Toxicologic PaJ/wlogy, 36:70-80, 2008
`Copyright © 2008 by Society of Toxicologic Pathology
`ISSN: 0192-6233 print/ 1533-1601 online
`DOI: IO.J 177/0192623307310949
`
`Biocompatibility: Meeting a Key Functional Requirement
`of Next-Generation Medical Devices
`
`1MrCHAEL N. H ELMUS, 2D ONALD F. G IBBONS, AND 3D AVID CEBON
`
`From 'Medical Devices, Biomaterials, Drug Delivery, and Nanotechnology, Wo~este,; Massachusetts, USA; 23M Corporation,
`North Oaks, Minnesota, USA; and 3Granta Design Limited, Cambridge, United Kingdom
`
`ABSTRACT
`
`The array of polymeric, biologic, metallic, and ceramic biomaterials will be reviewed with respect to their biocompatibility, which has tradition(cid:173)
`ally been viewed as a requirement to develop a safe medical device. With the emergence of combination products, a paradigm shift is occurring that
`now requires biocompatibility to be designed into the device. In fact, next-generation medical devices will require enhanced biocompatibility by
`using, for example, pharmacological agents, bioactive coatings, nano-textures, or hybrid systems containing cells that control biologic interactions to
`have desirable biologic outcomes. The concept of biocompatibility is moving from a "do no harm" mission (i.e., nontoxic, nonantigenic, nonmuta(cid:173)
`genic, etc.) to one of doing "good," that is, encouraging positive healing responses. These new devices will promote the formation of nonnal healthy
`tissue as well as the integration of the device into adjacent tissue. In some contexts, biocompatibility can become a disruptive technology that can
`change therapeutic paradigms (e.g., drug-coated stents). New database tools to access biocompatibility data of the materials of construction in exist(cid:173)
`ing medical devices will facilitate the use of existing and new biomaterials for new medical device designs.
`
`Keywords: Biomaterial; biocompatibility; bioactive; biostable; biodegradable; drug e luting; implant; database.
`
`INTRODUCTION
`
`Materials used in medical devices, particularly in those
`applications in which the device either contacts or is temporar(cid:173)
`ily inserted or permanently implanted in the body, are typically
`described as biomaterials and have unique design requirements.
`The National Institute of Health Consensus Development
`Conference of November 1982 defined a biomaterial as "any
`substance (other than a drug) or combination of substances,
`synthetic or natural in origin, which can be used for any period
`of time, as a whole or as a part of a system which treats, aug(cid:173)
`ments, or replaces any tissue, organ, or function of the body"
`(Boretos and Eden, 1984, pp. 27-88, 128-132, 193-253).
`The required material properties are determined by the spe(cid:173)
`cific device application and the functional life of the device,
`which ranges from temporary use to permanent implant.
`Devices can be used in (I) blood-contacting applications such
`as extracorporeal devices that remove and return blood from
`the body, devices that are inserted into a blood vessel, or
`devices that are permanently implanted; (2) soft-tissue device
`applications, such as soft-tissue augmentation; (3) orthopedic
`and dental applications for joint, bone, and tooth replace(cid:173)
`ment and repair, (4) specific organ applications (e.g., neural);
`and (5) scaffolds for tissue engineering for tissue and organ
`replacement.
`
`Address correspondence to: Michael N. Helmus, PhD, Consultant: Medical
`Devices, Biomaterials, Drug Delivery, and Nanotechnology, 2 Jamesbury Dr.,
`Worcester, MA 01609; e-mail: Mhelmus57J@aol.com.
`Abbreviations: Co-Cr-Mo, cobalt-chrome-molybdenum; ISO, International
`Standards Organization; OCP, FDA's Office of Combination Products; PMMA,
`polymethylmethacrylate; PTFE, poly(tetrafluoroethylene); PVC, poly(vinyl chlo(cid:173)
`ride); SIBS, styrene-isobutylene-styrene triblock copolymer or Poly(Styrene(cid:173)
`b-isobutylene-b-styrene); ULT!, ultra low temperature isotropic carbon.
