Computational Model of Direct Injection Into the Spinal Cord Using in Vivo Diffusion Tensor Imaging

2008 ◽  
Author(s):  
Jung Hwan Kim ◽  
Xiaoming Chen ◽  
Garrett W. Astary ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Predictive Models ◽  
Diffusion Tensor ◽  
Direct Injection ◽  
Extracellular Fluid ◽  
Therapeutic Agents ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Flow And Transport

Local infusion, i.e., convection-enhanced delivery (CED), is increasingly being considered as a means to deliver therapeutic agents to nervous tissues. These infusion techniques bypass the blood-brain barrier and overcome problems associated with slow diffusion [1, 2]. Predictive models of extracellular fluid flow and transport during and following CED would be useful in treatment optimization and planning. To account for large infusion volumes, such infusion models should incorporate tissue boundaries and anisotropic tissue properties.

Computational Model of Interstitial Transport in the Rat Brain Using Diffusion Tensor Imaging

2007 ◽  
Author(s):  
Jung Hwan Kim ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Diffusion Tensor ◽  
Therapeutic Potential ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Large Molecules ◽  
Macromolecular Drugs ◽  
Interstitial Transport ◽  
Blood Spinal Cord Barrier ◽  
The Brain

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.

scholarly journals Voxelized Model of Interstitial Transport in the Rat Spinal Cord Following Direct Infusion Into White Matter

2009 ◽  
Vol 131 (7) ◽  
Author(s):  
Jung Hwan Kim ◽  
Garrett W. Astary ◽  
Xiaoming Chen ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Spinal Cord ◽  
Transport Theory ◽  
Diffusion Tensor ◽  
Rat Spinal Cord ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Modeling Approach ◽  
Delivery Technique ◽  
Interstitial Transport

Direct tissue infusion, e.g., convection-enhanced delivery (CED), is a promising local delivery technique for treating diseases of the central nervous system. Predictive models of spatial drug distribution during and following direct tissue infusion are necessary for treatment optimization and planning of surgery. In this study, a 3D interstitial transport modeling approach in which tissue properties and anatomical boundaries are assigned on a voxel-by-voxel basis using tissue alignment data from diffusion tensor imaging (DTI) is presented. The modeling approach is semi-automatic and utilizes porous media transport theory to estimate interstitial transport in isotropic and anisotropic tissue regions. Rat spinal cord studies compared predicted distributions of albumin tracer (for varying DTI resolution) following infusion into the dorsal horn with tracer distributions measured by Wood et al. in a previous study. Tissue distribution volumes compared favorably for small infusion volumes (<4 μl). The presented DTI-based methodology provides a rapid means of estimating interstitial flows and tracer distributions following CED into the spinal cord. Quantification of these transport fields provides an important step toward development of drug-specific transport models of infusion.

scholarly journals Increased extracellular fluid is associated with white matter fiber degeneration in CADASIL: in vivo evidence from diffusion magnetic resonance imaging

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xinfeng Yu ◽  
Xinzhen Yin ◽  
Hui Hong ◽  
Shuyue Wang ◽  
Yeerfan Jiaerken ◽  
...  
Keyword(s):  
White Matter ◽  
Diffusion Tensor ◽  
Small Vessel Disease ◽  
Extracellular Fluid ◽  
Free Water ◽  
Inverse Correlation ◽  
Brain Regions ◽  
Fiber Density ◽  
Four Levels

