Biomedical Materials/Polymers Lecture 1 (PDF)

Introduction Biomedical materials/polymers Aránzazu del Campo Biomaterials Science: An introduction to Materials in Medicine, 3rd Edition www.leibniz-inm.de Edited by B. D. Ratner, A. S. Hoffman, F. J....

Introduction Biomedical materials/polymers Aránzazu del Campo Biomaterials Science: An introduction to Materials in Medicine, 3rd Edition www.leibniz-inm.de Edited by B. D. Ratner, A. S. Hoffman, F. J. Schoen, J. E. Lemons, Elsevier 2013 1 Lecture plan Dates Topic Lecture 15.10.2024 Fundamentals Biomedical Materials. Selection criteria for biomaterials for medical devices del Campo Physicochemical properties of polymer materials of relevance for biomedical applications, 22.10.2024 Müller, Asensio and methods to characterize them 29.10.2024 Synthetic biomedical polymers, resorbable (I) del Campo 05.11.2024 Synthetic biomedical polymers, resorbable (II) del Campo 12.11.2024 Synthetic biomedical polymers, non-resorbable (I) del Campo 19.11.2024 Biomedical hydrogels Asensio 26.11.2024 Additive Manufacture of biomedical polymers Steudter 03.12.2024 Protein adsorption on surfaces. Non-fouling and non-thrombogenic polymers Sankaran 10.12.2024 Immune response to biomaterials Trujillo 17.12.2024 Smart Textiles, Intelligent Implants, Wearable devices and biosensors Sankaran 07.01.2025 Case studies: medical devices del Campo 14.01.2025 Case studies: medical devices del Campo 28.01.2025 EXAM (multiple choice text) 04.02.2025 Presentations students del Campo, Asensio 11.02.2025 Presentations students del Campo, Asensio 18.02.2025 Presentations students del Campo, Asensio Evaluation consists of two parts: 1) Exam (multiple choice) 2) Oral presentation of a commercial biomaterial as part of www.leibniz-inm.de a commercial medical device (list will be provided) 2 Biomaterial Definition “A material intended to interface with “A material designed to take a form which biological systems, to evaluate, treat, can direct, through interactions with living augment or replace any tissue, organ or systems, the course of any therapeutic or function of the body” diagnostic procedure” Consensus Conference on Definition of Biomaterials, Consensus Conference on Definitions of Biomaterials 1986 for the Twenty-First Century, 2018 3 Are these biomaterial? 4 Biomedical material Definition “An instrument, apparatus, implement, A biomaterial machine, contrivance, in vitro reagent, or other similar or related article, including any “A material designed to take a form which component, part or accessory, which is can direct, through interactions with living intended for use in the diagnosis of disease systems, the course of any therapeutic or or other conditions, or in the cure, mitigation, diagnostic procedure” treatment of prevention of disease in a man” „ Consensus Conference on Definition of Biomaterials, Consensus Conference on Definitions of Biomaterials 1986 for the Twenty-First Century, 2018 5 Examples of medical devices where biomaterials are important external medical devices: contact lenses, bandages, skin and wound dressings, dialysis membranes… implanted medical devices: restorative implants, sutures, stents, pacemakers, brain electrodes, implants to regulate fertility... scaffolds for regenerative medicine and tissue engineering aesthetic implants (i.e. breast implant) carriers for drugs (nanomedicine) man-machine interface/wearable electronics cell culture dishes or microarrays for diagnostics/teranostic assays 6 Biomaterials across all material classes Metal, ceramic, polymeric, composites 7 https://www.mdpi.com/2227-9717/9/11/1949 Why using polymers as biomaterials? − Stiff / Flexible /Ductile − Easy to process (low temperatures, different morphologies) − Light − Organic, flexible chemistry and functionalization − Hydrated (hydrogels) − Cheap 8 Outline 01 History/Overview Biomaterials 02 Selection Criteria of Biomaterials 03 Classification of Biomaterials www.leibniz-inm.de 9 Biomaterials science is a young field No „Biomaterial“ concept 50 years ago Today: No medical device manufacturers Expected continuous growth (with except for external prosthesis (limbs, advancing healthcare and aging fracture fixation, glass eyes, dental society) devices) Relevant market, stringent regulation No regulations, no understanding of Multidisciplinary: chemistry + biology biocompatibility, no courses on + medicine + materials engineering biomaterials 10 Prehistory of Biomaterials 3000 BC: Egyptians used linen sutures for wound closure (alternative to cautery) 600 AC: Mayans used sheashells (nacre) for artificial teeth, including bone integration 1775: first example of bone fracture fixation with metal wire (Drs. Lapuyade & Sicre, Toulouse) 1829: HS Levert performed first toxicity study in dogs (Gold, silver, platinium, lead) 1860: Adolf Fick invents and experiments with glass contact lens 1936 PMMA contact lenses were developed, Contact lenses entered the market in 80‘s 1860s: Aseptic surgical materials by J Lister (Glasgow) 1870: Listers materials for aseptic surgery (uptaken by Germans during Franco-Prussian war) 11 https://www.woehlk.com/startseite.html 12 Joseph Lister (1827-1912), Professor of surgery in Glasgow Joseph Lister is the surgeon who introduced new principles of cleanliness which transformed surgical practice in the late 1800s. We take it for granted that a surgeon will guard a patient's safety by using aseptic methods. But this was not always the case, and until Lister introduced sterile surgery, a patient could undergo a procedure successfully only to die from a postoperative infection known as ‘ward fever’. Lister worked in Glasgow in 1860 as Professor of Surgery. He read Pasteur‘s work on micro-organisms and decided to experiment with using one of Pasteur's proposed techniques, that of exposing the wound to chemicals. He chose dressings soaked with carbolic acid (phenol) to cover the wound and the rate of infection was vastly reduced. Lister then experimented with hand-washing, sterilising instruments and spraying carbolic in the theatre while operating, in order to limit infection. His lowered infection rate was very good and Listerian principles were adopted throughout many countries by a number of surgeons. Lister is now known as the ‘father of antiseptic surgery’. sciencemuseum.org.uk 13 Prehistory of Biomaterials 1886: studies of Nickel-plated sheet steel with nickel-plated screws to treat bone fractures 1930 introduction of metals suitable for orthopedic applications (stainless steel, titanium, cobalt chromium alloys) 1938 development of total hip prosthesis concepts 1950‘s first sucessful hip prosthesis with femoral stem, ball head and plastic acetabular cup 1952 osteointegration of Ti was discovered by chance 1981 HDPE cup 1968 total knee replacements 1912: Nobel in Medicine to Dr. Alexis Carrel for development methods to suture blood vessels (anastomose) 14 wikipedia Alexis Carrel, France 1873-1944 Vascular suture The technique of "triangulation", using three stay-sutures as traction points in order to minimize damage to the vascular wall during suturing, was inspired by sewing lessons he took from an embroideress and is still used today. Between 1901 and 1910, Alexis Carrel, using experimental animals, performed every feat and developed every technique known to vascular surgery today. He had great success in reconnecting arteries and veins, and performing surgical grafts, and this led to his Nobel Prize in 1912. Nobel Prize in Physiology or Medicine in 1912 for pioneering vascular suturing techniques 15 The era of the „surgeon hero“ (1940-60) Paralell development of „polymer materials/plastics“ Development of high performance metals, ceramics and especially polymers Materials manufactured for cars or airplanes were taken „off the shell“ by surgeons and applied to medical problems NO regulation. Solutions tested ad hoc. 1941: Nylon as suture material 1939: cellulose for wrapping blood vessels (and detection of „fibrotic“ reaction) 1940‘s implanted PMMA, Nylon 1947 implanted PE 1943 first dializer; 60‘s Teflon membrane for dialysis 1949 evidence that additives in plastics „sweat out“ and can cause foreign body reaction 1949 discovery pacemaker: 1958 development of first wearable pacemaker, 1959 development fully implantable pacemaker 1957 first artificial heart pump implanted, first successfull artificial hearts implanted in 80‘s in the clinics 50‘s PVA sponges implanted for breast augmentation 60‘s silicone implants with acceptable performance 16 The first „plastics“ https://www.chem4us.be/plastics-and-bioplastics-a-200-year-history-of-research-and-development/ 17 The era of Designed Biomaterials In the 60‘s materials started to be designed specifically for medical applications. New materials were designed de novo, specifically for medical use, such as biodegradable polymers and bioactive ceramics. New technologies for biomaterials fabrication: polyesters fibers, wovens, cellulose acetate as hollow fibers for dialysis membranes) In the 70‘s deveopment of Poly(ethylene oxyde) as protein resistant coating for implants Some materials were modified to provide special biological properties/response (heparin surface modification for anticoagulant surfaces). 