A biomaterial is a substance that has been engineered to interact

with biological systems for a medical purpose – either a therapeutic (treat,

augment, repair, or replace a tissue function of the body) or
a diagnostic one. The corresponding field of study, called biomaterials
science or biomaterials engineering, is about fifty years old.[needs update] It
has experienced steady growth over its history, with many companies
investing large amounts of money into the development of new products.
Biomaterials science encompasses elements
of medicine, biology, chemistry, tissue engineering and materials science.

A biomaterial is different from a biological material, such as bone, that is

produced by a biological system. However, "biomaterial" and "biological
material" are often used interchangeably. Further, the word "bioterial" has
been proposed as a potential alternate word for biologically-produced
materials such as bone, or fungal biocomposites. [citation needed] Additionally, care
should be exercised in defining a biomaterial as biocompatible, since it is
application-specific. A biomaterial that is biocompatible or suitable for one
application may not be biocompatible in another. [1]

IUPAC definition

Material exploited in contact with living tissues, organisms, or

microorganisms.[2][a][b][c]

Introduction

[edit]

Biomaterials can be derived either from nature or synthesized in the

laboratory using a variety of chemical approaches utilizing metallic
components, polymers, ceramics or composite materials. They are often
used and/or adapted for a medical application, and thus comprise the whole
or part of a living structure or biomedical device which performs, augments,
or replaces a natural function. Such functions may be relatively passive, like
being used for a heart valve, or maybe bioactive with a more interactive
functionality such as hydroxy-apatite coated hip implants. Biomaterials are
also commonly used in dental applications, surgery, and drug delivery. For
example, a construct with impregnated pharmaceutical products can be
placed into the body, which permits the prolonged release of a drug over an
extended period of time. A biomaterial may also be
an autograft, allograft or xenograft used as a transplant material.[citation needed]

Bioactivity
[edit]

The ability of an engineered biomaterial to induce a physiological response

that is supportive of the biomaterial's function and performance is known as
bioactivity. Most commonly, in bioactive glasses and bioactive ceramics this
term refers to the ability of implanted materials to bond well with
surrounding tissue in either osteo conductive or osseo productive roles.
[4]
Bone implant materials are often designed to promote bone growth while
dissolving into surrounding body fluid. [5] Thus for many biomaterials good
biocompatibility along with good strength and dissolution rates are desirable.
Commonly, bioactivity of biomaterials is gauged by the surface
biomineralization in which a native layer of hydroxyapatite is formed at the
surface. These days, the development of clinically useful biomaterials is
greatly enhanced by the advent of computational routines that can predict
the molecular effects of biomaterials in a therapeutic setting based on
limited in vitro experimentation.[6]

Self-assembly

[edit]

Self-assembly is the most common term in use in the modern scientific

community to describe the spontaneous aggregation of particles (atoms,
molecules, colloids, micelles, etc.) without the influence of any external
forces. Large groups of such particles are known to assemble themselves
into thermodynamically stable, structurally well-defined arrays, quite
reminiscent of one of the seven crystal systems found
in metallurgy and mineralogy (e.g., face-centered cubic, body-centered
cubic, etc.). The fundamental difference in equilibrium structure is in the
spatial scale of the unit cell (lattice parameter) in each particular case.

Molecular self assembly is found widely in biological systems and provides

the basis of a wide variety of complex biological structures. This includes an
emerging class of mechanically superior biomaterials based on
microstructural features and designs found in nature. Thus, self-assembly is
also emerging as a new strategy in chemical synthesis and nanotechnology.
Molecular crystals, liquid crystals, colloids, micelles, emulsions, phase-
separated polymers, thin films and self-assembled monolayers all represent
examples of the types of highly ordered structures, which are obtained using
these techniques. The distinguishing feature of these methods is self-
organization.[7][8][9]

Structural hierarchy
[edit]

Nearly all materials could be seen as hierarchically structured, since the

changes in spatial scale bring about different mechanisms of deformation
and damage.[10] However, in biological materials, this hierarchical
organization is inherent to the microstructure. One of the first examples of
this, in the history of structural biology, is the early X-ray scattering work on
the hierarchical structure of hair and wool by Astbury and Woods.[11] In bone,
for example, collagen is the building block of the organic matrix, a triple helix
with diameter of 1.5 nm. These tropocollagen molecules are intercalated with
the mineral phase (hydroxyapatite, calcium phosphate) forming fibrils that
curl into helicoids of alternating directions. These "osteons" are the basic
building blocks of bones, with the volume fraction distribution between
organic and mineral phase being about 60/40.

