emen s in o he cu en di ec i es and
he pa icula equi emen s laid down in his egula ion. The manu ac u e shall collec ,
e alua e and submi o he no i ied body in o ma ion conce ning changes ega ding he
animal issue o de i a i es used o he de ice o ega ding he isk o he de ice.
Two new Eu opean Heal h P oduc s Regula ions came in o o ce on 26 May 2017.
The i s one, he Regula ion (EU) 2017/745 o medical de ices, which modi ies Di-
ec i e 2001/83/EC and subsequen de i ed egula ions, epealing Council Di ec i es
90/385/EEC and 93/42/EEC, had been applied om 26 May 2020. The second one, Regu-
la ion (EU) 2017/746 o
in i o
medical de ices, which epeals bo h Di ec i e 98/78/EC
and he commission 2010/227/EU decision, will apply om 26 May 2022. These new
egula ions ep esen an impe a i e change in he medical de ices ield and will necessi a e
s ingen obliga ions o all ma ke ope a o s, which esul s in an inc ease in anspa ency
and aceabili y gua an ees o he p oduc u he leading o sa e y and eliabili y [
155
,
156
].
As hyd ogels a e conside ed a medical de ice class III by he new Eu opean egula ion,
his egula ion mus be conside ed no only in he scale-up p ocess bu also in he ini ial
phases o he ma e ial’s and he machine’s in en ion. The egula ion also conside s ha
he ac i e implan able medical de ices and medical de ices o class III a e subjec o he
con o mi y assessmen p ocedu es be o e being placed on he ma ke o pu in o se ice,
demanding he adop ion o mo e de ailed speci ica ions ela ing o he isk analysis and
managemen . I is also conside ed o he elabo a ion o he egula ion, he con enience
o laying down addi ional p o isions on he use o animal by-p oduc s no in ended
o human consump ion, he adop ion o se e al opinions on speci ied isk ma e ials
and on minimizing he isk o ansmi ing animal spongi o m encephalopa hy agen s.
The egula ion conside s ha i is app op ia e o he membe s a es o e i y ha he
no i ied bodies, designa ed o assess he con o mi y o hose medical de ices, ha e all he
necessa y expe ise and up- o-da e knowledge o pe o m his ask. The pe iod o sc u iny
g an ed o he compe en au ho i ies o he membe s a es conce ning he no i ied bodies.
The summa y e alua ion epo should be sho e o medical de ices manu ac u ed
using s a ing ce i ied ma e ials han in cases whe e unce i ied ma e ials a e used. The
egula ion also bases i s decisions on he con enience o he p o ision o an adequa e
ansi ional pe iod allowing o ac i e implan able medical de ices al eady co e ed by an
EC design-examina ion ce i ica e o by an EC ype-examina ion ce i ica e o con inue o
be placed on he ma ke and pu in o se ice, and ha he measu es p o ided o in his
egula ion a e in acco dance wi h he opinion o he Commi ee on Medical De ice [157].
Gels 2021,7, 207 32 o 32
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CLINICAL RESOURCE: A Case S udy Using Ac i Heal
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