1.

INTRODUCTION

Plastic and polymeric products are now being a part of our life and living
without them is almost beyond thoughts. Plastic products got popularized
and widely being accepted because of many reasons mainly light in weight,
moldability in any shape, non-corrosive in nature, variety of colors, save the
use of plant woods for house hold furniture and above all reusability etc.
plastics are polymeric in nature, so in general inert in nature and suppose to
cause no intracellular reachability and reactivity. The applications of plastic
are rapidly increasing all over the world. Glance of their usages pattern in
daily life indicates that we are approximately surrounded by 70-80% of
them ranging from packaging materials, automobiles, kitchenware and
children toys to the components of the designed products, aircrafts or the
biomedical devices.
Plastics are used in a variety of other consumer and industrial products viz.
textile, fibers, packaging, paints, automobiles, alternate building materials
etc. Due to their versatile properties, plastics are also used in the electronics
such as television, refrigerators, air conditioners, agricultures etc. In
hospital, plastic medical devices are being used for storage and transfusion
of life saving fluids, syringes, blood bags, biomedical implants, tubing and
heart valves for the cardiac patients.
In the present scenario, we find the plastic usage pattern such as in various
sectors. The 33% of plastic is being used for the packaging purpose, 20% in
building construction, 10% in electrical and electronic items, 7% in
automobiles, 5% in agriculture and 25% in the other sectors such as medical

and leisure. Plastic use is dominated by single use or short term use, and at
the same time most plastics are extremely persistent in the environment.
Plastics are important in our society and offer many benefits for human
health and the environment, for instance.1, 2
Plastic packaging protects food and goods from getting wasted and/or
contaminated and thereby saves resources.
The light weight packaging material saves fuel and decreases
emissions during transportation.
Plastic water supply systems and storage containers/tanks provide
clean water.
Light plastic materials in cars and aircraft save fuel and decreases
emissions.
Plastic protective clothing and safety equipment (e.g. fire proof
materials, helmets, air bags) protects from injury.
Plastic products for medical applications are very important and
contribute to improved heath (e.g. blood pouches, tubings, disposable
syringes, prosthesis).
The plastic industries in India started with the introduction of products likecellulose acetate, acrylics and vinyl. The newer plastics, such as
polyethylene, polypropylene, polystyrene, polycarbonate, polymethyl
methacrylate, polyurethane, polyester and silicones joined polystyrene and
PVC in wide applications. Plastics have increasingly provided the desired
performance characteristics that fulfill consumer requirements at all levels.
They are used in such a wide range of applications because they are capable
of offering desired properties that offer consumer benefits unsurpassed by
any other material. More recently, because of a better understanding of the

importance of surface, avoidance of contamination, and control of

molecular weight and molecular weight distribution, the use of synthetic
polymers in the biomedical sciences is increasing.
Polymers are viewed as important biomedical materials for a number of
reasons, some of which appear contradictory-but only because of different
uses require different properties. Some of the important properties are the
ability to tailor make structures, surface control, strength, flexibility,
rigidity, inertness/reactivity, lightweight, ease of fabrication, ability to
achieve a high degree of purity, compatibility, and the ability of some of
them to withstand long term exposure to the human body a truly hostile
environment. Surface hydrophobicity / hydrophilicity, presence/absence of
ionic groups, chemical and physical surface are all important considerations
as one design a material for a specific application. In 1997, Dow introduced
syndiotactic polystyrene under the trade name Questra. Targeted areas
include medical, automotive, and electronic applications. Index, an
ethylene-styrene interpolymer, was introduced in 1998 and is intended to
compete with block copolymers such as styrene-butadiene, flexible PVC,
polyurethanes and polyolefins. It is being used as a modifier for polystyrene
and polyethylene. A number of new materials have been developed because
of the health fears associated with the monomer Bisphenol A, which is the
comonomer for most polycarbonates. The replacement should possess
similar properties to polycarbonates and also be available in large quantity
and inexpensive. One material that has become available is copolymer
polyester developed by Eastman. The structure for this material, Tritan, is
proprietary but is believed to be based on the diol tetramethylcyclo-

butanediol. The ring system contributes the necessary stiffness and the
methylenes supply the flexibility. 3

H 3C

CH 3
OH

OH
H 3C

CH 3

Tritan

The global medical device industry is estimated to be between U.S. $ 220

and 250 x 109 in value. This industry continues to show a healthy growth
rate overcoming many economic slowdowns. It is projected to grow from
about U.S. $ 100 billion to almost U.S. $ 300 x 109 in 2015. Figure 1.1
shows the growth from 2000 projected to 2013. 4
300

Value US $ Billion

250
200
150
100
50
0
2000

2005

2008

2009

2010

2013

Year
Figure1.1 Global medical device markets

The U S has about 40% of the global market share, followed by Europe,
Japan, and the rest of the world (Figure 1.2). Germany is the largest market
in Europe followed by France, Italy, and the United Kingdom. Japan is the
second largest country by market share next to the U. S. The rest of the
world comprises regions like China, India, and Latin America. These
regions are seeing 10-15% annual growth rates in the medical device
market. One of the reasons for this growth is the population increases in
these regions compared to the United States and Europe. The demand for
health care and medical devices as a result continues to increase for these
regions and globally as well. 4

