biopolymers: making materials nature's way

Biopolymers: Making Materials Nature's Way

September 1993

OTA-BP-E-102NTIS order #PB94-107638

Recommended Citation:U.S. Congress, Office of Technology Assessment, Biopolymers: MakingMaterials 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 fifty-fold. This extraordinary growth has raised serious concerns about current pat-terns of production and consumption. As society has increased its understandingof the environmental implications of its industrial practices, greater attention

has been given to the concept of sustainable economic systems that rely on renewablesources of energy and materials. The use of biologically derived polymers—biopoly -mers-could emerge as an important component of this new paradigm of economicdevelopment.

By transforming agricultural or marine feedstocks, or harnessing the enzymesfound in nature, a new class of renewable, biodegradable, and biocompatible materials isbeing introduced. Emerging applications of biopolymers range from packaging to indus-trial chemicals, to medical implant devices, to computer storage media. In addition toproducing “green” materials with unique physicaI and functional properties, the process-es used to create biopolymers could lead to new manufacturing approaches that minimizeenergy consumption and waste generation.

As the United States and other countries address a growing list of environmen-tal problems, the possibility of using proteins, carbohydrates, and other biopolymers tomeet the materials requirements of an expanding economy is likely to receive increasingattention. However, as with other nascent technologies, difficult engineering and eco-nomic hurdles stand in the way of biopolymer commercialization efforts. With its currentareas of emphasis, the extensive U.S. public investment in agricultural science andbiotechnology can only be expected to provide modest assistance in overcoming some ofthese barriers. Advances in biopolymer technology have been driven principally byindustry and academia, with Federal programs being relatively limited in scope. Becausebiopolymers have applications in many different sectors of the economy, their wide-spread use could have important competitive implications. At present, Japan and theEuropean Community are sponsoring major programs in biopolymer science and manu-facturing. Due to the potential importance of biopolymer technology, the Federal role inthis interdisciplinary field warrants closer scrutiny.

This Background Paper was requested by the Senate Committee on Energy andNatural Resources. The study provides a basic introduction to biopolymer technology;profiles some of the more promising polymer materials; reviews research activities in theUnited States, Europe, and Japan; and describes the principal technical challenges andregulatory issues that may affect biopolymer commercialization efforts.

OTA appreciates the assistance provided by its contractors and the manyreviewers whose comments helped to ensure the accuracy of the study.

Roger C. Herdman, Director

.,.Ill

Reviewers and Contributors

G. Graham AlIanUniversity of Washington

Norbert BikalesU.S. National Science Foundation

James BrownU.S. National Science Foundation

Robert CampbellU.S. Army Research Office

David ClementsU.S. Department of AgricultureCongressional Research Service

Yoshiharu DoiInstitute of Physical and Chemical

Research (RIKEN), Japan

Greg EyringU.S. CongressOffice of Technology Assessment

Thomas BarringtonAshland Chemical Co.

Joel HirschornHirschorn & Associates, Inc.

David JensenU.S. CongressOffice of Technology Assessment

David KaplanU.S. Army ResearchDevelopment & Engineering

Center

Dai KimHiechst-Celanese Research Co.

Gretchen KolsrudU.S. CongressOffice of Technology Assessment

Randolf LewisUniversity of Wyoming

Bernard LieblerHealth Industry Manufacturers

Association

David ManyakAdheron Corp.

Michael MarronOffice of Naval Research

Edward MuellerU.S. Food and Drug Administration

Wolf-Rudiger MullerStuttgart University, Germany

Ramani NarayanMichigan Biotechnology Institute

D.A. NicholsonProcter and Gamble Co.

Norman OblonOblon, Spivak, McClelland, Maier,

and Neustadt, P.C.

Kevin O’ConnorU.S. CongressOffice of Technology Assessment

Julie SaadICI America/Zeneca Bio Products

Steven ScaleTennessee Valley Authority

Karen ShannonOblon, Spivak, McClelland, Maier,

and Neustadt, P.C.

Steven SikesUniversity of South Alabama

Kenneth SmithNational Sanitation Foundation

Rodney SobinU.S. CongressOffice of Technology Assessment

Graham SwiftRohm and Haas Co.

Ken TracyWarner-Lambert Co.

John WalkerU.S. Environmental Protection

Agency

A.P. WheelerClemson University

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the reviewers andcontributors. The reviewers and contributors do not, however, necessarily approve, disapprove, or endorse this backgroundpaper,OTA assumes full responsibility for the background paper and the accuracy of its contents.

iv

—- . —.—-—- .—

Peter D. BlairAssistant Director, OTA(beginning February 1993)Industry, Commerce,

and InternationalSecurity Division

Energy and Materials ProgramManager

(until August 1993)

Lionel S. JohnsAssistant Director, OTA(until February 1993)Energy, Materials,

and InternationalSecurity Division

Matthew WeinbergProject Director

Joe RagusoAnalyst

ADMINISTRATIVE STAFF

Lillian ChapmanOffice Administrator

Linda LongAdministrative Secretary

Tina AikensSecretary

Preject Staff

CONTRACTORS

Oliver PeoplesAnthony Sinskey Bio Information AssociatesBoston, MA

Florence PoillonEditor

Emilia GovanEnergy and Materials Program

Manager(beginning August 1993)

v

contents

1 Introduction 1Polymers: A Primer 4Biopolymers 5Impact of Genetic Engineering on Biopolymer

Technology 8The Role of Chemistry in Biopolymer

Technology 12The Policy Context 12

2 Technical Overview of Biopolymer Field 19Selected Polymers Produced by Microbial

Systems 19Selected Polymers of Plants and Higher

Organisms 35Polymers Produced by Chemical Polymerization of

Biological Starting Materials 43

3 Biopolymer Research and Development inEurope and Japan 51Europe 51Japan 59

4 Biopolymer Research and Development inthe United States 67Activities of the Federal Government 67Private Sector Activities 73

vii

—

T

Introduction 1

hroughout history, humans have relied extensively onbiological materials like wool, leather, silk, and cellu-lose.l Today, such natural polymers can be tailored tomeet specific needs. The advent of modern biotechnol-

ogy has fundamentally transformed the way scientists vieworganisms and the materials they produce. For example, thegenetic manipulation of some plant species could give rise to anew source of structural polymers that supplant traditionalcommodity plastics. By harnessing the enzymes found in nature,or transforming agricultural or marine feedstocks, a new class ofbiodegradable, biocompatible, and renewable materials is on thehorizon.

Polymers play a central role both in the natural world and inmodern industrial economies. Some natural polymers, such asnucleic acids and proteins, carry and manipulate essentialbiological information, while other polymers such as thepolysaccharides—nature’s family of sugars-provide fuel forcell activity and serve as structural elements in living systems.With advances in chemistry and materials science, a vast array ofnovel synthetic polymers has been introduced over the pastcentury. Synthetic polymers such as nylon, polyethylene, and

1 These four materials are natural polymers. Polymers are substances composed ofrepeating structural units that are linked together to form long chains.

1

2 Biopolymers:

.——.

Making Materials Nature’s Way

polyurethane have transformed daily life.2 Fromautomobile bodies to packaging, compact discs toclothing, and food additives to medicine, man-made polymers pervade virtually every aspect ofmodern society.3

However, the growing reliance on syntheticpolymers has raised a number of environmentaland human health concerns. Most plastic materi-als, for instance, are not biodegradable and arederived from nonrenewable resources.4 The veryproperties of durability and strength that makethese materials so useful also ensure their persis-tence in the environment and complicate theirdisposal. In addition, the synthesis of somepolymeric materials involves the use of toxiccompounds or the generation of toxic bypro-ducts.5

These problems have focused increased atten-tion on polymers that are derived from biological

precursors or are produced by using the methodsof modern biotechnology.6 Such biopolymersmay prove to have a variety of environmentalbenefits. Possible applications range from agri-culturally or bacterially derived thermoplasticsthat are truly biodegradable, to novel medicalmaterials that are biocompatible, to water treat-ment compounds that prevent mineral buildupand corrosion.7 However, because materials typi-cally have many different properties, in certainapplications biopolymers may not necessarilyprovide environmental advantages over conven-tional polymers.8 In practice, it is extremelydifficult to develop testing methods that assessthe environmental characteristics of materials.9

In recent years, a number of significant techni-cal developments, particularly in the area ofgenetic engineering, have enhanced the commer-

2 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), and0.5 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 tomedical care. It is important to note that toxicity is often determined by the dose or concentration of a substance, so many compounds that posehealth 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 emulatethe 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. GovernmentPrinting Office, February 1992).

7 Conventional water treatment chemicals employed as flocculants, corrosion inhibitors, and antiscalants are generally used at very lowconcentrations 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 possiblethat the widespread use of some biopolymers may have unanticipated effects on ecosystems or waste streams. It should be noted that somenaturally occurring polymers have varying degrees of toxicit y. Some examples of natural toxicants include the protein toxins from pathogenicbacteria, 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 andsurface-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 environmentalevaluation 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 .10The advent of recombinant DNA technology hasallowed researchers to exercise unprecedentedcontrol over the purity and specific properties ofpolymers.

11 Advances in genetic engineering have

also enabled scientists to study how biologicalsystems produce complex polymers. It is remark-able that living organisms are able to createsophisticated materials (e.g., spider silk) at nor-mal temperature and pressure, without causingenvironmental disruption. This is certainly not thecase for many man-made materials. *2 Thus, bio-polymer research could also lead to the develop-ment of new environmentally sensitive manufac-turing methods.

Biopolymers area diverse and versatile class ofmaterials that have potential applications invirtually all sectors of the economy. For example,they can be used as adhesives, absorbents, lubri-cants, soil conditioners, cosmetics, drug deliveryvehicles, textiles, high-strength structural materi-als, and even computational switching devices.Currently, many biopolymers are still in thedevelopmental stage, but important applicationsare beginning to emerge in the areas of packaging,food production, and medicine. Some biopoly -mers can directly replace synthetically derivedmaterials in traditional applications, whereasothers possess unique properties that could openup a range of new commercial opportunities.Novel biopolymer compounds are being investi-gated by established agricultural and chemicalfirms, as well as small biotechnology enterprises.

Yet despite the promise of these new materials,a series of economic and engineering hurdles mayimpede their introduction to the market in the near

Chapter I—Introduction

term. Even if some biopolymers are shown

3

tohave environmental characteristics that are pref-erable to conventional polymers, much workneeds to be done to bring down the costs ofbiologically derived materials. Commercially avail-able biopolymers are typically two to five timesmore expensive than synthetic resins. In only afew specialized applications, such as biomedi-cine, are the relatively high costs of biopolymermaterials not likely to impede market growth.Since many biopolymers are in the early phases ofdevelopment, it is difficult to determine whethereconomy-of-scale manufacturing will be able tobring down their current high production costs.The commercialization difficulties facing bio-polymers in many ways resemble the problemsconfronting other emerging technologies such asphotovoltaic cells and fuel cells.13

At present, government-sponsored researchand development efforts in the biopolymer areaare relatively small in scope, but many ongoingFederal activities in biotechnology and agricul-ture have an indirect bearing on biopolymerscience. Unlike Japan and the European Commu-nity, the United States does not have a well-defined biopolymer policy. The United States is,for the moment, well positioned in some areas ofbiopolymer development because of its strongagricultural base, expertise in polymer engineer-ing, and active biotechnology sector. However,the relative competitive position of the UnitedStates could be enhanced by fostering greatercollaboration among researchers in government,industry, and academia. Fundamental researchbarriers in the biopolymer field could also bebetter 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 througheconomy-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 ofdifferent Federal agencies. The formidable eco-nomic and technical obstacles facing biopoly-mers, as well as the interdisciplinary nature of thebiopolymer field itself, pose difficult challengesfor policymakers and industry managers alike.

POLYMERS: A PRIMERPolymers are a class of “giant” molecules

consisting of discrete building blocks linkedtogether to form long chains. Simple buildingblocks are called monomers, while more compli-cated building blocks are sometimes referred to as‘‘repeat units’ (see figure l-l). When only onetype of monomer is present, the polymer isreferred to as a homopolymer. Polyethylene—thematerial commonly used in plastic bags—is ahomopolymer that is composed of ethylene build-ing blocks. A copolymer is formed when two ormore different monomers are linked together. The

Linear homopolymer

Branched homopolymer

Linear copolymer

Block copolymer

process by which the monomers are assembledinto polymers, either chemically or biologically,is referred to as polymerization. Polymers can beeither linear or branched (figure l-l).

The distinguishing features of a polymer aredetermined by the chemical properties of themonomeric units (i.e., what the polymer isspecifically composed of), the way in which themonomeric units are linked together, and the sizeor molecular weight of the polymer. (The size ofthe polymer is determined by the number ofmonomers linked together.) Each of these para-meters contributes to the physical properties ofthe polymer product. Understanding the relation-ship between polymer structure and physicalproperties remains one of the most active andchallenging areas of current research. In practice,polymers that are created by conventional chemi-cal approaches lack uniformity in length, compo-sition, and spatial orientation. Thus, a centralaspect 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 universallyrecognized in all organisms

Biological catalysts (enzymes), growthfactors, receptors, structural materials(wool, leather, silk, hair, connectivetissue); hormones (insulin); toxins;antibodies

Structural materials in plants and somehigher organisms (cellulose, chitin);energy storage materials (starch,glycogen); molecular recognition (bloodtypes), bacterial secretions

Microbial energy reserve materials.

Structural materials in plants (Iignin), soilstructure (humics, peat), plant defensemechanisms (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 butmodern polymer science is concerned with reduc- are derived from biological starting materialsing 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, biochemical structure of their monomeric units, and

polymers fall into two principal categories: indicates the functions that these polymers servein living organisms. For example, DNA (deoxyri-

■ polymers that are produced by biological sys- bonucleic acid), which carries the essential ge-tems such as microorganisms, plants, and netic information of living systems, is a linearanimals; and copolymer composed of four monomer nucleo-

tides. 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 dealof 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!ltists tO 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 planwere 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 andbe 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 chainstogether.SOURCE: U.S. Congress, Office of Technology Assessment, Com-mercial Biotechnology: An International Analysis, OTA-BA-218 (Wash-ington, DC: U.S. Government Printing Office, January 1984).

a pair of helical sugar-phosphate backbones (seefigure 1-2). As an industrial polymer, DNA iscurrently not of commercial interest, althoughsome researchers are beginning to examine thisbiopolymer for the purpose of assembling nano-structural materials, as well as for its electricalproperties. 17

Proteins-also referred to as polypeptides—are complex copolymers composed of up to 20different amino acid building blocks. There arevirtually a limitless number of proteins that can beformed from these 20 monomers, just as there area vast number of words that can be made from the26 letters of the alphabet (see box l-A). Proteinscan contain a few hundred amino-acid units orthousands of units. Each protein has a specificchemical composition and three-dimensional shape.The amino-acid building blocks are linked byamide bonds in specific sequences determined bythe DNA code of the corresponding gene.18

Protein polymers are unique in that the sequenceof the monomers in the polymer chain is predeter-mined by the template specific reamer of thepolymerization process (i.e., they are copied froma genetic blueprint. )19 The sequence diversity ofproteins is responsible for the wide array offunctions performed by these materials in livingorganisms. Proteins typically account for morethan 50 percent of the dry weight of cells, and arethe primary means of expressing the geneticinformation coded in DNA. In recent years,researchers have been able to synthesize variouspolypeptides that are similar to natural proteinsfound, for example, in biominerals such as shellsor bones. Synthetic polypeptides are usuallycreated from amino-acid precursors (e.g., asparticacid).

Polysaccharides are polymers or macromole-cules composed of simple sugars. The polysac-charides have two principal functions. Some,such as starch, store energy for cell activity, andothers, 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. Chenand 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 segmentof DNA.

19 Each d. acid ~ a prote~ c- is represented by three nucleotides from the DNA. Thus, different nucleotide COmbiMtiO~ give riseto 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.mctionsof these biopolymers, see Albert Lehninger, Biochemisoy (New Yorlq NY: Worth Publishers, 1975).


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 extraordinarilyvast number of structures that are possible? If, for example, a polymer consists of k types of monomersand has a total Iength N, t he number of possible polymeric structures that can be generated is kN. Thisnumber becomes extremely large when the polymer is of even moderate length. For instance, proteinsconsist 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 ofnucleotides), and N = 1 million, so 4106 (about 10600,000, or 1 followed by 600,000 zeros) structures arepossible. 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 equalto 1 (i.e., there is basically a 100 percent chance that the correct polymer will be created). This highprobability is due principally to the presence of biological catalysts (enzymes) that eliminate therandomness associated with chemical transformations and thereby ensure the “uniqueness” ofbiochemical processes. Enzymes play a central role in DNA replication and protein production, as wellas in polysaccharide biosynthesis. It should also be noted that some biological monomers have certainchemical 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 degreeof 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 andcomplex group of biopolymers. This is becausethe bonds linking the sugar monomers can beformed at different positions on the sugar units(illustrated in figure 1-3 for homopolymers ofglucose). By simply linking glucose monomerstogether at different positions, polymers withvery different properties are produced (see chap-ter 2). At least 20 different sugars have beenidentified in a variety of polysaccharides frombiological sources, and thus a great range ofpolymer structures can be created (see box l-A).

Many polysaccharides contain branched struc-tures and are chemically modified by the additionof 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 polysaccha-ride repeat units and the associated polymeriza-tion processes are not dependent on a template orgenetic blueprint, but are specified by the en-zymes (biological catalysts) involved in an orga-nism’s “biosynthetic pathway. ”21 This processin biological systems is often referred to ascontemplate polymerization.

Other biopolymers include polyhydroxyalkanoates(PHAs), nature’s biodegradable thermoplastics22

(chapter 2); polyphenols, a class of structuralmaterials; 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 finalproduct that is usually quite different from the starting materials.

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

.- . - . . . . .


Figure 1-3-Anatomy of a Natural Sugar

(6)

I Bond(s)

(5) – o

‘/~P\a

B(1-4)

(4)

l \

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

/ ~(3) — - ( 2 ) a a(l-4), a(1 -6)

Polymer

Cellulose

Yeast glucan

Starch

The different types of linkages found in some glucose homopolymers are illustrated. The glucosemonomer (above) is made up of six linked carbon atoms. The bond that joins two different sugar unitsis 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 wouldbe described as B(1-4). In amylopectin (depicted below), a form of starch, the main polymer chainconsists of a(l-4) bonds and the branched chain is connected by a(l-6) bonds.

CH2OH Branch 6C H20H

k - - -0

/ -— 0

\ 5 \

J0 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 discussedreport. 23

IMPACT OF GENETIC ENGINEERINGBIOPOLYMER TECHNOLOGY

in this living systems. Genetic engineering permits ex-traordinary control over the time, place, level, andtype of ‘‘gene expression. ”24 The simplest case

ON applies to protein polymers. Having access to thegenetic 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 docontain 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 functioningproduct, usuaLly a protein. This involves several steps: In a process called transcriptio~ the DNA double helix is locally unzipped near the geneof interest and an intermediate product known as ‘‘messenger’ RNA, is synthesized. The messenger RNA transmits the instructions foundin the DNA code to the protein-synthesizing machinery of the cell, and a protein is created. Proteins are composed of amino aci& Each arninoacid in a protein chain is represented by three nucleotides from the DNA. See Commercial Biotechnology, op. cit., footnote 6, pp. 34-35.


Some bacteria can store energy in polymer-bearing granules (polyhydroxyalkanoates) that can be collectedand made into truly biodegradable packaging like these plastic bottles made from Alcaligenes bacteria byZeneca Bio Products.

the polymer itself. Recombinant DNA techniques recombinant DNA method is necessarily morepermit the creation of polymer chains that are economical, but that it is possible to generatevirtually uniform in length, composition, and polymers of exceptional structural purity, as wellstereochemistry or spatial orientation25 (see box as manipulate the biopolymer production systeml-B). For example, the protein polymer silk that to create new materials. In addition, the recentlyis produced commercially by silkworms can now developed ability to chemically synthesize DNAbe made in recombinant microorganisms.26 The allows scientists to construct entirely new genesadvantage 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 onlyfrom “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 anygiven 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 theperspective of production efficiency.

z~ See David L. Kaplanet ~., “Biosynthesis and Processing of Silk Proteins, ’ Mafenals Research Sociery Bu//erin, vol. 17, N0. 10, October1992, pp. 41-47.

