Novel Drug Delivery for Pediatric Medulloblastoma
Group 37 Members: Chris Peng, Blessan Sebastian (presenter), Arvin SoepriatnaClient: Mike Sabo - Pulse Therapeutics, Inc.December 4, 2013
Background & NeedsBrain and CNS tumor: 198.9/million person-years
between 2004 and 2008.[1]
Medulloblastoma: Originates in the brain and unlike most brain tumors,
spreads through cerebrospinal fluidsaccounts for 15% of all brain tumors in age group 0-
14[1]
Current Drug Delivery Processes [2][3] :Dispersed and non-specificMinimal control
[1] “CBTRUS Statistical Report: Primary Brain and Central Nervous Tumors Diagnosed in the United States in 2004-2008.” Central Brain Tumor Registry of the US, 23 Mar. 2012 Revision. Web. Retrieved 29 Sep. 2013 www.cbtrus.org[2] Pankhurst, Q. A., J. Connolly, S. K. Jones, and J. Dobson. "Applications of Magnetic Nanoparticles in Biomedicine." Journal of Physics D: Applied Physics 36.13 (2003): R167-181. Print.[3] McBain, Stuart C., Yiu, Humphrey HP, and J. Dobson. "Magnetic Nanoparticles for Gene and Drug Delivery." Int. Journal of Nanomedicine 2008:3(2): 169-180. Print
Background & NeedsNeeds:
More effective chemotherapeutic drug delivery system
Ability to target specific locationsIncreased drug dosage without side-effects
Alternative chemotherapy solution: drug-conjugated magnetic nanoparticles
Design Process3 Major Components
Magnetic Device Design
Imaging Modality
Imaging Phantom Design
Specific Design RequirementsParameters Specifications
Imaging Phantom Size < 3x3 ft
Imaging Phantom Weight ≤ 40 lbs
Magnet Device Dimensions < 3x3 ft
Magnetic Field Strength < 1 T
Imaging Depth < 10 cm
Standard Operation Time < 4 hrs
System Power Inlet Standard 110V
Budget $15,000
Design OverviewMagnet Device Design
Rectangular vs. Conical vs. Spherical System
Imaging ModalityDoppler Ultrasound
Imaging Phantom 3D Brain Tumor Phantom
Magnetic Device Design - Overview
Magnetic Device Design - Parts
Magnetic Device Design – Rotation Assembly
• Functions: Support the rest of the device and allow the rotation around the x-axis – axial motor at Joint B
• Ball Bearings – minimize friction at Joint B
Magnetic Device Design – Tilting Assembly
• Provides circular coverage by the magnet - Controlled by tilt motor at Joint A.
• Steel rod going through support block rotates to provide tilt motion.
• Stabilizing block prevents unwanted movements.
Motor Analysis – Joint A
1. Determine Moment at Joint A2. P = ; = 20 deg/sec P = 0.85 W • Friction is only minimized by ball bearings. • Power of motor must be at least 4 Watts. Torque over 10 Nm.
• Same analysis performed for Joint B.
Parameters Motor for Joint A Motor for Joint B
Type of Motor Stepper Motor Stepper Motor
Torque 10 Nm 300 Nm
Power 5 W 100 W
Size < 15 cm in all 3 axis < 15 cm in all 3 axis
Step Angle < 2o < 5o
Weight < 10 lbs < 20 lbs
AC/DC DC DC
Cost < $500 < $500
Motor Requirements
• Stepper Motor: DC motor that divides a full revolution into a discrete number of steps; signal from manual control commands the motor to rotate at a precise step angle
Joint A MotorParameters Specifications
Voltage (in V) 24 V
Current (in A) 1.4 A
Holding Torque Range (Nm) 10 ~ 37 Nm
Step Angle 0.072o
Size 9 cm in all 3 axis
Weight 10 lbs
AC/DC DC
Cost $729
Part Number PK566BW-N10
• OrientalMotor PK566BW-N10 stepper motor
Power = VI = 33.6 W > 4 W Required
Joint B Motor
Parameters Specifications
Watts 200 W
Holding Torque
Range(Nm)
5 -110 Nm
Size 21.8 cm x 10.4 cm x 15.4
cm
Weight 20 lbs
AC/DC DC
Cost $650
Part Number BLV620K 50F-2
• Orientalmotor Brushless motor BLV620K 50F-2
Power = 200 W > 100 W Required
Control Device
Parameters Specifications
Monitor LED
Cable Length 5 m
Operating Ambient
Temperature
0o to 40oC
Weight 0.25 kg
Size 7.2 cm x 9.6 cm x 2.1 cm
Cost (per unit) $300
• Oriental Motors Control Module (OPX-2A)
• Portable• Control Module is compatible with both motors
Imaging Modality - OverviewParameters Specifications
Exposure Safety High, up to 4 hours
Resolution High, up to 8 cm deep
Compatibility with Dynamic
Magnetic Field
High
Imaging Approach Non-invasive
Image Acquisition Duration Real-time Imaging
Size Small enough to allow free
movement of magnets around
the patient’s head
Maneuverability High
Signal to Noise Ratio (SNR) High
Imaging Modality - OverviewMagneto-Motive Ultrasound Imaging
Magnetic NPs are ‘subjected to modulating magnetic fields and these modulations are detected as frequency shifts in Doppler ultrasound measurements’ [1].
NPs must be superparamagnetic and made of iron oxide (Fe3O4) particles [1].
Iron oxide NPs : χ = 69.34 emu/gr [1]. Tissue: 11 x10-6 emu/gr < χ < -7.0 x 10-6 emu/gr [1]. Noticeable contrast in Color Doppler Imaging.
1] John, Renu, and Stephen A. Boppart. Current Medical Chemotherapy 14th ser. 18 (2011): 2103-114. National Institute of Health. Web. 8 Nov. 2013.
