Materials and Biomedical Aplications

Materials and Their Biomedical Applications
Min Wang, The University of Hong Kong, Pokfulam, Hong Kong

Bin Duan, University of Nebraska Medical Center, Omaha, NE, United States
© 2018 Elsevier Inc. All rights reserved.
Introduction 2
Materials Classification 2
Primary Bonds and Secondary Bonds 2
Structure of Materials 2
Crystalline Solids 2
Common crystal structures 3
Crystalline defects 3
Polycrystalline structures 4
Anisotropy of materials 4
Amorphous Materials 5
Glasses 5
Metallic glasses 5
Polymers 5
Monomer and chain structures 5
Amorphous polymers 5
Semi-crystalline polymers 6
Homopolymers and copolymers 6
Hydrogels 6
Composite Materials 6
Membranes and Thin Films 6
Natural Materials 6
Processes for Materials 7
Solidification of Metals and Phase Transformation 7
Recovery, Recrystallization and Grain Growth of Metals 8
Polymer Crystallization 8
Glass Transition of Amorphous Polymers 9
Diffusion in Solids 9
Processing–Structure–Property Relationships for Materials 9
An Introduction to Biomedical Materials 10
History of Biomaterials 10
Interdisciplinary Nature of Biomaterials Development 10
Human Body Environment 11
Biocompatibility of Materials 11
In Vitro Assessment of Biomaterials 11
In Vivo Evaluation of Biomaterials 12
Ex Vivo Evaluation of Biomaterials 12
Standards for Biomaterials 12
Government Regulations 13
Biomaterials in Action 13
Materials in Orthopedics 13
Materials in Wound Dressings 14
Materials in Dentistry 14
Materials in Ophthalmology 15
Materials for Cardiovascular Devices 15
Materials in Drug Delivery and Controlled Release 15
Materials in Reconstructive Plastic Surgery and Cosmetic Surgery 16
Materials in Bioelectrodes and Biosensors 16
Looking Into the Future 16
Cancer Theranostics 16
Bioprinting 17
Organs-on-Chips 17
Acknowledgments 17
Further Reading 18
Encyclopedia of Biomedical Engineering https://doi.org/10.1016/B978-0-12-801238-3.99860-X 1

2 Materials and Their Biomedical Applications
Glossary
Biomaterial A biomaterial is a non-viable material used in a medical device, intended to interact with biological systems.
Biocompatibility Biocompatibility is the ability of a material to perform with an appropriate host response in a specific
application.
Ex vivo Ex vivo is Latin, meaning “out of the living.” Ex vivo experiments refer to investigations or measurements conducted in
or on tissue from an organism in an external environment with minimal alteration of natural conditions.
In vitro In vitro is Latin, meaning “in the glass.” In vitro experiments are performed with biological species (biological
molecules, cells, microorganisms, etc.) outside their normal biological environment. They are generally conducted in labware
such as test tubes, flasks and Petri dishes.
In vivo In vivo is Latin, meaning “within the living.” In vivo studies are those in which the effects are investigated inside the
whole, living organisms including animals and humans.
Introduction
The history of mankind is characterized by the materials used and the naming of ages of civilizations effectively emphasizes the
importance of materials—the stone age, bronze age, iron age, cement age, steel age, silicon age and now new materials age. Looking
at our society as it is now and as it will be in the future, every field in the engineering world requires new materials, with the
biomedical field being no exception. Novel biomaterials and structures are needed for improving the performance of existing
medical devices and for developing new devices to tackle currently insurmountable medical problems. Modern biomaterials science
and engineering rests on two pillars: materials science and engineering, and biological and clinical sciences. A good understanding
of fundamentals of materials science and engineering paves the way for the successful development of new biomaterials.
Materials Classification
For whichever the engineering field, materials are classified into four categories: metals, polymers, ceramics, and composite
materials. Metals are strong and ductile; polymers are light, easily processable and flexible; ceramics are hard and brittle. When
the property of metals, polymers or ceramics are not good enough for the targeted application or new property is needed for the
application, a composite material is designed and developed. Needlessly to say that Nature, the best designer and maker of
materials, makes natural composites such as wood and nacre. Metals, polymers, ceramics and composites can be made into
different forms (particles, fibers, films and membranes, non-porous bodies, porous bodies, etc.) for different functions. The
structures made of these materials can be as small as having nanometer dimensions and as large as structures covering kilometers.
Primary Bonds and Secondary Bonds

Properties (mechanical, electrical, thermal, acoustical, optical, etc.) of metals, polymers and ceramics differ greatly. What makes
them different lies in the interatomic forces that bind the atoms together in these materials. Atoms form bonds because the
compounds formed by them are more stable than the alternative arrangements of isolated atoms. For all materials, there are three
types of primary interatomic bonds: ionic bonding, covalent bonding, and metallic bonding. Molecules are formed when atoms are
bonded together by strong primary bonds. Polymer long chains have covalent bonds, metals possess metallic bonds and in
ceramics, the bonds can be either ionic, covalent or a combination of both. While the primary bonds in materials are strong
bonds with high bonding energies, there are secondary bonds which are weak physical bonds such as hydrogen bonding and exist
between virtually all atoms or molecules. Hydrogen bonding forms between some molecules that have hydrogen atoms as one of
the constituents. Hydrogen bonding is important in the biological systems and hence in the biomedical field.
Structure of Materials
Crystalline Solids
The physical structure of solid materials highly depends on the arrangements of atoms, ions or molecules that form the material.
Crystalline solids are materials in which atoms are arranged in a repeating 3D pattern over large atomic distances (i.e., long-range
order). Examples of crystalline solids include metals and ceramics. Crystalline solids are in contrast to amorphous/noncrystalline
materials, whose atoms or ions are not arranged in long-range repeating 3D patterns. Liquid water is a representative material of this
group.
The repeated 3D arrangement of atoms in crystalline solids is called space-lattice, which means a 3D array of points coinciding
with atom positions. The geometrical configuration of a space lattice can be described through a unit cell. A unit cell is normally the
smallest group of atoms that form a repetitive pattern of the crystalline solid and maintains the characteristics of the overall crystal.
Materials and Their Biomedical Applications 3
In a perfect crystal, all the atom positions can be generated by translations of the unit cell at integral distances along each of its edges.
Three lattice vectors a, b, and c is used to describe the geometrical features of the unit cell. The lattice constants of the unit cell
include the axial lengths (a, b, and c) and the interaxial angles (a, b, and g). Fig. 1 exhibits a unit cell with the lattice vectors and
constants.
Common crystal structures

