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H u m a n life e x p e c t a n c y h a s n e a r l y d o u b l e d i n t h e l a s t 1 50 y e a r s a n d , a l o n g
w i t h t h e s e d e m o g r a p h i c c h a n g e s, s o h a s t h e p e r c e n t a g e o f t h o s e s u f fe r in g
f r o m s e v e r e p h y s i c a l d i s a b i l i t y ( F i g. 9 .1 ) . T h e l o ss o f f u n c t i o n , w h e t h e r
r e s u l t i n g f r o m i n j u r y o r d i s e a s e , i s a m a j o r h e a l t h c a r e p r o b l e m a n d t h e
o p t i o n o f t r a n s p l a n t a t i o n o f t is s u e s o r o r g a n s f o r t h e s e p a t i e n t s c a n n o t
b e m e t f r o m t h a t s o u r c e a l o n e d u e t o a l a c k o f a v a i l a b i l i ty o f s u i t a b l e
d o n o r s ( w w w . u n o s . o r g ). I m p r o v e d m e d i c a l d e v ic e s t o r e s t o re or r e p l a c e
f u n c t i o n a r e n e c e s s a r y t o m e e t t h e e x p e c t a t i o n s fo r a c o n t i n u a t i o n o f a
' n o r m a l ' a n d a c t iv e li fe s ty le t h r o u g h i n t o ol d a g e. I t is e s t i m a t e d t h a t
s o m e 4 0 % o f w o m e n o v e r t h e a g e o f 5 0 w i ll s u ff er a n o s t e o p o r o t i c f r a c t u r e
( w w w . b o n e j o i n t d e c a d e . o r g ) . H e n c e m e c h a n i c a l d e v ic e s a n d p r o s t h e s e s p l a y
a n i m p o r t a n t r o le i n t h e r e p l a c e m e n t o r r e p a i r o f d e t e r i o r a t i n g b o d y p a r t s .
I n t h e c o n t e x t o f t h i s a r t i c l e , a b i o m a t e r i a l c a n s i m p l y b e d e f i n e d a s
a n y m a t e r i a l t h a t is u s e d t o r e p l a ce p a r t o f a l iv i ng s y s t e m o r t o f u n c t i o n
i n i n t i m a t e c o n t a c t w i t h t h e l i v i n g s y s t e m . A m o r e d e t a i l e d d e f i n i t i o n w a s
p r o p o s e d b y W i l li a m s e t a l [1] i n 1 9 92 , wh o s u g g e s t ed t h a t '% b io m a te r i a l is
a n y s u b s t a n c e , o t h e r t h a n a d r u g , o r a c o m b i n a t i o n o f s u b s t a n c e s , s y n t h e t i c
o r n a t u r a l i n o r ig i n , w h i c h c a n b e u s e d f o r a n y p e r i o d o f t i m e , a s a w h o l e
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o r a s a p a r t o f a s y s t e m w h i c h t r e a t s , a u g m e n t s , o r r e p l a c e s a n y t i s s u e ,
o r g a n , o r f u n c t i o n o f t h e b o d y . T h e r e a r e m a n y e x a m p l e s o f t h i s s u c h a s
h i p a n d k n e e j o i n t r e p l a c e m e n t s , h e a r t v a l v e r e p l a c e m e n t s , b r e a s t i m p l a n t s
a n d d e n t a l f i l l i n g m a t e r i a l s ( s e e T a b l e 9 . 1 ) . I n f a c t , t h e c h a n c e s a r e t h a t
m a n y o f t h e r e a d e r s o f t h i s a r t i c l e w i l l h a v e a b i o m a t e r i a l r e p l a c i n g p a r t o f
t h e i r b o d y . I n c o n t r a s t , a b i o l o g i c l m t e r i l i s a m a t e r i a l o f n a t u r a l o r i g i n
s u c h a s c o l l a g e n , c e l l u l o s e o r k e r a t i n .
T h e c o s t o f p r o v i d i n g r e p l a c e m e n t p a r t s f o r t h e h u m a n b o d y h a s b e e n
v a r i o u s l y e s t i m a t e d t o b e i n t h e r e g i o n o f I 0 b i l l i o n . I n t h e U K h e a r t v a l v e
r e p l a c e m e n t a c c o u n t s f o r a p p r o x i m a t e l y 2 0 ~ 0 o f o p e n h e a r t s u r g e r y i n N a -
t i o n a l H e a l t h S e r v i c e h o s p i t a l s w i t h s o m e 7 0 0 0 a r t i f i c i a l h e a r t v a l v e b e i n g
i n s e r t e d a t a c o s t t o t h e N H S o f 1 2 - 1 5 m i l l i o n ( w w w . c t s n e t . o r g / s e c t i o n /
o u t c o m e ) . A l t h o u g h n o t a s d r a m a t i c a s t h e l i f e t h r e a t e n i n g s i t u a t i o n a s s o -
c i a t e d w i t h a f a i l i n g h e a r t , t h e a n n u a l c o s t o f m a t e r i a l s a l o n e f o r r e p l a c i n g
l o s t t o o t h t i s s u e w i t h f i l l i n g s a n d p r o s t h e s e s c a n b e c o n s e r v a t i v e l y e s t i m a t e d
t o b e i n t h e r e g i o n o f 5 0 m i l l i o n f o r t h e U K a l o n e .
T o s o m e d e g r e e , a l l b i o m a t e r i a l s u s e d i n t h e p r o d u c t i o n o f m e d i c a l d e -
v i c e s t o t r e a t h u m a n d i s e a s e m a y b e c o n s i d e r e d s m a r t i n t h a t t h e y b r i n g
t h e i r i n d i v i d u a l p r o p e r t i e s t o t h e a i d o f t h e s u r g e o n . H o w e v e r , t h e y g e n -
e r a l l y a l s o b r i n g t h e i r o w n i n t r i n s i c d e f i c i e n c i e s t h a t l i m i t b o t h t h e i r u s e -
f u l n e s s a n d l i f e s p a n . T h e h i s t o r y o f m e d i c a l d e v i c e s h a s , u n t i l n o w , b e e n
o n e o f a d o p t i o n , a d a p t a t i o n a n d r e f i n e m e n t . A d o p t i o n f r o m o t h e r e n -
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Introduction 223
g i n e e r in g s c ie n c es , a d a p t a t i o n f or m e d i c a l u s e a n d r e f in e m e n t i n t h e
f ac e o f c h a l le n g e s p r e s e n t e d b y t h e h u m a n b o d y . T h e d e g r e e t o w h i c h
t h e s e b i o m a t e r i a l s m a y b e c o n s i d e r e d t r u l y s m a r t o r i n t e l l i g e n t i s s u b j e c t
t o d e b a t e . T h i s a r t i c l e e x p l a i n s t h e r e l a t i o n s h i p b e t w e e n p r o p e r t i e s , d e s i g n
a n d p e r f o r m a n c e f o r m a t e r i a l s u s e d i n m e d i c i n e , a n d a r g u e s t h a t o n l y n o w
a r e we t r u l y o n t h e v e r g e o f c r e a t in g s m a r t b i o m a t e r i a ls t h a t e n h a n c e t h e i r
o w n cl in i ca l p e r f o r m a n c e b y r e s p o n d i n g t o t h e i r e n v i r o n m e n t a n d t h e l iv i n g
b o d y .
I n t e r m s o f i n t e l l i g e n c e , m a n y b i o m a t e r i a l s c a n b e c o n s i d e r e d t o i n -
d u c e a n a p p r o p r i a t e r e s p o n s e w h e n p l a c e d i n c o n t a c t w i t h t h e c o m p l e x
b io lo g ic a l e n v i r o n m e n t o f t h e h u m a n b o d y . W h a t is c o n s id e r e d a p p r o p r i a t e
o r s m a r t w i ll v a r y f r o m d e v i c e t o d e v i c e . I n d e n t i s t r y t h e r e is a t o o t h -
c o l o u r e d f i l l i n g m a t e r i a l c a l l e d a g l a s s - i o n o m e r c e m e n t , w h i c h h a s b e e n i n
c li n ic a l u s e s in c e i ts i n v e n t i o n b y s c i e n t is t s a t t h e L a b o r a t o r y o f G o v e r n -
m e n t C h e m i s t in 1 96 8. T h i s m a t e r i a l is s m a r t b e c a u s e it is t o o t h - c o l o u r e d
a n d b l e n d s i n w i t h t h e a d j a c e n t t e e t h s o a s t o b e d i f f i c u l t t o d i f f e r e n t i a t e
f r o m th e n a t u r a l t e e t h . M o r e i m p o r t a n t l y , i t a ls o h a s th e c a p a c i t y to re l e as e
f lu o r id e s u c h t h a t i t p r o v i d e s lo c a l p r o t e c t i o n a g a i n s t t h e r a v a g e s o f t o o t h
d e ca y . H o w e v e r , i t is s ti ll n o t a s s m a r t a s h u m a n t o o t h e n a m e l t h a t h a s
a n i s o t r o p i c m e c h a n i c a l p r o p e r t i e s t h a t p r o t e c t i t f r o m e x c es si v e m e c h a n i c a l
l o a d in g , a n d a ls o h a s l i m i t e d c a p a c i t y fo r s e lf -r e p a ir . A n o t h e r e x a m p l e o f
a s m a r t b i o m a t e r i a l i s t h e r e s o r b a b l e s u t u r e m a d e f r o m p o l y ( l a ct ic a ci d )
T a b l e 9 . 1 E x a m p l e s o f b i o m a t e r i a l s a n d m e d i c a l d e v i c e s u s e d t o r e p l a c e o r a u g m e n t
h u m a n o r g a n f u n c t i o n .
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S u t u r e t i s s u e a d h e s i v e s
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A r t i f i c i a l s t a p e s c o c h l e a r i m p l a n t
H i p j o i n t b o n e p l a t e i n t r a m e d u l l a r y r o d
b o n e c e m e n t
K i d n e y d i a l y s i s m a c h i n e c a t h e t e r
S k u l l f r a c t u r e r e p a i r p l a t e h y d r o c e p h a l u s s h u n t
R e s t o r a t i v e f i l l i n g m a t e r i a l s
p e r m u c o s a l d e n t a l i m p l a n t s
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224 Sm ar t B iomater ia l s Out -Sma r t ing the Body ' s De fense Sys tems
o r s im i l a r s o lu b le p o l y m e r s . W h a t c a n b e s m a r t e r t h a n p e r f o r m i n g t h e j o b
i n t e n d e d , a n d w h e n t h e p e r i o d o f u s e fu l n e ss h a s c o m e t o a n e n d t o s i m p l y
d i s a p p e a r w i t h o u t a n y p e r m a n e n t a d v e r se e ve nt T h e l a t t e r is a v e r y i m p o r -
t a n t c o n s i d e r a t i o n a s t h e b i o m a t e r i a l m u s t b e b i o c o m p a t i b l e , w h i c h m e a n s
t h a t i t m u s t n o t c a u s e a n y a d v e r s e r e a c t i o n w h e t h e r l o c al o r s y s te m i c . B i o-
c o m p a t i b i l it y m a y b e d e fin e d a s t h e a b i l it y o f a m a t e r i a l t o i n d u c e / p e r f o r m
w i t h a n a p p r o p r i a t e h o s t r e s p o n s e i n a s p ec if ic a p p l i c a t i o n [2 ]. T h e r e s p o n s e
s h o u l d b e s u c h a s t o e n s u r e t h e c o n t i n u e d s a f e a n d e f f e c t i v e p e r f o r m a n c e o f
t h e m a t e r i a l . F u r t h e r m o r e , s u c h m a t e r i a l s s h o u l d n o t b e t o x i c o r h a v e u n -
f a v o u r a b l e p r o p e r t i e s d u e e i t h e r t o d i r e c t c o n t a c t o r b r e a k d o w n p r o d u c t s .