`
`70
`
`Materials for medical devices can be characterized as syn(cid:173)
`thetic polymers, biodegradable polymers, bioactive materials,
`natural macromolecules (i.e., biopolymers), metals, carbons,
`and ceramics (Boretos and Eden, 1984; Helmus and Tweden,
`1995; Helmus, 2003). They can be implanted for permanent
`replacement, as in an artificial heart valve or hip prosthesis, or
`for temporary use, such as an intravenous catheter or bone
`plates and rods. The sterilized device, and by default, the mate(cid:173)
`rials of which it is constructed, need to meet basic biocompat(cid:173)
`ibility requirements, generally as defined by the ISO 10993
`standards, to be nontoxic, nonthrombogenic, noncarcinogenic,
`nonantigenic, and nonmutagenic (Helmus, 2003). In blood(cid:173)
`contacting applications, it must be nonthrombogenic to mitigate
`complications from thrombi and emboli. Potential complications
`will vary with a device and its application. Biodegradation and
`infection become increasingly important in longer term appli(cid:173)
`cations such as central venous catheters and permanently
`implanted devices. Because of the large surface area in extra(cid:173)
`corporeal circuits, activation of biologic pathways, such as the
`coagulation, fibrinolytic, and complement pathways, may be
`magnified. Patients who are treated by extracorporeal methods
`(e.g., hemodialysis) are repeatedly exposed to leachable plasti(cid:173)
`cizers and sterilant residuals.
`Many devices, such as heart valves, artificial hearts, and hip
`implants are constructed of multiple materials. Joining meth(cid:173)
`ods can affect material properties that can reduce strength,
`fatigue life, and biostability. The material's form and size, how
`it interfaces with the body, and its required duration of use will
`determine its required properties. One material property alone
`is unlikely to lead to a successful and durable device, whereas
`a lack of a single key property can lead to failure.
`Coatings for improved biocompatibility and as carriers for
`drug delivery have an increasingly important role. Bioactive
`
`Novartis Exhibit 2182.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Vol. 36, No. I, 2008
`
`BIOCOMPATIBILITY
`
`71
`
`materials, which tend to use the nature of natural material or
`mimic natural materials, have applications in orthopedic implants
`to enhance bone attachment, antimicrobials to mitigate infection,
`and antithrombotics to mitigate thrombus. Drug-polymer combi(cid:173)
`nations have been used in drug-eluting stents, heparin-release
`coatings for catheters, and steroid-releasing electrodes for pace(cid:173)
`makers (Helmus and Tweden, 1995; Ranade et al., 2004; Ranade
`et al., 2005; Stokes, 1987). These drug-eluting devices are repre(cid:173)
`sentative of combination devices that have the potential to create
`potent new therapies by using the best properties of drug-device,
`biologic-device, or drug-biologic combinations. The Food and
`Drug Administration's Office of Combination Products (OCP)
`has broad responsibilities covering the regulatory life cycle of
`these combination products and will determine which Center has
`primary regulatory responsibility (Helmus, 2007). For example,
`the drug-eluting stent is primarily regulated by Center for Devices
`and Radiological Health, but Center for Drug Evaluation and
`Research has secondary responsibility for the analysis of drug
`content and compounding and manufacturing requirements.
`The phenomena controlling the bioresponse are basically
`wound healing in the presence of a sterile medical device. The
`outcome of this healing process can have profound implications
`on the success of a device and can depend on material proper(cid:173)
`ties such as texture, crystallinity, wettability, surface chemistry,
`cytotoxic leachables, and degradation products (Andrade et al.,
`1987; Brash, 2(XX); Helmus and Tweden, 1995). These proper(cid:173)
`ties determine primarily the interaction between the materials
`and proteins in the biological environment, and subsequently,
`the interactions with the cells and tissues. The biologic response
`to materials, e.g., inflammation and thromboresistance, is an
`important consideration in the design of medical devices. Chronic
`inflammatory responses resulting in a thick fibrous capsule
`and the persistence of white cells, is undesirable and can lead
`to damage to surrounding tissue and to failure of the device.