There are 14 different unit cells for all crystalline materials that are used today, representing 14 primary crystal structures. Among
them, body-centered cubic (BCC), face-centered cubic (FCC), and hexagonal close-packed (HCP) are the most common structures
in metals. Fig. 2 shows schematic drawings (unit cells) of these three crystal structures. In FCC and BCC which are both cubic, there
is only one axial length a, In HCP, there are two axial lengths: a and c. FCC and HCP are the densest unit cells. They have the highest
“atomic packing factor (APF).” APF is used to calculate the percentage of space occupied by atoms in a unit cell, assuming the atoms
are spherical. In the BCC structure, a central atom is surrounded by eight atoms which are located at all eight corners. The center and
corner atoms touch one another along the cube diagonals. Each BCC unit cell includes two atoms: the central atom is a complete
one, and each corner atom is shared by eight unit cells. The APF of BCC crystals is 0.68. FCC is also cubic, with atoms existing at the
corners and centers of all the cube faces. An FCC unit cell has the equivalent of four atoms, with each corner atom accounting for a
1/8 atom and each face center atom accounting for a 1/2 atom. The APF of FCC crystals is 0.74. Therefore, FCC crystals are more
closely packed than BCC crystals. HCP structure is also important but not often encountered. Each HCP unit cell has six atoms. The
APF of HCP is the same as that of FCC, that is, 0.74. A value of 0.74 for APF signifies the closest packing possible of “spherical
atoms.”
Crystalline defects
In reality, perfect crystalline solids do not exist. Various types of defects are present in crystals and considerably affect their physical
and mechanical properties. The classification of crystalline defects is made according to their geometry and shape. The four types,
from zero dimension to three dimensions, of crystalline imperfections are: (1) point defects, (2) linear defects, (3) interfacial
defects, and (4) bulk or volume defects.
Vacancies, the simplest point defects, are the absence of atoms at the regular lattice points and can be generated during
solidification as a result of local disturbances. Another type of point defects is interstitials, which means a small atom can occupy
an interstitial site between surrounding regularly-sited atoms in a crystal. Both vacancies and interstitials are important for diffusion
in crystalline solids.
Linear defects are also known as dislocations. Dislocations can be generated during material solidification. Other processes
(vacancy condensation, plastic deformation, etc.) can also create dislocations. There are two types of dislocations: edge dislocation
and screw dislocation (Fig. 3). The combination of these two types is called mixed dislocation. An edge dislocation can be
considered as the insertion of an additional half-plane of atoms in an otherwise perfect crystal. A screw dislocation can be created
by applying shear stresses with opposite directions to perfect crystalline structure.
Interfacial defects, or “planar defects,” include external surfaces, grain boundaries, and stacking faults. Grain boundaries and
stacking faults are two major types of interfacial defects. Grain boundaries exist in polycrystalline materials (“Grains” are individual
crystals in polycrystalline materials). They are surface defects that separate grains with different crystallographic orientations. This
region is about two to five atomic diameters in width and is a region of atomic mismatch between adjacent grains. The atomic
packing in grain boundaries is lower than within the grains. Grain boundaries also have some atoms in strained positions that raise
χ β α
b
y
γ α
a
x
Fig. 1 A unit cell with x, y, z axes, showing lattice vectors and constants.
Fig. 2 Three common crystal structures (from left to right: BCC, FCC, and HCP).
Fig. 3 Edge dislocation (left) and screw dislocation (right). (For the edge dislocation, the red dotted line refers to the linear defect. In the right figure, the red arrows
indicate the forces that cause the screw dislocation, which occurs on the blue plane.)
the energy of the grain boundary region. Grain boundaries can be generated during solidification of metals when different nuclei
grow simultaneously to form different grains and meet each other. Stacking faults mainly occur in HCP and FCC structures. HCP
and FCC crystals are formed by stacking of atomic planes (e.g., A, B, and C planes): ABABAB. . . for HCP structures and
ABCABCABC. . . for FCC structures. During the growth of these structures, one or more stacking planes may be missing, resulting
in stacking faults.
Bulk or volume defects include pores, cracks, and foreign inclusions in crystalline materials. Pores can occur when a cluster of
point defects combine together to form a three-dimensional imperfection. This type of defects has a tremendous effect on the
performance of materials.
Polycrystalline structures
Polycrystalline materials are solids that consist of many small crystals (the “grains”). The grains are separated by grain boundaries
and normally have random crystallographic orientations. The size of the grains may vary from nanometers to millimeters. During
the solidification of polycrystalline materials, small nuclei initially form at different positions of the liquid with random crystal-
lographic orientations. These nuclei grow into larger crystals by absorption of atoms in surrounding liquid. Eventually, the crystals
impinge on one another forming a granular or polycrystalline structure. In such a structure, a region grown out from the nucleus
with the same crystal orientation is called a grain. Grains are separated by grain boundaries, the interfaces across which the crystal
orientation suddenly changes. The atoms are packed loosely in the region of grain boundaries, making them mechanically and
chemically unstable. Thus cracks and corrosion occur more frequently at grain boundaries.
Anisotropy of materials
Anisotropy is the directionality of properties, which implies different values of the same property in different directions. On the
contrary, isotropy is the situation that properties are independent of directions. For single crystals, physical properties, such as elastic
modulus and electrical conductivity, of many substances are anisotropic. These properties vary by the crystallographic direction in
which the measurements are taken. In many polycrystalline materials, the orientations of individual grains are entirely random.
Therefore, even though each grain is anisotropic, most polycrystalline materials are isotropic.
Amorphous Materials
In contrast to crystalline solids, the atomic structures of amorphous materials lack long-range order because of factors that inhibit
the formation of a periodic arrangement of atoms. Atoms in amorphous materials are sited on random positions instead of distinct
spatial positions like the atoms in crystals. Fig. 4 provides schematic drawings for crystalline materials and amorphous materials.
Most polymers, glasses and some metals (“metallic glasses”) are amorphous materials.
Glasses
Glasses are amorphous solids that are usually transparent. They are mainly used for technological and decorative applications. The
most common type of glasses is silicate glass for windows, which generally consists of the chemical compound silica and has the
oldest history for glass applications. Other types of glasses include fiber glasses, network glasses, organic glasses, etc. In the viscous
liquid state of glasses, the molecules have limited mobility. The formation of the crystalline structure is thus inhibited and the
amorphous structure dominates after solidification.
Metallic glasses
Metallic glasses are a type of metals that are formed as non-crystalline solids under specific conditions. Compared to normal glasses,
metals have high mobility in the molten state and are very difficult to form amorphous structures. Metal alloys with a high
percentage of semi-metals, such as Si and B, can form metallic glasses through hyper-quenching. The cooling rate is usually between
105 and 109 degrees celsius per second, which is high enough so that the atoms do not have enough time to form crystalline
structures. Metallic glasses are ductile with exceptional mechanical strength. They also possess excellent anticorrosion properties
since grain boundaries do not exist in the amorphous structures.
Polymers
A polymer is a macromolecule that contains many chemically bonded subunits. Natural polymers, such as rubber and silk, have
been used by humans for centuries. Various natural polymers including DNA, proteins, enzymes and cellulose play vital roles in
biological processes of living creatures. From last century, many synthetic polymers have been invented and widely utilized in many
industries and daily life due to their broad range of properties.
Monomer and chain structures

A polymer can be synthesized through chemical combinations of many small molecules, which is termed as monomers. For a
monomer, the number of its available sites for bonding with other monomers under specific polymerization conditions is termed as
functionality. A monomer must have at least two active sites so that it can bond with two other monomers to form polymer chains.
Bifunctional monomers can only enter into two linkages with other monomers since each of them only has two sites available.
Polyfunctional monomers can be linked together as nonlinear structures.
According to the chain structure, polymers can be categorized into four groups—linear, branched, cross-linked, and network
polymers. If the monomers are linked together in a linear manner, the resulting structure is called a linear polymer. For branched
polymers, the monomers are joined together in a branched manner. Cross-linked polymers are formed when the monomer units are
linked in multiple chains and have interconnections between chains. Network polymers are the cases that cross-linked polymers
possess sufficient interconnections between chains. The chain structures of polymers are related to the functionality of monomers.
The combination of bifunctional monomers produces a linear polymer. Polyfunctional monomers can be linked together to form
nonlinear polymers, include branched, cross-linked, and network polymers.
Amorphous polymers
The structure of polymers can also be categorized as amorphous and semi-crystalline. Most polymers have non-crystalline
(“amorphous”) structures. Their chains are randomly entangled like noodles in a large scale. The physical entanglement of the
Fig. 4 Schematic drawings for crystalline materials (left, crystalline silica) and amorphous materials (right, amorphous polymers).
chains with the dipole secondary bonds between chains enhances the strength of amorphous polymers. For branched polymers,
their side branches can create loose packing of the chains, leading to amorphous structures.
Semi-crystalline polymers
In the crystalline parts of polymers, individual polymer chains are folded and packed in ordered arrangement. However, an entirely
crystalline structure cannot be achieved for polymers since there are always amorphous region in the long polymer chains. A semi-
crystalline polymer consists of many small crystalline regions interspersed with amorphous regions. Each crystalline region
possesses a particular alignment. Semi-crystalline polymers generally have enhanced mechanical properties, increased fatigue
strength and distinctive thermal behaviors as compared to amorphous polymers.
Homopolymers and copolymers

Polymers that are formed by single repeating units are termed homopolymers, while polymers made up of two or more different
repeating units are called copolymers. The sequence of a homopolymer molecular chain is like AAAAA. . . (“A” represents the single
repeating unit). For copolymers, four types of arrangement exist: random, alternating, block, and graft. For a random copolymer,
different monomers are randomly arranged in the molecular chains, such as ABBAAABABBB. . . (“A” and “B” represent different
types of repeating units). In an alternating copolymer, the monomers are arranged alternatively, like ABABABAB. . .. Block
copolymers are the molecules that different monomers are arranged in long blocks of the same type, like AAAAABBBBAAABBBBB. . ..
Graft copolymers are the cases that chains consisting of one type of monomer are grafted on the long chain of another type of
monomer.
Hydrogels
Hydrogels, as a group of polymeric materials, are semi-solid, cross-linked macromolecular networks made from hydrophilic
polymers. Because of the hydrophilic functional groups attached to the polymer backbone, the three-dimensional networks of
hydrogels can absorb and retain significant amounts of water in the cross-linked structures. The resistance of hydrogels to
dissolution arises from the cross-links between network chains. The crosslinks in hydrogels can be formed by physical cohesion
forces, ionic bonds or covalent bonds. Hydrogels can be classified as homogeneous or heterogeneous according to their network
structure. Homogeneous hydrogels possess an isotropic (random distribution) network structure, with relatively mobile chains and
pores in the network. Heterogeneous hydrogels exhibit an anisotropic network structure caused by the strong interpolymer
interaction.
Composite Materials
Composite materials are solids that consist of two or more chemically distinct phases which are separated by interface(s). In most
cases, composites consist of two phases—the matrix phase (metal, polymer or ceramic), which is the continuous phase that provides
the overall structure, and the reinforcing phase in the form of particulates or fibers. Composites can be categorized by the form of the
reinforcing phase. There are three major forms of reinforcing phases: particle-reinforced, fiber-reinforced, and structural-reinforced.
In particle-reinforced composites, the particles (reinforcing phase) are dispersed in the matrix. For fiber-reinforced composites, the
reinforcing phase has the geometry of a fiber. Structural-reinforced composites include structures such as laminates. With the matrix
and reinforcing phase, composites can combine the desirable properties from both constituents to meet specific application
requirements.
Membranes and Thin Films