I n a d d i t i o n , f a c t o r s i n c l u d i n g p h y s i c a l , m e c h a n i c a l p r o p e r t i e s , d e s i g n , a n d
s u r f a c e c h e m i s t r y s h o u l d a l s o b e c o n s i d e r e d c a r e f u l l y .
T h e s a f e t y o f m e d i c a l d e v ic e s is a m a t t e r o f g r e a t c o n c e rn . N u m e r -
o u s b i o m a t e r i a l s h a v e b e e n d i r e c tl y a s s o c i a t e d w i t h t h e o n s e t o f m e d i c a l
p r o b l e m s f o ll ow i n g i m p l a n t a t i o n . I n s o m e c as e s t h i s w a s d u e t o p o o r m a t e -
r i m s e l e c t i o n o r d e v i c e d e s i g n , s u c h a s t h e P r o p l a s t ( ~ ) t e m p o r o m a n d i b u l a r
j o in t ( T M J ) m a r k e t e d b y th e V i t e k C o r p o r a t i o n i n t h e U S . T h i s br o k e
d o w n s h o r t l y a f t e r s u r g e r y , r e l e a s i n g d e b r i s i n t o t h e p a t i e n t ' s t i s s u e s t h a t
f r e q u e n t l y r e s u l t e d in c h r o n ic i n f l a m m a t i o n a n d p a i n . E v e n w h e r e t h e m e d -
i c a l d e v i c e c o u l d n o t b e d i r e c t l y r e l a t e d t o a r e p o r t e d m e d i c a l c o n d i t i o n ,
b i o m a t e r i a l m a n u f a c t u r e r s h a v e f o u n d th e m s e l v e s i n c o u r t . T h e e x p e ri e n c e
w i t h s il ic o n e b r e a s t i m p l a n t s w a s a s a l u t a r y l es so n f or c o m p a n i e s e n g a g e d i n
t h e b u s in e ss o f d e v e lo p i n g a n d m a r k e t i n g o f i m p l a n t s . T h o u s a n d s o f w o m e n
c l a im e d t h a t b r e a s t i m p l a n t s i n s e r t e d d u r i n g t h e 1 98 0s a n d 1 99 0s w e r e t h e
c a u s e o f a v a r i e t y o f d i s e a s es i n c l u d i n g b r e a s t h a r d e n i n g , s h a p e lo ss , c h r o n i c
p a i n in t h e m u s c le s a n d j o in t s , a u t o i m m u n e p r o b l e m s a n d o t h e r s y m p t o m s .
W h i l e s o m e o f t h e p r o b l e m s w e r e k n o w n s i de e ff ec ts o f b r e a s t a u g m e n t a t i o n ,
m a n y a l l e g e d d i s e a se s w e r e d i ff ic u lt o r i m p o s s i b l e t o d i a g n o s e . S u r g e o n s s u s -
p e c t e d t h a t s o m e p a t i e n t s s u ff er ed f ro m p s y c h o l o g i c a l p r o b l e m s r a t h e r t h a n
s i l ic o n e - r e l a t e d m e d i c a l c o n d i t i o n s . D e s p i t e t h e l a c k o f s c ie n t if ic e v id e n c e ,
D o w C o r n i n g w e r e fo r ce d t o s e t tl e m a n y o f t h e c l a im s f o r c o m p e n s a t i o n .
T h e c o s t o f l i t i g a t i o n a n d d a m a g e s r a n i n t o b il li o n s o f d o l l a rs , a n d D o w
C o m i n g h a d t o file fo r b a n k r u p t c y p r o t e c t i o n . T h i s c a se r a i se d m a n y w i d e r
c o n c e r n s re g a r d i n g t h e p r o t e c t i o n o f m e d i c a l d e v i ce m a n u f a c t u r e r s f r o m
i ll -d e fi ne d p r o b l e m s r e p o r t e d b y t h e r e c i p i e n t s o f t h e i r p r o d u c t s . A t o n e
t im e , t h e e n t i r e m e d i c a l s il ic o n e r u b b e r i n d u s t r y w a s t h r e a t e n e d b y t h i s
l i t i g a t i o n a n d a l m o s t c o l la p s e d . M e d i c a l si li c o n e r u b b e r s a r e u s e d in a l-
m o s t e v e r y b r a n c h o f m e d i c in e ( f r o m c a t h e t e r s t o h y d r o c e p h a l u s s h u n t s ) ,
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ntroduction 5
a n d i t s l o s s w o u l d h a v e b e e n d i s a s t r o u s . T h i s n i g h t m a r e s c e n a r i o w a s o n l y
n a r r o w l y a v e r t e d . O n e m o r e p o s i t i v e o u t c o m e o f t h i s a n d s i m i l a r c a s e s w a s
t h e d e v e l o p m e n t o f i m p r o v e d r e g u l a t i o n s f o r m e d i c a l d e v i c e m a n u f a c t u r e .
A l l m e d i c a l d e v i c e s n o w h a v e t o u n d e r g o r i g o r o u s s a f e t y t e s t i n g p r o c e -
d u r e s b e f o r e t h e y c a n b e m a r k e t e d a n d u s e d o n p a t i e n t s . T h e p r o c e s s o f
C E m a r k i n g w a s i n t r o d u c e d d u r i n g t h e 1 9 9 0 s f o r a l l m e d i c a l d e v i c e s t o b e
u s e d i n t h e E u r o p e a n C o m m u n i t y . I t i s a i m e d a t e n s u r i n g t h a t m e d i c a l
d e v i c e s a r e s a f e a n d f i t f o r t h e i r i n t e n d e d p u r p o s e . T h e r e i s e q u i v a l e n t l e g -
i s l a t i o n i n t h e U S p r o v i d e d b y t h e F o o d a n d D r u g A d m i n i s t r a t i o n ( F D A ) .
H o w e v e r , d e s p i t e t h e m a n y s a f e t y t e s t s c a r r i e d o u t , t h e r e c a n n e v e r b e a
g u a r a n t e e t h a t a b i o m a t e r i a l w i l l b e 1 0 0 s a f e , a n d p o s t - m a r k e t s u r v e i l -
l a n c e i s e x t r e m e l y i m p o r t a n t . I n t h e U K , s e v e r e a d v e r s e i n c i d e n t s a r e r e -
p o r t e d t o t h e M e d i c a l D e v i c e s A g e n c y , w h o w i l l t h e n d e c i d e w h a t a c t i o n i s
n e c e s s a r y ( w w w . m e d i c a l - d e v i c e s . g o v . u k / m d a - a i c ) . O t h e r s y s t e m s a i m e d a t
m o n i t o r i n g t h e e x t e n t o f a d v e r s e r e a c t i o n s p r o v i d e s u p p l e m e n t a r y i n f o r m a -
t i o n o n t h e s a f e u s e o f b i o m a t e r i a l s , s u c h a s t h e a d v e r s e r e a c t i o n r e p o r t i n g
p r o j e c t f o r d e n t a l m a t e r i a l s ( w w w . s h e f . a c . u k / u n i / p r o j e c t / a r r p ) . T h i s r e l a -
t i v e l y n e w r e g u l a t o r y e n v i r o n m e n t h a s p r o v e d b o t h a h a n d i c a p a n d b e n e f i t
i n t h e d e v e l o p m e n t o f i m p r o v e d b i o m a t e r i a l s a n d m e d i c a l d e v i c e s . I t i s
c e r t a i n l y n o b a d t h i n g t h a t m a n u f a c t u r e r s a n d c l i n i c i a n s h a v e c l e a r g u i d e -
l i n e s o n g o o d p r a c t i c e s r e l a t e d t o d e v i c e d e s i g n , m a n u f a c t u r e a n d u s e . I n
a d d i t i o n , w h e n p r o b l e m s o c c u r t h e y a r e i n v e s t i g a t e d f u l l y b y t h e M D A a n d
a p p r o p r i a t e a c t i o n i s d e m a n d e d . T h e o n l y d i f f i c u l t y i s t h a t n e w i n n o v a -
t i o n s m u s t b e m o r e c a r e f u l l y r e s e a r c h e d b e f o r e c l i n i c a l u s e i n r e a l p a t i e n t s .
H o w e v e r , t h i s i s a s m a l l p r i c e t o p a y f o r i n c r e a s e d c o n f i d e n c e i n o u r m e d i c a l
d e v i c e s a n d b i o m a t e r i a l s .
T h e s u c c e s s f u l d e v e l o p m e n t o f n e w b i o m a t e r i a l s i n m e d i c i n e a n d d e n -
t i s t r y d e p e n d s o n a m u l t i t u d e o f f a c t o r s , s u c h a s m a t e r i a l s p r o p e r t i e s , d e -
s i g n a n d t h e b i o c o m p a t i b i l i t y o f t h e m a t e r i a l s u s e d . T h i s m u s t t h e r e f o r e
b e b a s e d a m u l t i d i s c i p l i n a r y a p p r o a c h a s i t r e q u i r e s a n i n p u t f o r m a t e r i a l s
s c i e n t i s t s , e n g i n e e r s , b i o l o g i s t s a n d c l i n i c i a n s . T h e c o m m o n t h r e a d t h a t
u n i t e s t h e s e i n d i v i d u a l s i s t h e d e s i r e t o d e v e l o p b e t t e r d e v i c e s f o r m e d i c a l
a p p l i c a t i o n s . I t w a s n o t u n t i l t h e m i d d l e o f t h e 2 0 T c e n t u r y t h a t t h i s c o m -
b i n a t i o n o f e x p e r t i s e b e g a n t o b e h a r n e s s e d i n a c o o r d i n a t e d w a y s u c h t h a t
n o w w e h a v e d e l i b e r a t e c o l l a b o r a t i o n s a c r o s s t h e v a r i o u s d i s c i p l i n e s .
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Sm ar t B iomater ia l s Out -Sm ar t ing the Body ' s De fense Sys tems
9 2 D u m b B i o m a t e r i a l s T h e F i r s t G e n e r a t i o n
T h e i d e a of u s in g n a t u r a l o r m a n - m a d e m a t e r i a ls t o r e p la c e p a r t s o f t h e
h u m a n b o d y a n d r e p l a c e f u n c t i o n h a s b e e n a r o u n d f o r m a n y c e n t u r i e s .
