U.S. patent application number 13/666773 was filed with the patent office on 2013-05-09 for compositions and methods for reducing edema.
This patent application is currently assigned to THE REGENTS OF THE UNIVERSITY OF CALIFORNIA. The applicant listed for this patent is Devin BINDER, Michael HSU, Devin McBRIDE, B. Hyle PARK, Victor G.J. ROGERS. Invention is credited to Devin BINDER, Michael HSU, Devin McBRIDE, B. Hyle PARK, Victor G.J. ROGERS.
Application Number | 20130115267 13/666773 |
Document ID | / |
Family ID | 48223839 |
Filed Date | 2013-05-09 |
United States Patent
Application |
20130115267 |
Kind Code |
A1 |
ROGERS; Victor G.J. ; et
al. |
May 9, 2013 |
COMPOSITIONS AND METHODS FOR REDUCING EDEMA
Abstract
The invention provides compositions and methods for the
treatment and/or reversal of an edema, e.g., including a central
nervous system (CNS) edema, e.g., a brain or a spinal edema, edema
in a burned or an injured tissue such as skin, or any tissue edema.
In alternative embodiments, the invention provides compositions and
methods for a direct treatment and reversal of an edema, e.g., CNS,
brain or spinal edema, including a membrane transport device, in
vitro and in vivo characterization of edema, and the sensitive
early optical detection of the edema, e.g., tissue, CNS or cerebral
edema.
Inventors: |
ROGERS; Victor G.J.;
(Riverside, CA) ; BINDER; Devin; (Riverside,
CA) ; McBRIDE; Devin; (Riverside, CA) ; HSU;
Michael; (Riverside, CA) ; PARK; B. Hyle;
(Riverside, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ROGERS; Victor G.J.
BINDER; Devin
McBRIDE; Devin
HSU; Michael
PARK; B. Hyle |
Riverside
Riverside
Riverside
Riverside
Riverside |
CA
CA
CA
CA
CA |
US
US
US
US
US |
|
|
Assignee: |
THE REGENTS OF THE UNIVERSITY OF
CALIFORNIA
Oakland
CA
|
Family ID: |
48223839 |
Appl. No.: |
13/666773 |
Filed: |
November 1, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61555351 |
Nov 3, 2011 |
|
|
|
Current U.S.
Class: |
424/443 ;
424/400; 514/1.1 |
Current CPC
Class: |
A61B 5/4878 20130101;
A61L 29/043 20130101; A61L 29/044 20130101; A61B 5/6868 20130101;
A61P 43/00 20180101; A61L 29/16 20130101; A61M 2027/004 20130101;
A61M 27/002 20130101; A61B 5/0066 20130101; A61K 38/38 20130101;
A61K 38/40 20130101 |
Class at
Publication: |
424/443 ;
424/400; 514/1.1 |
International
Class: |
A61M 25/00 20060101
A61M025/00; A61M 25/14 20060101 A61M025/14; A61P 43/00 20060101
A61P043/00; A61K 38/38 20060101 A61K038/38 |
Goverment Interests
GOVERNMENT RIGHTS
[0002] This invention was made with government support under grant
number NIH K08 grant NS-059674, awarded by the National Institutes
of Health (NIH), and grant number DGE 0903667, awarded by the
National Science Foundation. The government has certain rights in
the invention.
