Wuolah Free Biomateriales

Biomateriales.
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Crespo_99
Introducción a los Biomateriales
3º Grado en Ingeniería Biomédica
Escuela Politécnica Superior

Universidad Carlos III de Madrid
Reservados todos los derechos.

No se permite la explotación económica ni la transformación de esta obra. Queda permitida la impresión en su totalidad.
CARLOS III UNIVERSITY OF MADRID
Bachelor’s Degree in Biomedical Engineering
Biological Systems
CLASS NOTES
David Crespo Acero

November 4, 2020
Supervised by:
a64b0469ff35958ef4ab887a898bd50bdfbbe91a-3354329
Contents
1 Introduction to biomaterials 5
1.1 Biomaterials: Basic concepts . . . . . . . . . . . . . . . . . . . 5
2 Polymers for biomedical applications 7

2.1 What is a polymer? . . . . . . . . . . . . . . . . . . . . . . . . 7
2.2 Polymer synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.2.1 Chain polymerization . . . . . . . . . . . . . . . . . . . 7
2.2.2 Step polymerization . . . . . . . . . . . . . . . . . . . 7
2.2.3 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . 8
2.3 Polymer structure . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.4 Polymer architecture . . . . . . . . . . . . . . . . . . . . . . . 9
2.4.1 Configuration state . . . . . . . . . . . . . . . . . . . . 9
2.4.2 State of aggregation . . . . . . . . . . . . . . . . . . . 9
2.5 Thermal properties . . . . . . . . . . . . . . . . . . . . . . . . 10
2.5.1 Thermoplastic . . . . . . . . . . . . . . . . . . . . . . . 10
2.5.2 Thermoset . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.6 Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.6.1 According to their origin . . . . . . . . . . . . . . . . . 11
2.6.2 Inert polymers . . . . . . . . . . . . . . . . . . . . . . 12
2.6.3 Biodegradable polymers . . . . . . . . . . . . . . . . . 12
2.6.4 Smart polymers . . . . . . . . . . . . . . . . . . . . . . 12
2.7 Important definitions . . . . . . . . . . . . . . . . . . . . . . . 12
2.8 Gene-based therapy . . . . . . . . . . . . . . . . . . . . . . . . 13
2.8.1 Viral gere therapy . . . . . . . . . . . . . . . . . . . . . 13
2.8.2 Non-viral gene therapy . . . . . . . . . . . . . . . . . . 13
3 Hydrogels for biomedical applications 14

3.1 Hydrogels: Concept . . . . . . . . . . . . . . . . . . . . . . . . 14
3.2 Hydrogels: reversible or physical hydrogels . . . . . . . . . . . 14
3.3 Hydrogels: permanent or chemical . . . . . . . . . . . . . . . . 15
3.4 Interpenetrating polymer networks (IPN) . . . . . . . . . . . . 15
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3.4.1 Semi- interpenetrating polymer networks (semi-IPNs) . 15
3.5 Injectable hydrogels . . . . . . . . . . . . . . . . . . . . . . . . 16
3.6 Nano/microgels . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4 Bioceramics (ceramics, glass-ceramics and bioactive glasses) 17
4.1 What is a ceramic? . . . . . . . . . . . . . . . . . . . . . . . . 17
4.2 Ceramic process and properties . . . . . . . . . . . . . . . . . 17
4.2.1 Biomineralization . . . . . . . . . . . . . . . . . . . . . 17
4.2.2 Steps in the classic ceramic process . . . . . . . . . . . 17
4.2.3 Properties of ceramic materials . . . . . . . . . . . . . 18
4.3 Classification of ceramics . . . . . . . . . . . . . . . . . . . . . 18
4.3.1 Crystalline ceramics . . . . . . . . . . . . . . . . . . . 18
4.3.2 Glasses . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.3.3 Cements . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.3.4 Glass-ceramics . . . . . . . . . . . . . . . . . . . . . . 19
4.4 Ceramics for biomedical applications . . . . . . . . . . . . . . 19

4.4.1 Reactivity of implants . . . . . . . . . . . . . . . . . . 20
4.5 Bioinert, Bioactive glasses and Calcium phosphate Bioceramics 21
4.5.1 Bioactive glasses . . . . . . . . . . . . . . . . . . . . . 21
4.5.2 Calcium phosphate bioceramics . . . . . . . . . . . . . 22
4.5.3 Porous Ceramic Scaffolds for Bone Tissue Engineering 22
5 Surface modifications 24
5.1 What is a surface and properties . . . . . . . . . . . . . . . . . 24
5.1.1 Surface-are-to-volume ratio . . . . . . . . . . . . . . . . 24
5.1.2 What is an interface . . . . . . . . . . . . . . . . . . . 25
5.1.3 (Excess) Surface Free Energy . . . . . . . . . . . . . . 25
5.1.4 Bulk properties vs surface modification . . . . . . . . . 25
5.2 Surface modification . . . . . . . . . . . . . . . . . . . . . . . 26
5.3 Surface modification methods . . . . . . . . . . . . . . . . . . 26
5.3.1 Physicochemical . . . . . . . . . . . . . . . . . . . . . . 26
5.3.2 Biological . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.3.3 Plasma discharge . . . . . . . . . . . . . . . . . . . . . 27
5.3.4 Chemical vapor deposition (CVD) . . . . . . . . . . . . 27
5.3.5 Physical vapor deposition (PVD) . . . . . . . . . . . . 27
5.3.6 Radiation Grafting and Photografting . . . . . . . . . . 27
5.3.7 Self-Assembled Monolayers . . . . . . . . . . . . . . . . 28
5.3.8 Solution coating . . . . . . . . . . . . . . . . . . . . . . 28
5.3.9 Langmuir-Blodgett Films . . . . . . . . . . . . . . . . . 28
5.3.10 Surface modifying additives . . . . . . . . . . . . . . . 29
5.3.11 Conversion Coatings . . . . . . . . . . . . . . . . . . . 29

