Initiation of Polymerization - American Chemical Society

28 Radiation-Induced Polymerization Reactions for Biomedical Applications

Downloaded by EAST CAROLINA UNIV on October 26, 2014 | http://pubs.acs.org Publication Date: April 19, 1983 | doi: 10.1021/bk-1983-0212.ch028

G. R. H A T T E R Y and V. D. McGINNISS Battelle Laboratories, Columbus, OH 43201

A partial survey of the growing field of radiation induced polymerization methods used in synthesizing both natural and synthetic polymers w i l l be discussed in this paper. To be included are such subjects as: a) b) c)

Grafting reaction - e.g., e-beam and 60 C o to graft substituents amenable to heparization. Crosslinking reaction - e.g., ultra high molecular weight polyethylene (UHMWPE) for joint replacement. Plasma polymerization - e.g., coating of polymeric surfaces with pinhole free thin layers of material to improve specific mechanical properties.

A review of both past and present work in the f i e l d w i l l be included along with several illustrations of various methods u t i l i z i n g different aspects of radiation chemistry to produce biomaterials. The interaction of electromagnetic radiation with certain types of organic substrates has found widespread interest in biomedi c a l research related applications. Many such studies involve interaction of electromagnetic radiation with organic substrates to develop crosslinked/insoluble network structures. For example, a preformed thermoplastic polymer upon direct interaction with certain types of ionizing radiation can develop crosslinked or network structures having higher melting points, greater tensile strengths and better chemical resistance than the starting thermoplastic polymer material. It is also possible to impregnate certain thermoplastic polymers with 0097-6156/83/0212-0393$06.00/0 © 1983 American Chemical Society In Initiation of Polymerization; Bailey, F., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

394

INITIATION OF

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low molecular weight compounds (drugs, chemical agents, etc.) followed by c r o s s l i n k i n g v i a r a d i a t i o n processing techniques to produce a composite s t r u c t u r e capable of c o n t r o l l e d release of the encapsulated compounds through the polymer network (Figure 1). S i m i l a r types of r a d i a t i o n induced polymerization reactions can be c a r r i e d out through the use of l i q u i d monomer, oligomer and polymer compositions containing r e a c t i v e v i n y l components (Figure 2).


In general, r a d i a t i o n induced polymerization r e a c t i o n s involve c o n s i d e r a t i o n of at l e a s t four major v a r i a b l e s , namely: (1) (2) (3)

type of r a d i a t i o n source type of organic substrate to be i r r a d i a t e d k i n e t i c s of the r a d i a t i o n induced polymerization or c r o s s l i n k i n g reactions network formation and f i n a l chemical, p h y s i c a l and mechanical p r o p e r t i e s of the c r o s s l i n k e d s t r u c t u r e .

(4)

The types of radiaton sources most encountered i n biomedical a p p l i c a t i o n s are o u t l i n e d i n Table I . Mechanisms associated

Table I. 6 0

Co

UV-Vis PLASMA

Radiation Sources X-RAYS 2 0 0 - 7 0 0 nm W A V E L E N G T H S OF LIGHT RADIO FREQUENCIES

with r a d i a t i o n induced polymerization r e a c t i o n s i n v o l v e f r e e r a d i c a l intermediates and can be depicted i n the generalized o u t l i n e s shown i n Figures 3 and 4. More complete d i s c u s s i o n s of r a d i a t i o n processing technologies can be found i n references

(1-5)

.

D i s c u s s i o n of r a d i a t i o n induced polymerization a r t i c l e w i l l focus on the f o l l o w i n g biomedical • • • • •

reactions i n this applications:

Bone P r o t h e s i s Polymer - Blood C o m p a t i b i l i t y Immobilization of Reaction Centers Immobilization of Enzymes C o n t r o l l e d Release of Drugs

In Initiation of Polymerization; Bailey, F., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

28.

HATTERY AND

MCGINNISS

Radiation-Induced


Electromagnetic

395

Radiation Source

Electromagnetic Radiation

Thermoplastic Preformed Polymer S t r u c t u r e

Reactions

^ ^

Thermoplastic preformed polymer s t r u c t u r e containing low molecular weight compounds (*)

C r o s s l i n k e d Network Polymers Figure 1. Interaction of electromagnetic radiation with preformed polymer structures.



INITIATION OF

POLYMERIZATION

Electromagnetic radiation source »J\\\ / / / \ \ \ Electromagnetic radiation / / / \ \ \ =

R vinyl monomers

Multifunctional =: — R vinyl monomers or oligomers Unsaturation J sites

= — R — = — R— z= — Unsaturated polymers photoinitiator is required for light-activated reactions

ν Reactive liquid f coating system

y Solid cross-linked film

Figure 2.

