review articlePublished online: 22 januarY 2010 | doi: 10.1038/nmat2614
To sustain ie and maintain bioogica unction, nature requiresseectivey taiored moecuar assembies and interaces thatprovide a specic chemica unction and structure, and which
change in their environment. Synthetic poymer systems (Fig. 1)with very simiar attributes are oen prepared or a broad range o appications, such as responsive biointeraces that are unctionay simiar to natura suraces1; controed drug-deivery and reease sys-tems2–4; coatings that are capabe o interacting with and respondingto their environment5–7; composite materias that actuate and mimicthe action o musces8; and thin ms and partices that are capabeo sensing very sma concentrations o anaytes9,10.
Tis artice ocuses on stimui-responsive macromoecuarnanostructures that are capabe o conormationa and chemicachanges on receiving an externa signa. Tese changes are accom-
panied by variations in the physica properties o the poymer.Te signa is derived rom changes in the materias’ environment,such as a change in temperature, chemica composition or appiedmechanica orce, or that can be triggered exogenousy by irradia-tion with ight or exposure to an eectrica and magnetic ed. Herewe anayse ony the very recent deveopments (that is, in the pastve years) on the route to appications using stimui-responsivenanostructured poymer materias and systems in thin ms andnanopartices; the systems covered are summarized in Fig. 1. Wediscuss two-dimensiona (2D) (ms) and three-dimensiona (3D)(particuates and their assembies) stimui-responsive systems romdierent architectures and undamenta approaches in the areao responsive materias. We then ook at how these undamentaapproaches to inducing stimui-responsiveness in each type o
system can be used or appications. Finay, chaenges in theory and modeing o these compex systems and uture prospectivesare examined.
rcc fc ppcReconstructabe suraces change their wettabiity and permeabiity,as we as their adhesive, adsorptive, mechanica and optica prop-erties. Emerging appications extend to materias with rapidy switchabe adhesion to interacting materias (rom sticky to non-sticky suraces) and wetting (rom wettabe to non-wettabe), withswitchabe appearance and transparency, and coatings capabe o rapid reease o chemicas, as we as se-heaing coatings.
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Principal architectures and mechanisms. Reconstructabe suracesa into severa categories: (1) poymer suraces ormed sponta-neousy in buk poymer materias; (2) graed poymer thin ms(here reerred to as poymer brushes); (3) thin ms o poymernetworks; and (4) se-assembed mutiayered thin ms. In com-paring dierent architectures one shoud consider dynamics (rateo response) and ampitude o changes o the materias’ properties,reversibiity o the changes and the intensity o the externa signathat coud trigger the changes.
Surace reconstruction o buk poymers oen resuts in ongresponse times (minutes to tens o hours), during which variouspoymer constituents either migrate to the surace rom the buk or rearrange ocay and decrease the interacia tension11,12. Teduration o that response is too sow or many appications. A rapid
response with no corruption o the mechanica properties o thebuk materia can be achieved through a thin poymer-m coating.By using new design techniques, response times in thin ms cannow be tuned smoothy rom seconds to hours.
A specic exampe o stimui-responsive thin ms invovesmacromoecues that are graed chemicay to a surace at su-cienty high graing densities so that the poymer chains experienceexcuded voume repusions and adopt a stretched conormation(that is, poymer brushes, Fig. 2a–c)6. Te behaviour o poymerbrushes is dictated by a combination o strong entropic repusionbetween poymer chains in the crowded monoayer, entropic stretch-ing costs and rozen constraints owing to irreversibe graing.
Te discovery o reversibe switching by externa stimui inpoymer brushes — which were prepared either through the ‘graing
to’ approach13,14
or the ‘graing rom’ approach15–20
— has oeredexciting possibiities or the abrication o adaptive and responsiveinteraces. Uniorm13–16,18, patterned17 and gradient brushes (brushesin which graing density and/or chemica composition graduay changes in one or two directions on the surace o the sampe)6,19,20 have been used to generate responsive ms on panar 13,15–20 andcurved (or exampe, nanopartice6,14) suraces.
For singe-component homopoymer brushes (Fig. 2a), respon-sive behaviour originates rom the properties o the graedpoymer chains and their graing densities. Various changes inthe environment o the brushes were used to trigger the recon-struction o and change in the brush properties. For exampe,
*A ull lst o authors and ther alatons appears at the end o the paper.
poy(N -isopropyacryamide) (PNIPAAM) brushes that possessa ower critica soution temperature undergo a phase transi-tion owing to changes in the sovent quaity and temperature 15.Poyeectroyte brushes respond with arge conormationa changesto aternating ionic strength and pH19, whereas some zwitterionicbrushes17 possess an upper critica soution temperature and changetheir wetting behaviour with temperature (Fig. 2d). Tese changesare reversibe, and the materia can sustain severa transitionsbackwards and orwards.
Te responsive behaviour o bock copoymer brushes (Fig. 2b)is based on the phase segregation o dierent bocks, specicay when sovent anities o each o the bocks are signicanty di-erent20. Te combination o dierent poymeric bocks in theresponsive thin m resuts in a broadening o the switching rangeo properties, so that the surace property o the m changes romthe property o one poymer to the property o the second poymer,or is ocked in some intermediate state. A tribock poy(styrene-bock-2-vinypyridine-bock-ethyene oxide) (PS-b-P2VP-b-PEO)copoymer brush is a representative exampe o a materia inwhich externa stimui are used to tune the baance among eec-trostatic, steric and hydrophobic orces by exposing one or twopoymers o these three constituent bocks to the thin-m bound-ary. Tis behaviour o the bock copoymer brushes was used totune interactions between the brush-decorated materias. For
exampe, the tribock-copoymer-coated pH-responsive cooidsdemonstrated switchabe aggregation–dissociation o the particeassembies (Fig. 2e)14.
