ma e ials
Opinion
Whi he Magne ic Hype he mia? A Ten a i e Roadmap
I ene Rubia-Rod íguez 1, An onio San ana-O e o 1, Simo Spasso 2, E elka Tombácz 3, Ch is e Johansson 4,
Pa icia De La P esa 5,6 , F ancisco J. Te an 1,7 , Ma ía del Pue o Mo ales 8, Sabino Vein emillas-Ve dague 8,
Nguyen T. K. Thanh 9,10 , Maximilian O. Besenha d 11 , Clai e Wilhelm 12, Flo ence Gazeau 12,
Quen in Ha me 13, E ic Mayes 13, Bella B. Manshian 14 , S e aan J. Soenen 14 , Yuanyu Gu 15,Ángel Millán15 ,
Eleni K. E himiadou 16, Je Gaude 17, Pa ick Goodwill 17 , James Mans ield 17, Uwe S einho 18 ,
James Wells 18, F ank Wiekho s 18 and Daniel O ega 1,19,20,*


Ci a ion: Rubia-Rod íguez, I.;
San ana-O e o, A.; Spasso , S.;
Tombácz, E.; Johansson, C.; De La
P esa, P.; Te an, F.J.; Mo ales, M.P. ;
Vein emillas-Ve dague , S.; Thanh,
N.T.K.; e al. Whi he Magne ic
Hype he mia? A Ten a i e Roadmap.
Ma e ials 2021,14, 706. h ps://
doi.o g/10.3390/ma14040706
Academic Edi o : Vadim Kessle
Recei ed: 2 Decembe 2020
Accep ed: 25 Janua y 2021
Published: 3 Feb ua y 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/).
1IMDEA Nanoscience, Fa aday 9, 28049 Mad id, Spain; i ene. [email p o ec ed] (I.R.-R.);
[email p o ec ed] (A.S.-O.); [email p o ec ed]g (F.J.T.)
2
Geophysical Cen e o he Royal Me eo ological Ins i u e, 1 ue du Cen e Physique, 5670 Dou bes, Belgium;
[email p o ec ed]
3Soós Wa e Technology Resea ch and De elopmen Cen e , Uni e si y o Pannonia,
8200 Nagykanizsa, Hunga y; [email p o ec ed]
4RISE Resea ch Ins i u es o Sweden, Senso s and Ma e ials, A id Hed alls Backe 4,
411 33 Gö ebo g, Sweden; ch is e [email p o ec ed]
5
Ins i u o de Magne ismo Aplicado UCM-ADIF-CSIC, A6 22,500 km, 29260 Las Rozas, Spain; [email p o ec ed]
6Depa amen o de Física de Ma e iales, Uni e sidad Complu ense de Mad id, A da. Complu ense s/n,
28048 Mad id, Spain
7Nano ech Solu ions, C a Mad id, 23, 40150 Villacas ín, Spain
8
Depa men o Ene gy, En i onmen and Heal h, Ins i u o de Ciencia de Ma e iales de Mad id (ICMM/CSIC),
So Juana Inés de la C uz 3, 28049 Mad id, Spain; [email p o ec ed] (M.P.M.); [email p o ec ed] (S.V.-V.)
9UCL Heal hca e Biomagne ics and Nanoma e ials Labo a o ies, 21 Albema le S ee , London W1S 4BS, UK;
[email p o ec ed]
10 Biophysics G oup, Depa men o Physics and As onomy, Gowe S ee , London WC1E 6BT, UK
11
Depa men o Chemical Enginee ing, Uni e si y College London, To ing on Place, London WC1E 7JE, UK;
[email p o ec ed]
12 Labo a oi e Ma iè e e Sys èmes Complexes MSC, Uni e si éde Pa is/CNRS, 75013 Pa is, F ance;
clai e.wilhelm@uni -pa is-dide o . (C.W.); lo ence.gazeau@uni -pa is-dide o . (F.G.)
13 Endomag, The Je eys Building, S John’s Inno a ion Pa k, Cowley Road, Camb idge CB4 0WS, UK;
[email p o ec ed] (Q.H.); [email p o ec ed] (E.M.)
14 Biomedical Sciences G oup, T ansla ional Cell and Tissue Resea ch Uni , Depa men o Imaging and
Pa hology, 3000 Leu en, Belgium; [email p o ec ed] (B.B.M.); [email p o ec ed] (S.J.S.)
15 INMA Ins i u o de Nanociencia de Ma e iales de A agón, Ped o Ce buna 12, 50009 Za agoza, Spain;
[email p o ec ed] (Y.G.); amillan@uniza .es (Á.M.)
16 Chemis y Depa men , Ino ganic Chemis y Labo a o y, Na ional and Kapodis ian Uni e si y o A hens,
Panepis imiopolis Zog a ou, 15771 A hens, G eece; [email p o ec ed]
17 Magne ic Insigh , Alameda, CA 94501, USA; [email p o ec ed] (J.G.);
[email p o ec ed] (P.G.); [email p o ec ed] (J.M.)
18
Physikalisch-Technische Bundesans al , Abbes aße 2-12, 10587 Be lin, Ge many; [email p o ec ed] (U.S.);
[email p o ec ed] (J.W.); [email p o ec ed] (F.W.)
19 Ins i u e o Resea ch and Inno a ion in Biomedical Sciences o he P o ince o Cádiz (INiBICA),
11002 Cádiz, Spain
20 Condensed Ma e Physics Depa men , Facul y o Sciences, Campus Uni e si a io de Pue o Real s/n,
11510 Pue o Real, Spain
*Co espondence: [email p o ec ed]
Abs ac :
The scien i ic communi y has made g ea e o s in ad ancing magne ic hype he mia
o he las wo decades a e going h ough a sizeable esea ch lapse om i s es ablishmen . All
he p og ess made in a ious opics anging om nanopa icle syn hesis o biocompa ibiliza ion
and
in i o
es ing ha e been seeking o push he o e on owa ds some new clinical ials. As
many, hey did no go a he expec ed pace. Today, ui ul in e na ional coope a ion and he wisdom
gain a e a ca e ul analysis o he lessons lea ned om seminal clinical ials allow us o ha e a
u u e wi h be e gua an ees o a mo e de ini i e akeo o his genuine nano he apy agains cance .
Delibe a ely gi ing p ominence o a numbe o c i ical aspec s, his opinion e iew o e s a blend o
Ma e ials 2021,14, 706. h ps://doi.o g/10.3390/ma14040706 h ps://www.mdpi.com/jou nal/ma e ials
Ma e ials 2021,14, 706 2 o 36
s a e-o - he-a hin s and glimpses in o he u u e o he he apy, conside ing he expec ed e olu ion
o science and echnology behind magne ic hype he mia.
Keywo ds:
magne ic hype he mia; magne ic nanopa icles; hys e esis losses; cance ; magne ic
pa icle imaging; he anos ics; nanopa icles syn hesis; he mome y; s anda diza ion; nano oxici y
1. In oduc ion
The scien i ic communi y in ol ed wi h magne ic hype he mia may be on he e ge
o ano he u ning poin a e some yea s wi hou ele an news on he ou comes o
clinical esea ch: new clinical s udies on di e en indica ions a e cu en ly aking place.
Fo example, MagFo ce AG ecen ly announced ha i s Ame ican subsidia y MagFo ce
USA, Inc. ob ained app o al om he U. S. Food and D ug Adminis a ion (FDA) o a
pi o al single-a m s udy o he ocal abla ion o in e media e- isk p os a e cance wi h
hei NanoThe m
®
he apy sys em [
1
]. In Eu ope, bo h he Vall d’Heb on Uni e si y
Hospi al and he Fuenlab ada Uni e si y Hospi al a e home o a new easibili y s udy on
ea ing locally ad anced panc ea ic duc al adenoca cinoma (PDAC) wi hin he emi o
he NoCanThe p ojec [2].
Wi hou any doub , behind he p og ess so a on he clinical ansla ion o magne ic
hype he mia, he e is an e e mo e in e wined scien i ic ne wo k wo ldwide ha is
keeping a cons an in lux o basic esea ch, consolida ing he de elopmen s unde he ligh
o consensual new p ocedu es, and expanding links wi h key ac o s in he ansla ional
and clinical a ena. In e na ional ne wo king ini ia i es, such as he “RADIOMAG” COST
ac ion [
3
], ha e helped in igh ing agains he geog aphical dispe sion o scien i ic and
human esou ces ela ed o magne ic hype he mia, as well as elimina ing duplica ion o
esea ch lines and con ibu ing o he ha moniza ion o key concep s and p ocedu es. In
any case, he coope a ion be ween clinical and non-clinical wo lds has become much mo e
luid, as i should be o achie e a sus ainable imp o emen in he coming decades [
4
]. The
exis ence o unique in as uc u es o eliable, dedica ed and widesp ead cha ac e iza-
ion echniques o nanomedicines is pa ing he way o a as e ansla ion o p omising
nanop oduc s. A sup ana ional example is he Eu opean Nanomedicine Cha ac e isa ion
Labo a o y [
5
], c ea ed back in 2015 unde he auspices o he H2020 amewo k p og am,
and a mo e es ablished na ional example is he Nano echnology Cha ac e iza ion Labo-
a o y in he USA, ounded by he Na ional Cance Ins i u e (NCI) in collabo a ion wi h
he FDA and he Na ional Ins i u e o S anda ds and Technology (NIST) [
6
]. Howe e , as
i could no be o he wise, he e a e some impo an issues s anding in he way o wide
clinical adop ion o magne ic hype he mia, some o which a e common o many o he
nanomedicines [
7
]. The economic bu den o aking he leap om basic nanomedicine
esea ch o ansla ion [
8
] appea s o be insu moun able in he opinion o he scien i ic
communi y, abo e all wi h he cu en unding schemes, which despi e being ega ded as
insu icien and poo ly coo dina ed, a e also beginning o su e signi ican cu s. This is
exempli ied by he ecen u moil a ound he decision o he Uni ed S a es Na ional Cance
Ins i u e (NCI) in hal ing unding o he Cen e s o Cance Nano echnology Excellence
(CCNEs) [
9
], he commen a y published by Kinam Pa k— he o me Edi o -in-Chie o he
Jou nal o Con olled Release—in a o o he con o e sial decision [
10
], and he coun e -
eac ion ha ollowed om he boa d o he Nanomedicine and Nanoscale Deli e y Focus
G oup o he Con olled Release Socie y [
11
] and he o me p esiden o he Eu opean
Resea ch Council [12].
Magne ic hype he mia he apy mainly comp ises wo key elemen s: injec able mag-
ne ic nanopa icles (MNPs) and a magne ic ield applica o , bo h o which we e app o ed
in mos cases as medical de ices. A leas in Eu ope, he e is s ill a deba e a ound whe he
a mo e speci ic egula o y amewo k—beyond he mo e ecen egula ion (EU) 2017/745
on medical de ices epealing he 93/42/EEC and 90/385/EEC di ec i es—is needed o
Ma e ials 2021,14, 706 3 o 36
nanomedical de ices. The ma e only wo sens when conside ing he p ocess in di e en
pha maceu ical ju isdic ions [
13
]. This unce ain y a ound well-de ined p e-no ma i e
and egula o y amewo ks is discou aging p i a e in es o s and pha maceu ical compa-
nies om aking he ini ia i e in leading new indus ial p ojec s o sponso ing he mos
p omising cu en de elopmen s. Added o his is he eluc ance o use MNPs in humans
a e se e al cases o wi hd awals o nanop oduc s bo h om he ma ke and om he
egula o y p ocess, in addi ion o he abandonmen o he p oduc ion o o he o mula ions
based on MNPs (see Sec ion 5).
All hese aspec s, along wi h many o he s shaping he p esen and he u u e o
magne ic hype he mia, a e commen ed on he e by in e na ional expe s, aking he cu en
s a e-o - he-a as a s a ing poin .
2. Es ablishing S anda d Ope a ional P ocedu es o S uc u al and Magne ic
Cha ac e iza ion o Magne ic Nanopa icles
Nowadays, nanoma e ials manu ac u e s ace a cons an inc ease o equi emen s
ega ding speed p ocess and p oduc quali y con ol ha need eal- ime cha ac e iza ion
echniques adap ed o nanoscale me ology and s anda dized ope a ional p ocedu es (SOP).
Indeed, SOP and au oma ed ins umen a ion o cha ac e izing magne ic nanoma e ials
will de ini i ely bene i bo h he indus ial demands in quali y con ol and also basic
esea ch. Recen ini ia i es, as he “RADIOMAG” COST ac ion [
3
], showed signi ican
a iabili y o esul s when compa ing physical pa ame e s, such as he speci ic abso p ion
a e (SAR) o speci ic loss powe (SLP), ob ained in magne ic colloids by di e en esea ch
labs [
14
]. Mo eo e , many physical pa ame e s o MNPs can be de e mined by dis inc
cha ac e iza ion echniques (see Table 1), inc easing he a iabili y o he esul s. Hence,
he e is a need o s anda dizing me hodologies o cha ac e izing ex emely ele an
pa ame e s such as magne ic losses o MNPs.
Table 1.
MNP pa ame e s and he co esponding cha ac e iza ion echniques. Adap ed om [
15
,
16
]. See lis o ac onyms a
he end o he documen .
S uc u al P ope ies
Pa icle, co e and agg ega e size
TEM, XRD, DLS, NTA, SAXS, HRTEM, SEM, AFM, EXAFS, FMR, DCS, MALDI,
NMR, TRPS, EPLS, magne ic suscep ibili y
Mo phology TEM, HRTEM, AFM, EPLS, FMR, 3D- omog aphy
Elemen al-chemical composi ion XRD, XPS, ICP-MS, ICP-OES, SEM-EDX, NMR, MFM, LEIS
C ys allini y XRD, EXAFS, HRTEM, elec on di ac ion, STEM
S uc u al de ec s HRTEM, EBSD
Chemical s a e–oxida ion s a e XAS, EELS, XPS, Mössbaue
Ligand-binding, su ace composi ion XPS, FTIR, NMR, SIMS, FMR, TGA, SANS
Colloidal P ope ies
Hyd odynamic and agg ega e size NTA, DLS, DCS, UV- is, SEM, TEM, C yo-TEM
3D isualiza ion 3D- omog aphy, AFM, SEM
MNP cha ge Ze a po en ial, EPM
Elemen concen a ion ICP-MS, UV- is, RMM-MEMS, PTA, DCS, TRPS
Magne ic P ope ies
Quasi-s a ic magne iza ion p ope ies SQUID, VSM, Mössbaue , MFM, FMR, XMCD,
Dynamical magne iza ion p ope ies AC suscep ome y and magne ome y, magne o elaxome y, magne ic pa icle
spec oscopy
Magne ic losses AC calo ime y, AC suscep ome y and magne ome y
Since his sec ion ocuses only on essen ial cha ac e iza ion echniques o magne ic
hype he mia (MH) applica ions, i is wo h no ing ha magne ic losses a e s ongly in lu-
enced by MNPs pa ame e s such as size [
17
] and shape [
18
,
19
], agg ega ion
deg ee [20,21]
magne ic aniso opy [
22
], magne ic dipola in e ac ions [
23
,
24
],
unc ionaliza ion [25,26]
,
iscosi y o he dispe sion medium [
27
,
28
], and al e na ing magne ic ield condi ions
Ma e ials 2021,14, 706 4 o 36
( ield equency and ampli ude) [
29
–
31
]. Se e al EU p ojec s ocused on s anda diza ion
and ha moniza ion o analysis me hods o MNPs ha e been/a e being ca ied ou , e.g.,
NanoMag, MagNaS and and RADIOMAG, as well as app o ed ISO s anda ds (ISO/TS
19807-1:2019) [
32
,
33
]. These achie emen s bene i he p epa a ion o SOPs o cha ac e izing
ele an pa ame e s such as magne ic losses o MNPs o he design o s anda d e e ence
nanoma e ials o ha monize he compa ison o esul s ob ained by dis inc esea ch g oups.
Hence, SOPs aim o homogenize p ocedu es o cha ac e izing physicochemical pa ame e s
o magne ic suspensions as he i s s ep owa ds In e na ional S anda ds. So a , e o s
wi h good esul s ha e been done o cha ac e ize and ha monize analysis me hods o
bo h suspended and immobilized MNPs [
15
,
16
,
33
,
34
]. He e we spo ligh selec ed essen ial
me hods o MH applica ion. A gene al desc ip ion o analysis me hods o magne ic
nanopa icle sys ems can be ound in e . [16].
2.1. S uc u al Cha ac e iza ion
Today, nanoscience canno exis wi hou nea - ield and elec on mic oscopy echniques
such as TEM, HRTEM, SEM, EDX, AFM, e c. Wi hin he la e , TEM is he mos widely
used o he s uc u al cha ac e iza ion o nanopa icles, which mainly comp ises MNP
co e size, co e size dis ibu ion, shape, agg ega ion, e c. Howe e , due o he inhe en
sample p epa a ion echniques, i is o en di icul o p ese e he o iginal colloidal s a e.
In his sense, he use o c yo-TEM is encou aged o be e cap u e he spa ial a angemen
o MNPs, hus p o iding mo e accu a e in o ma ion abou hei agg ega ion s a e.
