13 Blood/Material Interface Problems Confronting Artificial Heart Development Interaction of Liquids at Solid Substrates Downloaded from pubs.acs.org by YORK UNIV on 12/09/18. For personal use only.
F R A N K W. HASTINGS National Heart Institute, Bethesda, Md. 20014
The Artificial Heart Program of NIH has 15 contracts trying to discover materials compatible with blood. We know that foreign
materials become coated with adsorbed
protein
within a few seconds after being exposed to blood and that the clotting process does not begin until some time later. Hageman factor is activated at the blood/material
inter-
face, but how and why this leads to clotting is not clear. Other proteins may be involved.
Blood agitated in contact
with foreign material will hemolyze, perhaps days later. The surfaces of blood vessels in contact with blood have a "slime layer" that contains heparinoid complexes, the function of which is not understood. this layer, show promise. the
need for
Hydrogels, which simulate
Related
better methods
for
to these programs is determining
protein
denaturation.
" p r o b a b l y t h e most serious t e c h n i c a l obstacle s t a n d i n g i n the w a y of the d e v e l o p m e n t of satisfactory b l o o d p u m p s of m a n y varieties is t h e b l o o d / m a t e r i a l interface p r o b l e m . T h e r e is n o m a t e r i a l t o d a y w h i c h has b e e n p r o v e n to b e satisfactorily c o m p a t i b l e w i t h b l o o d . T h i s is not a p r o b l e m that c a n b e s o l v e d b y the p h y s i c i a n s a n d hematologists a l o n e b u t m u s t b e s o l v e d b y a t e a m effort i n v o l v i n g these i n d i v i d u a l s a n d also the p h y s i c a l a n d p o l y m e r chemists a n d others w h o s e expertise is p e r i odically required. ficial
R e c o g n i z i n g t h e e n o r m i t y of this p r o b l e m t h e A r t i -
H e a r t P r o g r a m of the N a t i o n a l H e a r t Institute has e s t a b l i s h e d
several projects i n this field. T h e s e projects i n c l u d e t h e f o l l o w i n g : ( 1 ) A t t e m p t s to d e v e l o p m o r e stable a n d m o r e satisfactory h e p a r i n surfaces o n v a r i o u s p o l y m e r s . ( 2 ) Studies a t t e m p t i n g to d e v e l o p materials w i t h v e r y l o w surface free energy. 175
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AT
SOLID
SUBSTRATES
( 3 ) A t t e m p t s to d e v e l o p p o l y e l e c t r o l y t e c o m p l e x resins i n t h e f o r m of h y d r o g e l s w h i c h w o u l d b e c o m p a t i b l e w i t h b l o o d . ( 4 ) A t t e m p t s to d e v e l o p p o l y m e r i c h y d r o g e l s w h i c h w o u l d b e c o m patible w i t h blood. ( 5 ) A t t e m p t s t o d e v e l o p n e w base p o l y m e r s w h i c h are m o r e patible with blood.
com-
( 6 ) A t t e m p t s t o d e v e l o p silicones w h i c h are m o r e c o m p a t i b l e w i t h blood. ( 7 ) A t t e m p t s to d e v e l o p p o l y m e r i c electrets w i t h n e g a t i v e l y c h a r g e d surfaces w h i c h are m o r e c o m p a t i b l e w i t h b l o o d . T h e r e are a n u m b e r of projects to s t u d y t h e effects that result f r o m the contact of b l o o d w i t h some of these f o r e i g n m a t e r i a l s . T h e last g r o u p is p r o b a b l y t h e most c r i t i c a l g r o u p .
T h e r e is n o satisfactory in-vitro test
for b l o o d / m a t e r i a l s c o m p a t i b i l i t y , n o r is there a c o m p l e t e l y satisfactory in-vivo test.
I t is possible that there is sufficient i n f o r m a t i o n a v a i l a b l e
t o d a y f u l l y to define the p r o b l e m i f i t c o u l d b e o r g a n i z e d p r o p e r l y .