1976: Regulation for testing and production of medical devices 18 Most biomaterials applied today in the clinic are based on biomaterials developed in the 60-80s Examples: 19 Poly(methyl methacrylate) = PMMA Lucite, Plexiglass Major component of: o injectable bone cement for orthopedic implants Liquid + (spinal surgery) powder o Intraocular lenses o hard contact lenses Amorphous, transparent and glassy at room temperature Commercial product: CeSys, Mathys Medical, https://www.mathysmedical.com 20 Poly(2-hydroxymethyl methacrylate) = pHEMA Mayor component in: soft, hydrogel contact lenses Transparent, hydrophilic, non fouling (low protein adsorption) Polymerizes in a mould for contact lens manufacturing Poly(acrylic acid) = PAA Major component of: Dental cements (glass ionomers) mixed with inorganic salts. Cations form ionic crosslinks with the COOH groups of the PAA chain Mucoadhesive (hydrogel) for mucosa drug delivery applications Hydrophilic, charged, forms crosslinked networks High Density Poly(ethylene) = HDPE Major uses: Artificial hips and prosthetic joints Tubing for drains and cathethers Mechanically resistant, tough, wear resistant Processable as thermoplastic in different forms http://luigigentilemd.com/HipKnee/THE%20CHARNLEY%20TO TAL%20HIP%20REPLACEMENT.htm 23 Poly(propylene) = PP Sutures, meshes for hernia repair Good chemical resistance, good tensile strength https://www.aesculapusa.com/products/wound-closure/non-absorbable-surgical- sutures/premilene-non-absorbable Poly(tetrafluorethylene) (=PTFE,Teflon) Catethers, vascular grafts (Gore-Tex), blood storage bags, dialysis tubes Flexible Low surface energy Low protein adsorption, good lubricity http://www.medicalnewstoday.com/articles/152902.php http://www.goremedical.com/resources/downloads/featu red/acusealvg/content/AP0064EN2.HEMODIALYSIS.BRO.F NL.MR.pdf Poly(dimethylsiloxane), PDMS Prostheses such as finger joints, heart valves, breast implants, nose reconstruction. Also used for catheters and drainage tubing and insulation for pacemaker leads Soft elastomer High oxygen permeability Low surface energy > low protein adsorption http://www.smw.ch/content/smw-2012-13614/ Poly(ethyleneterephthalate), PET (Dacron) Sutures, fabrics, meshes for fixation hernia repair, ligament reconstruction High tensile strength, mostly used in fiber form http://www.textileworld.com/textile-world/textile-news/2001/12/textiles-to-the-rescue/  Poly(D,L-lactide-co-glycolide), PLGA For resorbable surgical sutures, drug delivery and orthopedic appliances such as fixation devices Degradable http://www.klsmartinnorthamerica.com/products/implants/maxillofacial/sonicweld- rxR/implant-selection/  Polyurethanes Pacemaker insulation, catheters, vascular grafts, heart assist balloon pumps, artificial heart bladders and wound dressing Tough elastomers, flexibility in properties depending on monomer selection http://www.businesswire.com/news/home/200808070053 https://www.wired.com/2005/01/artificial-hearts-the-beat-goes-on/ 43/en/CardioWest-TM-Artificial-Heart-Approved-Highest- Reimbursement Biomaterials development: from research to biomedical product www.leibniz-inm.de https://www.nature.com/articles/natrevmats201640 30 Not part of this lecture The contemporary era: Responsive carriers for drug delivery Resorbable, responsive Carriers for drug delivery https://doi.org/10.1016/B978-0-323-91668-4.00012-5 The contemporary era Drug delivery devices: microneddle skin patches https://www.tandfonline.com/doi/full/10.1080/21691401.2017.1304409 DOI: 10.1016/S0140-6736(17)30575-5 Research stage, not yet approved in the clinic The contemporary era Drug eluting microneedles for the delivery of drugs to the eye https://www.nature.com/articles/s41467-018-06981-w 33 Not part of this lecture The contemporary era: Biomaterials for tissue engineering 3D Scaffolds to encapsulate cells and support tissue regeneration 34 Not part of this lecture Evolution biomaterials for tissue engineering 3D Scaffolds to encapsulate cells and support tissue regeneration 35 https://www.nature.com/articles/s41578-020-0209-x Not part of this lecture Biomaterials for tissue engineering Morphology + Physical properties + Bioactivity (drugs) www.leibniz-inm.de 36 The contemporary era: 3D Bioprinting 3D Printed medical devices 3D Printed organs 37 Mostly at research stage, expected rapid translation to clinical devices The contemporary era: devices for health monitoring Wearables for sensing with mutiple integrated functions