Polymeric Membranes for Artificial Lungs - American Chemical Society

c o n s i s t e n t q u a l i t y ( i . e . lack o f pin-holes) and t h i n n e s s . If the ... configuratio n polyethylen e base d oxygenato r. 1955...
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9 Polymeric Membranes for Artificial Lungs DON N. GRAY

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Owens-Illinois, Inc., Corporate Technology, Toledo, OH 43666

Artificial membrane lungs are devices that perfuse c i r c u l a t i n g blood by membrane transport of gases. The development of membrane lungs was prompted by a need for an e f f i c i e n t device that could be used longer and that would damage the blood less than the d i r e c t blood-gas contact oxygenators. The evolution of the membrane lung during the last twenty-five years was dependent on advances made in permselective and microporous polymers with the required c h a r a c t e r i s t i c s for the critical membrane portion of the device. In most commercial membrane artificial lungs, the most s i g n i f i c a n t resistant to gas-transfer is the laminar boundary layer of blood near the membrane. Artificial lungs designed to improve the e f f i c i e n c y of gas transfer per unit area of membrane by minimizing the effect of the stagnant blood boundary layer are now a v a i l a b l e . These new designs take advantage of the inherently high permeability of new membrane materials. B r e a t h i n g i s s o m e t h i n g we do c o n t i n u a l l y from b i r t h t o d e a t h a b o u t t e n t i m e s a m i n u t e , 600 t i m e s an h o u r o r 1 4 , 0 0 0 t i m e s a day t o change t h e c o m p o s i t i o n o f t h e gaseous m i x t u r e i n c o n t a c t w i t h o u r l u n g s . The l u n g i s one o f t h e most c o m p l e x v i t a l o r g a n s and t h e one o f t e n a s s a u l t e d by p o l l u t e d a i r , b i o l o g i c a l enemies and i n d i v i d u a l s e l f - d e s t r u c t i v e h a b i t s and l a c k o f concern. C e r t a i n l y w i t h t h e modern e m p h a s i s on a r t i f i c i a l body r e p l a c e m e n t p a r t s and t h e s u c c e s s o f i m p l a n t e d b i t s o f h a r d w a r e and a s s i s t d e v i c e s f o r t h e h e a r t ( v a l v e s , h e a r t b y p a s s and p a c e makers) and k i d n e y s ( r e n a l d i a l y s i s ) , a s u b s t i t u t e d e v i c e f o r t h e n a t u r a l l u n g s h o u l d be c o n s i d e r e d . A r t i f i c i a l l u n g s a r e used d a i l y f o r s h o r t - t e r m ( 3 - 4 h o u r s ) h e a r t - l u n g bypas i n l a r g e , specialized health care centers. These a r e e x t r a c o r p o r e a l

0097-6156/ 84/ 0256-0151 $06.00/ 0 © 1984 American Chemical Society

In Polymeric Materials and Artificial Organs; Gebelein, C.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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POLYMERIC MATERIALS AND ARTIFICIAL ORGANS

