The Chemistry of Some Selected Methacrylate Hydrogels - Hydrogels

7 The Chemistry of Some Selected Methacrylate Hydrogels

Downloaded by COLUMBIA UNIV on October 14, 2014 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch007

DONALD E. GREGONIS, CHWEN M. CHEN, and JOSEPH D. ANDRADE Department of Materials Science and Engineering, University of Utah, Salt Lake City, Utah 84112

H y d r o g e l s have been d e s c r i b e d as b i o c o m p a t i b l e m a t e r i a l s Q J . P o l y m e r s o f h y d r o x y e t h y l m e t h a c r y l a t e (HEMA) a r e t h e most s t u d i e d s y n t h e t i c hydrogels ( 2 J . A t p r e s e n t , polymers o f t h i s m a t e r i a l a r e w i d e l y used i n c o r r e c t i v e c o n t a c t l e n s e s ( 3 ) ; i t has been used as a c o a t i n g f o r c a t h e t e r s and o t h e r m e d i c a l d e v i c e s ( 4 - 6 J . In o u r i n v e s t i g a t i o n s , we wanted t o s t u d y a v a r i e t y o f h y d r c i p i r i l i c m e t h a c r y l a t e polymers t o e v a l u a t e t h e i r b i o l o g i c a l behavior i n r e l a t i o n t o t h e c o n c e n t r a t i o n and t y p e o f g r o u p s i n c o r p o r a t e d i n to the polymer. In o r d e r t o p u r s u e t h i s g o a l , a t h o r o u g h u n d e r standing o f the bulk properties of the hydrogels i s r e q u i r e d . In t h i s work t h e e q u i l i b r i u m w a t e r c o n t e n t o f t h e g e l s i s r e g u l a t e d by v a r y i n g c o p o l y m e r r a t i o s . Charged g r o u p s a r e i n c o r p o r a t e d i n t o t h e p o l y m e r by c o p o l y m e r i z a t i o n w i t h a c i d i c o r b a s i c m e t h a c r y l a t e s . The monomers t h a t a r e b e i n g i n v e s t i g a t e d a r e shown i n T a b l e I. The amount o f w a t e r i n t h e e q u i l i b r a t e d p o l y m e r s c o v e r e d t h e r a n g e f r o m 3 . 5 % t o g r e a t e r t h a n 90% ( T a b l e I I ) . For t h i s s t u d y , h y d r o x y e t h y l m e t h a c r y l a t e was s e l e c t e d as t h e f u n d a m e n t a l monomer b e c a u s e o f p a s t work and a v a i l a b i l i t y . TABLE

I.

H y d r o p h i l i c M e t h a c r y l a t e Monomers

1. 2. 3. 4. 5. 6. 7.

R i = OH, R = H; h y d r o x y e t h y l m e t h a c r y l a t e (HEMA). R i = 0CH CH 0H, R = H; h y d r o x y e t h o x y e t h y l m e t h a c r y l a t e ( H E E M A l R i = 0CH CH20CH2CH 0H,R = H; h y d r o x y d i e t h o x y e t h y l m e t h a c r y l a t e (HDEEMA). R i = -OCH3, R = H; m e t h o x y e t h y l m e t h a c r y l a t e (MEMA). R i = 0CH CH 0CH , R = H; m e t h o x y e t h o x y e t h y l m e t h a c r y l a t e (MEEMA). R i = 0CH CH 0CH CH 0CH , R = H; m e t h o x y d i e t h o x y e t h y l m e t h a c r y l a t e (MDEEMA). R i = CH2OH, R = OH; 2 , 3 - d i h y d r o x y p r o p y l methacrylate(DHPMA). 2

2

2

2

2

2

2

2

2

2

3

2

2

2

2

2

3

2

2

88

In Hydrogels for Medical and Related Applications; Andrade, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

7.

GREGONis E T AL.

TABLE I I . Water S w e l l i n g o f P u r e Homopolymers

Equilibrium


89

Methacrylate Hydro gels

1.

pHEMA

-

0.40*

5.

pMEEMA

2.

pHEEMA

-

0.80

6.

pMDEEMA

3.

pHDEEMA

-

>0.90

7.

pDHPMA

4.

pMEMA

-

0.62 -

>0.90 0.70

t o >0.90

H)

0.035

*Water f r a c t i o n (W ) = weight o f water i n polymer/weight hydrated polymer f

Monomers (See T a b l e

of

I)

The l a b o r a t o r y s y n t h e s i s o f t h e s e monomers i s a c c o m p l i s h e d by t h e f o l l o w i n g c l a s s i c a l c h e m i c a l r e a c t i o n s : 1. Reaction of methacryl c h l o r i d e with the corresponding alcohol :

*

" - τ * * — U n i *

(Monomers 1-7) 2. T r a n s e s t e r i f i c a t i o n o f methyl m e t h a c r y l a t e w i t h t h e corresponding a l c o h o l : 0 ^ — ! L ' 3.

0 + R0H 0CH

τ > Η o r base

3

0

H

+ »

4. Acid catalyzed hydrolysis methacrylate (8-9).

of

0 C ^ ( / N/

0

0 —

> '

+ CH-0H OR

(Monomers 1-7) of g l y c i d y l methacrylate (7):