In another level of complexity, the hydroxyapatite crystals are mineral

platelets that have a diameter of approximately 70 to 100 nm and thickness
of 1 nm. They originally nucleate at the gaps between collagen fibrils. [12]

Similarly, the hierarchy of abalone shell begins at the nanolevel, with an

organic layer having a thickness of 20 to 30 nm. This layer proceeds with
single crystals of aragonite (a polymorph of CaCO3) consisting of "bricks"
with dimensions of 0.5 and finishing with layers approximately 0.3 mm
(mesostructure).[13]

Crabs are arthropods, whose carapace is made of a mineralized hard

component (exhibits brittle fracture) and a softer organic component
composed primarily of chitin. The brittle component is arranged in a helical
pattern. Each of these mineral "rods" (1 μm diameter) contains chitin–protein
fibrils with approximately 60 nm diameter. These fibrils are made of 3 nm
diameter canals that link the interior and exterior of the shell.

Applications

[edit]

Biomaterials are used in:

1. Joint replacements

2. Bone plates [14]

3. Intraocular lenses (IOLs) for eye surgery

4. Bone cement
 5. Artificial ligaments and tendons

6. Dental implants for tooth fixation

7. Blood vessel prostheses

8. Heart valves

9. Skin repair devices (artificial tissue)

10. Cochlear replacements

11. Contact lenses

12. Breast implants

13. Drug delivery mechanisms

14. Sustainable materials

15. Vascular grafts

16. Stents

17. Nerve conduits

18. Surgical sutures, clips, and staples for wound closure[15]

19. Pins and screws for fracture stabilisation[16]

20. Surgical mesh[17][18]

Biomaterials must be compatible with the body, and there are often issues
of biocompatibility, which must be resolved before a product can be placed
on the market and used in a clinical setting. Because of this, biomaterials are
usually subjected to the same requirements as those undergone by
new drug therapies.[19][20] All manufacturing companies are also required to
ensure traceability of all of their products, so that if a defective product is
discovered, others in the same batch may be traced.

Bone grafts

[edit]

Calcium sulfate (its α- and β-hemihydrates) is a well known biocompatible

material that is widely used as a bone graft substitute in dentistry or as its
binder.[21][22]

Heart valves
[edit]

In the United States, 49% of the 250,000 valve replacement procedures

performed annually involve a mechanical valve implant. The most widely
used valve is a bileaflet disc heart valve or St. Jude valve. The mechanics
involve two semicircular discs moving back and forth, with both allowing the
flow of blood as well as the ability to form a seal against backflow. The valve
is coated with pyrolytic carbon and secured to the surrounding tissue with a
mesh of woven fabric called Dacron (du Pont's trade name for polyethylene
terephthalate). The mesh allows for the body's tissue to grow, while
incorporating the valve.[23]

Skin repair

[edit]

Main article: Tissue engineering

Most of the time, artificial tissue is grown from the patient's own cells.
However, when the damage is so extreme that it is impossible to use the
patient's own cells, artificial tissue cells are grown. The difficulty is in finding
a scaffold that the cells can grow and organize on. The characteristics of the
scaffold must be that it is biocompatible, cells can adhere to the scaffold,
mechanically strong and biodegradable. One successful scaffold is
a copolymer of lactic acid and glycolic acid.[23]

Properties

[edit]

As discussed previously, biomaterials are used in medical devices to treat,

assist, or replace a function within the human body. The application of a
specific biomaterial must combine the necessary composition, material
properties, structure, and desired in vivo reaction in order to perform the
desired function. Categorizations of different desired properties are defined
in order to maximize functional results.[24][25]

Host response

[edit]

Host response is defined as the "response of the host organism (local and
systemic) to the implanted material or device". Most materials will have a
reaction when in contact with the human body. The success of a biomaterial
relies on the host tissue's reaction with the foreign material. Specific
reactions between the host tissue and the biomaterial can be generated
through the biocompatibility of the material.[25][26]

Biomaterial and tissue interactions

[edit]

The in vivo functionality and longevity of any implantable medical device is

affected by the body's response to the foreign material. [27] The body
undergoes a cascade of processes defined under the foreign body
response (FBR) in order to protect the host from the foreign material. The
interactions between the device upon the host tissue/blood as well as the
host tissue/blood upon the device must be understood in order to prevent
complications and device failure.