d e v i c e s l i k e k i d n e y d i a l y s i s u n i t s r a t h e r than i m p l a n t s l i k e h e a r t a s s i s t d e v i c e s . These d e v i c e s f u n c t i o n l i k e f i s h " g i l l s " e x c h a n g i n g b l o o d g a s e s d i r e c t l y ( F i g u r e 1) r a t h e r t h a n a s s i s t i n g r e s p i r a t i o n l i k e a b e l l o w s o r r e s p i r a t o r . The t e c h n o l o g y o f t h e s e d e v i c e s i s now a t t h e s t a t e , many e x p e r t s b e l i e v e , t h a t a r t i f i c i a l k i d n e y s were t h i r t y y e a r s a g o . The w i d e s p r e a d use and a c c e p t a n c e o f t h i s t e c h n i q u e w i l l depend t o a l a r g e e x t e n t on t h e a v a i l a b i l i t y o f s i m p l e r , e a s i e r t o u s e , s a f e r and l o w e r cost devices. The p r i m a r y p u r p o s e o f t h e n a t u r a l l u n g i s t o b r i n g a i r i n t o c o n t a c t w i t h t h e l u n g membrane. B l o o d on t h e o t h e r s i d e o f t h e membrane r e l e a s e s c a r b o n d i o x i d e and t a k e s up o x y g e n . Two f l u i d movement s y s t e m s a r e i n v o l v e d i n t h i s dynamic p r o c e s s , one moving a i r and t h e o t h e r ( t h e h e a r t ) moving b l o o d . The s u r f a c e a r e a o f t h e n a t u r a l l u n g i s v e r y h i g h ( o v e r 70 s q u a r e m e t e r s ) , w h i l e t h e a r t i f i c i a l l u n g membrane s u r f a c e a r e a i s much lower (3~6 s q u a r e m e t e r s ) . F o r t u n a t e l y , a r t i f i c i a l membrane l u n g s c a n f u n c t i o n t o a c h i e v e a d e q u a t e gas exchange w i t h lower s u r f a c e a r e a s b e c a u s e , w h i l e the n a t u r a l lung r e c e i v e s i n s p i r e d a i r c o n t a i n i n g o n l y 21% o x y g e n , t h e membrane o f t h e a r t i f i c i a l l u n g s e e s 100% o x y g e n . The d e v e l o p m e n t o f a p p a r a t u s t o o x y g e n a t e b l o o d p r e c e d e d modern a d v a n c e s i n c a r d i a c and t h o r a c i c s u r g e r y and was a b s o l u t e l y n e c e s s a r y f o r open h e a r t s u r g e r y . Between t h e 1930's and 1950 s, s u r g e o n s e x p e r i m e n t e d w i t h b l o o d o x y g e n a t o r s by t a k i n g the s t r a i g h t f o r w a r d a p p r o a c h o f c o n t a c t i n g w h o l e venous b l o o d w i t h a i r o r oxygen and r e c i r c u l a t i n g t h e o x y g e n a t e d form i n t o t h e body's c i r c u l a t o r y s y s t e m . T h i s p r o c e d u r e gave t h e s u r g e o n what he needed most, t i m e f o r s u r g i c a l r e p a i r o f a s t i l l h e a r t . To i n c r e a s e t h e b l o o d - g a s c o n t a c t s u r f a c e a r e a i n t h e s e d e v i c e s , oxygen was b u b b l e d t h r o u g h t h e b l o o d ( b u b b l e o x y g e n a t o r s ) o r d i s c s were used t o c o n s t a n t l y e x p o s e t h e b l o o d s u r f a c e t o t h e gas phase ( d i s c o x y g e n a t o r s ) . D i r e c t c o n t a c t o f b l o o d and gas l e a d s t o p r o t e i n d e n a t u r a t i o n and b l o o d c e l l d e s t r u c t i o n w h i c h l i m i t s t h e u s e o f b u b b l e and d i s c o x y g e n a t o r s t o a maximum o f s i x h o u r s ; p e r f e c t l y s a t i s f a c t o r y f o r most s u r g i c a l p r o c e d u r e s . I t i s i n t e r e s t i n g t h a t o t h e r a p p r o a c h e s were a l s o t r i e d w i t h some s u c c e s s , s u c h as u s i n g a human donor t o c o n s t a n t l y "breathe" f o r a p a t i e n t v i a cross blood c i r c u l a t i o n °. Even more d a r i n g was s u c c e s s f u l e x - v i v o u s e o f d i s s e c t e d , s p e c i a l l y t r e a t e d a n i m a l l u n g s f o r b l o o d oxygénâtion ,an i n t e l l e c t u a l p r e c u r s o r i n t h e d e v e l o p m e n t o f t h e a r t i f i c i a l membrane l u n g . As e a r l y as 1955, K o l f f and B a l z e r d e s c r i b e d a d e v i c e p a t t e r n e d a f t e r an e a r l y r e n a l d i a l y s i s u n i t ( t h e Inouye a r t i f i c i a l k i d n e y ) w h e r e i n p o l y e t h y l e n e t u b i n g was used i n a c o i l configuration. W h i l e t h e c o n c e p t was s o u n d , t h e membrane m a t e r i a l c h o i c e s a v a i l a b l e a t t h a t t i m e were l i m i t e d . In 1956 Clowes and c o w o r k e r s d e s c r i b e d an o x y g e n a t o r u s i n g f l a t s h e e t s o f membrane t o s e p a r a t e t h e b l o o d and gas ( F i g u r e 2). Clowes examined T e f l o n , e t h y l c e l l u l o s e , p o l y e t h y l e n e , c e l l o -

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1

1

2

3

1

9

,

2

21

H

5

In Polymeric Materials and Artificial Organs; Gebelein, C.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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9.

