Summary

Biomaterials

Marten Leenders
Lecture 1

Introduction

Biomaterials

A biomaterial is a nonviable material used in a medical device,

intended to interact with biological systems. So, the material is used
inside living systems, intended to interact with components of that living
system. It is intended to interface with biological systems to
evaluate, treat or replace any tissue, organ, or function of the
body. Another definition is: 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
diagnostic procedure, in human or veterinary medicine.

The difference between a biological material and a biomedical material is

that a biological material is produced by living systems, and a biomaterial
is aimed to be used in living systems. Examples of biological materials are
for instance, bone, muscle, blood, etc cetera.

Examples of different
medical devices made of
different biomaterials are
often orthopedic
implants:

 Hip implants.
 Knee implants.
 Shoulder implants.
 Acetabular cups.
 Screws.
 Plates
 Etc.

Other devices are cardiovascular devices, like valve replacements.

Dental implants like crowns. Scaffolds, which are materials used for
tissue engineering. They help to regrow certain tissue.

Biomaterials can be grouped using four types of classifications:

1. Origin: synthetic, natural.

2. Type (composition and structure): metallic, polymeric, ceramic,
composites.
3. Functional properties: (non)degradable, inert/bioactive,
responsive, osteo-conductive/inductive (meaning stimulating growth
of bone tissue, and the ability to stimulate osteogenic cells
differentiating into bone cells).
 4. Clinical application: orthopedics, cardiovascular, dentistry,
neurology.

The biomaterials science is the study of materials and their interactions

with living systems. Biomaterials engineering regards the application of
the principles of biomaterials science and its foundation disciplines to find
solutions for technical problems of human health.

Biomaterials is an interdisciplinary field, it focuses on the interaction

between living and nonliving materials, stemming from the interaction
between engineering and medicine:

Biocompatibility

Biocompatibility is the ability of a biomaterial to perform with an

appropriate host response in a specific application. Biocompatibility is the
combination of functionality, safety, and application. So:
biocompatibility refers to 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. There are many different aspects of biocompatibility, like
mechanical, chemical or cytobiocompatibility.

We must study the interactions at the interface between biomaterials and

tissue components. At this interface, a lot of interaction takes place. One
interaction can also influence other processes, in a cascade. One example
of a cascade is schematically shown below:
The interactions can take place at different size scales and different
length scales. Important examples of factors that should be taken into
account are wear of the device, fracture due to insufficient mechanical
compatibility, and many different factors in the biological side. In a bone
implant, in the end you want the biomaterials to work together with the
living tissue.

To assess the biocompatibility of materials, we use in vitro and in vivo

research models. In vitro mimics the physical/chemical conditions of in
vivo models, which are animal models that are relevant to the clinical
applications. The pathway of testing is shown below:
So, you start with the research on biomaterials using the different
research models. Then, you must through all the steps to in the end go
through to regulatory approval and finally go into commercialization. Of
course, the real “tests” happen when the medical device is used in clinical
applications.

The complete cascade from idea to clinical use is shown below. Most of
the time, the innovation is driven by a clinical need:

Sometimes, for instance when a medical device fails, you have access to
an explant, which can be very valuable to improve the design for newer
devices.

The rules and regulations are so strict because the materials have to be
used inside human bodies. Thus, we must take the biological environment
into account. Our body is very complex and there are high demands to
biocompatibility. This is because it has a milieu of chemical activity
combined with highly variable spectrum of mechanical stresses. Our body
is a complex control system, so if the body notices a foreign implant, our
immune system will want to get rid of it. This is because there is a
constant of physical conditions and compositions in the body, and the
introduction of a foreign material will determine a host response with
local, systemic and remote effects. This host response will always be
there, and we want to control the response. General characteristics of the
human body are (macroscopic characteristics):

Physicochemical conditions in humans are:

The (inorganic) composition of the human body:

Mechanical conditions in the human body:

In vitro test models are:

 Physiological: controlled chemical (inorganic) and thermal

conditions. Simulated body fluids exist for this. These mimic the
inorganic compositions of body fluids.
 Biophysiological: addition of suitable types and concentrations of
active cell products.
 Biological: addition of viable, active cells.
 Pericellular: the conditions in the proximity of appropriate, viable
cells.

Following up to this, in vivo, clinical trials are performed.

Regulations

When the clinical trials are done, the regulatory approval must be done.
After that the medical devices can be placed on the market. In the US, the
FDA is responsible for the regulatory approval.

This regulatory approval must be done for all medical devices: an

instrument, apparatus or machine including any component or accessory
that is intended for use in the diagnosis of disease, or in the mitigation,
treatment, or prevention of disease in humans:

In the US, the FDA is responsible for these regulatory approvals and the
follow up on the regulations. This ensures the safety and efficacy of
medical devices and radiation emitting products. The responsible body is
the FDA-Centre for device and radiological health (CDRH). They:

 Evaluate devices for marketing.

 Monitor devices after approval.
 Act against firms when the law is violated.
 Perform research, develop standard methods.
 Educate professionals and consumers on safe use of devices.

They do not:

 Test new devices.

 See all medical devices, they base their judgement on scientific data
you provide them.
 Regulate medical procedures.

Medical devices are classified in three different groups, depending on

invasiveness of the device (Class I, II or III, from minimally to the most
invasive).

The relationship among biomaterials, biomaterial-based medical products,

regulatory science and regulatory authorities is shown below:
The development of regulatory science resulted in the founding of the
MDIC, the Medical Device Innovation Consortium, a public private
partnership, meaning the industry, FDA and nonprofit organizations work
together to develop regulatory science. This is a common platform for
industry, government, non-profit organizations with a mission to improve
health through the application of shared knowledge in medical device
regulatory science:

Regulatory science is defined as the development of new tools,

standards, procedures and scientific approaches for improved
understanding and evaluation of device safety, quality, effectiveness, and
manufacturing technology.
In biomaterials, you also find ethical and legal aspects, for instance in:

 Animal tests, you must prove you do the least amount of animal
testing as possible.
 Clinical trials, they involve patients and the medical devices have
not been approved officially. Who, for instance, is covering the
financial costs?
 You need industrial support for research, but the research objective
may change due to a shift in market needs, so you must find
consensus with the financial goals of the company.

Legal aspects in biomaterials are risky, because no products last forever

and implantable medical devices have side effects. Usually, the company
are liable for failure of devices because they are best able to discover and
correct defects in its products before they cause harm, and they can cover
the costs involved in product related injuries. So, companies must be
defensive in manufacturing and marketing.

The biomaterials is a gigantic market, with billions of dollars in it:

The mission of biomaterial scientists and engineers is the improvement

of human health and quality of life.
The evolution of biomaterials

Initially, ordinary “off-the-shelf” materials were used for the development

of biomedical devices. From the timeline you can see for instance steel,
stainless steel, and after the second world war, PMMA and Ti alloys. The
first designed biomaterials started to show up in the 1960s.

First, biomaterials were selected on bioinertness, meaning non-toxic for

the human body. Then, the goal became bioactivity, biomaterials that
have a controlled reaction with the physiological environment (e.g. bone
bonding, drug release). Then, the 3rd generation biomaterials had the
goal of regenerating functional tissue, stimulating specific cell responses:
Lecture 2

Classes of biomaterials I

Classes of biomaterials

There are four main classes of biomaterials:

 Metallic
 Polymeric
 Ceramic
 Composite

We often find multiple classes of biomaterials in the same medical device.

In a total hip replacement, we have metallic, ceramic, and polymeric
parts. It is quite a challenge to combine all these different materials.

Some properties of the different material classes are shown below. The
reason we use metallic biomaterials for structural components is because
they are very tough:

Metallic biomaterials

From the periodic table, we can see that most materials are metals:
Counterintuitively, for biomaterials we do not have that much choice. We
can mostly choose from the following:

 Stainless steels (SS)

 Cobalt based alloys
 Titanium and its alloys (Ti)
 Porous tantalum (Ta)
 Zirconium-Niobium (Zr-Nb)

There are also degradable metals under development:

 Magnesium
 Zinc
 Iron

In the field of metallic biomaterials, it is important to see the most

important properties for biomedical devices:

 Corrosion resistance, for instance to make sure implants maintain

their quality for a long time.
 Chemical biocompatibility, you do not want materials that have
cytotoxic effects.
 High yield and strength and ultimate strength.
 A compatible (low) Young’s modulus, that is close to the one of
bones.
 Fatigue strength, because total implants have a lot of cyclic loading.
 Ductility, materials should not fracture.
 Wear resistance.
 Manufacturing, you want high quality products at low cost to make
the devices available for as many people as possible.
 Surface properties, (chemistry, topography, surface free energy,
etc.).
Stainless steels are steels that have a lower concentration of carbon
than normal steels. Carbon in contact with chromium form carbides that
may decrease the corrosion resistance, thus stainless steels have a good
corrosion resistance. This is also because they form a chromium-oxide
layer that prevent many forms of corrosion. Stainless steels are mostly
used for temporary devices, because some patients experience allergic
reactions or cytotoxic effects.