It
m i g h t t h e n b e possible to p l a c e m o r e emphasis o n areas a n d t e c h n i q u e s of i m p o r t a n c e . M a n y of t h e m a t e r i a l s that a r e b e i n g tested t o d a y d o look p r o m i s i n g w i t h t h e tests that are a v a i l a b l e . Investigators c o n t i n u e to find m o r e a n d m o r e m a t e r i a l s w h i c h d o n o t clot b l o o d w h e n passed i n test tubes m a d e of these m a t e r i a l s f o r l o n g p e r i o d s of t i m e , w e l l b e y o n d t h e t i m e n o r m a l l y r e q u i r e d f o r c l o t t i n g r e s u l t i n g f r o m t h e a c t i v a t i o n of H a g e m a n factor. W h a t is some of t h e i n f o r m a t i o n t h a t w e h a v e t o d a y ?
I n t h e first
p l a c e m u c h of t h e i n f o r m a t i o n a v a i l a b l e t o d a y is i n c o n c l u s i v e a n d s t i l l more theoretical than factual. F o r example, w e k n o w that b l o o d pract i c a l l y never clots i n d i r e c t contact w i t h a f o r e i g n m a t e r i a l . T h a t statement a l w a y s r e q u i r e s c l a r i f i c a t i o n . W e k n o w t h a t f o r e i g n materials b e c o m e coated w i t h adsorbed
p r o t e i n w i t h i n a v e r y f e w seconds after
being
exposed t o b l o o d a n d that t h e c l o t t i n g process does n o t b e g i n u n t i l some t i m e after that occurs.
H o w m a n y steps there are b e t w e e n t h e p r o t e i n
contact w i t h a f o r e i g n m a t e r i a l a n d t h e a c t u a l c l o t t i n g of b l o o d is somew h a t s p e c u l a t i v e , b u t c e r t a i n l y there is g o o d e v i d e n c e
that H a g e m a n
factor, o n e of t h e proteins i n t h e b l o o d , is a c t i v a t e d as a result of t h i s b l o o d / m a t e r i a l contact
a n d this a c t i v a t e d
H a g e m a n factor,
initiates a c h a i n r e a c t i o n w h i c h results i n t h e c o n v e r s i o n of fibrin,
i n turn,
fibrinogen
to
the m a t r i x of b l o o d clots. W e k n o w t h a t t h e H a g e m a n factor i n
b l o o d , i f i t b e c o m e s a d s o r b e d o n a surface, c e r t a i n l y does n o t r e m a i n fixed
there.
I t is e v e n possible that t h e a c t i v a t i o n of H a g e m a n factor
results f r o m t h e a c t i v a t i o n of some other p r o t e i n w h i c h does r e m a i n m o r e firmly a t t a c h e d t o t h e m a t e r i a l , b u t this has n o t b e e n d e m o n s t r a t e d .
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Artificial Heart Development
W h a t a c t u a l l y h a p p e n s i n the a c t i v a t i o n of H a g e m a n factor? c h e m i c a l reaction?
We
k n o w that H a g e m a n factor c a n b e
Is i t a
activated
a n d c l o t t i n g s t i l l p r e v e n t e d as a result of the a d d i t i o n of oxylate or citrate to the b l o o d to tie u p the c a l c i u m i o n . T h i s b l o o d c o n t a i n i n g a c t i v a t e d H a g e m a n factor c a n t h e n b e a l l o w e d to s t a n d for a p e r i o d of t i m e a n d the H a g e m a n factor w i l l b e d e a c t i v a t e d .
W h a t e v e r the r e a c t i o n that is
i n v o l v e d , therefore, i t is a r e v e r s i b l e r e a c t i o n a n d p r o b a b l y does not r e q u i r e a n y a p p a r e n t c h e m i c a l resynthesis. S i n c e H a g e m a n factor is t h o u g h t to b e h e l i c a l i n f o r m , as is t r u e w i t h other b l o o d proteins, it is possible that the a d s o r p t i o n forces b e t w e e n it a n d the surface result i n a n u n f o l d i n g of the h e l i x w i t h exposure
of
c e r t a i n active sites w h i c h i n t u r n i n i t i a t e the c l o t t i n g of b l o o d . T h i s seems l i k e a reasonable t h e o r y , b u t of course at this stage c a n b e
considered
n o t h i n g m o r e t h a n that. W h a t h a p p e n s to the other proteins that are a d s o r b e d o n f o r e i g n m a t e r i a l s ? W e k n o w that m a n y proteins are q u i t e firmly b o u n d to the surface a n d that i t is difficult to w a s h some of these off.
