6. Preface
Biological substances appeared in marine environments at the dawn of evolution. At
that moment, the first organisms acquired the ability to synthesize polymer chains
which were the basis, in their turn, for the formation of the building blocks that
fueled the so-called self-assembling process. They, in their turn, produced more
complicated structures. The phenomenon of three main organic structural and scaf-
folding polymers (chitin, cellulose, and collagen) probably determined the further
development and evolution of bioorganic structures and, of course, the organisms
themselves. All the three biopolymers, notwithstanding their differences in chemical
composition, have the common principles in their organization: nanofibrils with the
diameter 1.5–2 nm, the ability to self-assemble, production of fibrillar and fiber-like
structures with hierarchical organization from nano—up to macrolevels, the ability
to perform both the role of scaffolds and the templates for biomineralization and
formation of the rigid skeletal structures. Chitin and collagen in particular played
the determining role in the formation of skeletal structure in marine invertebrate
organisms.
These two biopolymers possess all the qualities needed to refer to them simulta-
neously as biological materials and biomaterials, the latter thanks to their successful
application in biomedicine.
The fact that modern science finds chitin and collagen both in unicellular and
in multicellular invertebrates in fossil and modern species confirms beyond a doubt
the success of these biological materials in the evolution of biological species during
millions of years. I realize that this success should be consolidated at genetic level
and the detection of corresponding conserved genes must be the main priority.
The abundance of silica as well as calcium and carbonate ions in the ancient
marine environments on one hand, and the existence of chitin and collagen primary
scaffolds in primitive biological form on the other hand led to the formation of
unique biocomposites, possessing completely new qualities. The diversity of skele-
tal forms of marine invertebrates impresses man both with its exceptionality and
strict conformity with mathematic and thermodynamic laws. Nature performs here
the role of the first, and doubtless brilliant, engineer without using any equipment
or computer support, which is inconceivable in the creation of any construction
nowadays.
v
7. vi Preface
Many engineering solutions that we observe in unicellar marine organisms can
also be found in further developed organisms. I think that the chitin system which
came into existence as a result of polymerization of N-acetylglucosamine into poly-
N-acetylglucosamine, already in ancient bacteria and fungi, is even older than the
collagen system.
Chitin is more resistant in extreme conditions: both to a wide pH range and to
changes in temperature up to 300◦C. But both polymers can be found in the cuticles
of many inhabitants related to the hydrothermal vent fauna and both materials can
also be found in marine organisms living in Arctic and Antarctic waters. How, and
on the basis of which chemical laws, the skeletal formation, for example, in silica–
chitin as well as silica–collagen-based deep-sea glass sponges at –1.5◦C takes place
is still a puzzle. If a rubber laying in a certain element of a spaceship is frozen, it can-
not be launched. People perish and a very complicated heavy-weight construction is
destroyed as happened in the tragedy of the Shuttle. But marine invertebrates, living
under the thick ice in Antarctic, manage not only to exist but also to swim, run away
and pursue, overtake, hold, gnaw, drill, suck, multiply, and live their life from an
egg or capsule, to larva, and to the grown-up species. Everywhere and at every level
biological materials, hard and sharp, elastic and gel-like, successfully perform their
role with the only aim—to survive, a mission that has been achieved over billions of
years. Even nowadays, when marine invertebrates are confronted with completely
foreign heavy metal and ion pollutants, the fight for survival is undiminished and
skeletal systems are built using nickel, strontium, or uranium. One can only learn
from them and think it over! Thus, Extreme Biomimetics could now be proposed as
the novel direction in biomaterials science.
If biomaterials science can be referred to as one of the directions in materials
science, the science of biological materials of marine origin does not exist at all,
including the classification of these materials. In my opinion, the level of modern
science nowadays allows the start of serious and systematic research into biological
materials of marine origin because their formation and the principles of their orga-
nization are the bases of the evolution of biomaterials of the highest level, like the
bones or teeth of human beings.
It is not a coincidence that the collagen of a primitive sponge is homologous to
that of a human being. All of us realize that it is not the interest in the peculiarities
of the shell skeletal construction that comprises the driving force in the development
of modern materials science, but elementary solutions for the human problems of
toothache or osteoporosis. Let us add to the appearance of such a unique direction
in science the field of Military Biomaterials.
Huge sums of money are spent on solutions for these very often artificially cre-
ated and painful problems of mankind. However, having invited them, our scientific
community is confronted with the problem of a lack of basic knowledge pertain-
ing to the peculiarities of biological material creation and is becoming aware of the
necessity for detailed research of the shell, crawfish, or diatom.
I was also faced with this problem, when in 2003 Professor Hartmut Worch
from Max-Bergmann Center of Biomaterials in Dresden, as an outstanding engi-
neer, asked me to work on a problem: the speedy creation of an artificial bone.
8. Preface vii
However, being a biologist, I decided before starting work on this task, to look back
at the sources of skeletal formation in living organisms. I found marine sponges to
be good representatives for this process and thus I started my “dive” into the strange
world of marine biological materials. My professor is a pensioner now, the best
brains in the world are still working hard in the field of artificial bone creation. To
tell you the truth, even if I live to become a pensioner, I am not sure that we will
be able to find out the exact mechanism for the skeleton formation of even primi-
tive marine sponge. I can mention the diversity of marine species, their habitat in
the depths, and unfavorable, to human beings at least, climate zones as restricting
factors. In spite of the great interest in the marine biological materials on the part of
scientists dealing with the problems of biotechnology, bioorganic and bioanalytical
chemistry, materials science, solid state physics, crystallography, mineralogy, bion-
ics, and biomimetics, there is not a single scientific center in the world today that
can claim as its focus this scientific research.
In my book on biological materials of marine origin I have made an attempt at
classifying them utilizing their great diversity of forms.
The book consists of 8 parts, an introduction, 35 chapters, an epilogue, and an
addendum including more than 2,000 references. Many of the photos have been
published for the first time. I have also paid much attention to the historic factors,
as it is my opinion that the names of the discoverers of unique biological structures
should not be forgotten. I am fully aware of the fact, that due to interaction of many
fields, I cannot satisfy the interest of the scientists in the above-mentioned fields of
science, but I hope that all of them will acquire new knowledge.
There are so many institutions and individuals to whom I am indebted for the gift
or loan of material for study that to mention them all would add pages to this mono-
graph. It may be sufficient to say that without their cooperation, this work could
hardly have been attempted. I also thank Prof. Catherine Skinner, Prof. Edmund
Bäeuerlein, Prof. Victor Smetacek, Prof. Dan Morse, Prof. George Mayer, Prof.
Hartmut Worch, and Prof. Eike Brunner for their support and permanent interest
in my research. I am grateful to Vasily V. Bazhenov, Denis V. Kurek, René Born,
Sebastian Hunoldt, and Andre Ehrlich for their technical assistance. To Dr. Allison
Stelling and Mrs. Tatiana Motschko, I am thankful for taking excellent care of
manuscripts and proofs. To my parents, my wife, and my children, I am under deep
obligation for their patience and support during hard times.
Dresden, Germany Hermann Ehrlich
9.
10. Introduction
We probably know more about the Moon than we do about the bottom of the sea
Ole Jorgen Lonne, Ph.D.
Abstract The first and generalized classification of biological materials of marine
origin is proposed as follows: Biomineralized Structures and Biocomposites;
Non-mineralized Structures; Macromolecular Biopolymers; Self-made Biological
Materials.
The biological, chemical, and materials diversity of the marine environment is
immeasurable and therefore is an extraordinary resource for the discovery of new
bioactive substances, drugs, toxins, pigments, enzymes, and bioluminescence-based
markers; as well as biopolymers, bioadhesives, bioelastomers, and hierarchically
structured biocomposites. Recent technological and methodological advances in
structure elucidation, genomics, proteomics, organic synthesis, bioinspired materi-
als chemistry, biological assays, and biomimetics have resulted in the isolation and
clinical evaluation of various novel pharmacological preparations and biomaterials.
These compounds range in structural class from simple linear peptides to complex
biopolymers. Equally as diverse are the molecular modes of action by which these
molecules impart their biological activity (Newman and Cragg 2004; Weiner 1997).
Beyond their importance as a food source, the world’s seas have always been boun-
tiful providers of special materials valued for human health and pleasure. Access to
this resource historically has been hindered by the apparent hostility of the seawater
environment to manufactured materials and engineering concepts of terra firma. In
spite of the extraordinary potential of the marine environment for new biomaterials,
the environmental risks and exploration costs have been prohibitive.