Claims
1. A product of manufacture or a device for reducing an edema, the
product of manufacture or device comprising: a protein,
carbohydrate, polysaccharide or polymer solution, or a non-rigid
hydrogel or gel, or a concentrated protein, carbohydrate,
polysaccharide or polymer solution, or a concentrated osmolyte
solution or rejected solute, or any combination thereof, wherein
optionally these solutions, non-rigid hydrogels or gels are
contained within a lumen or a hollow fiber of the device wherein
optionally the lumen solution or lumen contents further comprise
nutrients, or drugs, and optionally the drugs and/or nutrients are
for the treatment or amelioration of the edema, of a burn or
injury, or an underlying disease or condition causing the edema,
and optionally the drugs comprise or are small molecules or
proteins, and optionally the drugs act as antibiotics,
anti-inflammatories, vasoconstrictors, vascular or tissue growth
stimulating agents; a semi-permeable hollow fiber membrane having a
lumen, or a bundle or a module having a lumen; and, a hollow fiber
device, wherein the concentrated protein, carbohydrate,
polysaccharide or polymer solution, or osmolyte solution or
rejected solute, or non-rigid hydrogel or gel, passes through the
lumen of a semi-permeable hollow fiber membrane, and the
concentrated protein, carbohydrate, polysaccharide or polymer
solution, or osmolyte solution or rejected solute, or non-rigid
hydrogel or gel, flowing through the semi-permeable fiber membrane,
which is in contact with the tissue, induces osmotic pressure that
drives water into a hollow fiber device where it is removed and
carried away from the edematous, e.g., the injured, tissue or area
of injury, wherein optionally an aqueous proteinaceous,
carbohydrate, polysaccharide, polymer solution, or osmolyte
solution or rejected solute, or non-rigid hydrogel or gel, is
flowed (e.g., by osmotic force) or is pumped or passively flows
(such as head pressure) through the semi-permeable hollow fiber
membrane lumen, wherein optionally the membrane completely or
substantially rejects a solute but allows (e.g., relatively allows)
easy passage of ions, electrolytes and water, and also nutrients
(such as oxygen or glucose) and small molecules, proteins and other
drugs, wherein optionally the hydrogel or an equivalent gel (e.g.,
a hydrophilic gel) can or is used to maintain a membrane-tissue
contact, and optionally the edema is a central nervous system (CNS)
edema, or a spinal or a brain edema, a tissue edema, an edema
secondary to an injury or a burn, and optionally the temperature of
the lumen solution is below about 37.degree. C., 36.degree. C.,
35.degree. C., 34.degree. C. or 33.degree. C., or below about
25.degree. C. to 30.degree. C., and optionally the hydrogel has a
sufficient permeability to allow (relatively) easy passage of
nutrients, drugs, ions, and water, and optionally the hydrogel is
used to membrane-tissue contact, and optionally the hydrogel is
rigid enough to maintain membrane-tissue contact and support the
semi-permeable hollow fiber membrane.
2. The product of manufacture or device of claim 1, wherein the
concentrated protein, carbohydrate, polysaccharide or polymer
solution, or the osmolyte solution or rejected solute solution, or
the non-rigid hydrogel or gel, comprises: a solute, a polymer, a
carbohydrate, an osmolyte or a rejected solute or a combination
thereof, wherein optionally the solute, polymer, carbohydrate,
osmolyte or rejected solute is partially or completely rejected by
the semi-permeable hollow fiber membrane, wherein optionally the
solute, polymer, carbohydrate, osmolyte or rejected solute is
present in a concentration of between about 1% to 50% in solution,
or between about 0.1% to 60% in solution, and optionally the lumen
solution comprises a serum albumin, or a human or bovine serum
albumin (BSA) or equivalent, or the lumen solution comprises an
artificial cerebrospinal fluid, or the lumen solution comprises a
serum albumin at about 350 g/L or between about 300 to 400 g/L,
optionally in an artificial cerebrospinal fluid, optionally at
between about pH 7.0 to pH 7.6, or at about pH 7.4.
3. The product of manufacture or device of claim 1, wherein the
solute, protein, carbohydrate or polymer is dissolved in an aqueous
solution comprising: a saline, carbohydrate, or saline and
carbohydrate solution, wherein optionally the saline solution is
hypotonic, hypertonic, or isotonic compared to healthy or
non-injured tissue surrounding the edematous or injured area; and
optionally the lumen solution or lumen contents further comprise
proteins, inorganic molecules, organic molecules, nutrients, or
drugs, and optionally the drugs and/or nutrients are for the
treatment or amelioration of the edema, of a burn or injury, or an
underlying disease or condition causing the edema, and optionally
the drugs comprise or are small molecules or proteins, and
optionally the drugs act as antibiotics, anti-inflammatories,
vasoconstrictors, vascular or tissue growth stimulating agents; and
optionally the solution comprises a cerebrospinal fluid or an
artificial cerebrospinal fluid, optionally at between about pH 7.0
to pH 7.6, or at about pH 7.4.
