The targeted stimulation of arteriogenesis, which is defined as the formation and lumenal expansion of the arterioles and arteries, is a promising treatment for ischemia caused by occlusive vascular disease. To date, attempts at creating therapeutic arteriogenesis have centered on the delivery of selected growth factor genes and proteins: Recently, we have developed an innovative new technique, based on contrast agent microbubble destruction with ultrasound, for stimulating arteriogenesis in and around regions of ischemia. This arteriogenic response, which may be targeted to selected tissue regions using the ultrasound beam, is accompanied by an increase in hyperemic capacity in the treated tissue, thereby demonstrating the potential of this technique for restoring blood flow to organs affected by arterial occlusion. In the clinical setting, this method has the potential to be performed with minimal invasiveness. This proposal consists of 4 specific aims that broadly address the clinical potential of the ultrasound- microbubble technique for enhancing blood flow and the rational manipulation of the technique for amplifying and potentially prolonging arteriogenesis. The first and second specific aims will respectively test the efficacy of ultrasonic microbubble destruction for enhancing blood flow to muscle that is chronically affected by vascular occlusion and establish which microvascular remodeling events create the flow enhancement. Studies for the third specific aim will determine how arteriogenesis and flow restoration can be controlled through alterations in user-controlled factors, namely microbubble size, microbubble dosage, ultrasound frequency, and application time. With this information, we will then develop an optimized protocol for generating arteriogenesis at a clinically relevant microbubble dosage. In the fourth specific aim, we will deliver polyethylenimine (PEI) nanocomplexes bearing genes for either a pro-arteriogenic growth factor (bFGF) or a pro-arteriogenic cytokine (MCP-1) to the arterially occluded muscle. These final studies will combine a state-of-the-art approach for cell transfection with an ultrasound targeted delivery strategy, with the goal of rationally manipulating the magnitude and longevity of the arteriogenesis response. Given the broad applicability of this targeted gene delivery method, it is likely these studies will have a significant impact on the investigation and treatment of many other pathologies and conditions. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074082-03
Application #
7418557
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Gao, Yunling
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$337,312
Indirect Cost
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Hsiang, Y-H; Song, J; Price, R J (2015) The partitioning of nanoparticles to endothelium or interstitium during ultrasound-microbubble-targeted delivery depends on peak-negative pressure. J Nanopart Res 17:
Meisner, Joshua K; Annex, Brian H; Price, Richard J (2015) Despite normal arteriogenic and angiogenic responses, hind limb perfusion recovery and necrotic and fibroadipose tissue clearance are impaired in matrix metalloproteinase 9-deficient mice. J Vasc Surg 61:1583-94.e1-10
Meisner, Joshua K; Song, Ji; Annex, Brian H et al. (2013) Myoglobin overexpression inhibits reperfusion in the ischemic mouse hindlimb through impaired angiogenesis but not arteriogenesis. Am J Pathol 183:1710-1718
Meisner, Joshua K; Niu, Jacqueline; Sumer, Suna et al. (2013) Trans-illuminated laser speckle imaging of collateral artery blood flow in ischemic mouse hindlimb. J Biomed Opt 18:096011
Burke, Caitlin W; Suk, Jung Soo; Kim, Anthony J et al. (2012) Markedly enhanced skeletal muscle transfection achieved by the ultrasound-targeted delivery of non-viral gene nanocarriers with microbubbles. J Control Release 162:414-21
Meisner, Joshua K; Sumer, Suna; Murrell, Kelsey P et al. (2012) Laser speckle flowmetry method for measuring spatial and temporal hemodynamic alterations throughout large microvascular networks. Microcirculation 19:619-31
Meisner, Joshua K; Song, Ji; Price, Richard J (2012) Arteriolar and venular remodeling are differentially regulated by bone marrow-derived cell-specific CX3CR1 and CCR2 expression. PLoS One 7:e46312
Burke, Caitlin W; Hsiang, Yu-Han J; Alexander 4th, Eben et al. (2011) Covalently linking poly(lactic-co-glycolic acid) nanoparticles to microbubbles before intravenous injection improves their ultrasound-targeted delivery to skeletal muscle. Small 7:1227-35
Burke, Caitlin W; Klibanov, Alexander L; Sheehan, Jason P et al. (2011) Inhibition of glioma growth by microbubble activation in a subcutaneous model using low duty cycle ultrasound without significant heating. J Neurosurg 114:1654-61
Burke, Caitlin W; Price, Richard J (2010) Contrast ultrasound targeted treatment of gliomas in mice via drug-bearing nanoparticle delivery and microvascular ablation. J Vis Exp :

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