Arizona Space Grant Consortium
Ultrasound as a Proposed Drug Release
Mechanism in Biomedical Microrobots
Presentation By:
Malcolm Gibson
UA Advanced Microsystems Laboratory
Dept. of Aerospace and Mechanical Engineering
Presentation Objectives
• Project Introduction
• Theory and Goals
• Research and Results
• Future Plans and Experiments
• Conclusion and Acknowledgments
• Questions and Discussion
Introduction - Biomedical Microrobots
• Biomicrorobotics research
is focused on building submm sized, untethered
robots for in-vivo medical
applications.
• Building a complete robotic
system that “swims” inside
the human body is quite a
challenge and requires an
innovative combination of
Micro- and NanoTechnology.
• Potential Applications:
–Navigating the vitreous
humor for retinal surgery.
–Targeted drug delivery.
– Small scale exploration.
IRIS - ETH Zurich
Introduction - Biomedical Microrobots
• Research can be divided into
two main areas:
– Building the microrobots
using MEMS/NEMS and
robotic micro-assembly
technologies.
– Applying and controlling
the microrobots for invivo applications.
• Medical Imaging
• Steering and
Movement
• Actuation
IRIS - ETH Zurich
Magnetic Steering and Guiding System
• Developed by IRIS (Swiss Federal Institute of Technology)
• The steering system uses two coaxial pairs of magnetic field
generating coils in Helmholtz and Maxwell configurations
respectively.
IRIS - Swiss Federal Institute of
Technology (ETH Zurich)
Co-Fluidic Encapsulation System
• Creates uniform alginate
droplets extruded in an oil
phase.
• Allows for encapsulation of
microrobots.
• Allows one to easily control
the droplet size and
extrusion rate.
QuickTime™ and a
decompressor
are needed to see this picture.
Pictures: MEMS Lab - Stephane Ritty, Dr. Enikov
Drug Release Mechanisms
• Current Method
– Diffusion
– Bare Robot
Surface Coating
• Proposed Method
– Ultrasonically Induced
Cavitation
– Encapsulated
Micro-Droplet
Quic kTime™ and a
dec ompres sor
are needed to see this pic ture.
Quic kTime™ and a
dec ompres sor
are needed to see this pic ture.
IRIS - ETH Zurich
Research - Investigating Ultrasound
• Decided to use surfacecoated droplets as opposed
to bare robots.
– Robot Skin
– Ferrite Powder
• Droplets provided a larger
drug entrapment matrix.
QuickTime™ and a
decompressor
are needed to see this picture.
QuickTime™ and a
decompressor
are needed to see this picture.
Hypothesis: Can ultrasonically induced cavitation be used to
destroy the droplet surface-coating (skin) and induce rapid,
diffusive drug release to the surrounding fluidic environment.
Experimental Procedure
• General Procedure:
– Create n droplets using the droplet extrusion system.
– Create surface coating for all droplets.
– Split droplets up into designated sample test tubes.
– Sonicate samples for various time intervals using the
laboratory aqua-sonic cleaner.
– Apply a chromogenic substrate to the sample and
measure the absorbance rate using the
spectrophotometer.
– Calculate HRP (drug substitute) concentration from the
Absorbance rate and generate release curve.
Experimental Results
Ultrasound
vs.
Diffusion
Comparative Release Curves
0.4
HRP Released (ug)
0.35
0.3
Skin
vs.
No Skin
0.25
0.2
0.15
0.1
0.05
0
0
20
40
60
80
Sonication Time (min.)
Sonicated with Skin
Vortexed Droplets
Diffusion with Skin
Diffusion No Skin
100
Vortex
Visual Release Study
Skin
Bare
Future Plans and Experiments
• Test release with metal robots
instead of Fe powder.
– Engineer resonant robots
that will resonate upon a
certain ultrasonic frequency.
– Use Piezoelectric elements
or speakers to generate
sound frequency.
• This will allow control
of the frequency.
• Specific frequency
would actuate droplet
release.
•
Design resonant robots
incorporating small air
pockets to make sonication
more effective.
•
Investigate the use of highfrequency magnetic pulsing
to actuate drug release.
•
•
Loop Robots
Eddy Currents
IRIS - ETH Zurich
Acknowledgements
Mentor:
Dr. Eniko T. Enikov (AME)
(Advanced Microsystems Laboratory)
Arizona Space Grant Consortium
Swiss Federal Institute of Technology
Questions/Discussion
Thank you for your attention.
Questions?
Comments?
UA Advanced Microsystems Laboratory
Dept. of Aerospace and Mechanical Engineering
Malcolm T. Gibson
Dr. Eniko T. Enikov
The Chemistry Behind the Droplets
Surface Skin Formation: Starting with a NaAlg. + HRP + Ferrite Powder Droplet
NaAlg./Fe/ HRP
Droplet
CaCl2
solution
Soaks for 4 min.
Polyethylenimine
solution
Soaks for 5 min.
Poly-l-lysine
solution
Calcium Chloride (Salt)
crosslinks with NaAlg.
Forming a tough, solid
droplet.
Soaks for 15 min.
PEI creates a surface coating PLL is believed to leak into the
NaAlg.+CaChl.crosslinking and
(skin) around droplet shell.
strengthen it.
The Chemistry Behind the Droplets
• Sodium Alginate was selected as a drug entrapment matrix because it is
easy to process and there is evidence supporting successful magnetic
modulation of drug release.
• Sodium Alginate is a linear polysaccharide.
– Cellulose fiber found in many plant cells.
–These fibers have high strength and durability.
–Comprised of mannuronic acid (M) and guluronic acid (G) residues.
•Chained in a repeating pattern:
GG-GM-MM-…
The Chemistry Behind the Droplets
HRP Enzyme as a Drug Substitute
– Horseradish Peroxidase (HRP).
•44,000 Da enzyme protein
– Enzymes are proteins that catalyze chemical reactions.
– They exert their catalytic activity upon substrates.
– HRP readily bonds with hydrogen peroxide (H2O2) (contained in
TMB substrate) and the resultant (HRP–H2O2) complex can oxidize a
wide variety of chromogenic hydrogen donors, resulting in color
change.
•This is what is being measured using the spectrophotometer.