Biopolymers: Making Materials Nature's Way

September 1993

OTA-BP-E-102

NTIS order #PB94-107638
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Biopolymers: Making

Materials Nature’s Way-Background Paper, OTA-BP-E-102 (Washington,

DC: U.S. Government Printing Office, September 1993).
Foreword

o

ver the past century, global economic activities have increased more than fiftyfold. This extraordinary growth has raised serious concerns about current patterns of production and consumption. As society has increased its understanding

of the environmental implications of its industrial practices, greater attention

has been given to the concept of sustainable economic systems that rely on renewable

sources of energy and materials. The use of biologically derived polymers—biopoly -

mers-could emerge as an important component of this new paradigm of economic

development.

By transforming agricultural or marine feedstocks, or harnessing the enzymes

found in nature, a new class of renewable, biodegradable, and biocompatible materials is

being introduced. Emerging applications of biopolymers range from packaging to industrial chemicals, to medical implant devices, to computer storage media. In addition to

producing “green” materials with unique physicaI and functional properties, the processes used to create biopolymers could lead to new manufacturing approaches that minimize

energy consumption and waste generation.

As the United States and other countries address a growing list of environmental problems, the possibility of using proteins, carbohydrates, and other biopolymers to

meet the materials requirements of an expanding economy is likely to receive increasing

attention. However, as with other nascent technologies, difficult engineering and economic hurdles stand in the way of biopolymer commercialization efforts. With its current

areas of emphasis, the extensive U.S. public investment in agricultural science and

biotechnology can only be expected to provide modest assistance in overcoming some of

these barriers. Advances in biopolymer technology have been driven principally by

industry and academia, with Federal programs being relatively limited in scope. Because

biopolymers have applications in many different sectors of the economy, their widespread use could have important competitive implications. At present, Japan and the

European Community are sponsoring major programs in biopolymer science and manufacturing. Due to the potential importance of biopolymer technology, the Federal role in

this interdisciplinary field warrants closer scrutiny.

This Background Paper was requested by the Senate Committee on Energy and

Natural Resources. The study provides a basic introduction to biopolymer technology;

profiles some of the more promising polymer materials; reviews research activities in the

United States, Europe, and Japan; and describes the principal technical challenges and

regulatory issues that may affect biopolymer commercialization efforts.

OTA appreciates the assistance provided by its contractors and the many

reviewers whose comments helped to ensure the accuracy of the study.

Roger C. Herdman, Director

.,.

Ill
Reviewers and Contributors

G. Graham AlIan

University of Washington

Norbert Bikales

U.S. National Science Foundation

James Brown

U.S. National Science Foundation

Robert Campbell

U.S. Army Research Office

David Clements

U.S. Department of Agriculture

Congressional Research Service

Yoshiharu Doi

Institute of Physical and Chemical

Research (RIKEN), Japan

Greg Eyring

U.S. Congress

Office of Technology Assessment

Thomas Barrington

Ashland Chemical Co.

Joel Hirschorn

Hirschorn & Associates, Inc.

David Jensen

U.S. Congress

Office of Technology Assessment

David Kaplan

U.S. Army Research

Development & Engineering

Center

Dai Kim

Hiechst-Celanese Research Co.

Gretchen Kolsrud

U.S. Congress

Office of Technology Assessment

Randolf Lewis

University of Wyoming

Bernard Liebler

Health Industry Manufacturers

Association

David Manyak

Adheron Corp.

Michael Marron

Office of Naval Research

Edward Mueller

U.S. Food and Drug Administration

Wolf-Rudiger Muller

Stuttgart University, Germany

Ramani Narayan

Michigan Biotechnology Institute

D.A. Nicholson

Procter and Gamble Co.

Norman Oblon

Oblon, Spivak, McClelland, Maier,

and Neustadt, P.C.

Kevin O’Connor

U.S. Congress

Office of Technology Assessment

Julie Saad

ICI America/Zeneca Bio Products

Steven Scale

Tennessee Valley Authority

Karen Shannon

Oblon, Spivak, McClelland, Maier,

and Neustadt, P.C.

Steven Sikes

University of South Alabama

Kenneth Smith

National Sanitation Foundation

Rodney Sobin

U.S. Congress

Office of Technology Assessment

Graham Swift

Rohm and Haas Co.

Ken Tracy

Warner-Lambert Co.

John Walker

U.S. Environmental Protection

Agency

A.P. Wheeler

Clemson University

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the reviewers and

contributors. The reviewers and contributors do not, however, necessarily approve, disapprove, or endorse this background

paper,OTA assumes full responsibility for the background paper and the accuracy of its contents.

iv
—- . —.—-—- .—

Peter D. Blair

Assistant Director, OTA

(beginning February 1993)

Industry, Commerce,

and International

Security Division

Energy and Materials Program

Manager

(until August 1993)

Lionel S. Johns

Assistant Director, OTA

(until February 1993)

Energy, Materials,

and International

Security Division

Matthew Weinberg

Project Director

Joe Raguso

Analyst

ADMINISTRATIVE STAFF

Lillian Chapman

Office Administrator

Linda Long

Administrative Secretary

Tina Aikens

Secretary

Preject Staff

CONTRACTORS

Oliver Peoples

Anthony Sinskey

 Bio Information Associates

Boston, MA

Florence Poillon

Editor

Emilia Govan

Energy and Materials Program

Manager

(beginning August 1993)

v
contents

1 Introduction 1

Polymers: A Primer 4

Biopolymers 5

Impact of Genetic Engineering on Biopolymer

Technology 8

The Role of Chemistry in Biopolymer

Technology 12

The Policy Context 12

2 Technical Overview of Biopolymer Field 19

Selected Polymers Produced by Microbial

Systems 19

Selected Polymers of Plants and Higher

Organisms 35

Polymers Produced by Chemical Polymerization of

Biological Starting Materials 43

3 Biopolymer Research and Development in

Europe and Japan 51

Europe 51

Japan 59

4 Biopolymer Research and Development in

the United States 67

Activities of the Federal Government 67

Private Sector Activities 73

vii
—

T

Introduction 1

hroughout history, humans have relied extensively on

biological materials like wool, leather, silk, and cellulose.l Today, such natural polymers can be tailored to

meet specific needs. The advent of modern biotechnology has fundamentally transformed the way scientists view

organisms and the materials they produce. For example, the

genetic manipulation of some plant species could give rise to a

new source of structural polymers that supplant traditional

commodity plastics. By harnessing the enzymes found in nature,

or transforming agricultural or marine feedstocks, a new class of

biodegradable, biocompatible, and renewable materials is on the

horizon.

Polymers play a central role both in the natural world and in

modern industrial economies. Some natural polymers, such as

nucleic acids and proteins, carry and manipulate essential

biological information, while other polymers such as the

polysaccharides—nature’s family of sugars-provide fuel for

cell activity and serve as structural elements in living systems.

With advances in chemistry and materials science, a vast array of

novel synthetic polymers has been introduced over the past

century. Synthetic polymers such as nylon, polyethylene, and

1 These four materials are natural polymers. Polymers are substances composed of

repeating structural units that are linked together to form long chains.

1
2 Biopolymers:

.——.

Making Materials Nature’s Way

polyurethane have transformed daily life.2 From

automobile bodies to packaging, compact discs to

clothing, and food additives to medicine, manmade polymers pervade virtually every aspect of

modern society.3

However, the growing reliance on synthetic

polymers has raised a number of environmental

and human health concerns. Most plastic materials, for instance, are not biodegradable and are

derived from nonrenewable resources.4 The very

properties of durability and strength that make

these materials so useful also ensure their persistence in the environment and complicate their

disposal. In addition, the synthesis of some

polymeric materials involves the use of toxic

compounds or the generation of toxic byproducts.5

These problems have focused increased attention on polymers that are derived from biological

precursors or are produced by using the methods

of modern biotechnology.6 Such biopolymers

may prove to have a variety of environmental

benefits. Possible applications range from agriculturally or bacterially derived thermoplastics

that are truly biodegradable, to novel medical

materials that are biocompatible, to water treatment compounds that prevent mineral buildup

and corrosion.7 However, because materials typically have many different properties, in certain

applications biopolymers may not necessarily

provide environmental advantages over conventional polymers.8 In practice, it is extremely

difficult to develop testing methods that assess

the environmental characteristics of materials.9

In recent years, a number of significant technical developments, particularly in the area of

genetic engineering, have enhanced the commer2 These materials have been widely adopted because they are lightweight, strong, versatile, damage-resistant and chemically inert.

3 In 1990, the United States produced 46.8 billion pounds of thermoplastics (e.g., polypropylene, polystyrene, polyethylene), 8,6 billion

pounds of thermosetting plastics (e.g., urethanes and epoxy compounds), 8.1 billion pounds of synthetic fibers (e.g., nylon and polyester), and

0.5 billion pounds of cellulosic fibers (e.g., rayon) (data compiled by BioInformation Associates, Boston, MA).

4 A biodegradable material is a material in which degradation results from the action of naturally occurring microorganisms such as bacteria,

fungi, and algae.

5 Although toxic intermediatcs are sometimes used in the manufacture of polymers, the final polymer products themselves are rarely toxic.

Few commercially important polymers have any toxicity at all, thus they are used in a broad range of applications from food packaging to

medical care. It is important to note that toxicity is often determined by the dose or concentration of a substance, so many compounds that pose

health or ecological risks at very high concentrations may pose little risk at low concentration.

6 Biotechnology, broadly defined, includes any technique that uses living organisms (or parts of organisms) to make or modify products,

improve plants or animals, or develop micro-organisms for specific uses. Biotechnology also includes the development of materials that emulate

the molecular structures or functions of living systems. For a comprehensive discussion of developments in this emerging field, see U.S.

Congress, Office of Technology Assessment, Commercial Biotechnology: An International Analysis, OTA-BA-218 (Washington, DC: U.S.

Government Printing Office, January 1984); U.S. Congress, Office of Technology Assessment, Biotechnology in a Global Economy,

OTA-BA-494 (Washington, DC: U.S. Government Printing Office, October 1991); and Federal Coordinating Council for Science,

Engineering, and Technology, Committee on Life Sciences and Health, Biotechnology~or the 21st Century (Washington DC: U.S. Government

Printing Office, February 1992).

7 Conventional water treatment chemicals employed as flocculants, corrosion inhibitors, and antiscalants are generally used at very low

concentrations where they are not known to produce toxic effects. However, these compounds are not typically biodegradable.

8 Little research has been done concerning the potential environmental impacts of biopolymers that are used in large quantities, It is possible

that the widespread use of some biopolymers may have unanticipated effects on ecosystems or waste streams. It should be noted that some

naturally occurring polymers have varying degrees of toxicit y. Some examples of natural toxicants include the protein toxins from pathogenic

bacteria, and certain plant proteins that act as natural pesticides. See Regulatory Toxicology and Pharmacology, vol. 12, No. 3, December 1990,

pp. S11-s77.

9 For example, the biodegradability of a particular material is determined by a set of complex factors such as material shape and

surface-to-volume ratio, as well as environmental conditions such as nutrient concentration, bacterial-fungi inoculation, pH, moisture level,

and temperature. Any or all of these factors may vary from location to location. For a discussion of the problems associated with environmental

evaluation methods, see U.S. Congress, Office of Technology Assessment, Green Products by Design: Choices for a Cleaner Environment,

OTA-E-541 (Washington, DC: U.S. Government Printing Office, October 1992).
cial prospects of biologically derived polymers .10

The advent of recombinant DNA technology has

allowed researchers to exercise unprecedented

control over the purity and specific properties of

polymers.

11 Advances in genetic engineering have

also enabled scientists to study how biological

systems produce complex polymers. It is remarkable that living organisms are able to create

sophisticated materials (e.g., spider silk) at normal temperature and pressure, without causing

environmental disruption. This is certainly not the

case for many man-made materials. *2 Thus, biopolymer research could also lead to the development of new environmentally sensitive manufacturing methods.

Biopolymers area diverse and versatile class of

materials that have potential applications in

virtually all sectors of the economy. For example,

they can be used as adhesives, absorbents, lubricants, soil conditioners, cosmetics, drug delivery

vehicles, textiles, high-strength structural materials, and even computational switching devices.

Currently, many biopolymers are still in the

developmental stage, but important applications

are beginning to emerge in the areas of packaging,

food production, and medicine. Some biopoly -

mers can directly replace synthetically derived

materials in traditional applications, whereas

others possess unique properties that could open

up a range of new commercial opportunities.

Novel biopolymer compounds are being investigated by established agricultural and chemical

firms, as well as small biotechnology enterprises.

Yet despite the promise of these new materials,

a series of economic and engineering hurdles may

impede their introduction to the market in the near

Chapter I—Introduction

term. Even if some biopolymers are shown

 3

to

have environmental characteristics that are preferable to conventional polymers, much work

needs to be done to bring down the costs of

biologically derived materials. Commercially available biopolymers are typically two to five times

more expensive than synthetic resins. In only a

few specialized applications, such as biomedicine, are the relatively high costs of biopolymer

materials not likely to impede market growth.

Since many biopolymers are in the early phases of

development, it is difficult to determine whether

economy-of-scale manufacturing will be able to

bring down their current high production costs.

The commercialization difficulties facing biopolymers in many ways resemble the problems

confronting other emerging technologies such as

photovoltaic cells and fuel cells.13

At present, government-sponsored research

and development efforts in the biopolymer area

are relatively small in scope, but many ongoing

Federal activities in biotechnology and agriculture have an indirect bearing on biopolymer

science. Unlike Japan and the European Community, the United States does not have a welldefined biopolymer policy. The United States is,

for the moment, well positioned in some areas of

biopolymer development because of its strong

agricultural base, expertise in polymer engineering, and active biotechnology sector. However,

the relative competitive position of the United

States could be enhanced by fostering greater

collaboration among researchers in government,

industry, and academia. Fundamental research

barriers in the biopolymer field could also be

better addressed by bringing greater coherence to

10 Advances have also occurred in the development of chemical analogues of natural polymers (see Ch. 2).

11 Recombinant DNA technology allows direct manipulation of the genetic material of individual cells. The ability to direct which genes

arc used by cells permits extraordinary control over the production of biological molecules. See discussion below.

12 Many advanced materials are synthesized at extremely high temperature and pressure, and require toxic substances at various stages of

processing.

13 Technologies that convert or use renewable energy face a number of commercialization barriers. Some barriers are technical, while others

relate to the high costs of production. There is a ‘ ‘chicken and egg’ problem of developing a market. Lower costs might be achieved through

economy-of-scale manufacturing, but without market demand, it is not possible to make the investments necessary to achieve those low costs.

Since fossil fuels are relatively inexpensive, it has been difficult for renewable energy technologies to make significant commercial inroads.
4 I Biopolymers: Making Materials Nature’s Way

Figure 1-1 —Some Basic Structural

m Monomer

SW-O Repeat Unit

Features of Polymers

Repeat units are formed when different monomers are linked together.

Four monomers are linked in this case.

SOURCE: Office of Technology Assessment.

the research and development (R&D) efforts of

different Federal agencies. The formidable economic and technical obstacles facing biopolymers, as well as the interdisciplinary nature of the

biopolymer field itself, pose difficult challenges

for policymakers and industry managers alike.

POLYMERS: A PRIMER

Polymers are a class of “giant” molecules

consisting of discrete building blocks linked

together to form long chains. Simple building

blocks are called monomers, while more complicated building blocks are sometimes referred to as

‘‘repeat units’ (see figure l-l). When only one

type of monomer is present, the polymer is

referred to as a homopolymer. Polyethylene—the

material commonly used in plastic bags—is a

homopolymer that is composed of ethylene building blocks. A copolymer is formed when two or

more different monomers are linked together. The

Linear homopolymer

Branched homopolymer

Linear copolymer

Block copolymer

process by which the monomers are assembled

into polymers, either chemically or biologically,

is referred to as polymerization. Polymers can be

either linear or branched (figure l-l).

The distinguishing features of a polymer are

determined by the chemical properties of the

monomeric units (i.e., what the polymer is

specifically composed of), the way in which the

monomeric units are linked together, and the size

or molecular weight of the polymer. (The size of

the polymer is determined by the number of

monomers linked together.) Each of these parameters contributes to the physical properties of

the polymer product. Understanding the relationship between polymer structure and physical

properties remains one of the most active and

challenging areas of current research. In practice,

polymers that are created by conventional chemical approaches lack uniformity in length, composition, and spatial orientation. Thus, a central

aspect of polymerization techniques is statistical
Chapter I–Introduction 5

Table 1-1—Biopolymers Found in Nature and Their Functions

Polymer Monomers Function(s)

Nucleic acids (DNA and RNA) Nucleotides

Proteins Alpha-ammo acids

Polysaccharides (carbohydrates) Sugars

Polyhydroxyalkanoates Fatty acids

Polyphenols Phenols

Polyphosphates Phosphates

Carriers of genetic information universally

recognized in all organisms

Biological catalysts (enzymes), growth

factors, receptors, structural materials

(wool, leather, silk, hair, connective

tissue); hormones (insulin); toxins;

antibodies

Structural materials in plants and some

higher organisms (cellulose, chitin);

energy storage materials (starch,

glycogen); molecular recognition (blood

types), bacterial secretions

Microbial energy reserve materials.

Structural materials in plants (Iignin), soil

structure (humics, peat), plant defense

mechanisms (tannins)

Inorganic energy storage materials

Polysulfates Sulfates Inorganic energy storage materials

SOURCE Blolnformatlon Associates, contractor report prepared for the Office of Technology Assessment, April 1993

control of key polymer characteristics. Much of ■ polymers that are synthesized chemically but

modern polymer science is concerned with reduc- are derived from biological starting materials

ing this variation in polymer properties.14 such as amino acids, sugars, natural fats, or

oils.15

BIOPOLYMERS Table 1-1 lists various types of naturally

The term “biopolymers’ is used to describe a occurring biopolymers defined on the basis of the

variety of materials. In general, however, bio- chemical structure of their monomeric units, and

polymers fall into two principal categories: indicates the functions that these polymers serve

in living organisms. For example, DNA (deoxyri-

■ polymers that are produced by biological sys- bonucleic acid), which carries the essential getems such as microorganisms, plants, and netic information of living systems, is a linear

animals; and copolymer composed of four monomer nucleotides. 16 The nucleotides are linked together along

14 ~1~ Fr~, ‘‘Polmer ~tcnals Science: Novel Synmesis and c~acteri~tion of supcrmokcuhu Structures, ” ~uren”uls Research

Sociery Bulletin, vol. 16, No. 7, July 1991.

15 poly~de~ (nylom), some epoxies, and other polym~s can be synthesized from natu~ly occ~g fa~ acids and oils. For example,

‘*nylon 11, ’ which is derived from castor oil, is now available commerically. The U.S. Department of Agriculture has sponsored a great deal

of work in this area (L. Davis Clements, U.S. Department of Agriculture, Cooperative State Research Service, Office of Agricultural Materials,

personal communication+ July 27, 1993).

16 me ~omt of DNA present in a cell is propofiio~ to he complexity of tie ce~. ~S was one of he clues @t led ,SCie!ltiststO COIlfkIll

that DNA is the bearer of genetic information. DNA can be thought of as a library that contains the complete plan for an organism. If the plan

were for a humau the library would contain 3,000 volumes of 1,000 pages each. Each page would represent one gene or unit of heredity and

be specifkd by 1,000 letters. The four nucleotide bases--adenine, cytosine, guanine, and thymine-are the letters of the chemical language.

A gene is an ordered sequence of these letters. Any particular sequence specifies the information necessary to create a protein.
Biopolymers: Making Materials Nature’s Way

Figure 1-2—Structure of DNA

Schematic diagram of the DNA double helix.

The DNA molecule is a double helix composed of two chains.

Sugar-phosphate backbones twist around around the outside,

with paired bases on the inside serving to hold the chains

together.

SOURCE: U.S. Congress, Office of Technology Assessment, Commercial Biotechnology: An International Analysis, OTA-BA-218 (Washington, DC: U.S. Government Printing Office, January 1984).

a pair of helical sugar-phosphate backbones (see

figure 1-2). As an industrial polymer, DNA is

currently not of commercial interest, although

some researchers are beginning to examine this

biopolymer for the purpose of assembling nanostructural materials, as well as for its electrical

properties. 17

Proteins-also referred to as polypeptides—

are complex copolymers composed of up to 20

different amino acid building blocks. There are

virtually a limitless number of proteins that can be

formed from these 20 monomers, just as there are

a vast number of words that can be made from the

26 letters of the alphabet (see box l-A). Proteins

can contain a few hundred amino-acid units or

thousands of units. Each protein has a specific

chemical composition and three-dimensional shape.

The amino-acid building blocks are linked by

amide bonds in specific sequences determined by

the DNA code of the corresponding gene.18

Protein polymers are unique in that the sequence

of the monomers in the polymer chain is predetermined by the template specific reamer of the

polymerization process (i.e., they are copied from

a genetic blueprint. )19 The sequence diversity of

proteins is responsible for the wide array of

functions performed by these materials in living

organisms. Proteins typically account for more

than 50 percent of the dry weight of cells, and are

the primary means of expressing the genetic

information coded in DNA. In recent years,

researchers have been able to synthesize various

polypeptides that are similar to natural proteins

found, for example, in biominerals such as shells

or bones. Synthetic polypeptides are usually

created from amino-acid precursors (e.g., aspartic

acid).

Polysaccharides are polymers or macromolecules composed of simple sugars. The polysaccharides have two principal functions. Some,

such as starch, store energy for cell activity, and

others, such as cellulose, serve as structural

IT Rese~hers ~ve USed the twisting strands of DNA to construct simple three-dimensional structures. These DNA 5tIUCWe5 could

conceivably be used to encase other molecules or to serve as a molecular scaffolding to which other molecules could be attached. See J. Chen

and N. SeemW ‘‘Synthesis from DNA of a Molecule with the Connectivity of a Cube, ” Nature, vol. 350, Apr. 18, 1991, pp. 631-633.

16 The term ‘‘gene “ is defined as the basic unit of heredity-an ordered sequence of nucleotide bases, constituting a distinct segment

of DNA.

19 Each d. acid ~ a prote~ c- is represented by three nucleotides from the DNA. Thus, different nucleotide COmbiMtiO~ give rise

to different amino-acid sequences, which give rise to different proteins.

zo u~e prote~s, polys.acc~des do not ~ve an tiormation+mg~ction. However, when polysaccharides we co~ected to Proteins,

they guide proteins to correct locations within a cell—a property that is useful in drug delivexy. For more detail on the respective fi.mctions

of these biopolymers, see Albert Lehninger, Biochemisoy (New Yorlq NY: Worth Publishers, 1975).
Chapter I–Introduction 7

Box l-A–Probability and the “Miracle” of Life

How is it that biological systems are able to produce the polymers that are needed to sustain life?

Stated another way, how can a particular kind of polymeric structure be created out of the extraordinarily

vast number of structures that are possible? If, for example, a polymer consists of k types of monomers

and has a total Iength N, t he number of possible polymeric structures that can be generated is kN

. This

number becomes extremely large when the polymer is of even moderate length. For instance, proteins

consist of 20 different types of amino acids and are about 100 units long. Therefore, 20100 (about 10130,

or 1 followed by 130 zeros) possible polymeric configurations exist. For DNA, k = 4 (four types of

nucleotides), and N = 1 million, so 4106 (about 10600,000, or 1 followed by 600,000 zeros) structures are

possible. Thus, the probability of the right polymer being created by chance alone is fantastically small.

However, biological systems are able to generate t he desired polymer wit h a probability virtually equal

to 1 (i.e., there is basically a 100 percent chance that the correct polymer will be created). This high

probability is due principally to the presence of biological catalysts (enzymes) that eliminate the

randomness associated with chemical transformations and thereby ensure the “uniqueness” of

biochemical processes. Enzymes play a central role in DNA replication and protein production, as well

as in polysaccharide biosynthesis. It should also be noted that some biological monomers have certain

chemical tendencies to form “nonrandom” polymers even under simple conditions of formation (e.g.,

simple thermal polymerization of am i no acids gives rise to compounds that have a relatively high degree

of order).

SOURCES: V. Averisov et al., “Handedness, Origin of Life, and Evolution,” /Physics Today, July 1991, pp. 33-41;

S. Fox and A. Pappelis, “Synthetic Molecular Evolution and Photocells,” The Quarterly Review of Biology, vol. 68,

No. 1, March 1993.

materials in living systems.

20 After proteins, units are often made up of more than one sugar

polysaccharides are among the most diverse and

complex group of biopolymers. This is because

the bonds linking the sugar monomers can be

formed at different positions on the sugar units

(illustrated in figure 1-3 for homopolymers of

glucose). By simply linking glucose monomers

together at different positions, polymers with

very different properties are produced (see chapter 2). At least 20 different sugars have been

identified in a variety of polysaccharides from

biological sources, and thus a great range of

polymer structures can be created (see box l-A).

Many polysaccharides contain branched structures and are chemically modified by the addition

of other molecules. The monomeric or repeat

molecule and consequently can be quite complex.

The xanthan gum repeat unit, for example,

contains five sugars. The assembly of polysaccharide repeat units and the associated polymerization processes are not dependent on a template or

genetic blueprint, but are specified by the enzymes (biological catalysts) involved in an organism’s “biosynthetic pathway. ”21 This process

in biological systems is often referred to as

contemplate polymerization.

Other biopolymers include polyhydroxyalkanoates

(PHAs), nature’s biodegradable thermoplastics22

(chapter 2); polyphenols, a class of structural

materials; and inorganic polyphosphates and

Z 1 me [Cm I t blo~wthetlc ~a~way is used to describe he step_ by-s(ep conversion of pr~ursor molecules into a flti produc~ with each

step in the process being carried out by a specific biological catalyst (enzyme), A pathway consists of a sequence of reactions leading to a final

product that is usually quite different from the starting materials.

22 ~ermoplastics me Polmers that will repeatedly soften when heated and harden When coded.
.- . - . . . . .

8 I Biopolymers: Making Materials Nature’s Way

Figure 1-3-Anatomy of a Natural Sugar

(6)

I

Bond(s)

(5) – o

‘/~

\aP

B(1-4)

(4)

l \

(1) B(1-3), B(1-6)

/ ~

(3) —-(2) aa(l-4), a(1 -6)

Polymer

Cellulose

Yeast glucan

Starch

The different types of linkages found in some glucose homopolymers are illustrated. The glucose

monomer (above) is made up of six linked carbon atoms. The bond that joins two different sugar units

is described by the respective numbers of the carbon atoms that are linked. For example, if the “B1”

position of the first sugar monomer is linked to position 4 of the second sugar monomer, the bond would

be described as B(1-4). In amylopectin (depicted below), a form of starch, the main polymer chain

consists of a(l-4) bonds and the branched chain is connected by a(l-6) bonds.

CH2OH Branch 6C H20H

k-- -

0

/ -

— 0

\

5 \

J

0 Branch point

(x(1 > 6)

I linkage

6CH 2

CH20H CH20H CH20H

Main a(1 >4) chain

Amylopectin (a form of starch)

SOURCE: Biolnformation Associates, contractor report prepared for the Office of Technology Assessment, April 1993.

polysulfates, which are not discussed

report. 23

IMPACT OF GENETIC ENGINEERING

BIOPOLYMER TECHNOLOGY

in this living systems. Genetic engineering permits extraordinary control over the time, place, level, and

type of ‘‘gene expression. ”24 The simplest case

ON applies to protein polymers. Having access to the

genetic blueprint (gene) of a particular protein

Modern biotechnology has given scientists polymer allows one to change both the system

revolutionary tools to probe and manipulate that produces the polymer and the composition of

23 new C ‘~org~c’ ~lwem Mve structural backbones that do not contain carbon atoms. However, the polymer side gmups often do

contain carbon. One type of inorganic polymer family is the polyphosphazenes. These compounds have unique elastic properties.

X Gene expression is the mechanism whereby the genetic instructions inanyparticular cell aredeeoded andproeessedinto afti functioning

product, usuaLly a protein. This involves several steps: In a process called transcriptio~ the DNA double helix is locally unzipped near the gene

of interest and an intermediate product known as ‘‘messenger’ RNA, is synthesized. The messenger RNA transmits the instructions found

in the DNA code to the protein-synthesizing machinery of the cell, and a protein is created. Proteins are composed of amino aci& Each arnino

acid in a protein chain is represented by three nucleotides from the DNA. See Commercial Biotechnology, op. cit., footnote 6, pp. 34-35.
Chapter I–Introduction 9

Some bacteria can store energy in polymer-bearing granules (polyhydroxyalkanoates) that can be collected

and made into truly biodegradable packaging like these plastic bottles made from Alcaligenes bacteria by

Zeneca Bio Products.

the polymer itself. Recombinant DNA techniques recombinant DNA method is necessarily more

permit the creation of polymer chains that are economical, but that it is possible to generate

virtually uniform in length, composition, and polymers of exceptional structural purity, as well

stereochemistry or spatial orientation25 (see box as manipulate the biopolymer production system

l-B). For example, the protein polymer silk that to create new materials. In addition, the recently

is produced commercially by silkworms can now developed ability to chemically synthesize DNA

be made in recombinant microorganisms.26 The allows scientists to construct entirely new genes

advantage of this new approach is not that the

25 me ~ee-dlmen~lo~ ~angement of ~ bi~l~gic~ polymer gives rise to specific types of biochemi~ activity. For example, the Spatial

arrangement of an enzyme results in some rmctions being greatly favored over others. It turns out that natural proteins are constructed only

from “left-h.andai” amino acids, and nucleic acids are made up only of “right-handed” sugars. Their mirror image structures (e.g.,

right-handed proteins) are not found in living systems. Although ‘left-handed’ and ‘right-handed’ versions (so-called stereoisomers) of any

given compound have identical chemical composition and physical properties, they react quite differently biologically and with some reagents.

Traditional chemical synthesis techniques usually produce left- and right-handed versions of a polymer, which is undesirable from the

perspective of production efficiency.

z~ See David L. Kaplanet ~., “Biosynthesis and Processing of Silk Proteins, ’ Mafenals Research Sociery Bu//erin, vol. 17, N0. 10, October

1992, pp. 41-47.