In mixed poymer brushes (Fig. 2c), at east two chemicay dierent poymers are graed to the same substrate. Phase segrega-tion causes the switching o the spatia distribution o the unctionagroups that are presented by the brush exterior so that the materias’properties are switched between the properties o two constituentpoymers, simiar to bock copoymer brushes. Switching o sur-
ace composition and reated physica properties in mixed brushesis a basic mechanism or dynamic changes o interactions betweenmaterias modied with the mixed brushes and their environment,incuding iquids and particuates. For exampe, a mixed poy-mer brush prepared rom poystyrene and P2VP macromoecueschanged the surace composition and wetting behaviour aer treat-ment in dierent sovents13. Te contact-ange change was oundto be strongy ampied on a rough surace where the wettingproperties switched rom compete wetting to utrahydrophobicbehaviour7. It was shown that a mixed brush made o poystyreneand poy(methymethacryate) can induce the oca motion (in therange o a ew nanometres) o adsorbed nanometre-scae objectsthrough sovent-induced topographica variations o the brushsurace (Fig. 2)18. A poy(ethyeneimine)–poy(dimethysioxane)mixed brush switched spontaneousy rom the hydrophiic state in
Aggregate
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Fgr 1 | ‘Galaxy’ o nanostructured stmul-responsve polymer materals. These materals rely on the phase behavour o macromolecule assembles nthn lms (polymer brushes, multlayered lms made o derent polymers, hybrd systems that combne polymers and partcles, thn lms o polymer
networks, and membranes that are thn lms wth channels/pores), and nanopartcles (mcelles, nanogels, capsules and vescles, core–shell partcles,
hybrd partcle-n-partcle structures, and ther assembles n solutons and at nteraces n emulsons and oams).
water to the hydrophobic one in air21. Tis adaptive behaviour o
mixed brushes was used to deveop materias with poor adhesionin a changeabe environment. Te surace coatings that were abri-cated rom mixed PEO–poy(dimethysioxane) brushes22 or romfuorinated nanopartices and PEO brushes23 were adaptive to iquidand vapour environments so that the suraces were spontaneousy transormed to non-sticky states in air and in water. Tis behaviourwas observed on severa cyces o exposure o the sampes to air andaqueous soutions. I poymer brushes are graed to a fexibe sub-strate, the osmotic pressure in the brush may cause a deormation orbending o the substrate (Fig. 2g).
Nanostructured thin network ms (that is, ge ms, which arein many cases hydroge ms prepared rom water-soube poy-mers) are materias in which surace connement brings a rangeo opportunities or engineering stimui-responsive properties. An
important attribute o ge thin ms is their ast kinetics o swe-ing and shrinking compared with buk ges. According to anakaand Fimore’s mode24, which shows the characteristic time o thesweing transition to be directy proportiona to the square o theinear size o the ge, the response times are ess than 1 s or ge msthat are thinner than 10 μm. Te sweing response o these msis highy anisotropic, because the attachment o the network to asurace prohibits in-pane sweing. Tus, the voumetric expansiono the network occurs excusivey in the direction perpendicuar tothe substrate pane25.
Crowe-Wioughby and Genzer reported26,27 on the ormationo poymeric materias with ast and tunabe response times (thatis, a ew seconds) by chemicay graing poy(vinymethysioxane)(PVMS) networks with akanethios bearing hydrophiic end groups(–COOH or –OH). Te rapid response (measured by the transition
rom a hydrophobic state with a 110° contact ange in water to a
hydrophiic one with a 55° contact ange) was aciitated by theiquid nature o the PVMS backbone, and it was ound to decreaseas the ength o the methyene spacer (–(CH2)n–) in the akanethiopendant group decreased (Fig. 3a–c). For n = 2 and n = 6, thesurace reconstructed amost instantaneousy, whereas specimenswith n = 11 resisted reconstruction because o strong van der Waasorces that ed to the ormation o semicrystaine regions.
Another important attribute can be ound or porous thin gems. It is we known that the sweing o porous buk ges resutsin an increase in pore size. In contrast, surace-attached porous gems demonstrate the opposite behaviour owing to the surace con-straints28. Switching between open and cosed pores in thin ge mson shrinking and sweing, respectivey, provides a unique opportu-nity or the reguation o transport through the m in a very broad
diusivity range rom the eve in soution down to a eve in soids29
.Tin responsive (hydro)-ge ms can be used as reestandingms or on various supports (adhered or covaenty graed). Tesems can accommodate various chemicas, biomoecues andnanopartices29. In Fig. 3d,e, a porous P2VP thin ge m on thesoid substrate shows pH-dependent porosity. Te P2VP m isaso responsive to choestero moecues (Fig. 3g,h). Tis responseis used to tune the permeabiity o eectrochemicay active ionsacross a ge m that is paced on the surace o an eectrode(Fig. 3i). Te pH-dependent sweing o the P2VP m, which isoaded with god nanopartices, is used to tune the coour o thecomposite m with changes in pasmon couping between godnanopartices (Fig. 3)30.