330-076 0 - 93 - 2 : QL 3


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

Recombinant DNA is formed whenpieces of DNA f from different organisms H \are joined together. The basic tech- V &

v~nique of preparing recombinant DNA is

\New DNA

Restrictionillustrated in the diagram shown. Spe-

Donor DNAcial biological catalysts known as “restric- ‘ n z y m e s //>

AQ - ““\tion enzymes” are used to cut donorDNA (usually from a higher organism)

o

U ‘(2.2into fragments, one of which contains k

~~~~~~sn Z Recombinant Bacteriumthe 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 vPlasmid DNA Replication

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

produces large producesa DNA molecule used to introduce for- amount of DNA proteineign 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, CommercialBiotechnology: 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 mol-ecules are inserted into plasm id DNA molecules to form the hybrid or recombinant DNA. Each plasm idvector contains a different donor DNA fragment. These recombinant DNA plasm ids are introduced intohost cells in a process called “transformation.” When the transformed host cells grow and divide, theplasm ids replicate and partition with the host daughter cells, ultimately providing many host cells thatcarry the same donor DNA fragment. This process of replication is known as cloning. The cloned genescan 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 recentyears, scientists have also developed methods of introducing genetic material into higher plants andanimals.

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 pro-mechanical and chemical properties of structural duction of biological catalysts (proteins known asproteins such as silk, elastin, and various adhesive enzymes), which are in turn responsible for thepolymers.28 production and polymerization of the building

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

enzymesent steps

Chapter I-Introduction I 11

Figure 1-4-A Genetically Engineered Biopolymer Production System

S1 S2 S1 S2

S3 S3 Biopolymer

IS4 S4 n

[ ‘--Structure 1J

—

< I

,Genetic engineering ‘

of biosynthesis t ocontrol structure

\ and function I

>

\‘ \\

“\‘\

Lr 1

Function

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

Applicatiion

--”

Unlike proteins, polysaccharides and other natural polymers are not created by following a geneticblueprint; rather, an organism outlines a “pathway” of synthesis in which each step of the pathway iscarried out by a specific enzyme. Some polysaccharide pathways can have more than ten steps andsometimes as many as a hundred steps. By using recombinant DNA techniques, enzymes from differentbiological sources (i.e. species) can be introduced into host organisms, thereby creating entirely newbiosynthetic pathways or polymer assembly lines. These new biological assembly lines could be usedto produce greater quantities of a particular polymer, or to design novel polymers with unique physicaland functional properties.

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

as being machines that carry out differ-on a biological assembly line. Through-

out the biological world there exists an extraordi-nary army of different machines (enzymes), allencoded by specific genes. Many of these en-zymes are present in only one species or strain oforganism. The genes for these enzymes are thenthe blueprints for the individual pieces of machin-ery, and remarkably, these blueprints are recog-nized and translated in the same way in allorganisms. By adding the appropriate signals andtransferring the gene into a new organism, the

organism can then produce a new enzyme,thereby giving the organism the capacity to carryout a particular step in the assembly line process.Genetic engineers now have the ability to add newmachines, or remove old ones, in practically anysystem.

The implications of these genetic techniquesare quite profound. It is now possible to geneti-cally modify an organism so that it producesgreater quantities of a particular polymer. As anexample, the introduction of a specific enzymehas allowed researchers to increase starch produc-


tion in genetically engineered plants.29 It is alsopossible to transfer an entire assembly line into anew host organism to improve a productionprocess. One illustration of this procedure is theproduction of the bacterial thermoplastic polyhy-droxybutyrate (PHB) in transgenic plant spe-cies.30 Finally, these new techniques allow orga-nisms to be modified so that truly novel materialscan be produced. For instance, a series of geneti-cally engineered xanthan gums has been devel-oped by removing specific enzymes from thexanthan assembly line (ch. 2). Ultimately, it maybe possible to construct biological systems for theproduction of entirely new classes of polymers.This could be accomplished by creating newassembly lines using enzymes from diverse sourcesand then introducing the correct blueprints into anappropriate host. The long-term objective of thistype of research is to design biological systemsthat produce specific polymers for specific appli-cations. For example, materials might be geneti-cally ‘‘customized’ to have a unique combina-tion of mechanical, chemical, andproperties.

THE ROLE OF CHEMISTRY INBIOPOLYMER TECHNOLOGY

degradative

Given the advances in genetic engineering,what is the role of traditional chemical synthesisin creating biopolymers? The most widely usedpolymers, such as polypropylene and polyester,are produced by standard chemical means. But asmentioned previously, the processes used tomanufacture these synthetic polymers can some-times have a number of drawbacks. Althoughtechnologies for producing proteins by chemical

synthesis have been developed, they are ex-tremely costly. Such methods are used primarilyfor the production of research chemicals or forvery high-value applications such as pharmaceu-ticals. There is no existing chemical technologycapable of producing the complex polysaccharidestructures made so readily by biological systems.Because of their structural and chemical specific-ity, enzymes are extremely efficient at producingpolymer compounds with high yield.31

Yet, chemistry still has an important role toplay in the development of biopolymers. Chemi-cal techniques can be used to modify the proper-ties of biopolymers to expand their range ofapplications, to polymerize biological startingmaterials, or to create new gene sequences thatcan lead to novel protein polymers through theapplication of recombinant DNA methods. Exam-ples of such chemical methods are presented inchapter 2.

THE POLICY CONTEXTAs noted in previous sections, there have been

significant advances in basic biopolymer science,with a wide range of new applications on thehorizon. Due to the versatility and potentialenvironmental benefits of biopolymer materials,R&D activities are likely to expand considerablyin coming years. While technical progress in thebiopolymer field is, for the most part, beingdriven by academia and industry, the FederalGovernment directly and indirectly affects bio-polymer development. In the following sections,the role of federally funded research and variousregulatory 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 plantswhose 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 stitablefor a particular application.

Role of Federal R&D ProgramsAlthough there is not a well-defined bio-

polymer research program in the United States,many ongoing Federal activities have a bearingon biopolymer science. Several Federal agenciesare sponsoring efforts in biopolymer research, aswell as related areas such as bioprocessing andgenetic engineering (see ch. 4). In February 1992,the White House Office of Science and Technol-ogy Policy announced the Biotechnology Re-search Initiative—a coordinated interagency ef-fort to strengthen and diversify Federal researchactivities in biotechnology .32 This initiative isdesigned to extend the ‘‘scientific and technicalfoundations’ of biotechnology, to “acceleratethe transfer of biotechnology research” to appli-cations in the commercial sector, and to expandinterdisciplinary research between biology andother fields, such as chemistry, physics, ormaterials science .33 The initiative calls for greaterattention to be paid to bioprocessing and manu-facturing, including bimolecular materials, bio-compatible materials, and metabolic engineering,and thus addresses many aspects of biopolyrnerscience.

However, the amount of funding specificallytargeted for biopolymer programs is relativelysmall. In FY 1993, only about 3 percent ($124million) of the total biotechnology budget ($4billion) is devoted to biologically derived com-pounds and industrial processing research (see ch.4); and only a small fraction of that 3 percent goesdirectly to biopolymer development. Some mem-bers of the research community have called formore explicit Federal goals in the biopolymerarea, particularly in the biomedical field (see box

Chapter l-introduction I 13

4-A). For example, the creation of a nationalcenter for biomaterials research at the NationalInstitutes of Health (NIH), as some observershave called for, could lend greater focus tobiopolymer programs in the medical area.

It is important to recognize, though, that whilemany important biopolymer applications are emerg-ing in the medical field, there are also promisingapplications in the industrial, agricultural, andwaste management sectors. As noted in a previ-ous Office of Technology Assessment report,Federal funding for biotechnology in the area ofmedicine dwarfs the funding directed towardagriculture, chemicals, energy, and other biotech-nology applications.

34 To ensure that promising

nonmedical biopolymer applications are not ig-nored, Federal programs could give greater em-phasis to areas such as the conversion of agricul-tural or aquatic materials into useful industrialfeedstocks and the production of environmentallysensitive materials .35

Despite the promise of new biopolymer pro-duction technologies, this nascent field faces thesame problems that have confronted other newtechnologies: development periods of 5 years orlonger, poor prospects for short-term gains, anduncertain demand in the marketplace because ofinexpensive alternatives (synthetic polymers arecurrently much less expensive than agriculturallyor microbially derived materials). Although somematerials are being used now, many biopolymersface a variety of technical and economic barriersthat will take several years to overcome. Theefforts of the private sector to overcome some ofthese 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 AgriculturalMaterials, 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 Pro-gram36 of the Department of Commerce, or thecooperative research and development programs(CRADAs) of the U.S. Department of Agriculture(USDA) and the various Department of Energynational laboratories.37

At present, Federal biopolymer research activi-ties are diffuse and for the most part, not wellcoordinated. Yet, given that biopolymer materialshave an extraordinarily broad range of possibleuses, the decentralized structure of the Federalresearch system should not necessarily be re-garded as a barrier to biopolymer development.Many biopolymer applications fall neatly into theresearch agendas of individual Federal agenciesand are already the subject of focused attention.On the other hand, a large number of biopolymerapplications involve a range of different scientificdisciplines, and thus some areas of biopolymerresearch could no doubt benefit from increasedcoordination of Government resources.

The recent White House initiative to classifybiotechnology research across the Federal re-search system is beginning to address this situa-tion and is intended to lead to greater cross-agency cooperation.38 Creating opportunities forincreased collaboration among academic, indus-trial, and Government researchers is an explicitobjective of the initiative. These efforts, evenwithout increased levels of funding, should bene-fit ongoing biopolymer research activities. Overthe long term, Federal R&D programs in thebiopolymer area might focus on:

exploratory work on biopolymer materials thatare genetically engineered to have uniquephysical and functional properties or that couldbe used as substitutes for the commodity resinscurrently derived from petroleum sources;utilization of agricultural or marine productsand byproducts;biopolymer processing technologies that couldpotentially lead to new environmentally sensi-tive manufacturing methods;approaches to lower the costs of productionassociated with various biopolymer manufac-turing technologies;research on the environmental impacts (posi-tive or negative) of biopolymers that areintroduced into solid and aqueous wastestreams or natural ecosystems.

As with other areas of technology develop-ment, the challenge for policymakers is to deter-mine where Government can best use its R&Dresources to complement, rather than replicate,the activities of the private sector.

Regulatory IssuesA number of existing or potential regulatory

factors could affect biopolymer development andcommercialization efforts. These include theFood and Drug Administration (FDA) approvalprocess for medical applications that use bio-polymers; the development of legal definitionsfor biodegradable materials, or regulations man-dating 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 developingbiopolymers 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’SAlternative Agriculture Research and Commercialization Center works with private industry to promote the commercialization of promisingnew materials. The Department of Energy has a large general effort in biotechnology at its national laboratories, including projects in mappingthe 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 NationalScience Foundation is supporting work in ceramics, composites, electronic and magnetic materials, superconductors, and biomaterials andbimolecular materials. See “NSF’s Pmticipation in Advanced Materials and Processing program (AMPP),” NSF document 93-68, May 7,1993.

applications such as packaging; regulations af-fecting the use of genetically engineered systemsfor producing biopolymers; and requirementsregarding the introduction of new industrialchemicals.

FOOD AND DRUG ADMINISTRATIONThe FDA is a regulatory agency responsible for

the safety of the Nation’s foods, cosmetics, drugs,medical devices, biological products, and radio-logical products. Since biopolymers have poten-tial uses in virtually all of these areas, the marketintroduction of many biopolymer compounds willbe governed by FDA guidelines.39 For example,biopolymer crystallization inhibitors such as poly-aspartate (see chapter 2) could be used in oralhealth care as tartar control agents. However,toothpaste and mouthwash additives are consid-ered “drugs,” and therefore require FDA ap-proval. The principal biopolymer applicationsaffected, however, will be drug delivery systemsand medical devices .40

To enter the U.S. market with a new drug or anadvanced drug delivery system that is beingpackaged with a new or existing drug, an applica-tion must be filed with the FDA before amanufacturer can begin human clinical trials.41

Following this step, a new drug application

Chapter I-Introduction 15

(NDA) is submitted with supporting evidence asto both safety and efficacy. Even if a proven drugdelivery system is packaged with a proven drug,anew application is required. Such safeguards arenecessary because a new delivery system-drugcombination will have new pharmacological prop-erties. This requirement can obviously affect therate at which various biopolymer drug deliverysystems are introduced into the market.

Medical device implants are also subject toFDA review through the Medical Device Amend-ments Act of 1976.42 The FDA evaluates thesafety and effectiveness of medical devices, butdoes not necessarily approve biomaterials per se.There is not an FDA list of approved medicalmaterials, but if a material is itself a product, suchas bone cement, the material does receive certifi-cation. However, the evaluation of materials inmedical devices is obviously an important part ofthe overall review process.43

In recent years, medical device manufacturershave expressed considerable concern about thelength of time required for FDA approval ofmedical 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 deviceinteractions. 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 deliverytechnology 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 solelyas a barrier that controls the rate of drug delivery by diffusion. Polylactidc and some polyamino-acid polymers are currently being evaluatedas 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, September1991, 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,

— . . . . . . .


tional Research Council made several recommen-dations 45 for improving the FDA approval proc-ess:

A biomaterials evaluation process should beestablished to facilitate the use of new materialsin medical devices. The material itself, onceproven safe and effective, should not be subjectto further testing in the event of its use withadditional medical devices.The FDA should establish a biomaterials advi-sory committee.The FDA should establish biomaterials guide-lines and standard test protocols.

Regardless of whether these proposals are adopted,the introduction of procedures that ensure productsafety, while reducing evaluation times and costs,will bean important objective of the FDA in yearsto come.46

BIODEGRADABLE MATERIALSScientifically based definitions and standards

relating to degradability have yet to be legallyestablished. While some studies on degradabilityhave been performed by the Environmental Pro-tection Agency (EPA) and the USDA, Congresshas not yet mandated technical standards in thisarea. However, in Public Law 100-556, Congressrequired that plastic ring carriers for bottles andcans be made of degradable material. In the

proposed rule for this law, EPA does not specifythat particular materials be used, but has insteadset performance standards for degradable materi-als. 47 The performance criteria include threefactors: a physical endpoint for degradation, atime limit for degradation, and marine environ-mental conditions.% By specifying performancegoals rather than particular materials, EPA hopesthat industry will have sufficient flexibility todevelop new classes of degradable polymers.Currently, beverage ring containers are made onlyfrom photodegradable materials, consisting ofethylene-carbon monoxide copolymers.49 In ad-dition to this Federal action, 27 States have passedlegislation prohibiting the use of nondegradablering carriers.

Although this EPA rule applies to a narrowproduct category, the precedent of setting per-formance standards for degradable substancescould facilitate the introduction of biopolymermaterials. If Federal or State action is taken toexpand the range of mandated degradable prod-ucts (e.g., personal hygiene products or diapers),market opportunities could develop for the newstarch, polylactic acid, and microbial polyesterbiopolymers. However, precise technical defin-itions and testing methods will be needed toconvince both manufacturers and consumers thatsuch 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 is r~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 submittedfor FDA approval. In the past every product submitted for approval was subject to the same administrative procedures. The new procedureswill 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 completelyassimilate into the environment regardless of the derivation of the material or the combination of degradation processes involved inassimilation” (see Federal Register, vol. 58, No. 65, Apr. 7, 1993).

48 Ibid.

49 scientists are still concerned w thae ‘‘dqp&ble’ materials may seine only to substitute one hazard fOr anOther ill @e waters. Thlitis, with the use of degradable plastics, the hazard of ingesting plastic fragments may reptace the hazard of entanglement in nondegradableplastics. 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 Inthis regard, the efforts of the American Society forTesting and Materials (ASTM) to develop scien-tific definitions and evaluation methods for de-gradable materials may serve to allay publicconcerns.51

GENETICALLY ENGINEERED BIOPOLYMERPRODUCTION SYSTEMS

The principal Federal regulatory guidelinesdealing with biotechnology were formulated inthe 1986 White House Office of Science andTechnology Policy report “Coordinated Frame-work for Regulation of Biotechnology. ’ Thedocument describes how novel chemicals, materi-als, and organisms, produced by the methods ofbiotechnology, fit into the existing corpus ofFederal legislation and regulation. In general,genetically engineered products are regulated onthe basis of their intended use, rather than themethod or process by which they are made. For

example, under current FDA rules, geneticallyengineered foods are treated the same way asconventional products. The FDA does not requirethat new products be approved or labeled, as longas such products are essentially similar in compo-sition, structure, and function to food itemsalready available on the market.52 However,USDA and EPA do regulate field tests of geneti-cally modified plants.53 As of 1993, more than400 permits have been granted for the field testingof genetically altered plants and other orga-nisms. 54

For the short term, genetically engineeredbiopolymers will be produced in “contained”fermentation systems where standard safety pro-cedures are well established.55 Thus, microbiallyderived biopolymer materials are unlikely to faceany significant regulatory obstacles.56 In thefuture, however, schemes that involve the produc-tion of biopolymers through the genetic modifica-tion of crops could face greater regulatory scru-

50 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-packagingcomponents as a consequence of accelerated degradation of a polymer. In the case of some proposed biopolymer packaging materials such aspullulan (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 oxidatiouchemicat degradation+ and biological degradation. It has developed standard Iabomtory test methods that measure the rate and extent ofdegradation for different materials, and is in the process of establishing a classification and marking system for polymer compounds. ASTMresearchers are currently attempting to determine the behavior of degradable polymeric materials in real disposal systems and are correlatingthese results with ASTM laboratory methods. This work could very well become the de facto industry baseline for defining and evaluating newpolymer materials, Already, EPA has used some of ASTM’s work in developing proposed performance standards for degradable beverage ringcarriers (op. cit., footnote 47; and see Rarnani NaryaIL “Development of Standards for Degradable Plastics by ASTM Subcommittee D-20.96on Environmentally Degradable Plastics, ’ 1992).

52 Some Commer ~oUpS ~ve expressd concerns that genetically engineered foods may be subject to microbial contm tio~ possesshigher levels of toxins, or expose consumers to allergy-producing compounds that are not naturally present in foods. The present consensusamong scientists is that the risks associated with genetically altered organisms are similar to those associated with nonengineered organismsor 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 ismade 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 SubstancesControl 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 exploringthe possibility of producing natural polyesterssuch as PHB by altering the enzyme machinery ofcorn or potatoes.57 Such approaches to bio-polymer manufacture will be subject to existingFederal rules governingagricultural organisms.

REGULATIONS RELATINGINDUSTRIAL CHEMICALS

genetically engineered

TO

In response to public concerns over the possi-ble health and environmental implications ofwidespread chemical use, Congress passed theToxic Substances Control Act (TSCA) in 1976,Under the provisions of TSCA, EPA is chargedwith assembling basic data on chemicals, review-ing industry tests of new and existing compounds,and reducing public risk. There are more than60,000 chemicals currently on the TSCA inven-tory, and roughly 1,000 new chemicals areproposed for manufacture each year.58 Beforemanufacturers can begin production of a new

chemical, they must submit aNotice to EPA. Only a small

Premanufacturenumber of the

premanufacture notices submitted to EPA areheld up for extended review.

59 In the vast majorityof cases, manufacturers can begin production ofa chemical 90 days after notifying EPA.

Since some of the more interesting biopolymercompounds are new chemical formulations, theywill also be subject to TSCA provisions.60 Yet,given that biopolymers are derived from naturalprecursors, most biopolymer products should nothave difficulty meeting current TSCA require-ments. 61 For instance, this should be the case forbiopolymers that are created by the chemicalpolymerization of naturally occurring monomers,such as polylactide and the poly amino acids.62

However, as indicated previously, some of theprocesses used to produce genetically engineeredbiopolymers may be subject to more detailedregulatory review (e.g., genetic modification ofplants).

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 newprocedures 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 treatmentchemicals, 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. B i o d e g r a d a b l e polyaspartate

compounds could be used to replace petroleum-derived polymers such as polyacrylate and polyacrylamide. However, it is not known whetherthe use of large quantities of natural polymers will have any adverse ecological effects.

Bblocks.

TechnicalOverview ofBiopolymer

Field 2copolymers can be produced through a variety ofmechanisms. They can be derived from microbialsystems, extracted from higher organisms such as plants,or synthesized chemically from basic biological buildingA wide range of emerging applications rely on all three

of these production techniques. Biopolymers are being devel-oped for use as medical materials, packaging, cosmetics, foodadditives, clothing fabrics, water treatment chemicals, industrialplastics, absorbents, biosensors, and even data storage elements.This chapter identifies the possible commercial applications anddescribes the various methods of production of some of the morepromising materials. Table 2-1 provides a partial list of thebiopolymers now in use. ’

SELECTED POLYMERSMICROBIAL SYSTEMS

PRODUCED BY

In recent years, considerable attention has been given tobiopolymers produced by microbes. It is on the microbial levelwhere the tools of genetic engineering can be most readilyapplied. A number of novel materials are now being developedor introduced into the market. In the following sections, three

I A comprehensive treatment of biopolymer compounds is beyond the scope of thisBackground Paper. The categories of biopolymers described here are designed toillustrate the diverse physical characteristics and the broad application range of thesematerials. 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 ChemicalSociety, 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


Table 2-l—A Snapshot of the Biopolymer Family

Polyesters Polysaccharides (plant/algal)Polyhydroxyalka noates Starch (amylose/amylopectin)Polylactic acid Cellulose

Proteins AgarSilks AlginateCollagen/gelatin CarrageenanElastin PectinResilin KonjacAdhesives Various gums (e.g., guar)Polyamino acids Polysaccharides (animal)Soy, zein, wheat gluten, casein, Chitin/chitosanSerum albumin Hyaluronic acid

Polysaccharides (bacterial) Lipids/s urfactantsXanthan Acetoglycerides, waxes, surfactantsDextran EmulsanGelIan PolyphenolsLevan LigninCurd Ian TanninPolygalactosamine Humic acidCellulose (bacterial) Specialty polymers

Polysaccharides (fungal) ShellacPullulan Poly-gamma-glutamic acidElsinan Natural rubberYeast 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 bio-polymers are profiled: polyesters, proteins, andpolysaccharides.

