1. Imaging Microbubbles Antony Hsu Shanti Bansal Daniel Handwerker Richard Lee Cory Piette

2. Topics of Discussion n Brownian Motion n What are these bubbles and why do we use them? n Following the Great Perrin - Diffusion and Gravitational Motion of Microbubbles n Optical Imaging of Microbubbles

3. What is ultrasound? n Ultrasound uses high frequency sound waves to image internal structures n The wave reflect off different density liquids and tissues at different rates and magnitudes n It is harmless, but not very accurate

4. Ultrasound and Microbubbles n Air in microbubbles in the blood stream have almost 0 density and have a distinct reflection in ultrasound n The bubbles must be able to fit through all capillaries and remain stable n We must examine the properties of microbubbles before using this technique

5. What is Brownian Motion? n Small particles are effected by so many different factors in a solution that they move around at in a random walk n Even if a solution seems stagnate, the microbubbles will still move

6. What is a Random Walk? n After every seconds, a particle moves in a direction at a velocity v n There is an equal probability that the particle will move in any direction no matter what its past direction was n Each particle is independent of all other particles

7. Characteristics of Random Walks n Particles have a net displacement of 0 (after  time) n Particles usually remain in one region and then wander to other regions

8. 1-  m Shell Air or High Molecular Weight Gases We’re all about Microbubbles (1)

9. We’re all about Microbubbles (4) n Used with ultrasound echocardiography and magnetic resonance imaging (MRI) n Diagnostic imaging - Traces blood flow and outlines images n Drug Delivery and Cancer Therapy

10. Left Arrow: Lipid-Coated Microbubble Right Arrow: Saline Microbubble We’re all about Microbubbles (2)

11. We’re all about Microbubbles (3)

12. We’re all about Microbubbles (5) Small (1-7  m) bubbles of air (CO2, Helium) or high molecular weight gases (perfluorocarbon). n Enveloped by a shell (proteins, fatty acid esters). n Exist - For a limited time only! 4 minutes-24 hours; gases diffuse into liquid medium after use. n Size varies according to Ideal Gas Law (PV=nRT) and thickness of shell.

13. How Bubbles Separate n Given a volume filled with different sizes of microbubbles, which bubbles move toward which end due to gravity? n Following Perrin, we look at the characteristic length (lambda) which will tell us about the motion of the bubble.  G = -c(x,t) D  T =  D +  G

14. How Bubbles Separate(2) How do we get lambda( )? == k T m eff g K =Boltzman’s constant (1.38x10 -23 J/K) T = Temperature in Kelvin (300K) g = gravity(9.81 m/s 2 ) m eff = effective mass m eff = (4/3)  r 3 (  p -  w )  p = density of particle  w = density of water(1g/cm 3 ) r = radius of bubble(cm) The size of of microbubbles is known(1-7mm). Therefore, the only factor to be determined is the density of the microbubble. With gas-filled bubbles, the thickness and density of the shell gives the bubble its mass.

15. How Bubbles Separate(3) n Why is all this important? Well, we want a bubble that will not “float” or “sink.” By adjusting the shell thickness to the force of gravity, we can achieve “neutral buoyancy.” n Basically, by designing the bubble such that the density as a whole has the density of water, then the bubble will undergo only diffusion flux.

16. Perrin’s light microscope n Perrin did research on diffusion and brownian motion n He conducted experiments to examine diffusion through emulsions n He built used a light microscope to visualize emulsions at different depths n Perrin determined depth of pictures by the following formula: H=CH’. C = relative refractive index of the two media which the cover-glass separates. H’ = height of microscope.

17. Perrin’s Light Microscope

18. Optical target tracking on image sequences n Computer equipment improvement has lead to higher resolution optical imaging n Most computerized optical pattern recognition filters today have been designed to process one image at a time. (isolated images) n These filters would prove ineffective in recording microbubbles moving through the blood stream (image sequencing). n Isolated images do not deal with changes in background, sequential imaging does n this problem leads to the development of the “two image system”--a model that takes into account two successive frames n this model is based on the maximum-likelihood (ML) estimation n The ML estimation takes into account the continuity between two successive frames

19. Optical target tracking (cont.) n One frame is taken at a known location, one at an “estimated” location n This estimated location will depend on location and size of the object n In this case, the size of microbubble will remain constant (approximately the size of a red blood cell). However, the location will vary. n Idle time between frames depends directly on probability factors. n The two frames are correlated, forming a clear and concise picture of the object’s movement.

20. A Novel Technique to Visualize Microbubbles n An optical tracking system is placed on Perrin’s light microscope n Allow easy visualization of microbubbles and analysis

21. A Novel Method of Microbubble Visualization

22. Future of Microbubbles n Using microbubbles as a pressure sensitive gauge (especially important for heart) n Enhancing ultrasound/ MR images. Novel gasses used for microbubbles. n Drug delivery