330-076 0 - 93 - 2 : QL 3
10 I Biopolymers: Making Materials Nature’s Way

Box l-B–The New Alchemy: Recombinant DNA Technology

Recombinant DNA is formed when

pieces of DNA f from different organisms H \

are joined together. The basic tech- V &

nique of preparing recombinant DNA is v~

\

New DNA

Restriction

illustrated in the diagram shown. SpeDonor DNA cial biological catalysts known as “restric- ‘

nzymes //>

Q -A““\

tion enzymes” are used to cut donor

DNA (usually from a higher organism)

o

U ‘(2.2

into fragments, one of which contains k

~~~~~~sn Z Recombinant Bacterium

the gene of interest. Restriction en-

\

/ DNA molecule

zymes recognize certain sites along t he A ,~ new DNA

DNA and can chemically cut the DNA at A ( ,/

those sites. The resulting DNA frag- { ~

K v

Plasmid DNA Replication ments are t hen inserted into a “vector,”- Expression

produces large produces

a DNA molecule used to introduce for- amount of DNA protein

eign genes into host cells. Plasmids,

circular segments of DNA that are not

part of chromosomal DNA, are t he most SOURCE: U.S. Congress, Office of Technology Assessment, Commercial

Biotechnology: An /nternationa/ Analysis, OTA-BA-218 (Washington, DC:

common types of vectors used. Thus, U.S. Government Printing Office, January 1984).

selected genes from donor DNA molecules are inserted into plasm id DNA molecules to form the hybrid or recombinant DNA. Each plasm id

vector contains a different donor DNA fragment. These recombinant DNA plasm ids are introduced into

host cells in a process called “transformation.” When the transformed host cells grow and divide, the

plasm ids replicate and partition with the host daughter cells, ultimately providing many host cells that

carry the same donor DNA fragment. This process of replication is known as cloning. The cloned genes

can then be “switched on, ” resulting in the creation of large quantities of the desired protein.

Recombinant DNA is grown principally in simple microorganisms such as bacteria and yeast. In recent

years, scientists have also developed methods of introducing genetic material into higher plants and

animals.

SOURCE: U.S. Congress, Office of Technology Assessment, Commercia/Biotechno/ogy:An Internationa/Ana/ysis,

OTA-BA-218 (Washington, DC: U.S. Government Printing Office, January 1984).

that encode unique protein polymers .27 Research- situation is more complicated. In these cases,

ers are now modifying genes to improve the genetic manipulation permits control of the promechanical and chemical properties of structural duction of biological catalysts (proteins known as

proteins such as silk, elastin, and various adhesive enzymes), which are in turn responsible for the

polymers.28 production and polymerization of the building

For biopolymers other than proteins, such as blocks that make up the final polymer products

polysaccharides and polyhydroxyalkanoates, the (see figure 1-4). A useful analogy is to view

27 A gene can be syn~esiz~ or Crea[d direcfly since the nucleotide sequence of the gene can be deduced from tie win~acid squence

of its protein product.

28 David Tirrell et d., ‘‘Genetic Engineering of Polymeric Materials, ” Material sResearch Society Bulletin, vol. 16, No. 7, July 1991, pp.

23-28.
enzymes

ent steps

Chapter I-Introduction I 11

Figure 1-4-A Genetically Engineered Biopolymer Production System

S1 S2 S1 S2

S3 S3 Biopolymer

I

S4 S4 n

[ ‘

Structure -- 1

J

—

< I

, Genetic engineering ‘

of biosynthesis t o

control structure

\ and function I

>

\

‘ \

\

“\‘\L

r

1

Function

S1, S2, S3, and S4 = Individual sugar groups

Applicatiion

--”

Unlike proteins, polysaccharides and other natural polymers are not created by following a genetic

blueprint; rather, an organism outlines a “pathway” of synthesis in which each step of the pathway is

carried out by a specific enzyme. Some polysaccharide pathways can have more than ten steps and

sometimes as many as a hundred steps. By using recombinant DNA techniques, enzymes from different

biological sources (i.e. species) can be introduced into host organisms, thereby creating entirely new

biosynthetic pathways or polymer assembly lines. These new biological assembly lines could be used

to produce greater quantities of a particular polymer, or to design novel polymers with unique physical

and functional properties.

SOURCE: Biolnformation Associates, contractor report prepared for the Office of Technology Assessment, April 1993.

as being machines that carry out differon a biological assembly line. Throughout the biological world there exists an extraordinary army of different machines (enzymes), all

encoded by specific genes. Many of these enzymes are present in only one species or strain of

organism. The genes for these enzymes are then

the blueprints for the individual pieces of machinery, and remarkably, these blueprints are recognized and translated in the same way in all

organisms. By adding the appropriate signals and

transferring the gene into a new organism, the

organism can then produce a new enzyme,

thereby giving the organism the capacity to carry

out a particular step in the assembly line process.

Genetic engineers now have the ability to add new

machines, or remove old ones, in practically any

system.

The implications of these genetic techniques

are quite profound. It is now possible to genetically modify an organism so that it produces

greater quantities of a particular polymer. As an

example, the introduction of a specific enzyme

has allowed researchers to increase starch produc-
12 I Biopolymers: Making Materials Nature’s Way

tion in genetically engineered plants.29 It is also

possible to transfer an entire assembly line into a

new host organism to improve a production

process. One illustration of this procedure is the

production of the bacterial thermoplastic polyhydroxybutyrate (PHB) in transgenic plant species.30 Finally, these new techniques allow organisms to be modified so that truly novel materials

can be produced. For instance, a series of genetically engineered xanthan gums has been developed by removing specific enzymes from the

xanthan assembly line (ch. 2). Ultimately, it may

be possible to construct biological systems for the

production of entirely new classes of polymers.

This could be accomplished by creating new

assembly lines using enzymes from diverse sources

and then introducing the correct blueprints into an

appropriate host. The long-term objective of this

type of research is to design biological systems

that produce specific polymers for specific applications. For example, materials might be genetically ‘‘customized’ to have a unique combination of mechanical, chemical, and

properties.

THE ROLE OF CHEMISTRY IN

BIOPOLYMER TECHNOLOGY

degradative

Given the advances in genetic engineering,

what is the role of traditional chemical synthesis

in creating biopolymers? The most widely used

polymers, such as polypropylene and polyester,

are produced by standard chemical means. But as

mentioned previously, the processes used to

manufacture these synthetic polymers can sometimes have a number of drawbacks. Although

technologies for producing proteins by chemical

synthesis have been developed, they are extremely costly. Such methods are used primarily

for the production of research chemicals or for

very high-value applications such as pharmaceuticals. There is no existing chemical technology

capable of producing the complex polysaccharide

structures made so readily by biological systems.

Because of their structural and chemical specificity, enzymes are extremely efficient at producing

polymer compounds with high yield.31

Yet, chemistry still has an important role to

play in the development of biopolymers. Chemical techniques can be used to modify the properties of biopolymers to expand their range of

applications, to polymerize biological starting

materials, or to create new gene sequences that

can lead to novel protein polymers through the

application of recombinant DNA methods. Examples of such chemical methods are presented in

chapter 2.

THE POLICY CONTEXT

As noted in previous sections, there have been

significant advances in basic biopolymer science,

with a wide range of new applications on the

horizon. Due to the versatility and potential

environmental benefits of biopolymer materials,

R&D activities are likely to expand considerably

in coming years. While technical progress in the

biopolymer field is, for the most part, being

driven by academia and industry, the Federal

Government directly and indirectly affects biopolymer development. In the following sections,

the role of federally funded research and various

regulatory issues are discussed.

29 see David M, Starket al., ‘‘Regulation of the Amount of Starch in Plant Tissues by ADP Glucose Pyrophosphorylase,’ Science, vol. 258,

Oct. 9, 1992, pp. 287-292.

30 we Cwly work ~ ~s ma is encoura g ing, many t~~c~ c~enges remain. SW Yves Pofier et al., ‘‘Polyhy&oxybu@te, a

Biodegradable Thermoplastic, Produced in Transgenic Plants,’ Science, vol. 256, Apr. 24, 1992, pp. 520-523. Transgenic plants are plants

whose hereditary DNA has been augmented by the addition of DNA from other species.

J] However, polynem that are created by biological processes such as fermentation may require further pu.rifkation before they me stitable

for a particular application.
 Role of Federal R&D Programs

Although there is not a well-defined biopolymer research program in the United States,

many ongoing Federal activities have a bearing

on biopolymer science. Several Federal agencies

are sponsoring efforts in biopolymer research, as

well as related areas such as bioprocessing and

genetic engineering (see ch. 4). In February 1992,

the White House Office of Science and Technology Policy announced the Biotechnology Research Initiative—a coordinated interagency effort to strengthen and diversify Federal research

activities in biotechnology .32 This initiative is

designed to extend the ‘‘scientific and technical

foundations’ of biotechnology, to “accelerate

the transfer of biotechnology research” to applications in the commercial sector, and to expand

interdisciplinary research between biology and

other fields, such as chemistry, physics, or

materials science .33 The initiative calls for greater

attention to be paid to bioprocessing and manufacturing, including bimolecular materials, biocompatible materials, and metabolic engineering,

and thus addresses many aspects of biopolyrner

science.

However, the amount of funding specifically

targeted for biopolymer programs is relatively

small. In FY 1993, only about 3 percent ($124

million) of the total biotechnology budget ($4

billion) is devoted to biologically derived compounds and industrial processing research (see ch.

4); and only a small fraction of that 3 percent goes

directly to biopolymer development. Some members of the research community have called for

more explicit Federal goals in the biopolymer

area, particularly in the biomedical field (see box

Chapter l-introduction I 13

4-A). For example, the creation of a national

center for biomaterials research at the National

Institutes of Health (NIH), as some observers

have called for, could lend greater focus to

biopolymer programs in the medical area.

It is important to recognize, though, that while

many important biopolymer applications are emerging in the medical field, there are also promising

applications in the industrial, agricultural, and

waste management sectors. As noted in a previous Office of Technology Assessment report,

Federal funding for biotechnology in the area of

medicine dwarfs the funding directed toward

agriculture, chemicals, energy, and other biotechnology applications. 34 To ensure that promising

nonmedical biopolymer applications are not ignored, Federal programs could give greater emphasis to areas such as the conversion of agricultural or aquatic materials into useful industrial

feedstocks and the production of environmentally

sensitive materials .35

Despite the promise of new biopolymer production technologies, this nascent field faces the

same problems that have confronted other new

technologies: development periods of 5 years or

longer, poor prospects for short-term gains, and

uncertain demand in the marketplace because of

inexpensive alternatives (synthetic polymers are

currently much less expensive than agriculturally

or microbially derived materials). Although some

materials are being used now, many biopolymers

face a variety of technical and economic barriers

that will take several years to overcome. The

efforts of the private sector to overcome some of

these barriers might be aided by such Federal

32 B1ofechno/ogy for the 21st Century, Op. cit., f~mote 6

33 Ibid.

34 Biotechnology in a Global Economy, op. Cit., fOO~Ote 6.

35 Nom~lC~ r~~~h ~ the biopo]~er Ma is being tied out or spo~ored by the office of Nav~ Research the U.S. Army Natick

Research Development and Engineering Center, the U.S. Army Research Oftlee, the U.S, Department of Agr@ulture’s OffIce of Agricultural

Materials, the National Science Foundation, and the National Oceanic and Atmospheric Administration (see ch. 4).
. . . . . . . . . . — . .

14 Biopolymers: Making Materials Nature’s Way

programs as the Advanced Technology Program

36 of the Department of Commerce, or the

cooperative research and development programs

(CRADAs) of the U.S. Department of Agriculture

(USDA) and the various Department of Energy

national laboratories.37

At present, Federal biopolymer research activities are diffuse and for the most part, not well

coordinated. Yet, given that biopolymer materials

have an extraordinarily broad range of possible

uses, the decentralized structure of the Federal

research system should not necessarily be regarded as a barrier to biopolymer development.

Many biopolymer applications fall neatly into the

research agendas of individual Federal agencies

and are already the subject of focused attention.

On the other hand, a large number of biopolymer

applications involve a range of different scientific

disciplines, and thus some areas of biopolymer

research could no doubt benefit from increased

coordination of Government resources.

The recent White House initiative to classify

biotechnology research across the Federal research system is beginning to address this situation and is intended to lead to greater crossagency cooperation.38 Creating opportunities for

increased collaboration among academic, industrial, and Government researchers is an explicit

objective of the initiative. These efforts, even

without increased levels of funding, should benefit ongoing biopolymer research activities. Over

the long term, Federal R&D programs in the

biopolymer area might focus on:

exploratory work on biopolymer materials that

are genetically engineered to have unique

physical and functional properties or that could

be used as substitutes for the commodity resins

currently derived from petroleum sources;

utilization of agricultural or marine products

and byproducts;

biopolymer processing technologies that could

potentially lead to new environmentally sensitive manufacturing methods;

approaches to lower the costs of production

associated with various biopolymer manufacturing technologies;

research on the environmental impacts (positive or negative) of biopolymers that are

introduced into solid and aqueous waste

streams or natural ecosystems.

As with other areas of technology development, the challenge for policymakers is to determine where Government can best use its R&D

resources to complement, rather than replicate,

the activities of the private sector.

 Regulatory Issues

A number of existing or potential regulatory

factors could affect biopolymer development and

commercialization efforts. These include the

Food and Drug Administration (FDA) approval

process for medical applications that use biopolymers; the development of legal definitions

for biodegradable materials, or regulations mandating the use of biodegradable materials for

36 The Advanc~ Tec~ology prograrn (ATP) has granted a small number of awards to companies working in the biotechnology Mm. Some

of the recent ATP grants have included biopolymer applications in the medical field. For example, Tissue Engineering, Inc., is developing

biopolymers derived from animal and marine sources that can be used as prosthetic devices or vascular grafts (Lxx GarriclG Tissue Engineering,

Inc., personal communication+ Aug. 23, 1993).

37 The Agricdturd Resemch service of the USDA has more active CRADAS than any other Government agency. ~ additiom the USDA’S

Alternative Agriculture Research and Commercialization Center works with private industry to promote the commercialization of promising

new materials. The Department of Energy has a large general effort in biotechnology at its national laboratories, including projects in mapping

the human genome and in structural biology.

38 Mother white House initiative tit relates to biopolymer research is the Federal Advanced Materials md pro~ssing pro-(~p).

AMPP is designed to encourage multidisciplinary research and new advances in materials science. For example, as part of AMPP, the National

Science Foundation is supporting work in ceramics, composites, electronic and magnetic materials, superconductors, and biomaterials and

bimolecular materials. See “NSF’s Pmticipation in Advanced Materials and Processing program (AMPP),” NSF document 93-68, May 7,

1993.
applications such as packaging; regulations affecting the use of genetically engineered systems

for producing biopolymers; and requirements

regarding the introduction of new industrial

chemicals.

FOOD AND DRUG ADMINISTRATION

The FDA is a regulatory agency responsible for

the safety of the Nation’s foods, cosmetics, drugs,

medical devices, biological products, and radiological products. Since biopolymers have potential uses in virtually all of these areas, the market

introduction of many biopolymer compounds will

be governed by FDA guidelines.39 For example,

biopolymer crystallization inhibitors such as polyaspartate (see chapter 2) could be used in oral

health care as tartar control agents. However,

toothpaste and mouthwash additives are considered “drugs,” and therefore require FDA approval. The principal biopolymer applications

affected, however, will be drug delivery systems

and medical devices .40

To enter the U.S. market with a new drug or an

advanced drug delivery system that is being

packaged with a new or existing drug, an application must be filed with the FDA before a

manufacturer can begin human clinical trials.41

Following this step, a new drug application

Chapter I-Introduction 15

(NDA) is submitted with supporting evidence as

to both safety and efficacy. Even if a proven drug

delivery system is packaged with a proven drug,

anew application is required. Such safeguards are

necessary because a new delivery system-drug

combination will have new pharmacological properties. This requirement can obviously affect the

rate at which various biopolymer drug delivery

systems are introduced into the market.

Medical device implants are also subject to

FDA review through the Medical Device Amendments Act of 1976.42 The FDA evaluates the

safety and effectiveness of medical devices, but

does not necessarily approve biomaterials per se.

There is not an FDA list of approved medical

materials, but if a material is itself a product, such

as bone cement, the material does receive certification. However, the evaluation of materials in

medical devices is obviously an important part of

the overall review process.43

In recent years, medical device manufacturers

have expressed considerable concern about the

length of time required for FDA approval of

medical products.

44 This has resulted in calls to

streamline FDA evaluation procedures. In 1989,

the Biomaterials Industry Subpanel of the Na-

—

39 FDA ~v~uatlon cffo~s focus on the development of in vitro (outside the body) assessment methods. This includes tie evaluation of cellul~

and molecular mechanisms of biomedical materials degradation and performance, as well as assessment of host system-medical device

interactions. Biotechnology for (he 21 St Century, op. cit., footnote 6.

40 fie three main blom~dicat mwket segments for biopol~ms me wound ma~gement products, polymeric (hl.lgs and dmg delivery

systems, and orthopedic repair products. The wound management segment is the most mature of the three markets, with both drug delivery

technology and orthopedic devices just beginning to establish a significant commercial presence.

41 A con~ol]cd-rc]easc d~~ system is a combination of a biologically active agent (i.e., the drug) and a suppofl vehicle. ‘f’he suPPort ‘etic]e

can be either a matrix or a reservoir device. In a matrix system an active drug is dissolved or dispersed uniformly throughout a solid polymer.

Drug release from the matrix dcvlce can be controlled by either a diffusion or an erosion process. In a reservoir system, the polymer acts solely

as a barrier that controls the rate of drug delivery by diffusion. Polylactidc and some polyamino-acid polymers are currently being evaluated

as drug vehicle materials (see ch. 2).

42 In 1990 congc~~ pa~$~ the Safe M~ical Device Act, which modified the 1976 ZiCL The 1990 law Wuires man~ac~~rs ‘e ‘teps

.

to evatuatc medical device performance after a device has been approved and distributed in the marketplace.

43 E. Mueller ct al., ‘ ‘Regulation of ‘Biomatcrials’ and Medicat Devices, ’ Materials Research Society Bulletin, vol. 16, No, 9, September

1991, pp. 39-41. Also see U.S. Department of Health and Human Services, Tripartite Biocompatibility Guidance for Medical Devices

(Washington, DC: 1986).

u ,L+e LIFDA Foot. Dragging Stymies Medical Device M*e~t “ Wall Street JournaZ, June 4, 1993, p. B2,
— . . . . . . .

16 I Biopolymers: Making Materials Nature’s Way

tional Research Council made several recommendations 45 for improving the FDA approval process:

A biomaterials evaluation process should be

established to facilitate the use of new materials

in medical devices. The material itself, once

proven safe and effective, should not be subject

to further testing in the event of its use with

additional medical devices.

The FDA should establish a biomaterials advisory committee.

The FDA should establish biomaterials guidelines and standard test protocols.

Regardless of whether these proposals are adopted,

the introduction of procedures that ensure product

safety, while reducing evaluation times and costs,

will bean important objective of the FDA in years

to come.46

BIODEGRADABLE MATERIALS

Scientifically based definitions and standards

relating to degradability have yet to be legally

established. While some studies on degradability

have been performed by the Environmental Protection Agency (EPA) and the USDA, Congress

has not yet mandated technical standards in this

area. However, in Public Law 100-556, Congress

required that plastic ring carriers for bottles and

cans be made of degradable material. In the

proposed rule for this law, EPA does not specify

that particular materials be used, but has instead

set performance standards for degradable materials. 47 The performance criteria include three

factors: a physical endpoint for degradation, a

time limit for degradation, and marine environmental conditions.% By specifying performance

goals rather than particular materials, EPA hopes

that industry will have sufficient flexibility to

develop new classes of degradable polymers.

Currently, beverage ring containers are made only

from photodegradable materials, consisting of

ethylene-carbon monoxide copolymers.49 In addition to this Federal action, 27 States have passed

legislation prohibiting the use of nondegradable

ring carriers.

Although this EPA rule applies to a narrow

product category, the precedent of setting performance standards for degradable substances

could facilitate the introduction of biopolymer

materials. If Federal or State action is taken to

expand the range of mandated degradable products (e.g., personal hygiene products or diapers),

market opportunities could develop for the new

starch, polylactic acid, and microbial polyester

biopolymers. However, precise technical definitions and testing methods will be needed to

convince both manufacturers and consumers that

such new materials are indeed environmentally

45 See * ‘Report of tie Comi[tee to Smey Needs and Opportunities for the Biomaterials Industry, ’ Marerials Research Sociev Bulletin,

vol. 16, No. 9, September 1991, pp. 26-32.

46 The ~A &s ~en some steps in MS &mtion witi isr~ntly annouced ‘‘expedited review’ process fOr innovative mediCtd devices.

The new procedures are intended to give administrative priority to potential ‘breakthrough devices, ” and to better classify products submitted

for FDA approval. In the past every product submitted for approval was subject to the same administrative procedures. The new procedures

will elimina te some of the review steps for relatively simple devices and give greater attention to more complex medical devices (see

‘‘Promising Medical Devices To Be Speeded to Market,’ Washington Post, June 25, 1993, p. A2).

47 me proposed EPA de smtes that the term ‘‘biodegradable Plastic” is used to “describe any plastic that is intended to completely

assimilate into the environment regardless of the derivation of the material or the combination of degradation processes involved in

assimilation” (see Federal Register, vol. 58, No. 65, Apr. 7, 1993).

48 Ibid.

49 scientists are still concerned wthae ‘‘dqp&ble’ materials may seine only to substitute one hazard fOr anOther ill @e waters. Thlit

is, with the use of degradable plastics, the hazard of ingesting plastic fragments may reptace the hazard of entanglement in nondegradable

plastics. See U.S. Congress, Offke of Technology Assessment, Facing America’s Trash: What Next for Municipal Solid Waste? OTA-0+24

(Washington DC: U.S. Government Printing Office, October 1989), pp. 18(L183.
Chapter I-Introduction 17

superior and do not affect product integrity.50 In

this regard, the efforts of the American Society for

Testing and Materials (ASTM) to develop scientific definitions and evaluation methods for degradable materials may serve to allay public

concerns.

51

GENETICALLY ENGINEERED BIOPOLYMER

PRODUCTION SYSTEMS

The principal Federal regulatory guidelines

dealing with biotechnology were formulated in

the 1986 White House Office of Science and

Technology Policy report “Coordinated Framework for Regulation of Biotechnology. ’ The

document describes how novel chemicals, materials, and organisms, produced by the methods of

biotechnology, fit into the existing corpus of

Federal legislation and regulation. In general,

genetically engineered products are regulated on

the basis of their intended use, rather than the

method or process by which they are made. For

example, under current FDA rules, genetically

engineered foods are treated the same way as

conventional products. The FDA does not require

that new products be approved or labeled, as long

as such products are essentially similar in composition, structure, and function to food items

already available on the market.52 However,

USDA and EPA do regulate field tests of genetically modified plants.53 As of 1993, more than

400 permits have been granted for the field testing

of genetically altered plants and other organisms. 54

For the short term, genetically engineered

biopolymers will be produced in “contained”

fermentation systems where standard safety procedures are well established.55 Thus, microbially

derived biopolymer materials are unlikely to face

any significant regulatory obstacles.56 In the

future, however, schemes that involve the production of biopolymers through the genetic modification of crops could face greater regulatory scru50 For emple, tie FDA is concerned about the possibility of a shortened shelf life of degradable food-packagm mattial. k @alua@

the safety of new additives in food-contact materials, the FDA must consider potential problems such as enhanced migration of food-packaging

components as a consequence of accelerated degradation of a polymer. In the case of some proposed biopolymer packaging materials such as

pullulan (ch. 2), there would have to be evidence that the food product is adequately protected. Ibid.

51 The ASTM De~a&ble Plastics subcommittee iS ex amining various degradation pathways, including photodegradatiou oxidatiou

chemicat degradation+ and biological degradation. It has developed standard Iabomtory test methods that measure the rate and extent of

degradation for different materials, and is in the process of establishing a classification and marking system for polymer compounds. ASTM

researchers are currently attempting to determine the behavior of degradable polymeric materials in real disposal systems and are correlating

these results with ASTM laboratory methods. This work could very well become the de facto industry baseline for defining and evaluating new

polymer materials, Already, EPA has used some of ASTM’s work in developing proposed performance standards for degradable beverage ring

carriers (op. cit., footnote 47; and see Rarnani NaryaIL “Development of Standards for Degradable Plastics by ASTM Subcommittee D-20.96

on Environmentally Degradable Plastics, ’ 1992).

52 Some Commer ~oUpS ~ve expressd concerns that genetically engineered foods may be subject to microbial contm tio~ possess

higher levels of toxins, or expose consumers to allergy-producing compounds that are not naturally present in foods. The present consensus

among scientists is that the risks associated with genetically altered organisms are similar to those associated with nonengineered organisms

or organisms genetically modifkd by traditional methods (Biotechnology in a Global Economy, op. ci~ footnote 6).

53 Cwenfly, rese~chers are required to give 30 days notice to the USDA before beg inning field tests. During that time, a determination is

made as to whether additional review or inspection is necessary. See Federal Register, “Genetically Engineered Organisms and Products;

Notification Procedures for the Introduction of Certain Regulated Articles; and Petition for Nonregulated Status, ” vol. 58, No. 60, Mar. 31,

1993. Also, EPA considers microorganisms that are released into the environment to be chemical substances subject to the Toxic Substances

Control Act of 1976. EPA is currently developing guidelines governing genetically engineered pesticides and other microbes.

54 For a dis~ssion on how scientis~ we assessing tie ecological impacts of genetically altered pb@ see M.J. ~awley et al.> ‘‘fiolo8Y

of Transgenic Oilseed Rape in Natural Habitats, ’ Nature, vol. 363, June 17, 1993, pp. 620-623.

55 ~hm developed ~idel~es tit prescfi~ Vfious Procedues of con~~ent for genetic expetien~. s= Federal Register,

“Guidelines for Research Involving Recombinant DNA Molecules, ” vol. 51, No. 88, May 7, 1986.

56 whe~er a biopolymer is re@ated will to a large degree depend on the application. For example, medical pmduc~ tit cont~

microbially-deriyed biopolymers will still be subject to FDA review.
1 8 Biopolymers: Making Materials Nature’s Way

tiny. Several researchers, for instance, are exploring

the possibility of producing natural polyesters

such as PHB by altering the enzyme machinery of

corn or potatoes.57 Such approaches to biopolymer manufacture will be subject to existing

Federal rules governing

agricultural organisms.

REGULATIONS RELATING

INDUSTRIAL CHEMICALS

genetically engineered

TO

In response to public concerns over the possible health and environmental implications of

widespread chemical use, Congress passed the

Toxic Substances Control Act (TSCA) in 1976,

Under the provisions of TSCA, EPA is charged

with assembling basic data on chemicals, reviewing industry tests of new and existing compounds,

and reducing public risk. There are more than

60,000 chemicals currently on the TSCA inventory, and roughly 1,000 new chemicals are

proposed for manufacture each year.58 Before

manufacturers can begin production of a new

chemical, they must submit a

Notice to EPA. Only a small

Premanufacture

number of the

premanufacture notices submitted to EPA are

held up for extended review. 59 In the vast majority

of cases, manufacturers can begin production of

a chemical 90 days after notifying EPA.

Since some of the more interesting biopolymer

compounds are new chemical formulations, they

will also be subject to TSCA provisions.60 Yet,

given that biopolymers are derived from natural

precursors, most biopolymer products should not

have difficulty meeting current TSCA requirements. 61 For instance, this should be the case for

biopolymers that are created by the chemical

polymerization of naturally occurring monomers,

such as polylactide and the poly amino acids.62

However, as indicated previously, some of the

processes used to produce genetically engineered

biopolymers may be subject to more detailed

regulatory review (e.g., genetic modification of

plants).

57 see 4$~ CJwch of tie P1astic potato, ’ ‘ Science, vol. 245, Sept. 15, 1989, pp. 1187-1189.

58 Michael Shapiro, “Toxics Substances Policy, ” Paul Portney (cd.), Pub/ic Policies for Environmental Prorecfion (Washington, DC:

Resources for the Future, 1990), p. 208.

59 Ofte% new chemicals me simply slight rnoditlcatioris of existing substances and are therefore not subjected to a rigorous review. However,

if EPA is concerned about a particular chemical, it can take ytxirs before deftitive toxicity data can be developed. This has led to calls for new

procedures in the TSCA chemical evalution process. Ibid.

60 Depenfig on tie tms Of applications ~volved, biopolymers could also be subject to the provisions Of the cl~n water Act and the Safe

Water Drinking Act. The Clean Water Act regulates contaminants discharged into surface waters, and the Safe Water Drinking Act safeguards

. . drmkmg water sources and prescribes drinking water standards. For a general discussion of the regulation of water pollutants and treatment

chemicals, see “Water Treatment Chemicals: Tighter Rules Drive Demand, ” Chemical & Engineering News, Mar. 26, 1990, pp. 17-34.

61 However, for most biopolyme~, the presumption that they pose little risk to human health and the environment has Yet to be conclusively

proven.

62 poly~no ac1d5 such a5 the polya5p~tes show co~iderable promise as wat~ b~tment additives. Biodegradable polyaspartate

compounds could be used to replace petroleum-derived polymers such as polyacrylate and polyacrylamide. However, it is not known whether

the use of large quantities of natural polymers will have any adverse ecological effects.
blocks.

B

Technical

Overview of

Biopolymer

Field 2

copolymers can be produced through a variety of

mechanisms. They can be derived from microbial

systems, extracted from higher organisms such as plants,

or synthesized chemically from basic biological building

A wide range of emerging applications rely on all three

of these production techniques. Biopolymers are being developed for use as medical materials, packaging, cosmetics, food

additives, clothing fabrics, water treatment chemicals, industrial

plastics, absorbents, biosensors, and even data storage elements.

This chapter identifies the possible commercial applications and

describes the various methods of production of some of the more

promising materials. Table 2-1 provides a partial list of the

biopolymers now in use. ’

SELECTED POLYMERS

