INNOVATIONS IN BIORESORBABLE STENTS BRS at the crossroad: technological development to reduce complications. Patrick W. Serruys

Transcription

1 INNOVATIONS IN BIORESORBABLE STENTS BRS at the crossroad: technological development to reduce complications Patrick W. Serruys PACIFICO Room (Main Arena) Thursday, 3 rd August 2017 (8:00-9:00) 1

2 Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Grant/Research Support Consulting Fees/Honoraria Company Abbott Arterius AstraZeneca Biotronik Boston scientific Cardialysis GLG Research Manli Medtronic Philips Sinomedical Sciences Technology Société Europa Digital Publishing, Stentys France Svelte Medical Systems Volcano Qualimed St. Jude Medical Xeltis

3 Current limitation of BRS If a bioresorbable scaffold is ultimately expected to have the same range of applicability as a durable metal stent, the gap in mechanical properties must be reduced. Currently, three primary limitations exist: Low tensile strength and stiffness which require thick struts to prevent acute recoil Insufficient ductility which limits the range of scaffold expansion during deployment Instability of mechanical properties and late structural discontinuity during dismantling

4 Tensile modulus of elasticity (GPa)) Let s take a crash course in material science Tensile strength (Mpa) Plastic elongation Elongation at break (%) Minimal ductility- Brittle fracture Medium ductility Ductile but with low ultimate stress

5 Tensile modulus of elasticity (GPa)) Let s take a crash course in material science Tensile strength (Mpa) Plastic elongation Elongation at break (%)

6 Mechanical properties of metal vs. PLLA Polymer/ metal Tensile modulus of elasticity (Gpa) Tensile strength (Mpa) Elongation at break (%) Poly(L-lactide) Poly (DL-lactide) Magnesium alloy Cobalt chromium Onuma and Serruys Circulation. 2011;123:

7 How improved scaffold technology can reduce clinical complication? Low tensile strength -> low radial force -> recoil -> thick strut Reduced ductility limited expansion. Quadratic thick struts with wide footprint. Difficult to embed into the vessel wall Disturb laminar flow (acute scaffold thrombosis) Increase local viscosity and thrombogenicity Slow down the cell coverage Use of biodegradable material non-thrombogenic: Magnesium Late structural discontinuity (dismantling). Late protrusion of biological struts with provisional matrix made of thrombogenic proteoglycan after biodegradation of the polymer. (very late scaffold thrombosis)

8 How to increase tensile strength and radial force by altering molecular orientation of PLLA Tensile Stress (MPa) Heated Die helps polymer to become plastic and stretch Heated Die helps polymer to become plas c and stretch. Semi-crystalline polymer created by stretching or drawing the fibers. Semi-crystalline polymer created by stretching or drawing the fibers Oriented PLLA Extruded PLLA Amorphous Amorphous polymer tube. tube Mandrel forces tube to extrude. forces tube to extrude Laser cutting of stent (standard technology) Laser cu ng of stent (standard technology) Tensile Strain (%) Tube wall thickness of < 95 µm can be achieved Scaffold tube thickness comparable to metallic DES 8

9 How to increase tensile strength and radial force by altering molecular orientation of PLLA Tensile Stress (MPa) 350 Material Ultimate tensile strength (MPa) Tensile Modulus (Gpa) Elongation (%) PLLA Oriented PLLA Mg Alloy Stainless Steel Cobalt Chrome ~ Oriented PLLA Extruded PLLA Tensile Strain (%) Oriented material properties significantly higher than un-oriented PLLA Favourable comparison to strength of metallic materials used in stent production 9

10 Ø ArterioS orb radial thicknes s, c How to increase tensile strength and St iffne ss force by altering molecular orientation of PLLA g with radially applied load Radial Bench Testing tes t performed by ProtomedL abs force s higher s tiffnes s than ABS ORB des pite a 95µm s trut ared to 157µm 6.0 Radial Force (N/mm2) 5.0 Scaffold ArterioSorb 3.5 mm 95 ArterioSorb 3.5 mm 120 Xience Metallic stent (81 µm) ArterioSorb (95µm) Absorb BVS (157µm) Be n ch T e st i Stiffness until Ø C rus h res is tan inflexion Ø IS O Radial force (N) Stiffness Until Inflexion Point by Unity of Length Wall Thickness (µm) ABSORB 3.5mm 157 ABSORB 3.0mm 157 Xience 3.0mm Metallic (DES) Crush resistance with radially applied load ISO test performed by ProtomedLabs (Marseille, France) Ø ArterioS orb thic knes s, c om Diameter (mm) Stiffness until inflexion 15.20NN N

