Hydrogels for Medical and Related Applications

---

23 Biological and Physical Characteristics of Some Polyelectrolytes E. O. LUNDELL, G. T. KWIATKOWSKI, J. S. BYCK, F. D. OSTERHOLTZ, W. S. CREASY, and D. D. STEWART

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

Union Carbide Corp., Chemicals and Plastics, Research and Development, Bound Brook, N. J. 08805

It has been recognized for some time that the surface charge of blood components plays a role in their interactions with the blood vessel wall.(1)Based largely on the results of Sawyer and coworkers (2), i t has also become apparent that surface charge, and electrochemical phenomena in general, can significantly influence blood/material interactions and that their control may be a necessary condition for development of a truly blood compatible material. Research stemming from ths concept, involving blood compatibility studies with metals and polymers, has led to the conclusion that a limiting level of negative charge density or negative potential may be required to achieve nonthrombogenic character, provided that other necessary conditions are also satisfied. This has prompted extensive research directed at development of anionic polyelectrolytes which might be expected to be blood compatible. As represented in Figure 1, the blood compatibility and, in particular, thromboresistance of carboxyl-containing copolymers would be expected to depend upon the interaction of several physical and chemical parameters. These include not only the total concentration of ionizable groups, the degree to which these are neutralized by various monovalent or divalent metal salts, but also the hydrophilicity of the total polymer system. This last property depends largely on the selection of the neutral comonomer. As was expected at the outset of this program, and has been confirmed by experimental results, none of these parameters can be considered to be a sufficient condition for blood compatibility. A l l must be controlled, however, as necessary conditions for compatibility.

305

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

HYDROGELS FOR MEDICAL AND RELATED APPLICATIONS

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

306

CONCENTRATION OF I O N I Ζ A B L E GROUPS (WT. % ACID)

C0 M 2

20

CH CH 2

CHCH

I

15

R

10 5 30

60

DEGREE OF NEUTRALIZATION

ETHYLENE/ACRYLIC ACID, ETHYLENE/VINYL •VINYL ACETATE/CROTONIC

SULFONATE

ACID

•VINYL Ρ Y R R O L I D O N E / A C R Y L I C

ACID

Figure 1. Schematic of the surface charge density and hydrophilicity of some polyelec­ trolytes

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

23.

LUNDELL

E T AL.

Characteristics of Polyelectrolytes

307

METHODS BIOLOGICAL COMPATIBILITY TESTING B i o l o g i c a l t e s t data d e s c r i b e d r e p r e s e n t the r e ­ s u l t s o f e v a l u a t i o n programs conducted by o t h e r i n v e s ­ t i g a t o r s under c o n t r a c t t o the N a t i o n a l H e a r t and Lung I n s t i t u t e o f the N a t i o n a l I n s t i t u t e s o f H e a l t h . Meth­ ods employed by t h e s e t e s t e r s a r e summarized i n t h i s section.

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

In

V i t r o T e s t Methods P a r t i a l Thromboplastin

Time.

Polymer samples were s u b m i t t e d i n t h e form o f tubes and s t i r r i n g p a d d l e s . G l a s s tubes (26 mm i . d . χ 100 mm) were s o l u t i o n c o a t e d on t h e e n t i r e i n t e r i o r s u r f a c e e x c e p t f o r a 0.5"-1.0" r i m a t t h e o r i f i c e . T h i s was a c c o m p l i s h e d by i n t r o d u c i n g 3 ml o f polymer s o l u t i o n i n t o the tube, f i t t i n g the tube t o a r o t a r y e v a p o r a t o r , t i l t i n g i t so t h a t the e n t i r e i n n e r s u r ­ f a c e would be c o a t e d (except f o r the r i m a t the o r i ­ f i c e ) , and a p p l y i n g heat t o the e x t e r i o r o f the e v a c ­ u a t e d tube w h i l e b e i n g r o t a t e d . S t i r r i n g p a d d l e s were p r e p a r e d by s o l u t i o n c o a t i n g g l a s s r e c t a n g l e s (3 mm χ 18 mm χ 120 mm) o r by c u t t i n g e q u i v a l e n t s i z e s t r i p s from compression molded polymer s h e e t . To c a r r y o u t the p a r t i a l t h r o m b o p l a s t i n time t e s t , 25 ml o f n a t i v e whole b l o o d was drawn i n t o a s i l i c o n e c o a t e d (G. Ε. D r i - F i l m SC-87) g l a s s s y r i n g e and imme­ d i a t e l y t r a n s f e r r e d t o t h e polymer c o a t e d t u b e . The p a d d l e was employed t o s t i r the b l o o d sample f o r f o u r minutes a t 60 rpm. A t t h e end o f t h i s t i m e , the sam­ p l e was a n t i c o a g u l a t e d by a d d i t i o n o f sodium c i t r a t e and the c e l l u l a r elements were removed by c e n t r i f u g a t i o n (425 g) a t 4°C. P a r t i a l t h r o m b o p l a s t i n time o f the r e s u l t a n t p l a t e l e t - p o o r plasma was determined ... a c c o r d i n g t o the methods o f L a n g d e l l ( 3 . ) a n d Rodman. Stypven