Eectrostatic ayer-by-ayer (LbL) assemby has been introducedas a universa method or the acie abrication o nanostructured,
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Fgr 2 | Cartoons and photographs llustratng varous archtectures and responsve behavour o polymers. , Sngle-component homopolymer brushes.
b, Block copolymer brushes. c, Mxed brushes. d, Change o the wettng characterstcs o zwtteronc 2-(methacryloyloxy)ethyldmethyl(3-sulphopropyl)
ammonum hydroxde brushes ater ncreasng the temperature rom 22 °C to 52 °C, where θAW s the advancng water contact angle. , Eectve dameter
o the slca partcles and ther aggregates covered wth trblock PS-b-P2VP-b-PEO copolymer brush as a uncton o pH. The error bars represent the
standard devaton od the expermental data (re. 14). , Atomc orce mcroscopy (AFM) mages acqured rom the same area on the polystyrene–
poly(methylmethacrylate) mxed brush covered wth slca nanopartcles ater a cycle o topographcal varaton o the thn lm n derent solvents. The
poston o three slca spheres relatve to the underlyng patterns o the brush can be pursued over cycles. The green arrow ndcates the dsplaced slca
partcle. g, Defecton o cantlever versus tme. Bas appled at the same tme. Wth the cantlever at negatve bas, the charges on the chan are drawn
towards the cantlever, leadng to large surace stresses and strong bendng. At opposte bas, the counterons move towards the surace, resultng n
organized, mutiayered, organic and hybrid thin ms (Fig. 4a–c)31,32
.In the abrication o LbL interacia assembies, Couombic inter-actions, ion pairing, hydrogen bonding, and poar and hydrophobicinteractions are expoited to aciitate aternative deposition o compementary species, incuding poyeectroytes, nanopartices,cooids and biomacromoecues, which orm unctionaized con-orma nanostructured interaces33.
Te mechanism o response o LbL assembies was anaysed by Rubner and co-workers34, who attributed the dramatic variationin the degree o sweing (up to 400%) to changes in the degreeo ionization o the weak poyeectroytes (that is, poy(ayaminehydrochoride), PAH) where surace constraints aect the ocaenvironment o the ionizabe groups. A sharp sweing and de-sweing transition detected or LbL ms at pH > 8.5 maniesteditse in reversibe pH-controed variations o sweing percentage,
surace roughness and reractive index (Fig. 4a). Te PAH sweingwas associated with the variation in ionization o its ree aminegroups, and a hysteresis oop was reated to the chain dynamicswithin swoen LbL ms.
Recent studies expoited stimui other than pH to ater theconormation and organization o the constituents o LbL ms,incuding a response triggered by ower critica soution temperatureat physioogicay reevant temperatures (25–35 °C) by incorporatingPNIPAAM interayers35; magneticay responsive ree-standing LbL
structures with incorporated iron oxide magnetic nanocrystas36; ormechanicay tunabe eastic LbL ms with a nanoporous interayeracting as open–cosed nanovaves when stretched and reeased romexterna mechanica stresses37.
Te architectures o the stimui-responsive suraces and mecha-nisms o their dynamic changes anaysed in this section were suc-cessuy appied or the deveopment o a range o stimui-responsivematerias and appications that are discussed beow.
Smart and sel-healing coatings. Reconstructabe poymer suracesorm a toobox or the rapidy deveoping ed o smart coatings 38.Te structure o the coatings can be programmed in the ormua-tion. Aer deposition, externa stimui aect the phase separationo the ingredients to se-assembe into a coating with programmed
properties. For exampe, cooida partices prepared by the emusioncopoymerization o acryate and fuorinated acryate monomerscan orm stratied m morphoogies, where the fuorinated phasecan be driven to the m/air or m/substrate interaces. As a con-sequence, static and kinetic coecients o riction can be controedat the m/air interace, resuting in superhydrophobic suraces 39.In another exampe o programmed behaviour, cooida particesare stabiized in an acidic aqueous soution by graed PS-b-P2VP-b-PEO tribock copoymers. Casting o the partice suspension athigher pH resuts in a m consisting o partice aggregates, and,hence, a textured coating. Te coating becomes superhydrophobicwhen heated to above the gass-transition temperature o poy-styrene bocks, because these bocks migrate to the top-most ayero the coating40.
Coatings with se-heaing capabiities a in the category o smart coatings with a programmed structure and response41. Amutiayered LbL system made up o poyeectroytes and a cor-rosion inhibitor coud hea the corrosive area on a meta substrateand reease the inhibitor during a corrosion attack. Te origin o such se-heaing behaviour ies in the breaking and re-estabishingo poyeectroyte compexes in response to changes in a corrosiveenvironment (that is, high ionic strength)42.
Biointeraces and bioseparation. Te responsive properties o reconstructabe thin poymer ms are reevant to many biotech-noogica and biomedica appications5,43,44, because these ms canundergo dynamic changes in accord with changes in iving systems.
Severa key aspects have attracted interest in stimui-responsive
poymeric biointeraces. First, the possibiity o tuning and switch-ing adhesion between stimui-responsive materias and proteinsand ces has been expored or the contro o ce 45 and protein46,47 adhesion, and used or tissue engineering and bioseparation.Second, the possibiity o exposing and masking unctiona moietiesat the biointerace is very important or the presentation o regua-tory signas and concomitant moduation o biomoecue activity 48 or ce research and bioengineering. Recenty, PNIPAAM and itscopoymers have been unctionaized with recognition moieties (orexampe, synthetic peptides) that interact with ce components.Ebara et al.49 used stimuus-responsive PNIPAAM-based copoy-mers to expose or mask arginine–gycine–aspartic acid (RGD)recognition sequences or ce binding.
