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BIOCOMPATIBILITY
OF PLASTICS

REVISED AND EDITED BY

KEVIN J. BIGHAM, PhD.

© 2010; © 2017
 BIOCOMPATIBILITY OF PLASTICS 2

INTRODUCTION

Plastics have many unique properties regarding their manufacturability and production
potential. These properties are increasingly being utilized in the production of medical
devices and medical packaging. The medical device industry is one of the fastest
growing areas for plastics with growth rates exceeding gross domestic product growth
for several years. This trend is predicted to continue into the future due to developments
of increasingly innovative medical devices, improvements in plastics technology (both
materials and processing), and an aging population. Despite this significant growth,
one thing remains constant: The application of any material in a medical device must
meet stringent safety requirements.

BIOCOMPATIBILITY

Biocompatibility is a general term used to describe the suitability of a material for

exposure to the body or bodily fluids with an acceptable host response.
Biocompatibility is dependent on the specific application and circumstance of the
material in question: A material may be biocompatible in one particular usage but may
not be in another. In general, a material may be considered biocompatible if it causes
no harm to the host. This is distinct, however, from causing no side effects or other
consequences. Frequently, material that is considered biocompatible once implanted in
the body will result in varying degrees of inflammatory and immune responses. For a
biocompatible material, these responses are not harmful and are part of body’s normal
responses.

Materials that are not biocompatible are those that do result in adverse (harmful) effects
to the host. Non-biocompatible materials can disrupt normal healing processes and can
have protracted and broad consequences. Indications that a material is not
biocompatible include:

• Chronic inflammation at the area of contact

• Production of cytotoxic substances
• Cell disruption
• Skin irritation
• Restenosis (narrowing of blood vessels after stenting)
• Formation of blood clots (thrombosis)
• Corrosion of implanted material

Thus, biocompatibility is a fundamental hurdle that any potential implantable device

or component must overcome.

Revised and edited by Kevin J. Bigham, PhD. ©2010 and ©2017 Zeus Industrial Products, Inc. 2
 BIOCOMPATIBILITY OF PLASTICS 3

TESTING AND ASSESSMENT

Testing and evaluation for biocompatibility vary widely based on the intended
application of the device or component. One set of tests for a particular material may
not be required for the material in a different application. Testing regimes are broad in
scope and encompass in vivo and in vitro evaluations. Biocompatibility test protocols
include those for cytotoxicity, hemocompatibility, genotoxicity, irritation,
implantation, sensitization, and system toxicity. Additionally, biocompatibility
protocols must account for potential misuse of the device or component.

ISO 10993: BIOLOGICAL EVALUATION OF MEDICAL DEVICES

The International Organization for Standardization (ISO) presents widely adopted

medical device guidelines that are aimed with a keen focus towards risk management.
Biocompatibility testing for these devices and device components is addressed by ISO
standard 10993. (There are other country-specific guidelines that largely overlap with
ISO 10993, however, but those programs shall not be discussed here). This set of
documents entitled, Biological evaluation of medical devices, is issued currently in
twenty parts and is regularly revised to reflect new findings (Table 1). Early
consideration in biocompatibility testing is given to material characterization. If the
material in question has a proven acceptably safe history of medical use, very often this
phase of evaluation can be omitted. For new materials or new applications for
previously used materials, ISO 10993 provides guidance on methodology and
appropriate test program.

Revised and edited by Kevin J. Bigham, PhD. ©2010 and ©2017 Zeus Industrial Products, Inc. 3
 BIOCOMPATIBILITY OF PLASTICS 4

Table 1: Structure and parts of ISO 10993:

Biological evaluation of medical devices

Part Title
1 Evaluation and testing
2 Animal welfare requirements
3 Tests for genotoxicity, carcinogeniticity and reproductive toxicity
4 Selection of tests for interaction with blood
5 Tests for cytotoxicity - in vitro methods
6 Tests for local effects after implantation
7 Ethylene oxide sterilization residuals
8 Clinical investigation of medical devices
9 Degradation of materials related to biological testing
10 Test for irritation and sensitization
11 Test for systemic toxicity
12 Sample preparation and reference materials
13 Identification and qualification of degradation products from polymers
14 Identification and qualification of degradation products from ceramics

15 Identification and qualification of degradation products from coated and uncoated metals and
alloys
16 Toxicokinetic study design for degradation products
17 Glutaraldehyde and formaldehyde residues in industrially sterilized medical devices
18 Chemical characterization of materials
19 Physico-chemical, morphological and topographical characterization of materials
20 Principles and methods for immunotoxicology testing of medical devices