Time.

a

Samples o f p l a t e l e t - p o o r plasma p r e p a r e d f o r de­ t e r m i n a t i o n o f p a r t i a l t h r o m b o p l a s t i n time were a l s o used t o measure Stypven time a c c o r d i n g t o the methods of M i a l e ( i ) and Hardisty.(£)

a

*

Dr. R. G. Mason, U n i v e r s i t y o f N o r t h C a r o l i n a , School of Medicine, Chapel H i l l , North C a r o l i n a

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

HYDROGELS FOR MEDICAL AND RELATED APPLICATIONS

308

In V i v o T e s t Methods b

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

Canine

Implantation Studies.

T e s t samples were i n the form o f vena cava ("Gott") r i n g s . These a r e 9 mm l o n g and have an o.d. o f 8 mm. Both i n f l o w and o u t f l o w o r i f i c e s were streamlined. E t h y l e n e / a c r y l i c a c i d copolymer and ionomer r i n g s had a w a l l t h i c k n e s s o f 1mm (6 mm i . d . ) , whereas a l l r e m a i n i n g samples had a w a l l t h i c k n e s s o f 0.5 mm (7 mm i . d . ) . The l a r g e r i . d . r i n g was the s t a n d a r d s i z e p r e s c r i b e d by G o t t . Vena cava r i n g s may be p r e p a r e d by compression m o l d i n g ( i . d . ) and machining ( o . d . ) , by i n j e c t i o n m o l d i n g , o r by s o l u t i o n c o a t i n g o f t h e t e s t polymer onto i n j e c t i o n molded h i g h d e n s i t y polyethylene rings. There was a s i n g l e c i r c u m f e r e n t i a l groove midway between the ends o f each r i n g t o p e r m i t the r i n g t o be t i e d i n p l a c e a f t e r i m p l a n t a t i o n . T e s t s were conducted by i n s e r t i n g t h e r i n g , u s i n g a s p e c i a l i n s e r t i o n d e v i c e , i n t o the c a n i n e i n f e r i o r vena cava through a s m a l l i n c i s i o n i n the r i g h t a t r i u m . A wrapping was p l a c e d over t h e r i n g e x t e r n a l t o the b l o o d v e s s e l t o p r e v e n t c u l de sac f o r m a t i o n and the r i n g was t i e d i n p l a c e . I n i t i a l l y t h r e e samples o f polymer were each i m p l a n t e d f o r two h o u r s , a f t e r which time they were removed and examined f o r the p r e s e n c e of adherent thrombi. Polymers which were r a t e d h i g h l y t h r o m b o r e s i s t a n t on the b a s i s o f t h i s a c u t e t e s t were t h e n i m p l a n t e d i n t h e same manner f o r a p e r i o d o f two weeks. Canine

Implantation Studies.

Implant samples were i n the form o f 30 mm l o n g tubes w i t h an o.d. o f 9 mm and a w a l l t h i c k n e s s o f 1 (7 mm i . d . ) . Both i n f l o w and o u t f l o w o r i f i c e s were streamlined. Tubes may be f a b r i c a t e d by the s e v e r a l methods noted above f o r vena cava r i n g s . The tubes were c i r c u m f e r e n t i a l l y grooved near each end.

* Dr. V. L. G o t t , Johns Hopkins U n i v e r s i t y , Dept. o f Surgery, B a l t i m o r e , Maryland. c

* Dr. P. N. Sawyer, S t a t e U n i v e r s i t y o f New York, Downstate M e d i c a l C e n t e r , B r o o k l y n , New York.

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

mm

23.

LUNDELL ET AL.