3. The product of manufacture or device of claim 1, wherein the
hollow fiber device is a flexible hollow fiber device, or wherein
the hollow fiber device comprises: fibers having an outer diameter
of between about 150 to 250 .mu.m, or about 200 .mu.m, a flexible
semi-permeable hollow fiber membrane, or several semi-permeable
hollow fiber membranes in a bundle or a module, wherein optionally
the hollow fibers have an outer diameter of between about 100 .mu.m
to about 1 cm, and optionally the hollow fibers have an inner
diameter of between about 50 to about 750 .mu.m; or and optionally
the hollow fibers comprise cellulose fibers, or regenerated
cellulose fibers, or a biocompatible material, or a bioinert
material; or and optionally the hollow fibers have a molecular
weight cut-off of less than about 100 daltons for a rejected
carbohydrate or a rejected salt; and optionally the hollow fibers
have a molecular weight cut-off of between about 100 to about 1000
Daltons for a carbohydrate or a polymer solution; and optionally
the hollow fibers have a molecular weight cut-off of between about
1 to about 60 kDa or greater than about 60 kDa, and optionally the
hollow fibers are reverse osmosis membranes.
4. The product of manufacture or device of claim 1, wherein the
hollow fiber device comprises cellulose fibers, or regenerated
cellulose fibers, or a biocompatible material, or a bioinert
material, wherein optionally the cellulose fibers, regenerated
cellulose fibers, biocompatible material or bioinert material have
a molecular weight cut-off of between about 5 to 20 kilodalton
(kDa), between about 1 to 30 kDa, or about 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 or more
kDa.
5. A method for: removing a fluid or a water from a tissue, an
edematous tissue, an injured or burned tissue, a central nervous
system (CNS) tissue, or a spinal or a brain tissue, in a controlled
fashion, or removing a fluid or a water from a central nervous
system (CNS) tissue, a spinal or a brain tissue, in a controlled
fashion to treat an edema, a central nervous system (CNS) edema, or
a spinal or a cerebral edema; or treat an edema, a CNS, spinal or a
brain inflammation or a CNS, spinal or a brain injury, or a burn
edema, comprising: using the product of manufacture or device of
claim 1, for applying or placing a concentrated protein,
carbohydrate, polysaccharide or polymer solution, or osmolyte
solution or rejected solute, or a non-rigid hydrogel, soft hydrogel
or gel, directly on and/or approximate to an edematous, burned or
injured tissue, or an exposed edematous, burned or injured tissue,
wherein the soft hydrogel substantially conforms to an edematous,
burned or injured area to maximize contact area with the edematous,
burned or injured tissue, wherein optionally an aqueous
proteinaceous, carbohydrate, polysaccharide or hydrogel solution is
pumped across the edematous, e.g., a burned or an edematous, burned
or injured, surface area through the semi-permeable hollow fiber
membrane lumen, wherein optionally a lumen solution induces an
osmotic pressure driving force for water removal, wherein
optionally the rate of flowing or pumping is controlled to allow
fluid from the tissue to flow up to the membrane device due to
osmotic pressure, wherein optionally a hydrogel or an equivalent
gel (e.g., a hydrophilic gel) with significantly large permeability
is used to maintain membrane-tissue contact.
