Structure, Testing, and Applications of Biomaterials - Advances in

28 Structure, Testing, and Applications of Biomaterials Downloaded by KTH ROYAL INST OF TECHNOLOGY on November 16, 2015 | http://pubs.acs.org Publication Date: July 27, 1982 | doi: 10.1021/ba-1982-0199.ch028

NICHOLAS A. PEPPAS Purdue University, School of Chemical Engineering, West Lafayette, IN 47907

T

he term biomaterials encompasses all materials used for medical applications that are interfaced with living systems. Although this definition

addresses specifically materials used in contact with living systems (intracorporeal uses), other systems developed for extracorporeal uses (1—4) are also commonly classified as biomaterials. Biomedical materials include metals, ceramics, natural polymers (biopolymers), and synthetic polymers of simple or complex chemical and/or

physical structure. This volume addresses, to a large measure, fundamental research on phenomena related to the use of synthetic polymers as blood-compatible biomaterials. Relevant research stems from major efforts to investigate clotting phenomena related to the response of blood in contact with polymeric surfaces, and to develop systems with nonthrombogenic behavior in short- and long-term applications. These systems can be used as implants or replacements, and they include artificial hearts, lung oxygenators, hemodialysis systems, artificial blood vessels, artificial pancreas, catheters, etc. (5). Other biomedical applications of polymers include sustained and controlled drug delivery formulations for implantation, transdermal and transcorneal uses, intrauterine devices, etc. (6, 7). Major developments have been reported recently on the use of biomaterials for skin replacement (8), reconstruction of vocal cords (9), ophthalmic applications such as therapeutic contact lenses, artificial corneas, intraocular lenses, and vitreous implants (10), craniofacial, maxillofacial, and related replacements in reconstructive surgery (1), and neurostimulating and other electrical-stimulating electrodes (1). Orthopedic applications include artificial tendons (11), prostheses, long bone repair, and articular cartilage replacement (1). Finally, dental materials and implants (12, 13) are also often considered as biomaterials. This chapter presents a brief analysis of important physical, chemical, and biological properties of biomaterials, which can serve as the basis for development of new candidate polymers.

0065-2393/82/0199-0465$06.00/0 ©1982 American Chemical Society In Biomaterials: Interfacial Phenomena and Applications; Cooper, S., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

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BIOMATERIALS: INTERFACIAL PHENOMENA AND APPLICATIONS

Criteria C a n d i d a t e p o l y m e r s for b i o m e d i c a l applications must c o m p l y w i t h a variety of r e q u i r e m e n t s characteristic of most biomaterials. T h e s e r e q u i r e ments arise e i t h e r f r o m the specific c h e m i c a l or p h y s i c a l structure of the p o l y m e r s (chemical, p h y s i c a l , a n d m e c h a n i c a l criteria) or f r o m the p h y s iological e n v i r o n m e n t w h e r e they w i l l be u s e d (biological criteria). Table I Downloaded by KTH ROYAL INST OF TECHNOLOGY on November 16, 2015 | http://pubs.acs.org Publication Date: July 27, 1982 | doi: 10.1021/ba-1982-0199.ch028

s u m m a r i z e s major c r i t e r i a for the d e s i g n a n d selection of p o l y m e r s as b i o materials. B i o m a t e r i a l s m u s t be free f r o m elutable i m p u r i t i e s , such as additives and r e s i d u a l substances. A d d i t i v e s i n c l u d e stabilizers, antioxidants, plasticizers, and fillers w h i c h are a d d e d to c o m m e r c i a l p o l y m e r s to i m p a r t specific p h y s i c a l or m e c h a n i c a l p r o p e r t i e s . Since l o n g - a n d short-term m i g r a t i o n of these c o m p o n e n t s to the adjacent tissues a n d biological fluids is h i g h l y u n d e s i r a b l e , additives must be e l i m i n a t e d before use. In a d d i t i o n , favorable p o l y m e r p r o p e r t i e s can be achieved w i t h o u t u s i n g additives v i a block or r a n d o m c o p o l y m e r i z a t i o n o f the candidate h o m o p o l y m e r w i t h other m o n o mers. Graft c o p o l y m e r i z a t i o n is also used to obtain p o l y m e r surfaces w i t h