Tissue injury caused by device implantation causes inflammatory and healing

responses during FBR. The inflammatory response occurs within two time
periods: the acute phase, and the chronic phase. The acute phase occurs
during the initial hours to days of implantation, and is identified by fluid and
protein exudation[28] along with a neutrophilic reaction.[29] During the acute
phase, the body attempts to clean and heal the wound by delivering excess
blood, proteins, and monocytes are called to the site. [30] Continued
inflammation leads to the chronic phase, which can be categorized by the
presence of monocytes, macrophages, and lymphocytes. [29] In addition, blood
vessels and connective tissue form in order to heal the wounded area. [31]

Compatibility

[edit]

Biocompatibility is related to the behavior of biomaterials in various

environments under various chemical and physical conditions. The term may
refer to specific properties of a material without specifying where or how the
material is to be used. For example, a material may elicit little or no immune
response in a given organism, and may or may not able to integrate with a
particular cell type or tissue. Immuno-informed biomaterials that direct the
immune response rather than attempting to circumvent the process is one
approach that shows promise.[32] The ambiguity of the term reflects the
ongoing development of insights into "how biomaterials interact with
the human body" and eventually "how those interactions determine the
clinical success of a medical device (such as pacemaker or hip
replacement)". Modern medical devices and prostheses are often made of
more than one material, so it might not always be sufficient to talk about the
biocompatibility of a specific material.[33] Surgical implantation of a
biomaterial into the body triggers an organism-inflammatory reaction with
the associated healing of the damaged tissue. Depending upon the
composition of the implanted material, the surface of the implant, the
mechanism of fatigue, and chemical decomposition there are several other
reactions possible. These can be local as well as systemic. These include
immune response, foreign body reaction with the isolation of the implant
with a vascular connective tissue, possible infection, and impact on the
lifespan of the implant. Graft-versus-host disease is an auto- and alloimmune
disorder, exhibiting a variable clinical course. It can manifest in either acute
or chronic form, affecting multiple organs and tissues and causing serious
complications in clinical practice, both during transplantation and
implementation of biocompatible materials.[34]

Toxicity

[edit]

A biomaterial should perform its intended function within the living body
without negatively affecting other bodily tissues and organs. In order to
prevent unwanted organ and tissue interactions, biomaterials should be non-
toxic. The toxicity of a biomaterial refers to the substances that are emitted
from the biomaterial while in vivo. A biomaterial should not give off anything
to its environment unless it is intended to do so. Nontoxicity means that
biomaterial is: noncarcinogenic, nonpyrogenic, nonallergenic, blood
compatible, and noninflammatory.[35] However, a biomaterial can be
designed to include toxicity for an intended purpose. For example,
application of toxic biomaterial is studied during in vivo and in vitro cancer
immunotherapy testing. Toxic biomaterials offer an opportunity to
manipulate and control cancer cells.[36] One recent study states: "Advanced
nanobiomaterials, including liposomes, polymers, and silica, play a vital role
in the codelivery of drugs and immunomodulators. These nanobiomaterial-
based delivery systems could effectively promote antitumor immune
responses and simultaneously reduce toxic adverse effects." [37] This is a
prime example of how the biocompatibility of a biomaterial can be altered to
produce any desired function.

Biodegradable biomaterials

[edit]

Biodegradable biomaterials refers to materials that are degradable through

natural enzymatic reactions. The application of biodegradable synthetic
polymers began in the later 1960s.[38] Biodegradable materials have an
advantage over other materials, as they have lower risk of harmful effects
long term. In addition to ethical advancements using biodegradable
materials, they also improve biocompatibility for materials used for
implantation.[38] Several properties including biocompatibility are important
when considering different biodegradable biomaterials. Biodegradable
biomaterials can be synthetic or natural depending on their source and type
of extracellular matrix (ECM).[39]

Biocompatible plastics

[edit]

