Abstract
Convection-enhanced delivery (CED) has been extensively studied for drug delivery to the brain due to its inherent ability to bypass the blood-brain barrier. Unfortunately, CED has also been shown to inadequately distribute therapeutic agents over a large enough targeted tissue volume to be clinically beneficial. In this study, we explore the use of constant pressure infusions in addition to controlled catheter movement as a means to increase volume dispersed (Vd) in an agarose gel brain tissue phantom. Constant flow rate and constant pressure infusions were conducted with a stationary catheter, a catheter retracting at a rate of 0.25 mm/min, and a catheter retracting at a rate of 0.5 mm/min. The 0.25 mm/min and 0.5 mm/min retracting constant pressure catheters resulted in significantly larger Vd compared to any other group, with a 105% increase and a 155% increase compared to the stationary constant flow rate catheter, respectively. These same constant pressure retracting infusions resulted in a 42% and 45% increase in Vd compared to their constant flow rate counterparts. Using constant pressure infusions coupled with controlled catheter movement appears to have a beneficial effect on Vd in agarose gel. Furthermore, constant pressure infusions reveal the fundamental limitation of flow-driven infusions in both controlled catheter movement protocols as well as in stationary protocols where maximum infusion volume can never be reliably obtained.
Issue Section:
Research Papers
References
1.
Louis
,
D. N.
,
Ohgaki
,
H.
,
Wiestler
,
O. D.
,
Cavenee
,
W. K.
,
Burger
,
P. C.
,
Jouvet
,
A.
,
Scheithauer
,
B. W.
, and
Kleihues
,
P.
, 2007
, “
The 2007 WHO Classification of Tumours of the Central Nervous System
,” Acta Neuropathologica
,
114
(2
), pp. 97
–109
.10.1007/s00401-007-0243-42.
Ostrom
,
Q. T.
,
Patil
,
N.
,
Cioffi
,
G.
,
Waite
,
K.
,
Kruchko
,
C.
, and
Barnholtz-Sloan
,
J. S.
, 2020
, “
CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013–2017
,” Neuro-oncology
,
22
(Suppl_1
), pp. iv1
–iv96
.10.1093/neuonc/noaa2003.
Wallner
,
K. E.
,
Galicich
,
J. H.
,
Krol
,
G.
,
Arbit
,
E.
, and
Malkin
,
M. G.
, 1989
, “
Patterns of Failure Following Treatment of Glioblastoma Mulitform and Anaplastic Astrocytoma
,” Int. J. Radiat. Oncol. Biol. Phys.
,
16
(6
), pp. 1405
–1409
.10.1016/0360-3016(89)90941-34.
Hochberg
,
F. H.
, and
Pruitt
,
A.
, 1980
, “
Assumptions in the Radiotherapy of Glioblastoma
,” Neurology
,
30
(9
), pp. 907
–911
.10.1212/WNL.30.9.9075.
Pardridge
,
W. M.
, 2005
, “
The Blood-Brain Barrier: Bottleneck in Brain Drug Development
,” J Am. Soc. Exp. NeuroTherapeutics
,
2
(1
), pp. 3
–14
.10.1602/neurorx.2.1.36.
Bobo
,
R. H.
,
Laske
,
D. W.
,
Akbasak
,
A.
,
Morrison
,
P. F.
,
Dedrick
,
R. L.
, and
Oldfield
,
E. H.
, 1994
, “
Convection-Enhanced Delivery of Macromolecules in the Brain
,” Proc. Natl. Acad. Sci. USA
,
91
(6
), pp. 2076
–2080
.10.1073/pnas.91.6.20767.
Wang
,
W.
,
Sivakumar
,
W.
,
Torres
,
S.
,
Jhaveri
,
N.
,
Vaikari
,
V. P.
,
Gong
,
A.
,
Howard
,
A.
,
Golden
,
E. B.
,
Louie
,
S. G.
,
Schönthal
,
A. H.
,
Hofman
,
F. M.
, and
Chen
,
T. C.
, 2015
, “
Effects of Convection-Enhanced Delivery of Bevacizumab on Survival of Glioma-Bearing Animals
,” Neurosurgical Focus
,
38
(3
), p. E8
.10.3171/2015.1.FOCUS147438.
Laske
,
D. W.
,
Youle
,
R. J.
, and
Oldfield
,
E. H.
, 1997
, “
Tumor Regression With Regional Distribution of the Targeted Toxin TF-CRM107 in Patients With Malignant Brain Tumors
,” Nat Med
,
3
(12
), pp. 1362
–1368
.10.1038/nm1297-13629.