Rest of the
World, 20%

United
States, 40%

Japan, 15%

Europe, 25%

Figure1.2. Global medical device market share by region

Medical devices range from simple devices like tongue depressors,
syringes, and bandages to highly sophisticated imaging machines and long
term surgical implants. Medical devices include surgical instruments,
catheters, tubings, coronary stents, pacemakers, MRI machines, X-ray
machines, prosthetic limbs, artificial hips, knees, surgical gloves, and
bandages. Medical device as defined by the U.S. FDA is anything used for

therapeutic and/or diagnostic purposes in humans or animals, which is not a

drug. In the European Medical Device Directive a medical device is defined
as a product with a medical intended purpose, whether for diagnosis,
treatment, or alleviation of a medical condition in humans and is not a drug.
Devices are classified into three classes: Class I, Class II, and Class III
depending upon their risk and criticality. Examples of Class I devices are
tongue depressors, bandages, gloves, and simple surgical devices. Class II
devices are wheel-chairs, X-ray machines, MRI machines, surgical needles,
catheters, and diagnostic equipment. Class III devices are used inside the
body. Most implants are Class III devices. Examples include heart valves,
stents, implanted pacemakers, silicone implants, and hip and bone
implants. 4
1.1 Types of Devices
Medical devices can be classified into two major categories- disposables
and non-disposables. Disposable devices include bandages, gloves, blood
bags, colostomy bags, catheters, syringes, IV kits, and tubing.
There is a wide spectrum of requirements that apply to materials used in
medical device applications. It is important to understand these
requirements and design the right part with the right material that fits the
intended use and the processing and assembly of the finished device.
Materials used in the design, production, and assembly of medical devices
include metals, ceramics, glass, and plastics. The use of plastics continues to
grow especially with the growth in disposable products (Figure 1.3).

Million Metric Tonnes

8
7
6
5
4
3
2
1
0
1985

1994

2000

2010

Year
Figure1.3 Global plastics volume in medical devices
Plastics have superior design flexibility compared to metals, ceramics, and
glass. They can be processed into different shapes, sizes, thickness, and
colors. Their properties can be tailored to meet a wide spectrum of physical,
mechanical, chemical, and biocompatibility requirements. 4
Table 1.1 Summary of Plastics in Medical Device Applications
Property

Commodity Plastics

Engineering

High Temp.

Thermoplastics

Engineering
Thermoplastics and
other polymers

Percent usage in
medical device
70% of all plastics

20% of all plastics

10% of all plastics

Types of

Polyethylene

Polyamides

Polyimides

Plastics

Polypropylene

Polyesters

Polyether imides

Polystyrene

Polycarbonates

Polysulfones

Applications

Polyvinyl chloride

Polyurethanes

Polyether ether

Acrylics

ketones

Acetals

Polyphenylene sulfide
Fluoropolymers
Liq. Crystalline
Polymers
Biopolymers
Thermosets and
adhesives

Medical Device Tubing

Surgical instruments

Surgical instruments

Applications

Films

Balloons

Surgical trays

Packaging

Blood set

Syringes

Connectors

Components

Implants

Blood bowls

Dental implants

Blood oxygenators

Bone implants

I V bags

Syringes

Moving part and

Catheters

Catheters

components

Labware

Pacemakers

Bioresorbable sutures

Drug delivery
components
Membranes
Sutures
Syringes

1.2 Types of Plastics

There are three major classes of plastics thermoplastics, thermosets, and
elastomers.
Thermoplastics are those, which once shaped can be softened by the
application of heat and can be reshaped repeatedly, till it loses its property.
e. g. Polyethylene, Polypropylene, Polyvinyl chloride, Polystyrene,
Polyamides,

Polyesters,

and

Polyurethanes.

High

temperature

thermoplastics include polyether ether ketones, liquid crystalline polymers,

Polysulfones, and polyphenylene sulfides.
Commodity plastics account for about 80% of plastics used for medical
devices in applications like lab ware, tubing, containers and molded
connectors.
Thermoplastics

can

be

further

categorized

into

amorphous

and

semicrystalline polymers. Amorphous thermoplastics are long chain

molecules that have no order. Semicrystalline (or crystalline) polymers have
short range order and can align together to form ordered, crystalline
structures within amorphous regions. The extent of alignment and the
amount of crystallinity are determined by the polymers chemical structure,
which determines how well the polymer chains can align with each other.
Semicrystalline thermoplastics are typically opaque compared to amorphous
thermoplastics. Semicrystalline polymers have better chemical resistance
than amorphous thermoplastics because they have a lower amount of
amorphous regions that are permeable to chemicals and solvents.
Thermosets are formed when two or more components chemically react
with each other under ambient conditions or when induced by radiation or

heat to form a highly cross linked network. The formation of thermosets is

an irreversible process. Thermosets are typically hard and rigid.
Elastomers are loosely cross linked polymers. They have the characteristics
of rubber in terms of flexibility and elasticity e.g. natural rubber, styrene
butadiene block copolymers, polyisoprene, polybutadiene, ethylene
propylene rubber, silicone elastomers, fluoroelastomers, polyurethane
elastomers, and nitrile rubbers.4
Poly (ethylene terephthalate) PET or PETE
It is clear, tough and has good gas and moisture barrier properties making it
ideal for carbonated beverages, food containers and life saving fluid bottles
etc.
Poly (vinyl chloride) PVC or V
In 1912 German chemist Fritz Klatte at Greisheim Electron unknowingly
made the first PVC in an attempt to create uses for large quantities of
acetylene gas fuel lamps. He had reacted acetylene with hydrochloric acid.
Not knowing what to do with the new material, it was stored for some time
and polymerization took place. It has excellent transparency, chemical
resistant, long term stability, and stable electrical properties. Vinyl products
can be broadly divided into rigid and flexible materials. The application
varies from water pipes and fittings to windows, laminates, blood bags,
medical tubing etc.
Polypropylene PP
It has excellent chemical resistance and thus commonly used in packaging.
It has high melting point making it ideal for hot fill liquids. Like other
plastics PP has excellent resistance to water, salt and acid solutions that are

