LABORATORY OF BIOLOGICAL STRUCTURE MECHANICS www.labsmech.polimi.it TECHNOLOGICAL INNOVATION FOR CORONARY STENTS Francesco Migliavacca Erice, 1 maggio 2015 International School of Cardiac Surgery
Introduction Patent search Heart valve Stent Francesco Migliavacca Roma 26 Novembre 2009
Introduction Mechanical cardiac valves Francesco Migliavacca Roma 26 Novembre 2009
Introduzione Stent Francesco Migliavacca Roma 26 Novembre 2009
# patents technological trend Introduction Mechanical heart valves Patent heart valve tot US+EP (1968-2000) technological trend of mechanical heart valves (1968-2000) 450 400 350 110 100 50 300 250 SCIENTIFIC RESEARCH TECHNOLOGICAL RESEARCH INDUSTRIAL RESEARCH 200 150 100 50 1 0 Courtesy of : R. Pietrabissa 1968 1970 1971 1975 1976 1980 1981 1985 1986 1990 1991 1995 1996 2000 years Francesco Migliavacca Roma 26 Novembre 2009
# patents Introduction Stent patents 7 F 5 F 2F? Size unexpanded stent bare self-ex DES absorbable model 10000 8000 6000 RISCIENTIFIC RESEARCH TECHNOLOGICAL RESEARCH INDUSTRIAL RESEARCH 4000? 2000 0 1992 1996 2000 2004 2008 2012 years 1995 1999 2003 2007 2011 2015 Francesco Migliavacca Roma 26 Novembre 2009
stent history http://www.admedes.com/literature Francesco Migliavacca Roma 26 Novembre 2009
30 days after implant in porcine coronaries Mg stent SS stent Waksman R. Adjunctive therapy: Biodegradable stents: They do their job and disappear. J Invas Cardiol 2006; 18: 70)74. Francesco Migliavacca Roma 26 Novembre 2009
Stent requirements Market issues Design requirements Price Clinical requirements Manufacturing technologies Drug adhesion Flexibility Trackability Radiopacity MR visibility Scaffolding Material properties Resistance to fracture Biodegradability Francesco Migliavacca Roma 26 Novembre 2009
Francesco Migliavacca Roma 26 Novembre 2009 Drug eluting stents
Drug carrier Polymer (biodegradable or not biodegradable) Drug eluting stents Inflammatory reaction Stent Drug Francesco Migliavacca Roma 26 Novembre 2009
Drug eluting stents van der Giessen, et al. Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries Circulation. 1996;94:1690-1697 Francesco Migliavacca Roma 26 Novembre 2009
Drug eluting stents Virmani, et al. Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent. Should We Be Cautious? Circulation. 2004;109:701-705 Francesco Migliavacca Roma 26 Novembre 2009
Drug carrier Polymer (biodegradable or not biodegradable) Drug eluting stents Inflammatory reaction Stent Regular Spacing between struts Conformability (minimal struts malapposition) Uniform and controlled drug release More drug in the blood stream than in the arterial wall Drug Francesco Migliavacca Roma 26 Novembre 2009
Drug eluting stents OCT Prati et al. European Heart Journal doi:10.1093/eurheartj/ehs095 Francesco Migliavacca Roma 26 Novembre 2009
Drug carrier Polymer (biodegradable or not biodegradable) Drug eluting stents Inflammatory reaction Stent Regular Spacing between struts Conformability (minimal struts malapposition) Uniform and controlled drug release More drug in the blood stream than in the arterial wall Drug Uniform and controlled drug release Toxicity Francesco Migliavacca Roma 26 Novembre 2009
Drug eluting stents LATE STENT THROMBOSIS Francesco Migliavacca Roma 26 Novembre 2009
Drug eluting stents Dauerman H, The Magic of Disappearing Stents J Am Coll Cardiol. 2011;58(15):1589-1591. Francesco Migliavacca Roma 26 Novembre 2009
Drug eluting stents Strut thickness of only 50/60 μm 100% Polymer-Free Drug Delivery Bio-resorbable Drug Matrix Sirolimus - Matrix Excipient: Probucol Source: www.bbraun.com Francesco Migliavacca Roma 26 Novembre 2009