MICROBIAL SYSTEMS

PRODUCED BY

In recent years, considerable attention has been given to

biopolymers produced by microbes. It is on the microbial level

where the tools of genetic engineering can be most readily

applied. A number of novel materials are now being developed

or introduced into the market. In the following sections, three

I A comprehensive treatment of biopolymer compounds is beyond the scope of this

Background Paper. The categories of biopolymers described here are designed to

illustrate the diverse physical characteristics and the broad application range of these

materials. For a more detailed discussion of biopolymers, see David Byrom (cd.),

Biomaterials: Novel Materia1sj70m Biological Sources (New York NY: Stockton Press,

199 1); Roger Rowell, Tor Schultz, and Ramani Narayan (eds.), Emerging Technologies

for Materials and Chemicals from Biomass (Washington, DC: American Chemical

Society, 1992); David Kaplan et al., ‘‘Nahmally Occurring Biodegradable Polymers,’ G.

Swift and R. Narayan (eds.), Polymer Systemdynthesis and Utility (New York+ NY:

Hanser Publishing, forthcoming 1994).

19
20 I Biopolymers: Making Materials Nature’s Way

Table 2-l—A Snapshot of the Biopolymer Family

Polyesters Polysaccharides (plant/algal)

Polyhydroxyalka noates Starch (amylose/amylopectin)

Polylactic acid Cellulose

Proteins Agar

Silks Alginate

Collagen/gelatin Carrageenan

Elastin Pectin

Resilin Konjac

Adhesives Various gums (e.g., guar)

Polyamino acids Polysaccharides (animal)

Soy, zein, wheat gluten, casein, Chitin/chitosan

Serum albumin Hyaluronic acid

Polysaccharides (bacterial) Lipids/s urfactants

Xanthan Acetoglycerides, waxes, surfactants

Dextran Emulsan

GelIan Polyphenols

Levan Lignin

Curd Ian Tannin

Polygalactosamine Humic acid

Cellulose (bacterial) Specialty polymers

Polysaccharides (fungal) Shellac

Pullulan Poly-gamma-glutamic acid

Elsinan Natural rubber

Yeast glucans Synthetic polymers from natural fats and oils (e.g.,

nylon from castor oil)

SOURCE David L Kaplan et al , “Naturally Occurring Biodegradable Polymers,” G Swift and R Narayan (eds ), Po/ymer

.Systems-Synthesis and Utility (New York, NY Hanser Publishing, forthcoming 1994)

different classes of microbially derived biopolymers are profiled: polyesters, proteins, and

polysaccharides.

 Microbial Polyesters:

Polyhydroxyalka noates

Much of the current interest in biopolymers

stems from the growing concern about the environmental impacts of synthetically produced

materials. In particular, the highly publicized

disposal problem of traditional oil-based thermoplastics has promoted the search for biodegradable alternatives (about 17 billion pounds of

thermoplastic packaging material was produced

in the United States in 1991). Apart from the

agriculturally derived biopolymers (e.g., starch)

being investigated for their biodegradable properties, there is a class of natural thermoplastic

materials that is drawing much attention. Polyhy -

droxyalkanoates (PHAs) area family of microbial

energy reserve materials that accumulate as

granules within the cytoplasm of cells. They are

genuine polyester thermoplastics with properties

similar to oil-derived polymers (melting temperatures between 50 to 180”C). Their mechanical

characteristics can be tailored to resemble elastic

rubber or hard crystalline plastic.3 The prototype

of this family, polyhydroxybutyrate (PHB), was

frost discovered in 1927 at the Pasteur Institute in

Paris. Commercialization of PHB was first attempted by W.R. Grace Co. in the 1950s. More

recently, a British company, Zeneca Bio Products

(formerly ICI Bio Products), initiated commercial

production of a series of PHA copolymers under

the trade name BIOPOLTM. Several companies

and government research organizations, particularly in Europe and Japan, have active research

and development (R&D) programs focusing on

these materials.

2 ~emopbtics we ~IPmtit ww ~eatedly soften when heated and Mden whm ~1~.

3 y. hi, ‘‘~crobiat synthesis and Properties of Polyhydroxyalkanoates, Materials Research Bulletin, vol. 17, No. 11, November 1992,

pp. 39-42.
Production of PHAs is carried out through

fermentation. The general process is illustrated in

figure 2-1. In their final stages of preparation,

they can be processed by standard extrusion and

molding techniques. Careful control of the carbon

sources (starting materials) and the choice of

production organism enables the production of an

entire family of PHA copolymers with different

properties. The PHB homopolymer is produced

by a variety of bacteria that use it as a source of

carbon and energy. The homopolymer is a brittle

material that is difficult to use and is thermally

unstable. However, by combining polyhydroxyvalerate (PHV) with PHB, a nonbrittle copolymer—

polyhydroxybutyrate-polyhydroxyvalerate (PHBV)--

can be created.4 Other PHA copolymers have also

been produced.5 Currently, Zeneca’s production

of PHBV (BIOPOL) uses the bacterium Alcaligenes eutrophus, which occurs widely in soil and

water. PHBV is formed when the bacterium is fed

a precise combination of glucose and propionic

acid. 6 It has properties similar to polypropylene

and polyethylene, including excellent flexibility

and toughness. The discovery and development

of PHBV and other PHA copolymers have proven

to be a major step forward in expanding the

potential industrial utility of the PHAs.

PHAs biodegrade in rnicrobially active environments. Since PHAs function as an intracellular

energy and carbon source, bacteria can degrade

PHAs and use them as reserve materials. Microorganisms attack PHBV by secreting enzymes

(depolymerases) that break down the polymer

Chapter 2–Technical Overview of

Figure 2-I—PHA Polymer

Raw materials

v

Media preparation

v

Fermentation

v

Cell disruption

v

Washing

v

Centrifugation

v

Drying

PHA Produc t

Biopolymer Field 21

Production Process

1. Carbon source

2. Growth of bacteria

and accumulation

of polymer

3. Purification of polymer

SOURCE: Biolnformation Associates, Boston, MA.

into its basic hydroxybutyrate (HB) and hy -

droxyvalerate (HV) constituents. The HB and HV

fragments are then consumed by the cells to

sustain growth. Under aerobic conditions, the

final biodegradation products are water and

carbon dioxide; under anaerobic conditions, methane is produced as well. The degradation of

PHBV can be quite rapid in biologically active

systems (see figure 2-2).7 A range of soil microor4 William D. Luzier, ‘Materials Derived from Biomass/Biodegradable Materials,’ National Academy of Sciences, vol. 89, Februmy 1992,

pp. 839-842.

5 For example, researchers at the Tokyo Institute of Technology have produced a versatile PHA copolymer of 3-hydroxybutyrate and

4-hydroxybutyrate. This material has been extracted and fermented from the bacterium AfcaJigenes eutrophu under starvation conditions. By

altering the ratio of the copolymers, the elasticity and strength of the material can be varied (Doi, op. cit., footnote 3).

6 Glucose is derived from agricultural feedstocks such as sugar beets and cereal crops, whereas propionic acid can be produced fi-om

petroleum derivatives or by fermentation of wood pulp waste.

7 When 50 bottles made of PHBV material were inserted into a compost heap (6 cubic meters of organic waste) for a period of 15 weeks,

at temperatures between 60 and 70”C, only about 20 percent (by weight) of the PHBV material remained . It is important to note, however, that

PHBV and other biopolymers will not degrade in sanitary Iandfiis, because they are essentially biologically inactive systems. See Petra Piichner

and Wolf-Rudiger Miiller, “Aspects on Biodegradation of PHA,” H.G. Schlegel and A. Steinbiichl (eds.), Proceedings International

Symposium on Bacterial Polyhydroxyalbnoates 1992 (GOttingen: GoI-Druc~ 1993).
22 Biopolymers: Making Materials Nature’s Way

Figure 2-2—Biodegradation of PHBV Polymers

100 — r

u

< 4 0

/’

L ‘-- -i ‘== i20 i /

o

L-------

10

~—-—20~ –-–--—30------

40

, I

50

o~

0 5 10 15 20 25 30 35

Time (weeks) Time (days)

Degradation of PHBV landfill simulation Anaerobic degradation of PHBV 27% copolymer

PHBV can degrade relatively quickly in biologically active systems. in a simulated landfill environment with an elevated moisture

content, PHBV showed a 40-percent weight loss In 40 weeks (left). Under anaerobic sewage conditions, where biodegradability

is measured by gas production, the PHBV polymer decomposed nearly 80 percent in 30 days (right). Other data indicates that

PHBV readily degrades under aerobic conditions.

SOURCES: Petra Pochner and Wolf-Rudiger Muller, “Aspects on Biodegradation of PHA,” H.G. Schlegel and A. Steinb(khl (eds.), Proceedings

hterrtafional Symposium on Bacterial Po/yhydroxyakarmates 7992 (G6ttingen, Goltze-Druck: 1993); William D. Luzier, “Materials Derived from

Biomass/Biodegradable Materials,” Proceedings iVationa/kademy of Sciences, vol. 89, February 1992, pp. 839-842.

ganisms, both bacterial and fungal, can utilize

PHAs as a source of carbon and energy.

CURRENT AND POTENTIAL APPLICATIONS

PHAs have many possible uses. The inherent

biocompatibility 8 of these bacterial materials

suggests several medical applications: controlled

drug release, surgical sutures, bone plates, and

wound care. PHAs could also be used as structural

materials in personal hygiene products and packaging applications. At present, higher-volume

commodity plastic applications are limited because of economic constraints. PHBV, for example, costs $8 to 9 per pound. However, costs have

fallen from about $800 per pound in 1980, and it

is believed that the price of PHBV can be brought

to around $4 per pound by 1995. (Petroleumbased polyethylene and polypropylene polymers

cost about 50 cents per pound.) PHBV is now

being used in a variety of molding applications in

the personal care sector (e.g., biodegradable

cosmetic containers-a market where the cost of

the container is almost negligible in relation to the

cost of the contents). In addition, Zeneca is in the

process of commercializing films and paper

coatings from BIOPOL resin. Mitsubishi Kasei

(Japan) is actively involved in the development of

PHAs for use as a biodegradable replacement of

monofilament fishing nets. Because of the desirable environmental characteristics of PHAs, the

number of such niche markets is likely to

multiply.

Over the past 5 years, there has been a

substantial increase in the number of publications

dealing with the biosynthesis, fermentation, and

characterization of the PHA family of biopoly -

mers. It soon may be possible for these polymers

to compete as specialty plastic products. The

ability to genetically engineer the different spea The final degradation product of one type of PHB is a normal constituent of human blood.
cies of bacteria used to produce PHAs (e.g., by

modifying the enzymes inside the bacteria) could

result in the creation of highly customized polymers. Researchers have made significant progress

in unraveling the biosynthetic pathways involved

in the production of PHAs. The genes encoding

the enzymes involved in PHA production have

been isolated and cloned, and thus scientists can

now tailor the biosynthesis process to produce

polymers with different properties. Over the long

term, there is the possibility that these materials

can be made economically in plant species.9

Recently, PHB was successfully synthesized

by using a genetically engineered experimental

plant (Arabidopsis thaliana).10 Researchers are

now exploring how to produce PHAs by modifying the enzyme machinery of corn or potatoes.11

Although significant technical challenges remain,

the PHA family could potentially become a major

agricultural commodity, either as a fermentation

product using raw materials (e.g., glucose) from

the starch industry or, in the longer term, as a new

crop.

 Recombinant Protein Polymers

Proteins are polymers composed of amino

acids. The specific amino acids used and the

sequence of amino acids in a protein polymer

chain are determined by the corresponding DNA

template. Many proteins are of commercial interest because of their catalytic (enzymatic) or

pharmaceutical properties. However, nature has

Chapter 2–Technical Overview of Biopolymer Field 23

Coatings based on corn protein (zein) have good

moisture and grease barrier properties and are being

used to replace polyethylene and wax-coated paper

and paperboard.

also provided a vast array of proteins whose

principal function is to form structural materials

in living organisms. Some of the more familiar

protein materials include wool, leather, silk, and

gelatin (jello is a simple, modified form of the

protein collagen12). Although many of these

structural proteins have been used throughout

history, the advances in recombinant DNA technology have presented new approaches and opportunities for the design and synthesis of protein

materials. In addition, many traditional proteins

prepared by the extraction of animal (e.g., collagen) or plant (e.g., soy or zein from corn) tissue

are being chemically or physically modified for

g The genetic manipulation of bacteria could also alter the economics of PHA production. However, the manufacturing costs for PHAs are

determined primarily by the purification steps rather than the bacterial production steps (see figure 2-l).

10 ~thou@ ~mly work ~ ~s mm is encowa@g, achievfig contro~~ gene expression of HiII plants is a formidable ~d~g.

Inserting the genes that encode the PHB-producing enzymes is relatively straightforward. However, regulating the PHB enzymes and the

existing plant enzymes is a more difficult challenge. See Yves Poirier, Douglas Dennis, Karen Klomparens, and Chris SomemiUe,

‘ ‘Polyhydroxybutyrate, a Biodegradable Thermoplastic, Produced in Transgenic Plants,” Science, vol. 256, Apr. 24, 1992, pp. 520-523.

I I Robert Pwj, c{rn Search of the pktic Potato, ” Science, vol. 245, Sept. 15, 1989, pp. 1187-1189.

12 Collagen is a fi~ous prote~ that is the principal comwnent of animal connective tissue. It is the most abundant of all proteti fo~d ~

mammals, typically accounting for more than 30 percent of body protein. The arrangement of collagen fibers depends on the nature of the tissue.

For example, in tendons, fibers are arranged parallel to one another to give a structure with the tensile strength of a light steel wire. In sk@

where strength and flexibility are required, collagen fibers are randomly oriented and woven together like felt.
2 4 Biopolymers: Making Materials Nature’s Way

Table 2-2—Repeat Units Found in Protein Materials

Protein Source Amino acid repeat unita

Silk Silk worm GAGAGS

Collagen Mammals GPPb

Adhesin Mussel AKPSYPPTYK

Elastin Pig VPGVG

Synthetic Chemically synthesized genes Various

aThere are 20 different amino acids, designated here in short form: A = alanine; G = 91Ycine; K = Iysine; p =

proline; S = Serine; T = threonine; V = valine; and Y = tyrosine. For a full list of amino acid symbols, see Albert

Lehninger, Biochemistry (New York, NY: Worth Publishers, 1975), p. 72.

baen one of the Prolines in collagen is hydrOWfJrOline.

SOURCES: Biolnformation Associates, Boston, MA; Office of Technology Assessment.

new applications in the biotechnology and food

industries. 13 The discussion here focuses on

protein polymers that are being developed by

using the methods of recombinant biotechnology.

PRODUCTION OF RECOMBINANT

PROTEIN POLYMERS

The extraordinary functional diversity of natural proteins underscores the potential advantages

associated with harnessing the genetic code. In

theory, proteins can be designed to have virtually

any structure, and thus specific physical and

chemical properties. The fact that onedimensional genetic sequences can specify proteins having complex three-dimensional structures over distances of hundreds of nanometers

reveals the power of nature’s material synthesis

processes. Current chemical synthesis techniques

are essentially limited to creating polymers in one

dimension only,14 with lengths of less than 10

nanometers .15

A number of proteins that form important

structural materials in various organisms have

been studied extensively. The fibrous proteins

such as collagen and silk have been the subject of

considerable attention. More specialized proteins,

such as the adhesive material that bonds the sea

mussel to the ocean bed and proteins that contribute to the formation of ‘ceramic-like’ materials

(e.g., oyster shells and teeth), are also being

actively studied. A common feature of many of

these proteins is the presence of repeated amino

acid sequences in the polymer product (see table

2-2). These proteins, or specific regions of these

proteins, have structural features similar to block

copolymers (see figure l-l).

Some of the structural proteins have been

chemically synthesized. In this approach, specific

peptides (sequences of amino acids) are created

and then linked together to form a polypeptide

(the protein polymer). However, chemical synthesis of proteins can be quite expensively 

and

rimarily as coatings for paper and paperboard. Soy paper coatings impart a smoother surface and improve 13 SOY and corn proteins ~ ~~ p

surface appearance. Zein has excellent grease and moisture barrier properties. Soy proteins are also being used as structuring agents in

water-based inks, bemuse they are regarded as environmentally preferable to solvent-based inks. See Thomas L. Krinski, “Emerging Polymeric

Materials Based on Soy Prote@” Rowell et al. (eds.), op. cit., footnote 1.

14 men ~Ve ~n some tiv~ces recently in the synthesis of two-dimensional synthetic polymers. However, this work k still smewht

prelimhmry. See Scientific American, “Flat Chemistry,” April 1993, p, 26.

15 See Joseph @@lo, ‘‘Genetic Production of Synthetic Protein Polymers,” Materials Research Bulletin, October 1992, pp. 4S-53.

IS ~ a few CmS, thou~ some fm have been able to develop relatively inexpensive approaches for synthesizing complex polypeptides.

For example, Monsanto developed comme~ial chemical methods for making sornatotrop~ a complicated polypeptide, for about $15 per

pound.
Chapter 2–Technical Overview of Biopolymer Field 25

Figure 2-3—Production of Recombinant Protein Polymers

-—-.— ..—————

/

- L–.-.--.--i.––——---J-. ‘ , Create a synthetic gene encoding the protein

I Genetic contruct (DNA) I

\ –..A polymer of Interest (regions coding for individual

repeat units are indicated by the hatched boxes).

I

Introduce the genetic material Into a suitable

production organism.

—.

v

/-” A

/

/’ 1 >r~y”,) Grow large volumes of the recombinant

\ (DNA ‘ ,, CIIIZ Protein polymer organism and switch on production of

the protein.

U--&-J--u

‘ \..

-. - ..-...-F?/

\

Purify the recombinant

“4 [~,

{ I \

El-L.-n~

protein.

Protein polymer product

SOURCE: Biolnformation Associates, Boston, MA.

typically does not yield products with sufficient produced or investigated by using recombinant

physical and chemical uniformity.

In contrast, the recombinant DNA approach

allows for the production of protein polymers that

have high purity, specific molecular weights, and

excellent lot-to-lot uniformity. This is possible

because the exact sequence of amino acids in the

polymer and the desired molecular weight are

specified by the DNA sequence of the gene. In the

long term, recombinant DNA technology could

become an important strategy for producing

high-value, ‘‘knowledge-intensive’ materials that

are custom-designed for specific applications.

The steps involved in producing recombinant

proteins are illustrated in figure 2-3, Currently, all

of the proteins shown in table 2-2 are being

DNA techniques. The fact that it is now possible

to chemically synthesize genes encoding any

repeat unit suggests almost limitless possibilities

for creating novel protein polymers with unique

physical and functional properties. Although

researchers are addressing major technical problems such as genetic instability, toxicity in

foreign hosts, and metabolic incompatibility,

considerable progress in genetically engineered

protein synthesis has occurred in recent years.17

Initial work in the synthesis of artificial genes has

led to the creation of proteins that could be used

as coatings and adhesives, membrane separators,

and medical and optical materials.18

17 Baause foreign DNA im~ses a metabolic burden on host cells, in some cases these DNA segments cm k destroyed. h ptic~m, he

highly repetitive gene sequences that are necessary to create artificial protein polymers are frequently unstable in microorganisms. In additio~

novel proteins that are encoded by .Synthetic genes maybe toxic to the host cells, thus causing cell death before the polymer an be accumulated

in useful quantities. See David A. Tirrell et al., ‘ ‘Genetic Engineering of Polymeric Materials, ’ Materials Research Bulletin, July 1991, pp.

23-28; see also Joseph Cappello, op. cit., footnote 15.

10 See R&d) Magazine, “Bioderived Materials, ” June 1990, pp. 58-64.

330-076 0 - 93 - 3 : QL 3
26 Biopolymers: Making Materials Nature’s Way

The marine mussel, Mytilus edulis, is shown suspended

in water by threads attached with adhesive to a glass

plate. Biotechnology research on adhesives produced

by rnarine organisms is leading to new adhesives that

can be used for many applications such as surgery and

undersea structures.

CURRENT AND POTENTIAL APPLICATIONS

More than 25 genetically tailored proteins have

been synthesized in microorganisms. Many of

these materials are being transformed into films,

gels, and fibers. One of the first genetically

engineered protein polymers to be introduced

commercially, ProNectin FTM,19 was designed to

serve as an adhesive coating in cell culture

vessels. The polymer was customized to have two

distinct peptide blocks: one block possesses the

strong structural attributes of silk; the other has

the cell-binding properties of the human protein

fibronectin. 20 The peptide blocks were chosen

after analyzing which particular structures could

provide the desired physical, chemical, and biological properties. ProNectin F has demonstrated

excellent adhesion to plastic surfaces such as

polystyrene and thus can be used to attach

mammalian cells to synthetic substrates.21

A similar application of recombinant DNA

technology has led to the development of a

bioadhesive based on a protein from the sea

mussel Mytilus 22 Researchers have genet- edulus.

ically modified yeast cells to produce the basic

mussel protein. An enzyme-catalyzed process

(the enzyme-a tyrosinase-modifies the tyrosine amino acids in the protein) was also developed to convert this recombinant protein into a

true adhesive.23 This polymer could be used as a

marine coating, as a wetting agent for fibers in

composite materials, or as a dental or surgical

adhesive.24 For example, it might be employed as

a sealant during eye surgery .25

A number of other protein polymers are being

investigated by using biotechnology methods.

One intriguing new material is a polypeptide

based on the natural protein elastin found in cows

19 me prote~ 15 produced by protein Polymer Technologies, bC., San Diego, CA.

20 Cappello, op. cit., footnote 15.

21 wi~ ce~ &P5 of ce~s, ProNcxfi F displayed adhesive characteristics superior to that of XMhmd athchment proteins inchK@

fibronectin. Ibid.

22 Enzon Corp. (formerly Genex Corp.) developed the genetically designed adhesive undez the name AdheraCell. See Chen”cal and

Engineering News, “Biotechnology Providing Springboard to New Functional Materials,” July 16, 1990, pp. 26-32.

23 ~5 enzyme.~~yz~ pr~~me is bOw w‘ ‘post-h~htio~’ modi.fkation. The sea mussel performs this rntikation titerpmtein

biosynthesis.

~ Chem’ca[ ad Engineering News, op. Cit., fOOb20te 22.

25 R~ Magazine, op. cit., footnote 18.
and pigs.

26 This rubberlike material responds to

changes in temperature and is able to convert

chemical energy into mechanical energy .27 As a

consequence, the material could be used as a

replacement for ligament tissue, blood vessels, or

any other tissues requiring the contractile properties of elastin.28 Because the peptide is similar in

composition to natural elastin, the polymer is not

expected to elicit an allergic reaction or unfavorable immune system response.

Another interesting material is the lightsensitive protein bacteriorhodopsin (BR). BR is a

retinal protein consisting of 248 amino acids.

When subjected to photons (light) of varying

energy intensity, BR undergoes reversible color

changes. Through substitution of specific amino

acids by genetic engineering, the photochemical

properties of BR can be precisely modified, which

means color changes can be carefully controlled.

The unique properties of BR could lead to

applications in optical data storage, image processing, light switching (computational processing), and holography. Some initial work indicates

that the optical performance of BR is comparable

to conventional materials such as liquid crystals.29

Chapter 2–Technical Overview of Biopolymer Field 27

Recombinant biotechnology is also being used

to modify materials that have been utilized for

thousands of years. Silk has always been a

material of great fascination. Spiders can process

silk protein into a material that has a tensile

strength 16 times greater than that of nylon30 and

a very high degree of elasticity .31 Researchers

have manipulated the genetic code to create

silklike materials with a variety of elasticities.32

Because of their exceptional tensile strength and

elastic properties, these polymers could be used

as fibers for reinforced plastics and other advanced composite materials. In the medical area,

the polymers could potentially be used as wound

dressings, artificial ligaments, and skin or as a

biocompatible coating for prosthetic devices.

However, the yields of genetically modified silk

polymers from microorganisms have thus far

been fairly 10W.

33

Most protein polymer research is focused on

high-technology applications, such as elastomers,

adhesives, bioceramics, and electro-optical materials. To date, commercial applications have

been limited to the use of genetically engineered

adhesives for fixing mammalian cells to culture

vessels. Because of extremely high production

costs, these products will probably have limited

24 Elastin fibers are elastic, load-bearing protein polymers found in connective tissue such as ligaments. Another protein similar to elastin

is resilim a rubberlike polymer found in insects.

‘7 See Science, “Heeding the Catl of the Wild, ” vol. 253, Aug. 30, 1991, pp. %5-%8.

ZB R~ Magazine, op. cit., fOO?210te 18.

29 See N. tipp, C. Brauchle, and D. Oesterhe16 “Mutated Bactenorhodopsins: Competitive Materials for Optical Information

Processing?” Materials Research Bulletin, vol. 17, No. 11, November 1992, pp. 56-60.

so silkworm silk is about two to three timeS stronger than nylon.

31 Spider dragline silk not only ~s=sses great streng~ but alSO has the ability to “sup~con~act.’ Silk fibm wifl con~act to less @@

percent of its original length when wet, This results in a nearly thousandfold decrease in the elastic modulus and an enhanced ability to extend

when necessary. This property allows the spider web to tighten each day when wetted with dew, while still maintaining its shape and tension.

Although some human-made materials can sup-contract in organic solvents, no synthetic materials can supercontract-as spider silk does-in

water alone. The web is constructed of several different silks, each of which is produced in a different spider gland. Some of the silk fibers

contain a number of water-soluble compounds that keep the fibecs wetted, allowing them to stretch and entangle prey that hit the web. See

Randolf V. Lewis, “Spider Silk: The Unraveling of a Mystery, “ Accounts of Chem”cal Research, vol. 25, No. 9, 1992, pp. 392-398.

32 ~otein po]ymer Technologies, Inc. has produced recombinant polymers based on silkworm silk. The company k developed m ~~lci~

silk gene that appears to be stable in host Escherichia coli cells. However, the stability of cloned silk genes in host systems still remains a

significant problem (R&D Magazine, op. cit., footnote 18; Chemical and Engineering News, op. cit., footnote 22. Also see David L. Kaplan

et al., “Biosynthesis and Processing of Silk Proteins, ’ Materials Research Bulletin, October 1992, pp. 4147.

J~ Lewis, op. cit., footnote 31.
. . . . .

28 Biopolymers: Making Materials Nature’s Way

Figure 2-&The Structure of Cellulose

CH20H

o o

H o

H

OH H

HO H

H OH

L

YFo

H ‘\!

O+OH H/”

H OH

H C H20 H

D

o

H

o OH H

H OH

n

H,OH

The cellulose molecule is composed of glucose units connected by B(1-4) bonds (see Figure 1 -3). Starch

has an identical chemical composition to cellulose except for its connecting bonds-a(l -4). The different

linkages in starch molecules endow them with a greater water volubility than cellulose. In humans, starch

can be digested while cellulose cannot be digested.

SOURCE: Office of Technology Assessment, 1993.

success (e.g., experimental quantities of the

genetically derived sea mussel adhesive were at

one time selling for about $45 per milligram, or

$20 million per pound). However, over the long

term, genetic techniques may allow production to

be scaled up significantly at reasonable cost.

Once programmed with the proper genetic instructions, bacterial cells can work in parallel by

the billions to produce polymer materials. 34

Although some biotechnology companies have

been involved in protein polymer research for 10

years, most recombinant protein materials are still

in early stages of development.

Nevertheless, this area of research is one of the

most active and better funded in the biopolymer

field. In addition to providing new materials,

genetic engineering is now enabling scientists to

study how biological systems transform proteins

into final products. It is remarkable that living

organisms are able to produce sophisticated

materials under mild processing conditions (i.e.,

low temperature and pressure in water-based

environments), without creating toxic byproducts. This is certainly not the case for a variety

of human-made materials.35 Spiders and silkworms, for example, can transform water-soluble

protein droplets into globally aligned insoluble

fibers. 36 The fibers are spun with very little

energy consumption. Thus, protein polymer research could also lead to the development of

radically new industrial processing methods that

pose little threat to the environment.

 The Microbial Polysaccharides

BACTERIAL CELLULOSE

Cellulose is the most abundant component of

biomass and the basic feedstock of the paper and

pulp industries. Traditionally extracted from plant

tissue (trees, cotton, etc.), cellulose can also be

produced by certain bacterial species by fermentation, yielding a very pure cellulose product with

unique properties.

34 s~i~~ce, op. cit., f00b30te 27.

3S my ~vmced mat~~s ~sw~es~~ at exhemely high temperature and pressure, and require toxic substi~s at various s@es of

processing. See U.S. Congress, Office of Technology Assessmen~ Advanced Materials by Design, OTA-E-351 (Washington, DC: U.S.

Government Printing Office, June 1988).

36 Sik fibers ~pu~ed from spiders, not forced out by pressure. The fibers are formed as they travel down a tubular duct kid@ from tie

gland to the exit valve. The key chemical and physical events that change the soluble proteins into solid fibers occur during this journey. As

the protein molecules travel down the duct, they align themselves into regular arrays. It appears that the mechanical and frictional forces at work

in the duct facilitate the transformation of the soluble protein droplets into solid fibers. See Lewis, op. cit., footnote31; Kaplau op. cit., footnote

32.
Chapter 2–Technical Overview of Biopolymer Field 29

Cellulose is a polysaccharide consisting of

linear glucose chains (see figure 2-4). Bacterial

cellulose is synthesized in a process whereby the

polymer material is extruded from the bacterial

cells. Most cellulose-producing bacteria (e.g.,

Acefobacter) extrude cellulose as a ribbonlike

product from a single fixed site on the cell surface.

This results in the formation of a network of

interlocking fibers.

Bacterial cellulose is produced under conditions of agitated fermentation. High polymer

production rates occur when the growth medium

contains glucose, salts, corn steep liquor, iron

chelators, and various productivity enhancers.

Current yields are more than 0.2 gram of cellulose

per gram of glucose, and production has been

demonstrated in commercial 50,000-gallon fermenters. After fermentation, the bacterial cells

are destroyed during a hot caustic treatment.

Bacterial cellulose is a water-insoluble material

that has a very large surface area because of its

large network of fibers, Bacterial fibers have

roughly 200 times the surface area of fibers from

wood pulp.37 This, coupled with their ability to

form hydrogen bonds, accounts for their unique

interactions with water. Bacterially derived cellulose materials can absorb up to six times their

weight of water, and when used as suspensions,

they have pseudoplastic thickening properties.

Sheets prepared from bacterial cellulose have

excellent mechanical properties.

CURRENT AND POTENTIAL APPLICATIONS

Considerable progress has been made in the

field of bacterial cellulose synthesis in the past

few years. Bacterial cellulose is now available in

limited quantities from Weyerhaeuser in the

United States and Ajinomoto in Japan. The most

prevalent applications of bacterial cellulose exCellulon@ engineered bacterial cellulose fiber is a

product under development at Weyerhaeuser

Company. The unique reticulated network of fine

fibers gives the biopolymer its thickening, binding,

and coating properties. The fibers have a typical

diameter of 0.1 microns (0.1 millionth of a meter),

while some wood pulp fibers have a diameter of

25 to 35 microns.

ploit its very large surface area and its ability to

absorb liquids. Consequently, very low concentrations of bacterial cellulose can be used to create

excellent binding, thickening, and coating agents.

Because of its thickening properties, many applications in the food industry are possible. Paper

that is coated with bacterial cellulose is extremely

smooth and protects the underlying fibers from

moisture. End uses in oil and gas recovery,

mining, paints, adhesives, and cosmetics are also

envisioned. This material is currently used by

Sony Corporation in the production of high-end

audio speaker systems because of its excellent

acoustic properties.38 In the last 10 years, at least

37 Weyerbeuser’s bactefi~ ~ll~ose fibers (the product is called Cellulon) have a typical diameter of 0.1 ~crons ~ oPPosed to some wood

pulp fibers that are 25 to 35 microns across. The small fiber diameter results in an extraordinarily high surface area and is responsible for much

of the fiber’s functionality as a thickener and binder. A. Robert Winslow, Cellulon Fiber Business Marketing Manager, Weyerhaeuser

Company, personal communication, Aug. 31, 1993.

38 me ~gh.fideliq headphones employ bacterial cellulose as diaphragms. The headphones retail fOr about $$,000 a wt.
30 I Biopolymers: Making Materials Nature’s Way

Figure 2-&The Structure of Xanthan Gum

AcOCH2 I w

—o

I OH O

OH

co*

I ) ‘---- o , u

,/

‘ OH

c o * , OCHL

‘\\\ 8’ ,/- --00

c ’ \ ~

OH

n

--@

4Ac M

n

CHEMICAL STRUCTURE BLOCK STRUCTURAL REPRESENTATION

The Xanthan gum repeat unit is made of 5 sugar groups: two glucose (G) groups, two mannose (M) groups, and one gluouronic