W e also k n o w
that m a n y of these proteins h a v e definite b i o l o g i c a l f u n c t i o n other t h a n m e r e l y osmotic a c t i v i t y . W e also k n o w t h a t the strength of these a d s o r p t i o n forces varies w i t h different proteins, b u t a p p a r e n t l y a d y n a m i c state exists w i t h proteins b e i n g a d s o r b e d , d e s o r b e d , a n d n e w proteins a d s o r b e d . It w o u l d seem q u i t e c o i n c i d e n t a l i f H a g e m a n factor w e r e the o n l y one of these proteins that a l t e r e d its b i o l o g i c a l f u n c t i o n as a result of this a d s o r p tion a n d desorption.
It seems q u i t e o b v i o u s that m a t e r i a l s w h i c h are
c o m p a t i b l e w i t h b l o o d must not a p p r e c i a b l y alter a n y of the v i t a l b l o o d proteins. H e p a r i n has b e e n i o n i c a l l y b o n d e d to surfaces for some t i m e a n d m o r e r e c e n t l y it has b e e n c o - v a l e n t l y b o n d e d to v a r i o u s materials.
Some
of these surfaces are q u i t e stable a n d the h e p a r i n r e m a i n s o n the surface i n h i g h c o n c e n t r a t i o n for l o n g periods of t i m e . T h e r e is n o longer a n y d o u b t that h e p a r i n surfaces per se r e t a r d c l o t t i n g a n d d o not r e q u i r e t h a t the h e p a r i n b e i n s o l u t i o n at the surface to a c c o m p l i s h this. T h e h e p a r i n o n the surface retards c l o t t i n g a n d its a c t i o n i n d o i n g this m a y b e somew h a t different t h a n its a c t i o n w h e n i n s o l u t i o n . P r o t e i n s , h o w e v e r ,
are
s t i l l a d s o r b e d onto h e p a r i n surfaces a n d the a d s o r p t i o n is f a i r l y strong. T h e fact that H a g e m a n factor
is not a p p a r e n t l y a c t i v a t e d b y
these
h e p a r i n surfaces does not necessarily m e a n t h a t other proteins are not altered.
A g a i n at this t i m e o u r i n f o r m a t i o n is far f r o m c o n c l u s i v e
on
this subject. W e k n o w that b l o o d that has b e e n i n contact w i t h f o r e i g n m a t e r i a l s a n d a g i t a t e d u n d e r these c o n d i t i o n s h e m o l y z e s .
W e k n o w that some of
this h e m o l y s i s or d e s t r u c t i o n of the r e d cells takes p l a c e because of
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a b n o r m a l flow c o n d i t i o n s w i t h i n t h e p u m p i n g devices.
SUBSTRATES
W e also k n o w
that some of these c o n d i t i o n s that seem to destroy b l o o d i n b l o o d p u m p s a n d oxygenators exist i n t h e b o d y a n d d o n o t cause h e m o l y s i s there. W e k n o w that t h e m a t e r i a l itself a p p a r e n t l y p l a y s some r o l e i n this h e m o l y s i s , b u t t h e extent of this role is n o t altogether clear. T h e r e is also e v i d e n c e that some of t h e adverse effects o n t h e r e d b l o o d c e l l d o n o t result i n d e s t r u c t i o n of t h e c e l l at that t i m e , b u t that this m a y o c c u r days later. D i r e c t contact w i t h a f o r e i g n m a t e r i a l a p p a r e n t l y shortens t h e l i f e of r e d cells.
T h e r e is also some e v i d e n c e that r e d cells w h i c h h a v e b e e n i n
contact w i t h a f o r e i g n m a t e r i a l d o n o t f u n c t i o n i n t h e transport o f C 0 and 0
2
2
as w e l l as t h e y n o r m a l l y d o . M u c h of this i n f o r m a t i o n is s t i l l
p o o r l y u n d e r s t o o d , to say t h e least, b u t a g a i n there does a p p e a r t o b e some r e a c t i o n b e t w e e n t h e f o r e i g n m a t e r i a l a n d t h e r e d b l o o d c e l l . T h e materials themselves are n o t e d f o r t h e fact t h a t t h e y are u s u a l l y c h e m i c a l l y i n e r t so t h e i n t e r a c t i o n b e t w e e n t h e r e d c e l l a n d f o r e i g n m a t e r i a l is p r o b a b l y n o t a c h e m i c a l r e a c t i o n i n t h e u s u a l sense of t h e t e r m .
