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\at\Medical Polymers \bla\Jennifer Hoffman, Ph.D., Tao Xu, Ph.D., Suresh Donthu, Ph.D. P.E. Exponent, Inc. Polymers offer a wide range of choices for medical applications because of their versatility in properties and processing. Polymers offer significant advantages over metals, including resistance to degradation in contact with physiological fluids, manufacturability/ ease of forming complex shapes and different form factors, the ability to tailor mechanical and physical properties to mimic tissue, and the ability to incorporate drugs for controlled drug delivery. Non-polymeric materials such as metals and glass preceded polymers for use in medical-device applications. However, throughout recorded human history and in various civilizations, there exist numerous references to the use of natural polymers for biological applications, including gutta percha, natural latex, etc. The turn of the 20th century witnessed the birth of the field of synthetic plastics and their use in medical applications, including contact lenses, ocular implants, dental implants, artificial kidneys, and heart valves. The early stages of synthetic plastics for medical applications were dominated by surgeon-visionary- entrepreneurs (sometimes called “surgeon heroes”) who were eager to experiment with these materials with the hope of providing even an incremental relief to their patients. Without even the rudimentary understanding of contemporary biomaterial toxicology, several of these early experiments with synthetic plastics for medical applications led to failures and such failures hindered the development of polymeric biomaterials. However, the rapid developments made in science and engineering of plastics in the second half of the 20th century paved the way for their acceptance in medical applications. Currently, there are many types and grades of polymers that have a history of successful use in medical applications. Over the last 80 years, polymers have been used in numerous types of implantable and 1 peripheral devices for variety of medical applications such as those addressing neurological, cardiovascular, ophthalmic, and reconstructive pathologies. They have also been found useful in temporary therapies such as hemodialysis, coronary angioplasty, blood oxygenation, electrosurgery, and wound treatment. The choices associated with polymer selection offer an opportunity as well as pose a challenge for researchers and developers in this field. A thorough understanding of the fundamentals of polymer composition-structure-property relationships together with an appreciation for the nuances specific to medical device product development form an important foundation for success as a developer and researcher in this field. The following sections provide a general overview of polymeric materials and the characteristics that make them a unique class of materials, common medical plastics, regulatory aspects of material selection, and current and future trends in medical polymers. \a\Composition, Structure, and Properties of Polymers Medical plastics are principally composed of a base resin and additives to create a useful portfolio of properties. The resin may be one or more polymers, while the additives include processing aids, antioxidants, fillers, reinforcing fibers, pigments, plasticizers, and impact modifiers that are blended with the base polymer to prolong the life of the material and improve its physical, chemical, and aesthetic properties. The properties of common synthetic medical polymers vary widely, and are governed by their chemical composition, molecular weight, molecular architecture, and morphology. More detailed information on polymer chemistry, processing, and properties can be found in the References section at the conclusion of this chapter. 2 \b\Chemical Composition of the Polymer Backbone Polymers are comprised of long chain-like molecules with repeat units of atoms known as monomers (polymer = many mers). The atoms within a molecule are held together by strong covalent bonds. The most common atoms in organic polymers are carbon, hydrogen, oxygen, and nitrogen, while silicones, based on silicon and oxygen atoms, are an important family of inorganic polymers. Functional groups attached to the backbone also determine critical characteristics of the polymer. The chemical composition of a given polymer describes the arrangement (configuration) of atoms along the backbone. Polymers that have a single repeat unit or a monomer are called homopolymers, while those with two or more types of monomers are called copolymers. For example, polyethylene consists of a single type of repeat unit, and is an example of a homopolymer, while ABS (acrylonitrile butadiene styrene) is a copolymer of three types of monomers: styrene, acrylonitrile, and butadiene. The properties of copolymers depend on the sequence of monomer units in the backbone (e.g., statistical, random, or alternating). Common medical copolymers include thermoplastic elastomers such as thermoplastic polyurethane (TPU) and polyether-block-amide (PEBA). The chemical nature of the monomers in a polymer will affect its interaction within the molecule and with neighboring molecules. For example, block copolymers will order and ultimately behave differently than random copolymers. Likewise, when two or more polymers are mixed to create a blend, intermolecular