Characteristics

of

Polyelectrolytes

309

I m p l a n t a t i o n was i n the c a n i n e i n f e r i o r vena cava through an i n c i s i o n i n t h a t v e s s e l . The tube i s t i e d i n p l a c e a t each groove, w i t h one t i e p r o x i m a l and one t i e d i s t a l t o the i n c i s i o n . F o r each polymer, one tube was employed as an a c u t e (2 hour) t e s t and two tubes as c h r o n i c (14 days) i m p l a n t s . POLYMER SYNTHESIS

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

E t h y l e n e / A c r y l i c A c i d Copolymers and Ionomers The f a m i l y o f e t h y l e n e / a c r y l i c a c i d copolymers seemed an e x c e l l e n t e x p e r i m e n t a l probe f o r a c c o m p l i s h i n g t h i s study f o r s e v e r a l r e a s o n s . Copolymers cont a i n i n g 2-20% by weight o f a c r y l i c a c i d a r e w e l l known m a t e r i a l s and c o u l d be r e a d i l y o b t a i n e d c o m m e r c i a l l y ; c o n v e r s i o n o f t h e s e polymers t o t h e i r p a r t i a l l y neut r a l i z e d a l k a l i m e t a l , a l k a l i n e e a r t h , and o r g a n i c amine s a l t s had been t h o r o u g h l y i n v e s t i g a t e d and c o u l d be c o n t r o l l e d over a range o f 0-70% n e u t r a l i z a t i o n ; and t h e s e polymers a r e tough, f l e x i b l e t h e r m o p l a s t i c s c a p a b l e o f b e i n g f a b r i c a t e d from s o l u t i o n o r i n the m e l t t o y i e l d h i g h l y s a t i s f a c t o r y t e s t samples. E t h y l e n e / V i n y l S u l f o n i c A c i d Copolymers and Ionomers E t h y l e n e / v i n y l s u l f o n i c a c i d copolymers were p r e p a r e d by a two-step p r o c e d u r e . I n the f i r s t s t e p , e t h y l e n e was c o p o l y m e r i z e d w i t h sodium v i n y l s u l f o n a t e i n a h i g h p r e s s u r e aqueous e m u l s i o n p o l y m e r i z a t i o n . The r e s u l t i n g f u l l y n e u t r a l i z e d sodium v i n y l s u l f o n a t e ionomers were c o n v e r t e d by t r e a t m e n t w i t h anhydrous HCL t o the d e s i r e d s u l f o n i c a c i d copolymers which c o u l d be t i t r a t e d w i t h base t o y i e l d p a r t i a l l y neut r a l i z e d ionomers. N - V i n y l P y r r o l i d o n e / A c r y l i c A c i d Copolymers and Ionomers (NVP/AA) In i n i t i a l s t u d i e s l e a d i n g t o p r e p a r a t i o n o f Nv i n y l p y r r o l i d o n e ( N V P ) / a c r y l i c a c i d (AA) copolymers, s y n t h e s i s was c a r r i e d o u t as a two-step p r o c e d u r e . I n the f i r s t s t e p , sodium a c r y l a t e was c o p o l y m e r i z e d w i t h NVP i n b u f f e r e d aqueous s o l u t i o n a t pH 7-8 a f t e r which the r e s u l t i n g f u l l y n e u t r a l i z e d ionomer was a c i d i f i e d t o y i e l d t h e d e s i r e d N-VP/AA copolymer. Potassium p e r s u l f a t e was employed as i n i t i a t o r i n the p o l y m e r i z a t i o n s t e p . A l t h o u g h the c o p o l y m e r i z a t i o n c o u l d be c a r r i e d o u t s u c c e s s f u l l y , attempts t o c a r r y o u t a c i d i f i c a t i o n with concentrated or half-concentrated