acid (GA) unit. Pyruvate (Pyr) and acetyl (Ac) units are also present in the mannose structures. The degree of pyruvate and acetate

substitution varies with the specific fermentation conditions. The charged pyruvate molecule alters xanthan’s electrical properties,

while the acetate serves to stabilize the conformation or spatial arrangement of xanthan.

SOURCE: Biolnformation Associates, Inc.., Boston, MA.

50 patents on the production and applications of

bacterial cellulose have been filed. Currently,

bacterial cellulose sells from $35 to $50 per

pound. If the material is to be used in commodity

as opposed to niche applications, production costs

will have to drop. A Japanese consortium was

recently formed to reduce the manufacturing

costs of bacterial cellulose.39

XANTHAN

Xanthan gum, a complex copolymer produced

by a bacterium, was one of the first commercially

successful bacterial polysaccharides to be produced by fermentation. The xanthan polymer

building blocks or “repeat units” contain five

different sugar groups (see figure 2-5). The

xanthan-producing bacterium, Xanthomonas campestris, is one of the frost bacterial polysaccharide

w The comemi~ venture in bacterial cellulose technology is supported fmrmcially by the Japan Key TectioIogY Center, a joint

organization under the Ministry of International Trade and Industry and the Ministry of Post and Telecommunications, along with six private

sector companies: Ajinomoto, Shimizu Construction N- Mitsubishi Paper, Niklciso, and Nakarnori Vinegar. The venture is called

Biopolymer Research Co., Ltd, and its principal focus will be the development of mass production techniques for cellulose that is made by

fermentation (Japan Chemical Daily, Apr. 13, 1992).
.-

Chapter 2–Technical Overview of Biopolymer Field 31

production systems targeted for genetic engineering. Under certain conditions, genetic modification of Xanthomonas by using recombinant DNA

technology has increased the rate of xanthan

production by more than 50 percent.40 In the

future, recombinant DNA technology may enable

entirely new xanthan biosynthetic pathways to be

created in host organisms.

Xanthan gum is produced by large-scale fermentation of X. campestris using a number of

different feedstocks including molasses and corn

syrup. The gum is extruded from the bacteria

during the polymerization process and can be

recovered by alcohol precipitation following

removal of the bacterial cells. For some applications such as enhanced oil recovery, the crude

culture broth can be used directly following

sterilization. Probably the most significant technical problem in the production of xanthan is the

fact that as the polymer is produced, the fermentation medium becomes increasingly viscous. This

increases the energy required for the mixing

process that feeds oxygen to the bacterial cells.

CURRENT AND POTENTIAL APPLICATIONS

The unusual physical and mechanical properties of xanthan gum make it an attractive polymer

for industrial and biological use. It is used

extensively in both the food and the nonfood

industries. Examples of industrial applications

include oil recovery (provides viscosity control in

drilling mud fluids), mineral ore processing (used

as a biocide), paper manufacturing (used as a

modifier), agriculture (acts as plant growth stimulator), pharmaceuticals (being evaluated for sustained drug release), and cosmetics (controls dust

release). Food applications include gelling agents

for cheese spreads, ice creams, puddings, and

other deserts. More recently, xanthan has been

used in the new clear-gel toothpastes. Reading the

labels on many of the processed foods in the

supermarket should give one a clear picture of the

wide use of this material. Good examples are

packet soups and many of the fat-free foods that

have recently become available.

In terms of production volume, xanthan gum is

the most widely used microbial polysaccharide.

Worldwide production is currently in the range of

10,000 to 20,000 tons. Companies such as ADM

and Merck have recently announced the expansion of their xanthan production facilities. About

60 percent of the xanthan produced is used in

foods, with the remaining 40 percent used in

industrial applications. Food-grade xanthan costs

about $8 to $10 per pound, while non-food grades

sell for about $5 per pound. Thus far, only

experimental samples of genetically modified

xanthan have been produced.41

DEXTRANS

Dextran is the generic name of a large family of

microbial polysaccharides that are assembled or

polymerized outside the cell by enzymes called

dextran sucrases. This class of polysaccharides is

composed of building blocks (monomers) of the

simple sugar glucose and is stored as fuel in

yeasts and bacteria. Dextrans are produced by

fermentation or enzymatic conversion of the

feedstock sucrose, a product of the sugar beet and

sugarcane industries. Most commercial dextran

@ See T.J. Pollack and J. Thorne, SphW COW., ‘‘Enhanced Manufacture of Xant.han Gum with Genetically Modif”ed Xandwnonas,”

European Patent Application EP 287,367. CA: 9358z; and M. Yalpani, Polysaccharide Synthesis, Modification, and StructurelProperty

Relations, Studies in Organic Chemistry 36 (Amsterdam: Elsevier, 1988).

q I TWO SIIMI1 biotecholog companies, Syntro (San Diego, CA) and Synergen (Boulder, CO), worked on genetically ememed x~ti

gums in the 1980s. Neither fii was successful in marketing these xanthan products because their manufacturing costs were much higher than

conventional xanthan production methods. The relatively high production costs of genetically moditled polymers is a major problem that could

seriously constrain biopolymer commercialization efforts. ‘‘Conventioml wisdom’ holds that biopolymer production costs must fafl below

$20 per pound for most niche market applications, and below $5 per pound for more general applications. Because of these manufacturing

hurdles, some producers of genetically derived biopolymer compounds are focusing on low-volume, high value-added applications such as

medical materials or specialized industrial adhesives. David Many~ President, Adheron Corporation personal communication Aug. 24, 1993.
32 Biopolymers: Making Materials Nature’s Way

production uses the microorganism Leuconstoc

mesenteroides. Dextran can be synthesized by

using either large-scale industrial fermentors or

enzymatic filtration methods. The latter approach

is generally favored since it results in an enhanced

dextran yield and a uniform product quality,

which allows the product to be readily purified.

Both of these production methods permit system

conditions to be adjusted so as to control the

molecular weight range of the products. This

feature is an integral requirement for polysaccharide biosynthesis.

CURRENT AND POTENTIAL APPLICATIONS

Dextran polymers have a number of medical

applications. Dextrans have been used for wound

coverings, in surgical sutures, as blood volume

expanders, to improve blood flow in capillaries in

the treatment of vascular occlusion, and in the

treatment of iron deficiency anemia in both

humans and animals. Dextran-hemoglobin compounds may be used as blood substitutes that have

oxygen delivery potential and can also function as

plasma expanders. Chemically modified dextrans

such as dextran sulfate have both antiulcer and

anticoagulant properties. Other modified dextrans such as Sephadex@ are used extensively in

the separation of biological compounds.

In the industrial area, dextrans are being

incorporated into x-ray and other photographic

emulsions. This results in the more economical

usage of silver compounds and at the same time

reduces surface gloss on photographic positives.

Dextrans are used extensively in oil drilling muds

to improve the ease and efficiency of oil recovery.

They also have potential use in agriculture as seed

dressings and soil conditioners. The protective

polysaccharide coatings are found to improve

germination efficiencies under suboptimal conditions.

Although many applications have been proposed for dextrans, only a small number of these

have been realized and developed on a large scale.

There is considerable potential for using low-molecularweight dextrans in the biomedical industry in

surgery and drug delivery systems. However,

low-molecular-weight dextrans sell for about $80

per pound. As new and higher-volume applications for these materials are developed, largescale production of dextrans may represent a

major new market for the sugarcane and sugar

beet industries.

PULLULAN

Pullulan is a water-soluble polysaccharide

produced outside the cell by several species of

yeast, most notably Aureobasidium pullulans.

Pullulan is a linear polymer made up of monomers that contain three glucose sugars linked

together (see figure 2-6).

For more than a decade, a Japanese firm,

Hayashibara Biochemical Laboratories, has used

a simple fermentation process to produce pullulan. A number of feedstocks are used for this

process, including waste streams containing simple sugars. Pullulan can be chemically modified

to produce a polymer that is either less soluble or

completely insoluble in water. The thermal and

ionic (electrical) properties of pullulans can also

be altered.

CURRENT AND POTENTIAL APPLICATIONS

Pullulan and its derivatives have a number of

useful properties and consequently have many

possible applications. Hayashibara Biochemical

Laboratories currently sells three different pullulan grades: industrial grade ($6.50 per pound),

food grade ($11 per pound), and medical grade

($15 per pound). Current efforts to increase the

yields of pullulan from the fermentation of

various strains of A. pullulans suggest lower

production costs are likely in the future. Pullulan

compounds are biodegradable in biologically

active environments, have high heat resistance,

and display a wide range of elasticities and

solubilities. This versatility allows them to be

utilized in many different ways.

Pullulan has many uses as an industrial plastic.

It can be formed into compression moldings that

resemble polystyrene or polyvinyl chloride in
Chapter 2–Technical Overview of Biopolymer Field 33

Figure 2-6-The Structure of Pullulan

CH2 CH20H CH2OH

}--- ------o }-- - -0 &——- o

K&L

OH

Wo’tio

OH OH

CH2 CH20H CH20H

~o ,~() L. ._()

Pullulan is made up of glucose sugars linked together in groups of three. The three member repeat units are

connected together in a branched fashion.

SOURCE: Office of Technology Assessment, 1993.

transparency, gloss, hardness, strength, and toughness, but is far more elastic. It decomposes above

200’C, apparently without the formation of toxic

gases.

42

A completely different application of pullulan

can be found in the food industry. It can be used

as a food additive, providing bulk and texture. It

is tasteless, odorless, and nontoxic. It does not

break down in the presence of naturally occurring

digestive enzymes and therefore has no caloric

content. Consequently, it can be used as a food

additive in low-calorie foods and drinks, in place

of starch or other fillers. In addition, pullulan

inhibits fungal growth and has good moisture

retention, and thus can be used as a preservative.

Pullulan can also be used as a water-soluble,

edible film for the packaging of food products. It

is transparent, impermeable to oxygen, and oiland grease-resistant. Foods can be either immersed in a solution of pullulan or coated by a

polymer spray. After the pullulan coating is dried,

an airtight membrane is formed. The membrane

can be used in the packaging of drugs and

supplements, as well as oil-rich food products that

are vulnerable to oxidation, such as nuts and fried

foods. It is not necessary to remove the pullulan

coating before eating or cooking. In the packaging

of tobacco, pullulan enhances product longevity

and retention of aroma. It also protects against

oxidative degradation as well as attack by mold.

Water insoluble coatings may be made by using

the esterified or etherified forms of pullulan.

Ester and ether derivatives of pullulan have

adhesive qualities similar to those of gum arabic.

Viscosity and adhesive properties depend on the

degree of polymerization. Modified pullulan can

be used as a stationary paste that gelatinizes upon

moistening. Fibers can be made from concentrated solutions of pullulan having high viscosity.

The fibers have a gloss resembling rayon and a

tensile strength similar to that of nylon fibers.

Pullulan and its ester or ether derivatives can also

be used as binders, in conjunction with other

materials, for the production of nonwoven fabrics. With or without the addition of other

vegetable pulps, it can be used to make paper that

is suitable for printing and writing. Because it is

42 However, it should be not~ that partial combustion of carbohydrates can produce cMbOn monofide.
34 Biopolymers: Making Materials Nature’s Way

an antioxidant, pullulan can substitute for gum

arabic in lithographic printing.

There are a plethora of other applications.

Pullulan can be used as a binding agent for solid

fertilizers, allowing time-released fertilization

and thereby avoiding the burning of crops by

controlling the release of nitrogen in the fertilizer.

As a binding agent in sand molds used for metal

casting, pullulan prevents the generation of dust

or toxic fumes. The biopolymer can be used as a

flocculating or aggregating agent for the precipitation of potash clays, uranium clays, and ferric

hydroxide from slurries used in the beneficiation

of mineral ores. (Currently, synthetic chemicals

are primarily employed in mineral processing.)

Pullulan can be used as an additive to resins and

paints, where its preservative and antioxidation

properties help retain color and gloss. Also,

pictures or illustrations printed on pullulan film

with edible ink can be transferred onto food

products. In the medical area, pullulan acts as a

plasma extender without undesired side effects.

After metabolic turnover, it is completely excreted. Pullulan compounds can also serve as

drug carriers, and can be used as medical adhesives.

Although markets for many of the applications

listed here are still relatively small, with some

applications only in the exploratory stage, pullulan appears to have long-term commercial potential. In sum, pullulan’s many disparate uses may

entitle it to become known as a biopolymer

‘‘wonder material.

GLUCANS

Glucans are, by definition, any homopolymer

of the simple sugar glucose. This large group

includes cellulose,

However, the term

pullulan, and yeast glucan.

‘‘glucan’ is commonly used

to describe the glucan component of the yeast cell

wall. A common source for this glucan is baker’s

yeast, Saccharomyces cerevisiae, although it is

also found in a number of other sources (bacteria,

fungi, lichen, and higher plants, e.g., barley).

Large supplies of inexpensive yeast are available from both the baking and the brewing

(brewer’s yeast) industries. Glucans are the most

abundant polymers in yeast, making up approximately 12 to 14 percent of the total dry cell

weight. Glucan is readily purified from yeast cells

by using hot alkali treatment to remove all other

cellular materials, thereby allowing recovery of

the insoluble glucan material. Yeast glucan particles purified by this method contain both high

molecular weight and lower molecular weight

polymers.

CURRENT AND POTENTIAL APPLICATIONS

Glucans have a number of potential medical

uses.

43 Glucans that are extracted from yeast cell

walls are found to markedly increase the ability of

some organisms (e.g., mice) to resist invading

foreign bodies. Because of its action as an

immunomodulator, or enhancer of the immune

system, a number of studies have been performed

exploring the use of glucan as an anti-infectious

agent. Glucan is also effective as an antiviral

agent in plants. For example, one form of glucan

is very effective in protecting many species of

tobacco plant against invasion by the tobacco

mosaic virus and tomato black ring virus. Plants

can be either injected or sprayed with the glucan

polymer.

43 s~ce polysacc~des play an important role in cell ad.lmsionand asmolecdar reCO@tiOn el~ents (JJlyCOprOtefi), tieypotm~y ~ve

a number of medical applications. Recent developments in the cloning and expression of enzymes known as oligosaccharyl transferases could

facilitate the creation of new carbohydrate-based pharmaceuticals. See ChemicaZ andEngineering News, “Race Is on ‘h Develop Sugar-Based

Anti-inft ammatory, Antitumor Drugs, ” Dec. 7, 1992, pp. 25-28. Apart from genetic engineering methods, some of these enzymes can also be

chemically isolated. A new enzyme isolation method is being used to simplify the synthesis of novel polysaccharide CQmpounds. Some of the

new compounds have been found to prevent bacterial pneumonia in animals and are also being evaluated as anti-infective drugs. Ihe enzymes

could also be used to create polysaccharides that act as industrial coatings (e.g., as coatings on ship hulls to improve fuel efllciency and prevent

marine corrosion). Stephen RotlL Neose Pharmaceuticals, personal communication, Sept. 3, 1993. Also see Chemical and Engineering News,

“Patent Grants Broad Protection to Enzymatic Carbohydrate Synthesis,” Mar. 29, 1993, pp. 24-27.
Chapter 2–Technical Overview of Biopolymer Field I 35

Several studies using different tumor models in

mice and rats have revealed that glucans can

inhibit tumor growth. The less toxic, soluble form

of glucan is effective as an antitumor agent,

although it is slightly less effective than the

particulate form. Many antitumor glucans are

currently being used in Japan on human subjects.

In the United States, one company (Alpha Beta

Technology of Worcester, Massachusetts) has

yeast glucans that are undergoing clinical trials as

immune-stimulating agents. Another interesting

property of glucans is that they are radioprotective (i.e., they appear to enhance survival

by preventing death due to postirradiation infection). This enhances the survival of test animals

after otherwise lethal doses of radiation.

Although glucans are being exploited principally for their antitumor, anti-infectious, and

radioprotective properties, they also have nonmedical applications. Glucans resist breakdown

when attacked by digestive enzymes, and thus can

be used as noncaloric food thickeners. Other

possible applications include use in sustainedrelease tablets, encapsulation of oxygen for mass

transfer in fermentation reactions, and as a solid

support material for chromatographic separations.

GELLAN

In addition to xanthan, pullulan, and glucan, a

number of other microbial polysaccharides are

being investigated for applications as thickening

agents. These include succinoglycan, scleroglucan, and the three structurally related polymers rharnsan, welan, and gellan. Among these,

gellan gum is the most recent microbial polysaccharide to be given Food and Drug Administration (FDA) approval for applications in food

products (September 1990). Gellan is a complex

polysaccharide having a four sugar repeat unit

(glucose-glucuronic acid-glucose-rhamnose). It

is produced by the bacterium Pseudomonas

elodea, which is derived from plant tissue.

The production of gellan follows essentially

the same fermentation process described for

xanthan. The properties of gellan can be easily

modified. A hot caustic treatment of gellan yields

a polymer that has the desirable characteristic of

low viscosity at high temperature. Cooling gellan

in the presence of various cations (e.g., calcium)

results in the formation of strong gels.

CURRENT AND POTENTIAL APPLICATIONS

Gellan gum represents the newest member of

the microbial polysaccharides to be developed

commercially. Developed and produced by the

Kelco Division of Merck under the trade names

Kelcogel and Gelrite, this polymer has applications in the food industry as a gelling agent in

frostings, glazes, icings, jams, and jellies. GelIan

currently sells for about $5 per pound.

SELECTED POLYMERS OF PLANTS AND

HIGHER ORGANISMS”

 Starch

Starch is the principal carbohydrate storage

product of higher plants. The term starch actually

refers to a class of materials with a wide range of

structures and properties. Starch polymers can be

extracted from corn, potatoes, rice, barley, sorghum, and wheat. The principal source of starch

for industrial and food purposes is corn. In the

United States, about 4.5 billion pounds of cornstarch is used annually for industrial applications. 45 Starches are mixtures of two glucan

polymers, amylose and amylopectin. 46 These

polymers are accumulated in plants as insoluble

energy storage granules, with each granule containing a mixture of the two polymers. Plant

~ Higher ~rga~sm (l.e,, eqotes) refer to all organisms except viruses, bacteri& and bhle-gr~ ~gae.

45 see us Congtis, Ofilce of Te~-moloW Assessmen6 Agn’culmral Cowdities as Indusvial Raw Materials, OTA-F-476 ~aS~tOrl+

DC: U.S. Government Printing Office, May 1991).

46 @ylose is a /inear ~lmer of glucose tits, w~e amylop~~ is a branched polymer of glucose W& (~ figure 1-3).
36 Biopolymers: Making Materials Nature’s Way

breeding techniques have been used to produce

new strains with altered ratios of amylose to

amylopectin (e.g., waxy corn contains only 0.8

percent amylose compared with natural corn,

which contains 28 percent amylose, and amylomaize can contain up to 80 percent amylose). The

ability to manipulate the ratio of amylose to

amylopectin by strain development has drastically reduced the economic costs associated with

physical separation of the two polymers. This is

important because amylose and amylopectin have

different properties and applications.

CURRENT AND POTENTIAL APPLICATIONS

Because of its low cost and widespread availability, starch has been incorporated into a variety

of products. Chemical modification of starch

polymers can lead to a number of useful derivatives. Current U.S. production of ethanol requires

about 400 million bushels of corn. An additional

several billion pounds of cornstarch is used for

nonfuel purposes. Approximately 75 percent of

the industrial cornstarch produced is transformed

into adhesives for use in the paper, paperboard,

and related industries. Because cornstarch can

absorb up to 1,000 times its weight in moisture, it

is used in disposable diapers (about 200 million

pounds annually), as a treatment for burns, and in

fuel filters to remove water. Cornstarch polymers

are also used as thickeners, stabilizers, soil

conditioners, and even road deicers.47

In recent years, starch has attracted considerable attention as a biodegradable additive or

replacement material in traditional oil-based commodity plastics. Although a number of starchplastic material blends have been used in different

products, particularly packaging and garbage

bags, there has been considerable controversy as

to whether these starch-polymer composites can

biodegrade.48 Starch itself degrades readily, and

is in fact one of main components of the

biological food chain. When added to petroleumderived polymers such as polyethylene, starch

can in theory accelerate the disintegration or

fragmentation of the synthetic polymer chains.

Microbial action consumes the starch, thereby

creating pores in the material, which weakens it

and enables it to break apart. Many have incorrectly characterized this process as a form of

biodegradation. Independent tests of polyethylenestarch blends show that starch may biodegrade,

but that the overall polymer formulation will not

biodegrade at any significant rate. Distintegration

of polyethylene-starch blends is not the same as

biodegradation. Moreover, studies indicate that

degradation rates vary considerably under different temperature, oxygen, and moisture conditions. In landfills, for example, degradation rates,

even for readily degradable materials, are extremely s10W.

49 Under optimal conditions, breakdown of starch-plastic blends that contain less

than 30 percent starch is quite slow. Some

research indicates that the starch composition

needs to exceed about 60 percent before significant material breakdown occurs.50

These problems have led to the development of

a new generation of biodegradable materials that

contain very high percentages of starch. Under

certain conditions, starch can be combined with

water and other compounds to create a resin that

is somewhat similar to crystalline polystyrene.

Warner-Lambert has recently introduced the

NOVON@ family of polymers that contain from

40 to 98 percent starch and readily dissolve in

water. The NOVON resins combine starch with

other biodegradable materials, and when dis47 U.S. Congress, op. cit., fmtnote 45, pp. ~W.

48 See “Dega&ble Plastics Generate Controversy h Solid WaStC Issues, ’ Chemical & Engineering News, June 25, 1990, pp. 7-14; and

“Degradable Plastics,” R&D Magazine, March 1990, pp. 51-56.

49 Safiw landfills me essentiwy biologically inactive environments. See the testimony of Joan Ham on “Degradable Plastics and

Municipal Solid Waste Management” before the Senate Committee on Governmental Affairs, July 18, 1989.

so us. Congess, Offlm of TedmoIogy Assessment op. cit., f~~ote 45) P. 96.
Chapter 2–Technical Overview of Biopolymer Field 37

posed in biologically active environments such as

compost facilities and wastewater treatment systems, display degradation characteristics similar

to lignocellulosic materials (e.g., leaves, woodchips, and paper) .51

Properties of these new materials can be varied

as the composition of starch and other material

components change. They can replace traditional

plastics used in food service, food packaging,

personal health care, agricultural, and outdoor

markets. Early applications of NOVON polymers

include compost bags, degradable golf tees,

loose-fill packaging, cutlery, pharmaceutical capsules, and agricultural mulch films. The company

opened a 100-million-pound NOVON manufacturing facility in 1992. The materials are being

targeted for markets where the benefits of their

biodegradability can be clearly demonstrated. To

fully take advantage of their environmental characteristics, however, a coordinated compost infrastructure will have to be established.52 Although

these starch-based resins cost two to four times

more than commodity resins ($1.50 to $3 per

pound), their novel properties might lead to the

creation of new specialty markets.

 Plant Cellulose

As mentioned previously, cellulose is one of

the most abundant constituents of biological

matter. 53 It is the principal component of plant

cell walls. Among the plant cellulose, cotton

fiber is the most pure, containing around 90

percent cellulose. Wood, on the other hand,

consists of about 50 percent cellulose. Cellulose

serves as an important material feedstock for

many industries. U.S. production of cellulose

fibers amounted to 485 million pounds in 1991.

By adding various functional groups to the basic

4

New starch-based thermoplastic biopolymers such as

the AMYPOLTM family of resins are water resistant

and can be extruded, pelletized, and injection-molded

into industrial and consumer products and films.

glucose building blocks of cellulose (see figure

2-4), a range of useful derivatives (cellulosics)

can be created.

CURRENT AND POTENTIAL APPLICATIONS

Chemically modified plant cellulose are used

in a remarkably diverse set of applications.

Cellulose derivatives are used to forma variety of

fibers, thickening solutions, and gels. For example, carboxymethylcellulose (CMC) is used as a

thickener, binder, stabilizer, suspending agent, or

flow control agent. The major markets for CMC

are detergents, food, toothpaste, shampoo, skin

lotions, textiles, paper, adhesives, ceramics, and

latex paints. In the biotechnology area, CMC gels

are used for separating molecules. Hydroxyethylcellulose (HEC) is a water-soluble compound

that has major applications in the oil industry.

HEC is used as a thickener in drilling fluids and

as a fluid-loss agent in cementing. Hydroxypropylcellulose (HPC) has excellent surface proper51 me ~ompmy rePf15 tit we end pr~ucts of these new materials are carbon dioxide, water, and bio~s, ~~ no Persistent syn~etic

residues. See the testimony of Ken Tracy, Vice-President of Environmental Technology, Warner Lambefl Company, before t.be Senate

Committee on Environment and Public Works, June 5, 1991.

52 For more on ~5 ~bj~t, SW us. congres5, off~~~ of T~~olo~ Assessment Facing Ameficu’~ Trash: Wh@N~t~or MUnicipa/ SO~id

Waste? OTA-O-424 (Washington, DC: U.S. Government Printing Oflice, October 1989).

53 B~ause of cell~ose’s abundance it sells for about 30 to W Cents per pound.

330-076 0 - 93 -4 : QL 3
38 Biopolymers: Making Materials Nature’s Way

A photomicrograph shows modified ethyl cellulose

films magnified by a factor of 2,000. The materials are

being evaluated as carriers for the controlled-release

of nitrogen fertilizers.

ties and forms highly flexible films. It is used in

coating pharmaceutical tablets, in molding operations, in paper coatings, and as a suspending agent

in inks, cleaners, and polishes. In the medical

area, hydroxypropylmethylcellulose (HPMC) has

shown considerable promise as an agent for

lowering blood cholesterol levels.54

There are many other useful derivatives. Cellulose acetate is a plastic-grade material that is

widely used in packaging, particularly for blisters, skins, transparent rigid containers, and

windows in folding or setup boxes.55 In addition,

cellulose acetate is used in some fabrics and as a

write-on pressure-sensitive tape (e.g., for credit

card receipts). Methylcellulose, created by treating cellulose fibers with methyl chloride, has

excellent absorption properties and is a good

thickener. It has been used in a variety of food

products, including salad dressings, pie fillings,

and baked goods. Nonfood applications include

adhesives, agricultural chemicals, tile cements,

plywood glues, printing inks, and cosmetics.

Cellulose is also receiving considerable attention as a potential feedstock for liquid fuels,

particularly ethanol. By either acid or enzymatic

treatment (biological enzymes break down the

cellulose into its basic sugars), cellulose can be

converted to fermentable glucose and then distilled to remove ethanol. Although not currently

competitive with ethanol derived from corn or

sugarcane, the economic attractiveness of cellulosederived fuel could very well change with advances in biotechnology .56

Cellulose will no doubt continue to be a major

material feedstock for a wide spectrum of industries. Future research is likely to focus on the

development of new chemical derivatives and the

creation of composites that combine cellulose

with other biodegradable materials.

 Lignin

Lignin is a polymer found in woody and

herbaceous plants. Its principal function is to

provide structural support in plant cell walls.

Lignin consists of phenylpropane building blocks

and belongs to the polyphenol family of polymers. Along with cellulose and hemicellulose,

lignin is one of the three chemically distinct

components occurring in plant tissue. Typically,

woody and herbaceous biomass consists of 50

percent cellulose, 25 percent hemicellulose, and

% see Genetic Engineering New$* “High Molecular Weight Cellulose Derivative Shown to Lower CholestemL” July 1993, p. 26.

55 However, cellulose esters such as cellulose acetate are not degmdable.

56 us. conue~s, office of Te~hnology Assmsm~~ Fueling DeVelOp~flt: Energy TeC/WWIOgieS for Developing c0U?lm”e5, OTA-E516

(Washington DC: U.S. Government Printing Office, April 1992), pp. 226-227.

57 ~addition t. ~ese we ~ficip~ bio~s compo~nts,-~ounts of o~er compounds CmbC prescntdependingon tkphlt Sp~itX.

Common examples include fatty acids, waxes, tannins, and more specialized compounds such as terpene (used as a substitute for

chlorofluorocarbons in electronics manufacturing) and taxol (a compound being explored as an anticancer dreg).
Chapter 2–Technical Overview of Biopolymer Field 39

25 percent lignin.57 Wood is a complex lingocelluolosic composite,58 Lignin polymers are highly

amorphous, three-dimensional structures that are

associated with hemicellulose and play a key role

in preventing decay of the lignocellulosic material. Lignin is generated in great quantities as a

byproduct of wood pulping processes and consequently is relatively inexpensive. The most common commercial form of lignin is lignosulfonate,

a compound derived from sulfite pulping. Higherpurity lignin can be obtained from “kraft”

pulping, but this process is more costly .59

CURRENT AND POTENTIAL APPLICATIONS

At present, most of the lignin that is isolated

from pulping processes is burned as an on-site

fuel source. However, the material is increasingly

being used in nonenergy applications.60 Because

lignin acts as a natural adhesive holding cellulose

fibers together in plant cell walls, many of its

commercial applications take advantage of this

property. Millions of pounds of lignosulfonates

are used annually for road dust control, Lignosulfonates are also employed as binding agents in

molding applications and in animal feed. Lignin

derivatives are beginning to be used as phenolic

adhesives that can replace formaldehyde-based

compounds in applications such as industrial

packaging and tape.

The ionic properties of lignosulfonates and

kraft lignins allow them to act as dispersants.

They are being used to prevent mineral buildup in

boilers and cooling towers, as thinning agents in

oil drilling muds and concrete admixtures, and as

dispersing agents in pesticide powders. Some

major chemicals are also produced from lignin

precursors. For example, vanillin, the principal

ingredient in artificial vanilla, is derived from the

aromatic components of lignin. In addition, chemically modified lignins are being explored for

possible pharmaceutical applications. The development of specialized lignin compounds, such as

electrically conducting polymers and engineering

plastics, is an area of considerable research.

 Chitin

Chitin, a polysaccharide, is one of the most

ubiquitous polymers found in nature. It is almost

as common as cellulose, and possesses many of

the structural and chemical characteristics of

cellulose (see figure 2-7). Chitin is an important

structural component of the exoskeleton of a great

number of organisms such as insects and shellfish. It also serves as a cell wall component of

fungi and of numerous plankton and other small

organisms in the ocean (see box 2-A for examples

of other marine polysaccharides). Because of the

different biological requirements of these various

species, chitin is an extremely versatile natural

polymer. Chitin and its most important derivative, chitosan, have a number of useful physical

and chemical properties, including high strength,

biodegradability, and nontoxicity. 61 Currently,

the principal source of chitin is shellfish waste,

but given the seasonal fluctuation of shellfish

harvests, genetically engineered microbial sys58 Apm from the~ &aditio@ use m wood products, Lignocellulosic fibers are being used tO CNate h@h-PrfOITIMInCe s~c~~ ~t~~s

(see Roger Rowell, “Opportunities for Lignocelhdosic Materials and Composites,” Rowell, et al. (eds.), op. cit., footnote 1).

59 ~ tie ~~t p~p~g prWe\s,fi~is isolated from the rest of the woody tissue by s~~ hy~xide treatment. Lignin can alSO be broken

down by enzymatic means-a process that is cleaner than kraft or sulfite pulping, but considerably more expensive.