`Leachables can cause local cytotoxicity and result in inflamma(cid:173)
`tion. Hypersensitivity reactions can occur to corrosion products
`and residual monomers, plasticizers, additives such as antioxi(cid:173)
`dants, and degradation products. Cytotoxic leachables and
`degradation products, which may exhibit systemic effects if the
`dose is high, may result from the fabrication and sterilization
`methods used as well as ambient degradation by processes such
`as hydrolysis and oxidation over time (Coury et al., 1988;
`Stokes, 1987; Takahara et al., 1992). Contamination by bacteria,
`endotoxins (the breakdown products of gram-negative bacteria),
`and particulate debris can have profound effects on inflammatory
`responses (Helmus et al., 1986). These responses are generally a
`matter of handling, processing, and minimizing wear and corro(cid:173)
`sion in vivo. The lack of bacteriological contamination can be
`designated as an incoming requirement on materials from a ven(cid:173)
`dor; however, wear and corrosion debris are inherent properties
`of materials and are a matter for appropriate materials selection.
`Biostability refers to the ability of a material to resist
`biodegradation mechanisms and maintain its properties in situ.
`Degradation may result from hydrolysis, oxidation, enzyme
`catalyzed enhancement of hydrolysis, oxidation, lipid absorp(cid:173)
`tion, swelling, and calcification. Biomaterials with enhanced
`
`Intemational standards for biological
`T ABLE 1.-
`evaluation of medical devices.•
`
`Reference
`
`ISO 10993-1
`ISO 10993-2
`ISO 10993-3
`
`ISO 10993-4
`ISO 10993-5
`ISO 10993-6
`ISO 10993-7
`ISO 10993-8
`ISO 10993-9
`ISO 10993-10
`ISO 10993- 11
`ISO 10993-12
`ISO 10993- 13
`
`ISO 10993-14
`ISO 10993- 15
`
`ISO 10993-16
`
`ISO 10993-17
`
`ISO 10993-18
`ISO 10993-19
`
`ISO 10993-20
`
`Title
`
`Guidance on selection of tests
`Animal welfare requirements
`Tests for genotoxicity, carcinogenicity, and
`reproductive toxicity
`Selection of tests for interactions with blood
`Tests for cytotoxicity: lo vitro methods
`Tests for local effects after implantation
`Ethylene oxide sterilization residuals
`Withdrawn: Clinical investigation of medical devices
`Evaluation of biodegradation of medical devices
`Tests for irritation and sensitization
`Tests for systemic toxicity
`Sample preparation and reference materials
`Identification and quantification of degradation products
`from polymers
`Static test to quantify in vitro degradation of ceramics
`Identification and quantification of degradation products
`from metallic materials used in medical devices
`Toxicokinetic study design for degradation products
`and leachables
`Glutaraldehyde and formaldehyde residues in
`industrially sterilized medical devices
`Characterization of materials
`Physico-chemical, morphological, and topographical
`characterization of materials
`Principles and methods for immunotoxicology testing
`of medical devices
`
`•Heln1us (2003); http://www.iso.org/iso/en/StandardsQueryFormHandler.StandarclsQuery
`FormHandler?scope=CATALOGUB&sortOrder=ISO&committee=ALL&isoDocType=
`ALL&title=true&keyword=l0993
`
`compatibility will combine new materials that have negligible
`leachables and exceptional biostability to mitigate adverse bio(cid:173)
`logic responses to leaching of additives and breakdown products.
`Styrene-isobutylene-styrene triblock elastomer, used as the carrier
`for paclitaxel in the drug-eluting stents (Ranade et al., 2004;
`Ranade et al., 2005), is an example of this type of new-generation
`material and is described in the last section of this article.
`Thromboresistance relates to the tendency of a material to
`reduce thrombus or emboli formation by formation of platelet(cid:173)
`based and/or fibrin -based clots. Thrombi can form a nidus for
`coagulation, and they can also form a site that is prone to bac(cid:173)
`terial colonization and infection. Consumption of blood ele(cid:173)
`ments may be an indication of microemboli and activation of
`thrombotic mechanisms and is w1desirable. Many bioprostheses,
`such as the bioprosthetic pericardia! heart valve, are considered
`thromboresistant, whereas mechanical heart valves made from
`a variety of materials require permanent anticoagulation ther(cid:173)
`apy. The effect of design and materials on thrombosis is diffi(cid:173)
`cult to separate in these cases. Materials such as poly(ester) fabrics
`are moderately thromboresistant but are suitable for their appli(cid:173)
`cation as vascular grafts larger than 6 mm in diameter. Intimal
`hyperplastic responses resulting in the excess thickening of
`vascular tissue limit the use of synthetic small-diameter vascular
`grafts (Boretos and Eden, 1984) and result in the chronic closure
`of vessels after angioplasty.