Microbial Polyesters:Polyhydroxyalka noates

Much of the current interest in biopolymersstems from the growing concern about the envi-ronmental impacts of synthetically producedmaterials. In particular, the highly publicizeddisposal problem of traditional oil-based thermo-plastics has promoted the search for biodegrada-ble alternatives (about 17 billion pounds ofthermoplastic packaging material was producedin the United States in 1991). Apart from theagriculturally derived biopolymers (e.g., starch)being investigated for their biodegradable proper-ties, there is a class of natural thermoplasticmaterials that is drawing much attention. Polyhy -

droxyalkanoates (PHAs) area family of microbialenergy reserve materials that accumulate asgranules within the cytoplasm of cells. They aregenuine polyester thermoplastics with propertiessimilar to oil-derived polymers (melting tempera-tures between 50 to 180”C). Their mechanicalcharacteristics can be tailored to resemble elasticrubber or hard crystalline plastic.3 The prototypeof this family, polyhydroxybutyrate (PHB), wasfrost discovered in 1927 at the Pasteur Institute inParis. Commercialization of PHB was first at-tempted by W.R. Grace Co. in the 1950s. Morerecently, a British company, Zeneca Bio Products(formerly ICI Bio Products), initiated commercialproduction of a series of PHA copolymers underthe trade name BIOPOLTM. Several companiesand government research organizations, particu-larly in Europe and Japan, have active researchand development (R&D) programs focusing onthese materials.

2 ~emopbtics we ~IPm tit 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 throughfermentation. The general process is illustrated infigure 2-1. In their final stages of preparation,they can be processed by standard extrusion andmolding techniques. Careful control of the carbonsources (starting materials) and the choice ofproduction organism enables the production of anentire family of PHA copolymers with differentproperties. The PHB homopolymer is producedby a variety of bacteria that use it as a source ofcarbon and energy. The homopolymer is a brittlematerial that is difficult to use and is thermallyunstable. However, by combining polyhydroxyval-erate (PHV) with PHB, a nonbrittle copolymer—polyhydroxybutyrate-polyhydroxyvalerate (PHBV)--can be created.4 Other PHA copolymers have alsobeen produced.5 Currently, Zeneca’s productionof PHBV (BIOPOL) uses the bacterium Alcali-genes eutrophus, which occurs widely in soil andwater. PHBV is formed when the bacterium is feda precise combination of glucose and propionicacid. 6 It has properties similar to polypropyleneand polyethylene, including excellent flexibilityand toughness. The discovery and developmentof PHBV and other PHA copolymers have provento be a major step forward in expanding thepotential industrial utility of the PHAs.

PHAs biodegrade in rnicrobially active envi-ronments. Since PHAs function as an intracellularenergy and carbon source, bacteria can degradePHAs and use them as reserve materials. Microor-ganisms attack PHBV by secreting enzymes(depolymerases) that break down the polymer

Chapter 2–Technical Overview of

Figure 2-I—PHA Polymer

Raw materialsv

Media preparation

vFermentation

vCell disruption

vWashing

vCentrifugation

vDrying

P H A P r o d u c t

Biopolymer Field 21

Production Process

1. Carbon source

2. Growth of bacteriaand accumulationof polymer

3. Purification of polymer

SOURCE: Biolnformation Associates, Boston, MA.

into its basic hydroxybutyrate (HB) and hy -droxyvalerate (HV) constituents. The HB and HVfragments are then consumed by the cells tosustain growth. Under aerobic conditions, thefinal biodegradation products are water andcarbon dioxide; under anaerobic conditions, meth-ane is produced as well. The degradation ofPHBV can be quite rapid in biologically activesystems (see figure 2-2).7 A range of soil microor-

4 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 and4-hydroxybutyrate. This material has been extracted and fermented from the bacterium AfcaJigenes eutrophu under starvation conditions. Byaltering 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-ompetroleum 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, thatPHBV and other biopolymers will not degrade in sanitary Iandfiis, because they are essentially biologically inactive systems. See Petra Piichnerand Wolf-Rudiger Miiller, “Aspects on Biodegradation of PHA,” H.G. Schlegel and A. Steinbiichl (eds.), Proceedings InternationalSymposium on Bacterial Polyhydroxyalbnoates 1992 (GOttingen: GoI-Druc~ 1993).


Figure 2-2—Biodegradation of PHBV Polymers

100 —ru< 4 0

/’

L ‘-- -i‘== i20 i /L------- ~—-— ~ –-–--— ------ ,I o~o 10 20 30 40 50 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 moisturecontent, PHBV showed a 40-percent weight loss In 40 weeks (left). Under anaerobic sewage conditions, where biodegradabilityis measured by gas production, the PHBV polymer decomposed nearly 80 percent in 30 days (right). Other data indicates thatPHBV 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.), Proceedingshterrtafional Symposium on Bacterial Po/yhydroxyakarmates 7992 (G6ttingen, Goltze-Druck: 1993); William D. Luzier, “Materials Derived fromBiomass/Biodegradable Materials,” Proceedings iVationa/kademy of Sciences, vol. 89, February 1992, pp. 839-842.

ganisms, both bacterial and fungal, can utilizePHAs as a source of carbon and energy.

CURRENT AND POTENTIAL APPLICATIONSPHAs have many possible uses. The inherent

biocompatibil i ty 8 of these bacterial materialssuggests several medical applications: controlleddrug release, surgical sutures, bone plates, andwound care. PHAs could also be used as structuralmaterials in personal hygiene products and pack-aging applications. At present, higher-volumecommodity plastic applications are limited be-cause of economic constraints. PHBV, for exam-ple, costs $8 to 9 per pound. However, costs havefallen from about $800 per pound in 1980, and itis believed that the price of PHBV can be broughtto around $4 per pound by 1995. (Petroleum-based polyethylene and polypropylene polymerscost about 50 cents per pound.) PHBV is nowbeing used in a variety of molding applications in

the personal care sector (e.g., biodegradablecosmetic containers-a market where the cost ofthe container is almost negligible in relation to thecost of the contents). In addition, Zeneca is in theprocess of commercializing films and papercoatings from BIOPOL resin. Mitsubishi Kasei(Japan) is actively involved in the development ofPHAs for use as a biodegradable replacement ofmonofilament fishing nets. Because of the desira-ble environmental characteristics of PHAs, thenumber of such niche markets is likely tomultiply.

Over the past 5 years, there has been asubstantial increase in the number of publicationsdealing with the biosynthesis, fermentation, andcharacterization of the PHA family of biopoly -mers. It soon may be possible for these polymersto compete as specialty plastic products. Theability to genetically engineer the different spe-

a 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., bymodifying the enzymes inside the bacteria) couldresult in the creation of highly customized poly-mers. Researchers have made significant progressin unraveling the biosynthetic pathways involvedin the production of PHAs. The genes encodingthe enzymes involved in PHA production havebeen isolated and cloned, and thus scientists cannow tailor the biosynthesis process to producepolymers with different properties. Over the longterm, there is the possibility that these materialscan be made economically in plant species.9

Recently, PHB was successfully synthesizedby using a genetically engineered experimentalplant (Arabidopsis thaliana).10 Researchers arenow exploring how to produce PHAs by modify-ing the enzyme machinery of corn or potatoes.11

Although significant technical challenges remain,the PHA family could potentially become a majoragricultural commodity, either as a fermentationproduct using raw materials (e.g., glucose) fromthe starch industry or, in the longer term, as a newcrop.

Recombinant Protein PolymersProteins are polymers composed of amino

acids. The specific amino acids used and thesequence of amino acids in a protein polymerchain are determined by the corresponding DNAtemplate. Many proteins are of commercial inter-est because of their catalytic (enzymatic) orpharmaceutical properties. However, nature has

Chapter 2–Technical Overview of Biopolymer Field 23

Coatings based on corn protein (zein) have goodmoisture and grease barrier properties and are beingused to replace polyethylene and wax-coated paperand paperboard.

also provided a vast array of proteins whoseprincipal function is to form structural materialsin living organisms. Some of the more familiarprotein materials include wool, leather, silk, andgelatin (jello is a simple, modified form of theprotein collagen12). Although many of thesestructural proteins have been used throughouthistory, the advances in recombinant DNA tech-nology have presented new approaches and op-portunities for the design and synthesis of proteinmaterials. In addition, many traditional proteinsprepared by the extraction of animal (e.g., colla-gen) or plant (e.g., soy or zein from corn) tissueare 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 aredetermined 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 H iII plants is a formidable ~d~g.

Inserting the genes that encode the PHB-producing enzymes is relatively straightforward. However, regulating the PHB enzymes and theexisting 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 VariousaThere 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 AlbertLehninger, 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 foodindustries. 13 The discussion here focuses onprotein polymers that are being developed byusing the methods of recombinant biotechnology.

PRODUCTION OF RECOMBINANTPROTEIN POLYMERS

The extraordinary functional diversity of natu-ral proteins underscores the potential advantagesassociated with harnessing the genetic code. Intheory, proteins can be designed to have virtuallyany structure, and thus specific physical andchemical properties. The fact that one-dimensional genetic sequences can specify pro-teins having complex three-dimensional struc-tures over distances of hundreds of nanometersreveals the power of nature’s material synthesisprocesses. Current chemical synthesis techniquesare essentially limited to creating polymers in onedimension only,14 with lengths of less than 10nanometers .15

A number of proteins that form importantstructural materials in various organisms havebeen studied extensively. The fibrous proteinssuch as collagen and silk have been the subject ofconsiderable attention. More specialized proteins,such as the adhesive material that bonds the seamussel to the ocean bed and proteins that contrib-ute to the formation of ‘ceramic-like’ materials(e.g., oyster shells and teeth), are also beingactively studied. A common feature of many ofthese proteins is the presence of repeated aminoacid sequences in the polymer product (see table2-2). These proteins, or specific regions of theseproteins, have structural features similar to blockcopolymers (see figure l-l).

Some of the structural proteins have beenchemically synthesized. In this approach, specificpeptides (sequences of amino acids) are createdand then linked together to form a polypeptide(the protein polymer). However, chemical synthe-sis of proteins can be quite expensively and

rimarily as coatings for paper and paperboard. Soy paper coatings impart a smoother surface and improve13 SOY and corn proteins ~ ~~ psurface appearance. Zein has excellent grease and moisture barrier properties. Soy proteins are also being used as structuring agents inwater-based inks, bemuse they are regarded as environmentally preferable to solvent-based inks. See Thomas L. Krinski, “Emerging PolymericMaterials 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 smewhtprelimhmry. 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 perpound.


Figure 2-3—Production of Recombinant Protein Polymers

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

I Genetic contruct ( D N A ) I\ –..A

polymer of Interest (regions coding for individualrepeat units are indicated by the hatched boxes).

I Introduce the genetic material Into a suitableproduction organism.

v—.

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

\ (DNA ‘ ,, CIIIZ Protein polymerorganism and switch on production ofthe protein.

U--&-J--u

‘ \..-. -..-...-F?/\

Purify the recombinant

“4 [~,{ I \

El -L.-n ~

protein.

Protein polymer product


produced or investigated by using recombinanttypically does not yield products with sufficientphysical and chemical uniformity.

In contrast, the recombinant DNA approachallows for the production of protein polymers thathave high purity, specific molecular weights, andexcellent lot-to-lot uniformity. This is possiblebecause the exact sequence of amino acids in thepolymer and the desired molecular weight arespecified by the DNA sequence of the gene. In thelong term, recombinant DNA technology couldbecome an important strategy for producinghigh-value, ‘‘knowledge-intensive’ materials thatare custom-designed for specific applications.The steps involved in producing recombinantproteins are illustrated in figure 2-3, Currently, allof the proteins shown in table 2-2 are being

DNA techniques. The fact that it is now possibleto chemically synthesize genes encoding anyrepeat unit suggests almost limitless possibilitiesfor creating novel protein polymers with uniquephysical and functional properties. Althoughresearchers are addressing major technical prob-lems such as genetic instability, toxicity inforeign hosts, and metabolic incompatibility,considerable progress in genetically engineeredprotein synthesis has occurred in recent years.17

Initial work in the synthesis of artificial genes hasled to the creation of proteins that could be usedas 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, hehighly 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 accumulatedin 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


The marine mussel, Mytilus edulis, is shown suspendedin water by threads attached with adhesive to a glassplate. Biotechnology research on adhesives producedby rnarine organisms is leading to new adhesives thatcan be used for many applications such as surgery andundersea structures.

CURRENT AND POTENTIAL APPLICATIONSMore than 25 genetically tailored proteins have

been synthesized in microorganisms. Many ofthese materials are being transformed into films,gels, and fibers. One of the first genetically

engineered protein polymers to be introducedcommercially, ProNectin FTM,19 was designed toserve as an adhesive coating in cell culturevessels. The polymer was customized to have twodistinct peptide blocks: one block possesses thestrong structural attributes of silk; the other hasthe cell-binding properties of the human proteinfibronectin. 20 The peptide blocks were chosenafter analyzing which particular structures couldprovide the desired physical, chemical, and bio-logical properties. ProNectin F has demonstratedexcellent adhesion to plastic surfaces such aspolystyrene and thus can be used to attachmammalian cells to synthetic substrates.21

A similar application of recombinant DNAtechnology has led to the development of abioadhesive based on a protein from the sea

22 Researchers have genet-mussel Mytilus edulus.ically modified yeast cells to produce the basicmussel protein. An enzyme-catalyzed process(the enzyme-a tyrosinase-modifies the tyro-sine amino acids in the protein) was also devel-oped to convert this recombinant protein into atrue adhesive.23 This polymer could be used as amarine coating, as a wetting agent for fibers incomposite materials, or as a dental or surgicaladhesive.24 For example, it might be employed asa sealant during eye surgery .25

A number of other protein polymers are beinginvestigated by using biotechnology methods.One intriguing new material is a polypeptidebased 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 andEngineering 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 convertchemical energy into mechanical energy .27 As aconsequence, the material could be used as areplacement for ligament tissue, blood vessels, orany other tissues requiring the contractile proper-ties of elastin.28 Because the peptide is similar incomposition to natural elastin, the polymer is notexpected to elicit an allergic reaction or unfavora-ble immune system response.

Another interesting material is the light-sensitive protein bacteriorhodopsin (BR). BR is aretinal protein consisting of 248 amino acids.When subjected to photons (light) of varyingenergy intensity, BR undergoes reversible colorchanges. Through substitution of specific aminoacids by genetic engineering, the photochemicalproperties of BR can be precisely modified, whichmeans color changes can be carefully controlled.The unique properties of BR could lead toapplications in optical data storage, image proc-essing, light switching (computational process-ing), and holography. Some initial work indicatesthat the optical performance of BR is comparableto conventional materials such as liquid crys-tals.29


Recombinant biotechnology is also being usedto modify materials that have been utilized forthousands of years. Silk has always been amaterial of great fascination. Spiders can processsilk protein into a material that has a tensilestrength 16 times greater than that of nylon30 anda very high degree of elasticity .31 Researchershave manipulated the genetic code to createsilklike materials with a variety of elasticities.32

Because of their exceptional tensile strength andelastic properties, these polymers could be usedas fibers for reinforced plastics and other ad-vanced composite materials. In the medical area,the polymers could potentially be used as wounddressings, artificial ligaments, and skin or as abiocompatible coating for prosthetic devices.However, the yields of genetically modified silkpolymers from microorganisms have thus farbeen fairly 10W.33

Most protein polymer research is focused onhigh-technology applications, such as elastomers,adhesives, bioceramics, and electro-optical ma-terials. To date, commercial applications havebeen limited to the use of genetically engineeredadhesives for fixing mammalian cells to culturevessels. Because of extremely high productioncosts, 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 elastinis 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 InformationProcessing?” 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 extendwhen 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-inwater alone. The web is constructed of several different silks, each of which is produced in a different spider gland. Some of the silk fiberscontain a number of water-soluble compounds that keep the fibecs wetted, allowing them to stretch and entangle prey that hit the web. SeeRandolf 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 asignificant problem (R&D Magazine, op. cit., footnote 18; Chemical and Engineering News, op. cit., footnote 22. Also see David L. Kaplanet al., “Biosynthesis and Processing of Silk Proteins, ’ Materials Research Bulletin, October 1992, pp. 4147.

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

. . . . .


Figure 2-&The Structure of Cellulose

CH20H

o o

H oHOH H

HO HH OH

L

YFoH ‘\!

O+OH H/”

H OH

H C H20 H

D

oH

o OH H

H OHn

H,OH

The cellulose molecule is composed of glucose units connected by B(1-4) bonds (see Figure 1 -3). Starchhas an identical chemical composition to cellulose except for its connecting bonds-a(l -4). The differentlinkages in starch molecules endow them with a greater water volubility than cellulose. In humans, starchcan be digested while cellulose cannot be digested.SOURCE: Office of Technology Assessment, 1993.

success (e.g., experimental quantities of thegenetically derived sea mussel adhesive were atone time selling for about $45 per milligram, or$20 million per pound). However, over the longterm, genetic techniques may allow production tobe scaled up significantly at reasonable cost.Once programmed with the proper genetic in-structions, bacterial cells can work in parallel bythe billions to produce polymer materials.34

Although some biotechnology companies havebeen involved in protein polymer research for 10years, most recombinant protein materials are stillin early stages of development.

Nevertheless, this area of research is one of themost active and better funded in the biopolymerfield. In addition to providing new materials,genetic engineering is now enabling scientists tostudy how biological systems transform proteinsinto final products. It is remarkable that livingorganisms are able to produce sophisticatedmaterials under mild processing conditions (i.e.,

low temperature and pressure in water-basedenvironments), without creating toxic bypro-ducts. This is certainly not the case for a varietyof human-made materials.35 Spiders and silk-worms, for example, can transform water-solubleprotein droplets into globally aligned insolublefibers. 36 The fibers are spun with very littleenergy consumption. Thus, protein polymer re-search could also lead to the development ofradically new industrial processing methods thatpose little threat to the environment.

The Microbial PolysaccharidesBACTERIAL CELLULOSE

Cellulose is the most abundant component ofbiomass and the basic feedstock of the paper andpulp industries. Traditionally extracted from planttissue (trees, cotton, etc.), cellulose can also beproduced by certain bacterial species by ferment-ation, yielding a very pure cellulose product withunique 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 tiegland to the exit valve. The key chemical and physical events that change the soluble proteins into solid fibers occur during this journey. Asthe protein molecules travel down the duct, they align themselves into regular arrays. It appears that the mechanical and frictional forces at workin the duct facilitate the transformation of the soluble protein droplets into solid fibers. See Lewis, op. cit., footnote31; Kaplau op. cit., footnote32.


Cellulose is a polysaccharide consisting oflinear glucose chains (see figure 2-4). Bacterialcellulose is synthesized in a process whereby thepolymer material is extruded from the bacterialcells. Most cellulose-producing bacteria (e.g.,Acefobacter) extrude cellulose as a ribbonlikeproduct from a single fixed site on the cell surface.This results in the formation of a network ofinterlocking fibers.

Bacterial cellulose is produced under condi-tions of agitated fermentation. High polymerproduction rates occur when the growth mediumcontains glucose, salts, corn steep liquor, ironchelators, and various productivity enhancers.Current yields are more than 0.2 gram of celluloseper gram of glucose, and production has beendemonstrated in commercial 50,000-gallon fer-menters. After fermentation, the bacterial cellsare destroyed during a hot caustic treatment.Bacterial cellulose is a water-insoluble materialthat has a very large surface area because of itslarge network of fibers, Bacterial fibers haveroughly 200 times the surface area of fibers fromwood pulp.37 This, coupled with their ability toform hydrogen bonds, accounts for their uniqueinteractions with water. Bacterially derived cellu-lose materials can absorb up to six times theirweight of water, and when used as suspensions,they have pseudoplastic thickening properties.Sheets prepared from bacterial cellulose haveexcellent mechanical properties.

CURRENT AND POTENTIAL APPLICATIONSConsiderable progress has been made in the

field of bacterial cellulose synthesis in the pastfew years. Bacterial cellulose is now available inlimited quantities from Weyerhaeuser in theUnited States and Ajinomoto in Japan. The mostprevalent applications of bacterial cellulose ex-

Cellulon@ engineered bacterial cellulose fiber is aproduct under development at WeyerhaeuserCompany. The unique reticulated network of finefibers gives the biopolymer its thickening, binding,and coating properties. The fibers have a typicaldiameter of 0.1 microns (0.1 millionth of a meter),while some wood pulp fibers have a diameter of25 to 35 microns.

ploit its very large surface area and its ability toabsorb liquids. Consequently, very low concen-trations of bacterial cellulose can be used to createexcellent binding, thickening, and coating agents.Because of its thickening properties, many appli-cations in the food industry are possible. Paperthat is coated with bacterial cellulose is extremelysmooth and protects the underlying fibers frommoisture. End uses in oil and gas recovery,mining, paints, adhesives, and cosmetics are also

envisioned. This material is currently used bySony Corporation in the production of high-endaudio speaker systems because of its excellentacoustic 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 muchof the fiber’s functionality as a thickener and binder. A. Robert Winslow, Cellulon Fiber Business Marketing Manager, WeyerhaeuserCompany, personal communication, Aug. 31, 1993.

38 me ~gh.fideliq headphones employ bacterial cellulose as diaphragms. The headphones retail fOr about $$,000 a wt.


Figure 2-&The Structure of Xanthan Gum

AcOCH2 Iw—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 gluouronicacid (GA) unit. Pyruvate (Pyr) and acetyl (Ac) units are also present in the mannose structures. The degree of pyruvate and acetatesubstitution 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 ofbacterial cellulose have been filed. Currently,bacterial cellulose sells from $35 to $50 perpound. If the material is to be used in commodityas opposed to niche applications, production costswill have to drop. A Japanese consortium wasrecently formed to reduce the manufacturingcosts of bacterial cellulose.39

XANTHANXanthan gum, a complex copolymer produced

by a bacterium, was one of the first commerciallysuccessful bacterial polysaccharides to be pro-duced by fermentation. The xanthan polymerbuilding blocks or “repeat units” contain fivedifferent sugar groups (see figure 2-5). Thexanthan-producing bacterium, Xanthomonas cam-pestris, 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 jointorganization under the Ministry of International Trade and Industry and the Ministry of Post and Telecommunications, along with six privatesector companies: Ajinomoto, Shimizu Construction N- Mitsubishi Paper, Niklciso, and Nakarnori Vinegar. The venture is calledBiopolymer Research Co., Ltd, and its principal focus will be the development of mass production techniques for cellulose that is made byfermentation (Japan Chemical Daily, Apr. 13, 1992).

.-


production systems targeted for genetic engineer-ing. Under certain conditions, genetic modifica-tion of Xanthomonas by using recombinant DNAtechnology has increased the rate of xanthanproduction by more than 50 percent.40 In thefuture, recombinant DNA technology may enableentirely new xanthan biosynthetic pathways to becreated in host organisms.

Xanthan gum is produced by large-scale fer-mentation of X. campestris using a number ofdifferent feedstocks including molasses and cornsyrup. The gum is extruded from the bacteriaduring the polymerization process and can berecovered by alcohol precipitation followingremoval of the bacterial cells. For some applica-tions such as enhanced oil recovery, the crudeculture broth can be used directly followingsterilization. Probably the most significant tech-nical problem in the production of xanthan is thefact that as the polymer is produced, the fermenta-tion medium becomes increasingly viscous. Thisincreases the energy required for the mixingprocess that feeds oxygen to the bacterial cells.

CURRENT AND POTENTIAL APPLICATIONSThe unusual physical and mechanical proper-

ties of xanthan gum make it an attractive polymerfor industrial and biological use. It is usedextensively in both the food and the nonfoodindustries. Examples of industrial applicationsinclude oil recovery (provides viscosity control indrilling mud fluids), mineral ore processing (usedas a biocide), paper manufacturing (used as amodifier), agriculture (acts as plant growth stimu-lator), pharmaceuticals (being evaluated for sus-