GRAY

Polymeric Membranes for Artificial Lungs

153

Blood i n l e t groove Gasket

P l a s t i c membranes Compressed a i r : 160mm Hg

Blood f i l m f l o w i n g ]' between p l a s t i c membranes

L o n g i t u d i n a l blood channel L o n g i t u d i n a l oxygen channel Oxygen f l o w i n g i n diagonal rubber grooves

Figure 2 . The Clowes membrane oxygenator. (Reproduced w i t h permission from Ref. 5 . Copyright 1 9 5 6 , J . Thoracic Surg.)

In Polymeric Materials and Artificial Organs; Gebelein, C.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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POLYMERIC MATERIALS A N D ARTIFICIAL ORGANS

phane, PVC, p o l y s t y r e n e , M y l a r and c h l o r i n a t e d r u b b e r . Note t h a t some o f t h e s e m a t e r i a l s a r e c o n s i d e r e d b a r r i e r p o l y m e r s ( M y l a r and c h l o r i n a t e d r u b b e r ) . However, e t h y l c e l l u l o s e and Teflon gave p r o m i s i n g r e s u l t s . T h e s e e a r l y w o r k e r s were u s i n g t h e p e r m s e l e c t i v e p r o p e r t i e s o f p o l y m e r i c membranes f o r g a s , a l t h o u g h one m i g h t s u s p e c t t h a t a p o r t i o n o f t h e gas p a s s a g e was due t o d i f f u s i o n v i a m i c r o p o r o u s d e f e c t s i n t h e f i l m s . Table 1 i s a c o m p a r i s o n o f t h e p e r m e a b i l i t y one hundred t i m e s t h a t o f Teflon . It i s i n t e r e s t i n g t o compare t h e h i s t o r i c a l t i m e t a b l e f o r c l i n i c a l a d v a n c e s v e r s u s t h e c o m m e r c i a l s t a t u s o f membrane m a t e r i a l a t t h e same p o i n t i n t i m e . (Table 2 - S i g n i f i c a n t M i l e s t o n e s - Development o f A r t i f i c i a l Membrane L u n g s ) . Note t h a t t h e f i r s t s y n t h e t i c m a t e r i a l used f o r b l o o d o x y g e n a t i o n (albeit i n a d v e r t e n t l y ) was c e l l o p h a n e , and t h e mode o f oxygen t r a n s f e r must have been v i a s o l u b i l i t y i n t h e h y d r a t e d "aqueous p h a s e " o f t h e s w e l l e d p o l y m e r . By 1955, t h e c l i n i c i a n s had e x p e r i m e n t e d w i t h and c o n c e p t u a l l y o p t i m i z e d t h e b a s i c g e o m e t r i e s o f membrane oxygenators. However, t h e membrane m a t e r i a l s a v a i l a b l e t o them were t h o s e o f f e r e d by i n d u s t r y f o r o t h e r p u r p o s e s , u s u a l l y packaging. The c r i t e r i a f o r c h o o s i n g t h e m a t e r i a l s w e r e s t r e n g t h , c o n s i s t e n t q u a l i t y ( i . e . l a c k o f p i n - h o l e s ) and t h i n n e s s . If the m a t e r i a l s had some d e g r e e o f p e r m e a b i l i t y , a l l t h e b e t t e r . T h e p e r i o d 1955-1956 was i m p o r t a n t t o the e v e n t u a l d e v e l o p m e n t o f s u p e r i o r p e r m s e l e c t i v e membranes. P r o f e s s o r Kammermeyer d i d h i s f i r s t s t u d i e s on t h e p e r m e a b i l i t y o f s i l i c o n e f i l m s t o gases a b o u t t h i s t i m e and p u b l i s h e d h i s much r e f e r e n c e d a r t i c l e " S i l i c o n e Rubber a s a S e l e c t i v e B a r r i e r " i n I n d u s t r i a l and E n g i n e e r i n g C h e m i s t r y d u r i n g 1957. The v e r y h i g h p e r m e a b i l i t y o f t h e s i l i c o n e f i l m s , e s p e c i a l l y compared w i t h m a t e r i a l s p r e v i o u s l y a v a i l a b l e , c o u p l e d w i t h what was known a b o u t optimum g e o m e t r i e s r e s u l t e d i n a number o f l a s t i n g d e v i c e d e s i g n s i n t r o d u c e d i n t h e e a r l y 1960's. The c o m m e r c i a l a v a i l a b l i t y o f m i c r o p o r o u s p o l y o l e f i n s and p e r f 1 u o r o - p o l y o l e f i n s i n t h e 1970's f o l l o w e d w i t h t h e i n t r o d u c t i o n o f membrane o x y g e n a t o r d e v i c e s u s i n g t h e s e materials. Note t h a t w i t h p o s s i b l e e x c e p t i o n o f s i l i c o n e p a s s i v a t e d , microporous c e l l u l o s e a c e t a t e ( t h e Rhone-Poulenc l u n g ) , no p o l y m e r i c m a t e r i a l i n any c o m m e r c i a l a r t i f i c i a l l u n g was e s p e c i a l l y designed f o r t h e purpose o f blood oxygenation. Howe v e r , two p o l y m e r s , e t h y l - e e l 1ulose p e r f 1 u o r o b u t y r a t e (EFB) and t h e p o l y ( a l k y l s u l f o n e s ) have been e s p e c i a l l y d e v e l o p e d s i n c e t h e mid 1970's a s t h e base f o r membranes f o r b l o o d o x y g e n a t o r s . E t h y l c e l l u l o s e p e r f 1 u o r o b u t y r a t e was d e v e l o p e d by N o r t h s t a r Research. The p o l y ( a l k y l s u l f o n e s ) were d e v e l o p e d by OwensI l l i n o i s and a r e now o f f e r e d under t h e BIOBLAND name by Shenandoah R e s e a r c h , I n c . W h i l e t h e m a t e r i a l s have n o t y e t been used c o m m e r c i a l l y i n d e v i c e s , c o n s i d e r a b l e e v a l u a t i o n and t e s t i n g on t h e s e m a t e r i a l s has been r e p o r t e d ( R e f s . 7 and 9 and p e r t i n ent r e f e r e n c e s c i t e d t h e r e i n ) . The e a r l y e x p e r i m e n t a l d e v i c e s were g r a d u a l l y improved by 6