@ See Robert Northey, “Low-Cost Uses of Lignin+” R. Rowel~ T. Schultq and R. Narayan (eda.), Emerging Techmdogiesfor Materials

and Chemicalsfiom Bionmss (Washington DC: American ChemicaJ Society, 1992).

61 whm c~~ a~tyl SOUPS (CH3CO) are replaced by hydrogen to form amino groups (NHJ, chitosan iscreat~ (fiWe 2-7). When exposed

to acids, these% groups attract hydrogen ions, forming (NHgH, impardng a net positive charge to the chitosanpolymer. This enables chitosm

to remove negatively charged compounds and contaminants from wastewater. The positively charged chitosan forms solid precipitates with

these negatively charged compounds. Chitosan is one of few natural polysaccharides that has this “ionic” property (i.e., a positive charge).
40 Biopolymers: Making Materials Nature’s Way

Figure 2-7-Chitin and Its Polysaccharide Relatives

CH20H CH2OH CH2OH CH20H

k—o ~o ~o +0

NHCOCH3

CH20H

Lo

B ti”

NH2

CH20H

k–—o

c JQ”OH

NH COCH3 NHCOCH3 NHCOCH3 ~

CH20H CH20H CH20H

Q’”o a’”o 0°

NH2 NH2 NH2

CH20H CH20H CH20H

A—o ~o ~o U“°Kd 0 w’ 0

OH OH OH

Although polysaccharides are made up of simple sugars, slight medications can lead to dramatically different

chemical and physical properties. Shown here are the structures of: A) chitin, B) chitosan, and C) cellulose. The

only difference between cellulose and chitosan is that cellulose has hydroxide (OH) groups instead of amino

(NH,) groups. Chitin is identical in composition except for the acetylated amine groups (NHCH,OH).

SOURCE: Office of Technology Assessment, 1993.

terns might be used to provide a stable supply of

high-grade chitin compounds.62

CURRENT AND POTENTIAL APPLICATIONS

The chitin family of polymers is being widely

used in medicine, manufacturing, agriculture, and

waste treatment. In the biomedical area, chitosan

is incorporated into bandages and sutures in

wound-healing treatment, because it forms a

tough, water-absorbent, oxygen permeable, biocompatible film. It can be used to accelerate tissue

repair and can be applied directly as an aqueous

solution to treat burns. Because of its high oxygen

permeability, chitosan is used as a material for

contact and intraocular lenses. Chitosan has also

been found to expedite blood clotting. The fact

that chitin compounds are biodegradable (the

human body breaks chitin down into simple

carbohydrates, carbon dioxide, and water) makes

them particularly appropriate for use in drug

delivery systems. Chitosan carriers can release

drugs slowly. This property is extremely valuable

in cancer chemotherapy since the agents are often

highly toxic and require long periods of time for

administration. A chitosan compound is also

62 Ceti ~gae, for ex~ple, produce a relatively pure form of chitin fiber that can be readily extracted and processed. However, these algae

grow quite slowly. The application of biotechnology may lead to the development of fast-growing strains of algae that produce large quantities

of chitin. In additiow some fimgi produce chitosan directly. By modifying these stmins, greater amounts of chitosan could be produced,

eliminating the need for chemical treatment of chitin. See New Scientisf, ‘‘Life after Death for E~ty Shells, ’ Feb. 9, 1991, pp. 464.S.
Chapter 2–Technical Overview of Biopolymer Field 41

Box 2-A–Polymers oft he Sea

As major repositories of the earth’s genetic diversity, the oceans are a rich source of proteins,

polysaccharides, and other polymeric compounds. Because marine organisms live in a variety of

different environments-some of them extremely harsh-they have developed polymers with a wide

range of properties. For example, the hard calcium carbonate shell of the abalone is held together by

a glue composed of proteins and sugars, and ocean species in polar climates are able to survive

extremely cold temperatures by producing antifreeze proteins. Other proteins regulate the mineralization processes involved in the creation of shells and crystals (e.g., the calcite crystals of sea urchin

spines). Polysaccharides serve as structural components in crustaceans (e.g., chitin), and in a number

of algal species such as kelp.

Chitin and some algal polysaccharides such as agar, alginate, and carrageenan are widely used

in industry and medicine. The market for these marine polymers is several hundred million dollars

annually. Agar, a major component of the cell walls of certain red algae, is used as a photographic

emulsifier; a gel for cosmetics, toothpaste, and medical ointments; an inert drug carrier, a corrosion

inhibitor, an adhesive, and a thickening agent in confectioneries and dairy products. Alginate is a

principal structural constituent of brown algae (rockweeds and kelps), and carrageenan is extracted

from red seaweed. Like agar, these two natural sugars have excellent gelling and colloidal (suspending)

properties. They are used extensively in the production of ice cream and other dairy items, as well as

in the textile, paper, printing, and biomedical (e.g., wound dressing and dental impression) industries.

Other marine-derived compounds are being used to formulate new drug agents, such as the

anti-inflammatory compound Fucoside B. Marine organisms provide a vast range of biological

processes and substances that could be genetically modified for novel medical and manufacturing

purposes. The Federal investment in marine biotechnology research was about $44 m ill ion in f iscal year

1992.

SOURCES: Federal Coordinating Council for Science, Engineering, and Technology, Committee on Life Sciences

and Health, Biotechnology for the 27st Century (Washington, DC: U.S. Government Printing Office, February 1992);

Office of Technology Assessment, 1993.

being investigated as an inhibitor of the AIDS strength of paper fibers, particularly when wet.

virus .

6 3

The high moisture retention and film-forming

characteristics of chitosan have resulted in a

number of applications in the cosmetics and

personal care areas. Chitosan is being utilized in

hair spray, skin cream, shampoo, soap, nail

polish, toothpaste, and personal hygiene products.64 In paper manufacturing, the addition Of 1

percent chitin by weight greatly increases the

Thus, chitin has been incorporated into diapers,

shopping bags, and paper towels.65 In addition to

paper-chitin composites, some researchers have

developed complexes of chitin and cellulose that

have excellent water-resistant properties.66 The

material can be molded or made into biodegradable plastic films. Eventually, high-strength chitin

polymers could be used in food packaging. One

company, Technics of Japan, in trying to replicate

63 mis research is being led by Ruth Ruprecht at Harvard University, See “Chitin Craze,” Science News, VO1. 144, Jdy 31, 1993, pp. 72-74.

~ New Scientist, op. cit., footnote 62.

65 Ibid.

~~ J, Hosokawa et al., ‘ ‘Biodegradable Film Derived from Chitosan and Homogenized Cellulose,’ Indusm”al Engineering Chemical

Rese~rch, vol. 29, 1990, pp. 800-805.
42 Biopolymers: Making Materials Nature’s Way

the acoustic properties of crickets’ wings, has

even constructed audio speaker vibrators from

chitosan materials.67

In terms of actual sales, agricultural end uses

constitute the largest and most successful market

for chitin and chitosan polymers. The fungiresistant properties of chitosan have resulted in its

application as a fertilizer, soil stabilizer, and seed

protector. It is a yield-enhancing agent for wheat,

barley, oats, peas, beans, and soybeans.68 Thus,

chitosan is used both as a seed coating and as a

plant growth regulator. Chitosan is also used to

recover protein wastes, particularly dairy products such as cheese whey, that are subsequently

added to animal feed.

Because of its binding and ionic properties

(i.e., in solution, the chitosan polymer carries a

positive charge), chitosan can be used as a

flocculating agent to remove heavy metals and

other contaminants from wastewater.69 Current

applications in this area include treatment of

sewage effluents, paper mill wastes, metal finishing residues, and radioactive wastes. In several

countries, particularly Japan, chitosan is used to

purify drinking water. Chitosan is also being

evaluated for use in the bioremediation of toxic

phenolic compounds.70 This could greatly improve the efficiency of pharmaceutical and plastic

manufacturing, by eliminating phenolic contaminates.

Chitin and its various derivatives have become

important constituents in a number of diverse

products and industrial processes. Pharmaceuticalgrade chitin sells for about $32 per pound, while

industrial grade chitin/chitosan compounds range

from about $7 to $27 per pound (specific cost

depends on the application). The unique chemical

properties and biodegradability of this family of

biopolymers presage an even wider range of

applications in the future.

 Hyaluronic Acid

Hyaluronic acid (HA) is a natural product that

is found throughout vertebrate tissue. It also

occurs as an extracellular polysaccharide in a

variety of bacteria. HA plays an important physiological role in many organisms. Research indicates that HA aids tissue formation and repair,

provides a protective matrix for reproductive

cells, serves as a regulator in the lymphatic

system, and acts as a lubricating fluid in joints.

Currently, most of the HA used for research and

commercial purposes is extracted from rooster

combs. In the future, it is likely that this biopolymer will be produced from fermentation

broths of Streptococcus and other bacteria.

Hyduronic acid, discovered in 1934, is a long,

unbranched polysaccharide chain, composed of

repeating twin sugar units. Because of the high

density of negative charges along the polymer

chain, HA is very hydrophilic (has a strong

affinity for water) and adopts highly extended,

random-coil conformations. This structure occupies a large volume relative to its mass and forms

gels even at very low concentrations. It is

extremely flexible and has a high viscosity.

CURRENT AND POTENTIAL APPLICATIONS

Since hyaluronic acid plays an important role

in many developmental and regulatory processes

of the body, it has been used principally in

biomedical applications. It is an extremely attractive polymer material because it is a natural

67 New scientist, op. cit., footnote 62.

68 ~~ p~c~ c~tow product is ~keted under the tradename YEA by Bentech bbomtorics. An es-te of b Potenw ~ket for

YEA is about $160 million amually (BioInformation Associates, Inc., “Technology and Commercial Opportunities in Biodegradable

Polymers, ” Boston, MA).

@ See Chemical and Engineen”ng News, “Chitin Removes Textile Dyes from Wastewater, ” July 12, 1993.

TO ~s application is being developed by Mfizyme Corp. (Hanover, MD) in collaboration with researchers at the University Of -tid.

Science News, op. cit., footnote 63.
Chapter 2–Technical Overview of Biopolymer Field 43

Table 2-3—Biomedical Uses of Hyaluronic Acid

Area Application

Disease indicator Identifies presence of liver cirrhosis, arthritis, scleroderma (tissue disease), and

tumors.

Ear surgery Scaffold material for ear surgery, healing of tympanic membrane perforations

Eye surgery Protects corneal tissue; used In retinal reattachment, and in glaucoma surgery

Wound healing Stimulates tissue repair.

Tendon surgery Repair of flexor tendon lacerations, degenerative joint disease in animals

Antiadhesion General surgery.

Scar control General surgery

SOURCE Blolnformatlon Associates, Boston, MA

product that degrades into simple sugars. Presently, its major uses are in eye surgery, treatment

of arthritis, and wound-healing preparations; it is

also being used in some cosmetic products.

Various biomedical applications for HA are listed

in table 2-3.

The unique physiochemical and structural

characteristics of hyaluronic acid make it an

excellent candidate for applications that require

biocompatibility. However, the prices of HA are

extremely high, more than $100,000 per kilogram. A recent survey estimates a total market for

HA of $425 million by 1996.71 The largest

segment of this market is for surgery. The

smallest segment is for cosmetics. Because of its

utility in surgical treatment, the demand for

hyaluronic acid is likely to expand. Some firms

are now investigating genetically engineered HA

produced by microbes. While the application of

genetic techniques may produce HA that has

greater polymer uniformity, switching to bacterial production (from rooster comb extraction)

probably will not lower total production costs

because of the need for expensive purification

steps .72

POLYMERS PRODUCED BY CHEMICAL

POLYMERIZATION OF BIOLOGICAL

STARTING MATERIALS

Polymers that are created by the chemical

polymerization of naturally occurring monomers

are attracting considerable commercial interest.

Although these polymers are not produced by

biological systems, the fact that they are derived

from basic biological building blocks confers on

them many of the same properties as microbially

or plant-derived biopolymers. These may include

nontoxicity, biodegradability, and biocompatibility. In addition, these polymers are by definition

drawing on feedstocks that are renewable. While

there are several different classes of chemically

synthesized biopolymers, two particular groups

stand out. One is the family of polymers produced

from lactic acid, a molecule used extensively in

the food industry. The other is the growing

ensemble of polyamino acid polymers.

 Polymers Synthesized from Lactic Acid

Lactic acid (lactate) is a natural molecule that

is widely employed in foods as a preservative and

a flavoring agent.73 It is also used in biomedical

71 See Genefic Engineering News, ‘‘Complex Carbohydrate Therapeutic Products: ‘Ibmorrow’s Billion $ Market, ” January 1993, pp. 6-7.

72 James Bro~, Division D&ctor, MOIWUIU and Cellular Biosciences, National Science Foundation perSOfKil COfnmUniCatiOn, JUIY 28,

1993.

73 hctic acid ca exist in NVO different forms: l-lactic acid and d-lactic acid. These two compounds are chemically identical except that they

are mirror images of each other. Such mirror image structures are called stereoisomers. Because the stereoisomers have different spatial

configurations, they have different reactive properties. Only the l-lactide is found in animals, whereas both the d and 1 forms of lactic acid are

found in lower organisms, such as the Luctobucilli, a class of bacteria used for centuries in the dairy industry.
44 Biopolymers: Making Materials Nature’s Way

Figure 2-8-Commodity-Scale Production of

Polylactide

Raw material .-

“-- 1

Monomer

Agricultural waste

Whey (dairy Industry)

Starch (potato processing) ‘ermentat’On>E

Chemical

condensation ~

r—‘- “–— ------- --w-.–,

A

, Low molecular weight

/’ PLA

Thermal //’ — ---–——

treatment,, /

/

,/’

Cyclic dimer-L’

Lactide 1

o\ o

Product

‘ c “ “CH 3

JRlng opening –

High molecular weight

HC A polymerization 1--- - ‘LA ---- -1

‘ o ” ‘ o

CH 3

(catalyzed)

SOURCE: Biolnformation Associates, Boston, MA.

applications in intravenous and dialysis solutions.

It is the main building block in the chemical

synthesis of the polylactide family of polymers.

This family includes polylactide homopolymers

(PLA) and copolymers with glycolic acid (PLAPGA). (Glycolic acid occurs naturally in sugarcane syrup and in the leaves of certain plants, but

is generally synthesized chemically).

Lactic acid is found in blood and muscle tissue,

where it is a product of the metabolic processing

of glucose. Although it can be synthesized

chemically, lactic acid is produced principally by

the microbial fermentation of sugars such as

glucose or hexose. These sugar feedstocks are

drawn from agricultural (potato skins and corn)

and dairy wastes. The lactic acid monomers

produced by fermentation can be used to create

either low or high molecular weight polylactide

polymers (figure 2-8). Variation of the reaction

conditions, such as temperature and choice of

catalyst, provides control over the molecular

weight of the polymer. In this way, the physical

and chemical properties of polylactide can be

adapted for different applications.

CURRENT AND POTENTIAL APPLICATIONS

Polylactide polymers are the most widely used

biodegradable polyester materials. Although their

principal area of application has been in the health

care field, agricultural and manufacturing uses

have been found as well. Polylactides are frequently used in combination with polyglycolic

acid. PLA-PGA copolymers are employed as

medical materials and as platforms for the sustained release of agricultural chemicals. In the

industrial sector, PLA commodity polymers are

being developed for use as pulping additives in

paper manufacturing and as degradable packaging materials.74 Commodity-grade polylactide

sells for about $5 per pound, but manufacturers

expect to bring the price down to the $2 to $3

range. Medical grade polylactide prices range

from $100 to $1,000 per pound. The properties of

these materials are being tailored to meet a variety

of different needs.

Most applications of PLA-PGA materials have

been for therapeutic purposes. Devices made of

PLA-PGA copolymers have been used for the

controlled release of antibiotics, anticancer and

antimalarial agents, contraceptives, hormones,

insulin, narcotic antagonists, and proteins.75 The

copolymers have been molded into microsphere

or microcapsules, pellets, implants, and hollow

fibers.

There are several other important medical

applications. Polylactide sutures are widely used

w c~~l, ~c. ~ b~d~ aw~ac- facility that will be capable of producing IOtion Pourlds of Polykctide ~~Y.me ~t~*

will be used as biodegradable plastics. See Wall Street Journal, “Concern WU Expand Move into Biodegradable Plastic,” May 20, 1993, p.

A7. Also, Dupont Chemical and ConAgra have formed a joint venture, like that is developing polylactide polymers.

75 PLA.PGA copolymms UC @ as drug delivery vehicles. Since protein-based drugs are quickly degraded in tie body, tirn~-reldelivery by PLA-PGA devices can decrease the rate of drug degradation.
Chapter 2–Technical Overview of Biopolymer Field 45

in surgery because they degrade within the body

after the incision has healed. Commercial absorbable sutures such as Vicryl@ are made of copolymers containing 90 percent PLA and 10 percent

PGA. This ratio creates fibers that have excellent

durability, absorbency, and tensile strength. Sutures made from PLA-PGA copolymers are stronger

and absorb faster than sutures, such as Dexon@,

made only of PGA. A considerable amount of

ongoing research is focused on the application of

PLA-PGA copolymers as sutures, clips, staples,

and reinforcement materials.

PLA-PGA copolymers have also been successfully applied in experimental orthopedic surgery.

Compression-molded copolymers have been used

as plates or screws for the treatment of fractures

and to fill in bone defects. The materials have also

been used as scaffolding to facilitate the formation of new cartilage material in the body.76

Copolymers of PLA and PGA are more useful

than homopolymers of PLA and PGA because

their rate of degradation can be adjusted. An

advantage of using prostheses made of PLA-PGA

copolymers is their biocompatibility and nontoxicity. The breadth of current research efforts

suggests that the range of biomedical applications

for PLA-PGA materials will expand considerably

in coming years.

 Polyamino Acids

Polyamino acids are an important class of

synthetic polymers produced by chemical polymerization of the same amino-acid building blocks

found in naturally occurring proteins.77 Polyamino acid chains are sometimes referred to as

polypeptides. Approximately 20 amino acids can

be found in proteins, and from these basic

building blocks a variety of homopolymers and

complex copolymers have been synthesized. Because of the great chemical diversity of aminoacid monomers—anionic, cationic, hydrophobic,

polar, nonpolar, thermally stable-polyamino

acids can be envisioned for virtually all types of

polymer applications.78

Currently, two principal chemical procedures

are used to produce polyamino acids. One approach specifically links amino-acid monomer

units together by amide bonds. These are the same

type of bonds that exist in natural proteins. This

particular type of chemical synthesis is a fairly

complex process and is used primarily to create

the high-purity materials needed for biomedical

applications. In the future, this method of synthesis may be supplanted by bacterial fermentation79

or recombinant DNA techniques. One type of

bacterial species, for example, can produce poly -

glutamic acid, a polypeptide that has many

therapeutic uses. As highlighted earlier, recombinant DNA technology is being used to develop a

new class of polymers based on spider silk (silk

is a natural polyamino acid).

Polymer chains consisting of glutamic acid,

aspartic acid (a component of NutrasweetT M

),

leucine, and valine are the polypeptides most

frequently used for biomedical purposes. Lysine

and methionine are also important amino-acid

building blocks in polypeptide polymers.80 Glutamic acid is the sodium salt form of monosodium

76 See Robefl ~nger and Joseph Vacanti, ‘‘Tissue Engineer ing,” Science, vol. 260, May 14, 1993, pp. 920-925.

77 As ~1~ lactlc acid (foo~ote 73), ~. acids ~so ~c~ as stereoisomers; titis, ~ righ~ndti (d) or lefthanded (1) mirror image

structures. One of the distinguishing features of proteins is that they are constructed only from left-handed amino acids. The synthetic polyamino

acids discussed here are for the most part derived ffom l-amino acids. Polymers that contain only l-isomers or only d-isomers are known as

homochiral structures. Like the phenomenon of DNA self-replication homochirality is a unique property of living systems. See V. Avetisov

et al., “Handedness, Origin of Life, and Evolutioq” Physics To&ry, July 1991, p. 33.

78 cc~o~c’ monomers are negatively Charged; “cationic” monomers are positively charged.

w New bacteri~ fmen~tion Prwesses tittivolve immobilized enzymatic reactions could POtentirdly lower the cost of PolY*o acid

production.

80 Lyslne ~dme~onine me widely us~ m food and animal feed additives. Methionine k prOdUCed chemically, wh~~s IYs~e is ~ct~a~Y

produced.
46 Biopolymers: Making Materials Nature’s Way

Polyamino acid microsphere can be used to

encapsulate bugs and agricultural chemicals,

thereby ensuring that such active agents can be

released in a controlled fashion. The microsphere

shown here have a diameter of about 1.5 microns

(1.5 millionth of a meter). Microsphere occur

naturally and figure prominently in a theory of

the origin of living cells over 3 billion years ago.

glutamate (MSG) and is a major product of the

fermentation industry, with an annual production

level of around 600 million pounds. A major

advantage of using glutamic acid is its low cost

and relative abundance. Glutarnic acid and aspartic acid are hydrophilic (they have high water

affinity), whereas leucine and valine are hydrophobic (low water affinity). When these hydrophilic and hydrophobic building blocks are combined, copolymers with vastly different rates of

biodegradation can be created. This allows the

copolymers to be used as delivery systems for a

variety of different drugs. The fact that homopolymers and copolymers of these simple

amino acids are nonimmunogenic (i.e., they do

not produce an immune response when injected

into animals) makes them particularly attractive

for medical applications. Polyamino acid microspheres—spheres ranging in size from 50 nanometers (billionth of a meter) to 20 microns (millionth of a meter)--are currently being developed

for oral drug administration.81 (Polyamin o acid

microsphere can also be used for the controlled

release of fertilizers.) In addition to drug delivery

systems, polyamino acids are being investigated

for use as biodegradable sutures, artificial skin,

and orthopedic support materials.

A less complex chemical procedure is used to

produce polyamino acids for commodity-scale

industrial applications. Polypeptides are made by

thermal polymerization of amino-acid building

blocks at moderately high temperature (160 to

240oC), followed by a mild alkaline treatment at

60 to 80°C to open ring structures that may form.

This process is not very specific and yields a

polymer product in which the monomers are

linked by two different types of bonds. However,

the advantage of this method is that large quantities of polypeptides can be synthesized at low

cost.

This approach has been used to create polyaspartate polymers from aspartic acid.82 The polyaspartate polymers are analogues of natural

proteins, particularly the aspartate-rich proteins

from oyster shells that play a key role in

81 fiotein-based drugs we exkmely diflicult to insert into the human body. Because proteins are easily tiokm down by digestive wzymes

and cannot readily pass through the skiq they are currently administered by injection. By eneasing protein drugs in polyarnino acid materials,

researchers are trying to protect the proteins long enough so that they can slip past digestive enzymes in the stomach and be absorbed into the

bloodstream. This would allow oral administration of genetically administered proteins. However, in animal studies ecmducted thus far, only

about IOpercent of an orally administered drug dose makes it to the bloodstream. One company involved in this area is Ehnisphere Tedmologies

of Hawthorne, NY. See “Stand and Deliver: Getting Peptide Drugs into the Body,” Science, vol. 260, May 14, 1993, pp. 912-913.

82 Asp~c acid is fairly inexpensive as it em be produced from -ofi and mdeic anhy~de.
...— ———

Chapter 2–Technical Overview of Biopolymer Field 47

Table 2-4-Possible Applications of Industrial Polyaspartates

Water treatment Antiscaling, anticorrosion, flocculation. Cooling towers, evaporators (for

example in pulp processing), desalinators, boilers

Dlspersants Detergents, paint pigments, drilling mud, portland cement, etc

Air pollution control Remove sulfur dioxide by preventing deposition of Insoluble sulfates

Ceramics Promotion of crystallization of specific minerals (e g insulators)

Oilfield applications Prevent mlneralization and corrosion in well holes

Fertilizer preparation Prevent calcification of phosphate slurrles

Mineral pocesslng Antiscalants used to keep ores at an optimum size after grlnding.

Textile Industry Addition of crystallization regulators results in better fibers

Antifouling Prevent growth of calcified organisms on marine/freshwater surfaces

Superabsorbents Diapers

Bioplastics At high molecular weights, polyaspartates become solid materials that may

have a number of uses,

Dental treatment Tartar control agents (toothpaste)

Biomedical devices Prosthetic devices (heart valves), prevention of pathological calcification,

microencapsulation for drug delivery, surface coatings for Implants to

promote crystallization

SOURCE Steven Sikes, Department of Biological Sciences, University of South Alabama, personal communication, Aug. 11, 1993

regulating mineralization, 83 Consequently, these

polymers have intrinsic antiscalant and anticorrosive properties that can prevent the buildup of

mineral deposits on the surfaces of ships, cooling

towers, heat exchangers, and other industrial

equipment. Since the polyaspartate compounds

are derived from natural precursors, they are

biodegradable 84 and can be used to replace

petroleum-derived polymers such as polyacrylate

and polyacrylamide.85 Because of their unique

mineralization and ionic properties, there exists

an enormous range of possible applications for

the polyaspartate materials (see table 2-4).

At present, markets for these synthetic biopolymers are only now being identified. Nevertheless, there exist opportunities to use polyaspartates for a variety of specialized biomedical

purposes, as well as a number of high-volume

applications such as flocculants, dispersants, and

superabsorbents. Industrial polypeptides, particularly water treatment chemicals, are likely to

become commercially available in the near future.86 It is expected that these compounds will

cost from one-third to twice the price of existing

synthetic chemicals such as the polyacrylamides

(about $1.30 to $2 per pound).

83 M(nx proteins from oysta shells me powerful regulators of mineral formation. These polypeptides CWI inhibit mineral deposition where

it is not wanted and, under certain conditions, can promote crystallization where it is needed. The formation of minerals in solution (e.g., the

calclum carbonate structure of oyster shells) is a fundamental process of living and nonliving systems, It is apparent that nature has produced

some extraordinary polymers to regulate the mineralization process. By investigating the properties of these natural polymers, researchers are

trying to develop new biopolymers that can be tailored for a variety of industrial applications. See C. S, Sikes and A. P. Wheeler, ‘ ‘Regulators

of Biomineraliz.ation,” Cherntech, October 1988, pp. 620-626.

84 ~eliminm tests of polya.spartate degradability are pmmishg. See A.P. Wh=lm and L.p. Kos~, “Large Scale Thermally Synthesized

Polympartate as a Substitute in Polymer Applications, ” Materials Research Society Symposium Proceedings, vol. 292, pp. 277-283.

85 Swtietic Polymas ~ving mu][iple positive or negative charges, such m Polyacrylrite ~d @YaWlti@~~dely us~ m wat~

treatment additives, components in paper manufacturing, active ingredients in detergents, and tartar control agents in toothpaste, Their

worldwide use amounts to billion of pounds annually, They are excellent materials in terms of their chemical activity and cost. However, they

are not biodegradable.

86 scver~ chemical and bio[echno]om Conlpafies ~ve ongoing R&D prog~ involving poly~~o acids. Steve Sikes, Department Of

Biological Sciences, University of South Alabama, personal communicatio~ July 9, 1993,
48 I Biopolymers: Making Materials Nature’s Way

SUGGESTED FURTHER READING

 Microbial Polyesters:

Polyhydroxyalkanoates

Sumner A. Barenberg, John L. Brash, Ramani

Narayan, and Anthony E. Radpath, Degradable

Materials: Perspectives, Issues and Opportunities (Boca Raton, LA: CRC Press, 1990).

James H. Brown, ‘‘Research Opportunities for

Biologists in Bimolecular Materials,” National

Science Foundation, Division Director, Molecular and Cellular Biosciences, internal report, June

1992.

Yoshiharu Doi, Microbial Polyesters (New

York, NY: VCH Publishers, 1990).

Oliver P. Peoples and Anthony J. Sinskey,

“Polyhydroxybutyrate (PHB): A Model System

for Biopolymer Engineering II,” E.A. Dawes

(cd.), Novel Biodegradable Microbial Polymers,

NATO Advanced Science Institute Series (Holland: Kluwer Academic Publishers, 1990), vol.

186, pp. 191-202.

I

 Recombinant Protein Polymers

James H. Brown, ‘‘Research Opportunities for

Biologists in Bimolecular Materials,” National

Science Foundation, Division Director, Molecular and Cellular Biosciences, internal report, June

1992.

D.R. Filpula, S.-M. Lee, R.L. Link, S.L.

Strausberg, and R.L. Strausberg, “Structure and

Functional Repetition in a Marine Mussel Adhesive Protein, ” Biotechnology Progress, vol. 6,

1990, pp. 171-177.

S.D. Gorham, “Collagen,” D. Byrom (cd.),

Biomaterials: Novel Materials from Biological

Sources (New York, NY: Stockton Press, 1991),

pp. 55-122.

D.L. Kaplan, S.J. Lombardi,, W.S. Muller, and

S.A. Fossey, ‘Silks, ’ D. Byrom (cd.), Biomaterials: Novel Materials from Biological Sources

(New York, NY: Stockton Press, 1991), pp. 1-53.

D. McPherson, C. Morrow, D.S. Minehan, J.

Wu, E. Hunter, and D.W, Urry, “Production and

Purification of a Recombinant Elastomeric Polypeptide, G-(VPGVG)19-VPGV from E.. coli,”

Biotechnology Progress, vol. 8, 1992, pp. 347-

352.

 Bacterial Cellulose

P. Ross, R. Mayer, and M. Benziman, “Cellulose Biosynthesis and Function in Bacteria,”

Microbiological Revues, vol. 55,1991, pp. 35-58.

D.C. Johnson, R.S. Stevens, and J.A. Westland,

“Properties and Uses of Bacterial Cellulose

Produced in Fermenters,’ presented at the American Chemical Society Meeting, Boston, MA,

Apr. 24, 1990.

D.C. Johnson, H.G. Folster, and A. BenBassat, “Bacterial Cellulose from Agitated Culture: Process Development, Scale-up and Applications, ’ presented at the Cellulose ’91 Conference,

New Orleans, December 1991.

 Xanthan

R.A. Hassler and D.H. Doherty, “Genetic

Engineering of Polysaccharide Structure: Production of Variants of Xanthan Gum, Xanthomonas

campestris, Biotechnology Progress, vol. 6, 1990,

pp. 182-187.

J.F. Kennedy and I.J. Bradshaw, “Production

and Applications of Xanthan, ” M.E. Bushell

(cd.), Progress in Indutrial Microbiology, vol.

19, 1984, pp. 319-371

 Dextrans

R.M. Alsop, “Industrial Production of Dextrans,’ M.E. Bushell (cd.), Progress in Industrial

Microbiology (Amsterdam: Elsevier, 1983), pp.

1-44.

C. Larsen, “Dextran Prodrugs-Structure and

Stability in Relation to Therapeutic Activity,”

Adv.Drug Delivery Review, vol. 3, No. 1, pp.

103-154.

 Pullulan

Chemical and Engineering News, “Japanese

Develop Starch-Derived Plastic, ” vol. 24, December 1973, p. 40.
Chapter 2–Technical Overview of Biopolymer Field 49

A. Jeanes, “Dextrans and Pullulans: Industrially Significant Alpha-D-Glucans,” P.A. Sandford and A. Laskin (eds.), Extracellular Microbial Polysaccharides, ACS Symposium Series,

vol. 45, 1977, pp. 284-298.

Y.C. Shin, Y.H. Kim, H.S. Lee, S.J. Cho, and

S.M. Byun, “Production of Exopolysaccharide

Pullulan from Inulin by a Mixed Culture of

Aureobasidium Pullulans and Kluyveromyces

Fragilis,’ Biotechnology & Bioengineering, vol.

33, 1989, pp. 129-133.

 Glucans

E. Cabib, R. Roberts, and B. Bowers, ‘Synthesis of the Yeast Cell Wall and Its Regulation, ’

Annual Review of Biochemistry, vol. 5, No. 17,

1982, pp. 63-793.

N.R. Di Luzio, D.L. Williams, R.B. McNamee,

B.F. Ewards, and A. Kitahama, “Comparative

Tumor-Inhibitory and Anti-Bacterial Activity of

Soluble and Particulate Glucan,” International

Journal of Cancer, vol. 24, 1978, pp. 773-779.

P.W.A. Mansell, G. Rowden, and C. Hammer,

“Clinical Experiences with the Use of Glucan,”

M.A. Chirigos (cd.), Immune Modulation and

Control of Neoplasia by Adjuvant Therapy (New

York, NY: Raven Press, 1978), pp. 255-280.

D.L. Williams, E,R. Sherwood, LW. Browder,

R.B. McNamee, E.L. Jones, and N.R. Di Luzio,

“The Role of Complement in Glucan-Induced

Protection Against Septic Shock,” Circulatory

Shock, vol. 25, 1988, pp. 53-60.

 Gellan

V.J. Morris, ‘ ‘Science, Structure and Applications of Microbial Polysaccharides, ” G.O. Phillips, D.J. Wedlock, and P.A. Williams (eds.),

Gums and Stabilizers for the Food Industry, vol.

5, 1990, pp. 315-328.

 Starch

R.L. Whistler, J.N. BeMiller, and E.F.

Paschall, Starch Chemistry and Technology, 2nd

Ed. (New York, NY: Academic Press, 1984).

R.P. Wool and S.M. Goheen, ‘‘Degradation

Mechanisms in Polymer-Starch Composites,”

International Symposium on Biodegradable Po[ymers, Biodegradable Plastic Society, October

1990, pp. 137-143.

 Lignin

W. Glasser and S. Sarkanen (eds.), Lignin:

Properties and Materials (Washington, DC: American Chemical Society, 1989).

Fred Boye, Utilization of Lignins and Lignin

Derivatives (Appleton, WI: Institute of Paper

Chemistry, 1985).

Robert Northey, “Low-Cost Uses of Lignin,”

R. Rowell, T. Schultz, and R. Narayan (eds.),

Emerging Technologies for Materials and Chemicals from Biomass (Washington, DC: American

Chemical Society, 1992).

 Chitin

G.G. Allan, L.C. Alturan, R.E. Bensinger, D.K.

Ghost, Y. Hirabayashi, A.N. Neogi, and S. Neogi,

“Biomedical Applications of Chitin and Chitosari, ’ J.P. Zikakis (cd.), Chitin, Chitosan and