5.4 Patterning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.5 Photolitography . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6 Exam questions 32

List of Figures
2.1 Example of the importance of the Mn and the Mw . . . . . . 8

2.2 Types of copolymers . . . . . . . . . . . . . . . . . . . . . . . 9
2.3 Graph showing the behaviour of a crystal and a glass . . . . . 10
3.1 IUPAC definitions for semi-IPNs and for IPNS . . . . . . . . . 16
4.1 Exam question . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.1 Comparison between the different types of interfaces according

to the matter state . . . . . . . . . . . . . . . . . . . . . . . . 25
5.2 LB process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.3 Photolitography process . . . . . . . . . . . . . . . . . . . . . 30
5.4 Photolitography process . . . . . . . . . . . . . . . . . . . . . 31
5.5 How to prepare a PDMS stamp . . . . . . . . . . . . . . . . . 31
6.1 Schematic illustration of the proton sponge effect leading to

endosomal or lysosomal burst and release of the cationic mag-
netic particles into the cytoplasm . . . . . . . . . . . . . . . . 37
Chapter 1
Introduction to biomaterials
1.1 Biomaterials: Basic concepts

A biomaterial is a substance that has been engineered to take a form which,

alone or as a part of a complex system, is used to direct, by control of
interactions with components of living systems, the course of any therapeutic
or diagnosis procedure
The medical applications of biomaterials are:
1. Replacement of diseased, damaged or aged part (hip, knees, heart

valve)
2. Assist in healing (sutures, screws)
3. Improve or correct function (pacemakers, lens ,stent, spinal rod)
4. Treat diseases: cancer, drug release
5. Aid to diagnosis (catheter)
6. Tissue engineering (artificial skin)
Biomaterials can be grouped in different families which are (1) polymers,

(2) ceramics, and (3) metals.
An important feature about biomaterials is biocompatibility, which
can be defined as the ability of a biomaterial to perform its desired function
with respect to a medical therapy, without eliciting any undesirable local or
systemic effects in the recipient or beneficiary of that therapy, but generating
the most appropriate beneficial cellular or tissue response in that specific
situation, and optimizing the clinically relevant performance of that therapy.

• Structural biocompatibility: adaptation of the implant structure to the
mechanical behaviour of the surrounding host tissue.
• Surface biocompatibility: adaptation of the chemical, physical, biolog-

ical and morphological surface properties of the implant to the needs
of the surrounding tissue aiming at a clinical desired interaction.

Chapter 2
Polymers for biomedical

applications
2.1 What is a polymer?

Polymers are the most versatile materials, made of long repeating chains of
molecules called monomers. Most polymers have carbon as the base elements.
2.2 Polymer synthesis

2.2.1 Chain polymerization
In chain polymerization, monomers are added to a growing polymer chain,
for example with the elimination of a double bond in the monomer. This
technique requires an initiator which will lead the activation of the reaction.
The entire monomer becomes part of the polymer and no small molecules or
atoms are eliminated during the reaction. The disadvantages of this method
is that is not very efficient and it is toxic (the initiator remains).
2.2.2 Step polymerization

This technique often involves more than one monomer species. It is per-
formed through functional groups (OH, COOH, NH2) with the release of
a molecule of water. Part of the monomer is released when the monomer
becomes part of the polymer. It is less toxic, as we do not need an initiator.

Figure 2.1: Example of the importance of the Mn and the Mw
2.2.3 Biosynthesis
Some polymers can be produced using bacteria, yeast or plants introducing
inside their genetic material a vector encoding for the polymer. The disad-
vantages of this method is that the purity of the polymer and the production
power are low.
2.3 Polymer structure

Polymer chains are of unequal length, resulting in a heterogeneous distribu-
tion of the molecular weight (Polymers are polydisperse).
• Mn: Number average molecular weight
• Mw: Weight average molecular weight
Polydispersity index (Mw/Mn) is a measure of the broadness of a

molecular weight distribution of a polymer. The larger the index, the broader
the molecular weight.
There are techniques to achieve a PDI equal to 1: Reversible-deactivation
radical polymerization (RDRP) is a form of polymerization propagated
by chain carriers the some of which at any instant are held in a state of
dormancy through an equilibrium process involving other species.
Figure 2.2: Types of copolymers
2.4 Polymer architecture

Polymers can be formed by identical monomers (holopolymers) or by differ-
rent polymers (copolymers). Inside the group of copolymers there exist (1)
alternating, (2) block, (3) random, and (4) graft polymers. An example of
block polymer’s application are micelles.
Polymers can be (1) linear, (2) branched, (3) cross-linked, and (4) den-
dritic.
2.4.1 Configuration state

Chains of polymeric molecules are not necessarily straight
2.4.2 State of aggregation

A solid crystal polymer will have a constantly increasing enthalpy of volume
when increasing the temperature until the melting temperature (Tm), when
it reaches the liquid phase and the enthalpy of the volume increases suddenly
with a different constant rate.

