Smart Hydrogels based on Responsive Star-Block Copolymers

Sma Hyd ogels Based on Responsi e S a -Block Copolyme s Disse a ion Zu E langung des akademischen G ades eines Dok o s de Na u wissenscha en (D . e . na .) im Fach Chemie de Fakul ä ü Biologie, Chemie und Geowissenscha en de Uni e si ä Bay eu h o geleg on Alexande Schmalz gebo en in München Bay eu h, 2011 Die o liegende A bei wu de in de Zei on Juli 2007 bis Ok obe 2011 in Bay eu h am Leh s uhl ü Mak omolekula e Chemie II un e de Be euung on He n P o . D . Axel H.E. Mülle ange e ig . Volls ändige Abd uck de on de Fakul ä ü Biologie, Chemie und Geowissenscha en de Uni e si ä Bay eu h genehmig en Disse a ion zu E langung des akademischen G ades eines Dok o s de Na u wissenscha en (D . e . na .) Disse a ion einge eich am: 06.12.2011 Zulassung du ch die P omo ionskommission: 14.12.2011 Wissenscha liches Kolloquium: 02.03.2012 Am ie ende Dekan: P o . D . Bea e Lohne P ü ungsausschuss: P o . D . Axel H.E. Mülle (E s gu ach e ) P o . D . Thomas Hellweg (Zwei gu ach e ) P o . D . Bi gi Webe P o . D . Ca lo Un e zag (Vo si zende ) In he beginning he Uni e se was c ea ed. This has made a lo o people e y ang y and has been widely ega ded as a bad mo e. Douglas Adams Table o Con en s 1 In oduc ion 1 1.1. S a -shaped polyme s 1 1.2. A om T ans e Radical Polyme iza ion 3 1.3. S imuli- esponsi e polyme s 5 1.3.1. Tempe a u e- esponsi e polyme s 6 1.3.2. pH- esponsi e polyme s 7 1.3.3. Mul i- esponsi e polyme s 8 1.4. Hyd ogels 8 1.4.1. De ini ion o a gel 8 1.4.2. Sma hyd ogels 9 1.5. Objec i e o his hesis 14 1.6. Re e ences 16 2 O e iew o his hesis 20 2.1. Double S imuli-Responsi e Beha io o Linea and S a -Shaped Poly(N,N- die hylaminoe hyl me hac yla e) in Aqueous Solu ion 21 2.2. Double Responsi e Hyd ogels Based on Te ia y Amine Me hac yla e S a -Block Copolyme s 23 2.3. Sma Hyd ogels Based on Responsi e S a -Block Copolyme s 27 2.4. Indi idual con ibu ions o join publica ions 31 3 Double S imuli-Responsi e Beha io o Linea and S a -Shaped Poly(N,N- die hylaminoe hyl me hac yla e) in Aqueous Solu ion 33 3.1. In oduc ion 34 3.2. Expe imen al sec ion 35 3.3. Resul s and Discussion 38 3.4. Conclusion 43 3.5. Re e ences 44 4 Double Responsi e Hyd ogels Based on Te ia y Amine Me hac yla e S a -Block Copolyme s 47 4.1. In oduc ion 48 4.2. Expe imen al sec ion 51 4.3. Resul s and Discussion 54 4.4. Conclusion 65 4.5. Re e ences 68 4.6. Suppo ing In o ma ion 70 5 Sma Hyd ogels Based on Responsi e S a -Block Copolyme s 73 5.1. In oduc ion 74 5.2. Expe imen al sec ion 77 5.3. Resul s and Discussion 80 5.4. Conclusion 95 5.5. Re e ences 97 5.6. Suppo ing In o ma ion 100 6 Summa y/Zusammen assung 107 7 Lis o Publica ions 111 Chap e 1 In oduc ion 1 1 In oduc ion 1.1. S a -shaped polyme s Polyme s a e p ima ily classi ied by hei composi ion, opology and unc ionali y, wi h o- pology being he ele an subjec he e. The e a e wo classes o opology, linea and b anched. S a -shaped polyme s o m a subclass o b anched polyme s on one side o he spec um wi h only a single b anching poin . The emaining subclasses a e b ush-like and hype b anched polyme s (Figu e 1.1). Figu e 1.1. Di e en subclasses o b anched polyme s wi h a) s a -shaped, b) comb-like and c) andomly b anched (dend i ic) polyme s. All b anched polyme s a e cha ac e ized by he numbe and unc ionali y o hei b anching poin s and he leng h o hei a ms o segmen s. As al eady men ioned, s a -shaped poly- me s a e de ined as ha ing only one, a leas i- unc ional, b anching poin . A second im- po an cha ac e is ic o s a -like beha io is he size o he co e compa ed o he size o he whole s a . When he co e is a leas one o de o magni ude smalle han he s a , i s in luence can be dis ega ded.1,2 S a polyme s can be di ided in o wo ca ego ies wi h e- spec o hei chemical composi ion o opological dis ibu ion. One ca ego y is symme ical s a s, whe e all a ms a e made o he same monome , he a ms ha e he same leng h and all s a s ha e he same numbe o a ms. The second ca ego y is composed o all s a s which show an asymme y in any o hei a ibu es. These asymme ies can be chemical in na u e, i.e. di e en a ms a e made o di e en monome s, o opological, i.e. he e a e dis ibu- ions in he a m leng h o a m numbe . The syn hesis o well-de ined symme ical s a s has long been o in e es .3 Chap e 1 In oduc ion 8 1.3.2. pH- esponsi e polyme s pH- esponsi e polyme s a e weak polyelec oly es whose solubili y and con o ma ion can be e e sibly manipula ed by changes in he ex e nal pH alue.22 Changes in pH al e he ionic in e ac ions, hyd ogen bonding and hyd ophobic in e ac ions o he polyme s wi h he sol en o i sel . The epea ing uni s can change om uncha ged hyd ophobic g oups o cha ged hyd ophilic g oups, depending on he p o ona ion/dep o ona ion o he unc ional g oups. The pH esponsi e polyme s can be di ided in o wo ca ego ies, polyacids and poly- bases. The mos common pH- esponsi e polyme s a e poly((me h)ac ylic acid) (P(M)AA) as polyacid and poly( inyl py idine) (PVP) as polybase (Figu e 1.5). 1.3.3. Mul i- esponsi e sys ems The e a e wo me hods o in oduce wo o mo e s imuli in o a polyme . Fi s he e is he possibili y o copolyme ize monome s ha espond o di e en s imuli, ei he as a andom copolyme 23-26 o as a block copolyme .27,28 Second, he e a e polyme s, he epea ing uni s o which a e esponsi e o di e en s imuli. One example, which combines sensi i i y o empe a u e and pH, is poly(2-(dime hylamino)e hyl me hac yla e) (PDMA). Plampe e .al. showed ha he LCST o linea and s a -shaped PDMA depends s ongly on he deg ee o p o ona ion o he chain, which is con olled by he solu ion pH.29-31 A numbe o e iews deal wi h his ype o polyme s.16,32 1.4. Hyd ogels 1.4.1. De ini ion o a gel A s uc u al de ini ion o a gel desc ibes i as a h ee-dimensional ne wo k, swollen in a sol- en o a ce ain ini e ex en .33 A mo e common de ini ion is ha a gel consis s o wo componen s, a solid and a liquid, whe e he solid is he mino i y componen and he liquid he majo i y componen . The solid phase ex ends h ough he en i e olume o he gel.34 In a ecen e iew, Nishina i de ines a gel as a sys em o molecules, pa icles, chains, e c. which a e pa ially connec ed o each o he in a luid medium.35 A mo e de ailed de ini ion can be Chap e 1 In oduc ion 9 de i ed om he heological p ope ies o he gel sys ems. Almdal and K ame de ined ha he s o age modulus G' should be independen o he equency a leas on he o de o seconds and he loss modulus G" should be conside ably lowe han he s o age modulus.34 Howe e , some sys ems do no ollow all o hese c i e ia, e.g. he s o age modulus is only sligh ly highe han he loss modulus e en hough he gel appea s o be ee-s anding. These sys ems ha e been cha ac e ized as “weak” gels.36 The mos commonly used de ini ion o ha d o weak gels goes back o he wo k o H id e .al., who ca ego ized gels wi h a s o age modulus on he o de o 104 Pa as “ha d” gels and gels wi h a s o age modulus on he o de o 101 Pa as “weak” gels. The c i ical poin o di e en ia ion be ween “ha d” and “so ” gels was de ined as he h eshold o 103 Pa.37 O e ime excep ions ha e been ound o e e y de ini ion o he gel poin p e iously p esen ed, making a simple uni e sal de ini ion nex o impossible. I is he e o e only sensible o look o de ini ions pe aining o pa icula ypes o sys ems and hei beha io . Nishina i wen so a as o s a e ha a gel migh be p esen i he sys em does no low unde g a i y.35 1.4.2. Sma hyd ogels Hyd ogels belong o a class o so ma e which has a ac ed a lo o a en ion in he e- cen yea s. The e a e wo p incipal classes o hyd ogels, co alen ly c osslinked and physical- ly c osslinked ones. Pa icula ly s imuli- esponsi e and physically c osslinked hyd ogels ha e many po en ial applica ions in biomedicine and ha e been he subjec o in ense sc u iny om he scien i ic communi y.38-43 The i s epo o empe a u e-sensi i e mic ogel pa icles based on c osslinked PNiPAAm was published in 198644 and since hen he e ha e been nume ous publica ions on his sub- jec . P og ess has been made ega ding he syn hesis45 and he cha ac e iza ion o mic ogels and nanopa icle mic ogel hyb ids.46 Co alen ly c osslinked gels such as hese show only one eac ion o a s imulus, which is swelling/deswelling. The deg ee and kine ics o his swelling ha e been ex ensi ely s udied.47-53 In he las decade, he e ha e been many appli- ca ions o which hese gels ha e been used54-56 and PNiPAAm has also been copolyme ized wi h a wide a ie y o o he monome s, i.e. poly(4- inylpy idine) o poly(ac ylic acid).57,58 Chap e 1 In oduc ion 10 O he polyme s besides PNiPAAm ha e also been s udied in he o m o co alen ly c oss- linked hyd ogels, such as poly(die hylene glycol me hyl e he me hac yla e) (PDEGMA).59 In he ollowing a b ie o e iew is gi en o e he s a e o he a o physically c oss-linked s imuli- esponsi e hyd ogels. The e ha e also been many e iews co e ing his opic.11,60-62 All s imuli p esen ed in he ollowing a e based upon hyd ophobic in e ac ions and o he ypes o in e ac ions, e.g. ionic in e ac ions,63,64 will no be men ioned. Chap e 1 In oduc ion 11 Figu e 1.8. Gela ion mechanism o a) s imuli- esponsi e di- and iblock copolyme s, whe e he A block is hyd ophilic and he B block is s imuli- esponsi e. Adap ed om Re . [58]. b) s imuli- esponsi e (AB)x diblock copolyme s, whe e he A block is hyd ophilic and he B block is s imuli- esponsi e Hyd ogels based on AB, ABA and BAB block copolyme s. Linea s imuli- esponsi e block copolyme s ypically ollow a micella gela ion mechanism, whe e he c osslinks can be o med ei he by micelle jamming, whe e gela ion occu s when he micella co onas o e - lap, o by in e micella b idging (Figu e 1.8).65 The i s mechanism is usually obse ed o AB diblock and ABA iblock copolyme s whe e he A block is hyd ophilic and he B block hyd ophobic. They o m micelles in wa e and a a su icien ly high concen a ion he mi- celles o m a closely packed sys em, hei co onas s a o o e lap, and his causing gela i- on.65-67 Micelle b idging is commonly obse ed o he in e se BAB iblock copolyme s (Fig- u e 1.8). The e a e h ee possibili ies o he iblock copolyme s o a ange hemsel es in aqueous solu ion in his scena io, bo h B blocks can occupy he same lowe -like micelle, hey can connec wo adjacen micelles o one o he B blocks o ms a dangling collapsed chain end. All h ee s a es ha e been p o en o exis .60 Micelle b idging e e s o he case whe e he chains connec adjacen micelles and his a o s gel o ma ion. The e a e wo ways o inc ease he ex en o micella b idging in such sys ems. Fi s , i he A block has polyelec oly e cha ac e , as he elec os a ic epulsion be ween he cha ged chains educes he possibili y o back- olding.68 Second, using mul i-a m (AB)x ype copolyme s lowe s he c i ical gela ion concen a ion by elimina ing he micelle o ma ion s ep.69-71 This will be discussed below. Tempe a u e-dependen gela o s. PNiPAAm has been used nume ous imes o p epa e empe a u e-dependen gela o s. A mes e .al. ha e p epa ed hyd ophilic poly(2- (me hac yloyloxy)e hyl phospho yl choline) (PMCP) end- unc ionalized wi h sho PNiPAAm blocks a bo h ends. This BAB iblock copolyme o ms a ne wo k o b idged lowe -like micelles abo e 32 °C a a concen a ion as low as 5 w %.72 The same polyme was also syn- hesized wi h a biodeg adable uni inside he A block. The esul ing gel o med unde physi- ological condi ions a 37 °C and could be u ned in o a ee- lowing liquid h ough he addi- ion o glu a hione, which clea ed he disul ide bond in oduced in o he cen al A block.73 McCo mick e .al. epo ed on he gela ion beha io o BAB iblock copolyme s wi h PNiPAAm ou e blocks and wa e -soluble poly(N,N-dime hylac ylamide) (PDMAAm) inne Chap e 1 In oduc ion 12 block. The copolyme o ms ee-s anding gels in PBS bu e a 37 °C a concen a ions o 10 w % and hei mechanical p ope ies a e in e es ing o issue enginee ing.74 The in e se ABA copolyme s wi h PDMAAm ou e blocks and PNiPAAm inne blocks also o m he mo- esponsi e gels due o jamming, bu a highe concen a ions.66 The e ha e also been s ud- ies o P(DEGMA-co-OEGMA) as a s imuli esponsi e block o hyd ogels. Bo h linea BAB iblock and s a -shaped (AB)x diblock copolyme s wi h an A block o poly(e hylene oxide) (PEO) ha e been p epa ed. The s a -shaped copolyme s we e able o o m gels upon hea - ing in PBS bu e solu ions a concen a ions o 15 w %, while hei linea ABA coun e pa s did no lead o highly cohesi e ne wo ks e en a concen a ions o 30w %.69 pH- esponsi e gela o s. A numbe o pH- esponsi e gela o s ha e been p epa ed using e - ia y amine me hac yla e monome s, like DMA, poly(2-(die hylamino)e hyl me hac yla e) (PDEA) and poly(2-(diisop opylamino)e hyl me hac yla e) (DPA). A iblock wi h he s uc- u e poly(me hyl me hac yla e)-poly(2-dime hylamino)e hyl me hac yla e)-poly(me hyl me hac yla e) P(MMA32-DMA224-MMA32) o ms a ha d gel in sal ee aqueous solu ions o 1 w % a pH 4 whe e he amino g oup is p o ona ed. When he pH is inc eased he solu ion u ns in o a iscous luid because he p o ona ion o he PDMA chain dec eases and i s lex- ibili y inc eases. When he pH is dec eased below 4, he ionic s eng h o he solu ion in- c eases and leads