tained drug release), and cosmetics (controls dustrelease). Food applications include gelling agentsfor cheese spreads, ice creams, puddings, andother deserts. More recently, xanthan has beenused in the new clear-gel toothpastes. Reading thelabels on many of the processed foods in thesupermarket should give one a clear picture of thewide use of this material. Good examples arepacket soups and many of the fat-free foods thathave recently become available.

In terms of production volume, xanthan gum isthe most widely used microbial polysaccharide.Worldwide production is currently in the range of10,000 to 20,000 tons. Companies such as ADMand Merck have recently announced the expan-sion of their xanthan production facilities. About60 percent of the xanthan produced is used infoods, with the remaining 40 percent used inindustrial applications. Food-grade xanthan costsabout $8 to $10 per pound, while non-food gradessell for about $5 per pound. Thus far, onlyexperimental samples of genetically modifiedxanthan have been produced.41

DEXTRANSDextran is the generic name of a large family of

microbial polysaccharides that are assembled orpolymerized outside the cell by enzymes calleddextran sucrases. This class of polysaccharides iscomposed of building blocks (monomers) of thesimple sugar glucose and is stored as fuel inyeasts and bacteria. Dextrans are produced byfermentation or enzymatic conversion of thefeedstock sucrose, a product of the sugar beet andsugarcane 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 StructurelPropertyRelations, 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~tigums in the 1980s. Neither fii was successful in marketing these xanthan products because their manufacturing costs were much higher thanconventional xanthan production methods. The relatively high production costs of genetically moditled polymers is a major problem that couldseriously 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 manufacturinghurdles, some producers of genetically derived biopolymer compounds are focusing on low-volume, high value-added applications such asmedical materials or specialized industrial adhesives. David Many~ President, Adheron Corporation personal communication Aug. 24, 1993.


production uses the microorganism Leuconstocmesenteroides. Dextran can be synthesized byusing either large-scale industrial fermentors orenzymatic filtration methods. The latter approachis generally favored since it results in an enhanceddextran yield and a uniform product quality,which allows the product to be readily purified.Both of these production methods permit systemconditions to be adjusted so as to control themolecular weight range of the products. Thisfeature is an integral requirement for polysaccha-ride biosynthesis.

CURRENT AND POTENTIAL APPLICATIONSDextran polymers have a number of medical

applications. Dextrans have been used for woundcoverings, in surgical sutures, as blood volumeexpanders, to improve blood flow in capillaries inthe treatment of vascular occlusion, and in thetreatment of iron deficiency anemia in bothhumans and animals. Dextran-hemoglobin com-pounds may be used as blood substitutes that haveoxygen delivery potential and can also function asplasma expanders. Chemically modified dextranssuch as dextran sulfate have both antiulcer andanticoagulant properties. Other modified dex-trans such as Sephadex@ are used extensively inthe separation of biological compounds.

In the industrial area, dextrans are beingincorporated into x-ray and other photographicemulsions. This results in the more economicalusage of silver compounds and at the same timereduces surface gloss on photographic positives.Dextrans are used extensively in oil drilling mudsto improve the ease and efficiency of oil recovery.They also have potential use in agriculture as seeddressings and soil conditioners. The protectivepolysaccharide coatings are found to improvegermination efficiencies under suboptimal condi-tions.

Although many applications have been pro-posed for dextrans, only a small number of thesehave been realized and developed on a large scale.There is considerable potential for using low-molecular-weight dextrans in the biomedical industry in

surgery and drug delivery systems. However,low-molecular-weight dextrans sell for about $80per pound. As new and higher-volume applica-tions for these materials are developed, large-scale production of dextrans may represent amajor new market for the sugarcane and sugarbeet industries.

PULLULANPullulan is a water-soluble polysaccharide

produced outside the cell by several species ofyeast, most notably Aureobasidium pullulans.Pullulan is a linear polymer made up of mono-mers that contain three glucose sugars linkedtogether (see figure 2-6).

For more than a decade, a Japanese firm,Hayashibara Biochemical Laboratories, has useda simple fermentation process to produce pullu-lan. A number of feedstocks are used for thisprocess, including waste streams containing sim-ple sugars. Pullulan can be chemically modifiedto produce a polymer that is either less soluble orcompletely insoluble in water. The thermal andionic (electrical) properties of pullulans can alsobe altered.

CURRENT AND POTENTIAL APPLICATIONSPullulan and its derivatives have a number of

useful properties and consequently have manypossible applications. Hayashibara BiochemicalLaboratories currently sells three different pullu-lan grades: industrial grade ($6.50 per pound),food grade ($11 per pound), and medical grade($15 per pound). Current efforts to increase theyields of pullulan from the fermentation ofvarious strains of A. pullulans suggest lowerproduction costs are likely in the future. Pullulancompounds are biodegradable in biologicallyactive environments, have high heat resistance,and display a wide range of elasticities andsolubilities. This versatility allows them to beutilized in many different ways.

Pullulan has many uses as an industrial plastic.It can be formed into compression moldings thatresemble polystyrene or polyvinyl chloride in


Figure 2-6-The Structure of Pullulan

CH2 CH20H CH2OH

}--- ------o }-- - -0 &——- o

K&LWo’tioOH 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 areconnected together in a branched fashion.

SOURCE: Office of Technology Assessment, 1993.

transparency, gloss, hardness, strength, and tough-ness, but is far more elastic. It decomposes above200’C, apparently without the formation of toxicgases. 42

A completely different application of pullulancan be found in the food industry. It can be usedas a food additive, providing bulk and texture. Itis tasteless, odorless, and nontoxic. It does notbreak down in the presence of naturally occurringdigestive enzymes and therefore has no caloriccontent. Consequently, it can be used as a foodadditive in low-calorie foods and drinks, in placeof starch or other fillers. In addition, pullulaninhibits fungal growth and has good moistureretention, 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. Itis transparent, impermeable to oxygen, and oil-and grease-resistant. Foods can be either im-mersed in a solution of pullulan or coated by apolymer spray. After the pullulan coating is dried,an airtight membrane is formed. The membranecan be used in the packaging of drugs andsupplements, as well as oil-rich food products that

are vulnerable to oxidation, such as nuts and friedfoods. It is not necessary to remove the pullulancoating before eating or cooking. In the packagingof tobacco, pullulan enhances product longevityand retention of aroma. It also protects againstoxidative degradation as well as attack by mold.Water insoluble coatings may be made by usingthe esterified or etherified forms of pullulan.

Ester and ether derivatives of pullulan haveadhesive qualities similar to those of gum arabic.Viscosity and adhesive properties depend on thedegree of polymerization. Modified pullulan canbe used as a stationary paste that gelatinizes uponmoistening. Fibers can be made from concen-trated solutions of pullulan having high viscosity.The fibers have a gloss resembling rayon and atensile strength similar to that of nylon fibers.Pullulan and its ester or ether derivatives can alsobe used as binders, in conjunction with othermaterials, for the production of nonwoven fab-rics. With or without the addition of othervegetable pulps, it can be used to make paper thatis suitable for printing and writing. Because it is

42 However, it should be not~ that partial combustion of carbohydrates can produce cMbOn monofide.


an antioxidant, pullulan can substitute for gumarabic in lithographic printing.

There are a plethora of other applications.Pullulan can be used as a binding agent for solidfertilizers, allowing time-released fertilizationand thereby avoiding the burning of crops bycontrolling the release of nitrogen in the fertilizer.As a binding agent in sand molds used for metalcasting, pullulan prevents the generation of dustor toxic fumes. The biopolymer can be used as aflocculating or aggregating agent for the precipi-tation of potash clays, uranium clays, and ferrichydroxide from slurries used in the beneficiationof mineral ores. (Currently, synthetic chemicalsare primarily employed in mineral processing.)Pullulan can be used as an additive to resins andpaints, where its preservative and antioxidationproperties help retain color and gloss. Also,pictures or illustrations printed on pullulan filmwith edible ink can be transferred onto foodproducts. In the medical area, pullulan acts as aplasma extender without undesired side effects.After metabolic turnover, it is completely ex-creted. Pullulan compounds can also serve asdrug carriers, and can be used as medical adhe-sives.

Although markets for many of the applicationslisted here are still relatively small, with someapplications only in the exploratory stage, pullu-lan appears to have long-term commercial poten-tial. In sum, pullulan’s many disparate uses mayentitle it to become known as a biopolymer‘‘wonder material.

GLUCANSGlucans 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 cellwall. A common source for this glucan is baker’syeast, Saccharomyces cerevisiae, although it isalso found in a number of other sources (bacteria,fungi, lichen, and higher plants, e.g., barley).

Large supplies of inexpensive yeast are availa-ble from both the baking and the brewing(brewer’s yeast) industries. Glucans are the mostabundant polymers in yeast, making up approxi-mately 12 to 14 percent of the total dry cellweight. Glucan is readily purified from yeast cellsby using hot alkali treatment to remove all othercellular materials, thereby allowing recovery ofthe insoluble glucan material. Yeast glucan parti-cles purified by this method contain both highmolecular weight and lower molecular weightpolymers.

CURRENT AND POTENTIAL APPLICATIONSGlucans have a number of potential medical

uses. 43 Glucans that are extracted from yeast cell

walls are found to markedly increase the ability ofsome organisms (e.g., mice) to resist invadingforeign bodies. Because of its action as animmunomodulator, or enhancer of the immunesystem, a number of studies have been performedexploring the use of glucan as an anti-infectiousagent. Glucan is also effective as an antiviralagent in plants. For example, one form of glucanis very effective in protecting many species oftobacco plant against invasion by the tobaccomosaic virus and tomato black ring virus. Plantscan be either injected or sprayed with the glucanpolymer.

43 s~ce polysacc~des play an important role in cell ad.lmsionand asmolecdar reCO@tiOn el~ents (JJlyCOprOtefi), tieypotm~y ~vea number of medical applications. Recent developments in the cloning and expression of enzymes known as oligosaccharyl transferases couldfacilitate the creation of new carbohydrate-based pharmaceuticals. See ChemicaZ andEngineering News, “Race Is on ‘h Develop Sugar-BasedAnti-inft ammatory, Antitumor Drugs, ” Dec. 7, 1992, pp. 25-28. Apart from genetic engineering methods, some of these enzymes can also bechemically isolated. A new enzyme isolation method is being used to simplify the synthesis of novel polysaccharide CQmpounds. Some of thenew compounds have been found to prevent bacterial pneumonia in animals and are also being evaluated as anti-infective drugs. Ihe enzymescould also be used to create polysaccharides that act as industrial coatings (e.g., as coatings on ship hulls to improve fuel efllciency and preventmarine 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 inmice and rats have revealed that glucans caninhibit tumor growth. The less toxic, soluble formof glucan is effective as an antitumor agent,although it is slightly less effective than theparticulate form. Many antitumor glucans arecurrently being used in Japan on human subjects.In the United States, one company (Alpha BetaTechnology of Worcester, Massachusetts) hasyeast glucans that are undergoing clinical trials asimmune-stimulating agents. Another interestingproperty of glucans is that they are radio-protective (i.e., they appear to enhance survivalby preventing death due to postirradiation infec-tion). This enhances the survival of test animalsafter otherwise lethal doses of radiation.

Although glucans are being exploited princi-pally for their antitumor, anti-infectious, andradioprotective properties, they also have non-medical applications. Glucans resist breakdownwhen attacked by digestive enzymes, and thus canbe used as noncaloric food thickeners. Otherpossible applications include use in sustained-release tablets, encapsulation of oxygen for masstransfer in fermentation reactions, and as a solidsupport material for chromatographic separa-tions.

GELLANIn addition to xanthan, pullulan, and glucan, a

number of other microbial polysaccharides arebeing investigated for applications as thickeningagents. These include succinoglycan, sclero-glucan, and the three structurally related poly-mers rharnsan, welan, and gellan. Among these,gellan gum is the most recent microbial polysac-charide to be given Food and Drug Administra-tion (FDA) approval for applications in foodproducts (September 1990). Gellan is a complexpolysaccharide having a four sugar repeat unit

(glucose-glucuronic acid-glucose-rhamnose). Itis produced by the bacterium Pseudomonaselodea, which is derived from plant tissue.

The production of gellan follows essentiallythe same fermentation process described forxanthan. The properties of gellan can be easilymodified. A hot caustic treatment of gellan yieldsa polymer that has the desirable characteristic oflow viscosity at high temperature. Cooling gellanin the presence of various cations (e.g., calcium)results in the formation of strong gels.

CURRENT AND POTENTIAL APPLICATIONSGellan gum represents the newest member of

the microbial polysaccharides to be developedcommercially. Developed and produced by theKelco Division of Merck under the trade namesKelcogel and Gelrite, this polymer has applica-tions in the food industry as a gelling agent infrostings, glazes, icings, jams, and jellies. GelIancurrently sells for about $5 per pound.

SELECTED POLYMERS OF PLANTS ANDHIGHER ORGANISMS”

StarchStarch is the principal carbohydrate storage

product of higher plants. The term starch actuallyrefers to a class of materials with a wide range ofstructures and properties. Starch polymers can beextracted from corn, potatoes, rice, barley, sor-ghum, and wheat. The principal source of starchfor industrial and food purposes is corn. In theUnited States, about 4.5 billion pounds of corn-starch is used annually for industrial applica-tions.45 Starches are mixtures of two glucanpolymers, amylose and amylopectin.46 Thesepolymers are accumulated in plants as insolubleenergy storage granules, with each granule con-taining 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).


breeding techniques have been used to producenew strains with altered ratios of amylose toamylopectin (e.g., waxy corn contains only 0.8percent amylose compared with natural corn,which contains 28 percent amylose, and amylo-maize can contain up to 80 percent amylose). Theability to manipulate the ratio of amylose toamylopectin by strain development has drasti-cally reduced the economic costs associated withphysical separation of the two polymers. This isimportant because amylose and amylopectin havedifferent properties and applications.

CURRENT AND POTENTIAL APPLICATIONSBecause of its low cost and widespread availa-

bility, starch has been incorporated into a varietyof products. Chemical modification of starchpolymers can lead to a number of useful deriva-tives. Current U.S. production of ethanol requiresabout 400 million bushels of corn. An additionalseveral billion pounds of cornstarch is used fornonfuel purposes. Approximately 75 percent ofthe industrial cornstarch produced is transformedinto adhesives for use in the paper, paperboard,and related industries. Because cornstarch canabsorb up to 1,000 times its weight in moisture, itis used in disposable diapers (about 200 millionpounds annually), as a treatment for burns, and infuel filters to remove water. Cornstarch polymersare also used as thickeners, stabilizers, soilconditioners, and even road deicers.47

In recent years, starch has attracted consider-able attention as a biodegradable additive orreplacement material in traditional oil-based com-modity plastics. Although a number of starch-plastic material blends have been used in differentproducts, particularly packaging and garbagebags, there has been considerable controversy as

to whether these starch-polymer composites canbiodegrade.48 Starch itself degrades readily, andis in fact one of main components of thebiological food chain. When added to petroleum-derived polymers such as polyethylene, starchcan in theory accelerate the disintegration orfragmentation of the synthetic polymer chains.Microbial action consumes the starch, therebycreating pores in the material, which weakens itand enables it to break apart. Many have incor-rectly characterized this process as a form ofbiodegradation. Independent tests of polyethylene-starch blends show that starch may biodegrade,but that the overall polymer formulation will notbiodegrade at any significant rate. Distintegrationof polyethylene-starch blends is not the same asbiodegradation. Moreover, studies indicate thatdegradation rates vary considerably under differ-ent temperature, oxygen, and moisture condi-tions. In landfills, for example, degradation rates,even for readily degradable materials, are ex-tremely s10W.49 Under optimal conditions, break-down of starch-plastic blends that contain lessthan 30 percent starch is quite slow. Someresearch indicates that the starch compositionneeds to exceed about 60 percent before signifi-cant material breakdown occurs.50

These problems have led to the development ofa new generation of biodegradable materials thatcontain very high percentages of starch. Undercertain conditions, starch can be combined withwater and other compounds to create a resin thatis somewhat similar to crystalline polystyrene.Warner-Lambert has recently introduced theNOVON@ family of polymers that contain from40 to 98 percent starch and readily dissolve inwater. The NOVON resins combine starch withother biodegradable materials, and when dis-

47 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 andMunicipal 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.


posed in biologically active environments such ascompost facilities and wastewater treatment sys-tems, display degradation characteristics similarto lignocellulosic materials (e.g., leaves, wood-chips, and paper) .51

Properties of these new materials can be variedas the composition of starch and other materialcomponents change. They can replace traditionalplastics used in food service, food packaging,personal health care, agricultural, and outdoormarkets. Early applications of NOVON polymersinclude compost bags, degradable golf tees,loose-fill packaging, cutlery, pharmaceutical cap-sules, and agricultural mulch films. The companyopened a 100-million-pound NOVON manufac-turing facility in 1992. The materials are beingtargeted for markets where the benefits of theirbiodegradability can be clearly demonstrated. Tofully take advantage of their environmental char-acteristics, however, a coordinated compost infra-structure will have to be established.52 Althoughthese starch-based resins cost two to four timesmore than commodity resins ($1.50 to $3 perpound), their novel properties might lead to thecreation of new specialty markets.

Plant CelluloseAs mentioned previously, cellulose is one of

the most abundant constituents of biologicalmatter. 53 It is the principal component of plantcell walls. Among the plant cellulose, cottonfiber is the most pure, containing around 90percent cellulose. Wood, on the other hand,consists of about 50 percent cellulose. Celluloseserves as an important material feedstock formany industries. U.S. production of cellulosefibers amounted to 485 million pounds in 1991.By adding various functional groups to the basic

4New starch-based thermoplastic biopolymers such asthe AMYPOLTM family of resins are water resistantand can be extruded, pelletized, and injection-moldedinto industrial and consumer products and films.

glucose building blocks of cellulose (see figure2-4), a range of useful derivatives (cellulosics)can be created.

CURRENT AND POTENTIAL APPLICATIONSChemically modified plant cellulose are used

in a remarkably diverse set of applications.Cellulose derivatives are used to forma variety offibers, thickening solutions, and gels. For exam-ple, carboxymethylcellulose (CMC) is used as athickener, binder, stabilizer, suspending agent, orflow control agent. The major markets for CMCare detergents, food, toothpaste, shampoo, skinlotions, textiles, paper, adhesives, ceramics, andlatex paints. In the biotechnology area, CMC gelsare used for separating molecules. Hydroxyeth-ylcellulose (HEC) is a water-soluble compoundthat has major applications in the oil industry.HEC is used as a thickener in drilling fluids andas a fluid-loss agent in cementing. Hydroxypro-pylcellulose (HPC) has excellent surface proper-

51 me ~ompmy rePf15 tit we end pr~ucts of these new materials are carbon dioxide, water, and bio~s, ~~ no Persistent syn~eticresidues. See the testimony of Ken Tracy, Vice-President of Environmental Technology, Warner Lambefl Company, before t.be SenateCommittee 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


A photomicrograph shows modified ethyl cellulosefilms magnified by a factor of 2,000. The materials arebeing evaluated as carriers for the controlled-releaseof nitrogen fertilizers.

ties and forms highly flexible films. It is used incoating pharmaceutical tablets, in molding opera-tions, in paper coatings, and as a suspending agentin inks, cleaners, and polishes. In the medicalarea, hydroxypropylmethylcellulose (HPMC) hasshown considerable promise as an agent forlowering blood cholesterol levels.54

There are many other useful derivatives. Cellu-lose acetate is a plastic-grade material that iswidely used in packaging, particularly for blis-ters, skins, transparent rigid containers, andwindows in folding or setup boxes.55 In addition,cellulose acetate is used in some fabrics and as awrite-on pressure-sensitive tape (e.g., for credit

card receipts). Methylcellulose, created by treat-ing cellulose fibers with methyl chloride, hasexcellent absorption properties and is a goodthickener. It has been used in a variety of foodproducts, including salad dressings, pie fillings,and baked goods. Nonfood applications includeadhesives, agricultural chemicals, tile cements,plywood glues, printing inks, and cosmetics.

Cellulose is also receiving considerable atten-tion as a potential feedstock for liquid fuels,particularly ethanol. By either acid or enzymatictreatment (biological enzymes break down thecellulose into its basic sugars), cellulose can beconverted to fermentable glucose and then dis-tilled to remove ethanol. Although not currentlycompetitive with ethanol derived from corn orsugarcane, the economic attractiveness of cellulose-derived fuel could very well change with ad-vances in biotechnology .56

Cellulose will no doubt continue to be a majormaterial feedstock for a wide spectrum of indus-tries. Future research is likely to focus on thedevelopment of new chemical derivatives and thecreation of composites that combine cellulosewith other biodegradable materials.

LigninLignin is a polymer found in woody and

herbaceous plants. Its principal function is toprovide structural support in plant cell walls.Lignin consists of phenylpropane building blocksand belongs to the polyphenol family of poly-mers. Along with cellulose and hemicellulose,lignin is one of the three chemically distinctcomponents occurring in plant tissue. Typically,woody and herbaceous biomass consists of 50percent 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 forchlorofluorocarbons in electronics manufacturing) and taxol (a compound being explored as an anticancer dreg).


25 percent lignin.57 Wood is a complex lingocel-luolosic composite,58 Lignin polymers are highlyamorphous, three-dimensional structures that areassociated with hemicellulose and play a key rolein preventing decay of the lignocellulosic ma-terial. Lignin is generated in great quantities as abyproduct of wood pulping processes and conse-quently is relatively inexpensive. The most com-mon commercial form of lignin is lignosulfonate,a compound derived from sulfite pulping. Higher-purity lignin can be obtained from “kraft”pulping, but this process is more costly .59

CURRENT AND POTENTIAL APPLICATIONSAt present, most of the lignin that is isolated

from pulping processes is burned as an on-sitefuel source. However, the material is increasinglybeing used in nonenergy applications.60 Becauselignin acts as a natural adhesive holding cellulosefibers together in plant cell walls, many of itscommercial applications take advantage of thisproperty. Millions of pounds of lignosulfonatesare used annually for road dust control, Lignosul-fonates are also employed as binding agents inmolding applications and in animal feed. Ligninderivatives are beginning to be used as phenolicadhesives that can replace formaldehyde-basedcompounds in applications such as industrialpackaging and tape.

The ionic properties of lignosulfonates andkraft lignins allow them to act as dispersants.They are being used to prevent mineral buildup inboilers and cooling towers, as thinning agents inoil drilling muds and concrete admixtures, and as

dispersing agents in pesticide powders. Somemajor chemicals are also produced from ligninprecursors. For example, vanillin, the principalingredient in artificial vanilla, is derived from thearomatic components of lignin. In addition, chem-ically modified lignins are being explored forpossible pharmaceutical applications. The devel-opment of specialized lignin compounds, such aselectrically conducting polymers and engineeringplastics, is an area of considerable research.

ChitinChitin, a polysaccharide, is one of the most

ubiquitous polymers found in nature. It is almostas common as cellulose, and possesses many ofthe structural and chemical characteristics ofcellulose (see figure 2-7). Chitin is an importantstructural component of the exoskeleton of a greatnumber of organisms such as insects and shell-fish. It also serves as a cell wall component offungi and of numerous plankton and other smallorganisms in the ocean (see box 2-A for examplesof other marine polysaccharides). Because of thedifferent biological requirements of these variousspecies, chitin is an extremely versatile naturalpolymer. Chitin and its most important deriva-tive, chitosan, have a number of useful physicaland chemical properties, including high strength,biodegradability, and nontoxicity. 61 Currently,the principal source of chitin is shellfish waste,but given the seasonal fluctuation of shellfishharvests, genetically engineered microbial sys-