6. A method for: removing water from a tissue, a central nervous
system (CNS) tissue, or a spinal or a brain tissue, in a controlled
fashion; or removing water from an edematous tissue, an edematous
or injured CNS, spinal or a brain tissue, in a controlled fashion
to treat or ameliorate an edema, or a CNS or a spinal or a cerebral
edema; or to treat or ameliorate a tissue, CNS, or a spinal or a
brain inflammation, or a CNS or a spinal or a brain injury,
comprising: using the product of manufacture or device of claim 1,
for applying or placing the hollow fiber membrane with a lumen
solution of a concentrated protein, carbohydrate, polymer, or other
rejected solute or osmolyte solution, or a soft hydrogel, directly
on and/or approximate to the tissue, or the edematous or the
injured tissue, or an exposed injured tissue, or on healthy tissue
approximate to or away from the tissue from which the water will be
removed, or the edematous or the injured tissue, wherein optionally
the soft hydrogel substantially conforms to an injured area to
maximize contact area with the tissue, the edematous or the injured
tissue and/or the healthy tissue from which the water will be
removed, and optionally the hollow fibers are in direct contact
with the tissue, and optionally the hollow fibers conform to the
surface of the injured or healthy tissue, and optionally a protein,
carbohydrate, polymer, or other rejected solute or osmolyte
solution is pumped or flowed across the tissue, the edematous
tissue, or the healthy or injured tissue surface area through the
semi-permeable hollow fiber membrane lumen, and optionally the
lumen solution induces an osmotic pressure driving force for water
removal, and optionally the rate of pumping or flow is controlled
to allow fluid from the tissue to flow up into the membrane device
due to osmotic pressure to alter the rate of water removal, and
optionally the amount or composition of a protein, carbohydrate,
polymer or other rejected solute or osmolyte solution in the lumen
solution is changed or modified to alter the rate of water removal,
and optionally the concentration of the protein, carbohydrate,
polymer, or other rejected solute or osmolyte in the lumen solution
is altered to between about 0.1 to about 50% to alter the rate of
water removal, and optionally the temperature of the lumen solution
is changed in the range of about 20.degree. C. to about 37.degree.
C. to alter the rate of water removal, and optionally a hydrogel
with significantly large permeability is used to maintain
membrane-tissue contact while providing (relatively) easy passage
of nutrients, ions, drug and/or protein treatments, and water, and
optionally the hydrogel conforms, or substantially conform, to the
surface of the tissue contact area, or the treatment area, and
optionally the hollow fibers are flexible and conform, or
substantially conform, to the treatment area.
7. A portable or a small kit comprising a product of manufacture or
device of claim 1, optionally comprising a tubing, a hollow fiber
device and an associated gel, wherein optionally the gel is a
hydrogel.
8. The portable or a small kit of claim 7, further comprising
instructions for practicing a method of claim 5.
9. The portable or a small kit of claim 7, further comprising
instructions for practicing a method of claim 6.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn.119(e) of U.S. Provisional Application No. 61/555,351,
filed Nov. 3, 2011. The aforementioned application is expressly
incorporated herein by reference in its entirety and for all
purposes.
TECHNICAL FIELD
[0003] This invention generally relates to medicine and medical
devices. The invention provides compositions and methods for the
treatment and/or reversal of an edema, e.g., including a central
nervous system (CNS) edema, e.g., a brain or a spinal edema, edema
in burned or an injured tissue such as skin, or any tissue edema,
injury or insult. In alternative embodiments, the invention
provides compositions and methods for a direct treatment and
reversal of an edema, e.g., CNS, brain or spinal edema, including a
membrane transport device, in vitro and in vivo characterization of
edema, and the sensitive early optical detection of the edema,
e.g., tissue, CNS or cerebral edema.
BACKGROUND
[0004] Cerebral edema, an increase in brain tissue water content,
is responsible for significant morbidity and mortality in many
different disease states, including traumatic brain injury (TBI),
stroke, infection, tumor, and a host of chemical and metabolic
intoxications. The two types of cerebral edema are vasogenic edema
and cytotoxic (cellular) edema. Vasogenic edema is characterized by
the disruption of the blood-brain barrier (BBB) and may be caused
by direct injury or by breakdown of the BBB (e.g., by tumors). BBB
disruption leads to the accumulation of blood components in the
brain and an influx of water into the interstitial space between
cells follows, causing swelling of the tissue. Cytotoxic edema is
characterized by the flux of water into brain cells (predominantly
brain glial cells) and is associated with trauma, ischemia and
toxins.
[0005] Glial cells have compensatory mechanisms to restore water
homeostasis across the cellular membrane, but following injury
these mechanisms may be disrupted. TBI is characterized by mixed
cytotoxic and vasogenic edema mechanisms, both contributing to
overall cerebral edema. After TBI, glial cells swell [1] due to
changes in the extracellular pH and concentrations of ions,
including potassium, sodium, and chloride [2]. The resulting
cytotoxic edema combines with the vasogenic edema caused by direct
BBB injury. Reduced blood flow to the affected brain area (cerebral
ischemia) leads to further ion shifts and cytotoxic edema. A
vicious cycle involving components of both types of edema can
proceed until the brain swells uncontrollably resulting in
permanent brain damage or death. A treatment aimed at breaking the
edema cycle and restoring normal ion and protein homeostasis within
the extracellular space would be ideal at reversing cerebral edema
and brain swelling following TBI.