Some of the most commonly-used biocompatible materials (or biomaterials)

are polymers due to their inherent flexibility and tunable mechanical
properties. Medical devices made of plastics are often made of a select few
including: cyclic olefin
copolymer (COC), polycarbonate (PC), polyetherimide (PEI), medical
grade polyvinylchloride (PVC), polyethersulfone (PES), polyethylene (PE), pol
yetheretherketone (PEEK) and even polypropylene (PP). To
ensure biocompatibility, there are a series of regulated tests that material
must pass to be certified for use. These include the United States
Pharmacopoeia IV (USP Class IV) Biological Reactivity Test and the
International Standards Organization 10993 (ISO 10993) Biological
Evaluation of Medical Devices. The main objective of biocompatibility tests is
to quantify the acute and chronic toxicity of material and determine any
potential adverse effects during use conditions, thus the tests required for a
given material are dependent on its end-use (i.e. blood, central nervous
system, etc.).[40]

Surface and bulk properties

[edit]

Two properties that have a large effect on the functionality of a biomaterial is

the surface and bulk properties.[41]

Bulk properties refers to the physical and chemical properties that compose
the biomaterial for its entire lifetime. They can be specifically generated to
mimic the physiochemical properties of the tissue that the material is
replacing. They are mechanical properties that are generated from a
material's atomic and molecular construction.

Important bulk properties:[42]

  Chemical Composition

 Microstructure

 Elasticity

 Tensile Strength

 Density

 Hardness

 Electrical Conductivity

 Thermal Conductivity

Surface properties refers to the chemical and topographical features on the

surface of the biomaterial that will have direct interaction with the host
blood/tissue.[43] Surface engineering and modification allows clinicians to
better control the interactions of a biomaterial with the host living system.

Important surface properties:[44]

 Wettability (surface energy)

 Surface chemistry

 Surface textures (smooth/rough)

 Topographical factors including: size, shape, alignment, structure

determine the roughness of a material.[45]

 Surface Tension

 Surface Charge

Mechanical properties

[edit]

In addition to a material being certified as biocompatible, biomaterials must

be engineered specifically to their target application within a medical device.
This is especially important in terms of mechanical properties which govern
the way that a given biomaterial behaves. One of the most relevant material
parameters is the Young's Modulus, E, which describes a material's elastic
response to stresses. The Young's Moduli of the tissue and the device that is
being coupled to it must closely match for optimal compatibility between
device and body, whether the device is implanted or mounted externally.
Matching the elastic modulus makes it possible to limit movement
and delamination at the biointerface between implant and tissue as well as
avoiding stress concentration that can lead to mechanical failure. Other
important properties are the tensile and compressive strengths which
quantify the maximum stresses a material can withstand before breaking
and may be used to set stress limits that a device may be subject to within
or external to the body. Depending on the application, it may be desirable for
a biomaterial to have high strength so that it is resistant to failure when
subjected to a load, however in other applications it may be beneficial for the
material to be low strength. There is a careful balance between strength and
stiffness that determines how robust to failure the biomaterial device is.
Typically, as the elasticity of the biomaterial increases, the ultimate tensile
strength will decrease and vice versa. One application where a high-strength
material is undesired is in neural probes; if a high-strength material is used in
these applications the tissue will always fail before the device does (under
applied load) because the Young's Modulus of the dura
mater and cerebral tissue is on the order of 500 Pa. When this happens,
irreversible damage to the brain can occur, thus the biomaterial must have
an elastic modulus less than or equal to brain tissue and a low tensile
strength if an applied load is expected.[46][47]

For implanted biomaterials that may experience temperature fluctuations,

e.g., dental implants, ductility is important. The material must be ductile for
a similar reason that the tensile strength cannot be too high, ductility allows
the material to bend without fracture and also prevents the concentration of
stresses in the tissue when the temperature changes. The material property
of toughness is also important for dental implants as well as any other rigid,
load-bearing implant such as a replacement hip joint. Toughness describes
the material's ability to deform under applied stress without fracturing and
having a high toughness allows biomaterial implants to last longer within the
body, especially when subjected to large stress or cyclically loaded stresses,
like the stresses applied to a hip joint during running.[46]

For medical devices that are implanted or attached to the skin, another
important property requiring consideration is the flexural rigidity, D. Flexural
rigidity will determine how well the device surface can
maintain conformal contact with the tissue surface, which is especially
important for devices that are measuring tissue motion (strain), electrical
signals (impedance), or are designed to stick to the skin
without delaminating, as in epidermal electronics. Since flexural rigidity
depends on the thickness of the material, h, to the third power (h3), it is very
important that a biomaterial can be formed into thin layers in the previously
mentioned applications where conformality is paramount.[48]

Structure

[edit]

The molecular composition of a biomaterial determines the physical and

chemical properties of a biomaterial. These compositions create complex
structures that allow the biomaterial to function, and therefore are necessary
to define and understand in order to develop a biomaterial. biomaterials can
be designed to replicate natural organisms, a process known as biomimetics.
[49]
The structure of a biomaterial can be observed at different at different
levels to better understand a materials properties and function.