58 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 Materialsand 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 exposedto acids, these% groups attract hydrogen ions, forming (NHgH, impardng a net positive charge to the chitosanpolymer. This enables chitosmto remove negatively charged compounds and contaminants from wastewater. The positively charged chitosan forms solid precipitates withthese negatively charged compounds. Chitosan is one of few natural polysaccharides that has this “ionic” property (i.e., a positive charge).


Figure 2-7-Chitin and Its Polysaccharide Relatives

CH20H CH2OH CH2OH CH20Hk—o ~o ~o +0

NHCOCH3

CH20HLo

B ti”NH2

CH20Hk–—o

c JQ”OH

NH COCH3 NHCOCH3 NHCOCH3 ~

CH20H CH20H CH20H

Q’”o a’”o 0°NH2 NH2 NH2

CH20H CH20H CH20HA—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 differentchemical and physical properties. Shown here are the structures of: A) chitin, B) chitosan, and C) cellulose. Theonly 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 ofhigh-grade chitin compounds.62

CURRENT AND POTENTIAL APPLICATIONSThe chitin family of polymers is being widely

used in medicine, manufacturing, agriculture, andwaste treatment. In the biomedical area, chitosanis incorporated into bandages and sutures inwound-healing treatment, because it forms atough, water-absorbent, oxygen permeable, bio-compatible film. It can be used to accelerate tissuerepair and can be applied directly as an aqueoussolution to treat burns. Because of its high oxygen

permeability, chitosan is used as a material forcontact and intraocular lenses. Chitosan has alsobeen found to expedite blood clotting. The factthat chitin compounds are biodegradable (thehuman body breaks chitin down into simplecarbohydrates, carbon dioxide, and water) makesthem particularly appropriate for use in drugdelivery systems. Chitosan carriers can releasedrugs slowly. This property is extremely valuablein cancer chemotherapy since the agents are oftenhighly toxic and require long periods of time foradministration. 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 algaegrow quite slowly. The application of biotechnology may lead to the development of fast-growing strains of algae that produce large quantitiesof 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.


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 surviveextremely cold temperatures by producing antifreeze proteins. Other proteins regulate the mineraliza-tion processes involved in the creation of shells and crystals (e.g., the calcite crystals of sea urchinspines). Polysaccharides serve as structural components in crustaceans (e.g., chitin), and in a numberof algal species such as kelp.

Chitin and some algal polysaccharides such as agar, alginate, and carrageenan are widely usedin industry and medicine. The market for these marine polymers is several hundred million dollarsannually. Agar, a major component of the cell walls of certain red algae, is used as a photographicemulsifier; a gel for cosmetics, toothpaste, and medical ointments; an inert drug carrier, a corrosioninhibitor, an adhesive, and a thickening agent in confectioneries and dairy products. Alginate is aprincipal structural constituent of brown algae (rockweeds and kelps), and carrageenan is extractedfrom 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 asin 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 theanti-inflammatory compound Fucoside B. Marine organisms provide a vast range of biologicalprocesses and substances that could be genetically modified for novel medical and manufacturingpurposes. The Federal investment in marine biotechnology research was about $44 m ill ion in f iscal year1992.

SOURCES: Federal Coordinating Council for Science, Engineering, and Technology, Committee on Life Sciencesand 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.v i r u s .6 3

The high moisture retention and film-formingcharacteristics of chitosan have resulted in anumber of applications in the cosmetics andpersonal care areas. Chitosan is being utilized inhair spray, skin cream, shampoo, soap, nailpolish, toothpaste, and personal hygiene prod-ucts.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 topaper-chitin composites, some researchers havedeveloped complexes of chitin and cellulose thathave excellent water-resistant properties.66 Thematerial can be molded or made into biodegrada-ble plastic films. Eventually, high-strength chitinpolymers could be used in food packaging. Onecompany, 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 ChemicalRese~rch, vol. 29, 1990, pp. 800-805.


the acoustic properties of crickets’ wings, haseven constructed audio speaker vibrators fromchitosan materials.67

In terms of actual sales, agricultural end usesconstitute the largest and most successful marketfor chitin and chitosan polymers. The fungi-resistant properties of chitosan have resulted in itsapplication as a fertilizer, soil stabilizer, and seedprotector. 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 aplant growth regulator. Chitosan is also used torecover protein wastes, particularly dairy prod-ucts such as cheese whey, that are subsequentlyadded to animal feed.

Because of its binding and ionic properties(i.e., in solution, the chitosan polymer carries apositive charge), chitosan can be used as aflocculating agent to remove heavy metals andother contaminants from wastewater.69 Currentapplications in this area include treatment ofsewage effluents, paper mill wastes, metal finish-ing residues, and radioactive wastes. In severalcountries, particularly Japan, chitosan is used topurify drinking water. Chitosan is also beingevaluated for use in the bioremediation of toxicphenolic compounds.70 This could greatly im-prove the efficiency of pharmaceutical and plasticmanufacturing, by eliminating phenolic contami-nates.

Chitin and its various derivatives have becomeimportant constituents in a number of diverseproducts and industrial processes. Pharmaceutical-grade chitin sells for about $32 per pound, whileindustrial grade chitin/chitosan compounds rangefrom about $7 to $27 per pound (specific costdepends on the application). The unique chemical

properties and biodegradability of this family ofbiopolymers presage an even wider range ofapplications in the future.

Hyaluronic AcidHyaluronic acid (HA) is a natural product that

is found throughout vertebrate tissue. It alsooccurs as an extracellular polysaccharide in avariety of bacteria. HA plays an important physio-logical role in many organisms. Research indi-cates that HA aids tissue formation and repair,provides a protective matrix for reproductivecells, serves as a regulator in the lymphaticsystem, and acts as a lubricating fluid in joints.Currently, most of the HA used for research andcommercial purposes is extracted from roostercombs. In the future, it is likely that this bio-polymer will be produced from fermentationbroths of Streptococcus and other bacteria.

Hyduronic acid, discovered in 1934, is a long,unbranched polysaccharide chain, composed ofrepeating twin sugar units. Because of the highdensity of negative charges along the polymerchain, HA is very hydrophilic (has a strongaffinity for water) and adopts highly extended,random-coil conformations. This structure occu-pies a large volume relative to its mass and formsgels even at very low concentrations. It isextremely flexible and has a high viscosity.

CURRENT AND POTENTIAL APPLICATIONSSince hyaluronic acid plays an important role

in many developmental and regulatory processesof the body, it has been used principally inbiomedical applications. It is an extremely attrac-tive 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 BiodegradablePolymers, ” 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.


Table 2-3—Biomedical Uses of Hyaluronic Acid

Area Application

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

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. Pres-ently, its major uses are in eye surgery, treatmentof arthritis, and wound-healing preparations; it isalso being used in some cosmetic products.Various biomedical applications for HA are listedin table 2-3.

The unique physiochemical and structuralcharacteristics of hyaluronic acid make it anexcellent candidate for applications that requirebiocompatibility. However, the prices of HA areextremely high, more than $100,000 per kilo-gram. A recent survey estimates a total market forHA of $425 million by 1996.71 The largestsegment of this market is for surgery. Thesmallest segment is for cosmetics. Because of itsutility in surgical treatment, the demand forhyaluronic acid is likely to expand. Some firmsare now investigating genetically engineered HAproduced by microbes. While the application ofgenetic techniques may produce HA that hasgreater polymer uniformity, switching to bacte-rial production (from rooster comb extraction)probably will not lower total production costsbecause of the need for expensive purificationsteps .72

POLYMERS PRODUCED BY CHEMICALPOLYMERIZATION OF BIOLOGICALSTARTING MATERIALS

Polymers that are created by the chemicalpolymerization of naturally occurring monomersare attracting considerable commercial interest.Although these polymers are not produced bybiological systems, the fact that they are derivedfrom basic biological building blocks confers onthem many of the same properties as microbiallyor plant-derived biopolymers. These may includenontoxicity, biodegradability, and biocompatibil-ity. In addition, these polymers are by definitiondrawing on feedstocks that are renewable. Whilethere are several different classes of chemicallysynthesized biopolymers, two particular groupsstand out. One is the family of polymers producedfrom lactic acid, a molecule used extensively inthe food industry. The other is the growingensemble of polyamino acid polymers.

Polymers Synthesized from Lactic AcidLactic acid (lactate) is a natural molecule that

is widely employed in foods as a preservative anda 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 theyare mirror images of each other. Such mirror image structures are called stereoisomers. Because the stereoisomers have different spatialconfigurations, they have different reactive properties. Only the l-lactide is found in animals, whereas both the d and 1 forms of lactic acid arefound in lower organisms, such as the Luctobucilli, a class of bacteria used for centuries in the dairy industry.


Figure 2-8-Commodity-Scale Production ofPolylactide

Raw material .-

“ - - 1

MonomerAgricultural wasteWhey (dairy Industry)Starch (potato processing)

‘ermentat’On>E

Chemicalcondensation ~

r—‘- “–—------- --w-.–,

A, Low molecular weight/’ PLA

Thermal /’ — ---–——/treatment,,

//

,/’Cyclic dimer-L’

Lactide 1o\ o Product

‘ c “ “CH 3J-

Rlng opening –

High molecular weight

HC A polymerization 11--- - ‘ L A - - - - -‘ o ” ‘ o

CH 3(catalyzed)


applications in intravenous and dialysis solutions.It is the main building block in the chemicalsynthesis of the polylactide family of polymers.This family includes polylactide homopolymers(PLA) and copolymers with glycolic acid (PLA-PGA). (Glycolic acid occurs naturally in sugar-cane syrup and in the leaves of certain plants, butis generally synthesized chemically).

Lactic acid is found in blood and muscle tissue,where it is a product of the metabolic processingof glucose. Although it can be synthesizedchemically, lactic acid is produced principally bythe microbial fermentation of sugars such asglucose or hexose. These sugar feedstocks aredrawn from agricultural (potato skins and corn)and dairy wastes. The lactic acid monomersproduced by fermentation can be used to create

either low or high molecular weight polylactidepolymers (figure 2-8). Variation of the reactionconditions, such as temperature and choice ofcatalyst, provides control over the molecularweight of the polymer. In this way, the physicaland chemical properties of polylactide can beadapted for different applications.

CURRENT AND POTENTIAL APPLICATIONSPolylactide polymers are the most widely used

biodegradable polyester materials. Although theirprincipal area of application has been in the healthcare field, agricultural and manufacturing useshave been found as well. Polylactides are fre-quently used in combination with polyglycolicacid. PLA-PGA copolymers are employed asmedical materials and as platforms for the sus-tained release of agricultural chemicals. In theindustrial sector, PLA commodity polymers arebeing developed for use as pulping additives inpaper manufacturing and as degradable packag-ing materials.74 Commodity-grade polylactidesells for about $5 per pound, but manufacturersexpect to bring the price down to the $2 to $3range. Medical grade polylactide prices rangefrom $100 to $1,000 per pound. The properties ofthese materials are being tailored to meet a varietyof different needs.

Most applications of PLA-PGA materials havebeen for therapeutic purposes. Devices made ofPLA-PGA copolymers have been used for thecontrolled release of antibiotics, anticancer andantimalarial agents, contraceptives, hormones,insulin, narcotic antagonists, and proteins.75 Thecopolymers have been molded into microsphereor microcapsules, pellets, implants, and hollowfibers.

There are several other important medicalapplications. 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~-rel-delivery by PLA-PGA devices can decrease the rate of drug degradation.


in surgery because they degrade within the bodyafter the incision has healed. Commercial absorb-able sutures such as Vicryl@ are made of copoly-mers containing 90 percent PLA and 10 percentPGA. This ratio creates fibers that have excellentdurability, absorbency, and tensile strength. Su-tures made from PLA-PGA copolymers are strongerand absorb faster than sutures, such as Dexon@,made only of PGA. A considerable amount ofongoing research is focused on the application ofPLA-PGA copolymers as sutures, clips, staples,and reinforcement materials.

PLA-PGA copolymers have also been success-fully applied in experimental orthopedic surgery.Compression-molded copolymers have been usedas plates or screws for the treatment of fracturesand to fill in bone defects. The materials have alsobeen used as scaffolding to facilitate the forma-tion of new cartilage material in the body.76

Copolymers of PLA and PGA are more usefulthan homopolymers of PLA and PGA becausetheir rate of degradation can be adjusted. Anadvantage of using prostheses made of PLA-PGAcopolymers is their biocompatibility and nontox-icity. The breadth of current research effortssuggests that the range of biomedical applicationsfor PLA-PGA materials will expand considerablyin coming years.

Polyamino AcidsPolyamino acids are an important class of

synthetic polymers produced by chemical polym-erization of the same amino-acid building blocksfound in naturally occurring proteins.77 Polyam-

ino acid chains are sometimes referred to aspolypeptides. Approximately 20 amino acids canbe found in proteins, and from these basicbuilding blocks a variety of homopolymers andcomplex copolymers have been synthesized. Be-cause of the great chemical diversity of amino-acid monomers—anionic, cationic, hydrophobic,polar, nonpolar, thermally stable-polyaminoacids can be envisioned for virtually all types ofpolymer applications.78

Currently, two principal chemical proceduresare used to produce polyamino acids. One ap-proach specifically links amino-acid monomerunits together by amide bonds. These are the sametype of bonds that exist in natural proteins. Thisparticular type of chemical synthesis is a fairlycomplex process and is used primarily to createthe high-purity materials needed for biomedicalapplications. In the future, this method of synthe-sis may be supplanted by bacterial fermentation79

or recombinant DNA techniques. One type ofbacterial species, for example, can produce poly -glutamic acid, a polypeptide that has man y

therapeutic uses. As highlighted earlier, recombi-nant DNA technology is being used to develop anew class of polymers based on spider silk (silkis a natural polyamino acid).

Polymer chains consisting of glutamic acid,aspartic acid (a component of NutrasweetT M) ,leucine, and valine are the polypeptides mostfrequently used for biomedical purposes. Lysineand methionine are also important amino-acidbuilding blocks in polypeptide polymers.80 Glu-tamic 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; tit is, ~ 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 polyaminoacids discussed here are for the most part derived ffom l-amino acids. Polymers that contain only l-isomers or only d-isomers are known ashomochiral structures. Like the phenomenon of DNA self-replication homochirality is a unique property of living systems. See V. Avetisovet 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 tit tivolve 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.


Polyamino acid microsphere can be used toencapsulate bugs and agricultural chemicals,thereby ensuring that such active agents can bereleased in a controlled fashion. The microsphereshown here have a diameter of about 1.5 microns(1.5 millionth of a meter). Microsphere occurnaturally and figure prominently in a theory ofthe origin of living cells over 3 billion years ago.

glutamate (MSG) and is a major product of thefermentation industry, with an annual productionlevel of around 600 million pounds. A majoradvantage of using glutamic acid is its low costand relative abundance. Glutarnic acid and aspar-tic acid are hydrophilic (they have high wateraffinity), whereas leucine and valine are hydro-phobic (low water affinity). When these hydro-philic and hydrophobic building blocks are com-bined, copolymers with vastly different rates of

biodegradation can be created. This allows thecopolymers to be used as delivery systems for avariety of different drugs. The fact that ho-mopolymers and copolymers of these simpleamino acids are nonimmunogenic (i.e., they donot produce an immune response when injectedinto animals) makes them particularly attractivefor medical applications. Polyamino acid micro-spheres—spheres ranging in size from 50 nanom-eters (billionth of a meter) to 20 microns (mil-lionth of a meter)--are currently being developedfor oral drug administration.81 (Polyamin o acidmicrosphere can also be used for the controlledrelease of fertilizers.) In addition to drug deliverysystems, polyamino acids are being investigatedfor use as biodegradable sutures, artificial skin,and orthopedic support materials.

A less complex chemical procedure is used toproduce polyamino acids for commodity-scaleindustrial applications. Polypeptides are made bythermal polymerization of amino-acid buildingblocks at moderately high temperature (160 to240oC), followed by a mild alkaline treatment at60 to 80°C to open ring structures that may form.This process is not very specific and yields apolymer product in which the monomers arelinked by two different types of bonds. However,the advantage of this method is that large quanti-ties of polypeptides can be synthesized at lowcost.

This approach has been used to create polyas-partate polymers from aspartic acid.82 The poly-aspartate polymers are analogues of naturalproteins, particularly the aspartate-rich proteinsfrom 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 wzymesand 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 thebloodstream. This would allow oral administration of genetically administered proteins. However, in animal studies ecmducted thus far, onlyabout IOpercent of an orally administered drug dose makes it to the bloodstream. One company involved in this area is Ehnisphere Tedmologiesof 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.

...— ———


Table 2-4-Possible Applications of Industrial Polyaspartates

Water treatment Antiscaling, anticorrosion, flocculation. Cooling towers, evaporators (forexample 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 mayhave 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 topromote 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 anticorro-sive properties that can prevent the buildup ofmineral deposits on the surfaces of ships, coolingtowers, heat exchangers, and other industrialequipment. Since the polyaspartate compoundsare derived from natural precursors, they arebiodegradable 84 and can be used to replacepetroleum-derived polymers such as polyacrylateand polyacrylamide.85 Because of their uniquemineralization and ionic properties, there existsan enormous range of possible applications forthe polyaspartate materials (see table 2-4).

At present, markets for these synthetic bio-polymers are only now being identified. Never-theless, there exist opportunities to use polyaspar-tates for a variety of specialized biomedicalpurposes, as well as a number of high-volumeapplications such as flocculants, dispersants, andsuperabsorbents. Industrial polypeptides, particu-larly water treatment chemicals, are likely tobecome commercially available in the near fu-ture.86 It is expected that these compounds willcost from one-third to twice the price of existingsynthetic 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 whereit is not wanted and, under certain conditions, can promote crystallization where it is needed. The formation of minerals in solution (e.g., thecalclum carbonate structure of oyster shells) is a fundamental process of living and nonliving systems, It is apparent that nature has producedsome extraordinary polymers to regulate the mineralization process. By investigating the properties of these natural polymers, researchers aretrying to develop new biopolymers that can be tailored for a variety of industrial applications. See C. S, Sikes and A. P. Wheeler, ‘ ‘Regulatorsof 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 SynthesizedPolympartate 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, Theirworldwide use amounts to billion of pounds annually, They are excellent materials in terms of their chemical activity and cost. However, theyare 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,


SUGGESTED FURTHER READING Microbial Polyesters:Polyhydroxyalkanoates

Sumner A. Barenberg, John L. Brash, RamaniNarayan, and Anthony E. Radpath, DegradableMaterials: Perspectives, Issues and Opportuni-ties (Boca Raton, LA: CRC Press, 1990).

James H. Brown, ‘‘Research Opportunities forBiologists in Bimolecular Materials,” NationalScience Foundation, Division Director, Molecu-lar and Cellular Biosciences, internal report, June1992.

Yoshiharu Doi, Microbial Polyesters (NewYork, NY: VCH Publishers, 1990).

Oliver P. Peoples and Anthony J. Sinskey,“Polyhydroxybutyrate (PHB): A Model Systemfor Biopolymer Engineering II,” E.A. Dawes(cd.), Novel Biodegradable Microbial Polymers,NATO Advanced Science Institute Series (Hol-land: Kluwer Academic Publishers, 1990), vol.186, pp. 191-202.

I Recombinant Protein Polymers

James H. Brown, ‘‘Research Opportunities forBiologists in Bimolecular Materials,” NationalScience Foundation, Division Director, Molecu-lar and Cellular Biosciences, internal report, June1992.

D.R. Filpula, S.-M. Lee, R.L. Link, S.L.Strausberg, and R.L. Strausberg, “Structure andFunctional Repetition in a Marine Mussel Adhe-sive Protein, ” Biotechnology Progress, vol. 6,1990, pp. 171-177.

S.D. Gorham, “Collagen,” D. Byrom (cd.),Biomaterials: Novel Materials from BiologicalSources (New York, NY: Stockton Press, 1991),pp. 55-122.

D.L. Kaplan, S.J. Lombardi,, W.S. Muller, andS.A. Fossey, ‘Silks, ’ D. Byrom (cd.), Biomateri-als: 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 andPurification of a Recombinant Elastomeric Pol-

ypeptide, G-(VPGVG)19-VPGV from E.. coli,”Biotechnology Progress, vol. 8, 1992, pp. 347-352.

Bacterial CelluloseP. Ross, R. Mayer, and M. Benziman, “Cellu-

lose 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 CelluloseProduced in Fermenters,’ presented at the Ameri-can Chemical Society Meeting, Boston, MA,Apr. 24, 1990.

D.C. Johnson, H.G. Folster, and A. Ben-Bassat, “Bacterial Cellulose from Agitated Cul-ture: Process Development, Scale-up and Appli-cations, ’ presented at the Cellulose ’91 Conference,New Orleans, December 1991.

XanthanR.A. Hassler and D.H. Doherty, “Genetic

Engineering of Polysaccharide Structure: Produc-tion of Variants of Xanthan Gum, Xanthomonascampestris, Biotechnology Progress, vol. 6, 1990,pp. 182-187.

J.F. Kennedy and I.J. Bradshaw, “Productionand Applications of Xanthan, ” M.E. Bushell(cd.), Progress in Indutrial Microbiology, vol.19, 1984, pp. 319-371

DextransR.M. Alsop, “Industrial Production of Dex-

trans,’ M.E. Bushell (cd.), Progress in IndustrialMicrobiology (Amsterdam: Elsevier, 1983), pp.1-44.

C. Larsen, “Dextran Prodrugs-Structure andStability in Relation to Therapeutic Activity,”Adv.Drug Delivery Review, vol. 3, No. 1, pp.103-154.

PullulanChemical and Engineering News, “Japanese

Develop Starch-Derived Plastic, ” vol. 24, De-cember 1973, p. 40.


A. Jeanes, “Dextrans and Pullulans: Industri-ally Significant Alpha-D-Glucans,” P.A. Sand-ford and A. Laskin (eds.), Extracellular Micro-bial Polysaccharides, ACS Symposium Series,vol. 45, 1977, pp. 284-298.

Y.C. Shin, Y.H. Kim, H.S. Lee, S.J. Cho, andS.M. Byun, “Production of ExopolysaccharidePullulan from Inulin by a Mixed Culture ofAureobasidium Pullulans and KluyveromycesFragilis,’ Biotechnology & Bioengineering, vol.33, 1989, pp. 129-133.

GlucansE. Cabib, R. Roberts, and B. Bowers, ‘Synthe-

sis 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, “ComparativeTumor-Inhibitory and Anti-Bacterial Activity ofSoluble and Particulate Glucan,” InternationalJournal 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 andControl of Neoplasia by Adjuvant Therapy (NewYork, 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-InducedProtection Against Septic Shock,” CirculatoryShock, vol. 25, 1988, pp. 53-60.

Ge l lanV.J. Morris, ‘ ‘Science, Structure and Applica-

tions of Microbial Polysaccharides, ” G.O. Phil-lips, D.J. Wedlock, and P.A. Williams (eds.),Gums and Stabilizers for the Food Industry, vol.5, 1990, pp. 315-328.

StarchR.L. Whist ler , J .N. BeMiller , and E.F.

Paschall, Starch Chemistry and Technology, 2ndEd. (New York, NY: Academic Press, 1984).

R.P. Wool and S.M. Goheen, ‘‘DegradationMechanisms in Polymer-Starch Composites,”International Symposium on Biodegradable Po[y-mers, Biodegradable Plastic Society, October1990, pp. 137-143.

LigninW. Glasser and S. Sarkanen (eds.), Lignin:

Properties and Materials (Washington, DC: Amer-ican Chemical Society, 1989).

Fred Boye, Utilization of Lignins and LigninDerivatives (Appleton, WI: Institute of PaperChemistry, 1985).

Robert Northey, “Low-Cost Uses of Lignin,”R. Rowell, T. Schultz, and R. Narayan (eds.),Emerging Technologies for Materials and Chem-icals from Biomass (Washington, DC: AmericanChemical Society, 1992).

ChitinG.G. Allan, L.C. Alturan, R.E. Bensinger, D.K.

Ghost, Y. Hirabayashi, A.N. Neogi, and S. Neogi,“Biomedical Applications of Chitin and Chito-sari, ’ J.P. Zikakis (cd.), Chitin, Chitosan andRelated Enzymes (New York, NY: AcademicPress, 1984), pp. 119-135.

A. Naude, “Drug and Cosmetic Uses Targetedfor Chitin Products,’ Chemical Marketing Re-porter, Dec. 11, 1989, pp. 24-25.

E.R. Pariser and D.P. Lombardi, Chitin Source-book: A Guide to the Chitin Research Literature(New York, NY: John Wiley & Sons, 1989).

Hyaluronic AcidA. Scheidegger, “Biocosmetics in Japan: New

Wrinkles Beneath the Make-Up, ” Trends inBiotechnology, vol. 7, 1989, pp. 138-144.

J. van Brunt, “More to Hyaluronic Acid thanMeets the Eye, ’ Biotechnology, vol. 4, 1986, pp.780-782.

Polymers Synthesized from Lactic AcidS.J. Holland, B.J. Tighe, and P.L. Gould,

‘‘Polymers for Biodegradable Medical Devices,


the Potential of Polyesters as Controlled Macro-molecular Release Systems, ’ Journal of Con-trolled Release, vol. 4, 1986, pp. 155-180.

M. Vert, P. Christel, M. Audion, M. Chanavaz,and F. Chabot, “Totally Bioresorbable Compos-ites Systems for Internal Fixation of Bone Frac-tures, ’ E. Chiellini et al. (eds.), Polymers inMedicine II (New York, NY: Plenum Press, 1985,pp. 263-275.

R.H. Wehrenberg, “Lactic Acid Polymers:Strong, Degradable Thermoplastics,” Mechani-cal Engineering , September 1981, pp. 63-66.

