Synthetic Polymeric Biomaterials - ACS Symposium Series (ACS

2 Synthetic Polymeric Biomaterials ALLAN S. HOFFMAN

Downloaded by UNIV ILLINOIS URBANA on April 29, 2013 | http://pubs.acs.org Publication Date: June 8, 1984 | doi: 10.1021/bk-1984-0256.ch002

Department of Chemical Engineering and Center for Bioengineering, University of Washington, Seattle, WA 98105

A review is presented of the applications of synthetic polymers in medicine. The major uses of these biomaterials are in devices and implants for diagnosis or therapy. The composition and properties, characterization, and biologic interactions of a wide variety of synthetic polymers are reviewed. Biologic testing and clearance of biomaterials for clinical use are also covered. Biomaterials and Their Uses There i s a wide v a r i e t y of m a t e r i a l s which are f o r e i g n to the body and which are used i n contact with body f l u i d s . These include t o t a l l y s y n t h e t i c m a t e r i a l s as w e l l as r e c o n s t i t u t e d or s p e c i a l l y treated human or animal t i s s u e s . Some are needed only for short term a p p l i c a t i o n s while others are, h o p e f u l l y , u s e f u l f o r the l i f e t i m e of the i n d i v i d u a l . The various uses of such f o r e i g n m a t e r i a l s , otherwise known as " b i o m a t e r i a l s " may be g e n e r a l l y categorized as devices or implants, f o r diagnosis or therapy. They include i n v a s i v e instrumentation (e.g., c a t h e t e r s ) ; implanted devices or instruments (e.g., pacemakers, hydrocephalus tubes); e x t r a - c o r p o r e a l devices i n s e r i e s with blood flow (e.g., a r t i f i c i a l kidney, heart-lung blood oxygenators); implanted parts (or whole) of hard s t r u c t u r a l elements (e.g., h i p j o i n t s , t e e t h ) ; implanted parts (or whole) of organs (e.g., heart valves, heart a s s i s t devices, s k i n ) ; and implanted s o f t t i s s u e s u b s t i t u t e s (e.g., blood v e s s e l s , tendon, u r e t e r ) . One may a l s o l i s t the " i d e a l " requirements f o r s e l e c t i n g a p a r t i c u l a r b i o m a t e r i a l f o r a p a r t i c u l a r end-use. The m a t e r i a l chosen should have the required p h y s i c a l p r o p e r t i e s (as strength, e l a s t i c i t y , p e r m e a b i l i t y ) ; i t must be e a s i l y p u r i f i e d , f a b r i c a t e d and s t e r i l i z e d ; i t should maintain the needed p h y s i c a l p r o p e r t i e s and f u n c t i o n i n v i v o over the d e s i r e d time period (1 hour, 1 day, 1 year, 10 years, p a t i e n t l i f e t i m e ) ; and i t should not induce undesirable host r e a c t i o n s (as blood c l o t t i n g , t i s s u e n e c r o s i s . 0097-6156/ 84/ 0 2 5 6 - 0 0 1 3 S 0 6 . 0 0 / 0

© 1984 American Chemical Society

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

POLYMERIC MATERIALS AND ARTIFICIAL ORGANS

14

carcinogenesis, a l l e r g e n i c responses, e t c . ) . I t should be noted that very few ( i f any) b i o m a t e r i a l s i n f a c t conform to a l l these criteria. Nevertheless, a wide v a r i e t y of b i o m a t e r i a l s have emerged and are i n d a i l y use i n the c l i n i c . Table I i d e n t i f i e s s i x c l a s s e s of b i o m a t e r i a l s , and the many d i f f e r e n t forms i n which they are found i n devices and implants. The f i r s t f i v e c l a s s e s are c l e a r l y separate types of m a t e r i a l s , while the s i x t h c l a s s , "Composites, includes systems which combine d i f f e r e n t forms o f m a t e r i a l s w i t h i n any one c l a s s (as a rubber diaphragm r e i n f o r c e d with a f a b r i c ) or d i f f e r e n t c l a s s e s of m a t e r i a l s (as a heart v a l v e made of a metal and d i f f e r e n t s y n t h e t i c polymers or of n a t u r a l animal t i s s u e s and d i f f e r e n t s y n t h e t i c polymers). This paper i s a review of the f i e l d of s y n t h e t i c polymeric b i o m a t e r i a l s and as such w i l l not attempt to cover n a t u r a l t i s s u e b i o m a t e r i a l s , carbons, metals, or ceramics. A general reference l i s t i s provided which does cover a l l of these m a t e r i a l s and t h e i r a p p l i c a t i o n s i n medicine.