In cobalt-based alloys, we can see higher concentrations of carbon. We

want chromium carbides, which will strengthen the material. This gives
them high wear resistance and high strength. Because of this, these
materials are used most in bearing applications.

Titanium and its alloys come in multiple grades and forms. Titanium
used to be cytotoxic, but a new form has been discovered that is far more
biocompatible, so it is now used often for biomedical applications.

From the properties of organic tissue and some biomaterials, we can see
that the ultimate strength of the metal types is quite similar, but because
titanium is less dense, it is more suitable for biomedical applications:
If the tensile modulus is too high, the implant will take all the load and the
bone does not take enough of the load for remodeling to be triggered.
These are all factors to consider when choosing a biomaterial.

This is called stress shielding, bone will not remodel, and the bone will
vanish due to large amounts of bone resorption. This is reduction of bone
density (osteopenia) as a consequence of removal of normal stress from
the bone by an implant:
The effects of stress shielding can be minimized using a porous surface
layer on the implant. This will make the difference in elastic modulus more
gradual, and it will reduce the young’s modulus at the interface with the
bone. Bone can grow in the porous structure:

Porous tantalum is one of the later inventions in metallic biomaterials. It

is one of the most inert materials on the table of elements, and has a
minimal interaction with the tissue. It has a high density, due to which it
can be seen well using an X-ray. It cannot be used in direct contact with
bone, due to the high elastic modulus. It can be formed into porous forms,
a trabecular metal with an open cell porous structure. With an 80%
porosity, this gave an elastic modulus of 3 GPa (instead of 190 GPa
without pores). The metal must be processed using chemical vapor
deposition (CVD). The porous structure is a good match with the
trabecular morphology of bone:

Bone can grow into this porous structure, it can grow into it:
For this reason, it is often used on for instance the backing of the
acetabular cups, on tibial knee components or on patella components:

A newer material is oxidized zirconium-niobium alloy (oxinium). Zr is a

biocompatible material, and the Zr-2.5Nb alloy has improved mechanical
properties. By heating it in air at 535 Celsius for 3-4 hours, an oxide layer
forms of about 5 μm thickness, which makes it wear resistant. This makes
it good for applications in the femoral head and femoral knee prosthesis
(bearing parts). You can recognize the material by its black color:
Additive manufacturing has transformed the industry, especially in
designing patient specific orthopedic implants, as the layer by layer
manufacturing of the implants can achieve intricate designs specific for
the anatomy of indivual people:

Titanium can be 3D printed. It works by selective laser melting (SLM). In

this process, a high-powered laser beam selectively scans and melts the
metal powder according to a digital design layer by layer. As each layer
solidifies, a new layer of powder is applied on top, and the laser melting
process repeats until the entire part is built. SLM enables the production
of complex geometries that would be difficult or impossible to achieve
with traditional manufacturing methods, like scaffolds with high detail.
An SLM Ti6AI4V scaffold:

Electron Beam Melting (EBM) is an additive manufacturing technique that

uses an electron beam as the power source to melt and fuse metal
powder particles together. This process occurs in a vacuum chamber to
prevent oxidation of the metal materials. Like Selective Laser Melting
(SLM), EBM builds parts layer by layer according to a 3D digital model. The
electron beam selectively scans the powder bed, melting the powder in a
precise pattern before a new layer of powder is spread over the previous
one. The process repeats until the entire part is constructed.

An EBM Ti6AI4V scaffold:

Titanium

Titanium and its alloys have many different applications, shown below:

Titanium have different microstructures, the α and β types. The α phase

has a hexagonal close paced structure (HCP), β has a body centered cubic
structure (BCC). For pure titanium, α turns into β at 885 celsius, but they
can coexist:
The properties of the material in the two different structures have
different material properties. We would prefer the β phase because it has
a much lower Young’s modulus, which is closer to the properties of the
bone. Another way to decrease the elastic modulus is by making the
material porous, but increasing the porosity too much can also decrease
the yield strength, and it will make the material weaker.

Compared to Co-Cr alloys, stainless steel, and ceramic materials, titanium

and its alloys are not appropriate for bearing applications, because of the
low wear resistance of the material. The wear resistance can be improved
by suitable surface modification (coating) techniques.

In an animal study, three types of biomaterials have been tested in a

rabbit leg, with three different Young’s moduli. A rod of the material was
placed into the tibial bone of the rabbit. The bone healing process was
recorded using X-ray. What was found is that in the case of stainless steel
(with the highest young’s modulus), bone resorption and callous formation
had occurred. This shows the importance of the Young’s modulus, and the
transfer of the forces:
A similar study has been done on osteointegration, integration of bone
with the implant. Small rods were placed in the femoral condyle of a
rabbit, and they tracked the contact between the implant. After eight
weeks we see that in the case of stainless steel, a black line has formed
between the implant and the bone, showing bad osteointegration. This
shows that stainless steel cannot be used in contact with the bone:

Nitinol

Ti-Ni (Nitinol) alloy is the most attractive shape memory alloy (SMA)
for biomedical applications because of its unique mechanical
characteristics, such as superelasticity, shape memory, good resistance to
fatigue and wear and relatively good biocompatibility (with some concerns
because of the nickel, which can create cytotoxic effects, however the
material has quite a good oxide layer).

The shape memory effect is the restoring of the original shape of a

plastically deformed sample by heating. This is a result of a crystalline
phase change known as thermoelastic martensitic transformation.

 An SMA undergoes a martensitic transformation when it is cooled

below a martensite start point, M s .
 The transformation is completed at a lower martensite finish
temperature, M f .
 Shape recovery begins at an austenite start temperature, A s and is
completed at a higher austenite finish temperature A f .
 This type of recovery is called the thermal shape memory effect.
 SME can be divided into one-way and two-way.

It has been schematically depicted below. The material is formed into a

certain shape at a high temperature (austenite), and you cool it into
twinned martensite. You can deform it, after which it will return to the
original shape when heated. This is one way SME:

Two way SME has one shape in in the austenitic state and another in the
martensitic state. The SME should be trained/programmed to obtain two-
way SME. This is done by cooling the sample below M f and bent to the
desired shape, then heating the material above A f and allowed freely to
take its austenitic shape. This procedure must be repeated 20-30 times to
complete the training:
Superelasticity of a material is due to the possibility to induce
martensite isothermally above A f temperature by the application of an
external mechanical load, which results in stress induced martensite
(SIM). When the stress is removed, the material returns to the austenite
phase. This superelasticity has a hysteresis stress strain loop:

This is important because it mimics organic material like bones and

tendons, which also exhibit this hysteresis loop. Nitinol shows both
superelasticity and shape memory effects. Other properties show that the
transformation temperatures can be tweaked very flexibly. The material
strength is quite high, but not as high as other titanium allys.
Some medical applications of this material are:

 Orthopedics.
 Cardiovascular, e.g. self-expanding stents.
 Medical instruments.
 Robotics.

A summary of all the discussed materials:

Biomedical components

A total hip replacement consists of the following parts:

The materials used in the materials:

For a total knee replacement:

And a total shoulder replacement:
Lecture 3

Classes of biomaterials II

Orthopedics

Orthopedics is the branch of medicine concerned with the nature and

correction of bones, joints (cartilage), ligaments or muscle disorders. The
physiological roles of bones are:

 Structural support.
 Protection of internal organs.
 Continuous source of Ca and P.
 Production of red blood cells (hematopoiesis).

The structural components of bone are:

 A collagen matrix, collagen is a protein with a high tensile

strength and viscoelastic properties.
 Hydroxyapatite crystals, calcium phosphate-based compound
with properties similar to ceramics.
 It has a hierarchical structure (nano-, micro-, & tissue scale).