Table I. Criteria for Development of Biomaterials Chemical and Physical Structure • C h e m i c a l l y inert materials • Materials free f r o m leachable i m p u r i t i e s , additives, and c o m p o u n d s rem a i n i n g after p o l y m e r i z a t i o n and c r o s s - l i n k i n g • Materials w i t h desirable physical structure (crystallinity, entanglements, e q u i l i b r i u m swelling) • Materials w i t h m i n i m a l mechanical degradation and e n v i r o n m e n t a l aging • O t h e r desirable properties ( p e r m e a b i l i t y , f r i c t i o n , electrical p r o p e r t i e s , etc.) Mechanical Behavior and Materials Processing • Materials w i t h satisfactory mechanical properties i n tension, c o m p r e s sion, and shear • Readily processable systems by conventional processing methods Biological Interactions • N o n t o x i c materials • N o n c a r c i n o g e n i c materials • Materials that do not cause teratological effects • Sterilizable materials • N o n b i o d e g r a d a b l e systems (unless biodégradation is desired) • Materials that do not i n d u c e i n f l a m m a t o r y reactions • Materials that do not cause thrombosis • Materials that do not alter the stability of biological fluids

In Biomaterials: Interfacial Phenomena and Applications; Cooper, S., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

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Structure, Testing, and Applications

u n i f o r m p r o p e r t i e s (14).

Initiator residues can be avoided b y e m p l o y i n g

p o l y m e r i z a t i o n reactions i n d u c e d b y ultraviolet radiation, electron beams, or 7-rays, w h i c h u s u a l l y p r o d u c e p o l y m e r grades of h i g h p u r i t y . Solvent residues a n d e m u l s i f i e r s are usually the result of solution, suspension, or e m u l sion p o l y m e r i z a t i o n m e t h o d s . T h e y can be e l i m i n a t e d b y p r o p e r devolatilization or a v o i d e d b y s w i t c h i n g to b u l k p o l y m e r i z a t i o n techniques

(15).

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U l t r a p u r e grades of biomaterials have b e e n p r e p a r e d recently b y plasma p o l y m e r i z a t i o n . S o m e r e s i d u a l m o n o m e r s of the p o l y m e r i z a t i o n reactions are toxic even at levels o f a few p p m . A l t h o u g h removal b y devolatilization and related techniques is u s e d to m i n i m i z e this residue, it is not always possible to e l i m i n a t e l o n g - t e r m diffusion of s m a l l amounts of m o n o m e r s to the tissue. C a n d i d a t e biomaterials must fulfill certain r e q u i r e m e n t s related to the physical a n d m e c h a n i c a l p r o p e r t i e s of the p o l y m e r . Parameters of interest i n c l u d e the g e o m e t r y of the d e v i c e , i m p l a n t or c o m p o n e n t , degree of s w e l l i n g at e q u i l i b r i u m , d e g r e e of c r o s s - l i n k i n g , v o l u m e degree of crystallinity, size of crystallites, s e q u e n c e a n d size of " b l o c k s " and "hard/soft segments" (for certain types of p o l y m e r s ) , elastic p r o p e r t i e s , response to tensile, shear, or compressive stresses u n d e r stress-relaxation, creep, q u a s i - e q u i l i b r i u m or oscillatory l o a d i n g , tear propagation, fatigue resistance,