o sc eening e ec s which cause a dec ease in iscosi y.75 In a di e en app oach, PDEA as well as PDPA we e used as esponsi e B blocks in BAB iblocks wi h a PMPC middle block. A 10 w % solu ion o PDPA-PMPC-PDPA o ms a liquid a pH 2 due o he p o ona ion o he amino g oups, bu gela ion occu s when he pH is inc eased o pH 7. The eason o his is he dep o ona ion o he DPA moie ies and he o ma ion o b idged “ lowe -like” micelles. To achie e compa able esul s wi h PDEA-PMPC-PDEA, he block leng h o he ou e pH esponsi e blocks had o be inc eased as well as a highe pH was needed. This is due o he less hyd ophobic cha ac e o he PDEA chains compa ed o he PDPA chains.76,77 The use o polyelec oly es as he cen al block su ounded by empe a u e sensi i e blocks in BAB iblock copolyme s leads o empe a u e and pH esponsi e hyd ogels. A double hyd ophilic iblock copolyme wi h a long PAA inne block and an ou e block o poly(N,N- die hylac ylamide) (PDEAAm) (LCST≈32 °C) o ms hyd ogels a physiological pH and 60 °C a concen a ions o 3 w %. Due o he high s e ching o he PAA block a his pH, b idging is Chap e 1 In oduc ion 13 a o ed o e looping, as can be seen in a high pla eau modulus and a low c i ical gela ion concen a ion (cgc). Bo h he con o ma ion o he inne block and he LCST o he ou e block a e sensi i e o ionic s eng h, adding ano he pa ame e ha can in luence he be- ha io o his sys em.78 Hyd ogels based on ABC iblock e polyme s. pH- and empe a u e-sensi i e sys ems de- signed a ound he ABC iblock e polyme concep ha e also been epo ed. Reinicke e .al. p epa ed ABC iblock e polyme s comp ised o P2VP-PEO-P(GME-co-EGE) blocks, wi h a pH-sensi i e block (poly(2- inylpy idine)), a hyd ophilic block (PEO) and a empe a u e- esponsi e poly(glycidyl me hyl e he -co-e hyl glycidyl e he ) copolyme block. The LCST o he las block can be easily con olled by he copolyme composi ion. A pH 7 and a concen- a ion o 18 w %, his block e polyme unde goes a gel-sol-gel ansi ion upon hea ing. A low empe a u es he gel is o med by a bcc packing o co e-shell-co ona micelles wi h a hyd ophobic P2VP co e, and a ele a ed empe a u es, he gel u ns in o a iscous liquid bu a 60 °C he gel s a e is es o ed because a ha empe a u e he P(GME-co-EGE) block be- comes insoluble and a ne wo k is o med h ough b idging. An addi ional gel s a e can be ound o pH 3 and high empe a u es, when only he P(GME-co-EGE) block is insoluble and again co e-shell-co ona micelles a e o med, his ime wi h a hyd ophobic P(GME-co-EGE) co e. The gel also esul s om micella jamming.79 The same g oup has p epa ed o he ABC sys ems wi h di e en he mo esponsi e C blocks, P2VP-PEO-PDMA and P2VP-PEO- P(DEGMA-co-OEGMA).80 The P2VP-PEO-P(DEGMA-co-OEGMA) sys em beha es simila o he P2VP-PEO-P(GME-co-EGE) sys em, as i unde goes a gel-sol-gel ansi ion a pH 7 wi h a concen a ion o 20 w %. The sys em wi h PDMA as he C block beha es di e en ly because o he dual- esponsi e na u e o he PDMA, i s LCST being s ongly dependen upon pH. Samples p epa ed a pH 8 showed a s ong gel a oom empe a u e and a gel-sol ansi ion upon hea ing, bu no second gel phase was ound, his is due o he elec os a ic epulsion be ween he micelles because o esidual p o ona ion o he DMA block. A pH 9 he e pol- yme o ms a weak gel a oom empe a u e, because he PDMA block is almos comple ely dep o ona ed and he e o e hyd ophobic. Upon inc easing he empe a u e, a gel-sol an- si ion is isible, ollowed e y quickly by ano he sol-gel ansi ion o a s ong gel abo e 32 °C. Chap e 1 In oduc ion 14 Hyd ogels based on (AB)x s a -shaped block copolyme s. The e is also a numbe o epo s o s a -shaped block copolyme s as gela o s. Li e .al. epo ed he syn hesis o h ee-a m s a copolyme s wi h inne blocks o PMPC and he ou e blocks composed o s a is ical co- polyme s o PDMA, PDEA and monome hoxy capped poly(poly(p opylene oxide) me hac y- la e) (PPOMA). (PMPC125-(PDMA50-co-PDEA50))3 o med ee-s anding hyd ogels a 37 °C a physiological pH and a concen a ion o 7 w %, while he inco po a ion o only 3 w % o hyd ophobic PPOMA lead o ee-s anding gels a 5 w % unde he same condi ions. In con- as , (PMPC125-PDPA100)3 o ms ee-s anding gels a 5 w %, bu only a 20 °C and pH 8.2.81 Lin e .al. epo ed on linea and s a -shaped block copolyme s o PEO and PNiPAAm and ound ha (PEO-PNiPAAm)4 showed a sol-gel ansi ion o a s ong gel a 37 °C and exhibi - ed he highes moduli compa ed o he o he polyme s.71 Fechle e .al. epo ed 4-a m s a s wi h PEO inne blocks and P(DEGMA-co-OEGMA) ou e blocks, which o med ully e e sible ee-s anding hyd ogels a 15 w % upon hea ing.69 All h ee g oups desc ibe ha he s a - shaped gela o s a e mo e e icien han hei linea coun e pa s. Pé ez e .al. epo ed hy- d ogels based on co alen ly linking a collagen-based pep ide o an 8-a m poly(e hylene gly- col) s a polyme . These polyme -pep ide conjuga es o med a hyd ogel a oom empe a- u e a a concen a ion o 4 w % and unde wen a e e sible gel-sol ansi ion upon hea ing abo e 50 °C, due o he dena u a ion and e olding o he collagen pep ide iple heilx.82 The e a e many mo e examples o hyd ogel o ma ion published, including a a ie y o o he s imuli, bu o he sake o b e i y hey ha e no been discussed he e. Fo u he in- o ma ion please e e o he ele an li e a u e.11,38-43,60-62 1.5. Objec i e o his hesis Since he e a e s ill many unsol ed p oblems in he ield o sma hyd ogels anging om syn hesis o cha ac e iza ion, he Ge man Science Founda ion in 2006 launched a p io i y p og am o de elop in elligen hyd ogels (SPP 1259), aimed a c ea ing new ways o syn he- size and cha ac e ize hese no el sys ems. This wo k was pa o a p ojec in he p io i y p og am wi h he in en o c ea e double e- sponsi e sys ems based on s a -shaped block copolyme s. The goal was o c ea e e icien Chap e 1 In oduc ion 15 gela o s, which would o m hyd ogels based on one igge whe e he gel s eng h would s ill espond independen ly o ano he igge . The ini ial design called o bo h blocks o he diblock copolyme a ms o he s a s o be double- esponsi e hemsel es. This s a egy was la e expanded o include one block ha was only esponsi e o empe a u e. These sys- ems we e syn hesized by ATRP and cha ac e ized in dilu e and concen a ed aqueous solu- ion o de e mine he pa ame e s which con ol hei gela ion beha io and gel s eng h. The ini ial monome s chosen we e DMA and DEA, because o ou knowledge o he double- esponsi e beha io o PDMA and because we suspec ed ha PDEA would beha e in a simi- la ma e . Due o he ac ha PDEA is mo e hyd ophobic han PDMA, we p edic ed ha he pH-dependen ansi ion empe a u es o PDEA would be consis en ly lowe han hose o PDMA, making i possible o igge hem independen ly. Chap e 1 In oduc ion 16 1.6. Re e ences 1. N. Dan and M. 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Colloid In e ace Sci., 2010, 158, 15-20. 58. D. Kuckling, A. Rich e and K.-F. A nd , Mac omol. Ma e . Eng., 2003, 288, 144-151. 59. J. A. Yoon, C. Gaya h i, R. R. Gil, T. Kowalewski and K. Ma yjaszewski, Mac omolecules, 2010, 43, 4791-4797. 60. J. Madsen and S. P. A mes, So Ma e , 2012, Ad ance A icle. 61. J.-F. Lu z, Ad . Ma e ., 2011, 23, 2237-2243. 62. C. Tsi silianis, So Ma e , 2010, 6, 2372-2388. 63. V. A. Kabano , A. B. Zezin, V. B. Rogache a, T. V. Pano a, E. V. Byko a, J. G. H. Joos en and J. B ackman, Fa aday Discuss., 2005, 128, 341-354. 64. A. B. Zezin, V. B. Rogache a and V. A. Kabano , J. In ell. Ma e . Sys . S uc ., 1994, 5, 144-146. Chap e 2 O e iew 25 he in luence o he inne hyd ophilic PDMA block. In bo h measu emen s only weak gels a e de ec ed o pH 8, e en a 20 w %. Howe e , a s ong ee-s anding gel is o med a pH 7 and 20 w % (Figu e 2.4c), illus a ing he in luence o pH on his sys em. This phenomenon is caused by he high cha ge densi y o he inne PDMA block, whose pKa alue is a ound 6.2, causing a s e ching o he PDMA block due o inc eased elec os a ic epulsion and he osmo ic p essu e o he coun e ions. An impo an di e ence be ween he measu emen s a pH 7 and pH 8 is he ac ha bo h moduli dec ease signi ican ly abo e 50 °C in he case o pH 8 and his beha io is no seen a pH 7. We a ibu e his o he inne PDMA blocks which s a o collapse abo e hei cloud poin o Tcl ≈ 50 °C a pH 8, leading o a weakening o he gel. A pH 7 he cloud poin o PDMA is abo e 80 °C and hus ou side ou measu emen ange. These indings suppo ou claim ha he block copolyme s a s can e e sibly o m hyd ogels ha a e able o change hei mechanical p ope ies because o he double- esponsi e na u e o he inne blocks. Chap e 2 O e iew 26 Figu e 2.4. Tempe a u e-dependen s o age (G') and loss (G'') moduli o a) a 15 w % solu ion o (DMA130DEA16)6 a pH 8, b) a 20 w % solu ion o (DMA130DEA16)6 a pH 8, c) a 20 w % solu ion o (DMA130DEA16)6 a pH 7 and d) a 10 w % solu ion o (DMA110DEA43)4 a pH 8. The block leng h o he ou e PDEA block also plays a signi ican ole in he p ope ies o he gels. When he block leng h is inc eased, he gel s eng h inc eases and he cgc dec eases (Figu e 2.4d). The sol-gel ansi ion empe a u e o (DMA110DEA43)4 is s ill highe han he cloud poin o PDEA, bu i is signi ican ly lowe han o (DMA130DEA16)6, which is due o he high mola ac ion o DEA. Chap e 2 O e iew 27 2.3 Sma hyd ogels based on dual esponsi e s a block copolyme s To ex end ou concep and possibly simpli y i , he decision was made o change he ou e block o ou diblock s a s o a polyme ha only esponds o a single s imulus, in ou case empe a u e. The iden ical PDMA homopolyme s a s as in he p e ious wo k we e em- ployed as p ecu so s and poly(die hylene glycol me hyl e he me hac yla e) was chosen as he empe a u e- esponsi e polyme . The syn he ic p o ocol had o be adjus ed sligh ly o compensa e o he new monome bu he syn hesis was ca ied ou success ully and p o- duced well de ined block copolyme s wi h a high blocking e iciency. Fou di e en diblock s a s we e syn hesized o in es iga e he pa ame e s ha con ol he gela ion beha io , (DMA150DEGMA40)4, (DMA150DEGMA100)4, (DMA130DEGMA60)6 and (DMA130DEGMA140)6. Based upon ou p e ious wo k we expec ed he beha io o he s a s o ollow he mechanism depic ed in scheme 2.1. Scheme 2.1. Agg ega ion and ne wo k o ma ion o dual- esponsi e s a block copolyme s in dependence o concen a ion and pH. Tu bidi y and DLS measu emen s we e used o in es iga e he beha io in dilu e aqueous solu ion. Bo h me hods e eal he double- esponsi e na u e o he s a block copolyme s. The collapse o he ou e block leads o he o ma ion o small lowe -like agg ega es (Rh,app ≈ 34 nm) ega dless o he solu ion pH. The inne block o PDMA on he o he hand is sensi i e o bo h empe a u e and pH, meaning ha a in e media e pH, e.g. pH = 7, PDMA is p o ona ed enough so i s cloud poin is e y high (≈ 80°C) and no second ansi ion is ob- Chap e 2 O e iew 28 se ed in ou expe imen al se up. A ele a ed pH on he o he hand, e.g. pH = 8, DMA is less p o ona ed and he cloud poin is dec eased (≈ 50°C) so ha an addi ional ansi ion is isi- ble in he measu emen s. This ansi ion is he collapse o he PDMA block and as a esul , la ge and la ge agg ega es a e o med and he polyme p ecipi a es wi h ime. Based on hese esul s, hyd ogel samples we e p epa ed a pH ≈ 8, o u ilize he second ansi ion o he block copolyme s a s o manipula e he mechanical p ope ies o he gels. These samples we e analyzed using ube-in e sion expe imen s and heology measu e- men s. The ube-in e sion e ealed ha only h ee o he s a s o med gels unde he condi- ions es ed. The s a wi h he lowes ac ion o DEGMA, (DMA150DEGMA40)4, does no o m gels a all. This sugges s ha a minimum ac ion o DEGMA, ƒDEGMA, exis s o success ully o m hyd ogels. The wo s a s wi h he nex highe ƒDEGMA o m s ong ee-s anding gels a concen a ions o 15 w % and he s a wi h he highes ƒDEGMA o ms gels a concen a ions as low as 10 w %. To ob ain a mo e de ailed pic u e, heology measu emen s we e pe - o med. Figu e 2.5 shows he empe a u e-dependen s o age (G') and loss (G'') moduli and an iso he mal equency sweep o he s a wi h he highes ƒDEGMA, (DMA130DEGMA140)6. Chap e 2 O e iew 29 Figu e 2.5. Tempe a u e-dependen s o age and loss moduli o (DMA130DEGMA140)6 a a concen a ion o a) 10 w % a a pH o 7.8, b) 15 w % a a pH o 8.0, c) 20 w % a a pH o 8.2 and d) an iso he mal equency sweep a 50 °C o he 10 w % sample. Inse s depic digi al pho og aphs o ube-in e sion expe imen s o he espec i e samples a 50 °C. The gels a all h ee concen a ions a e ee-s anding and s ong, as he pla eau alues o G' a e abo e 1 kPa and G' is highe han G'' o he whole equency ange measu ed in he equency sweep. Unexpec edly, he gels do no show any change in he moduli when he empe a u e is inc eased abo e 50 °C; we a ibu e his o he high gel s eng h, which can impede s uc u al changes. Howe e , when he samples a e p epa ed a highe pH alues, e.g. close o 9 he si ua ion changes. The inc ease in pH causes a dec ease in p o ona ion, which in u n leads o a dec ease in he e ec i e olume ac ion o he s a s and inally o a so ening o he gels. In addi ion, he ansi ion empe a u e o he PDMA block is lowe ed o a ound 30 °C, as seen o he cloud poin in u bidime y. A such pH alues, a change in bo h moduli can be obse ed o empe a u es abo e 35 °C o 40 °C, depending on he pol- yme