Magnetic latex particles for bionanotechnology and biosensors

HAL Id: tel-01430413

https://tel.archives-ouvertes.fr/tel-01430413

Submitted on 9 Jan 2017

HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Talha Jamshaid

To cite this version:

Talha Jamshaid. Magnetic latex particles for bionanotechnology and biosensors. Biotechnology. Uni-versité de Lyon, 2016. English. �NNT : 2016LYSE1061�. �tel-01430413�

N°d’ordre NNT : /<6(

THESE de DOCTORAT DE L’UNIVERSITE DE LYON

L’Université Claude Bernard Lyon 1

Ecole Doctorale

Ecole Doctorale de Chimie

Spécialité de doctorat

Soutenue publiquement le 24/05/2016, par :

Talha Jamshaid

Synthèse de latex magnétique submicronique et fonctionnalisé pour application

en Biocapteur

Devant le jury composé de :

Saidi Salima Professeur Université d’Oran Rapporteur Carbonnier Benjamin Professeur Université Paris-Es Rapporteur Laayoun Ali Chercheur BioMérieux,S.A Grenoble ExaminatHXU Chehimi Mohamed Mehdi DR-CNRS Université Paris-Est ExaminatHXU Briançon Stéphanie Professeur Université Lyon-1 Examinatrice Elaissari, Abdelhamid DR-CNRS Université Lyon-1 Directeur de thèse Errachid El-Salhi Abdelhamid Professeur ISA,Université Lyon-1 Co-directeur de thèse

Président de l’Université

Vice-président du Conseil d’Administration

Vice-président du Conseil des Etudes et de la Vie Universitaire Vice-président du Conseil Scientifique

Directeur Général des Services

M. François-Noël GILLY

M. le Professeur Hamda BEN HADID M. le Professeur Philippe LALLE M. le Professeur Germain GILLET M. Alain HELLEU

COMPOSANTES SANTE

Faculté de Médecine et de Maïeutique Lyon Sud – Charles Mérieux

Faculté d’Odontologie

Institut des Sciences Pharmaceutiques et Biologiques Institut des Sciences et Techniques de la Réadaptation

Département de formation et Centre de Recherche en Biologie Humaine

Directeur : M. le Professeur J. ETIENNE Directeur : Mme la Professeure C. BURILLON Directeur : M. le Professeur D. BOURGEOIS Directeur : Mme la Professeure C. VINCIGUERRA Directeur : M. le Professeur Y. MATILLON Directeur : Mme. la Professeure A-M. SCHOTT

COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE

Département Biologie

Département Chimie Biochimie Département GEP

Département Informatique Département Mathématiques Département Mécanique Département Physique

UFR Sciences et Techniques des Activités Physiques et Sportives Observatoire des Sciences de l’Univers de Lyon

Polytech Lyon

Ecole Supérieure de Chimie Physique Electronique Institut Universitaire de Technologie de Lyon 1 Ecole Supérieure du Professorat et de l’Education Institut de Science Financière et d'Assurances

Directeur : M. F. DE MARCHI

Directeur : M. le Professeur F. FLEURY Directeur : Mme Caroline FELIX Directeur : M. Hassan HAMMOURI

Directeur : M. le Professeur S. AKKOUCHE

Directeur : M. le Professeur Georges TOMANOV

Directeur : M. le Professeur H. BEN HADID Directeur : M. Jean-Claude PLENET

Directeur : M. Y.VANPOULLE

Directeur : M. B. GUIDERDONI Directeur : M. P. FOURNIER Directeur : M. G. PIGNAULT

Directeur : M. le Professeur C. VITON

Directeur : M. le Professeur A. MOUGNIOTTE Directeur : M. N. LEBOISNE

Acknowledgements

)LUVW RI DOO , DP YHU\ WKDQNIXO WR P\ *RG ZKR JLYHV PH WKLV RSSRUWXQLW\ WR DFKLHYH WKH GHVLUHGJRDO,ZRXOGOLNHWRH[SUHVVP\VSHFLDO DSSUHFLDWLRQDQGWKDQNVWRP\VXSHUYLVRU Dr. Abdelhamid Elaissari director of research at CNRS, vice director of LAGEP at Lyon,

France and editor-in-chief of JOURNAL OF COLLOID SCIENCE AND BIOTECHNOLOGY.

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¶VWKHIXQQLHVWDGYLVRUDQGRQHRI WKHVPDUWHVWSHRSOH,NQRZ ,KRSHWKDW ,FRXOG EHDVOLYHO\HQWKXVLDVWLFDQGHQHUJHWLFDV 'U $EGHOKDPLG (ODLVVDUL ,Q DGGLWLRQ WR RXU DFDGHPLF FROODERUDWLRQ , JUHDWO\ YDOXH WKH FORVHSHUVRQDOUDSSRUWWKDWKHDQG,KDYHIRUJHGRYHU WKH \HDUV $QG DOVR , ZLOO QRW IRUJHW IRU ZKROH P\ OLIH DW WLPH ZKHQ , ZDV LOO DQG KHWUHDWHGPHPRUHWKDQOLNHDIDWKHU, DPDOVRH[WUHPHO\ LQGHEWHGWRP\JXLGHP\co- supervisor Professor Abdel Hamid Errachid El-Salhi full professorDWWKH8QLYHUVLW\&ODXGH%HUQDUG/\RQ  DQG head of

the Micro/Nanotechology group,  ZKR SURYLGHG PH DOOQHFHVVDU\LQIUDVWUXFWXUHDQG

UHVRXUFHV WR DFFRPSOLVK P\ UHVHDUFK ZRUN LQ KLV ODE XQGHU KLV NLQG VXSHUYLVLRQ DQG JXLGDQFH ,ZRXOGDOVROLNHWRWKDQN'U Nadia ZineZKRFDPHWLPHWRWLPHLQP\ODEDQG JXLGHPHVLGHE\VLGH

,ZRXOGOLNHWRWKDQNVRPHRIP\VHQLRUEURWKHUVZKLFKJXLGHGPHIURPHDUO\GD\VRIP\ UHVHDUFK SHULRG 0RKDPHG (LVVD DVVRFLDWH SURIHVVRU LQ 3RO\PHUV 'HSDUWPHQW 1DWLRQDO 5HVHDUFK &HQWUH *L]D (J\SW $KPHG %LWDU $EGRXOODWLI %DUDNHW .DULP 0LODGL  DQG 1DYHHG$KDPHGZKRHQFRXUDJHGPHDORWIRUGRLQJWKLVUHVHDUFKJRDO

,DSSUHFLDWHWKHSURPSWUHVSRQVHIURPWHFKQLFDO HQJLQHHULQJVWDIIWKDW DVVLVWV PH WR VROYH P\WHFKQLFDOSUREOHPV ,DP JUDWHIXOWR 1DGLD &KDSHO VHFUHWDU\WRRXUODE¶VGLUHFWRUDQG *DUULJXHV 2OLYLHU DV P\ FRPSXWHU DGPLQLVWUDWRU IRU KLV FRRSHUDWLRQ LQ GLIIHUHQW DGPLQLVWUDWLYH ZRUNV DQG FRPSXWHU SUREOHPV DOVR WKDQNV WR *HUDOGLQH $JXVWL IRU KHU NLQGVKHOSUHJDUGLQJWR7(0DQG7*$FKDUDFWHUL]DWLRQV

,W¶VP\IRUWXQHWRJUDWHIXOO\DFNQRZOHGJHWKHVXSSRUWRI0XKDPPDG$KDVDQ%DVKLUIRUKLV VXSSRUWJHQHURXVFDUHDQGWKHKRPHO\IHHOLQJDW/\RQ+HZDVDOZD\VEHVLGHPHGXULQJWKH KDSS\DQGKDUGPRPHQWVWRSXVKPHDQGPRWLYDWHPH

/DVWEXWQRWWKHOHDVW,ZRXOGOLNHWRWKDQNP\SDUHQWVZKRUDLVHGPHVXSSRUWHGPHWDXJKW PH DQG ORYHG PH , ZRXOG DOVR OLNH WR WKDQN P\ \RXQJHU EURWKHU Usama Jamsaid ZKR VXSSRUWHGPHLQWLPHRIGLIILFXOWLHVDQGHQFRXUDJHGPHWLPHWRWLPH

,ZRXOGDOVROLNHWRWKDQNVP\EHORYHGZLIHNadiah Zafar,ZKRWRRNFDUHRIPHLQWLPHRI EDG VLWXDWLRQV DQG KHOSHG PH VLGH E\ VLGH 0\ GHHSHVW JUDWLWXGH WR WKH FRPSDVVLRQ H[WHQGHG E\ P\ PRWKHULQODZ IDWKHULQODZ DQG VLVWHULQODZ ZKR VXSSRUWHG PH WKURXJKRXWWKLVMRXUQH\

, WKDQNWRP \  *RG DQG P\ JRRG IDWKHUprofessor Dr.Muhammad Jamshaid IRU OHWWLQJ PH WKURXJK DOO WKH GLIILFXOWLHV DQG P\ PRWKHU Riffat Jamshaid ZKR

WKDQN P\ RQO\ SDWHUQDO DXQW Tasneem Bibi ZKR VDFULILFHG KHU OLIH IRU GHYHORSLQJ

DQGEXLOGLQJD JRRGIDPLO\ +HUVXSSRUWLYHHQFRXUDJLQJ SDWLHQFH DQG

XQFRQGLWLRQDOORYHDQGHQFRXUDJHPHQWJHQHURXVO\SDYHGWKHZD\IRUGHYHORSPHQWDVD UHVHDUFKHUIDPLO\:HDUHDOOSURXGRIKHU*RGEOHVVKHUDQGKHUIDPLO\$PHHQ $WHQG,DPWKDQNIXOWRUniversity of Lahore, PakistanIRUSURYLGLQJVFKRODUVKLSWR FRPSOHWHP\3K'JRDO