11 Crimped OD (mm) esting Bench Scaffold Testing Crimping Scaffold and Crimping Expansion and Expansion Low crimp profiles for Expansion and post-dilatation ArterioSorb compared to ArterioSorb -95µm iles Low for crimp ArterioSorb other profiles bioresorbable for compared ArterioSorb to other scaffolds compared bioresorbable to other bioresorbable scaffolds riosorb 95 µm How to increase ductility and expansion index by altering molecular orientation of PLLA 1.22 mm ArterioSorb µm ArterioSorb BVS 120 µm DESolve BVS Crimped 3.5mm (nominal) 4.0mm (postdilatation) DESolve 4.5mm (postdilatation) d DESolve crossing BVS profiles and DESolve from Ormiston; crossing EuroIntervention profiles from Ormiston; February EuroIntervention 2015 February mm BVS images from Foin; EuroIntervention July

12 Oriented polylactide, stronger and thinner strut Reducing the protrusion without increase of recoil ArterioSorb-95 µm Arteriosorb-120 Arteriosorb from Arterius Absorb from Abbot Protrusion distance: 89±7 µm Protrusion distance: 150±9 µm Absorb BVS-157 µm Scaffold Arteriosorb-95 (n=6) Lumen diameter (mm) Balloon-artery ratio Scaffold-artery ratio Acute recoil (%) 2.97± ± ± ±3.9 Courtesy of Dr. Onuma, Rasha Al-Lamee, Guy Leclerc (AccelLAB, Montreal) 12 15

13 Tenekecioglu E, Torii R, Serruys PW et al. Non-Newtonian pulsatile shear stress assessment: a method to differentiate bioresorbable scaffold platforms. Eur Heart J 2017 ehx358. doi: /eurheartj/ehx358 Reduced struts protrusion, reduces low-shear stress (dark-blue color), reduces risk of thrombus peri-strut ArterioSorb Absorb BVS

14 How improved scaffold technology can reduce clinical complication? Low tensile strength -> low radial force -> recoil -> thick strut Reduced ductility limited expansion. Quadratic thick struts with wide footprint. Difficult to embed into the vessel wall Disturb laminar flow (acute scaffold thrombosis) Increase local viscosity and thrombogenicity Slow down the cell coverage Use of biodegradable material non-thrombogenic: Magnesium Late structural discontinuity (dismantling). Late protrusion of biological struts with provisional matrix made of thrombogenic proteoglycan after biodegradation of the polymer. (very late scaffold thrombosis)

15 Embedded Protruded Embedment depth stratified by underlying plaque type (μm) 157 μm* Only Absorb BVS arm: L = 79 / Strut N= 667 N = 138 N = 320 N = 37 N = ± ± ± ±51.1 p < (ANOVA) Sotomi et al. Circ J. 2016;80(11): Normal vessel Fibroatheroma Fibrocalcific plaque A B C D Fibrous plaque *strut thickness of BVS

16 PSP: Pressure transmitted to the vessel wall by the 2 devices with different footprints Absorb struts Large strut area Poor penetration (less embedded) Small expansion XIENCE struts Small strut area Good penetration (well embedded) Large expansion P =F/A P =F/A Poor penetration Good penetration Serruys et al. JACC Cardiovasc Interv. 2015;8(7):910-3.

