Application of Biomaterials in Medical Devices PDF

Application of Biomaterials in Medical Devices Lecture 4 Application of Biomaterials in Medical Devices Asst. Prof. Dang Thuy Tram [email protected] BG4231 & BG6001 – Advanced Biomaterials 1 Applications of Biomaterials in Medical Devices Lecture Outline 1. Overview of biomaterials in medica...

Application of Biomaterials in Medical Devices Lecture 4 Application of Biomaterials in Medical Devices Asst. Prof. Dang Thuy Tram [email protected] BG4231 & BG6001 – Advanced Biomaterials 1 Applications of Biomaterials in Medical Devices Lecture Outline 1. Overview of biomaterials in medical devices 2. Biocompatibility of materials 3. Structural compatibility and mechanical durability 4. Biomaterials for Cardiovascular applications 5. Biomaterials for Opthamologic applications 6. Emerging classes of polymeric biomaterials for medical devices 2 Application of Biomaterials in Medical Devices Overview of biomaterials in biomedical devices • FDA definition : A biomedical device is an instrument, apparatus, machine, implant, in vitro reagent… which is intended for  (1) use in the diagnosis of disease or other conditions,  Or (2) in the cure, mitigation, treatment, or prevention of disease  Or (3) intended to affect the structure or any function of the body  And DOES NOT achieve any of its primary intended purposes through chemical action or upon being metabolized • World-wide market for medical devices is over $300 billion • Biomaterials constitute multiple components of these medical devices Cardiovascular applications Opthamologic applications Dental applications Orthopedic applications Other applications • Adhesive & sealants • Burn dressing & skin substitute • Diagnostics http://www.istockphoto.com 3 Application of Biomaterials in Medical Devices Overview of biomaterials in biomedical devices http://247wallst.com Implantable medical devices No. of procedure In USA Annual Expense (USD) Cost per Major procedure Manufacturers 1. Artificial Eye Lenses 2.582M $8-10B 3.2-4.5k Alcon Lab/Norvatis; Abbott, Bausch & Lomb 2. Ear Tubes 0.715M $1-2B $1-4.5k N/A 3. Coronary Stents 0.569M $7.5B $13k Boston Scientific, Abbot 4. Artificial Knees 0.543M $12B $22k Zimmer, Depuy/J&J, Stryker, Biomet, Smith & Nephew 5. Metal screws, pins, plates.. 0.453M $4.5B $2-20k Synthes 6. Intra-Uterine Devices 0.425M $0.34B $0.8k Teva Pharm, Bayer Healthcare 7. Spine crews, rods, discs 0.413M $10B $25k Medtronic 8. Breast implants 0.366M $0.992B $3.35k Allergan, Mentor 9. Heart pacemakers 0.235M $4.5B $20k Medtronic, St Jude Med, Boston Sci 10. Artificial hips 0.230M $10.5B $45k Zimmer, Depuy/J&J, Stryker, Biomet, Wright Medical 11. Cardioverter Defibrillator $0.133M $5.5B $40k Medtronic, St Jude Med, Boston Scientific 4 Application of Biomaterials in Medical Devices Biocompatibility of materials • Primary consideration for application of biomaterials in medical devices is treatment outcome, very application-specific • Key material properties needed for each application is uniquely dependent on the physiological environment of the application. • Material design and selection are based on (1) pathological conditions requiring the implant, (2) desired functionality, (3) potential harmful biomaterial-tissue interaction • Important to understand material-tissue interaction which are critical for complications following implantation of medical devices • Biocompatibility – an evolving concept : “ the ability of a material to perform with an appropriate host response in a specific application” – D.F Williams  The material should exhibit functional performance and not merely exist in the host tissue  The response has to be appropriate for the desired application  The nature of the response may vary depending on specific application • Do not confuse “biocompatibility” with “cytocompatibility”, “biological inertness”, “blood compatibility”, “tissue-compatibility” 5 Application of Biomaterials in Medical Devices Structural Compatibility and Mechanical Durability of Devices • Classification of body tissues : soft vs hard tissues  Soft tissues : lower Young modulus (stiffness), lower tensile strength (weaker) eg skin, tendon, arterial tissues  Hard tissues , eg bone, tooth, • Structural compatibility : optimal matching of the implant to host tissue in terms of mechanical and structural properties  Stiffness, strength to high mechanical loading, fatigue strength, wear resistance  Mismatch can cause poor functionality and pathological complication eg faillure of bone replacement by ceramic or cement implant, or mismatched compliance of the prosthetic polymeric vascular graft and native blood vessels 6 Application of Biomaterials in Medical Devices Applications of biomaterials in medical devices Important consideration in