HydrophilicâHydrophobic Domain Polymer Systems - ACS Publications

Chapter 30 Hydrophilic—Hydrophobic Domain Systems

Polymer

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on June 2, 2015 | http://pubs.acs.org Publication Date: July 18, 1991 | doi: 10.1021/bk-1991-0467.ch030

Kishore R. Shah Ethicon, Inc., Somerville, NJ 08876

It is the objective of this paper to review the chemistry of hydphobically modified water soluble and other hydrophilic polymer systems, and their biocompatibility for potential use in biomedical and pharmaceutical applications. The systems reviewed include block copolymers, graft copolymers, polymer blends, and networks which exhibit hydrophilic/hydrophobic microphase domain structures. Enhanced biocompatibility and mechanical strength appear to be a general characteristic of such systems as compared to single phase hydrophilic polymers. Water soluble polymers play a very important role in biological systems and are of considerable interest in industrial, biomedical, and pharmaceutical applications. It is the purpose of this paper to review the chemistry of hydrophobically modified water soluble and other hydrophilic polymer systems, and their biocompatibility for potential use in biomedical and pharmaceutical applications. The hydrophobically modified polymer systems include block copolymers, graft copolymers, polymer blends, and networks which exhibit hydrophilic/hydrophobic microphase domain structures. Covalent and ionically crosslinked networks of hydrophilic polymers, commonly referred to as hydrogels in their hydrated state, have been known for a long time and have found a number of biomedical applications, such as soft contact lenses, wound management, and controlled drug delivery. The methods of preparation of these hydrogels are subject to the constraints imposed by their thermosetting nature, and consequently they do not enjoy the benefits of thermoplastic processing. In addition, such hydrogels are mechanically weak, which further limits their usefulness. On the other hand, the hydrophobic/hydrophilic domain polymer systems which hydrate to form hydrogels are of special interest on account of their unique morphological features which greatly influence their properties. The hydrophobic domains in such systems behave as thermally labile pseudocrosslinks. Their two-phase hydrophobic/hydrophilic nature is also responsible for their enhanced 0097-6156/91/0467-0468$06.00/0 © 1991 American Chemical Society

In Water-Soluble Polymers; Shalaby, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

30.

Hydrophilic—Hydrophobic

SHAH

Domain

Polymer

469

Systems

biocompatibility and superior mechanical strength as compared to that of covalently crosslinked hydrophilic polymers. Few such systems have been reported to date, and the ones reported are of relatively recent origin. Some of these polymer systems will be discussed here.


B L O C K COPOLYMERS Okano, etal. (1,2) have prepared A - B - A type block copolymers of 2-hydroxyethyl methacrylate, H E M A (A) and styrene, St (B) by condensation of aminosemitelechelic-oligo H E M A (Prepolymer A) with isocyanate-telechelic-oligo-St (Prepolymer B) under the condition of [NH ]/[NCO] = 1.2 (synthetic scheme I). The Prepolymer A , in turn was prepared by free radical initiated oligomerization of H E M A in the presence of 2-aminoethanethiol, used as a chain transfer agent. The Prepolymer Β was prepared by photooligomerization of styrene initiated by ρ,ρ'-diisocyanate diphenyl disulfide. 2

CH

ι

3

OCN-

H—(C—CH2) —S—CHj—CH -NH, r

n

I

W

k

—S—(CHj—CH-

-N=C=0

c=o I ο I CH

2

CH

2

OH CH

3

I

H

- ( C - C H 2 ) - S — ( C H ) - -NH—CO—ΝΉn

2

n

I

CH

C=0

I

H—(C—CH ) —S 2

I

c=o

2

I ο I

I

CH

I

(CHi)

3

I

I

ο I

CH

NH—CO—NH

2

I OH

Scheme I

CH

2

CH

2

OH


n

470

WATER-SOLUBLE POLYMERS


The wettability (Figure 1) of the block copolymers, as measured by cosine of the contact angle of water on the copolymer film, increased with an increase in the mole fraction of H E M A . However, the block copolymer was less wettable than a random copolymer of similar composition because of the presence of hydrophobic domains of polystyrene, which are clearly seen in the transmission electron micrographs (Figure 2). As one would expect, PHEMA-St block copolymers show spherical domains at high and low H E M A weight fractions. Whereas, the 60:40 PHEMA-St block copolymer exhibits lamellar morphology. Hemocompatibility is an important attribute required of materials for many biomedical applications. Hemocompatibility is also one of the more stringent 1.0 f

1

—

0.8

ο

ι 0

• 0.2

^ 0.4

• 0.6

• 0.8

1 1.0

HEMA mole fraction in copolymer

Figure 1: Relation between wettability and copolymer composition: ( φ ) P H E M A - S t ΑΒΑ-type block copolymer system; ( O ) P H E M A - S t cooligomer system. (Reprinted with permission from réf. 1. Copyright 1978 Wiley.)