7

7DOKD -DPVKDLG





8QLYHUVLWp&ODXGH%HUQDUG/\RQ



)UDQFH



Résumé

/¶REMHFWLI GH FH WUDYDLO GH UHFKHUFKH HVW GH UHPSODFHU OHV SURFpGpV ORQJV HW IDVWLGLHX[ FRPPHODILOWUDWLRQHWODFHQWULIXJDWLRQTXLVRQWJpQpUDOHPHQWXWLOLVpHVGDQVOHGLDJQRVWLF ELRPpGLFDO in-vitro SDU O¶XWLOLVDWLRQ GH SDUWLFXOHV GH ODWH[ PDJQpWLTXH &HV SDUWLFXOHV PDJQpWLTXHV DSUqV IRQFWLRQQDOLVDWLRQ VRQW pJDOHPHQW XWLOLVpHV QRQV HXOHPHQW FRPPH VXSSRUW GH ELRPROpFXOHV PDLV DXVVL SRXU DPpOLRUHU OH VLJQDOH O RUV G¶XWLOLVDWLRQ HQ ELRFDSWHXUV

/HV SDUWLFXOHVGHODWH[PDJQpWLTXHVHWVXEPLFURQLTXHV HQWDLOOHVRQWSUpSDUpHVHQXWLOLVDQW XQH pPXOVLRQ KXLOH IHUURIOXLGH RUJDQLTXH GDQV O¶HDX /D UpDOLVDWLRQ G¶XQH pWXGH V\VWpPLTXHHQIRQFWLRQGHODFRPSRVLWLRQFKLPLTXHUDWLRVW\UqQHGLYHQ\OEHQ]HQHQDWXUH FKLPLTXH G¶DPRUFHXU D FRQGXLW DX[ FRQGLWLRQV G¶REWHQWLRQ GH SDUWLFXOHV j F°XU PDJQpWLTXH HW pFRUFH SRO\PqUH PRUSKRORJLH FRUHVKHOO /D IRQFWLRQQDOLVDWLRQ GH FHV SDUWLFXOHVDpWpUpDOLVpHHQXWLOLVDQWVRLWXQDPRUFHXUGHSRO\PpULVDWLRQIRQFWLRQQHO D]RELV DFLGH F\DQRSHQWDQRLTXH $&3$ RXj  O¶XWLOLVDWLRQ G¶XQ PRQRPqUH IRQFWLRQQHO FRPPH O¶DFLGH PpWKDFU\OLTXH &HV SDUWLFXOHV GH ODWH[ PDJQpWLTXHV VRQW XWLOLVpHV SDU OD VXLWHFRPPHVXSSRUWGHELRPROpFXOHVFKLPLTXHPHQWJUHIIpHV

&HV SDUWLFXOHV GH ODWH[ PDJQpWLTXHV VRQW XWLOLVpHV FRPPH VXSSRUW GH ELRPROpFXOHV DSUqV JUHIIDJH VXU XQV XEVWUDW DPLQp SRXU OD GpWHFWLRQ GH O¶2FKUDWR[LQH $ TXL H[LVWH GDQV OHV SURGXLWVDOLPHQWDLUHVpFKpV/DGpWHFWLRQDpWpPLVHHQpYLGHQFHHQXWLOLVDQWGHVDQWLFRUSV DQWL2FKUDWR[LQH$IOXRUHVFHQWV/HVSDUWLFXOHVPDJQpWLTXHVVHQVLELOLVpHVSDUO¶DQWLFRUSV $E VSpFLILTXH jO ¶DQWLJqQH 6$%6$ VRQW pJDOHPHQW XWLOLVpHV SRXU DXJPHQWHU OD VHQVLELOLWp GX ELRFDSWHXU VSpFLILTXH j O¶DQWLJqQH SUpDODEOHPHQW JUHIIp j OD VXUIDFH G¶XQ VXEVWUDWHQ2U

II. Bibliography 8

II.1. Ferrofluids: From Preparation to Biomedical Applications 11

II.2. Soft Hybrid Nanoparticles: from Preparation to Biomedical Application 30 II.3. Characterization methodologies TGA and Magnetization 63

II.4. Magnetic particles: From preparation to lab-on-achip, biosensor microsystems 76

And microfluidics applications III. Experimental Part 99

III.1 Elaboration of submicron hybrid magnetic latex particles 102

III.2 Carboxylic magnetic latex particles and enhacement with Methacrylic acid 112

III.3 Ochratoxin A detection with Carboxylic magnetic latex particles 124

III.4 Magneto-biosensor for Sulfaperidine detection 144

IV. Discussion and Conclusion 156

V. Perspective 160

PART I

DWWKHDWRPLFDQGPROHFXODUOHYHOV:LWKWKHSDVVDJHRIWLPHQDQRWHFKQRORJ\KDVLQWURGXFHG VHYHUDO GLYHUVLILHG IXQGDPHQWDO DQG DSSOLHG DVSHFWV VXFK DV QDQRELRWHFKQRORJ\ ELRQDQRWHFKQRORJ\ VXUIDFHHQKDQFHG 5DPDQ VFDWWHULQJ 6(56 TXDQWXP GRWV DQG DSSOLHG

PLFURELRORJ\ LQ PDWHULDOV VFLHQFH DQG HQJLQHHULQJ 1DQRSDUWLFOH LV D QDQRVL]HG  HQWLW\

ZKLFKPD\EHFU\VWDOOLQHDQDQRFU\VWDODPRUSKRXVRUQRQFU\VWDOOLQHDUUD\DFOXVWHUVXFKDV

D IXOOHUHQH ,W LV WKH LQWHJUDO FRPSRQHQW LQ WKH PDQXIDFWXUH RI D QDQRVWUXFWXUH ,W LV PRUH

LQILQLWHVLPDO WKDQ RUGLQDU\ REMHFWV WKDW DUH JRYHUQHG E\ 1HZWRQ¶V ODZV RI PRWLRQ KRZHYHU ODUJHUWKDQDWRPVRUVLPSOHPROHFXOHVWKDWIROORZTXDQWXPPHFKDQLFV$QDQRSDUWLFOHLVDQ\ VRUWRISDUWLFOHZLWKDWOHDVWRQHGLPHQVLRQOHVVWKDQQP1DQRSDUWLFOHVSURIRXQGO\DIIHFWD QXPEHURIDUHDVHQFRPSDVVLQJSKDUPDFHXWLFDOVDGYDQFHGPDWHULDOVHQYLURQPHQWDOGHWHFWLRQ DQGPRQLWRULQJHWF

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SRO\HWK\OHQHSRO\PHWK\OPHWKDFU\ODWHSRO\DPLGHVHWF/LNHZLVH ELRGHJUDGDEOHLQRUJDQLFQDQRSDUWLFOHVFRQVLVWRILURQR[LGHPDJQHWLVP]LQFR[LGHFDOFLXP SKRVSKDWHHWFZKLOHQRQELRGHJUDGDEOHLQRUJDQLFQDQRSDUWLFOHVFRQVLVWRIFDUERQQDQRWXEHV TXDQWXPGRWVJROGVLOYHUQLFNHODOXPLQXPWDOFFHULXPR[LGHFRSSHUPDQJDQHVHELVPXWK DQGWLWDQLXPHWF1DQRSDUWLFOHVKDYHSHUIRUPHGDVXEVWDQWLDOUROHLQGUXJGHOLYHU\LPDJLQJ WLVVXHHQJLQHHULQJGHWR[LILFDWLRQDQGWKHUDQRVWLFV &ROORLGDOSDUWLFOHVRIIHUYHU\FRQYHQLHQWGLDJQRVWLFVROXWLRQVZLWKFRQVLVWHQWUHVXOWVWKURXJK HIIHFWLYH VFUHHQLQJ DSSURDFKHV IRU QXPHURXV PDODGLHV 7KHVH HQFRPSDVV FHOO VRUWLQJ

LPPXQRDVVD\ QXFOHLF DFLG FDSWXULQJ DQG GHWHFWLRQ HWF 'XULQJ WKH ODVW WHQ \HDUV VHYHUDO

FROORLGDO SDUWLFOHV KDYH EHHQ IDEULFDWHG DQG H[WHQVLYHO\ LQYHVWLJDWHG IRU PHGLFDO SXUSRVHV

JURXS ±6+ DPLQH JURXS ±1+ FDUER[\OLF JURXS ±&22+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

