Challenges and Opportunities for Applied Nanotechnology to the Regeneration of the Central Nervous System Gabriel A. Silva, M.Sc., Ph.D. Departments of Bioengineering and Ophthalmology, Whitaker Institute for Biomedical Engineering and Neurosciences Program University of California, San Diego A Working Definition of Nanomedicine Understanding, preventing, and treating diseases using tools, materials, and approaches that take advantage of and operate at the nanoscale. (NIH Nanomedicine Roadmap Initiative meeting, May 4, 2004) Model of Applied Nanotechnology to Medicine and Physiology Nanoscience and Nanotechnology Biology, Physiology, and Medicine Our research group focuses on experimental and theoretical neural bioengineering aimed at increasing our fundamental understanding of neuroscience and developing new approaches for the clinical regeneration of the neural retina and central nervous system (CNS). We approach this, in part, through the development and application of targeted nanotechnologies. The Central Nervous System (CNS) National Library of Medicine- www.nlm.nih.gov The Central Nervous System (CNS) Gray’ s Anatomy Online- http://www.bartleby.com The Central Nervous System (CNS) Gray’ s Anatomy Online- http://www.bartleby.com The Central Nervous System (CNS) Gray’ s Anatomy Online- http://www.bartleby.com The Central Nervous System (CNS) Nature Encyclopedia- http://www.els.net The Cellular and Sub-Cellular Scales Challenges faced by CNS Nanotechnologies 1. Integration with a highly specialized extracellular environment 2. Targeting to specific molecular elements (e.g. receptors, other proteins), in particular intracellular targets 3. A very heterogeneous cellular environment 3. Highly restricted anatomical access 4. The complexity of the CNS’ s functional “ wiring” 5. Multiple specific targeted effects and/or responses 6. Optimization of desired integrated responses and minimization of local and systemic “ side effects” The Successful Development Of CNS Nanotechnologies Advancements in basic and clinical neuroscience The integration of the two Advancements in The fundamental chemistry, physics, and materials science of nanotechnology Neural Specific Bioactive Peptide Amphiphile Networks O OH NH2 H O H O H O H O H O H O H O N N N N N N N N N N N N N OH O H O H O H O H O H O H O C16H31O-NH-AAAAGGGEIKVAV-COOH Hydrophobic Tail Spacer Region Functional Peptide Region Stupp Research Group, Northwestern University- Jeffery Hartgerink and Elia Beniash Neural Specific Bioactive Peptide Amphiphile Networks Stupp Research Group, Northwestern University- SEM by Dan Harrington Neural Specific Bioactive Peptide Amphiphile Networks Stupp Research Group, Northwestern University- Gabriel Silva Neural Specific Bioactive Peptide Amphiphile Networks Stupp Research Group, Northwestern University- Gabriel Silva Neural Specific Bioactive Peptide Amphiphile Networks N * NF 2 m Stupp Research Group, Northwestern University- Gabriel Silva Neural Specific Bioactive Peptide Amphiphile Networks: Cell Viability/Cytotoxicity 100 IKVAV-PA gel PDL 1 DIV 7 DIV 22 DIV 1 DIV 7 DIV 22 DIV Live cells (%) 80 60 40 20 100 um 0 Days in vitro Stupp Research Group, Northwestern University- Gabriel Silva 70 ** 60 50 40 * 30 20 10 0 1 DIV 7 DIV IKVAV-PA gel 1 DIV 7 DIV Laminin 1 DIV 7 DIV PDL GFAP+ cells/ total number of cells (%) -tubulin+ cells/ total number of cells (%) Neural Specific Bioactive Peptide Amphiphile Networks 25 20 15 10 5 0 * 1 DIV 7 DIV 1 DIV 7 DIV 1 DIV 7 DIV PDL IKVAV-PA gel Laminin Stupp Research Group, Northwestern University- Gabriel Silva Nanoengineering Mesenchymal Stem Cells Differentiation into Photoreceptor Neurons Silva Research Group, UCSD- Diana Yu and Mai Ho Nanoengineering Mesenchymal Stem Cells Differentiation into Photoreceptor Neurons Silva Research Group, UCSD- Diana Yu and Mai Ho Functionalized Quantum Dot Targeting of Reactive Gliosis Silva Research Group, UCSD- Smita Pathak Functionalized Quantum Dot Targeting of Reactive Gliosis Silva Research Group, UCSD- Smita Pathak and Julie Schallhorn Functionalized Quantum Dot Targeting of Reactive Gliosis Culture model of reactive gliosis Untreated retinal glial cells Ouabain treated retinal glial cells Secondary treated retinal glial cells Functionalized Quantum Dot Targeting of Reactive Gliosis Silva Research Group, UCSD- Julie Schallhorn Functionalized Quantum Dot Targeting of Reactive Gliosis Silva Research Group, UCSD- Julie Schallhorn and Smita Pathak URL: www.silva.ucsd.edu Email: gsilva@ucsd.edu Acknowledgments and Collaborators Silva Lab, University of California, San Diego Marie Davidson Smita Pathak Julie Schallhorn Elizabeth Cao Yvette Valenzuela Dr. Sungho Jin, University of California, San Diego Funding Jacobs School of Engineering, University of California, San Diego Jacobs Retina Center, University of California, San Diego Dr. Warren Chang, University of Toronto Whitaker Foundation Quantum Dot Corporation, Hayward, California Stein Institute for Research on Aging Stupp Lab, Northwestern University Prof. Samuel Stupp Krista Niece Dr. Elia Beniash Dr. Jeff Hartgerink Institute for Bionanotechnology in Advanced Medicine, Northwestern University Kessler Lab, Northwestern University Dr. Jack Kessler Catherine Czeisler Dr. Vijay Sarthy, Northwestern University