High Definition (HD) IVUS: A New Approach to Improve Conventional IVUS Neil J. Weissman, MD MedStar Health Research Institute Washington Hospital Center Washington, D.C. Disclosures - Institutional Grant Support from Boston Scientific

State of IVUS - 2010 IVUS technology has been clinically available for almost 20 years. Yet. . . Image quality has not improved in the last 10 years. Poor spatial resolution and catheter-to-catheter imaging inconsistency are problematic. Current IVUS systems are not capable of resolving structures <100 μm in size (thin cap fibroatheroma). Poor image quality often requires expert interpretation, inhibits confidence in new users, and is a primary obstacle to maximizing growth and adoption of IVUS technology.

But what if. . . . What if we could start from scratch to design an IVUS system – transducer, catheter, catheter interface, console, etc – using 2010 technology as well as 20 years of knowledge. . . What would this system look like? However, building a high-definition image requires optimizing the entire system. Improvements to any one system component (e.g., transducer) may enhance performance, but not optimizing each component of the imaging chain will not yield the targeted improvements. This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 3

What determines image quality? Pulse Duration Frequency Transducer Bandwidth Image Quality Image quality is made up of many different factors. Much more than just frequency. Transducer shape Signal/Noise Ratio Pulse Length

But, how is image quality defined? Temporal Resolution Image Quality Contrast Resolution Penetration Resolution defines image quality – just like in TVs When you buy an HDTV you don’t care about the technical details of an LCD or a picture tube, you care about the resolution of the set! Axial Resolution Lateral Resolution

What is resolution? Axial resolution is the ability to distinguish echoes from reflectors which are closely spaced along the ultrasound beam axis. Shorter wavelengths (higher frequencies) improve axial resolution. Lateral resolution is the ability to distinguish echoes from reflectors which are closely spaced on an axis perpendicular to the ultrasound beam axis. Near zone (Fresnel zone): beam width is essentially the same as the transducer diameter. Far zone (Fraunhofer zone): beam width diverges. Contrast resolution is the ability to distinguish differences in the strength of echoes returning from different types of reflectors. Transducer sensitivity, system signal integrity, analog-to-digital conversion, grayscale compression curves, and display monitor properties impact contrast. Temporal resolution is the ability to generate and receive echoes faster than the motion of the reflectors. The maximum imaging distance (limited by speed of sound in tissue) combined with the number of scan lines per frame determine the frame rate.

Transducer The ultrasonic transducer is the heart of the system. No amount of signal processing can overcome poor signal fidelity from the transducer. Standard measures of performance of ultrasonic transducers are pulse width and fractional bandwidth. A well-designed imaging transducer is sensitive over a broad band of frequencies. Well-designed ceramic transducers are capable of fractional bandwidths >50%, yet current IVUS transducers have fractional bandwidths <35%. This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 7

Transducer Axial resolution is improved by increasing the frequency domain (fractional bandwidth) of the transducer and by shortening the time domain (impulse) response Lateral resolution is improved by increasing the effective aperture (surface area) and focusing the transducer (concave surfaces). However, larger transducer sizes must be balanced against the increases size of the catheter. Sensitivity is the efficiency of the conversion from an electrical impulse to an acoustic wave (transmit) and vice versa (receive). Improved sensitivity results in better signal to noise ratio and increases penetration. This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 8

Transducer Commercial Transducer #2 (B) Spherically-focused Polymer Film Transducer This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Second generation transducers will incorporate new materials and geometries. Several candidate materials that are currently under investigation include thin and thick film piezoelectric materials and composite materials. Chandrana et al., IEEE Ultrasonics Symposium, 2007 9

Transducer Single Flat Transducer Dual Transducer Second generation HD-IVUS transducers may also include dual transducer configurations that will be optimized for very broadband imaging applications, including harmonic imaging, and multiband fusion imaging. This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 10