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

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

310

HYDROGELS FOR MEDICAL AND RELATED APPLICATIONS

h y d r o c h l o r i c a c i d , f o l l o w e d by d r y i n g a t e l e v a t e d temperatures, r e s u l t e d i n d e c o m p o s i t i o n and d i s c o l o r a t i o n of the product. A l t h o u g h t h e r e had i n i t i a l l y been c o n c e r n t h a t d i r e c t a c i d i f i c a t i o n might, t h e r e f o r e , not be p o s s i b l e , i t was s u b s e q u e n t l y found t h a t s a t i s f a c t o r y c o l o r l e s s polymers c o u l d be o b t a i n e d i f two p r e c a u t i o n s were t a k e n . F i r s t , a c i d i f i c a t i o n was c a r r i e d o u t a t temperatures below 10°C. Second, exh a u s t i v e p u r i f i c a t i o n o f the polymer, by d i s s o l v i n g i n water and r e p r e c i p i t a t i n g w i t h a c e t o n e , was re~q u i r e d t o remove a l l t r a c e s o f a c i d b e f o r e d r y i n g . I t was a l s o found t h a t t h i s p u r i f i c a t i o n p r o c e d u r e p r o duced a drop i n a c r y l i c a c i d c o n t e n t , as determined by t i t r a t i o n , presumably by removing i m p u r i t i e s o f a c r y l i c a c i d homopolymer. Even a f t e r removal o f t h e s e imp u r i t i e s , however, t h e p r o d u c t s were c o n s i s t e n t l y found t o have h i g h e r AA/NVP r a t i o s than i n the o r i g i n a l monomer f e e d . By r u n n i n g a p o l y m e r i z a t i o n t o p a r t i a l c o n v e r s i o n , w i t h c o n t i n u o u s f e e d o f monomers and c o n t i n u o u s removal o f r e a c t i o n m i x t u r e , i t was p o s s i b l e t o c o n v e n i e n t l y c o n t r o l u n r e a c t e d monomer r a t i o s t o p r e p a r e a u n i f o r m copolymer throughout the c o u r s e o f the r e a c t i o n . Vinyl Acetate/Crotonic Acid Ionomers

(VA/CA) Copolymers

and

V i n y l a c e t a t e and c r o t o n i c a c i d were p o l y m e r i z e d under aqueous e m u l s i o n c o n d i t i o n s a t 6 5 - 6 9 ° C ( s l i g h t v i n y l a c e t a t e r e f l u x ) , w i t h p o t a s s i u m p e r s u l f a t e emp l o y e d as i n i t i a t o r . S m a l l amounts o f sodium a c e t a t e were used as b u f f e r f o r the c r o t o n i c a c i d . Emulsions were p r e p a r e d w i t h f i n a l s o l i d s c o n t e n t o f a p p r o x i m a t e l y 50%. A t low c r o t o n i c a c i d (CA) c o n t e n t ( 8%), the r e a c t i o n was s l i g h t l y e x o t h e r m i c , whereas w i t h CA l e v e l s h i g h e r than 10% the r e a c t i o n was more s l u g g i s h . R e a c t i o n t i m e s ranged from 20-30 minutes f o r 5% CA copolymers t o 15-20 hours f o r copolymers c o n t a i n i n g ^15% c r o t o n i c a c i d . The polymer e m u l s i o n o b t a i n e d p r o v e d t o be v e r y s t a b l e and d i f f i c u l t t o c o a g u l a t e . I s o l a t i o n was b e s t a c c o m p l i s h e d by g r a d u a l a d d i t i o n o f methanol t o the t h i c k l a t e x a t 0-5°C, w i t h c o n t i n u o u s removal o f t h e s l i m y p r o d u c t . T h i s was d r i e d under vacuum t o y i e l d r e l a t i v e l y b r i t t l e polymer o f o n l y modest m o l e c u l a r w e i g h t . High m o l e c u l a r w e i g h t s a r e u n o b t a i n a b l e because o f the c h a i n t r a n s f e r a c t i v i t y of crotonic a c i d .

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

23.

LUNDELL

ET AL.