Membranes are often used for purification and separation applications. They are often developed to possess high permeability and
sufficient selectivity while matching the process conditions such as temperature and pressure. Therefore, membranes often have
certain amounts of pores with specific pore sizes. Common membrane materials include polymers, inorganics (e.g., nanoporous
silica), and metal-organic framework (MOF). Each type membrane has its own structural features. For example, silica membranes
can be mesoporous with high uniformity. In biomedical field, membranes have great potential for biosensing, biosorting,
immunoisolation, and drug delivery.
Thin films are layers of materials (metals, polymers, and ceramics) with a thickness ranging from nanometers to micrometers. In
many applications including biomedical applications, coating a thin film on the substrate is highly important. A stack of thin films
is termed a multilayer and multilayered structures can provide distinctive properties. Thin films are vital for many industries since
they can provide excellent properties of the materials to fulfill application requirements.
Natural Materials
Numerous materials from the Nature have been used by human beings since the stone age and many of them (stone, wood, cotton,
etc.) still play important roles nowadays. Structures of natural materials vary tremendously, from crystalline structures like the
diamond to composites like wool. Among the natural materials, some are attractive for biomedical applications. A good example is
silks, which possess high mechanical strength and good biocompatibility. Silk materials are produced by different species with
unique properties. For silk made by silkworms, two main proteins, sericin and fibroin, form the main body of the silk. Fibroin is the
structural center of the silk, which is surrounded by sericin. The polymer chains in silk materials are bonded by both cross-links and
mechanical adhesion. Another natural material which is as biomaterials is collagen, a group of structural proteins that widely exists
in human and animals. Collagens are used in medical treatments for humans and have been intensively studied for tissue
engineering applications.
Processes for Materials

Solidification of Metals and Phase Transformation
In industrial applications, metals are usually melted and then cast into a mold to form products of designed shapes. The
solidification of metals is thus crucial for metal processing. Two major steps are included in the solidification process: (1)
nucleation, which is the formation of stable nuclei in the molten metals, and (2) growth of nuclei into crystals to form the granular
structure. In the nucleation process, the formation of stable nuclei in liquid metals can be either homogeneous or heterogeneous. In
homogeneous nucleation, metal itself provides the atoms for nuclei formation. When the temperature of a pure molten metal is
below a solidification point, many slow-moving atoms bond together to form numerous homogeneous nuclei. Heterogeneous
nucleation can occur on the nucleating agent, such as insoluble impurities, surfaces of the container of liquid metal and other
materials in a liquid. The nucleating agent must be wetted by the molten metal. Compared with heterogeneous nucleation,
homogeneous nucleation requires a large amount of undercooling, which may not be achievable in the industrial casting process.
After the formation of stable nuclei in liquid metal, nuclei begin to grow into crystals with different orientations. During the
solidification process, the crystals grow and join together to form grains and grain boundaries in the final solidified metal. With
more nuclei in the liquid metal, the average grain size will be smaller. Most engineering metal products have small grain sizes, which
is beneficial for mechanical strength and uniformity. In general, two major types of grain structure can be produced without using
grain refiners: equiaxed grains and columnar grains. Equiaxed grains form when crystals in the liquid metal grow equally in all
directions during solidification, while columnar grains are long, thin, coarse grains that form in the presence of a steep temperature
gradient during slow solidification.
Phase is a homogeneous portion with uniform physical and chemical properties in a system such as a metal alloy. If two or more
phases exist in a given system, there will be a boundary separating the phases, and each phase has its specific characteristics. For
example, steam, water, and ice in a container are considered to be three phases since they are physically different. Phase diagram is
the chart that exhibits conditions, such as pressure and temperature, under which distinct phases coexist at equilibrium. A general
phase diagram for this three-phase system is shown in Fig. 5. Phase transformations happen when phase boundaries (the red curves)
are crossed due to the changes of conditions. The arrow in Fig. 5 is an example of phase transformation—ice melts into water.
Phase transformation occurs during processing of materials and affects greatly their properties. In metal processing, control of
phase transformation can produce distinct materials to achieve desired properties. The driven force of phase transformation is the
difference of free enthalpy between two phases. Free enthalpy, or Gibbs free energy, is a function of the enthalpy (internal energy of
the system) and entropy (randomness of the atoms/molecules). The temperature for a phase transformation to occur is the
thermodynamic equilibrium temperature shown in the phase diagram. Phase transformations frequently start by the nucleation
process. The fluctuations of large amplitude of the structure/composition can lead to nucleus formation. With the growth of
nucleus, atoms/molecules will be absorbed to the nucleus at the interfaces between transforming phases, just like crystal growth
during the solidification of metals.
Liquid (Water)
Pressure
Solid (Ice)
Gas(Steam)
Temperature
Fig. 5 Schematic phase diagram for the ice-water-steam phase system.
Recovery, Recrystallization and Grain Growth of Metals

Cold working, such as rolling, forging, extrusion and other metal forming processes that are conducted under the “cold” condition,
strengthens metals through plastic deformation. The cold-worked metal has many dislocations and other defects. Metals that have
undergone cold working possess superior mechanical strength but are much less ductile. To enhance the ductility of cold-worked
metals, a process called annealing can be conducted for the metals. During annealing, the cold-worked metal is heated to a
sufficiently high temperature with adequate time, and three steps of changes occur: recovery, recrystallization, and grain growth.
A cold-worked metal has higher dislocation density and internal energy than the original one. When the cold-worked metal is
heated in the recovery temperature range, sufficient thermal energy is supplied to the dislocations to increase atomic diffusion. As a
result, some dislocations are annihilated and some other dislocations move and rearrange themselves into states with lower energy.
The internal stress of the metal is thus partially relieved. The recovery temperature range is just below the recrystallization
temperature range. After recovery, the mechanical strength of the metal is reduced slightly, while the ductility is often greatly
increased.
Recrystallization is the process that new strain-free grains form and grow in the metal after the recovery process. The newly
formed grains have low dislocation densities and are characteristic of conditions before cold working. The driving force of the
nucleation of strain-free grains is the difference of internal energy between the strained and unstrained material. The progress of
recrystallization depends on both temperature and time. The mechanical strength of metals decreases notably during
recrystallization.
Grain growth starts after recrystallization. If the temperature is high enough, the newly formed strain-free grain continue to grow.
With a sufficiently long time and proper temperature, the new grains grow and completely replace the previous ones, resulting in an
entire reduction in the internal energy. The internal energy is associated with the area of grain boundaries, which decrease when the
grains increase in size. The reduction of internal energy is the driving force for grain growth. Large grains grow at the expense of small
ones which shrink and eventually disappear. The Hall–Petch equation is applied to correlate the average grain size with yield
strength of polycrystalline materials.
Polymer Crystallization
Crystallization in polymers is different from that in metals and ceramics. Polymer crystallization is a process which transforms an
amorphous, crystallizable polymer into a semi-crystalline material that its molecular chains are partially aligned. The folded and
aligned polymer chains constitute an area called lamellae. Fig. 6 shows schematically structures of amorphous and semi-crystalline
polymers. Polymer crystallization can be conducted through different processes, such as solidification from the melt and solvent
evaporation.
The solidification of molten polymers starts by nucleation in which some chains in the polymer become parallel. Like the
solidification of metals, nucleation for semi-crystalline polymers also has two mechanisms: homogeneous, and heterogeneous. Due
to heat motion, some polymer chains occur parallel and result in homogeneous nucleation. Heterogeneous nucleation is initiated
by impurities or additives. After nucleation, crystal growth occurs at the temperature between the crystalline melting temperature Tm
and the glass transition temperature Tg. At this step, more folded chain segments are added on the nuclei. When the temperature
gradient is high enough, the direction of crystal growth correlates with the steepest gradient. If the polymer has an isotropic and
static temperature distribution, the crystal (lamellae) grows radially and forms a large aggregated called spherulite.
Solvent evaporation can also crystallize polymers. Generally, the polymer is dissolved in a solvent to form a dilute solution,
where the polymer chains are separated from each other, and the polymer chains can fold to form single-chain crystals. When the
solvent evaporate, the concentration of the solution increases and interactions between polymer chains occur to form semi-
crystalline polymers. The solvent evaporation process may generate polymers with the highest degree of crystallinity.
lamellae
Fig. 6 Schematic drawings for structures of amorphous polymers (left) and semi-crystalline polymers (right).
Glass Transition of Amorphous Polymers

