BIOCOMPATIBILITY OF PLASTICS - Zeus
SPECIAL EDITIONRESINATEYour quarterly newsletterto keep you informedabout trusted products,smart solutions, andvaluable updates.BIOCOMPATIBILITYOF PLASTICSREVISED AND EDITED BYKEVIN J. BIGHAM, PhD. 2010; 2017
BIOCOMPATIBILITY OF PLASTICS2INTRODUCTIONPlastics have many unique properties regarding their manufacturability and productionpotential. These properties are increasingly being utilized in the production of medicaldevices and medical packaging. The medical device industry is one of the fastestgrowing areas for plastics with growth rates exceeding gross domestic product growthfor several years. This trend is predicted to continue into the future due to developmentsof increasingly innovative medical devices, improvements in plastics technology (bothmaterials and processing), and an aging population. Despite this significant growth,one thing remains constant: The application of any material in a medical device mustmeet stringent safety requirements.BIOCOMPATIBILITYBiocompatibility is a general term used to describe the suitability of a material forexposure to the body or bodily fluids with an acceptable host response.Biocompatibility is dependent on the specific application and circumstance of thematerial in question: A material may be biocompatible in one particular usage but maynot be in another. In general, a material may be considered biocompatible if it causesno harm to the host. This is distinct, however, from causing no side effects or otherconsequences. Frequently, material that is considered biocompatible once implanted inthe body will result in varying degrees of inflammatory and immune responses. For abiocompatible material, these responses are not harmful and are part of body’s normalresponses.Materials that are not biocompatible are those that do result in adverse (harmful) effectsto the host. Non-biocompatible materials can disrupt normal healing processes and canhave protracted and broad consequences. Indications that a material is notbiocompatible include: Chronic inflammation at the area of contactProduction of cytotoxic substancesCell disruptionSkin irritationRestenosis (narrowing of blood vessels after stenting)Formation of blood clots (thrombosis)Corrosion of implanted materialThus, biocompatibility is a fundamental hurdle that any potential implantable deviceor component must overcome.Revised and edited by Kevin J. Bigham, PhD. 2010 and 2017 Zeus Industrial Products, Inc.2
BIOCOMPATIBILITY OF PLASTICS3TESTING AND ASSESSMENTTesting and evaluation for biocompatibility vary widely based on the intendedapplication of the device or component. One set of tests for a particular material maynot be required for the material in a different application. Testing regimes are broad inscope and encompass in vivo and in vitro evaluations. Biocompatibility test protocolsinclude those for cytotoxicity, hemocompatibility, genotoxicity, irritation,implantation, sensitization, and system toxicity. Additionally, biocompatibilityprotocols must account for potential misuse of the device or component.ISO 10993: BIOLOGICAL EVALUATION OF MEDICAL DEVICESThe International Organization for Standardization (ISO) presents widely adoptedmedical device guidelines that are aimed with a keen focus towards risk management.Biocompatibility testing for these devices and device components is addressed by ISOstandard 10993. (There are other country-specific guidelines that largely overlap withISO 10993, however, but those programs shall not be discussed here). This set ofdocuments entitled, Biological evaluation of medical devices, is issued currently intwenty parts and is regularly revised to reflect new findings (Table 1). Earlyconsideration in biocompatibility testing is given to material characterization. If thematerial in question has a proven acceptably safe history of medical use, very often thisphase of evaluation can be omitted. For new materials or new applications forpreviously used materials, ISO 10993 provides guidance on methodology andappropriate test program.Revised and edited by Kevin J. Bigham, PhD. 2010 and 2017 Zeus Industrial Products, Inc.3