17 Percenrage Distribution of embedment depth of BVS and CoCr-EES Less embedded (%) 16 Percentage EC.1 Absorb Less embedded 157 µm P<0.001 BVS Median: 50μm [IQR: 42, 59] XIENCE CoCr-EES Absorb BVS BVS CoCr-EES Median: 84μm [IQR: 67, 98] N=81 N=43 Absorb japan More embedded Xience More embedded 81 µm Embedment depth (μm) Onuma et al. Eurointervention Oct 20;12(9):

18 PSP: Post-dilatation at high pressure (16 atm) by 2.5 mm non-compliant balloon (4.91 mm 2 ) Before postdilatation * Malapposed MLA 3.09 mm 2 * * After postdilatation Disruption * Apposed MLA 4.43 mm 2 Overstretched Minimum lumen EI 0.74 Minimum lumen EI 0.74

19 Late structural discontinuity (dismantling). Late protrusion of biological struts with provisional matrix made of thrombogenic proteoglycan after biodegradation of the polymer. (very late scaffold thrombosis) How improved scaffold technology can reduce clinical complication? Low tensile strength -> low radial force -> recoil -> thick strut Reduced ductility limited expansion. Quadratic thick struts with wide footprint. Difficult to embed into the vessel wall Disturb laminar flow (acute scaffold thrombosis) Increase local viscosity and thrombogenicity Slow down the cell coverage Use of biodegradable material non-thrombogenic: Magnesium

20 Fusion of Angio and OCT, pulsatile flow, non-newtonian shear stress immediately after Absorb implantation in a human being Tenekecioglu E, Poon E, et al. Serruys PW. The Nidus for Possible Thrombus Formation: Insight From the Microenvironment of Bioresorbable Vascular Scaffold. JACC Cardiovasc Interv Oct 24;9(20): Tenekecioglu et al. Int J Cardiol Jan 15; 227:

21 Virtual pullback in early diastole Fusion of Angio and OCT, pulsatile flow, non-newtonian fluid: Significant number of low ESS regions (BLUE colour) in the scaffold region

22 Non-Newtonian (corpuscular behavior) shear stress and viscosity in early systole Navier Stokes (ESS) and Quemada (viscosity) equations Flow Direction High Oscillatory Shear Index (OSI) Pink fuzzy areas are regions with low shear stress with high viscosity

23 Thick strut creates low shear stress peri-strut that increases the viscosity and triggers thrombosis and exuberant neointima 90D 28D Day 3 LUMEN Surface RCA, Patient ID RCA, patient

24 The effect of thick (150 µm), quadratic strut on flow reversal, recirculation, fibrin deposition and endothelial migration and coverage 0-24 hr hr Hsiao ST et al. Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase. Cardiovasc Res Dec;112(3):

25 The effect of thick (150 µm), quadratic strut on flow reversal, recirculation, fibrin deposition and endothelial migration and coverage Circular strut (next slide) With Rho-associated protein kinase (ROCK) inhibition Without ROCK inhibition Hsiao ST et al. Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase. Cardiovasc Res Dec;112(3):

26 CIRCULAR STRUTS (mono fiber) PENETRATE INTO THE VESSEL WALL BETTER THAN THE QUADRATIC STRUTS 1125 µm Inverse relationship between contact radius and contact pressure 157 µm Mean Protrusion: 76 ± 25 µm Mean Protrusion: 125 ± 29 µm

27 In a porcine model (n=8), strut protrusion and shear stress differentiated the two devices MIRAGE BRMS ABSORB BVS 52% in the Mirage BRMS and 70% of the scaffolded surface in the Absorb BVS was exposed to a low (<1Pa) athero-promoting ESS environment Note the intense recirculation area behind the quadratic strut in flow model Tenekecioglu, Serruys, et al. Int J Cardiol. 2017;227: Tenekecioglu, Serruys, et al. Int J Cardiovasc Imaging [Epub ahead of print]

28 Shear stress (fusion of OCT and angiography) is now available in patients

29 The circular struts of the Mirage scaffold are better embedded than the quadratic struts of Absorb, irrespective of the underlying tissue Tenekecioglu E, Torii R, Serruys PW et al. The Effect of Strut Protrusion on Shear Stress Distribution: Hemodynamic Insights From a Prospective Clinical Trial. JACC: Card ESS (Pa): 3.48± ± ± ± ± ±0.52 Interventions 1.77± ± JACC: Card Interventions, July Tenekecioglu E, Serruys PW et al. 2017, in-press.