The hierarchical structure of bone is shown below. We can see that the
bone is built up of different structural units at different length scales:

We have spongy/porous bone, and on the edges, we have

dense/cortical bone. The bone is built up from an assembly of different
structural units at different length scales. The largest structure is the
osteon, made from lamella, which are built up from bundles of collagen
fibers, and if we zoom in even more, we see the collagen fibrils with
bone crystals embedded in them.
Bone is hard tissue, vascular and enervated. It has the ability to heal
once damaged, and to feel pain, when a bone is broken for instance. The
mechanical properties of bone are as follows:

These properties depend on the type of mechanical testing, the

anatomical location that is tested, the age of the patient and whether the
bone has been affected by disease. Also, the direction of the fibers are
responsible for the different properties in different directions.

Bone is a living material, consisting of cells:

 Osteoblasts are bone forming cells.

 Osteoclasts are bone removing cells.
 Osteocytes are receptors of mechanical and chemical changes in
the environment, communication with osteoblasts and osteoclasts
to elicit the required cellular response.

Bone responds to its environment, and it can do two things, bone

modeling and bone remodeling:
  Bone modeling is bone growth, in length and in cross-sectional
area. This mainly happens in younger people and stops at some
point in a human’s life.
 Bone remodeling is the removal and rebuilding of bone, a
continuous recycling of bone material. This remodeling prevents the
accumulation of microcracks that lead to fatigue failure.

Bone develops and responds in reaction to the loading it experiences. This

is called Wolff’s law. If there is not sufficient loading, bone resorption
happens. If there is too much load, bone deposition occurs.

Cartilage

Cartilage has the physiological role of being a

low friction bearing surface of the articular
joints like the knees, hip, and shoulder.
Articular cartilage is called hyaline cartilage.
It consists of an extracellular matrix, with
proteoglycans (PGs) and collagen. The living
cells in cartilage are called chondrocytes, and
the weight fraction of water is about 60-80%.

Cartilage is split up in multiple zones, with the superficial zone, with

collagen fibers spread horizontally, providing a smooth articular surface.
The transitional zone has collagen fibers in random directions, and the
radial zone has collagen fibers distributed along the radial direction with
respect to the bone, to help it withstanding compressive forces. It is a
functionally graded material, because the material properties gradually
change in along the different zones.

Cartilage tissue is an avascular tissue, meaning it has limited ability to

heal once damaged. It is also loaded mostly in compression, water is
released and partially resorbed during the cyclic loading. Because
cartilage is not enervated, cartilage degradation is often advanced once
patients start to feel pain. Hyaline cartilage also has especially low
friction:

Total joint replacements

Total joint replacements (TJR) are necessary when the articular

cartilage in a joint has been destroyed or damaged. This can happen due
to osteoarthritis, the degradation of the articular cartilage due to aging,
injury, obesity or heredity:

A total hip replacement (THR), or hip arthroplasty, can be performed.

This is a surgical procedure in which a damaged or diseased hip joint is
replaced with an artificial joint or prosthesis:
Polymers

Polymers are large molecular structures, produced from monomer

units which are polymerized. These materials can have on of three
structures that influence the mechanical properties of the material:

Polymers are attractive to use because they have the greatest versatility
in chemistry and processing. They are lighter than metals, and they can
be used as composite materials with ceramics.

They have the following requirements:

 Chemical biocompatibility
 Sterilization stability

And depending on the application:

  Low friction coefficient
 Wear resistance
 Creep resistance
 Degradability
 Responsive polymers

Concerns in the use of polymers are:

 Long-term chemical biocompatibility

 Wear debris

Polymers can be used in total joint replacements as cartilage

replacement, for instance UHMWPE, being used as articular bearing
surface in TJR, or silicone rubber in hand joints. Or, they polymers can
be used for implant fixation, for which PMMA is used.

Polymers are also used in the fixation of parts for bone fracture,
meaning plates and screws. They are useful because polymers can be
made for controlled biodegradability, avoiding a second surgery.

Polymers can be used for tissue engineering and regenerative

medicine. Some polymers are chemically biocompatible and possibly
biodegradable materials to match tissue properties and sustain cell
growth, for instance PLLA, PGA, PLGA, polysaccharide-based
hydrogels, and PLGA-hydroxyapatite composites.

Lastly, polymers can be used in local drug delivery, used as coatings or

micro/nanospheres.

The most important polymeric biomaterials in orthopedics are

polymethyl methacrylate (PMMA), and ultrahigh molecular weight
polyethylene (UHMWPE):

The properties of polymeric biomaterials are shown below. The young’s

modulus and tensile strength are lower than metallic materials, showing
that they are not appropriate to use as structural materials.
PMMA is a bioinert polymer, meaning that once placed in the human
body they do not initiate a significant biological response, they are
inactive with respect to the biological systems of the body. It has a linear
chain structure, and it is an amorphous material, meaning it is a solid
without a well-defined crystal structure.

In orthopedics, PMMA is used as bone filler, meaning it fills the space

between the bone tissue and the metallic implant. It achieves quick
fixation of a total joint implant within the medullary canal, and it
minimizes the need for a perfect fit between bone and the implant. It is
mostly used for patients with relatively poor bone quality, and it can be
loaded with antibacterial agents.

PMMA bone cement contains a liquid and a solid component:

 The liquid contains the monomer (methyl, methacrylate), a curing

accelerator (N,N-dimethyl-p-toluidine), and a polymerization
inhibitor (hydroquinone).
 The solid contains PMMA powder, an initiator for the polymerization
(benzoyl peroxide) and a radio-opaque additive (BaSO4), for
imaging.
The materials are brought together using a standard procedure.

There are side-effects to using PMMA bone cement:

 The polymerization is an exothermic reaction, meaning the

temperature can get very high (80-124 Celsius), meaning the
procedure must be done carefully to prevent damage to the cells.
 The material produces debris through fatigue and biological
processes, increasing the risk of osteolysis, or third body wear of the
acetabular cup and/or femoral head where a particle of PMMA
becomes stuck between the interface.
 It introduces an extra interface (bone-cement-implant), which can
reduce the life span of the implant by loosening.
 The implant may be difficult to remove and replace in case of
revision surgery.

Alternative implant fixation has been developed, i.e. modification of the

implant surface to promote osseointegration, where the bone tissue grows
into the implant surface.

UHMWPE is bioinert as well. It has a linear chain, it is semicrystalline,

which results in high strength, ductility, and wear resistance.

You can see the crystalline regions alternating with the amorphous
regions. The crystalline regions are responsible for the strength of the
material, and the amorphous regions are mostly responsible for the
ductility and wear resistance:

The material is used to build acetabular cups, patella components,

shoulder replacements, knee implants, tibial tracers, et cetera. The
materials are used to replace articular cartilage and create a low friction
bearing surface in the articular joints. We cannot mimic the functionally
graded material properties of cartilage.

The friction coefficients in articulating couples in the hip joint are shown
below. The coefficients of materials that we use is still much higher than
cartilage on cartilage, but it does relief pain for patients.

With using UHMWPE there are sterilization issues. Originally, they were
sterilized using gamma irradiation in air, but this can lead to oxidative
degradation of the material over time. The gamma irradiation initiates
oxidative chain scission, breaking down the polymer chains, and also
induces cross-linking, which can alter the material's mechanical
properties. These changes can reduce the wear resistance of UHMWPE
and increase the production of wear debris, potentially leading to implant
failure and complications in the joint area. Addressing these issues has
been a significant focus in the development of newer UHMWPE materials
and alternative sterilization methods:

The oxidative degradation affected the fatigue and fracture properties,

and the wear resistance of the material. This resulted in delamination
wear, and abrasive wear due to wear debris. The wear debris around the
implant can initiatie a cellular response, osteolysis. Wear debris
generated around the articulating surfaces migrates to the bone-implant
interface, macrophages phagocytize wear debris and are stimulated to
release inflammatory mediators. Precursors are recruited and osteoclastic
bone resorption is initiated and maintained, resulting in periprosthetic
bone resorption that leads to loss of fixation and a painfully loose implant:

Wear debris induced osteolysis is called small particle disease, bone

loss mediated by cellular processes in response to wear debris released
around the implants.

The wear debris problem can be fixed by using highly cross-linked,

vitamin E stabilized UHMWPE. The material has been highly cross-
linked, a process that creates bonds between polymer chains, increasing
the material’s wear resistance, and vitamin E stabilization is a process
used to prevent oxidation of UHMWPE, which can occur during the
sterilization procedure.

