Biology subjects

Borden, M. A.

Publications and source records attributed to Borden, M. A..

8 recordsLinked to original sources

bioRxiv2024

Combined Nanodrops Imaging and Ultrasound Localization Microscopy for Detecting Intracerebral Hemorrhage

ObjectiveAdvanced imaging methods are crucial for understanding stroke mechanisms and discovering effective treatments to reduce bleeding and enhance recovery. In preclinical in vivo stroke imaging, MRI, CT, and optical imaging are commonly used to evaluate stroke outcomes in rodent models. However, MRI and CT have limited spatial resolution for rodent brains, and optical imaging is hindered by limited imaging depth of penetration. Here we introduce a novel contrast-enhanced ultrasound imaging method to overcome these challenges and characterize intracerebral hemorrhage with unique insights. MethodsWe combined microbubble (MB)-based ultrasound localization microscopy (ULM) and nanodrop (ND)- based vessel leakage imaging to achieve simultaneous microvascular imaging and hemorrhage detection. ULM maps brain-wide cerebral vasculature with high spatial resolution and identifies microvascular impairments around hemorrhagic areas. NDs are sub-micron liquid-core particles which can extravasate due to blood-brain barrier (BBB) breakdown, serving as positive contrast agents to detect hemorrhage sites. ResultsOur findings demonstrate that NDs could effectively accumulate in the hemorrhagic site and reveal the location of the bleeding areas upon activation by focused ultrasound beams. ULM further reveals the microvascular damage manifested in the form of reduced vascularity and decreased blood flow velocity across areas affected by the hemorrhagic stroke. ConclusionThe results demonstrate that sequential ULM combined with ND imaging is a useful imaging tool for basic in vivo research in stroke with rodent models where brain-wide detection of active bleeding and microvascular impairment are essential.

bioengineering↗

bioRxiv2024

Effect of Microbubble Size, Composition and Multiple Sonication Points on Sterile Inflammatory Response in Focused Ultrasound-Mediated Blood-Brain Barrier Opening

Blood-brain barrier opening (BBBO) using focused ultrasound (FUS) and microbubble (MBs) has emerged as a promising technique for delivering therapeutics to the brain. However, the influence of various FUS and MB parameters on BBBO and subsequent sterile inflammatory response (SIR) remains unclear. In this study, we investigated the effects of MB size and composition, as well as the number of FUS sonication points, on BBBO and SIR in an immunocompetent mouse model. Using MRI-guided MB+FUS, we targeted the striatum and assessed extravasation of an MRI contrast agent to assess BBBO and RNAseq to assess SIR. Our results revealed distinct effects of these parameters on BBBO and SIR. Specifically, at a matched microbubble volume dose (MVD), MB size did not affect the extent of BBBO, but smaller (1 {micro}m diameter) MBs exhibited a lower classification of SIR than larger (3 or 5 {micro}m diameter) MBs. Lipid-shelled microbubbles exhibited greater BBBO and a more pronounced SIR compared to albumin-shelled microbubbles, likely owing to the latters poor in vivo stability. As expected, increasing the number of sonication points resulted in greater BBBO and SIR. Furthermore, correlation analysis revealed strong associations between passive cavitation detection measurements of harmonic and inertial MB echoes, BBBO and the expression of SIR gene sets. Our findings highlight the critical role of MB and FUS parameters in modulating BBBO and subsequent SIR in the brain. These insights inform the development of targeted drug delivery strategies and the mitigation of adverse inflammatory reactions in neurological disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/591538v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@5c8905org.highwire.dtl.DTLVardef@127e812org.highwire.dtl.DTLVardef@f52dbaorg.highwire.dtl.DTLVardef@8d3aef_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Comprehensive Assessment of Blood-Brain Barrier Opening and Sterile Inflammatory Response: Unraveling the Therapeutic Window