Abstract Background White matter hyperintensities (WMHs) are one of the hallmarks of cerebral small vessel disease (CSVD), but the pathological mechanisms underlying WMHs remain unclear. Recent studies suggest that extracellular fluid (ECF) is increased in brain regions with WMHs. It has been hypothesized that ECF accumulation may have detrimental effects on white matter microstructure. To test this hypothesis, we used cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a unique CSVD model to investigate the relationships between ECF and fiber microstructural changes in WMHs. Methods Thirty-eight CADASIL patients underwent 3.0 T MRI with multi-model sequences. Parameters of free water (FW) and apparent fiber density (AFD) obtained from diffusion-weighted imaging (b = 0 and 1000 s/mm2) were respectively used to quantify the ECF and fiber density. WMHs were split into four subregions with four levels of FW using quartiles (FWq1 to FWq4) for each participant. We analyzed the relationships between FW and AFD in each subregion of WMHs. Additionally, we tested whether FW of WMHs were associated with other accompanied CSVD imaging markers including lacunes and microbleeds. Results We found an inverse correlation between FW and AFD in WMHs. Subregions of WMHs with high-level of FW (FWq3 and FWq4) were accompanied with decreased AFD and with changes in FW-corrected diffusion tensor imaging parameters. Furthermore, FW was also independently associated with lacunes and microbleeds. Conclusions Our study demonstrated that increased ECF was associated with WM degeneration and the occurrence of lacunes and microbleeds, providing important new insights into the role of ECF in CADASIL pathology. Improving ECF drainage might become a therapeutic strategy in future.

Voxelized 3D Computational Transport Model of Infusions Into the Ventral Hippocampus: Comparison With Experimental Studies

2011 ◽  
Author(s):  
Jung Hwan Kim ◽  
Garrett Astary ◽  
Svetlana Kantorovich ◽  
Thomas H. Mareci ◽  
Paul R. Carney ◽  
...  
Keyword(s):  
Transport Model ◽  
Diffusion Tensor ◽  
Experimental Studies ◽  
Distribution Patterns ◽  
Treatment Method ◽  
Ventral Hippocampus ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Delivery Technique ◽  
Mr Diffusion

Convection enhanced delivery (CED) is a promising local delivery technique for overcoming the blood brain barrier (BBB) and treating diseases of the central nervous system (CNS). For CED, infusate is infused directly into brain tissue and the drug agent is spread through the extracellular space, which is considered highly tortuous porous media. Previous studies have indicated that the infusion of therapeutic agents into the hippocampus is a potential treatment method for epilepsy [1]. In this study, a 3D interstitial transport modeling approach is presented in which tissue properties and anatomical boundaries are assigned on a voxel-by-voxel basis using tissue alignment data from magnetic resonance (MR) diffusion tensor imaging (DTI). The developed model was used to predict CED transport in the ventral hippocampus and predicted tracer distributions were compared with experimental studies. In rat CED experiments, T1-weighted contrast-enhanced MR images were acquired to measure Gd-DTPA albumin tracer distributions after infusion into the ventral hippocampus. Similar infusate distribution patterns were obtained demonstrating the reliability and repeatability of this modeling scheme. Qualitative comparisons between predicted and measured distribution patterns, volumes and shapes were also conducted to determine the model’s proficiency.

Real-time image-guided direct convective perfusion of intrinsic brainstem lesions

2007 ◽  
Vol 107 (1) ◽  
pp. 190-197 ◽  
Author(s):  
Russell R. Lonser ◽  
Katherine E. Warren ◽  
John A. Butman ◽  
Zenaide Quezado ◽  
R. Aaron Robison ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Real Time ◽  
Therapeutic Agents ◽  
Convection Enhanced Delivery ◽  
Similar Treatment ◽  
Brainstem Lesions ◽  
Treatment Paradigm ◽  
Diffuse Pontine Glioma ◽  
And Control

✓Recent preclinical studies have demonstrated that convection-enhanced delivery (CED) can be used to perfuse the brain and brainstem with therapeutic agents while simultaneously tracking their distribution using coinfusion of a surrogate magnetic resonance (MR) imaging tracer. The authors describe a technique for the successful clinical application of this drug delivery and monitoring paradigm to the brainstem. Two patients with progressive intrinsic brainstem lesions (one with Type 2 Gaucher disease and one with a diffuse pontine glioma) were treated with CED of putative therapeutic agents mixed with Gd–diethylenetriamene pentaacetic acid (DTPA). Both patients underwent frameless stereotactic placement of MR imaging–compatible outer guide–inner infusion cannulae. Using intraoperative MR imaging, accurate cannula placement was confirmed and real-time imaging during infusion clearly demonstrated progressive filling of the targeted region with the drug and Gd-DTPA infusate. Neither patient had clinical or imaging evidence of short- or long-term infusate-related toxicity. Using this technique, CED can be used to safely perfuse targeted regions of diseased brainstem with therapeutic agents. Coinfused imaging surrogate tracers can be used to monitor and control the distribution of therapeutic agents in vivo. Patients with a variety of intrinsic brainstem and other central nervous system disorders may benefit from a similar treatment paradigm.