Ceramic biomaterials

Ceramics are compounds of metallic and non-metalic elements, bound by

strong ionic bonds. They can be classified as inert ceramics and
bioactive ceramics. The main attractive properties for biomedical
applications are:

 They are dense and hard materials, they are scratch resistant.
 They have the ability to be polished to an ultra smooth finish.
 They have high wear resistance and low friction.
 They can be either inert or bioactive

Main limitations of this material are:

 They are very brittle.

 They have low tensile strength and bending strength.
 They have a low fracture strength.
 The processing is difficult to control.
The main orthopedic applications of ceramic biomaterials are:

 Total joint replacements (bearing surfaces).

 Coatings for implant fixation.
 Bone filler.
 Vehicles for drug delivery.

Relative to the other classes, ceramics are brittle materials, with a high
young’s modulus, and they have comparable friction coefficients to other
materials, they are acceptable as bearing materials.

Alumina (Al2O3) is one type of ceramic used in THRs and TKRs. Because
of the brittleness, the FDA approval for alumina-alumina (ceramic on
ceramic) came only in 2003. They are often only used in patients that are
succeptible to some metals. When you have a ceramic implant, you have
to be careful with your activities to ensure safety and prevent fracture.

Zirconia (ZrO2) has a lower Young’s modulus, lower wear rates in

combination with UHMWPE, and increased fracture toughness compared
to alumina. The fracture toughness is increased when it is stabilized with
Y2O3. The increased toughness is due to a phase transformation around
the crack, from a tetragonal to a monoclinic grain, that results in
compressive stress around the tip of the crack. This limits the propagation
of the crack:

Zirconia can degrade under moist atmospheres, resulting in a more rough

surfaces and wear of the articular surface. Thus, nowadays composites
with alumina are created.
Bioactive ceramics are bioactive because they have a certain degree of
chemical activaty when in interaction with body fluids and the bone
matrix. There are calcium based ceramics:

 Ca3(PO4)2 – tricalcium phosphates (TCP)

 Ca10(PO4)6(OH)2 – hydroxyapatite (HA, OHAp)

The applications of these materials is for:

 Synthetic bone substitutes (in bulk).

 Coatings on metallic devices, resulting in improved fixation.
 In composites with bioglasses and polymers.

Bioglasses are mineral-rich structures, designed to bond to bones

through a sequence of chemical reactions at the interface. They are
composites, with different components responsible for structure, bonding
and solubility.

The sequence of interfacial reactions involved in forming a bond between

tissue and bioactive glass is as follows:

Ceramic biomaterials can be very inert, but they can also be very
bioactive, up until fully bioreactive. The bioactive materials will result in
more interfacial bone tissue when implanted, because of the chemistry
between implant surface and bone tissue components.
The figure above illustrates the relative bioactivity of different ceramic
biomaterials over time, post-implantation, measured by the percentage of
interfacial bone tissue.

 Type 1 (Nearly inert): Examples include Al2O3 and Si3N4. These

materials show very little change in interfacial bone tissue over
time, indicating minimal interaction with the bone.
 Type 2 (Porous ingrowth): This type allows bone tissue to grow into
the material's pores, increasing interfacial contact over time.
 Type 3 (Bioactive): These materials, including 45S5 Bioglass and
other bioactive glasses, exhibit rapid increase in bone contact,
peaking early after implantation.
 Type 4 (Resorbable): Represented by the sharp peak and
subsequent decline for one of the materials, this type is gradually
resorbed and replaced by bone tissue.

Bioactive Materials (A, B, C):

 45S5 Bioglass (A) and other bioactive glasses (C) show a rapid
increase in bone bonding, indicating a high level of bioactivity. The
graph suggests that this bonding begins quickly after implantation
and remains high.
 KGS Ceravital (B) also shows good bioactivity but with a more
gradual increase and a slightly later peak compared to 45S5
Bioglass.

Nearly Inert Materials (F, G):

 Hydroxyapatite (HA) (E) and KGX Ceravital (F) show a steady

increase in bone contact over time, indicating they are less
bioactive than the bioglasses but still promote bone bonding.
  Alumina (Al2O3) (G) demonstrates the least bioactivity with very low
interfacial bone contact that does not increase significantly over
time.

THR

A total hip replacement includes the replacement of the femoral head and
acetabular cup. The forces used in the procedure are quite high and the
procedure is done quite forcefully. The THR variables are the biomaterials
used, the design and the fixation. Of course, we in this course only deal
with the biomaterials. The materials also influence the fixation method,
and vice versa, because you can choose for a cemented and an
uncemented fixation method. The different materials used for the two
cases are shown below:

As can be seen, there are different combinations of the ball and socket
materials, and these all come with different advantages and
disadvantages.

The biomaterial related failures of THRs are wear (osteolysis) and implant
associated infections, stress shielding, long-term stability, fracture and
corrosion of metallic parts.

Upon implementation, four overlapping phases describe the tissue-

biomaterial interactions:

 Hemostasis, protein, platelet adhesion, coagulation, provisional

matrix formation.
 Inflammation, cytokines, recruitment of inflammatory cells
(neutrophils, monocytes, lymphocytes, macrophages), release of
growth factors.
  Proliferation/initial repair, proliferation and population of the
biomaterials with cells that can repair the lost or damaged tissue
(capsule formation/direct bone apposition).
 Remodeling, neotissue is becoming functional tissue.

Osseointegration is a fundamental process in implantology, particularly

relevant in orthopedics and dental implants. It refers to the direct
structural and functional connection between living bone and the surface
of a load-bearing artificial implant.

Conclusions from the lecture:

 Polymers and ceramics can be used in orthopedics as bone cement,

bearing surfaces in TJRs, scaffolds, drug carriers, bone fillers,
coatings on metallic implants.
 Their configuration and properties are determined by tissue type,
tissue site and pathology – not necessarily the same structure and
composition as the host tissue.
 Biomaterial – possible cause of implant failure (e.g., particles
induced osteolysis, fracture of ceramic components).
 Bio-implant interface complex and interrelated interactions that
require fundamental understanding.
Lecture 4

Joint arthroplasty clinical performance

Osteoarthrosis

In the Netherlands, it is mandatory to register artificial joints, so we know

there are over a million, being hip, knee, shoulder, thumb, elbow, wrist,
and ankle replacements. A normal hip looks like this:

The articular cartilage can degenerate or deteriorate, or the cartilage

metabolism is disturbed, leading to cartilage damage. This is called hip
osteoarthritis, or coxarthrosis. This comes in a few different forms:

 Primary osteoarthrosis (coxarthrosis), with a genetic predisposition,

a gradually developing cartilage degeneration at an older age. It is
associated with aging and general wear.
 Secondary osteoarthrosis (coxarthrosis), due to congenital disease,
or e.g. being born with an abnormal formed joint, trauma, fracture,
infection, rheumatoid arthritis, malposition of femoral head or
obesity.

It is important to note that osteoarthritis is not simply a worn-out

mechanism, like in machine bearings. It is a very complex thing.

Some history

The idea of hip replacements started in 1923, with hip resurfacing. Initial
attempts failed, and it was not until the forties and fifties that it was
attempted again. The femoral head was covered by a metal helmet and
fixated to the bone with just a tight fitting. This was the Aufranc Turner
cup. This resulted in a happy patient, but horrible X-ray outcomes (2019).
In the sixties, the femoral head was covered with a metal helmet, with a
polyethylene cup in the acetabulum, creating a double cup. They were
both fixed to the bone using bone cement. This failed due to the thin
polyethylene cup, in combination with the large metal head resulted in
excessive wear of the polyethylene, with microparticles of polyethylene
being released. In the nineties, the so-called sports hip, or the
Birmingham hip, was invented. This hip did not use polyethylene, but
instead it used a metal-on-metal combination with a CoCr alloy. A large
femoral head was used, cemented on the femoral head, in combination
with a cementless bone ingrowth acetabulum cup. The femoral head had
a short round stem, with the intention to preserve the femoral head, so it
was just resurfacing, which have been shown to need far more revisions in
the years following the primary procedure.

Resurfacing did not work because it resulted in excessive wear, releasing

nano metal particles inducing body reactions, resulting in serious
complications. So, the double cup was not tried again.