Figure 2.3: Graph showing the behaviour of a crystal and a glass
A solid amorphous polymer will have a similar behaviour until a temper-

ature called glass temperature (Tg) is reached (Tg<Tm). At this point the
solid undergoes a liquid/rubery-like state until the temperature equals Tm,
when it becomes a liquid.
• Tg: change in the state of an amorphous polymer from a solid/glassy-
like to a liquid/rubery-like state and it is reversible
• Tm: occurs in crystaline polymers. Melting happens when the polymer
chains fail out of their crystal structures, and become a disordered
liquid.
2.5 Thermal properties

2.5.1 Thermoplastic
1. Long linear polymers with intermediate intermolecular forces of attrac-
tion
2. Polymers become soft after heating but again gets rigidness after cool-
ing (without changes in their composition)
10

3. Can be reshaped but degradation can occur at high temperatures if
covalent bonds are broken.
2.5.2 Thermoset
1. Become permanently hard when heated, they do not soften (covalent
crosslinking between polymer chains)
2. They can not be reshaped and its chemical composition gets changed
after heating
2.6 Classification
2.6.1 According to their origin
Synthetic

• Advantages:
Easily mass-produced and sterilized
Properties can be tailored for specific applications (surface modifi-
cations)
• Disadvantages
Some degrade into unfavourable products (toxicity)
Usually do not interact with tissues
Natural
• Advantages
Biocompatibility
Interact with tissues and respond to changes
Capables of chemical modification
Enzymatically biodegradable
• Disadvantages
Enzymatically biodegradable: uncontrolled rate of degradation
Poor reproductibility and purity of the sample (uncontrolled struc-
ture)
Weak in terms of mechanical strength
11

Semi-synthetic
Chemically-treated polymers of natural origin
2.6.2 Inert polymers

Non biodegradable, not undergo any chemical change in vivo, “do not do
anything inside the body”.
2.6.3 Biodegradable polymers

Degrade within the body (enzymes, oxidation, hydrolysis), they do not need
to be removed surgically, for short term applictions
2.6.4 Smart polymers

Polymer that experiences changes in response to small external changes in
the environmental conditions. These transitions can be reversible.
• Physical stimuli: pressure, ultrasound, temperature, light, and electric

and magnetic field
• Chemical stimuli: pH, ionic factors, glucose
• Biochemical stimuli: Enzymes, antigens
2.7 Important definitions

• Biodegradation: breaking chemical bonds within the material. Polymer
molecular weight decreases.
Bulk degradation: in hydrophilic materials. Loss of the material
throughout the entire scaffold
Surface degradation: limited to the surface
• Bioerosion: change in the size of the material that may be caused or

not by degradation.
12
2.8 Gene-based therapy
2.8.1 Viral gere therapy
It is based on the ability of a virus to inject genetic material inside a host
cell (the genetic material is packaged into a viral particle).
2.8.2 Non-viral gene therapy

It is based on physical methods and chemical carriers (virtually unlimited
gene material, low toxicity, simple production).
A technique used in non-viral gene therapy is the so called “proton
sponge”. The genetic material is linked to a polycation with a ligand molecule,
it formes an endosome as it enters the cell membrane. This endosome has
different pH to that of the cell, so protons enter the endosome to compensate
it as well as water to compensate the osmotic unbalance, making the endo-
some to swell and release the complex. The genetic material must enter the

nucleus if it is DNA but if it is ARN it will work without entering it.
13

Chapter 3
Hydrogels for biomedical

applications
3.1 Hydrogels: Concept

Hydrogels are three-dimensional high-molecular weight networks composed
of hydrophilic polymer backbone and water.
They are highly biocompatible, simillar to tissue ECM (soft),and they
supports cell proliferation and migration (nutrient diffusion).
They are used for drug delivery, wound dressing, tissue engineering and
microfluidics.
Hydrogels can be produced by using natural (biocompatible, physically
crosslinked, non toxic, but vary in composition and molecular weight) or
synthetic polymers (control of the composition and molecular weight, but
requires mild crosslinking that do not compromise cell viability), which can be
biodegradable or non-biodegradable. Hybrid hydrogels are the combination
of natural polymers (biocompatibity) and synthetic polymers (mechanical
properties).
3.2 Hydrogels: reversible or physical hydro-

gels
The polymer networks are held together by molecular entanglements, and/or
secondary forces including ionic, H-bonding or hydrophobic forces. They are
not homogeneous (domains) and interactions are reversible.
• Thermoresponsive: hydrogels formation due to alteration solvation and

phase transition with respect to temperature
14

• pH-responsive: removal of repulsive electrostatic interactions during
neutralization, allowing amine groups to interact via inter-molecular
hydrogen.
3.3 Hydrogels: permanent or chemical
• Covalently-crosslinked networks
• Disulfide crosslinking: Bonds between two thiols in an oxidative envi-

ronment (extracellular space) and remain unreactive in reduced state
(cytoplasm)
• Schiff base crosslinking
• Enzyme-mediated crosslinking
• Click chemistry: joining modular entities. Thiol–ene click reaction is

a radical mediated addition of a thiol moiety and an alkene in the
presence of light
• Michael addition: nucleophile (thiols or amine) is added to unsaturated

carbonyl compounds (aldehydes, ketones etc...)
3.4 Interpenetrating polymer networks (IPN)