concen a ion (Figu e 2.6). G' and G'' e en ually each a pla eau, because he PDMA block canno collapse comple ely since he polyme is al eady in he gel s a e. Chap e 2 O e iew 30 Figu e 2.6. Tempe a u e-dependen s o age and loss modulus o (DMA130DEGMA140)6 o concen a ions o a) 15 w % a a pH o 8.8 and b) 20 w % a a pH o 8.7. These esul s con i m ha ou mechanism is co ec e en hough he pH a which a dual- esponsi e gel exis s is highe han expec ed. To b oaden ou app oach e en mo e, he inne PDMA block was qua e nized and ans- o med in o a s ong polyca ion. The inc eased elec os a ic epulsion and he osmo ic p es- su e o he coun e ions cause a s e ching o he DMA chains, which leads o an inc ease o he e ec i e olume ac ion and o a signi ican educ ion o he c i ical gela ion concen a- ion. The qua e nized six-a m s a (qDMA130DEGMA140)6 o example o ms hyd ogels a concen a ion as low as 2 w %. Addi ionally, he qua e nized block can be u ilized o he inco po a ion o nanopa icles o he in oduc ion o ligh -sensi i i y h ough ligh -sensi e mul i alen coun e ions, gene a ing an LCST beha iou . In conclusion, ou concep o he o ma ion o sma hyd ogels based on dual- esponsi e s a -shaped block copolyme s has p o en o be mos ly co ec in p edic ing he beha io o he syn hesized s a s. This concep can hus be ex ended u he by eplacing PDMA and PDEGMA wi h o he polyme s ha a e esponsi e o one o mo e s imuli. Chap e 2 O e iew 31 2.4 Indi idual con ibu ions o join publica ions The esul s p esen ed in his hesis we e ob ained in collabo a ion wi h o he s and ha e been published o a e submi ed o publica ion as indica ed below. In he ollowing, he con ibu ions o all he coau ho s o he di e en publica ions a e speci ied. The as e isk deno es he co esponding au ho . Chap e 3 This wo k was published in Polyme 2010, 51, 1213-1217 unde he i le: “Double S imuli-Responsi e Beha io o Linea and S a -Shaped Poly(N,N- Die hylaminoe hyl me hac yla e) in Aqueous Solu ion” by Alexande Schmalz, Ma hias Hanisch, Holge Schmalz* and Axel H.E. Mülle * I conduc ed all he expe imen s and w o e he publica ion. Ma hias Hanisch was in ol ed in he syn hesis o he DEA polyme s. Holge Schmalz and Axel H.E. Mülle we e in ol ed in he discussions and he co ec ion o he manusc ip . Chap e 4 This wo k is accep ed by Z. Phys. Chem. unde he i le: “Double- esponsi e hyd ogels based on e ia y amine me hac yla e s a block copoly- me s” by Alexande Schmalz, Holge Schmalz* and Axel H.E. Mülle * Chap e 2 O e iew 32 I conduc ed all he expe imen s and w o e he manusc ip . Holge Schmalz and Axel H.E. Mülle we e in ol ed in he discussions and he co ec ion o he manusc ip . Chap e 5 This wo k is published in So Ma e , 2012, 8 (36), 9436-9445 unde he i le: “Sma Hyd ogels based on dual esponsi e s a block copolyme s” by Alexande Schmalz, Holge Schmalz* and Axel H.E. Mülle * I conduc ed all he expe imen s and w o e he manusc ip . Holge Schmalz and Axel H.E. Mülle we e in ol ed in he discussions and he co ec ion o he manusc ip . Chap e 3 Double S imuli-Responsi e Beha io 33 3 Double S imuli-Responsi e Beha io o Linea and S a -Shaped Poly(N,N-Die hylaminoe hyl Me hac yla e) in Aqueous Solu ion Alexande Schmalz, Ma hias Hanisch, Holge Schmalz*, Axel H. E. Mülle * Mak omolekula e Chemie II, Uni e si ä Bay eu h, D-95440 Bay eu h Chap e 3 Double S imuli-Responsi e Beha io 34 Abs ac We epo on he syn hesis and cha ac e iza ion o linea and s a -shaped poly(N,N- die hylaminoe hyl me hac yla e) (PDEA). The syn hesis was accomplished by A om T ans e Radical Polyme iza ion (ATRP) ia a co e- i s app oach using suga -based mul i unc ional ini ia o s. The in es iga ion o he solu ion p ope ies in wa e shows ha PDEA is bo h pH- and empe a u e- esponsi e, analogous o he beha io o poly(N,N-dime hylaminoe hyl me hac yla e) (PDMA). In li e a u e, PDEA is equen ly e e ed o as being only pH- sensi i e. The c i ical pH alues o he agg ega ion a e close o he appa en pKa alues in all cases, i.e. a high cha ge densi y is necessa y o keep he polyme s soluble. The cloud poin s show a s ong dependence on he pH alue o he solu ion bu no dependence on ei he molecula weigh o a chi ec u e. Thus, he wo polyme s di e only quan i a i ely as PDEA has cloud poin s abou 40 K lowe han PDMA and c i ical pH alues which a e 1.5 - 2 uni s lowe han PDMA. 3.1. In oduc ion S imuli- esponsi e polyme s ha e ecei ed much a en ion in he las yea s because o hei use in hyd ogels, ac ua o s, memb anes and o he applica ions [1-6]. The mos ex ensi ely s udied he mo- esponsi e polyme is poly(N-isop opylac ylamide) due o i s lowe c i ical solu ion empe a u e (LCST) a a ound 32 °C in wa e [7-9]. In he ield o pH esponsi eness a ypical polyme is poly(me hac ylic acid) [10]. Mo eo e , double s imuli-sensi i e polyme s a e o inc easing in e es , because some applica ions may equi e an independen esponse o se e al ac o s [11]. Since he numbe o double s imuli- esponsi e monome s is e y lim- i ed, a he mo-sensi i e monome is o en copolyme ized wi h a pH-sensi i e one, e.g., ac ylic acid, o ob ain a double s imuli- esponsi e polyme [12-14]. One class o p omising candida es as double s imuli- esponsi e monome s a e N,N- dialkylaminoe hyl me hac yla es. A well s udied example o his ype o polyme is poly(N,N- dime hylaminoe hyl me hac yla e) (PDMA), bu i has been used mos ly o i s he mo- esponsi eness [15-21]. Only ecen ly, he ocus has shi ed o i s esponsi eness o bo h pH and empe a u e [22-34]. Chap e 3 Double S imuli-Responsi e Beha io 41 To p o e he assump ion ha PDEA shows empe a u e- esponsi e beha io oo, he polyme was dissol ed in bu e solu ions o pH 6 and pH 7 (1 g/L), espec i ely. The samples we e hea ed om 20°C o 90°C a a a e o 1 K/min, and he changes in u bidi y we e measu ed. The cloud poin s, Tcl, we e de e mined using he onse me hod [33]. Figu e 3.2b shows he esul s o he empe a u e-dependen measu emen s. Fo bo h pH alues he cloud poin s do no show a signi ican dependence on molecula weigh and a - chi ec u e, i.e. a m numbe . Howe e , a clea dependence on pH can be de ec ed. The cloud poin s dec ease om a ound 70 °C o pH 6 o a ound 40 °C o pH 7. This is mos likely due o he cha ge densi y inside he s a s, as elec os a ic in e ac ions would p e en he agg e- ga ion o he polyme chains, and he cha ge densi y is highe o pH 6. This beha io ag ees well wi h esul s p e iously epo ed by ou g oup o PDMA [31, 33]. A compa ison o he pH dependen beha io be ween s a -shaped PDEA and PDMA (Figu e 3.3a) shows simila ends. The cloud poin o PDMA shows a sligh dependence on molecula weigh [33]. Howe e , his is only obse ed a high pH alues, i.e. lowe p o ona ion, which is inaccessi- ble o PDEA. A pH 7 he cloud poin s o PDMA a y be ween 77 °C and 80 °C, whe eas he alues o PDEA a e a ound 40 °C (Fig. 3.3b). This can be a ibu ed o he mo e hyd ophobic alkyl subs i uen s a he amino g oup o he epea ing uni . Fig. 3.3 a) Cloud poin s o linea and s a -shaped PDEA and PDMA in dependence o pH ( (DEAn)x;  DMA108;  (DMA100)3.1;  (DMA170)18), and b) cloud poin s plo ed agains molecula weigh o linea and s a -shaped PDEA () and PDMA () a pH 7. The lines a e only a guide o he eye. Re- sul s o PDMA aken om e e ence [33]. Chap e 3 Double S imuli-Responsi e Beha io 42 The measu emen s o PDMA we e pe o med a 0.1 g/L whe eas he measu emen s o PDEA we e pe o med a 1.0 g/L. The e is a concen a ion dependence o he cloud poin as we mo e along he bimodal, which has i s minimum in he LCST. Bu since he e ec is only in he o de o a ew Kel in in he ele an concen a ion ange [33], i is no discussed he e. Plampe e al. [33] we e able o measu e PDMA s a s in bu e solu ions o a pH up o 10 (Figu e 3.3a). This was impossible o PDEA because o he poo solubili y o a pH > 7. In ad- di ion, PDMA loses i s LCST below pH 7 (i.e. Tcl > 100 °C), whe eas PDEA s ill exhibi s a cloud poin a pH = 6. Unde iden ical condi ions, PDEA always shows lowe c i ical alues. A a gi en pH, e.g. pH 7, he cloud poin o PDEA is ca. 40 K lowe han ha o PDMA, and o high empe a u es, he c i ical pH alue o PDEA is 1.5 – 2 uni s below ha o PDMA. 3.4. Conclusions S a -shaped PDEA was success ully syn hesized by he co e- i s me hod employing ATRP. The ini ia o s and condi ions used esul ed in s a polyme s wi h a m numbe s anging om 3 o 8, and polydispe si y indices be ween 1.08 and 1.35. Ou expe imen s showed ha PDEA is a double s imuli- esponsi e polyme in con as o li e a u e, whe e i has only been desc ibed as pH-sensi i e. In ac , i esponds o bo h a ia ions in pH and empe a u e, jus like he analogous PDMA. Consequen ly, he di e ences be ween hese wo polyme s a e pu ely quan i a i e in na u e and no quali a i e, as hey only di e in he magni ude o hei c i ical alues. PDEA exhibi s a c i ical pH a which he p o ona ion o i s pendan ami- no g oups is no longe su icien o keep i soluble in wa e . A his pH he chains collapse and agg ega e. The empe a u e- esponsi e beha io o PDEA does no depend on molecu- la weigh o a chi ec u e, i.e. a m numbe . Howe e , he cloud poin does s ongly depend on pH, as i a ec s he o e all cha ge o he s a . Upon lowe ing he pH om 7 o 6 he cloud poin inc eased d ama ically om 40°C o 70°C. In compa ison o PDMA, all c i ical alues o PDEA a e lowe . The cloud poin s a a gi en pH lie 40 K below hose o PDMA, and he c i ical pH alues o PDEA a e 1.5 – 2 uni s lowe , ega dless o a chi ec u e o molecula weigh . Chap e 3 Double S imuli-Responsi e Beha io 43 Acknowledgemen s: We hank he Ge man Science Founda ion (DFG) o inancial suppo wi hin he P io i y P og am SPP 1259. Chap e 3 Double S imuli-Responsi e Beha io 44 3.5. Re e ences [1] Yu L, Ding J. Chem. Soc. Re . 2008;37:1473-1481. [2] Ha DS, Geh ke SH. J. Pha m. Sci. 2007;96:484-516. [3] Guen he M, Kuckling D, Co en C, Ge lach G, So be J, Suchaneck G, A nd KF. Sens. Ac ua- o s B 2007;126:97-106. [4] Cal e P, Pa a P, Duggal D. P oc. SPIE-In . Soc. Op . Eng. 2007;6524:M1-6. [5] Tachibana Y, Ku isawa M, Uyama H, Kakuchi T, Kobayashi S. Chem. Le . 2003;32:374-375. [6] Beebe DJ, Moo e JS, Baue JM, Yu Q, Liu RH, De adoss C, Jo B-H. Na u e 2000;404:588-590. [7] Kuckling D, Vo CD, Adle HJP, Völkel A, Cöl en H. Mac omolecules 2006;39:1585-1591. [8] Zhang X-Z, Zhuo R-X. Eu . Polym. J. 2000;36:643-645. [9] Pa k TG, Ho man AS. J. Polym. Sci., Pa A: Polym. Chem. 1992;30:505-507. [10] He H, Li L, Lee LJ. Polyme 2006;47:1612-1619. [11] Dong L-C, Ho man AS. J. Con olled Release 1991;15:141-152. [12] Xu F-J, Kang E-T, Neoh K-G. Bioma e ials 2006;27:2787-2797. [13] Bae SJ, Joo MK, Jeong Y, Kim SW, Lee WK, Sohn YS, Jeong B. Mac omolecules 2006;39:4873- 4879. [14] Lin HH, Cheng YL. Mac omolecules 2001;34:3710-3715. [15] Xia J, Johnson T, Gayno SG, Ma yjaszewski K, DeSimone J. Mac omolecules 1999;32:4802- 4805. [16] Zeng F, Shen Y, Zhu S, Pel on R. Mac omolecules 2000;33:1628-1635. [17] Fang Z, Kennedy JP. J. Polym. Sci., Pa A: Polym. Chem. 2002;40:3679-3691. [18] Lee Sang B, Russell Alan J, Ma yjaszewski K. Biomac omolecules 2003;4:1386-1393. [19] Zheng G, S oe e HDH. Mac omolecules 2003;36:7439-7445. Chap e 3 Double S imuli-Responsi e Beha io 45 [20] Mao B, Gan L-H, Gan Y-Y, Li X, Ra i P, Tam K-C. J. Polym. Sci., Pa A: Polym. Chem. 2004;42:5161-5169. [21] Lee H-I, Pie asik J, Ma yjaszewski K. Mac omolecules 2006;39:3914-3920. [22] Schache F, Müllne M, Schmalz H, Mülle AHE. Mac omol. Chem. Phys. 2009;210:256-262. [23] Schache F, Ulb ich M, Mülle AHE. Ad . Func . Ma e . 2009;19:1040-1045. [24] Huang J, Cusick B, Pie asik J, Wang L, Kowalewski T, Lin Q, Ma yjaszewski K. Langmui 2007;23:241-249. [25] Yamada K, Shibuya M, Takagi C, Hi a a M. J. Appl. Polym. Sci. 2006;99:381-391. [26] Teoh SK, Ra i P, Dai S, Tam KC. J. Phys. Chem. B 2005;109:4431-4438. [27] Lee SB, Russell AJ, Ma yjaszewski K. Biomac omolecules 2003;4:1386-1393. [28] Shen Y, Zeng F, Zhu S, Pel on R. Mac omolecules 2001;34:144-150. [29] Bü ün V, A mes SP, Billingham NC. Polyme 2001;42:5993-6008. [30] Plampe FA, Wal he A, Mülle AHE, Ballau M. Nano Le e s 2007;7:167-171. [31] Plampe FA, Schmalz A, Peno -Chang E, D echsle M, Jusu i A, Ballau M, Mülle AHE. Mac omolecules 2007;40:5689-5697. [32] Plampe FA, Schmalz A, Ballau M, Mülle AHE. J. Am. Chem. Soc. 2007;129:14538-14539. [33] Plampe FA, Ruppel M, Schmalz A, Bo iso O, Ballau M, Mülle AHE. Mac omolecules 2007;40:8361-8366. [34] Plampe FA, Mülle AHE, Ballau M. Polym. Ma e . Sci. Eng. 2007;96:799. [35] Ma Y, Tang Y, Billingham NC, A mes SP, Lewis AL. Biomac omolecules 2003;4:864-868. [36] Liu S, Wea e JVM, Tang Y, Billingham NC, A mes SP, T ibe K. Mac omolecules 2002;35:6121- 6131. [37] Mao BW, Gan LH, Gan YY, Tam KC, Tan OK. Polyme 2005;46:10045-10055. [38] He E, Ra i P, Tam KC. Langmui 2007;23:2382-2388. [39] Jiang X, Zhang G, Na ain R, Liu S. So Ma e 2009;5:1530-1538. Chap e 3 Double S imuli-Responsi e Beha io 46 [40] Shahalom S, Tong T, Emme S, Saunde s BR. Langmui 2006;22:8311-8317. [41] Yusa S-i, Sugaha a M, Endo T, Mo ishima Y. Langmui 2009;25:5258-5265. [42] Tunce Cayka a SK, Eylem Tu an. Polym. In . 2007;56:532-537. [43] Rusen E, Ma culescu B, Bu ac L, Zeche u T, Miculescu F, Ro a iu T. J. Op oelec on. Ad . Ma- e . 