Browsing by Author "Hinckley, Jonathan"

Now showing 1 - 7 of 7
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    Biocompatibility of the fiberoptic microneedle device chronically implanted in the rat brain
    Kani, Yukitaka; Hinckley, Jonathan; Robertson, John L.; Mehta, Jason M.; Rylander, Christopher G.; Rossmeisl, John H. Jr. (Elsevier, 2022-03)
    The fiberoptic microneedle device (FMD) is a fused-silica microcatheter capable of co-delivery of fluids and light that has been developed for convection-enhanced delivery and photothermal treatments of glioblastoma. Here we investigate the biocompatibility of FMD fragments chronically implanted in the rat brain in the context of evaluating potential mechanical device failure. Fischer rats underwent craniectomy procedures for sham control (n & nbsp;= 16) or FMD implantation (n = 16) within the brain. Rats were examined daily after implantation, and at 14, 30, 90, and 180 days after implantation were evaluated via computed tomography of the head, hematologic and blood biochemical profiling, and necropsy examinations. Clinical signs of illness and distant implant migration were not observed, and blood analyses were not different between control and FMD implanted groups at any time. Mild inflammatory and astrogliotic reactions localized to the treatment sites within the brain were observed in all groups, more robust in FMD implanted groups compared to controls at days 30 and 90, and decreased in severity over days 90-180 of the study. One rat developed a chronic, superficial surgical site pyogranuloma attributed to the FMD silica implant. Chronically implanted FMD fragments were well tolerated clinically and resulted in anticipated mild, localized brain tissue responses that were comparable with other implanted biomaterials in the brain.
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    Burst sine wave electroporation (B-SWE) for expansive blood–brain barrier disruption and controlled non-thermal tissue ablation for neurological disease
    Campelo, Sabrina N.; Salameh, Zaid S.; Arroyo, Julio P.; May, James L.; Altreuter, Sara O.; Hinckley, Jonathan; Davalos, Rafael V.; Rossmeisl, John H. Jr. (AIP Publishing, 2024-05-30)
    The blood–brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE’s transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond.
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    Canine Snake-Eye Myelopathy: Clinical, Magnetic Resonance Imaging, and Pathologic Findings in Four Cases
    Rossmeisl, John H. Jr.; Cecere, Thomas E.; Kortz, Gregg D.; Geiger, David A.; Shinn, Richard L.; Hinckley, Jonathan; Caudell, David L.; Stahle, Jessica A. (Frontiers, 2019-07-05)
    Intramedullary signal change (ISC) is a non-specific finding that is frequently observed on magnetic resonance imaging (MRI) examinations of the canine spinal cord. ISC can represent a variety of primary pathological processes such as neoplasms or myelitides or secondary changes such as edema, cysts, gliosis, or myelomalacia. An unusual phenotype of ISC is the "snake-eye" myelopathy (SEM), which refers to bilaterally symmetric T2 hyperintensities preferentially affecting the ventral horn gray matter on transverse MR images, which resemble a pair of snake's eyes. The pathophysiology of SEM is poorly understood in humans, and this imaging finding may be associated with cervical spondylotic myelopathy, spinal cord ischemia, ossification of the posterior longitudinal ligament, amyotrophic lateral sclerosis, and Hirayama disease. Here we describe four dogs with cervical MRI examinations consistent with an SEM-like phenotype. All dogs initially presented with a central cord syndrome or tetraparesis referable to a C6-T2 neuroanatomic localization, which was attributed to disc-associated spinal cord compression in three cases, while one dog had the SEM-like phenotype with no identifiable etiology. Once the SEM-like phenotype was present on MRI examinations, dogs demonstrated insidious clinical deterioration despite therapeutic interventions. Deterioration was characterized by lower motor neuron weakness and neurogenic muscle atrophy progressing to paralysis in the thoracic limbs, while neurological functions caudal to the level of the SEM-like lesion remained largely preserved for months to years thereafter. Neuropathological features of the SEM-like phenotype include multisegmental cavitations and poliomyelomalacia of laminae VI-IX of the caudal cervical spinal cord, although the lesion evolved into pan-necrosis of gray matter with extension into the adjacent white matter in one case with an 8 years history of progressive disease. Although the pathophysiology of SEM remains unknown, the topographical distribution and appearance of lesions is suggestive of a vascular disorder. As the SEM-like phenotype was uniformly characterized by longitudinally and circumferentially extensive neuronal necrosis, results of this small case series indicate that dogs with clinical signs of central cord syndrome and the SEM-like phenotype involving the cervicothoracic intumescence on MR examinations have a poor prognosis for the preservation or recovery of thoracic limb motor function.