H o w e v e r , i t w a s th e a d v e n t o f a n e s t h e s i a , a s e p t ic s u r g i c a l t e c h n i q u e s a n d t h e
d i s c o v e r y o f t h e b e n e f i t s o f x - r a y s d u r i n g t h e l a t t e r p a r t o f t h e 19 th c e n t u r y
t h a t p a v e d t h e w a y fo r t h e d e v e l o p m e n t o f n o v el b i o m a t e r i a l s. B e f or e t h e n ,
t h e u s e o f b i o m a t e r i a l s h a d n o t p r o v e d p a r t i c u l a r l y s u c c es s fu l d u e t o t h e
p r o b l e m s o f i n fe c t io n a n d p e r s i s t e n t d r a i n a g e w a s t h e r u le . B o n e r e s o r p t i o n
a n d e x t r u s i o n o f t h e i m p l a n t w e r e c o m m o n p r o b l e m s [2 ]. E v e n n o w in f e c ti o n
c o n t i n u e s t o b e a c o m m o n p r o b l e m a s i t is p o s si b le f or b lo o d b o r n e b a c t e r i a
t o a t t a c h t h e m s e l v e s t o a n i m p l a n t a n d f o r m a b i o f i l m , w h i c h p r o t e c t s
t h e b a c t e r i a f r o m a t t a c k f ro m t h e b o d y s n a t u r a l d e fe n se s y s t e m o r t h e
a d m i n i s t r a t i o n o f a n t i b io t i c s . T h i s is a n a l o g o u s t o th e f o r m a t i o n o f p l a q u e
o n t e e t h , w h i c h p r e v e n t s t h e s a l i v a f r o m n e u t r a l i s i n g t h e a c i d g e n e r a t e d
b y th e b a c t e r i a a s t h e s e d ig e s t c a r b o h y d r a t e s ( s u g a r s) , r e s u l t i n g in t h e
d i s s o lu t i o n o f t h e e n a m e l s u r f a ce o f t h e t o o t h .
I n t h e e a r l y 1 9 0 0 s b o n e p l a t e s w e r e b e g i n n i n g t o b e u s e d a s a m e a n s
o f p r o v i d i n g f i x a t io n o f f r a c t u r e s o f t h e l o n g b o n e s. T h i s m o v e t o w a r d s
i n t e r n a l p r o s t h e s e s s t e m m e d f r o m a k n o w l e d g e t h a t f o re ig n b o d i e s s u c h
a s b u l l e ts o r s h r a p n e l m a y b e t o l e r a t e d b y t h e b o d y f or m a n y y e a r s [2 ].
U n f o r t u n a t e l y , p r o b l e m s a r o s e d u e t o p o o r m e c h a n i c a l d e s i g n o r t h e w r o n g
c h o ic e o f m a t e r i a ls . A m a t e r i a l s u c h a s v a n a d i u m s te e l w a s f o u n d t o c o r r o d e
r a p i d l y in th e h o s ti le e n v i r o n m e n t o f t h e h u m a n b o d y a n d t h e c o rr o si o n
p r o d u c t s w e re f o u n d a d v e r s e l y t o a ff e ct th e w o u l d h e a l in g p r oc e ss . T h e
s i t u a t i o n i m p r o v e d w i t h t h e i n t r o d u c t i o n o f s t a in l e s s s te e ls a n d c o b a l t -
c h r o m i u m a ll o y s a n d m u c h b e t t e r r e s u l t s w e r e a c h i ev e d f or fr a c t u r e f i x a ti o n .
A l t h o u g h t h e f ir st h i p j o i n t r e p l a c e m e n t w a s a t t e m p t e d in 1 93 8, i t w a s
n o t u n t i l th e i n t r o d u c t i o n o f t h e c e m e n t e d h i p p r o s t h e s i s b y C h a r n l e y i n
1 9 58 t h a t t h e fi rs t c o n s i s t e n t r e s u l t s w e r e p r o d u c e d ( F i g . 9 . 2) . P o l y m e t h y l
m e t h a c r y l a t e ( P M M A ) w a s u se d i n t h e s e e a rl y c as es fo r t h e c e m e n t a t i o n
o f t h e h i p j o in t . T h e s u g g e s t i o n fo r u s i n g P M M A w a s m a d e b y D r. D e n n i s
S m i t h , a d e n t i s t w o r k i n g in M a n c h e s t e r U n i v e r si ty . P M M A is w i d e l y u s e d
f or t h e c o n s t r u c t i o n o f a c r y li c d e n t u r e s a n d h a s h a n d l i n g c h a r a c t e r i s t i c s
t h a t m a k e s it s u i t a b l e a s t h e c e m e n t f or h o l d i n g t h e h i p j o i n t i n p l a c e .
A l s o , i t w a s k n o w n f r o m w a r t i m e e x p e r i e n c e s i n W o r l d W a r I I t h a t a i r
c r ew w h o h a d s uf fe re d in ju r ie s , w h e r e f r a g m e n t s o f P M M A h a d b e c o m e
e m b e d d e d in t h e i r b o d i e s, d i d n o t a p p e a r t o su ff er a n y c h ro n i c a d v e r s e
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227
Fig. 9.2 Stainless steel hip joint and high density polyethylene acetabular cup.
reactions. On the basis of this observa tion PMM A was being explored in
the 1940s for corneal replacement. The combination of stainless hip joints
and P MMA bone cement has since proved very effective and to this day
most hip replacements are still cemented with PMMA.
A few years after Charnley s success, anothe r o rt hopaed ic su rgeon by
the name of Br/inemark [3] made a fortuitous discovery regarding the bi-
ological response to titanium. He had developed a rabbi t model to study
blood flow through the peripheral blood vessels by creating a glass win-
dow set in a ring of tit anium. When he wanted to reuse these windows he
found that they were extremely difficult to remove because the cartilage of
the ear had become strongly attached to the alloy. Further experiments in
bone showed that the biological response to titanium was quite different
from that experienced with stainless steel or cobalt-chromium alloys. For
stainless steel and Co-C r alloys, the body s response tends to be a pro-
cess of fibrous encapsulation of the implant . This is a defense mechanism
against the invasion of a foreign body and is commonly seen with a lot of
synthetic materials. In contrast, t ita nium was found to stimulate an inti-
mate relationship between the implant and the bone, such that the implant
becomes embedded in the bone. Br/inemark called this type of response
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228 Smart Biomaterials -- Out-Smarting the Body's Defense Systems
Fig 9 3 Dental implants made from commercia lly pure tit ani um protrudi ng from the
soft tissue
osseintegration
d i s t i n g u i s h e d f r o m o t h e r b i o l o g i c a l r e s p o n s e s b y t h e c l o s e
a d a p t a t i o n o f b o n e t o t h e s u rf ac e o f t h e i m p l a n t w i t h o u t t h e f o r m a t i o n o f a
f ib r o u s c a p s u le . T h i s o b s e r v a t i o n h a s l e a d t o t h e d e v e l o p m e n t o f c e m e n t l e s s
f i x a ti o n o f h i p p r o s t h e s e s u s i n g T i6 A 1 4V a l lo y s a n d t h e d e v e l o p m e n t o f t h e
h i g h l y s u c c e s s f u l p e r m u c o s a l d e n t a l i m p l a n t s ( o f t e n r e f e r r e d t o a s s c r e w - i n
t e e t h ) u s i n g c o m m e r c i a l l y p u r e t i t a n i u m ( F ig . 9 .3 )
S i m u l t a n e o u s l y i n t h e c a r d i o v a s c u l a r f i e l d i t w a s a l s o n o t i c e d t h a t s o m e
m a t e r i a l s p e r f o r m e d b e t t e r i n c o n t a c t w i t h b l o o d t h a n o t h e rs . O n e o f t h e
b o d y ' s p r i m a r y d e f e n s e m e c h a n i s m s w h e n i n j u r e d i s f o r a b l o o d c l o t t o f o r m
s o a s t o p r e v e n t f u r t h e r b l e e d i n g f r o m t h e d a m a g e d b l o o d v e s s e l s . I n t h e
s a m e w a y , w h e n b l o o d c o m e s i n c o n t a c t w i t h a f o r e i g n o b j e c t i t s e t s o f f
the c lo t t ing p rocess , s ince we have no t y e t d i scove red a way o f inse r t ing
i m p l a n t s w i t h o u t c a u s i n g lo c a l t i s s u e d a m a g e . T h i s h a s p r o v e d a s e r io u s
h u r d l e i n t h e d e v e l o p m e n t o f b l o o d c o n t a c t i n g d e v i c es s u c h a s t h e a r ti fi c ia l
h e a r t , b l o o d v e s s e l s , o x y g e n a t o r s a n d k i d n e y d i a l y s i s m a c h i n e s .
G r a d u a l l y t h e r e w a s a r e a l i s a t i o n t h a t d i f f e r e n t m a t e r i a l s c a n i n d u c e
w i d e l y d i ff e re n t r e s p o n s e s i n th e b i o lo g i ca l e n v i r o n m e n t . T h e r e f o r e , i n o r d e r
t o o v e r c o m e t h e p r o b l e m s e n c o u n t e r e d i n t h e u s e o f s y n t h e t i c m a t e r i a l s , it
w a s n e c e s s a ry t o d e v e l o p s m a r t
biomaterials
t h a t is m a t e r i a l s t h a t a c t i v e l y
e n g a g e w i t h t h e b i o l o g i c a l e n v i r o n m e n t i n s u c h a w a y a s t o a c h i e v e t h e
des i r ed r e su l t .
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229
9 . 3
P l a n n i n g a n d R e f i n e m e n t
m a t e r i a l s
S e c o n d G e n e r a t i o n B i o
W h i l e a n u m b e r o f u s e fu l fi rs t g e n e r a t i o n b i o m a t e r i a l s w e r e d is c o v e re d ,
i t w a s a p p a r e n t t h a t t h e y o f t e n s u f f e r e d l i m i t a t i o n s i n m o r e d e m a n d i n g
a p p l i c a t i o n s , e s p e c i a ll y i n t h e l o n g e r t e r m . I n l o a d b e a r i n g i m p l a n t s , i t
is v e r y i m p o r t a n t t h a t t h e r e is a n a p p r o p r i a t e t r a n s f e r o f s t re s s b e t w e e n
t h e i m p l a n t a n d t h e b o n e . B o n e is a v e r y s m a r t m a t e r i a l . I f b o n e is n o t
s u b j e c t e d t o s t r e s s i t w i l l r e s o r b o n t h e b a s i s t h a t t h e m e s s a g e i t r e c e i v e s
is t h a t i t is n o l o n g e r n e e d e d i f n o t s t r e s s e d , a p ro c e s s k n o w n a s
s t r e s s
s h i e l d i n g .