30 How improved scaffold technology can reduce clinical complication? Low tensile strength -> low radial force -> recoil -> thick strut Reduced ductility limited expansion. Quadratic thick struts with wide footprint. Difficult to embed into the vessel wall Disturb laminar flow (acute scaffold thrombosis) Increase local viscosity and thrombogenicity Slow down the cell coverage Speed of bioresorption Use of biodegradable material non-thrombogenic: Magnesium Late structural discontinuity (dismantling). Late protrusion of biological struts with provisional matrix made of thrombogenic proteoglycan after biodegradation of the polymer. (very late scaffold thrombosis)

31 The rate of biodegradation has important impact on bioresorption and dismantling Sotomi, Onuma, Collet, Tenekecioglu, Virmani, Kleiman, Serruys. Circ Res. 2017;120: Magnesium PLLA (A) Absorb (B) DESolve (C) ART (D) Magmaris PLLA Hydrolysis Lactic acid Krebs cycle Radial support Molecular weight Polymer mass Mg + 2 H 2 O Mg(OH) 2 + H 2 Mg(OH) 2 + HPO Ca 2+ + H 2 O Ca x (PO 4 ) y n H 2 O + H 3 O + + Mg 2+ Radial support unpublicized Mg Ca x (PO 4 ) y n H 2 O Time (months) CO 2 + H 2 O

32 MIRAGE ABSORB The rate of biodegradation has important impact on bioresorption and dismantling Post-Procedure 6-Month Follow-up 12-Month Follow-up 32

33 How improved scaffold technology can reduce clinical complication? Low tensile strength -> low radial force -> recoil -> thick strut Reduced ductility limited expansion. Quadratic thick struts with wide footprint. Difficult to embed into the vessel wall Disturb laminar flow (acute scaffold thrombosis) Increase local viscosity and thrombogenicity Slow down the cell coverage Speed of bioresorption Use of biodegradable material non-thrombogenic: Magnesium Late structural discontinuity (dismantling). Late protrusion of biological struts with provisional matrix made of thrombogenic proteoglycan after biodegradation of the polymer. (very late scaffold thrombosis)

34 Comparison of Acute Thrombogenicity for Metallic and Polymeric Bioabsorbable Scaffolds: Magmaris vs ABSORB in a Porcine Arteriovenous Shunt Model Waksman R et al. Circulation: Cardiovascular Interventions. July 2017, in-press 34

35 How improved scaffold technology can reduce clinical complication? Low tensile strength -> low radial force -> recoil -> thick strut Reduced ductility limited expansion. Quadratic thick struts with wide footprint. Difficult to embed into the vessel wall Disturb laminar flow (acute scaffold thrombosis) Increase local viscosity and thrombogenicity Slow down the cell coverage Speed of bioresorption Use of biodegradable material non-thrombogenic: Magnesium Late structural discontinuity (dismantling). Late protrusion of biological struts with provisional matrix made of thrombogenic proteoglycan after biodegradation of the polymer. (very late scaffold thrombosis)

36 Late discontinuities of a scaffold in human on OCT 2D-3D Baseline - 1 year - 2 years Late discontinuity is an expected phenomenon related to bioresorption. 22% Overhanging strut *Non-truly serial 42% Onuma, Serruys, et al. JACC Cardiovasc Interv. 2014;7(12):

37 Frequency of late discontinuities between 2 and 3 years (truly serial analysis at lesion level) re At 2 years At 3 years procedure At 2 years At 3 years At 3 years At 2 years -by courtesy of Prof. Kimura LA m LA A 8.96 Mean Meanmm LA 8.76 mm mm 2 LA Mean 8.76 mm Meanmm LA 6.30 mm 2 Mean LA Mean 6.30 mm SA m SA A 9.40 Mean Meanmm SA 10.5 mm mm 2 SA Mean 10.5 mm Meanmm SA L= mm 2 Mean SA Mean 8.98 mm 2 years FU B B B B* Scaffold Scaffold C I SA Proximal discontinuity * mm2la C I SA LA mm C * Uncovered and Apposed L=3 mm2 B Covered and Malapposed L=1 C C C discontinuity discontinuity discontinuity C L=2 Uncovered and Apposed L=1 L=1 L=1 LA mm2 discontinuity discontinuity discontinuity Covered Distal Distal C Distal Scaffold Scaffold C I SA C LA B Uncovered and Malapposed L=10 L=1 and Malapposed discontinuityl=3* A B B mm2 * L=68 AUncovered discontinuity B B LA LA mm mmla 8.68 C mm C Proximal Proximal * A Distal B * A A A A Distal ic marker * metallic marker B A Scaffold *B Proximal A A 3 years FU Scaffold A A Distal Proximal A Proximal Post-procedure L=4 L=2 Covered and Malapposed L=1 and Apposed Covered and Apposed L=12 L=24 No Discontinuity No Discontinuity L=59# L=32 2 years 3 years C * Two lesions were not analyzable at 3 years. # Eight lesions were not analyzable at 3 years.