Again
i t m a y b e t h a t proteins i n t h e w a l l of t h e r e d c e l l m a y b e affected i n m u c h the same w a y as H a g e m a n factor a n d p o s s i b l y other b l o o d proteins are affected. W e also k n o w that patients w h o h a v e b e e n k e p t o n oxygenators f o r l o n g p e r i o d s of t i m e d e v e l o p p r o b l e m s w h i c h are p o o r l y u n d e r s t o o d b u t i f these p r o b l e m s are a l l o w e d to c o n t i n u e t h e y i n e v i t a b l y result i n d e a t h . A n i m a l s that are p u t o n t o t a l heart r e p l a c e m e n t u s i n g a n artificial heart p u m p also d i e e v e n t u a l l y w i t h some v e r y p o o r l y u n d e r s t o o d p h y s i o l o g i c changes.
T h e s e changes m a y w e l l result f r o m d e n a t u r e d e n z y m e s a n d
hormones w i t h i n the body. T h e changes t h a t take p l a c e seem to differ s o m e w h a t d e p e n d i n g o n w h e t h e r t h e b l o o d m e r e l y passes over a f o r e i g n m a t e r i a l o r w h e t h e r i t is a c t i v e l y p u m p e d b y a f o r e i g n m a t e r i a l . I t is possible t h a t t h e c o m b i n e d a c t i o n o f t h e a d s o r p t i o n forces of p r o t e i n o n f o r e i g n surfaces a n d t h e forces c r e a t e d b y t h e flexing d i a p h r a g m m a y exceed some of t h e forces of t h e c h e m i c a l b o n d s , c a u s i n g r u p t u r e of p r o t e i n c h a i n s a n d b r e a k d o w n of some of these proteins to p o l y p e p t i d e s . through
T h e s e p o l y p e p t i d e s m a y pass
c a p i l l a r y w a l l s i n t o t h e extravascular spaces
upsetting the
osmotic e q u i l i b r i u m a n d c r e a t i n g some of t h e e d e m a that is f r e q u e n t l y seen u n d e r these circumstances.
A g a i n , i t appears that t h e degree of
difficulty that arises f r o m use of oxygenators, artificial k i d n e y s , artificial b l o o d p u m p s a n d t h e l i k e is d e p e n d e n t o n t h e a m o u n t of b l o o d c o m i n g i n contact w i t h a f o r e i g n m a t e r i a l . T h u s , oxygenators w h i c h are u s e d t o oxygenate t h e entire " c a r d i a c " o u t p u t c a n b e u s e d f o r o n l y a f e w h o u r s w h i l e i f o n l y a t e n t h of t h e c a r d i a c o u t p u t is o x y g e n a t e d this p e r i o d of t i m e c a n b e g r e a t l y extended.
Artificial kidneys w h i c h allow only a
13.
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HASTINGS
f r a c t i o n of the t o t a l m i n u t e v o l u m e of the heart to pass t h r o u g h t h e m c a n also b e u s e d for l o n g periods of t i m e .
C a r d i a c assist p u m p s seem
to
d e v e l o p d i f f i c u l t y i f t h e y p u m p a v e r y large f r a c t i o n of the t o t a l c a r d i a c o u t p u t for l o n g p e r i o d s of t i m e . It m i g h t b e w i s e at this t i m e to take a q u i c k look at the i d e a l surface, t h e surface of b l o o d vessels. T h e i m m e d i a t e surface i n contact w i t h b l o o d is s o m e w h a t
of a " s l i m e l a y e r " w h i c h contains h e p a r i n o i d
complexes.
T h e c o n c e n t r a t i o n of these h e p a r i n o i d complexes, h o w e v e r , is not h i g h a n d it is not c l e a r l y u n d e r s t o o d h o w i m p o r t a n t they are. It is b e c a u s e of the existence of this " s l i m e l a y e r " that h y d r o g e l s w e r e expected to s h o w p r o m i s e , the t h e o r y b e i n g that i t w o u l d b e difficult for p r o t e i n to
be
a d s o r b e d onto a surface w h i c h w a s 80 to 9 0 % w a t e r a n d , since the p r o t e i n w o u l d not be w e l l a d s o r b e d , d e n a t u r a t i o n m i g h t b e m i n i m i z e d .