In the past decade, new tools in biotechnology have been introduced that are
producing extraordinary new products and assays based on the new understanding
of genetic factors and their expression as complex biological molecules. Applying
these tools to the marine environment provides opportunities to unlock similar
micro-molecular vaults of marine biomedical products so that they can join other
ix
11. x Introduction
macro-biomaterials that have already been harvested from the sea for thousands of
years (Weber 1993).
Dramatic developments in understanding the fundamental underpinnings of life
have provided exciting opportunities to make marine bioproducts. This achievement
using marine biotechnology is an important part of the economy in the USA, Japan,
China, Korea, Russia as well as in European Community (Attaway 1993; Powers
1995).
According to MarineBiotech.org (www.marinebiotech.org), marine biotechnol-
ogy, as the name implies, utilizes the rich biodiversity found in the world’s
oceans for applications in biotechnology. Marine biotechnology has recently been
embraced as a field of great potential by both molecular biologists and the biotech-
nology industry. The oceans cover nearly 70% of the earth’s surface and comprise
90–95% of the biosphere by volume of living organisms on earth and thus contain a
Fig. 1 We probably know more about the Moon than we do about the bottom of the sea (image
from the IMAX film “Volcanoes of the Deep Sea,” courtesy Rutgers University and The Stephen
Law Company)
12. Introduction xi
tremendous range of diverse biological resources and unique conditions. For exam-
ple, the largely unexplored deep-sea hydrothermal vents (Fig. 1) represent a treasure
trove of biodiversity, as do extreme ocean environments such as cold polar waters
and the deep ocean floor characterized by intense pressure.
Although deep ocean exploration is still in its infancy, many experts now believe
that the deep sea harbors are some of the most diverse ecosystems on earth. This
diversity holds tremendous potential for human benefit. More than 15,000 natural
products have been discovered from marine microbes, algae, and invertebrates, and
this number continues to grow. The uses of marine-derived compounds are varied,
but the most exciting potential uses lie in the medical realm. More than 28 marine
natural products are currently being tested in human clinical trials, with many more
in various stages of preclinical development (Maxwell et al. 2005). Marine biotech-
nology focuses not only on the growing use of marine life in the food, cosmetic, and
agricultural industries such as aquaculture, but also on little known forms of deep
ocean life.
While the goal of modern marine biotechnology is on biomedical applications
of natural marine products, we also should consider how these organisms and
molecules will be renewably collected from marine life or mined from the sea sur-
face, the subsurface, and the seafloor. Selection of suitable materials and coatings for
sea surface or underwater processing facilities will be critical to minimize environ-
mental impact and to maximize process efficiency. Self-cleaning and drag-reducing
materials also have a key role to play as assistive technologies in the seeding,
harvesting, and development of natural marine products.
Bioprospecting inspires businessmen to consider the value of marine conserva-
tion, because new cures and new materials help to put a price tag on the value of
biodiversity research. Theoretically, nature has an “inspiration value” that justifies
its protection.
1 Species Richness and Diversity of Marine Biomaterials
An exciting “marine pipeline” of new drugs and biomaterials has emerged from
intense efforts over the past decade to more effectively explore the rich biological,
chemical, and materials diversity offered by marine life.
The number of marine taxa, particularly the large complex forms, increased dra-
matically with the onset of the Cambrian explosion about 540 million years ago
(Knoll 2001). Sepkoski’s classic work documented a steady increase in the num-
ber of taxa during the Phanerozoic, with the exception of five big events during
which diversity suffered mass depletion (see for review Sala and Knowlton 2008).
The events at the end of the Ordovician, Permian, and Cretaceous periods were due
to only mass extinctions, whereas the loss in diversity in the late Devonian and at
the end of the Triassic was a result of low origination as well as high extinction.
However, this paradigm of monotonic increase broken only by mass extinction
events has been recently questioned because of sampling artifacts associated with
the fossil record and some authors suggest that during some geological periods
taxonomic diversity might have remained stable (Bambach et al. 2004).
13. xii Introduction
Ecosystems have also changed over geological time with feedbacks that have
changed earth’s physical properties (e.g., creation of the present atmosphere).
Although the information on ecosystem diversity over geological times is not as
good as that on taxonomic diversity, it is clear that the number of marine ecosys-
tems and ways of making a living has increased since the primordial pre-Cambrian
ocean. Examples include the marine Mesozoic revolution (MMR) that followed the
end-Permian mass extinction. During the MMR, there was a proliferation of new
plant and animal taxa associated with an increase in trophic diversity, from infau-
nal suspension and detritus feeders (animals that live in the sediment and filter the
water or eat detritus on the bottom) to nektonic carnivores (animals that swim and
eat invertebrates and fish in the water column).
Understanding mass extinctions is of particular importance because some have
argued that the impact of humans could potentially approach the scale of that caused
by asteroids. We clearly have yet to approach the 98% species extinction level that
occurred at the end of the Permian, but this should not be used to justify com-
placency, as threshold effects could result in rapid collapses with little warning.
Extinction events associated with global warming are potentially very informative
with respect to understanding how marine organisms might respond to a warmer
world.
Knowledge about changes in biodiversity in the past is essential to understanding
potential scenarios of change in the future. Identifying the knowable unknowns will
help us to identify research priorities and understand the limitations of management.
Before humans began to significantly exploit the ocean, the only disturbances
resetting the successional clock and causing sudden declines in biodiversity at all
levels were environmental disturbances of the type outlined above. However, human
activities are without doubt now the strongest driver of change in marine biodiversity
at all levels of organization; hence, future trends will depend largely on human-
related threats (Barnes 2002).
Although marine species richness may only total 4% of global diversity, life
began in the sea and much of the diversity in the deep branches of life’s tree is
still primarily or exclusively marine (Briggs 1994). For example, 35 animal phyla
are found in the sea, 14 of which are exclusively marine, whereas only 11 are ter-
restrial and only one exclusively so (Ormond et al. 1997). It is not truly known how
many species inhabit the world’s oceans; however, it is becoming increasingly clear
that the number of microbial species is many times larger than previously estimated,
enough that marine species in total may approach 1–2 million.Our understanding of
major changes in marine diversity over deep time is comparatively good, thanks
to the excellent fossil record left by many marine organisms, although consider-
able sampling problems limit the potential for accurate, fine grained analyses. In
contrast, our knowledge of marine diversity at present is poor compared to our
knowledge for terrestrial organisms and an appreciation for the dramatic changes
in marine ecosystems that have occurred in historic times is only just beginning to
emerge.
There are approximately 300,000 described marine species, which represent
about 15% of all described species. There is no single listing of these species, but
14. Introduction xiii
any such listing would be only an approximation owing to uncertainty from several
sources. As a consequence, the total number of marine species is not known to even
an order of magnitude, with estimates ranging from 178,000 species to more than
10 million species (Poore and Wilson 1993). The two biggest repositories of marine
biodiversity are coral reefs (because of the high number of species per unit area)
and the deep sea (because of its enormous area). Estimates for coral reefs range
from 1 to 9 million species, but are very indirect, as they are based on a partial
count of organisms in a large tropical aquarium or on extrapolations stemming from
terrestrial diversity estimates. Estimates for the deep sea are calculated using actual
field samples, but extrapolations to global estimates are highly controversial. The
largest estimate (10 million benthic species) was based on an extrapolation of ben-
thic macrofauna collected in 233 box cores (30 × 30 cm each) from 14 stations,
although others suggested 5 million species as a more appropriate number (Grassle
and Maciolek 1992; Gray 2001; O’Dor and Gallardo 2005; Pimm and Raven 2000).
What is clear from these data is that we have a remarkably poor grasp of what
lives in the ocean today, although ongoing programs such as the Census of Marine
Life (Malakoff 2003) should yield greatly improved estimates in the not too distant
future. However, intensive surveys of individual groups point to the enormous scale
of the task ahead.
Thus, marine biotechnology’s promising future reflects the tremendous biodi-
versity of the world’s oceans and seas. The promise of marine biotechnology also
reflects many marine organisms’ need to adapt themselves to the extremes of tem-
perature, pressure, and darkness that are found in the world’s seas. The demands
of the marine environment have led these organisms to evolve unique structures,
metabolic pathways, reproductive systems, and sensory and defense mechanisms.
Many of these same properties have important potential applications in the human
world.
There are no doubts that diversity of biological materials of marine origin is
almost equivalent to the marine biodiversity. However, in contrast to zoological
classification of species, the corresponding classification of biological materials is
not yet established. I make an attempt here to represent a very preliminary and
generalized classification of biological materials of marine origin as follows:
• Biomineralized Structures and Biocomposites (skeletal formations, macro-
and microscleres, spicules, spines, bristles, cell walls, cyst walls, loricae,
etc.)
• Non-mineralized Structures (bioelastomers like abductin, resilin, gorgonin, spon-
gin; antipathin, bioadhesives like byssus and related DOPA-based polymers;
biocements, and glues)
• Macromolecular Biopolymers (marine polysaccharides of algal origin; chitin,
collagen).
