U.S. patent application number 13/563787 was filed with the patent office on 2013-02-07 for multidirectional microfluidic drug delivery devices with conformable balloons.
This patent application is currently assigned to ALCYONE LIFESCIENCES, INC.. The applicant listed for this patent is PJ Anand. Invention is credited to PJ Anand.
Application Number | 20130035660 13/563787 |
Document ID | / |
Family ID | 47627379 |
Filed Date | 2013-02-07 |
United States Patent
Application |
20130035660 |
Kind Code |
A1 |
Anand; PJ |
February 7, 2013 |
MULTIDIRECTIONAL MICROFLUIDIC DRUG DELIVERY DEVICES WITH
CONFORMABLE BALLOONS
Abstract
The methods, systems, and devices disclosed herein generally
involve convection-enhanced delivery of drugs to a target region
within a patient. Microfluidic catheter devices are disclosed that
are particularly suitable for targeted delivery of drugs via
convection, including devices capable of multi-directional drug
delivery, devices that control fluid pressure and velocity using
the venturi effect, and devices that include conformable balloons.
Methods of treating various diseases using such devices are also
disclosed, including methods of treating cerebral and spinal
cavernous malformations, cavernomas, and hemangiomas, methods of
treating neurological diseases, methods of treatment using multiple
microfluidic delivery devices, methods of treating hearing
disorders, methods of spinal drug delivery using microfluidic
devices, and methods of delivering stem cells and therapeutics
during fetal surgery. Methods of manufacturing such devices are
also disclosed.
Inventors: |
Anand; PJ; (Ayer,
MA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Anand; PJ |
Ayer |
MA |
US |
|
|
Assignee: |
ALCYONE LIFESCIENCES, INC.
Ayer
MA
|
Family ID: |
47627379 |
Appl. No.: |
13/563787 |
Filed: |
August 1, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61513935 |
Aug 1, 2011 |
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61513939 |
Aug 1, 2011 |
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61513943 |
Aug 1, 2011 |
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61513948 |
Aug 1, 2011 |
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61513952 |
Aug 1, 2011 |
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61513954 |
Aug 1, 2011 |
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61513961 |
Aug 1, 2011 |
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61615939 |
Mar 27, 2012 |
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Current U.S.
Class: |
604/500 ;
604/103.09; 604/173; 604/96.01 |
Current CPC
Class: |
A61M 5/16804 20130101;
A61B 5/14503 20130101; A61M 25/0023 20130101; A61M 25/0026
20130101; A61B 5/4839 20130101; A61M 2205/50 20130101; A61B 5/036
20130101; A61M 5/172 20130101; A61M 2025/0042 20130101 |
Class at
Publication: |
604/500 ;
604/173; 604/96.01; 604/103.09 |
International
Class: |
A61M 25/14 20060101
A61M025/14; A61M 25/10 20060101 A61M025/10 |
Claims
1. A microfluidic convection-enhanced-delivery (CED) device,
comprising: an insertion support scaffold having a proximal end and
a distal end; a shank coupled to the support scaffold; a first
fluid delivery conduit extending longitudinally through the shank
having an inlet port and at least one outlet port; a second fluid
delivery conduit extending longitudinally through the shank having
an inlet port and at least one outlet port; wherein the at least
one outlet port of the second fluid delivery conduit is spaced
longitudinally a distance apart from the at least one outlet port
of the first fluid delivery conduit.
2. The device of claim 1, wherein the at least one outlet port of
the second fluid delivery conduit is disposed closer to the distal
end of the shank than the at least one outlet port of the first
fluid delivery conduit.
3. The device of claim 1, wherein the scaffold has a width in the
range of about 0.02 .mu.m to about 2000 .mu.m.
4. The device of claim 1, wherein the scaffold is rigid.
5. The device of claim 1, wherein the scaffold is semi-rigid.
6. The device of claim 1, wherein the scaffold is fully
degradable.
7. The device of claim 1, wherein the first and second fluid
delivery conduits each has a diameter in the range of about 0.02
.mu.m to about 500 .mu.m.
8. The device of claim 1, further comprising an inflatable member
coupled to the shank, an interior of the inflatable member being in
fluid communication with the first fluid delivery conduit via the
at least one outlet port of the first fluid delivery conduit.
9. The device of claim 8, wherein the inflatable member comprises a
reinforced conformable balloon.
10. The device of claim 8, wherein the inflatable member has at
least a deflated configuration in which it occupies a first volume
and an inflated configuration in which it occupies a second volume
that is greater than the first volume.
11. The device of claim 1, wherein the device is MRI and
stereotactic surgery compatible.
12. The device of claim 1, further comprising at least one
radiopaque marker.
13. The device of claim 1, further comprising a microsensor
embedded in at least one of the first and second fluid delivery
conduits.
14. A method of delivering a drug to a cavernous malformation
within a patient, comprising: implanting a microfluidic
convection-enhanced-delivery (CED) probe into the cavernous
malformation, the probe comprising an insertion scaffold and at
least one fluid delivery conduit; and delivering fluid comprising
the drug under positive pressure through the at least one fluid
delivery conduit and into the cavernous malformation.
15. The method of claim 14, wherein the drug comprises an
antiangiogenesis compound.
16. The method of claim 15, wherein the antiangiogenesis compound
is selected from the group consisting of celecoxib, bortezomib,
interferon, and rapamycin.
17. The method of claim 14, wherein the drug comprises a plurality
of antiangiogenesis compounds.
18. The method of claim 14, wherein the drug comprises
nanoparticles encapsulated with therapeutic molecules or
antiangiogenesis compounds.
19. The method of claim 14, wherein the at least one fluid delivery
conduit comprises a first fluid delivery conduit having an outlet
port formed therein and a second fluid delivery conduit having an
outlet port formed therein.
20. The method of claim 19, wherein the probe is implanted such
that the outlet port of the first fluid delivery conduit is
disposed at the surface of the cavernous malformation and the
outlet port of the second fluid delivery conduit is disposed within
the core of the cavernous malformation.
21. The method of claim 20, further comprising delivering the fluid
under positive pressure to the surface of the cavernous
malformation via the first fluid delivery conduit and to the core
of the cavernous malformation via the second fluid delivery
conduit.
22. The method of claim 19, wherein the probe is implanted such
that the outlet port of the first fluid delivery conduit is
disposed within the core of the cavernous malformation and the
outlet port of the second fluid delivery conduit is disposed within
the core of the cavernous malformation.
23. The method of claim 22, further comprising delivering the fluid
under positive pressure to the core of the cavernous malformation
via the second fluid delivery conduit and then inflating a balloon
in fluid communication with the outlet port of the first fluid
delivery conduit to apply pressure to the fluid and force it into
the surrounding cavernous malformation.
24. The method of claim 23, wherein the drug includes a hydrogel or
other substance having adhesive properties.
25. The method of claim 14, wherein the cavernous malformation is
formed in the central nervous system of the patient.
26. The method of claim 14, wherein the drug is formulated to
tamponade and/or completely coat the cavernous malformation.
27. The method of claim 14, wherein the probe comprises a balloon
at the distal end operable to compress the fluid into the cavernous
malformation.
28. The method of claim 14, further comprising adjusting delivery
of the fluid based on feedback from at least one microsensor
embedded in the probe.
29. A method of delivering a therapeutic agent to a patient,
comprising: advancing a microfluidic convection-enhanced-delivery
(CED) device into a target region of the patient, the CED device
comprising: an insertion support scaffold having a proximal end and
a distal end; a shank coupled to the support scaffold; a first
fluid delivery conduit extending longitudinally through the shank
having an inlet port and at least one outlet port; a second fluid
delivery conduit extending longitudinally through the shank having
an inlet port and at least one outlet port, the at least one outlet
port of the second fluid delivery conduit being spaced
longitudinally a distance apart from the at least one outlet port
of the first fluid delivery conduit; supplying a fluid comprising
the therapeutic agent under positive pressure to at least one of
the first and second fluid delivery conduits; and ejecting the
fluid from at least one of the first and second fluid delivery
conduits to deliver the fluid to the target region.
30. The method of claim 29, further comprising allowing the
scaffold to degrade and thereby release a corticosteroid
impregnated in the scaffold.
31. The method of claim 29, wherein the method is used to treat at
least one condition selected from central-nervous-system (CNS)
neoplasm, intractable epilepsy, Parkinson's disease, Huntington's
disease, stroke, lysosomal storage disease, chronic brain injury,
Alzheimer's disease, amyotrophic lateral sclerosis, balance
disorders, hearing disorders, and cavernous malformations.
32. The method of claim 29, further comprising inflating an
inflatable member in the target region to augment delivery of the
therapeutic agent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/513,935 filed on Aug. 1, 2011, U.S. Provisional
Application No. 61/513,939 filed on Aug. 1, 2011, U.S. Provisional
Application No. 61/513,943 filed on Aug. 1, 2011, U.S. Provisional
Application No. 61/513,948 filed on Aug. 1, 2011, U.S. Provisional
Application No. 61/513,952 filed on Aug. 1, 2011, U.S. Provisional
Application No. 61/513,954 filed on Aug. 1, 2011, U.S. Provisional
Application No. 61/513,961 filed on Aug. 1, 2011, and U.S.
Provisional Application No. 61/615,939 filed on Mar. 27, 2012,
which are each hereby incorporated by reference in their
entirety.
FIELD
[0002] The present invention relates to methods for treatment of
human and veterinary diseases and devices for delivery of
therapeutics as well as to devices to provide diagnostic data via
aspiration to stratify treatment and trials. In particular, the
present invention relates to microfluidic drug delivery devices and
associated treatment methods.
BACKGROUND
[0003] In convection-enhanced delivery (CED), drugs are infused
locally into tissue through a cannula inserted into the tissue.
Transport of the infused material is dominated by convection, which
enhances drug penetration into a target tissue compared with
diffusion-mediated delivery or systemic delivery.
[0004] CED has emerged as a leading investigational delivery
technique for the treatment of several disorders. For example, one
of the fundamental barriers to treatment of chronic
neuropathological conditions is the Blood-Brain-Barrier (BBB). The
BBB protects the brain by very selectively allowing only molecules
of very small size and that are soluble in fat. Larger molecule
drugs that have the potential to cure patients with neurological
disorders cannot cross the BBB. Direct targeted intraparenchymal
injection and/or via CED can be used to bypass the blood-brain
barrier by infusing compounds through a needle, cannula, or
microcatheter directly into brain parenchyma or a brain tumor.
Clinical trials using existing devices show mixed results and
suggest that the outcome of the therapy depends strongly on the
extent of penetration and distribution of the drug into the brain,
which is determined by infusion velocity, the relative rates of
convection and elimination during CED, and various properties of
the target tissue.
[0005] To increase the infusion velocity, flexible microcatheter
designs have been constructed to reduce backflow of the
drug-containing fluid between the tissue and needle-shaft
interface. To reduce the elimination rate and thereby extend the
penetration distance, infused compounds have been incorporated into
nanoparticles such as liposomes or polymeric beads, which protect
the compounds during transport. However, backflow of drug during
CED treatment still remains a critical problem in clinical practice
and the transport of nanoparticles through the brain is hindered,
because the size of the nanoparticles is comparable to the size of
a typical "pore" of the extracellular space. In addition, the
poroelastic nature of the brain tissue contributes to backflow or
reflux. Furthermore, it can be difficult to control the spatial
distribution of infused molecules and nanoparticles when tissue
characteristics vary within the treatment region, such as in
heterogeneous tissue and near white matter tracts in the brain.
There is therefore a need for improved CED devices, e.g., CED
devices with increased penetration distance and/or increased
control over the spatial distribution of the infused drug.
SUMMARY
[0006] The methods, systems, and devices disclosed herein generally
involve convection-enhanced delivery of drugs to a target region
within a patient. Microfluidic catheter devices are disclosed that
are particularly suitable for targeted delivery of drugs via
convection, including devices capable of multi-directional drug
delivery and devices that control fluid pressure and velocity using
the venturi effect. Methods of treating various diseases using such
devices are also disclosed, including methods of treating cerebral
and spinal cavernous malformations, cavernomas, and hemangiomas,
methods of treating neurological diseases, methods of treatment
using multiple microfluidic delivery devices, methods of treating
hearing disorders, methods of spinal drug delivery using
microfluidic devices, and methods of delivering stem cells and
therapeutics during fetal surgery. Methods of manufacturing such
devices are also disclosed.
[0007] Microfluidic convection-enhanced-delivery (CED) devices and
methods of use are disclosed wherein the devices have an insertion
support scaffold and a plurality of fluid delivery conduits
extending longitudinally that are oriented to deliver a therapeutic
agent in different directions. The conduits can also be used to
aspirate fluid samples. In some embodiments, the conduits can be
disposed on different side surfaces of the scaffold, e.g.,
circumferentially in a spaced-apart relationship around the side
surface of the scaffold. In other embodiments, each conduit can
also have a plurality of outlet ports spaced-apart from each other
longitudinally and oriented to deliver therapeutic agents in
different directions.
