smart bio materials

8/11/2019 smart bio materials

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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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F i g 9 1 I nc r e a s i ng d i s a b i li t y w i t h a ge f or t he m a l e a nd f e m a l e pop u l a t i on

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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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 ) ,


5/27

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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6

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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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

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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Planning and Ref in em ent Second Generat ion Biom ater ials

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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Planning and Refinement Second Generation iomaterials

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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232 Smart Biomaterials Out-Smarting the Body's Defense Systems

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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Planning and Refinement Second Generation iomaterials

233

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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2 3 4 Smart Biomaterials -- Out-Smarting the Body's Defense Systems

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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235

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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3 6 Smart Biomaterials Out-Smarting the Body's Defense Systems

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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S m a r t S u r fa c e s T h i rd G e n e r a t i o n i o m a t e r i a l s

239

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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2 4 0 Sm ar t B iomater ia l s Out -Smar t ing the Body ' s De fense Sys tems

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 ,


21/27

S m ar t S u r f a c e s T h i r d Generation iomaterials

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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Really Smar t iomaterials The Next Generation

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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