Glass transition, or glass-liquid transition, is the transition of a hard and brittle glassy state into a softer and rubbery state for
amorphous and semi-crystalline polymers. Glass transition occurs at a narrow temperature range termed as glass transition
temperature Tg, which is usually lower than the crystalline melting temperature Tm. For semi-crystalline polymers, the glass
transition only occurs at the amorphous regions, while this process happens in the entire structure of amorphous polymers.
The glass transition can be illustrated by a typical specific volume-temperature curve as shown in Fig. 7. The green line refers to
the curve of an amorphous polymer, while the black line represents a semi-crystalline polymer. In the blue zone, the amorphous
polymer is heated at a low temperature. Here, the polymer expands at a constant rate with an increase in temperature. When
reaching Tg, the volume expansion rate increase instantly to a higher level, meaning the hard and brittle glassy state changes to the
soft and rubbery state in the yellow zone. Upon further heating, the amorphous polymer gradually transforms to the liquid state in
the red zone. For the semi-crystalline polymer upon heating, the change at Tg is less intense since glass transition does not happen in
the crystalline regions. In the yellow zone, the semi-crystalline polymer is in a state that crystals dispersed in a rubbery amorphous
matrix. At Tm, the volume of the semi-crystalline polymer expands drastically due to melting of the crystalline regions in the
polymer.
Diffusion in Solids
The phenomenon in which matter is transported through matter is defined as diffusion. Diffusion is achieved by atomic motion.
Atomic movements in gases and liquids are relatively easy and rapid. In solids, such motion is restrained because of bonding of
atoms to the equilibrium position. Thermal vibrations in solids can enhance atomic mobility and thus allow some atoms to move
from high concentration areas to low concentration areas. Solid-state reactions are usually related to diffusion. The recrystallization
of cold-worked metals is an example of diffusion.
The diffusion in a crystalline solid is the stepwise migration of atoms from lattice sites to lattice sites. Vacancy diffusion and
interstitial diffusion are the two major mechanisms of diffusion in a crystalline lattice. Vacancy diffusion, also termed as
substitutional diffusion, is a mechanism by which atoms with sufficient thermal energy move from original sites to vacancies or
other crystal defects in the lattice. Interstitial diffusion is the mechanism by which atoms migrate from interstitial positions to
neighboring empty ones. In this mechanism, the moving atoms must have sufficiently small sizes as compared to the matrix atoms.
Atoms such as hydrogen, carbon, oxygen, and nitrogen can diffuse in metals via this mechanism.
Steady-state and non-steady-state diffusions are often involved in the study of diffusion. Steady-state diffusion is the situation
that the diffusion flux and concentration gradient do not vary with time. On the contrary, in non-steady-state diffusion, the
diffusion flux and concentration gradient change with time. Steady-state diffusion is only suitable for specific situations that a high-
pressure non-reacting gas diffuses through a metal foil to a region where the pressure of this gas is low. Non-steady-state diffusion
works for most practical diffusion situations. Steady-state diffusion and non-steady-state diffusion are dealt with by Fick’s first law
and Fick’s second law of diffusion, respectively.
Processing–Structure–Property Relationships for Materials

Processing, structure, and property are three essential components in materials science and engineering. The relationships among
these components play a vital role in the design and application of materials. Basically, how a material is processed result in its
specific structure, while the structure of a material leads to distinct properties. A linear progression can be made from processing to
Specific volume
Temperature Tg Tm
Fig. 7 Specific volume-temperature curves of amorphous and semicrystalline polymers. (The blue zone is the region of the glassy state. Yellow zone represent the
range of rubbery state. Red zone is the liquid region.)
structure, then to the properties, resulting finally in the specific performance and applications of a material. If a specific property is
needed for the application, the structure of the material must be suitably tuned, and hence the appropriate processing route must be
selected and processing parameters must be controlled. This article has mainly discussed structures of materials. Other article in this
encyclopedia will discuss manufacture and properties of materials in the context of biomedical applications.
An Introduction to Biomedical Materials
Many materials, including metals, polymers, ceramics and composites, are now used for biomedical applications and hence they are
called “biomedical materials.” Some of these materials were not intended as biomedical materials originally. But their use in the
biomedical applications has been successful and therefore they extended their service into the biomedical field. In the middle of the
last century, modern biomaterials science and engineering began. Since then, many materials are designed and have been developed
specifically for biomedical applications.
History of Biomaterials
The concept of biomaterials is a relatively new idea and term, although biomaterials have actually been used for a very long time.
A biomaterial is a material that is capable of being introduced into the body or living tissue without inducing a harmful biological
response. Today, they are extremely widely used in the healthcare field for many different purposes, ranging from sutures to
permanent implants. For many years, people were using biomaterials to help solve medical problems without realizing what a
biomaterial was and why they worked or did not work. For a long time, there were no medical device companies producing
biomaterials, besides some externally used materials, and materials were not being made for the purpose of using them as
biomaterials. This means that there were no regulations or standards to follow when using materials for use in the human body,
and there were mixed results in the safety and efficacy of the materials.
The earliest used biomaterials were made from basic materials found in nature that were easily usable. There were sutures made
of linen or catgut, as well as evidence of using seashells as dental implants. Some groups of people also used the jaws of large ants to
hold wounds closed in lieu of sutures. As technology and the processing of materials advanced, so too did the biomaterials used in
medical procedures. The use of metals as biomaterials allowed for stronger devices, such as metal sutures and a variety of implants,
including dental implants. The longer these metals were used as biomaterials, people realized that there were problems with some
of them, and the concept of biocompatibility was born. Many metals were tested and some were kept for use as biomaterials and
some were discarded due to their adverse effects on the body. Eventually, plastics were developed, which allowed for a wider variety
of properties for biomaterials from which to make medical devices. This leads to an advancement in the types of devices that could
be created from the biomaterials. The polymeric biomaterials are tested for their biocompatibility, now that it is standard for testing.
There are constantly new biomaterials, like hydrogel for example, being created and tested for different applications. Hydrogels are
polymers that can swell but not dissolve in the water, which brings more new ideas to the world of biomaterials. The 1980s and
1990s were the golden era of ceramic biomaterials with many inventions and innovations on bioceramics. Biodegradable
bioceramics are found to be useful for hard tissue regeneration in this century when tissue engineering and regenerative medicine
have attracted great attention. Composite biomaterials play no lesser role in the biomedical field. They have found many
biomedical applications, ranging from biosensors, bioseparation, drug delivery devices, to human tissue repair and regeneration.
Interdisciplinary Nature of Biomaterials Development

Developing new biomaterials is a complicated process that requires a variety of skills and knowledge. To create and use new
biomaterials, knowledge is needed in chemistry, biology, engineering, medicine, and other related areas. Due to this fact, it unlikely
that one person has obtained all of the knowledge and skills necessary to develop a new biomaterial. This leads to people working
together to develop, test, and use biomaterials.
Chemistry and materials science and engineering knowledge is used in the development of new types of biomaterials and in
optimizing existing materials. It helps with knowing how materials react in the presence of other materials and bodily substances.
Biological and medical knowledge is key in understanding the reaction of the body to the biomaterials. It also helps in being able to
determine what biological processes can be avoided and which to use to the materials advantage. Engineering skills are used to
utilize biomaterials into devices or processes that can be used to solve a problem. These skills can be used to determine the
properties of the biomaterials and how those properties are suited for certain biomedical applications. Experience in medicine
enable people to know what types of biomaterials and devices are needed to make their jobs easier and to make clinical outcomes
better. They can lead to looking at new ways to do things. The people with medical skills also have the ability to test the new
biomaterials and devices made from them and are in charge of using them most of the time.
The fact that so many different pieces are put into making a biomaterial, and a device from the biomaterial, makes a need for
developing them to be interdisciplinary. Different sets of knowledge contribute to the development at different stages, and some
contribute throughout the process. If people with all of these sets of knowledge can work together seamlessly, then the development
of a biomaterial and its associated devices can run smoothly and quickly and could turn into a quality product.
Human Body Environment