SUMMARY
[0006] In alternative embodiments, the invention provides
compounds, e.g., products of manufacture or devices, for reducing
an edema, including e.g., a central nervous system (CNS) edema, or
a spinal or a brain edema, or any tissue edema. In alternative
embodiments, products of manufacture or devices of the invention
comprise a concentrated protein, carbohydrate, polysaccharide or
polymer solution, or osmolyte solution or rejected solute, a
non-rigid hydrogel or gel, (or a combination thereof), and a
semi-permeable hollow fiber membrane or a bundle or a module having
a lumen, and a hollow fiber device, wherein the concentrated
protein, carbohydrate, polysaccharide or polymer solution, or
concentrated osmolyte solution or rejected solute, or non-rigid
hydrogel or gel, passes through the lumen of the semi-permeable
hollow fiber membrane, bundle or module, and the concentrated
protein carbohydrate, polysaccharide or polymer, non-rigid hydrogel
or gel, or concentrated osmolyte solution or rejected solute,
induces an osmotic pressure that drives water into the hollow fiber
device where it is removed and carried away from the edematous
tissue, e.g., from the burned, traumatized or injured area. An
exemplary device of the invention is illustrated in FIG. 1, as
discussed in detail, below.
[0007] In alternative embodiments, the invention provides
compounds, e.g., products of manufacture or devices, for reducing
an edema, e.g., a central nervous system (CNS) edema, or a spinal
or a brain edema, a tissue edema, an edema secondary to an injury
or a burn, the product of manufacture or device comprising:
[0008] a protein, carbohydrate, polysaccharide or a polymer
solution, or an osmolyte solution or a rejected solute, or
non-rigid hydrogel or gel, or a concentrated protein, carbohydrate,
polysaccharide or polymer solution, wherein optionally these
solutions, non-rigid hydrogels or gels are contained within a lumen
or a hollow fiber of the device,
[0009] wherein optionally the lumen solution or lumen contents
further comprise nutrients, or drugs, and optionally the drugs
and/or nutrients are for the treatment or amelioration of the
edema, of a burn or injury, or an underlying disease or condition
causing the edema, and optionally the drugs comprise or are small
molecules or proteins, and optionally the drugs act as antibiotics,
anti-inflammatories, vasoconstrictors, vascular or tissue growth
stimulating agents;
[0010] a semi-permeable hollow fiber membrane or bundle/module
membrane; and,
[0011] a rigid or a semi-rigid hydrogel,
[0012] wherein the concentrated protein, carbohydrate,
polysaccharide or polymer solution, or osmolyte solution or
rejected solute, or non-rigid hydrogel or gel, passes through the
lumen of a semi-permeable hollow fiber membrane, and the
concentrated protein, carbohydrate, polysaccharide or polymer
solution, or osmolyte solution or rejected solute, or non-rigid
hydrogel or gel, flowing through the semi-permeable fiber membrane,
which is in contact with the tissue, induces osmotic pressure that
drives water into the hollow fiber device where it is removed and
carried away from the edematous, e.g., the injured or burned,
tissue or area of trauma, insult or injury,
[0013] wherein optionally an aqueous proteinaceous, carbohydrate or
polysaccharide solution, or non-rigid hydrogel or gel, is flowed
(e.g., by osmotic force) or is flowed or pumped or passively flows
(such as head pressure) through the semi-permeable hollow fiber or
bundle/module membrane lumen,
[0014] wherein optionally the membrane completely or substantially
rejects a solute but allows (relatively) easy passage of ions,
electrolytes and water, and also nutrients (such as oxygen or
glucose) and small molecules, proteins and other drugs,
[0015] wherein optionally the hydrogel or an equivalent gel (e.g.,
a hydrophilic gel) can or is used to maintain a membrane-tissue
contact,
[0016] and optionally the edema is a central nervous system (CNS)
edema, or a spinal or a brain edema, a tissue edema, an edema
secondary to an injury or a burn,
[0017] and optionally the temperature of the lumen solution is
below about 37.degree. C., 36.degree. C., 35.degree. C., 34.degree.