In Polymeric Materials and Artificial Organs; Gebelein, C.; ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

9.

GRAY

155

Polymeric Membranes for Artificial Lungs

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Table I P e r m e a b i l i t y o f v a r i o u s polymers to oxygen and carbon d i o x i d e Polymer

p

Polydimethyl siloxane Silicone r u b b e r / p o l y c a r b o n a t e c o p o l y m e r ( M E M 213

160

970

60

250

50

250

Poly ( 4 - m e t h y l p e n t e n e - ï ) (TPX

30

90

5

13

2

9

0.4

1.8

0.08

0.016

Polyvinylchloride (unplasticized)

0.045

0.016

Polyethylene terephthalate-oriented

0.035

0.017

)

)

Poly (tetrafluoroethylene ) (Teflon

)

P o l y p r o p y l e n e (density 0.91) Polyethylene (density Pre

2

2700

Ethylcellulose perfluorobutyrate (EFB)

Poly ( a l p h a - h e x a d e c e n e sulfone) (Biobland-16 1955

)

co

500

Cellulose acetate

Units =

0.96)

(unplasticized)

cm

3

(STP), cm

n

2

,sec, cm H g

--i

Ο

73

π > r Ο

> 73 Η

α

>

GO

73

m

ο

73

m

Ο

9.