and

time-tem-

perature viscoelastic b e h a v i o r . P r o p e r d e s i g n of biomaterials, especially for l o n g - t e r m applications, should c o n s i d e r m e c h a n i c a l degradation a n d e n v i r o n m e n t a l aging p r o b l e m s . T h e r m a l degradation is of lesser i m p o r t a n c e i n biomaterials, due to the relatively small fluctuations of the t e m p e r a t u r e i n most b i o m e d i c a l applications. Biomaterials s h o u l d be cast r e a d i l y or m o l d e d i n f i l m s , rods, tubings, or m o r e c o m p l e x g e o m e t r i c a l shapes. Injection a n d rotational m o l d i n g , reaction injection m o l d i n g , a n d casting are desirable p o l y m e r processing techniques. F i n a l l y , c h e m i c a l l y i n e r t systems are r e q u i r e d i n most b i o m e d i c a l a p p l i cations. C h e m i c a l (e.g., h y d r o l y t i c ) cleavage s h o u l d be avoided. E x c e p t i o n s i n c l u d e b i o d e g r a d a b l e or b i o e r o d i b l e controlled-release systems, w h i c h b i o degrade b y e n z y m a t i c or c h e m i c a l mechanisms at p r e s c r i b e d rates. B i o l o g i c a l a n d p h y s i o l o g i c a l c r i t e r i a are related to the specific applications of biomaterials i n the b o d y . F u n d a m e n t a l s of b l o o d c o m p a t i b i l i t y are analyzed e x p e r t l y i n the o v e r v i e w b y H o f f m a n (16) i n c l u d e d i n this v o l u m e . B l o o d - c o m p a t i b l e biomaterials s h o u l d not cause cancer or teratological effects, a n d they s h o u l d not be toxic. Toxicity may be related to functional groups of the p o l y m e r surface structure, or to m i g r a t i o n of residual m o n o mers u n d e r q u i e s c e n t or flow c o n d i t i o n s . Biomaterials s h o u l d be sterilizable, w i t h o u t any alterations i n f o r m or p r o p e r t i e s , and w i t h o u t p e r m a n e n t adsorption of s t e r i l i z i n g agents. T h e y s h o u l d not i n d u c e i n f l a m m a t o r y reactions w h e n i n contact w i t h natural tissue, a n d they s h o u l d not degrade i n the presence of naturally c i r c u l a t i n g enzymes in biological fluids.


468


D e p e n d i n g o n the specific a p p l i c a t i o n , a d d i t i o n a l properties may he necessary. F o r example, adequate d r u g p e r m e a t i o n t h r o u g h p o l y m e r m a trices is important for controlled-release systems. L o w friction properties are desirable i n articular cartilage materials. H e m a t o l o g i c a l c r i t e r i a call for materials that d o not cause thrombosis, d o not alter the stability o f soluble o r cellular materials i n the b l o o d , a n d do not allow allergic, toxic, aging, or c e l l


fragility reactions.

Testing of Physical Properties D e t e r m i n a t i o n o f the physical properties of p o l y m e r i c systems is necessary before they can b e used as biomaterials. D e p e n d i n g o n the application

Table II. Major Tests of Physical Behavior of Biomaterials Macromolecular Structure • M o l e c u l a r weights and m o l e c u l a r w e i g h t d i s t r i b u t i o n s b y d i l u t e solution v i s c o m e t r y , light scattering, m e m b r a n e o s m o m e t r y , and g e l p e r m e a t i o n chromatography • D e g r e e of c r o s s - l i n k i n g and degree o f s w e l l i n g b y s w e l l i n g e x p e r i m e n t s , d i l a t o m e t r y , laser light scattering, a n d r u b b e r elasticity • O r d e r e d (crystalline) structure b y differential scanning c a l o r i m e t r y , x-ray diffraction, electron microscopy, infrared spectroscopy, sonic m o d ulus, mechanical testing, etc. Other Properties and Macroscopic Structure • T h e r m a l characterization b y differential scanning c a l o r i m e t r y , t h e r m o gravimetric analysis, a n d t h e r m o m e c h a n i c a l analysis • F r i c t i o n properties • E l e c t r i c a l properties • Porosity b y p o r o s i m e t r y • P e r m e a t i o n analysis b y solute diffusion studies Mechanical Behavior • Tensile, compressive, a n d shear experiments • Stress-relaxation e x p e r i m e n t s • C r e e p experiments • Testing u n d e r oscillatory l o a d i n g • A c c e l e r a t e d aging tests Surface Characterization • Roughness analysis • Contact-angle measurements • X - r a y photoelectron spectroscopy • Total reflectance i n f r a r e d spectroscopy • A u g e r electron spectroscopy • Secondary i o n mass s p e c t r o m e t r y


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c o n s i d e r e d , a range of physical analyses w i l l have to be c a r r i e d out. Table II summarizes some of the i m p o r t a n t experiments for a p r e l i m i n a r y evaluation of candidate materials. E x t e n s i v e analysis of physical and p h y s i c o c h e m i c a l techniques

for the investigation of the structure of h o m o p o l y m e r s ,

co-

p o l y m e r s , blends, a n d composites can be f o u n d i n standard references (17-19).