2.2. Colloidal P ope ies
These a e gene ally cha ac e ized unde andom condi ions, namely pu e wa e ,
bu e s (o en phospha e solu ions), e c. A p io i well-quali ied samples, howe e , o en
end up ailing
in i o
due o a signi ican loss o e icacy and/o he onse o oxici y [
35
].
The easons behind his obse a ion can be di e se: sample con amina ion, MNPs ag-
g ega ion, and in e acial in e ac ions wi h cell memb anes o blood componen s, among
o he s [
36
]. MNPs quali ica ion mus be pe o med unde condi ions ha mimic he
in i o
en i onmen , mainly pH and salini y, bu also including p o eins, ca bohyd a es and lipids.
In gene al, MNPs’ in e ac ions a bio-nano in e aces a e mainly de e mined by size, cha ge
and hyd ophilici y/hyd ophobici y [
37
]. In ac , hese p ope ies a e closely ela ed o
he pa en colloid s abili y— ia elec ic, s e ic and elec os e ic s abiliza ion—and pa icle
agg ega ion in poo ly s abilized magne ic luids. Dynamic ligh sca e ing (DLS) is one
o he mos employed me hods o measu e hyd odynamic sizes and size dis ibu ions
in dilu e colloids by analyzing he in ensi y luc ua ion o sca e ed ligh caused by he
B ownian mo ion o he cons i uen nanopa icles. The main sou ce o unce ain y he e
is polydispe si y, bu in he li e a u e, he “DLS size” is o en p o ided wi hou epo ing
some ele an measu emen condi ions like pH o ionic s eng h, making i di icul o
es ablish he sou ce o polydispe si y. The la e could eside in he p ima y pa icles and
hei agg ega ion due o weak colloidal s abili y [
35
], and i has a majo impac bo h on
he sample’s shel li e and i s subsequen use. Fo example, app op ia e and inapp op ia e
MNP manu ac u ing has been illus a ed in he li e a u e by human blood smea es s [
36
].
MNP cha ge can be cha ac e ized ia ze a po en ial (
ζ
) measu emen s, which is
no cha ac e is ic o su ace cha ge as ound in he li e a u e [
15
]. I highly depends on
he pH and ionic s eng h o he medium and he quali y and quan i y o speci ic ions
(phospha es in bu e s, ca boxyla es, su ac an ions, e c.). I MNPs a e s abilized only
elec os a ically,
ζ
alues highe han |25–30| mV, measu ed a low ionic s eng h, indica e
good colloidal s abili y. A high sal concen a ion,
ζ
becomes ze o. A null alue also
occu s bo h a a pH coinciding wi h he isoelec ic poin and in he p esence o speci ic
ions, causing ζ e e sal. Consequen ly, epo ing ζ alues wi hou p o iding in o ma ion
on pH, ionic s eng h, speci ic ions, e c., o he dispe sion solu ions is meaningless. In he
case o concen a ed magne ic suspensions and gels, DLS canno be used; in hese cases,
mo e powe ul sca e ing me hods such as SAXS and SANS a e needed [
38
]. The co e-shell
Ma e ials 2021,14, 706 5 o 36
s uc u e and he p obabili y o agg ega ion in samples can be measu ed in p is ine samples
as used in bio- ele an media, e en highly concen a ed o embedded in a gel. The hi d
ele an colloidal pa ame e is he hyd ophilici y/hyd ophobici y o he MNP coa ing. O
pa icula no e in he case o MNPs in ended o biological media is he p o ein adso p ion,
leading o he so-called “p o ein co ona” a ound nanopa icles since i masks he o iginal
cha ac e o he MNP su ace [35].
2.3. AC Suscep ome y
In AC suscep ibili y (ACS) s. equency measu emen s, a sinusoidal magne ic ield
o cons an ampli ude is applied o e he sample, and he exci a ion equency is swep a
a cons an empe a u e [
39
–
42
]. A supe imposed DC magne ic ield can also be applied.
The AC ield in ensi y is gene ally su icien ly small, ul illing he low- ield limi whe e he
magne iza ion is linea o he ield. The in-phase componen ( eal pa ) and ou -o -phase
componen (imagina y pa ) o he ACS a e measu ed e sus exci a ion equency. In
o de o calib a e he signal ampli ude and phase, he sys em should be calib a ed, e.g.,
wi h a sample wi h a known dynamic magne ic equency esponse, o ins ance, he
pa amagne ic ma e ial Dy
2
O
3
in powde o m [
43
]. This also allows o compensa e o any
ampli ude and phase e o s and also o con e he measu ed ACS in o a calib a ed olume,
mola o mass suscep ibili y. ACS s. equency measu emen s ha e been ou inely used
by nume ous g oups o cha ac e ize MNPs [
43
–
46
]. F om he ACS esponse, i is possible o
es ima e he SLP alue by s udying he magne ic losses ob ained om he ACS ou -o -phase
componen [41,47].
In AC suscep ibili y s. empe a u e measu emen s a cons an exci a ion equency, a
small ampli ude sinusoidal magne ic ield is also used, and i s equency can be a ied up
o abou 10 kHz [
48
]. In a ecen pape , an induc ion-based ACS sys em ha can be used a
lowe empe a u es was designed o equencies up o he MHz ange [
49
]. Calib a ion
is done in almos he same way as he ACS s. equency me hod using a sample wi h
known dynamic magne ic p ope ies. The in-phase and ou -o -phase componen s o he
ACS a e measu ed e sus he empe a u e o he sample. In addi ion, in his case, a
supe imposed DC magne ic ield can be applied. In a speci ic empe a u e ange, he
esponse becomes equency-dependen , and he ACS esul s p o ide in o ma ion abou
he magne ic elaxa ion p ope ies o he MNP ensemble [
49
–
55
]. Thus, measu ing he
dynamic magne ic p ope ies gi es in o ma ion on he magne iza ion dynamics in he
sample by a ying he AC d i e equency (di e en ime scales). Tempe a u e-dependen
ACS is a s anda d echnique o cha ac e iza ion o MNPs, o ins ance, o de e mine
blocking empe a u es, magne ic elaxa ion p ope ies o magne ic in e ac ions; indeed,
i is impo an o quan i y magne ic in e ac ions as hey will a ec he ene gy abso p ion
and, he e o e, he hype he mia hea ing p ope ies [17,56–58].
2.4. DC Magne iza ion
In DC magne ome y (DCM), he magne ic momen o a sample is measu ed as
a unc ion o bo h applied magne ic ield and empe a u e. DCM measu emen s a e
ypically pe o med in comme cially a ailable magne ome e s, based on SQUID echniques,
ib a ing sample magne ome e s (VSM) o al e na ing g adien magne ome e s (AGM) [
59
].
The maximum magne ic ields in he DCM me hod should be la ge enough o sa u a e
he sample magne iza ion in o de o de e mine he in insic sa u a ion magne iza ion.
DCM magne ome e s a e calib a ed agains a magne ic sample wi h known sa u a ion
magne iza ion o suscep ibili y. The basic pa ame e s om a magne iza ion e sus ield a e
in insic sa u a ion magne iza ion, whe e he measu ed magne ic momen is no malized
o he mass o olume o he magne ic ma e ial unde in es iga ion. In addi ion, he
emanence and coe ci i y om he hys e esis loop can be de e mined. Likewise, he
abso bed ene gy by he MNP sys em a equilib ium can be ob ained by calcula ing he
a ea enclosed unde he hys e esis loop [
60
]. DC magne iza ion measu emen s cons i u e

Ma e ials 2021,14, 706 6 o 36
a basic magne ic cha ac e iza ion echnique ha has been ou inely used by nume ous
g oups o cha ac e ize MNPs sys ems [61–64].
2.5. AC Calo ime y
Calo ime y is he mos employed echnique o quan i y magne ic losses in MNP
suspensions subjec ed o an AC ield. The p ocedu e is based on measu ing he ini ial
empe a u e inc ease a e immedia ely a e applying he AC ield. This expe imen al
me hod has been widely employed and has con ibu ed o unde s and he in luence o
in insic—s uc u al, colloidal, magne ic—o ex insic pa ame e s—AC ield—on SLP and
ILP alues [
20
,
23
,
24
,
26
,
30
,
31
,
36
,
47
,
56
–
58
,
63
,
65
–
68
]. Calo ime ic measu emen s a e usually
pe o med unde non-adiaba ic condi ions since adiaba ic ones a e a ely
a ained [69,70]
.
Such non-adiaba ic sys ems equi e pa icula da a analysis o emo e a i ac s om di e -
en e o sou ces [71,72].
2.6. AC Magne ome y
AC magne ome y quan i ies he enclosed a ea o AC magne ic hys e esis loops o
de e mine SLP alues (
≈
a ea unde loops
×
ield equency). The applica ion o his
echnique o measu e magne ic colloids is ecen , and mos o he ob ained esul s ha e
been pe o med using home-made equipmen [
73
–
76
] since comme cial equi alen s a e
e y sca ce. AC magne ome y has he ad an age ha he calcula ion o SLP alues is
no in luenced by he mal pa ame e s o condi ions, allowing o quan i y o magne ic
losses when MNPs a e inside biological ma ices, like cells o issues [
28
]. The analysis
o hys e esis loops unde AC ields can shed ligh on he e ec o pa icle size, shape,
agg ega ion, aniso opy, iscosi y and ield ampli ude and equency on he magne ic
losses [27,28,77–79]. Howe e , dedica ed SOP a e also needed o his echnique.
In summa y, he exis ence o SOP and au oma ed ins umen a ion o quan i y ele an
physicochemical pa ame e s o magne ic hype he mia will wa an he eliabili y and
ep oducibili y o he ob ained alues, which is manda o y o ensu e a eliable ansla ion
o MH o clinics.
3. Scalable Syn hesis P o ocols
3.1. Gene al Challenges
Today’s li e a u e p o ides a a ie y o p o ocols o syn hesize uni o m e i e MNPs
wi h di e en sizes and shapes, sui able o magne ic hype he mia [
80
]. In many cases,
epo ed nanopa icle p ope ies a e supe io o hose o cu en ly app o ed p oduc s
and, he e o e, ha e he po en ial o inc ease he e iciency o hype he mia ea men s by
eaching highe empe a u es a lowe nanopa icle concen a ions unde milde magne ic
ield condi ions. Howe e , la ge-scale p oduc ion o hese MNPs wi h imp o ed o op imal
p ope ies is associa ed wi h obs acles such as low yield and, mos impo an ly, limi ed
ep oducibili y due o poo con ol and documen a ion o syn hesis condi ions. These
challenges need o be add essed o a syn he ic p oduc o each ma ke ma u i y.
On he o he hand, a cu en esea ch challenge is unde s anding nanopa icle o ma-
ion mechanisms and kine ics ha a e essen ial o guide he de elopmen o syn heses ha
a e ep oducible in a sys ema ic, con ollable and scalable manne . Since con inuous p o-
cesses can p o ide ad an ages o e ba ch p ocesses o ep oducible and scalable syn hesis
p o ocols, hey ha e ecen ly gained inc eased in e es .
The inal s ep ela ed o nanopa icle unc ionaliza ion is s ill a di icul ask ha needs
special a en ion o achie e scalable p oduc ion. The coa ing and he numbe o ac i e
su ace si es a e c ucial o nanopa icle dispe sion/s abili y, and he e o e pa icle–pa icle
magne ic in e ac ions and he pa icle hea ing p ope ies independen ly on he media
iscosi y and he concen a ion, i.e.,
in i o
and
in i o
condi ions. I is impo an o
es ablish a ep oducible yield o he coa ing s ep and pu i ica ion o any byp oduc .
Ma e ials 2021,14, 706 7 o 36
3.2. P epa a ion o MNPs and Func ionaliza ion
We ha e iden i ied some majo challenges in he p epa a ion o uni o m MNPs wi h
di e en syn he ic me hods, classi ied by he media whe e nuclea ion and g ow h ake
place, i.e., aqueous and pola o nonpola o ganic sol en s. We ocus on magne ic i on
oxide nanopa icles (IONPs) as hey ha e al eady been app o ed o humans [
81
] and a e
he e o e he mos p omising hea ing agen candida es.
The main challenge o syn hesizing IONPs o hype he mia in aqueous media is he
p oduc ion o la ge (~20 nm) pa icles wi h good con ol o size and shape dis ibu ion.
Despi e p og ess and b oad u iliza ion o he wa e -based co-p ecipi a ion me hod due
o he high yield, he e a e se e al d awbacks, such as subop imal size (<15 nm, wi h
excep ions, e.g., o me hods wi h a slow pH inc ease [
82
]), high polydispe si y, poo
c ys allini y con ol, and consequen ly poo sa u a ion magne iza ion. Rega ding la ge
pa icles o hype he mia applica ion wi h sa u a ion magne iza ion alues nea he bulk,
hey can be ob ained by oxida i e p ecipi a ion o Fe(II) sal s in aqueous media (>15 nm).
Recen ly, oxida i e p ecipi a ion has been scaled up o 20 g pe ba ch [
83
] and was made a
con inuous p ocess [
84
,
85
]. The combina ion o low-cos eagen s such as FeSO
4
, NaOH,
NaNO3and e hanol/wa e mix u es was shown o yield uni o m nanopa icles.
The main challenge o he mal decomposi ion syn hesis in high boiling poin o ganic
media (commonly nonpola sol en s such as 1-oc decene o pola polyol sol en s) is he
s anda diza ion o expe imen al p ocedu es and con ol o syn he ic condi ions. This is
due o he complexi y o he o ma ion p ocess o magne i e and he consequence o a se
o he mally ac i a ed chemical eac ions [
83
]. E en sub le changes o chemical aspec s
such as p ecu so / eagen concen a ion can p o oke conside able modi ica ions o he
decomposi ion and o nuclea ion empe a u e wi h d ama ic consequences on he inal
nanoma e ial p oduc .
One pa ame e dese ing special a en ion is he hea ing a e, as i is known o a -
ec (o used o con ol) nanopa icle sizes [
86
]. Since he hea ing a e can a y wi h he
expe imen al p ocedu e, o example, he size and geome y o he eac ion essel (wi h
limi s o la ge olumes in e ms o hea inpu ), ep oducing hea ing p o iles om small
o especially la ge-scales is no i ial. Tempe a u e p o iles o he eac ion media should
he e o e be documen ed ca e ully; epo ing hea e se ings is no enough. Conside ing
scalable p oduc ion, e icien hea ing sou ces a e equi ed o acili a e homogeneous em-
pe a u e p o iles (he e, he mixing sys em plays an impo an ole) and su icien hea ing
a es. Hea ing ia mic owa e adia ion is a p omising al e na i e o classical hea e s and
was shown o enable scale up he p oduc ion up o 1 kg [
87
]. Mic owa e hea ing was also
used o syn hesis o lowe -like mul i-co e IONPs wi h good con ol o e co e sizes and
usion be ween hem depending on he eagen s, empe a u e and hea ing ime. O he
hea ing sys ems such as hyd o he mal using au ocla es p esen s he d awback o needing
a special pilo plan o scale up sa ely he lab-scale p ocedu e.
In addi ion o hea ing a es, also eagen s o age, pu i y and supplie , s i ing con-
di ions (s i ing speed, ype and dimension o p opelle /s i e used), ine /non-ine
gas condi ions du ing syn hesis [
88
] and washing/cen i uga ion p o ocols need o be
documen ed and/o eco ded accu a ely du ing syn hesis o ob ain good ep oducibili y.
Only accu a e documen a ion, and epo ing, allows esea che s in o he labo a o ies o
un a he mal decomposi ion syn hesis “in he same way”, i.e., a bes possible deg ee o
simila i y.
Al hough (classical) he mal decomposi ion syn heses in nonpola sol en s can yield
magne ic pa icles wi h excellen size and shape uni o mi y, as well as c ys allini y and
magne iza ion, hey a e e y high in p ice, especially due o expensi e o ganic p ecu so s,
and gene a e many byp oduc s. Polyol me hods a e usually cheape , bu scalable p o ocols
o syn hesize pa icles o magne ic hype he mia a e s ill a he esea ch s age.
Func ionaliza ion is ano he signi ican aspec , which d aws in e es when aiming o
use nanoma e ials o magne ic hype he mia. Much wo k has been done in his aspec , and
he p o ocols o coa ing he nanopa icles wi h laye s o o ganic o ino ganic agen s and
Ma e ials 2021,14, 706 8 o 36
hei unc ionaliza ion depending on he applica ion a e gene ally well-es ablished [
89
].
Thei limi a ions a e well-known and o en ela ed o he la ge polydispe si y ha is
gene a ed by he coa ing o agg ega es, he limi ed colloidal s abili y and i s deg ada ion
when s o ed o a long ime. Mos p o ocols use highly dilu ed suspensions and a e di icul
o scale up. A special p oblem ha needs mo e a en ion is ela ed o he o e all in luence
o he coa ings on he hype he mia pe o mance in i o and in i o.