Acid catalyzed hydrolysis 0

t 7

(Monomer 7) isopropylidineglyceryl

0 0 J

LL^V-C

0

^

,+CH~C-CH~ TKOH OH (Monomer 7) 0

H

0



90

HYDROGELS

FOR MEDICAL

A N D RELATED APPLICATIONS

A t h o r o u g h s u r v e y o f h y d r o p h i l i c m e t h a c r y l a t e monomers c o v e r i n g b o t h l a b o r a t o r y and i n d u s t r i a l s y n t h e s i s i s a v a i l a b l e (10). M o d e r a t e amounts o f monomer (0.1 t o 1 £ . ) s a t i s f i e s most o f our r e q u i r e m e n t s . A d e s c r i p t i o n o f o u r p u r i f i c a t i o n scheme i s p r e s e n t e d b e l o w . Normal p r e p a r a t i v e c h r o m a t o g r a p h i c t e c h n i q u e s a r e i m p r a c t i c a l f o r t h e p u r i f i c a t i o n o f t h i s q u a n t i t y o f monomer. The p r e p a r a t i o n o f monomers 1, 2 , and 3 i s c o m p l i c a t e d by the formation of dimethacrylate e s t e r s . These d i e s t e r s a r e u n d e s i r e d i n t h e p r o d u c t b e c a u s e t h e y a c t as c r o s s l i n k i n g a g e n t s . They may be removed f r o m t h e p r o d u c t by e x t r a c t i o n t e c h n i q u e s . Since the d i e s t e r s are l e s s s o l u b l e i n water than the c o r r e s p o n d i n g m o n e s t e r s , t h e i m p u r e monomer i s d i s s o l v e d i n w a t e r ( M : l r a t i o , v/v) and e x t r a c t e d w i t h a n o n - p o l a r s o l v e n t , s u c h as c a r b o n t e t r a c h l o r i d e , benzene o r p e t r o l e u m e t h e r (1J_). The l e s s water s o l u b l e d i e s t e r s are e x t r a c t e d i n t o the o r g a n i c phase. The d e s i r e d monomer i s i s o l a t e d by s a t u r a t i o n o f t h e aqueous s o l u t i o n w i t h s o d i u m c h l o r i d e and e x t r a c t i o n w i t h a more p o l a r s o l v e n t , u s u a l l y methylene c h l o r i d e . E t h e r s o l v e n t s a r e n o t used f o r any e x t r a c t i o n u n l e s s t h e y have been r i g o r o u s l y p u r i f i e d . A n h y d r o u s e t h e r s r e a d i l y a i r o x i d i z e t o f o r m p e r o x i d e s , w h i c h a r e good p o l y m e r i z a t i o n i n i t i a t o r s . The monomer i s c a r e f u l l y e x t r a c t e d t o remove a c i d i c and b a s i c i m p u r i t i e s and t h e n e l u t e d t h r o u g h Grade II n e u t r a l a l u m i n a t o remove o t h e r p o l a r i m p u r i t i e s . The monomers s h o u l d f i n a l l y be p u r i f i e d by vacuum d i s t i l l a tion. The vacuum s y s t e m must be a b l e t o c a r r y o u t d i s t i l l a t i o n s as l o w as 0.1 mm Hg. p r e s s u r e . Inhibitor is required to deter p o l y m e r i z a t i o n when t h e p r o d u c t i s d i s t i l l e d . Cuprous c h l o r i d e o r c o p p e r powder i s r o u t i n e l y added t o t h e d i s t i l l a t i o n f l a s k and o f f e r s t h e a d v a n t a g e o f n o t c o - d i s t i l l i n g w i t h t h e monomer. H y d r o q u i n o n e o r p - m e t h o x y p h e n o l a r e more e f f e c t i v e i n h i b i t o r s and a r e r e q u i r e d i n d i s t i l l a t i o n s above 1 0 0 ° C , b u t t h e y c o - d i s t i l l with the product. A n i t r o g e n bleed i n t o the d i s t i l l a t i o n f l a s k l a r g e l y e l i m i n a t e s the d e l e t e r i o u s e f f e c t s o f oxygen. Table III g i v e s t h e b o i l i n g p o i n t s o f t h e monomers,

1. 2. 3. 4. 5. 6. 7.

TABLE III. B o i l i n g P o i n t s o f H y d r o p h i l i c M e t h a c r y l a t e Monomers Monomer B o i l i n g P o i n t , °C Hydroxyethyl methacrylate(HEMA) 6 9 ° @ 0.1 mm Hg H y d r o x y e t h o x y e t h y l m e t h a c r y l a t e 9 7 - 9 9 ° @ 1 mm Hg ( 2 ) (HEEMA) H y d r o x y d i e t h o x y e t h y l m e t h a c r y l - 1 2 0 - 1 2 2 ° @ 0 . 4 mm Hg a t e (HDEEMA) Methoxyethyl methacrylate(MEMA) 5 7 ° @ 8 mm Hg M e t h o x y e t h o x y e t h y l m e t h a c r y l a t e 6 5 - 7 0 ° @ 0.1 mm Hg (MEEMA) M e t h o x y d i e t h o x y e t h y l m e t h a c r y l - 9 5 - 1 0 1 ° @ 0.1 mm Hg a t e (MDEEMA) 2 , 3 - d i h y d r o x y p r o p y l m e t h a c r y l a t e 1 4 0 ° @ 0.6 mm Hg (DHPMA)


(£)


7.

GREGONis E T AL.