Rand
,
R. W.
,
Kreitman
,
R. J.
,
Patronas
,
N.
,
Varricchio
,
F.
,
Pastan
,
I.
, and
Puri
,
R. K.
, 2000
, “
Intratumoral Administration of Recombinant Circularly Permuted Interleukin-4-Pseudonomas Exotoxin in Patients With High-Grade Glioma
,” Clin Cancer Res.
,
6
(6
), pp. 2157
–2165
.https://aacrjournals.org/clincancerres/article/6/6/2157/288376/Intratumoral-Administration-of-Recombinant10.
Weber
,
F. W.
,
Floeth
,
F.
,
Asher
,
A.
,
Bucholz
,
R.
,
Berger
,
M. S.
,
Prados
,
M.
,
Chang
,
S.
, and
Bruce
,
J.
, 2003
, “
Local Convection Enhanced Delivery of IL4-Pseudonomas Exotoxin (NBI-3001) for Treatment of Patients With Recurrent Malignant Glioma
,” Acta Neurochir [Supp]
,
88
, pp. 93
–103
.10.1007/978-3-7091-6090-9_1511.
Lidar
,
Z.
,
Mardor
,
Y.
,
Jonas
,
T.
,
Pfeffer
,
R.
,
Faibel
,
M.
,
Nass
,
D.
,
Hadani
,
M.
, and
Ram
,
Z.
, 2004
, “
Convection-Enhanced Delivery of Paclitaxel for the Treatment of Recurrent Malignant Glioma: A Phase I/II Clinical Study
,” J. Neurosurgery
,
100
(3
), pp. 472
–479
.10.3171/jns.2004.100.3.047212.
Kunwar
,
S.
,
Prados
,
M. D.
,
Chang
,
S. M.
,
Berger
,
M. S.
,
Lang
,
F. F.
,
Piepmeier
,
J. M.
, et al., 2007
, “
Direct Intracerebral Delivery of Cintredekin Besudotox (IL13-PE38QQR) in Recurrent Malignant Glioma: A Report by the Cintredekin Besudotox Intraparenchymal Study Group
,” J. Clin. Oncol.
,
25
(7
), pp. 837
–844
.10.1200/JCO.2006.08.111713.
Weaver
,
M.
, and
Laske
,
D. W.
, 2003
, “
Transferrin Receptor Ligand-Targeted Toxin Conjugate (Tf-CRM107) for Therapy of Malignant Gliomas
,” J. Neuro-Oncology
,
65
(1
), pp. 3
–14
.10.1023/A:102624650078814.
Kunwar
,
S.
,
Chang
,
S.
,
Westphal
,
M.
,
Vogelbaum
,
M.
,
Sampson
,
J.
,
Barnett
,
G.
, et al., 2010
, “
Phase III Randomized Trial of CED of IL13-PE38QQR versus Gliadel Wafers for Recurrent Glioblastoma
,” Neuro-oncology
,
12
(8
), pp. 871
–881
.10.1093/neuonc/nop05415.
Sampson
,
J. H.
,
Archer
,
G.
,
Pedain
,
C.
,
Wembacher-Schröder
,
E.
,
Westphal
,
M.
,
Kunwar
,
S.
, et al., 2010
, “
Poor Drug Distribution as a Possible Explanation for the Results of the PRECISE Trial
,” J. Neurosurg.
,
113
(2
), pp. 301
–309
.10.3171/2009.11.JNS09105216.
Vogelbaum
,
M. A.
,
Brewer
,
C.
,
Barnett
,
G. H.
,
Mohammadi
,
A. M.
,
Peereboom
,
D. M.
,
Ahluwalia
,
M. S.
, and
Gao
,
S.
, 2018
, “
First-in-Human Evaluation of the Cleveland Multiport Catheter for Convection-Enhanced Delivery of Topotecan in Recurrent High-Grade Glioma: Results of Pilot Trial 1
,” J. Neurosurg.
, 130(2), pp. 476
–485
.10.3171/2017.10.JNS17184517.
Elenes
,
E. Y.
, and
Rylander
,
C. G.
, 2017
, Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part II: Arborizing Catheter for Convection-Enhanced Delivery in Tissue Phantoms
,
Glioblastoma
,
S.
De Vleeschouwer
, ed.,
Exon Publication
,
Brisbane, Australia
, pp. 359
–372
.18.