Characteristics

of Polyelectrolytes

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

Coating o f P o l y e l e c t r o l y t e Hydrogels pylene

onto

311

Polypro-

The h y d r o p h o b i c PE s u r f a c e can be made w e t t a b l e w i t h water by t r e a t m e n t w i t h chromic a c i d " c l e a n i n g solution". The PE tubes were suspended i n a m i x t u r e of c o n c e n t r a t e d s u l f u r i c a c i d c o n t a i n i n g s o l i d c h r o m i um t r i o x i d e and t h e m i x t u r e s t i r r e d a t room temperat u r e f o r one day. The tubes were r i n s e d w e l l w i t h d i s t i l l e d water f o l l o w e d by a r i n s e w i t h methanol. After t h i s t r e a t m e n t the tubes were n o t a l l o w e d t o d r y and were touched o n l y w i t h methanol r i n s e d c l e a n r u b b e r gloves. They were s t o r e d u n t i l used i n a j a r c o n t a i n i n g methanol. The tubes were p l a c e d i n a F e r r i s wheel a p p a r a t u s and c o a t e d w i t h a 10% (wt/wt) s o l u t i o n o f Union C a r b i d e A-174 s i l a n e a d h e s i o n promoter i n methan o l e i t h e r by s p r a y i n g o r d i p p i n g . The tubes were d r i e d and heat t r e a t e d (80°/0.5 hr) i n an oven w h i l e t u r n i n g w i t h t h e i r c y l i n d r i c a l a x i s p a r a l l e l t o the axis of rotation. The tubes were then c o a t e d w i t h a s o l u t i o n o f polyelectrolyte. A f t e r the d e s i r e d amount o f p o l y e l e c t r o l y t e had been c o a t e d onto the PE r i n g the c o a t i n g was h e a t c u r e d (80°/l h r ) . VA/CA s o l u t i o n c o n t a i n i n g 10% by weight polymer i n methanol was used. Two complete immersions o f t h e tube i n the s o l u t i o n , f o l lowed by d r y i n g , produced a d e f e c t - f r e e c o a t i n g o f p r o per t h i c k n e s s . A f t e r each d i p , a d r o p l e t o f s o l u t i o n r o l l e d around i n s i d e the tube as i t i s r o t a t e d i n the 80°C oven u n t i l the s o l v e n t i s e v a p o r a t e d . I n the c a s e VP/AA, a s o l u t i o n c o n t a i n i n g 5% by w e i g h t polymer i n methanol was used. One immersion f o l l o w e d by s h a k i n g to remove any e x c e s s drops i s used t o i n s u r e t h a t the e n t i r e tube has some f i n i t e c o a t i n g o f t h e polymer. A f t e r e v a p o r a t i n g o f f the r e m a i n i n g s o l v e n t a 0.15 ml d r o p l e t o f the s o l u t i o n i s p l a c e d i n s i d e the tube f o l lowed by e v a p o r a t i o n o f s o l v e n t w i t h r o t a t i o n . For i r r a d i a t i o n c r o s s l i n k i n g the p r e s e n c e o f a c o n t r o l l e d amount o f water i n the c o a t i n g and the absence o f oxygen both enhanced the e f f i c i e n c y o f c r o s s l i n k i n g o f the c o a t i n g . Water c o u l d be added t o the c o a t i n g by e x p o s i n g t h e tubes t o a humid atmosphere. The a b s o r p t i o n o f 2% by weight water by a 20 ml w i t ness s t r i p was used a s a g u i d e . The dampened tubes were s e a l e d under n i t r o g e n o r a r g o n i n a PE bag and i r r a d i a t e d w i t h the Van de G r a a f f . The dosages r e q u i r e d were 35 megarads f o r VA/CA and 100 megarads f o r NVP/CA. However, v a r i a t i o n i n h y d r o g e l d e n s i t y were a t t a i n a b l e i n t h e NVP/AA case o v e r a range o f 80-200 megarads.

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

312

HYDROGELS FOR MEDICAL AND RELATED APPLICATIONS

D i r e c t Graft Polymerization of V i n y l Acetate/Crotonic A c i d from P o l y p r o p y l e n e The p o l y p r o p y l e n e o b j e c t s t o be c o a t e d w i t h hyd r o g e l were p l a c e d i n a f l a s k c o n t a i n i n g e i t h e r an aqueous e m u l s i o n o r an e t h a n o l s o l u t i o n o f v i n y l acet a t e , c r o t o n i c a c i d , sodium c r o t o n a t e and a s u r f a c t a n t ( T e r g i t o l 12-P-12). The c o n c e n t r a t i o n o f monomers was e i t h e r 25% o r 50% by weight, and the s u r f a c t a n t was 1% by weight. The s o l u t i o n (emulsion) was deoxygenated w i t h n i t r o g e n , p l a c e d i n a C o ^ s o u r c e and i r r a d i a t e d at a r a t e o f 50,000 r a d / h r w h i l e a g i t a t i o n was maint a i n e d by n i t r o g e n . A f t e r i r r a d i a t i o n the samples were removed from the f l a s k and t h o r o u g h l y washed w i t h e t h a n o l t o remove any adsorbed polymer. The samples were then e q u i l i b r a t e d w i t h water.