Polyamino AcidsJ.M. Anderson, K.L. Spilizewski, A. and

Hiltner, “Poly Alpha-Amino Acids as Biomedi-cal Polymers, ’ D. F. Williams (cd.), Biompatibil-ity of Tissue Analogs, vol. 1 (Boca Raton, FL:CRC Press, 1985), pp. 67-88.

C.S. Sikes and A.P. Wheeler, “Regulators ofBiomineralization,’ Chemtech, October 1988,pp. 620-626.

.

BiopolymerResearch andDevelopment

in Europeand Japan 3

s ignificant biopolymer research efforts have been underway for many years in both Europe and Japan. In theEuropean Community (EC), advances in biopolymertechnology have been driven principally by the private

sector. However, a number of basic and applied researchprograms have been initiated recently at the national andsupranational (EC) levels. The Japanese Government, as it hasdone with other emerging technological fields, is activelysponsoring and coordinating biopolymer research among Japa-nese companies and scientific institutes. In both Europe andJapan, biopolymer research has two principal areas of focus:degradable materials that serve as substitutes for traditionalcommodity plastics and biomedical applications,

EUROPESeveral factors are stimulating European research and devel-

opment (R&D) efforts in the biopolymer area. The emergence ofa strong environmental movement has caused European govern-ments to search for new methods and materials to address solidwaste problems and other ecological concerns. As a conse-quence, there is considerable interest in developing biodegrada-ble products that are derived from renewable resources. l

1 Although about 15 percent of all materials used for commercial purposes are derivedfrom petroleum, only about 3 percent of petroleum supplies are used as feedstocks forpetrochemicals and synthetic resins. Thus, large-scale use of biopolymers for materialsapplications will not significantly affect oil consumption patterns. Biopolymers areimportant primarily because of their biodegradability and other physical properties. Formore on petroleum feedstock applications, see U.S, Bureau of Mines, NonrenewableOrganic Materials, May 1993. For more on industrial energy use, see U.S. Congress,Office of Technology Assessment, lndustrial Energy Efficiency, OTA-E-560 (Washing-ton, DC: U.S. Government Printing Office, August 1993).

51


The large agricultural surpluses that have resultedfrom the EC’s Common Agricultural Policy(CAP)2 potentially represent an abundant sourceof feedstocks that could be used for large-scalecommercial production of biologically derivedfuels and materials.3

Existing and proposed environmental regula-tions could provide a major impetus for theintroduction of products containing biopolymers.4

The proposed EC directive on a‘ ‘Framework forWaste” provides regulatory guidance on howmember states should handle the disposal ofmunicipal waste. This framework embraces ahierarchy of waste management techniques, simi-lar to that enunciated by the U.S. EnvironmentalProtection Agency (EPA).5 It will be left toindividual governments to devise specific plansto implement this waste management strategy.The role of biodegradable materials is not deline-ated in this directive. However, the frameworkdoes call for the introduction of “environmen-tally safe” products, and it is proposed that suchproducts be exempted from various environ-mental duties.6 If biopolymer manufacturers candemonstrate that their products are environmen-tally safe, they could benefit from this proposeddirective. However, no standards or evaluationmethods have been established to determine what

constitutes an environmentally safe product, andthus the ultimate commercial impact of thedirective is uncertain. Moreover, many environ-mental advocacy groups do not view biodegrada-tion as a solution to solid waste problems. Apartfrom medical products, these organizations be-lieve that the introduction of biodegradable ma-terials into the marketplace will undermine recy-cling efforts and, depending on the extent of theirdegradation, exacerbate litter problems.7

The development of labeling programs forenvironmentally preferred products could alsopromote the development of biopolymer materi-als. The European Commission has proposed ascheme whereby a single label would be grantedto products that satisfy a range of ecologicalcriteria. These criteria relate to all aspects of aproduct’s manufacture, distribution, use, anddisposal. 8 An eco-label will be granted to aproduct that has a clear environmental advantageover other products in its category. Commodityitems such as packaging or plastics that containbiodegradable additives could become primecandidates for an eco-label. However, as men-tioned previously, the methodologies for makingsuch evaluations have yet to be developed. Up tonow, the process of creating environmental meas-urement 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 hasled to enormous crop surpluses, massive public expenditures, higher food prices, and a net transfer of wealth from urban to rural regions. Thesesurpluses have led to the dumping of European agricultural products in overseas markets and have, not surprisingly, exacerbated internationaltrade 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 currentenergy 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 dangeroussubstances 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, andchemical form); and 3) safe disposal of unavoidable waste. See European Community Bulletin ‘‘Framework for Waste’ Directive, document375 L 0442, September 1989.

6 Examples of products that could be subject to environmental taxes include nonreturnable bottles, gasoline, tropical wood, natural gas, andcoal. 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 GreenProducts 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 hadbeen set for implementing the EC eco-labelprogram.

EC Research ProgramsThe European Community is currently funding

several R&D programs that directly and indi-rectly involve biopolymer technology. Theseprograms are attempting to develop new nonfoodapplications for agricultural commodities, alter-native energy sources, and materials with superiorenvironmental properties, Figure 3-1 outlinesEurope’s major biopolymer research programs.

The ECLAIR (European Collaborative Link-age of Agriculture and Industry Through Re-search) program (1988-93), with a budget ofroughly $95 million, is designed to promoteagroindustrial applications of new and improvedvarieties of plants and microorganisms. Theprogram is concentrating on the extraction andtransformation of biological materials such assugars, starches, oils, and fats into useful com-mercial products. For example, ECLAIR is pro-viding half of the $4.6-million research budget fora consortium consisting of Zeneca, Inc. (UnitedKingdom) and the universities of Hull (England),Ghent (Belgium), and Goettingen (Germany).The consortium is investigating microbial polyes-ter production by the bacterium Alcaligeneseutrophus (see chapter 2). This program alsoincludes research on genetically engineeredplants for the production of natural polyestermaterials.

The AIR (Agricultural and Agro-Industry,Including Fisheries) program (1991-94) is focus-ing on “land and water-based biological re-sources, ’ and has a planned 3-year budget ofabout $90 million. Research will focus on proc-

Figure 3-l—European Initiatives

ECprograms

STEPECLAIRJOULE

AIRBRITE

Germanprogram

b’

and Japan 53

and Programsin Biopolymers

n

Researchinstitutes

4Technology transfer . (’ Private

Information ‘I, companies

SOURCES: Blolnformation Associates, Boston, MA; V%lf-RfidigerMiller, Institut ftir!%xlungswasserbau, WassergOte-und Abfalhvirtschaftder Universit~t Stuttgart, Federal Republic of Germany, personalcommunication, July 26, 1993.

esses for transformingg materials from agriculture,horticulture, forestry, fisheries, and aquicultureinto industrial products. One aspect of the pro-gram is to examine the biodegradability andlarger ecological impacts of biopolymer materi-als.10 As part of a wider effort in materials andpolymer science, the Basic Research on IndustrialTechnologies in Europe (BRITE) program (1991-94) is examining polymeric materials with prop-erties that ‘‘minimize environmental impact, ’including a study of biodegradable packagingmaterials.11

Other efforts include the STEP (Science andTechnology for Environmental Protection) andJOULE (Joint Opportunities for Unconventionalor Long-Term Energy Supply) programs. STEPbegan in 1989 with a budget of $90 million. It isfocusing on the development of technologies thatsafeguard environmental quality. One element ofthe program includes an assessment of biodegrad-

9 Product impacts on the environment are almost always multidimensional in character. Any g;ven product 1S ~ely to have pOsltive as wellas negative environmental attributes. Existing methodologies for evaluating the ‘‘environmental quality’ of a produc4 such as life-cycleanalysis, 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.


able materials. The JOULE program, also begunin 1989, was given an initial budget of $145million. The program is principally designed toimprove long-term energy security by exploringways of reducing the reliance on imported energysupplies. One part of the program is analyzing thepotential of biomass as an energy source. Deriva-tives of cellulose and starch, for instance, can beused as transportation fuels.

These programs, with funding exceeding $400million, demonstrate the EC’s strong interest indeveloping new commercial products and energysupplies from renewable resources. Each programseeks academic and industrial participation. Re-search supporting the creation of ‘‘next-generation’ materials-materials derived princi-pally from agricultural or microbial sources-isan important component of these collaborativeprograms.

Research in GermanyAmong individual European states, Germany

has launched a set of research initiatives that arespecifically designed to advance biopolymertechnology. Germany is being extremely aggres-sive in dealing with solid waste problems andother environmental issues.

12 These factors have

led to the development of a 5-year biotechnologyprogram that will focus on: conversion of biomassinto alternative fuels and commodity plastics;new strains of plants to establish new routes forthe development of nonfood renewable resources;fermentation technology for hydrogen produc-tion;13 and new bioprocessing techniques.

The Federal Ministry of Research and Technol-ogy is coordinating and funding this program.Industry and academia are the principal recipientsof research money. It has a substantial budget ofDM 1 billion ($590 million) for the period1990-95. 14 No other government in Europe hascommitted this level of funding to biotechnologyR&D. Thus, German industry could be wellpositioned to exploit the expected demand forproducts that are derived from renewable re-sources (see table 3-l). German companies havethe potential to become major players in thedevelopment of next-generation biopolymer ma-terials.

Private Sector Activity

DEGRADABLE POLYMERSA number of so-called biodegradable plastic

products were marketed in Europe in the 1980s.These first-generation products were basicallytraditional oil-derived polymers, such as polyeth-ylene, containing a low percentage (4 to 6percent) of starch. Most of these products weremade by the North American companies ArcherDaniels Midland and St. Lawrence Starch. Con-troversy surrounding the degradability of theseproducts has essentially stopped their production.A new generation of starch-based products is nowbeing introduced by several fins. These materi-als have a cornstarch content ranging from 40 tonearly 100 percent. Manufacturers believe that byincreasing the starch content of the polymer, thetime for degradation will be reduced (see chapter2).

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 todurable products, such as automobiles and electronics, in the near future. See U.S. Congress, OffIce of Technology Assessment, op. cit., footnote8.

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, September1990),

14 The Ge~nbiot~bnology program is designed to promote research in the areas of the environment, public herd~ nutritiOtL energy, andnatural resources. Another area of focus is pharmaceuticals. However, recent budgetary pressures associated with the costs of Germanunification 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 technologyprogram

Europe’s highest concentration of Limited venture capital presence.biotechnology In pharmaceutical andchemical fields

High-quality science training and research Dominance of large companies could limitbase small market opportunities typical in

biotechnology.Strong industry-university relationships

SOURCE U S Congress, Office of Technology Assessment, Biotechnolgy in a Global Economy, OTA-BA-494 Washington, DC U S Government Printing Office, October 1991)

Companies are presently divulging little infor-mation about the functional properties, mechani-cal characteristics, degradation times, and finaldegradation products of these polymers. Ferruzzi,the parent company of Montedison, has devel-oped a thermoplastic mixture of starch and ahydrocarbon in which the starch constitutesbetween 40 and 70 percent of the total weight.The hydrocarbon is described as a hydrophiliccarbon-hydrogen-oxy gen polymer with a molecu-lar weight low enough to accelerate degradation,but high enough to maintain the strength of thealloy. The company claims that the materialbehaves like polyethylene in its processing char-acteristics, but that the starch content reduces thetensile strength. The company contends that a70-percent starch mixture takes about 3 weeks todegrade, but it does not provide details of thedegradation conditions.

15 The starch-hydrocar-

bon blend is being used in packaging and diaperlinings.

Battelle, an international research institutebased in Switzerland, has also developed astarch-based technology that is able to incorpo-rate up to 90 percent starch in its plastic. A t

present, however, there is likely to be limitedapplication for this technology because of thepolymer’s susceptibility to moisture. Battelle hasrecently announced a plan to use vegetableoil-based polymers to overcome the moistureproblem. Warner-Lambert of the United Stateshas been marketing its NOVON starch-basedmaterials (40- to 98-percent starch content) inEurope since 1991, with sales in the millions ofpounds (see chapter 2). NOVON polymers areamenable to different plastic processing methods,including injection molding and film extrusion.

The entrance of companies making microbiallyderived products will also have an effect on thedegradable polymer market. One company, ZenecaBio Products (formerly ICI Biological Products,United Kingdom), has developed a microbiallyderived polymer with excellent degradation char-acteristics (chapter 2). The polymer, calledBIOPOL, is produced through the bacterial fermentat-ion of glucose and propionic acid.16 The poly-mers derived from the fermentation process arelinear polyesters that are true thermoplastics.Zeneca will have a production capacity of around10 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 Polymmformulation does not biodegrade at any significant rate. Distintegration of polyethylene-starch blends is not the same as biodegradation. Thebiodegradability of a particular material is determined by a set of complex factors such as material shape and surface-to-volume ratio, as wellas environmental conditions such as nutrient concentration, bacterial-fimgi inoculation pH, moisture level, and temperature. Any or all of thesefactors may vary from location to location.

16 Glucose is derived from a@cultura] feedstocks such as sugar beets and cer~l crops, while propionic acid can be produced from petroleum

derivatives or by fermentation of wood pulp waste.


use of BIOPOL resin was in 1990, as consumerpackaging. It has since entered other markets inEurope and Japan. The material is being targetedfor use in moldings, films, and paper coatings forboth rigid and flexible packaging, as well as avariety of specialty applications.17 Some manu-facturers are prepared to pay a premium price forBIOPOL because they believe that they will beable to market this product as an ‘ ‘environmen-tally friendly” material. It currently sells forapproximately $8 to 9 per pound, but Zenecabelieves that with economies of scale in manufac-turing, the price can be brought to around $4 apound.

Other companies that are conducting researchinto microbial-based and agricultural-based poly-mers are Boehringer Ingelheim KG, Ems-ChemieAG, BASF, and Schering of Germany; Petro-chemie Danubia of Austria; Montedison of Italy;and Tubize Plastics SA of Belgium. Some prod-ucts are available now, whereas others are in theresearch stage and are not likely to enter themarket until 1995. Table 3-2 summarizes theactivities of firms currently developing or market-ing next-generation biopolymers. Many of thesecompanies have demonstrated considerable abil-ity in incorporating synthetic processes intosurrogate organisms and in improving their effi-ciency of production. European biotechnologyfirms will undoubtedly prove to be formidablecompetitors as markets for genetically engineeredpolymers begin to expand.

BIOMEDICAL MATERIALSOne industry survey estimates that the total

European market for degradable biomedical ma-terials will rise from $650 million in 1990 to$1.17 billion in 1995; this represents an averageannual growth rate of 12.5 percent.18 There arethree principal market segments for biopolymers

in Europe: wound management products, drugdelivery systems (DDS), and orthopedic repairproducts. Each market is discussed in turn.

Wound Management: Absorbable wound clo-sure products have represented a sizable portionof the European biomedical market for more than15 years. The market size for wound managementproducts is estimated to grow at an annual rate of8.5 percent from $600 million in 1990 to $900million in 1995.19 This segment represented 100percent of the total biomedical materials marketin 1988, but will decrease to about 75 percent ofthe total market in 1995 as DDS and orthopedicrepair product markets expand. The main poly-mers used in this market are polylact ic-polyglycolic acid and related derivatives (seechapter 2).

The primary absorbable products in this marketsegment are sutures, ligation clips, and to a lesserextent, staples and wound meshes. Biodegradablepolymers have been used in surgery for manyyears. Wound closure products (absorbable su-tures) were introduced more than 20 years ago.The primary advantages of biopolymer suturesover catgut sutures are that they have a morepredictable rate of absorption and produce lessinflammation around wound sites. Two Americanfins, Ethicon and Davis& Geck, monopolize theEuropean market for these products. Absorbableligation clips and staples are also used duringsurgery and trauma care. In addition, biodegrada-ble wound closure polymers are being used forother surgical applications, such as tissue andbone adhesives. Companies in the bioabsorbablesurgical device market are rapidly expanding therange of applications for their polymer products.The introduction of vascular support meshes (forblood vessel regeneration) and other forms ofwound dressing products is envisioned for thefuture. 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 Commentsapplication entry date

Zeneca BioProducts(formerly ICI)

BASF

Schering

BoehringerIngelheim KG

Tubize PlasticsSA

Ferruzzi(Montedison)

PetrochemieDanubia

Battelle

Warner-Lambert

UnitedKingdom

Germany

Germany

Germany

Belgium

Italy

Austria

Switzerland

United States

BIOPOL (microbialpolyester)

Microbial- andagricultural-based polymers

Same as above

Polylactidepolymers

BIOCELLAT(celluloseacetate)

Agriculturalpolymers

Microbial polymers

Vegetable oil-based polymers;starch-basedpolymers

NOVON starch-based polymers(injectionmolding andvarious filmgrades)

Rigid andflexiblepackaging:films,moldings,papercoatings

Packaging

Packaging

Packaging,medicaldevices

Packaging

Packaging

Packaging

Packaging

Multiple usestructuralmaterials

Now

1995

1995Now

Now

1995

1995

Unknown

Now

1990 pilotplant InEngland;assessingfullproductionplant

In R&D stage

In R&D stage

In R&D stage

In R&D stage

Working withGermanindustrialpartners

100-million-pound U.Sproductionfacilityopened in1992


Drug Delivery Systems: For many years themajor focus of drug research has been on the

synthesis or discovery of new drugs. Althoughthis continues to be important, increasing empha-sis has been placed on the development of noveldrug delivery systems. These systems first en-tered the European market in 1989; the totalEuropean market value for DDS in 1995 isestimated to be $250 million.

21 The principal

materials being used for drug matrices in Europeare copolymers of polylactic acid (PLA) andpolyglycolic acid (PGA). The use of biopolymer

materials for drug delivery can minimize tissuereaction and allow drugs to be administered innonconventional ways.

The use of biopolymers in these formulationshas thus far been restricted to a narrow set ofapplications. There are several European compa-nies developing products for this market, prod-ucts that are technically comparable to thosemade by U.S. firms. Drug formulations incorpo-rating polymer DDS are currently undergoingregistration and are likely to make an impact onthe 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 notpossible to obtain separate estimates for the delivery system (BioInforrnation Associates, op. cit., footnote 18).


The major area of application for these novel

sustained-release systems is in the treatment ofcancers and diseases of the elderly. Some promis-ing cancer treatment drugs are peptides or pro-teins, which are unsuitable for oral administra-tion. 22 Similarly, products developed from geneticengineering may be toxic and thus may requirenonconventional approaches for administration.Sustained delivery of a drug close to the site ofaction from an implanted or injected depot meansthat much smaller amounts of the drug need beused, thus reducing the possible side effects.23 Inthe treatment of hormone disorders and geriatricdiseases, biopolymer delivery systems allowdrugs to be administered occasionally (evenannually in some presentations). More impor-tantly, these systems ensure patient compliance,which is often a problem for the elderly. Many ofthe drugs most suitable for presentation in acontrolled fashion are for geriatric illnesses suchas cancer and Parkinson’s disease. It is in thesemarkets that DDS will likely have the greatestimpact.

European companies have an important strate-gic interest in DDS and have been instrumental indeveloping biopolymer technologies. The drugcompanies view biopolymer-based drug deliveryas an important technological advance, because itcan be applied to drugs that cannot be adminis-tered by conventional routes. Many companies

also view this technology as an important tool forcircumventing price restrictions that are beingapplied by European governments. Biopolymer-based drug delivery can offer important costsavings over conventional methods (e.g., injec-tion) of drug administration.

The following European companies are cur-rently developing products for the DDS market:Sanofi (France), Ciba Geigy (Switzerland), Cap-sugel 24 (Switzerland), Zeneca Bio Products (UnitedKingdom), Beam Tech (United Kingdom), andInnovative Biosciences (United Kingdom). Zenecais hoping to develop DDS applications for itsBIOPOL biopolymer discussed earlier. The othercompanies listed here would not divulge theproducts they are developing for this market, butdid indicate strong interest in biopolymer drugdelivery systems.

Orthopedic Repair Products: Biopolymer or-thopedic repair products were expected to enterthe biomedical market in 1992, with the introduc-tion of absorbable pins and fixation devices fromboth Ethicon and Davis & Geck. The majority ofbiopolymers currently used for these applicationsare based on polyglycolide and polylactide poly-mers, with the latter being the most frequentlyused materials. There are a large number of lacticacid suppliers in Europe who provide this biolog-ical 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 hgsbefore they can be absorbed into the bloodstream. By encasing protein drugs in biopolymer materials such as polylactide, some nxearchersare 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 andDeliver: 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 ~stictdrug activity to the site of the tumor and therefore protect normal tissue from exposure to toxicity. David ManyalG Adheron Corp., personalcommunication, Aug. 25, 1993.

u Capsugel is a division of warner.~bert. Capsugel is producing starch-based capsules made from NOvON polymers. one Of tie Oldesttherapeutic applications of biopolymers has been in the area of pharmaceutical capsules. Gelatin (a protein polymer) capsules have been inwidespread use for many years. Gelatin and starch-based capsules are commonly used to deliver aspirin and antibiotics. The worldwide marketfor 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. CdaColloids markets lactic acid produced by a fermentation process. The other major lhropean supplier of fermented lactic acid is C.C.A. Biochemin the Netherlands. Chemically synthesized lactic acid is marketed by Sterling Chemicals and Musachino Company of Japan. The price of thisform of lactic acid is 20 percent higher than that of the fermented product.

Chapter 3-Biopolymer

to the required pharmaceutical standard (80 to 88percent purity).

It is estimated that by 1995, the Europeanmarket for biopolymer-based orthopedic repairproducts will reach $20 million.26 Orthopedicrepair products will probably represent only about2 percent of the total market for medical bio-materials in 1995. Absorbable polyglycolidefixation devices for the treatment of porous bonefractures, joint reconstruction, and surgical altera-tion and realignment of bones are currentlyundergoing licensing. Fixation devices for thetreatment of malleolar (leg and ankle) fracturesare also undergoing licensing and should beavailable within 1 to 2 years. These devices aremanufactured in Finland and are already used insome European countries. Orthopedic plates andscrews are also likely to be developed within thenext few years. A more speculative application isthe use of biopolymer materials as scaffolding inthe formation of new cartilage in the body.27 Withthe advantage of biocompatibility, biopolymersare likely to be used in many more novelorthopedic applications.

JAPANSince the end of World War II, the Japanese

Government has played an active role in encour-aging the development of new technologies. Thetargeting of specific technologies for specialgovernment support has been part of a broadereffort to influence the level and composition ofJapan’s national output. The central componentsof this national industrial policy have includedfinancial aid, government sponsorship of pricing,investment, R&D cartels, and protection of thedomestic market.28 These initiatives have playedan important role in enhancing the competitive-

Research and Development in Europe and Japan 59

ness of the automobile, steel, and semiconductorindustries, In recent years, however, the efficacyof industrial targeting has been questioned both inJapan and elsewhere. While industrial policy hasled to successes in some industries, there havebeen failures in others.29 Nevertheless, it is stillsignificant when the Japanese Government notonly targets a sector, but also funds the initialresearch to stimulate its development. Two Japa-nese ministries, the Ministry of InternationalTrade and Industry (MITI) and the Ministry ofHealth and Welfare (MHW), have committedfunds and organizational support to the develop-ment of biologically derived materials. The dif-ferent Japanese biopolymer programs are de-scribed below.

Government Biopolymer ProgramsMITI is actively sponsoring and coordinating

biopolymer research among Japanese companies,academic researchers, and scientific institutes. Amajor MITI initiative was the formation of theJapanese BioIndustry Association (JBA) in 1982.30