C. or 33.degree. C., or below about 25.degree. C. to 30.degree.
C.,
[0018] and optionally the hydrogel has a sufficient permeability to
allow (relatively) easy passage of nutrients, drugs, ions, and
water,
[0019] and optionally the hydrogel is used to membrane-tissue
contact, and optionally the hydrogel is rigid enough to maintain
membrane-tissue contact and support the semi-permeable hollow fiber
membrane.
[0020] In alternative embodiments, the hollow fiber device is a
flexible hollow fiber device, or wherein the hollow fiber device
comprises:
[0021] fibers having an outer diameter of between about 150 to 250
nm, or about 200 .mu.m,
[0022] a flexible semi-permeable hollow fiber membrane, or several
semi-permeable hollow fiber membranes in a bundle or a module,
[0023] wherein optionally the hollow fibers have an outer diameter
of between about 100 .mu.m to about 1 cm,
[0024] and optionally the hollow fibers have an inner diameter of
between about 50 to about 750 .mu.m; or
[0025] and optionally the hollow fibers comprise cellulose fibers,
or regenerated cellulose fibers, or biocompatible material, or
bioinert material; or
[0026] and optionally the hollow fibers have a molecular weight
cut-off of less than about 100 daltons for a rejected carbohydrate
or a rejected salt;
[0027] and optionally the hollow fibers have a molecular weight
cut-off of between about 100 to about 1000 Daltons for a
carbohydrate or a polymer solution;
[0028] and optionally the hollow fibers have a molecular weight
cut-off of between about 1 to about 60 kDa or greater than about 60
kDa,
[0029] and optionally the hollow fibers are reverse osmosis
membranes.
[0030] In alternative embodiments, the invention provides
compounds, e.g., products of manufacture or devices, wherein the
concentrated protein, carbohydrate, polysaccharide or polymer
solution, or non-rigid hydrogel or gel, comprises:
[0031] a solute, a polymer, a carbohydrate, an osmolyte, a rejected
solute, wherein optionally the solute, polymer, carbohydrate,
osmolyte or rejected solute is partially or completely rejected by
the semi-permeable hollow fiber membrane,
[0032] wherein optionally the solute, polymer, carbohydrate,
osmolyte or rejected solute is present in a concentration of
between about 1% to 50% in solution, or between about 0.1% to 60%
in solution,
[0033] a serum albumin, or a human or bovine serum albumin (BSA),
or
[0034] a lumen solution of 350 g/L of a serum albumin in an
artificial cerebrospinal fluid at pH 7.4.
[0035] In alternative embodiments, the hollow fiber device
comprises or is a flexible hollow fiber device, optionally
comprising fibers having an outer diameter of between about 150 to
250 .mu.m, or about 200 .mu.m. In alternative embodiments, the
hollow fiber device comprises cellulose fibers, or regenerated
cellulose fibers, optionally with a molecular weight cut-off of
between about between about 5 to 20 kilodalton (kDa), between about
1 to 30 kDa, or about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19 or 20 or more kDa.