RUJDQLFPDWHULDO0RUHRYHUJROGQDQRSDUWLFOHVFDQFDSWXUHOLJKWRYHUDEURDGVSHFWUDOUDQJH

IURP WKH YLVLEOH WR QHDULQIUDUHG DQG FDQ EH HPSOR\HG IRU GLDJQRVLV DV RSWLFDOO\ WXQHDEOH

FDUULHUV EHFDXVH RI WKHLU VKDSH DQG VL]H +\EULG QDQRSDUWLFOHV FDUU\ ERWK RUJDQLF DQG

LQRUJDQLF PRLHWLHV VLPXOWDQHRXVO\ 7KH\ DOVR H[KLELW LQWHUHVWLQJ RSWLFDO PDJQHWLF DQG

PHFKDQLFDO IHDWXUHV _{ 6HYHUDO WHFKQLTXHV VXFK DV DGVRUSWLRQ RI SRO\PHUV RQF ROORLGDO}

SDUWLFOHV DGVRUSWLRQ RI SRO\PHUV YLD OD\HUE\OD\HU VHOIDVVHPEO\ DGVRUSWLRQ RI

QDQRSDUWLFOHV RQ FROORLGDO SDUWLFOHV FKHPLFDO JUDIWLQJ RI SUHIRUPHG SRO\PHUV

SRO\PHUL]DWLRQIURPDQGRQWRFROORLGDOSDUWLFOHVFOLFNFKHPLVWU\DWRPLFWUDQVIHUUDGLFDO

SRO\PHUL]DWLRQ $753 UHYHUVLEOH DGGLWLRQIUDJPHQWDWLRQ FKDLQWUDQVIHU UDGLFDO 5$)7

SRO\PHUL]DWLRQ QLWUR[LGHPHGLDWHG SRO\PHUL]DWLRQ 103DQG FRQYHQWLRQDO VHHG UDGLFDO

SRO\PHUL]DWLRQKDYHEHHQHVWDEOLVKHGIRUWKHIDEULFDWLRQDQGFKDUDFWHUL]DWLRQRIVRIWK\EULG

FRUHVKHOOFROORLGDOSDUWLFOHV

6LQFH WKH ODVW GHFDGH PDJQHWLF QDQRSDUWLFOHV VXSHUSDUDPDJQHWLVP KDYH SOD\HG DQ LPSHUDWLYHUROHLQin-vitro DQGLQin-vivo ELRPHGLFDOVFLHQFH6\QWKHWLFPHWKRGRORJLHVVXFK DVVHSDUDWLRQRILURQVDOWVIURPDTXHRXVVROXWLRQVE\SUHFLSLWDWLRQWKHUPDOGHFRPSRVLWLRQRI LURQSUHFXUVRUVLQRUJDQLFRUDTXHRXVPHGLDDQGZDWHULQRLOZRPLFURHPXOVLRQKDYHEHHQ HQJDJHGIRUWKHGHYHORSPHQWRIKRPRJHQRXVDQGPRQRGLVSHUVHVXSHUSDUDPDJQHWLFLURQR[LGH QDQRSDUWLFOHV63,21,QSDUWLFXODUPDJQHWLFFROORLGDOSDUWLFOHVKDYHFRQWULEXWHGUHPDUNDEOH DSSOLFDWLRQV LQ D QXPEHU RI ELRPHGLFDO DQG WKHUDSHXWLF GLDJQRVWLF DSSOLFDWLRQV 7KHVH SDUWLFOHVDUHHPSOR\HGDVVROLGVXSSRUWIRUELRPROHFXOHVVXFKDVEDFWHULDYLUXVHVHWFLQ RUGHU WRLPSURYHWKHVHQVLWLYLW\RIin-vitro ELRPHGLFDOGLDJQRVLV 2QWKHEDVLVRIPDJQHWLFSDUWLFOHVELRQDQRWHFKQRORJ\KDVYDULRXVSURPLVLQJDSSOLFDWLRQV ,Q WKHSDVWPDJQHWLFSDUWLFOHVKDYHEHHQH[SORLWHGIRUWKHLURXWVWDQGLQJDSSOLFDWLRQVLQGLIIHUHQW ILHOGVVXFKDVFRQWUROOHGGUXJGHOLYHU\FDWDO\VLVQXFOHLFDFLGLVRODWLRQLPDJLQJEDFWHULDDQG YLUXVHVGHWHFWLRQVHQVLQJDQGWDUJHWHGGUXJGHOLYHU\PDJQHWLFUHVRQDQFHLPDJLQJFHOOVRUWLQJ UHFRJQLWLRQRIIOXRUHVFHQWDQWLERG\VSHFLILFEDFWHULDDQGYLUXVHVVHSDUDWLRQGHWHUPLQDWLRQRI WLWHU RI QXFOHLF DFLG DV DY DFFLQH FDUULHU DQG in-vitro GLDJQRVLV 7KH XWLOL]DWLRQ RI FROORLGDO SDUWLFOHVDVDVROLGVXSSRUWGHPDQGVVHYHUDOWHGLRXVDQGWLPHFRQVXPLQJLVRODWLRQWHFKQLTXHV VXFK DV ILOWUDWLRQ DQG FHQWULIXJDWLRQ ZKLFK KLQGHU WKH DXWRPDWLRQ RI GLDJQRVWLF SURFHGXUHV UHVXOWLQJLQSURORQJHGGLDJQRVLV2QWKHRWKHUKDQGPDJQHWLFSDUWLFOHVSURYLGHDGYDQWDJHE\ FLUFXPYHQWLQJWKHVHSUREOHPV7KHFKLHIDGYDQWDJHSURYLGHGE\PDJQHWLFSDUWLFOHV LV

DVVRFLDWHG ZLWK TXLFN SDUWLFOH LVRODWLRQ XSRQ DSSO\LQJ HYHQ ORZ PDJQHWLF ILHOG 7KXV WKH

PDJQHWLFSDUWLFOHVIDFLOLWDWHWKHSURFHVVRIDXWRPDWLRQWKHUHE\OHVVHQLQJWLPHGHOD\V

1RZDGD\V WKH NH\ HPSKDVLV LQ ELRPHGLFDO GLDJQRVLV LV WR LPSURYH WKH VSHFLILFLW\ DQG VHQVLWLYLW\DQGWRPLQLPL]HWLPHFRQVXPSWLRQ2QHZD\WRDFKLHYHWKLVJRDOLVWRLQFUHDVHW K H 

IURPWKHLUQDQRVL]HV 7KHKDYHFRQWULEXWHGVHYHUDORXWVWDQGLQJDSSOLFDWLRQVLQGLIIHUHQW LQGXVWULDO DQG ELRPHGLFDO GLDJQRVWLF ILHOGV IRU LQVWDQFH UDSLG VHSDUDWLRQ XSRQD SSO\LQJ

HYHQ ORZ PDJQHWLF ILHOG SXULILFDWLRQ DQG GHWHFWLRQ RI ELRPROHFXOHV HWF $ QXPEHU RI

PHWKRGRORJLHV KDYH EHHQ SXW IRUZDUG IRU WKH IDEULFDWLRQ RI PDJQHWLF ODWH[ SDUWLFOHV IRU GLDJQRVWLF SXUSRVHV 7KHVH PHWKRGV DUH EDVHG RQ FODVVLFDO SRO\PHUL]DWLRQ LQ GLVSHUVHG

PHGLDOLNHHPXOVLRQVXVSHQVLRQPLQLHPXOVLRQGLVSHUVLRQFRPELQDWLRQRIGLIIHUHQW

SRO\PHUEDVHG SURFHVVDQG LQYHUVH HPXOVLRQ KRZHYHU DOO WKHVH WHFKQLTXHV OHDGV WR

XQZDQWHGOLPLWDWLRQVVXFKDVORZPDJQHWLFFRQWHQWKHWHURJHQRXVGLVWULEXWLRQRIPDJQHWLF

QDQRSDUWLFOHV ORZ PDJQHWLF VHSDUDWLRQ XQGHU PDJQHWLF ILHOG HWF 7KH SLRQHHU ZRUN

UHJDUGLQJ WKH SUHSDUDWLRQ RI PDJQHWLF ODWH[HV DQG WKHLU XVH IRU ELRPHGLFDO GLDJQRVWLF

SXUSRVHV ZDV FRLQHG E\ 8JHOVWDG 5HFHQWO\ 0RQWDJH HW DOKDV UHSRUWHG DS URFHVV IRU

REWDLQLQJKLJKO\PDJQHWLFVXEPLFURQPDJQHWLFODWH[SDUWLFOHV7KLVSURFHVVLVFDOOHGVHHG HPXOVLRQ SRO\PHUL]DWLRQ 3UHYLRXVO\ PDJQHWLF ODWH[ SDUWLFOHV KDYH EHHQ HPSOR\HG IRU FDSWXULQJ RI ELRORJLFDO VDPSOHV IRU QXFOHLF DFLG H[WUDFWLRQ DQG SXULILFDWLRQ VSHFLILF

DQWLJHQGHWHFWLRQLQPRQLWRULQJRISURWHLQDGVRUSWLRQDQGGHVRUSWLRQ

0LFURIOXLGLF V\VWHPV DUH GHYLFHV WKDW GHDO ZLWK VXE1DQR OLWHU YROXPHV RI IOXLGV

7KHVHGHYLFHVSRVVHVVUHGXFHGGLPHQVLRQVDQGWRJHWKHUZLWKFROORLGVSOD\DQLPSRUWDQWUROH

LQ WKH GHYHORSPHQW RI PRQRGLVSHUVHG FROORLGDO SDUWLFOHV LQ D FRQWLQXRXV PRGH

0LFURIOXLGLFUHDFWRUVDUHHPSOR\HGIRUWKHIRUPDWLRQRIQDQRSDUWLFOHV7KHIORZSURFHVVKDV DQ LPSRUWDQW UROH LQ WKHVH GHYLFHV 7KLV IORZ FDQ EH UHJXODWHG E\ WKH DSSOLFDWLRQ RI IRUFH PRWLRQRIFROORLGDOPLFURSDUWLFOHVLQPLFURFKDQQHO5HJDUGLQJELRORJ\RIKXPDQERG\WKH

PROHFXODU HYHQWV SOD\ D VLJQLILFDQW UROH LQ ELRPHGLFDO GLDJQRVLV ZKLFK FDQ EH

DFFRPSOLVKHG E\ H[HFXWLQJ YDULRXV ELRORJLFDO WHVWV LQ VSHFLILF ODERUDWRULHV 7KHVH WHVWV LQYROYH PXOWLVWHS DQG LQWULFDWH SURFHVVHV VXFK DV VDPSOH FROOHFWLRQ SUHSDUDWLRQ DQG VSHFLILFLGHQWLILFDWLRQRIELRPROHFXOHVUHTXLULQJERWKODERUDQGSURORQJGXUDWLRQ