interactions determine miscibility. If the polymers interact strongly, they will be miscible and create a single phase with blended properties, while less favorable interactions can create a two-phase morphology with different attributes. \b\Molecular Weight Polymeric materials contain a large number of individual chains with varying lengths and mass, and therefore a range of molecular weights that cannot be fully described by a single number. In general, as 3 molecular weight increases, the mechanical property performance such as resistance to creep and stress relaxation increases because longer molecules tend to have more entanglements with neighboring molecules and it is more difficult for chains to move and slide past each other (see Fig. 1). However, above a critical molecular weight for a given polymer, the melt viscosity increases exponentially with marginal improvements in properties creating difficulties during melt processing such as injection molding (see Error! Reference source not found.Fig. 2). Thus, a balance of high and low molecular weights is needed to obtain good physical properties and permit reasonable processing conditions. Intrinsic viscosity and melt flow index are fairly quick and inexpensive methods that provide indirect measurements of average molecular weight of thermoplastic materials and can be used for quality control purposes and troubleshooting part failures. Intrinsic viscosity is measured from the flow time of a solution through a capillary. Melt flow index is a measure of the ease of flow of the melt of a thermoplastic polymer. It is defined as the mass of polymer, in grams, flowing in ten minutes through a capillary of a specific diameter and length under a specified pressure. The melt flow index is a point measurement associated with specific testing conditions and is often provided on technical data sheets as a guide to processability. It can be a useful comparator between lots, or within a specific polymer family. The molecular weight distribution of thermoplastics can be more fully evaluated using gel permeation chromatography (GPC). The molecular weight is described in terms of statistical averages: Mn = number average, Mw = weight average and Mz = z-average. A typical molecular distribution plot is shown in Error! Reference source not found.Fig. 3 and is characterized by polydispersity index (PDI), which is the ratio of the weight average and number average molecular weights (Mw/Mn), and is an indicator of the breadth of the molecular weight distribution. Physical properties often track with Mw, and melt processing via extrusion generally correlates most closely with Mz. 4 \b\Molecular Architecture Polymer molecules can be linear, branched, or crosslinked into a three-dimensional network. In the bulk, polymers can be either amorphous or semi-crystalline. Amorphous polymers tend to have irregularity in their chain structure and often contain large side groups, which prevents the chains from forming ordered structures or crystalline zones. On the other hand, crystalline polymers are more regular and ordered than amorphous polymers, but are truly only semi-crystalline (partly crystalline, partly amorphous) as a consequence of their long-chain nature and subsequent entanglements. Linear semi-crystalline polymers (e.g. high density polyethylene) typically have higher levels of crystallinity than branched polymers (e.g. low density polyethylene); branches make it difficult for polymer chains to pack closely together and form crystals. Amorphous polymers are characterized by a major thermal transition called the glass transition. The glass transition temperature (Tg) is generally defined as the temperature above which polymers show segmental chain motion. As a result, going through Tg results in dramatic changes in properties such as permeability, creep resistance and stiffness. At temperatures below Tg, amorphous polymers tend to be glassy, hard and brittle, while above Tg, they tend to be rubbery. In contrast to amorphous polymers, semi-crystalline polymers exhibit two major thermal transitions, the glass transition and melting, which is defined by the melting temperature (Tm). During melt processing of thermoplastics, amorphous polymers must be heated above Tg and semi-crystalline polymers above Tm. Semi-crystalline polymers tend to exhibit greater shrinkage from the melt due to crystallization. In structural (load-bearing) applications, amorphous polymers must be used at temperatures below Tg while, semi-crystalline polymers are structurally useful below Tm. 5 \b\Morphology Morphology describes form and structure and polymer morphology is related to the distribution and association of structural units. A polymeric material contains thousands or millions of molecules that entangle with each other and interact through secondary bonding (e.g., weak van der Waals forces or hydrogen bonding). Morphology develops as a result of structural aspects of a polymer, such as crystal size and distribution in semi-crystalline polymers, molecular orientation from melt-processing, size/shape/distribution of fillers/reinforcements, and the degree of phase separation for copolymers. For example, extruded polymers tend to have a high degree of molecular orientation and a higher strength/stiffness in the extrusion direction. Copolymers offer excellent examples of the importance of morphology: they can behave