2008;10:3436-3441. [44] B ady C, Bell SEJ, Pa sons C, Go man SP, Jones DS, McCoy CP. J. Phys. Chem. B 2007;111:527- 534. [45] Plampe FA, Becke H, Lanzendö e M, Pa el M, Wi emann A, Ballau M, Mülle AHE. Mac omol. Chem. Phys. 2005;206:1813-1825. [46] Ma yjaszewski K, Shipp DA, Wang J-L, G imaud T, Pa en TE. Mac omolecules 1998;31:6836- 6840. [47] Zeng F, Shen Y, Zhu S. Mac omol. Rapid Commun. 2002;23:1113-1117. Chap e 4 Double Responsi e Hyd ogels 47 4 Double esponsi e hyd ogels based on e ia y amine me hac y- la e s a block copolyme s Alexande Schmalz, Holge Schmalz*, Axel H. E. Mülle * Mak omolekula e Chemie II, Uni e si ä Bay eu h, D-95440 Bay eu h Chap e 4 Double Responsi e Hyd ogels 48 Abs ac Double hyd ophilic s imuli- esponsi e s a block copolyme s wi h poly(2-(dime hylamino)e hyl me hac yla e) (PDMA) inne blocks and poly(2-(die hylamino)e hyl me hac yla e) (PDEA) ou e blocks we e syn hesized using ATRP. Di e en mul i unc ional ini ia o s based on suga sca olds we e employed in a co e- i s app oach wi h sequen ial polyme iza ion o bo h blocks yielding s a s wi h 4 and 6 a ms, espec i ely, and a ying leng h o he PDEA ou e block. The s a block copolyme s show pH- and empe a u e- esponsi e agg ega ion as e ealed by dynamic ligh sca e ing and u bidime y. The impac o pH, PDEA block leng h and a m numbe on he gela ion beha - io was in es iga ed by ube in e sion and heology. 4.1. In oduc ion ‘Sma ’ hyd ogels a e polyme ne wo ks ha ha e he abili y o o m/b eak o ex- pand/con ac in esponse o ex e nal s imuli. Sui able s imuli a e pH, empe a u e, ionic s eng h, ligh , o ex e nal magne ic and elec ic ields.1,2 The wo mos commonly applied s imuli a e empe a u e3 and pH.4 Responsi e hyd ogels ind widesp ead applica ions, e.g. in ime-con olled elease o ac i e compounds,5-7 issue enginee ing2,8-10 and mic o luidics.11 O e he las yea s he e has been g ea in e es in he mechanisms o gel o ma ion,2 shape-change o gels in esponse o an applied ield1 and he con olled disin e- g a ion o gels.12 The e a e wo classes o ne wo ks, chemically and physically c oss-linked ones. Chemically c oss-linked sys ems based on poly(N-isop opylac ylamide) (PNIPAAm) ha e been s udied mos ex ensi ely because o i s Lowe C i ical Solu ion Tempe a u e (LCST) a a ound 32 °C in wa e .13-15 The ad an age o physically c oss-linked ne wo ks is he e e sibili y o he gela ion p ocess, and he ac ha he ne wo k o ma ion i sel can be igge ed by ex e nal s imuli.2,4,7 Mos ly linea ABA16,17 and ABC18,19 iblock copolyme s, based on a hyd ophilic middle block B and s imuli- esponsi e ou e blocks A and C, we e used o cons uc physical gels. In addi ion, s a -shaped block copolyme s, (AB)x, wi h s imuli- esponsi e ou e blocks we e also used.20 Conside able wo k has been de o ed o s a s whe e he inne hyd ophilic Chap e 4 Double Responsi e Hyd ogels 49 block is poly(e hylene glycol) (PEG), wi h he mo- esponsi e ou e blocks o PNIPAAm, 21 poly(oligo(e hylene glycol) me hac yla e) (POEGMA)22, as well as s a s wi h biodeg adable ou e blocks o poly(lac ic acid) (PLA)23,24 o poly( ε -cap olac one) (PCL).24,25 Fo pH espon- si e s a block copolyme s P2VP was used as an in elligen block26 as well as di e en 2-(dialkylamino)e hyl me hac yla es such as poly(2-(dime hylamino)e hyl me hac yla e) (PDMA), poly(2-(die hylamino)e hyl me hac yla e) (PDEA) and poly(2-(diisop opyl)e hyl me hac yla e) (PDPA).27,28 Howe e , in s udies ela ed o s a -shaped block copolyme s hus a only he o ma ion/disin eg a ion o he ne wo k is subjec o ex e nal pa ame e s, as only he ou e blocks o he s a s we e s imuli esponsi e. Thus, he esul ing gels hem- sel es canno espond o a second, di e en s imulus. Ne e heless, i he inne blocks o he s a s would exhibi esponsi e beha io , oo, hen a second igge could possibly lead o addi ional in elligen beha io , such as sh inking. We ha e ecen ly shown ha linea and s a -shaped PDMA as well as PDEA homopolyme s a e esponsi e o bo h pH and empe a- u e.27-32 The cloud poin s o PDEA a e signi ican ly lowe han hose o PDMA a any pH alue. Thus, choosing he p ope condi ions i should be possible o igge a consecu i e collapse o PDEA and PDMA in espec i e block copolyme a chi ec u es. In his sec ion we p esen he syn hesis o double s imuli- esponsi e s a -shaped block copolyme s based on wo di e en 2-(dialkylamino)e hyl me hac yla e monome s, DMA and DEA. Scheme 4.1 illus a es he p oposed mechanism, by which ne wo k o ma ion o sel -assembly occu s depending on polyme concen a ion, simila o he model desc ibed by S epánek e al. and Tak ak e al.24,33 A low concen a ions, in amolecula collapse o agg ega ion o small micella agg ega es is a o ed and leads o he o ma ion o lowe -like micelles. A high concen a ions, on he o he hand, in e molecula collapse is p e e ed, esul ing in b idging be ween mul iple hyd ophobic domains and hus gela ion. He e, we ha e combined wo double esponsi e monome s o syn hesize double s imuli- esponsi e s a -shaped block copolyme s, which can e e sibly o m hyd ogels in dependence o pH and empe a u e. Chap e 4 Double Responsi e Hyd ogels 50 Scheme 4.1. Agg ega ion and ne wo k o ma ion o double esponsi e s a block copoly- me s Chap e 4 Double Responsi e Hyd ogels 57 can be a ibu ed o s e ic hind ance caused by he bulky na u e o he monome and he ela i e small size o he ini ia o . The de e mined ini ia ion e iciencies o he (PDMA-b- PDEA)x diblock copolyme s a s ange om 67% o 75%, which is consis en wi h p e ious wo k.29,30 Table 4.1. Molecula cha ac e is ics o he linea and s a -shaped diblock copolyme s and hei gela ion beha io block polyme a, b M n [10 3 g/mol] b PDIc DEA a m d gela ion beha io DMA143DEA40 29.9 1.19 0.22 --- (DMA150DEA12)4 104 1.11 0.07 no gela ion (DMA110DEA43) 4 102 1.16 0.28 ee-s anding gels (DMA130DEA16)6 142 1.27 0.11 ee-s anding gels a (DMAnDEAm)x: n and m deno e he numbe a e age deg ee o polyme iza ion o he blocks, and x is he numbe a e age a m numbe . b Calcula ed by compa ing he molecula weigh o he a ms ob ained by a m clea age wi h he heo e ical molecula weigh om con e - sion da a. c De e mined by DMAc-SEC applying a calib a ion wi h linea PMMA s anda ds. d Mola ac ion o DEA uni s pe a m. Agg ega ion in dilu e solu ion. The pH- and empe a u e-dependen solu ion beha io o he s a block copolyme s was in es iga ed by u bidime y and dynamic ligh sca e ing (DLS). P io in es iga ions (Figu e S4.2, Suppo ing In o ma ion p.71) showed ha a any gi en pH alue he cloud poin o PDEA homopolyme s a s is 30 – 40 K lowe han ha o PDMA s a s.29 This indica es ha he egion be ween pH 7 and pH 8 is in e es ing because he cloud poin s o bo h s a s a e in an accessible empe a u e ange, e.g., 40 °C o PDEA and 80 °C o PDMA a pH 7, and 20 °C o PDEA and 50 °C o PDMA a pH 8, espec i ely. Consequen ly, upon inc easing he empe a u e he PDEA ou e blocks o he (PDMA-b- PDEA)x diblock copolyme s a s a e expec ed o collapse i s and hus induce agg ega ion. Figu e 4.3 shows he cloud poin s (Tcl) o he diblock copolyme s a s a di e en pH al- ues. In analogy o he PDMA and PDEA homopolyme s a s29,30 (Figu e S4.2, Suppo ing In- o ma ion p.71) he cloud poin dec eases wi h inc easing pH, wi h cloud poin s anging Chap e 4 Double Responsi e Hyd ogels 58 om 80 °C a pH 7 o 30 °C a pH 10, espec i ely. No signi ican in luence o a m numbe , a m leng h and DEA con en on he cloud poin can be de ec ed. Fu he mo e, i espec i e o he lowe cloud poin expec ed o PDEA wi h espec o ha o PDMA a a gi en pH al- ue (Figu e S4.2, Suppo ing In o ma ion p.71), he obse ed alues a e e y close o ha o PDMA homopolyme s a s. This obse a ion can be explained by he ac ha he u bidi y senso used canno de ec he o ma ion o small micella agg ega es wi h sizes well below he wa eleng h o isible ligh , as his does no gi e ise o an inc eased u bidi y o he so- lu ion. Because o he low concen a ion o he solu ions and he low a e age deg ee o polyme iza ion o he PDEA ou e blocks wi h espec o ha o he PDMA inne blocks, ag- g ega ion o small micella agg ega es, i.e., lowe -like micelles, is a o ed o e in e molecu- la agg ega ion and co esponding b idging be ween micelles ha would gi e ise o la ge s uc u es and, hence, an inc ease in u bidi y (Scheme 4.1). As a esul , a signi ican in- c ease in u bidi y is obse ed only unde condi ions whe e he PDMA blocks also become insoluble and hus he diblock copolyme s a s collapse comple ely and o m la ge agg e- ga es. Figu e 4.3. pH-dependen cloud poin s o he syn hesized s a block copolyme s a c = 1 g/L () (DMA150DEA12)4, () (DMA110DEA43) 4 and () (DMA130DEA16)6. A close insigh in o he agg ega ion beha io o he (PDMA-b-PDEA)x diblock copolyme s a s in dilu e solu ion can be de i ed om dynamic ligh sca e ing (DLS) expe imen s (Fig- Chap e 4 Double Responsi e Hyd ogels 59 u e 4.4). The depic ed g aphs show he esul s o he (DMA130)6 homopolyme s a a pH = 7 and 8 (Figu es 4.4a,b) as well as o he s a block copolyme s (DMA130DEA16)6 and (DMA110DEA43)4 a pH = 7 (Figu es 4.4c,d). Fi s , he esul s o he PDMA homopolyme s a a e discussed. A pH = 7 he appa en hyd odynamic adius, Rh,app, o he PDMA s a dec eases sligh ly wi h empe a u e (Figu e 4.4a). This co esponds o he expec ed con ac ion o he s a a empe a u es well below i s cloud poin (Tcl = 80 °C a pH = 7). The collapse o he s a abo e i s cloud poin canno be de ec ed wi h he used equipmen as i is ou side o he accessible empe a u e ange. Howe e , a pH = 8 his ansi ion is shi ed o lowe empe a u es (Tcl ≈ 50 °C) and hus in- side he measu emen ange. The empe a u e-induced collapse and subsequen agg ega- ion o he PDMA s a is clea ly demons a ed by he sha p inc ease in Rh,app be ween 40 °C and 50 °C which is accompanied by a signi ican na owing o he size dis ibu ion (Figu e 4.4b). A simila beha io was epo ed o hyd ophobically modi ied PNIPAAm and PEG- g a ed PNIPAAm, oo.37 I is no ed, ha he pH = 8 sample becomes u bid unde hese condi ions, which d ama ically inc eases he p obabili y o mul iple sca e ing. Thus, he ob ained hyd odynamic adii and polydispe si y indices a e appa en alues as he DLS heo- y elies on single sca e ing. Chap e 4 Double Responsi e Hyd ogels 60 Figu e 4.4. Tempe a u e-dependen appa en hyd odynamic adii and polydispe si y indices de i ed om cumulan analysis o a) (DMA130)6 a pH = 7, b) (DMA130)6 a pH = 8, c) (DMA110DEA43)4 a pH = 7 and d) (DMA130DEA16)6 a pH = 7 (all measu emen s we e pe - o med a c = 1 g/L and θ = 90°). The lines a e guides o he eye. We now u n o he empe a u e-dependen agg ega ion beha io o he (PDMA-b-PDEA)x diblock copolyme s a s a pH = 7, i.e., unde condi ions whe e he inne PDMA blocks a e soluble o e he en i e in es iga ed empe a u e ange (Figu es 4c,d). I is no ed ha he size o he unimolecula ly dissol ed (DMA130DEA16)6 s a s is la ge wi h espec o ha o he (DMA110DEA43)4 s a s a pH = 7 and low empe a u es, i espec i e o he compa able o e all deg ee o polyme iza ion o he a ms in bo h s a s. This is a ibu ed o he highe block leng h o he PDMA inne block as well as he highe a m numbe in (DMA130DEA16)6. As he pKa o s a -shaped PDMA (pKa = 6.2)32 is abou 1 uni lowe compa ed o ha o PDEA (pKa ≈ 7 – 7.5)29 he PDMA block exhibi s a highe deg ee o p o ona ion a pH = 7, which esul s in a la ge Rh,app alue o he s a wi h he longe PDMA inne block. In addi ion, Chap e 4 Double Responsi e Hyd ogels 61 he highe a m numbe is supposed o inc ease he his e ec as elec os a ic epulsion be- ween posi i ely cha ged PDMA uni s and osmo ic p essu e o he coun e ions inc ease wi h he numbe .38,39 Bo h diblock copolyme s a s show a oughly 50% inc ease in Rh,app a abou 40 °C o 45 °C, which co esponds well o he cloud poin o he PDEA ou e blocks a pH = 7 (Tcl = 40 °C, Figu e S4.2, Suppo ing In o ma ion p.71). In addi ion, he polydispe si y index, PDI, dec eases subs an ially a he same ime as Rh,app inc eases. Consequen ly, he obse ed inc ease in Rh,app can be a ibu ed o he o ma ion o small lowe -like agg ega es consis ing o only a ew s a s, as depic ed in Scheme 4.1. This is consis en wi h he obse a- ions o o he diblock copolyme s a s epo ed in li e a u e.24,40 A empe a u es abo e 50 °C he size o he o med lowe -like micelles dec eases sligh ly indica ing a u he con- ac ion o he inne PDMA block, which is mos p onounced o (DMA110DEA43)4. This be- ha io co esponds well o ha obse ed o he PDMA homopolyme s a a pH = 7 (Fig- u e 4.4a) and indica es ha he block copolyme s a s a e ac ually double- esponsi e, i.e., he inne block is s ill esponsi e e en a e he collapse o he ou e block has been ig- ge ed. Angle-dependen DLS measu emen s p o ide u he e idence o he o ma ion o low- e -like micelles upon swi ching he PDEA ou e blocks insoluble. Figu e 5 displays he decay a e, Γ , in dependence on he squa ed sca e ing ec o , q2, o (DMA130DEA16)6 a 60 °C and pH = 7, i.e., he PDEA blocks a e expec ed o be comple ely collapsed while he inne PDMA blocks a e s ill soluble and a leas pa ly s e ched. The obse ed linea dependence poin s o a pu ely ansla ional di usion o he o med lowe -like agg ega es and may be aken as a u he indica ion o he assumed sphe ical shape o he agg ega es.41,42 Chap e 4 Double Responsi e Hyd ogels 62 Figu e 5. Decay a e s. squa ed sca e ing