11

Table I .

Classes and Forms of B i o m a t e r i a l s

CLASSES I.

Polymers a) f i b e r s b) rubbers c) p l a s t i c s

II.

III.

IV.

V.

FORMS f i l m s or membranes f i b e r s or f a b r i c s tubes powders or p a r t i c l e s molded shapes bags or c o n t a i n e r s , e t c . liquids s o l i d s (adhesives)

Metals

cast or molded shapes powders or p a r t i c l e s fibers

Ceramics

molded shapes powders or p a r t i c l e s liquids s o l i d s (cements)

Carbons

machined shapes coatings fibers

Natural Tissues

fibers n a t u r a l forms a l s o , r e c o n s t i t u t e d as f i l m s , tubes, f i b e r s , e t c .

VI.

Composites

coatings f i b r o u s f e l t s or sheets f i b e r or f a b r i c - r e i n f o r c e d shapes, e t c .


2.

HOFFMAN

Synthetic Polymeric


Synthetic Polymeric

Biomaterials

Biomaterials

Synthetic polymers make up by f a r the broadest and most d i v e r s e c l a s s of b i o m a t e r i a l s used. This i s mainly because s y n t h e t i c polymers are a v a i l a b l e with such a wide v a r i e t y of compositions and p r o p e r t i e s and a l s o because they may be f a b r i c a t e d r e a d i l y i n t o complex shapes and s t r u c t u r e s . In a d d i t i o n , t h e i r surfaces may be r e a d i l y modified p h y s i c a l l y , chemically, or b i o c h e m i c a l l y . This wide v a r i e t y of s y n t h e t i c polymeric b i o m a t e r i a l s can be seen i n Figures 1-3, which are separated i n t o c a t e g o r i e s of s o l i d , l i q u i d , or water-soluble polymer systems (Figure 1). The s o l i d polymeric b i o m a t e r i a l s may be subdivided i n t o s o f t and/or rubbery m a t e r i a l s , amorphous and hard m a t e r i a l s , and s e m i - c r y s t a l l i n e m a t e r i a l s . Figure 2 shows examples i n each of these categories f o r a wide v a r i e t y of b i o m a t e r i a l s applications. Water s o r p t i o n i n b i o m a t e r i a l s i s very important to the f u n c t i o n i n g of some polymers, such as hydrogels i n s o f t contact lenses. Water uptake may a l s o lead to absorption of ions and other molecules, as enzymes, which can cause biodégradation of the polymer, e s p e c i a l l y i f i t contains s u s c e p t i b l e bonds. Figure 3 l i s t s the r e l a t i v e water s o r p t i o n of a v a r i e t y of polymeric b i o m a t e r i a l s . Figure 4 i n d i c a t e s the most commonly encountered biodegradable repeating bond u n i t s i n polymer backbones. Such polymers g e n e r a l l y degrade v i a h y d r o l y s i s r e a c t i o n s B i o d e g r a d a b i l i t y may or may not be d e s i r e d i n a polymeric implant An a d d i t i o n a l complication of p o l a r i t y or p o l a r a d d i t i v e s i polymers i s the p o s s i b i l i t y of e x t r a c t i o n of polymer a d d i t i v e s , smaller molecules, etc. i n t o the surrounding b i o l o g i c a l f l u i d s . This can lead to l o c a l or even systemic t o x i c responses (see below). Table I I l i s t s some p o t e n t i a l e x t r a c t a b l e s i n polymers. Table I I . — — — — — — — — — —

Some P o t e n t i a l E x t r a c t a b l e s i n Commercial Polymers

C a t a l y s t fragments Anti-oxidants U.V. s t a b i l i z e r s Plasticizers Low molecular weight polymer molecules Surface a c t i v e agents ( l u b r i c a n t s , wetting agents, a n t i - s t a t i c agents) Dyes Flame retardants Fragments of f i l l e r s , r e i n f o r c i n g agents Polymer degradation byproducts

B i o l o g i c a l l y A c t i v e Polymers Reactable s i t e s as -OH, -COOH, or -NH2 may be present on the polymer backbone, or may be introduced v i a a f r e e r a d i c a l




(I)

SOLID POLYMERS

(2)

LIQUID POLYMER SYSTEMS

(3)

LOW WATER

SORPTION

HIGH WATER SORPTION GEL

OR SOLID

REMAIN

LIQUID

WATER SOLUBLE POLYMERS

NOTE ·• ANY OR A L L OF T H E S E POLYMERS MAY: (a) (b)

BIODEGRADE AND AT VARYING RATES HAVE IMMOBILIZED DRUGS, ENZYMES,

ANTIBODIES CULES

Figure 1.