[0008] Methods of treating neurological disorders are disclosed
whereby a microfluidic intraparenchymal delivery, neuro-ventricular
delivery, or convection-enhanced-delivery (CED) probe is implanted
into a brain of a patient (e.g., a human or animal), the probe
comprising a semi-rigid or degradable scaffold and a fluid delivery
conduit; and a fluid comprising at least one therapeutic agent
under positive pressure is delivered through the conduit and into
the brain. In various embodiments, the therapeutic agent can be a
chemotherapeutic agent, an antibody, a nucleic acid construct, an
RNAi agent, an antisense oligonucleotide or a gene therapy vector.
In other embodiments, a cofactor such as a corticosteroid can be
co-administered via the conduit with the therapeutic agent. The
neurological disorders can include, without limitation,
central-nervous-system (CNS) neoplasms, epilepsy, Parkinson's
Disease, movement disorders, Huntington's Disease, ALS, Alzheimer's
Disease, stroke, brain injury, and neurological diseases.
[0009] Methods of delivering a therapeutic agent directly to a
target site within a region of the central nervous system of a
patient are disclosed using a plurality of microfluidic
convection-enhanced-delivery (CED) probes whereby the probes are
positioned in a spaced relationship around the target site such
that one or more fluid outlet ports formed in the probes are
aligned with the target site; and a fluid comprising a therapeutic
agent under positive pressure is supplied through one or more fluid
conduits formed in each of the plurality of probes to deliver the
fluid through the one or more fluid outlet ports and into the
target site. For example, the target site can be a tumor and the
probes are inserted through either a single or multiple openings in
the skull. In another aspect of the invention, the pressure at
which fluid is supplied to each of the plurality of probes can be
adjusted based on feedback from a microsensor disposed within at
least one of the plurality of probes.
[0010] Methods of treating balance or hearing disorders are
disclosed, in which an opening is formed in a skull of a patient to
access a portion of an ear of the patient, a microfluidic
convection-enhanced-delivery (CED) probe is implanted into the
portion of the ear, and a fluid comprising at least one therapeutic
agent is delivered under positive pressure through the conduit and
into the portion of the ear. In one embodiment, the probe can
include a degradable scaffold and a fluid delivery conduit and the
target region for therapy can be the inner ear, the cochlea, the
organ of Corti or the basilar membrane. In another aspect, the
therapeutic agent can be a gene therapy vector, e.g., to deliver a
human atonal gene. The method can further include delivering a
cofactor, such as a corticosteroid, to the portion of the ear to
improve fluid delivery.
[0011] Methods of delivering a therapeutic agent to a target region
within a spinal canal of a patient are disclosed in which a
microfluidic convection-enhanced-delivery (CED) probe is implanted
into a target area, a fluid comprising the therapeutic agent under
positive pressure is delivered through the conduit and into the
target region, and substantially none of the delivered fluid mixes
with cerebrospinal fluid (CSF) of the patient. In one embodiment,
the probe includes a degradable scaffold and a fluid delivery
conduit. In another aspect, the therapeutic agent can include stem
cells for the treatment of ALS.
[0012] Microfluidic convection-enhanced-delivery (CED) devices are
disclosed having a substrate; a conduit layer deposited on the
substrate, the conduit layer defining therein at least one fluid
delivery conduit with at least one fluid outlet port and a flow
restriction formed within the at least one fluid delivery conduit
at or near the outlet, the flow restriction being configured to
adjust a pressure of fluid being directed through the at least one
fluid delivery conduit. In certain embodiments, the flow
restriction includes a constricted region of the at least one fluid
delivery conduit having a cross-sectional area that is less than a
cross-sectional area of a proximally-adjacent portion of the at
least one fluid delivery conduit, and preferably at least about 20%
less than the cross-sectional area of the proximally-adjacent
portion.
[0013] Methods of delivering a therapeutic agent during fetal
surgery are disclosed in which a microfluidic
convection-enhanced-delivery (CED) probe is implanted into a target
region of a fetus or a patient in which the fetus is disposed, the
probe comprising a degradable scaffold and a fluid delivery
conduit. In one embodiment, the method also includes delivering
fluid comprising the therapeutic agent under positive pressure
through the conduit and into the target region. The target region
can be or can include an umbilical cord, an umbilical artery, an
umbilical vein, a placenta, and/or a uterine wall. In one
embodiment, the therapeutic agent comprises stem cells.
[0014] In some embodiments, microfluidic CED devices are disclosed
in which a plurality of fluid delivery conduits are provided having
longitudinally staggered outlet ports. An inflatable member such as
a reinforced conformable balloon can be coupled to and in fluid
communication with one or more of the fluid delivery conduits.
Methods of delivering a drug such as an anti-angiogenesis factor to
a cavernous malformation are also disclosed herein. In some
embodiments, the method can include delivering the drug to the
cavernous malformation using a microfluidic CED device and then
inflating an inflatable member within the cavernous malformation to
compress the drug into the surrounding tissue.
[0015] A cavernous malformation (CCM) is a collection of small
blood vessels (capillaries) in the central nervous system (CNS)
that is enlarged and irregular in structure. In CCM, the walls of
the capillaries are thinner than normal, less elastic, and prone to
leaking. Cavernous malformations can occur anywhere in the body,
but usually only produce symptoms when they are found in the brain
and spinal cord. Some people with CCM--experts estimate 25
percent--will never experience any related medical problems. Others
will have serious symptoms such as seizures (most commonly),
headaches, paralysis, hearing or vision changes, and bleeding in
the brain (cerebral hemorrhage).
[0016] There are no effective cures for CCM. Seizures are usually
treated with antiepileptic drugs. If seizures don't respond to
medication, or there is recurring bleeding in the brain, surgical
removal of the lesion(s) using microsurgical techniques is
sometimes necessary.
[0017] Cavernomas occur sporadically (spontaneously in a
non-inherited manner) in the majority of cases, but in some cases
may demonstrate inheritance (familial; i.e., a positive or strong
family history of cavernous malformations). In familial cases, a
specific chromosome 7 gene abnormality has been demonstrated, and
familial cavernous malformation has been reported to be more common
in Hispanic (especially Mexican-American) persons. In familial
cases, cavernous malformations are more commonly multiple (i.e.,
two or more cavernomas present at the time of diagnosis), and may
also involve the spinal cord.
[0018] Cavernomas may be asymptomatic, or may present with seizures
(60%) or with progressive neurological impairment or "deficits"
(50%). Some can present with hydrocephalus or raised intracranial
pressure (headache, nausea, vomiting, visual disturbance,
sleepiness) depending on their size and location. It is uncommon
for cavernomas to cause sudden catastrophic or devastating
neurological injury, but the progressive brain (or spinal cord)
injury associated with cavernomas may be severely disabling as time
goes on.
[0019] This is due at least in part to repeated bouts of hemorrhage
in the cavernoma. Different cavities of the cavernoma may have
different ages of blood products. The walls are fragile, and the
growth of micro blood vessels into these lesions results in blood
product (hemosiderin) leeching around the cavernoma, and cycles of
cavernoma growth through hemorrhage and re-hemorrhage. The
hemorrhage is rarely a large devastating hemorrhage.
[0020] Antiangiogenic therapy inhibits the growth of new blood
vessels. Because new blood vessel growth plays a critical role in
many disease conditions, including disorders that cause blindness,
arthritis, and cancer, angiogenesis inhibition is a "common
denominator" approach to treating these diseases. Antiangiogenic
drugs exert their beneficial effects in a number of ways: by
disabling the agents that activate and promote cell growth, or by
directly blocking the growing blood vessel cells. Angiogenesis
inhibitory properties have been discovered in more than 300
substances, ranging from molecules produced naturally in animals
and plants, such as green tea extract, to new chemicals synthesized
in the laboratory. A number of medicines already approved by the
U.S. Food and Drug Administration (FDA) have also been found to
possess antiangiogenic properties, including celecoxib (Celebrex),
bortezomib (Velcade), and interferon. Many inhibitors are currently
being tested in clinical trials for a variety of diseases in human
patients, and some in veterinary settings.
[0021] Rapamycin (now called Sirolimus) is a drug used to keep the
body from rejecting organ and bone marrow transplants. It is now
known that Rapamycin blocks certain white blood cells that can
reject foreign tissues and organs (antiangiogenic). It also blocks
a protein that is involved in cell division. It is a type of
antibiotic, a type of immunosuppressant, and a type of
serine/threonine kinase inhibitor.
[0022] In one aspect of at least one embodiment of the invention, a
microfluidic convection-enhanced-delivery (CED) device is provided
that includes an insertion support scaffold having a proximal end
and a distal end and a plurality of fluid delivery conduits
extending longitudinally therethrough, each conduit having an inlet
port and at least one outlet port. The plurality of conduits can be
disposed near the distal end of the scaffold and oriented to
deliver a therapeutic agent in different directions. The plurality
of conduits can be configured to aspirate fluids.
[0023] Each of the plurality of conduits can be coupled to a
respective one of a plurality of side surfaces of the scaffold
and/or the plurality of conduits can be positioned in a spaced
relationship about a continuous circumferential side surface of the
scaffold.
[0024] The at least one outlet port can include a plurality of
outlet ports spaced a distance apart from one another between
proximal and distal ends of each conduit. Each of the plurality of
outlet ports can have an area that is greater than an area of any
outlet port positioned proximally thereto. The plurality of
conduits can be formed from at least one of a parylene composition,
a silastic composition, a polyurethane composition, and a PTFE
composition, and/or can be disposed within a plurality of
corresponding recesses formed in the scaffold.
[0025] The device can also include a fluid reservoir in fluid
communication with the inlet ports of the plurality of conduits and
configured to supply a fluid thereto under positive pressure. The
plurality of conduits can be flexible.
[0026] At least one of the plurality of conduits can include an
embedded microsensor, which can include at least one of an
interrogatable sensor, a pressure sensor, a glutamate sensor, a pH
sensor, a temperature sensor, an ion concentration sensor, a carbon
dioxide sensor, an oxygen sensor, and a lactate sensor.
[0027] The scaffold can be rigid, semi-rigid, and/or degradable,
and the distal end of the scaffold can have an atraumatic shape
configured to penetrate tissue without causing trauma. The scaffold
can be formed from a degradable thermoplastic polymer (e.g., a
degradable thermoplastic polyester and/or a degradable
thermoplastic polycarbonate). In one embodiment, the scaffold is
formed from poly(lactic-co-glycolic acid) (PLGA).
[0028] The scaffold can contain a quantity of a drug, can be coated
with a drug, and/or can be impregnated with at least one of an
antibacterial agent and an anti-inflammatory agent. For example,
the scaffold can be impregnated with a corticosteroid, such as
dexamethasone.
[0029] Each of the plurality of conduits can be in fluid
communication with a respective micro-capillary tube. The scaffold
can include a body and an elongate distal tip, and the device can
further include a nose disposed at an interface between the body
and the distal tip such that the nose encapsulates a distal portion
of the body.
[0030] In another aspect of at least one embodiment of the
invention, a method of delivering a therapeutic agent to a brain of
a patient is provided that includes forming an opening through a
skull of the patient, advancing a scaffold through the opening in
the skull and into the brain, and supplying a fluid comprising the
therapeutic agent under positive pressure to a plurality of fluid
delivery conduits, each of the plurality of conduits being coupled
to a respective side surface of the scaffold. The method also
includes ejecting the fluid from one or more outlet ports formed in
each of the plurality of conduits to deliver the fluid to the brain
in a radial pattern substantially 360 degrees around the
scaffold.
[0031] The method can also include allowing the scaffold to degrade
within the brain and thereby release a corticosteroid impregnated
in the scaffold and/or delivering an enzyme through the plurality
of conduits in unison with the fluid to enhance penetration of the
therapeutic agent into the brain.
[0032] In another aspect of at least one embodiment of the
invention, a method of delivering a therapeutic agent to a patient
is provided. The method can include advancing a scaffold into a
target region of the patient, supplying a fluid comprising the
therapeutic agent under positive pressure to a plurality of fluid
delivery conduits, each of the plurality of conduits being coupled
to a respective side surface of the scaffold, and ejecting the
fluid from one or more outlet ports formed in each of the plurality
of conduits to deliver the fluid to the target region in multiple
directions.
[0033] The method can include allowing the scaffold to degrade and
thereby release a corticosteroid impregnated in the scaffold. The
method can include delivering an enzyme through the plurality of
conduits in unison with the fluid to enhance penetration of the
therapeutic agent into the target region. In some embodiments,
ejecting the fluid can include delivering the fluid to the target
region in a radial pattern substantially 360 degrees around the
scaffold. The method can be used to treat at least one condition
selected from central-nervous-system (CNS) neoplasm, intractable
epilepsy, Parkinson's disease, Huntington's disease, stroke,
lysosomal storage disease, chronic brain injury, Alzheimer's
disease, amyotrophic lateral sclerosis, balance disorders, hearing
disorders, and cavernous malformations.
[0034] In another aspect of at least one embodiment of the
invention, a method of treating central-nervous-system (CNS)
neoplasm is provided that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising at least one therapeutic
agent under positive pressure through the conduit and into the
brain.
