Sunday, February 07, 2010
8:00am - 1:40pm and 2:00pm - 5:40pm

Lecturers: Dean Ho, Wing Kam Liu, Eiji Osawa, Michael A. Teitell

Course Description and Outline
Nanoengineered materials represent a class of technologies that can be applied towards the treatment of a broad spectrum of medical challenges, ranging from cancer, cardiovascular disease, regenerative medicine, and beyond. Requisites for optimized therapy include the design of materials that serve as platforms in that they are capable of delivering multiple forms of therapeutics, from proteins to antibodies and small molecules, etc; possess high surface area-to-volume ratios for enhanced drug loading; are capable of consistent clearance; improve opportunities for targeted/specific drug release, and are amenable towards scalable synthesis and fabrication techniques, among others. By pairing these technological attributes with emerging findings towards enhanced combinatorial/sequential drug release methodologies, nanoengineered material-mediated therapy will generate important new routes towards improving patient treatment outcomes while minimizing side effects.

Nanocarbons represent a class of emerging materials with unique attributes that can address key requirements in medicine and biology. For example, graphene is being explored as a novel material for electronics/energy applications, as well as multifunctional materials for polymeric nanocomposite synthesis. Furthermore, Nanotubes have found applications in bio-electronics and sensing, and are being explored as platforms for diagnostic imaging agents. Furthermore, nanotube-based devices are being fabricated as nanomaterial-based mimics of gecko-inspired adhesives. The fruition of nanocarbon systems towards realized relevance as multifunctional materials for nanoengineered medicine requires a clear interface between multi-scale simulation/modeling and experimental interrogation of the material properties which contribute to their unique performance capabilities. For example, carbon-based nanodiamonds possess several unique characteristics that serve as the foundation of their translational potential. Nanodiamonds can be scalably produced; batch functionalized, interfaced with nearly any type of therapeutic, is immensely biostable, and has highly-ordered aspect ratios which contribute to their bio-amenability. They are also capable of generating consistent, 'zero-order' release profiles. The ability to investigate, understand, and direct the behavior of nanocarbon systems relies upon the marriage of simulation-based and experimental validation. This course will examine current developments towards nano-engineered materials and its role in next-generation therapeutics, providing insight into fundamental material properties/design, in vitro/in vivo application, and prospects for clinical translation.

Module 1 - Presented by Michael A. Teitell
Cancer: Defining Disease and the Need for Nanoengineered Materials

Cancer is a heterogeneous group of diseases characterized by uncontrolled cell proliferation and/or altered cell death. A typical tumor may contain billions of cells, with subsets of tumor cells in each cancer displaying a spectrum of biophysical, biochemical, and drug resistant phenotypes. A consensus is evolving that for many malignancies new modes of molecularly-targeted, combinatorial therapy will be required to generate long lasting remissions and cures. Targeted, combinatorial therapies will represent a significant advance over traditional non-selective chemotherapy and radiation therapy approaches that will undoubtedly require major advances in therapeutic delivery vehicles and modalities. In my presentation, I will set the stage for the following tutorial discussions of nanoengineered materials in therapy and diagnostics by describing many of the complexities of disease, using a discussion of human cancer as a model. Some general topics briefly explored will include cancer origins, evolution, remission and recurrence, and current and emerging diagnostic modalities.

Module 2 - Presented by Eiji Osawa
Recent Progress in the R&D of Single-Nano Diamond Particles

In the past 40+ years, R&D in detonation nanodiamond has long suffered from the persistent covalent aggregation among primary particles. Although the nature of this tight assembly has not yet been thoroughly understood, it is most likely that, as in all other nanocarbons including soot (carbon black) and carbon nanohorn formed by the bottom-up processes, primary particles of nanodiamond were glued to each other through C-C bonding as they are formed under high-temperature high-pressure conditions to form secondary particles of 60-200 nm in size. It was impossible to disintegrate the covalent aggregates since its discovery in 1963 until 2002, when we applied wet stirred-media milling with zirconia beads to disintegrate them by brute force. The resulting colloid is diaphanous, although pitch black in high concentration, but surprisingly stable. Dried residue from the milled colloid is van der Waals aggregates of primary particles, and can be re-dispersed quickly in water and a few organic solvents by sonication to form stable colloidal solution which is transparent and forms no precipitates after long-standing.