• Self-made Biological Materials (tubular structures of marine invertebrates like
some foraminifera or worms which are made due to co-agglutination of external
mineral debris, sand grains, or other particles).
15. xiv Introduction
Fig. 2 Diversity of biological materials from marine invertebrates: (a) sea urchin (calcareous
spines and tests, echinochrom-like pigments); (b) holoturia (collagens, Cuvierian tubules as bioad-
hesives), (c) bivalvia molluscs (shell, mother pearl, nacre, byssus); (d) sea stars (mineralized
structures, adhesives) (image courtesy A.V. Ratnikov)
In principle, each marine organism possesses both mineralized and non-
mineralized structures (Fig. 2); however, there are numerous species which are
lacking a mineral component. In these cases, some species use complex cross-
linking-based biochemical reactions which lead to hardening (sclerotization) of
organic matter; while another species developed unique constructs wherein min-
eralized and non-mineralized skeletal parts are distributed alternately (e.g., Isididae
bamboo corals). All of the examples listed above have in common their tremendous
biomimetic potential—the driving force for bioinspiration and development of novel
materials as well as technologies. For example, some marine organisms are sessile
and must employ sophisticated methods to compete for a place to anchor. Barnacles
and mussels, which depend on their ability to attach to solid surfaces for survival,
have developed bio-adhesives that stick to all kinds of wet surfaces (Deming 1999;
Dickinson et al. 2009). Current research into the ways that marine organisms adhere
to wet surfaces, or prevent other organisms from adhering to them, is yielding useful
new technologies. These technologies include both adhesion inhibitors (e.g., anti-
fouling coatings for ship hulls) and new types of adhesive such as medical “glues”
for joining tissue or promoting cell attachment in tissue engineering applications
(Dalsin et al. 2003; Cha et al. 2008; Hwang et al. 2007a, b; Kamino 2008).
In spite of the sea’s vast potential as a source of new biotechnologies, this
domain remains relatively unexplored and few marine biotechnology products and
services have been commercialized to date. Indeed, the vast majority of marine
16. Introduction xv
organisms (primarily microorganisms) have yet to be identified. Even for known
organisms, there is insufficient knowledge to permit their intelligent management
and application.
References
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natural products, vol I. Plenum, New York
Bambach RK, Knoll AH, Wang SC (2004) Origination, extinction, and mass depletions of marine
diversity. Paleobiology 30:522–522
Barnes DKA (2002) Biodiversity – invasions by marine life on plastic debris. Nature 416:808
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Dalsin JL, Hu BH, Lee BP, Messersmith PB (2003) Mussel adhesive protein mimetic polymers
for the preparation of nonfouling surfaces. J Am Chem Soc 125:4253
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Dickinson GH, Vega IE, Wahl KJ et al (2009) Barnacle cement: a polymerization model based on
evolutionary concepts. J Exp Biol 212:3499–3510
Grassle JF, Maciolek NJ (1992) Deep-sea species richness: regional and local diversity estimates
from quantitative bottom samples. Am Nat 139:313–321
Gray JS (2001) Marine diversity: the paradigms in patterns of species richness examined. Sci Mar
65:41–46
Hwang DS, Gim Y, Yoo HJ, Cha HJ (2007a) Practical recombinant hybrid mussel bioadhesive
fp-151. Biomaterials 28:3560–3567
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fused with RGD peptide. Biomaterials 28:4039–4045
Kamino K (2008) Underwater adhesive of marine organisms as the vital link between biological
science and materials science. Mar Biotechnol (NY) 10(2):111–121
Knoll AH (2001) Life on a young planet: the first three billion years of evolution on earth.
University Press, Princeton, NJ
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O’Dor R, Gallardo VA (2005) How to census marine life: ocean realm field projects. Sci Mar
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26. Part I
Biomaterials
The union of biology with materials science and engineering
represents one of the most exciting scientific prospects of our
time. As currently few biologists know much about engineering
and even fewer engineers know much about biology, the
expectations of future advances seem unbounded.
Robert O. Ritchie (2008)
Materials Science and Engineering is a young and vibrant discipline that has, since
its inception in the 1950s, expanded into three directions: metals, polymers, and
ceramics (and their mixtures, composites). Biological materials are being added to
its interests, starting in the 1990s, and are indeed its new future (Meyers et al. 2008).
Biomaterials represent a central theme in a majority of the problems encountered.
These fields have evolved into a very interdisciplinary arena building on traditional
engineering principles that bridge advances in the areas of materials science, life
sciences, nanotechnology, and cell biology, to name a few (Wnek and Bowlin 2008).
This trend of interdisciplinary research to solve the most challenging yet compelling
medical problems has been embraced in the field and is leading to the betterment of
human health. It is evident that the fields of biomaterials and biomedical engineering
are continually changing due to the rapid creation and advancement in technology in
more traditional areas as well as rapidly developing areas (e.g., tissue engineering).
Indeed, the field of biomaterials has become one of the fastest growing areas in
materials science, as bioengineering has become in engineering (Ritchie 2008).
References
Meyers MA, Chen PY, Lin AYM et al (2008) Biological materials: structure and mechanical
properties. Prog Mater Sci 53:1–206
Ritchie RO (2008) Editorial. J Mech Behav Biomed Mater 1(3):207
Wnek GE, Bowlin GL (2008) Encyclopedia of biomaterials and biomedical engineering, 2nd ed
(four-volume set). Informa Healthcare. London, New York
27.
28. Chapter 1
Biomaterials and Biological Materials, Common
Definitions, History, and Classification
Abstract Biomaterial can be defined as any material used to make devices to
replace a part or a function of the body in a safe, reliable, economic, and physiolog-
ically acceptable manner. Biological material is a material produced by a biological
system. Most biological materials can be considered as composites. Composite
materials are those that contain two or more distinct constituent materials or phases,
on a microscopic or macroscopic size scale. The modern biomaterials science is
defined and explained through the introduction of biotechnology and advances in
the understanding of human tissue compatibility. Developing from bio-inert mate-
rials to biodegradable materials, biomaterials are widely used in medical devices,
tissue replacement, and surface coating applications. In this chapter the history of
biomaterials, their classification, requirements, state of the art, as well as a future
are discussed.
1.1 Definitions: Biomaterial and Biological Material
According to Williams (1999), biomaterials science is the study of the structure and
properties of biomaterials, the mechanisms by which they interact with biological
systems and their performance in clinical use.
I agree with the explanation of biomaterial and biological material proposed by
Park and Lakes in the third edition of their renowned book (Park and Lakes 2007).
According to these authors, a biomaterial can be defined as any material used to
make devices to replace a part or a function of the body in a safe, reliable, economic,
and physiologically acceptable manner.
A variety of devices and materials are used in the treatment of disease or injury.
Commonplace examples include sutures, tooth fillings, needles, catheters, bone
plates. A biomaterial is a synthetic material used to replace part of a living sys-
tem or to function in intimate contact with living tissue. The Clemson University
Advisory Board for Biomaterials has formally defined a biomaterial to be “a sys-
temically and pharmacologically inert substance designed for implantation within
or incorporation with living systems” (cited by Park and Lakes 2007).
3H. Ehrlich, Biological Materials of Marine Origin, Biologically-Inspired Systems 1,
DOI 10.1007/978-90-481-9130-7_1, C Springer Science+Business Media B.V. 2010
29. 4 1 Biomaterials and Biological Materials
By contrast, a biological material is a material, such as bone, skin, or artery,
produced by a biological system.
The major difference between biological materials and biomaterials (implants) is
viability. There are other equally important differences that distinguish living mate-
rials from artificial replacements. First, most biological materials are continuously
bathed with body fluids. Exceptions are the specialized surface layers of skin, hair,
nails, hooves, and the enamel of teeth. Second, most biological materials can be
considered as composites (Park and Lakes 2007).
Composite materials are those that contain two or more distinct constituent mate-
rials or phases, on a microscopic or macroscopic size scale. The term “composite”
is usually reserved for those materials in which the distinct phases are separated
on a scale larger than the atomic, and in which properties such as the elastic mod-
ulus are significantly altered in comparison with those of a homogenous material.
Accordingly, fiberglass and other reinforced plastics as well as bone are viewed
as composite materials, but alloys such as brass or metals such as steel with car-
bide particles are not. Natural composites often exhibit hierarchical structures in
which particulate, porous, and fibrous structural features are seen on different length
scales.