These
h y d r o g e l s that h a v e b e e n tested to date h a v e not b e e n q u i t e as e n c o u r a g i n g as h a d b e e n h o p e d b u t this is not altogether the f a u l t of the m a t e r i a l s themselves. T h e r e is c e r t a i n l y h o p e that as t i m e goes o n a n d m o r e w o r k has b e e n a c c o m p l i s h e d i n this field t h a t w e c a n l e a r n w h e t h e r
these
h y d r o g e l s d o i n fact h a v e p r o m i s e . A l l of this tends to i n d i c a t e that w e m a y b e m a k i n g a m i s t a k e w h e n w e look o n l y at the c l o t t i n g p r o b l e m r e s u l t i n g f r o m the b l o o d / m a t e r i a l i n t e r a c t i o n . T h i s m a y m e r e l y b e a v e r y v i s i b l e effect of the d e n a t u r a t i o n of one p a r t i c u l a r p r o t e i n i n the b l o o d .
T h e s o l u t i o n of the c l o t t i n g p r o b -
l e m m a y v e r y w e l l o n l y a l l o w us to r e c o g n i z e the fact t h a t other factors are i n v o l v e d a n d that w e h a v e f a i l e d to look at the t o t a l p i c t u r e . T w o p r o g r a m s m a y b e r e q u i r e d : ( 1 ) d e v e l o p m e n t of better m e t h o d s for d e t e r m i n i n g the d e n a t u r a t i o n of p r o t e i n a n d ( 2 )
development
materials w h i c h are satisfactorily c o m p a t i b l e w i t h b l o o d .
of
T h e f o r m e r is
a v e r y difficult p r o b l e m w h i c h m a y almost p r o v e to b e i n s u r m o u n t a b l e for m a n y years.
W e k n o w t h a t the b i o l o g i c a l f u n c t i o n of some of the
enzymes i n the b o d y c a n be a l t e r e d b y v e r y m i n o r changes of c e r t a i n c r i t i c a l side chains a n d that w e d o not h a v e g o o d tests for this b i o l o g i c a l f u n c t i o n for m a n y enzymes.
In-vivo testing is difficult since the b o d y is
c o n t i n u o u s l y t r y i n g to correct the a b n o r m a l i t i e s w h i c h it sees. F o r exa m p l e , the l e v e l of p l a s m a h e m o g l o b i n i n the b o d y is d e t e r m i n e d i n p a r t b y the body's a b i l i t y at that m o m e n t to r e m o v e the p l a s m a h e m o g l o b i n f r o m the b l o o d a n d this a b i l i t y varies c o n s i d e r a b l y f r o m t i m e to t i m e as a result of factors that are o n l y p a r t i a l l y u n d e r s t o o d .
T h e same is t r u e
w i t h the i n f u s i o n of a l t e r e d proteins. T h e b o d y w i l l r e m o v e t h e m a n d r e p l a c e t h e m just as r a p i d l y as it p o s s i b l y c a n a n d its a b i l i t y to d o t h i s w i l l v a r y as a result of m a n y factors that w i l l p r o b a b l y b e o n l y p a r t i a l l y u n d e r s t o o d f o r m a n y years.
T h e development
of m a t e r i a l s w h i c h are
t r u l y c o m p a t i b l e w i t h b l o o d is also v e r y difficult. O n e of the first p r o b l e m s i n a c h i e v i n g this, of course, is to d e t e r m i n e w h a t is i n c o m p a t i b l e a b o u t
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p r e s e n t l y a v a i l a b l e m a t e r i a l s . O n t h e other h a n d , o n l y as a result of d e v e l o p i n g better m a t e r i a l s a r e some of t h e m o r e subtle p r o b l e m s r e c o g nized.
T h e r e m u s t , therefore, b e a constant exchange
of i n f o r m a t i o n
b e t w e e n these groups. T h e r e o b v i o u s l y is a great n e e d f o r t h e chemists i n t h e n a t i o n t o w o r k i n this field f r o m m a n y p o i n t s of v i e w . RECEIVED
October 2 7 , 1 9 6 7 .