A femoral head replacement was introduced in 1950. A large metal head

conform the original femoral head articulating on the acetabular cartilage,
so no acetabular cup was introduced in the patient. A straight stem was
hammered in the curved hollow femur, the stem was just fixated in three
different points. The stem surface had two windows for bone ingrowth.

Later, a total hip prosthesis was introduced, with a ball-and-socket joint

like the femoral head replacement, but also with an acetabular cup. The
ring cup was fixated using a screw. Despite initial success, there were
loosening issues, and the techniques used became more advanced, so
eventually it was abandoned in the 1980’s.

Polyethylene wear was also a big problem for some time, as it caused
polyethylene particle disease. Polyethylene wear microparticles are about
1 μm in size. They are resorbed by macrophages, eventually causing bone
resorption.

Current hip prostheses

A hip prosthesis is an endoprosthesis, meaning it is an artificial joint

inside the human body. Arthroplasty is human joint replacement by
prosthesis. They do not always look like human joints, and it is important
to remember that a prosthesis will not last forever.

There is a difference between a total hip replacement and a head-

stem (hemi) hip. A total hip is a head, stem, and cup. It is a ball-and-
socket hip prosthesis. A head-stem (hemi) prosthesis do not have an
acetabular cup. Both types of prostheses are used for fractures.

The cemented hip prosthesis and the surface of the prosthesis

Bone cement is made of PMMA, polymethyl methacrylate. Powder and

fluid PMMA are mixed, causing polymerization. It is a filler, not a glue, and
when the powder and fluid PMMA react, it is an exothermic reaction that
should not reach temperatures higher than 70 degrees to prevent damage
to cells. A cement-prosthesis unit is created, the cement increases the
surface area in contact with the bone, which enhances the stability. There
is no chemical reaction between the cement and the bone, so a fibrous
layer may form between them, contributing to fixation. The cement has
less torsion resistance than bone, making it more susceptible to forces
that involve twisting or rotational stress. The material may be prone to
fatigue cracks and debonding from bone, especially in areas subject to
repeated stress. Handling techniques could release free monomers,
potentially leading to toxic effects. Modern handling techniques include
vacuum mixing, pressurization, cement syringe, etc.

The bone cement interface in cemented joint arthroplasty plays a crucial

role in the stability and long-term success of the implant. There is typically
a thin fibrous membrane between the bone and the cement. The cement
serves as a grout or filler to anchor the prosthesis to the bone. There are
nano-level movements at the bone-cement interface that can result from
factors such as physiological loading, changes in the mechanical
environment, and the body’s response to the implant. Movement less than
50 microns are clinically irrelevant.

There are two different concepts for cemented fixation, a standard

concept with CoCr stem, where the femoral head is made of stiff CoCr,
with a smooth finished surface that reduces friction. It provides a rigid and
stable construction, and it has a collar locking the cemented column.

The Exeter concept has a hyper polished surface, the prosthesis is loose
but there is maximal close contact within the cement mantle. It does not
have a collar. The design philosophy of the Exeter allows for slight
movement, allowing the implant to settle in response to dynamic forces,
potentially leading to a more stable long-term fixation.

The cemented hip prosthesis and the surface of the prosthesis

Cementless hip prostheses exist too, they originated

in 1960, as a cementless ring hip prosthesis, with
stem, head, and cup of a CoCr alloy, with metal-on-
metal articulation. The stem was fixated by jamming,
and two holes were left in the stem for bone to grow
into. The cup was fixated by a long screw. There was
no bone ingrowth on the metal surface of the stem,
but there was three fixation points in the femoral
shaft.

Cementless fixation to the bone nowadays happens

with porous coated metal implants, where bone can
grow inside the pores on the surface of the metal. The quality of the
fixation depends on the size of the pores:

In 1983 the AML THA was a cementless coated prosthesis, with a

porocoat, the surface coating of the prosthesis, which consists of small
metal balls creating a porous surface. The open pores are designed to
facilitate the growth of bone into the surface of the implant, a process
known as osseointegration, leading to biological fixation, relying on the
body’s natural healing process to integrate the implant into the bone. The
coating enlarges the surface area of the prosthesis that comes into
contact with the bone, enhancing the potential for bone ingrowth. The
particular implant had a porosity of 30%, with a pore size of 50-500
microns. The implant was made of a CoCr metal alloy with an elasticity
modulus of 220 Gpa.

In 1984, the first cementless CoCr

(chromium-cobalt), with Porocoat,
the porocoated ingrowth acetabular
cup was introduced to the market. It
had the trademarked Porocoat
coating, with a surface of CoCr metal
alloy particles sintered on a substrate
of the same material. Sintering is
compressing powdered material and
heated until the particles adhere to
eachother. The implant had a
porosity of 30%, with a pore size of
50-500 microns. The pores are open
and interconnected. The open pores are not a barrier for migration of
particle debris/wear in the periprosthetic area. The stiff metal alloy
resulted in stress shielding. Due to the sintering of the material, particles
could loosen.
In 1985, a newer cementless cup was a titanium alloy fibre mesh bone
ingrowth acetabular cup, with large open pores and an inner liner of
polyethylene and a fibre mesh titanium coating. There even was an option
for screw fixation through holes. The average pore size was 300 microns,
and the volume porosity was 50%. The cup allowed for abundant bone
ingrowth, but the liner in the shell allowed for excessive wear, and the
holes give access to migration debris in periprosthetic space.

The Ringloc cementless cup was another cementless titanium alloy

porous coated cup had a standard titanium shell and a polyethylene liner
for smooth articulation, with a stable fixation of the liner. The outer
surface of the shell was caoted with titanium plasma spray to create a
porous structure, PPS (plasma porous structure). The pores were closed,
protecting against the migration of small particles. It had a pore size of of
100-1000 microns, with a porosity of 65%. The porous structure allowed
for abundant ingrowth.

It is important for multiple cup sizes to be available, as this influences the

success of the fixation. This is part of the job of the
Surgeon.

The CUT THA was a type of implant with extreme

open porosity, with pores of 1000-4000 microns. The
pores were open and interconnected. It showed
good fixation due to abundant bone ingrowth. This also made the
prosthesis very difficult to remove. The implant also had a modular neck,
resulting in metal wear at the neck-stem connection. It was made of CoCr,
so it had a stiff stem and cup, and a short metaphyseal stem.

The ingrowth of bone cells is not only influenced by the pore size or the
choice of metal, inlay’s, surface structures, features, coatings, screws, and
combinations of those all play a role in the success of an implant.

We until now discussed the use of CoCr and titanium in implants, but
more recent evolutions in the field also involve the use of other materials,
like trabecular metal and tantalum foam:

Today, two types of fixations are used in total hip replacements:

cemented and uncemented. Cemented THRs come with two different
types of stems, made of CoCr alloy with an E modulus of 220 GPa, a
smooth finished surface in standard stems or stainless steel with an E
modulus of 200 GPa, hyperpolished for Exeter stems. The function of the
cement is to enlarge the bone contact area, and the cement is fixated
using interdigitation and pressurization of cement into bone. The cup
made of polyethylene (at least the liner). The elastic modulus of bone
cement is 15 GPa.

The cementless cup and stem are press fit, made from α - β titanium alloy
for the stem, Ti-6AI-4V. This material is highly biocompatible, with an E
modulus of 110 GPa. First the optimal fit is chosen with good sizing, then
it is reliant on ingrowth. Secondary to the fit is the osseointegration of the
Ti coated stem. The coating is plasma porous sprayed PPS Ti, with extra
hydroxyapatite (HA) coating when desired. The bone contact area is
enlarged by the porous surface. The cup is made from α - β titanium or
tantalum, PPS coated, textured, rough blasted or tantalum trabecular
material.

The Charnley low friction concept is the idea of using a metal femoral
head in combination with a polyethylene lined cup, aimed to minimize
wear and friction. It used a very small metal head, with a thick
polyethylene cup. Initially this was done with conventional polyethylene,
later new polyethylene inventions came out.
HXLP, highly cross-linked polyethylene,
involves additional cross-linking of the
polyethylene molecules, resulting in a more
wear-resistant material. Cross-linking helps
reduce the rate of wear compared to
conventional polyethylene, potentially
extending the lifespan of the implant.
Vitamin E can also be added for more stable
oxidation resistance. With radiation the
exitated molecules dissociate after
absorption of energy. The hydrogen atom is
evolved and the left-over radical form the
bond. The result is C-C chemical bonds between adjacent molecules.
Cross-linking makes the polyethylene more resistant to wear, abrasion
and heat.

