1. College of Medicine and Public Health USDA & Nanotech Delivery of (Bio)molecules ? Mauro Ferrari, Ph.D. Associate Vice President, Health Sciences, Technology and Commercialization Edgar C. Hendrickson Professor of Biomedical Engineering Associate Director, Dorothy M. Davis Heart and Lung Research Institute Professor of Internal Medicine & Mechanical Engineering M.D. student USDA – November 18, 2002

2. College of Medicine and Public Health From a Drug-Delivery Perspective Proposed Analogy: –Smart drug-delivery systems & smart delivery of nutrients? Smart = any combination of: –Spatially Directed –Time-Controlled Release Profile –Intelligent Control: Remotely regulated Pre-programmed Self-regulated

3. College of Medicine and Public Health En route to self-regulated…. Integration of: –Sensing of target trigger –Intelligence onboard –Release technology on delivery implant or particulates for oral, intravascular, transdermal or aerosol delivery

4. College of Medicine and Public Health Crucial Bottlenecks * Stability of Implanted Sensing Technology: To Develop Antifouling Tech, or Fouling- Insensitive Strategies? Availability of Appropriate Disease Markers (On-board Logics Linkage Between Sensing and Therapeutic Delivery) “SMART” DELIVERY TECHNOLOGY *From NIH BECON’s Active Disease Management, 6/25/02

5. College of Medicine and Public Health Three examples of use of (top-down) nanotech Nanopores for controlled release of biomolecules Nanopores for immunoprotected implantation of cell bioreactors Multifunctional particles for the oral delivery of biological molecules (from my lab and iMEDD, Inc – please note that I have a financial interest in iMEDD)

6. College of Medicine and Public Health Silicon Wafer Etch Trenches Deposit Sacrificial Oxide Layer Deposit Poly Silicon Structural Layer NanoPORE Fabrication Process

7. College of Medicine and Public Health Planarized Apply Etch Stop Back Etch Remove Etch Stop NanoPORE Fabrication Process

8. College of Medicine and Public Health Remove Sacrificial Oxide NanoPORE Fabrication Process

9. College of Medicine and Public Health Array of NanoPORE Channels NanoPORE Fabrication Process

10. College of Medicine and Public Health NanoPUMP Implantable Drug Delivery Device Iso-osmotic electrolyte primer solution Check valve (closed) Anode Cathode Plunger Vent Switch (open) Release orifice Drug/electrolyte solution Nanopore membrane array Battery pack Biocompatible encasement Check valve (opened) Advancing Plunger Vent Switch (closed) Released Drug Drug/electrolyte solution

11. College of Medicine and Public Health NanoPORE Array SEM showing top views of parallel 50 nanometer pores (each 45  m long) Pore Anchor Top View Poly Silicon Beam

12. College of Medicine and Public Health Molecular Dimensions 500 nm NanoPORE Array Cross Section View

13. College of Medicine and Public Health NanoGATE Glucose Diffusion

14. College of Medicine and Public Health Albumin Diffusion Kinetics Time (Days) Cumulative Percent Release

15. College of Medicine and Public Health Robotic surgery meets nanotech

16. College of Medicine and Public Health BIOCAPSULE/1 History of Cell Encapsulation lActive research field for over three decades lPrevious focus has been entirely on natural or synthetic polymeric biocapsules [Chang, 1967; Lim & Sun, 1980; Lacy, 1991; Lanza, 1992; Soon-Shiong, 1993; Scharp; Hubbell; and many more...] l Limitations associated with premature biodegradation, chemical and mechanical instability, and broad pore size distributions

17. College of Medicine and Public Health Figure 11. Non fasting blood glucose concentration and body weight in STZ-diabetic Lewis rat after biocapsule implantation Cell Transplant Biocapsule  Implant containing cells to produce insulin (or other therapeutic agent)  Membrane protects transplanted cells from immune attack  Phase 2 SBIR Grant application Figure 8. IgG Diffusion into biocapsule

18. College of Medicine and Public Health The Programmable Pill By Alexandra Stikeman Technology Review May 2001 Vol. 104/No.4, pp.78-83 Starting with oral…..

19. College of Medicine and Public Health Enteric coating protects drug- loaded particles in acidic stomach Capsule dissolves in intestines releasing drug- loaded particles Particles adhere to intestinal wall and transport contents into the blood stream Oral Peptide Delivery: Transport through the GI Tract

20. College of Medicine and Public Health Anatomy of Intestinal Mucosa

21. College of Medicine and Public Health Intestinal Mucosa: Tight Junction Complex

22. College of Medicine and Public Health 120  m (a) Particles on Substrate (b) Released Particle (c) Pores in Particle Size: 150 – 300  m Thick: 25  m Pore Size: 20 – 100 nm Porosity: 70% Microfabricated Porous Silicon Particles

23. College of Medicine and Public Health Porous Silicon Particles

24. College of Medicine and Public Health NH 2 H2NH2N H2NH2N H2NH2N NH HN Porous Silicon Particles

25. College of Medicine and Public Health NH HN NH HN

26. College of Medicine and Public Health Vasculature Intestinal epithelial cells Intestinal mucin Microfabricated Trans-Mucosal Patch For Delivery of Biologically Active Peptides and Proteins Intestinal lumen NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH 1. Lectin mediates binding of particle to mucosa NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH

27. College of Medicine and Public Health Vasculature Intestinal epithelial cells Intestinal mucin Microfabricated Trans-Mucosal Patch For Delivery of Biologically Active Peptides and Proteins Intestinal lumen 2. Thru-particle hydration releases drug + enhancer NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH

28. College of Medicine and Public Health Vasculature Intestinal epithelial cells Intestinal mucin Microfabricated Trans-Mucosal Patch For Delivery of Biologically Active Peptides and Proteins Intestinal lumen 3. High local concentration of enhancer + drug.................................................................................................................................................................................................................................................................................................................................................................................................................................................................................... NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH

29. College of Medicine and Public Health Vasculature Intestinal epithelial cells Intestinal mucin Microfabricated Trans-Mucosal Patch For Delivery of Biologically Active Peptides and Proteins Intestinal lumen.................................................................................................................................................................................................................................................................................................................................................................................................................................................................................... 4. Enhancer opens tight junctions NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH

30. College of Medicine and Public Health Vasculature Intestinal epithelial cells Intestinal mucin Microfabricated Trans-Mucosal Patch Intestinal lumen.................................................................................................................................................................................................................................................................................................................................................................................................................................................................................... 5. Drug passes between cells and enters blood stream............................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................ NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH NHNH For Delivery of Biologically Active Peptides and Proteins

31. College of Medicine and Public Health Relative Size of Trans-Mucosal Patch

32. College of Medicine and Public Health 0 5% 10% 15% 20% 25% Control OralMEDDSParticles Transport of Insulin (% of dose/hr) (~2%) (~22%) Enhanced Transport of Insulin CACO-2 Intestinal Model Oral MEDDS Particles

33. College of Medicine and Public Health Strategy: Need FACILITIES Science Village at Ohio State MicroMD First Dedicated bioMEMS/Nanotechnology R&D Facility

34. College of Medicine and Public Health Thanks Ferrari.5@osu.edu