application of biomaterials for medical devices • Underlying pathology of the diseased conditions that the device is designed to treat • Criteria for material design and selection • Important complications to be circumvented Selected applications • Cardiovascular applications  Heart valves  Endovascular stents • Opthamologic applications  Contact lens  Intraocular lens 7 Application of Biomaterials in Medical Devices Cardiovascular Applications Heart Valves Pathology of Heart valve failure • Heart valve function : open and close once/second, 40M/year and 3B in 75yr lifetime • Dysfunction  Stenosis : obstruction of flow  Regurgitation : reverse flow across the valve (leaky valve) • Most common valve disease requiring valve replacement : calcific aortic stenosis • Whenever possible, repair is preferred over replacement http://www.medicinenet.com/ https://www.youtube.com/watch?v=DzoLce84cag Time : 0:05-1:45 8 Application of Biomaterials in Medical Devices Cardiovascular Applications Heart Valves Design criteria for replacement valve • • • • • • Non-thrombogenic Non-hemolytic Infection resistant Chemically inert Durable Easily inserted Common complications • Formation of blood clots – Thromboembolic complication • Valve infection • Structural valve dysfunction due to material degradation Classification of artificial valves • Mechanical valves caged-ball tilting disk B bi-leaflet tilting disk • Bio-prosthetic valves porcine bovine 9 Application of Biomaterials in Medical Devices Cardiovascular Applications Heart Valves Materials for heart valve component Pyrolytic carbon - High strength, fatigue/wear resistance - Highly resistant to blood clotting Cobalt-chrome, Titanium alloy - Structural integrity Teflon (PTFE) , Dacron (PETE) - Flexible - Easy to suture - Minimal irritation to adjacent tissues 10 Application of Biomaterials in Medical Devices Cardiovascular Applications Endovascular Stents and Vascular Graft Pathology of vascular diseases • Atherosclerosis : slowly progressive asymmetric thickenings (plaques) • Small arteries : plaques blocking blood flow to downstream organ, leading to ischemia and tissue death (e.g heart attack) • Larger arties : advanced atherosclerosis can weaken vessel wall, resulting in rupture 11 Application of Biomaterials in Medical Devices Cardiovascular Applications Endovascular Stents and Vascular Grafts Materials for endovascular stents • Bare metal stents (stainless steel, nitinol) • Drug-eluting stents • Completely resorbable stents (PLLA, PLGA) Common complications • Early thrombosis • Late restenosis What are the design criteria/material characteristics required for stents? 12 Application of Biomaterials in Medical Devices Cardiovascular Applications Endovascular Stents and Vascular Grafts First FDA-approved resorbable stent 13 Application of Biomaterials in Medical Devices Opthalmologic Applications Eye anatomy and diseases • Eye anatomy • Common eye diseases  Myopia (short-sightedness)  Hyperopia (far-sightedness)  Cataract (progressive clouding of the lens with ages)  Glaucoma (damage of optic http://www.freepik.com/free-vector/eye-anatomynerve, often due to increased vector_760161.htm intraocular pressure) Myopia/shortsightedness Hyeropia/far-sightedness  Age-related macular degeneration (AMD)  Diabetic retinopathy 14 Application of Biomaterials in Medical Devices Opthalmologic Applications Contact lenses Leonardo de Vinci’s idea German co-inventors of first glass contact lenses wikidepia image Adolf Fick Material design criteria for contact lens Opthamologist August Muller Glass blower • 100% optical transparency, have reflective indices larger or equal to the cornea • Chemically stable and wettable • Oxygen and nutrient permeability • Low competitive manufacturing cost 15 4 Application of Biomaterials in Medical Devices Opthalmologic Applications Contact lenses Hard contact lenses (now obsolete) • Before 1938, all hard contact lenses were made from glass, despite its impermeability to oxygen. Small holes on the in the peripheral areas allowing some oxygen and tear fluid exchange • After 1938, polymethylmethacrylate (PMMA) : lightweight, more durable to molding technique, good light transmission PMMA TRIS Rigid gas permeable contact lenses (~26% of dispensed contact lenses) • PMMA incorporating silicone or fluorine-containing macromers e.g methacryloxypropyl tris(trimethylsiloxy)silane (TRIS) • Increase oxygen permeability • Silicone is lipophilic and might have some increased biofouling • Fluoro-derivatives have better anti-biofouling properties • Ride loosely on cornea, good for patients with astigmatism or non-spherical corneal surface • Require more patient adaptation http://www.allaboutvision.com/c ontacts/rgps.htm 16 Application of Biomaterials in Medical Devices Opthalmologic