BIOCOMPATIBILITY OF PLASTICS4Table 1: Structure and parts of ISO 10993:Biological evaluation of medical devicesPartTitle1Evaluation and testing2Animal welfare requirements3Tests for genotoxicity, carcinogeniticity and reproductive toxicity4Selection of tests for interaction with blood5Tests for cytotoxicity - in vitro methods6Tests for local effects after implantation7Ethylene oxide sterilization residuals8Clinical investigation of medical devices9Degradation of materials related to biological testing10Test for irritation and sensitization11Test for systemic toxicity12Sample preparation and reference materials13Identification and qualification of degradation products from polymers14Identification and qualification of degradation products from ceramics1516Identification and qualification of degradation products from coated and uncoated metals andalloysToxicokinetic study design for degradation products17Glutaraldehyde and formaldehyde residues in industrially sterilized medical devices18Chemical characterization of materials19Physico-chemical, morphological and topographical characterization of materials20Principles and methods for immunotoxicology testing of medical devicesThe selected test program depends on several factors based on the device categorydetermined by ISO 10993. The material used, contact regime, and time duration ofcontact with the device help determine the test program (Table 2). Contact time isbroken into three periods: short duration ( 24 hours), prolonged contact (24 hours to30 days), and permanent contact ( 30 days). Contact regime describes how the devicewill come in contact with the body such as via blood, skin, bone, etc. These elementshelp provide a foundation for biological evaluation of medical devices. ISO 10993 isnot a formal checklist but a guide to the typical information requirements for approvalauthorities. ISO 10993 is intended to assist manufacturers and engineers in designingan appropriate testing program for their device. Testing details are thus specific to eachdevice and its application though there may be testing commonalities for multipledevice types.Revised and edited by Kevin J. Bigham, PhD. 2010 and 2017 Zeus Industrial Products, Inc.4
BIOCOMPATIBILITY OF PLASTICS5Table 2: Device categories and biological evaluation ofmedical devices for ISO (from ISO 10993: Part 1).DevicecategoryContact regimeSkinContact TimescaleExample productsLimitedElectrodes, external prostheses, fixation tapes,compression bandages, monitors of sMucous membraneProlongedPermanentBreached orcompromised surfacesLimitedProlongedPermanentLimitedBlood path indirectProlongedContact lenses, urinary catheters, intravaginaland intraintestinal devices (stomach tubes,sigmoidoscopes, colonoscopes, gastroscopes),endotracheal tubes, bronchoscopes, dentalprostheses, orthodontic devices, IUDsUlcer, burn and granulation tissue dressings orhealing devices, occlusive patchesSolution administration sets, extension sets,transfer sets, blood administration setsPermanentExternallycommunicatingdevicesTissue / bone / dCirculating bloodProlongedPermanentLimitedTissue / bone tedTime SpanKey:Limited: 24 hoursRevised and edited by Kevin J. Bigham, PhD.Intravascular catheters, temporary enator tubing and accessories, nts and immunoadsorbentsOrthopedic pins, plates, replacement joints,bone prostheses, cements and intraosseousdevices, pacemakers, drug supply devices,neuromuscular sensors and simulators,replacement tendons, breast implants,artificial larynxes, subperiosteal implants,ligation clipsPermanentPacemaker electrodes, artificial arteriovenousfistulae, heart valves, vascular grafts, internaldrug delivery catheters, ventricular assistdevicesProlonged: 24 hrs - 30 dPermanent: 30 daysProlongedBloodLaparoscopes, arthroscopes, draining systems,dental cements, dental filling materials, skinstaples 2010 and 2017 Zeus Industrial Products, Inc.5
BIOCOMPATIBILITY OF PLASTICS6OTHER REGULATIONSIn conjunction with ISO 10993, in the United States the Food and Drug Administration(FDA) regulates medical devices. FDA guidelines largely agree with ISO 10993regulations. (ISO test results are generally acceptable for applications in the UnitedStates). European Union device manufacturers under the authority of the EuropeanCommission are governed by Regulations (EU) 2017/745-6 for general medicaldevices and in vitro diagnostic medical devices. Collectively, these organizationsaddress nearly all conceivable medical device testing concerns. Readers areencouraged to refer to individual parts of ISO 10993, the FDA, or EU Medical DeviceDirectives for further information on specific testing.UNITED STATES PHARMACOPOEIA (USP)In some areas, the USP has been superseded by ISO 10993 for medical deviceevaluation. Some manufacturers, however, continue to use USP standards. One suchexample is USP 88 Biological Reactivity Tests for in vivo testing. This protocol is usedto rate and categorize plastics into Classes I to VI. These tests measure the biologicalresponse of animals to plastics by direct or indirect contact and by injection of extractsfrom the material. The tests include systemic injection (intravenous andintraperitoneal), intracutaneous, and implantation. These tests are directly related to theintended 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 ofthree 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 (includingpolyethylene glycol, ethanol, saline, or cottonseed oil) are also part of USP 88 testingto facilitate extraction. These screening tests characterize the biocompatibility ofplastics 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
