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Synthesis, Physicochemical and Surface Characteristics of Polyurethanes

Synthesis, Physicochemical and Surface Characteristics of Polyurethanes

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6. Developments in Design and Synthesis

of Biostable Polyurethanes ................................................................. 160

Pathiraja A. Gunatillake, Gordon F. Meijs, and Simon J. McCarthy

6.1 Introduction ................................................................................ 160

6.2 Biostability and Polyurethane Structure ....................................... 161

6.3 Development of Degradation-Resistant Polyurethanes ................. 163

6.4 Conclusion .................................................................................. 170

7. Surface Modification of Polyurethanes ............................................... 175

Hans J. Griesser

7.1 Introduction ................................................................................ 175

7.2 Rationale for Surface Modification .............................................. 176

7.3 Common Pitfalls in Surface Modification .................................... 178

7.4 Surface Modification Types ......................................................... 185

7.5 Synthetic Functionalization with Chemical Groups ..................... 186

7.6 Plasma Surface Modifications ...................................................... 188

7.7 Surface Immobilization of Biologically Active Molecules ............. 191

7.8 “Non-fouling” Polyurethane Surfaces .......................................... 200

7.9 Coatings for Cell Colonization .................................................... 205

7.10 Surface Modifying Additives and End Groups ........................... 206

7.11 Other Surface Modifications ...................................................... 208

7.12 Summary and Conclusions ........................................................ 209

8. Biomedical Applications of Polyurethanes .......................................... 220

Mylène Bergeron, Stéphane Lévesque, and Robert Guidoin

8.1 Introduction ................................................................................ 220

8.2 Polyurethanes for Cardiovascular Applications ............................. 220

8.3. Polyurethane for Reconstructive Surgery ..................................... 235

8.4. Gynecology and Obstetrics ......................................................... 240

8.5 Conclusion .................................................................................. 241

9. The Future of Polyurethanes .............................................................. 252

Robert Guidoin and Hans J. Griesser

9.1. Cardiovascular Applications ........................................................ 254

9.2. Reconstructive Surgery ............................................................... 256

9.3. Gynecology and Obstetrics ......................................................... 257

9.4. Organ Regeneration in Tissue Engineering ................................. 258

9.5. Medical Supplies ......................................................................... 258

9.6. Summary .................................................................................... 259

Abbreviations ..................................................................................... 261

Index .................................................................................................. 265



EDITORS

Patrick Vermette

Hans J. Griesser

CSIRO Molecular Science

Clayton South, Australia

The Cooperative Research Centre

for Eye Research and Technology (CRCERT)

The University of New South Wales

Sydney, Australia

e-mail: hans.griesser@molsci.csiro.au

Chapters 2, 3, 5, 7, 9

Gaétan Laroche

Robert Guidoin

Institut des Biomatộriaux du Quộbec,

Hụpital St-Franỗois d'Assise

Centre Hospitalier Universitaire de Québec

Québec, Canada

e-mail: gaetan.laroche@chg.ulaval.ca

robert.guidoin@crsfa.ulaval.ca

Chapters 1, 3, 4, 8, 9



CONTRIBUTORS

Sahar Al-Malaika

Polymer Processing and Performance

Research Unit

Aston University

Birmingham, England, U.K.

e-mail: S.Al-Malaika@aston.ac.uk

Chapter 2



Mylène Bergeron

Institut des Biomatộriaux du Quộbec

Hụpital St-Franỗois d'Assise

Centre Hospitalier Universitaire de

Quộbec

Chapter 8



Martin Castonguay

Institut des Biomatộriaux du Quộbec

Hụpital St-Franỗois d'Assise

Centre Hospitalier Universitaire de

Quộbec

Quộbec, Canada

e-mail:

martin.castonguay@crsfa.ulaval.ca

Chapter 1



Nathalie Dube

Institut des Biomatộriaux du Quộbec

Hụpital St-Franỗois d'Assise

Centre Hospitalier Universitaire de

Québec

Départment de Chirurgie

Université Laval

Sainte-Foy, Québec, Canada

e-mail: ndube@mediom.qc.ca

Chapter 2



Pathiraja Gunatillake

Cooperative Research Centre for Cardiac

Technology

CSIRO Molecular Science

Clayton South, Victoria, Australia

e-mail:

pathiraja.gunatillake@molsci.csiro.au



Gordon F. Meijs

Cooperative Research Centre for Cardiac

Technology

CSIRO Molecular Science

Clayton South, Victoria, Australia

e-mail: gordon.meijs@molsci.csiro.au

Chapter 6



Chapters 2, 6



Jeffrey T. Koverstein

Institute of Materials Science

Department of Chemical Engineering

and Applied Chemistry

New York, New York, U.S.A.

e-mail: jk1191@columbia.edu

Chapter 1



Stéphane Lévesque

Institut des Biomatộriaux du Quộbec

Hụpital St-Franỗois d'Assise

Centre Hospitalier Universitaire de

Quộbec

Dộpartment de Chirurgie

Université Laval

Sainte-Foy, Québec, Canada

e-mail: slev@mediom.qc.ca

Chapters 2, 5, 8



Yves Marois

Institut des Biomatộriaux du Quộbec

Hụpital St-Franỗois d'Assise

Centre Hospitalier Universitaire de

Quộbec

Quộbec, Canada

e-mail: ymarois@hotmail.com

Chapter 4



Simon J. McCarthy

Cooperative Research Centre for Cardiac

Technology

CSIRO Molecular Science

Clayton South, Victoria, Australia

Chapter 6



Denis Rodrigue

Départment de Génie Chimique

Université Laval

Québec, Canada

e-mail: drodrigu@gch.ulaval.ca

Chapter 2



Ze Zhang

Institut des Biomatộriaux du Quộbec

Hụpital St-Franỗois d'Assise

Centre Hospitalier Universitaire de

Québec

Québec, Canada

e-mail: ze.zhang@chg.ulaval.ca

Chapter 1



PREFACE



P



olyurethanes form a large family of polymeric materials with an enormous

diversity of chemical compositions and properties. They have found wide

spread application in a number of technological areas and a range of commodity products, such as polymers for clothing (Lycra® being a well-known example), automotive parts, footwear, furnishings, construction, and in paints and

coatings for appliances. The wide range of properties that can be achieved with

polyurethane chemistry also attracted the attention of developers of biomedical devices who saw promise in, for instance, the mechanical flexibility of these materials

combined with their high tear strength. Thus, polyurethanes were tried in a number

of biomedical applications, as discussed in this book. However, a number of drawbacks

quickly became apparent, most importantly their unexpected lack of stability in the

living host environment. Early studies were mostly done with “available” polyurethanes developed for quite different uses; hence, in retrospect, their failure to meet

the requirements of biomedical applications may not be altogether surprising. The

clinical findings of adverse consequences with early polyurethanes led to a large

number of studies aiming to elucidate the reasons for polymer degradation in the

biomedical environment, and the synthesis of customized polyurethanes guided by

biomedical considerations. This work is still continuing; promising improved materials have been developed and are now undergoing detailed testing, and this raises

the possibility of commercialization in the near future of the “ultimate” biomedical

polyurethane(s) optimized for specific biomedical requirements.

Another avenue towards improving the biomedical performance of polyurethanes,

which is of more recent origin than synthetic approaches, comprises the application of

surface modification or coating technologies. This type of approach has been featured

in a substantial number of studies. It offers the promise of enabling use of an “available”

polyurethane whose biomedical response has been improved by the alteration of its

surface chemistry.