Two or more polymer networks that least partially interlaced on the molec-
ular scale but without any covalent bonds between them, which cannot be
separated unless chemical bonds are broken
They are used because single-network hydrogels have weak mechanical
properties and slow response at swelling.
3.4.1 Semi- interpenetrating polymer networks (semi-

IPNs)
A polymer comprising one or more networks and one or more linear or
branched polymer characterized by the penetration on a molecular scale of
at least one of the linear or branched macromolecules.
15

Figure 3.1: IUPAC definitions for semi-IPNs and for IPNS
3.5 Injectable hydrogels

The system can effectively deliver a wide array of therapeutic agents like
drugs, growth factors, fillers and even cells. Its advantages are:
• Easier handling
• Can reach very deep tissue defects
• Minimally invasive
• Complete defect filling leading to neovascularization from healthy tis-

sues
3.6 Nano/microgels
Hydrogels can be in the form of macroscopic networks or confined to smaller
dimensions such as nano/microgels, which are crosslinked polymeric particles.
When is submicron range, nanogels.
16
Chapter 4
Bioceramics (ceramics,
glass-ceramics and bioactive
glasses)

4.1 What is a ceramic?
A ceramic is a solid material formed by the application of heat and/or pres-
sure, comprising an inorganic compound of metal, non-metal or ionic and
covalent bonds. They are present in hard tissues of vertebrates (enamel is
the hardest substance in the body, hydroxyapatite) and protective tissues in
invertebrates.
Ceramics are formed by a combination of covalent and ionic bonds
4.2 Ceramic process and properties

4.2.1 Biomineralization
It is the formation of an inorganic solid within a biological system, and it
takes place through a precipitation reaction in water solution; it involves
three steps of supersaturation, nucleation, and growth, controlled by the
living species in question.
4.2.2 Steps in the classic ceramic process

1. Compounding: Mix and homogenize ingredients into a water based sus-
pension (slurry) or into a solid plastic material (non-reversible shape)
containing water called a clay
17

2. Forming: The clay or slurry is made into parts by pressing into mold
(sintering, to make crystalline structures). The fine particulates are
often fine grained crystals. Atomic diffusion helped by heating to a
temperature below the melting point.
3. Drying The formed object is dried, usually at room temperature to the
so-called leathery
4. Firing: Heat in furnace to drive off remaining water. Typically pro-

duces shrinkage, so producing parts that must have tight mechanical
tolerance requires care
4.2.3 Properties of ceramic materials

• Very stable: High hardness, electrical and thermal insulating, chemical
stability (pH, T, corrosion resistance), and high melting temperatures

• High wear resistance: resistance to the release of small debris when two
materials are in contact (and motion)
• High compressive strength but low tensile strength because of the gap
propagation (and compression involves the breaking of many bonds at
the same time)
• They can be crystalline or amorphous
• Brittle (low fracture resistance): ceramics have a mixture of planes (co-

valent and ionic bonds) so the translation of the planes is very difficult
A material is brittle if, when subjected to stress, it breaks without signif-

icant deformation (strain)
4.3 Classification of ceramics

4.3.1 Crystalline ceramics
Crystalline ceramic are inorganic, mostly crystalline compounds that contain
metallic and non-metallic elements, for which inter-atomic bonding is ionic
or covalent, and which are generally formed at high temperatures
18

4.3.2 Glasses
Glasses are (1) an inorganic product of fusion that has cooled to a rigid
condition without crystallization (vitrification) or (2) an amorphous solid
(silicon based materials)
4.3.3 Cements
Cements sets or cures when mixed with water which causes a series of hy-
dration chemical reactions. The cement dissolves and precipitates and the
entanglement of the precipitated crystals is the mechanism responsible for
cement hardening. Usually amorphous.
4.3.4 Glass-ceramics
Glass-ceramic are polycrystalline solids prepared by the controlled crystal-
lization (devitrification) of glass. Amorphous phase and one or more crys-

talline phases and are produced by a so-called “controlled crystallization”
4.4 Ceramics for biomedical applications

Ceramics are commonly used to repair hard tissue in humans (when in con-
tact with living tissues are bioceramics) in orthopedics and dentistry.
• Orthopedics: the main sources for bone are the iliac crest and the
chin. Examples: hip components, coatings, space filling and vertebral
prostheses. Alumina is very used because of its excellent corrosion
resistance, its good biocompatibility, its high wear resistance and its
high strength
• Dentistry: dental restorations, implants and orthodontics (brackets)
One remarkable effect is the so ccalled shield effect, that corresponds to

the fact that the metal inside the bone will absorb all the stresses and then
the bone will undergo demineralization.
• An allograft is a transplanted organ or tissue from a genetically non-

identical member of the same species. Most human tissue and organ
transplants are allografts.
• A transplanted organ or tissue from a genetically identical donor, i.e.