Chosen Ultrasound SystemParameters Specifications
Parts Number P07662-03
Dimensions (length
x width x height)
30.2cm x 27.4cm x 7.9cm
Modes Color, pulse wave, and
continuous wave Doppler
Weight 3.04kg
Dynamic Range Up to 165 dB
Power Supply AC: 100-240 VAC, 50/60
Hz input
Price $24,900
• Sonosite M-Turbo Ultrasound System
• Portable• Imaging Modes: Color, Pulse Wave, Continuous Wave
Imaging Modality – Transducer OverviewParameters Specification
Frequency Range 3-5 MHz
Type of Array Linear Phased Array
Imaging Depth 40-60 mm
Resolution 1 mm axial x 1 mm
lateral
Steering Angle 60-90 degrees
Cost <$10,000• Linearly phased array transducer uses small array footprint that allows the ultrasound beam to bypass the skull. [1]
• Medulloblastomas tend to be found near the cerebellum – depth of at least 40-60 mm[2]
• High Steering Angle• For transcranial Doppler ultrasound in children, the optimal
frequency range of the transducer is between 3-5 MHz [2]
[1] Cole, David, and Antonio Sassano. Ultrasound: Physics and Technology. By Vivien Gibbs. 3rd ed. Vol. 1. China: Elsevier, 2009. 37-50. Print.[2] Coley, Brian D., Lynn A. Fordham, and Harris L. Cohen. “Transcranial Doppler Ultrasound Examination for Adults and Children.” Medical Ultrasound (2012):1-12. American Institute of Ultrasound in Medicine. Wev. 25 Oct 2013
Imaging Modality – Chosen Transducer
Parameters M-Turbo P21x Transducer
Parts Number P07698-23
Frequency Range 1-5 MHz
Type of Array Linear Phased Array
Imaging Depth 35 cm
Dimensions (face length x
face width x transducer
length)
24mm x 17 mm x 120 mm
Steering Angle 53.5o
Price $7,000[25]
• M-Turbo P21x Transducer
• Covers Frequency Range 3-5 Hz• Large imaging depth
Imaging Modality – P21x Transducer Analysis
Time delay between pulses[1]: = sin
= time delay, d = element width, co = coefficient of piezoelectric material, and = steering angle
Piezoelectric material: lead-zirconate titanate - coefficient of 4620m/s, d= [2]
= sin (53.5o) = 0.057 µs
[1] Ray Liu, K. J. "Digital 3D/4D Ultrasound Imaging Array." Handbook on Array Processing and Sensor Networks. By Simon S. Haykin. 2nd ed. New Jersey: Wilsons, 2009. 378-86. Print.[2] Cobbold, R. "Fundamentals of Biomedical Ultrasound." Oxford University Press, New York 2007
Phantom Design – Overview Two functions:
1. Provide a proof of concept for the clinical setting that an external magnetic device can control NP movement in three dimensions.
2. Show that the position of the particles can be tracked using an imaging modality.
Phantom Design AnalysisCerebrospinal fluid is a Newtonian fluid, the
forces in the fluid are proportional to the rate of change in velocity vector due to viscosity [1]
viscosity of cerebrospinal fluid is between 0.7 and 1.0 mPas at 37[36]
viscosity of phosphate-buffer saline at 37 is slightly greater at approximately 0.720 mPas [2]
[1] Roselli, Robert J., and Kenneth R. Diller . Biotransport: Principles and Applications. 1st ed. New York: Springer Science Business Media, 2011. p. 139. eBook.[2] Understanding effects of viscosity in the BioFlux system."www.fluxionbio.com, 27 Jan 2001. Web. 22 Nov 2013. <http://www.iul-instruments.de/pdf/168_BioFlux_Viscosity_TechNote-1038-01.pdf>
Phantom Design Analysis
magnetic susceptibility of the magnetic particle; is the magnetic susceptibility of the medium.
In the case of biological systems, can be ignored [1].At a distance of 200mm, NP (10 nm) accel.=0.066
mm/s2
[1] Dobson, Jon. "Magnetic Nanoparticles for Drug Delivery." Drug Development Research. 67. (2006): 55-60. Print.
Phantom Design - Components“Head” – The Phantom
Laboratory (SK100 - $5000)
RANDO® - urethane formulation which simulates x-ray absorbency, atomic number, magnetic susceptibility, and specific gravity of human tissue
Phantom Design - ComponentsComponent I.V. tubing PBS
Solution
Acrylic Plastic
Ball
Company
Selling
U.S. Plastic
Corp.
Life
Technologies
U.S. Plastic
Corp.
Item No. 56312 1001023 91618
Price $0.42 per
foot
$17.62 $16.41
Quantity 4 1 1
Dimensions 1/8" ID; 1/4”
OD
500 mL 2”
Diameter
Parameter Specification
Component Magnetic NPs Solution (10
nm)
Company Selling Sigma-Aldrich
Item No. 725358
Price $405.50
Quantity 1
Volume 5 mL
Concentration 5mg/mL in H2O
SafetyPrimary hazards categorized with
HIGH risk level:
Drawing-in nearby magnetic materials during testing.Rotating magnet gets too close to user or patient.Machine Instability due to improper device positioning.Excessive force/exertion due to careless handling of
magnetic device.
ConclusionsFuture Direction
Precise control method – programmed control algorithm to replace manual control
IP – design patentModification to current patent by Dr. Francis M.
Creighton, patent number US 8313422 B2We have proposed a way to provide a proof of
concept through an in vitro procedure with the rotating magnetic device, in which a phantom replicates NP behavior in brain ventricles and an imaging technology is used to show the ability to track these NPs.
Thank You – Questions?
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