GRAY

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o p t i m i z i n g membrane m a t e r i a l a n d f l o w c h a r a c t e r i s t i c s , a n d by t h e e a r l y 1 9 7 0 ' s s u f f i c i e n t e x p e r i m e n t a l d a t a was a v a i l a b l e t o i n d i c a t e t h a t membrane o x y g e n a t o r s were l e s s damaging t o b l o o d t h a n the blood-gas d i r e c t c o n t a c t type ( d i s c and b u b b l e ) . Therefore, t h e newer b l o o d o x y g e n a t o r s c o u l d be used f o r l o n g e r p e r i o d s ' . The improvements made i n m a t e r i a l s a n d o x y g e n a t o r designs a l l o w e d c l i n i c i a n s t o c o n s i d e r l o n g - t e r m (days r a t h e r t h a n h o u r s ) oxygenation f o r the f i r s t time. Here a g a i n t h e hope was t o "buy t i m e " n o t f o r s u r g e r y , b u t f o r an i n j u r e d o r d i s e a s e d l u n g t o r e p a i r i t s e l f o r h e a l . The w o r k e r s d e v e l o p i n g t h e s e t e c h n i q u e s w e r e u s i n g a s a model a w e l l - p r o v e n e x t r a c o r p o r e a l t e c h n i q u e temporary d i a l y s i s w i t h the a r t i f i c i a l kidney. A distinct d i f f e r e n c e between r e n a l d i a l y s i s a n d l o n g - t e r m o x y g e n a t i o n i s t h a t r e n a l d i a l y s i s may be i n t e r m i t t e n t and s t i l l be e f f e c t i v e , w h i l e o x y g e n a t i o n must be c o n t i n u o u s i n o r d e r t o be e f f e c t i v e . T h i s r e q u i r e m e n t p u t s g r e a t e r demands on t h e r e l i a b i l i t y o f t h e s u p p o r t d e v i c e s . As n a t u r a l h e a l i n g o f t e n d i d n o t o c c u r d e s p i t e b u y i n g t i m e w i t h a r t i f i c i a l l u n g s , p h y s i c i a n s have now t u r n e d t h e i r thoughts t o u s i n g a r t i f i c i a l lungs as support o r r e p l a c e ment d e v i c e s f o r i n s u f f i c i e n t n a t u r a l l u n g s . M a t e r i a l s used f o r t h e g a s t r a n s f e r membrane i n a r t i f i c i a l l u n g s c a n be o f two t y p e s , p e r m s e l e c t i v e s u c h a s t h o s e p r e v i o u s l y discussed o r microporous. In e i t h e r c a s e , g a s p a s s a g e p r o p e r t i e s must be h i g h , b l o o d c o m p a t i b i l i t y must be o p t i m a l a n d t o x i c a g e n t s must n o t be r e l e a s e d f r o m t h e membranes. Z a p o l a n d Ketteringham g i v e the f o l l o w i n g c h a r a c t e r i s t i c s r e q u i r e d f o r membrane m a t e r i a l s f o r an a r t i f i c i a l l u n g : 1. They must have h i g h o x y g e n a n d c a r b o n d i o x i d e p e r m e a b i l i t y . 2. They s h o u l d be c h e m i c a l l y s t a b l e w i t h o u t l e a c h a b l e m o i e t i e s and be b l o o d c o m p a t i b l e , m i n i m i z i n g t h r o m b o s i s , p l a t e l e t a c t i v a t i o n and i n j u r y , and p r o t e i n d e n a t u r a t i o n . 3. They must be s t r o n g , p i n h o l e - f r e e a n d c a p a b l e o f w i t h s t a n d i n g a p r e s s u r e g r a d i e n t o f 15 p s i f r o m t h e b l o o d s i d e w i t h o u t l e a k i ng. k. They must be c a p a b l e o f s t e r i l i z a t i o n p r e f e r a b l y by e t h y l e n e o x i d e o r by a u t o c l a v i n g . 5. They s h o u l d be e a s i l y f a b r i c a t e d i n t o p i n h o l e - f r e e membranes ( c o n t a i n i n g a s u p p o r t i n g component i f n e c e s s a r y ) w i t h a s u r f a c e c o n f o r m a t i o n w h i c h can be d e s i g n e d t o augment s e c o n d a r y blood flow a g a i n s t the s u r f a c e . 6. T h e b a s i c c o s t o f t h e m a t e r i a l a n d e a s e o f f a b r i c a t i o n must p e r m i t e c o n o m i c a l d i s p o s a b l e d e v i c e s t o be c o n s t r u c t e d . A number o f c o n f i g u r a t i o n s a r e used f o r c o m m e r c i a l membrane l u n g s ; t h o s e b a s e d on f l a t s h e e t s a r e Bramson, G . E . - P i e r c e , Lande-Edwards and T r a v e n o l . A m o d i f i c a t i o n o f the f l a t sheet c o n f i g u r a t i o n i s t h e K o l o b o w / S c i - M e d s p i r a l c o i l membrane l u n g . H o l l o w f i b e r membrane l u n g s a r e r e p r e s e n t e d by t h e Dow and t h e Terumo a r t i f i c i a l l u n g s . B l o o d f l o w i n g p a s t a membrane, a t l e a s t a s t h e f l u i d v e l o c i t i e s p e r m i t t e d i n membrane l u n g s , f o r m s a l a m i n a r b o u n d a r y l a y e r