Recommended reading: https://www.nature.com/articles/s41587-019-0045-y 38 Outline 01 History of Biomaterials 02 Selection Criteria of Biomaterials 03 Classification of Biomaterials www.leibniz-inm.de 39 The major factors determining a biomaterials choice 1. Functional performance 2. Biocompatibility 3. Manufacturing criteria 4. Economic issues 40 The major factors determining a biomaterials choice 01 Functional performance: material shows and retains suitable properties under application conditions 41 Functional performance of a resorbable suturing thread Function: Relevant material design properties: Temporal tissue fixation Mechanical strength vs. time Resorbability … 42 Functional Performance of a knee joint replacement Function: Relevant material design properties: Load transmission and stress distribution High mechanical stability Articulation Low friction Wear resistance https://www.victrex.com/en/news/2021/01/peek-knee 43 Functional Performance of a Intraocular contact lens Function: Relevant material design properties: Light focusing Transparency Refractive Index Stability No biofouling 44 The major factors determining a biomaterials choice 01 Functional performance: material shows and retains suitable properties under application conditions Specific optical, electrical, thermal properties Mechanical stability (wear, stress damage, fracture, cold deformation) Degradability Physicochemical stability against fouling (absorption biomolecules), water absorption (softening) Chemical stability (hydrolisis, enzymes, mineral deposition) Electrochemical stability (corrosion, caveating) 45 The major factors determining a biomaterials choice 02 Biocompatibility: The ability of a material to perform with an appropriate host response in a specific application Non toxic Non immunogenic Non fouling, resistant to infection Non thrombogenic 46 Toxicity To what/whom? time scale? cytotoxicity, sensitization, irritation, intracutaneous reactivity, systemic toxicity, subacute and chronic toxicity, genotoxicity , carcinogenicity, reproductive or developmental toxicity… 47 Immune response to a biomaterial Foreign body reaction cascade Lecture on 10.12! Grainger, Nature Biotechnology 2013 Sequence of Host Reactions following Implantation of Medical Devices Injury (distorsion of vascular system) Blood-material interactions Provisional matrix formation (coagulation – platelets, fibrin…) Accute inflammation: exudation of fluid and plasma proteins (edema) and emigration of leukocytes (predominantly neutrophiles) to phagocytose (recognition, engulfment, degradation) biomaterial and possible microorganisms. Chronic inflammation: Presence of macrophages, monocytes and lymphocytes, with the proliferation of blood vessels and connective tissue as a consequence of persistent inflammatory stimuli. Granulation tissue (rosa tissue in injuries): Within day 1 after implantation, the healing response is initiated by monocytes and macrophages. Fibroblasts and entothelial cells at injury site proliferate and form granular tissue, i.e., the specialized tissue of healing inflammation. Small blood vessels form by sprouting endothelial cells from existing ones (angiogenesis). Fibroblasts synthesize coll and proteoglycans to form a fibrous capsule. Macrophages are also part of the granulaion tissue Foreign-body reaction: layer around the material composed of foreign body giant cells and the components of granulation tissue. It might persist over life time of implant, and isolate the material from surrounding tissue Fibrosis, encapsulation last stage of healing response to biomaterials 49 Host reaction/ to Biomaterials Our body has defense mechanism (immune system) to protect from deleterious external threats: bacteria, injury, or foreign bodies like biomaterials In contrast to living organ transplants, biomaterials are not generally „rejected“. The process of organ rejection denotes an inflammatory process that results from a specific immune response and which causes tissue death. Synthetic materials do not generate specific immunological reaction, but nonspecific inflammation (i.e. foreign body reaction or host reaction): - Macrophages attempt to phagocytise the material (engulfment and degradation, not successfull). They get activated in this fight and secrete cytokine that stimulate inflammation or fibrosis. The more biocompatible the material ist, the less inflammatory response. The late tissue reaction is encapsulation by a relatively thin fibrous tissue capsule (composed of coll and fibroblasts). - Mononuclear giant cells in the vecinity of the biomaterial are considered evidence for strong inflammatory response 50 Evolving view of biomaterial interactions with the immune system www.leibniz-inm.de https://www.nature.com/articles/natrevmats201640 51 Fouling, Biofilms, Infection Lecture on 03.12! 