Medtronic Non-Polymeric DES Development: Update on the Drug Filled Stent Josiah N. Wilcox, Ph.D. Vice President and Resident Scholar Science and Technology Medtronic CardioVascular

Disclosures I am a full time employee of Medtronic CardioVascular I will be talking about products and product concepts that are currently not approved for use in the USA Resolute, DFS, S10/CoreWire

1Internal Bench Test Data on file at Medtronic, Inc. Integrity BMS Superior Deliverabilty1 129% trackability improvement vs. Biotronik PRO-Kinetic Energy 116% trackability improvement vs. Abbott Multi-link Vision Conformability Excellent post-deployed wall apposition with minimal vessel straightening Radial Strength No compromise – equivalent to leading competitive stents Add radial strength? Hong Kong, Nov. 2009 1Internal Bench Test Data on file at Medtronic, Inc.

Continuous Sinusoid Technology A New Standard in Stent Design & Manufacturing Conventional Stent Design Medtronic Modular Design vs. Slotted Tube Modular Design Medtronic’s Continuous Sinusoid Technology Drug Filled Stent is made possible by Continuous Sinusoid Technology, a new revolution in stent design & manufacturing from Medtronic Sinusoidal Formed Wire Helical Wrap Laser Fused 4 4

Continuous Sinusoid Technology Continuous sinusoid technology allow greater stent flexibility Stiff Flex Separate stiff and flexible segments limit range of motion Flex Continuous sinusoid technology will flex continually 6

Continuous Sinusoid Technology The Next Revolution in Stent Technology Drug-Filled Stent Enabling designs that could not be attempted in the past Bare Metal Stents Drug-Eluting Stents Resolute Integrity Integrity It would not be possible to create a thinner strut cobalt alloy stent (< 0.003”) without compromising radiopacity. That’s where Core Wire and New alloys allow stent designs that would not otherwise be possible without major compromise. Core Wire New Alloys Platforms for next gen DES coatings BioLinx (Resolute) PC Technology (Endeavor) Bioabsorbable polymer Nanoporous Product concepts not currently approved for us in the USA

Continuous Sinusoidal Technology Core Wire and New Alloy Stents Program Targets Maintain / extend Medtronic lead in stent technology Enhance performance w/o compromising strength & opacity Create a backbone for DES coating technologies 0.0038" Cobalt Chromium 0.0034" Core Wire 0.0030" 0.0025" New alloys 0.0020" Product concepts not currently approved for us in the USA

Continuous Sinusoidal Technology Core Wire Stents 0.0345’’ Integrity 0.0404’’ Visibility with “old” lab equipment: >20% thinner struts, yet more opaque Integrity (same as Driver) Core Wire vs. Integrity (3.5 x 18mm size) 15% reduction in crossing profile 22% thinner stent struts 45% improvement in flexibility 25% improvement in trackability Increased visibility Core Wire Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology Polymer Free Drug Delivery Innovative DES design Essentially a BMS surface No drug carrier issues such as Polymer biocompatibility Inflammation upon polymer degradation Surface coating durability Allows for controlled, prolonged, and tailored elution profiles Has not been achievable with other non-polymeric approaches With CST, Medtronic is working to bring a new concept in DES – a polymer-free Drug Filled Stent Drug is contained in a small diameter hollow core running the length of the stent and elutes in a controlled fashion via tiny holes This design is not possible with laser cut technology From the start, it has a bare metal surface with no durability, biocompatibility, or inflammation issues associated with durable or bioabsorble polymers Elution rates can be controlled by mechanical means – the size (diameter) and number of the holes Product concepts not currently approved for us in the USA

DFS R&D Process (abbreviated) Stent Forming Welding Hole Drilling De-Coring Drug Filling Finishing Drug Extraction Pre-Clinical Proof Product concepts not currently approved for us in the USA 11

Drug Filled Stent (DFS) Technology Core Wire Construction Core Material Co Alloy Shell Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology Elution Hole Drilling Product concepts not currently approved for us in the USA

Laser Hole Drilling Facilitate drug filling and elution 500 – 5000 holes per stent (18 mm) Variable hole diameter and shape Automation Throughput Reliability Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology Elution Hole Drilling – Most Recent Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology Elution Hole Drilling – The Future Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology De-Coring Process Etching Gas + Sacrificial Core Vapor Phase Etched Core (sublimates) Etching Gas Sacrificial Core Vapor Sacrificial Core Vapor Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology De-Coring Process X-Ray with Core X-Ray without Core Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology Radial Strength Structural Analysis Calculated moment of inertia (I) for various drug channel sizes on a percent basis. The “strength” of a stent comes from the stiffness of its struts, and their resistance to bending. Based on a simple beam in bending analogy, the stiffness of a stent strut is directly proportional to the moment of inertia (I) of the strut. For a round cross-section, like that of the Integrity stent, the moment of inertia (I) of a strut is directly proportional to the radius of the strut to the fourth power. In the case of the drug filled stent, the radius of the inner lumen does decrease the moment of inertia (I) of the strut; however, due to the proportionality of the radius being to the fourth power, the moment of inertia is dominated by the outer radius of the strut. Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology Radial Strength Structural Analysis Radial Crush Test – Stent is placed in an iris that decreases the diameter during which the force being measured is the outward force of the stent against the iris. The graph show Force rising as the stent diameter is reduced (from left to right along x-axis). Hollow stents appears higher than the solid wire (implying greater radial strength), but in this case it is due to the different diameters of the hollow wire stent and solid wire (Integrity) stent being tested. The hollow wire has a thickness of 0.0040” and the solid wire Integrity is 0.0036”. Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology Possible Elution Mechanism Here we provide one theory for how the drug can elute, namely diffusion. It is also likely that dissolution and convection play a part of the drug release from the drug filled stent. First we are showing how the concentration changes over time. The concentration will continuously move from the higher to lower concentration. In this example the concentration would most likely not reach a 50/50 equilibrium as the drug is the tissue is being used up by the cells or diffusing farther away from the strut causing the concentration to remain lower than in the strut itself. (upon click) Fick’s 2nd law of diffusion appears, which is the governing equation that describes how the concentration changes with time. Product concepts not currently approved for us in the USA

DFS Prototype Elution Comparison Drug Filled Stent (DFS) Technology Controllable Elution Standard non-polymeric elution DFS Prototype Elution Comparison 70% 60% 50% 40% 30% 20% 10% 0% % Eluted Time Design 1 Design 2 Design 3 Design 4 Design 5 Design 6 Resolute Elution can be controlled by the size of the holes and the number of holes in each strut. Testing suggests a variety of elution profiles possible Product concepts not currently approved for us in the USA

Drug Filled Stent (DFS) Technology In Vitro Elution into Agar Gel Product concepts not currently approved for us in the USA

Design Comparisons Elution Product concepts not currently approved for us in the USA

Percent Drug In Tissue – DFS vs Resolute Product concepts not currently approved for us in the USA

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