A Benchtop Approach to the Location Specific Blood Brain Barrier Opening using Focused Ultrasound in a Rat Model

Rich, Megan; Whitsitt, Quentin; Lubin, Farah D.; Bolding, Mark

doi:10.3791/61113

Cited by 5 publications

(5 citation statements)

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“…FUS can open the BBB in target locations on the order of millimeters, enabling entry of RLPs and viral vectors to specific brain regions including deep brain structures. We have shown previously that we were able to achieve location specific protein expression following FUS-mediated delivery of AAV9-hsyn-GFP [17].…”

Section: Discussionmentioning

confidence: 97%

“…For a detailed protocol on MRI and FUS procedures please refer to our published protocol [17]. Male Sprague Dawley rats weighing 250-300g were obtained from Charles River Laboratories and housed in accordance with UAB Institutional Animal Care and Use Committee (IACUC) guidelines.…”

Section: Mri Proceduresmentioning

confidence: 99%

“…Rats had free access to water and rat chow, and were maintained on a 12:12 light:dark cycle. Animals were anesthetized with isoflurane (2 -3%) and placed in a 3D printed stereotaxic frame, equipped with an MRI fiducial [17], [31]. Animals were maintained under isoflurane anesthesia throughout the MRI and FUS procedures.…”

Section: Mri Proceduresmentioning

confidence: 99%

“…Furthermore, FUS BBB opening can be used in combination with MRI contrast agents to confirm the location of delivery [9], [14]- [16]. Recently, it has been shown by our group [17] and others [18]- [20] that focused ultrasound (FUS) BBB disruption can be used to provide noninvasive delivery of adeno associated virus (AAVs) including AAVs for the expression of ChR2 [20]. However, this study still required the implantation of an optic fiber cable and therefore, was not a completely noninvasive optogenetic system [20].…”

Section: Introductionmentioning

confidence: 97%

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A Noninvasive Approach to Optogenetics Using Focused Ultrasound Blood Brain Barrier Disruption for the Delivery of Radioluminescent Particles

Rich

Zhang

Dickey

et al. 2020

Preprint

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Optogenetics, the genetic incorporation of light-sensitive proteins such as Channelrhodopsin-2 (ChR2) into target mammalian neurons, has enabled activation, silencing, and receptor subtype specific neuromodulation with high spatiotemporal resolution. However, the essential components of the ontogenetic system require invasive procedures with very few non-invasive alternatives preventing its use as a translational tool. The implantation of light emitting fibers deep within brain structures is both technically demanding and causes tissue scarring in target brain regions. To overcome these limitations, while maintaining the highly-tuned components of optogenetics we have developed a novel noninvasive alternative. Our approach replaces fibers with light-emitting radioluminescent particles (RLPs) that can be activated non-invasively with X-ray exposure. Here, we report successful noninvasive delivery of RLPs to target brain regions using MRI-guided focused ultrasound (FUS) blood brain barrier opening. In addition, FUS BBBO can be used to deliver viral vectors for light sensitive channel expression. Combined, these components can provide a completely non-invasive optogenetic system.

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Section: Discussionmentioning

confidence: 97%

Section: Mri Proceduresmentioning

confidence: 99%

Section: Mri Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 2 more Smart Citations

A Noninvasive Approach to Optogenetics Using Focused Ultrasound Blood Brain Barrier Disruption for the Delivery of Radioluminescent Particles

Rich

Zhang

Dickey

et al. 2020

Preprint

Self Cite

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“…Blood–Brain Barrier permeability detection was performed as follows 15 : the fur on the head of 12 healthy SD rats was removed using depilatory cream. After anesthesia, 3% Evans blue dye (EBD, 1 mL/Kg) was injected into the tail vein and circulated for 5 min in vivo .…”

Section: Methodsmentioning

confidence: 99%

Ultrasound-Targeted Microbubble Destruction Increases BBB Permeability and Promotes Stem Cell–Induced Regeneration of Stroke by Downregulating MMP8

