Daniel McNerny, B.S. Ph.D. candidate in the Department of Chemical Engineering Dan McNerny received his B.S. in Chemical Engineering and Biomedical Engineering from Carnegie Mellon Univeristy in 2005 and M.S. in Chemical Engineering at UM in 2007. Dan's research within the M-NIMBS involves synthesizing bi-functional delivery platforms utilizing PAMAM dendrons as part of the nanomedicine graduate program.

Douglas Mullen, BSE PhD program in the Macromolecular Science and Engineering Doug did his undergraduate BSE degree in Mechanical Engineering and Materials Science at Duke University in 2005. At Duke University, Doug did research in the Atomic Force Microscopy and Nanomechanics Lab at the Center for Biologically Inspired Materials and Material Systems. Doug currently pursues a PhD degree in the Macromolecular Science and Engineering Program.

For his graduate work at Michigan, he is working witihin the M-NIMBS in the Nanobiology certificate program on the development of targeted chemotherapeutic agents that can be employed in a combinatorial manner to provide a wide array of functional materials.

Paul Makidon, DVM Ph.D. Candidate in Biomedical Engineering While earning his DVM degree (1998) at Michigan State University (MSU), Paul Makidon worked on research projects at the Laboratory of Comparative Orthopedic Research and the Endocrinology Section of the Animal Health Diagnostics Laboratory at MSU. He then worked in a clinical practice setting for several years. However, recognizing his deep interest in research, he started the PhD program at the Department of Biomedical Engineering at the University of Michigan (UM) in

Fall 2005 and earned candidacy in Fall 2007. He works under mentorship of Dr. James R. Baker Jr., Director of the Michigan Nanotechnology Institute for Medicine and Biological Sciences (M-NIMBS). He is concurrently a research fellow with the Unit for Laboratory Animal Medicine (ULAM) at UM where he is funded from a NIH/NCRR T-32 grant.

Paul is interested in biomedical applications of nanomedicine. He has been actively involved in development of nanoemulsion based, needle-free, nasal spray adjuvant vaccine development for Hepatitis B. His doctoral research project focuses on the development of an antimicrobial nanoemulsion based inhalation therapeutic to prevent infection or treat antibiotic resistant infections in patients with Cystic Fibrosis, a disease that affects more than 53,000 children worldwide. He will continue this research to complete his Ph.D. degree and then hopes to start an academic research career that is similarly clinically oriented, nanomedicine based and further examines treatment options that will improve the health status of Cystic Fibrosis patients.

Paul will defend his thesis: Tuesday, December 2, 2008, 2:30 PM
Location: 1170A and 1150B BSRB
Chair: James R. Baker, Jr.

Department of Biomedical Engineering Final Oral Examination

Paul Edward Makidon

OIL-IN-WATER NANOEMULSIONS AS MUCOSAL VACCINE ADJUVANTS:
CHARACTERIZATION, MECHANISM, FORMULATION, AND DEVELOPMENT OF A
NANOEMULSION-BASED BURKHOLDRERIA CENOCEPACIA VACCINE

Surface active oil-in-water nanoscale emulsions have been developed as
mucosal vaccine adjuvants capable of producing robust systemic, mucosal,
and cellular immune responses against diverse microbial and recombinant
antigenic proteins. This dissertation examines the development of
nanoemulsion (NE) as a new generation nasopharyngeal adjuvant. Part of
the thesis is organized to address the characterization of NE-induced
immune response and includes the pre-clinical studies of a novel NE-based
recombinant hepatitis B vaccine (HBsAg-NE). Our results suggest that nasal
immunization with HBsAg-NE may be a safe and effective hepatitis B
vaccine. The adjuvant induces specific IgG, mucosal IgA, and a Th1-biased
cellular immunity. Immunogenicity is comparable to the standard
alum-based vaccine. HBsAg-NE is stable for months at elevated
temperatures because of the physical association of NE and antigen and its
stability was enhanced with buffered salt diluents. We also report that
NE-based vaccines do not require specially engineered delivery devices.
The prolonged stability and ease of delivery are direct advantages for use
of NE-based vaccines in developing populations.