Methacrylate Hydrogeh

91

Gas c h r o m a t o g r a p h y ( G C ) , h i g h p r e s s u r e l i q u i d c h r o m a t o g r a p h y (HPLC) and t h i n - l a y e r c h r o m a t o g r a p h y (TLC) (1_2) a r e used f o r analysis of purity. C e r t a i n i m p u r i t i e s t h a t c a n n o t be d e t e c t e d by one t e c h n i q u e a r e e a s i l y d e t e c t e d by a n o t h e r t e c h n i q u e . Both UV a b s o r b a n c e and r e f r a c t i v e i n d e x a r e m o n i t o r e d w i t h t h e h i g h pressure l i q u i d chromatograph. The m e t h a c r y l a t e s y s t e m o f f e r s a w i d e v a r i e t y o f monomers, w h i c h we c a l l g e l m o d i f i e r s , t o c o p o l y m e r i z e w i t h t h e h y d r o p h i l i c monomers t o change t h e c h a r a c t e r i s t i c s o f t h e g e l . For example, copolymerization with methacrylic acid introduces negatively charged groups i n t o the g e l . D i m e t h y l a m i n o e t h y l m e t h a c r y l a t e may be used t o i n t r o d u c e p o s i t i v e c h a r g e s i n t o t h e g e l . Some o f t h e c o m m e r c i a l l y a v a i l a b l e monomers used f o r g e l m o d i f i c a t i o n a r e l i s t e d i n F i g u r e 1. M o d i f i e r s 11-14 i n F i g u r e 1 a r e n o t d i s c u s sed f u r t h e r i n t h i s p a p e r . M e t h a c r y l a t e d i e s t e r s a r e a l s o c o m m e r c i a l l y a v a i l a b l e . These d i e s t e r s f u n c t i o n as c r o s s ! i n k i n g a g e n t s . The c r o s s ! i n k e r s t h a t we have u s e d a r e t h e d i m e t h a c r y l a t e s o f e t h y l e n e g l y c o l (EGDMA) and t e t r a e t h y l e n e g l y c o l (TEGDMA)(2^133 · The l a t t e r i s more s o l u b l e i n w a t e s Initiators M e t h a c r y l a t e s may be p o l y m e r i z e d by e i t h e r r a d i c a l o r anionic i n i t i a t o r s (14). r a d i c a l i n i t i a t i o n we s e l e c t e d a c l a s s o f a z o i n i t i a t o r s . These a z o i n i t i a t o r s a r e r e a d i l y a v a i l a b l e and decompose a t a u n i f o r m r a t e u n a f f e c t e d by s o l v e n t o r i n d u c e d d e c o m p o s i t i o n ( 1 5 ) . The a z o i n i t i a t o r s may be m o d i f i e d so t h a t t h e end g r o u p s i n t r o d u c e d i n t o t h e p o l y m e r c h a i n a r e v e r y s i m i l a r t o t h e mer u n i t . They t h e r m a l l y decompose a t a r e a s o n a b l e t e m p e r a t u r e (16) and c a n be decomposed a t l o w t e m p e r a t u r e s by UV l i g h t . In t h i s s t u d y , e s t e r s f r o m a z o b i s i s o b u t y r o n i t r i l e (AIBN) were p r e p a r e d by t h e f o l l o w i n g method ( 1 7 ) . Mild a c i d a l c o h o l y s i s o f AIBN c o n v e r t s t h e n i t r i l e g r o u p t o i m i n o e s t e r s a l t s , which p r e c i p i t a t e from the r e a c t i o n s o l u t i o n . The p r o d u c t i s i s o l a t e d by f i l t r a t i o n and t h e i m i n o - e s t e r g r o u p i s hydrolyzed to form the e s t e r (Figure 2 ) . A z o b i s ( m e t h y l i s o b u t y r a t e ) (Compound 16) has been p r e v i o u s l y prepared (17-19). More w a t e r s o l u b l e a z o i n i t i a t o r s were p r e p a r e d f r o m t h e m o n o m e t h o x y g l y c o l s (Compounds 17 and 1 8 ) . I n i t i a t o r a z o b i s ( m e t h o x y d i e t h o x y e t h y l i s o b u t y r a t e ) (Compound 18) i s completely water s o l u b l e . In o t h e r work we have shown t h a t a l l t h r e e AIBN d e r i v a t i v e s i n i t i a t e p o l y m e r i z a t i o n o f HEMA a t an e q u a l r a t e , w h i c h i s s l i g h t l y f a s t e r t h a n AIBN ( 2 0 ) . For bulk p o l y m e r i z a t i o n , 7.84 m i c r o m o l e s o f i n i t i a t o r a r e used p e r m i l l i l i t e r o f monomer. T h i s r a t i o i s k e p t c o n s t a n t and does n o t v a r y with water content. For p o l y m e r i z a t i o n o f high w a t e r c o n t e n t g e l s , t h e more w a t e r s o l u b l e d e r i v a t i v e s o f AIBN a r e u s e d . P r o v i d i n g no a c t i v e h y d r o g e n s a r e p r e s e n t i n t h e monomer o r s o l v e n t , a n i o n i c i n i t i a t o r s may be u s e d . These c o n d i t i o n s p r o h i b i t p o l y m e r i z a t i o n o f t h e h y d r o x y l i c monomers 1, 2 , 3 , 7 o r F

o

r



92

HYDROGELS FOR MEDICAL AND RELATED APPLICATIONS

t h e use o f w a t e r o r a l c o h o l s as s o l v e n t s . The a n i o n i c i n i t i a t o r s a r e o r g a n o m e t a l l i c compounds, s u c h as η - b u t y l l i t h i u m , o r s t r o n g b a s e s , s u c h as l i t h i u m t - b u t o x i d e . Although there are disadvan t a g e s t o t h e s e i n i t i a t o r s , t h e y a r e used t o p o l y m e r i z e m e t h a c r y l a t e s i n a wide range o f t a c t i c i t i e s from c h a i n s having high s y n d i o t a c t i c t r i a d s to chains having high i s o t a c t i c t r i a d s . Our group i s i n v e s t i g a t i n g such polymers t o determine t h e e f f e c t o f t a c t i c i t y on t h e p r o p e r t i e s o f t h e h y d r o g e l s (21). F o r c e r t a i n s t u d i e s s o l u b l e p o l y m e r s were r e q u i r e d ( 2 2 ) . R a d i c a l p o l y m e r i z a t i o n of the m e t h a c r y l a t e system w i t h o u t s o l v e n t g i v e s a p o l y m e r t h a t s w e l l s t o a h i g h d e g r e e i n good s o l v e n t s , b u t does n o t d i s s o l v e . I t i s f e l t t h a t some c r o s s ! i n k i n g o f t h e p o l y m e r o c c u r s by r a d i c a l c h a i n t r a n s f e r mechanisms ( 2 3 ) . S o l u b l e m e t h a c r y l a t e p o l y m e r s may be o b t a i n e d w i t h a r a d i c a l i n i t i a t o r a t h i g h d i l u t i o n s o f t h e monomer. We r o u t i n e l y p o l y m e r i z e t h e monomers i n e t h a n o l ( l : 1 0 , v / v ) . These s o l u t i o n s have been used f o r s o l v e n t c a s t i n g (24) and g e l c o a t i n g s ( 2 2 ) . P r e p a r a t i o n o f Gel