The selected test program depends on several factors based on the device category
determined by ISO 10993. The material used, contact regime, and time duration of
contact with the device help determine the test program (Table 2). Contact time is
broken into three periods: short duration (< 24 hours), prolonged contact (24 hours to
30 days), and permanent contact (> 30 days). Contact regime describes how the device
will come in contact with the body such as via blood, skin, bone, etc. These elements
help provide a foundation for biological evaluation of medical devices. ISO 10993 is
not a formal checklist but a guide to the typical information requirements for approval
authorities. ISO 10993 is intended to assist manufacturers and engineers in designing
an appropriate testing program for their device. Testing details are thus specific to each
device and its application though there may be testing commonalities for multiple
device types.

Revised and edited by Kevin J. Bigham, PhD. ©2010 and ©2017 Zeus Industrial Products, Inc. 4
 BIOCOMPATIBILITY OF PLASTICS 5

Table 2: Device categories and biological evaluation of

medical devices for ISO (from ISO 10993: Part 1).
Device
Contact regime Contact Timescale Example products
category
Limited Electrodes, external prostheses, fixation tapes,
Skin Prolonged compression bandages, monitors of various
Permanent types

Limited Contact lenses, urinary catheters, intravaginal

and intraintestinal devices (stomach tubes,
Surface
Mucous membrane Prolonged sigmoidoscopes, colonoscopes, gastroscopes),
devices
endotracheal tubes, bronchoscopes, dental
Permanent prostheses, orthodontic devices, IUDs
Limited
Breached or Ulcer, burn and granulation tissue dressings or
Prolonged
compromised surfaces healing devices, occlusive patches
Permanent
Limited
Solution administration sets, extension sets,
Blood path indirect Prolonged transfer sets, blood administration sets
Permanent
Limited Laparoscopes, arthroscopes, draining systems,
Externally Tissue / bone / dentin
Prolonged dental cements, dental filling materials, skin
communi- communicating
Permanent staples
cating
devices
Limited Intravascular catheters, temporary pacemaker
electrodes, oxygenators, extracorporeal
Circulating blood oxygenator tubing and accessories, dialyzers,
Prolonged dialysis tubing and accessories,
hemoadsorbents and immunoadsorbents
Permanent

Limited Orthopedic pins, plates, replacement joints,

bone prostheses, cements and intraosseous
devices, pacemakers, drug supply devices,
Tissue / bone implant
Prolonged neuromuscular sensors and simulators,
devices
replacement tendons, breast implants,
Implant artificial larynxes, subperiosteal implants,
devices Permanent ligation clips
Limited Pacemaker electrodes, artificial arteriovenous
Prolonged fistulae, heart valves, vascular grafts, internal
Blood
drug delivery catheters, ventricular assist
Permanent devices
Time Span
Limited: < 24 hours Prolonged: 24 hrs - 30 d Permanent: > 30 days
Key:

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 BIOCOMPATIBILITY OF PLASTICS 6

OTHER REGULATIONS

In conjunction with ISO 10993, in the United States the Food and Drug Administration
(FDA) regulates medical devices. FDA guidelines largely agree with ISO 10993
regulations. (ISO test results are generally acceptable for applications in the United
States). European Union device manufacturers under the authority of the European
Commission are governed by Regulations (EU) 2017/745-6 for general medical
devices and in vitro diagnostic medical devices. Collectively, these organizations
address nearly all conceivable medical device testing concerns. Readers are
encouraged to refer to individual parts of ISO 10993, the FDA, or EU Medical Device
Directives for further information on specific testing.

UNITED STATES PHARMACOPOEIA (USP)

In some areas, the USP has been superseded by ISO 10993 for medical device
evaluation. Some manufacturers, however, continue to use USP standards. One such
example is USP 88 Biological Reactivity Tests for in vivo testing. This protocol is used
to rate and categorize plastics into Classes I to VI. These tests measure the biological
response of animals to plastics by direct or indirect contact and by injection of extracts
from the material. The tests include systemic injection (intravenous and
intraperitoneal), intracutaneous, and implantation. These tests are directly related to the
intended use of the plastic component.

USP 88 also specifies routes of administration of the device or extract being tested.
The systemic injection test and the intracutaneous test use extracts prepared at one of
three standard temperature and time regimes: 50 °C (122 °F) for 72 hours, 70 °C
(158 °F) for 24 hours, or 121 °C (250 °F) for 1 hour. Different media (including
polyethylene glycol, ethanol, saline, or cottonseed oil) are also part of USP 88 testing
to facilitate extraction. These screening tests characterize the biocompatibility of
plastics and define them as USP Class I to VI.