Related Enzymes (New York, NY: Academic

Press, 1984), pp. 119-135.

A. Naude, “Drug and Cosmetic Uses Targeted

for Chitin Products,’ Chemical Marketing Reporter, Dec. 11, 1989, pp. 24-25.

E.R. Pariser and D.P. Lombardi, Chitin Sourcebook: A Guide to the Chitin Research Literature

(New York, NY: John Wiley & Sons, 1989).

 Hyaluronic Acid

A. Scheidegger, “Biocosmetics in Japan: New

Wrinkles Beneath the Make-Up, ” Trends in

Biotechnology, vol. 7, 1989, pp. 138-144.

J. van Brunt, “More to Hyaluronic Acid than

Meets the Eye, ’ Biotechnology, vol. 4, 1986, pp.

780-782.

 Polymers Synthesized from Lactic Acid

S.J. Holland, B.J. Tighe, and P.L. Gould,

‘‘Polymers for Biodegradable Medical Devices,
50 Biopolymers: Making Materials Nature’s Way

the Potential of Polyesters as Controlled Macromolecular Release Systems, ’ Journal of Controlled Release, vol. 4, 1986, pp. 155-180.

M. Vert, P. Christel, M. Audion, M. Chanavaz,

and F. Chabot, “Totally Bioresorbable Composites Systems for Internal Fixation of Bone Fractures, ’ E. Chiellini et al. (eds.), Polymers in

Medicine II (New York, NY: Plenum Press, 1985,

pp. 263-275.

R.H. Wehrenberg, “Lactic Acid Polymers:

Strong, Degradable Thermoplastics,” Mechanical Engineering , September 1981, pp. 63-66.

 Polyamino Acids

J.M. Anderson, K.L. Spilizewski, A. and

Hiltner, “Poly Alpha-Amino Acids as Biomedical Polymers, ’ D. F. Williams (cd.), Biompatibility of Tissue Analogs, vol. 1 (Boca Raton, FL:

CRC Press, 1985), pp. 67-88.

C.S. Sikes and A.P. Wheeler, “Regulators of

Biomineralization,’ Chemtech, October 1988,

pp. 620-626.
.

Biopolymer

Research and

Development

in Europe

and Japan 3

s

ignificant biopolymer research efforts have been under

way for many years in both Europe and Japan. In the

European Community (EC), advances in biopolymer

technology have been driven principally by the private

sector. However, a number of basic and applied research

programs have been initiated recently at the national and

supranational (EC) levels. The Japanese Government, as it has

done with other emerging technological fields, is actively

sponsoring and coordinating biopolymer research among Japanese companies and scientific institutes. In both Europe and

Japan, biopolymer research has two principal areas of focus:

degradable materials that serve as substitutes for traditional

commodity plastics and biomedical applications,

EUROPE

Several factors are stimulating European research and development (R&D) efforts in the biopolymer area. The emergence of

a strong environmental movement has caused European governments to search for new methods and materials to address solid

waste problems and other ecological concerns. As a consequence, there is considerable interest in developing biodegradable products that are derived from renewable resources. l

1 Although about 15 percent of all materials used for commercial purposes are derived

from petroleum, only about 3 percent of petroleum supplies are used as feedstocks for

petrochemicals and synthetic resins. Thus, large-scale use of biopolymers for materials

applications will not significantly affect oil consumption patterns. Biopolymers are

important primarily because of their biodegradability and other physical properties. For

more on petroleum feedstock applications, see U.S, Bureau of Mines, Nonrenewable

Organic Materials, May 1993. For more on industrial energy use, see U.S. Congress,

Office of Technology Assessment, lndustrial Energy Efficiency, OTA-E-560 (Washington, DC: U.S. Government Printing Office, August 1993).

51
52 Biopolymers: Making Materials Nature’s Way

The large agricultural surpluses that have resulted

from the EC’s Common Agricultural Policy

(CAP) 2 potentially represent an abundant source

of feedstocks that could be used for large-scale

commercial production of biologically derived

fuels and materials.3

Existing and proposed environmental regulations could provide a major impetus for the

introduction of products containing biopolymers.4

The proposed EC directive on a‘ ‘Framework for

Waste” provides regulatory guidance on how

member states should handle the disposal of

municipal waste. This framework embraces a

hierarchy of waste management techniques, similar to that enunciated by the U.S. Environmental

Protection Agency (EPA).5 It will be left to

individual governments to devise specific plans

to implement this waste management strategy.

The role of biodegradable materials is not delineated in this directive. However, the framework

does call for the introduction of “environmentally safe” products, and it is proposed that such

products be exempted from various environmental duties.6 If biopolymer manufacturers can

demonstrate that their products are environmentally safe, they could benefit from this proposed

directive. However, no standards or evaluation

methods have been established to determine what

constitutes an environmentally safe product, and

thus the ultimate commercial impact of the

directive is uncertain. Moreover, many environmental advocacy groups do not view biodegradation as a solution to solid waste problems. Apart

from medical products, these organizations believe that the introduction of biodegradable materials into the marketplace will undermine recycling efforts and, depending on the extent of their

degradation, exacerbate litter problems.7

The development of labeling programs for

environmentally preferred products could also

promote the development of biopolymer materials. The European Commission has proposed a

scheme whereby a single label would be granted

to products that satisfy a range of ecological

criteria. These criteria relate to all aspects of a

product’s manufacture, distribution, use, and

disposal. 8 An eco-label will be granted to a

product that has a clear environmental advantage

over other products in its category. Commodity

items such as packaging or plastics that contain

biodegradable additives could become prime

candidates for an eco-label. However, as mentioned previously, the methodologies for making

such evaluations have yet to be developed. Up to

now, the process of creating environmental measurement standards has proven to be an extremely

2 The Common Agricultural Policy was devised to mitigate the impact of technological change on rural Europe. However, the CAP has

led to enormous crop surpluses, massive public expenditures, higher food prices, and a net transfer of wealth from urban to rural regions. These

surpluses have led to the dumping of European agricultural products in overseas markets and have, not surprisingly, exacerbated international

trade tensions. See U.S. Congress, Office of Technology Assessment, Biotechnology in a Global Economy, OTA-BA-494 (Washington, DC:

U.S. Government Printing Office, October 1991), p. 161.

3 Biologically derived fuels such as ethanol and methanol and other bioenergy crops could potentially provide 10 to 20 percent of current

energy needs, See U.S. Congress, Office of Technology Assessment Environmental Impacts of Bioenergy Crop Production (forthcoming).

4 The EC has adopted more than 100 environmental directives on matters ringing from toxic emissions and the labeling of dangerous

substances to the quality of drinking water. Many more directives are in draft form or are awaiting amendments.

5 In order of priority, the hierarchy is: 1) waste prevention and reduction at the source;2) recycling and reuse (in energy, material, and

chemical form); and 3) safe disposal of unavoidable waste. See European Community Bulletin ‘‘Framework for Waste’ Directive, document

375 L 0442, September 1989.

6 Examples of products that could be subject to environmental taxes include nonreturnable bottles, gasoline, tropical wood, natural gas, and

coal. Levies between 20 and 200 percent could be imposed on products deemed harmful to the environment. Ibid.

7 See “Degradable Plastics Generate Controversy in Solid Waste Issues, ” Chemical & Engineering News, June 25, 1990, pp. 7-14.

8 These ‘life-cycle” criteria would evaluate factors such as raw material usage, energy consumption, emissions from manufacture and use,

and waste disposal impacts. For a detailed discussion of eco-labeling issues, see U.S. Congress, Office of Technology Assessment Green

Products by Design: Choices for a Cleaner Environment, OTA-E-541 (Washington DC: U.S. Government Printing Office, October 1992).
Chapter 3-Biopolymer Research and Development in Europe

difficult undertaking.9 At this writing, no date had

been set for implementing the EC eco-label

program.

 EC Research Programs

The European Community is currently funding

several R&D programs that directly and indirectly involve biopolymer technology. These

programs are attempting to develop new nonfood

applications for agricultural commodities, alternative energy sources, and materials with superior

environmental properties, Figure 3-1 outlines

Europe’s major biopolymer research programs.

The ECLAIR (European Collaborative Linkage of Agriculture and Industry Through Research) program (1988-93), with a budget of

roughly $95 million, is designed to promote

agroindustrial applications of new and improved

varieties of plants and microorganisms. The

program is concentrating on the extraction and

transformation of biological materials such as

sugars, starches, oils, and fats into useful commercial products. For example, ECLAIR is providing half of the $4.6-million research budget for

a consortium consisting of Zeneca, Inc. (United

Kingdom) and the universities of Hull (England),

Ghent (Belgium), and Goettingen (Germany).

The consortium is investigating microbial polyester production by the bacterium Alcaligenes

eutrophus (see chapter 2). This program also

includes research on genetically engineered

plants for the production of natural polyester

materials.

The AIR (Agricultural and Agro-Industry,

Including Fisheries) program (1991-94) is focusing on “land and water-based biological resources, ’ and has a planned 3-year budget of

about $90 million. Research will focus on procFigure 3-l—European Initiatives

EC

programs

STEP

ECLAIR

JOULE

AIR

BRITE

German

program

b’

and Japan 53

and Programs

in Biopolymers

n

Research

institutes

4

Technology transfer . (’ Private

Information ‘I, companies

SOURCES: Blolnformation Associates, Boston, MA; V%lf-Rfidiger

Miller, Institut ftir!%xlungswasserbau, WassergOte-und Abfalhvirtschaft

der Universit~t Stuttgart, Federal Republic of Germany, personal

communication, July 26, 1993.

esses for transformingg materials from agriculture,

horticulture, forestry, fisheries, and aquiculture

into industrial products. One aspect of the program is to examine the biodegradability and

larger ecological impacts of biopolymer materials.10 As part of a wider effort in materials and

polymer science, the Basic Research on Industrial

Technologies in Europe (BRITE) program (1991-

94) is examining polymeric materials with properties that ‘‘minimize environmental impact, ’

including a study of biodegradable packaging

materials.11

Other efforts include the STEP (Science and

Technology for Environmental Protection) and

JOULE (Joint Opportunities for Unconventional

or Long-Term Energy Supply) programs. STEP

began in 1989 with a budget of $90 million. It is

focusing on the development of technologies that

safeguard environmental quality. One element of

the program includes an assessment of biodegrad9 Product impacts on the environment are almost always multidimensional in character. Any g;ven product 1S ~ely to have pOsltive as well

as negative environmental attributes. Existing methodologies for evaluating the ‘‘environmental quality’ of a produc4 such as life-cycle

analysis, are in early stages of development and necessuily employ a great deal of subjective decisionmalun‘ g. Ibid.

10 Wolf-RUdiger Muller, Institut fti Siedlungswasserbau, Wassergiite-und Abfallwirtschaft der Universitht Stuttgart, Federal Republic of

Germany, personal communicatio~ July 26, 1993.

11 Ibid.
54 Biopolymers: Making Materials Nature’s Way

able materials. The JOULE program, also begun

in 1989, was given an initial budget of $145

million. The program is principally designed to

improve long-term energy security by exploring

ways of reducing the reliance on imported energy

supplies. One part of the program is analyzing the

potential of biomass as an energy source. Derivatives of cellulose and starch, for instance, can be

used as transportation fuels.

These programs, with funding exceeding $400

million, demonstrate the EC’s strong interest in

developing new commercial products and energy

supplies from renewable resources. Each program

seeks academic and industrial participation. Research supporting the creation of ‘‘nextgeneration’ materials-materials derived principally from agricultural or microbial sources-is

an important component of these collaborative

programs.

 Research in Germany

Among individual European states, Germany

has launched a set of research initiatives that are

specifically designed to advance biopolymer

technology. Germany is being extremely aggressive in dealing with solid waste problems and

other environmental issues.

12 These factors have

led to the development of a 5-year biotechnology

program that will focus on: conversion of biomass

into alternative fuels and commodity plastics;

new strains of plants to establish new routes for

the development of nonfood renewable resources;

fermentation technology for hydrogen production; 13 and new bioprocessing techniques.

The Federal Ministry of Research and Technology is coordinating and funding this program.

Industry and academia are the principal recipients

of research money. It has a substantial budget of

DM 1 billion ($590 million) for the period

1990-95. 14 No other government in Europe has

committed this level of funding to biotechnology

R&D. Thus, German industry could be well

positioned to exploit the expected demand for

products that are derived from renewable resources (see table 3-l). German companies have

the potential to become major players in the

development of next-generation biopolymer materials.

 Private Sector Activity

DEGRADABLE POLYMERS

A number of so-called biodegradable plastic

products were marketed in Europe in the 1980s.

These first-generation products were basically

traditional oil-derived polymers, such as polyethylene, containing a low percentage (4 to 6

percent) of starch. Most of these products were

made by the North American companies Archer

Daniels Midland and St. Lawrence Starch. Controversy surrounding the degradability of these

products has essentially stopped their production.

A new generation of starch-based products is now

being introduced by several fins. These materials have a cornstarch content ranging from 40 to

nearly 100 percent. Manufacturers believe that by

increasing the starch content of the polymer, the

time for degradation will be reduced (see chapter

2).

12 For ex~ple, tie German GOVernmerit has instituted a mandatory ‘‘take-back’ program for several different typeS of prOduCt packaging.

The take-back law requires manufacturers to recover and recycle various materials used in packaging. This scheme is likely to be appLied to

durable products, such as automobiles and electronics, in the near future. See U.S. Congress, OffIce of Technology Assessment, op. cit., footnote

8.

13 Hy&ogen is ~ exmmely clean fiel. Hydrogen-powered vehicles emit only water vapor and small amounts of fi~ogen oxides. See U.S.

Congress, Office of Technology Assessment, Replacing Gasoline, OTA-E-364 (Washingto% DC: US Government Printing Office, September

1990),

14 The Ge~nbiot~bnology program is designed to promote research in the areas of the environment, public herd~ nutritiOtL energy, and

natural resources. Another area of focus is pharmaceuticals. However, recent budgetary pressures associated with the costs of German

unification could result in cutbacks in these efforts (Wolf-Rudiger Muller, op. cit., footnote 10).
Chapter 3–Biopolymer Research and Development in Europe and Japan 55

Table 3-l—Strengths and Weaknesses: Biotechnology Research in Germany

Strengths Weaknesses

First nation to establish biotechnology Public opposition to genetic technology

program

Europe’s highest concentration of Limited venture capital presence.

biotechnology In pharmaceutical and

chemical fields

High-quality science training and research Dominance of large companies could limit

base small market opportunities typical in

biotechnology.

Strong industry-university relationships

SOURCE U S Congress, Office of Technology Assessment, Biotechnolgy in a Global Economy, OTA-BA494 Washington, DC U S Government Printing Office, October 1991)

Companies are presently divulging little information about the functional properties, mechanical characteristics, degradation times, and final

degradation products of these polymers. Ferruzzi,

the parent company of Montedison, has developed a thermoplastic mixture of starch and a

hydrocarbon in which the starch constitutes

between 40 and 70 percent of the total weight.

The hydrocarbon is described as a hydrophilic

carbon-hydrogen-oxy gen polymer with a molecular weight low enough to accelerate degradation,

but high enough to maintain the strength of the

alloy. The company claims that the material

behaves like polyethylene in its processing characteristics, but that the starch content reduces the

tensile strength. The company contends that a

70-percent starch mixture takes about 3 weeks to

degrade, but it does not provide details of the

degradation conditions.

15 The starch-hydrocarbon blend is being used in packaging and diaper

linings.

Battelle, an international research institute

based in Switzerland, has also developed a

starch-based technology that is able to incorporate up to 90 percent starch in its plastic. A t

present, however, there is likely to be limited

application for this technology because of the

polymer’s susceptibility to moisture. Battelle has

recently announced a plan to use vegetable

oil-based polymers to overcome the moisture

problem. Warner-Lambert of the United States

has been marketing its NOVON starch-based

materials (40- to 98-percent starch content) in

Europe since 1991, with sales in the millions of

pounds (see chapter 2). NOVON polymers are

amenable to different plastic processing methods,

including injection molding and film extrusion.

The entrance of companies making microbially

derived products will also have an effect on the

degradable polymer market. One company, Zeneca

Bio Products (formerly ICI Biological Products,

United Kingdom), has developed a microbially

derived polymer with excellent degradation characteristics (chapter 2). The polymer, called

BIOPOL, is produced through the bacterial fermentation of glucose and propionic acid.16 The polymers derived from the fermentation process are

linear polyesters that are true thermoplastics.

Zeneca will have a production capacity of around

10 million pounds by 1995. The first commercial

15 It should be notti that independent tests of polyethylene-starch blends show that although starch nMy biodegrade, the overd Polymm

formulation does not biodegrade at any significant rate. Distintegration of polyethylene-starch blends is not the same as biodegradation. The

biodegradability of a particular material is determined by a set of complex factors such as material shape and surface-to-volume ratio, as well

as environmental conditions such as nutrient concentration, bacterial-fimgi inoculation pH, moisture level, and temperature. Any or all of these

factors may vary from location to location.

16 Glucose is derived from a@cultura] feedstocks such assugar beets and cer~l crops, while propionic acid can be produced from petroleum

derivatives or by fermentation of wood pulp waste.
56 Biopolymers: Making Materials Nature’s Way

use of BIOPOL resin was in 1990, as consumer

packaging. It has since entered other markets in

Europe and Japan. The material is being targeted

for use in moldings, films, and paper coatings for

both rigid and flexible packaging, as well as a

variety of specialty applications.17 Some manufacturers are prepared to pay a premium price for

BIOPOL because they believe that they will be

able to market this product as an ‘ ‘environmentally friendly” material. It currently sells for

approximately $8 to 9 per pound, but Zeneca

believes that with economies of scale in manufacturing, the price can be brought to around $4 a

pound.

Other companies that are conducting research

into microbial-based and agricultural-based polymers are Boehringer Ingelheim KG, Ems-Chemie

AG, BASF, and Schering of Germany; Petrochemie Danubia of Austria; Montedison of Italy;

and Tubize Plastics SA of Belgium. Some products are available now, whereas others are in the

research stage and are not likely to enter the

market until 1995. Table 3-2 summarizes the

activities of firms currently developing or marketing next-generation biopolymers. Many of these

companies have demonstrated considerable ability in incorporating synthetic processes into

surrogate organisms and in improving their efficiency of production. European biotechnology

firms will undoubtedly prove to be formidable

competitors as markets for genetically engineered

polymers begin to expand.

BIOMEDICAL MATERIALS

One industry survey estimates that the total

European market for degradable biomedical materials will rise from $650 million in 1990 to

$1.17 billion in 1995; this represents an average

annual growth rate of 12.5 percent.18 There are

three principal market segments for biopolymers

in Europe: wound management products, drug

delivery systems (DDS), and orthopedic repair

products. Each market is discussed in turn.

Wound Management: Absorbable wound closure products have represented a sizable portion

of the European biomedical market for more than

15 years. The market size for wound management

products is estimated to grow at an annual rate of

8.5 percent from $600 million in 1990 to $900

million in 1995.19 This segment represented 100

percent of the total biomedical materials market

in 1988, but will decrease to about 75 percent of

the total market in 1995 as DDS and orthopedic

repair product markets expand. The main polymers used in this market are polylacticpolyglycolic acid and related derivatives (see

chapter 2).

The primary absorbable products in this market

segment are sutures, ligation clips, and to a lesser

extent, staples and wound meshes. Biodegradable

polymers have been used in surgery for many

years. Wound closure products (absorbable sutures) were introduced more than 20 years ago.

The primary advantages of biopolymer sutures

over catgut sutures are that they have a more

predictable rate of absorption and produce less

inflammation around wound sites. Two American

fins, Ethicon and Davis& Geck, monopolize the

European market for these products. Absorbable

ligation clips and staples are also used during

surgery and trauma care. In addition, biodegradable wound closure polymers are being used for

other surgical applications, such as tissue and

bone adhesives. Companies in the bioabsorbable

surgical device market are rapidly expanding the

range of applications for their polymer products.

The introduction of vascular support meshes (for

blood vessel regeneration) and other forms of

wound dressing products is envisioned for the

future. 20

17 ~nma ~an ~ement to sell BIOPOL to Wella of G rmany for use in cosmetic bottles.

18 The ~ey WM conduct~ by BioInformation Associates of Bosto~ MA.

‘g Ibid.

Zo See Ro~fi @er and Joseph Vacanti, “Tissue Engineering, ” Science, vol. 260, May 14, 1993, pp. 920-925.
Chapter 3-Biopolymer Research and Development in Europe and Japan 57

Table 3-2—Current and Potential Suppliers of Next Generation Biopolymers in Europe

Company Location Product/status Potential Likely Comments

application entry date

Zeneca Bio

Products

(formerly ICI)

BASF

Schering

Boehringer

Ingelheim KG

Tubize Plastics

SA

Ferruzzi

(Montedison)

Petrochemie

Danubia

Battelle

WarnerLambert

United

Kingdom

Germany

Germany

Germany

Belgium

Italy

Austria

Switzerland

United States

BIOPOL (microbial

polyester)

Microbial- and

agriculturalbased polymers

Same as above

Polylactide

polymers

BIOCELLAT

(cellulose

acetate)

Agricultural

polymers

Microbial polymers

Vegetable oilbased polymers;

starch-based

polymers

NOVON starchbased polymers

(injection

molding and

various film

grades)

Rigid and

flexible

packaging:

films,

moldings,

paper

coatings

Packaging

Packaging

Packaging,

medical

devices

Packaging

Packaging

Packaging

Packaging

Multiple use

structural

materials

Now

1995

1995

Now

Now

1995

1995

Unknown

Now

1990 pilot

plant In

England;

assessing

full

production

plant

In R&D stage

In R&D stage

In R&D stage

In R&D stage

Working with

German

industrial

partners

100-millionpound U.S

production

facility

opened in

1992

SOURCE: Biolnformation Associates, Boston, MA.

Drug Delivery Systems: For many years the

major focus of drug research has been on the

synthesis or discovery of new drugs. Although

this continues to be important, increasing emphasis has been placed on the development of novel

drug delivery systems. These systems first entered the European market in 1989; the total

European market value for DDS in 1995 is

estimated to be $250 million.

21 The principal

materials being used for drug matrices in Europe

are copolymers of polylactic acid (PLA) and

polyglycolic acid (PGA). The use of biopolymer

materials for drug delivery can minimize tissue

reaction and allow drugs to be administered in

nonconventional ways.

The use of biopolymers in these formulations

has thus far been restricted to a narrow set of

applications. There are several European companies developing products for this market, products that are technically comparable to those

made by U.S. firms. Drug formulations incorporating polymer DDS are currently undergoing

registration and are likely to make an impact on

the market over the next 5 years.

21 ne esttit~ market value of degradable DDS reflects the combined value of the drug and the delivery SystemS, because it wu not

possible to obtain separate estimates for the delivery system (BioInforrnation Associates, op. cit., footnote 18).
58 Biopolymers: Making Materials Nature’s Way

The major area of application for these novel

sustained-release systems is in the treatment of

cancers and diseases of the elderly. Some promising cancer treatment drugs are peptides or proteins, which are unsuitable for oral administration. 22 Similarly, products developed from genetic

engineering may be toxic and thus may require

nonconventional approaches for administration.

Sustained delivery of a drug close to the site of

action from an implanted or injected depot means

that much smaller amounts of the drug need be

used, thus reducing the possible side effects.23 In

the treatment of hormone disorders and geriatric

diseases, biopolymer delivery systems allow

drugs to be administered occasionally (even

annually in some presentations). More importantly, these systems ensure patient compliance,

which is often a problem for the elderly. Many of

the drugs most suitable for presentation in a

controlled fashion are for geriatric illnesses such

as cancer and Parkinson’s disease. It is in these

markets that DDS will likely have the greatest

impact.

European companies have an important strategic interest in DDS and have been instrumental in

developing biopolymer technologies. The drug

companies view biopolymer-based drug delivery

as an important technological advance, because it

can be applied to drugs that cannot be administered by conventional routes. Many companies

also view this technology as an important tool for

circumventing price restrictions that are being

applied by European governments. Biopolymerbased drug delivery can offer important cost

savings over conventional methods (e.g., injection) of drug administration.

The following European companies are currently developing products for the DDS market:

Sanofi (France), Ciba Geigy (Switzerland), Capsugel 24 (Switzerland), Zeneca Bio Products (United

Kingdom), Beam Tech (United Kingdom), and

Innovative Biosciences (United Kingdom). Zeneca

is hoping to develop DDS applications for its

BIOPOL biopolymer discussed earlier. The other

companies listed here would not divulge the

products they are developing for this market, but

did indicate strong interest in biopolymer drug

delivery systems.

Orthopedic Repair Products: Biopolymer orthopedic repair products were expected to enter

the biomedical market in 1992, with the introduction of absorbable pins and fixation devices from

both Ethicon and Davis & Geck. The majority of

biopolymers currently used for these applications

are based on polyglycolide and polylactide polymers, with the latter being the most frequently

used materials. There are a large number of lactic

acid suppliers in Europe who provide this biological starting material to polymer manufacturers.25

The manufacturers further purify the raw material

22 @I atis~ation of protein drugs is not possible because digestive enzymes quickly break down proteins and thus destroy tie hgs

before they can be absorbed into the bloodstream. By encasing protein drugs in biopolymer materials such as polylactide, some nxearchers

are trying to protect the proteins from the digestive e-es in the stomach long enough for them to be absorbed into the bloodstream. However,

this approach has had limited success in animals. Current biopolymer drug delivery systems are therefore used as implants. See “Stand and

Deliver: Getting Peptide Drugs into the Body,” Science, vol. 260, May 14, 1993, pp. 912-913.

23 Most cancm~gs me generally toxic to normal cells as well as cancerous cells. Delivery of anticancer drugs in polyme~ can help ~stict

drug activity to the site of the tumor and therefore protect normal tissue from exposure to toxicity. David ManyalG Adheron Corp., personal

communication, Aug. 25, 1993.

u Capsugel is a division of warner.~bert. Capsugel is producing starch-based capsules made from NOvON polymers. one Of tie Oldest

therapeutic applications of biopolymers has been in the area of pharmaceutical capsules. Gelatin (a protein polymer) capsules have been in

widespread use for many years. Gelatin and starch-based capsules are commonly used to deliver aspirin and antibiotics. The worldwide market

for simple biopolymer capsules is close to $400 million annurdly. Ken Tracy, Warner-Larnbert Co., personal cmnrmmicatiorL July 30, 1993.

25 BOe~ger Inge~eim KG of Ge~ny is one company that produces polylactide polymers for the OfthOpdiC repair market. Cda

Colloids markets lactic acid produced by a fermentation process. The other major lhropean supplier of fermented lactic acid is C.C.A. Biochem

in the Netherlands. Chemically synthesized lactic acid is marketed by Sterling Chemicals and Musachino Company of Japan. The price of this

form of lactic acid is 20 percent higher than that of the fermented product.
Chapter 3-Biopolymer

to the required pharmaceutical standard (80 to 88

percent purity).

It is estimated that by 1995, the European

market for biopolymer-based orthopedic repair

products will reach $20 million. 26 Orthopedic

repair products will probably represent only about

2 percent of the total market for medical biomaterials in 1995. Absorbable polyglycolide

fixation devices for the treatment of porous bone

fractures, joint reconstruction, and surgical alteration and realignment of bones are currently

undergoing licensing. Fixation devices for the

treatment of malleolar (leg and ankle) fractures

are also undergoing licensing and should be

available within 1 to 2 years. These devices are

manufactured in Finland and are already used in

some European countries. Orthopedic plates and

screws are also likely to be developed within the

next few years. A more speculative application is

the use of biopolymer materials as scaffolding in

the formation of new cartilage in the body.27 With

the advantage of biocompatibility, biopolymers

are likely to be used in many more novel

orthopedic applications.

JAPAN

Since the end of World War II, the Japanese

Government has played an active role in encouraging the development of new technologies. The

targeting of specific technologies for special

government support has been part of a broader

effort to influence the level and composition of

Japan’s national output. The central components

of this national industrial policy have included

financial aid, government sponsorship of pricing,

investment, R&D cartels, and protection of the

domestic market.28 These initiatives have played

an important role in enhancing the competitiveResearch and Development in Europe and Japan 59

ness of the automobile, steel, and semiconductor

industries, In recent years, however, the efficacy

of industrial targeting has been questioned both in

Japan and elsewhere. While industrial policy has

led to successes in some industries, there have

been failures in others.29 Nevertheless, it is still

significant when the Japanese Government not

only targets a sector, but also funds the initial

research to stimulate its development. Two Japanese ministries, the Ministry of International

Trade and Industry (MITI) and the Ministry of

Health and Welfare (MHW), have committed

funds and organizational support to the development of biologically derived materials. The different Japanese biopolymer programs are described below.

 Government Biopolymer Programs

MITI is actively sponsoring and coordinating

biopolymer research among Japanese companies,

academic researchers, and scientific institutes. A

major MITI initiative was the formation of the

Japanese BioIndustry Association (JBA) in 1982.30

A nonprofit organization designed to promote

biotechnology and the bioprocessing industry,

JBA serves as the principal coordinating agency

for biopolymer activity in Japan. JBA’s main

function is to disseminate basic research information across industry, academia, and government.

Its other roles are to define new directions for

cooperative R&D programs, to assist in the

formulation of product standards, and in some

cases, to undertake biotechnology research projects directly. JBA is sponsoring a variety of

development activities in the biopolymer materials area.

The most notable of these programs is an

8-year, 5 billion ($45 million) effort focusing on

z~ B1oI~om[lon Associates, op. cit., footnote 18.

17 Robert Langcr and Joseph Vacami, op. cit., footnote 20.

‘8 See U.S. Congress, Office of Technology Assessment, Competing Economies: America, Europe, and the Pacific Rim, OTA-ITE-499

(Washington. DC: U.S. Government Printing Office, October 1991).

‘y For example, the Japanese have not been able to develop a presence in the commercial aviation industry. Ibid.

w ~e orl~nal ~me of the organization was the BioIndustry Development Center @IDEC).
60 Biopolymers: Making Materials Nature’s Way

the development of biodegradable polymers from

microbial organisms. 31 This research program

will concentrate on the following areas: developing probes for use in gene cloning; developing

mass culture technology; improving natural polymer materials; developing technologies for molecular design and accurate polymerization of

synthetic polymers; and testing and evaluation

methods for biodegradable materials.

At the National Institute of Biosciences and

Human Technology, a MITI laboratory in