,Q UHFHQW \HDUV FRQVLGHUDEOH DGYDQFHPHQW KDV EHHQ PDGH LQ PLFURIOXLGLF WHFKQRORJ\ ,W SRVVHVVHV QXPHURXV SURPLVLQJ DSSOLFDWLRQV LQ SKDUPDFHXWLFDO LQGXVWU\ OLIH VFLHQFH DQG FKHPLFDO UHVHDUFKHV ,W GHDOV ZLWK PLQLDWXUL]DWLRQ DQG FRPELQDWLRQ RI PROHFXODUOHYHO ELRORJLFDOWHVWVLQWRKLJKSHUIRUPDQFHDQGXOWUDILQHV\VWHPVWKDWFDQLQWHJUDWHPLQLDWXUL]HG ODERUDWRU\ IXQFWLRQV VXFK DV VHSDUDWLRQ DQG DQDO\VLV RI FRPSRQHQWV RI D PL[WXUH RQ D VLQJOHPLFURSURFHVVRUFKLSXVLQJYHU\PLQXWHIOXLGYROXPHVIURPQDQROLWHUVWRSLFROLWHUVLQ DQ RUJDQL]HG IDVKLRQ %DVHG RQP LFURHOHFWURPHFKDQLFDO WHFKQRORJ\ PLFURIOXLGLF WHFKQRORJ\ LQWHJUDWHV DQG PLQLDWXUL]HV WKH VHSDUDWLQJ UHDFWLRQ DQG PL[LQJ GHYLFHV LQ JHQHUDOODERUDWRULHVRQWR D YHU\ WLQ\ FKLS FDOOHG /DERQDFKLS V\VWHP DOVR NQRZQ DV D

PLFURWRWDODQDO\WLFDO V\VWHP — 7$6 RU PLFURIOXLGLFV GHYLFH 7KHVH GHYLFHV DUH YHU\

FRQYHQLHQW GXH WR   WKHLU H[FOXVLYH SURSHUWLHV VXFK DV UHGXFWLRQ RI VROYHQW UHGXFWLRQ RI VDPSOH FROOHFWLRQ LPSURYHPHQW RI PDVV DQG KHDW WUDQVIHU RZLQJ WR D KLJK VXUIDFHWR YROXPH UDWLR 7KHVH PLFURGHYLFHV KDYH FHUWDLQ PHULWV VXFK DV OHVV WLPH FRQVXPSWLRQ

0DJQHWLF ODWH[ SDUWLFOHV DUH JHQHUDOO\ XVHG LQ PLFURIOXLGLFV DQG IRU HQYLURQPHQWDO FRQWHQW 2XUDLPLVWRLQYHVWLJDWHKRZWKHVHPDJQHWLFODWH[SDUWLFOHVFDQEHXVHGWRHQKDQFHVHQVLWLYLW\ RUKRZWRIXQFWLRQDOL]HVXUIDFHRIELRVHQVRU

,QRUGHUWRWDUJHWVXFKREMHFWLYHRXUDLPLVWRSUHSDUHVXEPLFURQPDJQHWLFODWH[SDUWLFOHVE\ XVLQJVHHGHPXOVLRQSRO\PHUL]DWLRQKDYLQJPDJQHWLFFRUHDQGSRO\PHU VKHOOFRUHVKHOOWR SURWHFW LURQ R[LGH LQVLGH SHUIHFW SRO\PHU VKHOO ZLWK VSHFLILF SURSHUWLHV VXFK DV VXSHUSDUDPDJQHWLFLQQDWXUHKLJKPDJQHWLFFRQWHQWJRRGFROORLGDOVWDELOLW\JRRGFKHPLFDO VWDELOLW\ WKHUH LV QR GHJUDGDWLRQ RI SDUWLFOHV DQG ZLWK DOPRVW QDUURZ VL]H GLVWULEXWLRQ )XQFWLRQDOLW\RIWKHVHSDUWLFOHVZDVGRQHZLWKFDUER[\OLFJURXSVIRULPPXQRDVVD\

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

7KH VHFRQG SDUW RI WKHVLV GHDOV ZLWK H[SHULPHQWDO VWXGLHV )LUVWO\ GLIIHUHQW SRO\PHUL]DWLRQ H[SHULPHQWVDUHSHUIRUPHGLQRUGHUWRJHWGHVLUHGPRUSKRORJ\ZLWKVXEPLFURQPDJQHWLFODWH[ SDUWLFOHV 6HFRQGO\ IXQFWLRQDOL]DWLRQ DQG HQKDQFHPHQW RI WKHVH PDJQHWLF ODWH[ SDUWLFOHV LV GRQH ZLWK FDUER[\OLF JURXSV )LQDOO\ WKHVH SDUWLFOHV DUH XVHG LQ ELRVHQVRU WR LQFUHDVH VHQVLWLYLW\DQGDOVRIRUVSHFLILFDQWLERG\GHWHFWLRQ

References:



 $XOD 6 et al. %LRSK\VLFDO ELRSKDUPDFHXWLFDO DQG WR[LFRORJLFDO VLJQLILFDQFH RI ELRPHGLFDOQDQRSDUWLFOHVRSC Adv. 5, ±

 %DUQDUG $ 6 0RGHOOLQJ RI QDQRSDUWLFOHV DSSURDFKHV WR PRUSKRORJ\ DQG HYROXWLRQRep. Prog. Phys. 73, 

 =DIDU1)HVVL+ (ODLVVDUL$&ROORLGDOSDUWLFOHVFRQWDLQLQJODEHOLQJDJHQWVDQG F\FORGH[WULQVIRUWKHUDQRVWLFDSSOLFDWLRQVInt. J. Pharm. 472, ±  *XSWD $ .  *XSWD 0 6\QWKHVLV DQG VXUIDFH HQJLQHHULQJ RI LURQR[LGH

QDQRSDUWLFOHVIRUELRPHGLFDODSSOLFDWLRQVBiomaterials 26, ±  0RUD+XHUWDV&()HVVL+ (ODLVVDUL$3RO\PHUEDVHGQDQRFDSVXOHVIRUGUXJ

GHOLYHU\Int. J. Pharm. 385, ±

 +EQHU ( et al. 6\QWKHVLV RI 3RO\PHU6LOLFD +\EULG 1DQRSDUWLFOHV 8VLQJ $QLRQLF3RO\PHUL]DWLRQ7HFKQLTXHVMacromolecules 43, ±

 /RR & /RZHU\ $ +DODV 1 :HVW -  'UH]HN 5 ,PPXQRWDUJHWHG 1DQRVKHOOVIRU,QWHJUDWHG&DQFHU,PDJLQJDQG7KHUDS\Nano Lett. 5, ± 

 *UDYDQR 6 0 'XPDV 5 /LX .  3DWWHQ 7 ( 0HWKRGV IRU WKH VXUIDF H IXQFWLRQDOL]DWLRQRIȖ)H2QDQRSDUWLFOHVZLWKLQLWLDWRUVIRUDWRPWUDQVIHUUDGLFDO SRO\PHUL]DWLRQ DQG WKH IRUPDWLRQ RI FRUH±VKHOO LQRUJDQLF±SRO\PHU VWUXFWXUHV J.

Polym. Sci. Part Polym. Chem. 43, ±

 %RPEDOVNL/'RQJ+/LVWDN-0DW\MDV]HZVN. %RFNVWDOOHU051XOO- 6FDWWHULQJ+\EULG3DUWLFOHV8VLQJ&RQWUROOHG5DGLFDO3RO\PHUL]DWLRQAdv. Mater.

KLJKO\ PDJQHWLF VXEPLFURQLF SRO\PHU SDUWLFOHV YLD D VWHSZLVH KHWHURFRDJXODWLRQ SURFHVVColloid Polym. Sci. 283, ±

 &KDUOHX[%'¶$JRVWR) 'HODLWWUH*LQHybrid Latex Particles HGV

+HUN$0YDQ /DQGIHVWHU.±6SULQJHU%HUOLQ+HLGHOEHUJ  .ROE+&)LQQ0* 6KDUSOHVV.%&OLFN&KHPLVWU\'LYHUVH&KHPLFDO

)XQFWLRQ IURP D )HZ *RRG 5HDFWLRQV Angew. Chem. Int. Ed. 40, ± 

 9RQ : HUQH 7  3DWWHQ 7 ( $WRP WUDQVIHU UDGLFDO SRO\PHUL]DWLRQ IURP QDQRSDUWLFOHVDWRROIRUWKHSUHSDUDWLRQRIZHOOGHILQHGK\EULGQDQRVWUXFWXUHVDQG IRUXQGHUVWDQGLQJWKHFKHPLVWU\RIFRQWUROOHGµOLYLQJ¶UDGLFDOSRO\PHUL]DWLRQVIURP VXUIDFHVJ. Am. Chem. Soc. 123, ±

 0RDG * 5L]]DUGR (  7KDQJ 6 + 5DGLFDO DGGLWLRQ±IUDJPHQWDWLRQ FKHPLVWU\LQSRO\PHUV\QWKHVLVPolymer 49, ±

 /DGPLUDO 9 0RULQDJD 7 2KQR . )XNXGD 7  7VXMLL < 6\QWKHVLV RI PRQRGLVSHUVH]LQFVXOILGHSDUWLFOHVJUDIWHGZLWKFRQFHQWUDWHGSRO\VW\UHQHEUXVKE\ VXUIDFHLQLWLDWHGQLWUR[LGHPHGLDWHGSRO\PHUL]DWLRQEur. Polym. J. 45, ± 

 * 3LEUH / +DNHQKRO] 6 %UDFRQQRW + 0RXD]L] DQG $ (ODLVVDULH 3RO\PHUV1R

 %LWDU$et al. )HUURIOXLGV)URP3UHSDUDWLRQWR%LRPHGLFDO$SSOLFDWLRQVJ. Colloid

Sci. Biotechnol. 3, ±

 (ODLVVDUL $  )HVVL + 5HDFWLYH DQG +LJKO\ 6XEPLFURQ 0DJQHWLF /DWH[HV IRU %LRQDQRWHFKQRORJ\$SSOLFDWLRQVMacromol. Symp. 288, ±

 0RQWDJQH)0RQGDLQ0RQYDO23LFKRW& (ODwVVDUL$+LJKO\PDJQHWLF ODWH[HVIURPVXEPLFURPHWHURLOLQZDWHUIHUURIOXLGHPXOVLRQVJ. Polym. Sci. Part

Polym. Chem. 44, ±

 <DQDVH 1 1RJXFKL + $VDNXUD +  6X]XWD 7 3UHSDUDWLRQ RI PDJQHWLF ODWH[ SDUWLFOHV E\ HPXOVLRQ SRO\PHUL]DWLRQ RI VW\UHQH LQ WKH SUHVHQFH RI D IHUURIOXLG J.

