Coatings Surface Modifications and BioAbsorbables John Wainwright Ph

Coatings, Surface Modifications, and Bio-Absorbables John Wainwright, Ph. D. Sr. R&D Manager, Medtronic plc Some of the technologies/devices discussed in this talk are not approved in the US WLNC 06/08/15

Reasons for Coatings and Surface Modifications Lubricious coatings Hydrophobic Hydrophilic Corrosion Resistance Material Choice Stainless steel, Co. Cr, Ni. Ti Passivation Electropolish Parylene coating Lower material thrombogenicity Electropolishing Silicon Carbide Heparin Phosphoryl Choline Bio-Absorbable stents

Lubricious Coatings Extremely dependent on processing conditions including: cleaning, activation/base coat, coating, curing Testing: Water droplet contact angle for hydrophilicity Friction for lubricity and durability Particulate testing for durability/device interactions Hydrophobic PTFE (fluoropolymers): longest use Inert but higher friction than PVP and HA Hydrophilic Hydroscopic (swell in fluid) PVP (polyvinylpyrrolidone): Most common hydrophilic PVP particles from Cook Shuttle/Slip-Cath has been associated with intraparenchymal hemorrhage in 3 patients (Hu et al 2014) HA (hyaluronic acid): more lubricious/biocompatible, but less stable

Corrosion Resistance Material Choice Stainless steel, Co. Cr, Nitinol Co. Cr more corrosion resistant without post processing due to composition Higher Breakdown Potential (Ebd)= more corrosion resistant Niti corrosion resistance (Trepanier 97) PA=Passivated EP= Electropolished HT= Heat treated AA= electropolished and then heat treated NT= non-treated Parylene coating- polymer coating applied through vapor deposition often applied for corrosion resistance Enterprise™ device is covered with a thin layer of Parylene (Heller 2011) “Lubricious Coating Our proprietary stent coating may facilitate stent tracking through the microcatheter. ” (Codman marketing brochure)

Lower material thrombogenicity Electropolishing EP Ni. Ti has shown to absorb less platelets and plasma than stainless steel (Thierry 2002) Inert titanium oxide surface Silicon Carbide Chemically inert, corrosion resistant, and may reduce thombogenicity (Harder et al 99) PHAROS Viteese ICAD stent and Rithron coronary stent Phosphoryl. Choline (PC) PC is naturally abundant on the surface of red blood cells 1 -10 Coating or treating a device surface with a PC-containing polymer results in physiologic mimicry of the cell membrane Heparin Actively prevents thrombus formation so could affect aneurysm occlusion BX VELOCITY stent with HEPACOAT and aspirin alone after the procedure was safe in select patients with de novo or restenotic lesions in native coronary arteries. (Mehran 2003) Carmeda® May heparin coating covalently bonded to surface be regulated as a drug/combination product

PC Surface Modification vs. Coating Method Adhesion to Substrate Thickness Process Shield Technology™ Surface Modification “Standard” PC Coating* Catheter or Stent Covalent Chemical Bonding Encapsulation < 3 nanometer (one braid wire=25400 nm) 500 -4000 nanometer Chemical Reaction Dipping, Spray or Brush SEM Images Bare Braid Shield Technology™ Early Development Work *Note: Standard PC Coatings are similar to EVAHEART LVAD (Clinical. Trials. gov Identifier: NCT 01187368), Endeavor (P 060033) and Biodiv. Ysio Stents (P 000011) Early Development Work Early Development

Ways to evaluate thrombogenicity Method Pro a. PTT (partial • Standard biocompatiblity and clinical test thrombo plastin time) Con • Not sensitive enough to detect differences • ~5% of thrombin is formed for clot time • Large blood sample to sample variation • Visually stimulating results • Limited number of samples per Blood flow run loop testing • Large blood sample to sample variation • Variation within test run Animal models: Difficult to titrate thrombogenic response. Safety Only • Multiple devices per animal • More pronounced Porcine endothelialization • More spasm • Possibly more correlative • Slower to endothelialize Rabbit aneurysm occlusion • Elastase model has high morbidity, expensive, no internal controls

Material Thrombogram Testing • Quantitative, Repeatable, Validated, method used clinically 11 -15 • Uses human platelets and plasma • Compare Peak Thrombin (n. M) • More sensitive to differences than a. PTT (industry standard) Girdhar et al 2015