ec o o (DMA130DEA16)6 a pH = 7 and 60 °C. Tu bidime y and DLS measu emen s on dilu e solu ions o (PDMA-b-PDEA)x s a s ha e p o en ha he collapse o he PDEA ou e blocks can be igge ed independen ly om he PDMA blocks. This esul s in he o ma ion o small, lowe -like agg ega es a low concen a- ions. Consequen ly, hyd ogel o ma ion ia open associa ion is expec ed a highe concen- a ions when he PDEA blocks a e swi ched insoluble (Scheme 4.1). Tube-in e sion expe i- men s and heology measu emen s we e ca ied ou o s udy he gela ion beha io o he diblock copolyme s a s. To his end, aqueous solu ions wi h concen a ions anging om 10 o 20 w % we e p epa ed a pH alues o 7 and 8. All samples we e subjec ed o ube- in e sion expe imen s and wo we e u he in es iga ed by heology. Agg ega ion in concen a ed solu ion. Tube-in e sion expe imen s (Figu e S4.3, Suppo - ing In o ma ion p.71) e ealed ha a pH = 8 and 40 °C, i.e., a empe a u es well abo e he cloud poin o he PDEA ou e blocks (Tcl = 20 °C), (DMA110DEA43)4 shows gela ion al eady a 10 w %, whe eas o (DMA130DEA16)6 a highe concen a ion o abou 15 w % is necessa y. In con as , (DMA150DEA12)4 shows no gela ion wi hin he in es iga ed concen a ion and empe a u e ange. This sugges s ha i espec i e o he a m numbe a minimum PDEA block leng h o mola a io o DEA epea ing uni s is necessa y o o m a hyd ogel (Table 4.1). Mo eo e , inc easing he DEA mola ac ion while keeping he DMA block leng h con- s an , like o (DMA130DEA16)6 and (DMA110DEA43)4, esul s in a shi o he c i ical gela ion Chap e 4 Double Responsi e Hyd ogels 63 concen a ion o lowe alues. A pH = 7 he sol-gel ansi ion o a 20 w % solu ion o (DMA130DEA16)6 is shi ed o highe empe a u es (ca. 50 °C) as compa ed o pH = 8, which is easonable as he cloud poin o PDEA is shi ed o highe empe a u es (Tcl = 40 °C), oo. When samples we e p epa ed a pH > 8 he solu ions gelled a ound o e en below oom empe a u e. To deduce mo e de ailed in o ma ion on he gela ion beha io o concen a ed (DMA130DEA16)6 and (DMA110DEA43)4 solu ions, he samples we e subjec ed o oscilla o y shea using a cone-pla e shea cell geome y (Figu e 4.6). Regimes, whe e he s o age mod- ulus, G', exceeds he loss modulus, G", a e de ined as he gel s a e wi h espec o common de ini ions, and G' > 1 kPa is aken as a cha ac e is ic alue o s ong, ee-s anding gels.43-45 Sol s a es, on he o he hand, a e cha ac e ized by G" > G'. We mainly ocused on solu ions a pH = 8, as he cloud poin s o bo h PDMA and PDEA lie wi hin he accessible empe a u e ange and hus allow us o p obe no only he sol-gel ansi ion bu also he in luence o he esponsi e PDMA inne block on he mechanical p ope ies o he hyd ogels. Chap e 4 Double Responsi e Hyd ogels 64 Figu e 4.6. Tempe a u e-dependen s o age (G') and loss (G'') moduli o a) a 15 w % solu- ion o (DMA130DEA16)6 a pH 8, b) a 20 w % solu ion o (DMA130DEA16)6 a pH 8, c) a 20 w % solu ion o (DMA130DEA16)6 a pH 7 and d) a 10 w % solu ion o (DMA110DEA43)4 a pH 8. Figu e 4.6a shows he empe a u e-dependen s o age and loss modulus o a 15 w % so- lu ion o (DMA130DEA16)6 a pH = 8, i.e., he lowes concen a ion o which gela ion was obse ed in he ube-in e sion expe imen s. A empe a u es well below 20 °C he loss modulus exceeds he s o age modulus which is consis en wi h he solu ion being in he sol s a e. This is he expec ed beha io , as a pH = 8 he cloud poin s o bo h PDMA and PDEA a e highe o equal o 20 °C, espec i ely (Figu e S4.2, Suppo ing In o ma ion p.71). Upon hea ing, bo h moduli inc ease wi h empe a u e un il a 35 °C a c oss-o e o he G' and G'' aces is obse ed, which is linked o he sol-gel ansi ion. Howe e , he maximum G' alue in he gel s a e (T > 35 °C) is only abou 100 Pa, showing ha a 15 w % ela i ely so gels a e o med. A 20 w % and pH = 8, he sol-gel ansi ion is shi ed o lowe empe a u es Chap e 4 Double Responsi e Hyd ogels 65 (Tsg = 27 °C) and he gel s eng h is sligh ly inc eased, wi h maximum G' alues o abou 400 Pa (Figu e 4.6b). The o ma ion o a s onge gel is a ibu ed o he highe concen a- ion o he solu ion, which in u n esul s in an inc eased numbe o physical c osslinking poin s. Fo bo h solu ions he sol-gel ansi ion empe a u es a e signi ican ly highe han he cloud poin o he PDEA ou e blocks a pH = 8 (Tcl = 20 °C). This can be explained by he in luence o he pola PDMA inne blocks which cause a shi o he PDEA cloud poin o highe empe a u es, a common phenomenon ha has been obse ed in p e ious s udies, oo.18,46 The de ec ed dec ease o Tsg wi h concen a ion migh be linked o he concen a- ion dependence o he PDEA cloud poin , i.e., he cloud poin dec eases wi h concen a ion as we mo e along he binodal which has i s minimum in he LCST. Figu e 4.6c shows a 20 w % solu ion o (DMA130DEA16)6 a pH = 7. He e, he c oss-o e o he G' and G'' aces occu s a 44 °C and a s ong ee-s anding gel wi h G' ≈ 4 kPa is o med. In consis ency wi h he inc eased cloud poin o he PDEA blocks a pH = 7 (Tcl = 40 °C), he sol-gel ansi ion is shi ed o highe empe a u es as compa ed o ha o he sample a pH = 8 (Figu e 4.6b). This esul is in ag eemen wi h he ube-in e sion expe imen s. The signi ican ly inc eased gel s eng h o he sample a pH = 7 wi h espec o ha a pH = 8 a iden ical concen a ion is a ibu ed o he highe cha ge densi y o he inne PDMA blocks a pH = 7 (pKa(PDMA) ≈ 6.2).31,32 This, in u n, esul s in an enhanced s e ching o he PDMA chains due o elec os a ic epulsion and he osmo ic p essu e o he bound coun e ions,38,39 and hus in an inc eased e ec i e olume ac ion o he (DMA130DEA16)6 diblock copolyme s a s. Bo h measu emen s on concen a ed (DMA130DEA16)6 solu ions a pH = 8 e eal, ha he s o age modulus in he gel s a e i s inc eases un il abou 50 °C and hen dec eases again a highe empe a u es (Figu es 4.6a,b). We a ibu e his o he inne PDMA blocks, which s a o collapse a empe a u es abo e hei espec i e cloud poin o Tcl ≈ 50 °C a pH = 8, (Figu e S4.2, Suppo ing In o ma ion p.71), esul ing in a weakening o he gels due o pa ial syne esis. In con as , no signi ican dec ease o he modulus was obse ed in he measu emen a pH = 7 (Figu e 4.6c), whe e he cloud poin o he PDMA blocks is a ound 80 °C and hus signi ican ly highe han he applied measu emen ange. This suppo s ou assump ion d awn om he DLS da a abou he double esponsi e na u e o he (PDMA-b-PDEA)x diblock copolyme s a s and, hence, o he co esponding hyd ogels. Consequen ly, gela ion can be igge ed by selec i ely swi ching he PDEA ou e blocks in- Chap e 4 Double Responsi e Hyd ogels 66 soluble, whe eas he mechanical p ope ies o he hyd ogels migh be u he uned u ilizing he esponsi e na u e o he PDMA inne blocks. Figu e 4.6d depic s he dynamic moduli o a 10 w % solu ion o (DMA110DEA43)4 a pH = 8 in dependence o empe a u e. This sample exhibi s a sol-gel ansi ion empe a u e a Tsg = 31 °C and he s o age modulus in he gel phase exceeds he limi o 1 kPa o s ong ee-s anding gels a su icien ly high empe a u es (T > 55 °C). Again, he sol-gel ansi ion empe a u e is highe han he cloud poin o he PDEA ou e blocks (Tcl = 20 °C). Howe e , i is s ill signi ican ly lowe han he sol-gel ansi ion obse ed o he 15 w % solu ion o (DMA130DEA16)6 (Tsg = 35 °C), i espec i e o he lowe concen a ion. This is a ibu ed o he ac ha he block leng h o he PDEA ou e blocks o (DMA110DEA43)4 is highe by a ac o o abou 3 wi h espec o (DMA130DEA16)6, while he PDMA block leng h is almos iden ical. Thus, he mola DEA ac ion (Table 4.1) is conside ably highe , which p esumably educes he in luence o he pola PDMA block on he cloud poin o PDEA. Mo eo e , G' exhibi s only a weak dependence on equency in he gel s a e a 60 °C and exceeds G'' o e he whole in es iga ed equency ange (10-2 – 102 Hz) wi h alues >1 kPa, showing he ex- is ence o a s ong ee-s anding gel o e a b oad equency ange (Figu e S4.4, Suppo ing In o ma ion p.72). In addi ion, he hyd ogel o med by (DMA110DEA43)4 (Figu e 4.6d) is signi - ican ly s onge han hose based on (DMA130DEA16)6 (Figu es 4.6a,b) a iden ical pH, despi e he lowe concen a ion used o (DMA110DEA43)4. This migh be a ibu ed o he inc eased PDEA block leng h, as a simila dependence on he block leng h o he esponsi e block was obse ed o hyd ogels based on iblock e polyme micelles wi h a he mo- esponsi e co- ona, oo.18,19 4.4. Conclusion Bo h blocks o he s a -shaped block copolyme s (DMA-DEA)x a e esponsi e o pH and empe a u e, as mani es ed by a s ong pH dependence o he espec i e cloud poin s. The collapse o he PDEA ou e blocks can be selec i ely igge ed i s upon hea ing. This is due o he signi ican ly lowe cloud poin o PDEA wi h espec o ha o PDMA a iden ical pH. Tu bidime y and angle-dependen DLS da a poin o he o ma ion o lowe -like micelles wi h a collapsed PDEA co e and a soluble PDMA co ona a empe a u es abo e he cloud Chap e 5 Sma Hyd ogels 73 5 Sma Hyd ogels Based on Responsi e S a -Block Copolyme s Alexande Schmalz, Holge Schmalz*, Axel H. E. Mülle * Mak omolekula e Chemie II, Uni e si ä Bay eu h, D-95440 Bay eu h Chap e 5 Sma Hyd ogels 74 Abs ac A se ies o sma hyd ogels based on dual esponsi e s a block copolyme s esponding o pH and empe a u e we e p epa ed ia a om ans e adical polyme iza ion (ATRP) employ- ing he co e- i s me hod. They consis o poly(2-(dime hylamino)e hyl me hac yla e) (PDMA) inne blocks and ou e blocks comp ised o poly(die hylene glycol me hyl e he me hac yla e) (PDEGMA). The agg ega ion beha io o hese block copolyme s a s is ana- lyzed depending on block leng h and a m numbe . The dual esponsi eness o he s a s is demons a ed by u bime y as well as dynamic ligh sca e ing in dilu e aqueous solu ion, and he gela ion beha io o concen a ed aqueous solu ions is s udied by heology. Abo e he ansi ion empe a u e o he PDEGMA ou e blocks he s a s o m lowe -like agg e- ga es in dilu e solu ion o ee-s anding gels a highe concen a ions. When he empe a- u e is inc eased u he abo e he ansi ion empe a u e o he PDMA inne block, he agg ega es s a o con ac and a weakening o he gels was obse ed o so gels, whe eas o s ong gels no in luence on he moduli was de ec ed. The beha io is con olled by bo h concen a ion and pH alue. In addi ion, we show ha he minimum polyme concen a ion o gel o ma ion can be lowe ed by qua e nizing he inne block o he s a s, bu a second esponse o s imuli is los du ing he p ocedu e. 5.1. In oduc ion Hyd ogels a e h ee-dimensional hyd ophilic ne wo ks ha can bind a la ge amoun o wa- e o biological luid.1,2 S imuli esponsi e hyd ogels, i.e.hyd ogels esponding wi h a la ge p ope y change on small a ia ions in hei physical and/o chemical en i onmen , ha e ga he ed much in e es o hei use as bioma e ials, wi h applica ions such as con olled d ug elease, cell ca ie s and issue enginee ing.1-5 In gene al, hyd ogels can be classi ied in o wo ca ego ies depending on hei c oss-linking me hod: chemical o physical. The ne - wo k is usually buil o wa e -soluble mac omolecula chains connec ed ei he h ough pe manen co alen bonds (chemical c oss-linking) o h ough empo a y junc ion poin s (physical c oss-linking). Chemically c osslinked gels can consis o wa e -soluble polyme s o o polyme s ha espond o ex e nal s imuli such as empe a u e o pH. Hyd ogels based on Chap e 5 Sma Hyd ogels 75 c osslinked poly(N-isop opylac ylamide) (PNiPAAm) ha e been s udied ex ensi ely because i s lowe c i ical solu ion empe a u e ( LCST ) is a ound 32°C in wa e , making i a p omising candida e o biomedical applica ions.6-10 Physical gels ypically consis o block copolyme s whe e he s imuli esponsi e blocks a e used o o m he empo a y c osslinking poin s, i.e. swi ching i insoluble by inc easing i s hyd ophobic in e ac ions. This can be based on a a i- e y o igge s, such as empe a u e, pH, ligh , edox eac ions o hos -gues in e ac ions.11,12 One eason ha much a en ion is being paid o physical hyd ogels is be- cause o hei po en ial o biomedical applica ions, e.g. injec able hyd ogels o d ug deli - e y o issue enginee ing.13 Howe e , in mos physical hyd ogels he “sma ” componen is only esponsible o he o ma ion/disin eg a ion o he gel, mos commonly seen in he o m o ABA iblock copolyme s whe e he B block only p o ides solubili y.14,15 The easies way o in oduce dual esponsi eness is o copolyme ize he mo-sensi i e monome s wi h monome s ha a e also sensi i e o o he igge s. This can be achie ed by a andom copol- yme iza ion wi h a pH- esponsi e monome like ac ylic acid16,17 bu ad ances in syn he ic p o ocols ha e led o mo e e o s in o block- ype s uc u es. Un il now only a limi ed num- be o double empe a u e-sensi i e ABC iblock e polyme s ha e been syn hesized,18,19 as well as dual empe a u e- and pH-sensi i e ABA diblock copolyme s20-22 and ABC iblock e polyme s.23 The same ad ances in syn hesis ha e also opened he way o a mo e com- ple e con ol o e he polyme a chi ec u e, leading o inc eased in e es in e.g. s a -shaped polyme s. Recen publica ions indica e ha a s a -shaped gela o is supe io o i s linea iblock coun e pa , i.e. hey ha e a lowe c i ical gela ion concen a ion (cgc).24,25 Howe - e , up un il now he e ha e been no epo s o double esponsi e gels based on s a poly- me s excep ou own e o s in ha a ea.26 Ou g oup has shown ha linea and s a -shaped