Membranes

Gel membranes w e r e r e q u i r e d f o r o u r d i f f u s i o n s t u d i e s (13) and were used f o r o u r work on w a t e r s w e l l i n g o f g e l s . Polymeri z a t i o n o f t h e monomer was i n i t i a t e d by a z o b i s ( m e t h y l i s o b u t y r a t e ) u s i n g t h e same c o n c e n t r a t i o n used f o r t h e p o l y m e r i z a t i o n o f b u l k g e l s , 7.84 m i c r o m o l e s p e r m i l l i l i t e r o f monomer. This r a t i o i s i n d e p e n d e n t o f w a t e r c o n c e n t r a t i o n . A l l g e l m o d i f i e r s and c r o s s l i n k i n g a g e n t s a r e e x p r e s s e d as m o l a r q u a n t i t i e s i n t e r m s o f t h e monomer v o l u m e . The membranes were p r e p a r e d by p o l y m e r i z a t i o n o f t h e monomer s o l u t i o n between f l a t p l a t e s u s i n g a s i l i c o n e rubber spacer to r e g u l a t e t h i c k n e s s . The p o l y m e r i z a t i o n c o n d i t i o n s w e r e s t a n d a r i z e d a t 60°C f o r 24 h r . A t l o w w a t e r c o n c e n t r a t i o n s (Wf < 0 . 2 0 ) , p o l y e t h y l e n e o r p o l y p r o p y l e n e mold p l a t e s a r e used; a t higher water c o n c e n t r a t i o n s , g l a s s p l a t e s are used. T h i s i s b e c a u s e g e l s p o l y m e r i z e d a t low w a t e r c o n c e n t r a t i o n a d h e r e strongly to the glass surface. P o l y m e r i z a t i o n o f membranes on a g l a s s s u r f a c e i s p r e f e r e d s i n c e i t has a more u n i f o r m s u r f a c e . The t h i c k n e s s o f t h e g e l membranes i s 0 . 7 5 mm u n l e s s o t h e r w i s e stated. S y n t h e s i s and P o l y m e r i z a t i o n o f C ^ - l a b e l e d HEMA To d e t e r m i n e t h e r e l a t i v e s t a b i l i t y o f t h e m e t h a c r y l a t e g e l s i n v a r i o u s m e d i a , C * - l a b e l e d HEMA was s y n t h e s i z e d by r e a c t i n g m e t h a c r y l c h l o r i d e and 1 , 2 - C * - e t h y l e n e g l y c o l , u s i n g e x c e s s c a r r i e r ethylene g l y c o l to prevent the formation of excessive amounts o f C - l a b e l e d d i e s t e r ( e t h y l e n e g l y c o l d i m e t h a c r y l a t e ). The C *-HEMA was p u r i f i e d u t i l i z i n g t h e " s a l t i n g o u t " t e c h n i q u e described e a r l i e r . The p r o d u c t was d i l u t e d w i t h c a r r i e r HEMA and was t h e n d i s t i l l e d by m i c r o - v a c u u m t e c h n i q u e s . The d i s t i l l a t e was d e t e r m i n e d t o have a s p e c i f i c a c t i v i t y o f 9.1 χ 1 0 dpm/ml. l l

l l

1 1 +

ll

5


7.

GREGONis E T AL.

93

Methacrylate Hydrogels

To c h e c k t h e r a d i o i s o t o p i c p u r i t y , a 1 ml a l i q u o t was c h r o m a t o g r a p h e d on 100g Grade I I a l u m i n a . The column was e l u t e d w i t h a l i n e a r g r a d i e n t f r o m 100% p e t r o l e u m e t h e r (250ml) t o 5% m e t h a n o l in d i e t h y l e t h e r (250ml). The r a d i o a c t i v i t y e l u t e d i n one p e a k , t h e f r a c t i o n s were combined and e v a p o r a t e d . The p r o d u c t e x h i b i t e d an i d e n t i c a l i n f r a - r e d s p e c t r u m t o c o n t r o l HEMA. To i n i t i a t e t h e p o l y m e r i z a t i o n o f C - H E M A , a z o b i s ( m e t h y l i s o b u t y r a t e ) was added ( 7 . 8 4 m i c r o m o l e / m l ) . The monomer was p o l y m e r i z e d i n a p o l y p r o p y l e n e m o l d . The mold d i m e n s i o n s w e r e 50mm χ 50mm χ 1mm. The s t a n d a r d p o l y m e r i z a t i o n c o n d i t i o n s w e r e 60°C f o r 24 h o u r s u n l e s s o t h e r w i s e n o t e d . A f t e r t h i s t i m e t h e mold was c o o l e d t o 0 ° C , and t h e C *-pHEMAwas removed and w e i g h e d . The C p H E M A w a s t h e n p l a c e d i n v a r i o u s s o l v e n t s a t 3 7 ° C . A l i q u o t s were removed a t v a r i o u s t i m e i n t e r v a l s and c o u n t e d u s i n g l i q u i d s c i n t i l l a t i o n techniques. The amount o f r a d i o a c t i v i t y f o u n d i n t h e s o l v e n t was c a l c u l a t e d as a p e r c e n t a g e o f t h e o v e r a l l r a d i o a c t i v i t y i n the polymer. F i g u r e 3 shows t h e p e r c e n t r a d i o a c t i v i t y e x t r a c t e d w i t h t i m e f o r some t y p i c a l g e l s . G e l s 1 and 2 a r e d u p licates. G e l 6 was p o l y m e r i z e d u n d e r i d e n t i c a l c o n d i t i o n s b u t was e x t r a c t e d w i t h 95% e t h a n o l . G e l 9 was p o l y m e r i z e d w i t h 45% w a t e r and e x t r a c t e d w i t h w a t e r . The r a d i o a c t i v i t y o f a l l g e l s e x t r a c t e d w i t h w a t e r l e v e l e d o u t a f t e r one d a y , b u t t h e r a d i o a c t i v i t y e x t r a c t e d w i t h e t h a n o l ( G e l 6) a p p e a r e d t o i n c r e a s e a f t e r t h i s t i m e a t a b o u t 0.5%/week. T a b l e IV p r o v i d e s a c o m p l e t e l i s t o f t h e C -HEMA p o l y m e r i z a t i o n c o n d i t i o n s , e x t r a c t i o n s o l v e n t s , and t h e p e r c e n t r a d i o a c t i v i t y e x t r a c t e d . The p e r c e n t r a d i o a c t i v i t y e x t r a c t e d was c a l c u l a t e d as t h e a v e r a g e o f t h e i s o t o p e found i n s o l u t i o n a t p o i n t s i n time from 4 days t o 5 weeks. llf


ll

l l L

1If

TABLE I V . J4 E l u t i o n o f R a d i o a c t i v i t y from C -pHEMA Gels E q u i l i b r a t e d i n Various Solvents % R a d i o a c t i v i t y in Solvent S o l v e n t a f t e r 5 wks. Gel# P o l y m e r i z a t i o n C o n d i t i o n s D i s t i l l e d H 0 4.7% + 0.13 1 24 h o u r s θ 60°C 24 h o u r s @ 60°C 2 D i s t i l l e d H 0 4 . 8 % + 0.08 24 h o u r s @ 60°C 3.6% + 0.27 Human R e f e r 3 e n c e Serum D i s t i l l e d H 0 4.8% + 0.14 3 1/2 h o u r s & 60°C D i s t i l l e d H 0 2.6% + 0.41 66 h o u r s @ 60°C 24 h o u r s @ 60°C 9.1% ± 0.90 95% E t h a n o l 24 h o u r s @ 60°C D i s t i l l e d H 0 2.9% + 0 . 3 0 ( G e l c o n t a i n e d 1% u n l a b e l e d EGDMA) D i s t i l l e d H 0 2 . 3 % ± 0.11 24 h o u r s @ 60°C ( G e l c o n t a i n e d 5% u n l a b e l e d EGDMA) D i s t i l l e d H 0 1.7% ± 0 . 0 9 24 h o u r s @ 60°C ( G e l c o n t a i n e d 45% H 0 v / v ) ,tf