10

destructive to metals. Typical applications include ketchups bottles,

medicine bottles and automobile battery casings.
Polystyrene PS
PS is used to make a wide variety of containers, including those known as
Styrofoam plates, dishes, cups, biomedical devices etc.
Other Plastics: Beside these various specialized plastic products can also
be seen in the market such as polycarbonate, polymethylmethacrylate,
Nylon, polyester, Glass fiber reinforced plastics, ABS copolymers, Teflon,
blends and multilayered combinations.
A medical device that is adequately designed for its intended use should be
safe for that use. The device should not release any harmful substances into
the patient that can lead to adverse effects. Some manufacturers believe that
biocompatibility is sufficiently indicated if their devices are made of
medical grade material or materials approved by FDA as direct or indirect
additives. The term medical grade does not have an accepted legal or
regulatory definition and can be misleading without biocompatibility
testing. There is no universally accepted definition for biomaterial and
biocompatibility, yet the manufacturer who ultimately markets a device
were required by FDA to demonstrate biocompatibility of the product as
part of the assurance of its safety and effectiveness. The manufacturer is
responsible for understanding biocompatibility tests and selecting methods
that best demonstrate the following:
The lack of adverse biological response from the biomaterial
The absence of adverse effects on patients
The diversity of the materials used, types of medical devices, intended uses,
exposures, and potential harms present an enormous challenge to design and

11

conduct well-defined biocompatibility testing programs. The experience

gained in one application area is not necessarily transferable to another
application. The same applies to different or sometimes slightly different
(variable) materials. Biocompatibility describes the state of a biomaterial
within a physiological environment without the material adversely affecting
the tissue or the tissue adversely affecting the material. Biocompatibility is a
chemical and physical interaction between the material and the tissue and
the biological response to these reactions. Biocompatibility assays are used
to predict and prevent adverse reactions and establish the absence of any
harmful effects of the material. Such assays help to determine the potential
risk that the material may pose to the patient. The proper use of
biocompatibility tests can reject potentially harmful materials while
permitting safe materials to be used for manufacturing the device. 5
These factors include the type of device, intended use, liability, degree of
patient contact, nature of the components, and potential of the device to
cause harm. There are no universal tests to satisfy all situations, and there is
no single test that can predict biological performance of the material or
device and reliably predict the safety of the device. The types and intended
uses of medical devices determine the types and number of tests required to
establish biocompatibility. Biological tests should be performed under
conditions that simulate the actual use of the product or material as closely
as possible and should demonstrate the biocompatibility of a material or
device for a specific intended use. These tests were more extensive for a
new material than for those materials that have an established history of
long and safe uses. All materials used in the manufacture of a medical
device should be considered for an evaluation of their suitability for

12

intended use. Consideration should always be given to the possibility of the

release of toxic substances from the base materials, as well as any
contaminants that might remain after the manufacturing process or
sterilization.
Biocompatibility is generally demonstrated by tests utilizing toxicological
principles that provide information on the potential toxicity of materials in
the clinical application. Biocompatibility should not be defined by a single
test. It is highly unlikely that a single parameter were able to ensure
biocompatibility; therefore it is necessary to test as many biocompatibility
parameters as appropriate. It is also important to test as many samples as
possible, therefore suitable positive and negative controls should produce a
standard response index for repeated tests. 5
Biocompatibility testing should be designed to assess the potential adverse
effects under actual use conditions or specific conditions close to the actual
use conditions. The physical and biological data obtained from
biocompatibility tests should be correlated to the device and its use.
Accuracy, reproducibility, and interpretability of tests depend on the method
and equipment used and the investigators skill and experience. 5
Toxicity may come from leachable components of the material due to
differences in formulation and manufacturing procedures.

Products are

frequently composed of components; however simple examples are a

disposable syringe (needle, barrel, plunger, lubricant, and stopper etc.).
Changing a component can significantly alter the biocompatibility of a
product, and certain components, by the nature of both their composition
and exposure to patients, are more likely to present biocompatibility
problems. An example is the common disposable plastic syringe, of which

13

billions are used each year. For the syringe, the most likely problem
component is the stopperthe flexible piece at the end of the plunger. The
stopper is most commonly made of natural rubber, and has direct contact
with fluids entering the body (and frequently a fluid path).
Plastics used in medical device applications must meet stringent
performance requirements through production, packaging, shipping, end
use, and disposal. Many devices and device kits are sterilized before they
are shipped for use. During manufacturing and during end use they also
come in contact with various chemicals, solvents, bodily fluids, skin,
organs, and tissues. The materials used in medical devices must be resistant
to the sterilization methods, chemicals, and fluids that they encounter, be
compatible with bodily fluids, skin and tissues and still maintain their
safety, effectiveness, and functionality. Requirements for plastics use in
medical device include the following:
Material characterization
Sterilization resistance
Chemical and lipid resistance
Extractables and leachables characterization
Biocompatibility and haemocompatibility
Shelf life and stability
Many devices need to be packaged and sterilized either before distribution
or before use. Examples of such device are exam and surgical gloves, clean
room garments, specimen cups, wound care products, sutures, needles,
syringes, catheters, drain bags, IV bags, fluid delivery systems, dialysis
equipments, implants, surgical instruments, dental instruments, surgery
supplies, and combination products.