`Basic schemes for testing the acceptability of materials in
`terms of cytotoxicity, hemolysis, and mutagenicity can be
`
`Novartis Exhibit 2182.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`72
`
`HELMUS ET AL.
`
`TOXICOLOGIC PATHOLOGY
`
`TABLE 2.- Selected examples of materials from Materials for Medical Devices database.'
`
`Material Examples
`
`Device Example
`
`ISO 10993 Tests
`
`Biocompatibility Citations for Soft Ttssue Response
`and Blood Compatibility
`
`Synthetic plastic
`Ultra high molecular
`weight polyethylene
`Synthetic elastomer
`Silicone rubber
`
`Synthetic textile
`Polyethylene terphthalate
`knitted/woven
`
`Biodegradable
`Polylactic acid
`
`Ttssue derived
`Bovine pericardium
`
`Bioderived
`2-methacryloyloxyethyl
`phosphorylcholine
`Passive coating
`Butyl methacrylate
`Bioactive
`Surfactant heparin
`
`Ttssue adhesive
`Albumin
`Metal
`Stainless steel
`
`Ceramics and carbon
`Pyrolytic carbon (LT!)
`
`Composites
`Silicone impregnated with
`barium sulfate
`Nanotechnology
`Nanostructured copolymer
`Styrene-isobutylene(cid:173)
`styrene (SIBS)
`
`Annuloplasty rings
`
`3, 4, 6, IO, 11
`
`Chowdhury et al. (2004), Takami et al. (1997), Hunter et al. (1995),
`Richardson et al. (1975)
`
`Sewing ring component
`pericardia] heart valve
`
`3, 5, 6, IO, II
`
`Mechanical heart valve
`
`3, 4, 5, 6, IO, 11
`
`Belanger et al. (2000), Harrnand and Briquet ( I 999), lomhair and
`Lavelle (1996), McCoy et al. (1989), Mirzadeh et al.
`(2003), Ertel et al. (1994), Bordenave et al.
`(1992), Ammar (1984), Van der Giessen et al. (1996),
`Spilizewski et al. (1987)
`
`Toes (1999), Bonchek et al. (1969), Radomski et al. (1987), Marois
`et al. (1999), Marois et al. (1996), Urayama et al. (1996),
`Granstrtlm et al. (1986)
`
`Biodegradable pericardia)
`replacement
`
`3, 4, 5, 6, IO, 11
`
`Nguyen et al. (2003), (Tamai et al. (2000), Kohn et al. (2004),
`Cutright and Hunsuck (1971), Su et al. (2003)
`
`Heart valve
`
`3, 4, 5, 6, IO, 11
`
`Fllrst and Banerjee (2005), Chang et al. (2001), Chang et al. (2002),
`Neuhauser and Oldenburg (2003)
`
`Stent coating
`
`3, 4, 5, 6, 7, IO, 11
`
`De et al. (2002), Galli et al. (2001), Rose et al. (2004), Malik et al.
`(2001), Goreish et al. (2004)
`
`Carrier for drug-eluting stent
`
`3, 4, 5, 6, IO, 11
`
`Sousa et al. (2001), Suzuki et al. (2001)
`
`Annuloplasty rings
`
`3, 4, 5, 6, 7, IO, 11
`
`Tonda et al. (2005), Lazar et al. (1999), Novello et al. (2000), Yang
`et al. (2005), De Scheerder et al. (1997)
`
`T issue sealant
`
`3, 5, 6, IO, II
`
`Skarja et al. (1997), Werthen et al. (2001), Marois et al. (1996)
`
`Endovascular stent
`
`3, 4, 5, 6, 7, IO, 11
`
`Selvaduray and Bueno (2004), Hao et al. (2005b),
`Wever et al. (1997), Indolfi et al. (2000)
`
`Mechanical heart valve
`
`3, 4, 5, 6, IO, 11
`
`Yannas (2004), Feng and Andrade (1994), Mantero et al. (2002),
`Yang et al. (1996), Maropis et al. (1977), Antoniucci et al. (2000)
`
`Annuloplasty ring
`
`3, 4, 5, 6, 7, IO, 11
`
`See silicone rubber above
`
`Carrier for drug-eluting stent
`
`3, 4, 5, 6, IO, 11
`
`Gallocher et al. (2006), Silber (2003), Ranade et al. (2004)
`
`Iso = International Standards Organization.
