CHAPTER 1

BIOMATERIALS

LEARNING OBJECTIVES
In this chapter you will learn what biomaterials are, how to classify biomaterials and a few
selected examples of commonly used biomaterials. By the end of this chapter, you should be able
to do the following:

• Define the following terms: biomaterial, biocompatibility, cytotoxicity, biodegradation,

and inflammation
• Evaluate if a material can be used as a biomaterial or not (Answer the question, is it a
biomaterial?)
• Describe the important considerations when selecting a biomaterial
• List common examples of biomaterials

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1.1 BIOMATERIALS AND BIOCOMPATIBILITY
Biomaterials are materials, synthetic or natural, which are engineered to augment, restore, or
replace a tissue or biological function (1). For example, contact lenses correct or augment vision,
removal of injured hip joints and implantation of hip implants replace the hip and wound
dressings help restore of the function of skin (the barrier function). Biomaterials can be implanted
on their own or as part of an implant, drug delivery device or artificial tissue. A material must be
nontoxic, biocompatible and either be nondegradable in the human body or biodegrade in the
human body. Biocompatibility must be evaluated based on the desired application, e.g., external
versus internal use must be specified.

Fig 1.1: Key characteristics of biomaterials

When you implant something into the human body, there are several potential physiological
responses to that implant. Harmful materials (toxic materials) that directly cause tissue damage
are not considered biocompatible and therefore are also not considered biomaterials. Toxic
materials can usually be identified by incubating cells with the biomaterial in vitro (outside of the
body). Materials that cause cell death are called cytotoxic and materials that do not affect cell
viability are cytocompatible. Cytocompatible materials can be further considered for
biocompatibility testing in vivo (inside of the body). The practical details of biocompatibility
testing in vitro and in vivo will be described in greater detail in Chapter 3.

Fig 1.2: Testing for biocompatibility in vitro and in vivo.

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Depending on how the body responds to the biomaterial upon implantation, biomaterials can be
categorized as inert or active. Inert materials are essentially ignored, and active materials will be
integrated into the tissue. Another potential response of the body would be rejection by the
immune system. The rejection can be mild, severe, or complete.
When a biomaterial encounters body fluid (e.g., blood, tears, saliva, interstitial fluid) the first
event that occurs is protein adsorption to its surface. Interstitial fluid (tissue fluid) is fluid found
within the local tissue area outside of the cells; that is, it is a part of the extracellular fluid. When
a material is implanted inside of the body, most commonly the biomaterial will be exposed to the
proteins in blood serum and interstitial fluid. The protein adsorption from these two sources
occurs within milliseconds. How and which proteins adsorb is determined by many factors, these
include but are not limited to surface charge/hydrophobicity (of the proteins and the biomaterial)
and ionic strength of the body fluid. Typically, protein adsorption occurs in a state of equilibrium,
as the bonds are often weak (hydrogen bonding). The proteins which adsorb strongly to the
surface (usually through ionic/hydrophobic/chemical interactions) as well as the conformational
state of adsorbed proteins will influence the physiological response. This is because the first cells
recruited to the site can distinguish different cell recognition sites, ligands (biomolecules
complexed to the proteins) and antigen sites (a molecule or a structure recognized by antibodies)
exposed by the proteins. For example, if fibrinogen, a blood clotting factor, sticks to a surface it
might initiate blood coagulation, which, in excess, can be detrimental. Some blood serum
proteins of the albumin family will also activate macrophages for acute inflammation.
Inflammation is the recruitment process of white blood cells to fight off foreign bodies, to
heal injuries, or both. Noninvasive/external use of biomaterials, for example contact lenses or
skin patches, should not cause any inflammation response. If they do, other biomaterials must
be considered. On the other hand, implantation/internal use of biomaterials always results in
inflammation, as it requires injury to tissues at the surgical and implantation site(s). If the
inflammation response is severe or not depends on the adsorbed proteins, antibody recognition,
immune cell recognition and tissue integration (2). A further potential cause of severe
inflammation could be contamination by viruses, bacteria, or other infectious microorganisms.
Therefore, it is of critical importance that biomaterials are sterilized before use. Sterilization in
this case refers to the complete removal of infectious microorganisms; it does not cover other
sources of contamination like manufacturing byproducts. Common sterilization protocols include
autoclaving, treatment with ethylene oxide gas and gamma irradiation, and these will be
discussed more in Chapter 3.
If a patient experiences normal inflammation, there will be local redness and swelling that
will abate as the tissue heals. A typical response to bioinert materials is the formation of a fibrous
capsule, which is a partial rejection of the implant. As the implant is too large to be removed by
the macrophages, the body recruits the local fibroblasts to form a relatively thick, scar-like
capsule around the implant to isolate it from the rest of the body. This is not a desirable effect
and can even result in pain and discomfort for the patient if the capsule is too thick or causes
chronic inflammation. Therefore, there is a significant push in materials research to avoid this
kind of response, whether by better masking of the implant using special coatings or by avoiding
the issue altogether by designing biomaterials for inducing tissue integration and/or restoration
of native tissue.