T h e m a c r o m o l e c u l a r structure can be investigated i n terms of the size, b r a n c h i n g , and d i s t r i b u t i o n of the m a c r o m o l e c u l a r chains, the o r d e r e d structure and orientation of the p o l y m e r , and the t h e r m o d y n a m i c c o m p a t i b i l i t y of the system w i t h biological fluids. T h e first type of analysis calls for evaluation of the molecular weight d i s t r i b u t i o n of the b u l k p o l y m e r before, d u r i n g , and after i m p l a n t a t i o n . Analysis of the o r d e r e d structure refers to investigation of the crystalline structure of the m a c r o m o l e c u l a r chains and its possible alteration due to application of stresses or to the possible s w e l l i n g by biological fluids. T h e r m o d y n a m i c c o m p a t i b i l i t y testing refers to the d y n a m i c and e q u i l i b r i u m s w e l l i n g behavior of biomaterials. O t h e r properties related to the structure of the candidate biomaterials i n c l u d e t h e r m a l , electrical, and tribological properties. Analysis of solute diffusion can be obtained by p o r o s i m e t r y (for m i c r o s c o p i c pores) and by diffusion/permeation experiments (for molecular-size structures of entangled or cross-linked chains). M e c h a n i c a l properties can be d e t e r m i n e d by a variety of standard tests, u n d e r both static and d y n a m i c l o a d i n g . A c c e l e r a t e d aging tests are necessary for long-term i m p l a n t a t i o n applications. Surface characterization is v e r y important i n the d e v e l o p m e n t of b l o o d compatible biomaterials, since the surface characteristics of the p o l y m e r have b e e n l i n k e d to p o l y m e r - t i s s u e a n d p o l y m e r - b l o o d interactions. F u r t h e r i n formation on surface characterization of biomaterials can be f o u n d elsewhere (20,

21).

Evaluation of Toxicity of Polymers as Biomaterials A m o n g various e x p e r i m e n t a l investigations, toxicity studies of potential biomaterials are r e q u i r e d to evaluate the ability of these systems to r e m a i n biologically inert d u r i n g i m p l a n t a t i o n or w h i l e i n contact w i t h biological fluids. Table III summarizes a series of r e c o m m e n d e d toxicity tests that are r e p o r t e d i n recent guidelines of N I H (20).

Toxicity experiments must be

p e r f o r m e d at logical points d u r i n g the b i o m a t e r i a l d e v e l o p m e n t . L e v e l I includes tests that are necessary for evaluating c o m m o n l y used biomaterials, that is, p o l y m e r s that were b i o c o m p a t i b l e i n previous investigations. L e v e l II tests are r e c o m m e n d e d for the assessment of new, m o d i f i e d , and p r e viously untested p o l y m e r s .


470



Table III. Toxicity Evaluation of Polymers for Biomedical Applications Level I: Initial Screening and Quality Control of Polymers • A g a r overlay response o f materials • A g a r overlay response o f materials extracts • I n h i b i t i o n o f c e l l g r o w t h b y water extracts o f materials • I n t r a d e r m a l i r r i t a t i o n test for materials extracts a n d leachable ponents

com-

Level II: Initial Evaluation of Novel Biomaterials • Tissue c u l t u r e test o n materials • Tissue c u l t u r e test o n materials extracts • C e l l g r o w t h i n contact w i t h test materials • H e m o l y t i c activity test • Intramascular i m p l a n t a t i o n o f materials • Test o f osmotic fragility o f erythrocytes • I n v i t r o m u t a g e n i c i t y test • Test o f m a t e r i a l extracts b y p e r f u s i o n o f isolated rabbit heart Source: Adapted from Ref. 20.