2

2

2

2

2

2

2

2


94

HYDROGELS FOR MEDICAL AND RELATED 0

0

Η

0

NH

OH

9

io

(MA A)

U

2

12

11

n

APPLICATIONS

(MA)

(DMAEMA)

0

0 n

\

0CH 13

14

15

(GMA)

(MAN)

(MMA)

3


MONOMERS - FOR GEL MODIFICATION Figure 1.

H*

- Ν=ΝC=N

Commercially available gel modifiers

C=N ι OR

C=N

AIBN

+

IMINOESTER SALT

16.

R=CH

17.

R = CH CH 0CH

18.

R= C H C H 0 C H C H 0 C H C H 0 C H

- N= N C=0

C=0

OR

OR

AZOBISISOBUTYROESTER

AZOBISMETHYLISOBUTYRATE

3

2

2

2

2

AZOBISMETHOXYETHYL ISOBUTYRATE

3

2

Figure 2.

Figure 3.

2

C=N ι \, OR Η

+

H

2

H 0

- Ν=Ν -

ROH

2

2

3

AZOBISMETHOXYDIETHOXYETHYLISOBUTYRATE

Preparation of azobisisobutyrate esters

Radioactivity extracted at given time for C-HEMA gel 14

TIME (WEEKS)


7.

GREGONis E T AL.

Methacrylate Hydrogeh

95

The amount o f u n p o l y m e r i z e d C *-HEMA o r C *-pHEMA t h a t d i s s o l v e d i n t h e s o l u t i o n s i s g i v e n i n T a b l e IV. The b e t t e r s o l v e n t , e t h a n o l (#6) c o n t a i n e d more r a d i o a c t i v i t y t h a n t h e poorer s o l v e n t , water (#1,2). At shorter polymerization times, more r a d i o a c t i v i t y was f o u n d i n t h e s o l v e n t t h a n a f t e r l o n g p o l y m e r i z a t i o n t i m e s (#4 v s . #5). T h e r e d i d n o t a p p e a r t o be any s i g n i f i c a n t d i f f e r e n c e , h o w e v e r , between G e l s 1, 2 and 4 . With h i g h e r p e r c e n t c r o s s l i n k e r , t h e amount o f r a d i o a c t i v i t y t h a t i s f o u n d i n t h e s o l v e n t d e c r e a s e d (#1, 7 and 8 ) . I t was somewhat s u r p r i s i n g t o f i n d t h a t t h e l e a s t r a d i o a c t i v i t y was f o u n d i n t h e s o l v e n t when C *-HEMA was p o l y m e r i z e d w i t h 45% w a t e r (#9). These p r e l i m i n a r y studies are c o n t i n u i n g . I s o l a t i o n and i d e n t i f i c a t i o n o f t h e e x t r a c t e d r a d i o a c t i v i t y w i l l be n e c e s s a r y t o d e t e r m i n e i f i t i s due t o u n r e a c t e d monomer o r t o p o l y m e r s . ll

ll


ll

Water S w e l l i n g o f pHEMA and pMEEMA

(£s)

Membranes

I s o t r o p i c s w e l l i n g i s assumed i n t h e g e l s . Linear and w a t e r f r a c t i o n (Wf) a r e d e f i n e d as f o l l o w s : £

= length of equilibrium swollen length of dry gel

S

y

= weight of water i n weight of hydrated

f %*s

%W

= W

f

χ

gel

gel gel

= wet l e n g t h - d r y l e n g t h wet l e n g t h f

swelling

m

100

E x p e r i m e n t s t o d e t e r m i n e t h e k i n e t i c s o f l i n e a r s w e l l i n g and w a t e r f r a c t i o n o f t h e g e l were p e r f o r m e d . The pHEMA g e l s p o l y merized w i t h d i f f e r e n t water c o n c e n t r a t i o n s reached e q u i l i b r i u m w a t e r c o n t e n t a f t e r 24 h o u r s . At e q u i l i b r i u m the water f r a c t i o n (Wf) i n t h e pHEMA g e l was 0 . 4 0 ± 0 . 0 5 ( F i g u r e 4 ) , w h e t h e r o r n o t t h e HEMA was p o l y m e r i z e d w i t h w a t e r . The same e x p e r i m e n t s were n o t done w i t h MEEMA s i n c e t h i s monomer i s n o t v e r y s o l u b l e i n w a t e r , h o w e v e r , a n h y d r o u s pMEEMA r e a c h e d an e q u i l i b r i u m w a t e r f r a c t i o n o f 0.62 a f t e r 48 h o u r s . The k i n e t i c s o f l i n e a r s w e l l i n g ( £ s ) do n o t f o l l o w t h e same p a t t e r n as t h e k i n e t i c s o f w a t e r u p t a k e as measured by t h e w a t e r fraction (W ). T h i s i s f o u n d i n b o t h pHEMA ( F i g u r e 5) and pMEEMA gels (Figure 6). F o r a pHEMA g e l p o l y m e r i z e d w i t h o u t w a t e r and t h e n a l l o w e d t o e q u i l i b r a t e i n w a t e r , t h e w a t e r f r a c t i o n (Wf) increased to 0.20, h a l f the f i n a l e q u i l i b r i u m water f r a c t i o n , but t h e l i n e a r s w e l l i n g ( i l s ) was measured t o be 1 . 0 1 5 , o n l y 5% o f t h e f i n a l equilibrium l i n e a r swelling (Figure 5). An a n a l o g o u s r e s u l t i s o b t a i n e d f o r pMEEMA g e l s ( F i g u r e 6 ) . In e f f e c t , t h e r e i s a much g r e a t e r i n i t i a l amount o f w a t e r t a k e n i n t o t h e g e l t h a n w o u l d be a n t i c i p a t e d f r o m j u s t t h e l i n e a r s w e l l i n g measurement. f




~05~

"

ΙΌ

15

20" 2A

TIME (HOURS) Figure 4.