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    High-Frequency Irreversible Electroporation (H-FIRE) Induced Blood-Brain Barrier Disruption Is Mediated by Cytoskeletal Remodeling and Changes in Tight Junction Protein Regulation
    Partridge, Brittanie R.; Kani, Yukitaka; Lorenzo, Melvin F.; Campelo, Sabrina N.; Allen, Irving C.; Hinckley, Jonathan; Hsu, Fang-Chi; Verbridge, Scott S.; Robertson, John L.; Davalos, Rafael V.; Rossmeisl, John H. Jr. (MDPI, 2022-06-11)
    Glioblastoma is the deadliest malignant brain tumor. Its location behind the blood–brain barrier (BBB) presents a therapeutic challenge by preventing effective delivery of most chemotherapeutics. H-FIRE is a novel tumor ablation method that transiently disrupts the BBB through currently unknown mechanisms. We hypothesized that H-FIRE mediated BBB disruption (BBBD) occurs via cytoskeletal remodeling and alterations in tight junction (TJ) protein regulation. Intracranial H-FIRE was delivered to Fischer rats prior to sacrifice at 1-, 24-, 48-, 72-, and 96 h post-treatment. Cytoskeletal proteins and native and ubiquitinated TJ proteins (TJP) were evaluated using immunoprecipitation, Western blotting, and gene-expression arrays on treated and sham control brain lysates. Cytoskeletal and TJ protein expression were further evaluated with immunofluorescent microscopy. A decrease in the F/G-actin ratio, decreased TJP concentrations, and increased ubiquitination of TJP were observed 1–48 h post-H-FIRE compared to sham controls. By 72–96 h, cytoskeletal and TJP expression recovered to pretreatment levels, temporally corresponding with increased claudin-5 and zonula occludens-1 gene expression. Ingenuity pathway analysis revealed significant dysregulation of claudin genes, centered around claudin-6 in H-FIRE treated rats. In conclusion, H-FIRE is capable of permeating the BBB in a spatiotemporal manner via cytoskeletal-mediated TJP modulation. This minimally invasive technology presents with applications for localized and long-lived enhanced intracranial drug delivery.
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    An Investigation for Large Volume, Focal Blood-Brain Barrier Disruption with High-Frequency Pulsed Electric Fields
    Lorenzo, Melvin F.; Campelo, Sabrina N.; Arroyo, Julio P.; Aycock, Kenneth N.; Hinckley, Jonathan; Arena, Christopher B.; Rossmeisl, John H. Jr.; Davalos, Rafael V. (MDPI, 2021-12-20)
    The treatment of CNS disorders suffers from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). Herein, we investigated high-frequency pulsed electric field (HF-PEF) therapy of various pulse widths and interphase delays for BBB disruption while selectively minimizing cell ablation. Eighteen male Fisher rats underwent craniectomy procedures and two blunt-tipped electrodes were advanced into the brain for pulsing. BBB disruption was verified with contrast T1W MRI and pathologically with Evans blue dye. High-frequency irreversible electroporation cell death of healthy rodent astrocytes was investigated in vitro using a collagen hydrogel tissue mimic. Numerical analysis was conducted to determine the electric fields in which BBB disruption and cell ablation occur. Differences between the BBB disruption and ablation thresholds for each waveform are as follows: 2-2-2 μs (1028 V/cm), 5-2-5 μs (721 V/cm), 10-1-10 μs (547 V/cm), 2-5-2 μs (1043 V/cm), and 5-5-5 μs (751 V/cm). These data suggest that HF-PEFs can be fine-tuned to modulate the extent of cell death while maximizing peri-ablative BBB disruption. Furthermore, numerical modeling elucidated the diffuse field gradients of a single-needle grounding pad configuration to favor large-volume BBB disruption, while the monopolar probe configuration is more amenable to ablation and reversible electroporation effects.
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    Phase I trial of convection-enhanced delivery of IL13RA2 and EPHA2 receptor targeted cytotoxins in dogs with spontaneous intracranial gliomas
    Rossmeisl, John H. Jr.; Herpai, Denise; Quigley, Mindy; Cecere, Thomas E.; Robertson, John L.; D'Agostino, Ralph B.; Hinckley, Jonathan; Tatter, Stephen B.; Dickinson, Peter J.; Debinski, Waldemar (2021-03)
    Background. The interleukin-13 receptor alpha 2 (IL13RA2) and ephrin type A receptor 2 (EPHA2) are attractive therapeutic targets, being expressed in similar to 90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection-enhanced delivery (CED) method. In this study, IL-13 mutant and ephrin A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy. Methods. In this phase I, 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI monitoring. The primary endpoint was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas. Results. Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40-94%). Cytotoxins were well tolerated over a dose range of 0.012-1.278 mu g/mL delivered to the target volume (median, 0.099 mu g/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 mu g/mL. Conclusions. This study provides preclinical data fundamental to the translation of this multireceptor targeted therapeutic approach to the human clinic.
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    Temporal Characterization of Blood–Brain Barrier Disruption with High-Frequency Electroporation
    Lorenzo, Melvin F.; Thomas, Sean C.; Kani, Yukitaka; Hinckley, Jonathan; Lee, Matthew; Adler, Joy; Verbridge, Scott S.; Hsu, Fang-Chi; Robertson, John L.; Davalos, Rafael V.; Rossmeisl, John H. Jr. (MDPI, 2019-11-23)
    Treatment of intracranial disorders suffers from the inability to accumulate therapeutic drug concentrations due to protection from the blood–brain barrier (BBB). Electroporation-based therapies have demonstrated the capability of permeating the BBB, but knowledge of the longevity of BBB disruption (BBBD) is limited. In this study, we quantify the temporal, high-frequency electroporation (HFE)-mediated BBBD in an in vivo healthy rat brain model. 40 male Fisher rats underwent HFE treatment; two blunt tipped monopolar electrodes were advanced into the brain and 200 bursts of HFE were delivered at a voltage-to-distance ratio of 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye) at time points of 1, 24, 48, 72, and 96 h after HFE. Contrast enhanced T1W scans demonstrated BBBD for 1 to 72 h after HFE but intact BBB at 96 h. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated that brief BBBD was induced with low magnitude electric fields, and BBBD duration increased with field strength. These data suggest the spatiotemporal characteristics of HFE-mediated BBBD may be modulated with the locally applied electric field.