38 Late discontinuity No1 Late discontinuity No2 Covered by neointima Protruded into the lumen

39 Malapposition Possible mechanical causes of scaffold thrombosis: insights from case reports with intracoronary imaging. Sotomi, Suwannasom, Serruys, Onuma. EuroIntervention ;12(14): Late Discontinuitiy Peri-strut low intensity area VLST at 19 months Uncovered strut Incomplete lesion coverage Recoil Pre-PCI Post-PCI Scaffold Thrombosis Restenosis Underdeployment Neoatherosclerosis Bifurcation No specific imaging findings Lorenz Ra ber et al. JACC 2015

40 THE GOOD NEWS Long-term (5 years) remodeling* Homogenizes shear stress towards physiological value of shear stress (>1 Pa) Eliminates the corrugate appearance of the scaffold (smooth surface at 5 years) ** Self-corrects the procedural overexpansion or underexpansion created by the operator ** * Serruys et al. Glagovian Appraisal of Arterial Remodeling in Absorb Bioresorbable Scaffolds and Xience Metallic Stents. JACC accepted. ** Serruys et al. Dmax for sizing, PSP-1, PSP-2, PSP-3 or OCT guidance: interventionalist's jargon or indispensable implantation techniques for short- and long-term outcomes of Absorb BRS?. EuroIntervention. 2017;12(17):

41 Serruys, Onuma. EuroIntervention. 2017;12(17): Thondapu V, Tenekecioglu E, Serruys PW et al. EHJ Card Imaging July 2017, in-press. FLYING THROUGH VIEW OF THE SHEAR STRESS DISTRIBUTION AT END SYSTOLE IN THE LUMINAL SURFACE OF CASE AFER POST-IMPLANTATION AND 5-YEAR FOLLOW UP Homogenizes shear stress towards physiological value of shear stress (>1 Pa) Eliminates the corrugate appearance of the scaffold (smooth surface at 5 years)

42 CASE OF PARTIAL OVEREXPANSION Expansion index: 1.32 E-Median ESS: 1.02 Pa E -Median ESS: 2.35 Pa D-Median ESS: 0.34 Pa D -Median ESS: 1.34 Pa Torii R, Tenekecioglu E, Serruys PW et al. EuroIntervention. 2017;12(17):

43 UNDEREXPANSION AT BASELINE AND ESS NORMALIZATION AT 5-YEAR FOLLOW-UP Torii R, Tenekecioglu E, Serruys PW et al. EuroIntervention. 2017;12(17):

44 How to accelerate that process and avoid the transient consequence of discontinuity??? Reducing the protrusion of the strut (stronger and thinner strut) -done- Better embedment of the struts -done- Changing the quadratic shape of the strut into a circular one -done- Faster Bioresorption without inducing an inflammatory vasculitis -major dilemma- will result in fast tissue coverage and firm encapsulation of the struts into the vessel wall. -The future is bright!-

45 A. Ooi F Gijsen P Barlis THANKS E Tenekecioglu C Bourantas R Torii V Thondapu E Poon H Jonker C Collet P Kitslaar Y Onuma PW Serruys

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48 Thick strut creates low shear stress peri-strut that increases the viscosity and triggers thrombosis and exuberant neointima 90D 28D Day 3 LUMEN Surface RCA, Patient ID RCA, patient