Composite materials offer a variety of advantages in comparison with homoge-
nous materials. However, in the context of biomaterials, it is important that each
constituent of the composite be biocompatible and that the interface between con-
stituents not be degraded by the body environment. Composites currently used in
biomaterial applications include the following: dental filling composites; bone par-
ticle or carbon fiber reinforced methyl methacrylate bone cement and ultrahigh
molecular weight polyethylene; and porous surface orthopedic implants (Park and
Lakes 2007).
A Biomedical material (Williams 1999) is material intended to interface with
biological systems to evaluate, treat, augment or replace any tissue, organ, or
function of the body.
There are numerous papers in the modern literature where authors use terms like
“nanomaterials” and “bionanomaterials.”
According to Williams (2008, 2009), the term “nanomaterial” should not exist
because it is senseless. The discussion about nanomaterial provides a hint of the
analysis of a biomaterial that follows, since a prefix which is an indicator of scale
cannot specify the integer that follows (in this case a material) unless that integer
can be qualified by that scale. In other words, it is very clear what a nanometer is
because nano means 10−9 and a meter is a measure of length. In the case of the term
nanomaterial, the question arises, what is it about the material that is 10−9? Is it the
dimension of a crystal within the material, or of a grain boundary, a domain, or a
molecule, or is it a parameter of a surface feature of the sample, or perhaps of the
resistivity or thermal conductivity of the material. “Clearly this is nonsense,—said
Williams,—but one has to accept that nanomaterials are here to stay, with even some
journal titles containing the word” (Williams 2009).
There are both nanobiomaterials and nanostructured biomaterials, which should
be differentiated from each other (Dorozhkin 2009). Nanobiomaterials refers to
30. 1.2 Brief History of Biomaterials 5
individual molecular level biomaterials, such as single proteins, while nanostruc-
tured biomaterials refers to any biomaterials whose structure or morphology can be
engineered to get features with nanometer-scale dimensions (Thomas et al. 2006).
In this book, I use the term “biological materials.” However, some of them,
like chitin and collagens from marine invertebrates as well as coral hydroxyapatite,
have been described in the literature as biomaterials because of their applications in
biomedicine and tissue engineering.
1.2 Brief History of Biomaterials
Development of biomaterials science from historical point of view has been thor-
oughly described by Popp (1939), Weinberger (1948), Harkins and Koepp Baker
(1948), Baden (1955), Sivakumar (1999), Ratner and Bryant (2004), Staiger et al.
(2006), Park and Lakes (2007). Based on data reported in these works, I take the
liberty to represent a brief history of biomaterials as follows.
The Egyptians during the reign of Ramses II had specialists for the treatment
of the teeth and the oral cavity. Palatal defects were treated at that time with lam-
inated sheets of gold. The Edwin Smith Papyrus, which is about 2000 years old,
contains accounts of fractures of the facial bones and several case reports, and Case
15 describing a traumatic perforation of the maxilla complicated by injury to the
zygomatic arch. It is likely that some forms of obturators were used in Egypt as
early as 2600 BC. Popp states that the ancient Egyptians also made artificial ears,
noses, and eyes. Galen in the second century BC described clefts of the palate. Some
of the earliest biomaterial applications were as far back as ancient Phoenicia where
loose teeth were bound together with gold wires to tie artificial ones to neighboring
teeth (Teoh 2004).
Amatus Lusitanus is credited with having invented the obturator between 1511
and 1561. The first scientific description of congenital and acquired defects of the
maxilla and their treatment was given by Pare in his Chirurgie in 1541. He specifi-
cally described defects of the palate with bone destruction caused by arquebus shots,
stab wounds, or syphilitic gumma, describing also the accompanying speech defi-
ciency and giving general principles of treatment. He used a flat, vaulted, metallic
plate in gold or silver with a sponge attached to it. The sponge was introduced
into the defect, where it expanded with readily absorbed nasal and oral secretions,
thus holding the obturator base in position. Pare mentioned the speech improvement
resulting from the use of the appliance. Hollerius in 1552, following Pare’s work,
also advocated the use of sponges fixed on a gold plate. In 1565 Alexander Petronius
described palatine obturators (De morbo Gallico). He used wax, tow, and sponges
for the bulb section of the appliance. Further progress was made by Guillemeau,
who described a technique for the construction of obturators around the year 1600.
Pierre Fauchard, often called “the Father of Dentistry,” described five types of
obturators in his classic work, Le Chirurgien-Dentiste. He was the first to discard
sponges and advocate an obturator-bulb fixed to a denture base. He also described
the retention of full upper dentures by means of atmospheric pressure, adhesion,
31. 6 1 Biomaterials and Biological Materials
and peripheral seal, methods which have application in obturator therapy. In 1756
Lorenz Heister further perfected Fauchard’s appliances. Iron wire was reported to
have been used as early as 1775 for fracture fixation (Wnek and Bowlin 2008).
Delabarre introduced the soft-hinged velum in 1820. Bourdet noticed the tendency
of acquired palatal defects to close spontaneously (which might be only an obser-
vation of local recurrence of malignant disease). He designed obturators consisting
of a plate of gold held by ligature wires to the abutment teeth. Until about 1820,
obturators were primarily used for the treatment of acquired defects of the hard
palate.
Claude Martin used for the first time on 13 April 1887 an immediate prosthetic
appliance in conjunction with surgery. The poor results obtained by his predecessors
in the restoration of the resected mandible (partial and hemi-resection) prompted
his work. According to Martin, immediate prosthesis consists of the replacement
of the resected bone fragment by an appliance fixed in the soft tissues before clo-
sure of the wound. This idea is the first hint of the modern principles of immediate
bone grafting, fixed Vitallium (cobalt–chromium–molybdenum alloys), or tantalum
implants used for the restoration of bone loss in the mandible in today’s plastic and
reconstructive surgery.
With the advent of the Iron Age and Industrial Revolution, steel materials were
used in the nineteenth century as bone plates and screws to fix fractures. Fixing
fractures with screws allowed a stronger fixity than the earlier method of fixing
with metallic wires. Steel made from nickel-plating steel and vanadium steel later
replaced carbon steel materials as steel corrodes easily in the human body. However,
these newer materials were not sufficiently corrosion resistant. It also became clear
that they become toxic inside the human body.
Historically speaking, until Dr. J. Lister’s aseptic surgical technique was devel-
oped in the 1860s, attempts to implant various metal devices such as wires and
pins constructed of iron, gold, silver, platinum were largely unsuccessful due to
infection after implantation. The aseptic technique in surgery has greatly reduced
the incidence of infection. Many recent developments in implants have centered
around repairing long bones and joints. In the early 1900s bone plates were suc-
cessfully implemented to stabilize bone fractures and accelerate their healing. Lane
of England designed a fracture plate in the early 1900s using steel. Sherman of
Pittsburgh modified the Lane plate to reduce the stress concentration by eliminat-
ing sharp corners. He used vanadium alloy steel for its toughness and ductility.
Subsequently, Stellite R
(Co–Cr-based alloy) was found to be the most inert material
for implantation by Zierold in 1924. Soon 18-8 (18 w/o Cr, 8 w/o Ni) and 18-8 s Mo
(2–4 w/o Mo) stainless steels were introduced for their corrosion resistance, with
18-8 s Mo being especially resistant to corrosion in saline solution. Later, another
alloy (19 w/o Cr, 9 w/o Ni) named Vitallium R
was introduced into medical practice.
The first use of magnesium was reported by Lambotte in 1907, who utilized a
plate of pure magnesium with gold-plated steel nails to secure a fracture involving
the bones of the lower leg (Lambotte 1932). The attempt failed as the pure magne-
sium metal corroded too rapidly in vivo, disintegrating only 8 days after surgery and
producing a large amount of gas beneath the skin.
32. 1.2 Brief History of Biomaterials 7
Albee and Morrison first studied calcium phosphate (CaP) compounds in 1920,
injecting tricalcium phosphate (TCP) into animals to test its efficacy as a bone
substitute.
A noble metal, tantalum, was introduced in 1939, but its poor mechanical prop-
erties and difficulties in processing it from the ore made it unpopular in orthopedics,
yet it found wide use in neurological and plastic surgery.
Smith-Petersen in 1931 designed the first nail with protruding fins to prevent rota-
tion of the femoral head. He used stainless steel but soon changed to Vitallium R
.
Thornton in 1937 attached a metal plate to the distal end of the Smith-Petersen nail
and secured it with screws for better support. Later in 1939, Smith-Petersen used
an artificial cup over the femoral head in order to create new surfaces to substi-
tute for the diseased joints. He used glass, Pyrex R
, Bakelite R
, and Vitallium R
.