3.3. Imp o ing Rep oducibili y
In o de o imp o e he ep oducibili y o all MNP syn hesis, we need o de elop
de ailed epo s o me hods and p ocedu es, including used chemical eagen s (e.g., pu i y,
supplie , and p oduc code), as well as SOPs ha should be published as supplemen a y
in o wi h he pape o be able o become bench-ma k syn heses o he communi y. In he
same way, accu a e epo ing o cha ac e iza ion p o ocols is essen ial. The use o ISO s an-
da ds ha a e in e na ionally ag eed by expe s and gua an eed quali y equi emen s (e.g.,
analysis o TEM images, usage o Sche e equa ion, DLS o size,
ζ
-po en ial, VSM-SQUID
o magne ic p ope ies, TGA o he de e mina ion o he amoun o o ganic ma e ial a he
pa icles su ace, ICP-OES elemen al analysis o pu e me al con en quan i ica ion) should
be used [
15
]. A good p ac ice is he publica ion o aw da a (especially TEM images, whe e
an image is no p esen a i e due o a limi ed numbe o pa icles ha can be obse ed).
In ac , in many cases, he e is a need o use a combina ion o di e en cha ac e iza ion
echniques in o de o ge a ull de ailed and eliable pic u e o a gi en sample. Al eady
published ISO s anda ds can help in he compa ison o he esul s and he samples.
In he same sense, he de elopmen o b oadly accep ed p o ocols o he magne ic
cha ac e iza ion o hype he mia- a ge ed nanopa icles will help o p o ide a highe
deg ee o eliabili y o hype he mia measu emen s a an in e na ionally accep ed le el. In
his way, he measu emen o bo h SLP and ILP ( o compa e measu emen s pe o med a
di e en equencies and ield s eng hs o using di e en ins umen s) will be mo e easily
compa able among all academic and non-academic pa ne s. These cha ac e iza ions will
conce n all possible o ms, such as colloidal dispe sions/ensembles and powde samples.
De ailed cha ac e iza ion o he nanopa icles is o ou s anding impo ance o es ablishing
a ep oducible syn hesis.
3.4. Scalabili y Possibili ies
P oduc ion a la ge scales can easily be achie ed due o epe i i e and pa allel
p oduc ion, bu syn heses using lab-scale eac o s (<100 mL) will ha dly be cos -e ec i e.
Only in ew cases, he solubili y o eagen s allows he la ge p oduc ion by inc easing he
eagen concen a ion while keeping he same sol en olume [
83
]. In mos cases, keeping
he p ecu so s/su ac an s/sol en s a io while scaling-up a gi en eac ion is no enough
o assu e i s ep oducibili y in hose la ge scales unless demons a ed. I should be aken
in o accoun ha he gap be ween he o dina y labo a o y scale (100 mL) and he indus ial
pilo plan scale (100 L) is h ee o de s o magni ude. Expe imen s o scaling up o 10 L
ha s ill could be done in he lab a e needed be o e going o he indus ial scale.
The key o a success ul scale-up is o unde s and he syn hesis’ c i ical p ocess pa am-
e e s, i.e., pa ame e s wi h a high impac on he nanopa icles’ c i ical quali y a ibu es ( o
example, in he case o hype he mia, pa icle size dis ibu ion, su ace unc ionaliza ion,
and mos impo an ly, he SLP). Hence, unde s anding nanopa icle o ma ion mechanisms
and kine ics a e impo an as i shows, o example, i mixing imes, hea ing a es, o
eagen addi ion ime scales (o a combina ion) is c ucial, i.e., i needs o be main ained a
la ge scales.
An in e es ing op ion o p oduce MNPs a la ge scales is he con inuous syn heses a
low [
85
,
90
–
92
] and high empe a u es [
93
–
96
] (Figu e 1). Bo h p ocesses can be au oma ized
a a labo a o y scale, bu up o now, none o hem ha e been passed o an indus ial pilo
plan scale.
Ma e ials 2021,14, 706 9 o 36
Ma e ials 2021, 14, x FOR PEER REVIEW 9 o 37
The key o a success ul scale-up is o unde s and he syn hesis’ c i ical p ocess pa-
ame e s, i.e., pa ame e s wi h a high impac on he nanopa icles’ c i ical quali y a ib-
u es ( o example, in he case o hype he mia, pa icle size dis ibu ion, su ace unc ion-
aliza ion, and mos impo an ly, he SLP). Hence, unde s anding nanopa icle o ma ion
mechanisms and kine ics a e impo an as i shows, o example, i mixing imes, hea ing
a es, o eagen addi ion ime scales (o a combina ion) is c ucial, i.e., i needs o be main-
ained a la ge scales.
An in e es ing op ion o p oduce MNPs a la ge scales is he con inuous syn heses
a low [85,90–92] and high empe a u es [93–96] (Figu e 1). Bo h p ocesses can be au om-
a ized a a labo a o y scale, bu up o now, none o hem ha e been passed o an indus ial
pilo plan scale.
Figu e 1. Schema ic ep esen a ion o a con inuous low se up o la ge-scale p oduc ion o magne ic nanopa icles.
Changes in he manu ac u ing p ocess can signi ican ly change pa icle p ope ies
such as size, shape, and pu i y. The e o e, obus nanopa icle p oduc ion ou es need o
be chosen. I is impo an o selec hose sol en s o highe chemical s abili y o a oid hei
deg ada ion. O u mos impo ance o scalable p ocesses (and ce ainly when ansla ing
ba ch p ocesses o low) is he equi ed eac ion ime. Fo p ac ical easons, highly exo-
he mic eac ions a e undesi able, al hough low eac o s p o ide a sa e al e na i e as
hey acili a e apid hea exchange.
Rega ding he scale-up o he unc ionaliza ion s ep, he common need o s i ing
may complica e he a emp s o scale up such expe imen s when applying a con inuous
low p ocess ins ead o “ba ch” ones. I needs u he s udies o ansla e he syn hesis and
unc ionaliza ion o MNPs in con inuous o segmen ed low eac o s o p oduc ion a
indus ial scales.
Besides he equi emen o ha ing a obus and ep oducible p ocess, wha o con-
side as la ge-scale p oduc ion should be pu in o pe spec i e o demand and alue o he
p oduc . Assuming ha a conse a i e es ima e 0.05% o he wo ld’s popula ion (8 billion)
would su e om cance ha can be ea ed ia magne ic hype he mia, and assuming
u he , ha each pa ien will need six cycles o ea men a yea equi ing each ime 0.3 g
o MNPs [97], he global demand would be 144 ons a yea . We need o imp o e he hea -
ing e iciency o IONPs, le us say h ee imes mo e, o educe he amoun o MNPs needed
o each ime o 0.1 g. Al hough his p oduc ion a e appea s challenging, i mus be con-
side ed oge he wi h he p oduc ion cos s. Assuming ha cos s o $100 pe ea men
wi h he nanopa icles a e accep able, a easonable cap o p oduc ion cos s migh be $50/g
(5% o ea men cos s). Al hough his is an ex emely o e simpli ied es ima ion, i indi-
ca es wha can be conside ed as an economic la ge-scale syn hesis o MNPs o hype he -
mia, i.e., a p ocess capable o ep oducibly p oducing he desi ed nanoma e ial a cos s <
$50/g. In biomedical applica ions, when a small amoun o nanopa icles is needed, an
al e na i e o scaling he p oduc ion o MNPs could be he ansla ion o he syn he ic
p ocess owa ds a dose-on-demand syn hesis in he clinic [98,99].
4. Long-Te m S abili y and Biodis ibu ion o Nano-Hea e s in Humans
One key issue in he use o magne ic nanopa icles o magne ic hype he mia he -
apy is hei biodis ibu ion, bio ans o ma ion and long- e m a e in he body.
A i s conce n is o de ine he ime window o magne ic hype he mia e icacy, i.e.,
how long he pa icles will keep hei magne ic p ope ies and will be able o hea . The
Figu e 1. Schema ic ep esen a ion o a con inuous low se up o la ge-scale p oduc ion o magne ic nanopa icles.
Changes in he manu ac u ing p ocess can signi ican ly change pa icle p ope ies
such as size, shape, and pu i y. The e o e, obus nanopa icle p oduc ion ou es need o
be chosen. I is impo an o selec hose sol en s o highe chemical s abili y o a oid hei
deg ada ion. O u mos impo ance o scalable p ocesses (and ce ainly when ansla ing
ba ch p ocesses o low) is he equi ed eac ion ime. Fo p ac ical easons, highly exo he -
mic eac ions a e undesi able, al hough low eac o s p o ide a sa e al e na i e as hey
acili a e apid hea exchange.
Rega ding he scale-up o he unc ionaliza ion s ep, he common need o s i ing
may complica e he a emp s o scale up such expe imen s when applying a con inuous
low p ocess ins ead o “ba ch” ones. I needs u he s udies o ansla e he syn hesis
and unc ionaliza ion o MNPs in con inuous o segmen ed low eac o s o p oduc ion a
indus ial scales.
Besides he equi emen o ha ing a obus and ep oducible p ocess, wha o conside
as la ge-scale p oduc ion should be pu in o pe spec i e o demand and alue o he
p oduc . Assuming ha a conse a i e es ima e 0.05% o he wo ld’s popula ion (8 billion)
would su e om cance ha can be ea ed ia magne ic hype he mia, and assuming
u he , ha each pa ien will need six cycles o ea men a yea equi ing each ime 0.3 g o
MNPs [
97
], he global demand would be 144 ons a yea . We need o imp o e he hea ing
e iciency o IONPs, le us say h ee imes mo e, o educe he amoun o MNPs needed o
each ime o 0.1 g. Al hough his p oduc ion a e appea s challenging, i mus be conside ed
oge he wi h he p oduc ion cos s. Assuming ha cos s o $100 pe ea men wi h he
nanopa icles a e accep able, a easonable cap o p oduc ion cos s migh be $50/g (5% o
ea men cos s). Al hough his is an ex emely o e simpli ied es ima ion, i indica es wha
can be conside ed as an economic la ge-scale syn hesis o MNPs o hype he mia, i.e., a
p ocess capable o ep oducibly p oducing he desi ed nanoma e ial a cos s < $50/g. In
biomedical applica ions, when a small amoun o nanopa icles is needed, an al e na i e o
scaling he p oduc ion o MNPs could be he ansla ion o he syn he ic p ocess owa ds a
dose-on-demand syn hesis in he clinic [98,99].
4. Long-Te m S abili y and Biodis ibu ion o Nano-Hea e s in Humans
One key issue in he use o magne ic nanopa icles o magne ic hype he mia he apy
is hei biodis ibu ion, bio ans o ma ion and long- e m a e in he body.
A i s conce n is o de ine he ime window o magne ic hype he mia e icacy, i.e.,
how long he pa icles will keep hei magne ic p ope ies and will be able o hea . The
subsequen clinical challenge is o de ine he numbe and he ime o magne ic ield
applica ions ha will be use ul o a ec he umo .
I has been shown ha in acellula con inemen o magne ic nanopa icles in lyso-
somes has a d ama ic impac on hei dynamical magne ic p ope ies and SLP, mos ly due
o dipola in e pa icle in e ac ions and loss o o a ional mobili y [
100
,
101
], e en i he
pa icles keep hei c ys alline in eg i y. Ano he c i ical aspec is ha he in acellula
magne ic pa icles a e exposed o he ha sh en i onmen o lysosomes ha combine acidic
pH (abou 4.5), enzymes ha egula e p o ein deg ada ion and edox egula o s. Since he
unc ion o lysosomes is o deg ade undesi able p o eins and xenobio ics, i is impo an o
de e mine o wha ex end lysosomes may be able o deg ade magne ic pa icles and make
hem lose hei s uc u al in eg i y and magne ic p ope ies?
Ma e ials 2021,14, 706 16 o 36
a e i has achie ed i s PMOA o hea ing. The e o e, he p ima y mode o ac ion would
emain as a de ice.
5.2.2. D ug-De ice Combina ion P oduc
Whe e a p oduc uses bo h d ug and de ice unc ions o achie e i s p ima y in ended
pu pose, i is classi ied as a d ug-de ice combina ion p oduc [
128
]. A hype he mia
pa icle ha has a a ge ing unc ion using a ecep o (i.e., chemical/pha macological
ac ion), as well as hea ing, would be classi ied as a combina ion p oduc . Fo combina ion
p oduc s in he US, he p ima y mode o ac ion de e mines whe he he p ima y egula o y
pa hway will be d ug o de ice. In Eu ope, combina ion p oduc s a e ei he egula ed
as d ugs o de ices depending on he p ima y e sus ancilla y unc ion. Fo pa icles
combining mo e han one ype o ac ion, he app op ia e egula o y pa hway will depend
on which mode o ac ion is p ima y, and ypical elemen s o bo h he d ug and de ice
pa hway a e ollowed, depending on he e i o y.
5.3. S eamlined De elopmen
Any would-be hype he mia he apy will need o demons a e clinical sa e y and
e icacy, and o his, he e is no sho -cu , bu he e a e ways o s eamline he o e all
p ocess. One app oach is o use an exis ing pa icle in a new way. Such “ e-pu posing” is
he basis o physician-led “o -label” use o he apies. Fo example, he e a e a numbe o
clinical s udies in es iga ing he use o pa icles app o ed o i on- eplacemen he apy
as MRI con as agen s [
129
]. The a ionale is ha i a p oduc is shown o be sa e in one
clinical indica ion, i will be easie o es ablish sa e y in a new one.
The p ocess can also be s eamlined by aking in o accoun he equi emen s o la e
s ages, e en in he ea lies s ages o pa icle de elopmen . Ensu ing ha manu ac u ing
ques ions such as oxici y, biocompa ibili y, s abili y and p ocess scalabili y a e consid-
e ed ea ly on can di ec he de elopmen away om “dead-ends” and sa e signi ican
cos and ime. Fo example, ano he nano echnology, quan um do s, show p omise o
cance he apy. Howe e , a i s , he mos commonly used co es con ained cy o oxic
cadmium [
130
]. While in heo y, hese co es could be coa ed o minimize cy o oxici y, in
p ac ice, es ablishing long- e m sa e y has p o ed challenging. Ini ial conside a ion o
biocompa ibili y could ha e accele a ed p og ess owa ds clinical use by di ec ing e o
owa ds he cadmium- ee non- oxic al e na i es now being explo ed [131].
In summa y, he challenging la e s ages o magne ic pa icle de elopmen can be
mo e easily nego ia ed i , a he ea ly-s ages, downs eam equi emen s such as GMP
manu ac u e, clinical sa e y and he egula o y pa hway can be inco po a ed and used o
guide he de elopmen . This kind o in eg a ed app oach can help has en a b igh u u e
o clinical magne ic hype he mia.
6. Nano oxici y o Nanopa icles o Magne ic Hype he mia
The inc easing use o magne ic hype he mia in (p e)clinical se ings wa an s a p ope
unde s anding and ca e ul e alua ion o how enginee ed nanoma e ials would be mos
op imally sui ed. This conce ns bo h he e icacy o he mal con e sion, wi h maximal
hea gene a ion o a minimal numbe o nanopa icles, as well as a comple e lack o any
po en ial oxici y on heal hy cells om he pa ien . To da e, a ious s udies ha e looked
in o he oxici y o IONPs, mainly d i en by hei clinical accep ance as con as agen s
o MRI [
132
,
133
]. The majo i y o hese s udies conce n
in i o
expe imen s, whe e cell
ypes o in e es a e used o e alua e po en ial oxici y upon exposu e o he enginee ed
nanopa icles [
134
,
135
]. While mo e limi ed, some s udies ha e also been pe o med in
p eclinical animal models, mainly mice and a s, o e alua e po en ial sys emic oxici y
om exposu e o he nanopa icles [136].
Howe e , inal conclusions ega ding he sa e y o oxici y o hese nanopa icles
emain di icul o answe , mainly d i en by he wide a ie y o model sys ems used, ex-
pe imen al se ings and nanopa icle p ope ies [
137
]. O e all, i is belie ed ha IONPs a e

Ma e ials 2021,14, 706 17 o 36
ai ly sa e, up o concen a ions o 5 mM o i on [
138
]. Ye , hese ea ly opinions ha e been e-
isi ed by a ious s udies, showing ha nanopa icle-speci ic p ope ies such as size, shape
and su ace chemis y can ha e a signi ican in luence on he oxici y o he pa icles [
139
].
O e all, oxici y has mainly been linked wi h cellula up ake le els, whe e IONPs end
o cause high le els o eac i e oxygen species, which, depending on he na u e o he
cells, can lead o oxida i e s ess [
140
]. This, in u n, can mani es i sel in di e en ways,
po en ially esul ing in geno oxici y, diminished s em cell di e en ia ion, neu o oxici y o
in lamma ion [
141
–
144
]. In iew o cance he apy, he seques a ion o dex an-coa ed
IONPs by umo -associa ed mac ophages has been shown o al e mac ophage s a us and
p omo e p oin lamma o y M1 pheno ype [
145
]. While his is po en ially in e es ing o
umo immuno he apy, he e ec o he pa icles on o he mac ophages and he induc ion
o in lamma o y esponses may cause se e e side-e ec s.