Appl. Polym. Sci. 50, ±

 'DQLHO -& 6FKXSSLVHU -/  GHFHDVHG 0 7 0DJQHWLF SRO\PHU ODWH[ DQG SUHSDUDWLRQSURFHVV

 5DPtUH] / 3  /DQGIHVWHU . 0DJQHWLF 3RO\VW\UHQH 1DQRSDUWLFOHV ZLWK D+ LJK 0DJQHWLWH &RQWHQW 2EWDLQHG E\ 0LQLHPXOVLRQ 3URFHVVHV Macromol. Chem. Phys. 204, ±

 'LQJ ; % 6XQ = + :DQ * ;  -LDQJ < < 3UHSDUDWLRQ RI WKHUPRVHQVLWLYHPDJQHWLFSDUWLFOHVE\GLVSHUVLRQSRO\PHUL]DWLRQReact. Funct.

Polym. 38, ±

 (ODLVVDUL $ 0DJQHWLF /DWH[ 3DUWLFOHV LQ 1DQRELRWHFKQRORJLHV IRU %LRPHGLFDO 'LDJQRVWLF$SSOLFDWLRQV6WDWHRIWKH$UWMacromol. Symp. 281, ±  'UHVFR3$=DLWVHY96*DPELQR5- &KX%3UHSDUDWLRQDQG3URSHUWLHVRI

0DJQHWLWHDQG3RO\PHU0DJQHWLWH1DQRSDUWLFOHVLangmuir 15, ±  8JHOVWDG-et al. LQMolecular Interactions in Bioseparations HG1JR77±

6SULQJHU86

 -DPVKDLG7et al. LQSoft Nanoparticles for Biomedical Applications DW 56&

WR '1$ VHSDUDWLRQ DQG SURWHLQ GLJHVWLRQ Houille Blanche-Rev. Int. Eau ± 

 /LX<+XJHQWREOHU&3 6KXP+&$0LOOLIOXLGLF$SSURDFKIRU&RQWLQXRXV *HQHUDWLRQRI/LTXLG0DUEOHVJ. Colloid Sci. Biotechnol. 2, ±  -RR-et al. $IDFLOHDQGVHQVLWLYHGHWHFWLRQRISDWKRJHQLFEDFWHULDXVLQJPDJQHWLF

QDQRSDUWLFOHVDQGRSWLFDOQDQRFU\VWDOSUREHVAnalyst 137, ±

 .XVFKHO01HXPDQQ7%DUWKPDLHU3 .UDW]PHLHU08VHRIODERQDFKLS WHFKQRORJ\ IRU SURWHLQ VL]LQJ DQG TXDQWLWDWLRQ J. Biomol. Tech. JBT 13, ± 

PART II

Introduction

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 UHYHUVLEOH DGGLWLRQ

IUDJPHQWDWLRQ FKDLQWUDQVIHU UDGLFDO 5$)7 SRO\PHUL]DWLRQ QLWUR[LGHPHGLDWHG

SRO\PHUL]DWLRQ 103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in-vitro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

1RZDGD\V WKH NH\ LPSRUWDQFH LQ ELRPHGLFDO GLDJQRVLV LV WR LPSURYH WKH VSHFLILFLW\ DQG VHQVLWLYLW\DQGWRUHGXFHWLPHFRQVXPSWLRQ2QHZD\WRUHDFKWKLVJRDOLVWRLQFUHDVHWKHWLWHU RI FDSWXUHG WDUJHWV VXFK DV DQWLJHQ YLUXVHV EDFWHULD DQG QXFOHLF DFLG SULRU WR WKH GHWHFWLRQ VWHS ,Q WKH SUHYLRXV GHFDGHV PDJQHWLF ODWH[ QDQRSDUWLFOHV 013V KDYH EHHQ JUDEELQJ HQRUPRXV DWWHQWLRQ RZLQJ WR WKHLU VXSHUSDUDPJQHWLF FKDUDFWHULVWLFV RULJLQDWLQJ IURP WKHLU QDQRVL]HV7KH\KDYHFRQWULEXWHGVHYHUDORXWVWDQGLQJDSSOLFDWLRQVLQGLIIHUHQWLQGXVWULDODQG ELRPHGLFDOGLDJQRVWLFILHOGVIRULQVWDQFHUDSLGVHSDUDWLRQXSRQDSSO\LQJHYHQORZPDJQHWLF ILHOGSXULILFDWLRQDQGGHWHFWLRQRIELRPROHFXOHVHWF

,QUHFHQW\HDUVFRQVLGHUDEOHDGYDQFHPHQWKDVEHHQPDGHLQPLFURIOXLGLFWHFKQRORJ\,WGHDOV ZLWKPLQLDWXUL]DWLRQDQGFRPELQDWLRQRIPROHFXODUOHYHOELRORJLFDOWHVWVLQWR KLJK

%DVHG RQP LFURHOHFWURPHFKDQLFDO WHFKQRORJ\ PLFURIOXLGLF WHFKQRORJ\ LQWHJUDWHV DQG PLQLDWXUL]HVWKHVHSDUDWLQJUHDFWLRQDQGPL[LQJGHYLFHVLQJHQHUDOODERUDWRULHVRQWRDYHU\ WLQ\ FKLS FDOOHG /DERQDFKLS V\VWHP DOVR NQRZQ DV D PLFURWRWDODQDO\WLFDO V\VWHP PLFUR7$6 RU PLFURIOXLGLFV GHYLFH 7KHVH GHYLFHV DUH YHU\ FRQYHQLHQW GXH WR WKHLU H[FOXVLYH SURSHUWLHV VXFK DV UHGXFWLRQ RI VROYHQW UHGXFWLRQ RI VDPSOH FROOHFWLRQ LPSURYHPHQW RI PDVV DQG KHDW WUDQVIHU RZLQJ WR D KLJK VXUIDFHWRYROXPH UDWLR 7KHVH PLFURGHYLFHV KDYH FHUWDLQ PHULWV VXFK DV OHVV WLPH FRQVXPSWLRQ LQH[SHQVLYHQHVV DQG LPSURYHGUHSURGXFLELOLW\HVVHQWLDOWRURXWLQHELRORJLFDOVDPSOHV

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 DQG SURYLGH KLJK VSHFLILF DUHD IRU LPPRELOL]DWLRQ RI ODUJH DPRXQW RI ELRPROHFXOHV 7KHVH SDUWLFOHV IXUQLVK VXUIDFH IXQFWLRQDOLW\ IRU FRYDOHQW JUDIWLQJ RI ELRPROHFXOHVDQGKLJKLURQR[LGHVXSHUSDUDPDJQHWLFFRQWHQWIRUUDSLGVHSDUDWLRQXQGHU DSSOLHGPDJQHWLFILHOG7KHPRUSKRORJ\RIWKHVHPDJQHWLFODWH[QDQRSDUWLFOHVVLJQLILFDQWO\ GHWHUPLQHV WKHLU XOWLPDWH XWLOL]DWLRQ 7KH FRUHVKHOO VWUXFWXUH RI WKH FROORLGDO PDJQHWLF QDQRSDUWLFOHV LV WKH PRVW DSSURSULDWH IRU ELRPHGLFDO GLDJQRVLV 7KLV PRUSKRORJ\ DOVR SUHYHQWV IURP PRGLILFDWLRQ RI WKHLU ELRORJLFDO SURSHUWLHV 6XUIDFH PRGLILFDWLRQ RU DWWDFKPHQW RI VSHFLILF IXQFWLRQDO JURXSV OLNH VXOIDWH FDUER[\O DPLQH DQG K\GUR[\O LV UHTXLUHG WR GLYHUVHO\ XWLOL]H PDJQHWLF SDUWLFOHV DV FDUULHU RI ELRPROHFXOHV HJ DQWLERG\ DQWLJHQ YLUXV EDFWHULD HWF DQG WKHQ WR GHVLJQ D /DE RQ&KLS V\VWHP XVLQJ WKH VDPH PDJQHWLF ODWH[ SDUWLFOHV DQG FRQVHTXHQWO\ H[SORULQJ WKH LPPRELOL]DWLRQ RI DQWLERGLHV IRU GLDJQRVWLFXVHV0DJQHWLFODWH[SDUWLFOHVDUHHPSOR\HGHIILFLHQWO\DVFDUULHURIELRPROHFXOHV LQPLFURV\VWHP

CHAPTER II.1

Ferrofluids: From Preparation to Biomedical

Applications

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

7KH SUHSDUDWLRQRI IHUURIOXLGV LQYROYHV PDJKHPLWH DQG PDJQHWLWH6HYHUDO PHWKRGV KDYH EHHQ XVHG IRU WKHLU SUHSDUDWLRQ LQFOXGH VL]H UHGXFWLRQ FKHPLFDO V\QWKHVLV FRSUHFLSLWDWLRQ WKHUPDO GHFRPSRVLWLRQ DQG PLFURHPXOVLRQ PHWKRGV HOHFWURGHFRPSRVLWLRQ WHFKQLTXHV HYDSRUDWLRQ RI PHWDOLQOLTXLGVDQGFDUULHUOLTXLGH[FKDQJH6L]HUHGXFWLRQDQG&KHPLFDO6\QWKHVLVPHWKRGVDUH IUHTXHQWO\HPSOR\HG

