scholarly journals Effect of ependymal and pial surfaces on convectionenhanced delivery

2008 ◽  
Vol 109 (3) ◽  
pp. 547-552 ◽  
Author(s):  
Jay Jagannathan ◽  
Stuart Walbridge ◽  
John A. Butman ◽  
Edward H. Oldfield ◽  
Russell R. Lonser
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mr Imaging ◽  
Real Time ◽  
Drug Distribution ◽  
Leading Edge ◽  
Volume Of Distribution ◽  
Clinical Effects ◽  
Convection Enhanced Delivery ◽  
Pia Mater

Object Convection-enhanced delivery (CED) is increasingly used to investigate new treatments for central nervous system disorders. Although the properties of CED are well established in normal gray and white matter central nervous system structures, the effects on drug distribution imposed by ependymal and pial surfaces are not precisely defined. To determine the effect of these anatomical boundaries on CED, the authors infused low MW and high MW tracers for MR imaging near ependymal (periventricular) and pial (pericisternal) surfaces. Methods Five primates underwent CED of Gd-diethylenetriamine pentaacetic acid (Gd-DTPA; MW 590 D) or Gd-bound albumin (Gd-albumin; MW 72,000 D) during serial real-time MR imaging (FLAIR and T1-weighted sequences). Periventricular (caudate) infusions were performed unilaterally in 1 animal (volume of infusion [Vi] 57 μl) and bilaterally in 1 animal with Gd-DTPA (Vi = 40 μl on each side), and bilaterally in 1 animal with Gd-albumin (Vi = 80 μl on each side). Pericisternal infusions were performed in 2 animals with Gd-DTPA (Vi = 190 μl) or with Gd-albumin (Vi = 185 μl) (1 animal each). Clinical effects, MR imaging, and histology were analyzed. Results Large regions of the brain and brainstem were perfused with both tracers. Intraparenchymal distribution was successfully tracked in real time by using T1-weighted MR imaging. During infusion, the volume of distribution (Vd) increased linearly (R2 = 0.98) with periventricular (mean Vd/Vi ratio ± standard deviation; 4.5 ± 0.5) and pericisternal (5.2 ± 0.3) Vi, but did so only until the leading edge of distribution reached the ependymal or pial surfaces, respectively. After the infusate reached either surface, the Vd/Vi decreased significantly (ependyma 2.9 ± 0.8, pia mater 3.6 ± 1.0; p < 0.05) and infusate entry into the ventricular or cisternal cerebrospinal fluid (CSF) was identified on FLAIR but not on T1-weighted MR images. Conclusions Ependymal and pial boundaries are permeable to small and large molecules delivered interstitially by convection. Once infusate reaches these surfaces, a portion enters the adjacent ventricular or cisternal CSF and the tissue Vd/Vi ratio decreases. Although T1-weighted MR imaging is best for tracking intraparenchymal infusate distribution, FLAIR MR imaging is the most sensitive and accurate for detecting entry of Gd-labeled imaging compounds into CSF during CED.

Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles

2007 ◽  
Vol 107 (3) ◽  
pp. 560-567 ◽  
Author(s):  
Nicholas J. Szerlip ◽  
Stuart Walbridge ◽  
Linda Yang ◽  
Paul F. Morrison ◽  
Jeffrey W. Degen ◽  
...  
Keyword(s):  
White Matter ◽  
Mr Imaging ◽  
Real Time ◽  
Volume Of Distribution ◽  
Quantitative Autoradiography ◽  
Clinical Effects ◽  
Convection Enhanced Delivery ◽  
Histological Data ◽  
The Central Nervous System ◽  
The Mean

Object Despite recent evidence showing that convection-enhanced delivery (CED) of viruses and virus-sized particles to the central nervous system (CNS) is possible, little is known about the factors influencing distribution of these vectors with convection. To better define the delivery of viruses and virus-sized particles in the CNS, and to determine optimal parameters for infusion, the authors coinfused adeno-associated virus ([AAV], 24-nm diameter) and/or feru-moxtran-10 (24 nm) by using CED during real-time magnetic resonance (MR) imaging. Methods Sixteen rats underwent intrastriatal convective coinfusion with 4 μl of 35S-AAV capsids (0.5–1.0 × 1014 viral particles/ml) and increasing concentrations (0.1, 0.5, 1, and 5 mg/ml) of a similar sized iron oxide MR imaging agent (ferumoxtran-10). Five nonhuman primates underwent either convective coinfusion of 35S-AAV capsids and 1 mg/ml ferumoxtran-10 (striatum, one animal) or infusion of 1 mg/ml ferumoxtran-10 alone (striatum in two animals; frontal white matter in two). Clinical effects, MR imaging studies, quantitative autoradiography, and histological data were analyzed. Results Real-time, T2-weighted MR imaging of ferumoxtran-10 during infusion revealed a clearly defined hypo-intense region of perfusion. Quantitative autoradiography confirmed that MR imaging of ferumoxtran-10 at a concentration of 1 mg/ml accurately tracked viral capsid distribution in the rat and primate brain (the mean difference in volume of distribution [Vd] was 7 and 15% in rats and primates, respectively). The Vd increased linearly with increasing volume of infusion (Vi) (R2 = 0.98). The mean Vd/Vi ratio was 4.1 ± 0.2 (mean ± standard error of the mean) in gray and 2.3 ± 0.1 in white matter (p < 0.01). The distribution of infusate was homogeneous. Postinfusion MR imaging revealed leakback along the cannula track at infusion rates greater than 1.5 μl/minute in primate gray and white matter. No animal had clinical or histological evidence of toxicity. Conclusions The CED method can be used to deliver AAV capsids and similar sized particles to the CNS safely and effectively over clinically relevant volumes. Moreover, real-time MR imaging of ferumoxtran-10 during infusion reveals that AAV capsids and similar sized particles have different convective delivery properties than smaller proteins and other compounds.