As men ioned abo e, one main p oblem lies in he seemingly con adic ing da a
a ailable in he li e a u e, which can be na owed down o expe imen al a ia ions. Mino
modi ica ions o nanopa icle p ope ies can ha e majo implica ions in iew o hei
biodis ibu ion and oxici y, and, he e o e, no gene al conclusion can e e be made. IONPs
also in e e e wi h a ious classical biochemis y es s, such as he MTT assay [
135
], and
ca e mus be aken o p ope ly design s udies wi h sui able con ols o in in e p e ing
da a om o he s udies. Fo IONPs, one aspec o in e es is hei biome abolism, whe e
cellula up ake o he nanopa icles esul s in hei lysosomal seques a ion. The e, he low
lysosomal pH and p esence o small molecules (e.g., ci a e) esul in he dissolu ion o he
nanopa icles and he elease o e ic ions ha a e hen shu led in o he cy oplasm and
become pa o he cellula labile i on pool [
138
]. While his deg ada ion esul s in p ope
biop ocessing o he nanopa icles, i will a ec he magne ic p ope ies o he nanopa icles
in he longe e m [
146
,
147
]. In he sho - e m, he kine ics o his deg ada ion mus be
ca e ully con olled, as apid dissolu ion is linked o excessi e e ic ion concen a ions
p esen locally ha can su pass oxic h esholds [
148
]. Ca e ully con olling he deg ada ion
kine ics by uning nanopa icle p ope ies, such as he su ace coa ing, can play a key ole
in de e mining he ole ance o he body o such nanopa icles.
In o de o u he exploi he clinical use o hese nanopa icles in hype he mia
applica ions, i is impe a i e ha he scien i ic ques ion is p ope ly posed. The ques ion:
“a e nanopa icles sa e” is oo gene ic and can simply no be answe ed. By eph asing
he sen ence in o “does o mula ion x cause any ha m when i is used o hype he mia
when adminis e ed by y a dose z?”, i de ines be e he esea ch ha needs o be pe -
o med in o de o p omo e his ield: (1) he exac nanopa icle o mula ion mus be
well cha ac e ized and desc ibed. (2) The ou e o adminis a ion o he pa ien mus
be clea ly de ined. (3) The dose and need o epea ed adminis a ions o no mus be
speci ied. (4) The abili y o pe o m hype he mia a i s op imal ou pu mus be e alua ed
and compa ed o cu en gold s anda ds and s a e-o - he-a me hods. While la ge se s o
li e a u e da a a e a ailable, he da a needed o answe he ques ion abo e emain sca ce.
Typical examples include classical oxici y s udies, in which nanopa icles a e adminis e ed
sys emically by in a enous adminis a ion, while o mos hype he mia applica ions, he
nanopa icles a e adminis e ed locally. IONPs ha e been s udied, bu o he nanoma e ials
ha a e e alua ed as hype he mia media o s wi h possibly highe he apeu ic e icacy a e
o en less commonly s udied [
149
,
150
]. The biodis ibu ion o he nanopa icles eleased
om he umo a e hype he mia applica ion would be mo e in e es ing o s udy han
sys emically adminis e ed nanopa icles. The oxici y o he nanopa icles on hei own is
impo an , bu hei e ec mus also be e alua ed a e hype he mia applica ion. I is likely
ha he su ace coa ing o he nanopa icles has changed due o he gene a ed hea , and
his may a ec nanopa icle beha io (biodis ibu ion and oxici y) qui e d as ically. Apa
om sa e y, he he apeu ic e icacy mus also be demons a ed. While his commonly
happens using classical ea men (e.g., doxo ubicin), his is o en a om eali y, and
clinically ele an ea men s, as well as o he no el s a e-o - he-a he apies, mus be used
as a compa ison (e.g., small molecules, immuno he apy, e c.).
Ma e ials 2021,14, 706 18 o 36
The clinical accep ance o a pa icula nanopa icle o mula ion also equi es egu-
la o y app o al. While guidelines o chemicals o pass clinical ials a e a he clea , o
nanopa icles, his emains a he ague. P og ess has been made, howe e , and wi h
u he op imiza ion and eamwo k be ween expe s in he ield, he h oughpu o clinical
ansla ion o nanomedicines will only inc ease. Thus, u he ad ances in he clinical ans-
la ion o nano echnologies can be expec ed in he nea u u e [
151
]. To da e, nanopa icles
can ei he be labeled as a “medical de ice” o as a “d ug”, which has majo implica ions on
how egula o y app o al o clinical use can be ob ained. The label o “medical de ice” was
p e iously p e e ed as i in ol ed less leng hy clinical s udies and was based on he no ion
ha he nanopa icles hemsel es did no change o we e an ac i e subs ance bu me ely a
ool by which he apy could be pe o med. As desc ibed in he excellen manusc ip by
Jones e al. [
152
], he slow p og ess in clinical ansla ion is no in i sel caused by a lack o
egula ions bu a he a b oad gap be ween heo e ical knowledge and p ac ice. This is in
pa due o he lack o academics in ol ed in se ing up he documen s ega ding sa e y
and e icacy es ing o medical de ices, esul ing in a lack o s anda dized me hods o
ga he ing and p esen ing da a. E o s o b idge his gap a e ongoing, wi h he se up o he
Nano echnology Cha ac e iza ion Labo a o y (NCL) o de elop s anda dized p o ocols
o oxicology, pha macology and e icacy e alua ion o nanoma e ials. Fo mos agen s,
he use o specialized clinical esea ch o ganiza ions (CROs) is wa an ed, who will design
and/o pe o m he p eclinical s udies equi ed o ile an applica ion o clinical s udies.
While a ious CROs exis wi h b oad expe ise in a wide ange o echnologies, CROs wi h
expe knowledge on nanopa icle use emains limi ed. P og ess in his domain is expec ed
as he ield o nanomedicine keeps expanding, whe e nano oxici y and nanomedicine
expe s can hen liaise wi h, o o m pa o , egula o y o ices and CROs dedica ed o
enhancing clinical p og ess in his exci ing ield.
7. Tempe a u e Measu ing and Moni o ing
7.1. Backg ound
Apa om hei gene al applica ion o dis ance con olled non-con ac hea ing,
MNPs p o ide an excellen oppo uni y o nano-ac ua ion. Fo ins ance, hey can be
used o selec i e hea ing o nano-objec s o induce poin eac ions a he nanoscale. This
ope a ion implies he gene a ion o empe a u e g adien s in he nano-objec wi h espec
o i s su oundings, which can only be de e mined by he mome e s wi h a spa ial eso-
lu ion also a he nanome e scale. Mo eo e , he simul aneous use o nanohea e s and
nano he mome e s could be employed o in es iga e phenomena o hea ans e a he
nanoscale, which is ac ually an unexplo ed e i o y and he objec o in ense deba e,
especially conce ning in acellula hea ans e [
153
,
154
]. The ecen de elopmen o
a e-ea h-doped luminescen MNPs has in oduced a new ield in he mal biosensing,
implying less in asi e expe imen s, no only in li ing cells bu also in mo e challenging
small animal models [
155
–
158
]. Joining he mome y and hea ing a he nanoscale can
also be pa icula ly in e es ing o he de elopmen o high-pe o mance non-in asi e
hype he mia he apy based on he local hea ing o speci ic in acellula si es o p o oke
cell apop osis, wi hou he need o o e all massi e hea ing o he whole cance umo .
The hypo hesis o local in acellula hype he mia a ises om he d awbacks o
he cu en s a egy o o e all umo hea ing and a massi e injec ion o MNPs di ec ly
in o he umo [
159
]. E en be o e being es ed, his hypo hesis has al eady been he
subjec o in ense deba e [
160
]. Objec ions come mos ly om s anda d he modynamic
conside a ions, which es ima e an in acellula concen a ion o MNPs equi ed o e adica e
umo s ha is i ually un easible [
160
]. A he cen e o his deba e is he ques ion o
whe he i is possible o c ea e a su icien ly high- empe a u e g adien in he icini y o
MNP dispe sed in a liquid o in acellula media [
154
]. Indeed, heo e ical he modynamic
calcula ions p edic he o ma ion o negligible empe a u e g adien s in MNPs when
subjec ed o al e na ing magne ic ields wi h espec o he bulk [
161
,
162
], and a ew
expe imen al epo s a e in ag eemen wi h hese p edic ions [
163
]. Howe e , nume ous
Ma e ials 2021,14, 706 19 o 36
expe imen al s udies ha e ound subs an ial local empe a u e g adien s a hese condi ions
ha sugges he exis ence o nanoscale hea ans e phenomena di e en om mac oscopic
sys em beha io [
160
,
164
–
169
]. I is hus pe emp o y o he ad ancemen in he ield o
dispose o eliable me hods o he de e mina ion o local empe a u e in he icini y o
MNPs, and he de i a ion o he modynamical models o in acellula hea ans e a
he nanoscale.
7.2. Luminescence Nano he mome y
Luminescence he mome e s a e p obably he bes op ion o non-con ac high spa ial
esolu ion he mome y in gene al [
155
] and in acellula he mome y in pa icula [
156
].
The e a e se e al ypes o luminescen he mome ic p obes acco ding o hei na u e: lumi-
nescen molecules (o ganic molecules such as dyes, p o eins like g een luo escence p o ein,
GFP), ino ganic compounds (quan um do s, Si-do s, nanodiamond, lan hanides) o hyb id
molecula o pa icula e ma e ials. Se e al empe a u es sensing op ical p ope ies a e also
used, such as he in ensi y o emission, li e ime o pola iza ion aniso opy [
157
]. Li e ime
measu emen s o e high sensi i i y and minimize in e e ences om o he luminopho es
p esen in he medium. This is especially ue when using lan hanides luminescence p obes
as hey show long li e imes, elimina ing any in e e ence e ec s om o he luminopho es.
Howe e , li e ime measu emen s equi e a sophis ica ed de ec ion sys em, and he e o e
in ensi y measu emen s, which can be pe o med on widely a ailable luo escence mic o-
scopes, a e usually p e e ed. The simples luo escence he mome ic sys em is based
on single emission in ensi y measu emen s, bu his sys em does no yield absolu e em-
pe a u es, and i is likely o be a ec ed by he concen a ion o emi e s, he in ensi y o
exci a ion ligh sou ce and he en i onmen . A way o o e come hese p oblems is o use
he a io o wo emissions as he he mome ic pa ame e ( a iome ic he mome y), which
is a mo e eliable, especially when he double emission comes om a single sou ce.
The e a e se e al ways o implemen luminescence nano he mome y in o a magne ic
nanohea e : he dual-pa icle app oach and he single-pa icle app oach [
157
]. The e a e
also se e al kinds o empe a u e measu ing [
155
–
157
,
169
]: indi ec single empe a u e
alue, di ec ins an , con inuous measu emen s o empe a u e changes, and in si u a io-
me ic absolu e empe a u e measu emen s. In he nex sec ion, we will conside he bes
a ailable op ions so a o magne ic hype he mia applica ions.
7.3. De e mina ion o Local Tempe a u e in MNPs
When con enien ly endo sed wi h a ge ing agen s, magne ic NPs ha e he capaci y
o selec i ely pene a e he memb ane o cance cells. P o iding ha hey can be di ec ed
o speci ic in acellula o ganelles, he hea gene a ed by hese NPs can be used o induce
local damage in hese o ganelles o igina ing cell apop osis wi hou he need o inc easing
he empe a u e o he whole cell and hus subs an ially educing he amoun o MNPs
necessa y o kill he cells. To e i y his hypo hesis, i is necessa y o check whe he he
hea gene a ed by he MNPs is su icien o main ain a empe a u e g adien be ween
he a ge ed o ganelle agains he hea conduc ion o he cy oplasm and he ex acellula
ma ix. Mo eo e , his concep o local hype he mia he apy wi h AC ields equi es
he use o MNPs wi h a high SLP a condi ions compa ible wi h
in i o
ea men . Dual
MNP- he mome e nanopa icle sys ems lack p ecision as he empe a u e is measu ed
a a dis ance om he hea e [
167
]. Single-pa icle sys ems based on he de achmen o
luo opho es om he MNP shell abo e ce ain empe a u e alues ha e been used o
ob ain empe a u e g adien s o abou 45
◦
C [
166
] and 8
◦
C [
167
] in he icini y o MNPs
unde AC magne ic ield induc ion. Howe e , hese me hods equi e pos -analysis o he
medium and he e o e canno be used o empe a u e moni o ing. The ideal solu ion
is o inco po a e in a single MNP a he mome ic p obe ha yields ins an in o ma ion
o he local absolu e empe a u e o he MNP du ing he applica ion o he al e na ing
magne ic ield. The e a e wo possible ways: deco a ing he MNP su ace wi h molecula
he mome e s o coa ing i wi h a solid he mome ic shell. The second case would o e
Ma e ials 2021,14, 706 20 o 36
be e chemical s abili y agains he complex in acellula en i onmen , bu i is s ill a he
s age o inding an adequa e ino ganic he mome ic coa ing o MNPs. Molecula lumi-
nescence p obes may su e om luminescence quenching and bleaching e ec s p oduced
by chemicals in he en i onmen . The e o e, he eal challenge in he design o his ype
o p obes is o shield hem agains he ac ion o he complex biological en i onmen o
p ese e hei op ical he mome ic p ope ies.
As in oduced in Sec ion 7.2, se e al ypes o ma e ials ha e been p oposed as em-
pe a u e nanop obes [
156
], some o hem ha e been e en used o in acellula he mom-
e y [
170
], i.e., ER he mo yellow [
171
], bu only a ew ha e been ac ually used in local
magne ic hype he mia s udies [
170
]. Fo ins ance, epo s o a 15
◦
C empe a u e g adien
we e epo ed on Mn- e i e NPs a ached o he memb ane o HEK 293 cells 15 s a e
he applica ion o AC ields using DyLigh 549 as a he mome ic p obe [
164
]. Ad ances
in his case also include he in si u measu emen o local empe a u e g adien s using
hodamine [
172
] and lan hanide luminescence complexes [
169
]. The emission li e ime o
GFP has also been used o epo la ge local empe a u es o 85
◦
C, al hough hey we e
es ima ed by ex apola ion o calib a ion cu es ob ained a much lowe empe a u es. The
p obes we e no a ached o he hea he s, bu independen ly sp ead inside he cells. Using
a double pa icle app oach, consis ing o MNPs and upcon e sion nanopa icles embedded
in a silica ma ix, and a iome ic empe a u e de e mina ion, g adien s o abou 20
◦
C we e
epo ed on nanopa icles suspended in a liquid a e a 5 min exposu e o AC ields [
168
].
Ongoing in acellula expe imen s in ou lab using simila nanop obes ha e yielded qui e
p omising esul s on 2D- empe a u e imaging o cells con aining MNPs du ing hype he -
mia ea men (Figu e 6). Mos o he he mome ic p obes desc ibed so a a e based on
isible ligh , lacking he necessa y issue pene a ion o body empe a u e moni o ing, and
he e o e can only be use ul in cell cul u e expe imen s. Howe e , he ield is also mo ing
owa ds he de elopmen o in a ed deep issue he mome y sys ems [
173
]. This op ion is
possible in he case o op ical hype he mia, whe e single nanopa icles wi h a hea ing and
empe a u e measu emen p ope ies a e al eady a ailable [
174
]. In a ed luminescence
empe a u e p obes can also be possibly coupled o magne ic hea ing nanopa icles.
Ma e ials 2021, 14, x FOR PEER REVIEW 21 o 37
moni o ing, and he e o e can only be use ul in cell cul u e expe imen s. Howe e , he
ield is also mo ing owa ds he de elopmen o in a ed deep issue he mome y sys-
ems [173]. This op ion is possible in he case o op ical hype he mia, whe e single nano-
pa icles wi h a hea ing and empe a u e measu emen p ope ies a e al eady a ailable
[174]. In a ed luminescence empe a u e p obes can also be possibly coupled o magne ic
hea ing nanopa icles.
Figu e 6. The mal images o MNPs in e nalized in cells, (a), be o e, and (b), du ing i adia ion wi h an AC magne ic ield;
(c), a e age empe a u e shi upon he applica ion o an AC magne ic ield.
We can easonably expec ha in a ew yea s, we would dispose o se e al ypes o
MNPs inco po a ing local empe a u e p obes, bo h molecula and solid na u e, ha can
yield eliable da a on he local empe a u e g adien gene a ed by MNPs exposed o al e -
na ing magne ic ields ha can be used o he de elopmen o less in asi e, mo e e icien
and mo e selec i e ad anced magne ic hype he mia ea men s.
8. T ea men Planning and Dosime y
T ea men planning—which ep oduces he dose needed o des oy he umo s p e-
se ing as much heal hy issue as possible— o many hype he mia modali ies ha e ben-
e i ed om he de elopmen s made in adio he apy [175–179]. In he pa icula case o
magne ic hype he mia, so a , he e is only one comme cially a ailable sys em o he
pu pose de eloped by MagFo ce, he NanoPlan
®
( o me ly known as Hype Plan
®
) [180].
The ypical wo k low o a hype he mia ea men planning (HTP) ool s a s wi h a 3D
model o he egion o in e es ha is buil om compu e ized omog aphy (CT), o MRI
scans om pa ien s; hen, elec omagne ic ields, SAR and empe a u e dis ibu ions a e
compu ed by sol ing Maxwell’s and biohea equa ions, espec i ely, unde he app op i-
a e bounda y condi ions. Rega ding he i ual models used, a mo e o less ex ensi e col-
lec ion is a ailable h oughou he li e a u e—see, o ins ance, e iew [181]. The use o
hese pa ien -based models—despi e adding complexi y o he HTP p ocess—has been
demons a ed o imp o e he es ima ion o SAR and empe a u e pa e ns compa ed o
homogeneous phan om-based models [182]. Many physical models used o simula ing
he in e ac ion o he applied elec omagne ic ields wi h issues ha e been p oposed [183–
188], mainly by de i ing om undamen al equa ions, like Maxwell’s equa ions— o cal-
cula ing elec omagne ic ields and SAR—and Penne’s biohea equa ion— o empe a u e
dis ibu ions. Un o una ely, modeling magne ic hype he mia wi hin he con ex o his
body o knowledge s ill p o es di icul mainly due o an impo an challenge: o couple
he di e en size scales— om 3D down o 1D, whe e he ele an magne ic and hea ing
phenomena s em om—in ol ed in he mul iple physical phenomena con e ging in his
he apy, namely luid dynamics, hea exchange, and elec omagne ic in e ac ion. Due o
i s inhe en complexi y, his is a longs anding p oblem ha needs o be add essed in he
Figu e 6. The mal images o MNPs in e nalized in cells, (a), be o e, and (b), du ing i adia ion wi h an AC magne ic ield;
(c), a e age empe a u e shi upon he applica ion o an AC magne ic ield.