3URSHUWLHVRIIHUURIOXLGVDUHDFUXFLDODUHDIRUWKHLUXOWLPDWHXVHLQDSSOLFDWLRQV)HUULWHVDUHLURQ R[LGHV KDYLQJ VSLQH W\SH FU\VWDO VWUXFWXUH 7KH FU\VWDOORJUDSKLF VWUXFWXUH RI WKH PDJKHPLWH LV LGHQWLFDOWRWKDWRIPDJQHWLWHZLWKWKHH[FHSWLRQRIFHUWDLQGHIRUPLWLHVDVVRFLDWHGZLWKR[LGDWLRQ UHGXFWLRQ0RVVEDXHUVSHFWURVFRS\LVWKXVIRUSURYHGWREHDPHWKRGRIFKRLFHWRLGHQWLI\H[DFW QDWXUHRILURQR[LGHV

0RUSKRORJ\ 6L]H DQG 6L]H 'LVWULEXWLRQ $QDO\VLV LV GRQH E\ XVLQJ DWRPLF IRUFH PLFURVFRS\ $)0 VFDQQLQJ HOHFWURQ PLFURVFRS\ 6(0 DQG WUDQVPLVVLRQ HOHFWURQ PLFURVFRS\ 7(0 0RUSKRORJ\DQGVKDSHRISDUWLFOHVPDLQO\GHSHQGXSRQSUHSDUDWLRQSURFHVV

:LWK UHJDUGV WR HOHFWURNLQHWLF SURSHUWLHV EHLQJ DPSKRWHULF LQ QDWXUHLURQ R[LGHV SRVVHVV QHJDWLYHFKDUJHLQEDVLFPHGLXPZKLOHWKH\DUHSRVLWLYHLQDFLGLFPHGLXP7KHUHIRUHWKHLUVWDWH RIGLVSHUVLRQGHSHQGVRQWKHVXUIDFHFKDUJHGHQVLW\6HYHUDOOLJDQGVKDYHEHHQVWXGLHGUHVXOWLQJ LQVWDEOHIHUURIOXLGVDWGLIIHUHQWS+UDQJHV$SDUWIURPPHFKDQLVPRIVWDELOL]DWLRQDWVSHFLILFS+ WKHLUVWDELOLW\GHSHQGVODUJHO\RQWKHQDWXUHRIOLJDQGIXQFWLRQDOJURXSVLQYROYHGLQFRPSOH[DWLRQ UHDFWLRQ

&ROORLGDO VWDELOLW\ LV DFKLHYHG E\ VXUIDFWDQW RU SRO\PHU PRGLILFDWLRQ RI WKH PDJQHWLF QDQRSDUWLFOHV 0DJQHWLF SURSHUWLHV DOVR DUH LPSRUWDQW GHWHUPLQDQW IRU WKHLU DSSOLFDWLRQV 0DJQHWLF QDQRSDUWLFOH¶V UHVSRQVH WR DSSOLHG PDJQHWLF ILHOG GHSHQGV RQ WKH VL]H RI SDUWLFOHV W\SLFDOO\EHWZHHQQPGHSHQGLQJRQWKHPDWHULDODVZHOODVLWVVWDWH

6XUIDFH )XQFWLRQDOL]DWLRQLV EDVHG RQW ZR PDLQ WHFKQLTXHV LH SK\VLFDO FKHPLVWU\ EDVHG DSSURDFKDQGFKHPLVWU\EDVHGSURFHVV3K\VLFDOFKHPLVWU\EDVHGDSSURDFKHVLQFOXGH VXUIDFH

,PPRELOL]DWLRQ DQG SRO\PHUV DGVRUSWLRQ ZKLOH WKH PRVW ZLGHO\ XVHG FKHPLVWU\ EDVHG DSSURDFKLVVLOLFDFRDWLQJRILURQR[LGHQDQRSDUWLFOHV

0DJQHWLFIHUURIOXLGVKDYHEHHQVXFFHVVIXOO\WULHGLQQXPHURXVDSSOLFDWLRQVLQFOXGLQJWKHLU XVHLQLQGXVWU\PDJQHWLFLQNVVHDOLQJSDLQWVIRUUHFRUGLQJWDSHVDQGUHFHQWO\LQELRPHGLFDO DSSOLFDWLRQV OLNH PDJQHWLF UHVRQDQFH LPDJLQJ 05,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

+\SHUWKHUPLDXVLQJQDQRWHFKQRORJ\EDVHGQDQRSDUWLFOHVKDVDWWUDFWHGVLJQLILFDQWDWWHQWLRQ UHFHQWO\ LQ FDQFHU WKHUDS\ &DQFHU LV WUHDWHG WKURXJK PDJQHWLF ILHOG PRGXODWHG FHOO PHPEUDQHGDPDJHH[SORLWLQJIHUURIOXLGVWKDWHPLWKHDWXSRQH[SRVXUHWRDOWHULQJH[WHUQDO PDJQHWLF ILHOG 7KH SURGXFHG KHDW FDQ HIIHFWLYHO\ NLOO FDQFHU FHOO DQG VSDUHV WKH QHLJKERULQJQRUPDOFHOOVDIHDWXUHYHU\PXFKGHVLUHGLQFDQFHUWKHUDS\,QFDQFHUWKHUDS\ REWDLQLQJKLJKVSHFLILFORVVSRZHU6/3LVDQHFHVVLW\WRHQVXUHHIIHFWLYHQHVVRIWKHUDS\ DQGDQDUHDIRUIXUWKHUH[SORUDWLRQ6LJQLILFDQWZRUNLVUHTXLUHGWRDGGUHVVWKLVKRWDUHDRI UHVHDUFK 9HU\ UHFHQWO\ PDJQHWLF HPXOVLRQV D QHZ IRUP RI IHUURIOXLGV KDYH EHHQ GHYHORSHGWKDWKROGJUHDWSURPLVHLQIXUWKHUELRPHGLFDODSSOLFDWLRQV

Delivered by Publishing Technology to: University of Lyon-1 IP: 134.214.70.27 On: Tue, 04 Nov 2014 14:58:35

Copyright: American Scientific Publishers

REVI

EW

Ferrofluids: From Preparation to Biomedical Applications

Ahmad Bitar1_{, Chariya Kaewsaneha}1 2_{, Mohamed M. Eissa}1 4 ∗_{, Talha Jamshaid}1_,

Pramuan Tangboriboonrat2_{, Duangporn Polpanich}3_{, and Abdelhamid Elaissari}1

1_{Université de Lyon, F-69622, Lyon, France; Université Lyon1, Villeurbanne, CNRS, UMR 5007,}

Laboratoired’Automatique et de Génie des Procédés, LAGEP-CPE-308G, 43 bd. 5 du 11 Nov.1918, F-69622, Villeurbanne, France

2_{Department of Chemistry, Faculty of Science, Mahidol University, Phyathai, Bangkok 10400, Thailand} 3_{National Nanotechnology Center (NANOTEC), Thailand Science Park, PathumThani 12120, Thailand}

4_{Polymers and Pigments Department, National Research Centre, Dokki, Giza 12622, Egypt}

Discovery of the magnetic property (superparamagnetism) of ferrofluid (i.e., magnetic fluid) and its effects on the other materials open wide varieties of applications in human daily life. Continually, new applications require different forms of magnetic materials, which have significant attractions nowadays. This review highlights the ferrofluids synthesis methods. All known methods are cited, and a special interest is focused on the most commonly used methods for preparation, which depends on size reduction and chemical co-precipitation. Furthermore, the industrial and biomedical applications of ferrofluids and their based particles are discussed. Finally, the new water based dispersed ferrofluids particles “magnetic emulsion” is also introduced.

Keywords: Magnetic Nanoparticles, Ferrofluid, Synthesis, Applications.

CONTENTS

1. Introduction . . . 3

2. Preparation Methods . . . 5

2.1. Physical Based Method (Size Reduction) . . . 6

2.2. Chemistry Based Processes . . . 6

3. Properties . . . 7

3.1. Chemical Structure Analysis (X-Ray, Mössbauer) . . . 8

3.2. Morphology, Size and Size Distribution Analysis . . . 9

3.3. Electrokinetic Properties . . . 9

3.4. Colloidal Stability . . . 10

3.5. Magnetic Properties . . . 10

4. Surface Functionalization . . . 11

4.1. Physical Chemistry Based Processes . . . 11

4.2. Chemistry Based Approaches . . . 12

5. Applications . . . 12 5.1. Industrial Applications . . . 12 5.2. Biocatalysis . . . 13 5.3. Biomedical Applications . . . 14 6. Conclusion . . . 16 Acknowledgment . . . 16

References and Notes . . . 16

1. INTRODUCTION

Magnetization or magnetic susceptibility is a value which indicates the magnetization degree of a magnetic mate-rial under the effect of an external magnetic field. The material response to magnetic field depends on its size

∗_{Author to whom correspondence should be addressed.}

meaning that there is difference between the magnetic behavior of bulk and nanoparticles under the magnetic field. Nanoparticles with a radius below 150 Å belong to “single domain particle,” which remains in a state of uniform magnetization at any magnetic field.1 _Moreover,

both particle shape and size are greatly considerable fac-tors when discussing the magnetic properties of particles.2

Consequently, the nanoparticles have also paramagnetism property which means that they possess magnetic proper-ties only when they are exposed to an external magnetic field. Iron oxide nanoparticles are found to have superpara-magnetic properties, which allow using these nanoparticles for wide range of applications.

Ferrofluids are stable magnetic dispersions comprised of ferromagnetic nanoparticles with a diameter of approxi-mately 10 nanometers dispersed in an aqueous or organic liquid carrier. Rosensweig has described them for the first time in 1966.3_{The preparation of a magnetic fluid is}

gen-erally performed in two main stages, including: (i) the synthesis of magnetic nanoparticles, and then (ii) the dis-persion of these particles in a solvent or in a liquid phase by the aid of a surfactant capable of generating repul-sive interactions between the particles. The stabilization of ferromagnetic particles in the continuous phase can be achieved by using two methods, in the first, the nanopar-ticles are stabilized by a surfactant or polymer, it is called ferrofluid nanoparticles bearing surfactant; in the second,

Delivered by Publishing Technology to: University of Lyon-1 IP: 134.214.70.27 On: Tue, 04 Nov 2014 14:58:35

Copyright: American Scientific Publishers

REVI

EW

Ferrofluids: From Preparation to Biomedical Applications Bitar et al.