Elenes
,
E. Y.
,
Mehta
,
J. N.
,
Hsu
,
F.-C.
,
Whitlow
,
C. T.
,
Debinski
,
W.
,
Rossmeisl
,
J.
,
Tatter
,
S.
, and
Rylander
,
C. G.
, 2021
, “
Convection-Enhanced Arborizing Catheter System Improves Local/Regional Delivery of Infusates Versus a Single-Port Catheter in Ex Vivo Porcine Brain Tissue
,” ASME J. Eng. Sci. Medical Diagnostics Ther.
,
4
(1
), p. 011003.10.1115/1.404893519.
Krauze
,
M. T.
,
Saito
,
R.
,
Noble
,
C.
,
Tamas
,
M.
,
Bringas
,
J.
,
Park
,
J. W.
,
Berger
,
M. S.
, and
Bankiewicz
,
K.
, 2005
, “
Reflux-Free Cannula for Convection-Enhanced High-Speed Delivery of Therapeutic Agents
,” J. Neurosurg.
,
103
(5
), pp. 923
–929
.10.3171/jns.2005.103.5.092320.
Gill
,
T.
,
Barua
,
N. U.
,
Woolley
,
M.
,
Bienemann
,
A. S.
,
Johnson
,
D. E.
,
Sullivan
,
S. O.
,
Murray
,
G.
,
Fennelly
,
C.
,
Lewis
,
O.
,
Irving
,
C.
,
Wyatt
,
M. J.
,
Moore
,
P.
, and
Gill
,
S. S.
, 2013
, “
In Vitro and In Vivo Testing of a Novel Recessed-Step Catheter for Reflux-Free Convection-Enhanced Drug Delivery to the Brain
,” J. Neurosci. Method
,
219
(1
), pp. 1
–9
.10.1016/j.jneumeth.2013.06.00821.
Yin
,
D.
,
Forsayeth
,
J.
, and
Bankiewicz
,
K. S.
, 2010
, “
Optimized Cannula Design and Placement for Convection-Enhanced Delivery in Rat Striatum
,” J. Neurosci. Method
,
187
(1
), pp. 46
–51
.10.1016/j.jneumeth.2009.12.00822.
Chen
,
M. Y.
,
Lonser
,
R. R.
,
Morrison
,
P. F.
,
Governale
,
L. S.
, and
Oldfield
,
E. H.
, 1999
, “
Variables Affecting Convection-Enhanced Delivery to the Striatum: A Systematic Examination of Rate of Infusion, Cannula Size, Infusate Concentration, and Tissue–Cannula Sealing Time
,” J. Neurosurgery
,
90
(2
), pp. 315
–320
.10.3171/jns.1999.90.2.031523.
Mehta
,
J. N.
,
McRoberts
,
G. R.
, and
Rylander
,
C. G.
, 2020
, “
Controlled Catheter Movement Affects Dye Dispersal Volume in Agarose Gel Brain Phantoms
,” Pharmaceutics
,
12
(8
), p. 753
.10.3390/pharmaceutics1208075324.
Kirby
,
B. J.
, 2010
, Micro-and Nanoscale Fluid Mechanics: Transport in Microfluidic Devices
,
Cambridge University Press
, New York.25.
Rosemberg
,
R.
, and
Karnopp
,
D.
, 1983
, Introduction to Physical Systems Dynamics
,
Mac Graw Hill
, New York.26.
Martanto
,
W.
,
Moore
,
J. S.
,
Couse
,
T.
, and
Prausnitz
,
M. R.
, 2006
, “
Mechanism of Fluid Infusion During Microneedle Insertion and Retraction
,” J. Controlled Release
,
112
(3
), pp. 357
–361
.10.1016/j.jconrel.2006.02.01727.
Hood
,
R. L.
,
Ecker
,
T.
,
Andriani
,
R.
,
Robertson
,
J.
,
Rossmeisl
,
J.
, and
Rylander
,
C. G.
, 2013
, “
Augmenting Convection-Enhanced Delivery Through Simultaneous Co-Delivery of Fluids and Laser Energy With a Fiberoptic Microneedle Device
,” Proc. SPIE BiOS 8576, International Society for Optics and Photonics
, p. 85760G
.10.1117/12.200485428.
Andriani
,
R. T.
, 2014
,
Design and Validation of Medical Devices for Photothermally Augmented Treatments
, M.S. thesis
, Master of Science in Mechanical Engineering,
Virginia Tech
,
Blacksburg, VA
.http://hdl.handle.net/10919/5050329.