Tests assessing the carcinogenicity, teratogenicity, and mutagenicity of biomaterials are d e s c r i b e d i n recent reviews ( 3 , 2 0 , 2 2 ) . D u e to the c o m p l e x ity of these tests, a w i d e range of e x p e r i m e n t a l protocols can be f o l l o w e d , although none of these protocols is w e l l e n o u g h established to be r e c o m m e n d e d as a standard test. H o w e v e r , p o l y m e r i c materials d e s i g n e d i n t e l ligently a n d fabricated for m e d i c a l applications s h o u l d have little t r o u b l e passing these toxicity tests, since the techniques that can be used for r e d u c ing leachable components have b e e n w e l l established. F i n a l l y , manufacture of conventional o r novel biomaterials is not c o m plete w i t h o u t p r o p e r sterilization. S t e r i l i z a t i o n methods i n c l u d e heat, steam, irradiation, and gaseous treatment (23,24). H e a t and steam sterilization can be r e c o m m e n d e d for p o l y m e r s that are relatively stable and do not exhibit d i m e n s i o n a l changes i n the range 3 0 ° - 1 5 0 ° C . Radiation sterilization at l o w dose levels (usually 0 . 5 - 2 M r a d s ) may be used for many h y d r o p h i l i c b i o materials. H o w e v e r , radiation can cause major structural changes of the biomaterial, such as c r o s s - l i n k i n g o r degradation. Gaseous sterilization e m ploys ethylene oxide, f o r m a l d e h y d e , and other sterilants. Residues o f some of these s t e r i l i z i n g agents o n biomaterials have caused m o n o n u c l e a r c e l l l e u k e m i a a n d malignant neoplasms i n laboratory animals. T h e r e f o r e , the p r o p e r choice o f sterilization m e t h o d for a candidate p o l y m e r for b i o m e d i c a l applications depends o n careful o p t i m i z a t i o n of a variety of effects of the m e t h o d on the c h e m i c a l , m e c h a n i c a l , and surface properties of biomaterials. Various tests for evaluating sterility o f biomaterials are s u m m a r i z e d i n an N I H report (20).


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Conclusions I m p o r t a n t considerations i n the d e v e l o p m e n t of n e w o r m o d i f i e d p o l y mers f o r b i o m e d i c a l applications i n c l u d e m a c r o m o l e c u l a r structure, p h y s ical, c h e m i c a l , a n d b i o l o g i c a l p r o p e r t i e s , a n d behavior o f the biomaterials i n the p h y s i o l o g i c a l e n v i r o n m e n t . A l t h o u g h systematic investigation of p o l y m e r properties is h i g h l y r e c o m m e n d e d before a particular use, the suggested Downloaded by KTH ROYAL INST OF TECHNOLOGY on November 16, 2015 | http://pubs.acs.org Publication Date: July 27, 1982 | doi: 10.1021/ba-1982-0199.ch028

tests may b e m i n i m i z e d i n t h e case of p r e v i o u s l y tested and w e l l - d o c u m e n t e d biomaterials. I n g e n e r a l , t h e process o f selection, design, and evaluation of n e w biomaterials is l o n g a n d painstaking. Just one example, indicative of the synthetic t h i n k i n g a n d o p t i m i z a t i o n o f properties r e q u i r e d i n the design of n e w b i o m a t e r i a l s , is the r e c e n t l y r e p o r t e d w o r k o n the d e v e l o p m e n t o f collagen-based materials for s k i n r e p l a c e m e n t (8,25). S i m i l a r experience can be o b t a i n e d b y s t u d y i n g the case histories of d e v e l o p m e n t of cellulose acetate dialysis m e m b r a n e s , p o r o u s p o l y t e t r a f l u o r o e t h y l e n e vascular grafts, e t h y l e n e - v i n y l acetate c o p o l y m e r s for controlled-release

o f drugs, poly(2-hy-

d r o x y e t h y l methacrylate) ( P H E M A ) for soft therapeutic contact lenses, etc. A w i d e range o f p o l y m e r i c materials has b e e n p r o p o s e d , tested, o r actually u s e d for b i o m e d i c a l applications. Table I V attempts to s u m m a r i z e

Table IV. Commercially Available and Potentially Useful Blood-Compatible Polymers Polymer Group H y d r o g e l s ( W a t e r - s w o l l e n networks) PHEMA O t h e r n o n i o n i c hydrogels P o l y e l e c t r o l y t e networks I n t e r p e n e t r a t i n g networks Polyurethanes Segmented polyurethanes Segmented polyether-polyurethanes P o l y u r e t h a n e - b a s e d b l o c k c o p o l y m e r s a n d blends

