MANDI HALAWANI DEPARTMENT OF BIOLOGICAL ENGINEERING NSF PHYSICS REU SUMMER PROGRAM Opening The Blood Brain Barrier (BBB)
M A N D I H A L AWA N I
D E PA RT M E N T O F B I O LO G I C A L E N G I N E E R I N G
N S F P H YS I C S R E U S U M M E R P RO G R A M
Opening The Blood Brain Barrier (BBB)
W O R K I N G C L O S E LY W I T H T H E G R A D UAT E S T U D E N T M I C H A E L VA L D E Z
& K E Y S S T U D E N T S H E L B Y Y UA N
A L O N G S I D E T H E L A B S A N D R E S E A R C H E R S O F :
T E R RY M AT S U N A G A & M A R E K R O M A N O W S K I
The Laboratory of Dr. Theodore Trouard
The Blood Brain Barrier (BBB)
Neurovascular Unit Isolates brain tissue from blood Blood vessels contain tight cell-cell
junctions Very few substances can cross over
Endothelial Cells
Astrocytes Tight junction
Red Blood cells
Methods that are currently used in Drug Delivery across the BBB
98% of therapies do not cross into the brain tissue
Alzheimer's
Parkinson’s
Brain Tumors
Drilling into the skull and injecting the brain directly
Administering higher doses
Chemo therapy
More costly pharmaceuticals
Waste of resources
U S E O F FO C U S E D U LT R A S O U N D ( F U S )
N O N I N VA S I V E FO R D E L I V E R I N G T H E R A P Y AC RO S S T H E B LO O D B R A I N B A R R I E R ( B B B )
U S E O F M I C RO B U B B L E S
A New Method
Microbubbles
Lipid-coated, gas bubbles
1µm diameter
Travel throughout vascular system
microbubbles
Focused Ultrasound (FUS)
Applied trans cranially
Can be targeted
Microbubbles cavitate and sometimes burst
Focused Ultrasound (FUS)
Microbubbles cavitate and sometimes burst
Endothelial cells temporarily open between junctions
M Y G OA L WA S C R E AT I N G A L I P O S O M E -M I C R O B U B B L E C O M P L E X T O E N C A P S U L AT E T H E R A P E U T I C A G E N T S
T E S T E D I D E A T H R O U G H T H E U S E O F M A G N E T I C R E S O N A N C E I M A G I N G
Developing the Method
Therapeutic Administration
Liposome-Microbubble Complex Spheres of lipids
100 nm liposome
Enclose an aqueous compartment
Able to conjugate about a microbubble
Adapted From: www.sciencedirect.com
µbubble 1 µmLiposomes 0.1 µm
Liposome Production
Freeze/Thaw 10x to make lipid bilayer
Extrude 5mL through 200nm filter & 100nm filter 5x
M AG N E T I C R E S O NA N C E I M AG I N G ( M R I )
N E E D E D TO I M AG E S E V E R A L SA M P L E S AT O N C E
F LO R E S C E N T M I C RO S C O P Y
Carrying out Research
Carrying out Research
Designed cartridge in Solidworks to hold samples centered in the MRI
Printed the cartridge with 3D Printer
Results
Encapsulate known [gadolinium]
MRI images greater intensity than
liposomes with no encapsulated agent
Gd liposomesT1 = .3884 secBlank
liposomesT1 = 2.517 sec
Gd Controls
PBS control
7T MRI
Results
Florescence Imaging
Coated liposomes with florescent pink DiI
Shook to conjugate complex
Successful Liposome-Microbubble Complex
uB + liposomes Conjugated
uB + liposomes Not Conjugated
Results
Liposomes released their cargo in the presence of heat
Gd Liposomes before Heat is applied Gd Liposomes after 15 min in 69 Celsius bath
Gd LiposomesT1 = .3884 sec
Gd Control Gd ControlGd LiposomesT1= .0755 sec
Carrying out Research
Experiments for FUS are currently being performed
WHAT THE FUTURE WOULD HOLD ONCE THE METHOD IS PERFECTED
Future Prospects
Future Prospects
Test method on a mouse
Demonstrate application of FUS releasing therapy
Future Prospects
Expanded development of therapy
Neurological Pathologies
Parkinson’s
Alzheimer's
Targeted anywhere in the body
Vital Organs
TumorsCancers
Diabetes
M I K E VA L D E Z
E V E R Y O N E I N T H E L A B S O F D R . T H E O D O R E T R O U A R D , D R . M A R E K R O M A N O W S K I , D R . T E R R Y M AT S U N A G A
N AT I O N A L S C I E N C E F O U N D AT I O N
D R . M A N N E , D R . P I T U C C O
&
P H Y S I C S R E U M E N T O R S A N D P E E R S
Special Thanks
Questions