Testing Performed by Dr. Wayne Chandler, Director of Coagulation Laboratory Houston Methodist Hospital Girdhar et al 2015 Bench Test results may not necessarily be indicative of clinical performance

Reduced Material Thrombogenicity Shield Technology™ only affects Surface Activation • Intimal damage • Device material Virchow’s Triad of Thrombosis Flow Disruption • Wall apposition • Stent design Bench Test results may not necessarily be indicative of clinical performance Hypercoagulable • Anti-platelet non-responder • HIT • Other

Bio-Absorable Stents Abbott BVS most researched absorbable stent (ABSORB study) Thicker stent struts More issues with malapposition and overexpansion than metal stents Harder for delivery 7% malapposition Rate of absorption varies ~2 yrs for Abbott Absorb BVS http: //www. cathlabdigest. com/articles/Bioabsorbable-Stents-%E 2%80%93 -Where-Are-We-Now

Future of innovation Access and delivery systems: more lubricious and durable coatings Flow Diverters and AB Stents: lower thrombogenic and enhanced endothelialization without perforator complications Intrasacular devices: ? ? ? Intracranial artery stenosis: address major complications of stroke and hemorrhage

References 1. Lewis, A. L. and P. W. Stratford, Phosphorylcholine-coated stents. J Long Term Eff Med Implants, 2002. 12(4): p. 231 -50. 2. Lewis, A. L. , et al. , Crosslinkable coatings from phosphorylcholine-based polymers. Biomaterials, 2001. 22(2): p. 99 -111. 3. Whelan, D. M. , et al. , Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries. Heart, 2000. 83(3): p. 338 -45. 4. Kuiper, K. K. , et al. , Phosphorylcholine-coated metallic stents in rabbit iliac and porcine coronary arteries. Scand Cardiovasc J, 1998. 32(5): p. 261 -8. 5. Chen, C. , et al. , Phosphorylcholine coating of e. PTFE grafts reduces neointimal hyperplasia in canine model. Ann Vasc Surg, 1997. 11(1): p. 74 -9. 6. Zheng, H. et al. Clinical experience with a new biocompatible phosphorylcholine-coated coronary stent. The Journal of invasive cardiology 11, 608 -614 (1999). 7. Galli, M. et al. Italian Biodiv. Ysio open registry (Biodiv. Ysio PC-coated stent): study of clinical outcomes of the implant of a PC-coated coronary stent. The Journal of invasive cardiology 12, 452 -458 (2000). 8. Grenadier, E. et al. Stenting very small coronary narrowings (< 2 mm) using the biocompatible phosphorylcholine-coated coronary stent. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions 55, 303 -308 (2002). 9. Boland, J. L. et al. Multicenter evaluation of the phosphorylcholine-coated biodiv. Ysio stent in short de novo coronary lesions: The SOPHOS study. International journal of cardiovascular interventions 3, 215 -225, doi: 10. 1080/14628840050515966 (2000). 10. Beaudry, Y. , Sze, S. , Fagih, B. , Constance, C. & Kwee, R. Six-month results of small vessel stenting (2. 0 -2. 8 mm) with the Biodivysio SV stent. The Journal of invasive cardiology 13, 628 -631 (2001). 11. Chandler, Wayne, and Roshal, Mikhail, Optimization of Plasma Fluorogenic Thrombin-Generation Assays, Am J Clin Pathol 2009; 132: 169 -179. 12. Gerotziafas, et al. , Towards a standardization of thrombin generation assessment: The influence of tissue factor, platelets and phospholipids concentration on the normal values of Thrombogram-Thrombinoscope assay , Thrombosis Journal 2005, 3: 16. 13. Hemker, et al. , Calibrated Automated Thrombin Generation Measurement in Clotting Plasma , Pathophysiol Haemost Thromb 2003; 33: 4 -15. 14. Spronk, et al. , Assessment of thrombin generation II: Validation of the Calibrated Automated Thrombogram in plateletpoor plasma in a clinical laboratory, Thromb Haemost 2008; 100: 362 -364. 15. Tepe, G. , et al. , Thrombogenicity of Various Endovascular Stent Types: An In Vitro Evaluation. Journal of Vascular and Interventional Radiology, 2002. 13(10): p. 1029 -1035.