I t is a p r o b l e m t h a t a s t r o n a u t s s u ff e r w h e n s p e n d i n g a l ot of
t i m e i n t h e w e i g h t l e s s e n v i r o n m e n t o f s p a c e . I n c o n t r a s t , w h e r e b o n e is
h i g h l y s t r e s s e d i t m a y t r y t o c o m p e n s a t e b y l a y i n g d o w n a d d i t i o n a l b o n e
s o a s t o r e d u c e t h e s t re s s . T h e c a l lu s t h a t f o r m s d u r i n g t h e h e a l i n g of a
f r a c t u r e d b o n e is a n e x a m p l e o f t h i s p r o c e ss . H o w e v e r , i f t o o h i g h l y s t r e s s e d
t h e n t h e b o n e w i l l r e c e d e i n o r d e r t o a v o i d t h e s e h i g h l y d a m a g i n g s t r e s s
l ev els . I n d e n t i s t r y , t h i s s m a r t b e h a v i o u r b y b o n e i s u t i li s e d t o m o v e t e e t h
a r o u n d , w h i c h m a y b e fo r a e s t h e t i c o r f u n c t i o n a l r e a s o n s. I t fo r m s th e b a s i s
o f t h e c l i n ic a l d i s c i p l in e o f o r t h o d o n t i c s .
I n t h e c a s e o f h i p p r o s t h e s e s , t h e d e s i g n a n d s t i f fn e s s c h a r a c t e r i s t i c s o f
t h e m a t e r i a l s u s e d a r e w i d el y di ff er e nt f r o m t h e n a t u r a l b o n e b e i n g r e p l a c e d
(s ee T a b l e 9 . 2 ). T h e h i g h s u c c e s s r a t e w i t h t h e e a r l y hi p j o i n t s c a n b e p a r t l y
a t t r i b u t e d t o t h e a g e of t h e p a t i e n t s , w h o w e r e t y p i c a l l y o l d e r t h a n 6 5 y e a r s
o f a g e. S u c h p a t i e n t s a r e n o t e s p e c i a ll y a c t i v e a n d t h u s t h e s t r e s se s to w h i c h
t h e i m p l a n t a n d t h e s u r r o u n d i n g b o n e a r e s u b j e c t e d a r e n o t h a s h i g h a s
w i t h y o u n g e r m o r e a c t i v e p a t i e n t s . Y e t , t h e r e i s c o n s i d e r a b l e d e m a n d f o r
j o i n t r e p l a c e m e n t s i n t h e y o u n g a n d p h y s i c a l l y a c t i v e p a t i e n t . T h i s p l a c e s
Table 9.2 Co mp arison of the m echanical properties of cortical bone and some imp lant
materials.
Tensi le Elas t ic
M a te r ia l S t r e n g th ( MP a ) Mo d u lu s ( G P a ) E lo n g a t io n ( )
Co rtica l bon e 136 18 1
Ti6A14V 860 110 12
Stain less s teel 550 200 50
Ca st C o- C r a l loy 650 240 10
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230 Sm ar t B iomater ia l s Out -Sma r t ing the Body ' s De fense Sys tems
Fig. 9.4 Fibrous encapsulation of a zirconia implant as indicated by the dark band
around the implant.
considerable demands on the effective functioning of these implants. Stress
shielding can result in aseptic loosening of the implant and is a significant
contr ibutor to implant failure. In addition, the acrylic bone cement does
not provide a very effective bond to the bone and the local micro-movement
that takes place has also been implicated in aseptic loosening of the joint.
The work on titanium showed tha t some materials may be able to induce
a response in bone cells that can be highly beneficial. The cementless
fixation made possible with titanium alloys has opened up the opportunity
to develop implants that provide a more benign stressing condition, which
can improve the longevity of the implant.
Titanium and its alloys are described as osseointegrating in that these
materials appear to allow direct bone contact after healing without the
intervent ion of a fibrous, soft tissue layer. Figure 9.4 is an example of the
fibrous encapsulation that occurs with zirconia, which contrasts with the
close apposition of bone to a composite ceramic made of hydroxyapatite
and zirconia Fig. 9.5).
While some researchers have argued that osseointegration is a feature of
the TiO2 oxide surface of the biomaterial, this is probably only part of the
story. The more generally accepted explanation is that it is careful surgery
that avoids the death of local bone that provides osseointegration around
dental and similar titanium implants.
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23
F ig . 9 .5 O s s e o i n t e g r a t e d i m p l a n t b a s e d o n a c o m p o s i t i o n o f 5 0 H A p a n d 5 0 z i rc o n ia .
S o m e b i o m a t e r i a l s a r e d e s c r i b e d a s h a v i n g o s t e o c o n d u c t i v e p r o p e r t i e s ,
a s t h e r e i s e v i d e n c e t h a t t h e y s t i m u l a t e g e n e r a t i o n o f n e w b o n e o n t h e i r s u r-
f ac e a f t er i m p l a n t a t i o n i n t o e s t a b l i s h e d b o n y ti s su e . W h i l e t i t a n i u m is n o t a
t r u l y o s t e o c o n d u c t i v e b i o m a t e r i a l , a n u m b e r d o e x i s t . S i n c e t h e 1 9 7 0 s , n e w
m a t e r i a l s h a v e b e e n d e v e l o p e d t h a t e n h a n c e b o n e f o r m a t i o n a n d h e a l i n g a t
t h e s i te o f s u r g er y . E x a m p l e s o f s u c h m a t e r i a l s a r e s y n t h e t i c h y d r o x y a p -
a t i te , b i o a c t i v e g l a ss e s e .g . B i o g l a s s ~ ) a n d o s t e o c o n d u c t i v e g l a s s - ce r a m i c s
e . g . a p a t i t e - w o l l o s t e n t i t e g l a s s - c e r a m i c s ) . W h i l e t h e e x a c t m e c h a n i s m i s
n o t k n o w n , t h e r e a r e t w o c o m p l i m e n t a r y t h e o r i e s s u p p o r t e d b y p u b l i s h e d
sc ien ti fi c ev idence . T he f i r s t is th a t speci fi c p ro te in s a r e ad so rbe d f rom the
b i ol o gi ca l e n v i r o n m e n t t h a t s u b s e q u e n t l y r e c r u i t c ells t h a t p r e c u r s o r s to
b o n e fo r m i n g c ell s o s t e o b l a s t s ) . T h e s e a d h e r e t o t h e b i o m a t e r i a l s u r f ac e
a n d p r o d u c e b o n e t i s s u e t h a t a s s i st s t h e o v e r a l l h e a l i n g p ro c e s s . I n s o m e
b i o m a t e r i a l s s u c h as B i o g l a ss ) , t h i s p ro c e s s is p r e c e d e d b y io n e x c h a n g e a t
t h e i m p l a n t s u r fa c e a n d d e v e l o p m e n t o f a c a l c iu m p h o s p h a t e l ay e r. T h i s r e-
a c t i o n i s b e l i ev e d t o a l l o w t h e f o r m a t i o n o f a d i r e c t c h e m i c a l b o n d b e t w e e n
t h e B i o g la s s a n d t h e m i n e r a l p h a s e o f n e w l y f o r m e d b o n e t i s s u e.
9 3 1
a l c i u m P h o sp h a t e e r a m i c s
T h e f a ct t h a t t h e m i n e r a l p h a s e o f b o n e a n d t o o t h t i s s u e is c o m p o s e d o f
c a l c i u m p h o s p h a t e s a l t s , h a s d i r e c t e d r e s e a r c h e r s t o i n v e s t i g a t e t h e s e m a -
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Fig. 9.6 Image of the interface between a HAp implant and bone taken using a scanning
electron microscope, showing direct contact between the bone and the implant.
t e ri a ls as p o t e n t i a l c a n d i d a t e s fo r b o n e s u b s t i t u t e s . A l t h o u g h t h e b o n e
m i n e r a l i s s i m i l a r t o h y d r o x y a p a t i t e
[ C a l 0 P O 4 ) 6 o g ) 2 ] ,
i t i s poor ly c rys-
t a ll in e i n s t r u c t u r e a n d c o n t a in s a w i d e r a n g e o f c a l c iu m p h o s p h a t e p h a s e s ,
i n c l u d i n g t r i c a l c i u m p h o s p h a t e , c a r b o n a t e d a p a t i t e a n d n u m e r o u s o t h e r
i on ic im p u r i t i e s s u c h a s fl uo r id e , m a g n e s i u m a n d s o d i u m [ 4] . F l u o r a p a t i t e
[ C a l0 P O 4 ) 6 F ) 2 ] e x h i b i t s th e s a m e s t r u c t u r e a s H a p , t h e o n l y dif fe re n ce
b e i n g t h a t t h e h y d r o x y l g r o u p s h a v e b e e n r e p la c e d b y f lu o r in e io n s. F A
i s m o r e s t a b l e t h a n H A p a t h i g h t e m p e r a t u r e s , a n d m o r e r e s i s t a n t t o a c i d
a t t ack . Tr i ca l c ium ph osp ha te [Caa PO4)2] can be found in two fo rms , c~-
T C P a n d t h e m o r e s t a b l e / 3 - T C P . B o t h f o r m s h a v e b e e n r e p o r t e d t o e x -
h i b i t r e l a t i v e l y h i g h d i s s o l u t i o n p r o p e r t i e s [ 5 ] . T h e s e m a t e r i a l s c a n b o n d
w i t h n a t u r a l b o n e w i t h o u t f i b r o u s t i s s u e e n c a p s u l a t i o n . C h e m i c a l b o n d i n g
o f c a l ci u m p h o s p h a t e c e ra m i c s t o b o n e c o m p r i s e s a p a r t i a l d i s s o l u t io n o f
t h e c e r a m i c s u r f a c e a n d t h e s u b s e q u e n t f o r m a t i o n a n d r e p r e c i p i t a t i o n o f
C O 3 - a p a t i t e c r y s t a l s t o g e t h e r w i t h b io m o l e c u l es of t h e s u r r o u n d i n g t is s u e
fluid [6] Fi g. 9.6 ).
T h e d e v e l o p m e n t o f s y n t h e t i c c a l c iu m p h o s p h a t e s h a s p r o v i d e d a w i d e
r a n g e o f m a t e r i a ls t o b e i n v e s t i g a te d f o r th e i r b o n e r e p l a c e m e n t p r o p e r t ie s ,
a l t h o u g h t h e i r a p p l i c a t i o n i s l i m i t e d d u e t o t h e i r p o o r m e c h a n i c a l p e r f o r -
m a n c e . A m a j o r a p p l i c a t i o n o f H A p is in lo w s t re s s b e a r i n g s i t u a t i o n s s u c h
as a lveola r r idge au gm en ta t io n [7; 8] F ig . 9 .7).
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Fig. 9.7 Localised alveolar ridge augmentation using HAp granules.
One way of overcoming this limitation is to apply the calcium phosphate
ceramic as a coating on the surface of a metallic implant. This concept of
utilising materials that induce the formation of new bone has been widely
explored as a means of coating the surface of implants. One technique is
to use plasma spraying [9] with smart biomaterials such as HAp that speed
up the process of osseointegration. In effect, the biological response is gov-
erned by the surface coating rather tha n the bulk material underneath. In
this situation the bulk material can provide the strength while the coating
provides the appropr iate biological response Fig. 9.8).