[0035] The therapeutic agent can include at least one of an
antibody (e.g., an anti-epidermal growth factor (EGF) receptor
monoclonal antibody) and a nucleic acid construct (e.g., a
ribonucleic acid interference (RNAi) agent, an antisense
oligonucleotide, a viral vector, an adenovirus, and/or an
adeno-associated viral vector). The method can also include
delivering a cofactor to the brain to improve fluid delivery. The
cofactor can include at least one of a corticosteroid impregnated
in the scaffold, a corticosteroid coated onto the scaffold, and a
propagation enhancing enzyme.
[0036] In another aspect of at least one embodiment of the
invention, a method of treating intractable epilepsy is provided
that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising an anti-convulsive agent
under positive pressure through the conduit and into the brain.
[0037] In another aspect of at least one embodiment of the
invention, a method of treating Parkinson's disease is provided
that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising a protein under positive
pressure through the conduit and into the brain. The protein can
include glial cell-derived neurotrophic factor (GDNF) or
brain-derived neurotrophic factor (BDNF) or genetic materials.
[0038] In another aspect of at least one embodiment of the
invention, a method of treating Huntington's disease is provided
that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising a nucleic acid construct
under positive pressure through the conduit and into the brain. The
nucleic acid construct can include at least one of a ribonucleic
acid interference (RNAi) agent and an antisense
oligonucleotide.
[0039] In another aspect of at least one embodiment of the
invention, a method of treating stroke is provided that includes
implanting a microfluidic convection-enhanced-delivery (CED) probe
into a brain of a patient, the probe comprising a degradable
scaffold and a fluid delivery conduit, and delivering fluid
comprising a neurotrophin under positive pressure through the
conduit and into the brain.
[0040] In another aspect of at least one embodiment of the
invention, a method of treating lysosomal storage disease is
provided that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising a protein under positive
pressure through the conduit and into the brain. The protein can
include lysosomal enzymes.
[0041] In another aspect of at least one embodiment of the
invention, a method of treating chronic brain injury is provided
that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising a protein under positive
pressure through the conduit and into the brain. The protein can
include at least one of brain-derived neurotrophic factor (BDNF)
and fibroblast growth factor (FGF).
[0042] In another aspect of at least one embodiment of the
invention, a method of treating Alzheimer's disease is provided
that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising at least one of
anti-amyloids and nerve growth factor (NGF), or genes or vectors,
under positive pressure through the conduit and into the brain.
[0043] In another aspect of at least one embodiment of the
invention, a method of treating amyotrophic lateral sclerosis is
provided that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a brain of a patient,
the probe comprising a degradable scaffold and a fluid delivery
conduit, and delivering fluid comprising a protein under positive
pressure through the conduit and into the brain. The protein can
include at least one of brain-derived neurotrophic factor (BDNF)
and ciliary neurotrophic factor (CNTF).
[0044] In another aspect of at least one embodiment of the
invention, a method of delivering a therapeutic agent to a target
region within a spinal canal of a patient is provided that includes
implanting a microfluidic convection-enhanced-delivery (CED) probe
into the target area, the probe comprising a degradable scaffold
and a fluid delivery conduit, and delivering fluid comprising the
therapeutic agent under positive pressure through the conduit and
into the target region. In one embodiment, substantially none of
the fluid mixes with cerebrospinal fluid (CSF) of the patient. The
therapeutic agent can include stem cells for the treatment of
ALS
[0045] In another aspect of at least one embodiment of the
invention, a method of delivering a therapeutic agent to a target
site within a brain of a patient using a plurality of microfluidic
convection-enhanced-delivery (CED) probes is provided. The method
includes positioning the plurality of probes in a spaced
relationship around the target site such that one or more fluid
outlet ports formed in each of the plurality of probes are aligned
with the target site. The method also includes supplying a fluid
comprising the therapeutic agent under positive pressure through
one or more fluid conduits formed in each of the plurality of
probes to deliver the fluid through the one or more fluid outlet
ports and into the target site.
[0046] In one embodiment, the target site can include a tumor. The
plurality of probes can be inserted through a single opening in the
skull or can be inserted through separate openings in the skull.
The method can also include adjusting a respective pressure at
which fluid is supplied to each of the plurality of probes based on
feedback from a microsensor disposed within at least one of the
plurality of probes. The microsensor can include at least one of an
interrogatable sensor, a pressure sensor, a glutamate sensor, a pH
sensor, a temperature sensor, an ion concentration sensor, a carbon
dioxide sensor, an oxygen sensor, and a lactate sensor.
[0047] In another aspect of at least one embodiment of the
invention, a microfluidic convection-enhanced-delivery (CED) device
is provided that includes a substrate, a conduit layer deposited on
the substrate, the conduit layer having formed therein at least one
fluid delivery conduit having a proximal end, a distal end, a fluid
inlet port, and at least one fluid outlet port, and a flow
restriction formed within the at least one fluid delivery conduit
at or near the distal end thereof, the flow restriction being
configured to adjust a pressure of fluid being directed through the
at least one fluid delivery conduit.
[0048] The device can also include an insertion support scaffold to
which the substrate is coupled. The substrate can be formed from
silicon and the conduit layer can be formed from parylene. In one
embodiment, the flow restriction includes a constricted region of
the at least one fluid delivery conduit having a cross-sectional
area that is less than a cross-sectional area of a
proximally-adjacent portion of the at least one fluid delivery
conduit.
[0049] The cross-sectional area of the constricted region can be
approximately 20% less, approximately 30% less, or approximately
40% less than the cross-sectional area of the proximally-adjacent
portion.
[0050] In one embodiment, the proximally-adjacent portion has a
height between about 1 micron and about 50 microns and the
constricted region has a height between about 1 micron and about 25
microns. In another embodiment, the proximally-adjacent portion has
a width between about 10 microns and about 100 microns and the
constricted region has a width between about 5 microns and about 50
microns.
[0051] The at least one fluid outlet port can include a plurality
of outlet ports spaced a distance apart from one another between
proximal and distal ends of the at least one fluid delivery
conduit. Each of the plurality of outlet ports can have an area
that is greater than an area of any outlet port positioned
proximally thereto. The at least one fluid delivery conduit can be
formed from at least one of a parylene composition, a silastic
composition, a polyurethane composition, and a PTFE composition.
The device can also include a fluid reservoir in fluid
communication with the fluid inlet ports of the at least one fluid
delivery conduit and configured to supply a fluid thereto under
positive pressure. The at least one fluid delivery conduit can
include an embedded microsensor. The embedded microsensor can
include at least one of an interrogatable sensor, a pressure
sensor, a glutamate sensor, a pH sensor, a temperature sensor, an
ion concentration sensor, a carbon dioxide sensor, an oxygen
sensor, and a lactate sensor. The at least one fluid delivery
conduit can be configured to aspirate fluids.
[0052] In another aspect of at least one embodiment of the
invention, a method of delivering a therapeutic agent to a patient
is provided. The method can include advancing a substrate to a
target region of the patient, the substrate having at least one
fluid delivery conduit, the at least one fluid delivery conduit
including a flow restriction formed at or near a distal end thereof
configured to adjust a pressure of fluid being directed through the
at least one fluid delivery conduit. The method can also include
supplying a fluid comprising the therapeutic agent under positive
pressure to the at least one fluid delivery conduit. The method can
also include ejecting the fluid from one or more outlet ports
formed in the at least one fluid delivery conduit to deliver the
fluid to the target region. The method can also include delivering
an enzyme through the at least one fluid delivery conduit in unison
with the fluid to enhance penetration of the therapeutic agent into
the target region. In some embodiments, the method can be used to
treat at least one condition selected from central-nervous-system
(CNS) neoplasm, intractable epilepsy, Parkinson's disease,
Huntington's disease, stroke, lysosomal storage disease, chronic
brain injury, Alzheimer's disease, amyotrophic lateral sclerosis,
balance disorders, hearing disorders, and cavernous
malformations.
[0053] In another aspect of at least one embodiment of the
invention, a method of treating balance or hearing disorders is
provided that includes forming an opening in a skull of a patient
to access a portion of an ear of the patient and implanting a
microfluidic convection-enhanced-delivery (CED) probe into the
portion of the ear, the probe comprising a degradable scaffold and
a fluid delivery conduit. The method also includes delivering fluid
comprising at least one therapeutic agent under positive pressure
through the conduit and into the portion of the ear.
[0054] The portion of the ear can include any one or more of an
inner ear, a cochlea, an organ of Corti, and a basilar membrane.
The therapeutic agent can include human atonal gene. In one
embodiment, the method also includes delivering a cofactor to the
portion of the ear to improve fluid delivery. The cofactor can
include at least one of a corticosteroid impregnated in the
scaffold, a corticosteroid coated onto the scaffold, and a
propagation enhancing enzyme. In one embodiment, the method also
includes allowing the scaffold to degrade within the portion of the
ear and thereby release a corticosteroid impregnated in the
scaffold.
[0055] In another aspect of at least one embodiment of the
invention, a method of delivering a therapeutic agent during fetal
surgery is provided that includes implanting a microfluidic
convection-enhanced-delivery (CED) probe into a target region of a
fetus or a patient in which the fetus is disposed, the probe
comprising a degradable scaffold and a fluid delivery conduit. The
method also includes delivering fluid comprising the therapeutic
agent under positive pressure through the conduit and into the
target region.
[0056] The target region can be or can include an umbilical cord,
an umbilical artery, an umbilical vein, a placenta, and/or a
uterine wall. In one embodiment, the therapeutic agent comprises
stem cells.
[0057] In another aspect of at least one embodiment of the
invention, a microfluidic convection-enhanced-delivery (CED) device
is provided that includes an insertion support scaffold having a
proximal end and a distal end, a shank coupled to the support
scaffold, a first fluid delivery conduit extending longitudinally
through the shank having an inlet port and at least one outlet
port, and a second fluid delivery conduit extending longitudinally
through the shank having an inlet port and at least one outlet
port. The at least one outlet port of the second fluid delivery
conduit is spaced longitudinally a distance apart from the at least
one outlet port of the first fluid delivery conduit.
[0058] In some embodiments, the at least one outlet port of the
second fluid delivery conduit is disposed closer to the distal end
of the shank than the at least one outlet port of the first fluid
delivery conduit. The scaffold can have a width in the range of
about 0.02 .mu.m to about 2000 .mu.m and/or can be rigid,
semi-rigid, and/or partially or fully degradable. The first and
second fluid delivery conduits can each have a diameter in the
range of about 0.02 .mu.m to about 500 .mu.m.
[0059] In some embodiments, the device can include an inflatable
member coupled to the shank, an interior of the inflatable member
being in fluid communication with the first fluid delivery conduit
via the at least one outlet port of the first fluid delivery
conduit. The inflatable member can be or can include a reinforced
conformable balloon. The inflatable member can have at least a
deflated configuration in which it occupies a first volume and an
inflated configuration in which it occupies a second volume that is
greater than the first volume.
[0060] The device can be MRI and stereotactic surgery compatible,
can include at least one radiopaque marker, and/or can include a
microsensor embedded in at least one of the first and second fluid
delivery conduits.
[0061] In another aspect of at least one embodiment of the
invention, a method of delivering a drug to a cavernous
malformation within a patient is provided. The method includes
implanting a microfluidic convection-enhanced-delivery (CED) probe
into the cavernous malformation, the probe comprising an insertion
scaffold and at least one fluid delivery conduit, and delivering
fluid comprising the drug under positive pressure through the at
least one fluid delivery conduit and into the cavernous
malformation.
[0062] In some embodiments, the drug can include one or more
antiangiogenesis compounds, such as celecoxib, bortezomib,
interferon, and/or rapamycin. The drug can include nanoparticles
encapsulated with therapeutic molecules or antiangiogenesis
compounds.
[0063] In some embodiments, the at least one fluid delivery conduit
comprises a first fluid delivery conduit having an outlet port
formed therein and a second fluid delivery conduit having an outlet
port formed therein. The probe can be implanted such that the
outlet port of the first fluid delivery conduit is disposed at the
surface of the cavernous malformation and the outlet port of the
second fluid delivery conduit is disposed within the core of the
cavernous malformation. The method can also include delivering the
fluid under positive pressure to the surface of the cavernous
malformation via the first fluid delivery conduit and to the core
of the cavernous malformation via the second fluid delivery
conduit.
[0064] The probe can be implanted such that the outlet port of the
first fluid delivery conduit is disposed within the core of the
cavernous malformation and the outlet port of the second fluid
delivery conduit is disposed within the core of the cavernous
malformation. The method can also include delivering the fluid
under positive pressure to the core of the cavernous malformation
via the second fluid delivery conduit and then inflating a balloon
in fluid communication with the outlet port of the first fluid
delivery conduit to apply pressure to the fluid and force it into
the surrounding cavernous malformation.