Radiation curing concepts (curing of reactive coatings).



HATTERY AND MCGiNNiss

Radiation-Induced

Reactions

Initiating free radicals Α· + π C H = Ç H - ^ A - f C H - C H ^ - * - A - { C H 2 - C H f 2

2

R

n

R

Monomer/unsaturated polymer

Growing polymer (free radical)

R

n

-fCHCH f 2

R

Cured polymer

Figure 3. Ionizing or high-energy electron curing mechanisms.

PI (Photoinitiator)

hv _ R. ^ (Free radicals)

High energy electrons

R- +

Multifunctional unsaturated monomers and polymers Figure 4.

Three-dimensional network formation

Light-induced or high-energy electron curing mechanisms.


398

INITIATION OF

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RADIATION TREATMENT OF POLYOLEFINS P o l y o l e f i n s , i n p a r t i c u l a r , polyethylenes, have been found to be extremely i n e r t during c l i n i c a l t e s t i n g of implant mate r i a l s . (6,7) These m a t e r i a l s are o f t e n wholly accepted by the body t i s s u e s with l i t t l e evidence of foreign-body c e l l r e a c t i o n i n the areas of implantation. For t h i s reason, HDPE (high d e n s i t y polyethylene) has been used i n a multitude of systems f o r biomedical a p p l i c a t i o n s . While the c l i n i c a l p r o p e r t i e s of these m a t e r i a l s are more than acceptable, s e v e r a l problems have a r i s e n with the physical-mechanical p r o p e r t i e s of the i n i t i a l material. Several groups have been involved with analyzing the e f f e c t of wear on these p r o p e r t i e s . (7,8,9) Some have a t tempted to determine whether any increase i n hardness or de crease i n c o l d flow could be c o r r e l a t e d to i r r a d i a t i o n . (7) Since s t e r i l i z a t i o n of most of the j o i n t implants i n v o l v i n g p o l y o l e f i n s i s done using r a d i a t i o n , most often Co-60, groups have looked at the properties both p r i o r to and f o l l o w i n g the s t e r i l i z a t i o n dose (10,11) Results i n a l l of these studies have shown s l i g h t but inconsequential increases i n the mechan i c a l p r o p e r t i e s . Indeed, studies have shown that s i g n i f i c a n t enhancement of mechanical p r o p e r t i e s does not occur u n t i l the HDPE i s subjected to doses greater than 10 times the s t e r i l i z a t i o n dose of 2.5 MRads. (12,13) At these dose r a t e s , coef i c i e n t of f r i c t i o n drops n o t i c e a b l y f o r HMPE. Very l i m i t e d work has a l s o been done on the d i f f e r e n c e between exposure to low f l u x Co-60 source i r r a d i a t i o n and exposure to Ε-beam r a d i a t i o n of HDPE (10) Results have i n d i c a t e d that the surface of the m a t e r i a l i s a f f e c t e d d i f f e r e n t l y by Ε-beam than by s i m i l a r doses of Co-60. It appears that the Ε-beam i r r a d i ated surface i s more s u s c e p t i b l e to s t r e s s cracking and erab r i t t l e m e n t than that of the Co-60 i r r a d i a t e d surface. R e a l i z i n g that exposure of HDPE to high l e v e l s of i o n i z i n g r a d i a t i o n i n an i n e r t atmosphere has l i t t l e e f f e c t on the p r o p e r t i e s of the m a t e r i a l , some groups (7_, 14,1^5) have begun to study the i n t e r a c t i o n of HDPE and i o n i z i n g i r r a d i a t i o n i n a r e a c t i v e atmosphere. One of the most a c t i v e groups i n t h i s arena has been the U n i v e r s i t y of P r e t o r i a group l e d by Grobbelaar. (7^16) They have studied the p r o p e r t i e s of HDPE i n the presence and absence of gaseous c r o s s l i n k i n g agents (Figure 5). Several s i g n i f i c a n t r e s u l t s can be drawn from t h e i r studies on the e f f e c t of a c e t ylene and a c e t y l e n e / c h l o r o t r i f l u o r o e t h y l e n e on i r r a d i a t e d HDPE. T h e i r studies i n d i c a t e d that d i f f u s i o n of the c r o s s l i n k i n g agents w i t h i n the HDPE matrix reached a depth of only 0.3 mm


28.