AND/OR OTHER BIOMOLE-

ATTACHED TO T H E M

Polymeric b i o m a t e r i a l s .


2.

HOFFMAN

Synthetic Polymeric

PROPERTIES

17

Biomaterials

EXAMPLES

USES

(o) SOFT (RUBBERY)


— L O W WATER SORPTION

-HIGH WATER SORPTION

(b) AMORPHOUS. HARD

(c)

SR, PU, P V C

TUBES, DIAPHRAGMS. COATINGS, IMPLANTS, PACEMAKERS, ADHESIVES, BLOOD BAGS

PHEMA

CONTACT L E N S , BURN DRESSING, COATINGS

PMMA

CONTACT LENS, IOL, DENTAL AND ORTHOPEDIC CEMENTS

PET, PP, PTFE

SUTURES, VASCULAR GRAFTS, SEWING ANCHORS, TISSUE INGROWTH

NYLONS, PGA PE PFEP CA

SUTURES, (BIODEGRADABLE) IUD, BONE JOINTS. CATHETERS HOLLOW FIBER DIALYSER, CONTACT L E N S

CELL

DIALYSIS MEMBRANE

SEMI-CRYSTALLINE LOW WATER SORPTION

-MODERATE WATER SORPTION Figure 2.

S o l i d polymeric b i o m a t e r i a l s . Symbols used: SR S i l i c o n e rubber ( c r o s s l i n k e d ) PU Polyurethane rubber PVC Poly(vinyl chloride) PHEMA Poly(hydroxyethyl methacrylate) PMMA Poly(methyl methacrylate) PET P o l y ( e t h y l e n e terephthalate) PP Polypropylene PTFE P o l y ( t e t r a f l u o r o e t h y l e n e ) PGA P o l y ( g l y c o l i c acid) PE Polyethylene PFEP P o l y ( p e r f l u o r o ethylene-propylene) CA C e l l u l o s e acetate Cell Cellulose


18

POLYMERIC MATERIALS AND ARTIFICIAL ORGANS "NON-POLAR" NEGLIGIBLE

POLARITY WATER


EXAMPLES

LOW

MED.

PTFE

SR

PE

PET

PP

PMMA

PU

HIGH

.5-l5%_-->l5%

1-5%

< 1%

SORPTION

"POLAR"

Nylon

Cellulose

PHEMA PAAm

Figure 3 . R e l a t i v e " p o l a r i t y " ( i . e . , water sorption) of some s o l i d polymeric b i o m a t e r i a l s . ( A d d i t i o n a l symbol: PAAm = polyacrylamide.)

-£-C-NH^-

Polyomides, polypeptides

Polyesters

Polyorthoesters R

OR

1

Polyocetols R

R

1

Polysocchondes

CN CH - C^ -

Poly (methyl cyonoocrylote )

2

C0 CH 2

3

Figure 4. Repeat u n i t s i n some biodegradable polymer backbones.


2.

HOFFMAN

Synthetic Polymeric

19

Biomaterials

g r a f t polymerization r e a c t i o n . Figure 5 l i s t s the v a r i e t y of process techniques which may be used to create macroradical s i t e s f o r g r a f t i n g p o l a r monomers onto more i n e r t polymer backbones. The presence of such groups on the surface of (or throughout) polymers can permit the chemical immobilization o f a wide v a r i e t y of b i o l o g i c a l l y f u n c t i o n a l molecules (Table I I I ) . Such a c t i v e compounds may a l s o be e l e c t r o s t a t i c a l l y "bound to the polymer by opposite charge or acid-base a t t r a c t i o n s , or they may be entrapped w i t h i n the polymer. 11