[0065] In some embodiments, the drug can include a hydrogel or
other substance having adhesive properties. The cavernous
malformation can be formed in the central nervous system of the
patient. The drug can be formulated to tamponade and/or completely
coat the cavernous malformation. The probe can include a balloon at
the distal end operable to compress the drug into the cavernous
malformation. The method can include adjusting delivery of the
fluid based on feedback from at least one microsensor embedded in
the probe.
[0066] In another aspect of at least one embodiment of the
invention, a method of delivering a therapeutic agent to a patient
is provided. The method can include advancing a microfluidic
convection-enhanced-delivery (CED) device into a target region of
the patient, the CED device including an insertion support scaffold
having a proximal end and a distal end, a shank coupled to the
support scaffold, a first fluid delivery conduit extending
longitudinally through the shank having an inlet port and at least
one outlet port, and a second fluid delivery conduit extending
longitudinally through the shank having an inlet port and at least
one outlet port, the at least one outlet port of the second fluid
delivery conduit being spaced longitudinally a distance apart from
the at least one outlet port of the first fluid delivery conduit.
The method can also include supplying a fluid comprising the
therapeutic agent under positive pressure to at least one of the
first and second fluid delivery conduits. The method can also
include ejecting the fluid from at least one of the first and
second fluid delivery conduits to deliver the fluid to the target
region. The method can also include inflating an inflatable member
in the target region to augment delivery of the therapeutic
agent.
[0067] In some embodiments, the method can include allowing the
scaffold to degrade and thereby release a corticosteroid
impregnated in the scaffold. The method can be used to treat at
least one condition selected from central-nervous-system (CNS)
neoplasm, intractable epilepsy, Parkinson's disease, Huntington's
disease, stroke, lysosomal storage disease, chronic brain injury,
Alzheimer's disease, amyotrophic lateral sclerosis, balance
disorders, hearing disorders, and cavernous malformations.
[0068] In another aspect of at least one embodiment of the
invention, a method of fabricating a delivery device having at
least one fluid channel is provided. The method can include
depositing an oxide mask on a backside of a silicon wafer,
patterning the oxide mask to define a perimeter of the delivery
device, depositing a polyimide layer on a frontside of the silicon
wafer, depositing sacrificial resist on the polyimide layer in a
shape of the at least one fluid channel, depositing a parylene
layer over the sacrificial resist and the polyimide layer,
depositing an aluminum mask over the parylene layer, and removing
the sacrificial resist using a solvent to form the at least one
fluid channel between the polyimide layer and the parylene
layer.
[0069] In some embodiments, the method can also include coupling a
micro-capillary tube to the delivery device such that the
micro-capillary tube is in fluid communication with the at least
one fluid channel. The method can also include etching a trench
into the backside of the silicon wafer according to the patterned
oxide mask. The method can also include applying an oxide etch stop
to the floor of the trench.
[0070] In another aspect of at least one embodiment of the
invention, a method of fabricating a delivery device having at
least one fluid channel is provided. The method can include etching
a frontside of a silicon wafer to define a perimeter of the
delivery device, applying a polyimide coat to the frontside of the
silicon wafer and to a backside of the silicon wafer, applying
sacrificial resist to the polyimide coat in a shape of the at least
one fluid channel, applying a parylene layer over the sacrificial
resist, depositing an aluminum mask over the parylene layer, and
removing the sacrificial resist using a solvent to form the at
least one fluid channel between the polyimide coat and the parylene
layer.
[0071] In some embodiments, the method can also include coupling a
micro-capillary tube to the delivery device such that the
micro-capillary tube is in fluid communication with the at least
one fluid channel.
[0072] In another aspect of at least one embodiment of the
invention, a microfluidic convection-enhanced-delivery (CED) device
is provided. The device can include a substrate that defines a
body, an elongate distal tip, and first and second proximal legs.
The device can also include a first fluid channel that extends
along the first leg, along the body, and along the distal tip, and
a second fluid channel that extends along the second leg, along the
body, and along the distal tip. The device can also include a first
micro-capillary tube coupled to the first leg portion and in fluid
communication with the first fluid channel, and a second
micro-capillary tube coupled to the second leg portion and in fluid
communication with the second fluid channel. The device can also
include a tubular sheath that encapsulates the first and second
legs and at least a portion of the first and second micro-capillary
tubes.
[0073] In some embodiments, the device can include a nose disposed
at an interface between the distal tip and the body that
encapsulates a distal portion of the body. The nose can be conical
or hemispherical.
[0074] The present invention further provides devices, systems, and
methods as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] The invention will be more fully understood from the
following detailed description taken in conjunction with the
accompanying drawings, in which:
[0076] FIG. 1 is a perspective schematic view of one exemplary
embodiment of a microfabricated CED device;
[0077] FIG. 2A is a perspective schematic view of another exemplary
embodiment of a microfabricated CED device;
[0078] FIG. 2B is a cross-sectional view of the microfabricated CED
device of FIG. 2A;
[0079] FIG. 3A is a perspective schematic view of another exemplary
embodiment of a microfabricated CED device;
[0080] FIG. 3B is a cross-sectional view of the microfabricated CED
device of FIG. 3A;
[0081] FIG. 4 is a schematic diagram of a fluid delivery system
operatively coupled to a microfabricated CED device;
[0082] FIG. 5A is a schematic top view of one exemplary embodiment
of a fluid delivery conduit of a microfabricated CED device;
[0083] FIG. 5B is a schematic top view of another exemplary
embodiment of a fluid delivery conduit of a microfabricated CED
device;
[0084] FIG. 6 is a electron micrograph of another exemplary
embodiment of a microfabricated CED device;
[0085] FIG. 7 is a schematic diagram of a microfabricated CED
device implanted into a brain of a patient;
[0086] FIG. 8 is a perspective view of a microfabricated CED device
coupled to a standard cannula;
[0087] FIG. 9 is a schematic diagram of a microfabricated CED
device implanted into a brain of a patient and an associated fluid
release spatial distribution pattern;
[0088] FIG. 10 is a schematic diagram of a plurality of
microfabricated CED devices positioned to surround a target site
within a brain of a patient;
[0089] FIG. 11 is an electron micrograph of another exemplary
embodiment of a microfabricated CED device;
[0090] FIG. 12 is a schematic diagram of a microfabricated CED
device implanted into a spinal canal of a patient;
[0091] FIG. 13 is a schematic cross-sectional view of a
microfabricated CED device implanted into an inner ear of a
patient;
[0092] FIG. 14 is a schematic side view of a microfabricated CED
device implanted into an inner ear of a patient;
[0093] FIG. 15 is a schematic view of microfabricated CED devices
implanted into various regions of a brain;
[0094] FIG. 16 is a schematic view of a microfabricated CED device
implanted into a target region during fetal surgery;
[0095] FIG. 17A is a schematic view of a microfabricated CED device
having fluid delivery conduits with longitudinally staggered outlet
ports;
[0096] FIG. 17B is a schematic view of a microfabricated CED device
having longitudinally staggered outlet ports and an inflatable
member;
[0097] FIG. 18A is a schematic view of the device of FIG. 17B
inserted into a cavernous malformation;
[0098] FIG. 18B is a schematic view of the device of FIG. 17B with
the inflatable member inflated within the cavernous
malformation;
[0099] FIG. 19 is a flowchart that depicts an exemplary method of
manufacturing a microfabricated CED device;
[0100] FIGS. 20A-20L are cross-sectional views of a CED device at
various stages of the process of FIG. 19;
[0101] FIG. 21A is a scanning electron microscope image of a
microfabricated CED device;
[0102] FIG. 21B is a scanning electron microscope image of the
distal tip of the CED device of FIG. 21A;
[0103] FIG. 22A is a schematic top view of a microfabricated CED
device;
[0104] FIG. 22B is a detail schematic top view of the distal tip of
the CED device of FIG. 22A;
[0105] FIG. 23A is a schematic view of a wafer layout that includes
a plurality of microfabricated CED devices;
[0106] FIG. 23B is a schematic view of the wafer layout of FIG. 23A
repeated a plurality of times on a silicon wafer;
[0107] FIG. 23C is an image of a plurality of microfabricated CED
devices produced using the layout of FIG. 23A;
[0108] FIG. 24A is a microscope image of a silicon substrate formed
during manufacture of a CED device;
[0109] FIG. 24B is another microscope image of the substrate of
FIG. 24A;
[0110] FIG. 24C is another microscope image of the substrate of
FIG. 24A;
[0111] FIG. 25A is a schematic top view of a microfabricated CED
device having an attached catheter portion;
[0112] FIG. 25B is a schematic end view of the device of FIG.
25A;
[0113] FIG. 25C is a schematic top view of the device of FIG. 25A
with a nose portion and catheter body coupled thereto;
[0114] FIG. 25D is a schematic end view of the device of FIG.
25C;
[0115] FIG. 26A is a top view image of an assembled CED device;
[0116] FIG. 26B is a perspective view image of the CED device of
FIG. 26A; and
[0117] FIG. 26C is a top view image of the CED device of FIG. 26A
shown with a reference scale.
DETAILED DESCRIPTION
[0118] Certain exemplary embodiments will now be described to
provide an overall understanding of the principles of the
structure, function, manufacture, and use of the methods, systems,
and devices disclosed herein. One or more examples of these
embodiments are illustrated in the accompanying drawings. Those
skilled in the art will understand that the methods, systems, and
devices specifically described herein and illustrated in the
accompanying drawings are non-limiting exemplary embodiments and
that the scope of the present invention is defined solely by the
claims. The features illustrated or described in connection with
one exemplary embodiment may be combined with the features of other
embodiments. Such modifications and variations are intended to be
included within the scope of the present invention.
[0119] The methods, systems, and devices disclosed herein generally
involve convection-enhanced delivery of drugs to a target region
within a patient. Microfluidic catheter devices are disclosed that
are particularly suitable for targeted delivery of drugs via
convection, including devices capable of multi-directional drug
delivery and devices that control fluid pressure and velocity using
the venturi effect. Methods of treating various diseases using such
devices are also disclosed, including methods of treating cerebral
and spinal cavernous malformations, cavernomas, and hemangiomas,
methods of treating neurological diseases, methods of treatment
using multiple microfluidic delivery devices, methods of treating
hearing disorders, methods of spinal drug delivery using
microfluidic devices, and methods of delivering stem cells and
therapeutics during fetal surgery. Methods of manufacturing such
devices are also disclosed.
[0120] The term "drug" as used herein refers to any functional
agent that can be delivered to a human or animal patient, including
hormones, stem cells, gene therapies, chemicals, compounds, small
and large molecules, dyes, antibodies, viruses, therapeutic agents,
etc. The terms "microfabricated CED device," "microfluidic delivery
device," "CED device," "probe," "microprobe," "catheter," and
"microcatheter" are generally used interchangeably herein.
[0121] Exemplary CED methods and devices are disclosed in U.S.
Publication No. 2010/0098767, filed on Jul. 31, 2009, the entire
contents of which are incorporated herein by reference.
[0122] FIG. 1 illustrates one exemplary embodiment of a
microfabricated CED device 10. The device 10 generally includes a
support scaffold 12 to which one or more shank portions 14 are
coupled. The shank portions 14 can include one of more fluid
delivery conduits 16 formed thereon or therein.
[0123] The illustrated support scaffold 12 is generally formed by
an elongate body having a proximal end 18, a distal end 20, and a
longitudinal axis 22 extending therebetween. A cross-section of the
illustrated scaffold 12 taken in a plane normal to the longitudinal
axis 22 has a substantially rectangular shape, however any of a
variety of cross-sectional shapes can be used, including circular,
hexagonal, and elliptical. The scaffold 12 can provide structural
rigidity to the device 10 to facilitate insertion into target
tissue. To assist with tissue penetration and navigation, the
distal end 20 of the support scaffold 12 can be tapered, pointed,
and/or sharpened. In the illustrated embodiment, the scaffold 12 is
provided with a rounded atraumatic tip so as to facilitate
insertion through tissue without causing trauma to the tissue.
[0124] The support scaffold 12 can be rigid or semi-rigid and can
be formed from a degradable thermoplastic polymer, for example, a
degradable thermoplastic polyester or a degradable thermoplastic
polycarbonate. In one embodiment, the support scaffold 12 is formed
from poly(lactic-co-glycolic acid) (PLGA) and is configured to
biodegrade within the target tissue. This can advantageously
eliminate the need to remove the support scaffold 12 once the
device 10 is positioned within target tissue, thereby avoiding the
potential to disrupt the positioning of the fluid delivery conduits
16. Any of a variety of other materials can also be used to form
the support scaffold 12, including silicon or various ceramics,
metals, and plastics known in the art.
[0125] The support scaffold 12 can contain or can be impregnated
with a quantity of a drug. Alternatively, or in addition, a surface
of the support scaffold 12 can be coated with a drug. Exemplary
drugs include anti-inflammatory components, drug
permeability-increasing components, delayed-release coatings, and
the like. In one embodiment, the scaffold 12 can be coated or
impregnated with a corticosteroid such as dexamethasone which can
prevent swelling around the injection site and disruptions to the
fluid delivery pattern that can result from such swelling.