Atomic structure

[edit]

Rutherford model of lithium-7's atomic structure

The arrangement of atoms and ions within a material is one of the most
important structural properties of a biomaterial. The atomic structure of a
material can be viewed at different levels, the sub atomic level, atomic
or molecular level, as well as the ultra-structure created by the atoms and
molecules. Intermolecular forces between the atoms and molecules that
compose the material will determine its material and chemical properties. [50]

The sub atomic level observes the electrical structure of an individual atom
to define its interactions with other atoms and molecules. The molecular
structure observes the arrangement of atoms within the material. Finally the
ultra-structure observes the 3-D structure created from the atomic and
molecular structures of the material. The solid-state of a material is
characterized by the intramolecular bonds between the atoms and molecules
that comprise the material. Types of intramolecular bonds include: ionic
bonds, covalent bonds, and metallic bonds. These bonds will dictate the
physical and chemical properties of the material, as well as determine the
type of material (ceramic, metal, or polymer).

Microstructure

[edit]

A unit cell shows the locations of lattice points

repeating in all directions.

The microstructure of a material refers to the structure of an object,

organism, or material as viewed at magnifications exceeding 25 times. [51] It is
composed of the different phases of form, size, and distribution of grains,
pores, precipitates, etc. The majority of solid microstructures are crystalline,
however some materials such as certain polymers will not crystallize when in
the solid state.[52]

Crystalline structure

[edit]

Crystalline structure is the composition of ions, atoms, and molecules that

are held together and ordered in a 3D shape. The main difference between a
crystalline structure and an amorphous structure is the order of the
components. Crystalline has the highest level of order possible in the
material where amorphous structure consists of irregularities in the ordering
pattern.[53] One way to describe crystalline structures is through the crystal
lattice, which is a three-dimensional representation of the location of a
repeating factor (unit cell) in the structure denoted with lattices.[54] There are
14 different configurations of atom arrangement in a crystalline structure,
and are all represented under Bravais lattices.[citation needed]

Defects of crystalline structure

[edit]

Main article: Crystallographic defect

During the formation of a crystalline structure, different impurities,

irregularities, and other defects can form. These imperfections can form
through deformation of the solid, rapid cooling, or high energy radiation.
[55]
Types of defects include point defects, line defects, as well as edge
dislocation.

Macrostructure

[edit]

Macrostructure refers to the overall geometric properties that will influence

the force at failure, stiffness, bending, stress distribution, and the weight of
the material. It requires little to no magnification to reveal the
macrostructure of a material. Observing the macrostructure reveals
properties such as cavities, porosity, gas bubbles, stratification, and fissures.
[56]
The material's strength and elastic modulus are both independent of the
macrostructure.

Natural biomaterials

[edit]

Biomaterials can be constructed using only materials sourced from plants

and animals in order to alter, replace, or repair human tissue/organs. Use of
natural biomaterials were used as early as ancient Egypt, where indigenous
people used animal skin as sutures. A more modern example is a hip
replacement using ivory material which was first recorded in Germany 1891.
[57]

Valuable criteria for viable natural biomaterials:

 Biodegradable

 Biocompatible

 Able to promote cell attachment and growth

 Non-toxic

Examples of natural biomaterials:

 Alginate[58]

 Matrigel

 Fibrin

 Collagen

 Myocardial tissue engineering[59]

Biopolymers

[edit]

Main article: Biopolymer

Biopolymers are polymers produced by living

organisms. Cellulose and starch, proteins and peptides,
and DNA and RNA are all examples of biopolymers, in which
the monomeric units, respectively, are sugars, amino acids, and nucleotides.
[60]
Cellulose is both the most common biopolymer and the most common
organic compound on Earth. About 33% of all plant matter is cellulose. [61]
[62]
On a similar manner, silk (proteinaceous biopolymer) has garnered
tremendous research interest in a myriad of domains including tissue
engineering and regenerative medicine, microfluidics, drug delivery. [63][64]