Founder and Chief Scientific Officer Enabling the Next Generation of Drug Delivery Through Implantable Medical Devices Kevin D. Nelson, Ph.D. Founder and Chief Scientific Officer TissueGen, Inc.

Disclosure Statement Dr. Nelson serves as Founder and Chief Scientific Officer for TissueGen, Inc. which has developed and markets products related to the research described in this presentation.

Overview Drug Delivery from Medical Fiber Tissue Engineering Applications

Drug Delivery from Medical Fiber Advantages of Fiber Slower Release than Microspheres Mechanical and Pharmaceutical Support Localized (Non-systemic) Drug Delivery

Drug Delivery from Medical Fiber Manufacturing Methods Melt Extrusion High temperature (typically > 200 degrees C) High shear stress Wet Extrusion Low temperature (typically at or below body temp) Low shear stress Harmful solvent exposure Residual solvent removal

Drug Delivery from Medical Fiber Polymers Poly(L-lactic co-glycolic acid) [PLGA] Poly(ԑ-caprolactone) [PCL] Poly(L-lactic acid) [PLLA] Poly(p-dioxanone) [PDO] Proprietary Blends Natural Polymers

Drug Delivery from Medical Fiber Fiber Formats Circular Ribbon Hollow Gel-filled Multi-lumen Over-the-wire

Drug Delivery from Medical Fiber Medical Device Formats Coils Stents Sutures Medical Textiles

Drug Delivery from Medical Fiber Pharmaceuticals hydrophilic hydrophobic

Drug Delivery from Medical Fiber Biologics Growth Factors Other Proteins Viral Particles

Drug Delivery from Medical Fiber Protection of Sensitive Proteins BDNF half life 22 hours in buffer system. Over 100 days release possible with protein protection within fiber.

Drug Delivery from Medical Fiber Controlled Sustained Release Profiles

Drug Delivery from Medical Fiber Tailored Release Profiles

Drug Delivery from Medical Fiber Drug Delivery and Tissue Engineering

Tissue Engineering Applications Nerve Growth Factor PC-12 Cell Assay PC-12 cells sprout neurites in presence of biologically active NGF NGF loaded fiber in culture with PC-12 cells Panel A: No NGF Panel B: 5 cm NGF fiber Panel C: 10 cm NGF fiber A B C

Tissue Engineering Applications Nerve Growth Factor Dose Response Neurite process length proportional to amount of biologically active NGF. Dose Response: 10cm fiber dosage nearly twice activity of 5cm fiber.

Tissue Engineering Applications Peripheral Nerve Regeneration Rat Sciatic Nerve Fiber Scaffold

Tissue Engineering Applications Axon Guidance Non-Drug Loaded Fibers

Tissue Engineering Applications Tissue Guidance by Concentration Gradient

Tissue Engineering Applications Aldose Reductase Inhibitor Release

Tissue Engineering Applications Diabetic Retinopathy

Tissue Engineering Applications Adenovirus Release from Gel-Bored Fiber

Tissue Engineering Applications Nicotine Release Promoting Angiogenesis in Mouse

Summary Drug Delivery from Medical Fiber Tissue Engineering Applications

Additional Information Kevin D. Nelson, Ph.D. TissueGen, Inc. knelson@tissuegen.com www.tissuegen.com