Predictions of Drug Distribution During Infusions Into the Brain Using an Axisymmetric Finite Element Biphasic Model That Includes Backflow

2013 ◽  
Author(s):  
Alejandro Orozco ◽  
Joshua H. Smith ◽  
José Jaime García
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Drug Distribution ◽  
Therapeutic Agents ◽  
Positive Pressure ◽  
Convection Enhanced Delivery ◽  
Biphasic Model ◽  
Limited Efficacy ◽  
The Central Nervous System ◽  
The Brain

Convection-enhanced delivery is a technique to infuse therapeutic agents into the brain under positive pressure for the treatment of disorders of the central nervous system. Recent clinical trials [1] have shown limited efficacy of this procedure, attributed to poor distribution of the infused agent that may be due to backflow, in which the infused fluid preferentially flows along the outside of the catheter toward the surface of the brain.

scholarly journals SCIDOT-02. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN (ONIVYDE) USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS: RESULTS THUS FAR

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi272-vi272
Author(s):  
Karishma Kumar ◽  
Nicholas Butowski ◽  
Manish Aghi ◽  
Krystof Bankiewicz ◽  
John Bringas ◽  
...  
Keyword(s):  
Real Time ◽  
Drug Distribution ◽  
Volume Of Distribution ◽  
High Grade ◽  
Convection Enhanced Delivery ◽  
Post Infusion ◽  
Fluid Convection ◽  
Nanoliposomal Irinotecan ◽  
High Grade Gliomas ◽  
Liposomal Irinotecan

Abstract BACKGROUND Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action. METHODS This is a 3 + 3 single dose escalation trial with 2 cohorts: 20mg/ml and 40mg/ml. Onivyde and GAD were co-infused via the same catheters in a one-time delivery. The total dose was personalized based on the patient’s tumor volume, and ranged from 20–680 mg of Onivyde, given via up to 4 catheters. Tumor diameters were allowed to be 1 – 4 cm, with injection volumes ranging from 2 – 17 mL of infusate. RESULTS 13 patients have been treated on this protocol, all in under 5 hours. There were 9 GBs, 1 gliosarcoma, 2 AAs, and 1 oligoastrocytoma. Utilizing imaging software, we correlated pre-infusion modeling of the drug distribution with post-infusion imaging. A number of technical challenges were overcome by real time monitoring; the total volume of distribution (Vd), and the Vd to volume infused (Vi) ratio for each infusion was ~2. Of all patients, the only notable AE was encephalopathy, which was resolved. CONCLUSIONS Image-guided distribution allows for safe real-time placement and adjustment of CED cannula of Onivyde into patient’s brains. Such methods allow for maximum tumor coverage and warrant further studies with repeat dosing.

scholarly journals Interventional MRI-guided catheter placement and real time drug delivery to the central nervous system

2016 ◽  
Vol 16 (6) ◽  
pp. 635-639 ◽  
Author(s):  
Seunggu J. Han ◽  
Krystof Bankiewicz ◽  
Nicholas A. Butowski ◽  
Paul S. Larson ◽  
Manish K. Aghi
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Nervous System ◽  
Real Time ◽  
Interventional Mri ◽  
Catheter Placement ◽  
The Central Nervous System ◽  
Mri Guided

scholarly journals Convection-enhanced delivery to the central nervous system

2015 ◽  
Vol 122 (3) ◽  
pp. 697-706 ◽  
Author(s):  
Russell R. Lonser ◽  
Malisa Sarntinoranont ◽  
Paul F. Morrison ◽  
Edward H. Oldfield
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Convective Flow ◽  
Clinical Applications ◽  
Systemic Delivery ◽  
Convection Enhanced Delivery ◽  
The Central Nervous System ◽  
Real Time Tracking

Convection-enhanced delivery (CED) is a bulk flow–driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS.

scholarly journals Design and Implementation ofReal-time Electrical Stimulation Artifact Suppression based on STM32

2021 ◽  
Vol 12 (5) ◽  
pp. 424-427
Author(s):  
Sangsoo Park, Hojun Yeom
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Electrical Stimulation ◽  
Embedded System ◽  
Muscle Contraction ◽  
Real Time ◽  
High Performance ◽  
Floating Point ◽  
Time Signal ◽  
Central Nervous System Damage

A biosignal is used as a control signal for electrical stimulation to restore weakened muscle function due to damage to the central nervous system. In patients with central nervous system damage, sufficient muscle contraction does not occur spontaneously. In this case, applying electrical stimulation can cause normal muscle contraction. However, it is necessary to remove the electrical stimulation artifact caused by the electrical stimulation. This paper describes a system design that removes electrical stimulation artifact in real time using a Cortex-M4-based STM32F processor. The STM32F is a very advantageous MCU for such DSPs, especially because it has a built-in floating point operator. Using STM32F's various high-performance peripherals (12-bit parallel ADC and 12-bit DAC, UART, Timer), an optimized embedded system was implemented.In this paper, the simulated and real-time results were compared and evaluated with the designed fir filter. In addition, the performance of the filter was evaluated through frequency analysis. As a result, it was verified that a high-performance 32-bit STM32F with floating point calculator and various peripherals is suitable for real-time signal processing

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