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Fig 1.3: Graphical depiction of protein adsorption and inflammation. Depending on the proteins that adsorb
to the surface of the biomaterial and the properties of the biomaterial itself, activated macrophages will
either heal the area around the implant or they will fuse into multinucleated giant cells and ultimately
surround the implanted material with a fibrous capsule, so as to isolate it from the rest of the body.

If a biomaterial is design to be replaced by native tissue, the biomaterial must degrade over time.
Therefore, the degradation rate of the biomaterial must match the healing rate of the tissue.
Furthermore, and we must revisit the concept of cytotoxic materials; as biomaterials degrade,
they release byproducts, the body may react differently to these molecule- or particle-sized
byproducts than they do to the bulk material. For example, acidic polymers like polylactic acid
(PLA) can cause local changes in pH as they degrade, potentially damaging the tissue.
Furthermore, degraded products that are not cleared properly might build-up in the liver
(improper biodistribution and/or clearance). A further component that must be studied is the
method of degradation. Typically, biomaterials degrade by erosion, hydrolysis, or active
enzymatic degradation. The method of degradation often is dependent on the type of material,
discussed in section 1.2.
To overcome issues surrounding tissue integration and biodegradation, biomaterials have
become more refined. As such, the properties that describe them have far expanded beyond
inert or active. Some examples of such other properties are biofunctional materials,
nanomaterials, and smart materials. Biofunctional refers to materials which are recognized by
the body and induce some sort of response by the body. For example, a material can contain cell
attachment sites, like RGD, to induce cell attachment; RGD and other important mechanisms of
cell attachment will be introduced in greater detail in Chapter 4. Smart materials refer to
materials that respond to some sort of environmental cue. For example, a drug delivery vehicle
could release its contents upon reaching a location with a certain pH, for example an acidic pH in
the stomach. To control their degradation rate, it is possible to introduce sites which are
recognized by (or invisible to) local digestive enzymes. How to select these properties and
engineer them, therefore, depends on the application.

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1.2 SELECTING BIOMATERIALS
Although the biological properties of biomaterials are the most important to consider, materials
classes, with their different mechanical and physiochemical properties (metals, ceramics,
polymers, and composites thereof), provide a good starting point when selecting a biomaterial.
For example, if you want a material that is hard and has a low friction surface, ceramics would be
suitable. If you want a material that is strong but also lightweight (high strength to density ratio),
metals would be suitable. If you want a temporary material, or a biodegradable material, a
polymer would be the best suited.

Fig 1.4: Characteristics of the three main material classes (ceramics, metals, polymers), the binding strength
found within their crystal structure (and therefore the elastic modulus, which will be discussed later in this
chapter) and examples of commonly used biomaterials from each materials class.

Ceramics and metals are engineering materials that are often used for bone or teeth
replacement, due to their advantageous mechanical properties. Biocompatible metals typically
include stainless steel, cobalt chrome alloys, titanium, and titanium alloys. Of these, only titanium
dioxide is known to promote tissue integration. Ceramics, on the other hand, can promote
osseointegration, and are also beneficial for replacement of the articular surface of joints due to
their low friction and high shear resistant surfaces. Typical ceramics for joint replacement are
zirconium oxide and aluminum oxide. However, it is important to note that ceramics are not
suitable for any application where the implant will be under tension, bending or torsional forces.
Examples of newer research into metals and ceramics involve the development of
nanoparticles for inducing magnetic fields (gold particles) and biomineralization (calcium
phosphates, bioglass and composites containing zirconium). These types of materials can be
considered for new imaging and biosensing applications as well as therapeutic uses (metals) (3)
and replacement of bone or improved tissue integration of bone implants (ceramics) (4).
However, these materials often have a fine line between their therapeutic and toxic dose,
therefore the materials class that dominates research and development efforts is polymers.

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 Organic polymers are long chains of carbon held together by covalent bonds. Although
less common, there are also examples of inorganic polymers, for example, polymers based on
silicon (Si). The diversity of polymers is derived in part by their monomer unit(s), the length of
the chain, the structure of the chain (branched, linear), how the chain folds and the networking
between the chains. Starting with the monomer, the main difference between each monomer
unit depends on the groups attached to the monomer unit.