Radiation-Induced

Reactions


(Figure 6). Extension of both time allowed f o r d i f f u s i o n and t o t a l i r r a d i a t i o n did nothing to change t h i s value. Thus, they have found that HDPE composite m a t e r i a l can be produced with a high c r o s s l i n k density at the surface to impart increased abrasion r e s i s t a n c e and l i m i t c o l d flow while the l i m i t e d c r o s s l i n k i n g i n the bulk of the m a t e r i a l leads to continued good shock and embrittlement r e s i s t a n c e (Figure 7). It i s ex pected that t h i s work w i l l stimulate i n t e r e s t i n studying im provement i n HDPE p r o p e r t i e s through r e a c t i v e gaseous d i f f u sion. Increased wear l i f e of these m a t e r i a l s w i l l be of great a s s i s t a n c e to those who must undergo t o t a l j o i n t replacement at an e a r l y age. POLYMER-CERAMIC COMPOSITE MATERIALS The use of ceramic and polymeric c o n s t i t u e n t s i n s p e c i a l a l l o y s and blends has become widespread i n recent years. These "polymeric cements" have been a p p l i e d to a v a r i e t y of uses from pavement r e p a i r and maintenance (17) to a r t i f i c i a l teeth ( 1 8 , ^ , ^ 0 ) and endosseous implantsT (21) Some of these techniques have r e l i e d on i n i t i a t i n g the p o l y m e r i z a t i o n r e a c t i o n by i o n i z i n g r a d i a t i o n . In p a r t i c u l a r , Kamel (21) at Drexel U n i v e r s i t y has been developing a bone r e s t o r a t i v e using an alumina- p o l y ( a c r y l i c a c i d ) composite produced by exposing an aqueous mixture of the blend to γ rad i a t i o n of 1 MRad (Figure 8). The p o r o s i t y and c r o s s l i n k density of the system were v a r i e d over wide ranges by varying monomer concentration and a heat treatment step to form anhydrides. Other c o n t r o l parameters included both chemical reactions and p h y s i c a l i n t e r a c t i o n s (Figure 9). V a r i a t i o n of these proper t i e s caused a concomitant change i n mechanical p r o p e r t i e s and water absorption. Such c o n t r o l allows the composite to be " t a i l o r e d " to a s p e c i f i c use. This m a t e r i a l can be e a s i l y f a b r i c a t e d and adapted to a number of d i f f e r e n t socket geo metries while allowing bone growth i n t o the porous m a t e r i a l . I n i t i a l studies have shown that n e i t h e r the b i o c o m p a t i b i l i t y of the m a t e r i a l nor the r e s i s t a n c e to body f l u i d d i f f u s i o n are a f f e c t e d to a major extent by t h i s c r o s s l i n k i n g method. Long term implantation studies are p r e s e n t l y underway to determine the ultimate e f f e c t of the m a t e r i a l on the implant area. RADIATION INDUCED GRAFTING FOR

INCREASED BLOOD COMPATIBILITY

Many groups have studied the g r a f t i n g of d i f f e r e n t f u n c t i o n a l i t i e s onto the backbone s t r u c t u r e of d i f f e r e n t polymers. Some of these have involved covalent or i o n i c coupling of b i o - a c t i v e compounds to i n e r t substances (22,23) while others have been concerned with exposing the monomer and polymeric substrate to i o n i z i n g r a d i a t i o n . (24,25,26,27)


399

400

INITIATION OF POLYMERIZATION

WEAR AND COLD " FLOW PROBLEMS

HDPE (UNTREATED) -

HDPE


HDPE

Figure 5.

RADIATION TREATMENT (y-RAY)

RADIATION TREATMENT (y RAY), HC = CH

Improved HDPE

IMPROVED SURFACE HARDNESS, }· WEAR AND COLD FLOW RESISTANCE PROPERTIES

prostheses through the use of radiation treatment.

High

crosslink

density

at t h e irradiated

surface

(depth o f penetration controlled

by monomer

diffusion)

Lower density

crosslink in t h e bulk

Surface

properties—resistance t o abrasion and

Bulk properties—better

cold shock

flow resistance

Figure 6. Effect of radiation treatment on bulk and surface of HDPE ^CH.

+


CH


HATTERY AND

MCGINNISS

Radiation-Induced

401

Reactions

1.5

Dose (kGy) Figure 7. Radiation treatment of HDPE with and without reactive acetylene monomer. (Reprinted from Ref. 7, copyright 1978, and Ref. 16, copyright 1977.)