Multifrequency Imaging 60MHz 20MHz Cross- Correlation of the two Frequencies

Harmonic imaging to detect vasovasorum by contrast bubble targeting Transmit Receive Before Injection After Injection Here you see that clinical applications that we believe this technology can be useful for: vasa vasorum detection and targeting the bubbles with surface ligand for particular tissue type or disease state. Some may also suggest that the bubbles themselves can also carry some therapeutic drug. You can see the two blue images here – the one on the left is before bubble injection and the one on the right is after bubble injection – you can see the increased in brightness in some region – we believe this qualitatively measures the density of vasa vasorum. The panel below these two blue images shows a more quantitative way to estimate the amount of enhancement at a particular region of interest. On the right, the histology indicates the presence of vasa vasorum and the hypothesis that this application is interesting because it might be a proxy for inflammation which might indicate the vulnerability of a lesion. Spend up to 1 minute on this slide unless there are pertinent questions then return to the index slide. One hypothesis is that Vasa Vasorum density correlates with the amount of inflammation and hence vulnerability of the lesion. during injection

Catheter and System Interface Necessary catheter improvements Improved handling performance Elimination of imaging core wind up Resolved flushing issues Improved transducer connections Decreased resistance Improved reliability Improved catheter/system interface High definition resolution Reduced image acquisition time Support for higher frequency devices This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 13

Front End Innovations: Transducer BSC 40MHz Transducer Small Bandwidth – Less Information Lower Frequency – Less Separation SVMI 60MHz Transducer Width of transducer similar to diameter of BSC (which is circular) but by doing a rectagular shape you get a larger transducer with more energy transmitted to tissue. Matching of backing material to piozelectric crystal - ring down fast - with lower burst count (blue background) for higher axial resolution Transducer Assembly Stack (0.6mm x 0.4mm) Large Bandwidth – More Information Higher Frequency – More Separation Confidential

Coherence Imaging Information-rich images enable substantial image enhancements through vector domain signal processing for mechanically rotating imaging catheters (4096 scan lines of information as compared to 256-512) 256 (volcano) or 512 (BSC) scan lines ; 4096 scan lines of information for SVMI

Comparison of In Vitro Human Cadaver LAD Segment Goal is to get below thin cap resolution - improvements noted even staying at 40 MhZ (so apples to apples comparison) Commercial 40MHz (135 microns resolution) SVMI 40 MHz (80 microns resolution) Confidential 2/13/2018

Comparison of In Vivo Stent Malapposition in Porcine Model B: 0.17mm A: 0.12mm Pig study with immediate post-stent implantation LightLab™ ImageWire OCT (with saline flush) SVMI HD-IVUS 50 MHz (in blood) Confidential 2/13/2018

Comparison of In Vivo Stent Malapposition in Porcine Model B: 0.17mm B: 0.17mm A: 0.12mm A: 0.12mm Commercial 40MHz SVMI HD-IVUS 50 MHz Confidential 2/13/2018

Product Performance Comparison SVMI HD-IVUS BSC iLab / Atlantis Volcano s5/Revolution Console OS Linux Windows XP Imaging Frequency 10-80MHz 10-40MHz 10-45MHz System Topology Direct RF Baseband Scanning Mechanism Mechanical Analog to Digital Converter 14-bit 400MS/s 12-bit 200MS/s 12-bit 40MS/s Digital Signal Processor Xilinx Virtex 5 Xilinx Virtex 3 Transducer Bandwidth 30MHz 13MHz 11MHz Axial Resolution 50 μm 150 μm 200 μm Lateral Resolution 100 μm 400 μm Maximum Pullback Rate 20mm/sec 1.0mm/sec Maximum Frame Rate 160 FPS 30 FPS Catheter Dead Zone 15mm 25mm 32mm Catheter Coating Hydrophilic Hydrophobic Linux a Unix type that is always on and does not go through a start up;

Superior Catheter Design Dead Zone Length SVMI Tip shape Wire channel Telescope Dead zone length Extra length Hydrophilic coating Boston Scientific Volcano 15mm 25mm 32mm

In Vitro Human Cadaver Image Comparison Commercial 40MHz SVMI 60MHz Confidential 2/13/2018

Simultaneous Multi-Frequency Operation Images acquired with the same catheter SVMI 60MHz catheter @ 60MHz SVMI 60MHz catheter @ 40MHz Confidential 2/13/2018