like rubber- toughened glassy materials at one extreme or glass-reinforced rubber materials at the other. For example, ABS typically behaves as a rubber-toughened glassy material. As shown in Error! Reference source not found.Fig. 4, the rigid SAN phase is the continuous phase while the grafted butadiene rubber segregates into domains that are dispersed throughout. The rubber imparts toughness to an inherently rigid material. \b\Viscoelasticity Physical properties of polymers are the result of their long chain nature, the interactions due to backbone chemistry, and the morphology that develops from molecular architecture and ordering. Due to their molecular nature, polymers exhibit both liquid- and solid-like characteristics. Similar to liquids, polymers deform slowly with time under stress (i.e. creep). Polymers also store some elastic energy when subjected to stress and may recover a portion of their deformation when stress is removed (elastic recoil). This hybrid nature is often modeled as combinations of dashpot (viscous) and spring (elastic) elements. Polymer properties are time and temperature dependent, as illustrated in Error! Reference source not found.Fig. 5. In general, at high strain rates (e.g. impact loading) and low temperatures, polymers 6 respond more like elastic solids. Conversely, at low strain rates and high temperatures, polymers behave more like viscous fluids as the polymer chains can disentangle and slide past each other. \a\Classification of Polymers There are many ways to classify polymers, including the polymerization method (how it was made), how the material deforms, or molecular origin or stability. \b\Polymerization Classification by polymerization is useful because polymers made by condensation or addition tend to have differing polydispersity, maximum molecular weight, and environmental stability. Addition polymers such as polyolefins and polyacrylates grow by sequential addition of monomers to growing chains. By controlling the initiation sequence, polymers of high average molecular weight and narrow molecular weight distribution can be synthesized. The monomers have essentially the same molecular formula as the resulting repeat unit. When they decompose, the mechanism is typically random scission or unzipping of the molecule. In contrast, condensation polymers grow by combining two monomers to create a repeat unit with a different molecular formula than those of the monomers from which it was produced. For example, polyester polymers are formed by the reaction of acids and alcohols, with water as a byproduct. Average molecular weight builds slowly, with a polydispersity index close to 2. Condensation polymers are subject to degradation when conditions favor the reverse of the polymerization reaction (e.g. when water is present at high temperatures, the equilibrium favors re-generation of monomers). \b\Thermomechanical Response Polymers are most commonly classified into three groups: thermoplastics, thermosets, and elastomers (rubbers), which are terms related to how the materials deform. The group most widely used for medical 7 applications is thermoplastics. Thermoplastics are linear or branched polymers that flow upon the application of heat; they can be molded and remolded using conventional melt processing methods, including thermoforming, extrusion, and injection molding. Thermosets (thermosetting polymers) are cross-linked polymers that are rigid and intractable (insoluble). They consist of a three-dimensional molecular network where the molecules are connected together by chemical links (covalent bonds). Thermosets form a permanent and infusible shape after the application of heat or a curing agent; they cannot be remelted and reformed once shaped and cured. Epoxy adhesives and silicone materials are examples of thermosets. These materials start off as liquid-like or semi-solid materials and an irreversible chemical reaction occurs that causes the material to harden (cure or crosslink). Rubber materials are thermosets that exhibit elastomeric properties (i.e. they can be stretched easily and will spring back when the stress is released). Rubber materials are relatively soft and deformable at ambient temperatures. Their primary uses are for seals, adhesives, and molded flexible parts. Silicone is an example of a common thermoset rubber material. A thermoplastic elastomer (TPE) is a thermoplastic material that can have rubber-like properties. TPEs are typically block copolymers that are comprised of hard and soft segments (blocks) that are phase separated in the solid state. The hard blocks impart stiffness and strength and the soft blocks impart flexibility. By varying the length and ratio of the hard and soft blocks, a wide range of properties can be achieved. Unlike thermosets, TPEs have physical crosslinks, which are relatively weak intermolecular bonds within and between blocks. These bonds break upon heating and reform upon cooling. 