402

INITIATION OF

POLYMERIZATION

Figure 8. Radiation-processed polyacrylic acid (FA A) composites for bone restoration. (Reprinted from Ref. 21. Copyright 1977.)

OBJECTIVE

D E V E L O P C O M P O S I T E M A T E R I A L S HAVING M A X I M U M FLEXIBILITY IN VARIATION O F M E C H A N I C A L PROPERTIES WHILE M A I N TAINING BIOCOMPATIBILITY

CONTROL FACTORS • A N H Y D R I D E F O R M A T I O N IS R E L A T E D T O C R O S S L I N K DENSITY • C R O S S L I N K DENSITY C O N T R O L S W A T E R SWELLING OF C O M P O S I T E • S T R O N G P O L Y M E R - F I L L E R INTERACTION Figure 9. Radiation-processed poly acrylic acid (PA A) composites for bone restoration.


28.

HATTERY AND

MCGINNISS

Radiation-Induced Reactions

403

A b r i e f survey of the f i e l d shows that by f a r the most p r e v a l ent polymer substrate i n use i s the s i l i c o n e f a m i l y ,


Wilson, at Bishop C o l l e g e , and Eberhart and Elkowitz at U n i v e r s i t y of Texas (27) have i r r a d i a t e d a s i l i c o n e substrate i n the presence of chloromethylstyrene monomer to produce a r e a c t i v e g r a f t polymer that can be quarternized with p y r i d i n e and reacted with sodium heparin to produce a thromboresistant heparinized product that has a higher blood c o m p a t i b i l i t y than the untreated s i l i c o n e . The same group has used e s s e n t i a l l y the same methods to create a heparin g r a f t e d polyethylene surface. The method developed by Wilson, et a l , y i e l d s an i o n i c a l l y bound heparin moiety that a f f e c t s the anticoagulant a c t i v i t y of the heparin molecule to a l e s s e r extent than does the t r a d i t i o n a l method (28) of simple s o l u t i o n coating of m a t e r i a l . Tests have shown that the maximum heparin removal rate i n nor mal s a l i n e i s s u f f i c i e n t to prevent c l o t t i n g i n hollow f i b e r a r t i f i c i a l kidneys as predicted by Schmer (29), Future work w i l l develop around a " p u r i f i e d " heparin prepared by Rosenberg and Lam (30) where one t h i r d of the s t a r t i n g mass of heparin contains 85% of the anticoagulant a c t i v i t y Several other groups have also studied the blood c o m p a t i b i l i t y of s i l i c o n e s with various r a d i a t i o n grafted copolymer con stituents, Chapiro, et a l (25) have g r a f t e d N - v i n y l p y r r o l i done using Co-60 onto s i l i c o n e i n both "bulk" and " s o l u t i o n " type r e a c t i o n s . It i s i n t e r e s t i n g to note that s i m i l a r work using Ε-beam r a d i a t i o n has not been as s u c c e s s f u l (26), C h a p i r o s studies have shown improvement i n blood c o m p a t i b i l i t y f o r samples with a g r a f t i n g weight increase of greater than 33% (Figure 10). Studies a l s o showed that the g r a f t i n g percent could be c o n t r o l l e d by varying the r a t i o of η-vinyl pyrrolidone i n the solvent. However, i t was found that above approximately 30% g r a f t i n g , the s i l i c o n e becomes b r i t t l e and loses mechanical p r o p e r t i e s . Attempts are presently underway to l i m i t the depth of g r a f t i n g of N - v i n y l pyrrolidone to j u s t the surface of the tubes so that the o r i g i n a l p r o p e r t i e s of the s i l i c o n e can be retained. 1

Other groups have concentrated on the a c r y l a t e and methacrylate hydrogel type m a t e r i a l s . Dincer (22) has shown that heparin can be attached c o v a l e n t l y to c r o s s l i n k e d beads of polymethyl a c r y l a t e to y i e l d increased blood c o m p a t i b i l i t y at very low r a t e s of desorption from the surface. These f i n d i n g s are i n l i n e with Salzman ( 3 2 ) , M e r r i l l (33) and Wong (34) statements that the antithrombogenic e f f e c t does not depend on leaching of heparin from a surface i n t o the blood stream. Further work by Hattery (35) showed that r a d i a t i o n g r a f t i n g of methyl a c r y l a t e


