Group 37 Members: Chris Peng, Blessan Sebastian (presenter), Arvin Soepriatna Client: Mike Sabo - Pulse Therapeutics, Inc. December 4, 2013.

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?