A nonprofit organization designed to promotebiotechnology and the bioprocessing industry,JBA serves as the principal coordinating agencyfor biopolymer activity in Japan. JBA’s mainfunction is to disseminate basic research informa-tion across industry, academia, and government.Its other roles are to define new directions forcooperative R&D programs, to assist in theformulation of product standards, and in somecases, to undertake biotechnology research proj-ects directly. JBA is sponsoring a variety ofdevelopment activities in the biopolymer materi-als area.

The most notable of these programs is an8-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).


the development of biodegradable polymers frommicrobial organisms. 31 This research programwill concentrate on the following areas: develop-ing probes for use in gene cloning; developingmass culture technology; improving natural poly-mer materials; developing technologies for mo-lecular design and accurate polymerization ofsynthetic polymers; and testing and evaluationmethods for biodegradable materials.

At the National Institute of Biosciences andHuman Technology, a MITI laboratory inTsukuba, researchers are working on biopolymerblends based on polyhydroxyalkanoates (PHAs)(microbial polyesters), starch, and polycaprolac-tone. 32 At MITI’s Shikoku Laboratories in Taka-matsu, biodegradable materials based on lami-nates of chitosan and cellulose are being investigated,and at the MITI research facility in Osaka,research on condensation polymers includingpolyesters and polyamides is being carried out.33

In addition to research at its own facilities, thegovernment is sponsoring biopolymer research atseveral universities.34 MITI has also providedabout 5 billion ($45 million) in funding to amulticompany venture in bacterial cellulose tech-nology. 35

Another program that could result in bio-polymer advances is the Protein EngineeringResearch Institute (PERI) project. PERI, a con-sortium of 14 chemical, pharmaceutical, and foodcompanies, will receive $150 million in govern-ment funding over a 10-year period. The focus ofPERI’s work is to develop a fundamental under-

standing of protein structure-function relation-ships, and thereby establish a competitive edge inprotein engineering.

36 protein research is impor-

tant to many areas of biotechnology, and couldvery well lead to new biopolymers with uniquephysical and functional properties, as well asbasic improvements in the processes used to makebiopolymers.

In addition to government-sponsored activi-ties, several companies have formed an associa-tion called the Biodegradable Plastics Society(BPS) to help coordinate their research efforts.Activities of BPS include: determining the feasi-bility of making commodity plastics from biode-gradable polymers; developing evaluation meth-ods for biodegradable plastics; surveying markettrends in plastics; and exchanging informationwith domestic and foreign organizations. Compa-nies involved in this research are the moretraditional chemical and plastics companies. Abouthalf of the 73 companies in BPS have alsoexpressed considerable interest in the medicalapplications of biopolymers.37

The relationships among the various Japanesebiopolymer research organizations are outlined infigure 3-2. The multifarious biopolymer researchactivities of Japanese Government and industryare designed to create new commercial opportuni-ties in plastics and medical materials. MITI’ssponsorship of biopolymer research is one indica-tor of the potential importance of this field. It ispart of MITI’s overall strategy to create a new,high-growth industry in biologically derived chem-

31 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, ShimizuConstruction, Nikki, Mitsubishi Paper, Nikkiso, and Nakarnori Vinegar. The venture is called Biopolymer Research Co., Ltd, and its principalfocus 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 (WMedKingdom) 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

aResearchinstitutes

X

/

/

?

/Consultation and

research

a/B,,,,;,d ➤ ;

n ElCOMPANIESMITI 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 theworld in microbial production of amino acids38

and industrial enzymes, and thus is well posi-tioned to take advantage of biopolymer advancesthat involve fermentation technology.

The Ministry of Health and Welfare is alsosupporting biopolymer research. MHW is encour-aging private sector cooperation in the drugdelivery systems field. Seven major pharmaceuti-cal companies have joined together to sponsorDDS research. With support from MHW, theDrug Delivery Systems Institute has been capital-ized at 1OO million ($900,000) and will focus ondeveloping glycocarrier (sugars) drug deliveryvehicles for central nervous system, bone, andkidney drugs. Although this amount is relativelysmall, the combined funding levels of programssponsored by MITI and MHW make it clear thatJapan is placing considerable emphasis on devel-oping biomedical applications for biopolymers.Table 3-3 summarizes the work being performedat Japanese research institutions on biopolymersthat could be used in the biomedical sector.

These collaborative programs are proceedingin earnest, although most companies interviewed

in Japan did not think that the commercialpotential for medical biomaterials would developfully until after 1995. If current R&D efforts reachfruition, biopolymers could make significantinroads into the biomedical market by the end ofthe decade. Japan’s multiyear research invest-ment will likely result in both product innovationsand a comprehensive review protocol againstwhich biodegradable medical products can betested.

Private Sector Activity

DEGRADABLE POLYMERSIn the area of degradable polymer research,

Japanese companies are focusing primarily on thedevelopment of materials derived completelyfrom microorganisms or agricultural feedstocks.The Japanese BioIndustry Association is theprincipal organization responsible for coordinat-ing research in this area. MITI is also workingwith various research institutes and companies,including the Biodegradable Plastics Society, toestablish evaluation methods, and to set upproduct specifications and standards for biude-

38 ~s commercial do minance may not last, because Archer Daniels Midland of the United States has reeently entered this field and in only1 to 2 years has captured 30 percent of the animal feed market for the amino acid lysine.

- -


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 ResearchInstitute

Kansai University

Japan Kokai Tokyo Koho

Natural polyesters (i e., Sutures; orthopedic repair Polymer similar toPHAs)

Polyglycolic acid

Gelatin (protein)

Leuclne-glutamineblomembrane(polyamino acids)

Lactic acid-maleic acidcopolymer

Copolymer amino acid(Ieuclne-benzylglutamate)

Sutures; orthopedic repair

Drug carrier to deliverimmunomodulators totissue cells

Drug delivery

Slow release earners foranticancer drugs suchas 5-fluorouracil

Artificial blood vessels

PHBV (BIOPOL);commercializationexpected in 2 to 3years

Cells ingest gelatin

Membrane reacts toacid-base changesby altering structureand admits or rejectsdifferent substances

Injected intobloodstream;polymer is absorbedby cancer cells andreleases drugs as itdegrades

Patented in 1986

SOURCE Bioinformation Associates Boston, MA

gradable products. This comprehensive programis being coordinated through JBA.

In addition to supporting biopolymer researchin the areas of recombinant DNA technology andlarge-scale bioprocessing, JBA has completed afeasibility study evaluating the potential of biode-gradable polymers as commodity materials. It islikely that biopolymer development efforts willreceive additional impetus as a result of thisstudy, with Japanese companies exploring a widerange of possible biopolymer applications. Apartial listing of companies participating in BPSis provided in table 3-4.

Potential producers of next-generation bio-polymer materials in Japan are listed in table 3-5.Scientists at the Tokyo Institute of Technologyhave produced a versatile polyester product frombacteria .39 Thi s ‘‘bioplastic’ is similar to thedegradable material BIOPOL produced by Zeneca

Bio Products in Europe. A copolymer of 3-hydroxybutyrate and 4-hydroxybutyrate (HB) hasbeen extracted and fermented from Alcaligeneseutrophus under starvation conditions (chapter 2).This polymer is thought to have improved func-tional properties over BIOPOL, since it can bemade more elastic by altering the ratio of thecopolymers, Researchers expect this polymermaterial to be commercialized (probably byMitsubishi Kasei) in 3 to 4 years; it will be

targeted first at the mulch film, marine (nets andlines), and medical markets.40

Other companies such as Hayashibara Bio-chemical are interested in expanding the applica-tions for their microbial polysaccharides (pullu-lans) into areas such as packaging (chapter 2). Thecompany is already producing a pullulan deriva-tive 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, amino-acld producer

Synthetic resin producer

Large rubber manufacturer

Plastic containers

Major producer of printingInk

Printing company

Major chemical company

Petrochemicals

Steelmaker

Leading fine chemicalmaker

Major chemical company

Largest all-aroundchemical company,mainline carbochemicals

Large petrochemicalenterprise

Mitsui Toatsu Chemicals

Nippon Kayaku

Nippon Shokubai KagakkuKogyo Co.

Sekisui Chemical Co.

Sekisui Plastics Co

Shyowa Denko KK

Sumitomo Bakelite

Sumitomo Chemical Co.

Sumitomo Metal Industries

Toagosei ChemicalIndustry Co.

Toyo Ink Manufacturing

Ube Industries

Unitika Ltd

Chemicals,fertilizers

Pharmaceuticals,agrichemicals,special resins

Petrochemicals,industrialchemicals

Plastics processor

Largest producerof foam plastics

Petrochemicals,industrialchemicals

Integratedprocessor ofsynthetic resins

Fine chemicals,agrlchemicals

Steelmaker

Plastics

Printing inkmaterials

Petrochemicals,cement

Textiles, plastics

SOURCE Biolnformation Associates Boston, MA

food. The biodegradability of pullulan makes it anextremely attractive material. Japanese compa-nies have developed sophisticated and advancedfermentation technologies that are ideally suitedfor developing biodegradable polymers frommicrobial metabolizes and polymer-producingmicroorganisms.

41 Thus, Japanesee compan ie s cou ld

emerge as very strong competitors in the area ofmicrobial biopolymers.

The British company Zeneca Bio Products,which has a subsidiary in Japan, is also a memberof BPS. Zeneca is supplying 30 to 40 Japanese

companies with research quanti t ies of i tsBIOPOL polymer. Zeneca successfully intro-duced BIOPOL cosmetic bottles in Europe in1990 and recently entered the Japanese marketwith another product—biodegradable golf tees.

BIOMEDICAL MATERIALSMost Japanese companies do not believe that

the medical biomaterials market will take off untilafter 1995. Since the use of biopolymers fortherapeutic purposes is still in the exploratorystage, 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~tionplants to produce new biological compounds (Norman Oblon and Karen Shannon, Oblon, Spivti McClelland, Maier, & Neustadt, P. C.,personal communication, Aug. 12, 1993).


Table 3-5—Current and Potential Suppliers of Next Generation Degradable Polymers in Japan

Company Country Product/Status Potential Likely Commentsapplication entry date

Mitsubishi Kaseiand TokyoInstitute ofTechnology

HayashibaraBiochemical

Kureha Chemical

Kyowa HakkoKogyo Co. Ltd

Kawasaki Steel

Showa Denko K.K

Showa HighPolymers, Ltd.

Zeneca BioProducts

Japan

Japan

Japan

Japan

Japan

Japan

Japan

United Kingdom

Microbial polyesterspoly(3HB)-(4HB)copolymer

Microbial poly-saccharides (e.g.,pullulan)

Microbial-basedpolymers




Packaging

Pullulanpackaging,edible/biodegradablefood wrap

Disposablepackaging

Packaging

Packaging

Mulch film;bags

BIONELLE—synthetic Packaging;“biodegradable” structuralpolyester materials

BIOPOL Cosmeticbottles,otherpackagingmaterials

1994-96

1993

Not known

Not known

Not known

1995

1994

Now

Can biodegrade in 4 to 6 weeks;similar to Zeneca’s PHBVcopolymer

Product available now

Assessing governmentregulations

Likely entrant

Working with establishedbiotechnologycompany—Clef-to researchand develop biodegradablepolymers

Assessing various polymertechnologies

7-million-pound manufacturingfacility in 1994

Pilot plant in England; asessingfull production plant


materials market in Japan will evolve. Table 3-6provides information on companies that eitherhave a product on the market or are known to havea product nearing introduction. Applications in-clude artificial skin, sutures, orthopedic implants,and drug delivery vehicles. Many products areawaiting approval by the Ministry of Health andWelfare.

Many companies that are members of theBiodegradable Plastics Society are also expectedto develop products for the biomedical market.However, it does not appear that these firms haveclearly defined product strategies. Some of thecompanies listed in table 3-6 are traditional

chemical companies that have expressed only ageneral interest in moving into the pharmaceuti-cal, biochemical, and biomaterials sectors. Al-though it is unlikely that any of these companieswill enter the biomaterials market before 1995,they may be presented with significant opportuni-ties as the market develops over the long term.

Japanese Industrial Policy RevisitedMITI’s sponsorship of biopolymer develop-

ment has raised concerns among some U.S.researchers that leadership in yet another promis-ing high-technology field might be ceded to theJapanese. 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 ToritsuUniversity

Chisso

Genzyme Japan

Kyowa Hakko Kyogo Co,

QP

Riken Vitamen

Seikagaku Kogyo

Shiseido Co Ltd

Yakult Honsha Co.

Mitsui Toatsu Chemicals

Koken and OkayamaUniversity

Johnson and JohnsonOrthopedic Co

Unitika

Takeda Chemical IndustriesLtd

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 andbotanical

Chemicals, amino acids

Cosmetics

Pharmaceuticals, cosmetics

Chemicals, fertilizers

Medical equipment

Healthcare products

Textiles

Pharmaceuticals (drugdelivery)

Pharmaceuticals, medicalequipment

Chemical preparations

Food Processor, amino acids

Leading manufacturer ofsynthetic fibers

Pharmaceuticals: circulatoryand respiratory

Pharmaceuticals” nervoussystem

Pharmaceuticals” antibiotics;foods

Pharmaceuticals antibiotics

Pharmaceuticals circulatoryand 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



Wound healing

Wound healing

Wound healing

Wound healing

Wound healing

Sutures

Membrane to prevent adhesionafter surgery

Not yet commercial ;fixation plate,pins, etc.

WiII be used for orthopedicsurgery

Joint venture with AbbottLaboratories (United States)

Phase Ill trials for anticancerdrug

DDS for osteoplastic factors

Member of Drug DeliveryInstitute (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). Thecant boost in its efforts to develop biopolymer 8-year MITI biopolymer program will undoubt-products. Indeed, with their expertise in fermenta- edly lend momentum to initial Japanese commer-tion technology, Japanese companies are in an cialization efforts.excellent position to exploit the market for some

. . . . .

66 I Biopolymers:

However, over


the long term, the concertedattempt of the Japanese Government to promotebiotechnology, and biopolymer applications inparticular, could be impeded by a number ofstructural and institutional factors. In contrast tothe United States, Japan has a weak basic researchbase in biotechnology, which has led manyJapanese firms to send their personnel abroad fortraining and to set up foreign research facilities.42

In addition, Japan’s pharmaceutical industry haslong been sheltered from international competi-tion and is only now beginning to developstate-of-the-art skills in drug development, test-ing, and marketing.

43 This could inhibit the entry

of Japanese companies into the lucrative globalbiomedical market. Because Japan is not afood-exporting country, its agricultural research

enterprise is narrowly focused, and it may not beable to compete with the biopolymer programs oflarge U.S. and European agricultural firms.44

Finally, the maturation of the Japanese economyhas reduced the relative importance of government-sponsored R&D programs. Many segments ofJapanese industry have become so successful thatthey are no longer willing to be guided intotargeted investments. MITI, for example, recentlyabandoned a bioprocessing project because of thereluctance of industry to cooperate.45 Neverthe-less, the commitment of Japanese industry andgovernment to biopolymer R&D is considerable,and it is therefore likely that in certain segmentsof the biopolymer field, Japanese companies willbe 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.

—

BiopolymerResearch andDevelopment

I

in theUnited States 4

I n recent years, there has been a steady expansion ofbiopolymer research activities in both the private and thepublic sectors. Concerns about the environmental impactsof petroleum-based polymers have led many companies to

investigate several different classes of biologically derivedpolymer materials. Advances in chemistry and the biologicalsciences have also stimulated research efforts in the biopolymerarea. As illustrated in chapter 2, the potential applications ofbiopolymer materials are extremely diverse, ranging frompackaging to food additives and industrial chemicals to pharmac-euticals. Novel biopolymer materials are being investigated byGovernment and university researchers, large agricultural andchemical firms, and small biotechnology enterprises. As inEurope and Japan, U.S. biopolymer technology is, for the mostpart, still in the early stages of development, and substantialcommodity markets for these materials are not likely to appearfor several years.

ACTIVITIES OF THE FEDERAL GOVERNMENTOne of the principal difficulties in describing the biopolymer

research efforts of the U.S. Government is that biopolymerscience is inherently interdisciplinary in nature. Broadly defined,biopolymer research covers a number of different areas, includ-ing materials science, chemistry, microbiology, biophysics, plantbiology, and structural biology. Thus, basic research in any ofthese disciplines can accelerate advances in biopolymer technol-ogy. Indeed, in many cases, biopolymer researchers have beenable to take advantage of innovations that have emerged from thebroad-based U.S. programs in biotechnology (e.g., recombinantDNA research).

67

. . . .

68 I Biopolymers:

.-


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, metabohc engmeenng (recombmant DNA research as It relates toIndustrial mlcroorganlsms), bloreactor design, blocatalysw or enzyme englneerlng, separation and purificationtechnology, process design, and process monitoring and controlbThe 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 Sciencesand 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 preem-inent in biotechnology, with strong researchprograms in biomedicine and agriculture.1 In FY1993, the Federal Government is spending about$4 billion to support research and development(R&D) in biotechnology-related areas.2 In rela-tive and absolute terms, the United States sup-ports more research relevant to biotechnologythan any other country. 3 However, only about 3percent ($124 million) of the total 1993 biotech-nology budget is devoted to biologically derivedcompounds and industrial bioprocessing research4

(see table 4-l). And a only a small fraction of that3 percent is targeted specifically to biopolymerdevelopment. A number of different Governmentagencies sponsor biopolymer research:

the Department of Defense (DOD),National Science Foundation (NSF),the Department of Health and Human Services(DHHS) and specifically the National Institutesof Health (NIH),the Department of Energy (DOE),the Department of Agriculture (USDA),the Department of Commerce (DOC),the Department of the Interior (DOI), andthe National Aeronautics and Space Administ-ration

The following sections describe those researchactivities that relate directly to the production ofbiopolymer materials or to the development ofnew 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 the21st 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 overfiscal 1992 levels (Federal Coordinating Council for Science, Engineering, and Technology, op. cit., foofnote 2, p. 42).

Chapter 4--B copolymer

Department of DefenseThe 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 ResearchOffice (Research Triangle Park, North Carolina).

OFFICE OF NAVAL RESEARCH BIOPOLYMERICMATERIALS PROGRAM

The ONR Biopolymers Materials Program isinvestigating biologically derived materials forpossible use in marine environments. There isparticular interest in materials that prevent bio-fouling and biocorrosion. Among the materialsbeing studied are thermoplastics, coatings, adhe-sives, and elastomers. One aim of this research isto achieve a greater understanding of the relation-ship between the microscopic structure of poly-mers and their macroscopic physical properties,such as elasticity, adhesion, piezoelectricity, non-linear optical properties, and tensile strength. Theprogram is also attempting to develop a funda-mental understanding of molecular assemblyprocesses. Many of the projects involve the studyof novel protein polymers (see chapter 2). Of the19 ongoing projects, 17 are being carried out inuniversities and 2 are in-house. The total annuallevel of funding is around $1.8 millions

U.S. ARMY PROGRAMS RELATED TOBIOPOLYMER SCIENCE AND TECHNOLOGY

1. U.S. Army Natick, RD&E Center: The U.S.Army RD&E Center is exploring a variety ofbiologically derived materials, as well as theprocessing mechanisms of biological systems.The ability of biological systems to produce a vastrange of materials under mild processing condi-tions (i.e., low temperature and pressure), withoutcreating toxic byproducts, could lead to new,environmentally sensitive manufacturing meth-

Research and Development in the United States 69

ods. The program has three principal areas offocus: advanced bimolecular materials, biode-gradable polymers, and “intelligent” materials.In-house research is funded at about $1.5 million,with additional supplemental funds provided forspecial programs such as a joint effort with theUSDA on biodegradable polymers for packaging.A significant percentage of the funding supportsuniversity projects. Cooperative programs arealso in place with a number of industrial partners.6

Research on bimolecular materials is con-cerned primarily with protein-based biopolymers,Work in this area includes isolation and character-ization of natural structural proteins (e.g., silk),cloning and expression of genes encoding thesematerials, molecular modeling to understandstructure-function relationships, elucidation ofthe processes involved in converting water-soluble polymers to water-insoluble materials,and formation of films and fibers.

The biodegradable polymer program is focus-ing on naturally occurring biodegradable poly-mers, including polysaccharides, polyesters, andproteins. Research covers numerous activities:fermentation production and plant sources, purifi-cation, chemical modification of natural poly-mers, blending, processing into blown films,injection molding, characterization of liquid cyrstal-line phases, determination of biodegradation ki-netics, evaluation of toxicity of materials inmarine and soil environments, consumer accep-tance studies, and product evaluation.7 Theseactivities are directed toward the development ofbiodegradable products for Army and Navy use.

Research in the area of intelligent materialsinvolves investigation of the interfaces betweenbiological materials and synthetic polymers. Thiswork is directed toward the development ofmaterials that sense and react to changes in theiroperating environment (e.g., materials that stiffenin 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.


under different temperature and pressure condi-tions). Specific areas of investigation include thestudy of energy transduction from proteins tosynthetic polymers, thin-film assemblies, biosen-sors, and nonlinear optical polymers generatedthrough biocatalytic processes.8

2. Army Research Office: The Army ResearchOffice is sponsoring biopolymer research inseveral different areas. Particular emphasis isbeing placed on understanding the mechanisms ofcomplex biopolymeric function, the macromolec-ular structures supporting such function, and thebiosynthetic pathways that lead to those struc-tures. Current efforts involve the use of moleculargenetics, protein engineering, and physicochemicalcharacterization to clarify how higher-order struc-ture is achieved in polymer materials, and howsuch structural features might be genetically orchemically manipulated for different applica-tions. The program isannually, with mostuniversity research.9

National Science

funded at about $1 millionof the funds supporting

FoundationThe National Science Foundation has many

programs that directly or indirectly support bio-polymer research. NSF is spending more than $30million annually on bioprocessing and bioconver-sion research, and about $12 million on bimolecu-lar materials research.10 Although most of thisfunding is not directed specifically toward bio-polymer development, these programs are likelyto have many positive spillover effects. For

example, NSF is supporting work in the areas ofgene transfer, macromolecular structure and func-tion, metabolic pathways, molecular self-assembly, biomimetic chemistry (processes thatutilize or mimic biological systems), gels andmicroemulsions, and material properties of mem-branes, surfaces, and interfaces.

There are currently about a dozen specificprojects investigating the properties of proteinpolymers and various methods for their produc-tion. This includes a pioneering project to pro-duce synthetic polyamino acids by genetic tech-niques.

11 Funding for these projects amount to

less than $1 million. In addition, NSF hassponsored studies of lignin copolymers, whichpotentially could be used for a variety of pur-poses, including degradable plastics.12 Anotherarea of emphasis is the field of tissue engineering,where biopolymer materials are being evaluatedfor their restorative properties and as potentialsubstitutes for damaged tissue.13

Department of AgricultureUSDA supports a variety of biotechnology

programs that bear on biopolymer research anddevelopment. Projects include gene cloning inmicroorganisms, nucleic acid hybridization, bio-logical and biochemical synthesis of nucleic acidsand proteins, improving the quality of woodyplants (for the extraction of cellulose), andmapping genes of agronomic importance. Severalprograms 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, andTechnology, 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. Theprogram 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 ofthe major projects involves the use of cornstarchfor degradable plastics. Proposed funding forbiodegradable materials research in FY 1993 is

$4.4 million. Another program, Advanced Ma-terials from Renewable Resources (total N 1993funding, $10 million), will also direct resources tothe development of biopolymers.15

In addition, the Cooperative State ResearchService (CSRS) Office of Agricultural Materialsand the Alternative Agriculture Research andCommercialization Center work with academiaand industry in the development and commercial-ization of new industrial uses of crops, includingbiopolymers. 16

National Institutes of HealthThe National Institutes of Health has played a

central role in advancing the fundamental under-standing of biological processes at the molecularlevel. NIH supports basic biotechnology researchin areas such as recombinant DNA techniques,gene mapping, and protein engineering. It alsosupports a broad range of research that supportsbiotechnology: genetics, cellular and molecularbiology, biological chemistry, biophysics, immu-nology, virology, macromolecular structure, andpharmacology.

17 Funding for NIH biotechnology

and related programs, in FY 1993, is approxi-mately $3 billion .18 As stated earlier, only a smallpercentage of these resources is allocated specifi-cally to biopolymer research. The principal areas