8 \b\Material Source and Stability Another way that polymers can be classified is based on the source of the monomers, or the polymers themselves. Natural polymers with applications in the medical arena include DNA, polysaccharides, proteins, silk, cellulose, etc. Most medical polymers are synthetic. Some natural and synthetic polymers are biodegradable (i.e., bioresorbable or bioabsorbable) and inherently degrade in physiological conditions, typically as the result of the presence of moisture (i.e. hydrolysis). The products from hydrolysis are further broken down and eliminated through normal metabolism. The rate of degradation can be tailored with chemical composition and molecular architecture. \a\Common Medical Polymers A majority of medical polymers are synthetic polymers, with properties that vary widely based on the attributes described above, including crystallinity (see Error! Reference source not found.Table 1). Common medical thermoplastics are listed in Error! Reference source not found.Table 2 and Error! Reference source not found.Table 3. Amorphous polymers are generally transparent while semi-crystalline polymers are usually translucent or opaque. Crystals tend to scatter light, particularly if their size or the distance between crystals is on the order of the wavelength of visible light. Thus, amorphous polymers are desirable for applications such as containers, syringes, and blood bags, which require transparency. Generally, semi-crystalline polymers tend to have better chemical resistance than amorphous polymers. However, modified acrylics have demonstrated fat and lipid resistance, which are important for applications such as disposable intravenous luer locks and filter housing components. 9 Engineering and high performance thermoplastics such as PSU (polysulfone), PC (polycarbonate), and PEEK (polyether ether ketone), possess aromatic ring structures in their backbone, which lends to higher glass transition temperatures, enhanced mechanical properties, and greater heat and chemical resistance compared to commodity thermoplastics such as ABS, PE (polyethylene), PS (polystyrene), and PMMA (poly(methyl methacrylate)). The engineering and high performance thermoplastics are typically used for surgical tools and implantable devices, while the commodity thermoplastics are more often used for disposables. PE is one of the most common commodity plastics used in medical-device applications. There are several types of PE that have different chain architecture and molecular weight, which affect their physical properties (see Error! Reference source not found.Table 4). Low density polyethylene (LDPE) and linear low density polyethylene (LLDPE) have branched side chains and a relatively low molecular weight, providing the processability and tear and puncture resistance required for bags, containers, and disposable packaging. Ultra high molecular weight polyethylene (UHMWPE) has extremely high molecular weight with significant molecular entanglements, providing enhanced wear resistance for use in joint prostheses. \a\Materials Selection When approaching the task of materials selection, polymers can be classified into three main groups as mentioned in the Classification of Polymers section. Each group of polymers has unique properties, which can be used as criteria for pre-screening. It is important to recognize that polymers exhibit time (frequency) and temperature dependent properties, as noted in the Viscoelasticity section, including non- linear stress and strain behavior. Other unique features that set polymers apart from metals and ceramics include: aging and weathering, chemical resistance, environmental stress cracking, notch sensitivity, residual stresses and weld lines from processing, process-driven morphology, and the effects of additives, fillers, and reinforcements. 10 Establishing relevant criteria can help guide the selection process. Ashby’s material selection strategy is described by the following four steps1: \bl\ Translate design requirements: Express as function, constraints, objectives, and free variables Screen using constraints: Eliminate materials that cannot do the job Rank using objective: Find the screened materials that do the job best Seek supporting information: Research the family history of top-ranked candidates Medical polymer selection criteria will be application dependent, but may include the following: \bl\ General o Aesthetics, cost Mechanical o Elastic moduli (Young’s, shear, bulk), elongation at break, yield strength, ultimate strength, compressive strength, impact resistance, hardness, fatigue endurance, stress relaxation, creep Thermal o Glass transition temperature, melting temperature, maximum/minimum continuous service temperature, thermal conductivity, specific heat, thermal expansion coefficient Environmental o Chemical resistance, UV resistance, thermo-oxidative stability, environmental stress cracking resistance 1 Ashby, M. F., Materials selection in mechanical design, 3rd ed., Elsevier, 2005. 11 Compatibility o Biocompatibility, USP classification, compatibility with other materials in the device, the manufacturing process, and sterilization and use conditions Others o Optical, electrical The information on product data sheets is most useful for screening materials and should not, alone, be used for purposes of design. Data sheets typically provide single point data (at ambient temperature) from short-term tests, rarely considering the effects of time and environmental conditions (temperature, humidity, and chemicals) on material properties. For design purposes, it is important to evaluate material properties at the end-use temperature (e.g. 37°C (98.6°F) for implantable applications) and under anticipated loading conditions. For example, if a polymeric medical component will be subjected to cyclic loading, then fatigue testing should be performed