Dispersed single-nano diamond (DSND) particles, as we temporarily call them, have a narrow size-distribution of 4.6±0.7nm irrespective of its origin and methods of determination. They behave distinctly different from the previously commercialized covalent aggregates (under the name of Ultradispersed Diamond) and exhibit long-dreamed size-dependent behavior of semi-quantum particles, a new breed in science and technology. Here we report some of our recent results obtained during preliminary scanning of the applicative possibilities of DSND particles.

Module 3 - Presented by Dean Ho
Nanodiamond-Based Therapeutic Delivery Agents For Enhanced Cancer Treatment

Nanodiamonds (NDs) possess multiple properties that enable their application as versatile drug delivery vehicles. For example, they can be functionalized with a broad array of therapeutics which includes small molecules, proteins, antibodies, and RNA/DNA for applications in cancer treatment, cardiovascular medicine, wound healing, and beyond. In addition, NDs possess uniform dimensions (~4nm in diameter per particle) and material stability that are coupled with observed biocompatibility in vitro and in vivo. Furthermore, NDs can be batch purified and functionalized for scalable and high yield processing. Among other functional groups, NDs also possess an abundance of surface-bound carboxyl groups which are conducive towards facile, application-dependent molecular linking/conjugation onto the diamond surface. Furthermore, NDs can be functionalized with additional chemical species to enable direct drug conjugation. Our previous studies have confirmed robust drug binding to NDs through transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) coupled with in vitro tracking of cellular internalization and quantitative demonstration of bio-amenable cell response through quantitative real time polymerase chain reaction (RT-PCR) assays of inflammatory and apoptosis-regulating gene expression programs. Furthermore ND-mediated drug release against HT-29 and Raw 264.7 cell lines has also been observed. Towards the broadening of ND applicability in clinically-significant treatment scenarios, recent work pertaining to simultaneous high-efficacy/high biocompatibility gene delivery, ND-based microfilm device formation for localized chemotherapy, pH-dependent therapeutic protein release, and pre-clinical studies will be discussed.

Module 4 - Presented by Wing Kam Liu
Science-Based Modeling and Simulation Methods for General Classes of Enabling Materials

It has been demonstrated from recent research that nanomaterial-enabled control and localization of drug delivery as cancer therapeutics represents an important component of optimized device functionality. Much of the ongoing research in the emerging nanomedicine area is based on the use of carbon nanotubes and bucky balls, which challenges their underlying translational relevance as innately compatible drug delivery. To the contrary, nanodiamonds (NDs) represent a much more viable alternative because they have much higher potential for mass production, yet still possess properties common to nanotubes and bucky balls such as the ultrahigh surface-to-volume ratio. In this presentation, we outline the roadmap for the development of ND-enabled drug delivery system capable of performing both therapeutics and diagnostics functions via seamless integration of simulation based engineering & science (SVE&S) and experimental validations.

The essential components of nanodiamond based multifunctional devices are nanodiamonds (ND), parylene buffer layer, doxorubicin (DOX) drugs and imaging bio marker molecules. In its simplest form, self-assembled and functionalized (with DOX and biomarkers) nanodiamonds are packed inside parylene capsule. The efficient functioning of the device is characterized by its ability to precisely detect targets (cancer cells) and then to release drugs at a controlled manner. The fundamental science issues concerning the development of the ND-based device includes (a) a precise identification of the equilibrium structure, surface electrostatics and self assembled morphology of nanodiamonds, (b) understanding of the drug/biomarker adsorption and desorption process to and from NDs, (c) rate of drug release through the parylene buffers, and finally, (d) device performance under physiological condition. In this study, we aim to systematically address these issues using a multscale computational framework. Specifically, quantum/atomistic calculation will predict the structure and electrostatics of the functionalized NDs. Atomistic-scale calculations will simulate the self-assembly process of the functionalized NDs, drug-ND/marker-ND interactions and drug diffusion. At the continuum-scale, the drug delivery process from the device to the targeted area will be modeled and simulated using a novel immersed diffusion finite element method (IDFEM) with information provided from sub-scale simulations.