of biopolymer work are in drug delivery systemswhere biocompatible polymers are used in sustained-release applications, and in biohybrid deviceswhere polymer materials are used as implants,prosthetic devices, and agents of tissue repair orregeneration. Because biopolymers have severalpotentially important applications in the biomedi-cal field, there have been proposals calling for adramatic increase in the level of NIH activity inthis area (see box 4-A).

Department of EnergyDOE has a large general effort in biotechnol-

ogy, including projects in mapping the humangenome and in structural biology. Research instructural biology is directed toward understand-ing the structure-function relationships of biolog-ical molecules and the synthesis of proteins. Anumber of different DOE programs are moredirectly involved with biopolymer research. TheNational Renewable Energy Laboratory is ex-ploring how cellulosic biomass can be convertedinto sugars that can then be fermented intoethanol .19 Enzymes are being used to break downcellulose polymers without attacking the productsugars that are subsequently fermented. OtherDOE programs are studying how biologicalfeedstocks can be used to create high-valuechemicals. Argonne National Laboratory, forexample, is investigating lactic acid-based de-gradable 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 similarto 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, personalcommunication, 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).


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 ofdeveloping specific recommendations for a national materials science and research agenda. Oneoutgrowth of these discussions was a detailed proposal calling for a national initiative in the area ofbiocompatible materials. The proposal identified several opportunities for health care cost reductionthrough the development of novel materials. For example, if an implantable artificial insulin deliverysystem could be designed, it is estimated that costs associated with the treatment of diabetes could bereduced by $2 to $4 billion annually. Since biomaterials research cuts across several differentdisciplines such as chemistry, microbiology, and materials science, many potentially innovativetechnologies may be overlooked by academia and the different Federal agencies. Consequently, theproposal calls for much greater coordination of Federal programs in the biomaterials area and adramatic increase in overall funding. This 10-year, $2.5 -billion program would be designed to greatlyexpand scientific understanding of the interaction between materials and biological systems, and toaccelerate biomedical commercialization efforts. The principal recommendations include the following:

●

●

●

●

●

The establishment of a new national institute of medical technology, within the National Instituteof Health (NIH), to act as a central coordinator and lead funding agency for biomaterialsresearch. The new institute would encourage interaction among medical clinicians, academicscientists, and industrial researchers.The establishment of several regional biomaterials research centers that would be funded at $10to $20 million each for 10 years. Total funding would be about $150 million per year. Suchcenters would be designed to promote interdisciplinary research and greater university-industrycooperation. 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 compatiblematerials, and nondestructive evaluation techniques.The creation within the National Science Foundation (NSF) of a biomaterials program, wherebiomaterials research is defined as “the study and knowledge of the interactions between livingand nonliving materials.” Funding levels for individual investigators would total $100 millionannually, and projects would be coordinated with t he institute of medical technology describedabove.The establishment of a national information center to serve as a clearinghouse for data on thephysical, surface, and biological properties of biomaterials. The center would also evaluate andcreate standard testing procedures for novel materials.The development of performance criteria for biomaterials to expedite the Food and DrugAdministration product approval process.

These recommendations were presented to the National Academy of Sciences and forwarded tothe White House Office of Science and Technology Policy (OSTP) in early 1991. In response, OSTPinitiated a cross-agency study that cataloged all Federal activity in the biomaterials area, andopportunities for greater coordination among Federal agencies were identified. In addition, funding forNIH and NSF biomaterials programs was increased slightly.

SOURCES: Materials Research Society, A /Vationa/ Agenda in hfateriak Science and Engineering: /rnp/ernar?fingthe MS&E Report, February 1991, Southeast Regional Conference on Materials Science and Engineering, FinaiReport, September 1990; E.P. Mueiier and S.A. Barenberg, “Biomateriais in an Emerging National MaterialsScience Agenda,” Materials Research ~u//etin, vol. XVI, No. 9, September 1991, pp. 86-87; Edward P. Mueller, Foodand Drug Administration, personai communication, Aug. 16, 1993.

Chapter 4-Biopolymer

Other AgenciesSeveral other Government research programs

pertain to biopolymers. NASA is investigatingnew separation processes for the purification ofbiological materials, and new fabrication meth-ods for biopolymer films and matrices. One majoreffort is in the area of protein crystal growth. Themicrogravity biotechnology program is utilizingthe space environment to gain a better under-standing of protein structure and formation.20

The Food and Drug Administration (FDA) hasa sizable biotechnology effort in order to dealwith the regulatory issues affecting geneticallyengineered pharmaceuticals and food products. Inaddition, the FDA is evaluating the use ofbiopolymers in medical devices. This research isconcerned principally with the degradation ofbiomaterials that are placed in the body.

Within the Department of Commerce, theNational Oceanic and Atmospheric Administra-tion (NOAA) is investigating polymer materialsproduced by marine organisms (e.g., musseladhesives and chitosan) that could have a varietyof commercial applications.

21 By studying howvarious organisms form polymeric films on sur-faces, NOAA researchers are also attempting todevelop methods of controlling biocorrosion andbiofouling. Another Commerce agency, the Na-tional Institute of Standards and Technology, isdeveloping new sensor technologies to measure

Research and Development in the United States 73

complexstudying

biochemical substances, and is alsoprotein structure and function.

PRIVATE SECTOR ACTIVITIESAs in Europe and Japan, American commercial

activity in biopolymers can be divided into twomajor market categories: degradable polymersthat can be used in lieu of traditional commodityplastics and materials that can be used forbiomedical applications.

DEGRADABLE POLYMERSWhen the frost materials containing biodegrad-

able additives were introduced in the late 1980s,controversy erupted as to whether they were trulydegradable. 22 The principal products involvedwere packaging materials and garbage bags. Mostof these goods were either withdrawn from themarket or no longer advertised as being biode-gradable. 23 These first-generation products weremade from oil-derived plastic resins such aspolyethylene that contained a low percentage (4to 6 percent) of starch.24 Although starch itselfreadily degrades, various studies indicate thateven under optimal conditions the starch compo-sition of these plastic-starch blends has to exceedabout 60 percent before significant materialbreakdown occurs. 25 Due to regulatory uncer-

tainty and the absence of clear standards forevaluating 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 intothe marketplace will undermine recycling efforts and, depending on the extent of their degradation, will exacerbate litter problems. In a previousstudy, the Office of Technology Assessment su~ested that a national municipal solid waste policy should be based on “the dual strategiesof 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 andbeverage ring carriers. Currently, only beverage carriers are made from E/CO; 27 StateS have passed legislation prohibiting the use ofnondegradable 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.


materials with low starch content has declineddramatically. The remaining market for thesematerials is limited primarily to compostablebags .26

While the Federal Trade Commission hasissued guidelines designed to prevent deceptiveenvironmental marketing claims, scientificallybased definitions and standards relating to de-gradability have yet to be formally established.27

Up to now, the process of creating environmentalmeasurement standards has proven to be anextremely difficult undertaking.28 A nonprofitprivate sector group, the American Society forTesting and Materials (ASTM), has developedsome standards for evaluating degradable materi-als in the laboratory .29 ASTM’s work has helpedto create a consensus on testing procedures forcertain categories of degradable materials (e.g.,photodegradable and compostable substances).Researchers at ASTM’s Institute for StandardsResearch are currently attempting to determinethe behavior of degradable polymeric materials inreal disposal systems and are correlating theseresults with ASTM laboratory methods .30 Thisresearch could lead to a better understanding of

how products degrade under different environ-mental conditions. Yet, even if more reliableinformation can be generated, consumer confi-dence in degradable products is not likely to berestored without the creation of coordinatedsystems of product disposal and waste manage-ment. If, for example, products are designed forcomporting, but end up being landfilled orincinerated, the design improvements are effec-tively nullified.31

Despite market and regulatory uncertainties,some companies are proceeding with the develop-ment and introduction of a new generation ofstarch-based products—materials that have astarch content ranging from 40 to nearly 100percent. 32 Agri-Tech Industries is developing a

material that is up to 50 percent starch by weight,and is targeting applications such as personalhygiene and disposable medical products.33 Warner-Lambert has recently opened a large productionfacility for its NOVON family of polymers—films that range from 40 to 98 percent starch byweight. Properties of these materials can be varieddepending on the specific types of starches andother biodegradable materials used. Early appli-

Z6 It is ~~ely tit compostable bags will provide a sustainable market for the partially degradable starch-ethylene blends. Current andproposed compost quality standards suggest that compost producers will be very concerned with the ultimate fate of materials accepted intotheir facilities. Several studies have demonstrated that plastic fragments, that do not degrade, have a negative impact on the productivity offarming soil.

27 See Feder~ Trade Cornmissio% ‘‘Guides for the Use of Environmental Marketing ClaimS,” July 1992. Congress has mandated the useof degradable materials for one product category: plastic ring carriers for bottles and cans. In the proposed rule for this law, EPA has set specificperformance 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 forDegradable 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 polymersare 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 derUniversity 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 bothtraditional chemical firms and agribusinesses, is promoting the use of materials derived from agricultural commodities and other renewableresources. The aims of the DPC are to “stimulate research and developmen~ coordinate efforts and communicate facts regarding degradableplastic 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 de-gradable golf tees, loose-fill packaging, compostbags, cutlery, pharmaceutical capsules, and agri-cultural mulch films.

NOVON materials are being targeted for mar-kets where the benefits of their biodegradabilitycan be clearly demonstrated. In the near termthese materials will most likely be limited tospecialized applications because their cost is twoto four times the price of commodity resins.Although these novel starch-based compoundsare not positioned to compete with commoditysynthetic polymers such as polystyrene, if pro-duction costs can be brought down, they mighteventually find a number of applications in thefood service, food packaging, personal healthcare, agricultural, and outdoor markets.

As highlighted in chapter 3, European compa-nies are also trying to develop a new generationof biopolymer plastics that will compete withAmerican products. Japanese companies haveessentially ignored starch-based materials and areconcentrating on materials derived principallyfrom microbial sources, whose development in-creasingly employs the techniques of geneticengineering. There are some limited efforts byU.S. companies to develop “next-generation”polymers for degradable plastic applications (i.e.,materials derived chiefly from agricultural andmicrobial sources). These efforts center on thedevelopment of polylactic acid (PLA) materials.Cargill and a Du Pont-ConAgra joint venture,EcoChem, have set up polylactide production

fermentation tech-facilities. These processes usenology to produce lactic acid monomers frompotato skins and corn (see chapter 2). PLAmaterials have some of the same mechanical andphysical properties as petroleum-based polymers,but degrade rapidly under a variety of conditions.However, as with other biopolymers, there is aconsiderable cost premium for PLA materials.Both Cargill and EcoChem are projecting pricesbetween $2 to $3 per pound for their PLAproducts. 34 Polylactide polymers that are used for

medical applications currently cost about $100per pound.

Although there is considerable academic inter-est in the area of microbially derived polyesters,no American company is actively pursuing thisline of research.35 Zeneca, Inc. of the UnitedKingdom is actively developing U.S. marketopportunities for its microbial polyester materi-als. A few companies are also pursuing thecommercial development of bacterial celluloseproducts (chapter 2). Table 4-2 lists current andpotential U.S. suppliers of advanced biopolymerplastics.

BIOMEDICAL MATERIALSBiomedical polymer science is one of the most

dynamic areas of materials research. Biologicallycompatible materials are increasingly being usedin a broad range of medical treatments.36 M o r ethan 2 billion pounds of polymeric materials areused annually in medical products. Althoughmost 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., personalcommunication, 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 substancescan be used for medical purposes, these substances are sometimes called biocompatible polymers even though they are not derived from naturalsources. Polyurethane, for example, although synthetically derived, is inert and compatible with blood, and is used in catheters and drug deliverydevices. 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 thusbegiming 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 Commentsapplications date

Zeneca Bio Products United Kingdom/UnitedStates

EcoChem (Du Pont- United StatesConAgra)

Cargill, Inc. United States

Battelle Institute and United StatesGolden Technologies

Argonne National United StatesLaboratory andKyowa Hakko, USA

Archer Daniels Midland United States

Warner-Lambert United States

Weyerhaeuser United States

BIOPOL resin (microbialpolyester)

Polylactic-polyg lycolicacid copolymers

Polylactide

Polylactic acid fromfermented corn

Polylactic acid fromfermented potato waste

Lactic acid supplier

NOVON starch-basedpolymers

Bacterial cellulose

Rigid and flexiblepackaging—film,moldings, papercoatings

Packaging ;somemedical products

Packaging

Packaging

Packaging

Packaging

Multiple-usestructural materials

Absorbent, thickener,and mating agent

Now

Customersamplingnow

Customersamplingnow

Not known

1995-96

Not known

Now

Now

1990 pilot plant in England;assessing full productionplant

100-million-poundproduction facility to openin 1995

10-million-pound productionfacility recently opened

Available for license

Available for license

Has not announcedproduction plans

100-million-poundproduction facility openedin 1992

Limited commercialquantities

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 poly-mers have captured significant shares of somemedical markets and are rapidly expanding intonew applications. A recent market survey esti-mates that the total U.S. market for biopolymermedical applications will grow from about $300million in 1990 to about $1 billion in 1995.37 A sin Europe, the three main biomedical marketsegments are wound management products, poly-meric drugs and drug delivery systems, andorthopedic repair products. The wound manage-ment segment is the most mature of the threemarkets, with both drug delivery technology andorthopedic devices only now beginning to estab-lish a significant commercial presence.38

WOUND MANAGEMENTThe main products in the U.S. wound repair

market are absorbable sutures, surgical mesh,clips, and staples. This market is dominated by ahandful of companies including Ethicon (Johnson& Johnson), U.S. Surgical Corporation, Davis &Geck, Du Pont, and Pfizer. The main polymersused in these products are polylactic-poly glycolicacid and related compounds such as polydioxan-one. Other biopolymer materials such as chitinand modified cellulose may also be used assutures in the near future.39 The principal advan-tage of biopolymer-based wound managementproducts is that they form natural bonds with

surrounding tissue and thereby facilitate

I 77

thehealing process.

Biopolymer based sutures (i.e., absorbablesutures) currently hold about 50 percent (about

$225 million) of the entire U.S. suture market andare expected to grow at an annual rate of morethan 10 percent for the next several years.40 Themajor factor explaining this growth is the prefer-ence shown by physicians for absorbable woundrepair products over nonabsorbable devices. Com-panies in the bioabsorbable surgical device mar-ket are rapidly expanding the range of applica-tions for their polymer products. Hyaluronic acid,a polysaccharide, is being used for surgical repairof soft tissue (particularly eye and ear tissue), andsome proteins, such as collagen, are being used aswound dressings and for tissue reconstruction .41Bioadhesives are a new class of materials thatcould serve as suture enhancements, and can beused for attaching prostheses, or for dentalapplications. Enzon Corporation and W.R. Gracehave launched programs to develop bioadhesivesthat are based on recombinant protein polymers.Adheron Corp. is developing a bioadhesive that isan exopolysaccharide-peptide complex derivedfrom marine bacteria. Other biodegradable poly-mers are being tested as aids in repairing damagedarteries. 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 legalliabilities, As a consequcncc, it is possible that shortages of some types of implantable medical devices could occur. These developments couldgive impetus to R&D activities involving new, biocompatible materials that are derived from natural sources. (Bernie Liebler, Health IndustryManufacturers 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 -es and

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.


serve as vascular support meshes for blood vesselregeneration .43

Drug Delivery SystemsDrug delivery systems (DDS) utilizing poly-

mers that degrade in the body have attractedconsiderable attention in recent years. The use ofbiopolymers for drug delivery can minimizetissue reaction and allow for the administration ofdrugs by methods other than injection.44 Acontrolled-release drug system is a combinationof a biologically active agent (i.e., the drug) anda support vehicle. The support vehicle can beeither a matrix or a reservoir device. In a matrixsystem, an active drug is dissolved or disperseduniformly throughout a solid polymer. Drugrelease from the matrix can be controlled by eithera diffusion or an erosion process. In a reservoirsystem, the polymer acts solely as a barrier thatcontrols the rate of drug delivery by diffusion.Polylactic and polyglycolic acid copolymers arethe most widely used drug vehicle materials.Other biopolymers being investigated includepoly amino acids, derivatives of chitin, and somechemically modified starches.45

The U.S. market for biodegradable drug deliv-ery systems is expected to grow from its 1990level of about $30 million to nearly $490 millionby 1995.46 One reason for this rapid growth is thelarge number of genetically engineered proteindrugs that are now being introduced,47 Encapsula-tion of proteins in biopolymer materials preventsthe proteins from being prematurely destroyed by

attacking enzymes. Another factor contributing tothe growth of drug delivery systems is that theyprovide a means for extending the patent life ofdrugs. The major area of application for thesenovel sustained-release systems is in the treat-ment of cancers and geriatric diseases.

For the most part, the industry leaders in drugdelivery systems are relatively small, technologi-cally sophisticated firms that frequently haveclose relationships with academic research cen-ters. Since DDS development lies outside thetraditional expertise of most pharmaceutical com-panies, large firms have typically acquired thistechnology through contracting, licensing, jointventures, and acquisitions. In recent years, how-ever, most large pharmaceutical companies haveinitiated modest in-house research efforts. Table4-3 lists the current and potential suppliers of drugdelivery systems.

Orthopedic Repair ProductsThe U.S. orthopedic implant market provides a

number of potentially interesting applications forbiodegradable polymers. Commercial opportuni-ties exist in the areas of joint prostheses technol-ogy such as artificial ligament coatings, ligamentattachment devices, and tendon implant materialsand bone trauma fixation devices such as plates,screws, pins, and rods used to stabilize fractures.Although only a few biopolymer devices arecurrently on the market (mostly bone fixationpins), 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, “TissueEngineering,” 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 ~er s~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 capsulesare commonly used to deliver aspirin and antibiotics. The world market for simple biopolymer capsules is close to $400 million annually. (KenTracy, 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, ~causeit was not possible to obtain separate estimates for the delivery systems. The estimate was provided by BioInforrnation Associates, BostoUMassachusetts. 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 newproduct introductions by 1995.

Orthopedic products face several technicalchallenges. In addition to high strength, bio-polymers must also have prolonged, well-controlled rates of degradation48 because com-plete ligament and tendon healing requires a 1-to2-year time frame. In addition, the degraded endproducts must be absorbed safely by the body.Even though the end product in most biodegrada-

Microsphere injectable forprotein drugs

Injectable delivery of anti-infective drugs andpeptides; surgical implantproducts

Targeted, time-releasedtherapies for anticancerand antiinfective drugs

Microsphere encapsulationof interferons, growthhormones

Implant for release of gyraseinhibitor

Controlled release of beta-Interferon;microencapsulation ofpeptide hormones

Process for developingmicrosphere

Implant for release ofestradiol in livestock

Oral delivery system forheparin, Zadaxin(hepatitis), and poultryvaccines

Microsphere forencapsulation of DNA-RNA for stimulation ofInterferon production

Implant and Injectabledevices

Polylactlc-poly glycolic acid

Polyanhydrides (syntheticdegradable polymer)

Polyanhydrides

Polylactic acid

Polylactic-poly glycolic acid


Polylactic acid


Polyamino acid


Not known

ble orthopedic devices is lactic acid, which ismetabolized by the body, the FDA will beassessing whether these devices cause soft tissueirritation or have toxic side effects. These sideeffects are of more concern in orthopedic devicesthan in drug delivery systems, because of thesignificantly larger mass of polymer used inorthopedic systems.

In 1990, the U.S. market for biopolymerorthopedic 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, someprogress is occurring in this area, Johnson& Johnson Orthopedics’ researchers have developed a polylactide bone fixation plate that exhibitssuperior strength over that of conventional bone fi~atlon plates. Animal testing of the device over a 2-year period has revealed no tissue irritationor toxic side effects.


is expected to grow to $80 million by 1995.49

However, market growth will depend in large parton the speed of the FDA approval process. Whiletwo companies, Johnson & Johnson and Davis&Geck, presently dominate the orthopedic repairmarket, several other health care companies areexpected to enter the field in the next few years:3M, Bristol Meyers Squibb, Pfizer, Allied Signal,Smith and Nephew, and Du Pont all have medicalimplant development programs. Potentially novelapplications include degradable bone screws thatobviate the need for followup operations, and theuse of biopolymers as scaffolding in the forma-tion of new ligament and cartilage material.50

Because more than 1 million operations a yearinvolve cartilage replacement, this particularbiopolymer application could grow dramaticallyin the future. As biopolymer science evolves,many more important advances in the area oforthopedic repair can be expected.

BIOPOLYMERS IN PERSPECTIVEBiopolymers are a diverse and remarkably

versatile class of materials that have potentialapplications in virtually all sectors of modernindustrial economies. Currently, many biopoly -mers are still in the developmental stage, butimportant applications are beginning to emerge inthe areas of packaging, food production, andbiomedicine. Some biopolymers can directlyreplace synthetically derived materials in tradi-tional applications, whereas others possess uniqueproperties that could open up a range of newcommercial opportunities. As a consequence,novel biopolymer materials are being investi-gated by established agricultural and chemicalfins, as well as small biotechnology enterprises.

At present, government-sponsored researchand development efforts in the biopolymer areaare relatively small in scope, but many ongoingFederal activities have an indirect bearing onbiopolymer science. Unlike Japan and the Euro-pean Community, the United States does not havea well-defined biopolymer policy. The UnitedStates is, for the moment, well positioned in someareas of biopolymer development because of itsstrong agricultural base, expertise in polymerengineering, and active biotechnology sector.However, the relative competitive position of theUnited States could be enhanced by fosteringgreater collaboration among researchers in gov-ernment, industry, and academia. Fundamentalresearch barriers in the biopolymer field couldalso be better addressed by bringing greatercoherence to the R&D efforts of various Federalagencies. In addition to the scientific and engi-neering hurdles that exist in the biopolymer area,formidable commercialization barriers remain.Even if some biopolymers are shown to haveenvironmental characteristics that are preferableto conventional polymers, much work needs to bedone to bring down the costs of biologicallyderived materials. In only a few specializedapplications, such as biomedicine, are the rela-tively high costs of biopolymer materials notlikely to impede market growth. These economicand technical obstacles, as well as the interdisci-plinary nature of the biopolymer field itself, posedifficult challenges for policymakers and industrymanagers 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).

biopolymers: making materials nature's way

Documents