Tird, the possibiity o dynamic contro o the permea-tion o chemicas through nanoporous membranes10,28–30,50 or the
a
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Fgr 3 | Responsve behavour o unctonal polymerc networks.
, Schematc llustratng the molecular orentaton o PVMS-S-(CH2)nOH
at the ar/sample and water/sample nteraces n the network samples.
b, Photographs o PVMS, PVMS-S-(CH2)6OH and PVMS-S-(CH2)11OH
specmens. The opaqueness o PVMS-S-(CH2)11OH s ndcatve o the
presence o crystalltes. c, Tme dependence o the deonzed water contact
angles (θDIW) or PVMS-S-(CH2)nOH suraces measured by dynamc
contact angle set-up. The error or θDIW s ± 1.5°. d,, AFM topography
mages (7.5 × 7.5 μm2) o a P2VP network thn lm wth pH-tunable
porosty at pH 5.5 (d) and pH 2 (). , Shts o the absorpton maxmum(Δλmax) acqured rom ultravolet–vsble spectra o a P2VP gel–gold
nanopartcle composte lm prepared on gold slands as a uncton o
pH. g,h, AFM topography mages (10 × 10 μm2) o a P2VP network lm
ater washng n a chloroorm soluton wth no cholesterol (g) and 0.13 M
cholesterol (h). , Normalzed values o the electron-transer resstance
(open squares, derved rom the Faradac mpedance spectra) and the
lm porosty (sold squares, derved rom AFM measurements) shown as
unctons o the cholesterol concentraton: Ret and Ret0 are the electron-
transer resstance values or the lm wth cholesterol and wthout
cholesterol, respectvely; P and P0 are the porostes o the lm wth and
interaction o biomoecues and ions with responsive suraces47,51,52 oers a unique opportunity or bioseparation52,53. Surace-graedstimui-responsive poymers provide an exciting means or contro-ing drug permeation through nano- and microporous membranes.Systematic work that expores the compex interreationship amongpore size, poymer moecuar weight, graing density and drug-permeation fux has ony recenty begun50,52,53.
Micro- and nanoactuation. Light-, pH- and temperature-responsive
thin poymer ms have been used or micro- and nanoactuation.Actuation by means o responsive poymer brushes originates rom variabe stretching o graed macromoecues as a resut o thestrong steric repusive interactions between neighbouring chains.In charged poyeectroyte brushes, osmotic and Couombic orcesoen ead to extra repusive interactions and increase the eve o reversibe chain stretching. Te orces that aect the conormationso tethered poymers on soid substrates can be harnessed or actua-tion by growing brushes on fexibe substrates. Te brush can trans-duce these orces into atera surace stresses54 that cause the substrateto bend. As a resut, bending can be moduated by charge screeningwith the use o soutions o varying ionic strength or pH55,56.
It was recenty demonstrated that appied eectric eds ead tothe actuation (1–5 Hz) o cantievers through the switching o sur-
ace stresses in poyeectroyte brush ms (Fig. 2g)57. Te presenceo triggered reversibe contraction and expansion o poymerbrushes oers a design rue or nanoscae actuation that does notrey on chemica ues such as acids and bases.
So ar a variety o actuation mechanisms (and thereore sensingmechanisms) have been reaized or fexibe structures (mosty siicon microbeams coated with organic ms) based on the swe-ing and de-sweing, wetting and de-wetting, or adsorption anddesorption o organic surace ayers58. Recent work on nanopatternedthermoresponsive brushes provides more insight into the chaengesthat ie ahead. In nanopatterned brushes, poymer chains are in asighty dierent chemica environment; some are in the midde o a ‘sea’ o poymer chains whereas others ie at the edge and wi berequired to wet and de-wet rom the surrounding surace. As a resut,
a chains show subte dierences in the degree o chain stretchingand thermoresponsive properties, thus eading to an overa broad-ening o the coapse temperature that is oen extremey narrow inthe buk 59,60. Te main disadvantage o the brush-based actuatorsis their reativey sow response compared with poymer-ge-basedsystems61,62, which probaby resuts rom a dierence in chain pack-ing. Te dense packing eads concurrenty to unique properties thatare ound ony in poymer brushes and that coud be idea or sensorappications. For exampe, arge end groups in dense brushes wi be‘expeed’ rom the brushes; any (reversibe) decrease in the size o these head groups wi ead to the rapid contraction o the associatedpoymer chains into the brush ayer 63.
Sensors. Tat stimui-responsive poymer systems aciitate ecient
transduction mechanisms makes them suitabe or use in sensorappications. For exampe, okareva et al.64 demonstrated the tun-ing o the pasmon-resonance couping between god nanoparticesand a god substrate mediated by a 20-nm-thick sweabe P2VPbrush ayer. Te m can be used as a highy sensitive pH-responsivenanosensor with short response times. Te authors demonstrateda arge (50 nm) shi in the pasmon-resonance position as a resuto changing pH vaues (within pH = 3.8 ± 0.5) caused by shrinkingo the brush thickness rom 22 to 7 nm. Interna stresses causedby conormationa transormations within brush ayers were usedto design pH-sensitive microsensors by graing PNIPAAM ontomicrocantievers15. Tis design provided a high eve o sensitiv-ity, reaching 121 nm o defection per pH unit. Te use o poy-l-ysine–PEO–biotin brushes graed inside a microchanne carvedwithin a microcantiever aowed or the subemtogram detection
o the seective binding o γ-IgG (immunogobuin G) in fuid,representing a dramatic improvement o sensitivity over a conven-tiona quartz microbaance65.