The human body is a complex system and environment. It has many different types of tissues, cells, proteins, growth factors, and
other biological components. To add to the complexity, each tissue has a unique extracellular matrix (ECM) that affects the local
environment of cells and other biological components. There are many different types of proteins in the body, all of which can
adsorb, desorb, denature, and increase or decrease in activity in the presence of different biological materials and chemicals. Blood
contains proteins that are reactive and can adhere to foreign bodies and injury sites and cause clotting and inflammatory responses.
Blood also contains cells that have the job of fighting and removing foreign bodies. Along with the biological components of the
body, the body parts feel mechanical forces. These mostly come from body motion and blood flow, and can affect the function and
wear of parts of the body. The goal of a working biomaterial is to not induce any unwanted reaction from any components of the
body, whether it is toxicity or unwanted wear and tear.
Biocompatibility of Materials
For a biomaterial to be safe and effective, it must be biocompatible. If a material is biocompatible, it means that a material does not
cause any harmful effects when it is in contact with the body. It also means that the material should perform its specific function
without any unplanned effects. In general, the harmful effects that should be avoided are producing or supporting toxic substances,
irritation due to movement, rubbing, or improper mechanical forces, and improper host reactions to the biomaterial. There are
biomaterials that are said to be bioactive. Not only do these biomaterials not cause an adverse reaction, but they actually cause
wanted reactions that may be used to enhance the positive healing responses to the material. Bioabsorbable materials degrade over
time into safe substances in the body, allowing healing to occur naturally in the implantation site. A biomaterial that is bioactive,
bioabsorbable, or both can have enhanced biocompatibility. A biomaterial must be viewed as a piece of a device. A biomaterial by
itself may cause a different reaction than it does in the context of a full device.
The goal of a biocompatible material is to have the minimized amount of inflammation possible. The initial reaction from the
body when an implant, or any foreign body, is introduced is to undergo a foreign body reaction, which is a form of non-specific
inflammation. If the foreign body is recognized as a foreign substance, then inflammation occurs as macrophages attempt to break
down and remove the substance. Even if it does not occur instantly, if particles break off of the biomaterial, this can occur. In some
cases cells that respond in inflammation can kill tissue around the biomaterial. Reducing inflammatory reactions reduces the risk of
damage.
Another important factor in biocompatibility is for the material to be non-toxic. This means that the material itself, or its
products, should not harm or kill cells or tissues. There are multiple types of toxicity that all must be avoided. These include
genotoxicity, carcinogenicity, reproductive toxicity, and cytotoxicity. Genotoxicity is the tendency of a chemical to mutate the genes
of a cell, carcinogenicity is the tendency to cause a cell to become cancerous, reproductive toxicity is the tendency to cause death of
reproductive cells, and finally, cytotoxicity is the tendency to kill living cells. The chemicals released by materials can cause any of
these forms of toxicity. Some materials are susceptible to bacterial growth and may cause an infection. A material cannot be
considered biocompatible if it has any form of toxicity or infection.
When a material comes in contact with blood, it can cause thrombosis, embolization, and the consumption of platelets and
coagulation factors. The biomaterials developed so far are never as resistant to thrombosis as natural endothelium in the body. The
materials that are exposed to blood and the vascular system for an extended period of time are especially susceptible to thrombosis.
Thrombosis can cause major problems in the function of the biomaterials and for the health of the person who received the
implant. For a material to be considered biocompatible, it must not cause any harm to the cells or tissue while performing as
intended in the body.
In Vitro Assessment of Biomaterials

The goal of in vitro assessment of biomaterials is to mimic how the biomaterials and cells react to each other, as they would in the
body, as closely as possible so that the biocompatibility of the material can be determined and also cell behaviors be assessed. The
focus of the tests is to identify the chemical components of the materials that might be release in vivo, and determine if those
chemicals are toxic to cells. Assays are used to determine the genotoxicity, carcinogenicity, reproductive toxicity, and cytotoxicity. All
of these can occur in multiple different ways, so they must be assessed thoroughly.
There are many standardized methods for the in vitro testing of biomaterials. Tests are designed to assess the characteristics of
chemicals that may be released by the material under development during its time in the body. This includes how the material reacts
to cells and fluids, as well as how the cells and fluids react to the material. A toxicology risk assessment is performed on the material
to identify hazardous chemicals coming from it, predict the potential exposure to the chemicals, determine the dose-response
relationship of the chemicals, and then use all of the information to characterize the potential risk to patient from the material. The
test is done with a worst case scenario in mind for the amount of chemicals a patient could be exposed to, in order to be sure that the
material is safe for less than the worst case. The tests for genotoxicity test for gene mutations in bacteria, as well as chromosomal
damage in mammalian cells. If either one is positive for damage, then an in vivo test most likely is needed. Since all genotoxic
chemicals are carcinogenic, a test for carcinogens should be performed before any testing on live animals is done. The carcinoge-
nicity tests check for change in cell morphology, anchorage-independent replication, and discorded colony growth, which are
indicators of malignant cells that have been formed. Reproductive toxicity testing does not need to be performed unless the
biomaterial is able to come in contact with an area of the body or cells that are associated with reproduction. In vitro cytotoxicity
tests determine whether or not a chemical from a material cause death to cells or disruption of essential process. Cytotoxic chemicals
can do this by changing the environment around the cells so that they do not work or by altering a specific part of the cell that
disrupts the proper function. Cytotoxicity can also lead to chronic inflammation. There is no single test that can fully characterize
the toxicities for all chemicals and hence multiple must be performed to assess the full extent of the material toxicity.
Due to the components and overarching importance of blood in the body, it is important to test the interaction between the
biomaterial and blood in vitro. The material should be tested for whether or not it causes thrombosis, how it interacts with platelets,
whether it damage red blood cells, or if it stimulates an immune response. The assessment models are designed to mimic the
conditions inside the body. This means that the constituents of the test fluid should have the coagulation factors, correct
temperature, flow, and other components that make the blood function in the body. Getting an assay to mimic clinical conditions
as closely as possible is important in the assessment of a material for any type of test.
There are needs to develop more in vitro toxicity tests to ensure that biomaterials are safe and effective without having to spend a
lot of time and money on testing. The tests need to be developed to mimic as closely as possible the in vivo environment, so that,
hopefully, an in vivo test would not be needed. It might not be completely realistic due to complexity differences between being in a
body and outside of one, but being able to test materials in vitro with accuracy and completely free of any in vivo tests would be the
ultimate goal.
In Vivo Evaluation of Biomaterials

In vivo evaluation of biomaterials is centered on testing the biocompatibility of the biomaterial in a complex biological environ-
ment and in many cases, determining the efficacy of the medical device made of the material. The evaluation of biomaterials in vivo
gives a better idea of how a biomaterial will react with the human body than in vitro tests. This is due to the complex nature of the
body environment. The in vivo tests help to determine whether or not a medical device and its associated biomaterials perform as
intended without any safety risks. The government regulatory bodies that have control over the use and testing of medical devices
issue protocols, guidelines, and standards that should be used for the in vivo assessment of medical devices. The in vivo tests are
different depending on what the intended use of the medical device is. They can also be used to test the individual biomaterials and
their reactions or the device as a whole.
The tests are based on the intended use of the device, and devices are grouped into different categories. These include the area of
tissue contact, which includes surface contact, external communicating devices, and implant devices, as well as the duration that the
device is in contact with the tissue, which includes limited (less than 24 h), prolonged (24 h–30 days), and permanent (more than
30 days). Biocompatibility tests in vivo include tests for sensitization reactions, irritation, intracutaneous reactivity, toxicity in all
forms, blood compatibility, carcinogenicity, degradation, and other immune responses.
Choosing the animal for tests is important when determining the safety and efficacy of a biomaterial or device. Some animals are
more closely related to humans in certain areas than in others, which means that using that animal for one test might work well, but
for another test it could mean nothing. For example, using a mouse model for tests with bone could work well to replicate humans
to an extent, but using a mouse for vascular tests would not translate well at all. Selecting the right animal model is crucial in
determining the safety and efficacy of the biomaterials. Certain knowledge of animal biology and the similarities and differences
between humans and animals is needed for determining which model(s) should be used for which purpose(s). The important part
of testing biomaterials in vivo is to match the human tissue as closely as possible in order to accurately and correctly model the
interaction of the biomaterial in the human body.
Ex Vivo Evaluation of Biomaterials

Ex vivo evaluation of biomaterials allows the testing to be done without having to have a large number of animals. It is done by
taking tissue from the animal to test against the biomaterial outside of the body. An ex vivo test can be done using a shunt to test the
blood interaction of the biomaterial. In ex vivo tests, the physical, chemical, mechanical and other properties of the tissue and
biomaterials that have interacted with them after being implanted for a time or during the interaction are analyzed. Ex vivo
evaluations of biomaterials are another way for ensuring the safety and efficacy of biomaterials.
Standards for Biomaterials