Raghavan
,
R.
,
Brady
,
M. L.
,
Rodriguez-Ponce
,
M. I.
,
Hartlep
,
A.
,
Pedain
,
C.
, and
Sampson
,
J. H.
, 2006
, “
Convection-Enhanced Delivery of Therapeutics for Brain Disease, and Its Optimization
,” Neurosurg. Focus
,
20
(4
), p. E12
.10.3171/foc.2006.20.4.730.
Lewis
,
O.
,
Woolley
,
M.
,
Johnson
,
D. E.
,
Fletcher
,
J.
,
Fenech
,
J.
,
Pietrzyk
,
M. W.
,
Barua
,
N. U.
,
Bienemann
,
A. S.
,
Singleton
,
W.
,
Evans
,
S. L.
, and
Gill
,
S. S.
, 2018
, “
Maximising Coverage of Brain Structures Using Controlled Reflux, Convection-Enhanced Delivery and the Recessed Step Catheter
,” J. Neuroscience Methods
,
308
, pp. 337
–345
.10.1016/j.jneumeth.2018.08.02931.
Elenes
,
E. Y.
, 2018
, “
An Arborizing, Multiport Catheter for Maximizing Drug Distribution in the Brain Via Convection Enhanced Delivery
,” Doctoral thesis
, The University of Texas at Austin, Austin, TX.http://hdl.handle.net/2152/6926532.
Cook
,
C. D.
, 2019
,
MRI Compatible Robotic Positioning System for an Arborizing Multiport Catheter
, M.S. thesis, Master of Science in Engineering,
The University of Texas at Austin
,
Austin, TX
.33.
Sudhakar
,
V.
,
Naidoo
,
J.
,
Samaranch
,
L.
,
Bringas
,
J. R.
,
Lonser
,
R. R.
,
Fiandaca
,
M. S.
, and
Bankiewicz
,
K. S.
, 2020
, “
Infuse-as-You-Go Convective Delivery to Enhance Coverage of Elongated Brain Targets
,” J. Neurosurg.
,
133
(2
), pp. 530
–8
.10.3171/2019.4.JNS1982634.
Varenika
,
V.
,
Dickinson
,
P.
,
Bringas
,
J.
,
LeCouteur
,
R.
,
Higgins
,
R.
,
Park
,
J.
,
Fiandaca
,
M. S.
,
Berger
,
M.
,
Sampson
,
J.
, and
Bankiewicz
,
K.
, 2008
, “
Detection of Infusate Leakage in the Brain Using Real-Time Imaging of Convection-Enhanced Delivery
,” J. Neurosurg.
,
109
(5
), pp. 874
–880
.10.3171/JNS/2008/109/11/087435.
Chen
,
Z. J.
,
Gillies
,
G. T.
,
Broaddus
,
W. C.
,
Prabhu
,
S. S.
,
Fillmore
,
H.
,
Mitchell
,
R. M.
,
Corwin
,
F. D.
, and
Fatouros
,
P. P.
, 2004
, “
A Realistic Brain Tissue Phantom for Intraparenchymal Infusion Studies
,” J. Neurosurg.
,
101
(2
), pp. 314
–322
.10.3171/jns.2004.101.2.031436.
Prabhu
,
S. S.
,
Broaddus
,
W. C.
,
Gillies
,
G. T.
,
Loudon
,
W. G.
,
Chen
,
Z. J.
, and
Smith
,
B.
, 1998
, “
Distribution of Macromolecular Dyes in Brain Using Positive Pressure Infusion: A Model for Direct Controlled Delivery of Therapeutic Agents
,” Surgincal Neurol.
,
50
(4
), pp. 367
–375
.10.1016/S0090-3019(97)00361-337.
Lam
,
M. F.
,
Foo
,
S. W.
,
Thomas
,
M. G.
, and
Lind
,
C. R.
, 2014
, “
Infusion-Line Pressure as a Real-Time Monitor of Convection-Enhanced Delivery in Pre-Clinical Models
,” J. Neurosci. Methods
,
221
, pp. 127
–131
.10.1016/j.jneumeth.2013.09.01938.
Vandergrift
,
W. A.
,
Patel
,
S. J.
,
Nicholas
,
J. S.
, and
Varma
,
A. K.
, 2006
, “
Convection-Enhanced Delivery of Immunotoxins and Radioisotopes for Treatment of Malignant Gliomas
,” Neurosurg. Focus
,
20
(4
), p. E13
.10.3171/foc.2006.20.4.839.