at the same frequency and loads. Modeling and simulation (e.g., finite element analysis or FEA) can also be a useful tool for assessing product performance based on material behavior at relevant temperatures, rates, or service histories. \b\Regulatory Aspects of Materials Selection Historically, plastics for medical applications have been grouped into six classes according to the guidelines developed by United States Pharmacopeia (USP), a non-governmental standard setting organization. In 1960, USP established the test methodology and performance requirements for plastic materials to be used in medical applications. The USP tests measure the biological reactivity of plastics in contact with mammalian cell cultures and via implantation of the plastics and injection of the plastic extractables into laboratory animals. The six USP classes are defined based on responses to three in-vivo tests for which extracts, materials, and routes of administration are specified. The three in-vivo tests are acute systemic toxicity test, irritation test, and implantation test. Error! Reference source not 12 found.Table 5 lists the in-vivo tests that a medical plastic needs to pass in order to receive one of the six classifications. For example, an USP class VI plastic would have passed the acute systemic toxicity test and irritation test when strips of the plastic are implanted into the animal. Though USP guidelines are adopted by most of the medical-device manufacturers, especially during the initial materials selection stage, these guidelines are meant for medical plastics alone and not for the plastics as part of a medical device. Whenever a plastic is used in a medical device, even if it is advertised as a USP class VI material, it should be tested according to the standards relevant to the amount of contact with the human anatomy as an integral part of the device. This is because factors such as the addition of colorants, processing, and the use of the plastic in combination with other materials and adhesives, can affect the biocompatibility characteristics of the material. Furthermore, as part of the device, the plastic may have been subjected to processing conditions unique to the application such as texturing, surface treatment, fabrication process, etc. that could potentially alter the biocompatibility response of a particular medical plastic. For these reasons, the device level tests should be performed, even if the same material is in use in another medical device. However, using a material that is already in use in another medical device for similar function that is known to have passed biocompatibility testing can instill some confidence that the material will pass testing in new application. Therefore, a designer should only use USP classification of plastics as a guide during initial materials selection screening process. \a\Failure Analysis and Prevention Despite the best efforts of designers, failures can and do happen during the development, clinical (in the case of medical-device manufacturers), pre-market, or post-market stages. Failure may be defined as a loss or unacceptable change in the fit, form, or function of a given component or structure. As much as possible, failure modes are anticipated during the development process and considered in the design, testing, and labeling of the product. When failures do occur, the failure analysis process allows investigators to determine the root cause of failures that arise at different stages of the product life cycle. 13 Failure investigations are performed to gather the necessary scientific and engineering information to make informed decisions and identify the best solution to a given problem. Knowledge gained from failure analysis enables prevention of future occurrences, and/or improvement of the performance of the component or device. Thus, failure analysis plays an important role in product development and design improvement, liability assessment, and planning and executing potential recall or replacement campaigns. \b\The Failure Analysis Process At any stage of a medical-device life cycle, the engineering and scientific investigation process used to determine the root cause is fundamentally similar. Specifically for post-market device failures, manufacturers should process and analyze failed devices per the Code of Federal Regulations (21CFR Part 820). An important step in any failure investigation is accurately and clearly defining the problem statement such that the true root-cause can be identified and proper corrective actions are implemented. The failure investigation and analysis help determine the actual failure mechanism and Section 820.100 provides guidelines for performing corrective or preventive actions. The failure analysis process entails information mining (fact collection), non-destructive examination (NDE), and possible destructive testing. When sufficient information is available, numerical modeling (such as finite-element analysis) can also be an effective tool for identifying and correcting the root cause of a failure. One advantage of this approach over experimental analysis is the ability to explicitly include more conditions than would be possible due to practical limitations associated with available materials, devices, or time. In addition, sensitivity analyses and analysis iterations can be performed quickly with a numerical model. Modeling can also provide an effective communication tool with regulatory bodies since it allows the user to create to both cross-sectional and overall images of devices throughout an analysis. 