These approaches to developing implant materials with a smart response
in the biological environment, can still be considered to be based on empir-
ical observation. In order to control and predict the biological response to
a biomaterial it is necessary to have a much more detailed understanding
of the mat eri al- tis sue interface interactions. Fortuna tely, at the same time
as materials scientists were exploring new materials, the biological sciences
were developing at a rapid pace.
9.3.2 i o a c t i v e G l a s s e s
In bioactive glasses, the composition is designed such that the surface un-
dergoes a selective chemical reaction with the physiological environment,
resulting in a chemical bond between tissue and the implant surface [10].
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i } i i i i ii i i i i i i i i i i i i i i i i i i ? : i l: : i i : i ; i ~ : i ;
i ii i i ii ii i i i ; i :
..................................................i ii ii ii ii ii ii ii i i ii ii ii ii ii ii ii ii ii i i ii ii ii ii ii ii ii i ~ . .. . . .. . .. . .. . .. . .. .. . . , ~ ~ ~ i
i::i?iiiiii?i iiiiiii i:i~i i~ii~=iiiiiiiiiii iil;/:iiiiii~iiiiiiiiii::ii N~i:i ....~Niiiiiiiiiii?iNiNiii i~iiiiNii
....... i;/~iili:i:ii ii~, iiii~i~iiiiiii,ii,~i)~ i~i?i ii) ::;:::
.................... ......................... :. i;i~ i i Ni~?%i~i:~i:~ii~ilili~ii i=::
F i g 9 8 P l a s m a s p r a y e d s u r f a c e c o a t i n g o f H A p o n t h e b o n e c o n t a c t i n g s u r f a c e o f a
m e t a l a c e t a b u l a r c u p .
T h e b o n d e d i n te r fa c e p r o t e c t s t h e i m p l a n t m a t e r i a l f r o m f u r t h e r d e t e r io r a -
t i o n w i t h t i m e . T h e f ir st m a n - m a d e m a t e r i a l s , w h i c h w e re f o u n d t o b o n d t o
l iv in g b o n e , w e r e g la s se s i n t h e s y s t e m N a 2 0 - C a O - S i O 2 - P 2 0 5 . T h e s e w e re
d i s c o v e r e d b y H e n c h
e t a l
[ 11 ] i n th e e a r l y 1 9 7 0s a n d n a m e d b i o g la s s es .
T h e b i o g l a s s m a t e r i a l s e e m s t o e n h a n c e b o n e - i m p l a n t i n t e r f a c e d e v e l o p -
m e n t a n d b o n d i n g w h e n i m p l a n t e d in b o n e. W h e n b io g la s se s a r e s u b j e c te d
t o a n a q u e o u s e n v i r o n m e n t , c a l c iu m a n d p h o s p h a t e i on s l ea c h fr o m t h e im -
p l a n t b u l k t o f o r m a c a lc i u m p h o s p h a t e - r i c h l a y er o n t h e i m p l a n t s u rf ac e ,
w h i c h is b e l ie v e d t o i m p a r t t h e b o n e b o n d i n g a b i l it y t o t h e b i o g l a ss e s . B i-
o l o g i c a l p r o c e s s e s , s u c h a s c o l l a g e n i n t e r d i g i t a t i o n , h a v e b e e n d e s c r i b e d b y
H e n c h
e t a l
[ 1 2 ] . S i n c e t h e d i s c o v e r y o f b i o a c t i v e g l a s s e s in e a r l y 1 9 7 0 s,
v a r i o u s k i n d s o f g l a ss e s a n d g l a s s - c e r a m i c s h a v e a ls o b e e n f o u n d t o b o n d t o
l i v i n g b o n e , a n d m a n y a r e n o w c l i n i c a l l y u s e d s u c h a s a n a r t i f i d i a l m i d d l e
e a r b o n e [ 11 ] a n d a l v e o l a r r i d g e m a i n t e n a n c e i m p l a n t s [ 1 3 ; 14]. B i o a c t i v e
g l a s s e s a r e a l s o u s e d a s a r t i f i c i a l v e r t e b r a e , i n t e r v e r t e b r a l s p a c e r s , i l i a c c r e s t
p r o s t h e se s , a n d g r a n u l e s f o r b o n e d e f e c t f il le r s [ 1 1 ; 1 2; 13 ]. A s w i t h t h e c a l -
c i u m p h o s p h a t e c e r am i c s t h e i r a p p l i c a t io n is l im i t e d t o l ow s tr e s s b e a r i n g
c o n d i t i o n s d u e t o p o o r m e c h a n i c a l p r o p e r t i e s .
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9 . 4
S m a r t S u r f a c e s T a i l o re d fo r S p e c i f i c p p l i c a t i o n s
T h i r d G e n e r a t i o n B i o m a t e r i a l s
9 . 4 . 1 M a t e r i a l s T i s s u e I n t e r f a c e
W h e n a b i o m a t e r i a l is i m p l a n t e d i n t h e b o d y , t h e s i te is i n v a d e d b y
m a c r o p h a g e s . I f t h e s e c e lls a r e a b l e t o e n g u l f t h e i m p l a n t t h e n t h e c e l ls w i ll
a t t e m p t t o b r e a k d o w n t h e o f f e n d i n g o b j e c t , a p r o c e s s k n o w n a s p h a g o -
c y t o si s. H o w e v e r , if t h e f o r ei g n o b j e c t is t o o l a r g e t h e n t h e m a c r o p h a g e s
w i ll a d h e r e t o t h e s u r f a c e th e i m p l a n t . T h e r e s u l t o f t h i s is t h a t a f o r e ig n
b o d y r e a c t i o n is i n i t i a te d , w h i c h m a n i f e s t s i ts e lf a s a n e n c a p s u l a t i o n o f t h e
i m p l a n t b y c o ll a g e n o u s c o n n e c t i v e t is s u e . T h e s e m a c r o s c o p i c ef fe ct s a r e
r e g u l a t e d b y n a n o - s c a l e p r o c es s es a n d t h e s u r f a c e p r o p e r t i e s o f t h e b i o m a -
t e r ia l h a v e a m a j o r i n fl u en c e o n t h e t y p e o f r e s p o n s e p r o d u c e d a s i t is t h e
s u r fa c e o f t h e b i o m a t e r i a l t h a t f ir st c o m e s i n c o n t a c t w i t h t h e b o d y [1 5].
I f t h e u p t a k e o f m a c r o p h a g e s a n d s u b s e q u e n t e n c a p s u l a t i o n is t o b e
a v o i d e d t h e n t h i s i s p o s s i b l e e i t h e r b y a j u d i c i o u s c h o i c e o f t h e b i o m a t e r i a l
b a s e d o n p a s t e x p e r i e n c e (e .g . T i ), o r b y m o d i f i c a t i o n o f t h e m a t e r i a l s
s u r fa c e c h e m i s t r y . T h e f o r m e r a p p r o a c h i s i n t r in s i c a l ly v e r y l i m i t i n g as
t h e r e a r e f ew m a t e r i a l s t h a t e li ci t t h e t y p e o f b i o lo g i ca l r e s p o n s e d e s i re d
a n d a ls o t h e n a t u r e o f t h e s e r e sp o n s e s is v e r y li m i t e d . T h e l a t t e r a p p r o a c h
is in e ff ec t a m e a n s of o u t - s m a r t i n g t h e b o d y s n a t u r a l d e f e ns e m e c h a n i s m
b y h i d i n g t h e b u l k m a t e r i a l , w h i c h m a y e l ic it a n i n a p p r o p r i a t e b i o lo g i c al
r e a c t i o n , b e h i n d a s u r f a c e l a y e r t a i l o r e d t o g i v e t h e d e s i r e d r e s p o n s e .
T h e b e h a v i o u r o f c ells i n o r g a n s a n d t is s u e s d e p e n d s o n c e l l- s u r f a c e in -
t e r a c t i o n s b o t h w i t h m o l e c u le s o n t h e s u r fa c e o f o t h e r c ells , t h e s u r fa c e o f
t h e s u b s t r a t e a n d w i t h th e e x t r a c e l l u l a r m a t r i x [ 16 ]. H e n c e t h e s u c ce s s o r
f a il u re o f t i ss u e e n g i n e e r e d d e v ic e s is d e p e n d e n t o n t h e c o m p l e x i n t e r p l a y
b e t w e e n c e lls a n d m a t e r i a l s . T h e r e s p o n s e o f c ells t o n a t u r a l o r s y n t h e t i c
m a t e r i a l s i s t h e r e f o r e c r u c i a l i n d e v e l o p i n g l a b o r a t o r y - b a s e d s t r a t e g i e s f o r
w o u n d c a r e a n d h e a l i n g . T h e s e c e l l - s u r f a c e i n t e r a c t i o n s i n f l u e n c e a n d c o n -
t r o l c e ll p h y s i o l o g y , su c h a s a d h e s i o n , s p r e a d i n g , m i g r a t i o n , p r o l i f e r a t i o n
a n d d i f f e re n t ia t io n . W h e n a b i o m a t e r i a l is i m p l a n t e d t h e f ir st t h i n g t h a t
t a k e s p l a c e is t h e a d s o r p t i o n o f p r o t e i n s , s u c h a s f i b r o n e c t i n , l a m i n i n , v i t -
r o n e c t i n a n d c o l la g e n , o r a v a r i e t y o f c e ll a d h e s i o n m o l e c u l e s ( C A M s ) , f r o m
t h e e x t r a c e l l u l a r m a t r i x . F r o m t h e w o r k o f c ell b i o lo g i st s w e h a v e l e a r n t
t h a t a ce ll s u r f a c e i s c o v e r e d b y a n a r r a y o f a d h e s i o n r e c e p t o r s , w h i c h h a v e
b e e n i d e n ti fi e d a s i m m u n o g l o b u l i n s , s e l ec t in s a n d i n t e g r i n s. T h e p r o t e i n s
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interact with these receptors on the cell surface and bind the cell to its
extracellualar matrix (ECM). The ECM acts as a soup with a wide variety
of ingredients such as cytokines and growth factors and orchestrates the
whole process.
It is therefore important that the right sort of proteins are adsorbed
onto the surface of the implant since these will determine the biological
response and thus eventually the fate of the implant. For instance, when
a surface is contacted with blood and the response is the formation of a
blood clot then such a material would be inappropriate for applications as
haemodialysers, artificial blood vessels or heart valves. Similarly the surface
a contact lens needs to be easily wetted by tear fluid as it will otherwise
damage the cornea. Lack of adhesion between a dental implant and the
mucosa would cause infection due to the infiltration of bacteria from the
oral environment into the gap.
It is unlikely th at off-the-shelf mate ria ls will be able to provide the
variety of different cell-surface interac tions desired. Hence, in order for
biomaterials to be accepted by the body, it is vital that the implant surface
is
esigne
so as to promote appropriate and highly selective interactions
with its biological environment. The nat ure of these interactions will be
governed by the appli cation of the biomaterial. Hence a material tha t
may have excellent properties for providing structural support, but does
not induce the appropriate biological response, can be made to do so by
coating it with a surface layer with a chemistry that is tailored to suit a
particular application.