an identical twin, is called an isograft
19

• A transplant from another species is termed a xenograft
• When a tissue is transplanted from one site to another on the same

patient, such as a skin graft or a tissue flap, it is termed an autograft.
• Bioinert: Material that retains its structure in the body after implan-
tation and does not induce any immunologic host reactions
• Bioactive: Material that forms direct chemical bonds with bone or even
with soft tissue of a living organism

• Biodegradable: Materials that degrade by chemical or cellular actions
(breakdown) in the body while they are being replaced by regenerating
natural tissue; the chemical byproducts of the degrading materials are
absorbed and released via metabolic processes of the body
The different types of implant-tissue response are:
• If the material is toxic, the surrounding tissue dies.
• If the material is nontoxic and biologically inactive (nearly inert), a

fibrous tissue of variable thickness forms (Movement at the biomaterial-
tissue interface eventually leads to deterioration)
• If the material is nontoxic and biologically active (bioactive), an inter-

facial bond forms.
• If the material is nontoxic and biodegradable, the surrounding tissue

replaces it.
4.4.1 Reactivity of implants

• Type I: relative movement and progressive development of a fibrous
capsule in soft and hard tissues. The presence of movement at the bio-
material–tissue interface eventually leads to deterioration in function
of the implant or the tissue at the interface, or both.
• Type II: is the ingrowth of tissue into pores on the surface or throughout
the implant. The increased interfacial area between the implant and
the tissues results in an increased resistance to movement of the device
in the tissue. The interface is established by the living tissue in the
pores.
20
Figure 4.1: Exam question
• Type III: time dependence of bonding, the strength of bond, the mech-
anism of bonding, and the thickness of the bonding zone differ for the
various materials

• Type IV: designed to degrade gradually over a period of time, and to
be replaced by the natural host tissue. This leads to a very thin or
nonexistent interfacial thickness.
4.5 Bioinert, Bioactive glasses and Calcium

phosphate Bioceramics
4.5.1 Bioactive glasses
Bioactive glasses when interacting with body fluids, form an apatite layer
on its surface. This layer plays a critical role for the attachment of proteins
which osteoblasts bind and proliferate.
Material-interface-natural bone
The bigger the surface degradation, the thicker the apatite layer.
Uses
• Middle ear devices and implants for the orbital floor in head and throat
surgery
• Dental implants (chemical bonding with bone tissue, elasticity similar

to bone tissue)
21

• Coating of Ti implants
Material classification for bone

• Osteoinduction: This term means that primitive, undifferentiated and
pluripotent cells are somehow stimulated to develop into the bone-
forming cell lineage (Osteogenesis, bone healing)
• Osteoconduction: This term means that bone grows on a surface. An

osteoconductive surface is one that permits bone growth on its surface
or down into pores, channels or pipes
• Osseointegration: Direct anchorage of an implant by the formation of

bony tissue around the implant without the growth of fibrous tissue at
the bone-implant interface.
• Heterotopically: placing this material in the skin or muscle to ensure

that a material is bioactive and will attract stem cells:

4.5.2 Calcium phosphate bioceramics
Hydroxyapatite
Due to brittle mechanical properties hydroxyapatite cannot be used as a
bulk material in load bearing applications but as coating bioceramic and
bone filler material.
Coatings of hydroxyapatite are often applied to metallic implants (most
commonly titanium/titanium alloys and stainless steels) to alter the surface
properties. Without the coating the body would see a foreign body and work
in such a way as to isolate it from surrounding tissues.
Tricalcium phosphates
Used as bone and tooth implant due to excellent biocompatibility and biore-
sorbility. Combinations of HA and -TCP. Cannot be used as a bulk material
in load bearing applications: coating bioceramic (better fixation), bone filler
material, drug delivery, maxillofacial reconstruction.
4.5.3 Porous Ceramic Scaffolds for Bone Tissue Engi-

neering
• Use porous scaffolds to either induce the formation of bone from sur-
rounding tissue or to act as a carrier for implanted bone-forming cells
22

or other biomolecular agents (eg growth or morphogenetic factors).
• Porosity and interconectivity are critical factors.
• Balance between porosity and mechanical properties.
23

Chapter 5
Surface modifications

5.1 What is a surface and properties
Surface is the shell of a macroscopic object (the inside) in contact with its en-
vironment (the outside world). The surface of an object determines its optical
appearance stickiness, wetting behavior, frictional behavior, and chemical re-
activity, e.g.
Bio/material surfaces exhibit remarkable heterogeneity in physical struc-
ture:
• Material dependant: Metals vs. Polymers vs. Ceramics vs. Gels
• Chemistry: Polar (charges, hydrophilic) vs. Apolar, Charge, Reactiv-

ity, Patterned, hydrophobic
• Morphology: Smooth, Rough (more cells attachment, more surface

area), Stepped, Patterned, Diffuse
• Order: Crystalline, Amorphous, Semi-Crystalline, Phases
• Environment: Hydration, Solvent Quality
5.1.1 Surface-are-to-volume ratio