We also evaluate the mechanism of NE adjuvant activity. NE promotes
antigen internalization in nasal epithelium and loading into mucosal DC.
Trafficking of the antigen to the submandibular lymph nodes and thymus
occurs within 24 hours of intranasal vaccination. Administration of NE
was not associated with the typical induction of local inflammation or
histopathological changes. Microarray analysis shows the upregulation of
only 1.6% of genes responsible for the production of acute phase
inflammatory cytokines including IL6. Hallmark inflammatory cytokines
such as IL4, and INF- were not measured in nasal secretions. The role of
IL6 in NE adjuvant activity was examined by evaluating immunogenicity in
IL6 mutant mice.

The final component of the dissertation addresses the development of a
NE-based Burkholderia cenocepacia outer membrane protein (OMP) vaccine.
We demonstrate that NE is as a strong mucosal adjuvant for OMP and OMP-NE
protects against experimental lung infections in mice.

Overall, these findings confirm that NE is an excellent mucosal stimulant
and support the further development of nanoemulsions as nasopharyngeal
adjuvants. We conclude that nanoemulsion exhibits all the major desired
characteristics of an adjuvant.

Christopher Kelly, B.S. Ph.D. Candidate in Applied Physics Christopher graduated with high honors in Physics from Oberlin College in 2003.  After working for a year at NASA Glenn Research Center on thin film solar cells, Christopher started graduate work at University of Michigan with Professors Orr and Banaszak Holl in 2004.  Christopher earned his Masters in Electrical Engineering in 2007 and is working towards his Ph.D.

in Applied Physics, focusing on the molecular details of the dendrimer-plasma membrane interaction.  Christopher has been awarded the Biophysics Training Grant and is a graduate fellow of the Graham Institute for Environmental Sustainability.

Christopher V. Kelly’s Thesis: "The Biophysics of nanoparticles interacting with the plasma membrane"

My research aims to guide the design of nanoparticles for both biomedical applications (e.g. targeted chemotherapeutics) and everyday applications (e.g. tennis rackets and sun screen) by understanding the detailed interactions of nanoparticles with the plasma membrane.  In particular, I will discuss the atomistic and molecular-level interactions of poly(amidoamine) (PAMAM) dendrimers with model plasma membranes.  Previous work has demonstrated that larger and more charged dendrimers induce greater membrane disruption, such as nanometer scale pores that allow cytoplasmic release from the cell.  I utilize all-atom molecular dynamics, isothermal titration calorimetry, transmission electron microscopy, dynamic light scattering, differential scanning calorimetry, and atomic force microscopy, to determine nanoparticle moieties and molecular-mechanisms that facilitate membrane degradation.  For example, sixth-generation PAMAM dendrimers have been determined to be a critical size for membrane degradation since larger dendrimers induce a nanoparticle-encased lipid vesicle complex whereas smaller dendrimers primarily flatten on the bilayer.

Bernell Williams, M.S. Doctoral Candidate, Biomedical Engineering Michigan Nanotechnology Institute for Medicine and Biological Science University of Michigan Bernell Williams graduated summa cum laude with a B.S. in Biology and Chemistry and a B.A in Mathematics from Oakwood College in 2001. He continued his studies at the University of Michigan where he received a M.S. in Biomedical Engineering in 2002 and is currently a Ph.D. candidate and in the nanomedicine

graduate program. Bernell's research focuses on the targeted delivery of diagnostics and therapeutics to prostate cancer using a polyvalent dendrimer platform.

Becky Lahti, B.S. University of Michigan Ph.D. program in Chemistry Becky graduated with high distinction from the University of Illinois at Urbana-Champaign in 2007 with a B.S. in Chemistry. At UIUC, she did research with Dr. Scott K. Silverman investigating DNA as a catalyst for bio-organic chemical reactions. Becky is currently pursuing a Ph.D. in Chemistry within M-NiMBS under the guidance of Professor Mark Banaszak-Holl.