52 Biofilm formation The first step of biofilm formation is attachment of bacteria to the biomaterial‘s surface The surface properties of the biomaterial determine the interactions between bacteria and biomaterial 53 Antifouling surfaces in nature Life-time lubricant infused surface Gland www.leibniz-inm.de 54 Example:Slippery liquid-infused porous surface (SLIPS) with non-fouling properties The slow release of a surface liquid layer prevents long-term attachment of organisms ACS Biomater. Sci. Eng. 2024, 10, 6, 3655-3672 55 Thrombogenicity Lecture on 03.12! Biomaterials in contact with blood When non phyiological surfaces contact blood, a sequence of thrombotic interactions occur: Plasma protein deposition (mainly fibronigen), which occurs in seconds Adhesion of platelets and leukocytes Blood coagulation >> cloth >> Thrombus These are the same reactions that the body activates to stop bleeding from injured blood vessels (coagulation cascade) 56 The coagulation cascade Nature Reviews Cardiology 2015 57 The coagulation cascade In response to injury (extrinsic pathway), the factor VIIa−tissue factor complex, assembled on a phospholipid surface, catalyzes conversion of factor X to activated factor X (Xa). Factor Xa, assembled on a phospholipid surface with its cofactor Va, catalyzes cleavage of prothrombin (factor II) to produce thrombin (IIa). Thrombin cleaves the soluble protein fibrinogen into a form that can undergo polymerization to form the fibrin clot. Small amounts of thrombin formed in the extrinsic pathway promote coagulation through the intrinsic pathway (involving the IXa-VIIIa complex), which also catalyzes the conversion of factor X to Xa. Thus, extrinsic and intrinsic pathways converge at the activation of factor X, with the remaining sequence of reactions (the common pathway) culminating in fibrin clot formation. The major factors determining a biomaterials choice 03 Manufacturing criteria Cost-effective processing, upscaling and manufacture Packaging Stability, Lifetime Marketing requirements Sterilization 59 What is the XXX Life of a medical device? − Shelf Life − Expiration Date − Expected Lifetime / Useful Life − End of Life − Service Life − Life Cycle Definition according to EU guidelines at: https://casusconsulting.com/eu-shelf-expiration-expected-lifetime-useful-service-life/ Exercise: What is the XXX Life of the contact lens TOTAL® 30 (Alcon)? https://total.myalcon.com/de/products/total30/ www.leibniz-inm.de 60 Sterilization www.leibniz-inm.de 61 Sterilization methods Moist heat or steam sterilization in autoclave (T,P) Ethylene oxide  Radiation Plasma, Microwave, light … 62 Moist heat sterilization (Autoclaving) Advantage: Easy, established, not dangerous/toxic Limitation: Not practicable for many nonmetallic biomaterials 63 Moist heat sterilization (Autoclaving) 64 Moist heat sterilization (Autoclaving) Exposure to saturated steam under pressure Process temperature 121-125°C in pressure-rated chamber All surfaces of the device need to be contacted by steam. Packaging has to allow steam to penetrate freely Typical process takes 15-30 mins Moist heat sterilization kills microoragnisms by destroying metabolic and structural components essencial for replication. The coagulation of essential enzymes and the disruption of protein and lipid complexes are the main lethal events Autoclaves are available in a range of sizes, from the small tabletop versions used by dentists and tattooists, to the industrial sized models found in large hospitals and kitchens. Main use in hospitals (sterilization metallic surgical instruments and supplies (linen drapes, dressings) and biological laboratories Advantages: cheap, efficient, quick and simple method, lack of chemicals/toxic residues Limitation: Not practicable for many nonmetallic biomaterials 65  Sterilization with Ethylene Oxide (EO) gas Advantages: efficacy at low temperatures, high penetration ability and compatibility with wide range of materials Disadvantages: toxicity of residual EO, release of EO in poststerilization manufacturing and storage areas 66 Sterilization with Ethylene Oxide (EO) gas EO is liquid below 11°C. Toxic and human carcinogen Lethal effect of EO on microorganisms is mainly due to akylation of amine groups on nucleic acids Process: Products contained within gas