Table I I I . Some B i o l o g i c a l l y A c t i v e Species which may be Immobilized on or w i t h i n Polymeric Biomaterials Enzymes Antibodies Antigens Anti-thrombogenic agents Antibiotics A n t i b a c t e r i a l agents Contraceptives Hormones Anticancer agents Drug antagonists Drug analogs Other drugs, i n general Sugars and polysaccharides Cells A wide v a r i e t y of drug d e l i v e r y systems has been developed f o r achieving a regulated or c o n t r o l l e d r e l e a s e of therapeutic agents over a sustained and pre-determined p e r i o d of time. Polymers may be u t i l i z e d as d i f f u s i o n - c o n t r o l l i n g b a r r i e r membranes ( i n " r e s e r v o i r " d e v i c e s ) , matrices f o r containment and r e l e a s e of a c t i v e agents ( i n " m o n o l i t h i c " d e v i c e s ) , or more simply as containers, conduits, or other components of the device. The polymers may be designed to r e s i s t attack or to erode or degrade. In p a r t i c u l a r , a number of biodegradable polymers have been s p e c i a l l y synthesized f o r r e l e a s e of a c t i v e agents i n s i d e the body, during or a f t e r which the polymer disappears as i t erodes or degrades and i s metabolized. Another i n t e r e s t i n g new combination of polymers and b i o l o g i c a l species may be synthesized by c o v a l e n t l y b i n d i n g b i o l o g i c a l l y a c t i v e molecules to the surface of polymeric p a r t i c l e s , such as those prepared i n microemulsion polymerizations. Thus, i f a p a r t i c u l a r antibody i s attached, the microp a r t i c l e s w i l l be a t t r a c t e d to s p e c i f i c a n t i g e n i c s i t e s i n the body. I f these s i t e s are on s p e c i f i c cancer c e l l s , and i f an a n t i - c a n c e r drug i s incorporated i n t o or onto the m i c r o - a r t i c l e , with the p o s s i b i l i t y of subsequent r e l e a s e from the p a r t i c l e , then s p e c i f i c drugs may be d e l i v e r e d to s p e c i f i c s i t e s i n the



Peroxide formation CH


ι

3

CH

3

CH

3

I I iV/V/V 3

H

ο

w w w

ί

CH

CH

3

I I L

Oxidizing Conditions

3

ο f 3CH3 ^ £ ! L c

3

, >/'//>/

+

0

.+3

n H t t f H

*

F e

Ceric ions OH

OH

OH

CHo CHo C H

Ce

+ 4

OH OH

0 CH

?

CH

2

CH

2

2

"Active Vapor" or rodicol transfer H

H

H

Ç3 Ç3 Ç3 }//V/ /

ο. Plosmo discharge atoms or Chemical catalyst r a d i c o l s

H

H

H

Ç2 Ç3 93 J v / ^ / / 1/ ' / +

R H

Ionizing radiation CH

CH

3

3

CH

6H

3

1 II

/ / / / / / / ~

Ionizing radiation

2

CH

ι

I

3

CH

3

I

/ / / / / /

*

H #

u.v. C H

ι

3

C H

j

')//////

3

C H

»

3

Λ

Α

Λ

Α

Α

ΑΛΛΛΛ

.

#

(PS)

υ.ν>

photosensitizer

CH CH CH I I I 2

3

3

> / ) / > / • (PS)H

Figure 5. Examples of techniques and r e a c t i o n s f o r generating r a d i c a l s on s u r f a c e s . (Note: The p r e c i s e nature of the r a d i c a l intermediates formed has not been e l u c i d a t e d i n some cases. Representations i n t h i s f i g u r e show s c h e m a t i c a l l y r a d i c a l species which might be formed.)


2. HOFFMAN

Synthetic Polymeric

Biomaterials

21

body, using the body's own c i r c u l a t o r y system to transport the particles. C e l l s may a l s o be c u l t u r e d w i t h i n or on the outside of hollow f i b e r exchange devices and a p a t i e n t ' s blood may be c i r c u l a t e d through the device f o r treatment of various diseases (e.g., using p a n c r e a t i c beta c e l l s f o r diabetes p a t i e n t s i n an " a r t i f i c i a l pancreas," or using l i v e r c e l l s i n an " a r t i f i c i a l l i v e r " during hepatic f a i l u r e ) . Table IV l i s t s some general examples of biomedical uses of immobilized biomolecule or c e l l systems.


Table IV.