Surface-area-to-volume ratio (sa/vol) is the amount of surface area per unit
volume of an object.
In large objects with small surface area A to volume V ratio (A/V) the
physical and chemical properties are primarily defined by the bulk (inside).
In small objects with a large A/V-ratio the properties are strongly influenced
by the surface
24
Figure 5.1: Comparison between the different types of interfaces according

to the matter state
5.1.2 What is an interface

An interface is the boundary region between two adjacent bulk phases
5.1.3 (Excess) Surface Free Energy

At the surface of a material, there are free electrons as the atoms are not
linked to other neighbor atoms. This free electrons are in fact energy that
resides at the surface of the material.
Systems will always try to minimize this free energy, for that purpose
they change its geometrical configuration (bending), bind other molecules
(as proteins) and/or do dynamic rearrangements (different orientations of
the molecules in polar and apolar solvents)
5.1.4 Bulk properties vs surface modification

The bulk structure governs the mechanical durability and functionality of
biomaterials. The biological response to biomaterials and devices, on the
other hand, is controlled largely by their surface chemistry and structure.
That is why we make surface modifications to the biomaterials: to retain
the mechanical and functionality properties of a biomaterial while modifying
only the outermost surface to influence the bioresponse related to the tissue.
25

5.2 Surface modification
Many can be considered postfabrication processing techniques while in other
cases, final surface modification is designed into the chemical nature of the
biomaterial.
An ideal technique would produce a surface treatment with the following
characteristics:
• Thin (to minimize effects on bulk properties)
• Resistant to delamination (extremely thin layers are more subject to

surface reversal and mechanical erosion)
• Simple and robust (commercialization)
In reality there are delamination, cracking and surface rearrangement.

Resistance to delamination is achieved covalently bonding the modified

region to the substrate, Resistance to surface rearrangement (surface rever-
sal, minimization of interfacial energy and enhanced by molecular mobility)
is achieved by crosslinking and sterically blocking the ability of surface struc-
tures to move.
5.3 Surface modification methods

5.3.1 Physicochemical
Surface treatment (use physical principles or chemical reactions to alter the
surface composition).
• Covalent surface coatings
• Non-covalent surface coating
• No overcoat: modify existing atoms at the surface but not attach a

distinct coating layer.
5.3.2 Biological
Involves the attachment of active biological molecules through a variety of
means, including physicochemical methods. The goal of biological surface
modification is to control cell and tissue responses to an implant by immobi-
lizing biomolecules on biomaterials. The surface properties of a material are
26

directly related to in vitro biological performance such as protein adsorption
and cell growth.
Elisa technique consists on detecting the amount of a certain protein in a
blood sample. An antibody with a color molecule is introduced in the sample
and we must measure the concentration of yellow color.
• Attachment via postfabrication method
• Attachment during synthesis
5.3.3 Plasma discharge

Plasma is the fourth state of matter formed by the addition of a cloud of
electrons to a gas. Very used for culture dishes (for the cells to adhere to it).
1. The cathode is the surface to be treated and has a negative potential

relative to the anode

2. Electrons travel from cathode to anode
3. Electrons must traverse the gas in the chamber and collide with the
molecules
5.3.4 Chemical vapor deposition (CVD)

In Chemical Vapor Deposition (CVD) a reactive gas is passed over the sub-
strate to be coated, inside of a heated, environmentally controlled reaction
chamber. Mixture of gases exposed to a sample at a high temperature re-
sulting in decomposition and deposition.
5.3.5 Physical vapor deposition (PVD)

Physical Vapor Deposition (PVD) may be from evaporation or sputtering.
Sputtering: energetic ions or atoms bombard a target material causing ejec-
tion of surface atoms. These atoms condense to form a thin film
5.3.6 Radiation Grafting and Photografting

A substrate is exposed to a radiation source of high energy, this allow chemi-
cal bonds of the polymer to be broken and reactive species to create covalent
bonding or to form a polymerized coating with monomer in solution.
27

5.3.7 Self-Assembled Monolayers
Self-assembled monolayers (SAMs) are surface films that spontaneously form
as highly ordered structures (two- dimensional crystals) on specific sub-
strates.
Process:
1. n-alkane thiol is added
2. Gold surface is immersed and reacts with the thiol

3. Self-assembled evolves to a covalent coating and van der Waals interac-
tions are stablished between alkyl chains leading to their crystallization.
The advantages of SAMs are their ease of formation, their chemical sta-
bility (often considerably higher than that of comparable LB films) and the
many options for changing the outermost group that interfaces with the ex-
ternal environment
5.3.8 Solution coating

Substrate is dipped in solution containing the dissolved coating material.
Substrate is left to dry and the coating is deposited on the surface. Layer-
by-layer (LbL) deposition (alternating layers of oppositely charged materials
with wash steps in between).
5.3.9 Langmuir-Blodgett Films

The Langmuir—Blodgett (LB) deposition method overcoats a surface with
one or more highly ordered layers of surfactant molecules. Each of the
molecules that assemble into this layer contains a polar “head” group and
a nonpolar “tail” group. It is a non covalent binding so if you wash it with
water it will be removed.
• Multilayer structures can be created
• The advantages of films deposited on surfaces by this method are their

high degree of order and uniformity
• Relative instability of the coating due to the fact that is not chemically
bonded to the surface
• The stability of LB films can be improved by cross-linking or internally

polymerizing the molecules after film formation
28
Figure 5.2: LB process

5.3.10 Surface modifying additives
Surface Modifying Additives (SMAs) are atoms or molecules that, when
added to the bulk material, will spontaneously rise to the surface, producing
a coating with characteristics dictated by the properties of the SMA. The
rationale for the surface modification of biomaterials: to retain the mechan-
ical and functionality properties of a biomaterial while modifying only the
outermost surface to influence the bioresponse related to the tissue
5.3.11 Conversion Coatings