Water uptake of pHEMA polymerized at different water contents

TIME (HOURS) Figure 5. Percent equilibrium hydration (0.40 w = 100% ) and percent equilibrium linear swelling (1.165 l = 100%) plotted vs. time for pHEMA gel f

8



7.

GREGONis E T AL.

Methacrylate

Hydrogeh

97

S i m i l a r r e s u l t s a r e o b s e r v e d by R e f o j o f o r pHEMA and o t h e r g e l s (25), A b s e n c e o f l i n e a r s w e l l i n g a t low w a t e r f r a c t i o n s i s o b s e r v e d by us i n a n a l t e r n a t i v e e x p e r i m e n t w i t h pHEMA g e l s . HEMA was p o l y m e r i z e d a t v a r i o u s w a t e r c o n c e n t r a t i o n s a n d t h e n allowed t o e q u i l i b r a t e i n d i s t i l l e d water (Figure 7 ) . I t i s f o u n d t h a t when HEMA i s p o l y m e r i z e d w i t h a w a t e r f r a c t i o n (Wf) o f 0.1 o r l e s s (Wf o f 0.1 i s 25% o f t h e e q u i l i b r i u m W f ) , t h e g e l s t i l l s w e l l s t o t h e same d e g r e e as an a n h y d r o u s pHEMA g e l . T h e s e r e s u l t s i n d i c a t e t h a t t h e r e i s f r e e volume o r " v o i d s " i n t h e h y d r o g e l s , and t h i s volume i s f i l l e d w i t h w a t e r m o l e c u l e s before the g e l i s able t o e x h i b i t any l i n e a r expansion. This c o n c e p t has been used t o e x p l a i n t h e s w e l l i n g and m e c h a n i c a l b e h a v i o r o f 3 - k e r a t i n ( 2 6 ) and o t h e r b i o p o l y m e r s (27_). S i m i l a r s t u d i e s on o t h e r h y d r o p h i l i c g e l s a r e i n p r o g r e s s . Copolymers In o r d e r t o o b t a i n g e l s t h a t w o u l d s w e l l i n w a t e r a s p e c i f i e d amount, c o p o l y m e r s o f t h e h y d r o p h i l i c monomers w e r e i n v e s t i gated. A t t h e same t i m e t h e w a t e r s o l u b i l i t y o f t h e comonomers was a l s o s t u d i e d . I t was hoped t h a t monomer s o l u b i l i t y b e h a v i o r w o u l d b e u s e f u l t o e x p l a i n some a s p e c t s o f s w e l l i n g o f t h e polymer. F i g u r e 8 shows HEMA-MEMA comonomers and c o p o l y m e r s and t h e i r r e l a t i o n s h i p t o s o l u b i l i t y and s w e l l i n g i n w a t e r . Water has a maximum s o l u b i l i t y o f 3.5% ( v / v ) i n MEMA monomers. HEMA monomer i s i n f i n i t e l y s o l u b l e i n w a t e r . The comonomer s o l u t i o n s e x h i b i t a w a t e r s o l u b i l i t y t h a t i n c r e a s e s s l i g h t l y a s t h e amount o f HEMA i s i n c r e a s e d up t o 40% MEMA-60% HEMA. A t t h a t p o i n t t h e w a t e r s o l u b i l i t y i n c r e a s e s g r e a t l y u n t i l 20% MEMA-80% HEMA where t h e comonomers become i n f i n i t e l y s o l u b l e . The c o p o l y m e r s o f MEMA-HEMA a p p e a r t o have a 1 i n e a r w a t e r f r a c t i o n (Wf) r e l a t i o n s h i p f r o m 0 . 0 3 5 w a t e r f o r p u r e pMEMA t o 0.40 f o r p u r e pHEMA. F i g u r e 9 shows t h e r e l a t i o n s h i p between MEEMA-HEMA and w a t e r s o l u b i l i t y and between t h e i r c o p o l y m e r s and t h e d e g r e e o f s w e l l i n g in water. I n t h i s c a s e , MEEMA monomer d i s s o l v e s o n l y a b o u t 8% w a t e r and a s HEMA monomer i s a d d e d , t h e amount o f w a t e r t h a t i t dissolves increases sharply. Near a 6 0 : 4 0 HEMA:MEEMA r a t i o , w a t e r becomes i n f i n i t e l y s o l u b l e i n t h e comonomers. The w a t e r s w e l l i n g o f t h e c o p o l y m e r s show t h e o p p o s i t e r e l a t i o n s h i p . pMEEMA s w e l l s t o 63% H 0 , a n d a s i n c r e a s i n g amounts o f HEMA a r e i n c o r p o r a t e d i n the copolymer, the degree o f s w e l l i n g decreases u n t i l a 40% H 0 u p t a k e i s r e a c h e d f o r pHEMA. These above r e s u l t s i n d i c a t e t h a t t h e h y d r o p h i l i c i t y o f t h e monomer and t h e d e g r e e o f c r o s s l i n k i n g o f t h e p o l y m e r ( 2 8 ) a r e not the only f a c t o r s t h a t determine the degree o f water s w e l l i n g of t h e polymer. In t h e m e t h a c r y l a t e s y s t e m , we have r a t i o n a l i z e d t h a t the length o f the e s t e r chain i s a t h i r d f a c t o r t h a t should be t a k e n i n t o a c c o u n t when d i s c u s s i n g s w e l l i n g . This i s probably due t o t h e f a c t t h a t t h e l o n g e s t e r f u n c t i o n a l i t y d e c r e a s e s t h e packing energy o f the m e t h a c r y l a t e polymer. 2

2




TIME (HOURS) Figure 6. Percent equilibrium hydration (0.62 w = 100% ) and percent equilibrium linear swelling (1.37 l = 100%?) plotted vs. time for pMEEMA gel f

8

Z

0

20

40

60

80

^rOC

PERCENT SWELLING

Figure 7. Plot of percent linear swelling vs. the initial amount of water in HEMA gel. Gel polymerized without water swells to 100%. 100

-

ο Ο »C0M0N0MER

/

•

/

= COPOLYMER

PERCENT HEMA

Figure 8. Water solubility of MEMA-HEMA comonomers (v/v) and the equilibrium water weight fraction, w , of MEMA-HEMA co polymers f


7.

