scholarly journals Enhancement of FUS Mediated Delivery of Stem Cells to Brain

2018 ◽  
Author(s):  
Paul S. Fishman
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Focused Ultrasound ◽  
Oxide Nanoparticles ◽  
Magnetic Targeting ◽  
External Magnet ◽  
Remarkable Advance ◽  
The Brain ◽  
Stem Cell Therapeutics ◽  
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We propose that magnetic targeting of super-paramagnetic iron oxide nanoparticles (SPION) labeled cells will enhance the delivery of stem cells to brain after focused ultrasound (FUS) mediated opening of the blood-brain barrier (BBB). FUS mediated opening of the BBB allowing stem cells to enter the brain from the blood is a remarkable advance in delivery of stem cell therapeutics over current invasive methods of brain injection. However the efficiency of cellular entry is low. SPIONs are taken up by stem cells, allowing for labeling of transplanted stem cells in brain both with histology and MRI. Our research shows that SPION labeled stem cells show enhanced brain retention near a magnet on the skull, in a rat model of traumatic brain injury. There is no experience combining these two minimally invasive strategies to deliver stem cells to the brain. We will assess the capacity of an external magnet to enhance the efficiency of delivery to brain of SPION loaded stem cells after transient opening of the BBB using FUS. We will evaluate SPION loaded neural stem cells delivered by intravenous infusion in rats that have undergone MRI targeted FUS opening of the BBB along with a magnet placed over the skull of the sonicated hemisphere, to animals with FUS alone. The number and distribution of stem cells will be quantitative for each group to assess enhancement of delivery of stem cells after BBB opening using FUS by the addition of SPION loading and an external magnet.

scholarly journals Pharmacodynamic Analysis of Magnetic Resonance Imaging-Monitored Focused Ultrasound-Induced Blood-Brain Barrier Opening for Drug Delivery to Brain Tumors

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Po-Chun Chu ◽  
Wen-Yen Chai ◽  
Han-Yi Hsieh ◽  
Jiun-Jie Wang ◽  
Shiaw-Pyng Wey ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Small Molecule ◽  
Focused Ultrasound ◽  
Therapeutic Agents ◽  
Tumor Treatment ◽  
Target Region ◽  
Pharmacodynamic Analysis ◽  
The Brain ◽  
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Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.

scholarly journals Claudin-5 binder enhances focused ultrasound-mediated opening in an in vitro blood-brain barrier model

2021 ◽  
Author(s):  
Ratneswary Sutharsan ◽  
Liyu Chen ◽  
Jonathan LF Lee ◽  
Esteban Cruz ◽  
Tishila Palliyaguru ◽  
...  
Keyword(s):  
Cell Line ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
General Strategy ◽  
Blood Brain ◽  
Barrier Opening ◽  
The Brain ◽  
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Rationale: The blood-brain barrier (BBB) while functioning as a gatekeeper of the brain, impedes cerebral drug delivery. An emerging technology to overcome this limitation is focused ultrasound (FUS). When FUS interacts with intravenously injected microbubbles (FUS+MB), the BBB opens, transiently allowing the access of therapeutic agents into the brain. However, the ultrasound parameters need to be tightly tuned: when the acoustic pressure is too low there is no opening, and when it is too high, bleeds can occur. We therefore asked whether BBB permeability can be increased by combining FUS+MB with a second modality such that in a clinical setting lower acoustic pressures could be potentially used. Methods: Given that FUS achieves BBB opening by the disruption of tight junction (TJ) proteins such as claudin-5 of brain endothelial cells, we generated a stable MDCK II cell line (eGFP-hCldn5-MDCK II) that expresses fluorescently tagged human claudin-5. Two claudin-5 binders, mC5C2 (a peptide) and cCPEm (a truncated form of an enterotoxin), that have been reported previously to weaken the barrier, were synthesized and assessed for their abilities to enhance the permeability of cellular monolayers. We then performed a comparative analysis of single and combination treatments. Results: We successfully generated a novel cell line that formed functional monolayers as validated by an increased transendothelial electrical resistance (TEER) reading and a low (< 0.2%) permeability to sodium fluorescein (376 Da). We found that the binders exerted a time- and concentration-dependent effect on BBB opening when incubated over an extended period, whereas FUS+MB caused a rapid barrier opening followed by recovery after 12 hours within the tested pressure range. Importantly, preincubation with cCPEm prior to FUS+MB treatment resulted in greater barrier opening compared to either FUS+MB or cCPEm alone as measured by reduced TEER values and an increased permeability to fluorescently labelled 40 kDa dextran (FD40). Conclusion: The data suggest that pre-incubation with clinically suitable binders to TJ proteins may be a general strategy to facilitate safer and more effective ultrasound-mediated BBB opening in cellular and animal systems and potentially also for the treatment of human diseases of the brain.