404

INITIATION OF

POLYMERIZATION


to s i l i c o n e followed by h e p a r i n i z a t i o n by the method of Flake (23) and Dincer (22) could y i e l d a surface that e x h i b i t e d good a n t i c l o t t i n g p r o p e r t i e s . Further t e s t i n g or r e p o r t i n g of these r e s u l t s have been delayed u n t i l a s a t i s f a c t o r y method f o r producing a uniform surface coating has been developed. Another group deeply i n t e r e s t e d i n r a d i a t i o n g r a f t i n g of a c r y l a t e s and methacrylates i s that of Hoffman, et a l at the U n i v e r s i t y of Washington. (26) They have a p p l i e d Co-60 r a d i a t i o n to the production of hydrogel type b i o m a t e r i a l s through g r a f t i n g of s p e c i f i c monomers onto an i n e r t polymer backbone. This work has looked at immobilization of b i o l o g i c a l l y a c t i v e molecules such as enzymes, a l b u m i n s and plasma p r o t e i n s o n t o g r a f t e d hydrogels of hydroxyethylmethacrylate (HEMA) and other f u n c t i o n a l g r a f t i n g agents such as n - v i n y l p y r r o l i d o n e . They have found that c e r t a i n metal ions or polar organic solvents can be used to vary the amount and penetration of the g r a f t monomer as w e l l as changing the r e a c t i o n r a t e . These are by no means the only groups working i n the f i e l d of blood c o m p a t i b i l i t y . However, the ones c i t e d are s u f f i c i e n t to provide i n s i g h t i n t o the progress of r a d i a t i o n synthesis as r e l a t e d to hemocompatibility research. IMMOBILIZATION OF REACTION CENTERS Another area of great i n t e r e s t i n biomaterials research has been that of immobilization of r e a c t i o n centers on an i n e r t substrate to create r e a c t i o n s p e c i f i c c i t e s . One group (36) has been i n t e r e s t e d i n s t a b i l i z a t i o n of c h l o r o p l a s t s f o r use i n s o l a r energy development (Figure 11). Various h y d r o p h i l l i c and hydrophobic monomers were mixed with i s o l a t e d c h l o r o p l a s t s i n a s p e c i f i c b u f f e r s o l u t i o n (Figure 12). The mixture was cooled to below -24C and i r r a d i a t e d with a Co-60 source to 1 MRad. A f t e r i r r a d i a t i o n , r e s i d u a l monomer and c h l o r o p l a s t were washed l e a v i n g the immobilized product stored i n a b u f f e r s o l u t i o n . The authors found that the h y d r o p h i l i c monomer d i d not a f f e c t the e v o l u t i o n of oxygen as much as the hydrophobic monomer. In a d d i t i o n , i t was reported that concentration of s t a r t i n g mater i a l and time a f t e r monomer a d d i t i o n decreased the e f f e c t i v e ness of the c h l o r o p l a s t i n evolving 0£.

The immobilization technique allowed the c h l o r o p l a s t to remain a c t i v e more than 7 times longer than the non-immobilized sample at a c t i v i t y l e v e l s as high as 40% of i n i t i a l values. This i n crease i n s t a b l e l i f e t i m e f o r p h o t o - a c t i v i t y may be tapped f o r f u t u r e use i n conversion of s o l a r energy to chemical and e l e c -


HATTERY AND M c G i N N i s s


GRAFT RATIO %

Radiation-Induced #TESTS

CLOTTED TUBES

Reactions

405

UNCLOTTED TUBES

0

16

7

16-22

5

H

9 1

31-39

19

7

12

11-17

9

1

8

Figure 10.

Improvement in short term hemocompatibility of silicone-g-NVP over silicone. Implants for 7 days in lamb carotid arteries.

Figure 11.

Stabilization of chloroplast. (Reprinted with permission from Ref. 36. Copyright 1981, John Wiley and Sons, Inc.)

Figure 12.

Stabilization of chloroplast.


406

INITIATION OF

POLYMERIZATION

t r i c a l energy. However, experiments p r e s e n t l y are only a t the lab stage and much work remains to be performed to determine the f e a s i b i l i t y of the approach.


RADIATION INDUCED POLYMERIZATION REACTIONS FOR ENZYME IMMOBILIZATION Several studies have been c a r r i e d out on the immobilization of enzymes by r a d i a t i o n ( i o n i z i n g and photochemical) induced polymerization r e a c t i o n s . (37-44) Most of these studies i n volved the use of combinations of h y d r o p h i l i c or hydrophobic monomer/polymer substrates f o r the entrapment of the enzyme catalyst. A l i s t i n g of t y p i c a l hydrophilic/hydrophobic polymer m a t e r i a l s i s contained i n Table I I . The e f f e c t s of hydro p h i l i c / h y d r o p h o b i c polymer p r o p e r t i e s i n enzyme a c t i v i t y are

Table II.