GREGONis E T AL.

Methacrylate


HEMA-Ionic M e t h a c r y l a t e

Hydrogels

99

Copolymers

I t h a s p r e v i o u s l y been shown t h a t marked s w e l l i n g i n w a t e r of crosslinked poly(methacrylic acid) gels i s a function o f the degree o f n e u t r a l i z a t i o n (29, 3 0 , 31). We needed t o know t h e e f f e c t o f s w e l l i n g i n h y d r o g e l s as a f u n c t i o n o f c h a r g e i n c o r porated i n t o t h eg e l . Forthis investigation, methacrylic acid (MAA) i s u s e d t o i n t r o d u c e a n i o n i c g r o u p s and d i m e t h y l aminoethy1 m e t h a c r y l a t e (DMAEMA) i s used t o i n t r o d u c e c a t i o n i c g r o u p s i n pHEMA. The g e l s w e r e p r e p a r e d by a d d i n g m o l a r amounts o f MAA a n d / o r DMAEMA t o t h e HEMA monomer a l o n g w i t h 40% v / v w a t e r a n d were p o l y m e r i z e d a s membranes u s i n g s t a n d a r d c o n d i t i o n s . The g e l s w e r e e q u i l i b r a t e d f o r two d a y s i n d i s t i l l e d w a t e r b e f o r e t h e e q u i l i b r i u m w a t e r f r a c t i o n (Wf) was d e t e r m i n e d . As shown i n F i g u r e s 10 and 1 1 , pHEMA g e l s p o l y m e r i z e d w i t h up t o 5 m o l a r p e r c e n t MAA o r DMAEMA show l i t t l e change i n e q u i l i b r i u m w a t e r c o n t e n t f r o m t h a t o f p u r e pHEMA g e l p o l y m e r i z e d a t i d e n t i c a l c o n d i t i o n s (Wf = 0 . 4 0 ) . This i s not s u r p r i s i n g s i n c e c a r b o x y l i c a c i d s a n d t e r t a r y amines a r e weak a c i d s a n d b a s e s and do n o t i o n i z e t o an a p p r e c i a b l e e x t e n t a t n e u t r a l p H . To f o r m c h a r g e d g r o u p s , t h e MAA-HEMA c o p o l y m e r s w e r e e q u i l i b r a t e d i n pH 10 NaOH s o l u t i o n f o r t w e l v e h o u r s and t h e DMAEMA-HEMA c o p o l y m e r s w e r e e q u i l i b r a t e d i n pH 3 HC1 s o l u t i o n f o r t w e l v e hours. A f t e r t h i s time they are e q u i l i b r a t e d i n d i s t i l l e d water f o r two d a y s , c h a n g i n g t h e w a t e r s e v e r a l t i m e s i n t h i s p e r i o d t o remove e x c e s s i o n s f r o m t h e g e l s . The c o n v e r s i o n o f MAA t o i t s c a r b o x y l a t e s a l t i n t h e g e l s d r a m a t i c a l l y increases the e q u i l i b r i u m water content o f t h e g e l (Figure 10). F o r e x a m p l e , t h e HEMA g e l c o n t a i n i n g o n l y 2 m o l a r p e r c e n t MAA e q u i l i b r a t e d w i t h a w a t e r f r a c t i o n g r e a t e r t h a n 0 . 9 0 . C o n v e r t i n g t h e HEMA-DMAEMA g e l t o i t s h y d r o c h l o r i d e s a l t d i d n o t show t h e same d r a m a t i c s w e l l i n g e f f e c t , even t h o u g h t h e w a t e r f r a c t i o n i n c r e a s e d w i t h i n c r e a s i n g c o n c e n t r a t i o n o f DMAEMA. The 5 m o l a r p e r c e n t DMAEMA g e l w a t e r f r a c t i o n measured 0 . 4 6 ( F i g u r e 11). I t i s known t h a t t e r t a r y amines a c t a s c h a i n t r a n s f e r agents w i t h the m e t h a c r y l a t e system ( 3 2 , 3 3 ) . In t h e s e e x p e r i m e n t s , t h e t e r t a r y amine w o u l d a l s o become p a r t o f t h e p o l y m e r chain. The e f f e c t o f t h i s w o u l d g i v e t h e DMAEMA-HEMA g e l s a higher c r o s s l i n k d e n s i t y , p o s s i b l y accounting f o r i t s lower degree o f s w e l l i n g i n w a t e r . F i g u r e 12 shows t h e e q u i l i b r i u m w a t e r c o n t e n t o f HEMA g e l s c o n t a i n i n g e q u a l m o l a r q u a n t i t i e s o f MAA and DMAEMA. When e q u i l i b r a t e d i n d i s t i l l e d water the water f r a c t i o n o f the g e l i n c r e a s e d s l i g h t l y w i t h i n c r e a s i n g m o l a r p e r c e n t MAA-DMAEMA t o a b o u t 0 . 5 w a t e r f r a c t i o n f o r t h e 5 m o l a r p e r c e n t g e l . The c a r b o x y l a t e g r o u p s were t h e n c o n v e r t e d t o t h e i r s o d i u m s a l t a n d t h e amino g r o u p s were c o n v e r t e d t o f r e e amines by e q u i l i b r a t i n g t h e g e l i n pH 10 NaOH s o l u t i o n f o r one d a y . The g e l s w e r e r e e q u i l i b r a t e d i n d i s t i l l e d w a t e r f o r two d a y s and a much g r e a t e r s w e l l i n g d e g r e e was o b s e r v e d . The 5 p e r c e n t MAA-DMAEMA g e l had


100


•• COMONOMER = COPOLYMER

Figure 9. Water solubility of MEEMAHEMA comonomers (v/v) and the equi librium water weight fraction, w , of MEEMA-HEMA copolymers

20


f

111 0 4 -

- Ο

- Ο

40

60

PERCENT HEMA

- Ο

-Ο

Ο

Ο

MOLAR PERCENT MAA IN HEMA GEL

Figure 10. Equilibrium water weight fraction, w , of HEMA-MAA copolymers f

CH •

· IONIZED

FORM

3

- N H CI " CH

3

ÇH Ο = UN-IONIZED

3

FORM - N

,^ • · « · · ^

~~

1

2

o

-ο

ο

3

4

5

MOLAR PERCENT DMAEMA IN HEMA GEL Figure

11. Equilibrium water weight fraction, w , of HEMA-DMAEMA copolymers f



GREGONis E T A L .