Mannitol enhances therapeutic effects of intra-arterial transplantation of mesenchymal stem cells into the brain after traumatic brain injury

2013 ◽  
Vol 554 ◽  
pp. 156-161 ◽  
Author(s):  
Yu Okuma ◽  
Feifei Wang ◽  
Atsuhiko Toyoshima ◽  
Masahiro Kameda ◽  
Tomohito Hishikawa ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Brain Injury ◽  
Therapeutic Effects ◽  
The Brain

scholarly journals Cell-Based Therapies for Traumatic Brain Injury: Therapeutic Treatments and Clinical Trials

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 669
Author(s):  
Celia Bonilla ◽  
Mercedes Zurita
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Clinical Trials ◽  
Brain Injury ◽  
Cell Therapy ◽  
Physical Damage ◽  
Clinical Models ◽  
Trauma Deaths ◽  
The Brain

Traumatic brain injury (TBI) represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. TBI contributes to 50% of all trauma deaths, with many enduring long-term consequences and significant medical and rehabilitation costs. There is currently no therapy to reverse the effects associated with TBI. An increasing amount of research has been undertaken regarding the use of different stem cells (SCs) to treat the consequences of brain damage. Neural stem cells (NSCs) (adult and embryonic) and mesenchymal stromal cells (MSCs) have shown efficacy in pre-clinical models of TBI and in their introduction to clinical research. The purpose of this review is to provide an overview of TBI and the state of clinical trials aimed at evaluating the use of stem cell-based therapies in TBI. The primary aim of these studies is to investigate the safety and efficacy of the use of SCs to treat this disease. Although an increasing number of studies are being carried out, few results are currently available. In addition, we present our research regarding the use of cell therapy in TBI. There is still a significant lack of understanding regarding the cell therapy mechanisms for the treatment of TBI. Thus, future studies are needed to evaluate the feasibility of the transplantation of SCs in TBI.

scholarly journals Traumatic Brain Injury and Stem Cells: An Overview of Clinical Trials, the Current Treatments and Future Therapeutic Approaches

Medicina ◽  
2020 ◽  
Vol 56 (3) ◽  
pp. 137 ◽  
Author(s):  
Giovanni Schepici ◽  
Serena Silvestro ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Clinical Trials ◽  
Stem Cell ◽  
Brain Injury ◽  
Brain Damage ◽  
Physical Damage ◽  
Safety And Efficacy ◽  
Cell Based Therapy ◽  
The Brain

Traumatic brain injury represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. The traumatic injury activates an important inflammatory response, followed by a cascade of events that lead to neuronal loss and further brain damage. Maintaining proper ventilation, a normal level of oxygenation, and adequate blood pressure are the main therapeutic strategies performed after injury. Surgery is often necessary for patients with more serious injuries. However, to date, there are no therapies that completely resolve the brain damage suffered following the trauma. Stem cells, due to their capacity to differentiate into neuronal cells and through releasing neurotrophic factors, seem to be a valid strategy to use in the treatment of traumatic brain injury. The purpose of this review is to provide an overview of clinical trials, aimed to evaluate the use of stem cell-based therapy in traumatic brain injury. These studies aim to assess the safety and efficacy of stem cells in this disease. The results available so far are few; therefore, future studies need in order to evaluate the safety and efficacy of stem cell transplantation in traumatic brain injury.

Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells

2021 ◽  
pp. 1-11
Author(s):  
Yi Wang ◽  
Matthew J. Anzivino ◽  
Yanrong Zhang ◽  
Edward H. Bertram ◽  
James Woznak ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Focused Ultrasound ◽  
Focal Epilepsy ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Brain Parenchyma ◽  
The Brain ◽  
Patient Confidence ◽  
Treatment Envelope ◽  
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OBJECTIVE Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage. METHODS Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB. RESULTS Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure. CONCLUSIONS These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.

scholarly journals The effect of transcranial focused ultrasound target location on the acoustic feedback control performance during blood-brain barrier opening with nanobubbles

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Bingbing Cheng ◽  
Chenchen Bing ◽  
Rajiv Chopra
Keyword(s):  
Feedback Control ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Target Location ◽  
Brain Barrier ◽  
Control Performance ◽  
Acoustic Feedback ◽  
Acoustic Control ◽  
The Brain ◽  
Bbb Opening

AbstractReal-time acoustic feedback control based on harmonic emissions of stimulated microbubbles may be important for facilitating the clinical adoption of focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening, both to ensure safe acoustic exposures, and to achieve repeatable and consistent opening. Previously our group demonstrated that successful BBB opening was achievable with both commercially available microbubbles and custom-made nanobubbles under acoustic feedback control. In a recent study, we demonstrated the acoustic control performance was not sensitive to the nanobubble concentration within 109–1011 bubbles/ml. The goal of this study was to examine the effect of the ultrasound target location in the rat brain on the acoustic control quality during BBB opening with nanobubbles. Temporal analysis of the received acoustic signals during each ultrasound pulse indicated that stable nanobubble oscillation was present throughout the entire 10 ms ultrasound exposure. The acoustic feedback control signals were very sensitive to the brain spatial location in rats. There appears to be a shared pattern of acoustic control stability in the brain across different animals, suggesting anatomical features are an underlying cause. The findings emphasize the importance of tuning acoustic feedback control algorithms for specific rodent brain regions of interest to ensure optimal performance.

scholarly journals Regenerative capacity of bone marrow stem cells with or without superparamagnetic iron oxide nanoparticles after facial nerve degeneration: A narrative review

2021 ◽  
Vol 20 (3) ◽  
pp. 300-304
Author(s):  
Noura Abd El-Latif ◽  
◽  
Mona Denewar ◽  
Rehab R. El-Zehary ◽  
Fatma M. Ibrahim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Facial Nerve ◽  
Superparamagnetic Iron Oxide ◽  
The Body ◽  
Cell Delivery ◽  
Oxide Nanoparticles ◽  
Magnetic Targeting ◽  
Stem Cell Delivery

Facial palsy can be defined as a kind of paralysis affecting facial muscles. It is termed Bell’s palsy if it is unilateral. It may occur due to trauma to the facial nerve, infections as herpes zoster, neoplastic lesions, or unknown cause. It may be also associated with metabolic and systemic diseases as hypertension, toxicity, amyloidosis, alcoholism, auto-immune diseases and diabetes mellitus. Mesenchymal stem cells (MSCs) are multipotent adult stromal cells that have many benefits as an evolving treatment modality. Bone marrow stem cells (BMSCs) divide progressively in culture, and differentiate into neurons exclusively with use of a simple protocol. Most ongoing preclinical and clinical cell treatment modalities composed of local or systemic transplantation of stem or progenitor cells. In addition, they depend on the migration and retention of transplanted cells at insult areas. Nevertheless, one of the main obstacles against this modality is how to detect the fate and exact location of these cells inside the body, and how to maintain the cells at this specific site. Magnetic targeting systems, which depends on cells labelled by magnetic carriers, have been assessed as a more efficient technique for stem cell delivery to target sites. These systems depend on loading stem cells with magnetic nanoparticles and attracting them to the exact intended area within the body by placing an external magnetic field. Superparamagnetic iron oxide nanoparticles (SPIONs) have been introduced in the last few years as a rising applicant of nanoparticles in a vast variety of medical fields as magnetic separation, drug delivery, magnetic resonance imaging (MRI) and magnetic hyperthermia. In addition, applications of SPIONs, as a site-specific drug carrier, diagnostic agent and stem cell delivery agent, receive most attention of researchers in that field. In this review, up-to-date information about Magnetic targeting of degenerated facial nerve by BMSCs labelled with SPIONs may suggest its capacity of better regeneration than injection of BMSCs alone.

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