1. Cardiac Catheters for Delivery of Cell Suspensions Donald Nick Jensen, DVM, MS Division of Cardiovascular Devices HHS/FDA/CDRH

2. FDA/CDRH/DCD Focus of Presentation Potential questions related to the interaction between cell suspension and catheter Standard questions for consideration - suggested to all sponsors of IND’s / cell delivery cardiac catheters Example cell delivery methods / devices Infusion of cells into coronary artery during balloon occlusion of artery Percutaneous, intracardiac, needle-tipped injection catheter for transendocardial injection into myocardium No cardiac catheters for cell delivery approved in U.S.

3. FDA/CDRH/DCD Infusion of Cells into Coronary Arteries Advantages - simplicity, ease of use Not suitable for all cell suspensions? Requires migration of cells from vasculature into myocardium? Potential for embolization / microembolization? Demonstrated during case series Acute MI (hours-to-days), commonly following emergency PCI / stenting Chronic MI / ischemia

4. FDA/CDRH/DCD Use of Balloon Catheters Balloon catheter occludes artery proximal to treatment region Cells infused via balloon catheter lumen or via infusion catheter lateral to balloon Allows infusion at > arterial pressure Increase dispersion within vasculature? Increase adhesion of cells to endothelium? Increase migration of cells into myocardium?

5. Strauer BE, et al. Circulation 2002;106:1913-18.

6. FDA/CDRH/DCD Ballon Angioplasty Catheters Designed to “stretch” occluded arteries and/or stents to desired diameters Can use balloon for occlusion. If guidewire lumen can potentially use for infusion of cell suspension. Considerations if angioplasty catheters are used for infusion of cell therapies 1.Potential for catheter materials to adversely affect viability / functionality of cells? Also - guidewire lumens commonly coated with lubricants.

7. FDA/CDRH/DCD Catheter – Cell Compatibility

8. FDA/CDRH/DCD Considerations - Angioplasty Catheters 2.Balloon designed to stretch artery must instead occlude artery without damaging artery wall Arterial stretch during angioplasty induces stenosis Essential to develop / demonstrate safe methods for balloon inflation during delivery of cell therapies Balloon pressure-diameter relationship (compliance) varies widely among angioplasty catheter designs Methods for one catheter may not work for others 3.Concentrated cell suspensions may clog lumen? 4.Balloon catheter guidewire lumens / connectors not tested to sustain high pressures?

9. FDA/CDRH/DCD Needle-Tipped Injection Catheters Advantages Direct injection into desired myocardial locations Potentially usable with all cell types Cardiac catheter or system (catheter plus sheaths) with retractable, distal injection needle None approved for sale in U.S. Some design requirements potentially similar to cardiac ablation catheters, endocardial biopsy caths Tip must be steerable / deflectable to various locations Sufficiently stiff to maintain tip contact with cardiac wall

10. Perin EC, et al. Circulation 2003;107:2294-2302.

11. FDA/CDRH/DCD Concerns - Needle Injection Catheters 1.Clogging of lumen by cell suspension? Small injection volume, concentrated cell suspension Small injection needle / lumen diameter 20+ injections per treatment session 2.Is cell viability / functionality adversely affected by lumen materials or by shear force? 3.Inadvertent injection into LV cavity? (systemic) May be difficult / impossible to ensure continuous contact between catheter tip and endocardium? Kalman JM, et al. American Heart J 1997;133:8-18.

12. FDA/CDRH/DCD Concerns - Needle Injection Catheters 4.Control / limit - maximum needle extension? Avoid injection / laceration of surrounding organs Safety if cell suspension is delivered pericardial / thoracic / systemic (via lymphatics)? Curves in catheter may alter needle extension Possibly difficult to avoid occasional injection into pericardial space if heart has minimal epicardial fat? Locally “thin” regions of the LV wall Compression / stretch of LV wall by catheter tip Force of injection may separate myocardial and epicardial cells?

13. FDA/CDRH/DCD Concerns - Needle Injection Catheters 5.Are depth and “spread” of injection critical aspects of therapy? Does injection of cells near “more ischemic” endocardial region = injection near less ischemic epicardium? Is a minimally dispersed bolus of cells at each injection site = wider dispersion of cells at each injection site? Catheter design, cell suspension characteristics, injection speed - all may affect depth and spread? Will different injection catheters deliver the same therapy? Animal studies can characterize depth and spread Is it important to characterize “therapy delivered” ?

14. FDA/CDRH/DCD Additional Discussion Nick Jensen Division of Cardiovascular Devices (301) 443-8517, x171 DNJ@cdrh.fda.gov Elias Mallis Branch Chief, Division of Cardiovascular Devices (301) 443-8517, x177 EYM@cdrh.fda.gov