We can easonably expec ha in a ew yea s, we would dispose o se e al ypes
o MNPs inco po a ing local empe a u e p obes, bo h molecula and solid na u e, ha
can yield eliable da a on he local empe a u e g adien gene a ed by MNPs exposed o
al e na ing magne ic ields ha can be used o he de elopmen o less in asi e, mo e
e icien and mo e selec i e ad anced magne ic hype he mia ea men s.
Ma e ials 2021,14, 706 21 o 36
8. T ea men Planning and Dosime y
T ea men planning—which ep oduces he dose needed o des oy he umo s p e-
se ing as much heal hy issue as possible— o many hype he mia modali ies ha e
bene i ed om he de elopmen s made in adio he apy [
175
–
179
]. In he pa icula case
o magne ic hype he mia, so a , he e is only one comme cially a ailable sys em o he
pu pose de eloped by MagFo ce, he NanoPlan
®
( o me ly known as Hype Plan
®
) [
180
].
The ypical wo k low o a hype he mia ea men planning (HTP) ool s a s wi h a 3D
model o he egion o in e es ha is buil om compu e ized omog aphy (CT), o MRI
scans om pa ien s; hen, elec omagne ic ields, SAR and empe a u e dis ibu ions a e
compu ed by sol ing Maxwell’s and biohea equa ions, espec i ely, unde he app op ia e
bounda y condi ions. Rega ding he i ual models used, a mo e o less ex ensi e col-
lec ion is a ailable h oughou he li e a u e—see, o ins ance, e iew [
181
]. The use o
hese pa ien -based models—despi e adding complexi y o he HTP p ocess—has been
demons a ed o imp o e he es ima ion o SAR and empe a u e pa e ns compa ed o
homogeneous phan om-based models [
182
]. Many physical models used o simula ing he
in e ac ion o he applied elec omagne ic ields wi h issues ha e been p oposed [
183
–
188
],
mainly by de i ing om undamen al equa ions, like Maxwell’s equa ions— o calcu-
la ing elec omagne ic ields and SAR—and Penne’s biohea equa ion— o empe a u e
dis ibu ions. Un o una ely, modeling magne ic hype he mia wi hin he con ex o his
body o knowledge s ill p o es di icul mainly due o an impo an challenge: o couple
he di e en size scales— om 3D down o 1D, whe e he ele an magne ic and hea ing
phenomena s em om—in ol ed in he mul iple physical phenomena con e ging in his
he apy, namely luid dynamics, hea exchange, and elec omagne ic in e ac ion. Due
o i s inhe en complexi y, his is a longs anding p oblem ha needs o be add essed in
he sho - e m o mo e owa ds wide clinical adop ion o magne ic hype he mia. A
uni ied magne ic hype he mia heo y should be made possible in he nea u u e, aking
ad an age o 3D-1D coupling s a egies based on opological model educ ion [189].
New HTP sys ems based on con olu ional neu al ne wo ks and deep-lea ning ech-
niques a e being es ed in a new clinical ial ocused on he ea men o locally ad anced
panc ea ic duc al adenoca cinomas [
2
], allowing o ob ain a 3D model o each pa ien
ins ead o elying on he s anda d ones al eady a ailable o pe o m he simula ions. The
main bene i o he HTP is ha all cases can be s udied be o ehand, e en hose ha ma ch
wi h any o he exclusion c i e ia, hus e alua ing hei isk and inally uling ou o no
hei sui abili y o he ea men . One o he exclusion c i e ia o p ospec i e pa icipan s
is ha no implan -bea ing pa ien s a e allowed, which may ep esen a p opo ion as high
as 60% o he ini ial coho . The eason o his is ha pa o o ally me allic implan s may
unde go no iceable hea ing du ing he he apy upon being exposed o he magne ic ield
needed o exci e he MNPs (Figu e 7), e en inducing issue damage i no p ope ly con-
olled. Ve y ecen esul s show how he implan hea ing p ocess akes place in di e en
indica ions, and di e en ways o eco e a sizeable pe cen age o he ini ially excluded
pa ien s ha e been p oposed [190,191].
Fu u e big imp o emen s in ea men planning o magne ic hype he mia a e on
hei way, coming om he hand o speci ic eme ging nano-enabled diagnos ic echniques,
like he case o magne ic pa icle imaging (MPI). The la e speci ically adds wha ea men
planning in magne ic hype he mia is cu en ly lacking, namely he p ecise quan i ica ion
and spa ial loca ion o he nanopa icles inside he body depending on he adminis a ion
means and he physical p ope ies o he issues in ol ed [
192
]. This ea u e allows o a
p elimina y quali y check o nanopa icle ins alla ion inside umo s, basing he p edic ions
on he numbe o nanopa icles ha ha e ac ually eached he a ge and no he ough
es ima ions made om he expec ed sp ead o he injec ed olume. In addi ion, he
possibili y o a eal- ime ollow-up o he pos -injec ion a e o nanopa icles is c ucial o
co ec he ini ial condi ions o simula ing subsequen ea men sessions. Conside ing
ha he de elopmen o MPI scanne s o humans is cu en ly mo ing on [
193
–
195
], he

Ma e ials 2021,14, 706 22 o 36
i s esul s om inco po a ing i in o he cu en HTP me hodologies may be seen in abou
wo yea s.
Ma e ials 2021, 14, x FOR PEER REVIEW 22 o 37
sho - e m o mo e owa ds wide clinical adop ion o magne ic hype he mia. A uni ied
magne ic hype he mia heo y should be made possible in he nea u u e, aking ad-
an age o 3D-1D coupling s a egies based on opological model educ ion [189].
New HTP sys ems based on con olu ional neu al ne wo ks and deep-lea ning ech-
niques a e being es ed in a new clinical ial ocused on he ea men o locally ad anced
panc ea ic duc al adenoca cinomas [2], allowing o ob ain a 3D model o each pa ien
ins ead o elying on he s anda d ones al eady a ailable o pe o m he simula ions. The
main bene i o he HTP is ha all cases can be s udied be o ehand, e en hose ha ma ch
wi h any o he exclusion c i e ia, hus e alua ing hei isk and inally uling ou o no
hei sui abili y o he ea men . One o he exclusion c i e ia o p ospec i e pa icipan s
is ha no implan -bea ing pa ien s a e allowed, which may ep esen a p opo ion as high
as 60% o he ini ial coho . The eason o his is ha pa o o ally me allic implan s may
unde go no iceable hea ing du ing he he apy upon being exposed o he magne ic ield
needed o exci e he MNPs (Figu e 7), e en inducing issue damage i no p ope ly con-
olled. Ve y ecen esul s show how he implan hea ing p ocess akes place in di e en
indica ions, and di e en ways o eco e a sizeable pe cen age o he ini ially excluded
pa ien s ha e been p oposed [190,191].
Figu e 7. Calcula ed ield and empe a u e pa e ns in and a ound he hip implan o a p ospec i e pa ien o magne ic
hype he mia o ea a p os a e umo .
Fu u e big imp o emen s in ea men planning o magne ic hype he mia a e on
hei way, coming om he hand o speci ic eme ging nano-enabled diagnos ic ech-
niques, like he case o magne ic pa icle imaging (MPI). The la e speci ically adds wha
ea men planning in magne ic hype he mia is cu en ly lacking, namely he p ecise
quan i ica ion and spa ial loca ion o he nanopa icles inside he body depending on he
adminis a ion means and he physical p ope ies o he issues in ol ed [192]. This ea-
u e allows o a p elimina y quali y check o nanopa icle ins alla ion inside umo s, bas-
ing he p edic ions on he numbe o nanopa icles ha ha e ac ually eached he a ge
and no he ough es ima ions made om he expec ed sp ead o he injec ed olume. In
addi ion, he possibili y o a eal- ime ollow-up o he pos -injec ion a e o nanopa icles
is c ucial o co ec he ini ial condi ions o simula ing subsequen ea men sessions.
Conside ing ha he de elopmen o MPI scanne s o humans is cu en ly mo ing on
[193–195], he i s esul s om inco po a ing i in o he cu en HTP me hodologies may
be seen in abou wo yea s.
Figu e 7.
Calcula ed ield and empe a u e pa e ns in and a ound he hip implan o a p ospec i e pa ien o magne ic
hype he mia o ea a p os a e umo .
Ano he signi ican s ep-up in HTP o magne ic hype he mia could be achie ed
in he nea u u e by combining he exis ing echnology wi h adiomics. The la e com-
p ises compu e -assis ed medical image analysis wi h dedica ed algo i hms o ea u e
ex ac ion—much bene i ed om he boom o a i icial in elligence—p o iding spa ial
and empo al in o ma ion ha is no a ained by da a om -omics [
196
,
197
]. Radiomics
mainly nu u es om compu e omog aphy and magne ic esonance imaging da a, bu
applying i s p inciples o MPI may b ing an unp eceden ed deg ee o accu acy o HTP in
magne ic hype he mia.
9. Fu he E olu ion in o The anos ics: Combining Magne ic Hype he mia and MPI
Combining he apy and diagnos ic imaging, o he anos ics has been an ac i e a ea o
esea ch ac oss nume ous biomedical ields o e he pas decade. Fo example, he anos ics
is an es ablished app oach in nuclea medicine whe eby he apy and diagnos ic imaging
a e pe o med using he same molecule o simila molecules. The anos ic agen s enable
simul aneous assessmen o clinical s a us, ea men , and con i ma ion o ea men dose.
In his sec ion, we discuss a new he anos ic app oach ha combines MPI and localized
magne ic hype he mia. Toge he , hese wo echnologies enable mapping o a MNP
dis ibu ion, p esc ibing a hea ing dose, and hen ca e ully applying hea pe he p esc ibed
hea dose o a local a ea.
MPI is an eme ging imaging echnology ha di ec ly quan i a es MNP concen a ion
in issue. MPI is ace -based and p oduces posi i e con as images, analogous o nuclea
medicine o op ical. The signal is di ec ly de ec ed om he nanopa icle ace s and has
he ad an age o being linea ly quan i a i e wi hou issue a enua ion. The physics ha
unde lie he signal gene a ion and image o ma ion can be unde s ood using classical
physics. An MPI sys em p oduces a s ong magne ic ield g adien con aining a ield- ee
egion (FFR)—a egion whe e he magne ic ield is app oxima ely ze o (Figu e 8a). MNPs
in he FFR a e magne ically unsa u a ed and p oduce a signal in a ecei e coil, while
sa u a ed supe pa amagne ic i on oxide nanopa icles (SPIOs) ou side he FFR p oduce no
signal. Images a e p oduced by as e scanning he FFR ac oss he subjec . Fi s published in
Ma e ials 2021,14, 706 23 o 36
2005 [
198
], he ield has g own apidly, and he e a e now comme cially a ailable p eclinical
MPI sys ems [199,200], and clinical-scale MPI sys ems a e unde de elopmen [193,194].
To da e, mos MPI has been pe o med o non-in asi ely image he dis ibu ion and
quan i y o MNPs in mu ine models. Tumo s can be de ec ed by he passi e accumula ion
o ace s h ough he enhanced pe meabili y and e en ion e ec [
201
], by he up ake
o phagocy ic umo -associa ed mac ophages [
202
], o h ough he a ge ed use o unc-
ionalized and a ge ed ace s [
203
,
204
]. No el nanopa icles enable new capabili ies o
MPI sys ems. Song e al. demons a ed he syn hesis o mul imodal FeCo nanopa icles
o imaging wi h nea -in a ed, MPI, MRI, and pho oacous ic echniques and he apeu ic
p ope ies wi h pho o he mal and magne o he mal sys ems [205].
As p e iously discussed, magne ic hype he mia o ac i a ion o MNPs o e s consid-
e able po en ial o nume ous biomedical applica ions, especially in he clinical ea men
o cance s. Magne ic hype he mia elies on he deli e y o MNPs o umo s ollowed
by he applica ion o AC ields, causing local hea ing o issue. The killing o umo cells
occu s ei he di ec ly o by enhancing he cy o oxic e ec s o adio, immune, o chemo he -
apy [
206
]. Magne ic hype he mia can be pe o med anywhe e in he body since AC
ields pene a e issue wi hou a enua ion. Human clinical ials ha e demons a ed he
bene i s o magne ic hype he mia o p os a e cance [
207
]; and, o e all su i al bene i s
wi h adio he apy in ecu en glioblas oma esul ed in Eu opean egula o y app o al in
2010 [
208
]. Despi e i s demons a ed e ec i eness, cu en magne ic hype he mia imple-
men a ions a e limi ed by he accumula ion o MNPs away om he lesion o in e es , he
inabili y o isualize MNP dis ibu ion du ing ea men , and limi ed abili y o moni o
issue empe a u e [
209
]. These limi a ions esul in poo MNP hea ing con ol, educed
he apeu ic e ec , and inc eased colla e al damage.
Recen ad ances ha e demons a ed ha applying he s ong g adien magne ic ield
used o imaging in MPI du ing magne ic hype he mia enables localized magne ic hype -
he mia, which can help o e come many o he limi a ions aced by adi ional magne ic
hype he mia echnologies. Localized magne ic hype he mia allows esea che s o exe
spa ial con ol o e which MNPs a e hea ed wi h millime e -scale
esolu ion [210–212]
. Tay
e al. demons a ed he use o a magne ically localized magne ic hype he mia sys em o
spa ially localize hea deposi ion o a umo while a oiding hea deposi ion o he heal hy
li e [212]. Fu he , he hea dose can be op imized in eal ime by mo ing, expanding, o
con ac ing he size o he FFR, changing he hea ing egion acco dingly.
Ma e ials 2021, 14, x FOR PEER REVIEW 24 o 37
Recen ad ances ha e demons a ed ha applying he s ong g adien magne ic ield
used o imaging in MPI du ing magne ic hype he mia enables localized magne ic hy-
pe he mia, which can help o e come many o he limi a ions aced by adi ional mag-
ne ic hype he mia echnologies. Localized magne ic hype he mia allows esea che s o
exe spa ial con ol o e which MNPs a e hea ed wi h millime e -scale esolu ion [210–
212]. Tay e al. demons a ed he use o a magne ically localized magne ic hype he mia
sys em o spa ially localize hea deposi ion o a umo while a oiding hea deposi ion o
he heal hy li e [212]. Fu he , he hea dose can be op imized in eal ime by mo ing,
expanding, o con ac ing he size o he FFR, changing he hea ing egion acco dingly.
Fu he imp o emen s in he accu acy o ea men can be made by combining bo h
MPI and localized magne ic hype he mia o a comple e he anos ic wo k low ha com-
bines imaging, ea men p esc ip ion, and applica ion o he apy (Figu e 8b). The im-
po an linking ac o ac oss he wo echnologies is he a ailabili y o MNPs ha a e bo h
isible in MPI and capable o being hea ed ia magne ic hype he mia [209,213]. In addi-
ion o nanopa icle biodis ibu ion, he MPI signal con ains in o ma ion on he MNP’s
mic oen i onmen and a combined MPI, and magne ic hype he mia can enable non-in-
asi ely measu ing empe a u e du ing hea ing [212,214,215]. Accu a e empe a u e
measu emen is pa icula ly impo an o p e en o e - and unde - ea men o umo s
whe he he issue is being hea ed o apop osis o as an immune-s imula ing adju an
he apy.
(a) (b)
Figu e 8. (a) MPI uses a selec ion ield o localize he nanopa icle signal. The di e ging magne ic ield lines p oduce a
unique FFR in he cen e . By a ying he applied magne ic ield, he FFR can be ansla ed ac oss he sample; (b) wo k low
o an MPI-di ec ed localized magne ic hype he mia he apy o solid umo s. Following ace adminis a ion, MPI was
pe o med o iden i y umo loca ion and size and o iden i y ace up ake in heal hy issue such as he li e . The meas-
u ed a ge dose and o - a ge a eas o isk a e hen used o op imize magne ic hype he mia ea men planning. Follow-
up scans can be pe o med o assess esponse o he apy o e ime. Rep in ed (adap ed) wi h pe mission om [212].
The combina ion o MPI, magne ic hype he mia and localized magne ic hype he -
mia opens new di ec ions o bo h esea ch and clinical ea men . In esea ch, new appli-
ca ions a e possible such as a no el, magne ic hype he mia ac ua ed nano he apeu ics
capable o he localized elease o d ugs o exp ession o hea -sensi i e gene ic p omo o s.