The latter was found more biologically compatible, and 30–40% of patients gained
usable joints. Similar mold arthroplastic surgeries were performed successfully by
the Judet brothers of France, who used the first biomechanically designed prosthe-
sis made of an acrylic (methyl methacrylate) polymer. The same type of acrylic
polymer was also used for corneal replacement in the 1940s and 1950s due to its
excellent properties of transparency and biocompatibility. Thus, according to Ratner
and Bryant (2004), the modern era of medical implants might be traced back to an
observation made by British ophthalmologist Harold Ridley in the late 1940s. While
examining Spitfire fighter pilots who had shards of canopy plastic unintentionally
implanted in their eyes from enemy machine gun fire, he noted that these shards
seemed to heal without ongoing reaction. He concluded that the canopy plastic,
poly(methyl methacrylate), might be appropriate for fashioning implant lenses for
replacing cataractous natural lenses. His first implantation of such a lens was in
1949. His observation and innovation led to the development of modern intraocular
lenses (IOLs) that are now being implanted in over 10 million human eyes each year
and have revolutionized treatment for those with cataracts. At about the same time
that Harold Ridley was innovating IOLs, Charnley was developing the hip implant,
Vorhees invented the vascular graft, Kolff was revolutionizing kidney dialysis, and
Hufnagel invented the ball and cage heart valve (Ratner and Bryant 2004). These
pioneers, in an era before principles for medical materials were established, proved
feasibility, saved lives, and evolved the foundations that we build on today.
In 1952, Ray et al. developed hydroxyapatite (HA), a combination of various
CaP compounds, testing healing of nonunions in rats and guinea pigs. However,
commercial application of HAs did not occur until the 1970s (Weiss 2003).
By the late 1960s engineers, chemists, and biologists, in collaboration with physi-
cians, were formalizing design principles and synthetic strategies for biomaterials.
In particular, the idea that the release of toxic leachables from biomaterials will
adversely affect healing was formalized—this toxicology idea is implicit in today’s
definition of biocompatibility.
As developments took place in biology and materials science, biomaterials
researchers were quick to incorporate these new ideas into biomaterials.
By the time of the 1950s–1960s, blood vessel replacements were in clinical trials
and artificial heart valves and hip joints were in development.
33. 8 1 Biomaterials and Biological Materials
Thus, till the polymer industry was developed in 1950s, the metallic mate-
rials were mainly used. The first quarter century, 1950–1975, of biomaterials
development was dominated by the characteristics of the materials intended for
prostheses and medical devices. Blood vessel implants were attempted with rigid
tubes made of polyethylene, acrylic polymer, gold, silver, and aluminum, but these
soon filled with clot. The major advancement in vascular implants was made by
Voorhees, Jaretzta, and Blackmore in 1952, when they used a cloth prosthesis
made of Vinyon R
N copolymer (polyvinylchloride and polyacrylonitrile) and later
experimented with nylon, Orlon R
, Dacron R
, Teflon R
, and Ivalon R
. Through the
pores of the various cloths a pseudo- or neointima was formed by tissue ingrowths.
This new lining was more compatible with blood than a solid synthetic surface,
and it prevented further blood coagulation. Heart valve implantation was made
possible only after the development of open-heart surgery in the mid-1950s. Starr
and Edwards in 1960 made the first commercially available heart valve, consisting
of a silicone rubber ball poppet in a metal strut. Concomitantly, artificial heart and
heart assist devices have been developed.
Important in the early days was the long-term integrity of the biomaterial as
well as its non-toxic nature. Biological interactions that were considered included
the non-toxic nature of the biomaterial as well as its normal inflammatory and
wound healing responses when implanted. Many materials were described as being
inert, but this was a confusing descriptor as it did not adequately and appropriately
describe material changes following implantation or cell and tissue responses to the
implanted biomaterial. It eventually became clear that materials could change with-
out adversely affecting the function and interaction of the biomaterial, prosthesis,
or medical device. Likewise, modulation of the inflammatory and wound healing
responses could occur without altering the function of the biomaterial, prosthesis,
or medical devices.
From 1970 to 2000, biological interactions with biomaterials started to be more
extensively investigated. The discovery by Hench and co-workers that a range of
compositions of modified phosphosilicate glasses has the ability to form a stable
chemical bond with living tissues (bone, ligament, and muscle) opened a completely
new field in biomedicine (Hench et al. 1971). Since then, many artificial biomateri-
als based on, or inspired by, Hench’s glasses have been developed and successfully
employed in clinical applications for repairing and replacing parts of the human
body. This field is continuously expanding: new processing routes have extended
the range of applications toward new and exciting directions in biomedicine (Hench
and Polak 2002), many of which still rely on the original Hench’s base formulation,
45S5 Bioglass, which has now become the paradigm of bioactive materials.
Advances in our knowledge of biological mechanisms, for example, the coag-
ulation, thrombosis, and complement pathways, led to a better understanding of
biological interactions with biomaterial surfaces. In the 1980s, the revolution in
techniques for the study of cell and molecular biology led to their application to
the investigation of interactions occurring at biomaterial interfaces. More recently,
with the advent of the areas of tissue engineering and regenerative medicine, heavy
emphasis has been placed on biological interactions with biomaterials.
What is the state of the art today? Surprisingly, gold is still quite popular!
34. 1.2 Brief History of Biomaterials 9
Recently, it was shown that implants of pure metallic gold release gold ions
which do not spread in the body, but are taken up by cells near the implant (Larsen
et al. 2008). It was hypothesized that metallic gold could reduce local neuron
inflammation in a safe way. Bioliberation, or dissolucytosis, of gold ions from metal-
lic gold surfaces requires the presence of disolycytes, i.e., macrophages, and the
process is limited by their number and activity.
Novel metal-based biomaterials were also developed during last decade. For
example, bulk metallic glasses (BMGs) are a promising biomaterial due to their
superior mechanical properties and corrosion and wear resistance over the metallic
biomaterials used currently (Ashby and Greer 2006). The in vitro and in vivo results
indicate that the BMGs are in general nontoxic to cells and compatible with cell
growth and tissue function. Unique about BMGs is that chemistry, atomic structure,
and surface topography (Kumar et al. 2009) can all be varied independently and
the effect of the individual contribution on the biocompatibility was revealed in this
work. The ability to precisely net-shape complex geometries combined in a single
processing step, with patterning of the surface, will enable us to program desirable
and predictable cellular response into a three-dimensional biomaterial (Schroers
et al. 2009).
The modern biomaterials science is defined and explained through the intro-
duction of biotechnology and advances in the understanding of human tissue
compatibility. Developing from bio-inert materials to biodegradable materials, bio-
materials are widely used in medical devices, tissue replacement, and surface
coating applications. Without doubts, the market situation is also one of the driv-
ing forces in recent times. Improved patient benefits form the most important factor
stimulating market growth for biomaterials, where major segments are as usual
ceramics, metals, polymers, and composites. Reconstructive surgery and orthobi-
ologics are the dominant segments in orthopedic biomaterials today. Placement of
endosseous implants has improved the quality of life for millions of people. It is
estimated that over 500,000 total joint replacements, primarily hips and knees, and
between 100,000 and 300,000 dental implants are used each year in the United
States alone (Wnek and Bowlin 2008). Total joint arthroplasty relieves pain and
restores mobility to people such as those afflicted with osteoarthritis, and den-
tal implants provide psychological and aesthetic benefits in addition to improving
masticatory function for edentulous patients.
Modern biomaterials found applications not only in orthopedic, cardiovascular,
gastrointestinal, wound care, urology, and plastic surgery, but in such directions
as brain repair (Zhong and Bellamkonda 2008). As reported in Nature Reviews
article (Orive et al. 2009), recently developed biomaterials can enable and aug-
ment the targeted delivery of drugs or therapeutic proteins to the brain, allow cell
or tissue transplants to be effectively delivered to the brain, and help to rebuild
damaged circuits. Similarly, biomaterials are being used to promote regeneration
and to repair damaged neuronal pathways in combination with stem cell thera-
pies. Many of these approaches are gaining momentum because nanotechnology
allows greater control over material–cell interactions that induce specific devel-
opmental processes and cellular responses including differentiation, migration and
outgrowth.
35. 10 1 Biomaterials and Biological Materials
1.3 Classification of Biomaterials
The reader can find different kinds of classification proposed for biomaterials in the
literature, especially in the books listed in the Table 1.1. Due to limited space, I
include in this chapter only very common information about this topic.
Table 1.1 Books related to biomaterials
Year Title Author(s) Publisher
1948 An Introduction to the
History of Dentistry with
Medical and Dental
Chronology and
Bibliographic Data
Weinberger BW The C.V. Mosby
Company, St. Louis,
D.D.S., New York
1967 Cell Wall Mechanics of
Wood Tracheids
Mark RE Yale University Press,
New Haven
1968 On Growth and Form, 2nd
ed.