Dierent LbL ms with embedded biomoecues and nano-partices have been expoited as so organized matrices orupoading nanopartices to abricate pH-responsive and biosens-ing nanomaterias based on the surace pasmon resonance (SPR)phenomena9. As we as conventiona meta nanopartices, whichshow SPR peaks in the range o 520–540 nm (res 64,66), recent
studies expanded this approach towards sensors that containgod nanorods67. Specicay, god nanorods were embedded incrossinked poy(methacryic acid) (PMAA)–PAH and PMAA–poy(N -vinypyrroidone) LbL ms to act as pH-responsive pas-monic sensors (Fig. 5). Sweing and de-sweing o these ges atpH 8 and pH 5, respectivey, resuted in reversibe and arge shis o a strong, easiy detectabe ongitudina pasmon resonance ocatedin the near-inrared region (≈700 nm) owing to variabe side-by-side nanorod interactions.
Coorimetric or eectromechanica detection methods that areused or the reversibe and dramatic reorganization o LbL coat-ings, and that are typicay triggered by pH or ionic strength, areachieved by the incorporation o inorganic nanopartices with thecharacteristic optica signature and the conorma nature o LbL
ms. For exampe, Kotov et al.68 demonstrated reversibe oadingand unoading o quantum dots in highy hydrated LbL ms rompoy(diaydimethyammonium choride) and poyacryic acid(PAA). Tese structura variations were accompanied by corre-sponding changes in fuorescence. Changes in photouminescenceand pasmon resonances in the visibe range have been observed orconventiona PAH–poy(styrene suphonate) (PSS) LbL ms andLbL ms that contain amine-terminated dendrimers69,70. A strongand easiy detectabe optica response was achieved by pacingLbL ms that contained either dyes or god nanopartices on godsubstrates to expoit either a quenching mechanism or coupingpasmon resonances.
Te responsive behaviour o thin hydroge ms has attractedgreat interest or a range o appications in sensors, incuding chem-
ica gating28–30,51
, microgravimetric, micromechanica or opticatransduction o chemica signas71,72. Responsive 3D 2-hydroxy-ethymethacryate hydroge and PNIPAAM cooida crystasshowed rapidy tunabe photonic bandgaps in inrared regions73,74;ree-standing fexibe PAH–PSS ms acted as pressure and acous-tic sensors75; and PNIPAAM–PAA microenses with tunabe ocaengths aowed or autonomous ocusing under externa pressure76.In the case o the PNIPAAM–PAA microenses, it has been sug-gested that the tuning o the oca ength is controed by variationsin the reractive index o the swoen or shrunken materia causedby protonation or deprotonation o the acidic groups, temperature,or physica crossinking or decrossinking events77 (such as bind-ing or reease o antibodies). Te tunabe microens arrays can beintegrated into microfuidic and ab-on-a-chip technoogies or bio-
sensing and medica diagnostics. Recenty, a reversibe switchingo piar arrays embedded in humidity sensitive ge ms that canbe used as tunabe microfuidic sensors has been demonstrated78;and an intriguing mode o mechanochemica transducing ges hasaso been constructed79. Te computer simuations in these stud-ies suggested that adaptive ge materias can sense oca stresses by generating chemica waves and thereore potentiay coud be usedas touch-sensitive sensors.
F w : pv pcStimui-responsive cooida partices represent a rapidy deveopingcass o stimui-responsive materias that nd appications in thestabiization, destabiization and inversion o cooida disper-sions (emusions, oams and suspensions), in cataysis, sensors anddrug-deivery capsues (Fig. 4b,c).
the interace between two immiscibe fuids (that is, iquid/iquid oriquid/gas), where the partices are strongy pinned owing to theirarge surace areas. Tey can then stabiize emusions and oams(Pickering dispersions), primariy as a resut o the ormation o amechanica barrier that prevents the coaescence o the dispersedphase and that reduces the bending rigidity o the interace. Morehydrophobic partices preerentiay stabiize water-in-oi emu-sions (because asymmetric positioning in the interace imposes atendency to curve towards the east preerred phase), and vice versa.Hence, a key parameter is the preerence o the partices or eitherphase. Te partices wi expose a arger raction o their surace to
the iquid phase that has a higher anity to the partice surace; thisphenomenon can be used to produce various eects. For exampe,detaching partices entirey rom the interace is possibe in the pres-ence o a sucienty strong shi (induced by externa stimui suchas a pH change) in the interaction baance towards a preerentiaiquid phase (Fig. 6c). Partices are then pued o the interace intothe seective phase14,95, and the emusions ‘break’. Mider shis eadto the inversion o emusions and oams (that is, rom air-in-wateroam to water-in-air powder)96,97.
Tunable catalysis. Te possibiity o exposing or hiding unctionagroups or nanopartices in the reconstructabe suraces has openednew directions in chemica and biochemica cataysis. For exampe,Baau et al.98,99 described a switchabe catayst that was made by synthesizing 10-nm meta nanopartices inside a thermoresponsive
poymer she that had been graed to the surace o a much argercooida partice. emperature-dependent sweing and shrink-ing o the she were used to aternativey expose and hide thesiver nanopartices on the surace o the cooids, thereby moduat-ing the cataytic activity o the composite partice. Conjugation o stimui-responsive poymeric systems with cataytic nanoparticesand enzymes coud thus create new opportunities or bio- andchemica technoogies.