14

All materials used in such medical devices including the plastics used in
them must be capable of being sterilized without loss of performance.
Sterilization can be defined as the removal or destruction of all living
organisms including resistant forms such as bacterial and fungal spores.
Pyrogens are substances that can cause a fever. A product may be sterile but
it still may contain pyrogens.
Cleanliness does not mean sterile.
The main sterilization methods used in medical devices are:
Autoclaving (steam, dry heat)
Ethylene oxide (EtO)
Radiation (gamma radiation, electron beam radiation)
Gamma radiation can negatively affect plastics in the following ways:
Formation of radicals leading to chain scission and degradation
Formation of radicals leading to cross linking
Color change
Chain scission leads to degradation and reduces toughness, elongation, and
impact strength. The high energy gamma radiation forms radicals along the
polymer chain. These radicals subsequently degrade the polymer to lower
molecular weight chains leading to reduce physical properties. However
many stabilizers like phenols, HALS (hindered amine light stabilizers),
phosphates etc have been used to absorb the energy or quench and capture
the free radicals formed, thus preventing degradation. Color correction tints
like ultramarine blue are used to compensate for the color change and
maintain a clear, transparent plastic after radiation. Those polymers that
require stabilization are given bellow:

15

Transparent polymers like polyvinyl chloride, acrylics, polycarbonates, and

polyurethanes have a tinting agent and some polymers also require free
radical scavengers or quenchers to prevent degradation.
Plastics used in medical devices can come into contact with various solvents
and chemicals either during the manufacturing process or during end use.
The medical devices must maintain their integrity, performance, and
aesthetics when exposed to such solvents and chemicals. Chemical can react
with the additives causing them to leachout of the part or form unwanted
byproducts. Chemicals used in a manufacturing environment include the
following:
Acids
Bases
Solvents (methylethyl ketone, tetrahydrofuran, methylene chloride,
ethylene oxide, alcohols, ethyl acetate)
Processing aids-greases, oils, mold release like silicones etc.
Solvents like MEK and THF are used in the joining of plastics. Ethylene
oxide and ethylene glycols are used in the sterilization of plastics. Many
plastics are exposed to mold release agents like silicon sprays during
production. 4
The following are some of the sources of possible toxic substances in
medical device materials. Each source is then discussed separately.
Residual monomers
Residual solvents
Degradation products
By-products from irradiation
Sterilization residuals

16

 Formulation additives
Inadvertent contaminants
Bacterial endotoxins
Residual monomers
Polymerization results in a distribution of molecular weights. Although
monomers are usually toxic, the toxicity of the polymeric unit generally
decreases as the molecular weight increases. Residual monomers result
from incomplete polymerization; their concentration can be controlled by
carefully regulating polymerization conditions.
Residual solvents
Solvents are often an integral part of manufacturing and may remain behind
in fluid materials such as adhesives, adhesive removers, barrier pastes, gels,
or lubricants. Some acrylate adhesive systems are now water-based, which
eliminates the concern for residual solvents. When the solvent is an integral
component of the final product, as with adhesive removers and certain
barrier pastes, its presence and potential transdermal absorption must be
addressed in labeling.5
Degradation products
Materials may undergo degradation during manufacture, sterilization, or
storage, or after application to or implantation in the body. During
manufacture, heat may thermally degrade a material; polyvinyl chloride is
especially susceptible to heat and may release hydrochloric acid, resulting in
an

autocatalytic

unzipping

process.

During

sterilization,

polytetrafluorethylene is susceptible to irradiation breakdown, resulting in

the release of hydrofluoric acid. Stored materials exposed to light and
oxygen may suffer ultraviolet degradation or oxidation. Implanted

17

materials, particularly metals, may corrode or be biologically degraded.

Stabilizers added to the polymer can protect against degradation. Materials

should be tested for degradation and biocompatibility only after both
manufacture and a suitable ageing period.
By-products from irradiation
Gamma irradiation is becoming an increasingly common method of
sterilization; 2-3 Mrad is the usual sterilization dose. It is also used to
facilitate cross-linking in certain formulations. As a result, many materials
undergo degradation. Polyglycolic acid, used in suture production, is
virtually destroyed by irradiation. Most medical polymers decrease in
molecular weight as a result of chain scission. Polypropylene and other
polymers may undergo chain scission, cross-linking, and oxidation. Any
material that is irradiation sterilized should be tested for biocompatibility
afterward, although most medical polymers remain useful.
Sterilization residuals
Chemical sterilization with ethylene oxide has a long history of use; the
main advantages are that the procedure is carried out at low temperatures
and the sterilization facility need not deal with radioactive sources. Ethylene
oxide, which is itself toxic, also degrades into toxic ethylene chlorohydrin
and ethylene glycol. Even after extensive degassing, some materials do not
release these toxic molecules. All materials that are to be ethylene oxide
sterilized must be tested for toxic residuals. The principle concerns with the
biocompatibility of polymers are additives, residual monomers, and
contaminants that are leachable in the body. The result of the additives and
contaminants being in plastic is that a range of toxic materials may be
leached from many plastics.

Identified toxic materials in polymers i.e.