Thompson DW Cambridge University
Press, Cambridge
1970 Strength of Biological
Materials
Yamada H (Edited by
Evans FG)
Williams and Wilkins
(Company,
Baltimore)
1970 Physical Properties of plant
and Animal Materials
Mohsenin NN Gordon and Breach
scientific Publishers
1971 Organic Chemistry of
Biological Compounds
Barker R Prentice-Hall,
Englewood Cliffs, NJ
1971 Biophysical Properties of
the Skin
Elden HR Wiley, New York
1972 Biomechanics: Its
Foundation and
Objectives
Fung YC, Perrone N,
Anliker M
Prentice-Hall,
Englewood Cliffs, NJ
1972 Keratins: Their
Composition, Structure,
and Biosynthesis
Fraser RDB, MacRae TP,
Rogers GE
Thomas, Springfield
1974 The Structure and Function
of Skin, 3rd ed.
Montagna W, Parakkal
PF
Academic Press, New
York
1974 The Physical Biology of
Plant Cell Walls
Preston RD Chapman and Hall,
London
1975 Structural Materials in
Animals
Brown CH Pitman, London
1975 Biology of the Arthropod
Cuticle
Neville AC Springer-Verlag, New
York
1976 Mechanical Design in
Organism
Wainwright SA, Biggs
WD, Currey JD,
Gosline JW
Princeton University
Press, Princeton
1976 Wood Structure in
Biological and
Technological Research
Jeronimidis G. In: Baas
P, Bolton AJ, Catling
DM
The University Press,
Leiden
1977 Chitin Muzzarelli RAA Pergamon Press, UK,
Oxford
36. 1.3 Classification of Biomaterials 11
Table 1.1 (continued)
Year Title Author(s) Publisher
1980 Guidelines for
Physicochemical
Characterization of
Biomaterials. Devices
and Technology Branch
National Heart, Lung
and Blood Institute
Baier RE NIH Publication No.
80-2186
1980 Mechanical Properties of
Biological Materials
Vincent JFV, Currey JD Cambridge University
Press, Cambridge
1980 Introduction to Composite
Materials
Tsai SW, Hahn HT Technomic Pub. Co.,
Westport, CT
1981 Mechanical Properties of
Bone
Cowin SC American Society of
Mechanical
Engineers, New York
1983 Biomaterials in
Reconstructive Surgery
Rubin LR The C.V. Mosby
Company, St. Louis,
MO
1984 Mechanical Adaptations of
Bone
Currey JD Princeton University
Press, Princeton
1984 The mechanical
Adaptations of Bones
Currey JD Princeton University
Press, Princeton
1985 Cellulose Chemistry and Its
Applications
Nevell TP, Zeronian SH Wiley, New York
1985 Cellulose Chemistry and Its
Applications
Nevell TP, Zeronian SH John Wiley and Sons,
New York
1986 Cellulose: Structure,
Modification, and
Hydrolysis
Young RA, Rowell RM John Wiley and Sons,
New York
1990 Biomechanics: Motion,
Flow, Stress, and Growth
Fung YC Springer-Verlag, New
York
1990 Handbook of Bioactive
Ceramics, Volume
II—Calcium Phosphate
and Hydroxyapatite
Ceramics
Yamamuro T, Hench L,
Wilson J
CRC Press, Boca Raton
1991 Biomaterials: Novel
Materials from
Biological Sources
Byrom D Macmillan
1991 Structural Biomaterials Vincent JFV Princeton University
Press, Princeton
1992 Materials Selection in
Mechanical Design
Ashby MF Butterworth-
Heinemann,
Oxford
1992 Allografts in Orthopedic
Practice
A. Czitrom and Gross A Williams & Wilkins,
Baltimore
1992 Biological Performance of
Materials: Fundamentals
of Biocompatibility
Black J Marcel Dekker, New
York
37. 12 1 Biomaterials and Biological Materials
Table 1.1 (continued)
Year Title Author(s) Publisher
1992 Biomaterials—An
Introduction, 2nd ed.
Park JB and Lakes RS Plenum Press, New
York
1992 Biological Performance of
Materials, 2nd ed.
Black J Marcel & Dekker, New
York
1993 Biomechanics: Mechanical
Properties of Living
Tissues, 2nd ed.
Fung YC Springer-Verlag, New
York
1993 Composite Materials for
Implant Applications in
the Human Body
Jamison RD and
Gilbertson LN
American Society of
Testing and Materials,
Philadelphia, USA
1994 Composite Materials:
Engineering and Science
Matthews FL and
Rawlings RD
Chapman & Hall,
London
1994 Applied Dental Materials McCabe JF Blackwell Science
Publications, Oxford
1994 Implantation Biology: The
Host Response and
Biomedical Devices
Greco RS CRC Press, London
1994 Hierarchical Structures in
Biology as a Guide for
New Materials
Technology
National Materials
Advisory Board,
Commission on
engineering and
Technical systems,
National research
Council, NMAB- 464
National Academy
Press, Washington,
DC
1994 Hierarchical Structures in
Biology as a Guide for
New Materials
Technology
Tirrell DA National Academy
Press, Washington,
DC
1995 Proteins at Interfaces II.
Fundamentals and
Applications
Horbett TA, Brash JL American Chemical
Society, Washington,
DC
1995 Self-reinforced
Bioabsorbable Polymeric
Composites in Surgery
Rokkamen P, Törmälaö P Tampereen, Pikakapio,
Tampere, Finland
1995 Biomedical Applications of
Synthetic Biodegradable
Polymers
Hollinger JO CRC Press, London
1996 Biomaterials Science: An
Introduction to Materials
in Medicine
Ratner BD, Hoffman AS,
Schoen FJ, and
Lemons JE
Elsevier Science, New
York
1996 An Introduction to
Composite Materials
Hull D and Clyne TW Cambridge University
Press, Cambridge,
UK
1997 Biomechanics: Circulation,
2nd ed.
Fung YC Springer-Verlag, New
York
1997 Protein-Based Materials McGrath KP, Kaplan DL Birkhäuser, Boston
38. 1.3 Classification of Biomaterials 13
Table 1.1 (continued)
Year Title Author(s) Publisher
1998 The Chemistry, Biology, and
Medical Applications of
Hyaluronan and Its
Derivatives
Laurent TC Portland Press, London
1998 Biomaterials in Surgery Walenkamp GHIM,
Bakker FC
New York, Stuttgart
1998 Design Engineering of
Biomaterials for Medical
Devices
Hill D John Wiley & Sons,
New York
1999 Basic Transport
Phenomena in
Biomedical Engineering
Fournier RL Taylor & Francis, PA,
Philadelphia
1999 A Primer on Biomechanics Lucas GL, Cooke FW,
Friis EA
Springer, New York
2000 The History of Metallic
Biomaterials, Metallic
Biomaterials,
Fundamentals and
Applications
Sumita M, Ikada Y, and
Tateishi T
ICP, Tokyo
2000 Bone Cements Kühn K-D Springer, Berlin
2001 Structural Biological
Materials
Elices M Pergamon
2001 Bone Biomechanics, 3rd ed. Cowin SC (ed) CRC Press, Boca Raton,
FL
2001 Chitin: Fulfilling a
Biomaterials Promise
Khor E Elsevier, Oxford
2002 Heterogeneous Materials:
Microstructure and
Macroscopic Properties
Torquato S Springer, New York
2002 Integrated Biomaterials
Science
Barbucci R Kluwer
Academic/Plenum,
New York
2002 Biomaterials Bhat SV Narosa Publishing
House, New Delhi,
India
2002 An Introduction to
Tissue-Biomaterial
Interactions
Dec KC, Puleo DA, and
Bigirs R
John Wiley & Sons,
New York
2002 Bones: Structure and
Mechanics
Currey JD Princeton University
Press, Princeton
2003 Calcium Phosphate Bone
Cements: A
Comprehensive Review
Weiss DD Journal of Long-Term
Effects of Medical
Implants,
13(1)41−47
2003 Failure in Biomaterials, in
Comprehensive
Structural Integrity
series, vol. 9
Teoh SH Elsevier, London, UK
39. 14 1 Biomaterials and Biological Materials
Table 1.1 (continued)
Year Title Author(s) Publisher
2004 Engineering Materials for
Biomedical Applications
Teoh SH World Scientific
Publishing Co. Pte.
Ltd.
2005 Biomaterials Science: An
Introduction to Materials
in Medicine
Ratner BD, Hoffman AS,
Schoen FJ, Lemons JE
Academic Press, New
York
2005 Surfaces and Interfaces for
Biomaterials
Vadgama P Woodhead Publishing
Ltd.
2005 Medical Textiles and
Biomaterials for
Healthcare
Anand SC, Miraftab M,
Rajendran S, Kennedy
JF
Woodhead Publishing
Ltd.