Modification of atoms at the surface of a metallic implant to form an oxide
layer by treating the material directly with acid or electrochemical process
called “anodization”
5.4 Patterning
Surface or substrate patterning is used to alter the surface properties of
biomaterials in a controlled manner, resulting in a geometric design of well-
defined regions with very different characteristics. It may be used on both
metals and polymers.
29

Figure 5.3: Photolitography process
5.5 Photolitography
30

Figure 5.4: Photolitography process
Figure 5.5: How to prepare a PDMS stamp
31

Chapter 6
Exam questions

1. Biocompatibility and mouse with the ear on its back
Biocompatibility is the ability of a biomaterial to perform
its desired function with respect to a medical therapy, with-
out eliciting any undesirable local or systemic effects in the
recipient or beneficiary of that therapy, but generating the
most appropriate beneficial cellular or tissue response in that
specific situation, and optimizing the clinically relevant per-
formance of that therapy.
The Vacanti mouse was a laboratory mouse that had what
looked like a human ear grown on its back. The “ear” was
actually an ear-shaped cartilage structure grown by seeding
cow cartilage cells into biodegradable ear-shaped mold and
then implanted under the skin of the mouse, with an external
ear-shaped splint to maintain the desired shape. Then the
cartilage naturally grew by itself within the restricted shape
and size.
2. PEGylation
PEGylation (often styled pegylation) is the process of both
covalent and non-covalent attachment or amalgamation of polyethy-
lene glycol (PEG) polymer chains to molecules and macrostruc-
tures, such as a drug, therapeutic protein or vesicle, which is
then described as PEGylated (pegylated). PEGylation is rou-
tinely achieved by the incubation of a reactive derivative of
PEG with the target molecule. The covalent attachment of
PEG to a drug or therapeutic protein can “mask” the agent
from the host’s immune system (reducing immunogenicity and
32
antigenicity), and increase its hydrodynamic size (size in so-
lution), which prolongs its circulatory time by reducing renal
clearance. PEGylation can also provide water solubility to
hydrophobic drugs and proteins.
3. Proton sponge
The proton sponge effect is a process by which we use poly-
mers to introduce genetic material inside a cell. A cationic
polymer is linked with the DNA or ARN and as it enters
the cell membrane of the cell, it is encapsulated inside an
endosome. The endosome undergoes then acidification (H+
and Cl- enter the structure). To compensate this pH, wa-
ter molecules will also enter the endosome making it to swell
and release the complex. The genetic material must enter the
nucleus if it is DNA but if it is ARN it will work without
entering it.

4. Titanium biocompatibility and why implants are sealed
Titanium is considered the most biocompatible metal due
to its resistance to corrosion from bodily fluids, bio-inertness,
capacity for osseointegration, and high fatigue limit. Tita-
nium’s ability to withstand the harsh bodily environment is
a result of the protective oxide film that forms naturally in
the presence of oxygen. The oxide film is strongly adhered,
insoluble, and chemically impermeable, preventing reactions
between the metal and the surrounding environment. The
mechanical properties of the material and the loading con-
ditions in the host have, conventionally, influenced material
selection for different clinical applications. Its ability to phys-
ically bond with bone gives titanium an advantage over other
materials that require the use of an adhesive to remain at-
tached. Titanium implants last longer and much higher forces
are required to break the bonds that join them to the body
compared to their alternatives. The surface properties of a
biomaterial play an important role in determining cellular re-
sponse (cell adhesion and proliferation) to the material. Ti-
tanium’s microstructure and high surface energy enable it to
induce angiogenesis, which assists in the process of osseointe-
gration.
5. Microfluidic chips of PDMS
33

A silicon based layer is covered by the photoresist that
will be illuminated and by the mask, which will describe the
silhouette of the PDMS stamp. This layers are exposed to
UV light and the irradiated area is washed away (positive re-
sist) or the unirradiated area is washed away (negative resist).
Once we have washed away, what rests is the master mold (it
can be used many times to prepare many PDMS). A poly-
dimethylsiloxane solution is poured above the master mold
and when pured and peeled off what we obtain are the chan-
nels. As they are opened, we must cover them with the same
material but without channels to obtain the final product.
6. Semi-IPN and IPN, chemical structure and how do you make them
IPN are composed by two or more polymer networks that
least partially interlaced on the molecular scale but without
any covalent bonds between them, which cannot be separated

unless chemical bonds are broken. Semi-IPN are polymers
comprising one or more networks and one or more linear
or branched polymer characterized by the penetration on a
molecular scale of at least one of the linear or branched macro-
molecules.
You can make them by three different ways: (1) simulta-
neusly, forming the polymer networks at the same time; (2)
sequentially, forming firstly one network and later the other;
and (3) selectively crosslinking a linear polymer, when the
network and the linear molecule are alredy formed.
7. Advantages, disadvantages, examples and applications of synthetic and