poly(2-(dime hylamino)e hyl me hac y- la e) (PDMA) as well as poly(2-(die hylamino)e hyl me hac yla e) (PDEA) homopolyme s a e esponsi e o bo h pH and empe a u e.27-29 We ha e ecen ly made a i s a emp o c e- a e hyd ogels om s a -shaped block copolyme s (AnBm)x, in which he A block is PDMA and he B block is comp ised o PDEA. Howe e , he gela ion beha io u ned ou o be e y complex, due o he double esponsi e na u e o bo h blocks. Thus, we decided o eplace Chap e 5 Sma Hyd ogels 76 he ou e block o he (AnBm)x s a block copolyme s wi h a polyme ha is esponsi e o empe a u e only. Recen ly, mo e and mo e a en ion has been gi en o a new class o he mo- esponsi e pol- yme s, he poly(oligo(e hylene glycol) me hyl e he me hac yla e)s (POEGMAs). By copoly- me izing di e en OEGMAs, i.e. me hac yla es wi h di e en numbe s o e hylene glycol uni s in he side chain, such as die hylene glycol me hyl e he me hac yla e (DEGMA) and OEGMA wi h 8.5 e hylene glycol uni s, he cloud poin o he copolyme can be uned ac- co ding o he mola a io o he wo monome s be ween 26 °C o pu e PDEGMA and 90 °C o pu e POEGMA.30-32 These polyme s ha e p o en o be e y e sa ile and ha e been ap- plied in senso s33, polyme -p o ein conjuga es34, pho o c osslinkable polyme s35 and he modi ica ion o na u al polyme s.36 The e ha e al eady been e o s o di ec ly c ea e chem- ically c oss-linked gels om PDEGMA37,38 as well as using PDEGMA and PDMA as s imuli e- sponsi e blocks in combina ion wi h o he monome s. PDMA-PDEGMA-PDMA block copol- yme s39 ha e been epo ed as well as double- esponsi e ABC iblock e polyme s whe e he C block was ei he P(DEGMA-co-OEGMA) o PDMA.40 The e has also been wo k pub- lished on s a -shaped gela o s wi h PDMA as he esponsi e ou e block.41 In his pape we combine hese app oaches o c ea e new hyd ogels based on s a -shaped block copolyme s consis ing o an ou e block o he mo- esponsi e PDEGMA and an inne block o he mo- and pH- esponsi e PDMA. We p opose ha gel o ma ion akes place ac- co ding o an open associa ion mechanism, wi h a sequen ial collapse o he blocks s a ing om he ou side upon an inc ease in empe a u e. The collapse o he inne PDMA block is con olled by he pH alue o he solu ion, i.e. he gel can change i s mechanical p ope ies depending on pH. This mechanism is illus a ed in Scheme 5.1. Ano he possibili y o u ilize he PDMA block is qua e niza ion o u n he inne block in o a pe manen ca ionic polyelec- oly e. This should lead o an inc ease in hyd ophilici y along wi h a s e ching o he inne block, i.e. an inc eased olume ac ion o he s a s in solu ion, and elimina e he pH- esponsi eness. Chap e 5 Sma Hyd ogels 77 Scheme 5.1. Agg ega ion and ne wo k o ma ion o dual esponsi e s a block copolyme s in de- pendence on concen a ion. 5.2. Expe imen al Ma e ials. E hyl 2-b omoisobu y a e, N,N,N',N'',N''',N'''-hexame hyl ie hylene e amine (HMTETA), coppe (I) chlo ide, 1,3,5- ioxane, iodome hane, and ime hylsilyldiazome hane we e pu chased om Ald ich and used wi hou u he pu i ica ion. The sol en s used we e o p.a. quali y. The monome s 2-(dime hylamino)e hyl me hac yla e (98%, Ald ich) and di- e hylene glycol me hyl e he me hac yla e (95%, Ald ich) we e des abilized be o e use by passing h ough a basic alumina column. The syn hesis o he suga -based ini ia o s wi h 5 and 8 2-b omoisobu y yl ini ia ion si es, based on glucose and saccha ose, espec i ely, is desc ibed in a p e ious publica ion.42 Fo dialysis, egene a ed cellulose memb anes (ZelluT ans wi h MWCO 4000-6000) we e used. Syn hesis o s a shaped block copolyme s. The iden ical PDMA p ecu so s a s we e used as in ou p e ious wo k, which we e syn hesized by ATRP wi h suga -based ini ia o s.26 Fo he second block he same p ocedu e was applied, excep ha ace oni ile was used as he sol en ins ead o anisole. The change o he sol en was necessa y o achie e a high blocking e iciency In a ypical eac ion 2 g o he 4-a m s a PDMA mac oini ia o (~ 0.084 mmol ini ia ion si es), 4.7 g o he monome die hylene glycol me hyl e he me hac y- la e (0.025 mol), 16.6 mg Cu(I)Cl (0.168 mmol), 38.7 mg HMTETA (0.168 mmol) and ace oni- ile (31.2 g) as sol en we e used. The ca alys complex solu ion was pumped in o he eac- Chap e 5 Sma Hyd ogels 78 ion essel, a sc ew cap ial equipped wi h a ubbe sep um, using a double- ipped me al needle wi h abou 0.5 ba o ni ogen p essu e o a oid con ac wi h ai . The polyme iza- ions we e ca ied ou a 50 °C. All eac ions o he second block we e pe o med using a ixed a io be ween monome , ini ia ion si es, ca alys and ligand o [M]0:[I]0:[Ca ]:[L]=100:1:2:2 a [M]0 ~ 0.063 mol/L. The a ms o he esul ing PDMA-b-PDEGMA s a block copolyme s we e clea ed o by an alkaline es e hyd olysis a ele a ed empe a u es, using a p ocedu e adap ed om Plampe e .al.27 To ci cum en he pH independen LCST o he PDEGMA block in wa e , a me hod in a non-aqueous sol en was chosen. The clea ing eac ion was ca ied ou in a 1M po assium hyd oxide solu ion in me hanol (1M KOH in MeOH) a 70 °C. The p oduc o his eac ion o bo h he PDMA and he PDEGMA block is poly(me hac ylic acid) (PMAA), as he pendan ou e g oups ge hyd olyzed unde he applied condi ions. The ob ained PMAA was ans- o med o poly(me hyl me hac yla e) (PMMA) using ime hylsilyldiazome hane o acili a e molecula cha ac e iza ion. The ac ual a m numbe o he p ecu so PDMA s a s was calcu- la ed by compa ing he heo e ical a m leng h, ob ained om con e sion, wi h he expe i- men al Mn o he clea ed a ms ob ained om MALDI-ToF. The block leng h o he PDEGMA block was calcula ed om NMR measu emen s by compa ing he signal o he me hoxy g oup o DEGMA wi h he signal o he dime hylamino g oup o DMA. The clea ed-o a ms o he block copolyme s a s we e used o con i m he blocking e iciency as being close o uni y. The qua e niza ion o he PDMA block o he s a block copolyme s was ca ied ou in a 0.5% w/w solu ion o ace one. Iodome hane was used as he qua e niza ion agen , wi h a 1.5 old excess compa ed o amino g oups. The eac ion was s i ed o e nigh a oom em- pe a u e and he p ecipi a ed p oduc was cen i uged o and washed h ee imes wi h pu e ace one. 1H-NMR spec oscopy. All measu emen s we e pe o med wi h a B uke A ance 300 spec- ome e using deu e a ed chlo o o m o deu e ium oxide as sol en . MALDI-ToF Mass Spec ome y. MALDI-ToF-MS measu emen s we e pe o med on a B uke Dal onics Re lex III ins umen equipped wi h an N2 Lase (337 nm) and an accele a- Chap e 5 Sma Hyd ogels 79 ion ol age o 20 kV in posi i e mode. Sample p epa a ion was done acco ding o he “d ied-d ople ” me hod. In de ail, ma ix ( ans-3-indoleac ylic acid, IAA, conc. 2 mg / mL), analy e (conc. 10 mg / mL) we e sepa a ely dissol ed in THF, subsequen ly mixed in a a io o 20 : 5 µL. 1.5 µL o he inal mix u e was applied o he a ge spo and le o d y unde ai . Size Exclusion Ch oma og aphy (SEC). The appa en molecula weigh dis ibu ions o he s a shaped homo- and copolyme s we e de e mined by SEC using dime hylace amide (DMAc) wi h 0.05% li hium b omide as eluen a a low a e o 0.8 mL/min. The equipmen consis ed o one p e-column and wo analy ical columns (PSS GRAM, 102 and 103 Å po e size, 7 µm pa icle size) and an Agilen 1200 RI de ec o . The measu emen s we e pe - o med a 60 °C. The PMMA samples ob ained om he a m clea age we e analyzed using a THF-SEC wi h a low a e o 1 mL/min. This se up was equipped wi h one p e-column, ou analy ical col- umns (PSS SDV, 102, 103, 104 and 105 Å po e size, 5 µm pa icle size) and a Shodex 101 RI de ec o . The measu emen s we e pe o med a 40 °C. Fo da a e alua ion a calib a ion wi h linea PMMA s anda ds was used in all cases. Cloud Poin Measu emen s. The empe a u e-dependen solu ion beha io was in es iga - ed using a i a o (Ti ando 809, Me ohm) equipped wi h a u bidi y p obe (Spec osense, Me ohm, λ 0 = 523 nm) and a empe a u e senso (P 1000, Me ohm). The cloud poin s (Tcl) we e de e mined by dissol ing 30 mg o polyme in 30 ml o bu e solu ions anging om pH 7 o pH 9 (NIST bu e , Ti ino m VWR). The solu ions we e degassed by applying acuum (50-100 mba ) o 15 min a oom empe a u e in o de o minimize bubble o ma ion du - ing he expe imen s. The measu emen s we e pe o med using a homemade he mos a a- ble essel and o he expe imen s a cons an hea ing a e o 1 K/min was applied using a he mos a (Lauda Ecoline S a edi ion RE 306, +/- 0.01°C). The cloud poin s we e de e - mined om he in e sec ion o he wo angen s applied o he wo linea egimes o he ansmi ance cu e a he onse o u bidi y. Dynamic Ligh Sca e ing. DLS was pe o med on an ALV DLS/SLS-SP 5022F compac goni- ome e sys em wi h an ALV 5000/E c oss-co ela o and a HeNe lase ( λ 0 = 632.8 nm). The Chap e 5 Sma Hyd ogels 80 solu ions we e p epa ed by dissol ing 2 mg o polyme in 2 ml o bu e solu ion o ei he pH 7 o 8 (NIST bu e , Ti ino m, VWR) and il e ed p io o he measu emen s wi h 0.45 µm sy inge il e s (cellulose ace a e, Ro h). Fo empe a u e-dependen measu emen s, he decaline ba h o he ins umen was he mos a ed using a LAUDA P oline RP 845 he mo- s a . A each empe a u e he sample was equilib a ed o 10 min p io o da a acquisi ion, which was done i e imes o he du a ion o 60 sec each. The au oco ela ion unc ions we e eco ded indi idually and e alua ed using 2nd o de cumulan analysis. Rheology. Rheology measu emen s we e conduc ed using a Physica MCR 301 heome e wi h a cone-and-pla e shea cell geome y (D = 50 mm, cone angle = 1°). Fo he empe a- u e-dependen measu emen s a equency o 1 Hz, a hea ing a e o 0.5 K/min and a s ain o 0.5%, which is inside he linea iscoelas ic egime, we e applied. The empe a u e was con olled by a Pel ie elemen . Fo he iso he mal equency sweeps (10-2 o 102 Hz) he desi ed empe a u e was adjus ed by hea ing he sample a a a e o 0.5 K/min. The samples we e p epa ed using a Di abis Cooling-The momixe MKR13. The polyme s we e di ec ly dissol ed in wa e a di e en low pH alues, i.e., pH = 2 o 3, o p oduce solu ions wi h inal pH alues o pH = 7 o 8, espec i ely. This p ocedu e a oids addi ional pH adjus men s a e sample p epa a ion, which would esul in sal (NaCl) o ma ion and consequen ly migh in luence he solu ion beha io o he polyelec oly e blocks. The samples we e shaken in he MKR13 a 10 °C o se e al hou s up o se e al days un il he polyme was comple ely dissol ed, and subsequen ly s o ed a 3 °C un il use. Mic o Di e en ial Scanning Calo ime y (µ-DSC). The calo ic measu emen s we e pe - o med wi h a Se a am µ-DSC III using closed “ba ch” cells a a scanning a e o 0.5 K min-1. Millipo e wa e was used as he e e ence subs ance. 5.3. Resul s and Discussion Syn hesis and molecula cha ac e iza ion o s a block copolyme s. We ha e syn hesized s a -shaped block copolyme s consis ing o a poly(2-(dime hylamino)e hyl me hac yla e) (PDMA) inne block and a poly(die hylene glycol me hyl e he me hac yla e) (PDEGMA) ou - e block. The syn hesis was ca ied ou wi h sligh modi ica ions acco ding o a p e iously Chap e 5 Sma Hyd ogels 81 published p o ocol employing ATRP wi h halogen exchange and subsequen monome addi- ion. A g a ing- om app oach wi h unc ionalized suga moie ies was used.26 This syn he ic ou e is shown in Scheme 5.2. The syn he ic p o ocol was es ed using a mono unc ional ATRP ini ia o , e hyl 2-b omoisobu y a e. Figu e 5.1 shows he SEC aces o he syn hesized linea PDMA-b-PDEGMA block copolyme , DMA75DEGMA140, and he co esponding PDMA p ecu so . The ace o he p ecu so is monomodal wi h a na ow dis ibu ion (PDI 1.13) while he block copolyme shows a small shoulde a highe elu ion olume bu s ill has a easonably na ow dis ibu ion (PDI 1.32). This shoulde co esponds o a small amoun o un eac ed homopolyme bu he peak o he block copolyme is comple ely shi ed o lowe elu ion olume. Fig. 5.1. SEC ace o he linea PDMA-b-PDEGMA block copolyme (solid line) and he co e- sponding PDMA p ecu so (dashed line). We syn hesized wo homopolyme s a p ecu so s wi h di e en a m numbe s bu almos iden ical PDMA block leng hs. The block leng hs o he ou e PDEGMA blocks we e chosen o p oduce wo di e en diblock copolyme s a s om e e y p ecu so . This esul ed in a o al o 4 diblock copolyme s a s wi h a ia ions in a m numbe and he leng h o he ou e block while keeping he leng h o he inne block almos cons an . Chap e 5 Sma Hyd ogels 82 Scheme 5.2. Syn hesis o (DMAnDEGMAm)x s a block copolyme s All s a s ha e na ow molecula weigh dis ibu ions wi h PDIs anging om 1.07 o 1.39 (Table 5.1). As an example, he SEC ace o he s a (DMA150DEGMA100)4 is shown in Figu e 5.2a. The shoulde a low elu ion olume, i.e. high molecula weigh , indica es some s a - s a coupling. Howe e , Figu e 5.2b shows a monomodal ace o he clea ed o a ms o he s a block copolyme . This indica es a blocking e iciency close o uni y and ha he coupling p ocess does no in ol e ecombina ion o wo chain-end adicals bu a he he amino side g oups o he PDMA block. The side chains o bo h blocks a e clea ed o du ing he p ocedu e and he coupled connec ions a e emo ed wi h hem, leading o he mono- modal dis ibu ion. Figu e 5.2. SEC aces o a) (DMA150DEGMA100)4 in DMAc and b) he co esponding a ms, ans o med o PMMA and measu ed in THF. Co e O B O + Anisole 60°C CuCl HMTETA OO N Cl OO N Co e O O OO N Co e O O Cl