18

Aluminium, Acrylonitrile (monomer), Arsenic, Benzene, Benzoic peroxide,

Bisphenol A, Cadmium, Carbon tetrachloride, Dibutyl tin, Epoxy curing
agents, Ethylene dichloride, Ethylene oxide, Formaldehyde, Ketones and
hydrocarbons, Lead, Mercaptobenzothiazole, Methyl chloride, Methylene
chloride, Methylene dianiline, Nickel, PAHs on carbon black, Pyrene,
Tricresyl phosphate, Triphenyl phosphate. 5
1.3 Plastics and their Additives
The finished plastic material is made by the chemical chain called as
monomer and several other chemicals added to give its desired shape, color
and several other properties which are known as additives. There are about
2000 additives utilized in various types of plastic and can be divided in
following common major classes:
Antiblocking agents, Antimicrobial agents, Antioxidants, Antistatic agents,
Coloring agents, Fillers, Impact modifiers, Mold release agents, Plasticizers,
Preservatives, Slip agents, Stabilizers (light and heat) etc.
1.3.1 Antioxidants
Antioxidants are additives that retard or inhibit the oxidative degradation of
the plastic material within the intended processing and usage limits of the
materials. Degradation is initiated by the action of highly reactive free
radicals caused by heat, radiation, mechanical shear, or metallic impurities.
The initiation of free radicals may occur during polymerization, processing,
or fabrication. Once the first step of initiation occurs, propagation follows.
The function of an antioxidant is to prevent the propagation steps of
oxidation. It must be effective at low concentration, non toxic, conveniently
and safely handled, and low in cost. Beside this, it must not impart
19

undesirable characteristics to the system in which it is used. Antioxidants

are classified as primary or secondary antioxidants depending on the
method by which they prevent oxidation. 7
The most widely used antioxidants in plastics are phenolics. Phenolics are
mainly used in polyolefins, styrenics, and engineering resins. Phenolics are
generally stain resistant and include simple phenolics (BHT), various
polyphenolics, and bisphenolics. A phenolic antioxidant may then be used
for long term protection. Primary antioxidants are generally radical
scavengers or H- donors i.e. hindered phenols such as BHT, Irganox1010,
or Irganox 1076, cyanox 2246 and 425 and bisphenol A. Long term
protection

for

the

polymer,

secondary

antioxidants

is

typically

hydroperoxide decomposers i.e. trivalent phosphorus compounds such as

tris-nonylphenyl phosphate

(TNPP)

is

the

most commonly

used

organophosphite followed by tris (2, 4-di-tert-butylphenyl) phosphate

(Irgafos 168). Organophosphite are used in polyolefins, styrenics, and
engineering resins. Phosphite can improve colour and engineering resins
stability, but can be corrosive if hydrolysed. Thioesters act as secondary
antioxidants and also provide high heat stability to a variety of polymers
(polyolefins and styrenics). Secondary antioxidants are typically used in
synergistic combination with primary antioxidants. Lactone stabilizers are a
new class of materials that are reputed to stop the autoxidation process
before it starts.

20

OH
C

BHT

C
O
HO

CH2

CH 2

H2
C

Irgnox 1010
C

P
O

Irgafos 168

21

1.3.2 Plasticizers
According to the ASTM D-883 definition, a plasticizer is a material
incorporated into a plastic to increase its workability, flexibility, or
dispensability. The addition of a plasticizer may lower the melt viscosity,
elastic modulus, and Tg. It should be relatively non volatile, non mobile,
inert, inexpensive, nontoxic, and compatible with the system to be
plasticized. The plasticizers are chemically and thermally stable organic
solvents or low melting solids which when mixed with a polymer modifies
its flow as well as the mechanical and electrical properties. Waldo Semon
patented the use of tricresyl phosphate as a plasticizer for PVC in 1933.
This was later replaced by the less toxic di-2-ethylhexyl phthalate (DEHP),
which is now the most widely used plasticizer. The worldwide production
of plasticizer is approximately 3.2 million tons annually. Volume wise,
about 90% of the plasticizers are used with PVC and PVC containing
systems. Plasticizers can be broadly classified into four types according to
their chemical constitution; phthalates, aliphatic esters, phosphates and
miscellaneous. The USEPA regulates many phthalates and adipates by
methods 606, 506-1, and 8061. There is a balance between compatibility
and migration. Generally, the larger the ester grouping the less the migration
up to a point where compatibility becomes a problem and where
compatibility now becomes the limiting factor. The development of
plasticizers has been plagued with toxicity problems. Thus, the use of highly
toxic polychlorinated biphenyls (PCBs) has been discontinued. Phthalic acid
esters, such as DEHP, may be extracted from blood stored in plasticized
PVC blood bags and tubing. These problems have been solved by using
oligomeric polyester as non migrating plasticizers instead of DEHP, in
22

appropriate situation. Recently, some limited tests have indicated a

relationship of prenatal exposure

to

phthalates

and

reproductive

abnormalities of male babies.