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

6

RESULTS AND

DISCUSSION

I n i t i a l l y , an attempt was made t o e l u c i d a t e the r e l a t i o n s h i p o f the s u r f a c e charge d e n s i t y o f a mate r i a l to i t s hemocompatibility. Two systems, e t h y l e n e / a c r y l i c a c i d (EAA) and e t h y l e n e / v i n y l s u l f o n a t e (EVS), were chosen f o r s t u d y . No member o f the EVS s e r i e s o f copolymers and ionomers showed s i g n i f i c a n t thromboresistance (7) and o n l y two members o f the EAA s e r i e s (the 19% a c r y l i c a c i d copolymer and i t s 60% sodium ionomer) showed s i g n i f i c a n t t h r o m b o r e s i s t a n c e . (JzW To e l u c i d a t e the thrombogenic dependence on hyd r o p h i l i c i t y , two systems, N - v i n y l p y r r o l i d o n e / a c r y l i c a c i d (NVP/AA) and v i n y l a c e t a t e / c r o t o n i c a c i d (VA/CA) copolymers and ionomers, were chosen f o r s t u d y . While no member o f the NVP/AA s e r i e s d i s p l a y e d any thrombor e s i s t a n c e (MLIJL?.) , members o f the VA/CA s e r i e s showed v a r i o u s degrees o f t h r o m b o r e s i s t a n c e . The 2% c r o t o n i c a c i d 60% sodium ionomer, i n p a r t i c u l a r , e x h i b i t e d a h i g h degree of t h r o m b o r e s i s t a n c e i n vena cava i m p l a n t studies. Ethylene/Acrylic Acids Polyelectrolytes A s e r i e s o f copolymers and ionomers was p r e p a r e d which r e p r e s e n t e d f o u r l e v e l s o f t o t a l c a r b o x y l conc e n t r a t i o n (4.0, 9.8, 14.7, and 19.2% a c r y l i c a c i d ) . A t each l e v e l , u n n e u t r a l i z e d copolymers were compared w i t h copolymers which had been c o n v e r t e d t o a p p r o x i m a t e l y 30% and 60% n e u t r a l i z e d ionomers. Counteranions i n v e s t i g a t e d i n c l u d e d l i t h i u m , sodium, potassium, magnesium, c a l c i u m , and d i m e t h y l e t h a n o l a m i n e . The

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

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

23.

LUNDELL ET AL.

Characteristics

of

Polyelectrolytes

313

polymers which comprise t h e s e r i e s o f twenty-one e t h y l e n e / a c r y l i c a c i d copolymers and ionomers were e x p e c t e d t o d i f f e r from one a n o t h e r i n a number o f ways. These d i f f e r e n c e s i n c l u d e d v a r i a t i o n i n measurable p h y s i c a l c h e m i c a l parameters by which such s u r f a c e p r o p e r t i e s as w e t t a b i l i t y and e l e c t r o c h e m i c a l b e h a v i o r can be c h a r a c t e r i z e d , as w e l l as v a r i a t i o n o f c h e m i c a l i n t e r a c t i o n s w i t h b l o o d on t h e m o l e c u l a r l e v e l . The c o n t a c t a n g l e s o f d i s t i l l e d water on t h e polymer s u r f a c e s ranged from a h i g h o f 8 7 ( s u r f a c e f r e e energy = 1 9 . 9 ergs/cm) f o r t h e u n n e u t r a l i z e d 9 . 8 % a c r y l i c a c i d copolymer t o a low o f 7 1 ( 3 1 . 6 ergs/cm) f o r h i g h l y n e u t r a l i z e d l i t h i u m and sodium ionomers o f t h e 1 9 . 2 % a c r y l i c a c i d copolymer. Zeta p o t e n t i a l s determined by Dr. Sawyer ana coworke r s (15/ ( T a b l e I) a t SUNY-Downstate M e d i c a l C e n t e r were large negative values, suggesting t h a t the electrochemic a l c o n d i t i o n s proposed f o r b l o o d c o m p a t i b i l i t y were satisfied. I n i t i a l e v a l u a t i o n s o f the thrombogenicity of these m a t e r i a l s was performed by Mason, e t a l . (S) , a t t h e U n i v e r s i t y o f N o r t h C a r o l i n a S c h o o l o f M e d i c i n e and Pennington (9^) a t B a t t e l l e Memorial I n s t i t u t e , u s i n g Stypven time and p a r t i a l t h r o m b o p l a s t i n time as a measure o f b l o o d c o m p a t i b i l i t y (Table I I ) . No member o f the s e r i e s o f twenty-one e t h y l e n e / a c r y l i c a c i d c o p o l y mers and ionomers appeared t o be h i g h l y t h r o m b o r e s i s t a n t on t h e b a s i s o f t h e d a t a . The v a r i a t i o n s i n p o l y mer s t r u c t u r e appear t o have no s i g n i f i c a n t e f f e c t on the Stypven time, s i n c e a l l polymers t e s t e d y i e l d e d values w i t h i n experimental error o f values obtained f o r the s i l i c o n i z e d g l a s s c o n t r o l s . I n t h e case o f t h e p a r t i a l t h r o m b o p l a s t i c t i m e s , however, t h e r e was f a r greater v a r i a b i l i t y . In v i r t u a l l y a l l cases, the p o l y mers appeared t o be more thrombogenic than t h e s t a n dards. I n o n l y two c a s e s — t h e 9 . 8 % a c r y l i c a c i d c o polymer and i t s 2 9 . 5 % n e u t r a l i z e d sodium ionomer — were v a l u e s seen w h i c h were s i g n i f i c a n t l y h i g h e r than t h e values f o r s i l i c o n i z e d glass. I n n e i t h e r c a s e , howe v e r , were h i g h v a l u e s r e g i s t e r e d by b o t h t e s t groups. In f a c t , t h e r e appeared t o be l i t t l e o b v i o u s c o r r e l a t i o n between t h e r e s u l t s o f t h e two p a r a l l e l s e t s o f tests. As an a d d i t i o n a l p o r t i o n o f t h e b a s i c i n v i t r o b l o o d c o m p a t i b i l i t y s t u d i e s performed a t B a t t e l l e Memorial I n s t i t u t e (9^) , a d h e s i o n o f e r y t h r o c y t e s and p l a t e l e t s t o t h e e x p e r i m e n t a l polymers was a l s o i n v e s tigated. The r e s u l t s o f t h e s e t e s t s i n d i c a t e d f a i r l y u n i f o r m b e h a v i o r throughout t h e s e r i e s o f polymers. In a l l c a s e s , adherence o f e r y t h r o c y t e s was v e r y l i g h t , w i t h some showing no adherence a t a l l .