Microbubbles (MBs) combined with focused ultrasound (FUS) have emerged as a promising noninvasive technique to permeabilize the blood-brain barrier (BBB) for drug delivery to the brain. However, the safety and biological consequences of BBB opening remain incompletely understood. This study investigates the effects of varying microbubble volume doses (MVD) and ultrasound mechanical indices (MI) on BBB opening and the sterile inflammatory response (SIR) using high-resolution ultra-high field MRI-guided FUS in mouse brains. The results demonstrate that both MVD and MI significantly influence the extent of BBB opening, with higher doses and mechanical indices leading to increased permeability. Moreover, RNA sequencing reveals upregulated inflammatory pathways and immune cell infiltration after BBB opening, suggesting the presence and extent of SIR. Gene set enrichment analysis identifies 12 gene sets associated with inflammatory responses that are upregulated at higher doses of MVD or MI. A therapeutic window is established between significant BBB opening and the onset of SIR, providing operating regimes for avoiding each three classes of increasing damage from stimulation of the NF{kappa}B pathway via TNFL signaling to apoptosis. This study contributes to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and sheds light on the underlying molecular mechanisms of the sterile inflammatory response. Significance StatementThe significance of this study lies in its comprehensive investigation of microbubble-facilitated focused ultrasound for blood-brain barrier (BBB) opening. By systematically exploring various combinations of microbubble volume doses and ultrasound mechanical indices, the study reveals their direct impact on the extent of BBB permeability and the induction of sterile inflammatory response (SIR). The establishment of a therapeutic window between significant BBB opening and the onset of SIR provides critical insights for safe and targeted drug delivery to the brain. These findings advance our understanding of the biological consequences of BBB opening and contribute to optimizing parameters for clinical applications, thus minimizing potential health risks, and maximizing the therapeutic potential of this technique.

bioengineering↗

bioRxiv2023

MRI-Guided Focused Ultrasound Blood-Brain Barrier Opening Increases Drug Delivery and Efficacy in a Diffuse Midline Glioma Mouse Model

Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-derived DMG cell line, BT-245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa PNP, 1 Hz PRF, 10 ms PL, 3 min treatment time) / (25 {micro}L/kg, IV) targeting to the tumor location. In animals receiving panobinostat (10 mg/kg, IP) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, with only insignificant increase of the drug in the forebrain. In mice receiving three weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes by MRI (p = 0.01). Furthermore, FUS/MB improved the mean survival from 21 to 31 days (p < 0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival. One Sentence SummaryFUS and microbubbles can increase the delivery of panobinostat to a patient-derived xenograft (PDX) orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

bioengineering↗

bioRxiv2022

Nanobubbles are Non-Echogenic for Fundamental-Mode Contrast-Enhanced Ultrasound Imaging

Microbubbles (1-10 {micro}m diameter) have been used as conventional ultrasound contrast agents (UCAs) for applications in contrast-enhanced ultrasound (CEUS) imaging. Nanobubbles (<1 {micro}m diameter) have recently been proposed as potential extravascular UCAs that can extravasate from the leaky vasculature of tumors or sites of inflammation. However, the echogenicity of nanobubbles for CEUS remains controversial owing to prior studies that have shown very low ultrasound backscatter. We hypothesize that microbubble contamination in nanobubble formulations may explain the discrepancy. To test our hypothesis, we examined the size distributions of lipid-coated nanobubble and microbubble suspensions using multiple sizing techniques, examined their echogenicity in an agar phantom with fundamental-mode CEUS at 7 MHz and 330 kPa peak negative pressure, and interpreted our results with simulations of the modified Rayleigh-Plesset model. We found that nanobubble formulations contained a small contamination of microbubbles. Once the contribution from these microbubbles is removed from the acoustic backscatter, the acoustic contrast of the nanobubbles was shown to be near noise levels. This result indicates that nanobubbles have limited utility as UCAs for CEUS.

bioengineering↗

bioRxiv2021

Colonic Oxygen Microbubbles Augment Systemic Oxygenation and CO2 Removal in a Porcine Smoke Inhalation Model of Severe Hypoxia