Bai,

Du,

Yang

et al. 2024

Cell Transplant

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The objective of this study was to evaluate the feasibility, safety, and effectiveness of intravenous stem cell delivery utilizing ultrasound-targeted microbubble destruction (UTMD) in a rat model of middle cerebral artery occlusion (MCAO), while investigating the underlying mechanisms. Acute cerebral infarction (ACI) was induced surgically in adult rats to create the MCAO rat model. Intravenous injection of SonoVue microbubbles and bone marrow–derived mesenchymal stem cells (BMSC) was performed concurrently, with or without ultrasound targeting the stroke. The animals were divided into four groups: sham-operated group, ACI-MCAO rats treated with phosphate-buffered saline (ACI+PBS), rats receiving intravenous delivery of BMSC expressing green fluorescent protein (GFP-BMSC; ACI+BMSC), and rats receiving intravenous GFP-BMSC with simultaneous UTMD exposure (ACI+BMSC+UTMD). The efficacy of the treatments was assessed by evaluating the animals’ neurological function using the Longa score and examining histopathological changes such as cerebral infarct volume, cerebral edema, and cell apoptosis. A rat cytokine array was utilized to identify the potential cytokines that may be responsible for the therapeutic effect of UTMD-mediated BMSC treatment. Optimal UTMD parameters resulted in an increase in blood–brain barrier (BBB) permeability after 30 min, which returned to baseline 72 h later without causing any residual injury. UTMD application significantly increased the homing of intravenously delivered BMSC, resulting in a 2.2-fold increase in GFP-BMSC cell count on day 3 and a 2.6-fold increase on day 7 compared with intravenous delivery alone. This effect persisted for up to 6 weeks after injection. Intravenous BMSC delivery significantly reduced the volume of cerebral infarct and decreased cerebral edema, leading to a lower Longa score. Furthermore, this effect was further enhanced by UTMD. Acute cerebral infarction induced by MCAO led to elevated matrix metalloproteinase 8 (MMP8) levels in the cerebrospinal fluid, which were significantly reduced following UTMD-mediated BMSC treatment. Ultrasound-targeted microbubble destruction facilitates the migration and homing of BMSC into the brain, possibly by transiently increasing blood–brain barrier (BBB) permeability, thereby improving therapeutic outcomes in an ACI rat model. The observed effect may be partly attributed to modulation of MMP8 levels. Advances in knowledge: UTMD-mediated intravenously delivered BMSC transplantation led to a significant increase in cell homing and reduction of MMP8 levels, resulting in increased therapeutic effect in an acute ischemic cerebral infarction model.

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Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control

Rich¹,

Sherwood

Bartley³

et al. 2020

Journal of Controlled Release

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There is an ongoing need for noninvasive tools to manipulate brain activity with molecular, spatial and temporal specificity. Here we have investigated the use of MRI-visible, albumin-based nanoclusters for noninvasive, localized and temporally specific drug delivery to the rat brain. We demonstrated that IV injected nanoclusters could be deposited into target brain regions via focused ultrasound facilitated blood brain barrier opening. We showed that nanocluster location could be confirmed in vivo with MRI. Additionally, following confirmation of nanocluster delivery, release of the nanocluster payload into brain tissue can be triggered by a second focused ultrasound treatment performed without circulating microbubbles. Release of glutamate from nanoclusters in vivo caused enhanced c-Fos expression, indicating that the loading capacity of the nanoclusters is sufficient to induce neuronal activation. This novel technique for noninvasive stereotactic drug delivery to the brain with temporal specificity could provide a new way to study brain circuits in vivo preclinically with high relevance for clinical translation.

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A Benchtop Approach to the Location Specific Blood Brain Barrier Opening using Focused Ultrasound in a Rat Model

Cited by 5 publications

References 0 publications

A Noninvasive Approach to Optogenetics Using Focused Ultrasound Blood Brain Barrier Disruption for the Delivery of Radioluminescent Particles

A Noninvasive Approach to Optogenetics Using Focused Ultrasound Blood Brain Barrier Disruption for the Delivery of Radioluminescent Particles

Ultrasound-Targeted Microbubble Destruction Increases BBB Permeability and Promotes Stem Cell–Induced Regeneration of Stroke by Downregulating MMP8

Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control

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