O

OR 1
OR 2

Phthalates
O

CH 3

CH 2CH3

CH3

CH 2 CH 3

DMP

DEP

O
O

DOP

23

CH2 CH 2 CH 2CH 3

CH 2CH2 CH2 CH 3

DBP
DEHP

1.3.3 Stabilizers
Stabilizers are used to prevent the degradation of a material due to high
processing temperatures or to extend their life stability under degrading
environmental conditions. The effectiveness of a stabilizer also depends on
the presence of oxygen i.e. some are effective in its presence while other are
less effective. The effectiveness of a stabilizer is very much dependent upon
the grade of resin (degree of polymerization) in which they are
compounded. Some stabilizers are highly effective in one grade of PVC but
only moderate in another. A judicious choice of stabilizers is therefore very
important in the formulation of plastic. The presence of other additives such
as plasticizers and fillers also sometimes strongly influence the efficiency of
a stabilizer for e.g. Phosphates and chlorinated extenders often reduce the
efficiency of a stabilizer. The major classes of stabilizers are mixed metal
salt blends, organotin compounds, alkyl/aryl organophosphate, epoxy
compounds, polyfunctional alcohols etc.

24

Light Stabilizers
Light stabilizers are used to protect plastics, especially polyolefins,
polystyrenes, from discoloration, embrittlement, and degradation by UV
light. The major classes of light stabilizers are:
UV absorbers excited state quenchers, and free radical terminators.
UV absorbing materials
UV absorbing materials are the substances which give characteristic
absorption peak in UV region. The commonly used UV absorbing materials
are

derivatives

of

benzophenones,

benzotriazoles,

phenyl

esters,

diphenylacrylates, which are added during the synthesis of plastic to protect

them from degradation from sunlight and fluorescent light. 7
Benzophenones UV absorbers have been used for many years in
polyolefins, PVC, and other resins. Some important benzophenones are, 2hydroxy-4-methoxybenzophenone, 2-hydroxy-4-n-octoxybenzophenone, 2,
4- dihydroxy-4-n-dodecycloxybenzophenone. 7

benzophenone

25

OH

OH

OCH 3

OC 8 H17

2-hydroxy-4-methoxybenzophenone

2-hydroxy-4-n-octoxybenzophenone

Benzotriazoles UV absorbers are highly effective in high temperature

resins such as acrylics and polycarbonate. Some important benzotriazole are
2-(2-hydroxy-5-methylphenyl)

benzotriazole,

2,

2-(2-hydroxy-5-tert-

octylphenyl) benzotriazole, 2-(32-tert-butyl-2-hydroxy-5 methylphenyl) -5

chlorobenzotriazole,

2-(32,

52-di-tert-butyl-22

hydroxyphenyl)-52

chlorobenzotriazole etc. 7

N
N
N
HO

CH 3

2-(2-hydroxy-5-methylphenyl) benzotriazole
(Tinuvin PED)

Benzoates and salicylates such as 3, 5-di-t-butyl-4-hydroxy benzoic acid

n- hexadecyl ester function by rearranging to 2-hydroxybenzophenone
analogs when to UV light to perform as UV absorbers.
Phenyl esters like 3, 5-di-t-butyl-4-hydroxybenzoic acid N-hexadecyl ester.

26

Diphenylacrylates like Ethyl-2-cyano-3, 3-diphenyl acrylate, 2-ethylhexyl2-cyano-3, 3-diphenyl acrylate.

Nickel compounds are used as excited state quenchers and hindered amine
light stabilizers (HALS) are used as free radical terminators. 7
1.4 Cytotoxicity
The cell or tissue culture including cytotoxicity methods is a fair predictor
of biocompatibility when used together with other appropriate tests.

8, 9

Several highly specialized cell culture methods are available to monitor the
biocompatibility of the raw materials used in manufacturing the device or
auditing the manufacturing process. Cell or tissue culture testing offers
several advantages, including the following:
It is simple, rather inexpensive, and easy to perform.
It allows testing of a biomaterial on human tissue.
It is sensitive to toxic material. It is easy to manipulate and allow
more than one end-point investigation.
It can be used to construct a dose-response curve.
It can give quick and quantitative results and allows direct access or
direct observation or measurement.
The objective of cell cytotoxicity testing is to screen the biocompatibility of
the polymeric and elastomeric portions of medical devices using
mammalian cell cultures. Cytotoxicity is a useful method for screening
material. It can also serve as a quality control mechanism for batch testing
programs, and is a basic part of all device biocompatibility evaluation. 10-12 It
is one of the oldest assays designed specifically to screen plastics for
toxicity.13 Given the extreme sensitivity of this test, materials found to be
cytotoxic must be assessed along with the results of in vivo and other

27

studies to evaluate the risk to human health. Unlike the other studies utilized
in biocompatibility testing, cytotoxicity is not a pass or fail test. Failure in
cytotoxicity is generally grounds for performing a confirmatory test such as
an implantation or intracutaneous reactivity.14 The great majority of toxic
compounds are chemically stable and produce their characteristic effects by
interference with biochemical or physiological homeostatic mechanisms.
Cytotoxicity assays measure loss of some cellular or intercellular structure
and/or functions, including cell death. They are generally simple to perform,
are reproducible, and have a clearly defined endpoint. A variety of cell lines
have been used, including corneal epithelial cells, lung fibroblasts, Chinese
hamster ovary (CHO) cells, canine renal cells, HeLa (human tumor cell
line) cells, and microorganisms. Most cells in culture are fibroblasts.
Primary cells that are taken directly from an animal often are difficult to
establish in culture and become fibroblasts, losing the normal functions of
growing differentiated cells. Numerous conditions have to be optimized for
obtaining good growth of differentiated cells. Most cultured cells have a
fibroblastic appearance, although they may not be true fibroblasts. For
example, cells grown under non optimum conditions can temporarily take
an appearance of fibroblasts. The fibroblasts in culture can take over
cultures because they grow readily on plastic surfaces. The recent success in
growing differentiated cells was partially due to techniques that have been
developed to remove and limit the growth of fibroblasts to allow other cells
to grow. The possible cytotoxicity end points are15-18 as follows:
Microscopic examination of cell morphology, membrane integrity, and
fragility, Cell population and density, Cell adhesiveness, Cytopathic effect,
Total protein content, Rate of growth, Rate of protein synthesis, Total DNA