Ul ima ely, as MPI and localized magne ic hype he mia a e clinically ansla ed, we can
expec wo k low simila o X- ay/CT guided Radia ion The apy.
10. S anda diza ion o Magne ic Colloids o Magne ic Hype he mia
10.1. Gene al Aspec s
The need o s anda diza ion o MNPs o magne ic hype he mia o ms pa o a
much b oade demand o eliable, ep oducible, s able and well-cha ac e ized nanos uc-
u ed magne ic ma e ials o use in eme ging applica ions in medicine and o he highly
demanding sec o s. Howe e , s anda diza ion also includes he p o ision o well-de ined
Figu e 8.
(
a
) MPI uses a selec ion ield o localize he nanopa icle signal. The di e ging magne ic ield lines p oduce a
unique FFR in he cen e . By a ying he applied magne ic ield, he FFR can be ansla ed ac oss he sample; (
b
) wo k low
o an MPI-di ec ed localized magne ic hype he mia he apy o solid umo s. Following ace adminis a ion, MPI was
pe o med o iden i y umo loca ion and size and o iden i y ace up ake in heal hy issue such as he li e . The measu ed
a ge dose and o - a ge a eas o isk a e hen used o op imize magne ic hype he mia ea men planning. Follow-up
scans can be pe o med o assess esponse o he apy o e ime. Rep in ed (adap ed) wi h pe mission om [212].
Ma e ials 2021,14, 706 24 o 36
Fu he imp o emen s in he accu acy o ea men can be made by combining bo h
MPI and localized magne ic hype he mia o a comple e he anos ic wo k low ha com-
bines imaging, ea men p esc ip ion, and applica ion o he apy (Figu e 8b). The impo -
an linking ac o ac oss he wo echnologies is he a ailabili y o MNPs ha a e bo h
isible in MPI and capable o being hea ed ia magne ic hype he mia [
209
,
213
]. In addi ion
o nanopa icle biodis ibu ion, he MPI signal con ains in o ma ion on he MNP’s mic oen-
i onmen and a combined MPI, and magne ic hype he mia can enable non-in asi ely
measu ing empe a u e du ing hea ing [
212
,
214
,
215
]. Accu a e empe a u e measu emen
is pa icula ly impo an o p e en o e - and unde - ea men o umo s whe he he
issue is being hea ed o apop osis o as an immune-s imula ing adju an he apy.
The combina ion o MPI, magne ic hype he mia and localized magne ic hype he mia
opens new di ec ions o bo h esea ch and clinical ea men . In esea ch, new applica ions
a e possible such as a no el, magne ic hype he mia ac ua ed nano he apeu ics capable o
he localized elease o d ugs o exp ession o hea -sensi i e gene ic p omo o s. Ul ima ely,
as MPI and localized magne ic hype he mia a e clinically ansla ed, we can expec
wo k low simila o X- ay/CT guided Radia ion The apy.
10. S anda diza ion o Magne ic Colloids o Magne ic Hype he mia
10.1. Gene al Aspec s
The need o s anda diza ion o MNPs o magne ic hype he mia o ms pa o a
much b oade demand o eliable, ep oducible, s able and well-cha ac e ized nanos uc-
u ed magne ic ma e ials o use in eme ging applica ions in medicine and o he highly
demanding sec o s. Howe e , s anda diza ion also includes he p o ision o well-de ined
and ep oducible measu emen me hods o he cha ac e iza ion o he ma e ials. These
me hods a e equi ed o eliably de e mine magne ic (and s uc u al) pa ame e s o e e -
ence ma e ials and o he MNPs employed in magne ic hype he mia. This s anda diza ion
need, he ela ed science o MNPs and hei cha ac e iza ion ha e been p e iously explo ed
in some de ail [
216
,
217
]. In he ollowing subsec ions, he key ools a ailable o aid in eal-
izing he s anda diza ion o MNPs o hype he mia he apy will be desc ibed. Combined,
he s eps desc ibed he e o m a oadmap o he u u e ealiza ion o a measu emen and
s anda diza ion in as uc u e o MNPs o hype he mia he apy.
10.2. Valida ing Me ological T aceabili y a Key Labo a o ies
While no a ealis ic goal o be achie ed a e e y measu emen labo a o y in he
cha ac e iza ion communi y, i is o g ea impo ance ha he me ological aceabili y
o SI uni s o a leas some measu emen labo a o ies is demons a ed o each in ol ed
cha ac e iza ion echnique. Na ional me ology ins i u es a e ypical loca ions o his
wo k o be unde aken, as hey combine he expe ise, equipmen and esou ces necessa y
o unde ake his c i ically impo an wo k. This is he only possible way o uly e i y
ha measu emen s a e accu a e, quan i a i e and cohe en , wi h e i ied unce ain ies.
Eu opean me ology ins i u es al eady ha e a gene alized amewo k in place o unde -
aking his kind o wo k, which has p e iously been applied o o he a eas o indus y
wi h g ea success. Hence, a , none o he magne ic measu emen s o MNPs ha e been
me ologically alida ed on calib a ed ins umen s, while some p elimina y wo k on o he
non-magne ic cha ac e iza ion echniques has al eady been unde aken [
218
]. Es ablishing
me ological aceabili y o SI uni s o key cha ac e iza ion echniques is necessa y o
alida e MNPs o hype he mia he apy. This wo k is o u mos impo ance o achie ing
s anda diza ion and dese es he highes p io i y. The ea ly in ol emen o he ele an
end-use indus y igu es will ensu e he long- e m success o he alida ion wo k.
10.3. In e labo a o y Ring Compa isons o Ha monize Measu emen s
In addi ion o es ablishing me ological aceabili y a indi idual key labo a o ies,
de eloping an unde s anding o he o e all le el o measu emen ag eemen , accu acy
and epea abili y ac oss he en i e measu emen communi y mus also be achie ed. Ring
Ma e ials 2021,14, 706 25 o 36
compa isons (also called in e labo a o y compa isons) a e he p o en ool o unde aking
his ype o wo k. By dis ibu ing iden ical sample se s o mul iple labo a o ies and
moni o ing he indings, a huge amoun o in o ma ion can be ob ained. By changing
a iables such as he use o in-house o cen ally de eloped ope a ing p ocedu es, he
ex en o unce ain ies in oduced by measu emen appa a us, measu emen p ocedu es
and analysis me hods can be isola ed, unde s ood and mi iga ed.
To da e, ing compa isons ha e been pe o med o a ious nanopa icle pa ame-
e s ele an o hype he mia cha ac e iza ion, including DLS [
219
], s a ic magne iza ion,
SLP/ILP and AC suscep ibili y measu emen s. Ala mingly, hese s udies ha e e ealed
a s ong need o u he ha moniza ion o achie e in e labo a o y ag eemen . Regula
ing compa isons a e he only ealis ic way o moni o p og ess in he ha moniza ion o
nanopa icle cha ac e iza ion echniques and e eal he ex en o in e labo a o y a ia ions.
10.4. De elopmen o Re e ence Ma e ials
To da e, no e i ied o accep ed e e ence ma e ials exis o any o he p ope ies o
MNPs ele an o magne ic hype he mia he apy. Re e ence ma e ial is cha ac e ized by
being homogeneous and s able wi h espec o a ce ain ma e ial cha ac e is ic: his can be
a physical quan i y like he ini ial magne ic suscep ibili y, bu i can also be a pe o mance
cha ac e is ic like colloidal s abili y. Fo e e ence ma e ials wi h de ined physical p ope -
ies, i is desi able o ha e a ce i ied measu emen o his p ope y (made wi h calib a ed
ins umen s in a manne ha is me ologically aceable o SI uni s), oge he wi h an
accu a ely ende ed unce ain y. Ma e ials o which his ype o alida ed measu emen
has been conduc ed, and which a e alida ed as being s able, a e called ce i ied e e ence
ma e ials (CRM). CRMs a e indispensable o e i ying he accu acy and empo al s abili y
o indi idual measu emen equipmen , o achie ing success ul ing compa isons and
accu a ely assessing in-house quali y assu ance sys ems.
A p esen , la ge manu ac u e s o MNPs use hei own in-house e e ence ma e ials o
e i y hei magne ic p ope ies measu emen s. Smalle companies and academic ins i u es
ypically ely on o he comme cial MNP p oduc s as quasi- e e ence ma e ials while lacking
de ailed knowledge abou he ac ual ba ch- o-ba ch o empo al s abili y o he ma e ial.
The de elopmen o alida ed CRMs o magne ic nanopa icle p ope ies will bene i all
le els o indus y and esea ch and is i al o he la ge-scale manu ac u ing o medical-
g ade MNP ma e ials sui able o magne ic hype he mia he apy. The de elopmen o
CRMs o his pu pose, he e o e, dese es o be he ocus o signi ican e o in he coming
yea s.
10.5. Calib a ion and Ce i ica ion o Measu emen De ices and Se ices
Indus ially accep ed es ing labo a o ies ypically ope a e unde s ic sys ems o
quali y con ol and managemen . Guidance o in o m bes p ac ice in de eloping hese
sys ems o biomedical p oduc s is a ailable om ISO [
220
]. Labo a o ies ha adhe e o
hese quali y s anda ds can gain acc edi a ion om na ional bodies ha ope a e unde
mu ual ecogni ion ag eemen s p o ided by he In e na ional Labo a o y Acc edi a ion
Coope a ion (ILAC) o ensu e ha labo a o ies p oduce esul s ha a e o a known quali y
ha is egula ly moni o ed. The le el o s anda diza ion in he MNP manu ac u ing and
cha ac e iza ion communi ies is no ye su icien ly ad anced o his s ep o be possible.
The equi emen s laid ou in poin s 10.2 o 10.4 mus be ealized i s . Gi en he economic
impo ance o MNPs and echnologies which ely on hem, i is in i sel a s iking inding
ha no one labo a o y in he wo ld can cu en ly issue acc edi ed es ce i ica es o he
hype he mia pe o mance o MNPs o ela ed cha ac e is ics.
10.6. De elopmen o Eu opean and In e na ional S anda ds Documen s
Laying a guably a he pinnacle o he s anda diza ion moun ain, documen s anda ds
issued by ISO, CEN ( he Eu opean Commi ee o S anda diza ion) o o he na ional o
in e na ional bodies p esen in clea e ms he ag eed bes p ac ices o a di e se a ie y
Ma e ials 2021,14, 706 32 o 36
98.
Lye , S.; Tie ze, R.; Un e wege , H.; Zaloga, J.; Singh, R.; Ma uszak, J.; Poe le , M.; F ied ich, R.P.; Due , S.; Cicha, I. Nanomedical
inno a ion: The SEON-concep o an imp o ed cance he apy wi h magne ic nanopa icles. Nanomedicine
2015
,10, 3287–3304.
[C ossRe ]
99.
Fe nández-Ba ahona, I.; Ruiz-Cabello, J.; He anz, F.; Pellico, J. Syn hesis o 68Ga co e-doped i on oxide nanopa icles o dual
posi on emission omog aphy/(T1) magne ic esonance imaging. JoVE (J. Vis. Exp. ) 2018, e58269. [C ossRe ]
100.
Le y, M.; Wilhelm, C.; Luciani, N.; De eaux, V.; Gend on, F.; Luciani, A.; De aud, M.; Gazeau, F. Nanomagne ism e eals he
in acellula clus e ing o i on oxide nanopa icles in he o ganism. Nanoscale 2011,3, 4402–4410. [C ossRe ]
101.
Di Co a o, R.; Espinosa, A.; La igue, L.; Tha aud, M.; Cha , S.; Pelleg ino, T.; Ménage , C.; Gazeau, F.; Wilhelm, C. Magne ic
hype he mia e iciency in he cellula en i onmen o di e en nanopa icle designs. Bioma e ials
2014
,35, 6400–6411. [C ossRe ]
[PubMed]
102.
Le y, M.; Luciani, N.; Alloyeau, D.; Elg abli, D.; De eaux, V.; Pechoux, C.; Cha , S.; Wang, G.; Va s, N.; Gend on, F. Long e m
in i o bio ans o ma ion o i on oxide nanopa icles. Bioma e ials 2011,32, 3988–3999. [C ossRe ] [PubMed]
103.
Kolosnjaj-Tabi, J.; Ja ed, Y.; La igue, L.; Vola on, J.; Elg abli, D.; Ma angon, I.; Pugliese, G.; Ca on, B.; Figue ola, A.; Luciani, N.
The one yea a e o i on oxide coa ed gold nanopa icles in mice. ACS Nano 2015,9, 7925–7939. [C ossRe ] [PubMed]
104.
Kolosnjaj-Tabi, J.; La igue, L.; Ja ed, Y.; Luciani, N.; Pelleg ino, T.; Wilhelm, C.; Alloyeau, D.; Gazeau, F. Bio ans o ma ions o
magne ic nanopa icles in he body. Nano Today 2016,11, 280–284. [C ossRe ]
105.
Le y, M.; Laga de, F.; Ma aloiu, V.-A.; Blanchin, M.-G.; Gend on, F.; Wilhelm, C.; Gazeau, F. Deg adabili y o supe pa amagne ic
nanopa icles in a model o in acellula en i onmen : Follow-up o magne ic, s uc u al and chemical p ope ies. Nano echnology
2010,21, 395103. [C ossRe ]
106.
La igue, L.; Alloyeau, D.; Kolosnjaj-Tabi, J.; Ja ed, Y.; Gua dia, P.; Riedinge , A.; Péchoux, C.; Pelleg ino, T.; Wilhelm, C.; Gazeau,
F. Biodeg ada ion o i on oxide nanocubes: High- esolu ion in si u moni o ing. ACS Nano 2013,7, 3939–3952. [C ossRe ]
107.
Kolosnjaj-Tabi, J.; Di Co a o, R.; La igue, L.; Ma angon, I.; Gua dia, P.; Sil a, A.K.; Luciani, N.; Clemen , O.; Flaud, P.; Singh, J.V.
Hea -gene a ing i on oxide nanocubes: Sub le “des uc u a o s” o he umo al mic oen i onmen . ACS Nano
2014
,8, 4268–4283.
[C ossRe ]
108.
Vola on, J.; Ca n, F.; Kolosnjaj-Tabi, J.; Ja ed, Y.; Vuong, Q.L.; Gossuin, Y.; Ménage , C.; Luciani, N.; Cha on, G.; Hémadi, M.
Fe i in p o ein egula es he deg ada ion o i on oxide nanopa icles. Small 2017,13, 1602030. [C ossRe ]
109.
Vola on, J.; Kolosnjaj-Tabi, J.; Ja ed, Y.; Vuong, Q.L.; Gossuin, Y.; Ne eu, S.; Luciani, N.; Hémadi, M.; Ca n, F.; Alloyeau, D.
Physiological emedia ion o cobal e i e nanopa icles by e i in. Sci. Rep. 2017,7, 1–10. [C ossRe ]
110.
Soenen, S.J.; Pa ak, W.J.; Rejman, J.; Manshian, B. (In a) cellula s abili y o ino ganic nanopa icles: E ec s on cy o oxici y,
pa icle unc ionali y, and biomedical applica ions. Chem. Re . 2015,115, 2109–2135. [C ossRe ]
111.
Mazuel, F.; Espinosa, A.; Luciani, N.; Re ay, M.; Le Bo gne, R.; Mo e, L.; Desboeu s, K.; Michel, A.; Pelleg ino, T.; Lala onne, Y.
Massi e in acellula biodeg ada ion o i on oxide nanopa icles e idenced magne ically a single-endosome and issue le els.
ACS Nano 2016,10, 7627–7638. [C ossRe ] [PubMed]
112.
Mazuel, F.; Espinosa, A.; Rad ke, G.; Bugne , M.; Ne eu, S.; Lala onne, Y.; Bo on, G.A.; Abou-Hassan, A.; Wilhelm, C. Magne o-
he mal me ics can mi o he long- e m in acellula a e o magne o-plasmonic nanohyb ids and e eal he ema kable
shielding e ec o gold. Ad . Func . Ma e . 2017,27, 1605997. [C ossRe ]
113.
Ja ed, Y.; La igue, L.; Hugounenq, P.; Vuong, Q.L.; Gossuin, Y.; Bazzi, R.; Wilhelm, C.; Ricolleau, C.; Gazeau, F.; Alloyeau, D.
Biodeg ada ion mechanisms o i on oxide monoc ys alline nano lowe s and unable shield e ec o gold coa ing. Small
2014
,10,
3325–3337. [C ossRe ] [PubMed]
114.
Sangnie , A.P.; Van de Walle, A.B.; Cu cio, A.; Le Bo gne, R.; Mo e, L.; Lala onne, Y.; Wilhelm, C. Impac o magne ic nanopa icle
su ace coa ing on hei long- e m in acellula biodeg ada ion in s em cells. Nanoscale
2019
,11, 16488–16498. [C ossRe ]
[PubMed]
115.
Van de Walle, A.; Sangnie , A.P.; Abou-Hassan, A.; Cu cio, A.; Hemadi, M.; Menguy, N.; Lala onne, Y.; Luciani, N.; Wilhelm, C.
Biosyn hesis o magne ic nanopa icles om nano-deg ada ion p oduc s e ealed in human s em cells. P oc. Na l. Acad. Sci. USA
2019,116, 4044–4053. [C ossRe ] [PubMed]
116.