bioresorbable stents Muramatsu et al. Progress in Treatment by Percutaneous Coronary Intervention: The Stent of the Future. Rev Esp Cardiol. 2013;66:483-96. Francesco Migliavacca Roma 26 Novembre 2009
bioresorbable stents Source: www.abbottvascular.com Francesco Migliavacca Roma 26 Novembre 2009
bioresorbable stents Source: www.abbottvascular.com Francesco Migliavacca Roma 26 Novembre 2009
Biodegradable stents BACKGROUND Use of simulations for bioabsorbable stent to predict the mechanical behaviour of stent (recoil, radial strength, flexibility, ) to predict the degradation behaviour to optimise the design for a prolonged/shortened degradation resistance francesco.migliavacca@polimi.it
Biodegradable stents DEGRADABLE MATERIALS FOR STENTING Metals: Magnesium alloys Iron alloys Corrosion Degradation mechanisms Polymers: PLLA polycarbonate PLGA/PCL-PGA salicyclic acid polymer Bulk vs surface degradation Surface Degradation (lollipop) undegraded [Levesque et al 2008] Bulk Degradation (sponge) 24 francesco.migliavacca@polimi.it
Biodegradable stents MAGNESIUM ALLOYS STENTS Hansi et al, Cath Cardiovasc Interv, 73:488-496, 2009. Bioresorbable Magnesium stent (BIOTRONIK, Berlin, Germany) [Erbel et al 2007] Degradation rate too fast!!! To improve corrosion resistance: alloying mechanical/heat treatments surface modifications and coatings TARGET: Degradation rate has to be reduced to ensure mechanical support to the vessel for a longer time 25 francesco.migliavacca@polimi.it
Stress Biodegradable stents MECHANICAL PROPERTIES OF MATERIALS FOR STENTS Material Stiffness E [GPa] yield stress σ y [MP] ultimate stress σ u [MP] Co-Cr 240 600 1100 Fe 210 150 210 SS 316L 200 190 490 WE43 44 150 210 PLLA 2-45 Strain 26 francesco.migliavacca@polimi.it
Biodegradable stents AMS (Biotronik, Germany): 4 struts with links MG - GEOMETRY [Erbel et al 2007] 84476 elements C3D8R 27 francesco.migliavacca@polimi.it
Stress [MPa] D ext =4.2 mm D int =2.4 mm Biodegradable stents MODEL OF STENTING PROCEDURE coronary vessel 3 hyperelastic layers: s adventitia =0.34 mm s media =0.32 mm s intima =0.24 mm [Holzapfel et al 2005] 66000 C3D8R elements stent material Strain 28 francesco.migliavacca@polimi.it
Biodegradable stents RESULTS: DEGRADATION OF STENT STRUCTURE Uniform Corrosion: 48 t Stress Corrosion: 48 t Combined Corrosion: 48 t Stress 120 MPa Damage 0.9 0 MPa 0 29 francesco.migliavacca@polimi.it
Biodegradable stents OPTIMISATION PROCEDURE 30 francesco.migliavacca@polimi.it
Biodegradable stents OPTIMISATION PROCEDURE strain original design optimized design Wu et al: FE shape optimization for biodegradable magnesium alloy stents Ann Biomed Eng, 2010. 31 francesco.migliavacca@polimi.it
Biodegradable stents OPTIMISATION PROCEDURE ZM21 original design optimized design 32 francesco.migliavacca@polimi.it
Biodegradable stents OPTIMISATION PROCEDURE 33 francesco.migliavacca@polimi.it
Biodegradable stents OPTIMISATION PROCEDURE strain AMS optimized 34 francesco.migliavacca@polimi.it
Late recoil Biodegradable stents DEGRADATION RESULTS 1 0.6 ML/M i 0.8 0.6 0.4 AMS magic optimized ott 0.5 0.4 magic ott 0.3 0.2 AMS magic optimized ott 0.2 0.1 0 0 10 20 30 40 50 60 70 80 Time 0 0 10 20 Time 30 40 50 080 40 50 60 70 80 after 14 t corrosion 35 francesco.migliavacca@polimi.it