14 NDE includes visual and/ or microscopic examination. Visual examination allows for examination of macroscopic features, including tell-tale signs such as discoloration and deformation, and to obtain dimensional measurements. Microscopic examination may be necessary to examine certain features at higher magnification, and to gain a deeper understanding of the failure mode. If the analysis is limited to NDE methods, the examination should be carefully planned before commencing the work, in order to negate the possibility of damaging the samples. An Environmental Scanning Electron Microscope (ESEM) is a common tool used for NDE of polymeric medical device parts because it does not require coating the sample with a conductive material prior to imaging. However, some level of vacuum is still generated, which may make the tool inappropriate for devices that may offgas or deform under these conditions. Other common tools used to investigate failures that are typically destructive include chemical, physical, and mechanical property evaluation. Fourier-transform infrared spectroscopy (FTIR) is a workhorse tool that can be used non-destructively or destructively to quickly ascertain the composition of polymeric materials and look for evidence of contamination and degradation. If there are trace contaminants or small amounts of degradation, other more sensitive methods such as various forms of chromatography and spectroscopy can be used. Thermal analysis techniques such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), thermomechanical analysis (TMA), and dynamic mechanical analysis (DMA) can be used to confirm that the material used met the specification for composition and exhibit similar critical attributes. Molecular weight analysis can also be used to confirm conformance with specifications, and it can be used as a tool to evaluate for evidence of molecular degradation in thermoplastic materials. Destructive testing is most effective when it includes comparative analyses with parts or devices from manufacturing lots that have not exhibited failures. For example, an injection molded part in a medical device may have cracked post-sterilization. The failure analyst should evaluate sterilized and non- 15 sterilized parts, as well as cracked and non-cracked parts from devices that have been sterilized for evidence of material degradation. \b\Plastic Product Failure Analysis Product failures can occur for many reasons, including deficient design, use of improper materials for the application, defective materials, mistakes in manufacturing, abuse during end-use or use in an unintended manner. Failure analysis of plastic parts should include recognition of the chemical, thermal, and physical responses that are unique to polymers. Failure mechanisms in polymers can be physical or chemical in nature. Each type of polymer has inherent weaknesses, which are a function of its composition and the application environment (temperature, stress, strain, duration, chemical exposure). Error! Reference source not found.Table 6 lists mechanisms of physical and chemical deterioration that may occur alone or in concert at various stages of a polymer history, from processing and assembly to storage and end-use. Moreover, the treatment of a material prior to use may predispose it to stable or unstable end-use behavior. A prominent example of biomaterial degradation caused by pre-implant processing is gamma irradiation sterilization of UHMWPE used in total joint prostheses. The process generates free radicals within the material that react with oxygen to produce undesirable oxidation products. Oxidation and chain scission can occur for periods of months to years, causing loss of strength and embrittlement, with limited shelf life. \c\Design.\ce\ When developing new products, engineers must consider the geometry (dimensions and tolerances) and the materials of construction. The geometry must be appropriate for the material (e.g. ease of processability) and the material must be appropriate for the application (e.g. sterilizable by available methods, biocompatible, possess critical physical and mechanical properties, etc.). A designer may have chosen a great material that has all of the desired attributes required for a given application, but if the 16 geometry is such that it exposes a weakness in the material, the component/device may fail due to an inherent design defect. For example, some thermoplastics are more notch sensitive than others, which means that properties such as impact strength are strongly dependent on notch radius. For notch sensitive materials such as rigid PVC, the impact strength drops precipitously with decreasing radius. This is shown in Error! Reference source not found.Fig. 6, which also illustrates that acrylic and ABS are not as notch sensitive as rigid PVC, and that notch size can affect the relative impact strength of rigid PVC compared to ABS. Therefore, generous inside corner radii are recommended to minimize stress concentrations and the potential for corner cracking, especially with notch-sensitive materials. \c\Aging and Environmental Effects.