The literature on the development and evaluation of polyurethanes intended

for biomedical applications is enormous and, on account of its multidisciplinary

nature, spread over a wide range of primary scientific and applied technological

journals. Biomedical polyurethanes also are featured in many patents. Of course the

subject of biomedical polyurethanes has been covered in many reviews, as well as an

excellent book (Lelah MD, Cooper SL. Polyurethanes in Medicine. Boca Raton, FL:

CRC Press, 1986); these previous surveys of the field, or parts thereof, are invaluable in conveying the history and status (at the time) of progress on applying polyurethanes to various biomedical applications. Yet, the field has over the last few

years continued to progress rapidly, and several conceptually new polyurethanes

have recently become available for detailed clinical testing. In addition, the application of surface modification and coating techniques, the use of polymer additives

and their effects on the biological response of polyurethanes and the development

of novel biostable polyurethanes were surveyed only very briefly in the most recent

book (Lamba NMK, Woodhouse KA, Cooper SL. Polyurethanes in Biomedical Applications. Boca Raton, FL: CRC Press LLC, 1998) dedicated to these materials.



Hence, we perceived a need for an up-to-date text, and we hope that the present work will

meet this need and convey information to both the novice and the expert in the field.

While presuming some background knowledge of biomaterials science, for the reader

who is a relative novice to the field we present and discuss a number of concepts that are

relevant to biomedical polyurethanes, in the hope of conveying the multifaceted task that

faces the developers of improved biomedical materials. Such materials must meet a diverse

number of criteria, some of which may be poorly defined. Of course some of these issues,

such as the question of what is “biocompatibility” and how one assesses it, applies to other

classes of biomedical materials as well. An exhaustive discussion of all aspects of biomedical requirements, tests, and responses obviously is beyond the scope of this work, and the

reader is encouraged to consult standard textbooks on biomaterials science, such as:

• Ratner BD, Hoffman AS, Schoen FJ, Lemons JE, Eds. Biomaterials Science: An

Introduction to Materials in Medicine. San Diego: Academic Press, 1996.

• Von Recum AF, Ed. Handbook of Biomaterials Evaluation. New York: Macmillan,

1986.

• Silver FH, Doillon C. Biocompatibility: Interactions of Biological and Implanted

Materials, Vol 1—Polymers. New York: VCH Publisher, 1989.

One challenge we faced in writing and editing this book is the wide range of technological fields that apply to the development and testing of biomedical materials. We

approached this challenge by assembling editors and authors from diverse technological

backgrounds — and geographical locations. Only once did the four editors meet in one

room to assess whether the contents might end up forming a cohesive unit. Nor did we

have an opportunity to meet all contributors in person in the course of writing. However,

modern communication technology has eliminated the obstacles of geographical location,

and all of us are richer for the experience of collaborating on his book across oceans,

different mother tongues, and different cultural backgrounds. There were misunderstandings, delays, and mishaps, but above all an overriding sense of goodwill and collaboration

that so much characterizes the international community of scientists.

A further challenge in writing and editing this book lies in the vague nature of some

of the terminologies used by many researchers. A prominent example is the term

“biocompatibility”. Innumerable biomaterials publications declare the development of

biocompatible materials, and polyurethanes are well represented in this. Why, then, is

development and testing still ongoing? If those publication titles were to be true in their

literal meaning, the challenge of developing the “ultimate” biomedical polyurethane would

appear to have been solved long ago; as a corollary, there would be no need for this book.

It is also regrettable that many researchers fail to acknowledge that “biocompatibility”

requirements may differ considerably for different biomedical applications. Thus, a polyurethane that performs well in one host body location may be unsuitable for another

biomedical purpose. Likewise, a number of publications report “blood-compatible (or

hemocompatible) polyurethanes”. Why is it, then, that these materials have not led to the

fabrication of “perfect” cardiovascular devices and efforts are continuing on improving the

hemocompatibility of these materials? Is it perhaps because informed researchers and device

manufacturers realize the true value of such claims based on tests that do not fully replicate



the real in vivo requirements? Regrettably, though, this situation leads to confusion for

novices and should be addressed.

Language is a wonderful communication tool but needs to be used with precision.

