Ultrasound as a Proposed Drug Release Mechanism in Biomedical Microrobots

Presentation By:

Malcolm Gibson

UA Advanced Microsystems Laboratory

Dept. of Aerospace and Mechanical Engineering

Arizona Space Grant Consortium

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 sub-mm 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 Nano-Technology.

• 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 in-vivo 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.

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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

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IRIS - ETH Zurich

Research - Investigating Ultrasound

• Decided to use surface-coated droplets as opposed to bare robots. – Robot Skin

– Ferrite Powder

• Droplets provided a larger drug entrapment matrix.

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.

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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

Comparative Release Curves

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 20 40 60 80 100

Sonication Time (min.)

HRP Released (ug)

Sonicated with Skin Vortexed Droplets

Diffusion with Skin Diffusion No Skin

Ultrasound vs.

Diffusion

Skinvs.

No Skin

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 high-frequency 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 EngineeringMalcolm T. GibsonDr. Eniko T. Enikov

The Chemistry Behind the Droplets

Surface Skin Formation: Starting with a NaAlg. + HRP + Ferrite Powder Droplet

Soaks for 5 min.

Poly-l-lysine solution

Soaks for 4 min.

Polyethylenimine solution

CaCl2 solution

NaAlg./Fe/ HRPDroplet

Calcium Chloride (Salt) crosslinks with NaAlg.Forming a tough, solid droplet.

Soaks for 15 min. PEI creates a surface coating

(skin) around droplet shell. PLL is believed to leak into the NaAlg.+CaChl.crosslinking and 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.