natural biomaterials
Natural polymers’ advantages: biocompatibility, biodegrad-
able, interact with tissues and respond to changes. Natural
polymers disadvantages: biodegradable, poor reproductibility
an purity of the sample, weak mechanical properties and vary
in composition and molecular weight. Examples and applica-
tions: collagen (tissue engineering matrices) and hyaluronic
acid (cosmetics).
Synthetic polymers’ advantages: easily mass-produced, prop-
erties can be tailored for specific applications (surface mod-
ifications), very interesting mechanical properties. Synthetic
34

polymers’ disadvantages: not biocompatible, inert, toxic. Ex-
amples and applications: polyethilene glycol (pegylation: drug
delivery) and polydimethilsiloxane (PDMS stamps: microflu-
idics)
8. Coating and not coating, SMAs, example and applications
When doing surface modifications you can add a coat (co-
valent or non-covalent bonded) or not (no overcoat). Exam-
ples of covalent overcoat: sprayed hydroxyapatite (osteointe-
gration) and self-assembled monolayers (biosensors). Exam-
ples of non-covalent overcoat: solution coating and Langmuir-
Blodgett Films (mimic the cell membrane). Examples of no-
overcoat: ion beam implantation (increase the roughness) and
conversion coating(oxide layer on titanium)
9. Figures of lines (Bone reaction to certain materials)

Figure 5.1
10. Paper: SLActive

R implant, why is in water?
11. Osteogenesis, osteoconduction and osseointegration

Osteogenesis is the name given to the process in charge of
generating new bone tissue. If induced: osteoinduction.
Osteoconduction is the process by which bone grows on a
surface
Osseointegration is the process by which bone tissue grows
around a material and anchors it, with minimal fibrous inter-
face
12. What is RGD, in what proteins it is found and what receptor familiy
recognizes it
RGD (R: arginine; G: glycine; D: aspartic acid)is a bio-
logical surface modification that improves the cell adhesion.
It is found in fibronectin, vitronectin and laminin proteins.
The family of membrane proteins known as integrins act as
receptors for these cell adhesion molecules
13. Four qualities of hydrogels for wound dressing and explain advantages
of injectable hydrogels
35

Hydrogels can simulate soft tissue, they allow diffusion
and vascularization, they degrade after some time and they
are biocompatible. The advantages of injectable hydrogels
are that they can reach very deep tissue defects, they are easy
handling, they are minimally invasive and they can completely
fill the defect leading to vascularization.
14. Explain gradients in biofilms

Usually when two materials are in contact, there is a gra-
dient in the concentration of both compositions: from one

material to the other.
15. Explain endothelialization in a blood contacting device and a strategy

for it in a stent
16. Explain how nickel causes an allergic reaction. Is it antigenic/immuno-

genic?
17. Explain role of macrophages, monocytes and foreign body giant cells
36
37
Figure 6.1: Schematic illustration of the proton sponge effect leading to

endosomal or lysosomal burst and release of the cationic magnetic particles
into the cytoplasm

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Biomateriales.

Introducción a los Biomateriales

3º Grado en Ingeniería Biomédica

Escuela Politécnica Superior

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Bachelor’s Degree in Biomedical Engineering

David Crespo Acero

2 Polymers for biomedical applications 7

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3 Hydrogels for biomedical applications 14

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4 Bioceramics (ceramics, glass-ceramics and bioactive glasses) 17

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2.1 Example of the importance of the Mn and the Mw . . . . . . 8

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3.1 IUPAC definitions for semi-IPNs and for IPNS . . . . . . . . . 16

4.1 Exam question . . . . . . . . . . . . . . . . . . . . . . . . . . 21

5.1 Comparison between the different types of interfaces according

6.1 Schematic illustration of the proton sponge effect leading to

1.1 Biomaterials: Basic concepts

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1. Replacement of diseased, damaged or aged part (hip, knees, heart

2. Assist in healing (sutures, screws)

3. Improve or correct function (pacemakers, lens ,stent, spinal rod)

4. Treat diseases: cancer, drug release

5. Aid to diagnosis (catheter)

6. Tissue engineering (artificial skin)

Biomaterials can be grouped in different families which are (1) polymers,

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• Surface biocompatibility: adaptation of the chemical, physical, biolog-

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Polymers for biomedical

2.1 What is a polymer?

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2.2 Polymer synthesis

2.2.2 Step polymerization

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2.3 Polymer structure

• Mn: Number average molecular weight

• Mw: Weight average molecular weight

Polydispersity index (Mw/Mn) is a measure of the broadness of a

2.4 Polymer architecture

2.4.1 Configuration state

2.4.2 State of aggregation

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A solid amorphous polymer will have a similar behaviour until a temper-

2.5 Thermal properties

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2.6.2 Inert polymers

2.6.3 Biodegradable polymers

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2.6.4 Smart polymers

• Physical stimuli: pressure, ultrasound, temperature, light, and electric

• Chemical stimuli: pH, ionic factors, glucose

• Biochemical stimuli: Enzymes, antigens

2.7 Important definitions

• Bioerosion: change in the size of the material that may be caused or

2.8.2 Non-viral gene therapy