7BIOCOMPATIBILITY OF PLASTICSMATERIAL CHARACTERIZATIONicaermThanchalMeWell-defined material characterization is aChemicalfundamental requirement in biocompatibilityassessment. This evaluation consists zation elements (Fig. 1). MaterialCharacterizationcharacterization is of particular importancefor plastics because nominally similar gradesof plastics can vary significantly in theirmaterial and chemical attributes. Plasticizers,stabilizers, and fillers added to plasticsduring manufacturing can affect their Figure 1: Elements of materialbiocompatibility. Leaching studies must be characterization: mechanical, thermal, andperformed on plastics with additives such as chemical.these to ensure that leachates from the plastics are non-toxic. The amount and type ofadditive will also affect the biocompatibility of the final plastic product.lCHEMICAL TESTINGChemical testing for material characterization uses a variety of techniques to revealimportant chemical facets of the material. These tests may include, but are notlimited to, infrared (IR) analysis, extraction analysis, chromatography, and tracemetal analysis. IR provides detailed qualitative and semi-qualitative information onthe types of material(s) present. Extraction analysis gives information of potentialleachates. Gas or liquid chromatography characterizes additives, residual polymermonomers, and degradation products that remain from manufacturing. Lastly, tracemetal analysis can be used to reveal the presence of lead, tin, barium, bismuth, orother metals which may have been added during processing of the plastics. Thesetests inform potential users of how devices and products will behave within thebody chemically and how that behavior may affect patients.MECHANICAL TESTINGImplantable devices have mechanical performance requirements dictated by theirintended function (application). The performance of the device is limited, however, bythe physical properties of the device materials and components. Mechanical testing istherefore necessary to determine properties such as elasticity, toughness, tensilestrength, stress-strain curves, and many others for the finished device. Mechanicalfailure indeed is every much a concern as biocompatibility failure for medical devices.While not a direct determinant of biocompatibility, mechanical evaluation allowsRevised and edited by Kevin J. Bigham, PhD. 2010 and 2017 Zeus Industrial Products, Inc.7
BIOCOMPATIBILITY OF PLASTICS8design engineers and manufacturers to choose a plastic which will perform best for theintended use.THERMAL TESTINGThermal testing is performed to assess a plastic’s response to heating. Techniques suchas differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) aretwo common test methods used for biocompatibility thermal testing. TGA measuresthe test material’s change in weight as it is heated. DSC compares the temperatures ofa reference material and an unknown (test) sample as they are heated. Tests such asthese (and others) can be used to gather critical information about the plastic beinginvestigated such as purity, phase structure, thermal history, melting point (Tm), andglass transition temperature (Tg). These tests help manufacturers and engineersevaluate a plastic (or other material) specifically and its viability as a medical deviceor component.STERILIZATIONAnother especially important consideration for biocompatibility and materialcharacterization is the effect of sterilization procedures on the device. Medical devicesand components necessarily will be in contact with the body, thus sterilization will berequired. Single use products, for example, need only be able to endure a singlesterilization event. On the other hand, some products will be used multiple times andmust be able to withstand repeated sterilization cycles. Multi-use products may alsorequire exposure to more than one type of sterilization protocol or procedure during itsusage lifetime. Biocompatible materials and products must survive sterilization withoutloss 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 PLASTICS9BIOCOMPATIBLE PLASTICSPure plastics are relatively chemically unreactive. Thus, they are very amenable to usesthat require contact with the body. However, compounds and variants of the naïveversion of these plastics may not be compatible as a biomaterial. Similarly, not allplastics may be suitable for certain demanding biomedical applications. Some plastics,such as PTFE and PEEK, have especially