Once we understand the essential physics of diffusion controlled drug release, our final effort will be paid to model a ND coated film device that basically incorporates the multiscale science learned from earlier. Results from this study will provide fundamental insight on the definitive targeting of infected cells and high resolution controlling of drug molecules.

Lecturers

		Dean Ho Assistant Professor, Departments of Biomedical Engineering and Mechanical Engineering, Robert R. McCormick School of Engineering and Applied Science Director, Laboratory for Nanoscale Biotic-Abiotic Systems Engineering (N-BASE), Robert H. Lurie Comprehensive Cancer Center, Northwestern University Dr. Ho is investigating the fabrication of nanodiamond-based technologies for drug delivery, glucocorticoid-functionalized materials as anti-inflammatory devices and post-operative treatment modalities, as well as localized and targeted chemotherapy using novel nanomaterial devices. He has published over 90 peer-reviewed journal and proceedings manuscripts in the areas of nanomedicine, drug delivery, and nanomaterials. Dr. Ho's research achievements have garnered news coverage on the CNN homepage, Nature, United Press International, Reuters, Yahoo, The Chicago Tribune, USA Today, MICRO/NANO, as well as BBC Radio. He has also given multiple plenary/keynote talks in international meetings pertaining to nanomedicine and nanomaterials. Dr. Ho is currently an Associate Editor of the Journal of Biomedical Nanotechnology, Journal of Nanotechnology Law and Business, and Advanced Science Letters, has served as a Guest Editor for multiple peer-reviewed publications, and is a member of Sigma Xi. He is a recipient of the Wallace H. Coulter Foundation Early Career Award for Translational Research, and one of fifteen cancer researchers in the nation awarded a V Foundation for Cancer Research V Scholars Award. In addition, Dr. Ho was recently named a recipient of the John G. Bollinger Outstanding Young Manufacturing Engineer Award of the Society of Manufacturing Engineers, presented with the Distinguished Young Alumnus Award from the UCLA School of Engineering, and honored by the New Faces of Engineering National Award presented by IEEE.
		Wing Kam Liu Walter P. Murphy Professor, Department of Mechanical Engineering Northwestern University Chair, ASME K&C Nanotechnology Council. Prof. Liu received his B.S. from the University of Illinois at Chicago; his M.S. and Ph.D. both from Caltech. He is a world leader in multiscale simulation-based engineering and science and has applied a spectrum of atomistic, quantum, and continuum strategies towards the understanding of nanomaterial function and biological processes. He was the first to develop concurrent multiscale methods for materials design. These methods have been used to design new alloys and nano-composites. Recently, he has developed the 3D immersed finite element method for modeling the microfluidic electrokinetic assembly of nano wires and filaments and bio-molecules. This transformative bio-nanotechnology has the potential to revolutionalize drug delivery system to achieve the desired therapeutic effects. Selected honors include the Robert Henry Thurston Lecture Award, the Gustus L. Larson Memorial Award, the Pi Tau Sigma Gold Medal and the Melville Medal, (all from ASME); the John von Neumann Medal from US Association of Computational Mechanics (USACM); and the Computational Mechanics Awards of the International Association of Computational Mechanics (IACM) and the Japanese Society of Mechanical Engineers. Liu chaired the ASME Applied Mechanics Division and is past president of USACM. He is listed by the Institute for Scientific Information as one of the most highly cited researchers in engineering. He is the editor of two International Journals and honorary editor of two journals and has been a consultant for more than 20 organizations. Liu has written three books, the Finite element book becomes a classical in the field and the Nano Mechanics and Materials book received a very favorable review by Nanotoday (Nov, 2006).