Applications Contact lenses Rigid gas permeable contact lenses 17 Application of Biomaterials in Medical Devices Opthalmologic Applications Contact lenses Standard hydrogel contact lenses • • • • • pHEMA Poly(2-hydroxyethyl methacrylate) or PHEMA offers stability to pH, temperature and osmolarity Oxygen permeability increases with water content But also increases biofouling, dehydration and fragility due to low modulus Increase oxygen transport by reducing lens thickness Disadvantages : limited in extended and overnight wear 18 Application of Biomaterials in Medical Devices Opthalmologic Applications Contact lenses Silicone hydrogel contact lenses • Functionalizing silicone macromers and TRIS-like monomers with hydrophilic group  better compatibility with hydrophilic components of hydrogels • For silicone lenses, oxygen permeability decreases with water content  Oxygen diffuses through siloxane-rich area due to the bulkiness and chain mobility of siloxane group  Water and ion diffuse through water19 rich/hydrophilic region Application of Biomaterials in Medical Devices Opthalmologic Applications Contact lenses Silicone hydrogel contact lenses • • • Siloxane-hydrogel lenses with higher oxygen and water permeability with acceptable water content Allow continuous wear for over two weeks. Limitation : surface compatibility issue due to siloxane groups migrating to the surface, leading to 20 biofouling, requiring surface modification to increase surface hydrophilicity Application of Biomaterials in Medical Devices Opthamologic Applications Intraocular lenses (IOLs) Cataract disease and surgery • • • Clouding of the lens, resulting in blurry, double-vision or glare. Cataract surgery to remove diseased lens Replacement with artificial polymerbased intraocular lens Material design criteria for IOLs • • Maintain a stable, clear optical path Long-term safe acceptance as a permanent implant (biocompatibility) http://www.webmd.com/eye-health/cataracts/ https://www.youtube.com/watch?v=Go82c4f1emc Time 0:00-3:00 21 Application of Biomaterials in Medical Devices Opthamologic Applications Intraocular lenses (IOLs) PMMA as an early IOL material • Physician’s observation that PMMA fragments from aircraft windshield embed in fighter pilots’ eyes without causing foreign body reaction • First IOL designed and implanted in 1950s • PMMA remains the material of choice for IOL for the next 40 years, till 1990s  Advantages : overall rigidity, resistance to tilt, biologically inert (minimal inflammatory reaction)  Limitation : requiring large incision, suturing needed, surgically-induced astigmatism http://rsbm.royalsocietypublishing.org/content/roybiogmem/53/285.full.pdf Harold Ridley 22 Application of Biomaterials in Medical Devices Opthamologic Applications Intraocular lenses (IOLs) Newer polymeric biomaterials for foldable IOLs Hydrophobic acrylic      Example : AMO Acrylic & Acrysof Most commonly used group Foldable at room temperature Low water content Limitations : edge glare, water inclusion Hydrophilic acrylic Abbot’s multifocal lens, FDA-approved in Jul 2016  High water content (up to 38%)  Cut in dehydrated state, then hydrated and stored in solution  Limitations : Epithelial cell ingrowth, opacification of lens Silicone  First material for foldable lenses but declining usage  Less lens opacification  Limitation : Risk of tearing at lensloop junction for some lens design, not suitable for monobloc open-loop design http://www.themonitordaily.com/intraocular-lensapproved-by-fda/212069/ 23 Application of Biomaterials in Medical Devices Opthamologic Applications Intraocular lenses (IOLs) Clinical complications Whitening & wrinkling contraction Decentralization Findl O. “Intraocular lens materials and design” • Lens epithelial cells grow onto the surface of IOL , laying down collagen resulting in the whitening, wrinkling or contraction of the lens 24 4 Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Anti-fouling polymeric coatings • Anti-fouling materials are materials that can resist protein adsorption or microbial adhesion • Potential application as coatings on implantable devices i.e heart valves, hip joint protheses, surface-based diagnostic devices, microfluidic devices Passive anti-fouling materials • Types of non-fouling surfaces, blue dots represent non-fouling chemical moiety (CH2CH2O)n • Poly(ethyleneglycol) or (PEGs) – earliest polymers reported to have protein-resistance, but face issues with auto-oxidation Cross-linked network of long polymeric chains Oligo-non-fouling group on a self-assembled monolayer Polymer brushes grown of the surface Surfactant absorbed On the surface 25 Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Anti-fouling polymeric coatings Active anti-fouling materials • Materials that non only resist protein/microbial binding but also have active selfcleansing and self-defending properties • Examples: Thermo- or pH-responsive coating, surface covalently attached with antibiotics or antimicrobial peptides Thermo-responsive “switchable” polymer coating 37oC 4oC Pappas et al, ACS Appl Mat Int 2015 26 Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Polymeric surfaces to direct biomaterial response Surface with biochemical cues • Strategies to modify surface of materials with biomolecules  covalent chemical attachment eg polymer surface with reactive functional groups (OH, NH2, COOH, SH..) can be conjugated with biomolecules directly or via a spacer linker.  