Revised and edited by Kevin J. Bigham, PhD. ©2010 and ©2017 Zeus Industrial Products, Inc. 6
 BIOCOMPATIBILITY OF PLASTICS 7

MATERIAL CHARACTERIZATION

Well-defined material characterization is a

Chemical
fundamental requirement in biocompatibility
assessment. This evaluation consists of
chemical, mechanical, and thermal
Material
characterization elements (Fig. 1). Material Characterization
characterization is of particular importance
for plastics because nominally similar grades

Me

al
ch

erm
of plastics can vary significantly in their

an

Th
ica
material and chemical attributes. Plasticizers,

l
stabilizers, and fillers added to plastics
during manufacturing can affect their Figure 1: Elements of material
biocompatibility. Leaching studies must be characterization: mechanical, thermal, and
performed on plastics with additives such as chemical.
these to ensure that leachates from the plastics are non-toxic. The amount and type of
additive will also affect the biocompatibility of the final plastic product.

CHEMICAL TESTING

Chemical testing for material characterization uses a variety of techniques to reveal

important chemical facets of the material. These tests may include, but are not
limited to, infrared (IR) analysis, extraction analysis, chromatography, and trace
metal analysis. IR provides detailed qualitative and semi-qualitative information on
the types of material(s) present. Extraction analysis gives information of potential
leachates. Gas or liquid chromatography characterizes additives, residual polymer
monomers, and degradation products that remain from manufacturing. Lastly, trace
metal analysis can be used to reveal the presence of lead, tin, barium, bismuth, or
other metals which may have been added during processing of the plastics. These
tests inform potential users of how devices and products will behave within the
body chemically and how that behavior may affect patients.

MECHANICAL TESTING

Implantable devices have mechanical performance requirements dictated by their

intended function (application). The performance of the device is limited, however, by
the physical properties of the device materials and components. Mechanical testing is
therefore necessary to determine properties such as elasticity, toughness, tensile
strength, stress-strain curves, and many others for the finished device. Mechanical
failure indeed is every much a concern as biocompatibility failure for medical devices.
While not a direct determinant of biocompatibility, mechanical evaluation allows

Revised and edited by Kevin J. Bigham, PhD. ©2010 and ©2017 Zeus Industrial Products, Inc. 7
 BIOCOMPATIBILITY OF PLASTICS 8

design engineers and manufacturers to choose a plastic which will perform best for the
intended use.

THERMAL TESTING

Thermal testing is performed to assess a plastic’s response to heating. Techniques such

as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are
two common test methods used for biocompatibility thermal testing. TGA measures
the test material’s change in weight as it is heated. DSC compares the temperatures of
a reference material and an unknown (test) sample as they are heated. Tests such as
these (and others) can be used to gather critical information about the plastic being
investigated such as purity, phase structure, thermal history, melting point (Tm), and
glass transition temperature (Tg). These tests help manufacturers and engineers
evaluate a plastic (or other material) specifically and its viability as a medical device
or component.

STERILIZATION

Another especially important consideration for biocompatibility and material

characterization is the effect of sterilization procedures on the device. Medical devices
and components necessarily will be in contact with the body, thus sterilization will be
required. Single use products, for example, need only be able to endure a single
sterilization event. On the other hand, some products will be used multiple times and
must be able to withstand repeated sterilization cycles. Multi-use products may also
require exposure to more than one type of sterilization protocol or procedure during its
usage lifetime. Biocompatible materials and products must survive sterilization without
loss of critical properties and without significant deleterious effects. Sterilization, thus,
should be considered at the earliest stages of material characterization.

Revised and edited by Kevin J. Bigham, PhD. ©2010 and ©2017 Zeus Industrial Products, Inc. 8
 BIOCOMPATIBILITY OF PLASTICS 9

BIOCOMPATIBLE PLASTICS

Pure plastics are relatively chemically unreactive. Thus, they are very amenable to uses
that require contact with the body. However, compounds and variants of the naïve
version of these plastics may not be compatible as a biomaterial. Similarly, not all
plastics may be suitable for certain demanding biomedical applications. Some plastics,
such as PTFE and PEEK, have especially good chemical resistance and have become
medical industry favorites. Other plastics have broad spectrum beneficial
biocompatible properties that make them useful for a variety of less critical applications
(Table 3). Complementing traditional plastics, new plastic products are continually in
development, and many are beginning to substitute for established ones.