`' ASM International (2006).
`
`found in the following standards and guidelines: American
`Society for Testing and Materials (ASTM) F-748 and the
`International Standards Organization 10993 standards; see
`Table I. These documents provide a method of testing by device
`application (Helmus, 2003).
`
`MEDICAL MATERIALS IINFORMATION
`
`Materials can be classified in a variety of different ways. The
`following, which is suitable for medical devices, sorts by type
`and application: synthetic polymer, biodegradable materials,
`tissue-derived materials, bioderived macromolecules, passive sur(cid:173)
`face coatings, bioactive and tissue-adhesive materials, metals,
`ceramics and glassy carbons, composites, and nano materials.
`Table 2 gives examples of materials in each category, a medical
`
`device in which it is used, a list of ISO 10993 tests that it passed
`when fabricated as part of that medical device, and literature
`citations on its blood and soft-tissue compatibility. These data
`were extracted from ASM lntemational's Materials for Medical
`Devices Database, Cardiovascular Implant Materials Module
`(ASM International and Granta Design, 2007).
`The database is an extensive resource, containing the enginee(cid:173)
`ring and biological performance of materials used in implantable
`cardiovascular devices as well as information about compati(cid:173)
`ble coatings and drugs, manufacturing processes, and an extensive
`database of relevant published literature. The data are compre(cid:173)
`hensively cross-linked and fully lraceable to original sources. The
`database can be used for information retrieval and selection of
`materials, drugs, and coatings for combination devices.
`
`Novartis Exhibit 2182.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Vol. 36, No. I, 2008
`
`BIOCOMPATIBILITY
`
`73
`
`TABLE 3.-Biocompatibility issues.
`
`Biomaterial Category
`
`Passive Bioactive Metals
`Ceramics &
`Synthetic Biodegradable Tissue Bioderived Coatings Coatings and Alloys Carbons Composites Nanomaterials
`
`Biocompatibility
`ADME, biodegradation
`byproducts, biodeposition
`Bioactivity
`Biodegradation particulates
`Biodegradation: Effect
`of infection, acid pH
`Biodegradation: Effect of
`hematoma, basic pH
`Calcification
`Cell membrane and blood-
`brain barrier passage
`Cells viability (cryopreserved
`allografts)
`Corrosion byproducts
`Cytotoxic preservatives
`Decellularization process
`Extrnctables
`Hypersensitivity reactions
`Immune responses
`Infectious contamination:
`Bacterial, viral,
`fungal, prion
`Lipid uptake
`Matching biomechanics of
`original tissue
`Necrotic cell death/apoptosis
`Purity
`Protein adsorption: Hydrophilic
`Protein adsorption: Hydrophobic
`Sterilization residuals
`Surface exposure of compounded
`particles
`Uptake in the reticuloendothelial
`system
`Thromboresistance
`
`Physical integrity
`Biostability
`Coating adherence
`Corrosion: Pitting, fretting, stress
`Cross-linking effects on properties
`Durability
`Fatigue life
`Fracture toughness
`In situ cure time: Bone cements,
`tissue adhesives
`Rate of biodegradation: Surface
`Rate of biodegradation: Bulk
`Wear
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`ADME = adsorption, deposition, excretion, and metabolism.
`
`Table 3 summarizes the types of biocompatibility issues that
`might be a consideration in each category of biomaterials
`described below. These considerations are general and are influ-
`enced by the nature of the material (e.g., biostable vs. biodegrad-
`able) and application (e.g., soft-tissue, blood, or hard-tissue
`applications). The issues highlighted are the ones of particular
`importance to that category. The physical integrity and failure of
`
`devices have profound influence on the safety and efficacy of
`the device and are therefore categorized in this table.