Inhalation injury can lead to pulmonary complications resulting in the development of respiratory distress and severe hypoxia. Respiratory distress is one of the major causes of death in critically ill patients with a reported mortality rate of up to 45%. The present study focuses on the effect of oxygen microbubble (OMB) infusion via the colon in a porcine model of smoke inhalation-induced lung injury. Juvenile female Duroc pigs (n=6 colonic OMB, n=6 no treatment) ranging from 39-51 kg in weight were exposed to smoke under general anesthesia for 2 h. Animals developed severe hypoxia 48 h after smoke inhalation as reflected by reduction in SpO2 to 66.3 % {+/-} 13.1% and PaO2 to 45.3 {+/-} 7.6 mmHg, as well as bilateral diffuse infiltrates demonstrated on chest x-ray. Colonic OMB infusion (75 - 100 mL/kg dose) resulted in significant improvements in systemic oxygenation as demonstrated by an increase in PaO2 of 13.2 {+/-} 4.7 mmHg and SpO2 of 15.2% {+/-} 10.0% out to 2.5 h, compared to no-treatment control animals that experienced a decline in PaO2 of 8.2 {+/-} 7.9 mmHg and SpO2 of 12.9% {+/-} 18.7% over the same timeframe. Likewise, colonic OMB decreased PaCO2 and PmvCO2 by 19.7 {+/-} 7.6 mmHg and 7.6 {+/-} 6.7 mmHg, respectively, compared to controls that experienced increases in PaCO2 and PmvCO2 of 17.9 {+/-} 11.7 mmHg and 18.3 {+/-} 11.2 mmHg. We conclude that colonic OMB therapy has potential to treat patients experiencing severe hypoxemic respiratory failure. One Sentence SummaryEnteral oxygen microbubbles increase systemic oxygen and decrease carbon dioxide levels in acutely hypoxic pigs after smoke inhalation-induced respiratory failure.

bioengineering↗

bioRxiv2020

Contrast-enhanced sonography with biomimetic lung surfactant nanodrops

Nanodrops comprising a perfluorocarbon liquid core can be acoustically vaporized into echogenic microbubbles for ultrasound imaging. Packaging the microbubble in its condensed liquid state provides distinct advantages, including in situ activation of the acoustic signal, longer circulation persistence, and the advent of expanded diagnostic and therapeutic applications in pathologies which exhibit compromised vasculature. One obstacle to clinical translation is the inability of the limited surfactant present on the nanodrop to encapsulate the greatly expanded microbubble interface, resulting in ephemeral microbubbles with limited utility. In this study, we examine a biomimetic approach to stabilizing an expanding gas surface by employing the lung surfactant replacement, Beractant. Lung surfactant contains a suite of lipids and surfactant proteins that provides efficient shuttling of material from bilayer folds to the monolayer surface. We therefore hypothesized that Beractant would improve stability of acoustically vaporized microbubbles. To test this hypothesis, we characterized Beractant surface dilation mechanics and revealed a novel biophysical phenomenon of rapid interfacial melting, spreading and re-solidification. We then harnessed this unique spreading capability to increase the stability and echogenicity of microbubbles produced after acoustic droplet vaporization for in vivo ultrasound imaging. Such biomimetic lung surfactant-stabilized nanodrops may be useful for applications in ultrasound imaging and therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/367235v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@b6b2f4org.highwire.dtl.DTLVardef@9eb8b7org.highwire.dtl.DTLVardef@71364corg.highwire.dtl.DTLVardef@a3c41d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2020

Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

Type 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing {beta}-cells within the pancreatic islets of Langerhans (insulitis), resulting in loss of glucose homeostasis. Early diagnosis during pre-symptomatic T1D would allow for therapeutic intervention prior to substantial loss of {beta}-cell mass at T1D onset. There are limited methods to track the progression of insulitis and {beta}-cell mass decline in pre-symptomatic T1D. During insulitis, the islet microvasculature increases permeability, such that sub-micron sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Sub-micron sized nanodroplet (ND) phasechange agents can be vaporized into micron-sized bubbles; serving as a circulating microbubble precursor. We tested if NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in NOD mice and NOD;Rag1ko controls, and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10w NOD mice following ND infusion and vaporization, but was absent in both the non-infiltrated kidney of NOD mice and pancreas of Rag1ko controls. High contrast elevation also correlated with rapid diabetes onset. In pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression to guide and assess preventative therapeutic interventions for T1D. SignificanceThere is a need for imaging methods to detect type1 diabetes (T1D) progression prior to clinical diagnosis. T1D is a chronic disease that results from autoreactive T cells infiltrating the islet of Langerhans and destroying insulin-producing {beta}-cells. Overt disease takes years to present and is only diagnosed after significant {beta}-cells loss. As such, the possibility of therapeutic intervention to preserve {beta}-cell mass is hampered by an inability to follow pre-symptomatic T1D progression. There are immunotherapies that can delay T1D development. However identifying at risk individuals, and tracking whether therapeutic interventions are impacting disease progression, prior to T1D onset, is lacking. A method to detect insulitis and {beta}-cell mass decline would present an opportunity to guide therapeutic treatments to prevent T1D.

bioengineering↗