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

314

HYDROGELS FOR MEDICAL AND RELATED APPLICATIONS

P l a t e l e t adherence s l i g h t aggregation c a n t e x c e p t i o n was which showed heavy gregation.

ranged from l i g h t t o moderate, w i t h i n some c a s e s . The o n l y s i g n i f i the dimethylethanolamine s a l t , p l a t e l e t adherence w i t h heavy a g -

TABLE I

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

ZETA POTENTIALS ACROSS SOME POLYELECTROLYTES SALINE/1000 SOLUTION INTERFACES AS OBTAINED FROM STREAMING POTENTIALS

% AA

% Ionomer

9.8 19.2 19.2 19.2 19.2 19.2 19.2 19.2

0 0 27.0% 25.5% 61.0% 61.5% 61.5% 34.5%

Mg; Ca Na Mg Ca DMEA

dE/dP* mv/cm Hg 325 350 355 315 390 340 365 325

Zeta P o t e n t i a l -17.2 -18.5 -18.8 -16.8 -20.7 -18.0 -19.5 -17.5

* dE/dP i s t h e average s l o p e o f t h e s t r e a m i n g pot e n t i a l v e r s u s p r e s s u r e r e l a t i o n from which t h e zeta p o t e n t i a l i s c a l c u l a t e d . I n v i v o b l o o d c o m p a t i b i l i t y s t u d i e s were a l s o p e r formed on many o f t h e e t h y l e n e / a c r y l i c a c i d copolymers and ionomers by Sawyer and coworkers(14) a t S t a t e U n i v e r s i t y o f New York Downstate M e d i c a l C e n t e r and G o t t (jL?.) and coworkers a t Johns Hopkins U n i v e r s i t y (Table I I I ) . Sawyer's r e s u l t s i n d i c a t e t h a t two o f t h e polymers e x h i b i t e d a moderate l e v e l o f t h r o m b o r e s i s tance. These were t h e 19% a c r y l i c a c i d copolymer and i t s h i g h l y n e u t r a l i z e d sodium ionomer. In both cases, two hour and two week i m p l a n t s were e i t h e r thrombusf r e e a t t h e end o f t h e i m p l a n t p e r i o d o r c o n t a i n e d o n l y m i n i m a l j u n c t i o n a l t h r o m b i . Based on t h e o b s e r v a t i o n s i n t h e s e experiments(UD , t h e s e two polymers appeared t o be m o d e r a t e l y t h r o m b o r e s i s t a n t , whereas copolymers a t lower n e u t r a l i z a t i o n o r lower a c r y l i c a c i d c o n t e n t , as w e l l as c a l c i u m ionomers, were thrombogenic. The h i g h e s t l e v e l o f thrombogenic a c t i v i t y was found i n t h e magnesium and d i m e t h y l e t h a n o l a m i n e ionomers. In G o t t s t e s t s , a l l o f t h e polymers d i s p l a y e d s i g n i f i c a n t l e v e l s o f thrombogenic a c t i v i t y , w i t h o n l y l i m i t e d v a r i a t i o n 1