Drug delivery . Recenty, stimui-responsive nanopartices andnanocapsues have attracted great interest because o the broad
opportunities or in vivo appications. Such nanosized capsuescoud store and protect various drugs, and reease them inside cesaer the capsue has been internaized. A smart drug-deivery poy-meric system shoud undergo a compex chain o responses to sur- vive in vivo, deiver the cargo, reease the drug into the target ces,and match the desired kinetics o the reease. Among the variousapproaches used to enhance the ecacy o chemotherapy is the useo carrier systems that reease a drug in response to stimui, such aschanges in pH, gutathione concentration, or the presence o specicenzymes that are seectivey encountered in reevant ce organees.
Hoow LbL capsues can be reed with various moecuesor drug deivery. Drug reease can be activated on demand by oca changes in pH or by remote physica stimui. For exampe,Skirtach et al.100 demonstrated the seective addressing o intraceuarLbL microcapsues with aser ight. Kre et al.101 demonstrated pH
500 nm 500 nm
gf e
21 nm
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pH 8
6000.0
0.2 A b s o r b a n c e0.4
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800 1,000
Wavelength(nm)
a b
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d
∆pH
Fgr 5 | Hydrogen-senstve LbL hydrogels. , LbL assembly o PMAA/poly(N-vnylpyrroldone) lms. b, Swellng crosslnked hydrogel n a soluton o gold
monitoring and LbL microcapsue tracking inside ces through theencapsuation o pH-sensitive dyes. One o the imitations o thecapsue appications is the size o the capsue. Athough most reportsconsider capsues in the micrometre range, ony a ew attemptshave been made to abricate LbL capsues smaer than 200 nm indiameter. It is prudent to stress that the optima size or an ecientdeivery to ces and internaization within them is considered to bein the range 25–100 nm.
Micee-ike nanopartices can easiy approach the submicrometre
scae. Severa types o such micee-ike nanopartice and vesicehave been prepared based on bock copoymers and poyeectroytecompexes. For exampe, inear-dendritic bock copoymers com-posed o a inear PEO bock and either a poyysine or poyesterdendron were used or the abrication o pH-responsive miceesor drug deivery 102. It was shown that an encapsuated agent can bestored in prepared micees at pH 7.4 and reeased at pH 5 by meanso gradua disintegration o micees into unimers.
In poyeectroyte micees, eectrostatic orces keep thesepartice assembies together. It is obvious that they respond to addedsat103. I the core is made o weak poyeectroytes the integrity o
the partices is pH-dependent, because the baance between thepositive and negative charges is aected. Such partices, oadedwith drugs and enzymes, become unstabe and reease the drugs onchanges in pH104.
Stimui-responsive nanoges represent another type o promisingmateria or drug deivery. Nagasaki’s team prepared nanoges roma crossinked, pH-sensitive poyamine core, surrounded by PEOchains that were conjugated to igands recognized by ce-specicreceptors105. Tese nanoges were internaized by ces through
receptor-mediated endocytic pathways. In the acidic endosome, thenanopartices sweed and reeased drugs sequestered in the particecore. Furthermore, a virus-mimetic nanoge was deveoped by Baeand coeagues106. Tese nanoges possess the trademark property o viruses to migrate rom one ce to another, eaving part o theircargo behind. Te virus-mimetic nanoges consist o a drug-oadedcopoymeric core surrounded by a PEO–bovine serum abumindoube she that is decorated with oate groups abe to bind to spe-cic ce receptors. Internaized virus-mimetic nanoges enter theendosomes, where the nanoges experience a pH-triggered voumeexpansion that is accompanied by the reease o the drug. However,the swoen nanoges disrupt the endosoma membranes and escaperom the endosome. Te nanoges then encounter a ess acidic pH,shrink back to their initia size, and migrate to another ce, just as
a virus does.Te discussed exampes demonstrate the essentia progress
in the area o smart drug-deivery systems. Capsues and vesicesshow much higher drug-oading capacity than micees and nano-ges. Capsues and nanoges are much more stabe than miceesand vesices. Te kinetics o drug reease can be adjusted across a very broad range by the conjugation o drugs with macromoecuesand the reguation o the transport across the capsue wa. Stabiity (both mechanica and chemica) can be reguated by crossinkingo the poymers. Proonged circuation in vivo has been accom-pished by modication o the outer she with PEO brushes, andtarget deivery coud be soved through the incorporation o spe-cic igands on the she. An idea drug-deivery device coud beoreseen as a 25–100 nm capsue decorated with the PEO brush and
igands (specic or target ces). Te she shoud be an imperme-abe m with stimui-responsive pores or triggered gating o thedrug reease. Te reease dynamics shoud be reguated by the pre-cise contro o the open-pore dimensions and/or by conjugation o the drugs with macromoecues.
Cg f g, yTe structure o stimui-responsive poymer systems is dictatedby a subte interpay among non-bonded interactions, the conor-mationa entropy o the macromoecues, and rozen constraintsresuting rom irreversibe graing and network ormation, orthe geometry o the substrates. Te description o these coectivephenomena requires a coarse-grained approach. Scaing consid-erations and se-consistent ed theory 107–109 as we as partice-
based simuations110,111
have been used in conjunction withcoarse-grained modes to investigate, inter alia, the properties o poymer brushes, poyeectroyte ayers and the phase separation inmuti-component networks.