Some Examples of Uses of Immobilized Biomolecule or C e l l Systems

Improved b i o c o m p a t i b i l i t y Drug d e l i v e r y C e l l " f i n d e r s " and "markers" (via antibody-antigen binding) Diagnostic

kits

Enzyme r e a c t o r s ( i n c l u d i n g a r t i f i c i a l organs) Biomedical sensors or electrodes

The Polymer B i o l o g i c I n t e r f a c e When a f o r e i g n surface i s exposed to a b i o l o g i c a l environment, there i s a n a t u r a l tendency to destroy (digest) the f o r e i g n object or, f a i l i n g that, to "wall i t o f f " and cover (encapsulate) the object. The b i o l o g i c species which are involved i n t h i s process are p r o t e i n s and c e l l s (Figure 6 ) . The f i r s t event i s g e n e r a l l y to coat the polymer surface with a l a y e r of p r o t e i n s ; the composition and o r g a n i z a t i o n of t h i s l a y e r w i l l i n f l u e n c e the subsequent c e l l u l a r events (see below). Thus, i t i s e s s e n t i a l that one c h a r a c t e r i z e and reproduce the surface of the b i o m a t e r i a l to be used i n any implant or device. There are a number of other important f a c t o r s which i n f l u e n c e the b i o l o g i c a l i n t e r a c t i o n and ultimate f a t e of a b i o m a t e r i a l i n the body. B i o m a t e r i a l p r o p e r t i e s , such as p u r i t y , tendency to absorb water and degrade are c l e a r l y important. Also, the design of the device or implant, the flow of b i o l o g i c a l f l u i d s by the f o r e i g n surfaces or movement of the implant w i t h i n a t i s s u e space, the t e s t techniques s e l e c t e d to assay b i o m a t e r i a l responses i n v i t r o or i n v i v o ( i n d i f f e r e n t animal s p e c i e s ) , and the implantation i t s e l f can a l l contribute to the ultimate f a t e of the implant device. Table V l i s t s these f a c t o r s and Table VI d e t a i l s important b i o m a t e r i a l surface p r o p e r t i e s .



22

Table V. Important Factors i n B i o m a t e r i a l - B i o l o g i c I.

Biomaterial A. B. C.

II.

Bulk p r o p e r t i e s Surface p r o p e r t i e s Handling, packaging

B i o l o g i c Environment AB.


Interactions

III.

2H v i t r o v s . i n vivo Species

Physical A. B. C.

System design; flow c h a r a c t e r i s t i c s Time, temperature A i r interface

Table VI.

I.

hydrophilic/hydrophobic polar/apolar high energy/low energy wettable/non-wettable acid/base anionic/cationic uniform/domain s t r u c t u r e

oriented structured "free"

"Compliance" — —

IV.

Properties

Sorbed Water — — —

III.

Important M a t e r i a l and Surface at the B i o m a t e r i a l I n t e r f a c e

Composition — — — — — — —

II.

Factors

f l e x i b i l i t y of chain ends, loops glass t r a i n s i t i o n

Roughness — — — —

s c a l e and i n t e n s i t y porosity l o c a l imperfections gas n u c l e i



2.

HOFFMAN

Synthetic Polymeric

Biomaterials

23

Over the past s e v e r a l years, a great deal o f e f f o r t has gone i n t o c h a r a c t e r i z i n g the b i o m a t e r i a l surface composition. Contact angle measurements, i n f r a - r e d r e f l e c t a n c e spectroscopy (MIRS, FTIR), and e l e c t r o n microscopy (XPS or ESCA) have been the most popular techniques u t i l i z e d . ESCA has become a very u s e f u l t o o l , since i t y i e l d s an average composition of the top 10-100 A of the b i o m a t e r i a l surface (although the measurement i s made at low temperature and under high vacuum). The surface topography i s a l s o very important, p a r t i c u l a r l y when compared to the s c a l e of p r o t e i n s and c e l l s (Figures 7, 8 ) . Surface roughness has been v i s u a l i z e d using o p t i c a l and ( e s p e c i a l l y ) scanning e l e c t r o n microscopy. P r o f i l o m e t r y has o c c a s i o n a l l y been used. Table VII l i s t s various common b i o m a t e r i a l s i n approximate categories of i n c r e a s i n g roughness. Table V I I .

R e l a t i v e Roughness of Some Biomaterials

Very Smooth:

P y r o l i t i c Carbons; Metals

Smooth:

S i l i c o n e Rubbers; Polyurethanes; Polyethylene; P o l y v i n y l c h l o r i d e

Microrough:

Grafted Polyethylenes; Micro-porous m a t e r i a l s (as PTFE)

Medium Rough:

Woven Dacron, T e f l o n f a b r i c s ; Medium p o r o s i t y m a t e r i a l s

Very Rough:

K n i t t e d , v e l o u r or non-woven f a b r i c s ; macro-porous m a t e r i a l s ; sand-blasted m a t e r i a l s