`
`SYNTHETICS
`
`Commonly available synthetic polymers are used in appli-
`cations such as sutures, housings for extracorporeal devices
`(e.g., blood oxygenators, hemodialysis, and plasmapheresis
`
`Novartis Exhibit 2182.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`74
`
`HELMUS ET AL.
`
`TOXICOLOGIC PATHOLOGY
`
`devices), vascular grafts, heart-valve stents, abdominal patches,
`periodontal patches, and low-cost, high-volume tubing, connec-
`tors, and bags.
`Examples include poly(amides), used as suture materials;
`poly(vinyl chloride) (PVC),1 used as tubing and bags for the
`storage of blood and pharmaceutical products; poly(ethylene
`terephthalate) textiles, used as large-diameter vascular graft
`materials and as sewing cuffs on mechanical and biological heart
`valves; polymethylmethacrylate (PMMA), used as a fixation
`cement for the orthopedic prosthetics and for housings for extra-
`corporeal devices; and poly(tetrafluoroethylene) (PTFE), used
`extensively as an expanded membrane material for medium-
`diameter vascular grafts, abdominal patches, periodontal mem-
`branes, and as anterior-cruciate-ligament prostheses (Helmus,
`2003). These materials tend to exhibit structural stability, relative
`biocompatibility, and low cost. Some vendors supply specifically
`designated biomedical grades. Master files are kept on the mate-
`rial production, and the vendors usually certify the material bio-
`compatibility based on standardized testing that shows that the
`materials as supplied are noncytotoxic and stable in the biologi-
`cal environment for certain periods of time and under certain
`conditions. Because of ongoing concerns with medical liability,
`some materials suppliers have limited the availability of their
`materials for use in permanent medical devices.
`Some of the unique properties of synthetic materials are
`being used in new-generation devices. Hydrogel coatings, such
`as poly(ethylene oxide), are used for blood contact because of
`low levels of protein adsorption and their exceptional lubricity
`(Helmus and Hubbell, 1993). Poly(ether urea urethanes) are an
`example of a thermoplastic elastomer with excellent fatigue
`resistance. This material is used in the pumping bladder of the
`artificial heart. Highly oriented and highly crystalline poly(eth-
`ylene terephthalate) film is used as a balloon in certain angio-
`plasty catheters because of its extraordinary bursting strength
`(Helmus and Hubbell, 1993). Table 3 summarizes the issues
`related to synthetic polymers.
`
`BIODEGRADABLES
`
`Biodegradable biomaterials are of high interest because of
`their ability to be absorbed gradually by the body (Kohn et al.,
`2004). The property of biodegradation in the biological envi-
`ronment makes these materials particularly appropriate for
`applications that are temporary in nature. These applications
`would normally require surgical removal.
`Biodegradable products must have breakdown products that
`are nontoxic and eliminated by the body’s metabolic pathways.
`The most widely used biodegradable materials are homopoly-
`mers or copolymers of alpha-hydroxy acids, such as lactic and/or
`glycolic acids (Williams, 1981). These materials can be formu-
`lated to degrade with a half-life for mass loss ranging from a few
`months to a few years. They are widely used as bioresorbable
`sutures and carriers for drug-eluting stents.
`Surface-erodible polymers are hydrophobic and are used to
`maintain the device’s physical strength for longer periods of time
`or to approach a zero-order release rate of pharmaceutical agents
`formulated into these surface-erodible polymers (Kohn et al.,
`
`2004). Examples include the polyanhydrides and polyorthoesters.
`Table 3 summarizes the issues related to biodegradables.
