Transcranial focused ultrasound (FUS) has been investigated for a range of applications in small and large animal models as well as humans. There is increased interest in using pulsed FUS (pFUS) in neurological applications (e.g. neurostimulation) due the two major advantages of non-invasiveness and high degree of localization. An exciting parallel development in neurology was triggered by the positive findings regarding the ability of human umbilical cord blood stem cells (UCBSCs) to restore limb functions even when transplanted days after the onset of ischemic stroke (in a small-animal stroke model). However, the therapeutic efficacy of the systemic administration of UCBSC is often limited by the inefficient homing and trafficking to the target tissue volumes. This limitatin may be addressed by the use of pFUS in conjunction with systemic administration of UCBSCs (specifically so-called non-hematopoietic umbilical cord blood stem cells (nh-UCBSCs)). This is motivated by recent results demonstrating that pFUS can improve cell-based therapies as noninvasive modality for homing and trafficking of therapeutic agents. We propose to design a dual-mode ultrasound array (DMUA) system capable of generating a range of localized sub-therapeutic pFUS exposures in the sensorimotor cortex of an in vivo rat stroke model. In addition, the system will be capable of generating imaging feedback with high specificity to the interaction between the pFUS exposure and the target tissue, e.g. thermal changes, acoustic radiation force (ARF) displacements and strains, cavitation. The successful implementation of the image-guided DMUA system will enhance the precision of homing and trafficking of the nh-UCBSCs to the target volume within and surrounding the ischemic tissue. Equally significantly, it will provide high specificity feedback on the nature of pFUS-tissue interactions thus allowing for better understanding of the key mechanisms leading to enhanced homing, with or without the use of microbubble ultrasound contrast agents. This will open the door for more efficient pre-clinical and clinical research on pFUS-enhanced homing and trafficking of UBCSCs in large-animal models of stroke and, subsequently, in human subjects.

Public Health Relevance

Only a small fraction of stroke victims are fortunate enough to receive intervention within the 3-hour time window allowing for preservation of speech and other motor functions. The transplantation of umbilical cord blood stem cells days after the stroke gives new hope of restoring function in patients who are currently left without options. However, the therapeutic efficacy is often limited by inefficient homing of systemically administered cells. The use of pulsed focused ultrasound in conjunction with systemic administration of stem cells could improve the efficacy of such treatments and bring the benefits of UCBSC treatment for this large patient population.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Koenig, James I
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University of Minnesota Twin Cities
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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Du, Juan; Liu, Dalong; Ebbini, Emad S (2016) Nonlinear Imaging of Microbubble Contrast Agent Using the Volterra Filter: In Vivo Results. IEEE Trans Ultrason Ferroelectr Freq Control 63:2069-2081
Haritonova, Alyona; Liu, Dalong; Ebbini, Emad S (2015) In Vivo application and localization of transcranial focused ultrasound using dual-mode ultrasound arrays. IEEE Trans Ultrason Ferroelectr Freq Control 62:2031-42