B i o l o g i c Responses One may imagine that the body i s d i v i d e d i n t o two systems: (1) the s o f t t i s s u e s , surfaces and spaces, organs and nerves, e x t e r n a l to c a r d i o v a s c u l a r system ( c a l l e d the e x t r a v a s c u l a r system); and (2) the c a r d i o v a s c u l a r - b l o o d system ( c a l l e d the i n t r a v a s c u l a r system). Tissue responses. The major response to f o r e i g n bodies i n the extravascular system i s the inflammatory process. Whether the f o r e i g n "body" i s a molecule or a s o l i d p a r t i c l e or object, there i s inflammation i n the v i c i n i t y and the p r o t e i n s and c e l l s attempt to d i g e s t the f o r e i g n element and convert i t to t o l e r a b l e metabolites. Most f o r e i g n devices or implants are not r e a d i l y or r a p i d l y metabolized and the a l t e r n a t e f a t e i s to be encapsul a t e d i n a f i b r o u s c o l l a g e n scar t i s s u e capsule. I f the b i o m a t e r i a l i s porous, t h i s t i s s u e may be deposited w i t h i n the pores, and such a process may be u s e f u l i n anchoring and/or plugging the implant. Indeed, some researchers have attempted to develop porous implants (as a f i b r o u s v e s s e l p r o s t h e s i s ) which would



24


Foreign Interface

..v.v.v.v

Bound Water, Ions, and Small Molecules

/ / / / / / / / / / /

{

2

H

0

Â

)

Figure 6. The primary i n t e r a c t i o n s at a f o r e i g n b i o m a t e r i a l i n t e r f a c e i n the body are f i r s t with p r o t e i n s and then with l i v i n g c e l l s . The drawing i s schematic, and not to s c a l e .

Smooth

Rough

mm/I

Porous

jytnmn

Figure 7. B i o m a t e r i a l surfaces may be "smooth," "rough," or "porous" (schematic).


7T77

2.

HOFFMAN

Synthetic Polymeric

Biomaterials

25


permit the r e c o n s t r u c t i o n of the t i s s u e being replaced while the implant i t s e l f slowly degrades and disappears. In some cases the m a t e r i a l may evolve t o x i c substances, and cause t i s s u e n e c r o s i s (the question of carcinogenesis i s considered below), or i t may be of a s p e c i f i c geometry (as asbestos f i b e r s ) to induce excessive c o l l a g e n f i b r o s i s , which can be undesirable. Figure 9 summarizes these responses. Blood responses. Blood i s the f l u i d which transports body n u t r i e n t s and waste products to and from the e x t r a v s c u l a r t i s s u e and organs, and as such i s a v i t a l and s p e c i a l body t i s s u e . The major response of blood to any f o r e i g n surface (which includes most extravascular surfaces of the body's own t i s s u e s ) i s f i r s t to deposit a l a y e r of p r o t e i n s and then, w i t h i n seconds to minutes, a thrombus composed of blood c e l l s and f i b r i n (a f i b r o u s p r o t e i n ) . The character of the thrombus w i l l depend on the r a t e and p a t t e r n of blood flow i n the v i c i n i t y . Thus, the design of the b i o m a t e r i a l system i s p a r t i c u l a r l y important f o r c a r d i o v a s c u l a r implants and devices. The thrombus may break o f f and flow downstream as an embolus and t h i s can be a very dangerous event. In some cases the b i o m a t e r i a l i n t e r f a c e may e v e n t u a l l y " h e a l " and become covered with a " p a s s i v e " l a y e r of p r o t e i n and/or c e l l s . Growth of a continuous monolayer of e n d o t h e l i a l c e l l s onto t h i s i n t e r f a c e i s the one most d e s i r a b l e end-point f o r a b i o m a t e r i a l i n contact with blood. Figure 10 summarizes p o s s i b l e blood responses to polymeric b i o m a t e r i a l s . T e s t i n g and