The term “biocompatible” means exactly that, i.e., full compatibility with all requirements; it does not mean “almost biocompatible” or “more compatible than polymer X”. It

is a pity that so many researchers use loose, ill-defined terminology instead of bringing

precision to their reports and declaring an improvement in performance in this-and-that

application as measured by this-and-that test. While of course such details are contained

in the body of reports, the use of unqualified, broad, imprecise statements in abstracts and

conclusions sections should be discouraged.

Having said this, we admit to using in this book terminology that is not always well

defined or implicitly clear in its meaning. Some terms have widely accepted usage in the

field, and we do rely in many instances on an implicit understanding of the contents and

limits of such usage. We beg the reader’s indulgence for such compromises and any confusion

and uncertainty we may bring about with our writing.

We hope that this book will prove to be of value to readers from various technical

backgrounds. Research and development of biomedical materials requires the expertise of

materials scientists, engineers, chemists, clinicians, surface scientists, biologists, and others,

pooled into a collective effort. It is difficult to structure a text such that it addresses the

needs of such a diverse audience and starts at realistic levels of pre-existing knowledge.

Those who have worked in the biomaterials field for a while may wish to skip many

sections, while others will undoubtedly feel that we left out some useful background

information. We do hope that every reader will derive some benefit.

Editing this book has been a challenging but most rewarding task. We thank all the

contributing authors for their efforts and timeliness; it has been a pleasure working with

you. We also express our sincere thanks to the reviewers who graciously consented to

donate their time for the careful review of draft Chapters and whose suggestions, much

appreciated by the authors, led to substantial improvements. We wish to acknowledge

partial financial support by the Fonds pour la Formation des Chercheurs et l’Aide à la Recherche (Fonds FCAR, Québec, Canada), the Cooperative Research Centre for Eye Research

and Technology, (Sydney, Australia) and the National Sciences and Engineering Research

Council of Canada (NSERC, Canada). Finally, we thank our loved ones for their

understanding and patience during the hours we spent on this book. It is to them that we

dedicate this work.

Patrick Vermette

Hans J. Griesser

Gaétan Laroche

Robert Guidoin

Clayton, Australia

Québec, Canada

January 2000



CHAPTER 1



Synthesis, Physicochemical and Surface

Characteristics of Polyurethanes

Martin Castonguay, Jeffrey T. Koberstein, Ze Zhang, and Gaétan Laroche



1.1 Introduction



T



his Chapter constitutes the starting point that will bring the reader to the other subjects

discussed in this book as, for example, the biological response and biostability related to

polyurethanes (PUs) are primarily driven at the first steps with their Synthesis and

processing. Many literature reviews have been published about the synthesis, phase separation,

mechanical, chemical, and surface characteristics of polyurethanes. However, it was the authors’

feeling that the concepts lying behind these subjects were often presented as having something

to do with black magic. First, the synthesis of polyurethanes is most of the time described as a

presentation of the various soft segments, hard segments and chain extenders that are currently

used for the preparation of theses polymers. In the present Chapter, many efforts were put in

presenting the experimental steps required to obtain polyurethanes, as well as the problems that

may be encountered during the synthesis. Second, the importance of selecting the appropriate

constituents and postsynthesis thermal treatments are also emphasized in relationship with the

mechanical and chemical properties that are expected. In connection with this section, we have

also compared the mechanical characteristics of PUs with other currently used biomedical polymers. Finally, the nature of the polyurethane composition implies a wide diversity of surface

characteristics, which in turn, are of prime importance when dealing with an eventual use of PUs

as biomaterials. Therefore, the means that should be put forward to modulate the PUs surface

composition as well as its significance with the biological response are presented.



1.1.1 Why Are Polyurethanes Different from Other Currently Used

Polymers?