Other materials used are ceramics, which have:

 Low friction.
 High wettability, resulting in the formation of an effective lubricating
film.
 Low wear, high E module and hardness.
 Biocompatability, bio-inert, minimal stem taper corrosion.

The wettability of the ceramic surface resulted in the highest degree of

biocompatibility, no long term adverse reactions to ceramic particles were
found. They are entirely biologcally inert. The material also cannot be
scratched by cement particles and surgical instruments.

Modern composite ceramics are ZTA’s, zirconic toughened alumina. In this

material, zirconium oxide particles act like airbags by absorbing impacting
forces due to crack propagation. This is conversion reinforcement. Platelet
reinforcement has strontium aluminate platelet shaped crystals, that
block the propagation of cracks, thereby increasing overall strength.

A larger head size increases the range of motion of a hip implant, and
decreases the risk of dislocation due to the greater surface area.
However, a too large head size can lead to impingement of the iliopsoas.

The hip head is positioned into the cup due to muscular tension, so
increasing the length of the head neck increases the tension. Larger
ceramic heads are used now in combination with modern HXL
polyethylene, resulting in less wear and more stability.

There is also large effects of offset and muscles on the hip mechanics. If
there is normal offset, the muscle work normally and the abductors have
the strength to stabilize the pelvis. With less offset, there is more
abducator strength required to stabilize the pelvis, and if there is not
enough abductor strength available, it might result in trendelenburg
limping, which is pelvic downward tilt in one leg.

Bones also differ from eachother in the angle between diaphysis, the
caput-collum-diaphysial angle.

The position of the cup also influences the stability of the implant:
Lecture 5

Joint arthroplasty clinical performance part II

A THA revision/reoperation is an operation where we replace one/more/all

parts of the prosthesis:

 The acetabular cup

 The acetabular liner
 Femoral head
 Femoral stem

The fixation to the bone is done either cemented or cementless. The most
frequent reasons for reoperating are loosening of the acetabular
copmonent, loosening of the femoral component, wear at the articulation
component, instability or luxation. Loosening of a cemented cup can also
be fixed by replacing it with a cementless cup.

A bone cutter can be placed around the neck of the femoral implant, to
remove a cementless cup with minimal bone removal. It only removes the
bone that is present on the coating of the cup, in the pores. A cemented
cup can be removed by one or several bore holes and corkscrews.

It is also a challenge to remove cement from the femur, as cement is

inside. This can be done with a femoral window, or cement melting.
Old lecture: THA revision

An acetabular cup consists of a liner and a shell. A THA revision is an

operation where we replace one or more parts of the total hip prosthesis.
The THA can be fixed to the bone either cemented or cementless, just a
preference of the orthopedic surgeon. Revision sometimes requires a
special revision implant.

A THA revision often occurs due to:

 Loosening of the acetabular cup

 Loosening of the femoral stem
 Wear of the polyethylene cup/liner, leading to particle disease
 Dislocation due to instability, the hip head popping out of the cup
(luxations)
 Implant associated infections, manifesting after a few days
 Periprosthetic fractures
 Fracture, especially for the elderly
 Girdlestone resection arthroplasty
 Symptomatic metal on emtal bearing, the worst disaster seen in
orthepedics, especially metal on metal resurfacing
 Squeaking hip
 Leg length inequality
 Material fracture of the head or stem, especially fatigue fractures
 Persistent pain
 Perarticular ossification

The expectations a patient has:

 No visible limping, walking in a crooked manner

 An acceptable scar
 Good walking function
 Painfree
 Minimal leg length difference
 Lifetime guarantee, no revision!

Both the cup and the stem can be cemented in place, and both can be
cementless, so hybrids exist. A hybrid is a cemented stem and a
cementless cup, and a reverse hybrid also exists, which is the other way
around. Altogether, there are about 700000 hips. Loosening is the main
cause for revision surgery. Younger people have a higher chance of
needing a revision, likely because they move much more. The propability
of revision is likely thus due to revision.

The professor uses a titanium cup with polyethylene liner and a titanium
HA stem. The revision is done using just another standard hip. Varus tilt of
prosthesis causes bad bone fixation. A longer revision prosthesis is used
because to remove cement, you often have to weaken the bone with a
cortical window.
When enormous loosening of the pelvis has happened and hardly any
bone is left, you can make custom fitted cups that also replaces part of
the bone, and it is screwed in place. These are very expensive.

A revision is not simply swapping out some parts. Everyime there are
general risks with bleeding, anaesthesia, fractue, thrombosis, infection, et
cetera. Specific risks in THA revision are bone loss by lysis or removal
previous hip, muscle weaknesses, hip instability and dislocations, or
making an even worse construction. There are even higher risks with
recurring revisions, and even more costs.

In 2010-2013, 1.4% had a revision operation within one year. Most often
this is due to dislocation, with loosening in a second place. Hip stability is
due to the muscles and the placement/positioning of the cup and femoral
head. So, hip stability is caused by muscles and the way the hip implant is
“installed”. Loosening of the stem due to bad varus position of good
cementing technique. Periprosthetic fracture is the thrid most common
cause, and 11.1% even due to infection. Peri articular ossificication is also
a reason for reoperation (too much bone growth, limiting dof).

Materials:

 Stainless steel, high elastic module, low fatigue strength, not used
anymore.
 CoCr, highest E module, better fatigue strength and yield, standard
for the cemented stem. Even CoCr stems can fracture.
Titanium is used most in the netherlands, then CoCr, and stainless steel is
still used sometimes as a cheap option. For the cups, mostly titanium,
some stainless steel, and fewer CoCr (for resurfacing) and tantalum
(expensive and new).

Polyethylene has been used in the wrong way in the past, with a lot of
ways wear can occur, and wear of course results in particle disease. If
polyethylene is used as the total cup, it must be cemented.

The most common causes for revision in the netherlands are: loosening of
the acetabular component, loosening of the femoral component, wear of
the bearing, dislocation, infection, periprosthetic fracture, girdlestone
resection arthroplasty, symptomatic metal on metal bearing.

Loosening happens to the femoral stems and acetabular cups. In

cemented cups, the cement can for instance loosen due to movement
during the operation. Cement is a filler, not a glue. Cement is used for
creating more surface, and the more surface area you have the better the
fixation. Cement has high compression resistance, but not good torque
resistance. The largest problem is the debonding from the bone and
prosthesis loosening. Cement is also not a barrier for polyethylene
particles, and there is no chemical reaction between cement and bone.

Cemented loosening can be done by mixing fluid and solid material,

mixing it in vaccum to prevent air bubbles, cleaning the bone with a water
pick, and a cement stop in the femur is necessary to compress the
cement. A clean bone bed is also important.

Another problem with cemented hips is loosening and debonding of

cement, creating a wiper motion. Cement is not a barrier for particles,
causing lysis of bone, resulting in even more loosening.

In younger patients, we preferably place cementless hips because the

chance of loosening is higher in cemented hips. Revision surgeries are
risky and difficult, but the cemented cups are less expensive. If you have
a low grade infection, operation is far more dangerous.

You can remove cement through a window in the femur. A new instrument
is the ultra drive cement remover.

Due to the cement removal and bone removal, you end up with massive
femoral defects. The bone quality is afwul. To fix this, bone allograft can
be performed. Bone, and even dead bone (any bone) always integrates
with living bone. Bone transplantations are thus used often (?).

Cementless loosening is always due to the lack of adequate bone

ingrowth. This is caused by surgical failure (e.g. bad positioning) or due to
a wrong prosthesis. There must be a very close contact between the
cementless prosthesis and the bone. Bad engineering has happened
before in hip prostheses. A smooth surface does not envoke bone
ingrowth, and smooth implants are just held in place by jamming. Two
holes for bone ingrowth in the implant does not work! Why should the
bone grow in the holes? Wrong coatings and screw-in cups also showed
more loosening than press-fit cups. So loosening is often due to bad
engineering or bad surgery.

Cementless cups can be removed using a bone cutter. They sometimes

must be removed due to incorrect orientation of the acetabular cup. The
cup shows well integrated bone ingrowth, but the position is wrong.

Polyethylene against the bone causes loosening and wear of the

polyethylene. So there cannot be contact with bone and polyethylene.