Fig 1.5: The basic monomer unit of organic polymers. Black lines represent covalent bonds between C: carbon
and H: hydrogen atoms.

The functional units of polymers can comprise alcohols (esters), amine and carboxyl groups.
Naturally occurring polymers in the human body are polyaminoacids (proteins), polysaccharides
(sugars) and nucleic acid chains (DNA/RNA). Although nucleic acids may be used in biomaterial
design, they are used more often in drug or gene delivery applications, and we will not discuss
them at great length here. If you are interested in learning more about drug and gene delivery,
we recommend this review (5).
Polysaccharides are comprised of monosaccharides, typically having the formula C nH2nOn,
which form carbon rings with hydroxy groups (OH groups). Between monomer units are
glycosidic bonds. The monomer unit of a protein is referred to as amino acids. There are 21 types
of amino acids depending on their functional group (R-group), which are classified as charged,
uncharged, hydrophilic, and special cases.

Fig 1.6: Basic monomer unit of a protein. R-groups are functional groups that define each amino acid type.
Black lines represent covalent bonds between C: carbon, H: hydrogen atoms, O: oxygen and N: nitrogen
atoms.

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Beyond the monomer unit, the most common factors that determine the physiochemical and
mechanical properties of a polymer are the molecular weight, crystallinity and how the polymer
networks. Molecular weight is not only related to the size of the monomer(s), but to the number
of times that the monomer(s) are repeated. That is, molecular weight is primarily dependent on
the average chain length of polymers found in the matrix. Polymers used in medical products
should ideally have a tight molecular weight distribution, to avoid batch-to-batch differences in
the polymers. Crystallinity (percentage of crystal structures in the polymer matrix) and polymer
network formation are dependent on the process used to solidify the polymer matrix as well as
the chemical properties of the polymer chains. Therefore, this will be discussed in greater detail
in Chapter 2.

Fig 1.7: Graphical representation of the crystallinity of polymers; blue/purple represents amorphous regions
and green stacked polymer chains forming crystals.

When selecting or engineering a polymer among these types (synthetic, natural protein, natural
polysaccharide) for a particular application, there is much to consider. Degradable or permanent,
synthetic or natural, soft or hard are some initial questions that might come to mind and are
usually application dependent. For example, for a polymer used for the lining of a joint
replacement the mechanical properties must be a top priority, whereas for creating artificial
muscle tissue the biological function might be the most important thing to consider. Some
common examples of non-degrading polymers used as biomaterials are polyethylene (PE)
(medical implants), polyimide (PI) (medical tubing) and polyether-ether-ketone (PEEK) (medical
implants). Some common examples of synthetic polymers used for tissue engineering are
polyethylenglycol (PEG), polylactic acid (PLA), poly(glycolic acid) (PGA) and poly(lactic-co-glycolic
acid) (PLGA). Some common examples of biomaterials based on natural polymers or their
derivatives are collagen, alginate, gelatin, hyaluronic acid, chitosan, and silks.

A CLOSER LOOK INTO SPIDER SILK

Silks are proteinaceous fibers produced by spiders, silkworms, and other insects for various
purposes such as a nest, a trap for pray, self-protection and reproduction. For centuries, silk has
been revered for its lustrous, smooth feel as a textile and its mechanical robustness as a
material for netting. Today, it is coveted as a biomaterial due to its “invisibility” to the innate
immune system and its slow biodegradation rate. Spider silk has shown to perform particularly
well in these aspects. Unfortunately, for medical applications, natural spider silk is difficult to

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harvest in the necessary quantities. Therefore, recombinant production of spider silk proteins in
bacteria was established and now recombinant spider silk proteins are beginning to be used for
cosmetic, textile and medical applications.

Fig 1.8: Biotechnological production of recombinant spider silk proteins based on specific components ADF-4
(C module proteins, blue) and ADF-3 (A and Q module proteins, green and orange). Top box: Derivation of the
engineered sequence based on the natural sequence and translation to E. coli codons. Bottom box: Examples
of how the individual modules can be produced in different lengths and patterns. Modified figure from
Microbial Factories, 3, Scheibel, T., Spider silks: recombinant synthesis, assembly, spinning, and engineering
of synthetic proteins, 2004; this is an Open Access article published by BioMed Central Ltd. and distributed
under the terms of the Creative Commons Attribution License (CC BY 2.0).