Figure 2: Electron micrographs of P H E M A - S t ΑΒΑ-type block copolymer films cast from D M F at 40 °C and having H E M A mole fractions of (A) 0.347, (B) 0.608, and (C) 0.884. (Reprinted with permission from Ref. 2. Copyright 1981 Wiley.)


30.

Hydrophilic-Hydrophobic

SHAH

Domain

Polymer

471

Systems


criteria for biological acceptance. It is of interest to note that copolymers having a balance of both hydrophilic and hydrophobic microphase domains were the most blood compatible. Hemocompatibility of the block copolymers was evaluated by their interaction with canine blood, which is known for its ease of coagulation. Minimum platelet adhesion was achieved for the block copolymer having lamellar morphology (0.6 mole fraction H E M A ) (Table I). In general, the block copolymers, having both hydrophilic and hydrophobic domains, were more resistant to platelet adhesion than either homopolymers of H E M A and styrene or their random copolymers. T A B L E I. Platelet Adhesion and Aggregation on the Surface of PHEMA-St Block Copolymer

Samples

H E M A Mole Fraction in Copolymer

Adhesion (%)

Morphology of Platelets

Polystyrene

0

33.8

Aggregation

ΑΒΑ-type block copolymer

0.347

19.7

Round


0.608

11.8

Round


0.884

17.6

Aggregation

PolyHEMA

1

26.8

Aggregation

Random copolymer

0.640

38.5

Aggregation

Glass beads

0

34.7

Spread out

Further evidence of antithrombogenicity of the block copolymer was lack of platelet aggregation and their round morphology, similar to that of native form. Platelet adhesion and aggregation in blood are believed to take place on a layer of proteins which are initially adsorbed on the material surface. Selective protein adsorption on the hydrophobic and hydrophilic domains has been observed (3). The organized surface protein layers on the domains of these block copolymers are believed to be responsible for their improved hemocompatibility. The chemistry, properties, and biomedical applications of multiblock copolymers, having alternating sequences of hydrophobic polyacrylonitrile and hydrophilic derivatives of acrylic acid, has been recently reviewed by S toy (4).



472

WATER-SOLUBLE P O L Y M E R S

The polyacrylonitrile sequences in the block copolymers, ΗΥΡΑΝ, form crystalline domains, and being incompatible they phase separate from the amorphous hydrophilic sequences (Figure 3). The existence of microphase separated crystalline domains was detected by x-ray diffraction (5). Controlled hydrolysis of polyacrylonitrile (PAN), the starting material for the synthesis of ΗΥΡΑΝ copolymers, in a homogenous medium yields P A N polyacrylamide multiblock copolymer. The mechanism of the multiblock copolymer formation first involves formation of a restricted number of amido groups amidst the P A N chains (6). Further hydrolysis involves only those nitrile groups that have an already formed amido group in their proximity, thus resulting in the formation of polyacrylamide blocks separated by P A N blocks. Next, acid catalyzed cyclization at elevated temperatures in an inert atmosphere results in the formation of the precursor, containing glutarimide units, to the ΗΥΡΑΝ copolymers (7). The hydrophilic sequences (soft block) of the ΗΥΡΑΝ copolymers are formed by ring opening of glutarimide units of the precursor copolymer by a base. The chemical composition of the soft blocks can vary depending upon the base employed for opening the glutarimide ring (synthetic scheme II). Depending on the character of the resulting amorphous soft blocks, ΗΥΡΑΝ copolymers can be neutral, cationic, anionic, or amphoteric.

Figure 3: Schematic representation of ΗΥΡΑΝ having permanent crystalline network. The P A N blocks (

HydrophilicâHydrophobic Domain Polymer Systems - ACS Publications

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