Tsukuba, researchers are working on biopolymer

blends based on polyhydroxyalkanoates (PHAs)

(microbial polyesters), starch, and polycaprolactone. 32 At MITI’s Shikoku Laboratories in Takamatsu, biodegradable materials based on laminates of chitosan and cellulose are being investigated,

and at the MITI research facility in Osaka,

research on condensation polymers including

polyesters and polyamides is being carried out.33

In addition to research at its own facilities, the

government is sponsoring biopolymer research at

several universities.34 MITI has also provided

about 5 billion ($45 million) in funding to a

multicompany venture in bacterial cellulose technology. 35

Another program that could result in biopolymer advances is the Protein Engineering

Research Institute (PERI) project. PERI, a consortium of 14 chemical, pharmaceutical, and food

companies, will receive $150 million in government funding over a 10-year period. The focus of

PERI’s work is to develop a fundamental understanding of protein structure-function relationships, and thereby establish a competitive edge in

protein engineering.

36 protein research is important to many areas of biotechnology, and could

very well lead to new biopolymers with unique

physical and functional properties, as well as

basic improvements in the processes used to make

biopolymers.

In addition to government-sponsored activities, several companies have formed an association called the Biodegradable Plastics Society

(BPS) to help coordinate their research efforts.

Activities of BPS include: determining the feasibility of making commodity plastics from biodegradable polymers; developing evaluation methods for biodegradable plastics; surveying market

trends in plastics; and exchanging information

with domestic and foreign organizations. Companies involved in this research are the more

traditional chemical and plastics companies. About

half of the 73 companies in BPS have also

expressed considerable interest in the medical

applications of biopolymers.37

The relationships among the various Japanese

biopolymer research organizations are outlined in

figure 3-2. The multifarious biopolymer research

activities of Japanese Government and industry

are designed to create new commercial opportunities in plastics and medical materials. MITI’s

sponsorship of biopolymer research is one indicator of the potential importance of this field. It is

part of MITI’s overall strategy to create a new,

high-growth industry in biologically derived chem31 y. “slubaru Doi, Institute of Physical and Chemical Research (RIKEN) Jap~ personal communication July 21, 1993.

32 Graham SwifC Rohm and Haas Co., personal communication July 13, 1993.

33 Ibid.

~ For ~-pie, ScientiSk at tie To&o ~ti~te of TeC~O@y are working on genetic modification Of pH.A ~ktis. and rese~bers at

Keio University are investigating water-soluble polymers based on starch oxidation products and vinyl monomers.

M me comemi~ venture in bactefi ce~ulose technology is financially supported by the Japan Key Technology Center, a joint

organization under MITT and the Ministry of Post and Telecommunications, and six private sector companies: Ajinomoto, Shimizu

Construction, Nikki, Mitsubishi Paper, Nikkiso, and Nakarnori Vinegar. The venture is called Biopolymer Research Co., Ltd, and its principal

focus will be the development of mass production techniques for cellulose that is made by fermentation (.lapan Chem”calDaily, Apr. 13, 1992).

36 U.S. Congress, oftlce of Technolo~ Assessment, op. cit., footnote 2, p. 157.

37 ~ ~dition t. tie 73 Jap~ese companies in BPS, a few foreign firms are also participating, including Zeneca Bio Products (WMed

Kingdom) and Rohm and Haas (United States).
.

Chapter 3-Biopolymer Research and Development in Europe and Japan 61

Figure 3-2-Japanese Initiatives and Programs in Biopolymers

aResearch

institutes

X

/

/

?

/

Consultation and

research

a

/B,,,,;,d ➤ ;

n El COMPANIES

MITI 4 Information ➤ JBA 4 Information ➤ BPS

SOURCES: Biolnformation Associates, Boston, MA; Yoshiharu Doi, Institute of Physical and Chemical Research

(RIKEN) Japan, personal communication, July 21, 1993.

icals and materials. Japan currently leads the

world in microbial production of amino acids38

and industrial enzymes, and thus is well positioned to take advantage of biopolymer advances

that involve fermentation technology.

The Ministry of Health and Welfare is also

supporting biopolymer research. MHW is encouraging private sector cooperation in the drug

delivery systems field. Seven major pharmaceutical companies have joined together to sponsor

DDS research. With support from MHW, the

Drug Delivery Systems Institute has been capitalized at 1OO million ($900,000) and will focus on

developing glycocarrier (sugars) drug delivery

vehicles for central nervous system, bone, and

kidney drugs. Although this amount is relatively

small, the combined funding levels of programs

sponsored by MITI and MHW make it clear that

Japan is placing considerable emphasis on developing biomedical applications for biopolymers.

Table 3-3 summarizes the work being performed

at Japanese research institutions on biopolymers

that could be used in the biomedical sector.

These collaborative programs are proceeding

in earnest, although most companies interviewed

in Japan did not think that the commercial

potential for medical biomaterials would develop

fully until after 1995. If current R&D efforts reach

fruition, biopolymers could make significant

inroads into the biomedical market by the end of

the decade. Japan’s multiyear research investment will likely result in both product innovations

and a comprehensive review protocol against

which biodegradable medical products can be

tested.

 Private Sector Activity

DEGRADABLE POLYMERS

In the area of degradable polymer research,

Japanese companies are focusing primarily on the

development of materials derived completely

from microorganisms or agricultural feedstocks.

The Japanese BioIndustry Association is the

principal organization responsible for coordinating research in this area. MITI is also working

with various research institutes and companies,

including the Biodegradable Plastics Society, to

establish evaluation methods, and to set up

product specifications and standards for biude38 ~s commercial dominance may not last, because Archer Daniels Midland of the United States has reeently entered this field and in only

1 to 2 years has captured 30 percent of the animal feed market for the amino acid lysine.
- -

62 I Biopolymers: Making Materials Nature’s Way

Table 3-3—Biopolymer Medical Research by Scientific Institutes in Japan

institution Polymer Potential Comments

Tokyo Institute of Technology

Kyoto University

Kyoto University

Industrial Products Research

Institute

Kansai University

Japan Kokai Tokyo Koho

Natural polyesters (i e., Sutures; orthopedic repair Polymer similar to

PHAs)

Polyglycolic acid

Gelatin (protein)

Leuclne-glutamine

blomembrane

(polyamino acids)

Lactic acid-maleic acid

copolymer

Copolymer amino acid

(Ieuclne-benzyl

glutamate)

Sutures; orthopedic repair

Drug carrier to deliver

immunomodulators to

tissue cells

Drug delivery

Slow release earners for

anticancer drugs such

as 5-fluorouracil

Artificial blood vessels

PHBV (BIOPOL);

commercialization

expected in 2 to 3

years

Cells ingest gelatin

Membrane reacts to

acid-base changes

by altering structure

and admits or rejects

different substances

Injected into

bloodstream;

polymer is absorbed

by cancer cells and

releases drugs as it

degrades

Patented in 1986

SOURCE Bioinformation Associates Boston, MA

gradable products. This comprehensive program

is being coordinated through JBA.

In addition to supporting biopolymer research

in the areas of recombinant DNA technology and

large-scale bioprocessing, JBA has completed a

feasibility study evaluating the potential of biodegradable polymers as commodity materials. It is

likely that biopolymer development efforts will

receive additional impetus as a result of this

study, with Japanese companies exploring a wide

range of possible biopolymer applications. A

partial listing of companies participating in BPS

is provided in table 3-4.

Potential producers of next-generation biopolymer materials in Japan are listed in table 3-5.

Scientists at the Tokyo Institute of Technology

have produced a versatile polyester product from

bacteria.

39 This ‘‘bioplastic’ is similar to the

degradable material BIOPOL produced by Zeneca

Bio Products in Europe. A copolymer of 3-

hydroxybutyrate and 4-hydroxybutyrate (HB) has

been extracted and fermented from Alcaligenes

eutrophus under starvation conditions (chapter 2).

This polymer is thought to have improved functional properties over BIOPOL, since it can be

made more elastic by altering the ratio of the

copolymers, Researchers expect this polymer

material to be commercialized (probably by

Mitsubishi Kasei) in 3 to 4 years; it will be

targeted first at the mulch film, marine (nets and

lines), and medical markets.40

Other companies such as Hayashibara Biochemical are interested in expanding the applications for their microbial polysaccharides (pullulans) into areas such as packaging (chapter 2). The

company is already producing a pullulan derivative that is used as an edible protective film for

39 See Yoshiharu Doi, “Microbial Synthesis and Properties of Polyhydroxyalkanoates,’ Materials Research Society Bulletin, vol. XVII,

No. 11, November 1992, pp. 39-42.

~ Yoshlha Doi, op. cit., .00tnOte 31.
Chapter 3–Biopolymer Research and Development in Europe and Japan! 63

Table 3-4-Biodegradable Plastics Society Member Companies in Japan

Company Core business Company Core business

Ajinomoto

Asahi Chemical Industry Co

Bridgestone Corp

Chou Kaguku Corp

Dai Nippon Ink & Chemicals

Dai Nippon Printing Co

Denki K K

Idemitsu Petrochemical

Japan Steel West

Kureha Chemical Industry Co

Mitsubishi Gas Chemical Co

Mitsubishi Kasei

Mitsubishi Petrochemicals

Food processor, aminoacld producer

Synthetic resin producer

Large rubber manufacturer

Plastic containers

Major producer of printing

Ink

Printing company

Major chemical company

Petrochemicals

Steelmaker

Leading fine chemical

maker

Major chemical company

Largest all-around

chemical company,

mainline carbochemicals

Large petrochemical

enterprise

Mitsui Toatsu Chemicals

Nippon Kayaku

Nippon Shokubai Kagakku

Kogyo Co.

Sekisui Chemical Co.

Sekisui Plastics Co

Shyowa Denko KK

Sumitomo Bakelite

Sumitomo Chemical Co.

Sumitomo Metal Industries

Toagosei Chemical

Industry Co.

Toyo Ink Manufacturing

Ube Industries

Unitika Ltd

Chemicals,

fertilizers

Pharmaceuticals,

agrichemicals,

special resins

Petrochemicals,

industrial

chemicals

Plastics processor

Largest producer

of foam plastics

Petrochemicals,

industrial

chemicals

Integrated

processor of

synthetic resins

Fine chemicals,

agrlchemicals

Steelmaker

Plastics

Printing ink

materials

Petrochemicals,

cement

Textiles, plastics

SOURCE Biolnformation Associates Boston, MA

food. The biodegradability of pullulan makes it an

extremely attractive material. Japanese companies have developed sophisticated and advanced

fermentation technologies that are ideally suited

for developing biodegradable polymers from

microbial metabolizes and polymer-producing

microorganisms.

41 Thus, Japanesee companies could

emerge as very strong competitors in the area of

microbial biopolymers.

The British company Zeneca Bio Products,

which has a subsidiary in Japan, is also a member

of BPS. Zeneca is supplying 30 to 40 Japanese

companies with research quantities of its

BIOPOL polymer. Zeneca successfully introduced BIOPOL cosmetic bottles in Europe in

1990 and recently entered the Japanese market

with another product—biodegradable golf tees.

BIOMEDICAL MATERIALS

Most Japanese companies do not believe that

the medical biomaterials market will take off until

after 1995. Since the use of biopolymers for

therapeutic purposes is still in the exploratory

stage, it is difficult to assess how the medical

41 ~ addition t. tie large chemical companies pursuing biopolymer production, some Japanese breweries arc retrofitting tieir fermen~tion

plants to produce new biological compounds (Norman Oblon and Karen Shannon, Oblon, Spivti McClelland, Maier, & Neustadt, P. C.,

personal communication, Aug. 12, 1993).
64 Biopolymers: Making Materials Nature’s Way

Table 3-5—Current and Potential Suppliers of Next Generation Degradable Polymers in Japan

Company Country Product/Status Potential Likely Comments

application entry date

Mitsubishi Kasei

and Tokyo

Institute of

Technology

Hayashibara

Biochemical

Kureha Chemical

Kyowa Hakko

Kogyo Co. Ltd

Kawasaki Steel

Showa Denko K.K

Showa High

Polymers, Ltd.

Zeneca Bio

Products

Japan

Japan

Japan

Japan

Japan

Japan

Japan

United Kingdom

Microbial polyesters

poly(3HB)-(4HB)

copolymer

Microbial polysaccharides (e.g.,

pullulan)

Microbial-based

polymers

Microbial-based

polymers

Microbial-based

polymers

Microbial-based

polymers

Packaging

Pullulan

packaging,

edible/biode

gradable

food wrap

Disposable

packaging

Packaging

Packaging

Mulch film;

bags

BIONELLE—synthetic Packaging;

“biodegradable” structural

polyester materials

BIOPOL Cosmetic

bottles,

other

packaging

materials

1994-96

1993

Not known

Not known

Not known

1995

1994

Now

Can biodegrade in 4 to 6 weeks;

similar to Zeneca’s PHBV

copolymer

Product available now

Assessing government

regulations

Likely entrant

Working with established

biotechnology

company—Clef-to research

and develop biodegradable

polymers

Assessing various polymer

technologies

7-million-pound manufacturing

facility in 1994

Pilot plant in England; asessing

full production plant

SOURCE: Biolnformation Associates, Boston, MA.

materials market in Japan will evolve. Table 3-6

provides information on companies that either

have a product on the market or are known to have

a product nearing introduction. Applications include artificial skin, sutures, orthopedic implants,

and drug delivery vehicles. Many products are

awaiting approval by the Ministry of Health and

Welfare.

Many companies that are members of the

Biodegradable Plastics Society are also expected

to develop products for the biomedical market.

However, it does not appear that these firms have

clearly defined product strategies. Some of the

companies listed in table 3-6 are traditional

chemical companies that have expressed only a

general interest in moving into the pharmaceutical, biochemical, and biomaterials sectors. Although it is unlikely that any of these companies

will enter the biomaterials market before 1995,

they may be presented with significant opportunities as the market develops over the long term.

 Japanese Industrial Policy Revisited

MITI’s sponsorship of biopolymer development has raised concerns among some U.S.

researchers that leadership in yet another promising high-technology field might be ceded to the

Japanese. For some observers, the past successes
Chapter 3–Biopolymer Research and Development in Europe and Japan 65

Table 3-6-Current or Potential Suppliers of Biomedical Materials

Company Core business Polymer of interest Comments

Ajinomoto Co.

Terumo and Tokyo Toritsu

University

Chisso

Genzyme Japan

Kyowa Hakko Kyogo Co,

QP

Riken Vitamen

Seikagaku Kogyo

Shiseido Co Ltd

Yakult Honsha Co.

Mitsui Toatsu Chemicals

Koken and Okayama

University

Johnson and Johnson

Orthopedic Co

Unitika

Takeda Chemical Industries

Ltd

Sumitomo Pharmaceutical &

Koken

Nitta Gelatin

Ajinomoto Co

Asahi Chemical Industry Co

Dalichi Seiyaku

Eisai Co Ltd

Meiji Selka

Shionogi

Tanabe Sekyaku

Foods, amino acids

Medical Instruments,

pharmaceuticals

Medicinal products and

botanical

Chemicals, amino acids

Cosmetics

Pharmaceuticals, cosmetics

Chemicals, fertilizers

Medical equipment

Healthcare products

Textiles

Pharmaceuticals (drug

delivery)

Pharmaceuticals, medical

equipment

Chemical preparations

Food Processor, amino acids

Leading manufacturer of

synthetic fibers

Pharmaceuticals: circulatory

and respiratory

Pharmaceuticals” nervous

system

Pharmaceuticals” antibiotics;

foods

Pharmaceuticals antibiotics

Pharmaceuticals circulatory

and respiratory

Biocellulose

Collagen

Hyaluronic acid (HA)

HA

HA

HA

HA

HA

HA

HA

Polylactic-polyglycolic acid

(PLA-PGA)

Collagen

PLA-PGA “Orthosorb”

Chitin/chitosan “Beschtin-W”

PLA-PGA Lupron Depot

Collagen

Collagen

Glycocarriers

Glycocarriers

Glycocarriers

Glycocarriers

Glycocarriers

Glycocarriers

Glycocarrier

Artificial skin

Artificial skin (animal studies)

Tissue repair, wound healing

Tissue repair, wound healing

Tissue repair, wound healing

Wound healing

Wound healing

Wound healing

Wound healing

Wound healing

Sutures

Membrane to prevent adhesion

after surgery

Not yet commercial ;fixation plate,

pins, etc.

WiII be used for orthopedic

surgery

Joint venture with Abbott

Laboratories (United States)

Phase Ill trials for anticancer

drug

DDS for osteoplastic factors

Member of Drug Delivery

Institute (DDI)

DDI

DDI

DDI

DDI

DDI

DDI

SOURCE Biolnformation Associates, Boston, MA.

of MITI-initiated technology programs suggest specific types of biodegradable polymers (e.g.,

that Japanese industry could be given a signifi- microbial polyesters and polysaccharides). The

cant boost in its efforts to develop biopolymer 8-year MITI biopolymer program will undoubtproducts. Indeed, with their expertise in fermenta- edly lend momentum to initial Japanese commertion technology, Japanese companies are in an cialization efforts.

excellent position to exploit the market for some
. . . . .

66 I Biopolymers:

However, over

Making Materials Nature’s Way

the long term, the concerted

attempt of the Japanese Government to promote

biotechnology, and biopolymer applications in

particular, could be impeded by a number of

structural and institutional factors. In contrast to

the United States, Japan has a weak basic research

base in biotechnology, which has led many

Japanese firms to send their personnel abroad for

training and to set up foreign research facilities.42

In addition, Japan’s pharmaceutical industry has

long been sheltered from international competition and is only now beginning to develop

state-of-the-art skills in drug development, testing, and marketing.

43 This could inhibit the entry

of Japanese companies into the lucrative global

biomedical market. Because Japan is not a

food-exporting country, its agricultural research

enterprise is narrowly focused, and it may not be

able to compete with the biopolymer programs of

large U.S. and European agricultural firms.44

Finally, the maturation of the Japanese economy

has reduced the relative importance of governmentsponsored R&D programs. Many segments of

Japanese industry have become so successful that

they are no longer willing to be guided into

targeted investments. MITI, for example, recently

abandoned a bioprocessing project because of the

reluctance of industry to cooperate.45 Nevertheless, the commitment of Japanese industry and

government to biopolymer R&D is considerable,

and it is therefore likely that in certain segments

of the biopolymer field, Japanese companies will

be formidable competitors.

42 us conwe~s, OffiW of Technology Assessment, Op. cit., foo~ote 2

. .

43 Ibid.

a Ibid.

45 over the past decade, the effofi of MITI to promote biotechnology as a key technology and to inte~ate it ~to exist~g ~dus~~ s~tom,

while bearing some frui~ have clearly been less successful than many observers anticipated. Ibid.
—

Biopolymer

Research and

Development

I

in the

United States 4

I

n recent years, there has been a steady expansion of

biopolymer research activities in both the private and the

public sectors. Concerns about the environmental impacts

of petroleum-based polymers have led many companies to

investigate several different classes of biologically derived

polymer materials. Advances in chemistry and the biological

sciences have also stimulated research efforts in the biopolymer

area. As illustrated in chapter 2, the potential applications of

biopolymer materials are extremely diverse, ranging from

packaging to food additives and industrial chemicals to pharmaceuticals. Novel biopolymer materials are being investigated by

Government and university researchers, large agricultural and

chemical firms, and small biotechnology enterprises. As in

Europe and Japan, U.S. biopolymer technology is, for the most

part, still in the early stages of development, and substantial

commodity markets for these materials are not likely to appear

for several years.

ACTIVITIES OF THE FEDERAL GOVERNMENT

One of the principal difficulties in describing the biopolymer

research efforts of the U.S. Government is that biopolymer

science is inherently interdisciplinary in nature. Broadly defined,

biopolymer research covers a number of different areas, including materials science, chemistry, microbiology, biophysics, plant

biology, and structural biology. Thus, basic research in any of

these disciplines can accelerate advances in biopolymer technology. Indeed, in many cases, biopolymer researchers have been

able to take advantage of innovations that have emerged from the

broad-based U.S. programs in biotechnology (e.g., recombinant

DNA research).

67
. . . .

68 I Biopolymers:

.-

Making Materials Nature’s Way

Table 4-1—Federal investment in Manufacturing/Bioprocessing Biotechnologya

($million)

FY1991 FY1992 FY1993 D

National Science Foundation $29.5 $32,3 $430

U.S. Department of Agriculture 17.6 18,8 23.6

Department of Defense 12,7 17,4 18,4

Department of Health and Human Services 16.7 17.0 17.7

Department of Energy 5.3 6.4 13.2

National Aeronautics and Space Administration 2,6 2.6 3.7

Department of Commerce 3,5 3.5 3,5

Department of the Interior 1,0 0.8 0.7

Total $88.9 $98.8 $123,8

aThe~e ~rogram~ cover research In the areas of blomolecular materials, medcal materials, blosensors,

bloelectromcs, plant- and-msect-derwed products, metabohcengmeenng(recombmant DNA research as It relates to

Industrial mlcroorganlsms), bloreactor design, blocatalysw or enzyme englneerlng, separation and purification

technology, process design, and process monitoring and control

bThe proposed FY 1994 budget C.dk for increases of about 7 per~nt over FY 1993

SOURCES Federal Coordmatmg Council for Science, Engmeerlng, and Technology, Committee on Life Sciences

and Health, Biotechnology for the 21s( Century (Washington, DC U S Government Pnntlng Office, February 1992),

Allcla Dustlra, Whtte House Office of Science and Technology Policy, personal commumcatlon, July 1993

By many measures, the United States is preeminent in biotechnology, with strong research

programs in biomedicine and agriculture.1 In FY

1993, the Federal Government is spending about

$4 billion to support research and development

(R&D) in biotechnology-related areas.2 In relative and absolute terms, the United States supports more research relevant to biotechnology

than any other country. 3 However, only about 3

percent ($124 million) of the total 1993 biotechnology budget is devoted to biologically derived

compounds and industrial bioprocessing research4

(see table 4-l). And a only a small fraction of that

3 percent is targeted specifically to biopolymer

development. A number of different Government

agencies sponsor biopolymer research:

the Department of Defense (DOD),

National Science Foundation (NSF),

the Department of Health and Human Services

(DHHS) and specifically the National Institutes

of Health (NIH),

the Department of Energy (DOE),

the Department of Agriculture (USDA),

the Department of Commerce (DOC),

the Department of the Interior (DOI), and

the National Aeronautics and Space Administration

The following sections describe those research

activities that relate directly to the production of

biopolymer materials or to the development of

new biopolymer applications.

I U.S. Congress, Office of Technology Assessment, Biotechnology in u Globul Economy, OTA-BA-494 (Washington DC: U.S.

Government Printing OffIce, October 1991).

2 Federal Coordinating Council for Science, Engineering, and Technology, Committee on Life Sciences and Health+ Biotechnology for the

21st Century (Washington, DC: U.S. Government Printing Office, February 1992).

J U.S. Congress, Office of Technology Assessment, op. cit., footnote 1.

4 The term bioprocessing refers to the steps involved in producing a material or a chemical by using biologicrd conversion processes such

as fermentation or special enzymatic treatment. The proposed $124 million in funding for bioprocessing represents a 25 percent increase over

fiscal 1992 levels (Federal Coordinating Council for Science, Engineering, and Technology, op. cit., foofnote 2, p. 42).
Chapter 4--B copolymer

 Department of Defense

The main programs sponsored by DOD are

funded by the Office of Naval Research (ONR)

Molecular Biology Program; the Army Research,

Development and Engineering (RD&E) Center

(Natick, Massachusetts); and the Army Research

Office (Research Triangle Park, North Carolina).

OFFICE OF NAVAL RESEARCH BIOPOLYMERIC

MATERIALS PROGRAM

The ONR Biopolymers Materials Program is

investigating biologically derived materials for

possible use in marine environments. There is

particular interest in materials that prevent biofouling and biocorrosion. Among the materials

being studied are thermoplastics, coatings, adhesives, and elastomers. One aim of this research is

to achieve a greater understanding of the relationship between the microscopic structure of polymers and their macroscopic physical properties,

such as elasticity, adhesion, piezoelectricity, nonlinear optical properties, and tensile strength. The

program is also attempting to develop a fundamental understanding of molecular assembly

processes. Many of the projects involve the study

of novel protein polymers (see chapter 2). Of the

19 ongoing projects, 17 are being carried out in

universities and 2 are in-house. The total annual

level of funding is around $1.8 millions

U.S. ARMY PROGRAMS RELATED TO

BIOPOLYMER SCIENCE AND TECHNOLOGY

1. U.S. Army Natick, RD&E Center: The U.S.

Army RD&E Center is exploring a variety of

biologically derived materials, as well as the

processing mechanisms of biological systems.

The ability of biological systems to produce a vast

range of materials under mild processing conditions (i.e., low temperature and pressure), without

creating toxic byproducts, could lead to new,

environmentally sensitive manufacturing methResearch and Development in the United States 69

ods. The program has three principal areas of

focus: advanced bimolecular materials, biodegradable polymers, and “intelligent” materials.

In-house research is funded at about $1.5 million,

with additional supplemental funds provided for

special programs such as a joint effort with the

USDA on biodegradable polymers for packaging.

A significant percentage of the funding supports

university projects. Cooperative programs are

also in place with a number of industrial partners.6

Research on bimolecular materials is concerned primarily with protein-based biopolymers,

Work in this area includes isolation and characterization of natural structural proteins (e.g., silk),

cloning and expression of genes encoding these

materials, molecular modeling to understand

structure-function relationships, elucidation of

the processes involved in converting watersoluble polymers to water-insoluble materials,

and formation of films and fibers.

The biodegradable polymer program is focusing on naturally occurring biodegradable polymers, including polysaccharides, polyesters, and

proteins. Research covers numerous activities:

fermentation production and plant sources, purification, chemical modification of natural polymers, blending, processing into blown films,

injection molding, characterization of liquid cyrstalline phases, determination of biodegradation kinetics, evaluation of toxicity of materials in

marine and soil environments, consumer acceptance studies, and product evaluation.7 These

activities are directed toward the development of

biodegradable products for Army and Navy use.

Research in the area of intelligent materials

involves investigation of the interfaces between

biological materials and synthetic polymers. This

work is directed toward the development of

materials that sense and react to changes in their

operating environment (e.g., materials that stiffen

in response to turbulence, or change properties

5 Michael Marron, Office of Naval Research Molecular Biology Program, personal communicatio~ June 30, 1993

b David Kapl~ U.S. Army Natick RD&E Center, Biotechnology, personal communicatio~ July 16, 1993.

7 Ibid.
 

70 I Biopolymers: Making Materials Nature’s Way

under different temperature and pressure conditions). Specific areas of investigation include the

study of energy transduction from proteins to

synthetic polymers, thin-film assemblies, biosensors, and nonlinear optical polymers generated

through biocatalytic processes.8

2. Army Research Office: The Army Research

Office is sponsoring biopolymer research in

several different areas. Particular emphasis is

being placed on understanding the mechanisms of

complex biopolymeric function, the macromolecular structures supporting such function, and the

biosynthetic pathways that lead to those structures. Current efforts involve the use of molecular

genetics, protein engineering, and physicochemical

characterization to clarify how higher-order structure is achieved in polymer materials, and how

such structural features might be genetically or

chemically manipulated for different applications. The program is

annually, with most

university research.9

 National Science

funded at about $1 million

of the funds supporting

Foundation

The National Science Foundation has many

programs that directly or indirectly support biopolymer research. NSF is spending more than $30

million annually on bioprocessing and bioconversion research, and about $12 million on bimolecular materials research.10 Although most of this

funding is not directed specifically toward biopolymer development, these programs are likely

to have many positive spillover effects. For

example, NSF is supporting work in the areas of

gene transfer, macromolecular structure and function, metabolic pathways, molecular selfassembly, biomimetic chemistry (processes that

utilize or mimic biological systems), gels and

microemulsions, and material properties of membranes, surfaces, and interfaces.

There are currently about a dozen specific

projects investigating the properties of protein

polymers and various methods for their production. This includes a pioneering project to produce synthetic polyamino acids by genetic techniques. 11 Funding for these projects amount to

less than $1 million. In addition, NSF has

sponsored studies of lignin copolymers, which

potentially could be used for a variety of purposes, including degradable plastics.12 Another

area of emphasis is the field of tissue engineering,

where biopolymer materials are being evaluated

for their restorative properties and as potential

substitutes for damaged tissue.13

 Department of Agriculture

USDA supports a variety of biotechnology

programs that bear on biopolymer research and

development. Projects include gene cloning in

microorganisms, nucleic acid hybridization, biological and biochemical synthesis of nucleic acids

and proteins, improving the quality of woody

plants (for the extraction of cellulose), and

mapping genes of agronomic importance. Several

programs are investigating the use of agricultural

8 Ibid.

9 Rolxfi Campbell, U.S. Army Research Office, personal communication July 29, 1993.

10 U.S. Congess, Office of Technology Assessment op. cit., footnote 1; Federal Coordinating Council for Science, Engineering, and

Technology, op. cit., footnote 2. A recent initiative includes NSF participation in the Federal Advanced Materials and Processing Program

(AMPP). The AMPP is designed “to support multidisciplinary research and to encourage bold new advances” in the materials area. The

program specifically focuses attention on polymers and biomolecdar materials.

1 I No~&fl B~eS, NatiO~ sCience FOUn&tiOn, p~soml communicatio~ July 22, 1993. ~so see D.A. Tirrell et d., “Genetic SyIl~eSIS

of Periodic Protein Molecules,” Journal of Bioactive and Biocompatible Polymers, vol. 6, October 1991, pp. 326-338,

12 us Congess, Offlce of Tec~olog Assessment, Agricultural Commodities as]~usm”alRaw Materials, 0’IA-F-476 ~Uh@to@ ~:

U.S. Government Printing OffIce, May 1991).

13 Feder~ coord~~g Comcfi for Science, Engineefig, and Technology, op. cit., foo~ote z; ~d RObm wgm md Joseph Vacanti,

“Tissue Engineering,” Science, vol. 260, May 14, 1993, pp. 920-925,
Chapter 4–Biopolymer Research and Development in the United States 71

commodities for industrial purposes,14 and one of

the major projects involves the use of cornstarch

for degradable plastics. Proposed funding for

biodegradable materials research in FY 1993 is

$4.4 million. Another program, Advanced Materials from Renewable Resources (total N 1993

funding, $10 million), will also direct resources to

the development of biopolymers.15

In addition, the Cooperative State Research

Service (CSRS) Office of Agricultural Materials

and the Alternative Agriculture Research and

Commercialization Center work with academia

and industry in the development and commercialization of new industrial uses of crops, including

biopolymers. 16

 National Institutes of Health

The National Institutes of Health has played a

central role in advancing the fundamental understanding of biological processes at the molecular

level. NIH supports basic biotechnology research

in areas such as recombinant DNA techniques,

gene mapping, and protein engineering. It also

supports a broad range of research that supports

biotechnology: genetics, cellular and molecular

biology, biological chemistry, biophysics, immunology, virology, macromolecular structure, and

pharmacology.

17 Funding for NIH biotechnology

and related programs, in FY 1993, is approximately $3 billion .18 As stated earlier, only a small

percentage of these resources is allocated specifically to biopolymer research. The principal areas

of biopolymer work are in drug delivery systems

where biocompatible polymers are used in sustainedrelease applications, and in biohybrid devices

where polymer materials are used as implants,

prosthetic devices, and agents of tissue repair or

regeneration. Because biopolymers have several

potentially important applications in the biomedical field, there have been proposals calling for a

dramatic increase in the level of NIH activity in

this area (see box 4-A).

 Department of Energy

DOE has a large general effort in biotechnology, including projects in mapping the human

genome and in structural biology. Research in

structural biology is directed toward understanding the structure-function relationships of biological molecules and the synthesis of proteins. A

number of different DOE programs are more

directly involved with biopolymer research. The

National Renewable Energy Laboratory is exploring how cellulosic biomass can be converted

into sugars that can then be fermented into

ethanol .19 Enzymes are being used to break down

cellulose polymers without attacking the product

sugars that are subsequently fermented. Other

DOE programs are studying how biological