Blake Erickson, B.S. University of Michigan Ph.D. degree program in Biophysics Blake graduated with in 2006 from the College of Creative Studies at the University of California, Santa Barbara with degrees in Physics and Literature. His undergraduate research, with Prof. Paul Hansma, focused on fracture mechanics of trabecular bone.   Blake started graduate work  at the University of Michigan with Professors Orr and Banaszak Holl in 2006 in the Biophysics program and the nanobiology graduate program. Blake's research focuses on the mechanisms of dendrimer internalization into

cells. Blake has been awarded the Biophysics Training Grant. Outside of the lab, Blake travels to various ballroom dance competitions around the country.

Rahul Rattan, M.S. University of Michigan Ph.D. degree program Biomedical Engineering Rahul graduated from Panjab University, India in 2006 with a BE in Biotechnology. He is currently pursuing Ph.D. in Biomedical Engineering and is part of the nanomedicine graduate program.   He is characterizing the impact of dendrimer based drug delivery on mammalian cells specifically the way these interact with cell membranes and unraveling the intricacies of how dendrimers

based on their charge, size, hydrodynamics etc enter a mammalian cell and eventually be able to model the loaded dendrimer’s interaction with specific cell types.

Damian Khan, B.S. University of Michigan PhD program in Applied Physics   Damian Khan received a B.S. in physics from Morehouse College and an M.S. in physics from Clark Atlanta University. He is currently an applied physics graduate student working with the Orr group and Banaszak Holl groups where he does STM imaging of coated gold surfaces as part of the Nanoscience graduate program.

Laura Devon Triplett, B.S. University of Michigan Ph.D. Program in Applied Physics   Devon received her B.S. in Physics from Virginia Polytechnic Institute and State University in 2007.  She is currently pursing her Ph.D. in Applied Physics under the guidance of Professors Orr and Banaszak Holl.  Her research focuses on using differential scanning calorimetry to study the interaction between dendrimers and model phospholipid membranes, as part of the Nanobiology certificate program .

Jiumei Chen, M.S. Ph.D. program in Macromolecular Science and Engineering Jiumei earned a double major at Tianjin University with a Bachelors of Engineering in Polymer Materials and Engineering and a Bachelors of Arts in English.  She then earned an MS in Materials Science and Engineering from Wayne State University.  She is now in the Nanobiology certificate program using patch clamp techniques to study the interactions between nanoparticles and biological membranes.  This work will help to

provide an understanding of nanoparticle toxicity and the mechanism of DNA transfection. In October 2006, Jiumei won the prestigious Materials Incorporated Award in recognition of her academic excellence in the Macromolecular Science and Engineering Center. The award was presented at the banquet of the annual symposium.

Ajdin Kavara, B.S. Ph.D. Candidate in Chemistry Ajdin is from Capljina, Bosnia & Hercegovinia.  He moved to Grand Rapids, Michigan in 1997 and earned his B.S. in chemistry from Grand Valley State University in 2004.  He did his undergraduate research with Prof. Kovacs on heterogeneously catalyzed breakdown of sugars.  His PhD work is focused on CH-activation chemistry using Sn, applications of the products to cross-coupling chemistry, and novel approaches to natural

products, an application within the Nanoscience graduate program.

Tin Mediated CH-Activation and Cross-Coupling in a Single Flask.  J. M. Bartolin, A. Kavara, J. Kampf, M. M. Banaszak Holl.  Organometallics 2006, 25, 4738-4740.

Song Ge, B.S. University of Michigan PhD program in Physics Song Ge obtained his B.S. from Shandong University in China. His research work employs SQUID imaging of magnetic nanoparticles as part of a larger project developing nanotherapeutics for cancer therapy as part of the nanomedicine graduate certificate program.