`
`TISSUE-DERIVED MATERIALS
`
`Processed tissues of human or nonhuman origin are used for
`ligaments, arteries, veins, and heart valves. Biodegradation and
`calcification during a period of 10 to 15 years has been an ongo-
`ing issue. Biologically derived materials are particularly suscep-
`tible to biodegradation mediated by proteolytic enzymes from
`plasma or from adherent cells. Calcification, seen particularly in
`biologically derived materials such as the bioprosthetic heart
`valve, can lead to stiffening and tearing of the bioprosthetic heart-
`valve cusps (Levy et al., 2003; Carpentier et al., 2007). Newer
`multiple-step processes entail treating the tissue to reduce anti-
`genicity and to increase longevity in vivo by enzyme digestion,
`detergent extraction, and/or cross-linking with glutaraldehyde or
`other bifunctional agents. Significant efforts in reducing calcifi-
`cation have been demonstrated with ethanol and aluminum chlo-
`ride treatments (Levy et al., 2003) as well as improvements in
`both calcification and thromboresistance with surfactant and
`alcohol treatment (Carpentier et al., 2007). Table 3 summarizes
`the issues related to tissue-derived materials.
`
`BIODERIVED MACROMOLECULES
`
`Purified macromolecules are used for cardiovascular and
`soft-tissue applications. Collagen, both from human and nonhu-
`man sources, is used as a space filler in cosmetic surgery, as a
`coagulation-inducing material, as a matrix to promote healing,
`and as a surface-treatment to make textile vascular grafts non-
`porous. Hyaluronic acid is being used as a coating to increase the
`lubricity of catheters and as an injectable into joints to reduce
`inflammation. Phosphorylcholine-derived polymers have been
`used to produce thromboresistant and biocompatible surfaces
`(De et al., 2002; Galli et al., 2001; Rose et al., 2004; Malik et al.,
`2001; Goreish et al., 2004). Human fibrin is used as a sealant and
`space filler in vascular and plastic surgery. Table 3 summarizes
`the issues related to bioderived macromolecules.
`
`PASSIVE SURFACE MODIFICATIONS AND COATINGS
`
`Specialized polymer coatings (e.g., silica-free silicones,
`hydrogels, and fluorocarbons), used to improve biocompatibil-
`ity, and in many cases, to increase lubricity, are being devel-
`oped for several cardiovascular applications (Hoffman, 1987).
`Plasma etching and plasma polymerization have also been used
`to modify surface properties. For example, the surface modifi-
`cation of vascular graft materials with nonpolymerizing gas
`plasmas (such as argon, oxygen, or nitrogen plasmas) has been
`observed to increase wettability and to generally increase the
`extent of cell attachment to materials. Treatment with a poly-
`merizing gas plasma, such as tetrafluoroethylene, has been
`used to place a very thin, highly cross-linked polymer over-
`layer on a variety of base polymer substrates. These processes
`allow modification of surface properties without changing the
`bulk physical properties of the materials. Ultra low temperature
`isotropic (ULTI) carbon is used to modify Dacron polyester
`
`Novartis Exhibit 2182.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Vol. 36, No. I, 2008
`
`BIOCOMPATIBILITY
`
`75
`
`sewing cuffs and vascular grafts to improve their "blood com(cid:173)
`patibility" properties (H aubold et al., 198 1). Table 3 summa(cid:173)
`rizes the issues related to surface coatings.
`
`B IOACTIVE COATINGS AND T ISSUE AoHBSIVBS
`
`Bioactivity refers to the inherent property of some materials
`to participate in specific biological reactions. Bioactive coat(cid:173)
`ings may be formed from molecules that prevent blood clotting
`or initiate the enzymatic degradation of thrombus. Heparin
`coatings have been applied on cardiovascular implants, includ(cid:173)
`ing stents, and annuloplasty rings. A heparin surfactant coating
`on polyester fabric of annuloplasty rings was shown in an
`arterio-venous shunt model to significantly reduce thrombus
`and platelet uptake (Helmus and Scott, 1999). Some negatively
`charged surfaces initiate the degradation of complement compo(cid:173)
`nents with the potential for fewer side effects for extracorporeal
`treatments such as dialysis (Chenoweth, 1987). Cell-adhesion
`peptides and proteins are being investigated for enhancing
`endothelialization and soft-tissue adhesion (Tweden et al., 1995).
`Antimicrobial surfaces have been fabricated by immo bilizing
`broad-spectrum antimicrobials such as silver, silver sulfadiazine,
`or specific antibiotics.