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a d j a c e n t t o t h e membrane. T h i s phenomena l i m i t s t h e gas t r a n s f e r p r o p e r t i e s , e x p e c i a l l y oxygen, o f the device. To e x p l o i t t h e t r u e , h i g h p o t e n t i a l g a s t r a n s f e r c a p a b i l i t i e s o f t h e membrane m a t e r i a l i n modern membrane l u n g s , B e l l house and c o w o r k e r s have i n v e s t i g a t e d v o r t e x s h e d d i n g , s e c o n d a r y f l o w t e c h n i q u e s t o i n c r e a s e membrane t o b l o o d g a s t r a n s f e r . T h i s i s a c c o m p l i s h e d by i m p r e s s i n g a s e c o n d a r y p u l s i t i l e f l o w on t h e c i r c u l a t o r y f l o w t o d i s t u r b t h e l a m i n a r l a y e r . Examples o f d e v i c e s u s i n g t h i s t e c h n i q u e a r e t h e O x f o r d p u l s e d f l a t s h e e t l u n g and t h e d e v i c e o f f e r ed by E x t r a c o r p o r e a l . T h e s e d e v i c e s t h a t augment m i x i n g and i n c r e a s e gas t r a n s f e r p e r u n i t a r e a have c a u s e d a r e - e v a l u a t i o n o f t h e membrane m a t e r i a l s used i n a r t i f i c i a l lungs. 1 1

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K e t t e r i n g h a m , d e F i l i p p i and B i r k e t t w o r k i n g w i t h a number o f p e r m s e l e c t i v e m a t e r i a l s f a b r i c a t e d i n t o u l t r a t h i n membranes have d e t e r m i n e d t h e CO2/O2 f l u x r a t i o f r o m i n v i t r o measurements u s i n g a s e r i e s o f a r t i f i c i a l l u n g s w i t h i n c r e a s i n g l y more e f f i c i e n t oxygen t r a n s f e r c h a r a c t e r i s t i c s . As c a n be seen f r o m T a b l e 1, f o r t h e p o l y m e r s t h a t a r e s e r i o u s c a n d i d a t e s a s memb r a n e s , t h e c a r b o n d i o x i d e p e r m e a b i l i t y i s much h i g h e r t h a n t h e oxygen p e r m e a b i l i t y . In d e v i c e s w i t h o u t i n d u c e d o r augmented s e c o n d a r y f l o w , t h e membrane a r e a r e q u i r e d t o m a i n t a i n a d e q u a t e oxygen t r a n s f e r t o t h e b l o o d was more t h a n a d e q u a t e f o r c a r b o n dioxide clearance. W i t h more e f f i c i e n t d e v i c e s t h a t e l i m i n a t e o r r e d u c e t h e d e l e t e r i o u s s t a g n a n t b l o o d l a y e r , t h e membrane area required f o r C 0 clearance i s a l s o o f concern. Figure 3 represents a s i m p l i f i e d presentation o f the information reported by K e t t e r i n g h a m . The r a t i o C 0 f l u x / 0 2 f l u x i s p l o t t e d v e r s u s the t o t a l oxygen f l u x . A t a f l u x r a t i o l e s s t h a n 0.82, insuffic i e n t C 0 i s c l e a r e d r e l a t i v e t o oxygen t r a n s f e r . T h e r e f o r e , any f u r t h e r improvement i n t o t a l o x y g e n t r a n s f e r i s o f no p h y s i o l o g i c a l advantage. The i n t e r c e p t o f t h e c u r v e d l i n e s w i t h t h e dotted l i n e y i e l d s the value f o r the highest usable 0 t r a n s f e r f o r a g i v e n m a t e r i a l . BIOBLAND 16 used i n t h e u l t r a t h i n memb r a n e c o n f i g u r a t i o n a p p r o a c h e s t h e gas t r a n s f e r c h a r a c t e r i s t i c s of t h e microporous m a t e r i a l s , but without the problems a s s o c i a t e d w i t h t h e m i c r o p o r o u s m a t e r i a l s . The p r o b l e m s most o f t e n a s s o c i a t e d w i t h t h e m i c r o p o r o u s membranes a r e p o s s i b l e b l o o d damage due t o gas m i c r o b u b b l e i n t r u s i o n , e x c e s s i v e w a t e r f l u x and p o s s i b l e seepage. 2