Old lecture 5

Atherosclerosis is the thickening of the vessel walls, which can give

problems if it restricts blood flow to much. Risk factors for atherosclerosis
are:

Environmental:

 Diet/obesity
 Smoking
 Inactivity

Risk factors:

 High cholesterol (bad cholesterol)

 Low HDL (good cholesterol)
 Hypertension
 Diabetes
 Gender

Genetic components:

 Familiar hypercholesterolemia (FH)

Endothelial cells get activated, and they express molecules that attach
monocytes to the endothelial cells. These monocytes attach, and they can
pass through the endothelial cells where they become macrophages.
These try to get rid of the high levels of cholesterol in the vessels. When
they become too big, they cannot leave the vessel anymore, and they die.
They become foam cells, and the molecules that are secreted attract even
more monocytes.
Plaque rupture can cause blood coagulation, causing acute myocardial
infarction. This causes a blood clot that travels until it blocks an important
vessel (thrombosis). Atherosclerosis can be treated by inserting a balloon
with a stent. The balloon is inflated and the stent is deployed, opening up
the artery and restoring blood flow. Drawback of this procedure, in 20-
30% of patients, the vessel wall is damaged due to the stent and this can
cause SMC’s to proliferate and this causes in-stent restenosis.

Nur77 is a nuclear hormone receptor, of the same family as the estrogen

and endrogen receptors. What’s important to know is that Nur77 inhibits
SMC growth. A nur77 cuff placed around the femoral artery in mice
showed less SMC-rich lesion formation. As a result, drug eluting stents can
be placed in the vessel. Drugs used nowadays inhibit the growth of all
cells, so not only SMC’s, but als0 endothelial cells. This is a problem,
because endothelial cells form the inner lining and protective layer of the
vessel. The stent must be nicely covered in these cells. This is a problem
because the body sees the stent as an injury, and this can cause instant
thrombosis. Patients thus need anti-platelet therapy for 1,5 years.

Nur77 cannot bind to a ligand to activate it, but researchers found that
6MP can activate Nur77. 6MP is an active metabolite of azathioprine, it is
antiinflammatory and immunosupressive. 6MP inhibits the SMC rich lesion
formation. 6MP also inhibits monocyte adhesion. 6MP does not affect EC
proliferation and migration. 6MP also decreases MCP-1 expression
(macrophages).

So 6MP:

 Inhibits MSC proliferation

 Inhibits monocyte adhesion to endothelial cells
 Inhibits macrophages
 Inhibits cytokine expression
 It keeps the endothelial cells happy.

The stents are coated on the outside with 6MP, so the drug is delivered
mainly to the vessel wall. BMS gives in-stent restenosis, the DES gives
acute thrombosis.
You have lawson staining and histology, and you can perform neointima
quantification.

Neointima formation is shown to be reduced with 6mp.

Endothelial coverage is shown to be improved using 6mp covered stents.

Lecture 6 old

Stents are the most often used cardiovascular medical devices. They can
be made out of different materials, all with different properties. CVD
accounts for 18,5 million deaths annually. This makes it leading cause of
death worldwide. 80% of these deaths are due to heart attack and stroke,
predominantly caused by atherosclerosis. There are 3.6 million new cases
of heart failure in Europe each year, and the costs are 170 billion euros
annually. Children are at increasing risk through active and passive
tobacco smoken, and lack of physical activity.

The cardiovascular system consists of the heart, as the muscular pumping

device, the closed system of blood vessels, and blood. The heart
provides the force necessary to circulate the blood through all tissues in
the body. It pumps about 5 liters of blood each minute. It can be seen as a
double, self adjusting pump. It has four chambers and three wall layers.

You can see that the ventricles have much thicker walls than the atria,
because they must pump the blood to the body.

The three layers of the heart wall are the epicardium, the myocardium
and the endocardium. The myocardium is very vascularized tissue. It is
responsible for the actual pumping of the heart as it contains all the
muscle cells.

The vessels consist of veins, arteries and capillaries. Smaller arteries are
called arterioles, smaller veins are called venules. In the capillaries the
oxygen and nutrients are exchanged with the tissue, for carbon dioxide
and rest products from metabolic activity.
The blood vessel can also be structured in three layers. The tunica intima,
the tunica media and the tunica externa. The tunica intima consists of
endothelial cells. The tunica media contains the smooth muscle cells. The
tunica externa mostly contains connective tissue.

Blood contains plasma, erythrocytes and the “buffy coat”, with leukocytes
and platelets. Red blood cells are red because they contain hemoglobin,
and they bind with oxygen to be distributed throughout the body. White
blood cells are part of the immune system, and platelets are responsible
for blood clotting. Too many platelets leads to too much clotting, while too
few platelets prevents blood from clotting.

Atherosclerosis is plaque in the inner lining of the coronary arteries,

narrowing their lumen and, consequently, restricting blood movement to
the tissue. This can be followed by thrombus formation if plaque ruptures,
and when blocking arteries this can lead to tissue death. Treatments for
atherosclerosis are bypass operations and percutaneous transluminal
coronary angioplasty (PTCA, balloon angioplasty).

In PTCA, a catheter mounted balloon is moved to the lesion site and

inflated, displacing the tissue and creating a wider lumen in the vessel.
Doctors use fluoroscopy to see if the procedure is going well. Angiography
is imaging the vessel with a type of X-ray. Catheters are most commonly
made of nitinol or stainless steel (?). A catheter is inserted in the groin or
in the wrist. A guidewire is first placed before the balloon is inserted.

The main limitations of PTCA are short term and long term. Short term
failure is the closure of the vessel within a few hours due to elastic recoil
of the vessel wall, thrombosis (clot formation) or acute dissection, where
blood flows in the vessel wall due to rupture of the wall during the
inflation of the balloon. Long term failure, in 40% of patients, restenosis
occurs after 4-6 months.

To make sure the lumen stays open for a long time, a stent is placed over
the balloon in PTCA. The balloon is inflated and deflated, while the stent
expands and stays in the artery to keep the lumen open.

The balloon is often inflated with a mixture of saline or contrast agent to

aid radiographic visualization. The materials used for catheters are silicon
rubber, teflon and polyurethane.

The definition of a stent is any material used to hold tissue in place or to

provide a support for a graft while healing is taking place. At first it was
some sort of was material for dental molding that was later used to keep
tissue in place while healing after surgery. Now the term is mostly used
for the vascular application.

Three main categories of stents currently exist: bare metals stents (BMS),
drug eluting stents (DES) and biodegradable stents (BDS).
Ideal stents have the following characteristics:

 A low profile, it must have the ability to be crimped around a

catheter.
 Good expandability, it should undergo sufficient expansion and
conform to the vessel wall.
 It should have sufficient radial hoop strength and negligeble recoil
because it must not collapse under arterial wall forces.
 It should be flexible as it must have the ability to travel through
small vessel diameters ar tortuous anatomy.
 It should result pulsatile fatigue, about 40x10^6 bts/y. (thus should
have high fatigue resistance).
 It should be radiopaque or MRI compatible to assist clinicians in
assessing the in-vivo location of the stent.
 It should thromboresistivity, blood compatibility, not promoting
platelet adhesion and deposition.
 It should have the capacity to delivevr drugs to prevent restenosis.

Biomaterials used for stents are:

Ceramic material class is missing, this is because those materials are far
too brittle to be used as expanding stents. Biodegradable are not yet used
clinically.

We have balloon expandable stents and self expandable stents. With a

balloon stent, the atomic structure of the material also changes because
the stent is plastically deformed. Nitinol self-expanding stents are in their
elastic region.
The difference between the yield strength and the ultimate tensile
strength must be large, so that the stent can be plastically deformed
without breaking. For instance in tantalum, this difference is quite small
and it is hard to be in that range. If stents have low mechanical properties,
the strut thickness must increase.

Stents should also be visible on an X-ray to help clinicians in performing

the procedure, so the density of the material should be high. Tantalum
has the highest density, while stainless steel is not that visible. Tantalum
markers can also be placed on a stent to improve visibility.