Standards for biomaterials are needed so that there is consistency in biomaterials R&D and in quality of biomaterials is maintained
around the world. Without the standards, there would be major problems with the manufacturing, quality control and use of the
biomaterials. The standards developed for a material are used by manufacturers, users, researchers, etc. to consistently define and
use a material every time. They specify what the chemical, mechanical, physical, and electrical properties of a material should be.
There are standards developed for material specifications, material uses, material testing, biocompatibility, and other important
standards. Material standards allow multiple manufacturers to make the same product, as well as letting the user know exactly what
they are getting every time.
Most standards are consensus standards, meaning they are developed by using popular opinion from a committee/community.
A test method standard is developed to specify the conditions of the test, type of and how many test subjects, and what data is
available to be analyzed from the test. These test method standards can be used to test a material by anyone after the standard has
been developed and approved. Getting a standard approved can be a long process. It starts with a need for a standard and a group of
people is formed and tasked to decide how a test should be done. They then send out materials to be tested to multiple laboratories
and write the draft standard. They review information from multiple sources and finally test and produce the document. From
beginning to end, it can take about 3–5 years to produce a standard for a material or test.
The main organization in the United States that makes standards for biomaterials is the American Society for Testing and
Materials (ASTM). Some other standardization bodies are the Association for the Advancement of Medical Instrumentation (AAMI),
which deals with medical electronics, sterilization techniques, vascular and cardiac valve materials, the American National
Standards Institute (ANSI), which deals with the reviewing and acceptance of standards documents, and the American Dental
Association (ADA), which deals with dental materials standards. The ANSI also stays in contact with the other standards
organizations, as well as the International Standards Organization (ISO) in order to help produce standards for international
use. Other countries have standards organizations similar to the ones in the United States that also work with ISO. ISO gathers the
standards from all of the standards organizations to create international standards. The international standards make it easier for
companies to manufacture materials and devices that can be sold and used internationally. The standards organizations make their
approved standards public so that they are available for use by everyone who needs them.
Government Regulations
Government regulations on medical devices, including biomaterials, are important in that they provide a way to ensure the safety
and efficacy of devices by providing a legally regulated path of approval. In the United States, the Food and Drug Administration
(FDA) was given the regulatory powder of medical devices in 1976. Along with the regulatory authorities in other countries, the FDA
regulates biomaterials on the basis of the risk associated with the intended use of the biomaterial. It is tasked to make sure that the
device or biomaterial is safe and functions as intended in the United States. This means that the biomaterial could be regulated one
way for one use and a different way for another use.
Since the regulations are based on the risk associated with use of the biomaterial, they are grouped into three main classes in the
United States. Class I medical devices and biomaterials are determined to be low risk. These devices and materials are mostly
external devices and are not intended to support life and failure of the device would not cause any real harm. The Class I medical
devices and biomaterials require the lowest regulatory control, as the risk of harm from them is very low. This allows them to be
quickly and easily passed through the regulatory process. Examples of Class I devices are bandage and dental floss. Class II medical
devices are found to pose moderate risk. These devices and materials are generally in contact with the body for a short period of time
or detect internal components of the body. They are devices and materials that are safe for the function they are designed for and will
not cause any major injury if failure occurs. Some of these devices are external and some are internally used. Due the moderate risk
factors and intended uses, Class II medical devices and biomaterials require more strict regulations than Class I medical devices,
with more stringent reviews of the technical documentation. Examples of Class II devices are gastroscope and magnetic resonance
imaging (MRI) equipment. Class III medical devices and biomaterials are determined to be high risk. These devices and materials
are used in extremely invasive procedures and life-sustaining devices. They can even be permanently implanted into the body. The
failure of Class III medical devices can cause major injury or even death. For this reason, they are subject to the most scrutiny for
approval. They must perform exactly the way they are specified without failure and that having them in the body will not harm the
body. To do this, Class III devices are tested in animals and clinical trials to be completely sure of their safety and efficacy. Examples
of Class III devices are heart valve, pacemaker and hip implant. As expected, the higher the risk, the higher amount of scrutiny is
given to the devices before they pass the regulatory process.
There are development and manufacturing regulations as well as premarket entry requirements. The development and
manufacturing requirements are mostly standard throughout the world but the premarket rules can vary depending on the country.
The easiest way for a medical device or biomaterial to get approved is to effectively compare it to one that has previously been
approved. If they are determined to be similar enough, the regulatory process may move quickly for the new device or biomaterial. If
not, tests and other work may be needed, which slows down the process. If a manufacturer wants to change a product slightly, this
may cause a need for a new review of the device or material. It is up to the manufacturers to prove the safety and efficacy of the
product that they are producing in order to pass the regulations. They must provide full documentation for the medical device or
biomaterial for gaining regulatory approval. The regulatory process is an ongoing and ever changing system with reviews and
adjustments going on all the time. Getting through the regulatory process can take a long time, which makes new medical devices
and biomaterials take a long time to get to clinical use.
Biomaterials in Action
Materials in Orthopedics
In orthopedics, biomaterials are generally chosen for their strength or for mimicking the structure and properties of bone. They are
also wanted for promoting the mineralization of tissue around the implants, which calls for bioactive materials. Many times, this
can mean the use of metals or ceramics. Calcium phosphate ceramics, particularly synthetic hydroxyapatite (HA), closely resemble
bone apatite and have been developed for bone tissue repair. They allow better bone growth in areas surrounding the ceramic
implant than any other material such as orthopedic metals. In some applications, there can be metal implants coated with a
bioactive ceramic material for the strength of metals and for the bioactivity (i.e., osteoconductivity) of calcium phosphates.
Metals for use in orthopedics include titanium and its alloys, cobalt’chromium alloys, and 316L stainless steel. Metals are usually
used for implants that require mechanical strength such as hip implants, bone screws, nails, pins, and fixation plates. Popular
bioceramics are bioactive glasses, glass-ceramics and calcium phosphates such as HA and b-tricalcium phosphate (b-TCP). Materials
such as silicon can be added to HA to enhance the biological property and promote bone growth. Bioactive bioceramics can be used
as coatings for metals and as bone defect fillers. Two “bio-stable” polymers, ultra-high molecular weight polyethylene (UHMWPE)
and poly(methyl methacrylate) (PMMA), are commonly used in hip joint replacements. UHMWPE is used for acetabulum cup
while PMMA is used to cement metal stem of the hip prosthesis to bone. Commonly used biodegradable polymers include poly
(e-caprolactone) (PCL), polylactide (PLA), polyglycolide (PGA), poly(2-hydroxyethylmethacrylate) (PHEMA), collagen and hya-
luronic acid. These polymers are used for a variety of applications based on their properties. They can be used to repair bone
fractures, as substitutes for bone, ligament and cartilage repair, sutures, fixation plates, etc. that will degrade over time. Bioactive
composite, such as HA reinforced high-density polyethylene (HDPE), are also developed for bone tissue repair.
Materials in Wound Dressings