Cu cio, A.; Van de Walle, A.; Se ano, A.; P é é al, S.; Pechoux, C.; Pignol, D.; Menguy, N.; Le e e, C.T.; Espinosa, A.; Wilhelm,
C. T ans o ma ion Cycle o Magne osomes in Human S em Cells: F om Deg ada ion o Biosyn hesis o Magne ic Nanopa icles
Anew. ACS Nano 2019,14, 1406–1417. [C ossRe ] [PubMed]
117.
Das, P.; Colombo, M.; P ospe i, D. Recen ad ances in magne ic luid hype he mia o cance he apy. Colloids Su . B
2019
,174,
42–55. [C ossRe ] [PubMed]
118.
Ad anced Magne ics Gains FDA Clea ance o MRI Con as Agen Ta ge ed a Li e . A ailable online: h ps://www.
diagnos icimaging.com/ iew/ad anced-magne ics-gains- da-clea ance-m i-con ac -agen - a ge ed-li e (accessed on 27 Jan-
ua y 2021).
119.
Rienso: Wi hd awal o he Applica ion o Change he Ma ke ing Au ho isa ion. A ailable online: h ps://www.ema.eu opa.eu/
en/medicines/human/wi hd awn-applica ions/ ienso (accessed on 27 Janua y 2021).
120. Che , T.; Szkla uk, J. MR con as agen s: Applica ions in hepa obilia y imaging. Appl. Radiol. 2010,39, 26.
121.
Xie, J.; Zhang, Y.; Yan, C.; Song, L.; Wen, S.; Zang, F.; Chen, G.; Ding, Q.; Yan, C.; Gu, N. High-pe o mance PEGyla ed Mn–Zn
e i e nanoc ys als as a passi e- a ge ed agen o magne ically induced cance he anos ics. Bioma e ials
2014
,35, 9126–9136.
[C ossRe ] [PubMed]

Ma e ials 2021,14, 706 33 o 36
122.
Van No man, G.A. D ugs and de ices: Compa ison o Eu opean and US app o al p ocesses. JACC Basic T ansl. Sci.
2016
,1,
399–412. [C ossRe ] [PubMed]
123.
Pa liamen , E. (Ed.) Regula ion (EU) 2017/745 o he Eu opean Pa liamen and o he Council o 5 Ap il 2017 (Medical
De ice Regula ion). 2017. A ailable online: h ps://eu -lex.eu opa.eu/legal-con en /EN/TXT/PDF/?u i=CELEX:32017R0745,
(accessed on 27 Janua y 2021).
124.
FDA App o es Magne ic De ice Sys em o Guiding Sen inel Lymph Node Biopsies in Ce ain Pa ien s wi h B eas Cance ,
FDA P ess Release. 24 July 2018. A ailable online: h ps://www. da.go /news-e en s/p ess-announcemen s/ da-app o es-
magne ic-de ice-sys em-guiding-sen inel-lymph-node-biopsies-ce ain-pa ien s-b eas (accessed on 27 Janua y 2021).
125.
MagFo ce Nano echnolgies AG Recei es Eu opean Regula o y App o al o i s Nano-Cance
®
The apy. A ailable online:
h ps://www.biospace.com/a icle/ eleases/mag o ce-nano echnologies- ecei es-eu opean- egula o y-app o al- o -i s-nano-
cance - - he apy-/?s=74 (accessed on 27 Janua y 2021).
126.
Eu opean Pa liamen -Eu opean Di ec i e 2001/83/EC Rela ing o Medicinal P oduc s o Human Use, Amended by Di ec i e
2004/27/EC; Eu opean Di ec i e 90/385/EEC and 93/42/EEC 2001. A ailable online: h ps://ec.eu opa.eu/heal h/si es/
heal h/ iles/ iles/eud alex/ ol1/di _2001_83_cons2009/2001_83_cons2009_en.pd (accessed on 27 Janua y 2021).
127.
FDA guidance-Classi ica ion o P oduc s as D ugs and De ices and Addi ional P oduc Classi ica ion Issues: Guidance o
Indus y and FDA S a . A ailable online: h ps://www. da.go / egula o y-in o ma ion/sea ch- da-guidance-documen s/
classi ica ion-p oduc s-d ugs-and-de ices-and-addi ional-p oduc -classi ica ion-issues (accessed on 27 Janua y 2021).
128.
FDA D a Guidance-P inciples o P ema ke Pa hways o Combina ion P oduc s Guidance o Indus y and FDA S a . A ail-
able online: h ps://www. da.go / egula o y-in o ma ion/sea ch- da-guidance-documen s/p inciples-p ema ke -pa hways-
combina ion-p oduc s. (accessed on 27 Janua y 2021).
129.
Wáng, Y.X.J.; Idée, J.-M. A comp ehensi e li e a u es upda e o clinical esea ches o supe pa amagne ic esonance i on oxide
nanopa icles o magne ic esonance imaging. Quan . Imaging. Med. Su g. 2017,7, 88. [C ossRe ] [PubMed]
130.
Rzigalinski, B.A.; S obl, J.S. Cadmium-con aining nanopa icles: Pe spec i es on pha macology and oxicology o quan um do s.
Toxicol. Appl. Pha macol. 2009,238, 280–288. [C ossRe ] [PubMed]
131.
Zhang, B.; Wang, Y.; Hu, R.; Roy, I.; Yong, K.-T. Cadmium- ee quan um do s o biopho onic imaging and sensing. Handbook o
Pho onics o Biomedical Enginee ing 2014, 1–27. [C ossRe ]
132.
Wei, H.; B uns, O.T.; Kaul, M.G.; Hansen, E.C.; Ba ch, M.; Wi´sniowska, A.; Chen, O.; Chen, Y.; Li, N.; Okada, S. Exceedingly small
i on oxide nanopa icles as posi i e MRI con as agen s. P oc. Na l. Acad. Sci. USA 2017,114, 2325–2330. [C ossRe ] [PubMed]
133.
Majumda , S.; Zoghbi, S.; Go e, J. Pha macokine ics o supe pa amagne ic i on-oxide MR con as agen s in he a . In es ig.
Radiol. 1990,25, 771–777. [C ossRe ]
134.
Ha is, G.; Palosaa i, T.; Magdoleno a, Z.; Mennecozzi, M.; Gines e, J.M.; Saa ed a, L.; Milcamps, A.; Huk, A.; Collins, A.R.;
Dusinska, M. I on oxide nanopa icle oxici y es ing using high- h oughpu analysis and high-con en imaging. Nano oxicology
2015,9, 87–94. [C ossRe ]
135.
Soenen, S.J.; De Cuype , M. Assessing i on oxide nanopa icle oxici y
in i o
: Cu en s a us and u u e p ospec s. Nanomedicine
2010,5, 1261–1275. [C ossRe ]
136.
A ami, H.; Khandha , A.; Liggi , D.; K ishnan, K.M. In Vi o deli e y, pha macokine ics, biodis ibu ion and oxici y o i on
oxide nanopa icles. Chem. Soc. Re . 2015,44, 8576–8607. [C ossRe ]
137.
F ús, A.; Smolko á, B.; Uzhy chak, M.; Luno a, M.; Ji sa, M.; Kubino á, Š.; Dejneka, A.; Luno , O. Analyzing he mechanisms o
i on oxide nanopa icles in e ac ions wi h cells: A oad om ailu e o success in clinical applica ions. J. Con ol. Release
2020
.
[C ossRe ]
138.
Pisanic II, T.R.; Blackwell, J.D.; Shubaye , V.I.; Fiñones, R.R.; Jin, S. Nano oxici y o i on oxide nanopa icle in e naliza ion in
g owing neu ons. Bioma e ials 2007,28, 2572–2581. [C ossRe ]
139.
Singh, D.; McMillan, J.M.; Kabano , A.V.; Sokolsky-Papko , M.; Gendelman, H.E. Bench- o-bedside ansla ion o magne ic
nanopa icles. Nanomedicine 2014,9, 501–516. [C ossRe ] [PubMed]
140.
Shubaye , V.I.; Pisanic II, T.R.; Jin, S. Magne ic Nanopa icles o The agnos ics. Ad . D ug Deli . Re .
2009
,61, 467–477. [C ossRe ]
[PubMed]
141.
Ko nbe g, T.G.; S ueckle, T.A.; Coyle, J.; De k, R.; Demok i ou, P.; Rojanasakul, Y.; Rojanasakul, L.W. I on Oxide Nanopa icle-
Induced Neoplas ic-Like Cell T ans o ma ion in Vi o Is Reduced wi h a P o ec i e Amo phous Silica Coa ing. Chem. Res. Toxicol.
2019,32, 2382–2397. [C ossRe ] [PubMed]
142.
Chen, Y.-C.; Hsiao, J.-K.; Liu, H.-M.; Lai, I.-Y.; Yao, M.; Hsu, S.-C.; Ko, B.-S.; Chen, Y.-C.; Yang, C.-S.; Huang, D.-M. The inhibi o y
e ec o supe pa amagne ic i on oxide nanopa icle (Fe uca bo an) on os eogenic di e en ia ion and i s signaling mechanism in
human mesenchymal s em cells. Toxicol. Appl. Pha macol 2010,245, 272–279. [C ossRe ] [PubMed]
143.
Manickam, V.; Dhakshinamoo hy, V.; Pe umal, E. I on oxide nanopa icles induces cell cycle-dependen neu onal apop osis in
mice. J. Mol. Neu osci. 2018,64, 352–362. [C ossRe ] [PubMed]
144.
Jin, R.; Liu, L.; Zhu, W.; Li, D.; Yang, L.; Duan, J.; Cai, Z.; Nie, Y.; Zhang, Y.; Gong, Q. I on oxide nanopa icles p omo e
mac ophage au ophagy and in lamma o y esponse h ough ac i a ion o oll-like Recep o -4 signaling. Bioma e ials
2019
,203,
23–30. [C ossRe ] [PubMed]
Ma e ials 2021,14, 706 34 o 36
145.
Zanganeh, S.; Hu e , G.; Spi le , R.; Lenko , O.; Mahmoudi, M.; Shaw, A.; Paja inen, J.S.; Nejadnik, H.; Goodman, S.; Moseley, M.
I on oxide nanopa icles inhibi umou g ow h by inducing p o-in lamma o y mac ophage pola iza ion in umou issues. Na .
Nano echnol. 2016,11, 986–994. [C ossRe ] [PubMed]
146.
Shubaye , V.I.; Pisanic, T.R., II; Jin, S. Magne ic Nanopa icles o The agnos ics. Ad . D ug Deli . Re .
2009
,61, 467–477.
[C ossRe ]
147.
Seonen, S.; Himmel eich, U.; Nuy en, N.; De Cuype , M. Cy o oxic e ec s o i on oxide nanopa icles and implica ions o sa e y
in cell labeling. Bioma e ials 2011,32, 195–205. [C ossRe ] [PubMed]
148.
Soenen, S.J.; Himmel eich, U.; Nuy en, N.; Pisanic, T.R.; Fe a i, A.; De Cuype , M. In acellula nanopa icle coa ing s abili y
de e mines nanopa icle diagnos ics e icacy and cell unc ionali y. Small 2010,6, 2136–2145. [C ossRe ] [PubMed]
149.
Umu , E.; Co¸skun, M.; Pineide , F.; Be i, D.; Güngüne¸s, H. Nickel e i e nanopa icles o simul aneous use in magne ic esonance
imaging and magne ic luid hype he mia. J. Colloid In e ace Sci. 2019,550, 199–209. [C ossRe ] [PubMed]
150.
Fa zin, A.; Hassan, S.; Emadi, R.; E esami, S.A.; Ai, J. Compa a i e e alua ion o magne ic hype he mia pe o mance and
biocompa ibili y o magne i e and no el Fe-doped ha dys oni e nanopa icles o po en ial bone cance he apy. Ma e . Sci. Eng.
C2019,98, 930–938. [C ossRe ]
151.
Foulkes, R.; Man, E.; Thind, J.; Yeung, S.; Joy, A.; Hoskins, C. The egula ion o nanoma e ials and nanomedicines o clinical
applica ion: Cu en and u u e pe spec i es. Bioma e . Sci. 2020,8, 4653–4664. [C ossRe ] [PubMed]
152.
Jones III, A.-A.D.; Mi, G.; Webs e , T.J. A s a us epo on FDA app o al o medical de ices con aining nanos uc u ed ma e ials.
T ends Bio echnol. 2019,37, 117–120. [C ossRe ] [PubMed]
153. Quin anilla, M.; Liz-Ma zan, L.M. Guiding ules o selec ing a nano he mome e . Nano Today 2018,19, 126–145. [C ossRe ]
154.
Ba ou, G.; Rigneaul , H.; Ma gue , D.; Jullien, L. A c i ique o me hods o empe a u e imaging in single cells. Na u e Me hods
2014,11, 899–901. [C ossRe ]
155.
B i es, C.D.; Lima, P.P.; Sil a, N.J.; Millán, A.; Ama al, V.S.; Palacio, F.; Ca los, L.D. The mome y a he nanoscale. Nanoscale
2012
,
4, 4799–4829. [C ossRe ]
156.
Uchiyama, S.; Go a, C. Luminescen molecula he mome e s o he a iome ic sensing o in acellula empe a u e. C i . Re .
Anal. Chem. 2017,36. [C ossRe ]
157.
Ca los, L.D.; Palacio, F. The mome y a he Nanoscale: Techniques and Selec ed Applica ions; Royal Socie y o Chemis y: Camb idge,
UK, 2015.
158.
Ximendes, E.C.; San os, W.Q.; Rocha, U.s.; Kagola, U.K.; Sanz-Rod íguez, F.; Fe nández, N.; Gou eia-Ne o, A.d.S.; B a o, D.;
Domingo, A.M.; del Rosal, B. Un eiling
in i o
subcu aneous he mal dynamics by in a ed luminescen nano he mome e s.
Nano Le . 2016,16, 1695–1703. [C ossRe ]
159.
Mahmoudi, K.; Bou as, A.; Bozec, D.; I ko , R.; Hadjipanayis, C. Magne ic hype he mia he apy o he ea men o glioblas oma:
A e iew o he he apy’s his o y, e icacy and applica ion in humans. In . J. Hype h. 2018,34, 1316–1328. [C ossRe ]
160.
Chiu-Lam, A.; Rinaldi, C. Nanoscale The mal Phenomena in he Vicini y o Magne ic Nanopa icles in Al e na ing Magne ic
Fields. Ad . Func . Ma e . 2016,26, 3933–3941. [C ossRe ] [PubMed]
161.
Rabin, Y. Is in acellula hype he mia supe io o ex acellula hype he mia in he he mal sense? In . J. Hype h.
2002
,18,
194–202. [C ossRe ] [PubMed]
162.
Keblinski, P.; Cahill, D.G.; Bodapa i, A.; Sulli an, C.R.; Ta on, T.A. Limi s o localized hea ing by elec omagne ically exci ed
nanopa icles. J. Appl. Phys. 2006,100, 054305. [C ossRe ]
163.
Gup a, A.; Kane, R.S.; Bo ca-Tasciuc, D.-A. Local empe a u e measu emen in he icini y o elec omagne ically hea ed magne i e
and gold nanopa icles. J. Appl. Phys. 2010,108, 064901. [C ossRe ]
164.
Huang, H.; Delikanli, S.; Zeng, H.; Fe key, D.M.; P alle, A. Remo e con ol o ion channels and neu ons h ough magne ic- ield
hea ing o nanopa icles. Na u e Nano echnol. 2010,5, 602–606. [C ossRe ] [PubMed]
165.
Polo-Co ales, L.; Rinaldi, C. Moni o ing i on oxide nanopa icle su ace empe a u e in an al e na ing magne ic ield using
he mo esponsi e luo escen polyme s. J. Appl. Phys. 2012,111, 07B334. [C ossRe ]
166.
Riedinge , A.; Gua dia, P.; Cu cio, A.; Ga cia, M.A.; Cingolani, R.; Manna, L.; Pelleg ino, T. Subnanome e Local Tempe a u e
P obing and Remo ely Con olled D ug Release Based on Azo-Func ionalized I on Oxide Nanopa icles. Nano Le .
2013
,13,
2399–2406. [C ossRe ]
167.
Dias, J.T.; Mo os, M.; delPino, P.; Ri e a, S.; G azú, V.; de la Fuen e, J.M. DNA as a Molecula Local The mal P obe o he Analysis
o Magne ic Hype he mia. Angewand e Chemie In e na ional Edi ion 2013,52, 11526–11529. [C ossRe ]
168.
Dong, J.; Zink, J.I. Taking he empe a u e o he in e io s o magne ically hea ed nanopa icles. ACS Nano
2014
,8, 5199–5207.
[C ossRe ]
169.
Pinol, R.; B i es, C.D.; Bus aman e, R.; Ma ínez, A.; Sil a, N.J.; Mu illo, J.L.; Cases, R.; Ca ey, J.; Es epa, C.; Sosa, C. Joining
ime- esol ed he mome y and magne ic-induced hea ing in a single nanopa icle un eils in iguing he mal p ope ies. ACS
Nano 2015,9, 3134–3142. [C ossRe ]
170.
Piñol, R.; B i es, C.D.S.; Sil a, N.J.; Ca los, L.D.; Millán, A. Chap e 6 - Nanoscale The mome y o Hype he mia Applica ions.