Radiation-Induced Immobilization of Enzymes WATER C O N T E N T (%)

POLYMER Ο

II

m N-CH -CH -CH -CH 2

2

2

PNVP

93.7

PAAm

84.8

PHEA

45.9

C H - C (CH )+ 2

3

m

COO ( C H ) OH 2

2

PHEMA

26.0

PHDMMA

13.5 m 2.5

-j-CH -C(CH )j-COOCH3 2

PMMA

3

2.1


28.


Radiation-Induced

Reactions

407


shown i n Figure 13· In many cases there are very complex r e l a t i o n s h i p s among matrix p o r o s i t y , polymer s t r u c t u r e and net work a r c h i t e c t u r e . Enzyme i n i t i a l a c t i v i t y i n a h y d r o p h i l i c polymer s t r u c t u r e decreased r a p i d l y with repeated use (enzyme leakage) but the hydrophobic polymer s t r u c t u r e s retarded l o s s of enzyme a c t i v i t y through repeated usage. Another advantage of using r a d i a t i o n processing techniques to immobilize enzyme m a t e r i a l s on polymer surfaces i s the a b i l i t y to achieve very homogeneous and smooth composite s t r u c t u r e s which are not a t t a i n a b l e by conventional p o l y m e r i z a t i o n techniques. (45) CONTROLLED RELEASE OF MATERIALS FROM RADIATION POLYMERIZED COMPOSITES The g e n e r a l i z e d concept f o r producing composite s t r u c t u r e s capable of c o n t r o l l e d a d d i t i v e r e l e a s e p r o p e r t i e s i n v o l v e s 1) s o l u t i o n or d i s p e r s i o n of a d d i t i v e s i n r e a c t i v e monomer/polymer systems, 2) s u b j e c t i n g the additive/monomer-polymer s o l u t i o n d i s p e r s i o n to r a d i a t i o n , and 3) formation of a c r o s s l i n k e d polymer network which encapsulates the s p e c i f i c agent (Figure 14). T y p i c a l monomer and c r o s s l i n k i n g oligomers u t i l i z e d i n these types of s t u d i e s are shown i n Table I I I . The e f f e c t s of

Table III. Controlled Release of Materials from RadiationPolymerized Composites MONOMERS METHYL A C R Y L A T E (MA) METHYL METHACRYLATE (MMA) 2 - H Y D R O X Y E T H Y L M E T H A C R Y L A T E (HEMA) CROSSLINKING OLIGOMERS POLYETHYLENE G L Y C O L #600 D I A C R Y L A T E (PEGDA) POLYETHYLENE G L Y C O L #400 D I M E T H A C R Y L A T E (PEGDMA) DIETHYLENE G L Y C O L D I M E T H A C R Y L A T E ( D E G D M A ) T R I M E T H Y L O L P R O P A N E T R I A C R Y L A T E (TMPTA) T R I M E T H Y L O L P R O P A N E TRIM ΕΤΗ A C R Y L A T E (TMPTMA)

monomer chemical s t r u c t u r e (hydrophilic/hydrophobic) on r e l e a s e of KC1 from a cured composite system are shown i n Table IV.


408

INITIATION OF

POLYMERS HYDROPHILIC

INCREASED ACTIVITY

% WATER HIGH

POLYMERIZATION

POROSITY DECREASES


50%

HYDROPHOBIC

DECREASED ACTIVITY

LOW

INCREASES

Figure 13.

Activity and properties of radiation-induced immobilization of enzymes.

Figure 14.

Controlled release of materials from radiation-polymerized composites.


28.