Clearance

of Polymeric

Biomaterials

Test techniques for both t i s s u e and blood responses of b i o m a t e r i a l s have evolved s i g n i f i c a n t l y over the past s e v e r a l years. Increased government r e g u l a t i o n of b i o m a t e r i a l s i n medical devices (as l e g i s l a t e d i n the U.S.A. i n 1976 by the Medical Devices Amendments Act) has stimulated the development of a number of common In v i t r o and i n v i v o animal t e s t systems f o r screening a wide v a r i e t y of b i o m a t e r i a l s and devices or implants f o r both t i s s u e and blood responses. Tissue t e s t s encompass a v a r i e t y of i n v i t r o and i n v i v o techniques. Blood t e s t s i n c l u d e i n v i t r o , ex v i v o , and i n v i v o techniques. I t i s u n l i k e l y that s u c c e s s f u l medical devices or implants can be p e r f e c t e d f o r human use without such p r e l i m i n a r y jLn v i t r o and ( e s p e c i a l l y ) animal t e s t s . U l t i m a t e l y , the b i o m a t e r i a l device or implant system must be tested c l i n i c a l l y , f i r s t i n small s c a l e s t u d i e s , then l a t e r , i f a l l goes w e l l , i n l a r g e r m u l t i - c e n t e r c l i n i c a l t r i a l s . The FDA, the device or implant manufacturer and t h e i r "monitor" (who w i l l i n t e r f a c e with the p h y s i c i a n ) , the p h y s i c i a n ("investigator") and h i s i n s t i t u t i o n a l review board, and f i n a l l y the p a t i e n t are a l l involved i n r e s p o n s i b l e r o l e s i n the c l i n i c a l t r i a l s , the clearance process, and the eventual general c l i n i c a l use.


26


Rough

Smooth

/

ν/-/

- //

Rounded-up c e l l s


Porous

vs. Spread C e l l s

Figure 8. The importance of the s c a l e and i n t e n s i t y of b i o m a t e r i a l surface "roughness" w i l l depend upon the r e l a t i v e s i z e and i n t e r a c t i o n of c e l l s on that surface (schematic).

CHEMICALLY INDUCED

PHYSICALLY INDUCED

[by leochobles, biodégradation products]

Mild

Inflammation

[by surface/volume ratio, shape, degree of surface roughness, movement]

Cell Ingestion (particles)

(suture absorption)

Fibrous Encapsulation

Fibrous Ingrowth

-βSevere

Excessive Fibrosis

Inflammation

(toxic substances evolved)

^

Τιssue Necrosis Granulomas Tumoriqenesis P )

Figure 9 . Tissue responses to f o r e i g n m a t e r i a l s i n the e x t r a v a s c u l a r space. The o v e r a l l process i n v o l v e d i n a l l cases i s c a l l e d the inflammatory process.


HOFFMAN

Synthetic Polymeric

Biomaterials

FOREIGN

SURFACE


Flowing blood PROTEIN

ADSORPTION Lower flow rate; venous

Higher flow rate; arterial

FIBRIN FORMATION

PLATELET AGGREGATION ("WHITE

THROMBUS") \ \

P L A T E L E T AGGREGATION

\ \

TRAPPED RED C E L L S

\

\

/

/("RED

THROMBUS")

EMBOLIZATION Figure 10. Blood responses to f o r e i g n m a t e r i a l s depend on the m a t e r i a l as w e l l as i t s design and the character of the blood flow near the b i o m a t e r i a l surface.



28


F i n a l l y , something should be s a i d about the p o s s i b i l i t y of biomaterial-induced carcinogenesis i n humans. In the absence of e v o l u t i o n of chemical carcinogens by the f o r e i g n m a t e r i a l , there i s no evidence f o r c a r c i n o g e n e s i s i n humans caused by the b i o m a t e r i a l s c u r r e n t l y used i n implants or devices. This i s i n contrast to the tumorigenic responses of rodents to many of these same b i o m a t e r i a l s . I f the l a t e n t p e r i o d f o r f o r e i g n body tumorigenesis i n humans i s merely much longer than that i n rodents, s u f f i c i e n t time may not have elapsed to conclude that tumors induced by implanted b i o m a t e r i a l s w i l l not e v e n t u a l l y be seen i n humans. On the other hand, i t i s even more l i k e l y that t h i s l a t e n t p e r i o d — i f i t e x i s t s — would be longer than the u s e f u l l i f e s p a n of the implant.

Literature Cited 1.

2. 3.

4. 5. 6.

7. 8. 9. 10. 11. 12.