		Eiji Osawa President, NanoCarbon Research Institute, Limited Shinshu University, Ueda, Japan Mr. Osawa is the President of NanoCarbon Research Institute Ltd., a private research company for industrialization of fullerenes. Since 1992 he has been the Representative Executive Member of the Fullerene-Nanotube Research Association, a subsidiary of the Chemical Society of Japan. He has been trained as an organic chemist in the Department of Industrial Chemistry of Kyoto University. After earning M. Eng. in chemistry in 1960, he joined Teijin Co., Ltd. as an engineer. In 1964 he returned to his alma mater as a stuff assistant when all the science-engineering departments in Japan and US were doubled in size, a countermeasure against the 'Sputnik shock'. After acquiring D. Eng. in chemistry by thesis he spent three years as a postdoctoral stint in the University of Wisconsin, Princeton University and the State University of New York at Stony Brook, and returned to Japan as an assistant professor of Hokkaido University in 1970. He moved to Toyohashi University of Technology as a full professor in July 1990. At the age of 65, he retired from TUT in 2001, and immediately set up a venture company NanoCarbon Research Institute with the help from Futaba Corporation in Chiba, east of Tokyo. He is known as the first scientist to conceive C60 as the molecule with special aromatic stability in 1970. While he is also one of the earliest computational chemists and most of the work in his earlier carrier has been devoted to applied theoretical chemistry, his main research interests center around fullerenes, ever since this wonder molecule was discovered experimentally in 1985. For the prediction of C60, he was awarded Chu-nichi Culture Prize in 2001.
		Michael A. Teitell MD, PhD Departments of Pathology and Pediatrics Chief, Division of Pediatric and Neonatal Pathology Co-Director, Cancer Cell Biology Program Area, Jonsson Cancer Center Dr. Michael Teitell is Chief of the Division of Pediatric and Neonatal Pathology in the Departments of Pathology & Laboratory Medicine and Pediatrics at UCLA. He earned Bachelors and Masters degrees as a Departmental Scholar in Biochemistry from UCLA in 1985, and M.D. and Ph.D. degrees from the UCLA Medical Scientist Training Program in 1993. Dr. Teitell is co-Director of the Cancer Cell Biology Program Area at UCLA and Chair of the UCLA Intercollegiate Athletic Committee. He received the FOCIS/Millenium Pharmaceuticals Award for Genomics Research and a Leukemia and Lymphoma Society Scholar Award. In 2004 he was elected to the American Society of Clinical Investigators (ASCI) and in 2008 was a Stohlman Scholar of the Leukemia and Lymphoma Society. Dr. Teitell develops new imaging and nanomechanical approaches to study development and cancer of the immune system. His group generated the first genetic model that accurately resembles the majority of lymphocyte cancers afflicting humans.
		Chun Li, Ph.D. Professor, Department of Experimental Diagnostic Imaging The University of Texas M. D. Anderson Cancer Center Chun Li, Ph.D. is a professor in the Department of Experimental Diagnostic Imaging at The University of Texas M. D. Anderson Cancer Center. Research in Dr. Li's laboratory is primarily focused on two areas: 1) the development of targeted imaging probes for noninvasive characterization of molecular events associated with tumor progression and regression and 2) the development of novel drug-delivery systems for selective delivery of diagnostic and therapeutic agents. Dr. Li, who earned his doctorate in chemistry at Rutgers-The State University of New Jersey and his undergraduate degree from Peking University in Beijing, has more than 70 papers published in peer-reviewed journals and 24 patents. A polymer-drug conjugate (PG-TXL) originated from his laboratory has advanced into clinical phase III trials studies.