Radiation-Induced

409

Reactions

Table IV. Controlled Release of KC1 from Radiation-Polymerized Composites


HYDROPHILIC MONOMERS

Ww RELEASE W(%) =— —— RATE Wp + Ww ( / / g / c m min > 2

HEMA PEGDA PEGDMA

32.5 30.7 21.6

4.37 3.87 3.01

HYDROPHOBIC MONOMERS MA MMA DEGDMA TMPTA TMPTMA

7.6 6.8 3.8 3.3 2.4

2.41 2.06 0.69 0.33 0.03

1/ 2

Those polymer composite systems having high W% values (hydrop h i l i c ) (Ww i s the weight of water absorbed to saturate the polymer and Wp i s the weight of the dry polymer) demonstrated higher release rate c a p a b i l i t i e s than those having low W% values. The f u n c t i o n a l i t y of the raonomer/crosslinking oligomer a l s o i n f l u e n c e s the rate of KC1 release i n that monofunctional monomers release f a s t e r than d i f u n c t i o n a l c r o s s l i n k i n g o l i g o mers which i n turn have higher release rates than the t r i f u n c t i o n a l c r o s s l i n k i n g oligomers. This may a l s o be due to the f a c t that t r i f u n c t i o n a l c r o s s l i n k i n g oligomers produce very t i g h t network s t r u c t u r e s r e l a t i v e to higher molecular weight d i f u n c t i o n a l c r o s s l i n k i n g oligomer s t r u c t u r e s . (46) The a d d i t i o n of h y d r o p h i l i c thermoplastic a d d i t i v e s to a ~ T e l a t i v e l y hydrophobic network can a l s o s t r o n g l y i n f l u e n c e the release of KC1 from i t s s t r u c t u r e (Figure 15). (jV7) An example of another type of drug c o n t r o l l e d release composite system i s shown i n Table V and Figure 16. (48)


410

POLYMERIZATION


INITIATION OF

0

1

2

3

4

Release Rate ( m g / c m ^ m i n Figure 15.

1 / 2

)

Controlled release of KCl from radiation-polymerized polyethylene 600 glycol (PEG 600).

DEGDMA/




28.

Radiation-Induced

Reactions

-Radiation Cured Composite Control Factors Effecting Drug Release Rates • Relative concentrations of each drug • Molecular weight of the drug • Content and composition of drugs • Polarity of the composite • Network of the polymer Figure 16.

Controlled release of multicomponent cytotoxic agents from radiationpolymerized composites.


411

412


Table V. Controlled Release of Multicomponent Cytotoxic Agents from Radiation-Polymerized Composites. CYTOTOXIC A G E N T S


1 ( 2 - T E T R A H Y D R O F U R Y L ) - 5 FLUOROURALIL (FT 207) M I T O M Y C I N C (MMC) A D R Y A M Y C I N (ADM) MONOMERS

POLYMERS

DEGDMA TMPTMA

PMMA PEG 1 0 0 0 PMAC

Source: Reprinted from Ref. 48. Copyright 1980.

Plasma polymerization r e a c t i o n s have a l s o been u t i l i z e d to modify hydrogel polymer surfaces f o r enhanced c o n t r o l l e d r e lease c a p a b i l i t i e s . In one study an ummodified polymer hydrog e l e x h i b i t e d very rapid release rates f o r an entrapped drug i n aqueous medium (Figure 17 and 18). M o d i f i c a t i o n o f the hydrog e l surface with an Argon i o n plasma ( c r o s s l i n k i n g or casing of the surface) or plasma polymerization of the surface i n the presence of t e t r a f l u o r o e t h y l e n e monomer (Figure 19) produced an improved s t r u c t u r e f o r drug c o n t r o l l e d release c a p a b i l i t i e s (Table VI),(49,50)

Table VI. Rates of Drug Release from Unmodified and Modified Hydrogel Structures HYDROGEL STRUCTURE

DRUG

RELEASE

UNMODIFIED

41.8/yg/hr-cm'

CASED

40

TFE

3-9

COATED

//g/hr-cm

RATE

2

/yg/hr-cm

2


28.


Radiation-Induced

Reactions

413


Objective—to modify hydrogel surface so as to control the rate of drug diffusion for release at a specified rate

Unmodified hydrogel Figure 17.

Hydrogel modification by plasma treatment.

Drug release

D r u g (D) in s w o l l e n hydrogel D r u g = pilocarpine, progesterone Figure 18. Control of drug release rate through hydrogels by plasma treatment. (Reprinted from Ref. 49. Copyright 1977.)



414

INITIATION OF

Figure 19.

POLYMERIZATION

Hydrogel modification by plasma treatment.


28. HATTERY AND MCGINNISS

Radiation-Induced Reactions

415

LITERATURE CITED


1.