physical adsorption eg immobilization of biomolecules via van der Waal forces, affinity binding or electrostatic interaction • Examples of functional surface modified with active biomolecules  Oligopeptide motifs (Arg-Gly-Asp or RGD) to increase cell-adhesion for surface  Surface modification with self-protein to inhibit macrophage activation and infiltration 27 Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Polymeric surfaces to direct biomaterial response Surface with biochemical cues Martin et al, JBMR, 2003 • Poly(HEMA) surface modified with osteopontin is able to promote binding of endothelial cells through an RGD-dependent mechanism 28 Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Polymeric surfaces to direct biomaterial response Surface with biochemical cues Kim YK et al, Adv Healthcare Mat, 2014 • Polystyrene surface modified with CD200 molecule to inhibit macrophage activation 29 in vitro and macrophage infiltration in vivo Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Polymeric surfaces to direct biomaterial response Surface with topological cues • Material surface with topographical features at different micro/nano length scales can be designed by multiple techniques (soft lithography, electrospining, e-beam lithography, self-assembly of polymer and colloids) • Typical surface features are grooves, ridges, fiber, pillar, islands and pits. • Microscale features affect cellular morphology, adhesion, migration and differentiation. Eg contact guidance is a wellestablished phenomenon in which cells become elongated, align and migrate in the direction of microgrooves with comparable dimension to that of individual cells. Nikkhah M et al, Biomaterials, 2012 30 Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Polymeric surfaces to direct biomaterial response Surface with topological cues • The effects of nanoscale features on protein adsorption and cellular response is currently less well understood. • Effects of surface features can vary widely depending on cell types. • Current understanding is limited to 2D surfaces in vitro while potential application for devices will need knowledge of 3D interaction in vivo Fibroblast Macrophage Keratinocytes Meyle J et al, JBMR, 1995 31 Application of Biomaterials in Medical Devices Emerging classes of polymeric biomaterials for implantable devices Polymeric surfaces to direct biomaterial response Shape-memory polymer • Shape-memory polymers (SMPs) are polymeric materials that have the ability to switch from a temporary to a permanent shape in response to external stimuli such as heat, infrared radiation, electrical signals, magnetic field, or immersion in water Molecular mechanism of a SMP Lendlein A et al, Angew. Chem. Int, 2002 Macroscopic effect of a stent fabricated from SMP Yakacki CM et al, Biomaterials , 2007 https://www.youtube.com/watch?v=vuoorVtYWgk https://www.youtube.com/watch?v=bw7oklXN2zk 32 Application of Biomaterials in Medical Devices Summary 1. Biocompatibility of materials used in medical devices 2. Structural compatibility and mechanical durability 3. Biomaterials for Cardiovascular Applications (Heart valves, Stents, Vascular grafts) 4. Biomaterials for Opthamologic Applications (Contact lenses, Intraocular lens) 5. Emerging classes of polymeric biomaterials for medical devices  anti-fouling materials  surface with biochemical/topological cues  shape-memory polymers 33 Application of Biomaterials in Drug Delivery Systems Textbook References Section II.5.1, II.5.3A &B, II.5.9A&B : Application of biomaterials Other key references • Dang TT, Nikkhah N, Memic A, and Khademhosseini A. " Polymeric Biomaterials for Implantable Prostheses" in " Natural and Synthetic Biomedical Polymers" edited by Sangamesh Kumbar, Cato Laurencin, and Meng Deng. Elsevier 2014 • http://247wallst.com/healthcare-economy/2011/07/18/the-eleven-most-implantedmedical-devices-in-america/ • Findl O. “Intraocular lens materials and design” in “Achieving Excellence in Cataract Surgery”. http://phaco.ascrs.org/sites/phaco.ascrs.org/files/textbooks/Achieving%20Excellence%20 34 in%20Cataract%20Surgery%20-%20Chapter%2012.pdf