\ce\ Medical-device designers must also consider shelf life/aging of the material to ensure that the material retains acceptable performance over its lifetime in the intended use environment. Unlike metals and ceramics, plastics are particularly susceptible to degradation from aging, which results from exposure to UV radiation and is accelerated at higher temperatures and in the presence of moisture. Typically, this leads to discoloration, loss of mechanical properties, or in extreme cases, disintegration of the plastic product. \d\Shelf-Life Aging Study- Case Study.\de\ Accelerated aging tests were performed on two polyether- block-amide (PEBA) copolymer tubing samples to evaluate the best sterilization method for extending shelf life. Samples were constructed with a 63D PEBA inner tube covered by a stainless steel coil and over-coated with extruded 25D or 40D PEBA outer tubing. The mechanical properties and hardness of PEBA materials are dependent on the ratio of ether soft blocks to amide hard blocks; hardness is reduced and flexibility is increased with increasing polyether content. Thus, tubing made with 25D PEBA is more flexible than tubing made with 40D PEBA. 17 Samples were sterilized using gamma or e-beam radiation followed by accelerated aging between 40 and 80°C (100 to 180°F). Assuming Arrhenius behavior for a first approximation, the failure times for e-beam sterilized samples, regardless of PEBA hardness, were longer. In addition, gamma sterilized 40D samples had longer failure times than the lower hardness 25D sample. Materials characterization was performed before and after sterilization and after aging to evaluate compositional changes. Based on FTIR analysis, it was determined that the polyether blocks were degrading during aging. Thus, the higher hardness 40D sample was more stable as a result of its decreased polyether block content. In addition, the estimated shelf life of 25D tubing samples is greatly increased when sterilized with e-beam radiation compared to gamma radiation. This study helped a medical device manufacturer select an appropriate sterilization method for their devices. \c\Processing.\ce\ Plastic components used in medical devices are often made using molding and extrusion processes, during which the plastic part is shaped by application of heat and pressure. These high-energy processes can result in residual stresses and latent defects due to improper processing conditions, and contamination during processing. Defects could also be introduced during casting, curing, and secondary processes such as assembly, packaging, and sterilization, which can result in subsequent product failures. \d\Polyurethane Medical Device Component – Case Study.\de\ A polyurethane medical device developed a through-wall crack during pre-clinical testing. Nondestructive visual examination revealed cracks on the exterior surface. Destructive examination was subsequently performed to characterize the nature and extent of the damage. Based on microscopic examination of the fracture surface, it was determined that the crack initiated on the exterior surface at an inclusion/defect with similar elemental composition as the device material (Error! Reference source not found.Fig. 7). The device component was manufactured by dip coating a mandrel in a vessel containing a polyurethane dispersion. The inclusion was most likely a hardened piece of polyurethane that sloughed from the side 18 walls of the vessel and got embedded in the device cross-section during successive dips into the dispersion. This inclusion acted as a stress concentrator. The root-cause of failure was contamination during processing. \d\Medical Balloons- Case Study.\de\ Medical balloons are used for a variety of medical procedures including angioplasty and stent delivery. Non-compliant nylon balloons were rejected during manufacturing due to the presence of various defects, including burnt polymer (e.g. ‘black specks’) and fibrous and particulate contamination. The defects were characterized using a combination of microscopy and spectroscopy methods to identify the location (surface or subsurface) and type of material (inorganic or organic) within the balloon wall. Due to the transparency and glossiness of the balloons, scanning electron microscopy (SEM) was more useful than optical microscopy for examining surface features. Energy dispersive X-ray spectroscopy (EDS) and FTIR were used to identify inorganic elements and organic materials, respectively. Based on SEM examination of the balloon surfaces, elliptical-shaped features were detected on the interior surface. The major axis of the features was essentially parallel to the extrusion direction of the tubing used to manufacture the balloon (Error! Reference source not found.Fig. 8). The defects had metallic particles partially embedded in the surface at symmetric positions about the major axis. These particles were likely introduced during extrusion, possibly from worn barrel or die surfaces. When the balloon shape was created by blow molding to radially expand the tubing, the elliptical shaped damage zone was created around the embedded particles. After the root cause was identified, the manufacturer instituted frequent purging of the extrusion lines and replacement of screen packs to mitigate the contamination problem. \a\Current and Future Trends in the Use of Medical Polymers The use of polymers in healthcare continues to expand in both disposable and non-disposable applications. With the growth of rapidly aging populations in many