References 26, 27 28-30 27, 31 32, 33 3 34-37 38 39-40

Heparinized polymers P o l y o l e f i n - b a s e d systems Hydrogels Other polymers

41, 42 4 3 , 44 45

Fibrinolytic enzyme-immobilized polymers

46, 47

M o d i f i e d collagen

48

Silicone elastomers

3

P y r o l i t i c carbons

49

O t h e r p o l y m e r i c systems Polyesters causing p s e u d o n e o i n t i m a formation P o l y p h o s p h a z e n e s (inorganic p o l y m e r s )

50 51


472


major categories of polymeric materials, which are either moderately suc cessful or promising for blood-compatible applications. Major references reviewing the structure and biocompatibility of these polymers are included also. This list only indicates the complexity of the problem of development of biomaterials and of the great potential of polymers in biomedical applica


tions.

Acknowledgment The author thanks B. D . Ratner for helpful suggestions.

Literature Cited 1. Park, J. B. "Biomaterials," Plenum: New York, 1979. 2. Szycher, M . ; Robinson, W. J. "Synthetic Biomedical Polymers," Technomic: Westport, Connecticut, 1980. 3. Bruck, S. D. "Properties of Biomaterials in the Physiological Environment," CRC: Boca Raton, Florida, 1980. 4. Bruck, S. D. "Blood Compatible Synthetic Polymers," Thomas: Springfield, Illinois, 1974. 5. Bruck, S. D. Ann. N.Y. Acad. Sci. 1977, 283, 332. 6. Langer, R. Chem. Eng. Commun. 1980 6, 1. 7. Langer, R.; Peppas, Ν. A. Biomaterials (Gildford, Engl.), 1981, 2, 195. 8. Yannas, I. V . ; Burke, J. F. J. Biomed, Mater. Res. 1980, 14, 65. 9. Peppas, Ν. Α.; Benner, R. E., Jr. Biomaterials (Gildford, Engl.) 1980, 1, 158. 10. Refojo, M . F. In "Synthetic Biomedical Polymers," Szycher, M . ; Robinson, W. J., Jr., Eds.; Technomic: Westport, Connecticut, 1980; p. 171. 11. Hodge, J. W., Jr.; Wade, C. W. R. In "Synthetic Biomedical Polymers," Szycher, M . ; Robinson, W. J., Jr., Eds.; Technomic: Westport, Connecticut, 1980; p. 201. 12. Brauer, G. M . Polym. Plast. Technol. Eng. 1977, 9, 87. 13. Grant, A. Br. Polym. J. 1978, 10, 241. 14. Ratner, B. D . ; Hoffman, A. S. In "Synthetic Biomedical Polymers," Szycher, M . ; Robinson, W. J., Jr., Eds.; Technomic: Westport, Connecticut, 1980; p. 133. 15. Odian, G. "Principles of Polymerization," McGraw Hill: New York, 1981. 16. Hoffman, A. S. et al. Chapter 6 in this book. 17. Rabek, J. F. "Experimental Methods in Polymer Chemistry," Wiley: New York, 1980. 18. Fava, R. Α., Ed. "Methods in Experimental Physics: Polymers," Academic: New York, 1980; Vol. 16A, 16B, 16C. 19. Ferry, J. D. "Viscoelastic Properties of Polymers," Wiley: New York, 1981. 20. Keller, K. H.; Andrade, J. D.; Baier, R. E.; Dillingham, E. O.; Ely, J.; Altieri, F. D . ; Morrisey, B. W.; Klein, E. "Guidelines for Physicochemical Character ization of Biomaterials," National Heart, Lung, Blood Institute, N.I.H. pub. No. 80-2186, 1980. 21. Ratner, B. D. Chapter 2 in this book. 22. Autian, J. Artif. Organs, 1977, 1, 53. 23. Bruck, S. D. J. Biomed. Mater. Res. 1971, 5, 139. 24. Block, B.; Hastings, G. W. "Plastics in Surgery"; Thomas: Springfield, Illinois, 1967. 25. Yannas, I. V. et al. Chapter 29 this book. 26. Ratner, B. D . ; Hoffman, A. S. In "Hydrogels for Medical and Related Applica tions," Andrade, J. D . , Ed.; ACS Symposium Series, No. 31, American Chem ical Society: Washington, D C , 1976; p. 1.



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