OO O OO O Ace oni ile 50°C CuCl HMTETA + x nn m O O x x Chap e 5 Sma Hyd ogels 89 Gel o ma ion o (DMAnDEGMAm)x diblock copolyme s a s a pH ≈ 8. All samples we e p epa ed by dissol ing he polyme s in wa e o app op ia e low pH o ob ain he desi ed pH alue close o 8, because he e he ansi ion empe a u e o PDMA is in he accessible empe a u e ange (≈50 °C).29 Thus, gel o ma ion is supposed o ake place igge ed by he collapse o he ou e PDEGMA block and upon eaching he ansi ion empe a u e o he inne PDMA block, he mechanical p ope ies o he gel should change because o he con- ac ion o he PDMA block (Scheme 1). Tube-in e sion e ealed ha a pH alues a ound 8 all he s a s, excep he one wi h he lowes PDEGMA ac ion, (DMA150DEGMA40)4, o med ee-s anding hyd ogels s a ing om 15 w %. (DMA150DEGMA40)4 does no o m gels a any concen a ion and pH alue es ed. DLS showed ha his s a has a e y b oad ansi ion in dilu e solu ion, making i likely ha he physical c osslinks ini ially o med by his s a a e no s ong enough o enable gela ion. On he o he hand, he s a wi h he highes DEGMA ac ion, (DMA130DEGMA140)6, o ms ee-s anding e en a concen a ions as low as 10 w %. To ob ain a mo e de ailed pic u e o he gela ion beha io o he block copolyme s a s se- lec ed samples we e in es iga ed by heology. We applied an oscilla o y s ess o he sam- ple using a cone-pla e shea cell geome y. Regimes whe e he s o age modulus, G', exceeds he loss modulus, G'', a e de ined as he gel s a e acco ding o he common de ini ions. The sol s a e is de ined by G' < G'', and G' > 1 kPa is aken as a cha ac e is ic alue o s ong, ee-s anding gels. 46-48 The poin a which G' and G'' in e sec is de ined as he sol-gel ansi ion empe a u e, Tsg. Chap e 5 Sma Hyd ogels 90 Figu e 5.6. Tempe a u e-dependen s o age and loss moduli o (DMA130DEGMA140)6 in a) a 10 w % solu ion a pH 7.8, b) a 15 w % solu ion a pH 8.0, c) a 20 w % solu ion a pH 8.2 and d) an iso he mal equency sweep a 50 °C o he 10 w % sample. Inse s depic digi al pho og aphs o ube-in e sion expe imen s o he espec i e samples a 50 °C. Figu e 5.6 shows ypical plo s o he empe a u e-dependen s o age and loss moduli o (DMA130DEGMA140)6 a di e en concen a ions and one iso he mal equency sweep. A empe a u es below 25 °C G'' exceeds G' and he solu ion is in he sol s a e, as bo h blocks a e benea h hei ansi ion empe a u e and hus ully soluble in wa e . Wi h inc easing empe a u e bo h moduli inc ease and a 30 °C, he ansi ion empe a u e o DEGMA, he solu ion c osses in o he gel s a e. E en ually G' eaches a pla eau wi h G' > 1 kPa, indica ing a s ong gel (Table 5.2). This is suppo ed by Figu e 5.6d, which shows he equency de- penden measu emen s a 50 °C, o he sample depic ed in Figu e 5.6a. G' is highe han G'' o e he whole measu ed equency ange, p o ing ha ee-s anding gels a e o med. In- c easing he polyme concen a ion om 10 w % o 20 w % (Figu e 5.6a-c) leads o a sub- s an ial inc ease in he gel s eng h because he numbe o physical c osslinks in he gel in- c eases acco dingly. Unexpec edly, he moduli show no change when he empe a u e is Chap e 5 Sma Hyd ogels 91 inc eased abo e 50 °C, he ansi ion empe a u e o DMA, which is a ibu ed o he high gel s eng h (G' > 1 kPa). Table 5.2. Gela ion beha io o (DMAnDEGMAm)x and (qDMAnDEGMAm)x diblock s a s. 5 w % ƒDEGMA a pH b Tsg [°C] c G' [kPa] d (qDMA130DEGMA60)6 e 0.32 qua . 55 0.73 (qDMA150DEGMA100)4 e 0.40 qua . 42 0.35 (qDMA130DEGMA140)6 e 0.52 qua . 36 0.79 10 w % ƒDEGMA a pH b Tsg [°C] c G' [kPa] d (qDMA130DEGMA60)6 e 0.32 qua . 53 2.0 (qDMA150DEGMA100)4 e 0.40 qua . 41 1.0 (qDMA130DEGMA140)6 e 0.52 qua . 36 1.8 (DMA130DEGMA140)6 0.52 7.8 32 1.1 15 w % ƒDEGMA a pH b Tsg [°C] c G' [kPa] d (DMA130DEGMA60)6 0.32 8.2 41 2.8 (DMA150DEGMA100)4 0.40 8.2 35 1.7 (DMA130DEGMA140)6 0.52 8.0 29 3.9 (DMA130DEGMA140)6 0.52 8.8 32 0.07 (0.27 ) 20 w % ƒDEGMA a pH b Tsg [°C] c G' [kPa] d (DMA130DEGMA60)6 0.32 8.3 40 2.8 (DMA150DEGMA100)4 0.40 8.4 34 1.9 (DMA130DEGMA140)6 0.52 8.2 29 5.0 (DMA130DEGMA140)6 0.52 8.7 31 0.13 (0.55 ) a mola ac ion o DEGMA uni s. b solu ion pH measu ed be o e heology. c sol-gel ansi ion empe a u e, de ined as he empe a u e when G' and G'' c oss o e . d alue o G' in he pla eau egion aken a 70 °C. e he deg ee o qua e niza ion is 85 – 88%. alue a maximum. Table 5.2 summa izes he esul s o he heology expe imen s o all measu ed samples o he s a block copolyme s and he co esponding plo s o G' and G'' can be ound in Figu es 5.6-5.8 and S5.5- S5.7. The e a e some gene al ends no iceable. The i s end is ha an inc ease in he polyme concen a ion esul s in a s eng hening o he hyd ogels. The se- cond impo an cha ac e is ic is he mola ac ion o DEGMA uni s, ƒDEGMA, which plays a Chap e 5 Sma Hyd ogels 92 e y impo an ole in he o ma ion o hyd ogels o hese diblock copolyme s a s. As men- ioned abo e, (DMA150DEGMA40)4 does no o m any hyd ogels unde he condi ions in es i- ga ed. This leads o he conclusion ha a minimum ƒDEGMA is necessa y o hyd ogel o - ma ion, bu mos impo an ly, ƒDEGMA con ols he sol-gel ansi ion empe a u e (Table 2). Tu bidi y measu emen s show ha he cloud poin dec eases wi h he DEGMA block leng h, hus Tsg should dec ease acco dingly. The gel s eng h on he o he hand, is in luenced by bo h ƒDEGMA and he a m numbe o he s a . This is easonable, as ƒDEGMA is p opo ional o he block leng h o he DEGMA block and a longe hyd ophobic block leads o s onge gels. The a m numbe de e mines he numbe o possible c osslinking poin s so ha a highe a m numbe means mo e c osslinking poin s and hus a s onge gel. Howe e , he e ec o he a m numbe is mo e p onounced, as he 6-a m s a wi h he lowes ƒDEGMA o ms s onge gels han he 4-a m s a wi h a highe ƒDEGMA a all concen a ions measu ed. This sugges s ha he concen a ion o c osslinking poin s is mo e impo an han he s eng h o he hy- d ophobic in e ac ions. The ansi ion empe a u e o he inne PDMA block is a ound 50 °C o pH alues a ound 8, so we expec ed he dynamic-mechanical beha io o he gels o change upon hea ing abo e 50 °C bu he e is no isible change in G' and G'' o he in es i- ga ed hyd ogels (Figu es 5.6 and S5.5). The high s eng h o he gels a ound pH 8 makes hem oo igid o espond o he inc ease in empe a u e abo e he ansi ion empe a u e o PDMA. This is simila o beha io we obse ed o gels based on PDMA-b-PDEA block co- polyme s a s.26 Fo ha eason we decided o in es iga e gels a highe pH. Chap e 5 Sma Hyd ogels 93 Figu e 5.7. Tempe a u e-dependen s o age and loss moduli o (DMA130DEGMA140)6 in a) a 15 w % solu ion a pH 8.8 and b) a 20 w % solu ion a pH 8.7. Gel o ma ion o (DMAnDEGMAm)x diblock copolyme s a s a pH ≈ 9. Figu e 5.7 shows he esul s o he heology measu emen s o (DMA130DEGMA140)6 a pH alues close o 9. The inc ease o he pH alue has wo consequences: i s , he cloud poin o he PDMA block is lowe ed o a ound 30 °C and second, he DMA chains a e less s e ched because he DMA blocks a e less p o ona ed. The lowe deg ee o p o ona ion oge he wi h he con ac ion o he chains causes a dec ease o he e ec i e olume ac ion o he s a s, making he gels a high pH so e compa ed o he gels a lowe pH alues. Again, gela ion occu s a ound 30 °C. Bo h samples ha e a lowe maximum alue o G' compa ed o hei coun e pa s a pH ≈ 8. The di e ence o he beha io a pH ≈ 8 becomes isible immedia ely a e he c osso e (Figu e 6). G' dec eases a e eaching a maximum a 35 °C ( o 15 w %) and 40 °C ( o 20 w %) be o e le eling o again a T > 60 °C. This indica es a u he con ac ion o he PDMA block a e gela ion because he sol en quali y o he wa e dec eases s eadily wi h inc easing empe a u e, making his gel dual esponsi e in i s o ma ion p ocess and i s me- chanical p ope ies in he gel s a e. The con ac ion o he chains is in ag eemen wi h he beha io o he PDMA blocks a ele a ed empe a u es in DLS. Howe e , since he polyme is al eady in he gel s a e he PDMA blocks canno comple ely collapse, which leads o he pla eau o G' a ele a ed empe a u es. In con as , (DMA150DEGMA100)4 and (DMA130DEGMA60)6 do no o m a gel unde hese con- di ions (G'max < 10 Pa, Figu e S6). A possible explana ion is ha (DMA130DEGMA140)6 is he only s a whe e he u bidi y and µ-DSC measu emen s show wo dis inc ansi ions e en a Chap e 5 Sma Hyd ogels 94 pH 9 (Figu es 5.3b, S5.2a). The ansi ion empe a u es o he PDMA blocks o he o he s a s coincide wi h hose o he PDEGMA blocks, making success ul hyd ogel o ma ion im- possible (Figu es 5.3, S5.2b). The measu emen s depic ed in Figu e S5.6 all show an inc ease in G' a ound 30 °C, he ansi ion empe a u e o DEGMA, bu be o e a gel can be o med he moduli d op sha ply. This is a ibu ed o he collapse o he PDMA block sho ly a e he PDEGMA block has collapsed. In hese cases s able c osslinking poin s canno be o med, making ne wo k o ma ion impossible. Gel o ma ion o qua e nized (qDMAnDEGMAm)x diblock copolyme s a s. In his sys em hyd ogel o ma ion akes place upon he collapse o he ou e PDEGMA block, he same as o he nonqua e nized diblock copolyme s a s. The esul ing gels will no be dual espon- si e as he he mo- and pH- esponsi eness o he inne PDMA block is los upon qua e niza- ion. This p edic ion is con i med by bo h ube in e sion and heology measu emen s. Tube- in e sion expe imen s show a signi ican dec ease o he c i ical gela ion concen a ion as compa ed o he nonqua e nized s a s. As an example, gel o ma ion o (qDMA130DEGMA140)6 akes place a concen a ions as low as 2 w %. This is due o he in- c eased s e ching o he PqDMA block because o he much highe cha ge densi y and he inc eased osmo ic p essu e o he coun e ions. Howe e , he heology measu emen s o (qDMA130DEGMA140)6 show ha he gels o med a 5 w % and lowe canno be ca ego ized as s ong ee-s anding gels bu a he a e conside ed o be so gels (G' < 1 kPa). Figu e 5.8 shows he heology measu emen s o (qDMA130DEGMA140)6 a concen a ions o 5 w % and 10 w % and he o he qua e nized s a s a e shown in Figu e S5.7. In Figu e 5.8 a sol-gel ansi ion is obse ed upon hea ing he samples and he s o age modulus does no dec ease again a e eaching he gel s a e. Chap e 5 Sma Hyd ogels 95 Figu e 5.8. Tempe a u e-dependen s o age and loss moduli o a) a 5 w % solu ion and b) a 10 w % solu ion o (qDMA130DEGMA140)6. An inc ease in he polyme concen a ion also leads o a s eng hening o he gel in analogy o he beha io o he nonqua e nized s a s. He e we can di ec ly compa e 10 w % samples o (DMA130DEGMA140)6 and (qDMA130DEGMA140)6 in e ms o sol-gel ansi ion empe a u e and gel s eng h (Table 2). Th ough qua e niza ion, Tsg shi s o sligh ly highe empe a u es because o he hyd ophilic PqDMA block, i.e. he ansi ion empe a u e o he PDEGMA block is inc eased, and he gel s eng h inc eases due o he highe e ec i e olume ac ion o he qua e nized s a s. The beha io o he qua e nized s a s is simila o ha o he non- qua e nized s a s, inso a as Tsg is solely con olled by ƒDEGMA and he gel s eng h is mainly con olled by he a m numbe o he s a s and o a lesse ex en by ƒDEGMA. 5.4. Conclusions Tu bidime y and dynamic ligh sca e ing ha e con i med ha (DMAnDEGMAm)x diblock copolyme s a s a e double- esponsi e in dilu e aqueous solu ion. Upon hea ing he ou e PDEGMA block collapses i s and lowe -like agg ega es a e o med. When he empe a u e is inc eased u he , he inne PDMA block esponds depending on he pH alue. I he pH is chosen co ec ly, a sequen ial collapse s a ing wi h he ou e block can be igge ed. The e- o e, in concen a ed aqueous solu ions, hyd ogel o ma ion akes place upon he collapse o he ou e PDEGMA block and he mechanical p ope ies o he gel can be manipula ed Chap e 5 Sma Hyd ogels 96 u he by empe a u e. Unexpec edly, he gels o med a pH ≈ 8 do no show a change in hei moduli when he empe a u e is inc eased abo e he ansi ion empe a u e o PDMA. This is a ibu ed o he ac ha in hese cases s ong gels a e o med (G'max > 1 kPa), which a e oo igid o be a ec ed. Howe e , when he gels a e p epa ed a pH ≈ 9 hey exhibi a signi ican ly educed gel s eng h and hus a d op o he moduli upon hea ing o e he an- si ion empe a u e o PDMA can be obse ed. To u he p o e he e sa ili y o ou sys em, he inne PDMA blocks we e qua e nized o om PqDMA, a s ong polyca ion. Fu he ad an ages o a qua e nized block a e he possi- bili ies o inco po a e nanopa icles o o in oduce a ligh sensi i i y h ough mul i alen coun e ions.28,49 Du ing he qua e niza ion he empe a u e and pH esponsi eness o he inne block is los bu so a e he es ic ions on he solu ion pH alue. The inc eased e ec- i e olume ac ion o he qua e nized diblock s a s leads o a signi ican dec ease in he c i ical gela ion concen a ion. Acknowledgemen s. 