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S i n c e membrane l u n g s a s e x t r a c o r p o r e a l d e v i c e s a r e i n w i d e u s e , t h o u g h t s have t u r n e d t o an i m p l a n t a b l e a r t i f i c i a l l u n g p r o s t h e s i s based on membrane t e c h n o l o g y . D e v e l o p i n g such a d e v i c e w i t h t h e a d e q u a t e c h a r a c t e r i s t i c s and l o n g - t e r m r e l i a b i l i t y i s a much more d i f f i c u l t t a s k t h a n e n c o u n t e r e d w i t h t h e e x t r a c o r p o r e a l d e v i c e d e v e l o p e d f o r i n t e r m i t t a n t u s e . However, a s m a l l p r o t o t y p e d e v i c e made o f p o r o u s T e f l o n has been f a b r i c a t e d and t e s t e d by R i c h a r d s o n a n d G a l l e t t i . The hopes f o r t h e use o f E x t r a c o r p o r e a l Membrane O x y g e n a t i o n (ECMO) f o r t r e a t i n g a c u t e r e s p i r a t o r y f a i l u r e went t h r o u g h a l o w p o i n t i n t h e mid 1970's a f t e r t h e r e s u l t s o f t h e N a t i o n a l I n s t i 1 3

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Figure 3 . Membrane e f f i c i e n c i e s . Key: MEM 2 1 3 , p o l y s i l o x a n e / p o l y c a r b o n a t e ; SSR, standard s i l i c o n e rubber UTEFB, u l t r a t h i n e t h y l c e l l u l o s e p e r f l u o r o b u t y r a t e ; UTSR, u l t r a t h i n s i l i c o n e rubber; and BIOBLAND 1 6 , poly(a-hexadecene s u l f o n e ) . (Reproduced w i t h permission from Ref. 1 2 . Copyright 1 9 7 6 , Academic Press.)