There are a variety of wounds, ranging from cuts and scrapes to ulcers and burns. This means wound dressings must be able to
perform different functions, depending on the type of wound. In general, wound dressings must stop the bleeding, keep the wound
clean and disinfected, absorb excess liquid and promote the proper gas and temperature levels in order to start and promote the
body’s healing process. The biomaterials used must also be able to be formed into sheets easily in order to function properly.
There are passive biomaterials that are used to just cover the wound and keep it clean. Traditional passive wound dressings are
made of woven fabrics and foams that assist healing by absorbing excess liquid and blocking outside sources of contamination.
Some wound dressings are able to promote the healing of wounds, allowing them to heal quicker and better, instead of just covering
them. Interactive dressings allow for the movement of substances such as water and oxygen to pass through them without allowing
contaminants to enter. These types of dressings are made of materials that can be made into thin films. Another type of wound
dressing that promotes healing is termed bioactive. These bioactives are made of materials that come from the body and are known
to aid in the healing processes. By bringing these materials to the wounds, the healing process can be sped up. These natural
biomaterials are hemostatic agents. Combining multiple types of biomaterials into one wound dressing can allow it to effective
cover multiple functions needed by a certain type of wound.
Some common synthetic biomaterials used in wound dressings include PLA, PGA, PCL, poly(lactic-co-glycolic acid) (PLGA),
poly(ethylene glycol) (PEG), polyesters, and polycarbonates. These biomaterials are able to be formed into sheets and sponges for
covering wounds. Some commonly used natural polymers are proteins such as fibrinogen, thrombin, collagen, gelatin and albumin
and polysaccharides such as chitin, chitosan and cellulose. These materials have been able to be made into sheets, sponges, gels,
powders, and liquids. These hemostatic materials help in regenerating new tissue in the wound due to the fact they are naturally
present in wound healing or support the growth without inflammation. Cotton is commonly used in bandages and gauze. Some
polymers such as hyaluronic acid and methacrylates can be used in hydrogels that support wound healing. A combination of
different biomaterials can be helpful, depending on the need for healing and how each material interacts with the wound.
Materials in Dentistry
Biomaterials used in dentistry are very similar to those used in orthopedics, since teeth are similar to bone and are anchored in bone.
Dental biomaterials include metals, polymers, ceramics, and composites. Using these materials is to either prevent or fix problems,
and different from the application of most other biomaterials, some of dental biomaterials are visible and hence matching the color
of the surrounding tissue can be important.
Metals are often used as anchors in dental implants. They provide the strength needed to hold the implant in the bone under the
stresses that the mouth goes through. The metals include titanium and its alloys, cobalt-based alloys and stainless steel. Dental
crowns and bridges can also be made of metal. Gold crowns are common. Dental amalgam, which is composed of mercury, copper,
tin, zinc, and silver, is used as a filler material for cavities after tooth decay.
Bioceramics are common dental biomaterials. In some cases, they can be used as the anchors of implants as well. Some
bioceramics, for example, medical grade alumina, have the high strength needed in the mouth and have low thermal conductivity,
while exhibiting a color similar to natural teeth. Calcium phosphates including HA are also commonly used. HA can be coated on
metal implants to promote osteointegration with bone.
Polymers are used mostly as cements or fillers in dentistry. Cements or fillers start out as liquids and/or solid powders and are
hardened to hold two solids together or fill holes. Some harden on their own after mixing, while others need to be hardened, for
example, by UV light. They are usually made by mixing solid and liquid components. There are cements made of zinc phosphate,
zinc polycarboxylate, glass ionomers such as calcium and aluminum silicate, resins such as urethanes, and other types that can be
used for specific purposes.
All dental biomaterials must survive the harsh and fluctuating conditions of the mouth. They are hard and stable material that
work together in multiple ways. The metals, ceramics, polymers and composites work together and allow for integration with the
host tissue.
Materials in Ophthalmology
Biomaterials used in ophthalmology are contact lenses, optical implants such as artificial corneas, intraocular implants, glaucoma
drainage tubes, scleral buckling materials, adhesives for repair of perforations and ulcers, etc. They are generally soft polymers,
considering the eyes are made of soft and delicate tissues. Some of the main biomaterials used are PMMA, silicones, and hydrophilic
polymers in the form of hydrogels.
PMMA is used for hard contact lenses but it does not have great oxygen permeability. Hence it can cause problems if used for too
long. It is also used for artificial cornea and intraocular lens. This hard polymer allows the artificial corneas and lenses to retain their
shape and not to break down easily. The clear material allows for good optics as well. Silicones are used in the forms of a hard
rubber, soft rubber, sponge, and liquid with high viscosity. Silicone rubber is used in some cases for contact lenses. It has high
oxygen permeability but can cause the formation of deposits due to its hydrophobicity. Soft silicone rubber and sponge are used in
retinal detachment surgeries as scleral buckling materials.
Materials for Cardiovascular Devices

The cardiovascular system needs a variety of biomaterials. Biomaterials for heart and blood vessels have different requirements.
A common requirement for all biomaterials for the vascular system is that they must not react or cause a reaction in the presence of
blood since they are in constant contact with blood for their entire lifespan. The materials also need to withstand mechanical
stresses because of the heart pumping and constant blood flow.
Metals, carbons, ceramics, and polymers are common biomaterials for cardiovascular applications. Metals have high structural
integrity. They are used in structural parts in heart valves, pacemakers, and stents. Some of the main metals for these purposes are
stainless steel, cobalt’chromium alloys and titanium alloys. Nickel’titanium shape memory alloy (SMA, e.g., Nitinol) is used in
vascular stents owing to its shape memory. Metals are also used in electrodes and wires in pacemakers. Platinum alloys are used in
electrodes, and stainless steel and tantalum are used in sensors and wires braids. Carbons, especially graphite, are used in pyrolytic
coatings of heart valve components. They are thromboresistant, have high lubricity and are resistant to wear. Sapphires have been
used in high speed blood pumps to reduce the amount of friction during rotation. Polymers such as polytetrafluorethylene (PTFE)
and polyester are used as small grafts and sutures. They help to repair tissue in blood vessels. Silicone has been used in artificial heart
valves as tissues and cells generally do not attach to it. Biological materials are generally used as coatings for other biomaterials. All
of the biomaterials used in the cardiovascular system must not cause thrombogenesis, must resist physical wear, and must not break
down over time.
Materials in Drug Delivery and Controlled Release

The goals of controlled drug delivery are to control the duration of release and the amount of drug released, to deliver the drug to a
specific part of the body, to get through tissue barriers, and to get through cellular barriers. Biomaterials used in drug delivery must
have right chemical compositions. Drugs can be delivered through the digestive systems, respiratory system, through skin or
muscles, intravenously, or through the respiratory system. Each delivery method needs a specific type of device or biomaterial to
deliver the drug effectively to the targeted area. The drug delivery methods are meant to control the amount of drug in the system
and where the drug is delivered to and even to overcome cellular barriers. Good delivery vehicles deliver the drug with an
appropriate amount to the proper location by releasing the drug or breaking down themselves under the conditions of the targeted
sites.
Controlled release means controlling the rate at which a drug is released into the system, as opposed to having the drug delivered
into the system in full at one point in time. The main mechanisms for controlled release are diffusion, chemical reaction, and
solvent activation and transport. The diffusion mechanism uses a polymeric material that creates a reservoir for the drug, or a
material in which the drug can be uniformly distributed throughout. In the delivery through chemical reaction, the biomaterial
making the delivery vehicle degrades in the presence of water or other agent. Solvent delivery uses a material that can swell in the
presence of water to release the drug that has been locked in the capsule or by osmotic effect. Polymers are the main biomaterials for
drug delivery and controlled release purposes. On the other hand, ceramics such as mesoporous silica can also be used for
controlled delivery.
Hydrogels are good for diffusion-based controlled release because they swell when exposed to water or other biological fluids.
This allows for drugs to diffuse out of the expanded gels. They can also be used for solvent activation. Some hydrogels can respond
to environmental factors such as ionization. They can increase the amount of swelling due to responses to the environment, which
can allow the drug to be released more quickly or slowly. Specific locations in the body can be targeted by creating a hydrogel that
binds to a specific tissue.
Materials in Reconstructive Plastic Surgery and Cosmetic Surgery

Reconstructive plastic surgery has the goal of repairing defects for the sake of the damaged tissue appearing normal and hopefully
regaining its function. Cosmetic surgery has the goal of changing the appearance of a bodily feature. Since they are closely related to
each other and have the hope of creating structures that will hold shape and last in the body, they can use similar biomaterials to
change and fix the structure of body parts. The biomaterials used in reconstructive surgery are intended to provide mechanically
stable structures of the tissue while allowing native tissue to use it as a scaffold to regenerate its proper structure. Some of the
materials are meant to degrade over time, while some integrate with the body. Much attention is paid to wound healing so as to
prevent the appearance of scars after surgery.
Most of the biomaterials for plastic surgery should be mechanically strong and chemically stable. There is also the reason for the
materials to have some bioactivity. If they are bioactive, they can integrate with the surrounding tissue, which means a better
functioning tissue repair that will heal to look normal. For support materials, PTFE, PMMA and titanium have been used but they do
not integrate well with the tissue due to low bioactivity. Therefore, for soft tissue, a biomaterial called acellular dermal matrix
(ADM) was developed. ADM integrates well with native tissue and allows for the healing process to occur through tissue
regeneration rather than scar tissue formation. This makes for better healing and less noticeable scarring. For hard tissue recon-
struction as in craniofacial reconstruction, calcium phosphates (HA and TCP) are often used. The bioactivity of these materials
allows for good integration with the bone. Some polymers are also used for facial defect repair. They include silicones, PGA, PLGA,
PCL, and PMMA. These are used for structures without being bioactive. Growth factors are commonly added for enhancing new
tissue formation.
Materials in Bioelectrodes and Biosensors

Bioelectrodes are devices that send an electrical signal to the body. Biosensors are devices that detect certain biochemical signals and
convert them to electrical signals that can be measured. Biosensors are made of a transducer with a biologically active molecule. The
biologically active molecule responds to the biochemical signal and relays that response to the transducer. Bioelectrodes and sensors
can be on the body surface or implanted. Implanted electrodes and sensors have many more needs for compatibility than the
surface ones.
Bioelectrodes are commonly made of metals of high electrical conductivity. A common metal is stainless steel due to its low
reactivity when in contact with the body. In some cases, copper, gold or platinum is used. Copper needs to be coated in the body as
it reacts to the biochemical conditions in the body. Biosensors are made of a transducer with a biologically responsive material. The
biologically active material responds to a certain biochemical factor which it wants to detect. This reaction in turn causes a slight
change in the material, which also affects a piezoelectric material that makes up the transducer. The slight change in the materials
causes a small electrical signal to be transmitted and measured. This is how the device measures the amount of a substance that is
present. The transducers can be made of pH- or ion-selective electrodes, thermistors, optical fibers, or piezoelectric crystals. The
biologically active material is what really makes the biosensor function. Materials that have been used as the biologically active
materials include enzymes, antibodies, DNA, organelles, microorganisms, cells, etc. Each of them can be selected or modified to
react specifically to certain biochemical signals. Purified enzymes are commonly chosen because they are specific in their reaction to
the factors of interest. Biosensor materials must be able withstand bodily factors, such as temperature, pH, movement and
chemically reactive substances while still functioning.
There is a new trend in using nanomaterials as biosensors. They include graphene, carbon nanotubes, nanowires, quantum dots
and nanocomposites. They have structures that allow them to be modified to detect certain biological factors. Their sensitivity,
response time, stability and specificity make them promising materials for future biosensors.
Looking Into the Future