Most of the polymers manufactured in industry possess a fairly simple chemical structure

as they are synthesized from one or two monomers therefore leading to the formation of

homopolymers or copolymers. Examples of these polymers are poly(ethyleneterephtalate) (PET),

poly(tetrafluoroethylene) (PTFE), poly(styrene), poly(ethylene), poly(propylene),

poly(butadiene), etc. On the other hand, polyurethanes possess more complex chemical structures that typically comprise three monomers: a diisocyanate, a macroglycol (which is an oligomeric macromonomer) and a chain extender. Because of the three “degrees of freedom” that are



Biomedical Applications of Polyurethanes, edited by Patrick Vermette, Hans J. Griesser,

Gaétan Laroche and Robert Guidoin. ©2001 Eurekah.com.



2



Biomedical Applications of Polyurethanes



available when considering the synthesis of a polyurethane, one may obtain a virtually infinite

number of materials with various physicochemical and mechanical characteristics. Due to this

unique composition, the structure of polyurethanes is quite different from that of other polymers. In fact, PU elastomers usually show a two-phase structure in which hard segment-enriched

domains are dispersed in a matrix of soft segments. The hard segment-enriched domains are

composed mainly of the diisocyanate and the chain extender, while the soft segment matrix is

composed of a sequence of macroglycol moieties. For this reason, polyurethanes are often referred

as segmented block copolymers. This particular molecular architecture, as well as the intrinsic

properties of each ingredient used for the synthesis of polyurethanes, explained the unique

characteristics of this class of materials when compared to other polymers.

Despite what is claimed in the literature, polyurethanes found a niche in biomedical

applications mainly because of their interesting mechanical properties rather than for their

biological response. Indeed, most of the studies related to the use of polyurethanes as biomaterials

state that they are both “biocompatible” and “hemocompatible” despite the fact that several

publications have clearly demonstrated that PUs degrade in the human body (Chapter 5) and

are not more blood compatible (Chapter 4) than the other materials currently used in vascular

surgery. However, it is clear that polyurethanes are characterized by unique mechanical properties

that may be very useful for particular applications, especially when fatigue resistance is required.



1.2 Chemistry

1.2.1 Polyurethane Structure

Polyurethane is the general name of a family of synthetic copolymers that contain the

urethane moiety in their chemical repeat structure (Fig. 1.1).

Since polyurethane was first synthesized in 1937 by Otto Bayer and co-workers,1 it has

achieved a variety of applications including elastomers, foam, paint, and adhesives. Such diversity

of applications originates from the tailorable chemistry of polyurethanes, i.e., the chemical composition of polyurethanes can be tailored, by choosing different raw materials and processing

conditions, to accommodate many specific requirements. As a family of biomaterials, polyurethanes

are most frequently synthesized as segmented block copolymers. In the following, we are going to

focus on the basic chemical reactions, raw materials, and synthesis of segmented polyurethanes.



1.2.2 Basic Chemical Reactions

Segmented polyurethanes can be represented by three basic components in the following

general form:

P-(D(CD)n-P)n

Where P is the polyol, D is the diisocyanate and C is the chain extender. Polyol, or the

so-called soft segment, is an oligomeric macromonomer comprising a “soft” flexible chain terminated by hydroxyl (-OH) groups. The chain extender is usually a small molecule with either

hydroxyl, or amine end groups. The diisocyanate is a low molecular weight compound that can

react with either the polyol or chain extender, leading to the interesting segmented structure

illustrated above. In linear polyurethanes, the three components have a functionality of two. If

a branched or crosslinked material is desired, multifunctional polyols, isocyanates, and sometimes chain extenders can be incorporated into the formulation. Due to the statistical nature of

the copolymerization, polyurethanes have both a distribution in total molecular weight and a



Synthesis, Physicochemical and Surface Characteristics of Polyurethanes



3



Fig. 1.1. Urethane linkage.



distribution in the hard segment sequence length, those copolymer sequences denoted as

D(CD)n, that follow essentially a most probable distribution.

The principle chemical reaction involved in the synthesis of polyurethanes is the

urethane-forming reaction, i.e., the reaction between isocyanate and hydroxyl groups (Fig. 1.2a).