1.2.1 MECHANICAL PROPERTIES

Mechanical properties of a material, or the way that a material tends to respond under a certain
type of mechanical force, are critical to determine the best material to choose for a particular
application. As implied in the previous section, the intrinsic mechanical properties of a material
are highly dependent on their chemical makeup, however, they are also highly dependent on the
processing conditions and final geometry of the fabricated part. These will be discussed in
Chapter 2, however, here we will briefly introduce some important aspects to evaluating the
mechanical behavior of materials and what can be determined from this data.

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 There are many ways to test the mechanical properties of materials, however, here we
will focus on tensile testing: Pulling a fixed test sample in one direction and measuring the
amount that the sample stretches (the strain) in response to the applied force on the geometry
(the stress). For typical samples, this results in an elastic region (reversible deformation of the
sample) with a linear relationship between stress and strain, followed by a plastic region
(permanent deformation of the sample) with a nonlinear relationship between stress and strain
and ultimately sample failure. The point where the sample transitions from reversible to
permanent deformation is called the yield strength and the maximum stress before the sample
begins to fracture the ultimate strength.

Fig 1.9: The basic characteristics that can be determined testing a sample, not including the Young’s modulus
(E) determined by the linear slop in the elastic region.

However, perhaps the most important factor to determine is the elastic modulus, aka the Young’s
modulus and the yield strength. This is important because most materials are not used for
applications outside of their elastic region, therefore, one should know what the elastic region
is, and how to predict behavior within the elastic region. Young’s modulus is determined by
calculating the rise over the run of the slope in the elastic region; that is, by determining this
constant, you should be able to predict how much a sample will strain under a given stress, and
vice versa. The relation between stress and strain is also referred to as Hooke’s Law (𝜎 = 𝐸 ∙ 𝜀).
Furthermore, the steeper the slope, or the higher the Elastic modulus, the stiffer the material is.

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This is important, because if medical products do not have a similar stiffness to the tissue they
are being used on, then stress shielding will occur at the interface, causing pain and discomfort
to the patient as well as product failure. Take for example contact lenses; if you were to use the
same glass that is typically used for making corrective lenses, you would likely tear the membrane
of the eye upon insertion. This is because the glass is hard and inflexible, whereas the eye is soft
and flexible. A similar example would be catheter tubing; if the needle used for insertion were to
remain in the patient, they would likely puncture all surrounding soft tissues by moving around
normally, whereas the catheter, although not always comfortable, has enough flexibility to move
with the patient.

Fig 1.10: Typical stress-strain curves for the different materials classes, demonstrating that ceramics are stiff
but with low toughness (brittle), metals relatively stiff with high toughness (ductile) and polymers show low
stiffness with moderate toughness (flexible).

Polymers can also exhibit non-linear elastic regions. This is because many types of polymers are
viscoelastic materials; that is, materials demonstrating both viscous (liquid) and elastic (solid)
behavior. This type of behavior will be discussed in greater detail in Chapter 6.

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QUESTION
What do you think one of the greatest challenges is to preparing materials for implantation and
why? When answering this question, think about the core purpose of the immune system.

materials.
for 10-30 minutes. This can lead to partial melting or changes in the crystal network of some
and high pressure. For wrapped items in a steam autoclave, this will be around 140 °C, 30psi
autoclaving, a common sterilization technique, kills microbes using a combination of high heat
viruses and microbials) without affecting the final material properties. For example,
is challenging to ensure that the material is completely free of contaminations (bacteria,
Answer: Sterilization of materials. When implanting materials, especially porous materials, it

REFERENCES AND FURTHER READING

1. National Institutes of Health (NIH) and National Institute of Biomedical Imaging and
Bioengineering (NIBIB). Science Education. https://www.nibib.nih.gov/science-
education.

2. G. Zhou and T. Groth. “Host Responses to Biomaterials and Anti‐Inflammatory

Design—a Brief Review”. Macromol. Biosci.2018, 18, 1800112.
https://doi.org/10.1002/mabi.201800112.

3. M. P. Nikolova, M. S. Chavali. “Metal Oxide Nanoparticles as Biomedical Materials”.

Biomimetics (Basel). 2020 Jun 8;5(2):27. https://doi.org/10.3390/biomimetics5020027.

4. C. I. Codrea et al. “Advances in Osteoporotic Bone Tissue Engineering”. J. Clin. Med.

2021, 10(2), 253. https://doi.org/10.3390/jcm10020253

5. O. S. Fenton et al. “Advances in Biomaterials for Drug Delivery”. Adv. Mater. 2018, 30,
1705328. https://doi.org/10.1002/adma.201705328

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