[0126] The scaffold 12 can have a width of approximately 100 .mu.m
to approximately 200 .mu.m and can have a length that varies
depending on the target tissue (e.g., depending on the depth at
which the target tissue is situated). In one embodiment, the
scaffold 12 is between 2 cm and 3 cm long.
[0127] The scaffold 12 can also include a recess or shelf portion
24 configured to retain or mate with the shank portion 14 of the
device 10. In addition, as described further below, the scaffold 12
can include multiple recesses or shelf portions for coupling to a
plurality of shank portions 14. In this case, the recesses or shelf
portions can be formed on multiple different surfaces of the
scaffold. A variety of techniques can be used to couple the shank
portion 14 to the support scaffold 12, such as surface tension from
a water drop, adhesives, and/or a biocompatible petroleum
jelly.
[0128] The device 10 can also include one or more shank portions 14
that are matable to the support scaffold 12. The shank portion 14
can be a flexible substrate having one or more fluid delivery
conduits 16 formed therein or thereon. The shank portion 14 can be
formed from any of a variety of materials, such as silicon or
Parylene.
[0129] One or more fluid delivery conduits 16 can be formed in or
on the shank portion 14 of the device. The conduits 16 can extend
along a surface of the shank portion 14 in a direction that is
generally parallel to the longitudinal axis 22 of the scaffold 12,
and can have one or more lateral portions 26 extending in a
direction that forms a non-zero angle with the longitudinal axis
22.
[0130] Each conduit 16 can include a fluid inlet port (not shown in
FIG. 1) and one or more fluid outlet ports 28. The fluid inlet port
can be positioned at a proximal end of the device 10, and can allow
the conduit 16 to be placed in fluid communication with a fluid
reservoir, e.g., via one or more pumps, meters, valves, or other
suitable control devices. Such control devices can be used to
regulate the pressure at which fluid is supplied to the device 10,
or the rate or volume of fluid that is supplied to the device
10.
[0131] Fluid supplied to the conduit 16 though the fluid inlet port
is directed through an inner lumen of the conduit and released
through the one or more fluid outlet ports 28. The fluid outlet
ports 28 can be sized, shaped, and/or positioned to control various
release parameters of the fluid. For example, the fluid outlet
ports 28 can be configured to control the direction in which fluid
is release from the device 10, the distribution of the fluid within
the target tissue, and the velocity or pressure at which the fluid
is released.
[0132] In the illustrated embodiment, the shank portion 14 includes
first and second parylene conduits 16A, 16B extending therethrough.
The conduits 16A, 16B include a longitudinal portion and a
plurality of lateral extensions 26 in which fluid outlet ports 28
are formed. The size of the fluid outlet ports 28 progressively
increases towards the distal end 20 of the device 10, which can
advantageously compensate for pressure loss that occurs along the
length of the device such that fluid is released from each of the
plurality of fluid outlet ports 28 at substantially the same
pressure. The illustrated fluid outlet ports 28 are also shaped to
control the release direction of the fluid. The ports 28A and 28C
open in a side or lateral direction, whereas the ports 28B and 28D
open towards the top of the device 10.
[0133] The device can also include one or more sensors 30 mounted
in or on the shank portion 14 or on the scaffold 12. The sensors 30
can include temperature sensors, pH sensors, pressure sensors,
oxygen sensors, tension sensors, interrogatable sensors, glutamate
sensors, ion concentration sensors, carbon dioxide sensors, lactate
sensors, neurotransmitter sensors, or any of a variety of other
sensor types, and can provide feedback to a control circuit which
can in turn regulate the delivery of fluid through the device 10
based on one or more sensed parameters. One or more electrodes 32
can also be provided in or on the shank portion 14 or the support
scaffold 12, which can be used to deliver electrical energy to
target tissue, e.g., to stimulate the target tissue or to ablate
the target tissue. In one embodiment, electrical energy is
delivered through the electrodes 32 while a drug is simultaneously
delivered through the fluid delivery conduits 16.
[0134] The device 10 can be used for CED of drugs to treat
disorders of the brain, ears, other neural tissue, or other parts
of a human or animal body. When used in the brain, the device 10
can circumvent the blood-brain barrier (BBB) by infusing drugs
under positive pressure directly into tissue. The device 10
provides a number of advantages, such as 1) a smaller
cross-sectional area compared with conventional needles used in
CED; 2) less disturbance to tissue when inserted into the brain
than conventional needles; 3) the elimination of backflow or reflux
along the outside of the inserted part, which in turn, permits
higher rates of drug delivery in the device 10 compared with
conventional needles; 4) minimal or no occlusion of the fluid
delivery conduits 16 during insertion into the brain; 5) multiple
parylene conduits 16 can be fabricated into the silicon shank 14,
each conducting a distinct fluid (drug), which allows simultaneous,
sequential, or programmed delivery of multiple agents; 6) the
device 10 has the potential to serve simultaneously as a drug
delivery system and as a sensor-equipped probe to measure local
tissue characteristics such as, but not limited to, pressure, pH,
ion-specific concentrations, location, and other parameters; and 7)
the device 10 allows for directional control of the drug release
pattern.
[0135] The device 10 can be functionally attached to the distal end
of a long, thin insertion vehicle such as a cannula or a needle in
or on which a fluid attachment could be made to the fluid inlet
ports of the device's fluid delivery conduits 16. This can be
especially advantageous in applications involving penetration of
relatively thick tissue, e.g., insertion through a human skull.
[0136] In addition to delivering a drug-containing fluid, the
device 10 can also be used to deliver enzymes or other materials to
modify tissue permeability and improve drug distribution in the
targeted tissue. For example, penetration of a drug-containing
nanoparticles into brain tissue can be enhanced by enzymatic
digestion of at least one brain extracellular matrix component and
intracranial infusion of the nanoparticle into the brain tissue. In
another embodiment, at least one enzyme can be immobilized to a
surface of the nanoparticle during the step of enzymatic digestion.
The device 10 can provide the ability to deliver enzymatic and/or
other materials that can, e.g., modify the drug delivery site, and
therapeutic materials, in virtually any order, sequencing, and/or
timing without the need to use different delivery devices and the
potential complications involved in doing so.
[0137] The device 10 can also be used to biopsy tissue, for example
by passing a stylet or a grasping tool through one of the conduits
16 to a target site and then withdrawing the stylet or grasping
tool from the target site with a biopsy specimen therein. In some
embodiments, the shank portions 14 or the support scaffold 12 can
have a larger-diameter lumen extending therethrough for biopsy
purposes, with smaller fluid conduits 16 formed on the exterior
thereof.
[0138] FIGS. 2A and 2B illustrate another exemplary embodiment of a
microfabricated CED device 110. The device 110 includes a
rectangular support scaffold 112 with shank portions 114 and
accompanying fluid delivery conduits 116 coupled to each of the
four side surfaces thereof. As shown in the cross-sectional view of
FIG. 2B, the shank portions 114 are disposed within corresponding
recesses 124 formed in the sidewalls of the support scaffold 112.
In an alternative embodiment, the shank portions 114 can be surface
mounted on the scaffold 112. Positioning of shank portions 114 and
fluid delivery conduits 116 on each of the four side surfaces of
the scaffold 112 can further facilitate 360 degree convective flow
of drug-containing fluid from the device 110.
[0139] The structure and function of the device 110 is otherwise
substantially the same as that of the device 10 described above,
and therefore a further description thereof is omitted here for the
sake of brevity.
[0140] FIGS. 3A and 3B illustrate another exemplary embodiment of a
microfabricated CED device 210. The device 210 includes a
cylindrical support scaffold 212 with shank portions 214 and
accompanying fluid delivery conduits 216 coupled in a spaced
relationship about the outer surface of the scaffold 212. As shown
in the cross-sectional view of FIG. 3B, the shank portions 214 are
disposed within corresponding recesses 224 formed in the sidewalls
of the support scaffold 212. In an alternative embodiment, the
shank portions 214 can be surface mounted on the scaffold 212. It
will be appreciated that the flexible nature of the shank portions
214 and the fluid delivery conduits 216 permits them to be curved
or otherwise contoured to match the surface profile of the scaffold
212. Positioning of shank portions 214 and fluid delivery conduits
216 about the outer surface of the scaffold 212 as shown can
further facilitate 360 degree convective flow of drug-containing
fluid from the device.
[0141] The structure and function of the device 210 is otherwise
substantially the same as that of the device 10 described above,
and therefore a further description thereof is omitted here for the
sake of brevity.
[0142] FIG. 4 is a schematic illustration of a drug delivery system
300 that includes a microcatheter CED device 310 which can be any
of the devices 10, 110, 210 described above. The system 300
includes a reservoir 302 of a drug-containing fluid that is coupled
to a pump 304 via a control valve 306. When the control valve is
opened, fluid in the reservoir 302 is supplied under pressure by
the pump 304 to a pressure regulator 308, which can adjust a
pressure at which the fluid is supplied to the catheter 310. The
control valve 306, pump 304, and regulator 308 can be operatively
coupled to a controller 301 which can include a microprocessor and
a memory and can be configured to execute a drug-delivery control
program stored in a non-transitory computer-readable storage
medium. The controller 301 can be configured to open or close the
valve 306, to turn the pump 304 on or off, to change an output
pressure of the pump 304, and/or to adjust a pressure set point of
the regulator 308. The controller 301 can also receive information
indicative of a sensed parameter via a feedback loop that includes
one or more sensors 330 mounted in or on the catheter 310. Thus, in
response to feedback from one or more sensors 330 implanted with
the catheter 310, the controller 301 can start or stop the flow of
fluid to the catheter 310, increase or decrease the pressure at
which fluid is supplied to the catheter 310, etc. In one
embodiment, the catheter 310 includes a pressure sensor 330 that
measures a fluid pressure in the vicinity of the catheter 310 and
the controller 301 is configured to maintain the fluid supply
pressure at a substantially constant level based on feedback from
the pressure sensor 330.
[0143] FIGS. 5A and 5B illustrate an alternative embodiment of a
fluid delivery conduit that can be used with the devices described
herein. In FIG. 5A, the fluid delivery conduit 416 includes first
and second upstream lumens 434, 436 which merge into a single
downstream lumen 438. The inside dimension of the combined lumens
434, 436 decreases gradually at the merge, which can advantageously
increase the velocity of fluid flowing through the downstream lumen
428. In the illustrated embodiment, the cross-sectional area of the
downstream lumen 438 is less than the cross-sectional area of the
first upstream lumen 434 and less than the cross-sectional area of
the second upstream lumen 436, such that a flow restriction is
formed in the delivery conduit 416.
[0144] Preferably, the constricted region formed by the downstream
lumen 438 has a cross-sectional area that is approximately 20% less
than the cross-sectional area of a proximally-adjacent portion of
the delivery conduit 416. More preferably, the constricted region
has a cross-sectional area that is approximately 30% less than the
cross-sectional area of the proximally-adjacent portion of the
delivery conduit. Even more preferably, the constricted region has
a cross-sectional area that is approximately 40% less than the
cross-sectional area of the proximally-adjacent portion of the
delivery conduit.
[0145] In one embodiment, the proximally-adjacent portion has a
height between about 1 micron and about 50 microns and the
constricted region has a height between about 1 micron and about 25
microns. In another embodiment, the proximally-adjacent portion has
a width between about 10 microns and about 100 microns and the
constricted region has a width between about 5 microns and about 50
microns.
[0146] This "step-down advantage" described above provides
additional pressure and velocity control for tailoring the delivery
profile of the device. As shown in FIG. 5B, a plurality of outlet
ports 428 can be disposed in fluid communication with the first and
second upstream lumens 434, 436, and/or in fluid communication with
the downstream lumen 438.
[0147] FIG. 6 is a an electron micrograph of one exemplary
embodiment of a microfabricated CED device 510 having a single
fluid delivery conduit 516 mounted on a single surface of a
degradable scaffold 512. As shown, the fluid delivery conduit 516
is approximately 25 .mu.m wide and the fluid outlet ports 528 are
spaced approximately 500 .mu.m apart in the lengthwise
direction.
[0148] The devices disclosed herein can be used to deliver a
drug-containing fluid under positive pressure to a target tissue
region. FIG. 7 illustrates one exemplary method for
convection-enhanced delivery of a drug to target tissue in a
patient's brain 40. After appropriate site preparation and
cleaning, a tissue opening can formed through the patient's scalp
and skull 44 to expose the brain 40. Before or after forming the
tissue opening, a pedestal 46 can optionally be mounted to the
patient as shown using an epoxy or other adhesive 48. The pedestal
46 can support a CED device 10 while it is inserted, and can be
particularly useful in long-term implantations.
[0149] The CED device 10 can optionally be coupled to a cannula 50
with a microfabricated interface for mating with the CED device 10,
as shown in FIG. 8. Any of a variety of cannulas can be used,
including standard cannulas configured to mate to a stereotactic
frame in guided surgery. In some embodiments, the cannula can
include a flexible catheter suitable for extended (e.g., 30 day)
implantation. The catheter can be about 15 cm long and about 2 cm
in diameter. The cannula can include a tubing portion that is
approximately 6 feet in length with connectors for fluid and
biosensor interface at the proximal end.