`Bioactive coatings for orthopedic and dental-implant applica(cid:173)
`tions consist of calcium phosphate ceramics. These materials
`promote biological fixation by direct bonding with bone because
`of their chemical similarity with bone mineral (Cook et al.,
`199 1). Interactions with the glycosaminoglycan molecules allow
`cellular deposition of collagen, which functions as a scaffold for
`mineralization.
`Tissue adhesives such as methyl cyanoacrylates were used
`before the 1960s in the United States, but the hydrolytic break(cid:173)
`down product was formaldehyde, which is cytotoxic. This
`resulted in a greatly restricted use of cyanoacrylate. Different
`cyanoacrylate analogues, such as octyl-2-cyanoacrylate, are
`currently being evaluated and do not appear to demonstrate
`cytotoxic responses (Nitsch et al., 2005).
`Fibrin glue is being investigated for producing microvascu(cid:173)
`lar anastomoses (Amrani et al., 200 1) and controlling excessive
`bleeding by acting as a hemostatic agent. Table 3 summarizes
`the issues related to bioactive coatings.
`
`METALS AND METALLIC ALLOYS
`
`Commonly used alloys include austenitic stainless steels,
`cobalt-chrome- molybdenum (Co-Cr-Mo), tantalum, and tita(cid:173)
`nium. Austenitic stainless steels, Co-Cr-Mo alloys, titanium,
`and titanium alloys are the preferred metals for orthopedic and
`dental applications.
`Although stainless steels are used for permanent implants, they
`have shown that nickel-ion release can result in nickel hypersensi(cid:173)
`tivity. Austenitic stainless steel is widely used in guidewires for
`angioplasty and angiography catheters, endovascular stents, frac(cid:173)
`ture plates, nails, screws, and joint replacement (Helmus, 2003).
`Titanium alloys are used for heart- valve and artificial-heart
`structural components because of their low density, high strength,
`low modulus (stiffness), low corrosion rate, and lack of cytotoxic
`effects. Titanium and its alloys are also used for pacem aker
`
`cases, fracture plates, nails and screws, and joint- replacement
`packaging for e lectrical stimulators because of these same
`properties (Helmus, 2003).
`Endovascular stents can be fabricated from titanium, tanta(cid:173)
`lum, nickel-titanium shape- memory alloys, austenitic stainless
`steel, and cobalt chrome. These devices can keep a vessel from
`rapidly closing after angioplasty if plaque rupture occurs.
`Anticoagulation and antiplatelet therapy is required for a few
`months with these devices. Most stents are crimped onto the
`end of an angioplasty catheter and expanded by the balloon at
`the site of the lesion to restore blood fl ow. Furthermore, the
`stent reduces but does not necessarily e liminate the restenosis
`that occurs because of the hyperplastic response of the lesion
`after injury caused by angioplasty. Other designs are self(cid:173)
`expanding and use the springlike property of the metallic alloy
`to be positioned. Nicke l- titanium alloys are typically used in
`these devices.
`Co-Cr alloys are used for dental implants, bone plates, wires,
`screws, nails, joint- replacement parts, and self-expanding stents
`and in heart valves and rings because of their corrosion resist(cid:173)
`ance, fatigue resistance, and strength (Helmus, 2003). Table 3
`summarizes the issues related to metal alloys.
`
`CERAMICS AND GLASSY CARBONS
`
`Ceramics have been used extensively in dental and orthopedic
`applications (Hench and Best, 2004). Specifically, dense, high(cid:173)
`purity alumina has been used as the ball and socket of total-hip
`endoprostheses (Griss and Heimke, 1981). Alumina has also been
`used in dental implants. Dense hydroxylapatite ceramics have
`been used in j aw reconstruction for maintenance of the alveolar
`ridge (Swart and Groot, 1987). Granules of hydroxylapatite have
`been used to fill bony, periodontal, and alveolar ridge defects.
`Carbons have been widely used as heart- valve components,
`particularl y as leaflets in mechanical valves, because of their
`resistance to degradation and their very high resistance to wear
`(Barenberg et al., 1990; Williams 198 1; Ritchie et al., 1990). In
`particular, pyrolytic carbons, produ