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

23.

LUNDELL

E T AL.

Characteristics

of Polyelectrolytes

315

TABLE I I

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

IN VITRO BLOOD COMPATIBILITY OF ETHYLENE/ACRYLIC ACID POLYELECTROLYTES

A c r y l i c Acid Cor ent

% Ionomer

Stypven Time*

P a r t i a l Thromboplastin Time* University of North C a r o l i n a Battelle

4.0%

0 24..0% Na 55..0% Na

— — —

— — —

109 99 101

9.8%

0 29.,5% Na 71..0% Na

98 98 97

76 115 95

137 83 89

14.7%

0 32., 0% Na 62.. 0% Na

97 98 98

106 85 74

101 99 86

19.2%

0 27.,0% L i 28.,0% Na 24.,0% Κ 27.,0% Mg 26.,5% Ca 34., 5% DMEA 65.,0% L i 61., 0% Na 40.,5% Κ 61., 5% Mg 61.. 5% Ca

100 98 103 101 99 103 104 98 96 100 107 97

74 78 62 59 79 68 84 78 89 94 65 74

92 70 94 83 91 78 103

··

* % of s i l i c o n i z e d glass control

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

—

— 109 99 104

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

% Neut.

0

29.0

71.0

0

62.0

0

% AA

9.8

9.8

9.8

14.7

14.7

19.2

—

Na

-

Ν,ι

Na

—

Cation

Q

φ φ φ φ

φ

H

HI HI

H

φ

Q

• i

H

I I

C C

φ

φ

t D H

φ

Q

I

• ϋ

L

φ

I

φ

• H Ρ

φ

•

•

φ

φ

t

I

φ

HI

Π

TABLE I I I

h

o

u

r

s

2

n o u r s

14 days

14 days

2 hours

18 hours

14 days

2 hours

14 days

14 days

2

14 days

14 days

2 hours

14 days

14 days

2 hours

14 days

14 days

Duration

I

k

Ο

Ο

L

I

j

Îi

Γ

L>

L

1

ι—

Ρ

,

-

—

0

%

1

I

I

1

1

90%

30%

50%

%

30%

junctional

clean

junctional

0

junctional

60%

10%

90%

1

1

9

%

5%

—

0

50%

20%

8

clean

1

J

1

1

1. ,ιτη 1

1

1

LT"

J B * ^ * _ J

I

Ο

©

Ο

Q

Ο

Ο

Ο

©

Ο

Ο

Ο

Ο

Ο

Ο

Q

Ο

% Occlusion

AND IONOMERS

Downstate Medical Center

OF ETHYLENE/ACRYLIC ACID COPOLYMERS

Johns Hopkins 2 hr". Implant

IMPLANTATION

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

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

26.5

34.5

61.0

60.5

61.5

61.5

19.2

19.2

19.2

19.2

19.2

27.0

19.2

19.2

Ca

Mg

Na

DMEA

Ca

Mg

•• •

EU ©

Ο • Ο •• ·

2 hours

Ο Ο

Ο 31 days 14 days

Ο

ο

2 hours

14 days

4 hours

2 hours

14 days

14 days

c

Ε»

c

Ο Ο C Ο C

Ο

2 hours

Ο

14 days

Ο cz

1

1

60%

Ο

50%

clean

junctional 50%

30%

90%

clean

clean

5% (jnl.)

2 0%

80%

60%

40%

10%

5%

60%

80%

Ο

©

14 days

2 hours

6 days

14 days

2 hours

14 days

14 days

TABLE I I I (Continued)

Downloaded by UNIV OF NORTH CAROLINA on June 7, 2013 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0031.ch023

1

C