2006 An Introduction to
Biomaterials
Guelcher SA, Hollinger
JO
CRC Taylor & Francis
2006 Mechanics of Biological
Tissue
Holzapfel GA, Ogden
RW
Springer, New York
2007 Cellular Transplants: From
Lab to Clinic
Halberstadt C and
Emerich DF
Academic Press
2007 The Gecko’s Foot Forbes P Fourth Estate, London
2007 Biomedical Polymers Jenkins M Woodhead Publishing
Ltd.
2008 Cellular Response to
Biomaterials
Di Silvio L Woodhead Publishing
Ltd.
2008 Shape Memory Alloys for
Biomedical Applications
Yoneyama T, and
Miyazaki S
Woodhead Publishing
Ltd.
2008 Orthopaedic Bone Cements Deb S Woodhead Publishing
Ltd.
2008 Natural-Based Polymers for
Biomedical Applications
Reis RL, Neves NM,
Mano JF, Gomez ME,
Marques AP, Azevedo
HS
Woodhead Publishing
Ltd.
2008 Bioceramics and Their
Clinical Applications
Kokubo T Woodhead Publishing
Ltd.
2008 Dental Biomaterials:
Imaging, Testing and
Modelling
Curtis RV and Watson
TF
Woodhead Publishing
Ltd.
2009 Orthodontic Biomaterials Matasa CG and Chirita
M
Technica-Info Kishinev
2009 Bulk Metallic Glasses for
Biomedical Applications
Schroers J, Kumar G,
Hodges TM, Chan S
and Kyriakides TM
JOM, 61, 21–29
2009 Mechanical Behaviour of
Materials
Meyers M, Chawla C Cambridge University
Press
2009 Biomaterials and
Regenerative Medicine in
Ophthalmology
Chirila TV Woodhead Publishing
Ltd.
2009 Bone Repair Biomaterials Planell JA, Best SM,
Lacroix D, Meroli A
Woodhead Publishing
Ltd.
2009 Biomaterials and Tissue
Engineering in Urology
Denstedt J and Atala A Woodhead Publishing
Ltd.
40. 1.3 Classification of Biomaterials 15
Table 1.1 (continued)
Year Title Author(s) Publisher
2009 Biomaterials for Treating
Skin Loss
Orgill DP, Blanco C Woodhead Publishing
Ltd.
2009 Materials Science for
Dentistry, 9th ed.
Darvell BV Woodhead Publishing
Ltd.
2009 Biomedical Composites Ambrosio L Woodhead Publishing
Ltd.
2010 Injectable Biomaterials:
Science and Applications
Vernon B Woodhead Publishing
Ltd.
2010 Biomaterials for Artificial
Organs
Lysaght M Woodhead Publishing
Ltd.
2010 Bioactive Materials in
Medicine: Design and
Applications
Zhao X, Courtney JM
and Qian H
Woodhead Publishing
Ltd.
2010 Surface Modification of
Biomaterials: Methods,
Analysis and
Applications
Williams R Woodhead Publishing
Ltd.
2010 Biotextiles as Medical
Implants
King MV and Gupta BS Woodhead Publishing
Ltd.
2010 Novel Biomedical
Hydrogels: Biochemistry,
Manufacture and
Medical Implant
Applications
Rimmer S Woodhead Publishing
Ltd.
2010 Regenerative Medicine and
Biomaterials for the
Repair of Connective
Tissues
Archer C and Ralphs J Woodhead Publishing
Ltd.
Based on the nature of material these can be further classified into following
manner: Metals and Alloys; Ceramics, Polymers, and Composites.
1.3.1 Metals and Alloys
Metals were among the first orthopedic biomaterials and are commonly used to this
day (see Section 1.2). Currently, most orthopedic implants are made from either
stainless steel, titanium or one of its alloys, or a cobalt–chrome alloy, although
tantalum and Nitinol metals have also been used.
1.3.2 Ceramics
These kinds of biomaterials are well described and classified in Encyclopedia of
Biomaterials and Biomedical Engineering (Wnek and Bowlin 2008).
41. 16 1 Biomaterials and Biological Materials
Biostable Ceramics. Aluminum oxide (alumina, ASTM F-603) and a zirconium
oxide (zirconia) compound (ASTM F-1873) are the two most common biostable
ceramics. Biostable ceramics neither resorb nor induce osteoblastic apposition on
their surfaces within the body.
Advantages are that both aluminum oxide and zirconium oxide are strong and
stable (so there is no need to follow degradation products); while the disadvan-
tages include having weak interface with bone or tissue, low shock resistance, high
modulus, and the potential for catastrophic failures.
Bioactive Ceramics. The most common examples are bioactive glasses
(Bioglass) (see Hench (1998)), bioactive glass-ceramics (Ceravitals A-W Ceramic).
Their main advantage is good bonding to tissue and bone; their disadvantage is that
they are not as strong as biostable ceramics (Hench 1998; Hench and Andersson
1993; Hench and Paschall 1973; Hench and West 1996).
Bioresorbable Ceramics. Various apatites and other calcium phosphate and
carbonate-containing bioceramics like Biobase and Cerasorb. (More detailed
reviewed by Dorozhkin 2009.)
Ceramic Bone Cements.Ceramic bone cements are another active area of research
and clinical use. Several different approaches have been taken in the development of
a variety of ceramic-based bone cements. Examples of bone cements are discussed
in detail in the reviews by Kühn (2000) and Weiss (2003).
1.3.3 Polymers
Most of the biodegradable polymeric products on the market are made from only
a few polymers, many of which were first used in sutures. The most common
suture materials are the polylactic and glycolic acid polymers and copolymers,
the trimethylene carbonate copolymers, and polydioxanone. The advantages of the
biodegradable polymeric products include the following: they disappear, so long-
term stress shielding is not a concern; there are no long-term device or materials
problems; and no second operation is required for removal. The biodegradable
polymeric products can be used for drug delivery.
1.3.4 Composites
Composite materials can be generally defined as those materials having two or more
distinct material phases. Porous materials may also be considered composite mate-
rials, with one phase composed of void or air spaces. Composite biomaterials for
dentistry, for example, are mostly based on combinations of silane-coated inorganic
filler particles with dimethacrylate resin. The filler particles used are either barium
silicate glass, quartz, or zirconium silicate and are usually combined with 5–10%
weight of 0.04 μm particles of colloids silica.
A hydroxyapatite–polyethylene composite has been developed for use in
orthopedic implants. The material knits together with bone, maintains good
mechanical properties, and can be shaped or trimmed during surgery using a scalpel.
42. 1.4 Requirements of Biomaterials 17
Interestingly, Wegst and Ashby (as reviewed by Anderson 2006) classify biolog-
ical (natural) materials into four groups:
Ceramics and ceramic composites: These are biological materials where the
mineral component is prevalent, such as in shells, teeth, bones, diatoms, and
spicules of sponges.
Polymer and polymer composites: Examples of these are the hooves of mam-
mals, ligaments and tendons, silk, and arthropod exoskeletons.
Elastomers: These are characteristically biological materials that can undergo
large stretches (or strains). The skin, muscle, blood vessels, soft tissues in
body, and the individual cells fall under this category.
Cellular materials: Typically are the light weight materials which are prevalent
in feathers, beak interior, cancellous bone, and wood.
1.4 Requirements of Biomaterials
The design or selection of a specific biomaterial depends on the relative impor-
tance of the various properties that are required for the intended medical application.
Physical properties that are generally considered include hardness, tensile strength,
modulus, and elongation; fatigue strength, which is determined by a material’s
response to cyclic loads or strains; impact properties; resistance to abrasion and
wear; long-term dimensional stability, which is described by a material’s viscoelas-
tic properties; swelling in aqueous media; and permeability to gases, water, and
small biomolecules. In addition to the mechanical, thermal, and surface properties
of materials, other physical properties could be important in particular applications
of biomaterials: electrical, optical, absorption of x-rays, acoustic, ultrasonic, density,
porosity, and diffusion (Park and Lakes 2007).
The success of a biomaterial in the human body depends on the controlled bulk
properties (mechanical as well as a match of tissues at the site of implantation) and
the surface properties on the micrometer and nanoscale (Fig. 1.1). The shape and
bulk properties of biomaterials should mimic the tissues which they are meant to
augment or replace. The surface chemistry and topography of the implant material
determine how the host tissues interact with the implant. Therefore, the ability to
fabricate complex shapes with a wide range of surface topographies is an important
property of a biomaterial (Schroers et al. 2009).