From an understanding of the factors that control cell-surface interac-
tions it is possible to devise methods of modifying the surface characteristics
of biomaterials that will have the effect of changing the local biological re-
sponse. One approach involves modif ication of the surface chemistry of
the biomaterial in order to regulate the type of proteins adsorbed onto the
surface, another other is to create highly selective interactions by graft-
ing biologically active molecules onto the surface of the biomater ial. The
manner of such surface modifications will be dictated by the nature of the
response required. For example, in devices tha t will be exposed to a bacte-
rial flora such as a synthetic voice box, cell attachment is to be discouraged
whereas for orthopaedic implants cell attachment is beneficial as long as
these are the right cells and they behave in an appropriate manner.
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9 . 4 . 2 F u n c t i o n a l i s e d S u r f a c e s
C e l l - s u r f a c e i n t e r a c t i o n s h a v e b e e n i n v e s t i g a t e d o n i o n - e x c h a n g e m a t e r i a l s
( c h a r g e d p o l y m e r s ) [ 17 ], s e lf a s s e m b l e d m o n o l a y e r s ( S A M s ) [1 8] a n d p l a s m a
polymers [19] .
S A M s f o r m e d b y t h e a d s o r p t i o n o f c h e m i c a l ch a i n s o n t o g o ld s u rf a c e s
c o n s i s t o f c h e m i c a l ly r o b u s t , o r d e r e d a r r a y s o f o r g a n i c m o l e c u le s t h a t h a v e
s h o w n c o n s i d e ra b l e p r o m i s e a s m o d e l s y s t e m s f or in v e s t i g a t i n g c e l l - m a t e r i a l
i n t e r a c t i o n s . B y s e l e c ti n g t h e e n d g r o u p o f t h e a d s o r b e d c h a i n i t is p o s s i b l e
t o t a i lo r t h e c h e m i s t r y o f t h e S A M s u r f a c e -m a k i n g S A M s i d ea l fo r f u n d a -
m e n t a l s t u d i e s o f p r o t e i n a d s o r b t i o n a n d c ell a d h e s i o n . U s i n g S A M s as
m o d e l s u b s t r a t e s w i l l i n c r e a s e k n o w l e d g e a b o u t c e l l u l a r i n t e r a c t i o n s w i t h
su r f ace s , bu t the i r end c l in ica l use i s l im i ted because the chemica l cha ins
a re a d s o r b e d o n t o g o ld l a ye r s o n gl as s s u b s t r a t e s . P l a s m a p o l y m e r s , b y
c o n t r a s t , h a v e t h e p o t e n t i a l t o t r e a t a ra n g e o f m a t e r i a l s f or e s s e n t ia l u s e
in pa t i en t c a r e .
F u n c t i o n a l i s e d s u r f a c e s a r e a b l e t o i n f l u e n c e c e l l b e h a v i o u r b y c o n t r o l -
l in g t h e n a t u r e o f t h e p r o t e i n l a y e r w h i c h s p o n t a n e o u s l y a d h e r e s t o t h o s e
sur f ace s in the b io log ica l env i ronment . The ce l l s a r e ab le to sense the p ro -
t e i n s u s i n g r e c e p t o r s a n d b i n d i n g s i t e s a n d i n t h i s w a y t h e c e l l b e h a v i o u r
c a n b e m o d i f ie d . T y p i c a l l y , t h e t y p e o f b e h a v i o u r t h a t t i s s u e e n g in e e r s fi n d
use fu l to in f luence o r con t ro l a r e ce ll a t t a c hm en t , c el l g ro w th ( an inc r ea se in
ce l l s i z e ) , and ce l l p ro l i f e r a t ion ( an inc r ea se in ce l l number ) . For example ,
c a r b o x y l i c a c i d f u n c t i o n a l i s e d s u r f a c e s c a n c o n t r o l s k i n c e l l a t t a c h m e n t a n d
p r o l i f e r a t i o n , w h i l s t s u r f a c e s c o n t a i n i n g n i t r o g e n c a n i n f l u e n c e h o w n e r v e
ce l l s r e spond .
A n i n t e re s t i n g f e a t u r e o f s o m e p l a s m a p o l y m e r s u r fa c e s is t h a t t h e y c a n
a l low ce l l r e l ea se a t an appropr ia t e s i t e . Th i s ha s been a cons ide rab le cha l -
l en g e fo r r e s e a r c h e r s - if a c ell is h a p p y t o a t t a c h t o a s u rf a ce w h y s h o u l d i t
t h e n w a n t t o le av e t h a t s u rf ac e ? E a r l y s tu d i e s o n a ci d fu n c t i o n a li s e d p l a s m a
p o l y m e r s sh o w t h a t t h e s u r fa c es e n c o u r a g e s k in ce ll a t t a c h m e n t , b u t a t t h e
s i te o f a w o u n d s u c h a s a d i a b e t i c f o o t u lc e r, t h e s u r f ac e d e g r a d e s a l lo w i n g
c e l l s t o b e r e l e a s e d i n t o t h e w o u n d s i t e t o k i c k - s t a r t t h e h e a l i n g p r o c e s s .
T h i s te c h n o l o g y c o u l d b r i n g t h e c o n c e p t o f a l iv in g b a n d a g e t o t h e w o u n d
h e a l in g m a r k e t .
B y u s i n g m a s k s t o d e p o s i t p l a s m a p o l y m e r s w i t h d i f f e r e n t f u n c t i o n a l
g r o u p s o n t o a s u b s t r a t e , f in e ly d e t a i l e d c h e m i c a l p a t t e r n s ( F ig . 9 .9 ) c a n b e
c r e a t e d a n d i m a g e d u s i n g t i m e o f f li gh t s e c o n d a r y io n m a s s s p e c t r o m e t r y
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Sm ar t B iomater ia ls Out -Sma r t ing the Body ' s De fense Sys tems
Fig. 9.9 ToF-SIM S im ag e of acrylic ac id stripes (m /z 16 + 17, dark) on a plasma
polym erised 1 ,7-oc tadien e backgrou nd (m /z 12 + 13, light).
( T o F S I M S ) . S u c h p a t t e r n s p o ss es s u n i q u e c h e m i c al p r o p e r t ie s w i th r e g a r d
t o h y d r o p h o b i c i t y / h y d r o p h i l i c i t y a n d c e ll a n d p r o t e i n b i n d i n g ( F ig . 9 .1 0 ).
S p a t i a l c o n t r o l o f s u r fa c e c h e m i s t r y i s a n e s s e n t i a l r e q u i r e m e n t i n e m e r g i n g
t e c h n o l o g i e s s u c h as t i s s u e e n g i n e e r i n g . F o r in s t a n c e , n i t r o g e n c o n t a i n i n g
Fig. 9.1 0 FIT C-IgG immobil ised on al lyl amine/1,7-octadiene plasma p a t t e r n s - 50pm
IgG ba rs w ith pa rt of the grid rim.
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Fig. 9.11 Actin stained cerebellar granule neurons grown on pat terned coverslips for
a) 5 hours, showing pat terned attachment; b) 1 day, showing patt ern ing of neurite
out-growth.
p l a s m a p o l y m e r s a r e a b l e t o s u p p o r t n e r v e c e l l a t t a c h m e n t a n d p r o c e s s
( n e u r i t e ) g r o w t h . T h e i n f lu e n ce o f s u r fa c e c h e m i s t r y o v er c ell a t t a c h m e n t
c a n b e u se d in t h e s p a t i a l c o n t ro l of a t t a c h m e n t . T h e a b i l it y t o p r o d u c e
s p a t i a l l y o r d e r e d n e r v e c e l l c u l t u r e s h a s b e e n u s e d t o a s s e s s t h e d i r e c t i o n a l
e ff ec ts o f e l e c tr i c al s t i m u l a t i o n o n n e u r o n s [2 0 ]. S u c h p a t t e r n s a l so p r o v i d e
a w a y t o i n v e s t i g a t e n e u r o n a l i n t e r a c t i o n s i n a n e t w o r k b y g r o w i n g t h e
neurons in a conf ined pa t t e rn (F ig . 9 . 11) . The re a r e poss ib i l i t i e s f o r use in
n e u r o n a l a n d a x o n a l r e g e n e r a ti o n , b y p r o v i d i n g n e u r o n s w i t h a n a t t r a c t i v e
p a t h w a y t o e x t e n d p r o c e s s e s a l o n g .
S u r fa c e p a t t e r n i n g u s i n g p l a s m a p o l y m e r s c a n a ll ow a n o b j e c t o f c o m -
p l ex 3 - D g e o m e t r y t o b e p a t t e r n e d [2 1]. O n e o f t h e c u r r e n t c h a l le n g es w i t h
3-D sca f fo lds i s to encourage ce l l s to g row in to the en t i r e sca f fo ld and no t
m e r e l y a t t a c h a t t h e f ir st a v a il a b le s u rf a c e, u s u a l l y t h e o u t e r e d g e s. B y p r o -
v i d i n g p a t t e r n e d p a t h w a y s w i t h i n t h e s c a f f o l d s t o p r o m o t e c e l l m i g r a t i o n
t h r o u g h t h e s t r u c t u r e , t h i s p r o b l e m c o u l d b e o v e r c o m e .
9 4 3 i o l og i ca l l y M odi f i ed Su r f a ces
T h e t e r m b i o lo g i c al m o d i f ic a t io n i m p li es a l te r i n g a m a t e r i a l s p e r f o r m a n c e
b y c o v a l e n t l y c o u p l i n g t o t h e m a t e r i a l s s u r f ac e a b i o l o g ic a l ly r e l e v a n t a n d
a c t iv e m o l e c ul e t h a t t h e t is s u e s u r r o u n d i n g t h e m a t e r i a l r ec o g n is e s t h r o u g h
a c e l l u l a r o r b i o m o l e c u l a r p a t h w a y [ 2 2 ] . V a r i o u s m o d e l s t h a t m i m i c b a s e -
m e n t m e m b r a n e s , c e l l s u r f a c e s a n d e x t r a c e l l u l a r m a t r i x h a v e b e e n d e v e l -
o p e d t o s t u d y t h e i n t e r a c t i o n o f c ells w i t h s u b s t r a t e s a n d h o w t h e s e in -
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ept ide
_
I
E M protein
Receptor
F i g . 9 .1 2 S c h e m a t i c o f a s m a r t b i o m a t e r i a l w i t h a p e p t i d e g r a f t e d o n t o i ts s u r f a ce s o
a s t o a t t r a c t t h e d e s ir e d p r o t e in f r o m t h e e x t r a c e l l u l a r m a t r i x w h i c h i n t u r n a t t r a c t s
t h e a p p r o p r i a t e c el l a t t a c h m e n t .
f luence ce ll beh avio ur . Such m odels involve the im m ob i l i sa t io n of b iolog-
i ca ll y ac t i ve l igands o f na tu r a l o r syn the t i c o r ig in on to va r ious su bs t r a t e s
to p rod uce ch em ica l l y de f ined b ioac t i ve su r faces . Th ese l igands inc lude
c e l l - m e m b r a n e r e c e p t o r f r a g m e n t s , a n t i b o d i e s , a d h e s i o n p e p t i d e s , e n z y m e s ,
a d h e s i v e c a r b o h y d r a t e s , l e c t i n s , m e m b r a n e l i p i d s a n d g l y c o s a m i n o g l y c a n
m a t r i x c o m p o n e n t s [ 2 3 ] .