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t u t e s o f H e a l t h - E x t r a c o r p o r e a l Membrane O x y g e n a t i o n s t u d y became known \ T h i s work d e s c r i b e s t h e f i n d i n g s o f a c o o p e r a t i v e study i n v o l v i n g n i n e prominent medical c e n t e r s w e l l versed i n e x p n a c o r p o r e a l p e r f u s i o n . N i n e t y i n d i v i d u a l s were c h o s e n whose c o n d i t i o n ( r e s p i r a t o r y f a i l u r e ) o f f e r e d them o n l y a t e n p e r c e n t c h a n c e o f s u r v i v a l u s i n g s t a n d a r d r e s p i r a t o r y t h e r a p y management. T h i s g r o u p was r a n d o m l y d i v i d e d i n t o two s m a l l e r , e q u a l g r o u p s (45 e a c h ) , one g r o u p b e i n g g i v e n ECMO s t a t e - o f - t h e - a r t s u p p o r t and t h e o t h e r g i v e n s t a n d a r d t h e r a p y . T h e r e were f o u r (4) s u r v i v o r s i n e a c h g r o u p i n d i c a t i n g t h a t t h e more d i f f i c u l t and e x p e n s i v e ECMO t h e r a p y a p p a r e n t l y y i e l d e d no b e n e f i t s . However, t h e gloomy p r o s p e c t has b r i g h t e n e d i n t h e l a s t f i v e years. In 1979 B a r t l e t t r e p o r t e d on t h e s u r v i v a l o f o n e - h a l f o f a g r o u p o f 32 m o r i b u n d i n f a n t s u s i n g ECMO t e c h n i q u e s and s t a t e d as a r e s u l t o f h i s f i n d i n g s t h a t " r e c o v e r y and s u r v i v a l s h o u l d be r o u t i n e i f ECMO i s i n s t i t u t e d i n t h e f i r s t two days o f life". As e a r l y a s 1978, K o l o b o w r e p o r t e d c a r b o n d i o x i d e c o u l d be removed f r o m b l o o d (and hence b l o o d pH c o u l d be p r o p e r l y m a i n t a i n e d ) by s h u n t i n g o n l y 10-30% o f t h e c a r d i a c o u t p u t t h r o u g h a membrane l u n g . T h i s s t u d y has been f o l l o w e d by more c l i n i c a l work by Kolobow and h i s a s s o c i a t e s ' . In one s t u d y a 63% s u r v i v a l r a t e was o b t a i n e d by s i m u l t a n e o u s l y u s i n g ECMO f o r c a r b o n d i o x i d e removal c o u p l e d w i t h c l a s s i c a l v e n t i l a t o r t e c h niques f o r oxygenation. T h e s e s t u d i e s have prompted a r e a p p r a i s a l o f t h e u s e o f ECMO t h e r a p y w i t h renewed e m p h a s i s on p a t i e n t c h o i c e and m o d i f i e d treatment t e c h n i q u e s . It i s e x p e c t e d t h a t w i t h t h e g r e a t e r a v a i l a b i l i t y o f s i m p l e r , more d e p e n d a b l e and l o w e r c o s t d i s p o s a b l e membrane o x y g e n a t o r s i n s u r g i c a l p r o c e d u r e s o f t h e h e a r t , t h e i r u s e w i l l i n c r e a s e . In t h i s c o u n t r y , a b o u t 500 i n d i v i d u a l s e a c h d a y u n d e r g o r o u t i n e heart surgery that requires extracorporeal o x y g e n a t i o n . Bubble o x y g e n a t o r s s t i l l d o m i n a t e , b u t t h e number o f p e r f u s i o n teams t h a t a r e s h i f t i n g t o membrane u n i t s i s i n c r e a s i n g . The t o t a l p o t e n t i a l m a r k e t (U.S.) f a r membrane l u n g s i s a b o u t $20 m i l l i o n / y e a r ( a t t h e p r e s e n t p r i c e o f $ 2 0 0 / u n i t ) making i t a r e l a t i v e l y small market as compared, f o r example, t o t h e a r t i f i c i a l k i d n e y ( d i a l y s i s ) m a r k e t o f $225 m i l l i o n / y e a r . T h e r e f o r e , one w o u l d n o t e x p e c t t o s e e many new "me-too" membrane o x y g e n a t o r d e v i c e s i n t r o d u c e d . Any new p r o d u c t w o u l d have t o o f f e r a c l e a r b e n e f i t o r f i l l a r e c o g n i z e d need t o c a p t u r e m a r k e t s h a r e . 1

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frequency positive pressure ventilation with extracorporeal removal of CO2(LFPPV-ECCO R).Trans. Am. Soc. Artif. Intern. Organs, 27, 289 (1981) Pesenti, Α., Pelizzola, Α., Mascheroni, D., Uziel, L, Pirovani, E., Fox, U., Gattinoni, L. and Kolobow, T., Low frequency positive pressure ventilation with extracorporeal CO removal(LFPPV-ECCO R)in acute respiratory failure (ARF); Technique. Trans. Am. Soc. Artif. Intern. Organs, 27, 263 (1981) Warden, H.E., Cohen, M., DeWall, R.A., Schultz, E.A., Buckley, J.J., Read, R.C., Lillehei, C.W. Experimental closure of intraventricular septal defects and further physiologic studies on controlled cross circulation. Surg. Forum, 5, 22 (1954) Warden, H.E., Cohen, M. Read, R.C., Lillehei, C.W. Controll­ ed cross circulation for open intracardiac surgery. J. Thorac. Surg., 28, 331 (1954) Campbell, G.S., Crisp, N.W., Brown, E.B. Total cardiac by­ pass in humans utilizing a pump and heterologous lung oxygen­ ator (dog lungs). Surgery, 40, 364 (1956) Gott, V.L., Extracorporeal Circulation: 1970-1982, Trans. Am. Soc. Artif. Inter. Organs, 28, 17 (1982) Galletti, P.M., Impact of the artificial lung on medical care, Int. J. of Artif. Organs, 3, 157 (1980) 2

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