Depending on the application, differing requirements may arise. Sometimes these
requirements can be completely opposite. In tissue engineering of the bone, for
instance, the polymeric scaffold needs to be biodegradable so that as the cells gen-
erate their own extracellular matrices, the polymeric biomaterial will be completely
replaced over time with the patient’s own tissue. In the case of mechanical heart
valves, on the other hand, we need materials that are biostable, wear-resistant, and
which do not degrade with time. Materials such as pyrolytic carbon leaflet and
titanium housing are used because they can last at least 20 years or more (Teoh
2004).
43. 18 1 Biomaterials and Biological Materials
Fig. 1.1 The foreign body reaction as illustrated here is the normal reaction by higher organisms to
an implanted synthetic material. A biomaterial implanted into the body, however, induces a differ-
ent response, termed the foreign body reaction. A biomaterial elicits nonspecific protein adsorption
immediately upon implantation. Many different proteins adsorb to the surface in a range of con-
formations from native to denatured. Nonspecific protein adsorption may be an instigator in the
foreign body reaction. A number of different cells, such as monocytes, leukocytes, and platelets,
adhere to these biomaterial surfaces and as a result may lead to upregulation of cytokines and
subsequent proinflammatory processes. The end stage of the foreign body reaction involves the
walling off of the device by an avascular, collagenous fibrous tissue that is typically 50–200 μm
thick (adapted from Ratner and Bryant 2004)
According to Teoh (2004), the requirements of biomaterials can be generally
grouped into four broad categories:
1. Biocompatibility: The material must not disturb or induce an un-welcoming
response from the host, but rather promote harmony and good tissue-implant
integration. An initial burst of inflammatory response is expected and is
sometimes considered essential in the healing process. However, prolonged
inflammation is not desirable as it may indicate tissue necrosis or incompatibility.
2. Sterilizability: The material must be able to undergo sterilization. Sterilization
techniques include gamma, gas (ethylene oxide (ETO)), and steam autoclaving.
Some polymers such as polyacetal will depolymerize and give off the toxic gas
formaldehyde when subjected to high-energy radiation by gamma rays. These
polymers are thus best sterilized by ETO.
3. Functionability: The functionability of a medical device depends on the ability of
the material to be shaped to suit a particular function. The material must therefore
44. 1.5 The Future of Biomaterials 19
be able to be shaped economically using engineering fabrication processes. The
success of the coronary artery stent—which has been considered the most widely
used medical device—can be attributed to the efficient fabrication process of
stainless steel from heat treatment to cold working to improve its durability.
4. Manufacturability: It is often said that there are many candidate materials that
are biocompatible. However, it is often the last step, the manufacturability of the
material that hinders the actual production of the medical device. It is in this last
step that engineers can contribute significantly.
1.5 The Future of Biomaterials
The future of new biomedical materials is dependent upon the development of an
enhanced knowledge base of molecular, cellular, and tissue interactions with mate-
rials. The general trend in biomaterials is to use and employ materials that play an
active role in tissue regeneration rather than passive and inert materials. Therefore,
understanding how a material interacts with the surrounding environments, includ-
ing cells and tissue fluid, allows material design to be tailored so that implants can be
constructed to promote a specific biological response, helping them better perform
their function. This class of materials has been described as the “Third Generation”
of biomaterials (Abou Neel et al. 2009).
Anderson (2006) proposed two goals of Materials Scientists to study
biomaterials:
(a) The “materials” approach of connecting the (nano-, micro-, meso-) structure
to the mechanical properties is different from the viewpoint of biologists and
chemists, since it analyzes them as mechanical systems. This has yielded novel
results and is helping to elucidate many aspects of the structure heretofore not
understood.
(b) The ultimate goal of synthesizing bioinspired structures is a novel approach
within the design and manufacture. This approach has yielded some early
successes such as Velcro (the well-known hook-loop attachment device) in
which the material components were conventional and their performance was
biomimicked.
A new direction consists of starting at the atomic/molecular level (bottom-up
approach) through self-assembly and to proceed up in the dimensional scale, incor-
porating the hierarchical complexity of biological materials. This approach is at the
confluence of biology and nanotechnology and is already yielding new architec-
tures that have potential applications in a number of areas, including quantum dots,
photonic materials, drug delivery, tissue engineering, and genetically engineered
biomaterials.
Unfortunately, war crises became to be an additional driving force in develop-
ment of novel biomaterials with specific features today. Thus, for example, the
Pentagon recently funds major initiatives in biomaterials. The US Department
45. 20 1 Biomaterials and Biological Materials
of Defense has selected Princeton engineers to lead two new multi-institutional
research initiatives, aimed at inventing materials that adapt themselves to chang-
ing loads and environments. The structural materials project will be led by Ilhan
Aksay, professor of chemical engineering, and is to receive $7.5 million. The grants
were among 69 recently announced by the Pentagon as part of its Multidisciplinary
University Research Initiative (MURI) program. The goal of the materials science
project, sponsored by the Army Research Office, is to develop adaptive materials
that are able to repair and strengthen themselves when needed. A key to replicating
such functions will be to develop porous materials, similar to the structure of bone,
through which new material can flow to repair weak spots. The researchers plan
to develop an embedded sensing system to monitor and locate which areas need
strengthening. They also will investigate methods for directing and moving fluid
within the material to where it is needed.
Similar investigation has been carried out at Center for Military Biomaterials
Research in New Jersey since 2004. Another research project, dedicated to develop-
ment of a combination of bone cement and antibiotics, was supported by research
grants from the US Army Medical Research Acquisition Activity (USAMRAA),
Orthopedic Trauma Research Program, and the National Institutes of Health Public
Health Service Awards. The study was published online on January, 2, 2009 in the
Journal of Orthopedic Research. In this work, researches used bone cement infused
with an antibiotic called colistin—one of the last-resort antibiotics for drug-resistant
Acinetobacter baumannii—to treat mice infected with samples of the bacteria taken
from soldiers wounded in Iraq and Afghanistan. After 19 days, only 29.2% of the
mice still had detectable levels of A. baumannii.
An antibiotic chosen for use with this “Surgical Simplex R
P bone cement” must
elute from the cement at high enough levels to provide antibacterial protection dur-
ing the initial 72 h after implantation while remaining at safe, non-toxic levels in
the serum and urine. To provide this effective release, the antibiotic must be able to
withstand the heat generated by polymerization.
The civil sector of the biomaterials market also seems to be optimistic.
Biomaterials products had a market size of $25.5 billion in 2008, and the bioma-
terial device market size was $115.4 billion in the same year, and is expected to
reach $252.7 billion in 2014. This massive revenue potential highlights the immense
opportunity in the market.
According to a new market research report, “Global biomaterials Market
(2009–2014),” published by Markets and Markets (http://www.marketsandmarkets
.com), the total global biomaterials market is expected to be worth US$58.1 bil-
lion by 2014, growing at a CAGR of 15.0% from 2009 to 2014. The US market is
expected to account for nearly 42% of the total revenues. The biomaterials market
today has already crossed $28 billion.
While the orthopedic biomaterials market was the biggest segment in 2008 with
$9.8 billion, the cardiovascular biomaterial market is estimated to be dominant seg-
ment in 2014 with an estimated $20.7 billion. The cardiovascular biomaterial market
is expected to grow with a CAGR of 14.5% from 2009 to 2014, mainly due to
increasing stress levels that have in turn increased the incidence of cardiac arrest.
46. References 21
The US market is the largest geographical segment for biomaterials and is
expected to be worth $22.8 billion by 2014 with a CAGR of 13.6% from 2009
to 2014. Europe is the second largest segment and is expected to reach $17.7 billion
by 2014 with a CAGR of 14.6%, and the Asian market size is estimated to increase
at the highest CAGR of 18.2% from the year 2009 to 2014.
Improvement in fabrication technology and new product development at com-
petitive prices will be the key to future market growth. The USA and Europe hold
a major share of the global biomaterials market; while emerging economies such as
China, India, Japan, Brazil, Russia, and Romania represent a high growth rate.
1.6 Conclusions
Biomaterials are either modified natural or synthetic materials which find applica-
tions in a wide spectrum of medical and dental implant and prosthesis for repair,
augmentation, or replacement of natural tissues.
The past decade has witnessed the emergence of a new set of tools, combinato-
rial and high-throughput screening, in biomaterials development. Numerous articles
as well as books cited in this chapter covers recent examples of high-throughput
and combinatorial studies of biomaterials. Assembly of nanoscale materials and
functional hierarchical structures is a big challenge now faced by nanotechnology.
Learning from biology, using biopolymers as scaffolds to control the synthesis and
organization of materials like living tissues provides the perfect solution to deter-
mine the progress in biomaterials science. In the following chapters, I want to
illustrate the biomimetic potential and discuss features, advantages and imperfec-
tions of a broad variety of unique biological materials of marine origin from nano-
to macroscale.
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