Ahmad Bitar was born in 1977 in Idleb, Syria. He received his B.Sc. in 2000, third/one hundred and twenty students, from the university of Aleppo, Syria. He received his M.Sc. in 2010 from the University of Lyon1, Lyon, France. In July 2013, he received his Ph.D. in nanoparticles synthesis for biomedical diagnostic application, in Engineering Processes and Automatic Laboratory (LAGEP), university Lyon-1, Lyon, France. Currently, he is working as post-doc in the university Lyon1 on the synthesis of active-loaded particles for cosmetic applications.

Chariya Kaewsaneha was born in 1984. She received Ph.D. (Polymer Science and Technol-ogy) from Mahidol University, Bangkok, Thailand in 2014. With financial support from the RGJ-TRF and French government, she has collaborative research with LAGEP Laboratory, Claude Bernard University Lyon-1, Lyon, France.

Mohamed M. Eissa is Associate Professor in Polymers Department, National Research Centre, Giza, Egypt. He has got Bachelor (1991), Master (1999) and Ph.D. (2006) from Chemistry Department, Faculty of Science-Cairo University, Egypt. His work is focused on polymer synthesis, and preparation of polymer composites and their applications in the industrial and biomedical domains. He has got four post doc scholarships in the period 2010– 2013 from the French government in the Engineering Processes and Automatic Laboratory (LAGEP-Lyon), France. Dr. Mohamed M. Eissa is Associate Editor in the Journal of Colloid Science and Biotechnology (JCSB) and he is a reviewer for many international Journals.

Talha Jamshaid is lecturer at the University of Lahore, Lahore, Pakistan. Currently, he is a Ph.D. scholar at LAGEP, University of Lyon-1, France. He received his first degree, Doctor of Pharmacy, from University of the Punjab, Lahore, Pakistan. He is doing research in the subject of Pharmaceutical Technology. He is particularly involved in the preparation of Magnetic latex particles to be used in microfluidic devices like Lab-on-a Chip, biosensors and microfluidics.

Pramuan Tangboriboonrat (Ph.D., Université de Haute Alsace, Ecole Nationale Supérieure de Chimie de Mulhouse, France in 1991) is full Professor at Department of Chemistry, Faculty of Science, Mahidol Univeristy. She experts in polymer colloids and surface mod-ification of natural rubber latex.

Delivered by Publishing Technology to: University of Lyon-1 IP: 134.214.70.27 On: Tue, 04 Nov 2014 14:58:35

Copyright: American Scientific Publishers

REVI

EW

Nanotechnology Center, National Science and Technology Development Agency, Thailand Science Park, Pathum Thani. Her research works focus on magnetic nanoparticles for bio-logical applications.

Abdelhamid Elaissari is the Director of research at CNRS, received his undergraduate education from Agadir University, Morocco in 1988. He moved to the Louis Pasteur Uni-versity (ICS), Strasbourg, France in which he received Ph.D. degree for polymers and colloids in 1991. He got a permanent position in CNRS in 1991 and then he joined CNRS-bioMerieux@ENS-Lyon laboratory, until 2007 in which he has developed colloids for biomedical applications including in vivo, in vitro and bionanotechnologies. In 2007, he moved to Engineering Processes and Automatic Laboratory (LAGEP@Lyon) in which he is acting not only as a director of research but also as the vice director of LAGEP.

the stabilization of nanoparticles is provided by creating charges on the surface of nanoparticles. This type of stabi-lization is obviously not possible in the aqueous medium, and the obtained dispersion is called “ionic ferrofluid.”

The originality of the ferrofluids is their behavior when subjected to a magnetic field. Indeed, the strong interac-tion between the nanoparticles and the solvent molecules provides a magnetic behavior for the entire fluid, which then acts as a “single phase” liquid. This unique property of the magnetic fluids can be exploited in many potential applications in various fields.

A magnetic fluid “ferrofluid” belongs to colloidal sus-pensions family and consists of stable colloidal fine nanoparticles in a carrier liquid. The magnetization prop-erties are related to the nanoparticle composition, which is essentially consisting of iron oxides. As a general tendency, metallic particles at nanometric size possess a long-range of magnetostatic attraction leading to their agglomeration and sedimentation. Therefore, when the particle size is less than 10 nm, a stabilizing agent is required to enhance the colloidal stability by reducing the attractive forces and raising the repulsive forces between the particles. In this regards, oleic acid is widely used as a stabilizing agent and many carrier liquids are employed in order to achieve a stable ferrofluid. Nowadays, ferrofluids are commercially available to serve the different applica-tions in several fields such as magnetic inks,4 5 _paints,6

and more interestingly in biomedical applications.7

This review highlights the ferrofluids synthesis meth-ods, emphasizing the two most important methmeth-ods, the physical size reduction and chemical coprecipita-tion, as well as properties and the applications based

on ferrofluids. Industrial applications including magnetic recording media, magnetic inks and sealing by ferroflu-ids are described. More interestingly, the newly adapted

in vivo and in vitro biomedical applications such as

mag-netic resonance imaging (MRI), therapeutic application, biological cells separation and nucleic acid extraction are reported. Moreover, the new form of ferrofluids, i.e., mag-netic emulsion is also discussed.

2. PREPARATION METHODS

Magnetite (Fe3O4 and maghemite (-Fe2O3 are the most

commonly ferrites used for preparation of ferrofluids. However, according to the magnetic properties desired, the ferrofluid can also consist of mixed oxides containing, iron, cobalt, manganese, barium or nickel. Magnetic fluid or ferrofluid could not be prepared by melting the ferro-magnetic metals such as iron, cobalt and nickel, because the ferromagnetic materials lose their strong magnetic properties when heated above its Curie temperature. More-over, for all known ferromagnetic materials this tempera-ture is always below their melting points.8 _{Therefore, to}

prepare a good and useful ferrofluid, it is necessary to coat the synthesized fine ferromagnetic particles with a stabiliz-ing layer of surfactant, followed by dispersion in a suitable liquid.

Regarding to preparation of magnetic nanoparticles, there are several methods (physical and chemical) used to produce ferromagnetic nanoparticles, e.g., size reduction, chemical synthesis (coprecipitation, thermal decomposi-tion and microemulsion methods), electro-decomposidecomposi-tion techniques, evaporation of metal in liquid, and carrier

Delivered by Publishing Technology to: University of Lyon-1 IP: 134.214.70.27 On: Tue, 04 Nov 2014 14:58:35

Copyright: American Scientific Publishers

REVI

EW

Ferrofluids: From Preparation to Biomedical Applications Bitar et al.

liquid exchange.9 10_{In the next section, size reduction and}

chemical synthesis methods are described in details. 2.1. Physical Based Method (Size Reduction)

Size reduction method is a physical based process related to grinding of the permanent magnets or ferromagnetic metals for more than 20 days in presence of oleic acid and organic solvent (heptane).11 _{The obtained particles have}

an average size from 50 to 200 Å and such suspension is considered as an apparently magnetically responsive con-tinuous liquid. Ostensibly, the ferrofluid is a homogenous liquid but in reality it is composed of very small magnetic particles suspended in a carrier solvent. Despite the long time and hard work needed by this technique it was widely used to synthesize ferrofluids. Rosensweig and coworkers used Papell’s grinding method to prepare the ferrofluids and they extensively studied their physical, thermal and hydrodynamic properties.12–16 _{Kaiser et al.}17 _{published his}

work on the preparation and the properties of stable fer-rofluid prepared by the same technique. In this paper they cited the most important works described the grinding pro-cess to prepare ferrofluids. Furthermore, due to the impor-tance and number of applications based on ferrofluids, the research and development in ferrofluids are drastically increased in this field as indicated from the number of papers and patents published (more than 1,000 patents and 1,900 papers) in the period of 1986–1990.18_The

ferroflu-ids obtained by size reduction method have good colloidal stability in solvent carriers with fine particle size in the range of 150 Å. However, this technique requires very long time and consumes high energy. In addition, particle size and particle size distribution of the obtained magnetic par-ticles are large as compared with those obtained by using other methods.

2.2. Chemistry Based Processes

Due to the considerable interest of ferrofluids and their wide applications, it is necessary to improve their syn-thesis methods. Thus, the chemical synsyn-thesis, including precipitation from iron salt solution and thermal decom-position of metal carbonyls, is considered as a good, fast, simple, cheap and controllable technique for ferrofluids production. Practically, ferrofluid preparation consists of two main steps: (i) nanoparticles preparation and (ii) their dispersion in a carrier liquid.

2.2.1. Coprecipitation Method

Chemical coprecipitation is the most conventional method used to prepare magnetic nanoparticles (MNPs). This can be attributed to the high yield of the magnetic ferrofluid which can be obtained; in addition to that this method is simple and cost-effective. Moreover, the reaction tem-perature and time consumed to complete the reaction are lower than other methods, e.g., thermal decomposition and hydrothermal techniques.