A Computational Model of Direct Infusion Into the Rat Brain: Corpus Callosum and Hippocampus

2009 ◽  
Author(s):  
Jung Hwan Kim ◽  
Garrett W. Astary ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Therapeutic Potential ◽  
Experimental Studies ◽  
Extracellular Fluid ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Macromolecular Drugs ◽  
Delivery Technique ◽  
The Central Nervous System ◽  
Brain And Spinal Cord ◽  
The Brain

Despite the high therapeutic potential of many macromolecular drugs, it has proven difficult to apply them to treatment of cancer and other degenerative diseases of the central nervous system (CNS) due to low capillary permeability and low diffusivity. To overcome these barriers, recent experimental studies have shown local infusion, i.e., convection-enhanced delivery (CED), to be a promising delivery technique in the brain and spinal cord [1–3]. Predictive models of extracellular fluid flow and transport during CED would be useful for treatment optimization and planning.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

In vivo diffusion tensor imaging of the neonatal rat brain development

2013 ◽  
Vol 44 (S 01) ◽  
Author(s):  
M Breu ◽  
D Reisinger ◽  
D Wu ◽  
Y Zhang ◽  
A Fatemi ◽  
...  
Keyword(s):  
Diffusion Tensor Imaging ◽  
Brain Development ◽  
Rat Brain ◽  
Diffusion Tensor ◽  
Neonatal Rat ◽  
Neonatal Rat Brain

Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma

2020 ◽  
Vol 26 (36) ◽  
pp. 4675-4684 ◽  
Author(s):  
Shabierjiang Jiapaer ◽  
Takuya Furuta ◽  
Yu Dong ◽  
Tomohiro Kitabayashi ◽  
Hemragul Sabit ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Drug Screening ◽  
Therapeutic Agent ◽  
Gelatin Zymography ◽  
Therapeutic Agents ◽  
Drug Candidate ◽  
Potential Therapeutic Agent ◽  
Sphere Formation ◽  
Improve Patient

Background: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes. Purpose: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications. Methods: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis. Results: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter. Conclusion: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.

scholarly journals Current Stimuli-Responsive Mesoporous Silica Nanoparticles for Cancer Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 71
Author(s):  
Thashini Moodley ◽  
Moganavelli Singh
Keyword(s):  
Cancer Therapy ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Mesoporous Silica Nanoparticles ◽  
Therapeutic Agents ◽  
Metal Species ◽  
Stimuli Responsive ◽  
Combination Drug ◽  
Incidence And Mortality

With increasing incidence and mortality rates, cancer remains one of the most devastating global non-communicable diseases. Restricted dosages and decreased bioavailability, often results in lower therapeutic outcomes, triggering the development of resistance to conventionally used drug/gene therapeutics. The development of novel therapeutic strategies using multimodal nanotechnology to enhance specificity, increase bioavailability and biostability of therapeutics with favorable outcomes is critical. Gated vectors that respond to endogenous or exogenous stimuli, and promote targeted tumor delivery without prematurely cargo loss are ideal. Mesoporous silica nanoparticles (MSNs) are effective delivery systems for a variety of therapeutic agents in cancer therapy. MSNs possess a rigid framework and large surface area that can incorporate supramolecular constructs and varying metal species that allow for stimuli-responsive controlled release functions. Its high interior loading capacity can incorporate combination drug/gene therapeutic agents, conferring increased bioavailability and biostability of the therapeutic cargo. Significant advances in the engineering of MSNs structural and physiochemical characteristics have since seen the development of nanodevices with promising in vivo potential. In this review, current trends of multimodal MSNs being developed and their use in stimuli-responsive passive and active targeting in cancer therapy will be discussed, focusing on light, redox, pH, and temperature stimuli.

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