Morrison
,
P. F.
,
Chen
,
M. Y.
,
Chadwick
,
R. S.
,
Lonser
,
R. R.
, and
Oldfield
,
E. H.
, 1999
, “
Focal Delivery During Direct Infusion to Brain: Role of Flow Rate, Catheter Diameter, and Tissue Mechanics
,” Am. J. Physiol.
,
277
(4
), pp. R1218
–R1229
.10.1152/ajpregu.1999.277.4.R121840.
Raghavan
,
R.
,
Mikaelian
,
S.
,
Brady
,
M.
, and
Chen
,
Z.-J.
, 2010
, “
Fluid Infusions From Catheters Into Elastic Tissue: I. Azimuthally Symmetric Backflow in Homogeneous Media
,” Phys. Med. Biol.
,
55
(1
), pp. 281
–304
.10.1088/0031-9155/55/1/01741.
Orozco
,
G. A.
,
Smith
,
J. H.
, and
Garcia
,
J. J.
, 2014
, “
Backflow Length Predictions During Flow-Controlled Infusions Using a Nonlinear Biphasic Finite Element Model
,” Med. Biol. Eng. Comput.
,
52
(10
), pp. 841
–849
.10.1007/s11517-014-1187-142.
Lueshen
,
E.
,
Tangen
,
K.
,
Mehta
,
A. I.
, and
Linninger
,
A.
, 2017
, “
Backflow-Free Catheters for Efficient and Safe Convection-Enhanced Delivery of Therapeutics
,” Med. Eng. Phys.
,
45
, pp. 15
–24
.10.1016/j.medengphy.2017.02.01843.
Sillay
,
K.
,
Hinchman
,
A.
,
Kumbier
,
L.
,
Schomberg
,
D.
,
Ross
,
C.
,
Kubota
,
K.
,
Brady
,
M.
,
Brodsky
,
E.
,
Miranpuri
,
G.
, and
Raghavan
,
R.
, 2013
, “
Strategies for the Delivery of Multiple Collinear Infusion Clouds in Convection-Enhanced Delivery in the Treatment of Parkinson's Disease
,” Stereotactic Funct. Neurosurgery
,
91
(3
), pp. 153
–161
.10.1159/00034527044.
Chen
,
Z. J.
,
Broaddus
,
W. C.
,
Viswanathan
,
R. R.
,
Raghavan
,
R.
, and
Gillies
,
G. T.
, 2002
, “
Intraparenchymal Drug Delivery Via Positive-Pressure Infusion: Experimental and Modeling Studies of Poroelasticity in Brain Phantom Gels
,” IEEE Trans. Biomed. Eng.
,
49
(2
), pp. 85
–96
.10.1109/10.97934845.
Gillies
,
G.
,
Allison
,
S.
, and
Tissue
,
B.
, 2002
, “
Positive Pressure Infusion of Fluorescent Nanoparticles as a Probe of the Structure of Brain Phantom Gelatins
,” Nanotechnology
,
13
(4
), pp. 484
–486
.10.1088/0957-4484/13/4/30846.
Casanova
,
F.
,
Carney
,
P. R.
, and
Sarntinoranont
,
M.
, 2012
, “
Influence of Needle Insertion Speed on Backflow for Convection-Enhanced Delivery
,” ASME J. Biomech. Eng.
,
134
(4
), p. 041006
.10.1115/1.400640447.
Casanova
,
F.
,
Carney
,
P. R.
, and
Sarntinoranont
,
M.
, 2014
, “
Effect of Needle Insertion Speed on Tissue Injury, Stress, and Backflow Distribution for Convection-Enhanced Delivery in the Rat Brain
,” PLoS One
,
9
(4
), p. e94919
.10.1371/journal.pone.009491948.
Sillay
,
K.
,
Schomberg
,
D.
,
Hinchman
,
A.
,
Kumbier
,
L.
,
Ross
,
C.
,
Kubota
,
K.
,
Brodsky
,
E.
, and
Miranpuri
,
G.
, 2012
, “
Benchmarking the ERG Valve Tip and MRI Interventions Smart Flow Neurocatheter Convection-Enhanced Delivery System's Performance in a Gel Model of the Brain: Employing Infusion Protocols Proposed for Gene Therapy for Parkinson's Disease
,” J. Neural Eng.
,
9
(2
), p. 026009
.10.1088/1741-2560/9/2/026009Copyright © 2022 by ASME
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