[0036] In alternative embodiments, the invention provides methods
for: removing a fluid or a water from an edematous tissue, e.g., a
central nervous system (CNS) tissue, or a spinal or a brain tissue,
or an injured, insulted (e.g., by chemical exposure) or burned
tissue, in a controlled fashion, or removing a fluid or a water
from an edematous area, e.g., a central nervous system (CNS)
tissue, a spinal or a brain tissue, or an injured, insulted (e.g.,
by chemical exposure) or burned tissue, in a controlled fashion to
treat the edema, e.g., the central nervous system (CNS) edema, or a
spinal or a cerebral edema; or treat or reverse a CNS, spinal or a
brain inflammation or a CNS, spinal or a brain injury, or an
inflammation due to an injury, a chemical exposure or a trauma,
comprising:
[0037] using the product of manufacture or device of the invention,
for applying or placing a concentrated protein, a carbohydrate, a
polysaccharide or a polymer solution, or an osmolyte solution or a
rejected solute, or a non-rigid hydrogel or a soft hydrogel or a
gel, directly on and/or approximate to an injured tissue, or an
exposed injured tissue, wherein the non-rigid or soft hydrogel or
gel substantially conforms to the tissue site, e.g., the edematous
tissue, e.g., the burned, traumatized or injured tissue area, to
maximize contact area with the edematous tissue,
[0038] wherein optionally an aqueous proteinaceous carbohydrate,
polysaccharide or polymer solution, or an osmolyte solution or a
rejected solute, or non-rigid or soft hydrogel or gel, is flowed
(e.g., by osmotic force) or is pumped or passively flows (such as
head pressure) across the edematous, e.g., a burned or an injured,
surface area through the semi-permeable hollow fiber membrane
lumen,
[0039] wherein optionally a lumen solution induces an osmotic
pressure driving force for water removal,
[0040] wherein optionally the rate of flowing or pumping is
controlled to allow fluid from the tissue to flow up to the
membrane device due to osmotic pressure,
[0041] wherein optionally a hydrogel or an equivalent gel (e.g., a
hydrophilic gel) with significantly large permeability is used to
maintain membrane-tissue contact.
[0042] In alternative embodiments, the invention provides portable
or a small kits comprising a product of manufacture or device of
any of the invention, optionally comprising a tubing, a hollow
fiber device and an associated gel, wherein optionally the gel is a
hydrogel.
[0043] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the description and drawings, and from the
claims.
[0044] All publications, patents, patent applications cited herein
are hereby expressly incorporated by reference for all
purposes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] The drawings set forth herein are illustrative of
embodiments of the invention and are not meant to limit the scope
of the invention as encompassed by the claims.
[0046] FIG. 1 illustrates an exemplary product of manufacture or
device of the invention in situ, in the brain of an individual;
where FIG. 1A illustrates a sagittal section of a patient's skull,
having implanted or placed in the brain an exemplary product of
manufacture or device of the invention, including an optical
coherence tomography (OCT) probe, the support gel of the exemplary
product of manufacture or device of the invention, and a draining
hollow fiber bundle assembly; and where FIG. 1B illustrates a
close-up of FIG. 1A, illustrating the direct of water flux (efflux)
(the flow direction of fluid in the CNS lumen) as effected by the
exemplary product of manufacture or device of the invention; as
discussed in detail, below.
[0047] FIG. 2 graphically illustrates how many concentrated solutes
and globular proteins (e.g., BSA, or bovine serum albumin) produce
non-linear osmotic pressures as concentrations are varied; and how
flow resistance in a fiber lumen, as measured by viscosity
(relative viscosity), also increases; as discussed in detail,
below.
[0048] FIG. 3 illustrates the early detection of cerebral edema
with a fiberoptic NIRS system using a broadband halogen light
source: FIG. 3A illustrates how a dual fiberoptic probe is passed
into the right cerebral cortex through a burr hole while the ICP
monitor is placed contralaterally; FIG. 3B Top: graphically
illustrates intracranial pressure measurements before and after the
injection of distilled water; FIG. 3B Bottom: graphically
illustrates NIR reflectance measurements obtained with fiberoptic
probe, where an optical trigger is depicted as a vertical blue
line; FIG. 3C graphically illustrates the latency between injection
of water (time point 0), optical trigger, and defined threshold ICP
values; as discussed in detail, below.
[0049] FIG. 4A graphically illustrates data acquired from optical
coherence tomography (OCT) imaging of excised murine brain tissue,
where (as illustrated in FIG. 4B) an image composed of 2048 depth
profiles (2 mm depth) spanning 5 mm in width was acquired over the
boundary between the two halves (indicated by arrow); as discussed
in detail, below.
[0050] FIG. 5 graphically illustrates the amount of water removed
(%) by a brain by each condition (see below) after 30 minutes of
contact with an exemplary product of manufacture of the invention,
the first column indicating fibers and gels, the second column
indicating fibers only, the third column indicating gel only, and
the fourth column (the right) the negative control; as discussed in
detail, below.