Cancer Theranostics
Cancer theranostics combine cancer diagnosis and therapy. Diagnostic and therapeutic substances can be incorporated in and
released from theranostics. The release can be stimulated by internal or external stimuli. Internal stimuli come from within the body
and include pH, redox potential, oxidative stress, enzymatic presence, temperature, etc. External stimuli come from outside of the
body and include light, ultrasound, magnetic field, etc. Using biomaterials that can respond to these factors have advantages.
Nanoparticles can be used to form theranostics. The nanoparticles can deliver diagnostic materials, such as dyes, that can be used
to image the target tumors. They can also deliver cancer drug to cancer cells. Metal nanoparticles are major biomaterials for cancer
theranostics. They include gold, silver, quantum dots, iron oxide, and other nanoparticles. There are magnetic metal nanoparticles
that can be tracked in the body and manipulated. Some nanoparticles can react to external stimuli, such as ultrasound, to kill the
cancer cells that they are attached to. There is a long list of polymers and other biomaterials that can be used in certain forms to react
to stimuli and release their cargo. These include modified PEG, PCL, PLGA, polyesters, and many others. The development of novel
nanoparticles and nanostructures will allow for better and more effective cancer theranostics in the future.
Bioprinting
Bioprinting uses additive manufacturing with biomaterials or biologics to create complex three-dimensional structures for regen-
erative medicine through the layer-by-layer additive processes. 3D bioprinting is able to create complex structures based on
computer designs. It can also create objects with personal anatomical structures on the basis of computer files of medical imaging.
It therefore uses a wide range of biomaterials for different types of applications. With a wide range of desired structures and
materials to use, there are a number of types of bioprinters. The three main types of bioprinting are based on inkjet, laser/light, or
extrusion. Inkjet bioprinting uses multiple mechanisms, such as thermal, piezoelectric actuator, laser-induced forward transfer, and
pneumatic pressure, to deposit tiny droplets of the biomaterial onto a substrate. These tiny droplets eventually build up into the
desired shape. Stereolithography/projection bioprinting uses lasers or other light sources such as UV light to project a 2D image on a
photopolymerizable material. During the process, a stage lowers and the next image is projected, and the layers are polymerized on
top of each other, creating a 3D structure. Extrusion-based bioprinting uses mechanical forces, such as air pressure or a motor, to
extrude material through a nozzle in a specific pattern. The biomaterials used must be able to be extruded but still able to hold their
shape once printed. Each bioprinting technique has advantages and limitations and use different materials.
The biomaterials used in bioprinting are called bioinks. Bioinks are biocompatible materials that can contain cells and other
biological factors. For a bioink to work, it must be able to be bonded to the layers below and above and to be able to hold its shape.
The bioinks can have a wide variety of properties, depending on the desired characteristics of the human body tissue it is meant to
mimic. Bioinks are made of biomaterials that are either curable or are mechanically tough materials that harden on their own after
printing and soft biomaterials. The soft biomaterials are capable of supporting cell growth, whereas the hard materials generally are
not suitable for this. Hence the harder materials are usually used as support structures while the softer biomaterials support the cells.
The hard biomaterials are generally curable and self-hardening polymers, while the soft bioinks are synthetic or natural polymers
that are often formed into hydrogels. Some synthetic polymers used in bioprinting are PEG, and its acrylated version and PCL. PCL
is a hard polymer with a melting temperature suited for bioprinting. Some natural polymers that are commonly used for bioprinting
are hyaluronic acid and its methacrylated version, collagen, gelatin, and alginate. The soft natural and synthetic polymers can be
made into hydrogels for bioprinting, which also allows them to support cellular life and biologics. The fact that they can support
cells makes them particularly valuable for 3D bioprinting for tissue regeneration. Each of these biomaterials has different
mechanical and biological properties and it is important to use the right biomaterial for a specific purpose. The development of
new bioinks and optimizing current ones with cells and biologics will help to realize the potential of bioprinting in tissue
engineering and regenerative medicine.
Organs-on-Chips
An organ-on-a-chip is a micro-scale system used for mimicking the human body environment. The goal for organ-on-a-chip is to
develop human tissue models for disease modeling and drug testing. They use microfluidics, along with cells, to imitate the
physiological and mechanical conditions experienced in the body. They can control the movement and behavior of materials and
cells by using channels, chambers, membranes, etc. The devices are manufactured using soft lithography and BioMEMS
(BioMicroElectroMechanical Systems), which allow for the micro scale details to be properly produced. These fabrication tech-
niques allow the use of different materials, including thermoplastics and thermoset polymers.
Most of the materials used to create organ-on-a-chip devices need to be optically clear for viewing and imaging purposes,
although whether they are stiff or flexible depends on the use of the device. The materials must also have the right chemistry and
reactivity so as to not improperly affect the system. Glass and silicone have been used as materials for microfluidic devices.
A commonly used soft, synthetic polymer is polydimethylsiloxane (PDMS). It is optically clear, easy to stretch and easy to fabricate
and has high oxygen permeability. Organ-on-a-chip systems that need to be mechanically stable can use thermoplastics such as
polystyrene. They are stiff materials with stable surface chemistries. Other synthetic polymers used in making organ-on-a-chip
systems are PMMA and polycarbonate. Natural materials, such as collagen, in the form of hydrogels have been used in organ-on-
a-chip systems to assist cell organization. In some cases, biodegradable materials are desired as scaffolds in the system. Materials
such as PLGA and polydioxanone (PDO) are thus used.
A major requirement for the materials used in organ-on-a-chip systems is that they need to be able to be manufactured with
small details. A major technique for manufacture is soft lithography, which normally uses PDMS as the material for chips. Hot
embossing and injection molding are also used to make devices from thermoplastics. 2D printing now appears promising for
constructing organ-on-a-chip systems.
Acknowledgments
The authors thank members of their respective research group in the The University of Hong Kong and University of Nebraska
Medical Center for assistance in writing this book chapter. Min Wang thanks The University of Hong Kong, Hong Kong Research
Grants Council and the National Natural Science Foundation of China and Bin Duan thanks University of Nebraska and American
Heart Association for funding their research in biomaterials and tissue engineering.
Further Reading
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Callister WD Jr. and Rethwisch DG (2014) Materials science and engineering—An introduction, 9th edn. Hoboken, NJ: John Wiley & Sons.
D’Souza SF (2001) Immobilization and stabilization of biomaterials for biosensor applications. Applied Biochemistry and Biotechnology 96: 225–238.
Ebewele RO (2000) Polymer science and technology. Boca Raton, FL: CRC Press.
Hench LL (ed.) (2013) An introduction to bioceramics, 2nd edn., Singapore: World Scientific.
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Skardal A and Atala A (2014) Biomaterials for integration with 3-D bioprinting. Annals of Biomedical Engineering 43: 730–746.
Teo AJT, Mishra A, Park I, et al. (2016) Polymeric biomaterials for medical implants and devices. ACS Biomaterials Science & Engineering 2: 454–472.
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Wang Y, Shim MS, Levinson NS, Sung HW, and Xia Y (2014) Stimuli-responsive materials for controlled release of theranostic agents. Advanced Functional Materials 24(27):
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Materials and Biomedical Aplications

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Materials and Biomedical Aplications

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Materials and Their Biomedical Applications

Min Wang, The University of Hong Kong, Pokfulam, Hong Kong

Encyclopedia of Biomedical Engineering https://doi.org/10.1016/B978-0-12-801238-3.99860-X 1

Primary Bonds and Secondary Bonds

Common crystal structures

Monomer and chain structures

Homopolymers and copolymers

Membranes and Thin Films

Processes for Materials

Recovery, Recrystallization and Grain Growth of Metals

Glass Transition of Amorphous Polymers

Processing–Structure–Property Relationships for Materials

An Introduction to Biomedical Materials

Interdisciplinary Nature of Biomaterials Development

Human Body Environment

In Vitro Assessment of Biomaterials

In Vivo Evaluation of Biomaterials

Ex Vivo Evaluation of Biomaterials

Standards for Biomaterials

Materials in Wound Dressings

Materials for Cardiovascular Devices

Materials in Drug Delivery and Controlled Release

Materials in Reconstructive Plastic Surgery and Cosmetic Surgery

Materials in Bioelectrodes and Biosensors

Looking Into the Future

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