Biodegradable stents Two FEA models of MAS in the simulation of degradation Optimized design (OPT) Patent design as control (CON) The ratio of mass per length unit is 1.93 : 2.64 Ren et al., An Absorbable Implantation Stent of Magnesium Metal, Chinese patent, 2006 36 francesco.migliavacca@polimi.it
Biodegradable stents INTERACTION BETWEEN OPT MODEL AND VESSEL DURING DEGRADATION When the stent degraded the vessel recoiled until then stent broke 37 francesco.migliavacca@polimi.it
Biodegradable stents RESULTS AFTER STENT IMPLANTATION OPT CON The distribution of residual stress 38 francesco.migliavacca@polimi.it
Biodegradable stents UNIFORM AND STRESS CORROSION EVLUTION Uniform corrosion OPT CON Faster stress corrosion evolution 39 francesco.migliavacca@polimi.it
Biodegradable stents LASER CUTTING AND ELECTRO-POLISHING OF THE MAS SAMPLES OPT CON Material: AZ31 tube 40 francesco.migliavacca@polimi.it
Biodegradable stents DEGRADATION EXPERIMENT OF THE TWO SAMPLES The two samples were crimped to 1.2 mm of outer diameter and expanded to 3.0 mm then recoiled freely. The expanded CON sample is shown below. The two expanded samples were immersed in the D-Hank s solution for 7 days, with ph 7.5 and and temperature 37 C. The two samples were observed with unaided eyes to check structural integrity when immersed in solution. Then they were taken out for the observation with stereo or scanning electron microscope (SEM) after 7 days of corrosion. 41 francesco.migliavacca@polimi.it
Biodegradable stents EXPERIMENTAL RESULTS: STRUCTURAL INTEGRITY After the first day of immersion, the CON sample had several broken points on the strut while the OPT sample kept the structural integrity until the third day of immersion. After 7 days of corrosion, the CON sample has scattered into pieces, while the OPT has not scattered even though it had several broken points. The result is compatible with simulation that the OPT model has better property to resist corrosion. OPT CON 42 francesco.migliavacca@polimi.it
Biodegradable stents EXPERIMENTAL RESULTS: UNIFORM AND STRESS CORROSION The SEM observation shows that corrosion layers caused by uniform corrosion, which were shedding from the stent matrix. The early broken points caused by stress corrosion can also be observed and are compatible with the expected location in simulation. 43 francesco.migliavacca@polimi.it
Biodegradable stents CONCLUSIONS FROM MATHEMATICAL MODELLING Both simulation and experiment indicated that the optimized MAS design can yield better property to resist corrosion. Both simulation and experiment showed that the degradation of MAS consists of uniform and stress corrosion. The experiment preliminarily verified that the proposed numerical approach can be an effective tool for novel MAS design and property comparisons. 44 francesco.migliavacca@polimi.it
In progress 45 francesco.migliavacca@polimi.it
Francesco Migliavacca Roma 26 Novembre 2009 Coronary bifurcation
Francesco Migliavacca Roma 26 Novembre 2009 different stent applications
# patents Introduction stent patents 10000 8000 6000 SCIENTIFIC RESEARCH TECHNOLOGICAL RESEARCH INDUSTRIAL RESEARCH 4000? 2000 0 1992 1995 1996 1999 2000 2003 2004 2007 Francesco Migliavacca Roma 26 Novembre 2009 2008 2011 2012 2015 years The optimal design, however, of scaffolds, polymers, antiproliferative drugs and their degradation/release kinetics is still under investigation.
Thank you Computational models presented here are carried out with the help of: Wei Wu Dario Gastaldi Lorenza Petrini Francesco Migliavacca Roma 26 Novembre 2009 francesco.migliavacca@polimi.it LABORATORY OF BIOLOGICAL STRUCTURE MECHANICS www.labsmech.polimi.it