28

content, Rate of DNA synthesis, Colony-forming efficiency, Trypan blue

uptake and other dye uptake, Biochemical assays of enzymes.
Much of the initial work on the range of cytotoxicity assays that have been
developed (and their end point measurement methods) was done with the
goal.19-25 Early cell culture methods merely estimated the numbers of living
or dead cells, but now morphological analysis by electron microscopy
reveals a spectrum of microcellular changes, and cell function tests measure
biochemical parameters, indicating the nature of cell stress. Although many
modifications have been made, cell culture tests are of four main types: gel
diffusion, direct contact, extracts dilution, and cell function tests.
As discussed above, several tissue culture methods are available for testing
biomaterials. These are divided into two major groups: one tests the toxicity
of a soluble extract of the material, and the other tests the toxicity by the
direct contact of cells with the material or components of the device.
The text extracts is incorporated into the culture medium, which is usually
double strength minimum essential medium supplemented with serum and
other essential nutrients at the maintenance level. The toxic effect on the
monolayer, such as cell lysis and microscopic observation of cell
morphology changes, is usually checked after 24 and 48 hr. Cell lysis can be
scored by direct microscopic observation or with the use of radiolabels or
tryphan blue dye uptake. The inhibition of cell growth is a more informative
test requiring more time and skill. Distilled water extract is incorporated
into the tissue culture medium and inoculated with the cells in the tissue
culture tubes. After 72 hr, the extent of cell growth is determined by total
protein assay, such as the Lowery photometric method, on the removed cells
from the individual tubes. Most cells in culture are fibroblasts. Primary

29

cells that are taken directly from an animal often are difficult to establish in
culture and become fibroblasts, losing the normal functions of growing
differentiated cells. Numerous conditions have to be optimized for obtaining
good growth of differentiated cells.
1.5 Testing medical disposables using the Limulus Amoebocyte
Lysate (LAL) test
The discovery of the horseshoe crab's most significant biological role in
recent medicine was made by Frederick Bang in the early 1950's. Bang
discovered that the horseshoe crab's blood cells, called amoebocytes,
contain a clotting agent that attaches to dangerous endotoxins produced by
gram negative bacteria. The test was accepted by the United States Food
and Drug Administration (FDA) in 1983 as a standard test for endotoxins.
In 1987, the FDA established guidelines for LAL testing of pharmaceuticals
and medical devices.
During the early days of the pharmaceutical industry it was noticed that
some solutions when injected into the bloodstream induced fevers.
Investigations found that almost all of these fevers were associated with a
group of contaminants termed pyrogens. These were classified as either
exogenous or endogenous pyrogens. Exogenous pyrogens are fever causing
materials found in the environment, of these endotoxins are the most
researched and are lipopolysacchrides (LPS), found in the outer membrane
of the cell wall of Gram -ve microorganisms, they are heat stable and can
cause severe patient reactions when present in parenterals or medical
devices.

Endotoxin toxicity is not dependent upon a living cell, heat

sterilization or other chemical/physical processes are ineffective control

measures as killing the cells actually releases 'free' endotoxin from the cell
30

wall. As all mammals can be affected by endotoxins (although sensitivity

levels vary) one of the first tests used to determine if endotoxins were
present, was the Rabbit Pyrogen Test (RPT). A rabbit was inoculated with
the test substance and then monitored it to see if a fever was induced. This
test however does not give a quantitative result, is time consuming and is
not suitable for products that may in themselves adversely affect the animal.
The most commonly used approach now is a Limulus Amoebocyte Lysate
or LAL test. The LAL test focuses in particluar on 2-keto-3-deoxyoctonoic
acid and it is this which is used as an indicator in the majority of endotoxin
assays. LAL is a reagent derived from the blood cells of the horseshoe crab,
unlike a mammal the crab does not have a developed immune system,
however the LAL component in its blood will bind to and inactivate
endotoxins, in the crab the resulting clot also forms a protective barrier
against bacterial infection. At its simplest the LAL test consists of adding
LAL reagent to the sample in a test tube, incubating at 37C for 1 hour. The
tube is then gently inverted if a gel or clot has formed then a positive result
is recorded.
The Gel-clot is the simplest and most widely used, it is also fully described
by most pharmacopeias. The method can be qualitative or semi-quantitative
when comparing a sample against a dilution series of an endotoxin standard.
Can be used to provide a pass/fail for a certain limit and is best used with
low sample numbers. The method may be performed manually with little or
no requirement for instrumentation. Because the potency of an endotoxin to
cause pyrogenic reaction will vary according to the nature of the toxin, the
FDA developed Endotoxin Units (EU) for result comparisons.