Th e p roce s s o f g ra f t i ng l i gands on to t he su r face o f t he su bs t r a t e i nvo lves
se l ec ti on o f a su i tab l e s ub s t r a t e c hem is try , wh ich m ay be m od i fi ed u s ing
such t echn iques a s p l a sm a po lym er i s a t i on desc r ibes above . Such a su r face
p rov ides h igh ly r eac t i ve spec i es fo r b ind ing t he b ioac t i ve l i gand on to t he
su r face F ig . 9 .12 ). Th e cho ice o f l i gand depend s on t he des i r ed ce l lu l a r
response .
9.4.3.1 B a c t e r i a l A d h e s i o n
De sp i t e t he u se o f a sep t i c t echn iques , ba c t e r i a l i n fec ti on i s a f r equen t com -
p l i c a t i o n a s s o c i a t e d w i t h i m p l a n t a b l e d e v i c e s . T h e p l a s m a p r o t e i n f i b r i n o -
g e n i s r e a d i l y a d s o r b e d o n t o m o s t s u r f a c e s a n d h a s b e e n s h o w n t o m e -
d i a t e t h e a d h e s i o n o f S t a p h y l o c o c c u s a u r e u s T h i s p a t h o g e n i s a s s o c i a t e d
w i t h a la r g e n u m b e r o f i m p l a n t - r e l a t e d in fe c ti on s. B a u m g a r t n e r et a l [24]
h a v e e x p l o r e d a s er ie s o f p h o s p h o n a t e d p o l y u r e t h a n e s a s a m e a n s o f r e-
d u c i n g b a c t e r i a l a d h e si o n . I n th e i r w o r k p o l y u r e t h a n e s w e r e sy n t h e si se d ,
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241
w h i c h d i r e c t l y i n c o r p o r a t e d a p h o s p h o r y l c h o l i n e l i g a n d i n t o t h e b a c k b o n e
o f t h e p o l y u r e t h a n e . G l y c e r o p h o s p h o r y l c h o l i n e w a s u se d a s t h e c h a i n e x-
t e n d e r in a m a t e r i a l c o m p o s e d o f m e t h y l e n e d i p h e n y le n e d i i s o c y a n a t e a n d
p o l y ( t e t r e m e t h y l e n e ) o x id e . T h e y f o u n d a r e d u c t i o n in b a c t e r i a l a d h e s i o n
t o t h i s m a t e r i a l .
9.4.3.2
o n e o n d i n g
Bone ce l l s have ce l l su r face r ecep to r s ( i n t eg r in s ) t ha t b ind r ead i l y t o t he
a m i n o a c i d s e q u e n c e a r g i n i n e - g l y c i n e - a s p a r t a t e ( R G D ) d o m a i n o n p r o t e i n s
s u c h a s f i b r o n e c t i n a n d v i t r o n e c t i n i n t h e e x t r a c e l l u l a r m a t r i x . R a t h e r t h a n
m o d i f y in g t h e f u n c t i o n a l c h e m i s t r y o f t h e s u b s t r a t e t o e n c o u r a g e s e l e ct iv e
p r o t e i n a d s o r p t i o n , s h o r t c h a i n p e p t i d e s c o n t a i n i n g t h e s e c e l l b i n d i n g s e -
q u e n c e s c a n b e g r a f t e d o n t o b i o m a t e r i a ls , t h u s m i m i c k i n g t h e m o r e c o m p l e x
pro t e in s su ch as f i b ronec t i n [25 ]. Var ious s t ud i es u s ing t h i s ap p ro ac h have
s h o w n t h a t c e l l a d h e s i o n c a n b e i m p r o v e d s i g n i f i c a n t l y u s i n g t h e s e R G D
sequ enc es [22; 26; 27] .
9.4.3.3
l o o d C o m p a t i b l e S u r f a c e s
M o s t o f t h e c u r r e n t l y u s e d a r t i fi c ia l b l o o d v e s se ls a r e m a d e f r o m e x p a n d e d
p o l y ( t e t r a f l u o r o e t h y l e n e ) o r w o v e n p o l y e s t e r . F o r c l i n i c a l s i t u a t i o n s w h e r e
the re i s h igh b lood f l ow and l ow res i s t ance ( e .g . ao r t i c b i fu rca t i on ) t hese
m a t e r i a l s h a v e p r o v e d c li n ic a ll y a c c e p t a b l e . H o w e v e r , in s i t u a t i o n o f lo w
b lood flow, w h ich i n e ff ec t m ean s b lood ves se l s o f l es s t h an 4m m d iam ete r ,
t h e g r a f t s r e a d i l y g e t b l o c ke d a n d t h e p a t e n c y d r o p s to o n l y 1 0 a f t e r
8 years [28].
T he i n t e r ac t i on o f b lood ce lls ( l eucocy t es ) w i th en do the l i a l cells , t he
ce l l s l in ing the wal l o f the b lood vesse l , i s h igh ly complex and involves
s e l e c t i n - m e d i a t e d r o l li n g a n d i n t e g r i n - m e d i a t e d a d h e s i o n ( F i g. 9 .1 3 ). F o r
t h is r e a s o n , o n e o f t h e p o t e n t i a l l y m o r e e f fe c ti ve m e t h o d s o f m a k i n g a b l o o d -
c o n t a c t i n g s u r f a c e h a e m o c o m p a t i b l e i s t o c r e a t e a s u r f a c e o n t h e b i o m a t e -
r i a l t h a t enc oura ges fu l l cove rage w i th a l aye r o f end on the l i a l ce lls . Th i s
i s poss ib le by graf t ing ce l l -adhes ive pro te ins such as f ib ronect in or ce l l -
a d h e s i v e o l i g o p e p t i d e s ( R G D s ) o n t o s u r f a c e s t o e n h a n c e t h e a d h e s i o n o f
end o the l i a l cell s. A n exa m ple o f t h i s is t he ca rb od i im id e m e tho d . Th i s sys-
t er n e m p l o y s a b l e n d o f p o l y ( c a r b o n a t e u r e t h a n e ) a n d p o l y ( h y d r o x y b u t u y l
ac ry l a t e ) [29 ] . A b i func t i ona l space r i s t hen app l i ed ( ca rboxy l i c d i ch lo r ide )
s u c h t h a t c a r b o x y l i c a c i d g r o u p s a r e o b t a i n e d , c r e a t i n g a s u r f a c e r e a d y f o r
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Smart Biomaterials -- Out-Smarting the Body's Defense Systems
Fig. 9. 1 3 Selectin-mediated rolling and intergin-m ediated adhesion of a cell to a sub-
strate.
p e p t i d e i m m o b i l is a t io n . T h e n e x t s t a g e is t h e f o r m a t i o n o f a c a r b o d i i m i d e -
c a r b o x y l a d d u c t a n d f i n a l l y t h e c a r b o d i i m i d e g r o u p i s d i s p l a c e d b y a n u -
c l e o p h i l i c a m i n e g r o u p , r e s u l t i n g i n a s t a b l e a n d c o v a l e n t l y b o n d e d p e p t i d e
(Fig . 9 .14) .
9 .5 R e a l l y S m a r t B i o m a t e r i a l s T h e N e x t G e n e r a t i o n
I n t h e p r e v i o u s s e c t io n s , w e h a v e se e n t h a t i n j u r y a n d d i se a se f r e q u e n t l y
r e s u l t i n l os s o f l i v in g t i s s u e o r f u n c t i o n , a n d t h a t m a n y c l i n ic a l t r e a t m e n t s
a r e b a s e d o n r e p l a c e m e n t o f l os t ti s s u e o r r e s t o r a t i o n o f f u n c t io n u s i n g
s y n t h e t i c b i o m a t e r i a l s a n d m e d i c a l d e v i c es . I n a n ef fo r t t o i m p r o v e c l in i ca l
r e s u lt s , i n c r ea s i n g ef fo r ts w e r e d i r e c t e d a t u n d e r s t a n d i n g t i s s u e - m a t e r i a l
i n t e r a c t i o n a n d d e v e l o p i n g b i o m a t e r i a l s w i t h i m p r o v e d c l i n i c a l p e r f o r m a n c e
( so c a l le d b i o a c t i v e o r s e c o n d g e n e r a t i o n b i o m a t e r i a l s ) . H o w e v e r , t h e
b e s t m a t e r i a l f or a n y s pe cif ic f u n c t i o n of t h e h u m a n b o d y is h e a l t h y
Endothe l i a l c e l l
F u n c t i o n a l
group j
P e p t i d e
pacer
lood ce l l wa l l
Fig. 9 .1 4 Schematic of the surfa ce of an artificial blood vessel [28]).
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243
l iv i n g t i ss u e . T h i s f a c t h a s g i v e n r is e t o a n e w p h i l o s o p h y i n t h e f ie ld
o f b i o m a t e r i a l s , t h a t o f t i ss u e e n g in e e r i n g . T i s s u e e n g i n e e r i n g h a s b e e n
d e f in e d as t h e u s e o f b i o l o g ic a l a n d e n g i n e e r i n g p r i n c i p l e s t o c o n s t r u c t
f u n c t i o n a l ti s s u e s t o r e p la c e o r s u p p l e m e n t d i s e a se d o r d e f e ct iv e b o d y p a r t s
( Y o r k s h i r e B i o m a t e r i a l s N e t w o r k , T i s s u e E n g i n e e r i n g G r o u p , A u g u s t 2 0 0 0 ) .
I n p r a c t i c a l t e r m s , t h e i d e a i s t o g r o w l i v e c e l l s o n a b i o m a t e r i a l s c a f f o l d
in t h e p r e s e n c e o f g r o w t h m e d i u m a n d b i o lo g i c a ll y a c t iv e m o l e c u le s . T h i s
c o m b i n a t i o n o f liv e c ells ( a n d a n y e x t r a c e l l u l a r m a t r i x t h e y p r o d u c e ) w i t h
t h e s c af fo ld is s u b s e q u e n t l y i m p l a n t e d i n to t h e s it e of n e e d i n th e b o d y a s
a c e l l - b i o m a t e r i a l c o n s t r u c t . I t is l ik e ly t h a t t is s u e e n g i n e e r i n g w il l r e m a i n
c l o se l y l i n k e d t o t h e f ie ld o f b i o m a t e r i a l s d u e t o t h i s n e e d f or a ce ll c a r r i e r
o r a r ti fi c ia l s ca f fo ld i n m o s t a p p l i c a ti o n s . T h e t e r m s u b s t i t u t i o n m e d i c i n e
h a s b e e n c o i n e d b y C l e m e n s v a n B l i t t e r s w i j k ( I s o T i s B V , N e t h e r l a n d s ) t o
c ov e r t h e w h o l e r a n g e o f t r e a t m e n t s b a s e d o n b o t h b i o m a t e r i a ls i n m e d i c a l
d e v i c e s a n d t i s s u e e n g i n e e r i n g . T i s s u e e n g i n e e r i n g i ts e l f is a r g u a b l y o n e
o f t h e f a s t e s t d e v e l o p i n g r e s e a r c h fi eld s i n t h e w o r l d ( T i m e m a g a z i n e a ls o
p l a c e s t i s s u e e n g i n e e r s a t t h e t o p o f i ts H o t t e s t J o b s o f t h e F u t u r e t a b l e ) .