[0150] Referring again to FIG. 7, the CED device 10 can be advanced
through the tissue opening and into the brain 40. As explained
above, the scaffold 12 of the CED device 10 can be rigid and can
include a pointed or sharpened tip 20 to facilitate penetration
through the brain tissue towards the target region. One or more
radiopaque markers can be included in the CED device 10 to permit
radiographic imaging (e.g., to confirm proper placement of the CED
device 10 within or in proximity to the target tissue). In
embodiments in which a degradable scaffold 12 is used, the scaffold
12 can degrade shortly after insertion to leave behind only the
flexible shank portion 14 and the fluid delivery conduits 16
mounted thereon. The flexible nature of the shank 14 permits the
CED device 10 to move with the brain 40 if the brain 40 shifts
within the skull 44 (e.g., in the direction of arrow 52), which
prevents localized deformation of brain tissue adjacent to the CED
device 10 that might otherwise occur with a rigid device. Such
deformation can lead to backflow of the pressurized fluid along the
surface of the device, undesirably preventing the fluid from
reaching the target tissue.
[0151] Once the CED device 10 is positioned within or adjacent to
the target tissue, injected media (e.g., a drug-containing fluid)
can be supplied under positive pressure to the CED device 10
through one or more fluid inlet ports of one or more fluid delivery
conduits 16 of the device 10. As shown in FIG. 9, the injected
media is expelled under pressure from the fluid outlet ports of the
fluid delivery conduits of the device 10 in the target region of
tissue. The delivery profile 54 can be adjusted by varying
parameters such as outlet port size, outlet port shape, delivery
conduit size, delivery conduit shape, fluid supply pressure, fluid
velocity, etc.
[0152] Drug delivery can be further enhanced by strategic
positioning of the CED device, and/or by using a plurality of CED
devices. For example, as shown in FIG. 10, a plurality of CED
probes 10A, 10B, 10C, and 10D can be positioned in a spaced
relationship around a target site 56 (e.g., a tumor) such that one
or more fluid outlet ports formed in each of the plurality of CED
devices are aligned with the target site. In this example, CED
devices having fluid outlet ports that are sized and positioned for
directional fluid release can be oriented (e.g., with radiographic
assistance) such that the direction of release is aimed towards the
target tissue. One or more drug-containing fluids can then be
delivered under positive pressure from the plurality of CED devices
to the target site such that the drug substantially surrounds and
saturates the target site or is delivered on several sides of the
target site. The pressure at which fluid is supplied, or any of a
variety of other delivery parameters, can be independently
controlled for each of the plurality of CED devices, e.g., based on
feedback from one or more microsensors disposed on the CED devices.
For example, in the illustrated embodiment in which four CED
devices are implanted to surround a target site, a controller can
be configured to increase or decrease the fluid pressure for each
of the four CED devices based on feedback from pressure sensors
affixed thereto, such that the release pressure of each of the four
CED devices is maintained at substantially the same level.
[0153] The plurality of CED devices can be inserted through a
single tissue opening, or a plurality of separate tissue openings
can be formed to facilitate insertion of the plurality of CED
devices.
[0154] As shown in FIG. 11, CED devices having a plurality of fluid
delivery conduits can advantageously be used to deliver one or more
cofactors along with the drug-containing fluid. For example,
anti-inflammatory agents, enzymes, and various other functional
agents can be delivered though a secondary conduit 16B before,
during, or after delivery of the drug-containing fluid through a
primary conduit 16A. Additional fluid delivery conduits can also be
used for sensing or monitoring.
[0155] It will be appreciated from the foregoing that the methods
and devices disclosed herein can provide convection-enhanced
delivery of functional agents directly to target tissue within a
patient. This convection-enhanced delivery can be used to treat a
broad spectrum of diseases, conditions, traumas, ailments, etc.
[0156] Central-nervous-system (CNS) neoplasm, for example, can be
treated by delivering an antibody (e.g., an anti-epidermal growth
factor (EGF) receptor monoclonal antibody) or a nucleic acid
construct (e.g., ribonucleic acid interference (RNAi) agents,
antisense oligonucleotide, or an adenovirus, adeno-associated viral
vector, or other viral vectors) to affected tissue.
[0157] In another exemplary embodiment, epilepsy can be treated by
delivering an anti-convulsive agent to a target region within the
brain. In another embodiment, Parkinson's disease can be treated by
delivering a protein such as glial cell-derived neurotrophic factor
(GDNF). In a further embodiment, Huntington's disease can be
treated by delivering a nucleic acid construct such as a
ribonucleic acid interference (RNAi) agent or an antisense
oligonucleotide.
[0158] The methods and devices disclosed herein can also be used to
deliver a neurotrophin under positive pressure to treat stroke,
and/or to deliver a protein such as a lysosomal enzyme to treat
lysosomal storage disease.
[0159] In another embodiment, the disclosed methods and devices can
be used to treat Alzheimer's disease by delivering anti-amyloids
and/or nerve growth factor (NGF) under positive pressure. In a
further embodiment, amyotrophic lateral sclerosis can be treated by
delivering a protein such as brain-derived neurotrophic factor
(BDNF) or ciliary neurotrophic factor (CNTF) under positive
pressure to the brain, spinal canal, or elsewhere in the central
nervous system. Chronic brain injury can be treated by delivering a
protein such as brain-derived neurotrophic factor (BDNF) and/or
fibroblast growth factor (FGF) under positive pressure in
accordance with the methods and devices disclosed herein.
[0160] It will be appreciated that use of the devices disclosed
herein and the various associated treatment methods is not limited
to the brain of a patient. Rather, these methods and devices can be
used to deliver a drug to any portion of a patient's body,
including the spine.
[0161] As shown in FIG. 12, a CED device 10 can be inserted through
a tissue opening formed adjacent to a vertebra 58 of a patient so
as to facilitate delivery of a therapeutic agent to a target region
within a spinal canal 60 of the patient. Traditional methods of
delivering drug-containing fluid to the spinal canal result in the
fluid mixing with the cerebrospinal fluid (CSF) of the patient,
which carries the drug away from the target tissue and can lead to
complications when the drug acts in non-target areas of the
patient. The minimal size of the CED devices disclosed herein,
coupled with the high flow rate of drug-containing fluid, on the
other hand, allows for extremely precise targeting of the drug
delivery, such that delivery into the cerebrospinal fluid (CSF) of
the patient can be avoided, while still allowing delivery into
specific target regions of the spinal canal. In one embodiment,
stem cells can be delivered into the spinal canal or elsewhere in
the central nervous system, for example to treat ALS.
[0162] The methods and devices disclosed herein can also be used to
treat balance or hearing disorders by injecting a drug-containing
fluid directly into a portion of a patient's ear. Existing
techniques for delivering a drug to the inner ear require entry
through the outer ear 62 and the ear canal 64, which can cause
damage to the delicate structures of the ear. In the present
embodiment, as shown in FIGS. 13-14, a tissue opening can instead
be formed in the skull 44 behind a patient's ear 66 to allow
insertion of a CED device 10. The device 10 can be inserted through
the tissue opening and into the target portion of the patient's ear
(e.g., inner ear 68, cochlea 70, organ of Corti, and/or basilar
membrane). A drug-containing fluid can then be delivered through
the device 10 under positive pressure to the target ear portion.
Any of a variety of drugs can be used to treat the ear, including
human atonal gene.
[0163] As shown in FIG. 15, the methods and devices disclosed
herein can be used to treat Alzheimer's Disease or other
neurological conditions by delivering a drug-containing fluid to
the cerebral cortex. The drug-containing fluid can be delivered to
any of a variety of regions of the brain, either individually or
together and either simultaneously or sequentially. These regions
can include the auditory cortex, the inferotemporal cortex, the
prefrontal cortex, the premotor cortex, the primary motor cortex,
the supplementary motor cortex, the somatosensory cortex, the
parietal cortex, the visual cortex, the gustatory cortex, etc.
[0164] As shown in FIG. 16, the methods and devices disclosed
herein can also be used to deliver therapeutics (such as stem
cells) to a fetus or to a patient in which the fetus is disposed.
This can be particularly advantageous in delivering therapeutics
during fetal surgery. As shown, a micro-fluidic CED device can be
used to deliver a drug-containing fluid to an umbilical cord, an
umbilical artery, an umbilical vein, a placenta, and/or a uterine
wall.
[0165] FIG. 17A illustrates another exemplary embodiment of a
microfluidic CED device 610 that includes a support scaffold 612,
at least one shank 614, and at least first and second fluid
delivery conduits 616A, 616B . The fluid delivery conduits 616A,
616B have differing lengths, such that the outlet ports 628A, 628B
of the fluid delivery conduits are staggered longitudinally along
the shank 614. In other words, the first and second fluid delivery
conduits 616A, 616B terminate at a distance D apart from one
another such that the outlet ports 628A, 628B thereof are staggered
in the longitudinal direction. In an exemplary embodiment, the
distance D is between about 0.02 .mu.m and about 100 mm, and
preferably between about 0.1 .mu.m and about 10 mm. The device 610
can also include one or more sensors 630 and/or electrodes 632, as
described above. The structure and function of the device 610 is
otherwise substantially the same as that of the device 10 described
above, and therefore a further description thereof is omitted here
for the sake of brevity.
[0166] In use, the device 610 can be inserted into a target region
(e.g., a cavernous malformation with a patient's central nervous
system) such that the outlet port 628B of the second fluid delivery
conduit 616B is disposed within a central portion of the target
region (e.g., the core of the cavernous malformation) and such that
the outlet port 628A of the first fluid delivery conduit 616A is
disposed within a peripheral portion of the target region (e.g.,
the exterior surface of the cavernous malformation). Accordingly,
the target region can be treated both from the inside-out and from
the outside-in. In the case of a cavernous malformation, the device
610 can allow a drug to be delivered into the core of the cavernous
malformation as well as to the surface of the cavernous
malformation where the vascular-type cells are proliferating.
[0167] FIG. 17B illustrates another exemplary embodiment of a
microfluidic CED device 710. The device 710 is substantially
identical to the device 610 of FIG. 17A, except that an inflatable
member 772 (e.g., a reinforced and/or conformable balloon) is
included in the device 710. The inflatable member 772 can be in
fluid communication with the first fluid delivery conduit 716A,
such that fluid can be supplied through the first fluid delivery
conduit 716A to inflate the inflatable member 772 and increase the
volume of the inflatable member 772 or increase the pressure within
the inflatable member 772. Similarly, fluid can be withdrawn from
the inflatable member 772 via the first fluid delivery conduit 716A
to reduce the volume of the inflatable member 772 or reduce the
pressure therein. The inflatable member 772 can be coupled to an
exterior of the device 710 (e.g., such that it substantially
surrounds a portion of the device 710), or can be configured to
deploy from within a recess formed in the device 710. The structure
and function of the device 710 is otherwise substantially the same
as that of the device 10 described above, and therefore a further
description thereof is omitted here for the sake of brevity.
[0168] As shown in FIGS. 18A-18B, the methods and devices disclosed
herein can be used to treat a cavernous malformation, for example
by delivering one or more drugs thereto. Referring to FIG. 18A, a
CED device such as the device 710 described above can be inserted
into a cavernous malformation 74 such that the outlet port 728A of
the first fluid delivery conduit 716A and the outlet port 728B of
the second fluid delivery conduit 716B are both disposed within the
cavernous malformation 74. Fluid containing a drug, such as one or
more antiangiogenesis factors can then be supplied to the interior
of the cavernous malformation 74 through the second fluid delivery
conduit 716B. At the same time, or shortly thereafter, fluid can be
supplied through the first fluid delivery conduit 716A to inflate
the inflatable member 772 and/or increase the pressure within the
inflatable member 772, as shown in FIG. 18B. As the inflatable
member 772 inflates within the cavernous malformation 74, and/or as
the pressure increases within the inflatable member 772, a
compressive force is exerted on the drug-containing fluid
previously released into the cavernous malformation 74, pressing
the fluid into the surrounding tissue.
[0169] The microfluidic CED devices disclosed herein can be
manufactured using any of a variety of techniques. For example, the
devices can be manufactured by micro-fabricating a silicon
substrate, and then coupling the finished piece to a catheter
portion that includes one or more micro-capillaries. In some
embodiments, a lithographic microfabrication process can be used to
manufacture a CED device. The process can include (1) back etching
a silicon substrate to form shank and tailpiece depths, (2) spin
coating polyimide on the top side of the silicon substrate, (3)
spin coating sacrificial resist to define the micro-channels, (4)
applying a parylene coat to the top side of the polyimide layer,
(5) applying an aluminum mask for removing the sacrificial resist
and thereby forming parylene channels, and (6) front etching the
silicon substrate to form device bodies. In other embodiments, the
process can include (1) front etching a silicon substrate to form
device bodies, (2) spray coating polyimide on both sides of the
silicon substrate without masking, (3) spray coating a sacrificial
resist on the polyimide, (4) applying a parylene coat to the top
side, and (5) applying an aluminum mask for removing the
sacrificial resist and thereby forming parylene channels.