feedstocks can be used to create high-value

chemicals. Argonne National Laboratory, for

example, is investigating lactic acid-based degradable plastics (see chapter 2).

14 TIKSe include thc usc of traditional crops such as corn and soybeans, as well as new crops such as guayule (robber) and kenaf (pulp similar

to wood) (U.S. Congress, Office of Technology Assessment, op. cit., footnote 12).

IS me two programs mentioned here me funded [hrough U.S. Department of Defense appropriations and are Jointly administer~ by tie us.

Army Natlck RD&E Laboratory and the U.S. Department of Agriculture, Cooperative State Research Service, Office of Agricultural Materials.

16 L, Dal,ls C]ements, Cooperative state Rese~~h Semice, Office of Agricul~~ Materials, personal communication, July 28, 1993.

I T U.S. Congress, Office of Technology Assessment, op. cit., footnote 1.

18 Fcdcr~ Coordinating Cc)uncl] for Science, Engineering, and Technology, op. cit., foomote 2. Proposed funding for FY 1994 iS

approximately 7 pcrccnt above FY 1993 levels (Alicia Dustira, White House Office of Science and Technology Policy, personal

communication, July 28, 1993. )

19 ccl]u]o~e from woody ~n(i herbaclous crops offers a low.cc)st a]termtilrc (O cornstarch a... the feedstock for etilnol. See U.S. Department

of Energy, CcJnser~’atiorr arrd Renewable Energy Technolo,qiesfor Transportation (Washington, DC: U.S. Government Printing Office, 1990).
72 Biopolymers: Making Materials Nature’s Way

Box 4-A–A Proposed Research Agenda for Medical Biomaterials:

Recommendations to the National Research Council

In 1990, the National Research Council sponsored four regional meetings with the aim of

developing specific recommendations for a national materials science and research agenda. One

outgrowth of these discussions was a detailed proposal calling for a national initiative in the area of

biocompatible materials. The proposal identified several opportunities for health care cost reduction

through the development of novel materials. For example, if an implantable artificial insulin delivery

system could be designed, it is estimated that costs associated with the treatment of diabetes could be

reduced by $2 to $4 billion annually. Since biomaterials research cuts across several different

disciplines such as chemistry, microbiology, and materials science, many potentially innovative

technologies may be overlooked by academia and the different Federal agencies. Consequently, the

proposal calls for much greater coordination of Federal programs in the biomaterials area and a

dramatic increase in overall funding. This 10-year, $2.5 -billion program would be designed to greatly

expand scientific understanding of the interaction between materials and biological systems, and to

accelerate biomedical commercialization efforts. The principal recommendations include the following:

●

●

●

●

●

The establishment of a new national institute of medical technology, within the National Institute

of Health (NIH), to act as a central coordinator and lead funding agency for biomaterials

research. The new institute would encourage interaction among medical clinicians, academic

scientists, and industrial researchers.

The establishment of several regional biomaterials research centers that would be funded at $10

to $20 million each for 10 years. Total funding would be about $150 million per year. Such

centers would be designed to promote interdisciplinary research and greater university-industry

cooperation. Areas of focus would include: genetically engineered biopolymers, “smart”

bioresponsive materials, polymer-tissue interaction, analytical surface science, in vitro testing

(faster materials testing and elimination of animal testing), environmentally compatible

materials, and nondestructive evaluation techniques.

The creation within the National Science Foundation (NSF) of a biomaterials program, where

biomaterials research is defined as “the study and knowledge of the interactions between living

and nonliving materials.” Funding levels for individual investigators would total $100 million

annually, and projects would be coordinated with t he institute of medical technology described

above.

The establishment of a national information center to serve as a clearinghouse for data on the

physical, surface, and biological properties of biomaterials. The center would also evaluate and

create standard testing procedures for novel materials.

The development of performance criteria for biomaterials to expedite the Food and Drug

Administration product approval process.

These recommendations were presented to the National Academy of Sciences and forwarded to

the White House Office of Science and Technology Policy (OSTP) in early 1991. In response, OSTP

initiated a cross-agency study that cataloged all Federal activity in the biomaterials area, and

opportunities for greater coordination among Federal agencies were identified. In addition, funding for

NIH and NSF biomaterials programs was increased slightly.

SOURCES: Materials Research Society, A /Vationa/ Agenda in hfateriak Science and Engineering: /rnp/ernar?fing

the MS&E Report, February 1991, Southeast Regional Conference on Materials Science and Engineering, Finai

Report, September 1990; E.P. Mueiier and S.A. Barenberg, “Biomateriais in an Emerging National Materials

Science Agenda,” Materials Research ~u//etin, vol. XVI, No. 9, September 1991, pp. 86-87; Edward P. Mueller, Food

and Drug Administration, personai communication, Aug. 16, 1993.
Chapter 4-Biopolymer

 Other Agencies

Several other Government research programs

pertain to biopolymers. NASA is investigating

new separation processes for the purification of

biological materials, and new fabrication methods for biopolymer films and matrices. One major

effort is in the area of protein crystal growth. The

microgravity biotechnology program is utilizing

the space environment to gain a better understanding of protein structure and formation.20

The Food and Drug Administration (FDA) has

a sizable biotechnology effort in order to deal

with the regulatory issues affecting genetically

engineered pharmaceuticals and food products. In

addition, the FDA is evaluating the use of

biopolymers in medical devices. This research is

concerned principally with the degradation of

biomaterials that are placed in the body.

Within the Department of Commerce, the

National Oceanic and Atmospheric Administration (NOAA) is investigating polymer materials

produced by marine organisms (e.g., mussel

adhesives and chitosan) that could have a variety

of commercial applications.

21 By studying how

various organisms form polymeric films on surfaces, NOAA researchers are also attempting to

develop methods of controlling biocorrosion and

biofouling. Another Commerce agency, the National Institute of Standards and Technology, is

developing new sensor technologies to measure

Research and Development in the United States 73

complex

studying

biochemical substances, and is also

protein structure and function.

PRIVATE SECTOR ACTIVITIES

As in Europe and Japan, American commercial

activity in biopolymers can be divided into two

major market categories: degradable polymers

that can be used in lieu of traditional commodity

plastics and materials that can be used for

biomedical applications.

DEGRADABLE POLYMERS

When the frost materials containing biodegradable additives were introduced in the late 1980s,

controversy erupted as to whether they were truly

degradable. 22 The principal products involved

were packaging materials and garbage bags. Most

of these goods were either withdrawn from the

market or no longer advertised as being biodegradable. 23 These first-generation products were

made from oil-derived plastic resins such as

polyethylene that contained a low percentage (4

to 6 percent) of starch.24 Although starch itself

readily degrades, various studies indicate that

even under optimal conditions the starch composition of these plastic-starch blends has to exceed

about 60 percent before significant material

breakdown occurs. 25 Due to regulatory uncertainty and the absence of clear standards for

evaluating degradable plastics, the production of

m Feder~ Coordinating Council for Science, Engineering, and Technology, Op. cit., fOOmOte 2.

21 Most of ~~ rc~emch is ~onduct~ at ~versltles ~der tie auspices of tie Natioml SM Gant college ~og~ (ibid).

22 Ap~ from questioning whethm tiese products do in fact degrade, many environmental advocacy f@uPs ad some ~d~~ fYouPs do

not view biodegradation as a solution to solid waste problems. These organizations believe that the introduction of biodegradable products into

the marketplace will undermine recycling efforts and, depending on the extent of their degradation, will exacerbate litter problems. In a previous

study, the Office of Technology Assessment su~ested that a national municipal solid waste policy should be based on “the dual strategies

of waste prevention and better materials management. ’ A comprehensive materials management perspective recognizes that recycling,

comporting, and incineration are complementary objectives. See U.S. Congress, Office of Technology Assessment, Facing America’s Trash;

What Ntzrt for Municipal Solid Wusre, OTA-O-424 (Washington, DC: U.S. Government Printing Office, October 1989).

23 ~otod~a~ble materials, consisting of ethylene-carbon monoxide (E/CO) copolymers, were also introduced for use kgmbage bags and

beverage ring carriers. Currently, only beverage carriers are made from E/CO; 27 StateS have passed legislation prohibiting the use of

nondegradable ring carriers. The main suppliers of photodegradable polymers are Union Carbide, Du Pon~ and Dow Chemicat.

~ Most of ~e~ produc~ were produced by the companies Archer Daniels Midland and St. bwrence smch.

~ U.S. Congess, Offke of Technology Assessment op. cit., footnote 12, P. 96.
74 I Biopolymers: Making Materials Nature’s Way

materials with low starch content has declined

dramatically. The remaining market for these

materials is limited primarily to compostable

bags.

26

While the Federal Trade Commission has

issued guidelines designed to prevent deceptive

environmental marketing claims, scientifically

based definitions and standards relating to degradability have yet to be formally established.27

Up to now, the process of creating environmental

measurement standards has proven to be an

extremely difficult undertaking. 28 A nonprofit

private sector group, the American Society for

Testing and Materials (ASTM), has developed

some standards for evaluating degradable materials in the laboratory .29 ASTM’s work has helped

to create a consensus on testing procedures for

certain categories of degradable materials (e.g.,

photodegradable and compostable substances).

Researchers at ASTM’s Institute for Standards

Research are currently attempting to determine

the behavior of degradable polymeric materials in

real disposal systems and are correlating these

results with ASTM laboratory methods .30 This

research could lead to a better understanding of

how products degrade under different environmental conditions. Yet, even if more reliable

information can be generated, consumer confidence in degradable products is not likely to be

restored without the creation of coordinated

systems of product disposal and waste management. If, for example, products are designed for

comporting, but end up being landfilled or

incinerated, the design improvements are effectively nullified.31

Despite market and regulatory uncertainties,

some companies are proceeding with the development and introduction of a new generation of

starch-based products—materials that have a

starch content ranging from 40 to nearly 100

percent. 32 Agri-Tech Industries is developing a

material that is up to 50 percent starch by weight,

and is targeting applications such as personal

hygiene and disposable medical products.33 WarnerLambert has recently opened a large production

facility for its NOVON family of polymers—

films that range from 40 to 98 percent starch by

weight. Properties of these materials can be varied

depending on the specific types of starches and

other biodegradable materials used. Early appliZ6 It is ~~ely tit compostable bags will provide a sustainable market for the partially degradable starch-ethylene blends. Current and

proposed compost quality standards suggest that compost producers will be very concerned with the ultimate fate of materials accepted into

their facilities. Several studies have demonstrated that plastic fragments, that do not degrade, have a negative impact on the productivity of

farming soil.

27 See Feder~ Trade Cornmissio% ‘‘Guides for the Use of Environmental Marketing ClaimS,” July 1992. Congress has mandated the use

of degradable materials for one product category: plastic ring carriers for bottles and cans. In the proposed rule for this law, EPA has set specific

performance standards for degradable materials. See Federal Register, vol. 58, No. 65, Apr. 7, 1993.

28 see us. ConBess, Office of Technolo~ Assessment, Green PrOd~ct~ by Design; Choice~~Or a cleaner Environment, OTA-E-541

(Washington DC: U.S. Government Printing Office, October 1992).

29 There tie more tin 170 me~en sem~ on the ASTM subcommittee on degradable plastics stantids. ~dustry, gover~ent, academia,

and consumer and public interest groups have representatives on the subcommittee. See Ramani Narya~ ‘‘Development of Standards for

Degradable Plastics by ASTM Subcommittee D-20.96 on Environmentally Degradable Plastics,” 1992.

m The USDA.CSRS OffiW of Agt-icdtm~ Materials is also sponsoring work on compost utilitization, in which biodegradable polymers

are among the materials being evaluated.

31 Ap@ from compost, bi~e~adable mate~s could *CI be us~ as feedstocks for biogas generation. The biogas could then be used to

produce electricity by fueling gas turbines. Wolf-Rudiger Miiller, Institut fir Siedlungswasserbau, Wassergiite-und Abfallwirtschaft der

University Stuttgart, Federal Republic of Germany, personal communication, July 26, 1993.

32 h addition t. the effo~ of individwl companies, the Degradable Plastics Council (DPC), a trade organization that includes both

traditional chemical firms and agribusinesses, is promoting the use of materials derived from agricultural commodities and other renewable

resources. The aims of the DPC are to “stimulate research and developmen~ coordinate efforts and communicate facts regarding degradable

plastic t~hnologies and materials” (Degradable Plastics Council, Washingto~ DC).

33 ~s ~te~ WaS developed at the U.S. Department of Agriculture and has been licensed exclusively to Agri-Tech.
. .

Chapter 4–Biopolymer Research and Development United States I 75

cations of these specialty polymers include degradable golf tees, loose-fill packaging, compost

bags, cutlery, pharmaceutical capsules, and agricultural mulch films.

NOVON materials are being targeted for markets where the benefits of their biodegradability

can be clearly demonstrated. In the near term

these materials will most likely be limited to

specialized applications because their cost is two

to four times the price of commodity resins.

Although these novel starch-based compounds

are not positioned to compete with commodity

synthetic polymers such as polystyrene, if production costs can be brought down, they might

eventually find a number of applications in the

food service, food packaging, personal health

care, agricultural, and outdoor markets.

As highlighted in chapter 3, European companies are also trying to develop a new generation

of biopolymer plastics that will compete with

American products. Japanese companies have

essentially ignored starch-based materials and are

concentrating on materials derived principally

from microbial sources, whose development increasingly employs the techniques of genetic

engineering. There are some limited efforts by

U.S. companies to develop “next-generation”

polymers for degradable plastic applications (i.e.,

materials derived chiefly from agricultural and

microbial sources). These efforts center on the

development of polylactic acid (PLA) materials.

Cargill and a Du Pont-ConAgra joint venture,

EcoChem, have set up polylactide production

facilities. These processes use fermentation technology to produce lactic acid monomers from

potato skins and corn (see chapter 2). PLA

materials have some of the same mechanical and

physical properties as petroleum-based polymers,

but degrade rapidly under a variety of conditions.

However, as with other biopolymers, there is a

considerable cost premium for PLA materials.

Both Cargill and EcoChem are projecting prices

between $2 to $3 per pound for their PLA

products.34 Polylactide polymers that are used for

medical applications currently cost about $100

per pound.

Although there is considerable academic interest in the area of microbially derived polyesters,

no American company is actively pursuing this

line of research.35 Zeneca, Inc. of the United

Kingdom is actively developing U.S. market

opportunities for its microbial polyester materials. A few companies are also pursuing the

commercial development of bacterial cellulose

products (chapter 2). Table 4-2 lists current and

potential U.S. suppliers of advanced biopolymer

plastics.

BIOMEDICAL MATERIALS

Biomedical polymer science is one of the most

dynamic areas of materials research. Biologically

compatible materials are increasingly being used

in a broad range of medical treatments. 36 Mor e

than 2 billion pounds of polymeric materials are

used annually in medical products. Although

most of these polymer materials are traditional

34 &anl N~ayan, i% fichig~ Biotechnology Institute, personal coITMIItiCatiOn, JUIY 19, 1993.

3S A recently f’om~~ ~oup, wc Bio~nvironmenta]]y Degradable Polymer Society, has a mission to increase awareness Of scientific advances

in the field of degradable polymers, The organization intends to focus principally on technical issues and plans to work closely with ASTM,

the Degradable Plastics Council (footnote 32), and similar Japanese and European organizations. (Grahm Swift, Rohm and Haas Co., personal

communication, July 13, 1993).

s~ A distinction is made in this repofi between polymers that are derived from biological sources and polymers ~~t me detived from

petroleum sources. Here, the term biopolyrners is used to refer to biologically derived materials. Because some petroleum-derived substances

can be used for medical purposes, these substances are sometimes called biocompatible polymers even though they are not derived from natural

sources. Polyurethane, for example, although synthetically derived, is inert and compatible with blood, and is used in catheters and drug delivery

devices. Synthetic polyesters such as Dacron arc used in membranes, grafts, and sutures, and polycarbomte is often used in orthopedic implants.

In many of these applications, however, biologically derived polymers offer superior biocompatibility (lower rejeetion response), and are thus

begiming to replace synthetic polymers. See ‘‘Biocompatiblc Polymers, ” Materials Technology, vol. 8, Nos. 1/2, January/Febmary 1993, p.

34.
Table 4-2-Current and Potential U.S. Suppliers of Next-Generation Biopolymer Plastics

Company Location Product Potential Likely entry Comments

applications date

Zeneca Bio Products United Kingdom/United

States

EcoChem (Du Pont- United States

ConAgra)

Cargill, Inc. United States

Battelle Institute and United States

Golden Technologies

Argonne National United States

Laboratory and

Kyowa Hakko, USA

Archer Daniels Midland United States

Warner-Lambert United States

Weyerhaeuser United States

BIOPOL resin (microbial

polyester)

Polylactic-polyg lycolic

acid copolymers

Polylactide

Polylactic acid from

fermented corn

Polylactic acid from

fermented potato waste

Lactic acid supplier

NOVON starch-based

polymers

Bacterial cellulose

Rigid and flexible

packaging—film,

moldings, paper

coatings

Packaging ;some

medical products

Packaging

Packaging

Packaging

Packaging

Multiple-use

structural materials

Absorbent, thickener,

and mating agent

Now

Customer

sampling

now

Customer

sampling

now

Not known

1995-96

Not known

Now

Now

1990 pilot plant in England;

assessing full production

plant

100-million-pound

production facility to open

in 1995

10-million-pound production

facility recently opened

Available for license

Available for license

Has not announced

production plans

100-million-pound

production facility opened

in 1992

Limited commercial

quantities

SOURCES Biolnformation Associates, Boston, MA, and Ramanl Narayan, Mlchigan Biotechnology Institute
Chapter 4–Biopolymer Research and Development in the United States

synthetic compounds, biologically derived polymers have captured significant shares of some

medical markets and are rapidly expanding into

new applications. A recent market survey estimates that the total U.S. market for biopolymer

medical applications will grow from about $300

million in 1990 to about $1 billion in 1995.37 A s

in Europe, the three main biomedical market

segments are wound management products, polymeric drugs and drug delivery systems, and

orthopedic repair products. The wound management segment is the most mature of the three

markets, with both drug delivery technology and

orthopedic devices only now beginning to establish a significant commercial presence.38

WOUND MANAGEMENT

The main products in the U.S. wound repair

market are absorbable sutures, surgical mesh,

clips, and staples. This market is dominated by a

handful of companies including Ethicon (Johnson

& Johnson), U.S. Surgical Corporation, Davis &

Geck, Du Pont, and Pfizer. The main polymers

used in these products are polylactic-poly glycolic

acid and related compounds such as polydioxanone. Other biopolymer materials such as chitin

and modified cellulose may also be used as

sutures in the near future.39 The principal advantage of biopolymer-based wound management

products is that they form natural bonds with

surrounding tissue and thereby facilitate

I 77

the

healing process.

Biopolymer based sutures (i.e., absorbable

sutures) currently hold about 50 percent (about

$225 million) of the entire U.S. suture market and

are expected to grow at an annual rate of more

than 10 percent for the next several years.40 The

major factor explaining this growth is the preference shown by physicians for absorbable wound

repair products over nonabsorbable devices. Companies in the bioabsorbable surgical device market are rapidly expanding the range of applications for their polymer products. Hyaluronic acid,

a polysaccharide, is being used for surgical repair

of soft tissue (particularly eye and ear tissue), and

some proteins, such as collagen, are being used as

wound dressings and for tissue reconstruction .41

Bioadhesives are a new class of materials that

could serve as suture enhancements, and can be

used for attaching prostheses, or for dental

applications. Enzon Corporation and W.R. Grace

have launched programs to develop bioadhesives

that are based on recombinant protein polymers.

Adheron Corp. is developing a bioadhesive that is

an exopolysaccharide-peptide complex derived

from marine bacteria. Other biodegradable polymers are being tested as aids in repairing damaged

arteries. 42 In the future, biopolymers may be used

to facilitate tissue and organ regeneration, and

37 me smey was conducted by BioInforrnation Associates of Bostou Massachusetts.

se New oppo~unllles for biopolymer medical applications may emerge, given the recent decisions of three traditional Wlymer suppliers

(Dow Plastics, Dow Corning, Du Pent) to withdraw some of their products from the market. The products involved are polyurethane, silicone,

polyester, polyacetal, polytetrafluorocthy lene, and others. The products have been wilhdrawn because of concern over actual and potential legal

liabilities, As a consequcncc, it is possible that shortages of some types of implantable medical devices could occur. These developments could

give impetus to R&D activities involving new, biocompatible materials that are derived from natural sources. (Bernie Liebler, Health Industry

Manufacturers Association, Washington, DC, personal communication Aug. 9, 1993).

39 ~t~, a polysaccharide tit can be ex~act~ from crab shells, maintains its high-strength characteristics for long periods and degrades

without causing allergic reactions or tissue irritation.

~ Bio~ormation Associates, op. Cit., fOOtnOte 37.

d 1 A ~cent s~dy, however, has raised some questions about the possible side effects of collagen implants that are used to tr~t -esand

scars in plastic surgery. See “Study Links Collagen With Ailments, But Maker of Implants Disputes Report,” WaZl Street Jourrud, June 15,

1993, p. B6.

42 Degradable polymers can act as an ‘internal scaffolding’ that prevent arteries from reclosing after they have been opened by angioplasty.

After an artery heals, the polymers dissolve. See “Patents,” New York Times, June 14, 1993, p. D2.
78 I Biopolymers: Making Materials Nature’s Way

serve as vascular support meshes for blood vessel

regeneration .43

 Drug Delivery Systems

Drug delivery systems (DDS) utilizing polymers that degrade in the body have attracted

considerable attention in recent years. The use of

biopolymers for drug delivery can minimize

tissue reaction and allow for the administration of

drugs by methods other than injection. 44 A

controlled-release drug system is a combination

of a biologically active agent (i.e., the drug) and

a support vehicle. The support vehicle can be

either a matrix or a reservoir device. In a matrix

system, an active drug is dissolved or dispersed

uniformly throughout a solid polymer. Drug

release from the matrix can be controlled by either

a diffusion or an erosion process. In a reservoir

system, the polymer acts solely as a barrier that

controls the rate of drug delivery by diffusion.

Polylactic and polyglycolic acid copolymers are

the most widely used drug vehicle materials.

Other biopolymers being investigated include

poly amino acids, derivatives of chitin, and some

chemically modified starches.45

The U.S. market for biodegradable drug delivery systems is expected to grow from its 1990

level of about $30 million to nearly $490 million

by 1995.46 One reason for this rapid growth is the

large number of genetically engineered protein

drugs that are now being introduced,47 Encapsulation of proteins in biopolymer materials prevents

the proteins from being prematurely destroyed by

attacking enzymes. Another factor contributing to

the growth of drug delivery systems is that they

provide a means for extending the patent life of

drugs. The major area of application for these

novel sustained-release systems is in the treatment of cancers and geriatric diseases.

For the most part, the industry leaders in drug

delivery systems are relatively small, technologically sophisticated firms that frequently have

close relationships with academic research centers. Since DDS development lies outside the

traditional expertise of most pharmaceutical companies, large firms have typically acquired this

technology through contracting, licensing, joint

ventures, and acquisitions. In recent years, however, most large pharmaceutical companies have

initiated modest in-house research efforts. Table

4-3 lists the current and potential suppliers of drug

delivery systems.

 Orthopedic Repair Products

The U.S. orthopedic implant market provides a

number of potentially interesting applications for

biodegradable polymers. Commercial opportunities exist in the areas of joint prostheses technology such as artificial ligament coatings, ligament

attachment devices, and tendon implant materials

and bone trauma fixation devices such as plates,

screws, pins, and rods used to stabilize fractures.

Although only a few biopolymer devices are

currently on the market (mostly bone fixation

pins), ongoing research and FDA testing are

43 The Protein Col]agep for ex~ple, induces new blood vessel and tissue growth. See Robert I-anger and Joseph Vacanti, “Tissue

Engineering,” Science, vol. 260, May 14, 1993, pp. 920-925.

44 Biopolvers me also king evaluat~ for or~ delivery of vaccines in which the polymer may aCt as ~ adjuvant to ~ers~ulate an

immune response.

45 one of fie oldest therapeutic applications of biopolymers hm been in the mea of p~aceuti~l capsules. Gelatin (a protein polymer)

capsules have been in widespread use for many years, and starch-based capsules have recently been introduced into the market. These capsules

are commonly used to deliver aspirin and antibiotics. The world market for simple biopolymer capsules is close to $400 million annually. (Ken

Tracy, Warner-Lambert Company, personal communication, July 30, 1993).

46 The estimt~ m~et v~ue of degradable drug delivery systems reflects the combined value of the drug and the delivery systems, ~cause

it was not possible to obtain separate estimates for the delivery systems. The estimate was provided by BioInforrnation Associates, BostoU

Massachusetts. This estimate for DDS does not include the market figure for simple capsules that are made from biopolymer materials.

47 The wow~ of he dmg de~very m~ket, however, could be slowed by the DA drug aPProv~ Pr~ess.
——

Chapter 4–Biopolymer Research and Development in the United States 79

Table 4-3—Current and Potential Suppliers in the U.S. Drug Delivery System Market

Company Product Application Polymer of interest

Abbott Laboratories Lupron Depot

Alza Corp Alzamet

Scios Novo, Inc

Enzytech

Merck and Co

Syntex Inc

Battelle Corp

American Cyanamid

Emisphere Technologies

Biodel

Prolease

In development

In development

In development

In development

In development

Southern Research Institute In development

Allergan In development

SOURCE Biolnformation Associates

expected to open the way for a number of new

product introductions by 1995.

Orthopedic products face several technical

challenges. In addition to high strength, biopolymers must also have prolonged, wellcontrolled rates of degradation48 because complete ligament and tendon healing requires a 1-to

2-year time frame. In addition, the degraded end

products must be absorbed safely by the body.

Even though the end product in most biodegradaMicrosphere injectable for

protein drugs

Injectable delivery of antiinfective drugs and

peptides; surgical implant

products

Targeted, time-released

therapies for anticancer

and antiinfective drugs

Microsphere encapsulation

of interferons, growth

hormones

Implant for release of gyrase

inhibitor

Controlled release of betaInterferon;

microencapsulation of

peptide hormones

Process for developing

microsphere

Implant for release of

estradiol in livestock

Oral delivery system for

heparin, Zadaxin

(hepatitis), and poultry

vaccines

Microsphere for

encapsulation of DNARNA for stimulation of

Interferon production

Implant and Injectable

devices

Polylactlc-poly glycolic acid

Polyanhydrides (synthetic

degradable polymer)

Polyanhydrides

Polylactic acid

Polylactic-poly glycolic acid

Polylactic-poly glycolic acid

Polylactic acid

Polylactic-poly glycolic acid

Polyamino acid

Polylactic-poly glycolic acid

Not known

ble orthopedic devices is lactic acid, which is

metabolized by the body, the FDA will be

assessing whether these devices cause soft tissue

irritation or have toxic side effects. These side

effects are of more concern in orthopedic devices

than in drug delivery systems, because of the

significantly larger mass of polymer used in

orthopedic systems.

In 1990, the U.S. market for biopolymer

orthopedic devices was about $15 million, and it

48 It has b~n difficult to develop biopolymcrs that display both optimal strength and the required degradation properties. However, some

progress is occurring in this area, Johnson& Johnson Orthopedics’ researchers have developed a polylactide bone fixation plate that exhibits

superior strength over that of conventional bone fi~atlon plates. Animal testing of the device over a 2-year period has revealed no tissue irritation

or toxic side effects.
80 I Biopolymers: Making Materials Nature’s Way

is expected to grow to $80 million by 1995.49

However, market growth will depend in large part

on the speed of the FDA approval process. While

two companies, Johnson & Johnson and Davis&

Geck, presently dominate the orthopedic repair

market, several other health care companies are

expected to enter the field in the next few years:

3M, Bristol Meyers Squibb, Pfizer, Allied Signal,

Smith and Nephew, and Du Pont all have medical

implant development programs. Potentially novel

applications include degradable bone screws that

obviate the need for followup operations, and the

use of biopolymers as scaffolding in the formation of new ligament and cartilage material.50

Because more than 1 million operations a year

involve cartilage replacement, this particular

biopolymer application could grow dramatically

in the future. As biopolymer science evolves,

many more important advances in the area of

orthopedic repair can be expected.

BIOPOLYMERS IN PERSPECTIVE

Biopolymers are a diverse and remarkably

versatile class of materials that have potential

applications in virtually all sectors of modern

industrial economies. Currently, many biopoly -

mers are still in the developmental stage, but

important applications are beginning to emerge in

the areas of packaging, food production, and

biomedicine. Some biopolymers can directly

replace synthetically derived materials in traditional applications, whereas others possess unique

properties that could open up a range of new

commercial opportunities. As a consequence,

novel biopolymer materials are being investigated by established agricultural and chemical

fins, as well as small biotechnology enterprises.

At present, government-sponsored research

and development efforts in the biopolymer area

are relatively small in scope, but many ongoing

Federal activities have an indirect bearing on

biopolymer science. Unlike Japan and the European Community, the United States does not have

a well-defined biopolymer policy. The United

States is, for the moment, well positioned in some

areas of biopolymer development because of its

strong agricultural base, expertise in polymer

engineering, and active biotechnology sector.

However, the relative competitive position of the

United States could be enhanced by fostering

greater collaboration among researchers in government, industry, and academia. Fundamental

research barriers in the biopolymer field could

also be better addressed by bringing greater

coherence to the R&D efforts of various Federal

agencies. In addition to the scientific and engineering hurdles that exist in the biopolymer area,

formidable commercialization barriers remain.

Even if some biopolymers are shown to have

environmental characteristics that are preferable

to conventional polymers, much work needs to be

done to bring down the costs of biologically

derived materials. In only a few specialized

applications, such as biomedicine, are the relatively high costs of biopolymer materials not

likely to impede market growth. These economic

and technical obstacles, as well as the interdisciplinary nature of the biopolymer field itself, pose

difficult challenges for policymakers and industry

managers alike.

49 Bio~o~ation Associates, op. Cit., fOOtIiOte 37.

50 some ~esmchem tie ~s@ a co~agen.g]yca template to wow new c~age~~ and Vacanti, op. cit., fOOblote 43).