Generally, this procedure begins with a mixture of FeCl3

and FeCl2 solution in water and then coprecipitation is

performed by the addition of a base, typically ammonium or sodium hydroxide. This reaction can be summarized as follow:

2FeCl3+ FeCl2+ 8NH4OH→ Fe3O4+ 4H2O+ 8NH4Cl

This process involves two stages: (i) a short burst of nucleation when the concentration of the species reaches critical supersaturation and (ii) a slow growth of the nuclei by diffusion of the solutes to the surface of the crys-tal. In order to produce monodisperse MNPs, the nucle-ation should be avoided during the period of growth.19_The

coprecipitation is affected by different parameters such as the type and concentration of salts (e.g., chlorides, sul-fates or nitrates), temperature, pH and the addition rate of the alkali solution.19–22 _{According to thermodynamics}

of this reaction, the precipitation of Fe3O4 should be

per-formed at pH between 8 and 14 with a stoichiometric ratio (Fe3+:Fe2+) of 2:1 under inert atmosphere at room temperature or at elevated temperature. Usually, ferromag-netic particles produced by this technique have an aver-age size larger than 20 nm and they are composed of mixture of-Fe2O3 and Fe3O4 depending on the reaction

conditions.23

Preparation of magnetic fluids by coprecipitation of fer-ric and ferrous salts in aqueous solution was first reported by Reimers et al.24 _{The reactants ratio (FeCl}

3:FeCl2) was

fixed at 2:1 and NH4OH was used to precipitate the iron

oxide nanoparticles. After the co-precipitation, the iron oxide nanoparticles were subjected to surfactant stabiliza-tion for improving their colloidal stability in the dispersion medium by using fatty acid derivatives to stabilize iron oxide nanoparticles either in organic or aqueous medium. Oleic acid (OA) is the most commonly dispersant agent used as water insoluble adsorption layer, thus OA-coated nanoparticles can be easily and highly dispersed in organic solvent.25_{At alkaline pH, the carboxyl groups at the chain}

end of oleic acid will be ionized enhancing its binding onto the nanoparticle surface, while the aliphatic chain forms the hydrophobic layer that helps the nanoparticles to dis-perse in non-polar solvent. Scheme 1 presents the main chemical reactions used to prepare ferrofluids.

To use the ferrofluid in hydrophilic media, one needs to coat the ferromagnetic nanoparticles by ionic layer. Massart et al.26–29 _{prepared aqueous ferrofluids without}

surfactants in acidic medium (nitric acid) to have ionic iron oxide nanoparticles. Furthermore, it was found that the size of precipitated particles can be controlled by adding the citrate ions or sodium dodecyl sulfate to the reaction medium.28 30 These ions, at a specific ratio, can control the particle size by inhibiting the growth process so rais-ing the number of nucleation. It was also reported that the addition of chelating organic anion stabilizer and/or reducing agents (carboxyl or hydroxyl carboxylate ions,

Delivered by Publishing Technology to: University of Lyon-1 IP: 134.214.70.27 On: Tue, 04 Nov 2014 14:58:35

Copyright: American Scientific Publishers

REVI

EW

Scheme 1. Chemistry based ferrofluid preparation methods.31

e.g., citric, gluconic or oleic acid or polymer surface com-plexing agents (e.g., dextran, carboxydextran, poly(vinyl alcohol) or starch) during the formation of magnetite can help to control the size of nanoparticles.19 20 _The

chela-tion of organic ions on the magnetic particles surface either prevents nucleation and then leads to larger particles or inhibits the growth of crystal nuclei, leading to small nanoparticles.

However, the particles prepared by this technique tend to be polydisperse. The control of particle size distribution is quite limited because only kinetic factors affect the crystal growth.

In the case of ionic ferrofluids, the iron oxide nanoparti-cles are negatively or positively charged depending on the pH of the medium. The overall neutrality of the colloidal solution is provided by the counter-ion of the base used in the coprecipitation reaction. According to the polariz-ing counter-ion power, the dispersion of nanoparticles of iron oxide in water is more or less effective. For example, the synthesis of iron oxide in ammonia medium results in aggregated nanoparticles due to the high polarizing power of NH4+ cation which reduces interaction between water molecules and the particles. Then, it is necessary to sub-stitute the ammonium cation in order to induce charges on the particles surface. The use of tetramethylammonium hydroxide (N(CH34OH) or perchloric acid (HClO4)

pro-vides stable anionic or cationic ferrofluid, respectively as shown in Scheme 2.

Ionic ferrofluids can also consist of mixed oxides. Indeed, depending on the final properties desired for the ferrofluid, the magnetic nanoparticles might contain man-ganese (MnFe2O3), cobalt (CoFe2O4), or more complex

Scheme 2. Synthesis of ionic (cationic or anionic) ferrofluids via copre-cipitation process. Adapted from [32], J. P. Jolivet, et al., Nouv J. Chim. 7, 325 (1983). © 1983.

alloys (Ni_xZn_yFe_zO4, withx + y + z = 3). In this case, the

preparation method remains similar, but the preparation of mixed oxides requires performing the coprecipitation reac-tion at higher temperatures.

2.2.2. Thermal Decomposition Method

To obtain MNPs with narrow size distribution, thermal decomposition is needed. Generally, thermal decom-position of organometallic compounds followed by oxidation in high-boiling temperature organic solvents containing stabilizing surfactants can lead to highly monodisperse MNPs. The process usually requires relatively higher temperatures and a complicated operation.20 33 _{The organometallic compounds include}

Fe(cup)3 (cup = N -nitrosophenylhydroxylamine),34

Fe(acac)3 (acac;acetylacetonate),35 or Fe(CO)5 (iron

pentacarbonyl).36 _{For instance, monodisperse}

-Fe2O3

nanocrystallites with size of 4–16 nm were prepared by thermal decomposition of Fe(CO)5 in the presence

of oleic acid at 100 C by controlling the experimen-tal parameters.36 _{The resulting iron nanoparticles were}

transferred to monodispersed -Fe2O3 nanocrystallites

by controlling oxidation using trimethylamine oxide as a mild oxidant. Although ferrofluid MNPs with controlled size and shape are obtained by thermal decomposition method, the resulting nanoparticles are generally dissolved only in nonpolar solvents, which is the drawback of this method.

3. PROPERTIES

For the vast majority of ferrofluids, whether aqueous or organic, the magnetic properties are provided by ferrite nanoparticles. More rarely, magnetic fluids composed of metal nanoparticles are also found. This latter case will not be discussed in this review.

Delivered by Publishing Technology to: University of Lyon-1 IP: 134.214.70.27 On: Tue, 04 Nov 2014 14:58:35

Copyright: American Scientific Publishers

REVI

EW

Ferrofluids: From Preparation to Biomedical Applications Bitar et al.

3.1. Chemical Structure Analysis (X-Ray, Mössbauer) Ferrites are metal oxides, which have a crystal structure of spinel type and whose main component is iron. Fer-rites MFe₂O₄ kind (whereM is a divalent cation) belongs

to the family of ferromagnetic compounds. In the spinel structure, the O2− ions form a face-centered cubic lattice. The divalent cations (M2+) and Fe3+ are located in the octahedral or tetrahedral cavities formed by the network of O2− ions. It is the particular arrangement of ions that give the material its magnetic properties. The spinel type crystal structure is shown in Scheme 3. Half of the octa-hedral sites are occupied by Fe3+ cations (site B) and the eighth of the tetrahedral sites by M2+cations (site A).

Magnetite (Fe3O4) is a mixed oxide of iron II and iron

III, which has an inverse spinel structure. In this type of structure, a quarter of the octahedral sites are occupied by Fe3+cations, another quarter is occupied by Fe2+ cations, and the eighth of the tetrahedral sites is occupied by Fe3+ cations. Maghemite (-Fe2O3) is formed by oxidation of

magnetite according to the following reaction: 2Fe3O4+

1

2O2→ 3-Fe2O3

The crystallographic structure of the maghemite is iden-tical to that of magnetite, with the exception of certain deficiencies caused by the iron oxidation reaction.

The crystallographic structure of iron oxide nanoparti-cles in its powder state was generally examined by X-ray diffraction technique. The typical spectrum of magnetite (Fe3O4) and maghemite (-Fe2O3) is shown in Figure 1.

This spectrum shows six major diffraction peaks relatively well defined, suggesting the formation of highly crystalline iron oxide.37 38_{The characteristic diffraction peaks of}

mag-netite (Fe3O4) and maghemite (-Fe2O3) are also shown

in the experimental spectrum.

To facilitate comparison with the more probable crys-tallographic structures of iron oxide, the experimental inter-reticular distances (dexp) relating to different groups

Scheme 3. Crystallographic structure of iron oxide Fe3O4. 31

Fig. 1. X-ray diffraction pattern of synthesized nanoparticles confirms the existence of magnetite (Fe3O4) and maghemite-Fe2O3. Reproduced

with permission from [38], N. Tran, et al., Int. J. Nanomedicine 5, 277 (2010). © 2010, Dove Medical Press Ltd.

of crystal planes {hkl} are calculated from the Bragg’s

equation:

n = 2d sin 

wheren is an integer,  is the wavelength of incident

radi-ation (CuK = 15418 Å), d is the spacing between the

planes in the atomic lattice, and  is the angle between

the incident ray and the scattering planes. The determined experimental distances (dexp) are then compared with the

values reported in the ASTM (American Society for Test-ing and Materials) for pure magnetite and maghemite, as represented in Table I.31

As clearly seen in Figure 1, the diffraction spectra of magnetite and maghemite are very close, since these two oxides have a crystallographic structure of inverse spinel. Furthermore, when the sample is composed of a heavy element such as iron, a portion of the incident radiation may be absorbed, which causes a shift of all the peaks of the spectrum. To confirm X-ray results, iron oxide was generally analyzed using Mössbauer spectroscopy. This technique allows measuring the hyperfine magnetic fields around iron cores. These fields are due to the electronic environment of the iron and thus to determine precisely the degree of oxidation. Indeed, in the maghemite, iron is

Table I. Comparison between the experimental distances (dexp) of iron

oxide nanoparticles derived from XRD with the standard data of mag-netite and maghemite in the ASTM (American Society for Testing and Materials).

Plane hkl dexp(Å) d (Fe3O4) (Å) d (-Fe2O3) (Å)

(220) 2955 2967 2953 (311) 2522 2532 2518 (400) 2091 2099 2089 (422) 1706 1714 1704 (511) 1608 1616 1607 (440) 1478 1484 1476