[0170] FIG. 19 illustrates an exemplary microfabrication process
for manufacturing a CED device. While various methods or processes
disclosed herein may be shown in relation to a flowchart or
flowcharts, it should be noted that any ordering of method steps
implied by such flowcharts or the description thereof is not to be
construed as limiting the method to performing the steps in that
order. Rather, the various steps of each of the methods disclosed
herein can be performed in any of a variety of sequences. In
addition, as the illustrated flowchart(s) are merely exemplary
embodiments, various other methods that include additional steps or
include fewer steps than illustrated are also within the scope of
the present invention.
[0171] In step S800, a cleaning process can be performed on a
silicon wafer from which the CED device will be fabricated. For
example, a hot nanostrip clean can be performed for 30 minutes at
50 degrees C., followed by a deionized ("DI") water rinse and spin
rinse drying ("SRD"), e.g., using a VERTEQ spin rinse dryer. In
other embodiments, an RCA clean is performed for 15 minutes at 70
degrees C. using NH4OH:H20, followed by 15 minutes at 70 degrees C.
using HCL:H20, followed by a DI water rinse and SRD.
[0172] In step S802, the wafer can undergo a dehydration bake. In
some embodiments, the wafer can be baked at 180 degrees C. for 5
minutes using a contact hotplate. The dehydration bake can be
omitted in some cases, as the wafer can be heated to 400 degrees C.
during the plasma-enhanced chemical vapor deposition ("PECVD") step
discussed below. Accordingly, the step time in the PECVD process
can be increased to accommodate extra dehydration time. Omitting
hotplate dehydration can also reduce contamination left behind by
prior uses of the hotplate.
[0173] In step S804 an oxide hard mark can be deposited on the
silicon wafer. In some embodiments, the hard mark can be deposited
by PECVD Oxide Deposition (2.5 .mu.m, N1.46 Oxide Recipe), and the
thickness can be confirmed using a measuring system, such as those
manufactured by FILMETRICS.
[0174] In step S806, the oxide hard mask 902 can be patterned on
the silicon wafer 900, for example as shown in FIG. 20A. An
exemplary patterning process includes:
[0175] Clean mask in hot strip bath (15 minutes, 70 degrees C.,
NMP/TMAH/PG with DI rinse and SRD.
[0176] Resist process (backside)
[0177] Vapor prime (this can be performed in an oven, such as those
manufactured by YIELD ENGINEERING SYSTEMS ("YES") and can be
important for the wet etch process)
[0178] Spin resist: S1813 (4000 rpm, 1000 rpm/sec, 30 sec)
[0179] Softbake: 115 degrees C.: 90 sec
[0180] Acetone swab removal of residual backside resist
[0181] Expose: MA6: Soft Contact: MASK1=DRIE (deep reactive
ion-etching) (Backside)
[0182] PE Wait: None
[0183] PE Bake: 115 degrees C.: 60 sec
[0184] Develop: HAMATECH 726MIF 60 secDP
[0185] Hardbake: 115 degrees C.: 60 sec
[0186] Descum using an etcher, such as an OXFORD 80 etcher (Oxygen
Plasma Clean, 150 wattsRF, 50 sccms 02, 60 mTorr, 15 sec)
[0187] Buffered Oxide Etch ("BOE") 6:1 Etch: 30 min, Extended DI
Rinse and SRD
[0188] Microscope Evaluation (with Saved Images)
[0189] Oxide Etch: OXFORD 80#2 (CHF3O2 Oxide Etch, 240 watts, 100
min (.times.5 twenty min cycles), 50 sccms CHF3, 2 sccms O2, 40
mTorr, 10 deg C., DC Bias 119 volts)
[0190] Strip Resist: OXFORD 80 (Oxygen Plasma Clean, 150 wattsRF,
50 sccms O2, 60 mTorr, 10 min)
[0191] Strip Resist: Hot Strip Bath (15 min 70 deg NMP/TMAH/PG), DI
Rinse and SRD
[0192] Strip Resist: Acetone Bath, isopropyl alcohol ("IPA") Bath,
DI Water Bath with DI Rinse and SRD
[0193] Strip Resist, e.g., using a hot piranha cleaning system
manufactured by HAMATECH
[0194] Because BOE is isotropic (i.e. etches at the same rate in
all directions) 30 min of BOE6:1 Etch can result in an
approximately 3 .mu.m undercut all around. This can increase the
critical dimensions of the structures beyond that in the CAD
layout. This can be compensated to some extent in the CAD layout
(e.g., by making the dimensions smaller than what is actually
desired by 3 .mu.m).
[0195] In some embodiments, instead of using wet BOE to pattern the
oxide, a CHF3O2 reactive ion "dry" etch can be used. One advantage
of using BOE is that it can be relatively inexpensive (no tool
charges and many wafers can be etched at the same time) and a
thinner resist can be used (such as S1813). One disadvantage,
however, is that the dimensions can extend out by 3 .mu.m all
around. This can be less of a concern when the critical feature
sizes are really large. Another potential problem is that BOE can
sometimes capillary underneath the resist layer (hence the need for
good adhesion) and etch in regions where etching is not intended.
For CHF3O2 reactive ion etch ("RIE"), the critical dimensions in
the CAD layout can be more reliably reproduced on the wafer so
there is no need to do any first-order size compensation in CAD.
Also, for CHF302, a thicker resist (SPR220-4.5) can be required to
etch through the 2.5 .mu.m PECVD oxide hard mask.
[0196] In some embodiments, the resist can be left in place during
the initial etching steps in the subsequent Bosch DRIE. Resist
stripping can be done with a first O2 plasma clean followed by a
wet chemical stripper followed by a DI rinse and dry N2 blow
dry.
[0197] In step S808 the silicon can undergo deep reactive ion
etching ("DRIE") to remove silicon from the wafer 900 in the
pattern defined by the oxide hard mask 902, for example as shown in
FIG. 20B. First, the edge bead is removed (if the resist was not
removed previously). Then, an etching system such as those
manufactured by UNAXIS can be used to etch through the wafer,
leaving 100 .mu.m remaining on the frontside. In some embodiments,
the etch can be performed using the following parameters:
[0198] Chamber Season: .times.100 Loops O-Trench
[0199] Wafer Etch: .about.800 Loops O-Trench (400 .mu.m into 500
.mu.m Wafer)
[0200] Step1: Deposition
[0201] RF1 Power: 0.1 watts, Flowrate: SF6: 2 sccms, Heat Exch1: 22
deg C.
[0202] RF2 Power: 850 watts, Flowrate: C4F8: 60 sccms, Heat Exch2:
40 deg C.
[0203] Pressure: 24 mTorr, Flowrate: Ar: 40 sccms, He Flow: 2.76
sccms
[0204] Time: 4.0 sec, Flowrate: O2: 0 sccms, He Pressure: 3.0
Torr
[0205] Step2: Etch1
[0206] RF1 Power: 8.0 watts, Flowrate: SF6: 70 sccms, Heat Exch1:
22 deg C.
[0207] RF2 Power: 850 watts, Flowrate: C4F8: 2 sccms, Heat Exch2:
40 deg C.
[0208] Pressure: 23 mTorr, Flowrate: Ar: 40 sccms, He Flow: 2.76
sccms
[0209] Time: 2.0 sec, Flowrate: O2: Osccms, He Pressure: 3.0
Torr
[0210] Step3: Etch2
[0211] RF1 Power: 8.0 watts, Flowrate: SF6: 100 sccms, Heat Exch1:
22 deg C.
[0212] RF2 Power: 850 watts, Flowrate: C4F8: 2 sccms, Heat Exch2:
40 deg C.
[0213] Pressure: 24 mTorr, Flowrate: Ar: 40 sccms, He Flow: 2.76
sccms
[0214] Time: 6.0 sec, Flowrate: O2: 0 sccms, He Pressure: 3.0 Torr
4
[0215] In some embodiments, an OERLIKON etching can be performed
instead. Thinner wafers (e.g., about 300 .mu.m thick as opposed to
about 500 .mu.m thick) can be used in some embodiments to reduce
the etching time, however this can increase cost and breakage rate.
The etching process can be followed by:
[0216] Strip Resist: OXFORD 80 (Oxygen Plasma Clean, 150 wattsRF,
50 sccms O2, 60 mTorr, 10 min)
[0217] Strip Resist: Hot Strip Bath (15 min 70 deg NMP/TMAH/PG), DI
Rinse and SRD
[0218] In step S810, a PECVD oxide etch stop can be performed on
the backside of the wafer, for example as shown in FIG. 20C. In
some embodiments, the PECVD oxide 904 can be deposited down at the
very bottom of the trenches formed in step S808, e.g., using PECVD
oxide deposition of 1.0 .mu.m on the backside of the wafer with
frontside etch stop. In some embodiments, a silicon on insulator
("SOI") wafer can be used, in which case the buried oxide ("BOX")
layer on the SOI wafer can act as the etch stop making the PECVD
stop layer and DRIE from the backside unnecessary. Vapor hydrogen
fluoride ("HF") can be used in such embodiments to release the
final device from the BOX.
[0219] In step S812, a polyimide layer 906 can be patterned on the
frontside of the wafer 900, for example as shown in FIG. 20D. In
some embodiments, the following process is used to pattern the
polyimide layer:
[0220] Spin polyimide (4000 rpm, 500 rpm/sec, 45 sec, .about.2
.mu.m). This can be performed using a aromatic polyimide precursor
solution such as Photoneece PW DC1000 manufactured by TORAY
[0221] Clean backside residue with acetone swab
[0222] Softbake: 115 degrees C.: 3 min (contact polyimide hot
plate)
[0223] Expose: MA6: Soft Contact: MASK2=POLY (Frontside)
[0224] PE Wait: None
[0225] PE Bake: None
[0226] Develop: HAMATECH 726MIF90 secDP
[0227] Microscope Evaluation (with Saved Images)
[0228] Descum: OXFORD 80 (Oxygen Plasma Clean, 150 wattsRF, 50
sccms O2, 60 mTorr, 15 sec)
[0229] Cross-Link Polyimide: Recipe3: YES Polyimide Oven:
300+degrees C.
[0230] Typical Process: 170 degrees C. for 30 minutes and 320
degrees C. for 60 minutes in Nitrogen Ambient
[0231] In step S814, the microfluidic channels can be defined using
sacrificial resist 908, for example as shown in FIG. 20E. In some
embodiments, the following process is used to define the
microfluidic channels:
[0232] Spin Resist: SPR220-7 (1600 rpm for 10 .mu.m, 500 rpm/sec,
45 sec)
[0233] Softbake1: 65 degrees C.: 1 min
[0234] Softbake2: 90 degrees C.: 1 min
[0235] Softbake3: 115 degrees C.: 2 min, or
[0236] Softbake: 90 degrees C., 30 min (Convection Oven)
[0237] Expose: MA6: Soft Contact: MASK3=CHANNEL (Frontside)
[0238] PE Wait: See Stanford process
[0239] PE Bake: See Stanford process
[0240] Develop: HAMATECH 726MIF120 secDP
[0241] Microscope Evaluation (with Saved Images)
[0242] Remove Edge Bead
[0243] Hardbake: 115 degrees C.: 1 min
[0244] Microscope Evaluation (with Saved Images)
[0245] Descum: OXFORD 80 (Oxygen Plasma Clean, 150 wattsRF, 50
sccms O2, 60 mTorr, 60 sec)
[0246] P10 profilometer evaluation (measure channel height and
width)
[0247] The thickness of the resist layer 908 can determine the
height of the microfluidic channel. Likewise, the width of the
resist layer 908 (after exposure and development) determines the
width of the microfluidic channel. To avoid cracking of the resist
908, this step can be done with a slow ramp up and ramp down.
[0248] In some embodiments, there can be some reflow of the resist
908 during the hardbake step which can cause it to have sloped
sidewalls for better aluminum coverage. Reflow of the resist is not
always necessary, however, as the wafer can also be coated using
conformal evaporation or sputter deposition with both of these
processes allowing many more wafers to be coated at the same time
as compared to the non-conformal evaporators.
[0249] In step S816, a layer of parylene 910 is deposited over the
polyimide layer 906 and the sacrificial resist 908, for example as
shown in FIG. 20F. In some embodiments, the parylene layer 910 can
have a thickness of approximately 5 .mu.m. The following process
can be used for the parylene deposition:
[0250] Roughen Resist Surface: OXFORD 80: 150 wattsRF, 50 sccms O2,
60 mTorr, 30 sec
[0251] Parylene C Deposition (3.5 grams=5 .mu.m)
[0252] Parylene can be a highly conformal layer and some material
can therefore be coated on the backside of each wafer. Parylene
deposition can be performed on, e.g., three wafers at one time. A
typical parylene deposition process can take approximately 6
hours.