31

1.6 Regulations for Medical Devices and Application to Plastics

Suppliers in India
The Central Drugs Standards Control Organization (CDSCO) under the
Ministry of Health and Family Welfare regulates the licensing, import,
manufacture, and sale of medical devices into the Country. Approval can be
facilitated by evidence of approval from the US FDA, the EU MDD (CECertificate) and approvals from Australia, Canada, Japan, and other
countries. ISO Certification for specific manufacturing practices (ISO
13485) is also accepted. Device master files must contain details of good
manufacturing practices including components and materials used in the
device. It must also include the manufacturing and quality assurance
processes, risk assessment, design verification, sterilization, stability,
biocompatibility, and toxicological data associated with the materials, and
production of the finished device.4
Various fillers and additives can be added to plastics to tailor their
properties for specific applications and performance requirements. Fillers
and additives can provide flexibility, stiffness, hardness, conducting
properties, colors, impact, toughness, thermal properties, moisture
transmission and gas barrier properties, and surface properties. In addition,
various degrees of chemical resistance, radiation resistance, and
biocompatibility can be achieved.

32

References
1. Plastics Europe (2009), Compelling facts about plastics, An analysis
of European plastics production, demand and recovery for 2008.
Brussles: Plastics Europe.
2. Andrady AL, Neal MA., (2009), Applications and societal benefits
of plastics, Phil Trans R Soc B, 364: 1977-1984.
3. Charles E. Carraher, (2010), Introduction to Polymer Chemistry,
Second Edition, CRC Press, Taylor and Francis Group, Boca Raton,
London, pp 464, 465, 471, 472.
4. Vinny R. Sastri, (2010), Plastics in Medical Devices, Properties,
Requirements,

and

Applications,

Elsevier/William

Andrew,

Amsterdam; Boston, pp 1, 3, 4, 7, 18, 26, 27, 28.

5. Shayne Cox Gad, (2002), Safety Evaluation of Medical Devices,
Second Edition, Eastern Hemisphere Distribution, Switzerland, pp 2,
3, 4, 58-59.
6. ISO 14040 (1997), Environmental management- life cycle
assessment- Principles and frame work.
7. Dr. Himadri Panda, Plastic Additives Technology Hand Book,
Engineers India Research Institute, Delhi, pp107, 161, 162, 267-269.

33

8. Wilsnack, R. E. (1976), Quantitative cell culture biocompatibility

testing of medical devices and correlation to animal tests, Biomat.
Med. Dev. Art. Org., 4:235261.
9. Gad, S. C. (2000), In Vitro Toxicology, Second Edition, Taylor and
Francis, Philadelphia.
10. AAMI. (1997), Biological Evaluation of Medical Devices,
Association for the Advancement of Medical Instrumentation,
Arlington, VA, pp. 6982.
11. CDRH. (1992) Regulatory Requirements for Medical Devices, Food
and Drug Administration, Rockville, MD.
12. ISO, (1993), ISO/DIS 10993-5, Biological Testing of Medical and
Dental Materials and DevicesPart 5: Tests for Cytotoxicity: In
Vitro Methods.
13. Rosenbluth, S. A., Weddington, G. R., Guess, W. L., and Autian, J.,
(1965), Tissue culture method for screening toxicity of plastic
materials to be used in medical practice, J. Pharm Sci., 54:156
159.
14. Barile, F. A. (1994), Introduction to in Vitro Cytotoxicity,
Mechanisms and Methods, CBC Press, Boca Raton, FL.

34

15. Caldwell, J. (1993), Biochemical basis of toxicity. In: General and

Applied Toxicology (B. Ballantyne, T. Marrs, and P. Turner, eds.).
Stockton, New York, pp. 169183.
16. Northup, S. J., (1986), Mammalian cell culture models, In:
Handbook of Biomaterials Evaluation (A. F. Von Recum, ed.)
Macmillan, New York, pp. 209225.
17. Northup, S. J., (1987), Cytotoxicity tests of plastics and elastomers,
Pharmacopoeial Forum, 13:29392942.
18. Northup, S. (1992), Cytotoxicity and mutagenicity, In: Guidelines for
Blood Material Interactions (P. Didisheim, L. Harker, and B. Ratner,
eds.), ASTM, Philadelphia.
19. Riddell, R. J., Clothier, R. H., and Balls, M., (1986), An evaluation
of three in vitro cytotoxicity assays, Food Chem. Toxicol.,
24:469477.
20. Rohde, B. H., (1992), In vitro methods in ophthalmic toxicology, In:
Ophthalmic Toxicology (G. C. Y. Chiou, ed.). Raven, New York, pp.
109165.
21. North-Root, H., Yackvien, F. Demetrulias, J., Gacula, M. Jr., and
Heinze, J. E., (1982), Evaluation of an in vitro cell toxicity test

35

using rabbit corneal cells to predict the eye irritation potential of

a surfactant, Toxicol. Lett., 14:207212.
22. Sina, J. F., Ward, G. J., Laszeh, M. A., and Gautheron, P. D., (1992),
Assessment of cytotoxic assays as predicators of ocular irritation
of pharmaceuticals, Fund. Appl.Toxicol., 18:515521.
23. Itagaki, H., Hagino, C., Kato, S., Kobayashi, T., and Umeda, M.,
(1991), An in vitro alternative to the Draize eye irritation test:
Evaluation of the crystal violate staining method, Toxicol. In
Vitro, 5:139143.
24. Scaife, M. C., (1985), An in vitro cytotoxicity test to predict the
oculara irritancy potential of detergent products, Food Chem.
Toxicol., 23:253258.
25. Kemp, R. B., Meredith, R. W. J., and Gamble, S. H., (1985),
Toxicity of commercial products on cells in culture: A possible
screen for the Draize eye irritation test, Food Chem. Toxicol.,
23:267270.

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