developed countries and the opening of emerging 19 markets, the demand for medical devices and medical polymers is anticipated to grow significantly. This provides tremendous impetus for the development of new grades of medical polymers, and newer applications and improvements in performance of the existing grades of materials. \b\High-Performance Polymers for Implants Materials used in prosthetic implant applications require high biocompatibility and mechanical properties that are stable over a long period of time while in contact with human body fluids. Traditionally, metals such as titanium have been used for these applications. Over the last decade, advances in high performance implantable polymers such as PEEK, other aromatic polymers, cross-linked UHMWPE, and composite formulations have enabled these materials to overcome some of the short-comings of polymeric materials for orthopedic applications. \b\Tissue Engineering Tissue engineering can be defined as an interdisciplinary field in which the principles of engineering and the life sciences are applied toward the generation of biological substitutes aimed at creation, preservation, or restoration of lost organ function. The ultimate goal of tissue engineering is to either implant tissues that have been grown on biomaterials outside the body or provide the body with appropriate biomaterial scaffolds and biological ingredients so that it can regenerate the diseased or missing tissue. One of the key components in the successful tissue engineering is the production of the correct scaffold using biomaterials. The scaffold should be biocompatible, highly porous, provide the correct biomechanical environment, degrade in tune with tissue growth and possess a surface that encourages cell attachment and growth. The scaffold can be permanent or bioabsorbable/ bioresorbable and can be surface functionalized to enhance biocompatibility and stimulate growth. Thus, the ideal scaffold should provide cells not only with a structural framework but also with appropriate mechanical and biochemical conditions so that these cells can proliferate and produce extracellular matrix to form tissue. 20 \b\Bioresorbable Polymers Bioresorbable polymers have found use in tissue scaffolds, orthopedic, and suture materials. These materials bring benefits of tailored duration, and their properties and persistence in the body can be tailored by chemistry and morphology. For example, properties and persistence of copolymers based on lactic and glycolic acids are directly related to the percent, arrangement and associated crystallinity. New bioresorbable materials such as PDO (polydioxinone) are finding use in medical devices. \a\Summary As in any end-use, polymer suitability is driven by structure-property-processing relationships and, with medical devices, the addition of biocompatibility requirements. This chapter provides an overview of these concepts and selected examples. Numerous resources (see Selected References) exist to provide a more in-depth understanding. 21 \e\References: Polymer Chemistry, Processing, and Properties Polymeric Biomaterials and Applications 1. Handbook of Biomedical Plastics, Henry Lee and Kris Neville, Pasadena Technology Press, 1971. 2. M. Moukwa, The Development of Polymer-Based Biomaterials Since the 1920s, J. of Materials, Feb 1997, 46-50. 3. Medical Applications of Plastics, Biomedical Materials Symposium No.1, Ed. Harry Gregor, Interscience Publishers, 1971. 4. Synthetic Biomedical Polymers-Concepts and Applications, Ed. M. Szycher, W.J.Robinson, Technomic Publishing Company, 1980. 5. Polyurethanes in Medicine, Michael Lelah and Stuart Cooper, CRC Press, 1986. 22 6. A.J. Coury, Chemical and Biomechanical Degradation of Polymers, Biomaterials Science: An Introduction to Materials in Medicine, B.D. Ratner, A.S. Hoffman, F.J. Schoen, and J.E. Lemons, Ed., Academic Press, 1996. 7. Ref 2 (original handbook) 8. Ref 3 (original handbook) 9. Ref 4 (original handbook) 10. Ref 6 (original handbook) 11. Ref 7 (original handbook) 12. Ref 8 (original handbook) 13. Ref 9 (original handbook) 14. Ref 10 (original handbook) 15. Ref 11 (original handbook) 16. Ref 12 (original handbook) 17. Ref 13 (original handbook) 18. Ref 14 (original handbook) Medical Device Design 19. Ashby, M. F., Materials selection in mechanical design, 3rd ed., Elsevier (2005). 20. The medical device R&D handbook, Theodore R. Kucklick, CRC press, 2006. 21. M. Helmus et.al, Biocompatibility: Meeting a Key Foundational Requirement of Next-Generation Medical Devices, Toxicologic Pathology, 36, 2008, 70-80. 22. FDA website (http://www.fda.gov/MedicalDevices/default.htm) 23. “Design Data for Plastics Engineers,” N. Rao and K. O’Brien, Hanser Gardner Publications, 1998. 23 24. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/ClassifyYourDevi ce/ucm051512.htm Failure Analysis 25. Characterization and Failure Analysis of Plastics, ASM International, 2003. 26. Handbook of Plastics Testing and Failure Analysis, Vishu Shah, 3rd edition, Wile-Interscience, 2007. 27. Kurtz, SM, The UHMWPE Handbook, Elsevier Academic Press, 2004. 28. Hoffman, JM, Reitman, MTF, and Ledwith, P, Society of Plastics Engineers Annual Technical Conference, ANTEC 2008, 1777-1781. 29. Sjong, A, Villagomez, F, and A Kendale, Society of Plastics Engineers Annual Technical Conference, ANTEC 2006, 1544-1548. 24
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