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Mac omolecules 2010, 43, 4791-4797. (39) Munoz-Bonilla, A.; Fe nandez-Ga cia, M.; Haddle on, D. M. So Ma e 2007, 3, 725-731. (40) Reinicke, S.; Schmalz, H. Colloid. Polym. Sci. 2011, 289, 497-512. Chap e 5 Sma Hyd ogels 105 Figu e S5.6. Tempe a u e-dependen s o age (G') and loss moduli (G'') o (DMA150DEGMA100)4 in a) a 15 w % solu ion a pH 8.9 and b) a 20 w % solu ion a pH 8.9 and o (DMA130DEGMA60)6 in c) a 15 w % solu ion a pH 9.0 and d) a 20 w % solu ion a pH 8.7. Chap e 5 Sma Hyd ogels 106 Figu e S5.7. Tempe a u e-dependen s o age (G') and loss moduli (G'') o (qDMA150DEGMA100)4 in a) a 5 w % solu ion and b) a 10 w % solu ion and o (qDMA130DEGMA60)6 in c) a 5 w % solu ion and d) a 10 w % solu ion. Chap e 6 Summa y 107 6 Summa y The wo k p esen ed in his hesis is ocused on he syn hesis o double- esponsi e s a - shaped block copolyme s and hei o ma ion o sma hyd ogels in esponse o di e en ex e nal s imuli, speci ically empe a u e and pH. Ou concep was based on (AB)x diblock copolyme s a s whe e bo h blocks a e esponsi e o empe a u e and pH. This app oach led o physically c osslinked hyd ogels, which could o m/disin eg a e in esponse o a i s igge , i.e. he ou e B blocks a e al e na ing be ween hyd ophilic and hyd ophobic. The mechanical p ope ies o he gels could s ill be manipula ed by a second, independen igge , i.e. upon applying he second igge , he inne A blocks con ac , leading o a change in mechanical p ope ies. The i s pa deals wi h he syn hesis and cha ac e iza ion o linea and s a -shaped poly((2-die hylamino)e hyl me hac yla e) (PDEA) o in es iga e i s double- esponsi e beha io and i s po en ial o he design o double- esponsi e gela o s. This polyme esponds o a ia ions in bo h pH and empe a u e, jus like he analogous poly((2-dime hylamino)e hyl me hac yla e) (PDMA). A a gi en empe a u e PDEA exhibi s a c i ical pH alue abo e which he chains collapse and agg ega ion akes place. The empe a u e- esponsi e beha io o PDEA does no depend on molecula weigh o a chi ec u e, i.e. a m numbe . Howe e , he cloud poin does s ongly depend on pH, as i a ec s he o e all cha ge o he s a . Fo he second pa we combined PDMA and PDEA o c ea e double- esponsi e s a -shaped block copolyme s (DMA-DEA)x whe e bo h blocks a e esponsi e o pH and empe a u e. The collapse o he PDEA ou e blocks is i s selec i ely igge ed by hea ing. This has been p o en by dynamic ligh sca e ing and is due o he signi ican ly lowe cloud poin o PDEA wi h espec o ha o PDMA a iden ical pH. The gela ion beha io was in es iga ed in dependence on block leng h and a m numbe . A high concen a ions hyd ogel o ma ion was obse ed unde condi ions whe e only he PDEA ou e blocks a e insoluble. Rheology measu emen s showed ha a minimum DEA ac ion is necessa y o gel o ma ion and ha he DEA ac ion s ongly in luences he p ope ies o he gels. Ano he ac o con olling he gela ion beha io o he diblock copolyme s a s is he pH alue, as he sol-gel ansi ion empe a u e a a gi en concen a ion is shi ed o lowe alues upon inc easing he pH. The Chap e 6 Summa y 108 mechanical p ope ies o some gel can be manipula ed, as a dec ease in he s o age modulus was only obse ed o so gels, i he empe a u e is inc eased abo e he ansi ion empe a u e o he inne PDMA block, i.e. when he PDMA blocks con ac . Thus, we success ully c ea ed double- esponsi e s a -shaped gela o s which o med e e sible hyd ogels ha we e s ill able o espond o a second igge . Howe e , he agg ega ion and hyd ogel o ma ion u ned o ou o be qui e complex, due o he high numbe o pa ame e s con olling hem. Finally, ou concep was ex ended o o he polyme s and simpli ied by changing he ou e block o he block copolyme s a s o a polyme ha is only esponsi e o empe a u e. This allows o an easie uning o he sol-gel ansi ion, as only one pa ame e is in ol ed. The new diblock s a s a e comp ised o PDMA inne blocks and ou e blocks o poly(die hylene glycol me hyl e he me hac yla e) (PDEGMA), which can be igge ed independen ly o each o he as con i med by u bidime y and dynamic ligh sca e ing. They o m hyd ogels a ela i ely low concen a ions upon hea ing abo e he ansi ion empe a u e o PDEGMA independen o he pH alue. The ac ion o DEGMA is an impo an pa ame e o he gela ion beha io o he (DMA-DEGMA)x s a s, he same as he DEA ac ion was o he (DMA-DEA)x s a s. Unexpec edly, he mechanical p ope ies o hese gels can also no be changed by hea ing abo e he ansi ion empe a u e o PDMA a pH alues a ound 8. The gels o med in his pH egion a e s ong and oo igid o be a ec ed, simila o s ong gels o med om (DMA-DEA)x s a s. Only when he pH is inc eased close o 9 and he subsequen ly o med gels a e so e , a dec ease in he moduli is obse ed. We also qua e nized he inne PDMA blocks o he (DMA-DEGMA)x s a s o ans o m hem i in o s ong polyca ions. This leads o an inc ease in he e ec i e olume ac ion o he s a s and consequen ly o a signi ican dec ease o he c i ical gela ion concen a ion. The qua e niza ion opens ou concep up o he in oduc ion o ligh sensi i i y h ough mul i alen coun e ions and he inco po a ion o nanopa icles. Chap e 6 Summa y 109 Zusammen assung Die o liegende A bei be ass e sich mi de Syn hese on doppel esponsi en s e n ö migen Blockcopolyme en und de en Ve wendung zu He s ellung on in elligen en Hyd ogelen die au meh e e Reize eagie en können, im Besonde en Tempe a u und pH- We . Unse Konzep basie au (AB)x Blockcopolyme -S e nen bei denen beide Blöcke au Tempe a u und pH-We eagie en können. Diese Vo gehensweise üh zu physikalisch e ne z en Hyd ogelen de en Bildung/Au lösung du ch einen ex e nen Reiz geschal e we den kann, d.h. die äuße en B Blöcke wechseln zwischen hd ophil und hyd ophob hin und he . Die mechanischen Eigenscha en de Gele können on einem unabhängigen zwei en Reiz e ände we den, d.h. die inne en A Blöcke sch ump en als Reak ion au den zwei en Reiz. Als e s es wu den linea e und s e n ö mige Poly((2-die hylamino)e hylme hac yla )e (PDEA) syn he isie und de en doppel esponsi es Ve hal en und das Po en ial zu He s ellung on doppel esponsi en Gela o en un e such . Das Polyme e eagie au Ände ungen de Tempe a u und des pH-We es ähnlich wie das analoge Poly((2-dime hylamino)e hyl me hac yla ) (PDMA). Je nach Tempe a u besi z PDEA einen k i ischen pH-We , obe halb dessen die Ke en kollabie en und Agg ega ion au i . Das empe a u - esponsi e Ve hal en on PDEA is nich om Molekula gewich ode de A chi ek u , d.h. de Zahl de A me, abhängig. Alle dings häng de T übungspunk s a k om pH-We ab, da diese die gesam e Ladung des S e ns beein luss . Im Anschluss wu den PDMA und PDEA kombinie um doppel esponsi e s e n ö mige Blockcopolyme e (DMA-DEA)x he zus ellen, de en beide Blöcke au pH-We - und Tempe a u ände ungen eagie en. De Kollaps des äuße en PDEA Blocks kann beim Heizen selek i als e s es ausgelös we den. Dies wu de du ch dynamische Lich s euexpe imen e bewiesen und lieg an dem signi ikan ie e liegenden T übungspunk on PDEA in Ve gleich zu PDMA, bei iden ischem pH-We . Das Gelie ungs e hal en wu de au seine Abhängigkei on Blocklänge und A mzahl hin un e such . Hyd ogele bilden sich in konzen ie en Lösungen un e Bedingungen bei denen nu de äuße e PDEA Block unlöslich is . Rheologische Messungen haben gezeig dass ein bes imm e minimale DEA-An eil nö ig is um Gele zu bilden und dass de An eil an DEA einen g oßen Ein luss au die Eigenscha en Chap e 6 Summa y 110 de Gele ha . Ein wei e e Fak o , de das Ve hal en beein luss , is de pH-We , da de Sol- Gel Übe gang sich bei gegebene Konzen a ion und s eigendem pH-We zu nied ige en Tempe a u en e schieb . Die mechanischen Eigenscha en einige de Gele können e ände we den, da de Speiche modul nu bei weichen Gelen abnimm , wenn die Tempe a u übe die Übe gangs empe a u des PDMA Blocks e höh wi d. Somi haben wi e olg eich doppel esponsi e s e n ö mige Gela o en he ges ell , die e e sible Hyd ogele bilden, die au einen zwei en Reiz eagie en können. Anschließend haben wi unse Konzep au ande e Polyme e e wei e und es e ein ach indem de äuße e Block du ch ein Polyme e se z wu de das nu au Tempe a u eagie . Die zwei e Maßnahme e laub eine ein ache e Anpassung des Sol-Gel Übe gangs, da nu ein einzige Pa ame e be eilig is . Die neuen Diblock-S e ne bes ehen im Inne en aus PDMA Blöcken und aus äuße en Blöcken aus Poly(die hylenglycol me hyle he me hac yla ) (PDEGMA), welche unabhängig oneinande geschal en we den können. Sie bilden bei ela i nied igen Konzen a ionen Hyd ogele, sobald die Tempe a u übe die Übe gangs empe a u on PDEGMA e höh wi d, unabhängig om pH-We . De An eil an DEGMA is ein wich ige Pa ame e ü das Gelie ungs e hal en de (DMA-DEGMA)x S e ne, genauso wie es de An eil an DEA ü die (DMA-DEA)x S e ne wa . En gegen unse e E wa ungen konn en die mechanischen Eigenscha en de Gele bei pH 8 nich du ch E wä men obe halb de Übe gangs empe a u des PDMA Blocks beein luss we den. Die Gele die in diesem pH Be eich gebilde we den sind s a k und zu es um manipulie zu we den, ähnlich den Gelen die on (DMA-DEA)x S e nen gebilde we den. Nu wenn de pH- We au as 9 e höh wi d und die dabei en s ehenden Gele weiche sind, wu de eine Abnahme de Moduli beobach e . Abschließend wu den die inne en PDMA Blöcke de (DMA-DEGMA)x S e ne qua e nisie um sie in s a ke Polyka ionen umzuwandeln. Dies ha eine Zunahme des e ek i en Volumenb uchs de S e ne zu Folge und üh zu eine deu lichen Abnahme de k i ischen Gelie ungskonzen a ion. Die Qua e nisie ung e ö ne die Möglichkei unse Konzep zu e wei e n, mi els de Ein üh ung on Lich sensi i i ä du ch meh we ige Gegenionen und de In eg a ion on Nanopa ikeln. Chap e 7 Lis o Publica ions 111 7 Lis o Publica ions Du ing he cou se o his hesis he ollowing pape ha e been published: 1. Plampe , F.A.; Schmalz, A.; Peno -Chang, E.K.; D echsle , M.; Jusu i, A.; Ballau , M.; Mülle , A.H.E., Syn hesis and Cha ac e iza ion o S a -Shaped Poly(N,N- dime hylaminoe hyl me hac yla e) and I s Qua e nized Ammonium Sal s, Mac omole- cules, 2007, 40, 5689-5697. 2. Plampe , F.A.; Ruppel, M.; Schmalz, A.; Bo iso , O.; Ballau , M.; Mülle , A.H.E., Tuning he The mo esponsi e P ope ies o Weak Polyelec oly es: Aqueous Solu ions o S a - Shaped and Linea Poly(N,N-dime hylaminoe hyl me hac yla e), Mac omolecules, 2007, 40, 8361-8366. 3. Plampe , F.A.; Schmalz, A.; Ballau , M.; Mülle , A.H.E., Tuning he The mo esponsi ness o Weak Polyelec oly es by pH and Ligh : Lowe and Uppe C i ical Solu ion Tempe a u e o Poly(N,N-dime hylaminoe hyl me hac yla e), J. Am. Chem. Soc., 2007, 129, 14538- 14539. 4. Schmalz, A.; Hanisch, M.; Schmalz, H.; Mülle , A.H.E., Double S imuli-Responsi e Beha - io o Linea and S a -Shaped Poly(N,N-die hylaminoe hyl me hac yla e) in Aqueous Solu- ion, 2010, Polyme , 51, 1213-1217. 5. Schmalz, A.; Schmalz, H.; Mülle , A.H.E., Double Responsi e Hyd ogels Based on Te ia y Amine Me hac yla e S a Block Copolyme s, Z. Phys. Chem., 2012, 226 (7-8), 695-709. 6. Schmalz, A.; Schmalz, H.; Mülle , A.H.E., Sma Hyd ogels Based on Responsi e S a - Block Copolyme s, So Ma e , 2012, 8 (36), 9436-9445. 110 Acknowledgemen s Fi s o all, I would like o hank my supe iso P o esso Axel H. E. Mülle o gi ing me he oppo uni y o wo k in his g oup. I app ecia e all he help he has p o ided me du ing he cou se o my hesis and he ime he has aken o discussions and o all he use ul ips. I am g a e ul o he nume ous oppo uni ies he has o e ed me, including sending me o se e al in e na ional con e ences o p esen my wo k. Special hanks go o D . Holge Schmalz, who has been o immense help o me du ing my esea ch. Thank you o all he ime spen in discussions and helping me co ec my manusc ip s. I wan o hank P o esso Ingo Rehbe g and D . Reinha d Rich e o p o iding access o hei heome e and Tobias Lang o helping me wi h all my p oblems wi h i . I would also like o hank D . Felix Plampe o eaching me mos o wha I know abou he syn hesis o s a s and o he ime spen in he lab oge he . Mos o all I ha e o hank he whole MC2 g oup o being such an inc edibly unny and in e es ing place o spend my ime du ing my hesis. Fi s a e he echnical assis an s Melanie Fö sch, Ma ie a Böhm, Annika P a enbe ge , Anne e K ökel, Sabine Wunde and Susanne Edinge o doing all my measu emen s o SEC, TEM, MALDI and o all he coun less o he hings hey did o me. In addi ion, I hank Gaby Oli e o all he help wi h adminis a i e p oblems and o all he humo she had wi h me. A big hank you goes o all my o me and p esen cowo ke s who managed o make his expe ience in o some hing amazing. Fo all he ime spen in ou “g oup ac i i ies” ei he in he lab o ou side, which made all he di e ence. So in no pa icula o de : And é P a , Sand ine Tea, Thomas Ruhland, Ma kus Müllne , And é G öschel, Alexande Majewski, S ephan Weiß, Joachim Schmelz, Ch is ophe Syna schke, E a Be hausen, And ea Wol , Zhicheng Zheng, S e an Reinicke, Hans-Joachim Voig lände , Felix Plampe , Felix Schache , Ma kus Ruppel, Ma kus Bu khad , Anja Goldmann, Jiayin Yuan, Youyong Xu, Manuela Schuhmache , Michael Wi and many mo e… 111 I also hank he Chemike Spass Gesellscha , CSG e.V., and all he people in ol ed o p o iding me and a lo o o he s wi h many, many g ea e enings and ac i i ies. I had a lo o un and hope ha I will con inue o do so as a membe o e he yea s. Mos impo an ly I ha e o hank my pa en s, my b o he and ina o hei unwa e ing suppo and encou agemen o e he yea s, wi hou which I couldn’ ha e made i o whe e I am oday. 112 E klä ung Die o liegende A bei wu de on mi selbs s ändig e ass und ich habe dabei keine ande en als die angegebenen Hil smi el und Quellen benu z . Fe ne habe ich nich e such ande wei ig, mi ode ohne E olg, eine Disse a ion einzu eichen ode mich de Dok o p ü ung zu un e ziehen. Bay eu h, den 06.12.2011 (Alexande Schmalz)