In Nanoma e ials o Magne ic and Op ical Hype he mia Applica ions; F a ila, R.M., De La Fuen e, J.M., Eds.; Else ie : Edinbu gh,
UK, 2019.
171.
A ai, S.; Suzuki, M.; Pa k, S.-J.; Yoo, J.S.; Wang, L.; Kang, N.-Y.; Ha, H.-H.; Chang, Y.-T. Mi ochond ia- a ge ed luo escen
he mome e moni o s in acellula empe a u e g adien . Chem. Comn. 2015,51, 8044–8047. [C ossRe ] [PubMed]
Ma e ials 2021,14, 706 35 o 36
172.
F eddi, S.; Si oni, L.; D’An uono, R.; Mo one, D.; Donà, A.; Cab ini, E.; D’Al onso, L.; Collini, M.; Palla icini, P.; Baldi, G. A
molecula he mome e o nanopa icles o op ical hype he mia. Nano Le . 2013,13, 2004–2010. [C ossRe ] [PubMed]
173.
Shen, Y.; Li an e, J.; Fe nández, N.; Jaque, D.; Ximendes, E. In Vi o Spec al Dis o ions o In a ed Luminescen Nano he mome-
e s Comp omise Thei Reliabili y. ACS Nano 2020,14, 4122–4133. [C ossRe ] [PubMed]
174.
Rocha, U.; Upend a Kuma , K.; Jacin o, C.; Rami o, J.; Caamano, A.J.; Ga cía Solé, J.; Jaque, D. Nd3+ doped LaF3 nanopa icles as
sel -moni o ed pho o- he mal agen s. Appl. Phys. Le . 2014,104, 053703. [C ossRe ]
175.
C ezee, H.; an Leeuwen, C.M.; Oei, A.L.; S alpe s, L.J.; Bel, A.; F anken, N.A.; Kok, H.P. The mo adio he apy planning:
In eg a ion in ou ine clinical p ac ice. In . J. Hype h. 2016,32, 41–49. [C ossRe ]
176.
Van Vulpen, M.; Raaymake s, B.W.; Lagendijk, J.J.; C ezee, J.; de Leeuw, A.A.; an Moo selaa , J.R.; Lig oe , C.M.; Ba e mann, J.J.
Th ee-dimensional con olled in e s i ial hype he mia combined wi h adio he apy o locally ad anced p os a e ca cinoma—a
easibili y s udy. In . J. Radia . Oncol. Biol. Phys. 2002,53, 116–126. [C ossRe ]
177.
Wus , P.; Gelle mann, J.; Beie , J.; Wegne , S.; Tilly, W.; T öge , J.; S alling, D.; Oswald, H.; Hege, H.-C.; Deu lha d, P. E alua ion
o segmen a ion algo i hms o gene a ion o pa ien models in adio equency hype he mia. Phys. Med. Biol.
1998
,43, 3295.
[C ossRe ]
178.
Ga azzi, S.; an Lie , A.L.; Zachiu, C.; Jansen, E.; Lagendijk, J.J.W.; S alpe s, L.J.A.; C ezee, H.; Kok, H.P. Ad anced pa ien -speci ic
hype he mia ea men planning. In . J. Hype h. 2020,37, 992–1007. [C ossRe ]
179.
Kok, H.; Wus , P.; S au e , P.R.; Ba da i, F.; Van Rhoon, G.; C ezee, J. Cu en s a e o he a o egional hype he mia ea men
planning: A e iew. Radia ion Oncol. 2015,10, 1–14. [C ossRe ]
180.
S eeni asa, G.; Gelle mann, J.; Rau, B.; Nadobny, J.; Schlag, P.; Deu lha d, P.; Felix, R.; Wus , P. Clinical use o he hype he mia
ea men planning sys em Hype Plan o p edic e ec i eness and oxici y. In J. Radia Oncol Biol Phys.
2003
,55, 407–419.
[C ossRe ]
181.
Maka o , S.N.; Noe sche , G.M.; Yanamadala, J.; Piazza, M.W.; Louie, S.; P okop, A.; Naza ian, A.; Nummenmaa, A. Vi ual
Human Models o Elec omagne ic S udies and Thei Applica ions. IEEE Re . Biomed. Eng.
2017
,10, 95–121. [C ossRe ]
[PubMed]
182.
Bellizzi, G.G.; Sumse , K.; VilasBoas-Ribei o, I.; Cu o, S.; D izdal, T.; an Rhoon, G.C.; F anckena, M.; Paulides, M.M. S an-
da diza ion o pa ien modeling in hype he mia simula ion s udies: In oducing he E asmus Vi ual Pa ien Reposi o y. In . J.
Hype h. 2020,37, 608–616. [C ossRe ] [PubMed]
183.
Baga ia, H.G.; Johnson, D.T. T ansien solu ion o he biohea equa ion and op imiza ion o magne ic luid hype he mia
ea men . In . J. Hype h. 2005,21, 57–75. [C ossRe ] [PubMed]
184.
And eozzi, A.; B unese, L.; Iasiello, M.; Tucci, C.; Vanoli, G.P. Modeling Hea T ans e in Tumo s: A Re iew o The mal The apies.
Ann. Biomed. Eng. 2019,47, 676–693. [C ossRe ]
185. Cha ny, C.K. Ma hema ical Models o Biohea T ans e . Ad . Hea T ans . 1992,22, 19–155. [C ossRe ]
186. Wissle , E.H. Pennes’ 1948 pape e isi ed. J. App. Phy. 1998,85, 35–41. [C ossRe ]
187.
Van Den Be g, P.M.; De Hoop, A.T.; Segal, A.; P aagman, N. A Compu a ional Model o he Elec omagne ic Hea ing o Biological
Tissue wi h Applica ion o Hype he mic Cance The apy. IEEE T ans. Biomed. Eng. 1983,BME-30, 197–805. [C ossRe ]
188.
Paulides, M.M.; S au e , P.R.; Neu eld, E.; MacCa ini, P.F.; Ky iakou, A.; Can e s, R.A.M.; Diede ich, C.J.; Bakke , J.F.; Van Rhoon,
G.C. Simula ion echniques in hype he mia ea men planning. In . J. Hype h. 2013,29, 346–357. [C ossRe ]
189.
Lau ino, F.; Zunino, P. De i a ion and analysis o coupled PDEs on mani olds wi h high dimensionali y gap a ising om
opological model educ ion. ESAIM M2AN 2019,53, 2047–2080. [C ossRe ]
190. Zenodo Open Reposi o y. A ailable online: h ps://doi.o g/10.5281/zenodo.4356040 (accessed on 2 Feb ua y 2021).
191.
Rubia-Rod íguez, I.; Zilbe i, L.; A duino, A.; Bo auscio, O.; Chiampi, M.; O ega, D. In silico assessmen o colla e al eddy
cu en hea ing in biocompa ible implan s subjec ed o magne ic hype he mia ea men s. In . J. Hype h. 2021, submi ed.
192.
Sou he n, P.; Pankhu s , Q.A. Commen a y on he clinical and p eclinical dosage limi s o in e s i ially adminis e ed magne ic
luids o he apeu ic hype he mia based on cu en p ac ice and e icacy models. In . J. Hype h.
2018
,34, 671–686. [C ossRe ]
[PubMed]
193.
G äse , M.; Thieben, F.; Szwa gulski, P.; We ne , F.; Gdaniec, N.; Bobe g, M.; G iese, F.; Möddel, M.; Ludewig, P.; an de Ven, D.
Human-sized magne ic pa icle imaging o b ain applica ions. Na . Commun. 2019,10, 1–9. [C ossRe ] [PubMed]
194.
Mason, E.E.; Cooley, C.Z.; Cauley, S.F.; G iswold, M.A.; Conolly, S.M.; Wald, L.L. Design analysis o an MPI human unc ional
b ain scanne . In . J. Magn. Pa . imaging 2017,3, 1703008. [PubMed]
195.
Goodwill, P. De elopmen o a comme cial Magne ic Pa icle Imaging pla o m o he de ec ion and quan i ica ion o localized
in lamma ion in cance . Small Business Inno a ion Resea ch (SBIR) g an om he Na ional Cance Ins i u e (NCI) o he Na ional
Ins i u es o Heal h. A ailable online: h ps://www.magne icinsigh .com/news/de elopmen -o -a-comme cial-magne ic-
pa icle-imaging-pla o m- o - he-de ec ion-and-quan i ica ion-o -localized-in lamma ion-in-cance / (accessed on 27 Janua y
2020).
196.
Lambin, P.; Leijenaa , R.T.H.; Deis , T.M.; Pee lings, J.; De Jong, E.E.C.; Van Timme en, J.; Sanduleanu, S.; La ue, R.T.H.M.; E en,
A.J.G.; Jochems, A.; e al. Radiomics: The b idge be ween medical imaging and pe sonalized medicine. Na . Re . Clin. Oncol.
2017,14, 749–762. [C ossRe ]
197.
Gillies, R.J.; Kinahan, P.E.; H icak, H. Radiomics: Images a e mo e han pic u es, hey a e da a. Radiology
2016
,278, 563–577.
[C ossRe ]
Ma e ials 2021,14, 706 36 o 36
198.
Gleich, B.; Weizenecke , J. Tomog aphic imaging using he nonlinea esponse o magne ic pa icles. Na u e
2005
,435, 1214–1217.
[C ossRe ]
199.
Chand asekha an, P.; Tay, Z.W.; Hensley, D.; Zhou, X.Y.; Fung, B.K.; Colson, C.; Lu, Y.; Fellows, B.D.; Huynh, Q.; Saayujya, C.
Using magne ic pa icle imaging sys ems o localize and guide magne ic hype he mia ea men : T ace s, ha dwa e, and u u e
medical applica ions. The anos ics 2020,10, 2965. [C ossRe ]
200.
Bul e, J.W. Supe pa amagne ic i on oxides as MPI ace s: A p ime and e iew o ea ly applica ions. Ad . D ug Deli . Re .
2019
,
138, 293–301. [C ossRe ]
201.
Yu, E.Y.; Bishop, M.; Zheng, B.; Fe guson, R.M.; Khandha , A.P.; Kemp, S.J.; K ishnan, K.M.; Goodwill, P.W.; Conolly, S.M.
Magne ic pa icle imaging: A no el in i o imaging pla o m o cance de ec ion. Nano Le . 2017,17, 1648–1654. [C ossRe ]
202.
Makela, A.V.; Gaude , J.M.; Scho , M.A.; Sehl, O.C.; Con ag, C.H.; Fos e , P.J. Magne ic pa icle imaging o mac ophages
associa ed wi h cance : Filling he oids le by i on-based magne ic esonance imaging. Mol. Imaging Biol.
2020
, 1–11. [C ossRe ]
203.
A ami, H.; Teeman, E.; T oksa, A.; B adshaw, H.; Saa chi, K.; Tomi aka, A.; Gambhi , S.S.; Hä eli, U.O.; Liggi , D.; K ishnan, K.M.
Tomog aphic magne ic pa icle imaging o cance a ge ed nanopa icles. Nanoscale 2017,9, 18723–18730. [C ossRe ] [PubMed]
204.
Du, Y.; Liu, X.; Liang, Q.; Liang, X.-J.; Tian, J. Op imiza ion and design o magne ic e i e nanopa icles wi h uni o m umo
dis ibu ion o highly sensi i e MRI/MPI pe o mance and imp o ed magne ic hype he mia he apy. Nano Le .
2019
,19,
3618–3626. [C ossRe ] [PubMed]
205.
Song, G.; Kenney, M.; Chen, Y.-S.; Zheng, X.; Deng, Y.; Chen, Z.; Wang, S.X.; Gambhi , S.S.; Dai, H.; Rao, J. Ca bon-coa ed FeCo
nanopa icles as sensi i e magne ic-pa icle-imaging ace s wi h pho o he mal and magne o he mal p ope ies. Na . Biomed.
Eng. 2020,4, 325–334. [C ossRe ] [PubMed]
206.
Ko anga h, P.; Ba ne , J.D.; Sha ma, A.; Hende son, E.T.; S ewa , J.; Yu, S.-H.; Kandala, S.K.; Yang, C.-T.; Case o, J.S.; Hedaya i,
M. Nanopa icle in e ac ions wi h immune cells domina e umo e en ion and induce T cell–media ed umo supp ession in
models o b eas cance . Sci. Ad . 2020,6, 1601. [C ossRe ]
207.
Johannsen, M.; Gne eckow, U.; Thiesen, B.; Taymoo ian, K.; Cho, C.H.; Waldö ne , N.; Scholz, R.; Jo dan, A.; Loening, S.A.; Wus ,
P. The mo he apy o p os a e cance using magne ic nanopa icles: Feasibili y, imaging, and h ee-dimensional empe a u e
dis ibu ion. Eu . U ol. 2007,52, 1653–1662. [C ossRe ]
208.
Maie -Hau , K.; Ul ich, F.; Nes le , D.; Nieho , H.; Wus , P.; Thiesen, B.; O awa, H.; Budach, V.; Jo dan, A. E icacy and sa e y o
in a umo al he mo he apy using magne ic i on-oxide nanopa icles combined wi h ex e nal beam adio he apy on pa ien s
wi h ecu en glioblas oma mul i o me. J. Neu o-Oncol. 2011,103, 317–324. [C ossRe ]
209.
Dha alika , R.; Bohó quez, A.C.; Rinaldi, C. Image-guided he mal he apy using magne ic pa icle imaging and magne ic luid
hype he mia. In Nanoma e ials o Magne ic and Op ical Hype he mia Applica ions; Else ie : Edinbu gh, UK, 2019; pp. 265–286.
210.
Mu ase, K.; Taka a, H.; Takeuchi, Y.; Sai o, S. Con ol o he empe a u e ise in magne ic hype he mia wi h use o an ex e nal
s a ic magne ic ield. Phy. Med. 2013,29, 624–630. [C ossRe ]
211. Shinkai, M. Func ional magne ic pa icles o medical applica ion. J. Biosci. Bioeng. 2002,94, 606–613. [C ossRe ]
212.
Tay, Z.W.; Chand asekha an, P.; Chiu-Lam, A.; Hensley, D.W.; Dha alika , R.; Zhou, X.Y.; Yu, E.Y.; Goodwill, P.W.; Zheng,
B.; Rinaldi, C. Magne ic pa icle imaging-guided hea ing
in i o
using g adien ields o a bi a y localiza ion o magne ic
hype he mia he apy. ACS Nano 2018,12, 3699–3713. [C ossRe ]
213.
Dennis, C.L.; I ko , R. Physics o hea gene a ion using magne ic nanopa icles o hype he mia. In . J. Hype h.
2013
,29,
715–729. [C ossRe ]
214.
S ehning, C.; Gleich, B.; Rahme , J. Simul aneous magne ic pa icle imaging (MPI) and empe a u e mapping using mul i-colo
MPI. In . J. Magn. Pa . Imaging 2016,2, 2.
215.
Mu ase, K.; Aoki, M.; Banu a, N.; Nishimo o, K.; Mimu a, A.; Kuboyabu, T.; Yaba a, I. Use ulness o magne ic pa icle imaging
o p edic ing he he apeu ic e ec o magne ic hype he mia. Open J. Med. Imaging 2015,5, 85. [C ossRe ]
216.
Schie , P.; Ba on, C.; Spasso , S.; Johansson, C.; Baumga en, D.; Kazako a, O.; Sou he n, P.; Pankhu s , Q.; Coisson, M.; G ü ne ,
C. Eu opean esea ch on magne ic nanopa icles o biomedical applica ions: S anda disa ion aspec s. In P oceedings o he
Polish Con e ence on Biocybe ne ics and Biomedical Enginee ing, Zielona Gó a, Poland, 25–27 Sep embe 2019; pp. 316–326.
217.
Pan, S.-P.; Weng, H.-F.; Lin, C.-M.; Liu, T.-S. Unce ain y analysis on p ecision measu emen o polys y ene nanosphe es using
dynamic ligh sca e ing. Jpn. J. Appl. Phys. 2010,49, 06GK05. [C ossRe ]
218.
Lange in, D.; Lozano, O.; Sal a i, A.; Kes ens, V.; Monopoli, M.; Raspaud, E.; Ma io , S.; Salonen, A.; Thomas, S.; D iessen,
M. In e -labo a o y compa ison o nanopa icle size measu emen s using dynamic ligh sca e ing and di e en ial cen i ugal
sedimen a ion. NanoImpac 2018,10, 97–107. [C ossRe ]
219.
ISO/IEC 17025: 2017. In Gene al Requi emen s o he Compe ence o Tes ing and Calib a ion Labo a o ies; In e na ional O ganisa ion
o S anda disa ion: Gene a, Swi ze land, 2017.
220.
ISO/TS 19807-1:2019. In Nano echnologies-Magne ic Nanoma e ials-Pa 2: Speci ica ion o Cha ac e is ics and Measu emen s o
Magne ic Nanosuspensions; In e na ional O ganisa ion o S anda disa ion: Gene a, Swi ze land, 2019.
221.
ISO/DTS 19807-2. In Nano echnologies-Magne ic Nanoma e ials-Pa 2: Pa 2: Speci ica ion o Cha ac e is ics and Measu emen Me hods
o Nanos uc u ed Magne ic Beads o Nucleic Acid Ex ac ion; In e na ional O ganisa ion o S anda disa ion: Gene a, Swi ze land,
(unde de elopmen ).