[0253] In step S818, aluminum hard mask evaporation can be
performed to apply an aluminum layer 912 over the parylene layer
910, as shown in FIG. 20G. The following process can be used for
the aluminum hard mask evaporation:
[0254] Roughen parylene surface: OXFORD 80: 150 wattsRF, 50 sccms
O2, 60 mTorr, 30 sec
[0255] Evaporate or sputter: aluminum: conformal: 150 nm (2
A/sec)
[0256] In step S820, the aluminum hard mask 912 can be patterned,
for example as shown in FIG. 20H. The following process can be used
to pattern the aluminum hard mask:
[0257] Liquid HMDS Prime: 10 sec
[0258] Spin Resist 914: SPR220-7 (1600 rpm, 500 rpm/sec, 45 sec,
.about.10 .mu.m)
[0259] Softbake1: 65 degrees C.: 1 min
[0260] Softbake2: 90 degrees C.: 1 min
[0261] Softbake3: 115 degrees C., or,
[0262] Softbake: 90 degrees C., 30 min (Convection Oven)
[0263] Expose: MA6: Soft Contact: MASK4=ALUMINUM (Frontside)
[0264] PE Wait: None
[0265] PE Bake: None
[0266] Develop: HAMATECH 726MIF120 secDP
[0267] Microscope Evaluation (with Saved Images)
[0268] Wet Aluminum Etch (5 min)--the wet aluminum etch can
undercut the resist etch mask 914 so the CAD layout can be adjusted
accordingly to accommodate for this.
[0269] Microscope Evaluation (with Saved Images)
[0270] Strip Resist: OXFORD 80 (Oxygen Plasma Clean, 150 wattsRF,
50 sccms O2, 60 mTorr, 10 min)
[0271] Strip Resist: Hot Strip Bath (15 min 70 deg NMP/TMAH/PG), DI
Rinse and SRD
[0272] Strip Resist: Acetone Bath, IPA Bath, DI Water Bath with DI
Rinse and SRD
[0273] In the above process, the chemical compatibility of the hot
strip bath, acetone, and IPA with the specific polyimide chosen
should be confirmed. Upon completion of step S820, a strip of
aluminum 912 has been deposited overtop of the parylene layer 910
to act as a hard etch mask as per FIG. 20H.
[0274] In step S822, etch removal of peripheral parylene can be
performed. For example, as shown in FIG. 20I, the parylene layer
910 is removed from peripheral regions 916 of the wafer 900. The
following process can be used to remove the parylene etch:
[0275] Spin Resist: SPR220-7 (1000 rpm, 100 rpm/sec, 45 sec,
DynamicDispense, FreshResist, .about.12.mu.m)
[0276] Softbake: 90 degrees C.: 30 min (Convection Oven)
[0277] Expose: MA6: Soft Contact: MASK5=PARYLENE (Frontside)
[0278] PE Wait: See Stanford process
[0279] PE Bake: See Stanford process
[0280] Develop: HAMATECH 726MIF90 secDP
[0281] Microscope Evaluation (with Saved Images)
[0282] Hardbake: 90 degrees C.: 4-12 hours (Overnight Convection
Oven, Slow Ramp)
[0283] Flood UV Expose: ABM: 2 min
[0284] Parylene Etch: OXFORD 80 (Frontside, Oxygen Plasma Clean,
150 wattsRF, 20-25 min, Complete Removal of 5 .mu.m Parylene
Layer)
[0285] Parylene Etch: OXFORD 80 (Backside, Oxygen Plasma Clean, 150
wattsRF, 10-15 min with Chips)
[0286] When etching the wafer backside, silicon chips can be used
to suspend the wafer above the platen so that the frontside of the
wafer isn't scratched or damaged. FIG. 20I illustrates the system
after parylene etch removal. As shown, the parylene has been etched
all the way down to the silicon surface in the peripheral regions
and 100 .mu.m of silicon around the periphery of each device is
holding the device affixed to the wafer. After the parylene etch,
it can be helpful to have at least 4 .mu.m of resist remaining that
can be subsequently used for etching the remaining 100 .mu.m of
silicon on the frontside. Accordingly, the resist layer can be made
thick enough to accommodate 5 .mu.m of parylene etching and 100
.mu.m of silicon etching. Otherwise, a new resist layer can be
applied.
[0287] In step S824, the device outline can be defined, for example
as shown in FIG. 20J. The following process can be used to define
the device outline:
[0288] Acetone Swab Removal of Edge Bead
[0289] Softbake: 90 degrees C.: 90 min (Convection Oven)
[0290] P10 profilometer evaluation: confirm remaining resist
thickness is >4 .mu.m
[0291] UNAXIS Etch: O-Trench (to clear 100 .mu.m of Si)
[0292] Strip Resist: 20 min Acetone Bath, 20 min IPA Bath, 20 min
DI Water Bath and SRD
[0293] Strip Resist: OXFORD 80 (Oxygen Plasma Clean, 150 wattsRF,
50 sccms O2, 60 mTorr, 2 min)
[0294] Strip Resist: 20 min Acetone Bath, 20 min IPA Bath, 20 min
DI Water Bath and SRD
[0295] In Mask5=PARYLENE, there can be provided two small "bridges"
of resist that protect the underlying parylene and that can be used
to hold the device in place. Upon completion, these devices can be
"broken out" from the wafer using tweezers. Preferably, these
bridges can be attached to the body of the device (and not the
shaft or the shoulder). Exemplary bridges 918 are shown in FIG.
21A, at the proximal end of the device body 920. As shown in FIG.
20K, after the resist strip, one can "see" through the PECVD oxide
membrane layer 904 that tethers around the periphery of each
device.
[0296] In step S826, holes can be opened in the parylene
channel(s). In this step, the aluminum 912 can be used as a hard
mask to open up access holes into the parylene channel.
Over-etching can be preferred here to make sure that the parylene
910 has been cleared and the sacrificial resist 908 is accessible.
Prior to this step, there is no access by any solvents to the
sacrificial resist 908 inside the channel. The following process
can be used to open holes in the parylene channel:
[0297] Parylene Etch: OXFORD 80: Oxygen Plasma Clean: 150 wattsRF,
50 sccms O2, 60 mTorr, 20-25 min Etch)
[0298] Microscope Evaluation (with Saved Images)
[0299] In step S828, a wet aluminum etch can be performed to remove
the etch mask, for example using the following process:
[0300] Wet Aluminum Etch, 15 min, DI Rinse and SRD
[0301] Microscope Evaluation (with Saved Images)
[0302] In step S830, a wet BOE etch can be performed to remove the
PECVD oxide stop layer 904, for example using the following
process:
[0303] BOE6:1 Etch, 10-15 min
[0304] In some embodiments, after the BOE etch, each device is held
in place only by the device "tabs" or "bridges" in the 1 .mu.m
silicon layer.
[0305] In step S832, the sacrificial resist 908 can be cleared, for
example as shown in FIG. 20L. The following process can be used to
clear the sacrificial resist:
[0306] Clear Resist: Acetone Bath: 4 hrs (Keep Wet)
[0307] Clear Resist: IPA Bath: 1 hr (Keep Wet)
[0308] Clear Resist: DI Water Bath: 12 hrs
[0309] In some embodiments, the wafers are not allowed to dry
in-between these bathing steps, which can prevent resist residue
from crystallizing at the inlet/outlet ports. After sacrificial
resist removal, the device cross section is as shown in FIG. 20L.
In some embodiments, the sacrificial resist is removed before the
individual devices are harvested (i.e., broken-out) from the wafer,
making the resist removal process less cumbersome and
time-consuming.
[0310] In step S834, the devices can be harvested from the wafer.
This can be performed, e.g., by using tweezers to push on the body
of each device until the tabs break and the device falls from the
wafer onto a clean wipe. Once separated from the wafer, the device
can be picked up from the clean wipe and placed into a tacky
GelBox, preferably with the access ports facing up.
[0311] In step S836, the devices can be assembled with PEEK tubing
to form a finished CED device. The contact surface of the PEEK
tubing can be treated using O2 plasma and mechanical roughening for
good adhesion, and then attached to the device using an adhesive
such as Epoxy 907 manufactured by MILLER-STEPHENSON.
[0312] In an exemplary embodiment, the finished devices can have an
1850 .mu.m catheter tip length, a 1750 .mu.m square body, a 1750
.mu.m shoulder length, and a nominal catheter tip width of 25
.mu.m. Leaving allowance for test areas around the periphery, 100
or more of such devices can be fabricated from a single 4-inch
wafer.
[0313] FIG. 21B illustrates a scanning electron microscope (SEM)
image of the tip 922 of a completed CED device 924. The sidewall
roughness shown in the image, which can undesirably result in crack
propagation, can be reduced by incorporating a wet flash etch of
the silicon into the above process.
[0314] The microfabricated portion 1002 of a multi-lumen CED device
1000 (manufactured, for example, using the above process) is
illustrated schematically in FIG. 22A. As shown, the
microfabricated portion 1002 includes a body portion 1004 with a
shank or tip 1006 extending distally therefrom and first and second
legs 1008, 1010 extending proximally therefrom. In exemplary
embodiments, the body portion can have a length of approximately
1.5 mm. First and second parylene channels 1012, 1014 are formed on
the silicon substrate. The first parylene channel 1012 extends
along the first leg 1008, across the body portion 1004, and along
the tip 1006. The second parylene channel 1014 extends along the
second leg 1010, across the body portion 1004, and along the tip
1006. As shown in FIG. 22B, the parylene channels 1012, 1014 can
include 90 degree turns at their distal end, such that the outlet
ports 1016, 1018 of the channels are aimed in a direction
perpendicular to the longitudinal axis of the tip 1006.
[0315] FIG. 23A illustrates a layout of eight microfabricated
portions 1002 having various lengths. As shown in FIG. 23B, the
layout of FIG. 23A can be repeated across the available surface
area of a silicon wafer. FIG. 23C illustrates a set of eight
microfabricated portions 1002 after having been harvested from the
wafer.
[0316] FIGS. 24A-24C illustrate SEM images of the microfabricated
portions 1002 of the device 1000, before creation of the parylene
channels 1012, 1014.
[0317] As shown in FIG. 25A, the multi-lumen CED device 1000 also
includes a proximal catheter portion 1020 which can be assembled
with the microfabricated portion 1002. The catheter portion 1020
can include a quartz double-bore body 1022 with first and second
PEEK micro-capillaries 1024, 1026 extending therethrough. The
catheter portion 1020 can be mated to the microfabricated portion
1002 by inserting the first and second legs 1008, 1010 into the
body 1022, such that the first and second micro-capillaries 1024,
1026 are in fluid communication with the first and second parylene
channels 1012, 1014. An adhesive can be used as described above to
couple the two portions 1002, 1020 of the device 1000 to one
another and to form a fluid-tight seal.
[0318] A proximal end-view of the device 1000 at this stage of
assembly is shown in FIG. 25B. As shown, the silicon body portion
1004 extending from the catheter portion 1020 has a flat, generally
rectangular shape, which if left exposed can make tissue
penetration with the device 1000 difficult. As shown in FIG. 25C, a
nose portion 1028 can be coupled to the device 1000 to encapsulate
the flat wafer body 1004. The nose portion 1028 can have any of a
variety of shapes, including conical, cylindrical, hemispherical,
and so forth, and can be sharp or blunt. The gradual taper provided
by the nose portion 1028 can facilitate insertion of the device
1000 into tissue and can also form a better seal with surrounding
tissue, thereby reducing the possibility for fluid delivered under
pressure through the device 1000 to migrate back along the exterior
surface of the device away from the target treatment area. In
exemplary embodiments, the nose portion 1028 has a maximum outside
diameter of between about 1 mm and about 1.5 mm. The nose portion
1028 can be formed using epoxy or it can be a separate
micro-machined part that is assembled onto the microfabricated
portion 1002. As also shown in FIG. 25C, a catheter/cannula body
1030 can extend over the catheter portion 1020 of the device 1000
to encapsulate the proximal end of the microfabricated portion 1002
and the micro-capillaries 1024, 1026. A proximal end view of the
device 1000 at this stage of assembly is shown in FIG. 25D. Images
of an exemplary assembled device are shown in FIGS. 26A-26C.
[0319] In some embodiments, the device 1000 can be configured to
deliver fluid at a flow rate between about 5 .mu.L per minute and
about 10 .mu.L per minute. To achieve such flow rates, the channels
1012, 1014 can each have a height of approximately 10 microns and a
width of approximately 20 microns in the case of a rectangular
channel, or can each have a diameter of about 20 microns in the
case of a round channel.
[0320] Any of the various treatments described herein can further
include delivering a cofactor to the target tissue, such as a
corticosteroid impregnated in the scaffold of the device, a
corticosteroid coated onto the scaffold, and/or a propagation
enhancing enzyme. In addition, any of the various treatments
described herein can further include long-term implantation of the
device (e.g., for several hours or days) to facilitate long-term
treatments and therapies.
[0321] Although the invention has been described by reference to
specific embodiments, it should be understood that numerous changes
may be made within the spirit and scope of the inventive concepts
described. Accordingly, it is intended that the invention not be
limited to the described embodiments, but that it have the full
scope defined by the language of the following claims.
* * * * *