Polymeric Biomaterials Cooper, S.L.; Hoffman, A.S.; Peppas, N.A.; Ratner, B.D., Eds.; "Morphology, Structure, and Interactions of Bio materials"; ADVANCES IN CHEMISTRY SERIES, American Chemical Society: Washington, D.C., 1982. Hoffman, A.S. J . Appl. Polymer Sci., Appl. Polymer Symp. 1977, 31, 313. Major biomaterials journals or annual publications: J. Biomed. Matls. Res. (Wiley); Biomatls., Med. Devices, Artif. Org. (M. Dekker); Biomaterials (IPC Sci. and Tech. Press); Trans. Soc. for Biomatls. (Soc. for Biomaterials) Kronenthal, R.L.; Oser, Ζ.; Martin, Ε., Eds.; "Polymers in Medicine and Surgery"; POLYMER SCIENCE AND TECHNOLOGY Vol. 8, Plenum Press: New York, 1975. Park, J.B. "Biomaterials: An Introduction"; Plenum: New York, 1979. Ratner, B.D.; Hoffman, A.S., in "Hydrogels for Medical and Related Applications"; Andrade, J.D., Ed.; ACS SYMPOSIUM SERIES No. 31, American Chemical Society: Washington, D.C., 1976; pp. 1-36. Sedlacek, B.; Overberger, C.G.; Mark, H., Eds.; "Medical Polymers: Chemical Problems"; POLYMER SYMPOSIUM No. 66, Interscience-Wiley: New York, 1979. Szycher, M.; Robinson, W.J., Eds.; "Synthetic Biomedical Polymers: Concepts and Applications"; Technomic Publ. Co.: Westport, CT, 1980. Winter, G.; Gibbons, D.; Plenk, Η., Eds. Proc. 1st World Congress on Biomaterials, Wiley: London, 1981. Implants and Devices Akutsu, T. "Artificial Heart: Total Replacement and Partial Support"; Excerpta Medica: Amsterdam, 1975. Baker, R.W.; Lonsdale, H.K. Chem. Tech. 1975, 5, 668. Chang, T.M.S. "Artificial Cells"; C.C. Thomas: Springfield, IL, 1972.


2.

13.

14. 15. 16.


17. 18. 19. 20.

21. 22. 23.

24. 25. 26.

HOFFMAN

Synthetic Polymeric

Biomaterials

29

Major journals or annual publications: Trans. Amer. Soc. Artif. Int. Org. (ASAIO); Artif. Org. (ISAO); J . Artificial Org. (Wichtig); Proceedings of the Devices and Technology Branch, Contractors Meeting 1979, NHLBI, NIH, U.S. Dept. of H.H.S., Publ. No. 81-2022, November 1980. Kolff, W.J. "Artificial Organs"; Wiley: New York, 1976. Kolff, W.J. Artif. Org. 1977, 1, 8. Tanquary, A.C.; Lacey, R . E . , Eds.; "Controlled Release of Biologically Active Agents"; ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Vol. 47, Plenum: New York, 1976. Modification and Characterization of Biomaterials Guidelines for Physicochemical Characterization of Biomaterials, Devices and Technology Branch, NHLBI, NIH, U.S. Dept. of H.H.S., Publ. No. 80-2186, September 1980. Hoffman, A.S., in "Science and Technology of Polymer Processing," Suh, N.P.; Sung, N.H., Eds.; MIT Press: Cambridge, MA, 1979; p. 200. Hoffman, A.S., in "Biomedical Polymers"; Dusek, Κ., Ed.; ADVANCES IN POLYMER SCIENCE special volume, Springer-Verlag: Berlin, to be published in 1983-84. Rembaum, A.S.; Yen, S.P.S.; Molday, R.S. J . Macromol. Sci. Chem. 1979, A13, 603. Biologic Responses, Testing and Clearance of Polymeric Biomaterials Bruck, S.C., "Properties of Biomaterials in the Physiologic Environment"; CRC Press: Boca Raton, FL, 1980. Dobelle, W.H.; Morton, W.A.; Lysaght, M.J.; Burton, E.M. Artif. Org. 1980, 4, 1. Everything You Always Wanted to Know about the Medical Device Amendments and Weren't Afraid to Ask, U.S. Dept. of H.H.S., FDA, 8757 Georgia Ave., Silver Spring, MD 20910, Publ. No. FDA-77-5006, 1977. Guidelines for Blood-Material Interactions, Devices and Technology Branch, NHLBI, NIH, U.S. Dept. of H.H.S., Publ. No. 80-2185, September 1980. Vroman, L . ; Leonard, E . F . , Eds.; "The Behavior of Blood and its Components at Interfaces"; ANNALS OF N.Y. ACADEMY OF SCIENCE, No. 283, 1977. Williams, D.F., Ed.; "Fundamental Aspects of Biocompatibility"; Vols. I and II; CRC Press: Boca Raton, FL, 1981.

RECEIVED March 19, 1984


Synthetic Polymeric Biomaterials - ACS Symposium Series (ACS

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