Chapiro, A., "Radiation Chemistry of Polymeric Systems", Interscience Publisher, a division of John Wiley and Sons, Inc., New York, 1962. 2 Wilson, J. E., "Radiation Chemistry of Monomers, Polymers, and Plastics", Marcel Dekker, Inc., New York, 1974. 3. McGinniss, V. D., Nowacki, L. J. and Nablo, S. V., ACS Symposium, No. 107, page 51-70, 1979. 4. McGinniss, V. D., National Symposium on Polymers in the Service of Man, ACS, 15th State-of-the-Art Symposium, pages 175-180, 1980. 5. Hollahan, J. R., and Bell, A. T., "Techniques and Applications of Plasma Chemistry", John Wiley and Sons, 1974. 6. Charnley, J., Clin Orth Rel Res., 95 pg. 9 (1978). 7. Grobbelaar, C. J. et a l , J. Bone Jt Sug, 60-B, pg. 370 (1978). 8. Dumbleton, J. H., Shen, C., Wear, 37, pg 279 (1976). 9. Nusbaum, H. J., et a l . , J. Appl Poly. Sc., 23, pg 777 (1979). 10. Hattery, G. R., unpublished report, Battelle Columbus Laboratories, 1980. 11. DuPlessis, T.A., Paper presented at Cong South Africa Assoc. Physicists Med Biology, Bellville, (1977). 12. Dumbleton, J. H., Shem, C., J. Appl. Poly. Sci., 18, pg 3493 (1974). 13. Dumbleton, J. H. et a l , Wear, 29, pg 163 (1974). 14. Mitsui, H. et a l , Polym. Jour., 13, pg 108 (1972). 15. Hagiwara, M. et a l , Poly. Sci, B, Polym. Let., 11, pg 613 (1973). 16. Grobbelaar, C. J. Radiat. Phys. Chem, 9, pg 647 (1977). 17. Nandi, U. S., Personal Communication, 1981. 18. Hodash, M. et a l , Oral Surg, 24, pg 831 (1967). 19. Young. F. A., J. Biomed Mater Res. Symp., 2, pg 281 (1972). 20. Reed, O. M. et a l , J. Biomed Mater Res. Symp., 2, pg 296 (1972). 21. Kamel, I. L., Radiat. Phys. Chem. 9, pg 711 (1977). 22. Dincer, A. K., Sc. D. Thesis, "Covalent Coupling of Heparin to Synthetic Polymer Surfaces", MIT, 1977. 23. Flake, J., S. M. Thesis, "Aminolysis and Heparinzation of Polymethylacrylate for Biomedical Application", MIT, 1976. 24. Hattery G. R., S. M. Thesis, "Radiation Induced Crosslinking in Polymethyl acrylate", MIT, 1978. 25. Chapiro, A. et a l , Radiat. Phys. Chem., 15, pg 423 (1980). 26. Hoffman, A. S. et a l , Trans. Amer. Soc. Artif. Internal Organ, 18, pg 10 (1972).


416 27. 28. 29. 30. 31.


32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50.


Wilson, J. E., et a l , J. Macromol Sci. Chem. A16, pg 769 (1981). Grode, G. A., et a l , J. Biomed Mater. Res. Symp., 3, pg 77 (1972). Schmer, G., Trans. Am. Soc. Aritif. Intern. Organ, 19, pg 188 (1973). Rosenberg, R. D., Lam. L. H., Ann. N.Y. Acad. Sci., 283, pg 404 (1977). Yosada, H., Reforjo, M. F., J. Polym. Sci, Part A-2, pg 5093 (1964). Salzman, E. W., Blood, 38, pg 509 (1971). Merrill, E. W., et a l , J. Appl. Physiol., 28, pg 723 (1970). Wong, P. S. L., et a l , Fed, Proc., p. 441 (1969). Hattery, G. R., Unpublished report, MIT, (1977). Yoshii, F., et a l , Biotech Bioeng, 23, pg 833 (1981). Kumakura, M. et a l . Journal of solid-phase Biochemistry, 2, No 3, 279 (1977). Kaetsu, I., Kumakura, M., and Yoshida, M., Biotech. Bioeng., 21, 867 (1979). Ibid, 863 (1979). Ibid, Polymer, 20, 3 (1979). Ibid, 9 (1979). Ichimura, K., and Watanabe, Poly. Sci. Poly. Chem., 18, 891 (1980). Yoshida, M., Kumakura, M., and Kaetsu, I., J. Macromol. Sci-Chem., A14, No. 4, 541 (1980). Ibid, 555 (1980). Kaetsu, I., et a l , Biomed. Mat. Res., 14, 199 (1980). Yoshida, M., Kumakura, M. and Kaetsu, I., Polymer, 19, 1375 (1978). Ibid, 1379 (1978). Kaetsu, I., et a l , Biomaterials, 1, 17 (1980). Colter, K. D., Shen, M., and Bell, A. T., Biomat., Med. Dev. Art. Org., 5, No 1, 13 (1977). Ibid, 1 (1977).

RECEIVED November 9, 1982


Initiation of Polymerization - American Chemical Society

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