Because this is a nucleophilic addition reaction, it is catalyzed by basic compounds such as

tertiary amines and by metal compounds such as organotin. Urethane formation is actually an

equilibrium reaction; the presence of catalyst therefore also increases the rate of the back reaction at high temperatures.

Another important basic reaction is the chain extension reaction which occurs between chain

extender (diol or diamine) and isocyanate. When a diol is used as chain extender, urethane will be

formed according to Figure 1.2a while urea will be formed according to Figure 1.2b if diamine is used.

Isocyanate not only reacts with primary amine, but can also react with secondary amine

such as the N-H in urethane or urea groups, even though the rate of reaction is much lower

compared with that of the primary amine. The nucleophilic addition nature of the reaction

with the secondary amine remains the same and so the chemical structure of the products

(allophanate and biuret, with respect to the reaction with urethane and urea) can be easily

predicted according to Figure 1.2. Allophanate or biuret formation leads to branching and

crosslinking and is favored when excessive isocyanate is present.

In addition to the above two basic reactions, the reaction of water with isocyanate must also

be mentioned. Because isocyanate is so active, it reacts with active or acidic hydrogen almost

instantly. This two-step reaction with water has become the most important side reaction that

should be avoided or minimized, except if a foam or high urea content is desired (Fig. 1.3).

The amine groups formed during the second step will further react with remaining isocyanate

to produce urea groups. The carbon dioxide formed (Fig. 1.3b) can be used to produce a

polyurethane foam. The net effect of this reaction on the ratio of reactants is the consumption

of one unit of isocyanate and the formation of one amine group. Further reaction of the amine

group with an isocyanate leads to the formation of an urea.



1.2.3 Raw Materials

Segmented polyurethane is composed of three raw material reactants: polyol, diisocyanate,

and chain extender (diamine or diol). The final properties of the polyurethane produced are

largely dependent on the chemical and physical nature of these three building blocks.



1.2.3.1 Polyol

Conventional polyols are usually a polyether (with a repeating structure of -R-O-R’-)

or a polyester (with repeating structure of -R-COO-R’-), with chain ends terminated by

hydroxyl groups. Unlike diisocyanate compounds and chain extenders, a polyol is oligomeric with a molecular weight normally ranging from a few hundred to a few thousand.

At room temperature, polyols can be liquid or solid (wax-like), depending on the

molecular weight. Due to their aliphatic structure and low intermolecular interaction,



4



Biomedical Applications of Polyurethanes



Fig. 1.2. Chain extension reaction occurs between chain extender (diol or diamine) and isocyanate. When a

diol is used as chain extender, (a) urethane will be formed, while (b) urea will be formed if diamine is used.



Fig. 1.3. The reaction of water with isocyanate must also be considered. Because isocyanate is so active, it reacts

with active or acidic hydrogen almost instantly. This two-step reaction with water has become the most important

side reaction that should be avoided or minimized, except if a foam or high urea content is desired.



particularly the abundant ether bonds, polyol molecules rotate and bend easily and are

therefore soft materials. Consequently, the polyol sequence of polyurethane-segmented

block copolymers is referred to as the soft segment. New polyol soft segment materials

including polyalkyl,2 polydimethylsiloxane3 and polycarbonate4 have also been developed

to fulfil the critical and specific requirements intrinsic to biomedical and industrial

applications. The chemical structures of four types of representative polyols are illustrated in Figure 1.4. Other types can be easily found in the literature. Some novel polyols

are presented in Chapter 6.



1.2.3.2 Isocyanate

The most important isocyanate used in polyurethane manufacture is diisocyanate, containing

two isocyanate groups per molecule. These two functional groups work to join together (by

chemical reaction) two other molecules (polyol or chain extender) to form a linear chain. When

the functionality is greater than two, a branch site is formed between the molecules, leading to

network or crosslink formation. Diisocyanate can be either aromatic or aliphatic, as represented by 4,4'-diphenylmethane diisocyanate (MDI) and hydrogenized MDI (HMDI). Another



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