Table 3: Selected plastics and their common biomedical applications.

Plastic family Typical applications

Polycarbonate Dialysis filter cartridges, highly transparent glass containers, tubing and
(PC) intravenous (IV) connectors, component for blood oxygenators, trocars
Polyetheretherketone
Prostheses, dental products, rigid tubing, replacements for metal implants
(PEEK)
Polyethersulfone Membranes: hemodialysis, gas separation, others; tubing, catheters,
(PES) implantable drug infusion device
Polyethylene Implantable products, sutures, surgical cables, orthopedic, and artificial
(PE, of various types) tendons, catheter inner lining
Polypropylene Suture material, meshes, laboratory containers and tubes, drug delivery
(PP) systems
Polysulfone
Implantable ports, dialyzers, surgical instruments, device housings
(PS)
Polytetrafluoroethylene
Vascular grafts, suture material, catheter base liners, prostheses
(PTFE)
Polyurethane
Artificial hearts, wound dressings, catheter tubing, surgical drains
(PU)
Polyvinylchloride
Blood bags, feeding tubes, catheters / cannulae, inflatable splints
(PVC)
Polyetherimide Machinable parts for reusable medical devices, IV sets, medical and dental
(PEI) instruments, pharmaceutical containers

FLUOROPOLYMERS AND BIOCOMPATIBILITY

Fluoropolymers have among the best biocompatibility of all plastics. As such, they are
have become thoroughly embedded in the medical sector with a multitude of
applications and products. These generally alkene-based plastics have many key
properties beneficial towards biomedical applications such as: lubricity, ability to be
sterilized, little to no chemical reactivity within the body, broad temperature tolerance,
and above all – biocompatibility. Class VI USP approved fluoropolymers include

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 BIOCOMPATIBILITY OF PLASTICS 10

ETFE, FEP, PFA, PTFE, and PVDF, to name but a few representatives from this group.
Because of these attributes, fluoropolymers often represent a good starting point when
choosing a plastic as a component or device that will be used within the body.

SUMMARY

Biocompatibility is a broad expression describing a material’s fitness for use within the
body. Implantable devices nearly always cause inflammatory or immune responses.
For a biocompatible material, these responses do not rise to the level of being harmful.
Testing for biocompatibility of materials is mainly centered on guidelines put forth by
ISO 10993, the FDA (United States), Regulations (EU) 2017/745-6 (European Union),
and the USP. The USP classification system for plastics groups them into Classes I –
VI defined by compliance testing and approval criteria. Fluoropolymer plastics, for
example, fall under USP Class VI.

For material evaluation specifically, testing includes chemical, mechanical, and

thermal analyses. An additional and crucial step in biocompatibility assessment is the
effect of sterilization on the material. Many plastic device components must tolerate
repeated sterilizations. As a group, fluoropolymers have many attractive qualities for
biocompatibility including near-inertness for chemical reactivity in the body, high
lubricity, and broad temperature tolerance. Despite these properties and the multiple
banks of testing necessary to attest to biocompatibility, absolute conclusive judgment
regarding safety is not realistic. Biocompatibility instead is characterization based on
current knowledge and the best judgment of accepted experts.

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 BIOCOMPATIBILITY OF PLASTICS 11

ABOUT ZEUS

Zeus is the world’s leader polymer extrusion technologies. For over 50 years, Zeus has
been serving the medical, aerospace, energy exploration, automotive, and fiber optics
industries. Headquartered in Orangeburg, South Carolina, Zeus employs
approximately 1,250 people worldwide and operates multiple facilities in North
America and internationally. You can find us at www.zeusinc.com.

CONTACT US

More information regarding the information discussed here is available by contacting

a Zeus technical account manager. They can be reached in the US toll-free at
1-800-526-3842 or internationally at +1-803-268-9500. You can also email us at
[email protected].

Zeus Industrial Products, Inc.

3737 Industrial Blvd.
Orangeburg, SC 29118
USA

Zeus Ireland - Tel +353-(0)74-9109700

Zeus China - 电话 +(86)20-38791260

RESINATE SPECIAL EDITIONS

As part of our efforts to provide you with relevant, useful, and timely information, we
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includes previous publications which we have retained in our library. RESINATE
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Revised and edited by Kevin J. Bigham, PhD. ©2010 and ©2017 Zeus Industrial Products, Inc. 11