good chemical resistance and have becomemedical industry favorites. Other plastics have broad spectrum beneficialbiocompatible properties that make them useful for a variety of less critical applications(Table 3). Complementing traditional plastics, new plastic products are continually indevelopment, and many are beginning to substitute for established ones.Table 3: Selected plastics and their common biomedical applications.Plastic familyTypical applicationsPolycarbonate(PC)Dialysis filter cartridges, highly transparent glass containers, tubing andintravenous (IV) connectors, component for blood oxygenators, trocarsPolyetheretherketone(PEEK)Prostheses, dental products, rigid tubing, replacements for metal implantsPolyethersulfone(PES)Membranes: hemodialysis, gas separation, others; tubing, catheters,implantable drug infusion devicePolyethylene(PE, of various types)Implantable products, sutures, surgical cables, orthopedic, and artificialtendons, catheter inner liningPolypropylene(PP)Suture material, meshes, laboratory containers and tubes, drug deliverysystemsPolysulfone(PS)Implantable ports, dialyzers, surgical instruments, device housingsPolytetrafluoroethylene(PTFE)Vascular grafts, suture material, catheter base liners, prosthesesPolyurethane(PU)Artificial hearts, wound dressings, catheter tubing, surgical drainsPolyvinylchloride(PVC)Blood bags, feeding tubes, catheters / cannulae, inflatable splintsPolyetherimide(PEI)Machinable parts for reusable medical devices, IV sets, medical and dentalinstruments, pharmaceutical containersFLUOROPOLYMERS AND BIOCOMPATIBILITYFluoropolymers have among the best biocompatibility of all plastics. As such, they arehave become thoroughly embedded in the medical sector with a multitude ofapplications and products. These generally alkene-based plastics have many keyproperties beneficial towards biomedical applications such as: lubricity, ability to besterilized, little to no chemical reactivity within the body, broad temperature tolerance,and above all – biocompatibility. Class VI USP approved fluoropolymers includeRevised and edited by Kevin J. Bigham, PhD. 2010 and 2017 Zeus Industrial Products, Inc.9
BIOCOMPATIBILITY OF PLASTICS10ETFE, 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 whenchoosing a plastic as a component or device that will be used within the body.SUMMARYBiocompatibility is a broad expression describing a material’s fitness for use within thebody. 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 byISO 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, forexample, fall under USP Class VI.For material evaluation specifically, testing includes chemical, mechanical, andthermal analyses. An additional and crucial step in biocompatibility assessment is theeffect of sterilization on the material. Many plastic device components must toleraterepeated sterilizations. As a group, fluoropolymers have many attractive qualities forbiocompatibility including near-inertness for chemical reactivity in the body, highlubricity, and broad temperature tolerance. Despite these properties and the multiplebanks of testing necessary to attest to biocompatibility, absolute conclusive judgmentregarding safety is not realistic. Biocompatibility instead is characterization based oncurrent knowledge and the best judgment of accepted experts.Revised and edited by Kevin J. Bigham, PhD. 2010 and 2017 Zeus Industrial Products, Inc.10
BIOCOMPATIBILITY OF PLASTICS11ABOUT ZEUSZeus is the world’s leader polymer extrusion technologies. For over 50 years, Zeus hasbeen serving the medical, aerospace, energy exploration, automotive, and fiber opticsindustries. Headquartered in Orangeburg, South Carolina, Zeus employsapproximately 1,250 people worldwide and operates multiple facilities in NorthAmerica and internationally. You can find us at www.zeusinc.com.CONTACT USMore information regarding the information discussed here is available by contactinga Zeus technical account manager. They can be reached in the US toll-free at1-800-526-3842 or internationally at 1-803-268-9500. You can also email us ateditor@zeusinc.com.Zeus Industrial Products, Inc.3737 Industrial Blvd.Orangeburg, SC 29118USAZeus Ireland - Tel 353-(0)74-9109700Zeus China - 电话 (86)20-38791260RESINATE SPECIAL EDITIONSAs part of our efforts to provide you with relevant, useful, and timely information, weregularly
failure indeed is every much a concern as biocompatibility failure for medical devices. While not a direct determinant of biocompatibility, mechanical evaluation allows Chemical M e c h a n i c a l T h e m a l Material Characterization Figure 1:Elements of material characterization: mechanical, thermal, and chemical.
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