Athough standard coarse-grained modes112 and systematiccoarse-graining procedures113,114 are avaiabe or simpe systems,the deveopment o coarse-grained modes o stimui-responsive,muticomponent systems in aqueous soution is sti in its inancy.
For practica appications, the kinetics o structura changes in thepresence o externa stimui is most reevant. Athough it is a prereq-uisite or designing systems with rapid switching times, it sometimesremains uncear i equiibrium can be attained on the pertinentexperimenta timescae. Tus, the kinetics may dictate the observedstructure. Te investigation o the tempora re-arrangements inresponse to externa stimui has just begun115,116.
a
b
c
d
Micelle
Nanogel
Oil Oil
Water Water
Core–shell
particle
Core–shell
particle
Fgr 6 | Varous conguratonal schematc desgns o stmul-responsve
nanopartcles. –d, Mcelles (), nanogels (b), and core–shell partcles n
Molecular modelling o responsive polymer layers. One importantaspect o responsive poymer ayers is the couping that exists betweenthe conormationa degrees o the chain moecues, the specic intra-and intermoecuar interactions, and the possibiity o reversiby reguating chemica reactions within the poymer ayer. Te basic
idea is to ook at each moecuar species with as much moecuardetai as possibe whie treating intermoecuar interactions within amean-ed approximation. Tese approaches predict both thermo-dynamic and structura properties and can incorporate many o thedierent interactions117–119, hydrogen bonding120 and chemica reac-tions118,121–123 present in these systems. Te incusion o moecuar-eve detai o the poymers aows the structure o the ayers to bedescribed in great detai using density unctiona theory 119,124, se-consistent ed theory 118,121,125, and singe-chain (moecuar) mean-ed theory 117,120,122. Te main dierences among these approachesare in the eve o detai with which the moecues are treated; inact, they become equivaent within certain imits117,124. Teseapproaches have shown good predictive power, but they aso havesevera imitations such as the ack o intermoecuar correationsand the assumption that the systems are ateray homogeneous so
that surace domains109,126 cannot be treated. Aso, the incorporationo eectrostatic interactions within a mean-ed approach can beprobematic in some regimes127.
An exampe o a highy compex responsive ayer is a redox-poymer-modied eectrode (Fig. 7a–e). Tis ayer responds to
changes in pH, sovent quaity, soution ionic strength and appiedeectrode potentia122,123. Figure 7 shows the predictive power o the-ory as a unction o pH and ionic strength or the reversibe curveso current density divided by scanning veocity versus potentia(Fig. 7b,c). Moreover, the theory expains the moecuar organiza-tion within the m. Te most important eature is that even withinthe 3 nm thickness o the m, the distribution o poymer segmentsand redox (osmium) sites (Fig. 7d), the oca proton concentrationand the apparent redox potentia (Fig. 7e) are highy inhomoge-neous. Tese very arge oca changes are important because they determine the true state o the m.
Particle-based simulations o large 3D assemblies. Computersimuations o partice-based modes require substantia computa-tiona resources. o study the se-assemby and phase separation o
z
+
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+
+
+
+
3
Polymer backbone
Osmium complex
Total
Gold electrode
Csalt = 1.2 M Csalt = 0.004 M
0.40
Theory
Experiment
0.35
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E p e a k
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+2
–SO3– + H+
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+ e–(Au)
P–Os(II)
P–NH3+
–SO3H
0
1 2 3 4 5
0.30
4 5 6
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j / v ( µ F
c m – 2 )
E 0 a
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)
ϕ i
a
b d e
c
E (V) z(nm) z(nm)
Fgr 7 | A gold electrode moded wth a mercaptopropane sulphonate (MPS) sel-assembled monolayer, wth adsorbed redox polymer. , Schematc
representaton, wth the poly(allylamne) backbone o the redox polymer–osmum (PAH–Os) shown as red curves and the tethered pyrdne–bpyrdne Os
complexes are shown as orange or blue spheres accordng to ther oxdaton state. The allylamne unts can be ether n a postvely charged protonated
state (plus sgns on the polymer-backbone lnes) or n a neutral deprotonated state, whch are related by an acd–base equlbrum. The sulphonate groups
n MPS are n acd–base equlbrum wth protons n soluton and thus could be protonated or deprotonated. The polymer-moded electrode s mmersed
n an aqueous electrolyte soluton contanng salt ons, protons and hydroxyls n thermodynamc equlbrum wth a bulk soluton. The normal drecton rom
the electrode s denoted by z and has ts orgn on the metal surace. b, Comparson o expermental (crcles, V = 0.025 V s–1
) wth theoretcal (sold lnes)current densty ( j) dvded by the scannng velocty (v) versus voltage (V ) plots measured or a Au/MPS/PAH-Os electrode n solutons o derent onc
strength and 1 mM HNO3 (pH 3). c, Plots o expermental and theoretcal peak potental poston as a uncton o bulk salt concentraton (lower axs, blue
symbols) and bulk pH (upper axs, red symbols) The error bars represent the standard devaton o the expermental observatons (re. 123). d, Theoretcal
volume-racton proles or the polymer backbone (red ull lne), the redox stes (blue dashed lne) and the whole redox polymer (black dot–dashed lne)
or E = E 0Os(ii)/Os(iii), concentraton (Csalt) = 0.1 M and pH = 3. The shaded regon (z < 0.5 nm) s occuped by the thol layer. , Dstance-dependant ormal
Os(iii)/Os(ii) redox potental (blue lne, let axs) and local pH (red lne, rght axs) as a uncton o the dstance rom the electrode calculated or the same
arge, 3D systems, coarse-grained modes with so potentias havebeen devised128. In these modes, the absence o excuded voumeaows the beads, which represent the centre o mass o a ewatoms, to overap. Tus, systems with an experimentay arge and
invariant degree o poymerization and reaistic fuctuations canbe described. Te so interactions can be pair-wise (or exampe,dissipative partice-dynamics modes129) or they can take the ormo a density unctiona mode, which aows or a cose connectionwith the moecuar, mean-ed approaches (described above) andwhich incorporates the rich thermodynamics o muticomponentsystems130. Tese modes have been appied or the study o, orexampe, the strong ampication o quenched fuctuations in thegraing-point density by the structure ormation in a mixed poymerbrush. Tis eect causes the morphoogy to be correated betweendierent cyces o stimui switching (that is, domain memory meas-ure131,132) and prevents the ormation o ong-range periodic order.Tus, the structure actor o atera density and composition fuc-tuations does not distinguish ceary between dierent disorderedmorphoogies. Tis absence o ong-range order is aso observed
in the phase-separated morphoogy o dibock copoymer brushes(Fig. 8), and Minkowski measures have been used to characterizethe structures o these brushes128.
