Biomedical application, patent repository, clinical trial and regulatory updates on hydrogel: an extensive review

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. This a icle is an open access a icle dis ibu ed unde he e ms and condi ions o he C ea i e Commons 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 32 134. Silicone Hyd ogel Con ac Lens (Daily). A ailable online: h ps://www.miaca e.com/weben/h ml/p oduc /show.aspx?num=27 (accessed on 19 June 2021). 135. CONFiDENCE (Daily)—Black/B own/Viole . A ailable online: h ps://www.miaca e.com/weben/h ml/p oduc /show.aspx? num=29 (accessed on 28 June 2021). 136. Cha coal Hyd ogel Unde Eye Masks. 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