Methacrylate

1

2

Hydrogeh

3

4

5

EQUAL MOLAR PERCENT MAA AND DMAEMA IN HEMA GEL

Figure 12. Equilibrium water weight fraction, w , of HEMA-MAA-DMAEMA terpolymers. MAA and DMAEMA are polymerized at equal molar concentrations. f



102


a water fraction measuring 0.81 (Figure 12). This same effect was not observed when the amine was converted to its hydrochloride salt by equilibrating the gel in pH 3 hydrochloric acid followed by two days equilibration in distilled water. The 5 percent MAA-DMAEMA had a water fraction of only 0.53 (Figure 12). It is not known at present why the carboxylate salt gel swells to a greater degree than the amine hydrochloride gel. Polymerization of the amine salt of DMAEMA with HEMA would possibly reduce the crosslink density due to chain transfer mechanisms found in free tertary amine groups. Careful experiments have to be designed in this regard since it is known that changing the pH changes the reactivity ratios of ionic methacrylates (34). Future experiments will be directed towards a correlation of equilibrium water fraction, monomer type, concentration of charge and groups and degree of covalent cross!inking in the gels. Acknowledgements We gratefully acknowledge NIH Grant HL 16921-01 for financial support of this research, and Hydro Med Sciences, Inc., for generous donations of pure hydroxyethyl methacrylate. Abstract A summary of hydrophilic methacrylate monomer synthesis is discussed. Radical polymerization of the methacrylate system was accomplished by azobisisobutyronitrile (AIBN) derivatives. Some new water soluble AIBN derivatives were prepared and used. Copolymers of various hydrophilic methacrylate monomers afford a method to control water uptake. Some water swelling parameters of poly(hydroxyethyl methacrylate) and poly(methoxyethoxyethy1 methacrylate) are described. The water uptake as measured by the water fraction is shown not to be a linear function of the degree of swelling. The water swelling behavior of poly(hydroxyethyl methacrylate) containing ionic groups is described using methacrylic acid for anionic groups and dimethylaminoethyl methacrylate for cationic groups. The synthesis of C -hydroxyethyl methacrylate is reported. After the radiolabeled monomer was polymerized, the amount of radioactivity in various solvents was measured. 14

Literature Cited 1. 2. 3. 4. 5.

Wichterle, O., and Lim, D., Nature (1960) 185, 117. Wichterle, O., Encyclopedia of Polymer Sci., (1971) 15, 273. Wichterle, O., U. S. Pat. 3,361,858 (1968). Majkus, V., Horakova, Z., Vymula, F., and Stol, M., J. Biomed. Mat. Res. (1969) 3, 443. Refojo, M. F., J. Biomed, Mat. Res. (1969) 3, 333. In Hydrogels for Medical and Related Applications; Andrade, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

7.

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13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

Methacrylate Hydrogek

103

Taylor, G. R., Warren, T. C., Murray, D. G., and Prins, W., J. Surgical Res. (1971) 11, 401. Refojo, M. F., J. Appl. Polymer Sci. (1965) 9, 3161. Fegley, V. W., and Roland, S. P., U. S. Patent 2,680,735. Rohm & Haas Co., British Patent 852,384 (1965). Yocum, R. H. and Nyquist, Ε. B., "Functional Monomers," Marcel Dekker, New York, Vol. 1, 1973, pp 299-487 and Vol. 2 (1974). Horsley, L. H., and Sheetz, D. P., U. S. Patent 3,162,677. Brinkman, U. A. Th., Van Schaik, T. A. M., deVries, G., and deVisser, A. C., this symposium. Wisniewski, S. J., Gregonis, D. E., Kim, S. W., and Andrade, J. D., this symposium. Lenz, R. W., "Organic Chemistry of Synthetic High Polymers," John Wiley & Sons, New York, 1967, p. 244. Pryor, W. Α., "Free Radicals," McGraw-Hill, New York, 1966, pp. 128-133. Walling, C., "Free Radicals in Solution," John Wiley and Sons, New York, 1957, p. 511. Mortimer, G. Α., J. Org. Chem. (1965) 30, 1632. Thiele, J., and Hauser, K., Ann. (1896) 290, 1. Lim, D., Coll. Czech. Chem. Comm. (1968) 33, 1122. Ma, S. Μ., Gregonis, D. E., Chen, C. Μ., and Andrade, J. D., this symposium. Russell, G. Α., Dalling, D. K., Gregonis, D. E., deVisser, A. C., and Andrade, J. D., this symposium. Ma, S. Μ., Gregonis, D. E., Van Wagenen, R., and Andrade, J. D., this symposium. Flory, P. J.,"Principles of Polymer Chemistry," Cornell University Press, Ithaca, New York, 1953, p. 384. Sorenson, W. R., and Campbell, T. W., "Preparative Methods of Polymer Chemistry," Interscience Publications, New York, 1961. Refojo, M. F., Contact and Intraocular Lens Med. J., (1975) 1, 153. Bradbury, J. H., and Leeder, J. D., J. Appl. Polymer Sci., (1963) 7, 533. Hiltner, Α., Case Western Reserve University, Cleveland, Ohio, personal communication. Flory, P. J., "Principles of Polymer Chemistry," Cornell University Press, Ithaca, New York, 1953, p. 581. Schaefgen, J. R. and Trivisonno, C. F., J. Am. Chem. Soc., (1951) 73, 4580. Schaefgen, J. R. and Trivisonno, C. F., J. Am. Chem. Soc., (1952) 74, 2715. Katchalsky, A. and Eisenberg, H., J. Polymer Sci., (1951) 6, 145. Lenz, R. W., "Organic Chemistry of Synthetic High Polymers," John Wiley and Sons, New York, 1967, p. 355.


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34.



The Chemistry of Some Selected Methacrylate Hydrogels - Hydrogels

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