Stainless steel has good mechanical properties for uses in stents. It

used to be the “golden standard” for bare metal stents. The yield strength
and UTS are good, and the corrosion resistance is quite good. It contains
chromium and nickel that form an oxide layer that prevent corrosion. SS is
not MRI-compatible because it is ferro-magnetic, it has a lot of iron. It is
not fluoroscopically visible due to the low density. It may generate allergic
reactions to nickel ions, and it may release chromium and molybdenum
ions which may trigger local immune response and inflammatory reaction
which in turn induce neointimal formation and in-stent restenosis.
CoCr has high tensile strength and allows for really thin struts. It has
excellent radial strength due to the high elastic modulus, limiting recoil.
The density is higher than SS, good X-ray visibility. The main limiting
factor is the Co, Cr and Ni release.

PtCr

Nitinol allows us to create self expandable stents due to the shape

memory effect and the superelasticity. It has high strain recovery, 8,5%. It
is MRI compatible, and it can be used for many applications because it can
bend a lot. It does however have poor X-ray visibility, and its main
concern is the release of nickel ions and their toxic effects. To improve its
corrosion resistance, the nickel concentration at the surface is being
reduced and TiO2 formation is promoted. The deployment of self
expanding stents can reduce local inflammatory reactions and plaque
rupture because the force with which the stent is pushed in the vessel
wall is not as large. It can thus be used for much more delicate plaques.

BMS stents cannot avoid endothelial and smooth muscle cell damage
while installed, which will lead to restenosis. It introduces an inflammatory
reaction. Long complications of stenting is in-stent restenosis, which
occurs within 6 months in 30% of the patients who are stented.
Optimization of the architecture and mechanical properties of the stents
has decreased restenosis, but not efficiently. System pharmacological
therapy failed to reduce restenosis because of its inability to deliver an
adequate drug dose at the site of injury. The drug should be deliverd
locally, so DES are used for that.

DES are stents loaded with therapeutic agents. Once delivered to the
injury site, the stent slowly releases the drug for a period of at least 30
days during which the biology of restenosis is known to occur. An ideal
DES sohuld inhibit proliferation of vascular smooth muscle cells, while not
impeding the restoration of endothelial cells to restore the natural vessel
wall. Endothelial cells should in the end cover the stent.

There are many different drugs for treatment of restenosis. They all block
neointimal proliferation, but may increase stent thrombogenicity. Some
drugs reduce thrombus formation and are not so good at neointimal
proliferation. Sirolimus and paclitaxel block neointimal formation but
increase stent thrombogenicity. Without reendotheliazation, the stent
remains a foreign object in the blood stream, which promotes platelet
activation.

Techniques for drug loading are attaching the drug directly onto the metal
surface, incorporating the drug into a polymeric coating and loading the
drugs into the pores of a metal porous stent.
Few DES exist on the market right now, one of the most used is made by
Cordis. It is a stainless steel 316L platform. The coating is a permanent
polymer, in which they placed the drug. The stent stops neointimal
growth, but the endothelial cells could also not really grow on this stent.
The delivery of a drug in polymer depends on the ability of the drug to
diffuse through the polymer material. The release should take at least 30
days to prevent restenosis.
To conclude, we have two options: balloon angioplasty and stent
implantation. Balloon angioplasty possibly has problems like elastic recoil,
thrombus formation, neointimal hyperplasia and late vessel remodeling.
Stent implantation has thrombus formation and neointimal hyperplasia.
Bare stents have restenosis and DES, thrombus formation is more likely to
occur due to poor reendothelialization.

BDS eliminate the ongoing processes that can result from the
interference of an artificial material with the vessel wall (long-term
endothelial dysfunction or inflammatory reactions). This is very good for
children, to prevent removal surgery. The stents can serve as support
devices as well as platforms for drugs and protein delivery to the conduit
wall.

Fe for biodegradable stents has good radial strength and elastic modules,
however the yield strength and tensile strength are close to eachother,
stents with thinner struts may fracture during deployment. Iron however
does have a low degradation rate, so sometimes problems still persist.

Magnesium alloys can be used, they need to be alloyed because mg has

bad mechanical properties. They also require quite thick stents, to provide
vessel wall support. Mg also degrade very fast, and it has a non-
controllable corrosion rate. It cannot be visualized in an X-ray, but is MRI
compatible. It reduces smooth muscle cell growth and enhances
reendotheliazation.
Polymeric BDS are also under testing, but they are not so visible on X-ray
and have low mechanical properties.

Challenges in DES are specific and efficient bioactives, effect of strut

thickness and coatings on performance of the stent, tissue response to
the changed chemistry and topography of coated stems, and an increased
risk of thrombosis of polymer coated DES. Polymer coating can promote
inflammatory responses and thus clot formation.

Old lecture 9

Bearing wear is an important failure mode in THR. There is wear at the

ball socket articulation, at the modular neck-stem connection, at the
modular stem-calcar connection and wear at the the modular head on
conus.

Tribology is wear at an articular surface. This happens at the head-cup

interface. The hip movement is not straightforward, the ball and socket
are in different locations depending on the phase of the step.

A total hip replacement is stabilized with muscles. The aim is minimal

wear. Less wear leads to fewer particles and less biological reaction. Less
osteolysis leads to a fewer number of revisions.

Metal on metal is an issue. With a lot of clearance, you get edge loading
and a lot of friction at the edge. A low clearance induces jamming. Both
cases result in a lot wear. This resulted in a lot of metal particles and Co
and Cr ions locally and systemically.
A later idea for a low friction hip was to include a polyethylene cup
(UHMWPE), and a small head to reduce travel in the articular interface.
Smaller head leads to less movement and friction, due to less sliding
distance and less volume wear.

Polyethylene wear is due to three wear modes, adhesive wear, abrasive

wear and fatigue wear. Conventional UHMWPE can have anisotrope,
creep, oxidation, fractury, pitting, delamination, wear and ductile
behavior. Polyethylene particles are about 1 micron in size, which are
relatively big. The mechanical and biological effects of polyethylene are:

Particle disease results in osteolysis, bone cysts, particle disease,

resulting in loosening of the prosthesis, spontaneous fractures and
pseudotumors. Polyethylene particle disease is caused by wear, the
macrophages eat them and explode at some point. This triggers
osteoclasts that eat bone. Bone resorption happens in the periprosthetic
space of the cup and stem. -> bone resorption, cyste formation,
scalloping, loosening of the prosthesis.

Below, the metal pushed and demolished due to excessive wear, so there
is contact between titanium and metal.

Mechanical wear modes are luxation, contact between polyethylene and a

screw, impingement of the neck. There is linear wear, stripe wear, bodies
and luxation.

Polyethylene wear can be reduced by improving the heads, like ion

treating CoCr heads or using ceramic coated heads. HXLPE polyethylene is
better, and it can also be vitamin E doped. There were also people who
went back to hard on hard bearings.
Ceramics have low friction, high wettability (loew contact angle). It has
low wear, high E modulus and high hardness. It also biocampatible, bio-
inert and has minimal taper corrosion. It fractures easily however.

Pure alumina on conventional polyethylene has less wear, at the tradeoff

of fracture. Zirconic heads were used later, they had fracture toughness,
but they were in practice more prone to fractures. Zirconic heads
produced warmth due to friction, increasing grain size and increasing
wear of the polyethylene.

Oxidized zirconic material (Oxinium), transforming the material at the

surface a layer into a ceramic surface. No fracture, chipping etc. However,
it turned out the corner of the cup could scratch the material easily.
Modern composite ceramics, zirconic toughened alumina.

The downside of ceramic on ceramic is all kinds of wear.

Metal on ceramic: no

Trunionosis is damage to the conus, or taper damage.

Dislocation is one of the most common failures of a thr. The cup must be
placed in a well manner, as well correct positioning of the stem, the
incorrect size, length of the head and offset. Impingement and poor head-
neck ratio is also important. Luxation is the word for dislocation. It
happens more in revision surgeries. The jumping distance is an important
factor, it depends on the size of the head. Extra tension of the muscles
can be achieved by more horizontal distance between the hip and pelvis
due to the abductor muscle. A small head-neck ratio results in a short
jumping distance and easy dislocation. A bigger head size also results in a
larger range of motion.

Infection is also an important problem for revision. Biofilm formation must

be prevented. IAI. Staphyloccocus is the most common infector. Silver
coated materials prevent biofilm formation.

Girdlestone resection is where the patient does not use a thr anymore
after too many surgeries.

Nanoparticles and microparticles have different reactions. Nanoparticles

are from metal on metal, microparticles have less reaction but still
osteolysis.

Resurfacing is also bad, with dead bone inside the cupe. The reaction from
nanoparticles are pain, pseudotumors, loosening, etc.