I n p a r t , t h i s i s d u e t o c o n v e r g e n c e o f s c ie n t if i c d is c i p li n e s , w h e r e a d v a n c e s
i n b i o l o g y , c h e m i s t r y a n d m a t e r i a l s s c i e n c e h a v e c o m e t o g e t h e r t o m a k e
a t is s u e e n g i n e e r i n g a p p r o a c h t o t r e a t m e n t o f d i s ea s e a v i a b le p r o p o s i t i o n .
G r o w t h h a s a ls o b e e n f u e ll ed b y t h e i n c r e a s i n g h e a l t h c a r e n e e d s o f a n a g e i n g
p o p u l a t i o n , c o u p l e d w i t h tr e m e n d o u s e x p e c t a t i o n o f t h e p o t e n t i a l im p a c t
o f t is s u e e n g i n e e r i n g o n t r e a t m e n t o f d i se a se .
U n t i l n o w , t h e b i o m a t e r i a l s c a f f o l d w a s c o m m o n l y m a d e f r o m a n e x -
i s t i n g b i o r e s o r b a b l e m a t e r i a l s u c h a s P L L A . A d e g r a d a b l e b i o m a t e r i a l i s
c o n s i d e r e d i d e a l, a s it w il l m o s t l ik e l y b e t o t a l l y r e s o r b e d b y t h e b o d y a f-
t e r i m p l a n t a t i o n . W h i l e u s ef u l, t h e s e b i o m a t e r i a l s h a v e n e v e r b e e n t r u l y
o p t i m i s e d fo r t i ss u e e n g i n e e r i n g a p p l i c a t io n s , a n d t h e y m a y n o t b e p e r -
f ec t b e c a u s e s o m e of t h e i r d e g r a d a t i o n p r o d u c t s m a y i n h i b i t ce ll g r o w t h
a n d d i f f e r e n t i a t i o n in c u l tu r e . R e s e a r c h is t h e r e f o r e b e i n g c a r r i e d o u t n o v e l
b i o m a t e r i a l s f o r s p e ci fi c a p p l i c a t i o n s i n t i s s u e e n g i n e e r i n g . O n e a r e a o f c o n -
s i d e r a b l e p r o m i s e i s t h a t o f b i o l o g i c a ll y f u n c t i o n a l i s e d s c af fo ld s , w h e r e t h e
s u r f a c e p r e s e n t e d b y t h e b i o m a t e r i a l p r o v i d e s i n f o r m a t i o n t o t h e c e l l s t h a t
a t t a c h t h e m s e l v e s . T h i s i n f o r m a t i o n m i g h t s im p l y d e t e r m i n e w h e r e ce lls
s h o u l d a n d s h o u l d n o t a d h e r e , o r i t m a y d e t e r m i n e o r i e n t a t i o n o r d i f f e r -
e n t i a ti o n . I t is a n t i c i p a t e d t h a t c u r r e n t r e s e a r c h w i ll u l t i m a t e l y p r o v i d e a
r a n g e o f d e s i g n e r s c a f fo l d s fo r sp e c if ic t is s u e e n g i n e e r i n g a p p l i c a t i o n s i n t h e
f u t u re . T h e m o d i f i c a t io n s w i ll m o s t l i k el y i n c l u d e e l e m e n t s o f t h e s u r fa c e
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244
Sm ar t B iomater ia l s Out -Sm ar t ing the Body ' s De fense Sys tems
e n g i n e e r i n g d e s c r i b e d p r e v i o u s l y , w i t h i n t e l l i g e n t d e g r a d a t i o n a n d i n c o r -
p o r a t i o n o f b i o l o g ic a l ly a c t iv e p e p t i d e s o r d r u g s . W h i l e t h e s e a d v a n c e s
a r e s o m e w a y o ff, t h e r e a r e c o n t e m p o r a r y e x a m p l e s o f i n t el li g e n t s u r f a ce
m o d i f i c a t i o n t o c o n t r o l c ell a d h e s i o n . O k a n o
et al .
[30] have dev e lope d a
t h e r m a l l y r e s p o n s i v e b i o m a t e r i a l s u r f a c e u s i n g p o l y ( N - i s p r o p y l a c r y l a m i d e )
whe re , be low 32C i t i s f u l ly hydra ted and above 32C i t i s hydrophob ic .
C e ll d e t a c h m e n t is p o s si b le b y r e d u c i n g t h e t e m p e r a t u r e b e lo w 3 2 C a f te r
g r o w i n g t h e c el ls a t 3 7 C . T h i s m a y b e v e r y u se f u l w h e n d e v e l o p i n g t is s u e
e n g i n e e r e d s k i n a n d t h e r e i s a n e e d t o d e t a c h t h e c ell s h e e t f r o m t h e c u l t u r e
s u b s t r a t e p r i o r t o a p p l i c a t i o n o n t h e w o u n d b e d .
D e s p i t e s o m e o f t h e a d v a n c e s a b o v e , t r u l y i n t el l ig e n t s c af fo l ds a r e th e
m a t e r i a l s o f t h e f u t u r e . I t r e m a i n s d if fi cu lt t o c r e a t e t h e r i g h t m o r p h o l o g -
i c a l a n d b i o c h e m i c a l e n v i r o n m e n t f o r d i r e c t e d c e l l a d h e s i o n , g r o w t h a n d
d i f f e re n t i a t io n t o f o r m s pe ci fi c f u n c t i o n a l t i ss u e s . T h e r e is n o d o u b t t h a t ,
a l o n g w i t h f u r t h e r b i o m a t e r i a l s r e s e a r c h , a d v a n c e s i n b i o l o g i c a l a n d m e d i -
c a l s c i e n c e s a r e r e q u i r e d t o p e r f e c t t i s s u e e n g i n e e r i n g t o t h e p o i n t t h a t i t s
u s e b e c o m e s c o m m o n p l a c e . W i d e r i s s u e s i n c l u d e c e l l s o u r c e ( i n c l u d i n g t h e
u s e o f s t e m c el ls ) a n d c u l t u r e c o n d i t i o n s ( i n c lu d i n g t h e u s e o f m e c h a n i c a l
s t i m u l a t i o n a n d b i o r e a c t o r s ) .
9 . 6 C o n c l u s i o n s
T r a d i t i o n a l l y , b i o m a t e r i a l s w e r e i d e n ti fi e d o n t h e b a s i s o f t h e i r m e c h a n i c a l
p r o p e r t i e s a n d n o n - t o x i c it y i n t h e b i o lo g ic a l e n v i r o n m e n t . W h e r e a s o n e
h u n d r e d y e a r s ag o t h e f ield o f b i o m a t e r i a l s w a s d o m i n a t e d b y t h e a p p r o a c h
o f t r ia l a n d e r ro r , n o w a d a y s a m u c h m o r e s o p h i s t i c a t e d a p p r o a c h i nv o lv -
i n g t h e c a r e f u l d e s ig n o f b i o m a t e r i a l s i s t a k e n . T h e t h r e a t o f l i t ig a t i o n i f
s o m e t h i n g g o e s w r o n g is s u ff ic ie n t a d e t e r r e n t t o p r e v e n t t h e c a va li er a p -
p r o a c h o f t h e e a r l y d a y s o f b i o m a t e r i a l s a n d m e d i c a l d e v i ce d e v e l o p m e n t .
Howeve r , many e f f ec t ive med ica l dev ice s s t i l l su f f e r f rom long t e rm f a i lu r e
d u e t o t h e i n t r i n s i c l i m i t a t i o n s o f i n e r t, n o n - l i v i n g s u b s t a n c e s . T h e d e v el -
o p m e n t o f s e c o n d g e n e r a t i o n o r s o - ca l le d b i o a c t iv e m a t e r i a l s h a s b e e n
c r it ic a l, n o t o n l y i n th e p r o d u c t i o n o f i m p r o v e d m e d i c a l d e v ic e s b u t a ls o as
a s i g n p o s t t o w a r d s t h e f u t u r e s t r a t e g y t h a t s h o u l d b e a d o p t e d . C o n t e m p o -
r a r y r e s e a r c h is b a s e d u p o n t h e c r e a t i o n o f a b e n ef ic i al i n t e r a c t i o n b e t w e e n
h o s t t is s u e s a n d t h e b i o m a t e r i a l. O n l y t h r o u g h t h i s r e s e a r c h w i ll w e d e-
ve lop long- la s t ing , e f f ec t ive med ica l dev ice s and eng inee red ce l l -b ioma te r i a l
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o n c l u s i o n s
245
c o n s t r u c t s t o r e p a i r o r r e p l a c e f a i l e d h u m a n t i s s u e s a n d o r g a n s . T h i s i s n o t
s t r a i g h t f o r w a r d a s d i se a se g e n e r a ll y c r e a te s a c a t a b o l ic e n v i r o n m e n t t h a t
c h a l le n g e s s u c c es s fu l in t e r v e n t i o n . M e d i c a l d e v ic e a n d t is s u e e n g i n e e r i n g
t e c h n o l o g i e s a r e s ti ll e v o l v in g a n d b i o m a t e r i a l s w il l u n d o u b t e d l y c o n t i n u e
t o p l a y a c e n t r a l r o l e i n t h e t r e a t m e n t o f d i s ea s e . T h i s a r t ic l e p r e d i c t s t h a t
f u t u r e d e v e l o p m e n t s i n b i o m a t e r i a l s w i ll a ri s e fr o m a cl os e w o r k i n g r e la t i o n -
s h i p b e t w e e n b i o l o g y a n d m a t e r i a l s s ci en c e. I n d e e d i t is l ik e ly t h a t t h e n e w
b i o m a t e r i a l s f o r f u t u r e t h e r a p e u t i c a p p l i c a t i o n s m a y d e p a r t q u i t e r a d i c a l l y
f ro m t h e b i o m a t e r i a l s o f t h e p a s t . N e w b i o m a t e r i a l s w ill b e m u c h s m a r t e r
i n t h a t t h e y w i l l e x p e c t e d t o i n t e r a c t w i t h t h e b i o l o g i c a l e n v i r o n m e n t i n
s u c h a w a y a s to m o d u l a t e p h y s i o lo g i c al f u n c t io n s a n d a c t iv e l y e n c o u r a g e
repa i r a nd c l in ica l r e cove ry . T he u l t im a te cha l l enge o f t i s sue r epa i r i s the
r e g e n e r a t i o n o f t h e o r ig i n a l t is s u e w i t h o u t t h e r e m n a n t s o f f o re ig n b i o m a -
terials [31].
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