“seeing” stem cells helps in fight against peripheral arterial disease dorota a kedziorek, md,...
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““Seeing” Stem Cells Helps in Fight Seeing” Stem Cells Helps in Fight Against Peripheral Arterial DiseaseAgainst Peripheral Arterial Disease
Dorota A Kedziorek, MD, Piotr Walczak, MD, PhD, Yingli Fu, PhD, Frank Wacker, MD,
Dara L Kraitchman, VMD, PhDJohns Hopkins University
School of MedicineRussell H. Morgan Department of Radiology and
Radiological ScienceBaltimore, MD
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Presenter Disclosure InformationPresenter Disclosure Information
I will discuss off label use and/or investigational use of contrast agents in my presentation.
Financial Relationships to disclose:• Bayer Schering Pharma AG• Boston Scientific Corporation• Surgi-vision, Inc.
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Peripheral Arterial Disease (PAD)Peripheral Arterial Disease (PAD)
• PAD affects ~8-12 million Americans.
• 1 in 5 patients with critical limb ischemia have severe enough disease to be ineligible for conventional medical or surgical revascularization therapy.
• Gene, protein, and cellular therapies offer an alternative means to attack the response to occlusion by “therapeutic arteriogenesis.”
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How to create new blood vessels?How to create new blood vessels?
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Problems with Current Cell TherapyProblems with Current Cell Therapy
1. Cannot “see” where cells are injected.
Needles marking injection sites
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Problems with Cell TherapyProblems with Cell Therapy
1. Cannot “see” where cells are injected.
2. Large number of cells die after administration
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Solution: Place Cells in “Seaweed Bubble”Solution: Place Cells in “Seaweed Bubble”
Courtesy: Ming Chen
Biocompatible- Provides surface for cell adhesion
Selective permeability- Blocks antibody and cellular destruction – good for transplanted donor cells- Permits diffusion of nutrients and waste products.
Lim and Sun, Science 1980 APA ≡APA ≡Alginate-poly-L-lysine-alginate
VEGF, PGE2,
IL-8, IL-6, HGF, etc.
IgG, IgM
O2, Glu
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What If Imaging Visible Capsules Were What If Imaging Visible Capsules Were Possible?Possible?
•Trimodal Imaging Agent•Bromine – X-ray•Perfluorocarbon – U/S•19F - MRI
“Liquid Oxygen”
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Imaging Sensitivity to PFOB CapsImaging Sensitivity to PFOB Caps5 10 25
2 cm
c-arm CT
19F MRI
Fu et al., SCMR 2009
capsules/dot:
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Five weeks post-injection
X-ray Monitoring of PFOB Caps Delivery in X-ray Monitoring of PFOB Caps Delivery in a Rabbit PAD Model a Rabbit PAD Model
Immediately after injection
UnlabeledPFOB Caps
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Can see the PFOB Cap, Can see the PFOB Cap, but is the cell alive?but is the cell alive?
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Bioluminescence ImagingBioluminescence Imaging B
iolu
min
esce
nce
Sig
nal High
Low
ATP
Light
Luciferin Oxyluciferin
Luciferase
Cells expressing luciferase
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Day 5
10
8
6
4
2
0
×103
10
8
6
4
2
0
×105
10
8
6
4
2
0
×105
10
8
6
4
2
0
×106
10
8
6
4
2
0
×106
Control Day 10
P/s/cm2/srP/s/cm2/srP/s/cm2/srP/s/cm2/srP/s/cm2/sr
A Bioluminescence imaging of Embryonic Bioluminescence imaging of Embryonic Stem CellsStem Cells
Cao F, et al. Circulation 2006;113:1005-14
Reporter Probe Dose Intravenous Injection: •Rabbit =10 X Rat!•Patient = 150 X Rat!
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Animal study #1
PFOB encapsulated transfected MSCs
“Naked” transfected MSCs
“Naked” transfected MSCs
Immediately post injection 24 hrs post injection
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How to Administer Reporter Probe?How to Administer Reporter Probe?
DynaCT – 24 hrs post
PFOB encapsulated transfected MSCs
Immediately post injection
Pure alginate caps
BLI
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Using Interventional Radiology to Guide Using Interventional Radiology to Guide Reporter Probe InjectionsReporter Probe Injections
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C-arm CT TargetingC-arm CT TargetingPFOB encapsulated transfected MSCs
Immediately post injection
48 hrs post injection
Pure alginate caps
24 hrs post injection
PFOB encapsulated transfected MSCs
PFOB encapsulated transfected MSCs
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Seaweed Plus Liquid Oxygen Seaweed Plus Liquid Oxygen Plus Firefly “Brew”Plus Firefly “Brew”
_
Seaweed (Protanal®) • Happy Cells• FDA-approved agents in
bubble• Better able to survive to
create new blood vessels for PAD
• Visible by X-ray for Interventional Radiologist to tailor therapy
LiquidOxygen(Oxygent®):
Firefly
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Acknowledgments• Mark Pittenger• Randall Young• Christine Lorenz• Tina Ehtati• Steve Shea• Wesley Gilson• Robert Krieg
• Aravind Arepally• Brad Barnett• Jeff Bulte• Lawrence Hofmann• Gary Huang
NIH R01-HL63439, R01-HL73223, K08 EB004348, R21-HL89029, R01-EB007825, and MD-SCRFII-0399-00
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ConclusionsConclusions• “Seaweed plus liquid oxygen plus firefly brew”:
Enhanced cell viability Enables visualization with X-ray and Optical
Imaging• C-arm CT provides a minimally invasive method
to target the reporter probe for localized injections to our X-ray visible capsules to reduce dose of reporter probe.
• First demonstration of X-ray visible stem cell therapeutic with ability to measure cell viability by imaging.
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Trimodal ImagingTrimodal Imaging
MRI
c-arm CT
US