permeable packaging are loaded in sterilization vessel. Vessel is evacuated, moisture is introduced for humidity 60-80%. EO or EO/N2/CO2 OR CFC mixture is injected at final concentration 600-800 mg/L. Temperature of the process 40-50°C. Time 2 to 16 hours depending on aereation time. Chamber is evacuated and flushed with air Eventually aereation at higher temperatures is required for removing residual EO Used to sterilize surgical sutures, intraocular lenses, ligament and tendon repair devices, adsorbable and nonadsorbable meses, vascular grafts and stents… Disadvantages: toxicity of residual EO, release of EO in poststerilization manufacturing and storage areas Advantages: efficacy even at low temperatures, high penetration ability and compatibility with wide range of materials 67 -Radiation Plant for sterilization Effects of -radiation in organic matter are chain scission and crosslinking. The  rays cause ionization of key cellular components, specially nucleic acids. This results in the death of the organisms. Advantages: simple, rapid, cost effective. Gamma rays are highly penetrating Disadvantages: high investment, chain scission in polymer biomaterials can alter properties, continuous decay of the isotope, which results in longer processing times and need for addidtional isotope for the irradiator 68  -Radiation Sterilization Ionizing irradiation involving either 60Co isotope (-radiation). Process and equipment: The 60Co isotope is contained in sealid stainless steel „pencils“ held in a planar array within a metal source rack. When the irradiator is not in use, the source rack is lowerd into a water-filled pool (25 feet deep). At this depth, the radiation cannot reach the surface and is safe for personell to enter the radiation cell. Outside walls and ceiling of the cell are constructed of thick, reinforced concrete for radiation shielding. Materials to be sterilized are moved around the raised source rack ensuring that radiation dose is uniformly delivered. Dosimeters (radiation measuring devices) are placed along the materials to in situ document the sterilization dose. The most commonly validated dose used to sterilize medical products is 25kGy. Mode of action: The radioactive decay of 60Co (5.3 years half time) results in the formation of 60Ni, the ejection of an electron and the release of  rays. The  rays cause ionization of key cellular components, specially nucleic acids, which result in the death of the organisms. Effects of -radiation in organic matter are chain scission and crosslinking. The ejected electron does not have suficcient energy to penetrate the wall of the pencyl and does not participate in the sterilization process. Polyethylene, polyesters, polystyrene, polysulfones and polycarbonates are compatible wiht -radiation sterilization. PTFE is not compatible because of extreme radiation sensitivity. -radiation is frequently used for medical products (surgical sutures, metallic bone implants, knee and hip prostheses, syringes) Advantages of -radiation sterilization: simple, rapid, cost effective. Gamma rays are highly penetrating Dissadvantages: high investment, incompatibility with some materials, continuous decay of the isotope, which results in longer processing times and need for addidtional isotope for the irradiator 69 Comparison operation conditions for different sterilization techniques Journal of Tissue Engineering 2016, Volume 7: 1–13 70 Comparison operation conditions for different sterilization techniques Journal of Tissue Engineering 2016, Volume 7: 1–13 71 The major factors determining a biomaterials choice Economic issues Regulations (market specific), safety Acceptance (eg. Syringes, taste of a drug formulation) Competing products Market size (european, american, asian…), patient number (rare diseases) Healthcare system 72 Outline 01 History of Biomaterials 02 Selection Criteria of Biomaterials 03 Classification of Polymeric Biomaterials www.leibniz-inm.de 73 Classification of Polymeric Biomaterials Attending to: Source Durability Safety/regulation (as part of medical devices) Synthetic Polymers Permament Class I: Short-term use, do not internally contact the user. silicones, acrylates, PP, PE, Resorbable (degradable) adhesive bandages PEEK… Natural polymers Class II: minorly invasive, external silk, chitosan, collagen, and relatively short-term. decellularized matrix… hearing aids, blood pumps, catheters, contacts, electrodes Class III: long-term, considerably invasive cardiac pacemakers, intraocular lenses, heart valves, orthopedic implants Part of this lecture 74