A Novel Method for the Generation of Realistic Lung Nodules Visualized Under X-Ray Imaging.

Objective: Image-guided diagnosis and treatment of lung lesions is an active area of research. With the growing number of solutions proposed, there is also a growing need to establish a standard for the evaluation of these solutions. Thus, realistic phantom and preclinical environments must be established.

Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system.

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes.

Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe.

Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making.

Active drug-coated flow diverter in a preclinical model of intracranial stenting.

Background: Flow diverters carry the risk of thromboembolic complications (TEC). We tested a coating with covalently bound heparin that activates antithrombin to address TEC by locally downregulating the coagulation cascade. We hypothesized that the neuroimaging evidence of TEC would be reduced by the coating.

Assessment of thrombectomy procedure difficulty by neurointerventionalists based on vessel geometry parameters from carotid artery 3D reconstructions.

Background: Diagnosing and treating acute ischemic stroke patients within a narrow timeframe is challenging. Time needed to access the occluded vessel and initiate thrombectomy is dictated by the availability of information regarding vascular anatomy and trajectory. Absence of such information potentially impacts device selection, procedure success, and stroke outcomes.

Tectonic infarct analysis: A computational tool for automated whole-brain infarct analysis from TTC-stained tissue.

Background: Infarct volume measured from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices is critical to stroke models. In this study, we developed an interactive, tunable, software that automatically computes whole-brain infarct metrics from serial TTC-stained brain sections.

Methods: Three rat ischemic stroke cohorts were used in this study (Total  = 91 rats; Cohort 1  = 21, Cohort 2  = 40, Cohort 3  = 30).

Development of an in-vitro model based on patient vessel geometry for simulated use testing in neurointerventional surgery.

Background: Neurointerventionalists use in-vitro vascular models to train for worst-case scenarios and test new devices in a simulated use environment to predict clinical performance. According to the Food and Drug Administration (FDA), any neurovascular navigation device should be able to successfully navigate two 360-degree turns and two 180-degree turns at the distal portion of the anatomical model. Here, we present a device benchmarking vascular model that complies with FDA recommendations.

Molecular Magnetic Resonance Imaging of Aneurysmal Inflammation Using a Redox Active Iron Complex.

Objectives: Inflammation plays a key role in driving brain aneurysmal instability and rupture, but clinical tools to noninvasively differentiate between inflamed and stable aneurysms are lacking. We hypothesize that imaging oxidative changes in the aneurysmal microenvironment driven by myeloid inflammatory cells may represent a noninvasive biomarker to evaluate rupture risk. In this study, we performed initial evaluation of the oxidatively activated probe Fe-PyC3A as a tool for magnetic resonance imaging (MRI) of inflammation in a rabbit model of saccular aneurysm.

Preclinical model of anterior circulation intracranial stenting.

Background: Preclinical testing of intracranial stents is currently performed in the peripheral circulation, and rarely in the basilar artery of the dog.

Objective: To test the feasibility of intracranial stenting in the middle cerebral artery (MCA) of the dog and explore the use of MRI to detect thromboembolic complications.

Methods: Six purpose-bred cross-hound dogs were used for proof-of-concept stenting of both MCAs in each animal.

High-frequency optical coherence tomography predictors of aneurysm occlusion following flow diverter treatment in a preclinical model.

Background: High-frequency optical coherence tomography (HF-OCT) is an intravascular imaging method that allows for volumetric imaging of flow diverters in vivo.

Objective: To examine the hypothesis that a threshold for both volume and area of communicating malapposition can be predictive of early aneurysm occlusion.

Methods: Fifty-two rabbits underwent elastase aneurysm formation, followed by treatment with a flow diverter.

Transvascular in vivo microscopy of the subarachnoid space.

Background: The micro-architectonics of the subarachnoid space (SAS) remain partially understood and largely ignored, likely the result of the inability to image these structures in vivo. We explored transvascular imaging with high-frequency optical coherence tomography (HF-OCT) to interrogate the SAS.

Methods: In vivo HF-OCT was performed in 10 dogs in both the posterior and anterior cerebral circulations.

Biophysical targeting of high-risk cerebral aneurysms.

Localized delivery of diagnostic/therapeutic agents to cerebral aneurysms, lesions in brain arteries, may offer a new treatment paradigm. Since aneurysm rupture leading to subarachnoid hemorrhage is a devastating medical emergency with high mortality, the ability to noninvasively diagnose high-risk aneurysms is of paramount importance. Moreover, treatment of unruptured aneurysms with invasive surgery or minimally invasive neurointerventional surgery poses relatively high risk and there is presently no medical treatment of aneurysms.

Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide.

Expansions of a GC repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient-derived cells and C9ORF72 BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of GC repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy.

Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep.

siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications.

Preclinical modeling of mechanical thrombectomy.

Mechanical thrombectomy to treat large vessel occlusions (LVO) causing a stroke is one of the most effective treatments in medicine, with a number needed to treat to improve clinical outcomes as low as 2.6. As the name implies, it is a mechanical solution to a blocked artery and modeling these mechanics preclinically for device design, regulatory clearance and high-fidelity physician training made clinical applications possible.

Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis.

Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber's congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients.

Efficacy of beveled tip aspiration catheter in mechanical thrombectomy for acute ischemic stroke.

Background: Direct aspiration thrombectomy techniques use large bore aspiration catheters for mechanical thrombectomy. Several aspiration catheters are now available. We report a bench top exploration of a novel beveled tip catheter and our experience in treating large vessel occlusions (LVOs) using next-generation aspiration catheters.

In situ decellularization of a large animal saccular aneurysm model: sustained inflammation and active aneurysm wall remodeling.

Objective: To investigate in situ decellularization of a large animal model of saccular aneurysm as a strategy for achieving aneurysmal growth and lasting inflammation.

Methods: 18 New Zealand White rabbits were randomized 2:1 to receive endoluminal sodium dodecyl sulfate infusion (SDS, 1% solution, 45 min) following elastase or elastase-only treatment (control). All aneurysms were measured by digital subtraction angiography every 2 weeks.

High-resolution image-guided WEB aneurysm embolization by high-frequency optical coherence tomography.

Background: High-frequency optical coherence tomography (HF-OCT) is an intra-vascular imaging technique capable of assessing device-vessel interactions at spatial resolution approaching 10 µm. We tested the hypothesis that adequately deployed Woven EndoBridge (WEB) devices as visualized by HF-OCT lead to higher aneurysm occlusion rates.

Methods: In a leporine model, elastase-induced aneurysms (n=24) were treated with the WEB device.

A neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy.

Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases.

Longitudinal Monitoring of Flow-Diverting Stent Tissue Coverage After Implant in a Bifurcation Model Using Neurovascular High-Frequency Optical Coherence Tomography.

Background: Tissue growth over covered branches is a leading cause of delayed thrombotic complications after flow-diverter stenting (FDS). Due to insufficient resolution, no imaging modality is clinically available to monitor this phenomenon.

Objective: To evaluate high-frequency optical coherence tomography (HF-OCT), a novel intravascular imaging modality designed for the cerebrovascular anatomy with a resolution approaching 10 microns, to monitor tissue growth over FDS in an arterial bifurcation model.