F cResponsive poymer systems can be used or a variety o appica-tions, such as switching suraces and adhesives, protective coatingsthat adapt to the environment, articia musces, sensors and drugdeivery. Biochemistry, environmenta sciences and biomedica sci-ences are just a ew exampes o important areas that wi benetgreaty rom urther deveopment o appications o stimuus-respon-sive poymeric materias. In act, it is a chaenge to deveop compexsystems that are responsive to biochemica signas or biomarkerstypicay present in a ess than nanomoar concentration range. Suchsystems-within-systems need a compex, hierarchica organizationo the responsive partices discussed here to accommodate variouspossibe ampication mechanisms. A hierarchica organization (orexampe, hierarchica compartmentaization) wi aso be importantor the deveopment o systems where the unctions o ‘receiving’
Fgr 8 | Molecular structure o a dblock copolymer brush observed by sngle-chan-n-mean-eld smulatons showng lateral phase separaton. The
system mmcs a PAA–polystyrene dblock copolymer brush n water at hgh pH value. , Top vew o morphologes or derent values o molecular
asymmetry (f ). PAA s shown n yellow, whereas polystyrene s depcted n red. On ncreasng the racton o the bottom block, PAA, we observe a gradual
crossover rom a contnuous, collapsed polystyrene layer (f = 0.25), a perorated layer (f = 0.5) to sphercal mcelles (f = 0.75). b, Reducton rom a 3Dsnapshot o a conguraton wth f = 0.75 (that s, dblock copolymers represented by NAA = 24 coarse-graned PAA segments and NS = 8 polystyrene
segments), by means o a contnuous 2D level mage to a 2D bnary contour wth derent threshold values, whch s analysed by Mnkowsk measures.
c, Mnkowsk measures characterzng the dsordered morphology: ractonal doman area, S, measured n unts o the lateral system sze, L2 = 256Reo2
(Reo beng the polymer’s end-to-end dstance), length o the doman boundary (U) n unts o L2 /Reo, and Euler characterstcs ( χ E). The Mnkowsk measures
are analysed as a uncton o the threshold, Σz ρ o the vertcally averaged densty ( ρ) derence provdng normaton about the type o morphology (rpple
versus dmple/sphercal mcelles), the segregaton and spatal extenson o the domans. The plateau value o χ E quantes the number o domans n the
dmple morphology (sphercal mcelles), whereas breakng up o the structures, sgnalled by large absolute values o χ E ndcates that they do not span the
the signa and ‘responding’ by changing the materia’s properties areseparate because, in some cases, the changes aected by the stimuimay interere with the desired changes in the materia’s properties.In iving systems, nature broady expoits the principe o partition-ing; oca dynamic changes take pace in compartments that are sep-arated by permseective membranes. Tis type o organization instimui-responsive materias wi provide great opportunities withregard to a programmabe, compex response o the materias.
Another chaenge is to deveop systems that can respond to
severa externa stimui in an inteigent way. Athough severa exam-pes o such ‘biocomputing’ systems51,90,133,134 and surace-encodedassembies o nanocusters135 have been reported recenty, muchmore remains to be done beore practica appications are viabe.
One signicant chaenge that is inherent to amost a organicsystems pertains to ong-term stabiity (that is stabiity to temper-ature, utravioet ight, sovent vapours and so on) and durabiity (that is, mechanica stabiity, abrasion and so on).
Responsive systems can be introduced into many products ata reativey ow cost, because oen ony a very thin (nanometre-thick) coating is required. Providing added unctionaity with sucha coating can enhance the vaue o a product signicanty — orexampe, materias that are capabe o repairing themseves in essthan an hour can be used in many coatings appications ranging
rom decoration to biomedica industries136. Te concepts presentedin this review wi be benecia or many new appications in theuture because they wi aow or the introduction o new aspectsand possibiities in the ed o conventiona materias.
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ackwgTe research was supported by Nationa Science Foundation (grants DMR-0706209,