[0051] FIG. 6 illustrates a diagram of a high-resolution
spectral-domain optical coherence tomography system integrated into
a fixed stage upright microscope; as discussed in detail,
below.
[0052] FIG. 7 illustrates a schematic of a wide field imaging
system; as discussed in detail, below.
[0053] FIG. 8 illustrates a schematic of an exemplary, optionally
portable, device of the invention, and this exemplary application
for a device, e.g., a portable device, of the invention; as
discussed in detail, below.
[0054] FIG. 9 illustrates an exemplary hollow fiber-hydrogel device
of the invention; with the left image illustrating an exemplary
hollow fiber attached to an inlet and an outlet port, and the right
image illustrating an application of an exemplary device with
multiple parallel hollow fibers embedded in a hydrogel to a brain
surface; as discussed in detail, below.
[0055] FIG. 10 (FIG. 10/14) illustrates how an exemplary hollow
fiber-hydrogel device of the invention improves survival in a mouse
model of cytotoxic cerebral edema: FIG. 10A graphically illustrates
the time to expiration (min.) for three treatment groups, measuring
no treatment (control), craniectomy (control) and craniectomy with
the exemplary hollow fiber-hydrogel device of the invention as a
function of time to expiration of the animal; FIG. 10B (FIG. 11/14)
graphically illustrates a Kaplan-Meier survival curve of percent
(%) survival over time (minutes, min.); as discussed in detail,
below.
[0056] FIG. 11 (FIG. 12/14) and FIG. 12 (FIGS. 13/14 and 14/14)
graphically illustrate the effectiveness of a hollow fiber-hydrogel
device of the invention in limiting the increase in brain tissue
water content: FIG. 11 graphically illustrates a percent (%)
increase in brain water content, as is shown for water-intoxicated
mice with no treatment (W), water-intoxicated mice treated with
craniectomy only (W+C), and water-intoxicated mice treated with
craniectomy+HFHD (W+C+D); FIG. 12A graphically illustrates the
percent (%) increase in brain water content is shown for
water-intoxicated mice with no treatment (W), water-intoxicated
mice no treatment, water-intoxicated craniectomy only ("C"), and
water-intoxicated mice treated with craniectomy+HFHD (W+C+D); and,
FIG. 12B graphically illustrates the percent (%) increase in brain
water content, as is shown for no water-intoxicated mice with no
treatment (W), no water and treated with craniectomy only (C),
craniectomy only ("C"), and no water-intoxication with the
exemplary device of the invention only, the "HFHD" ("D"); as
discussed in detail, below.
[0057] Like reference symbols in the various drawings indicate like
elements.
[0058] Reference will now be made in detail to various exemplary
embodiments of the invention, examples of which are illustrated in
the accompanying drawings. The following detailed description is
provided to give the reader a better understanding of certain
details of aspects and embodiments of the invention, and should not
be interpreted as a limitation on the scope of the invention.
DETAILED DESCRIPTION
[0059] The invention provides compositions (product of
manufactures, devices) and methods for the treatment and/or
reversal of a CNS, a spinal or a brain edema. In one embodiment,
the invention provides compositions and methods for a direct
treatment and reversal of a CNS, a spinal or a brain edema,
including a membrane transport device, in vitro and in vivo
characterization of edema, and the sensitive early optical
detection of the CNS, a spinal or a cerebral edema. The product of
manufacture/device of the invention can eliminate water from
edematous CNS, a spinal or brain tissue directly and in a
controlled fashion.
[0060] In one embodiment, the invention provides a device using
concentrated a protein, carbohydrate or polysaccharide or a polymer
solution, or an osmolyte solution or a rejected solute, or a
non-rigid hydrogel or a gel or any combination thereof, that pass
through the lumen of a semi-permeable hollow fiber membrane or
bundle/module. In one embodiment, the protein, carbohydrate,
polysaccharide polymer solution, or a non-rigid hydrogel or a gel,
induces osmotic pressure that drives water into the hollow fiber or
bundle/module device where it is removed and carried away from the
edematous site, e.g., the injured or burned area (the solution is
not in direct contact with the fluid from the tissue; it is the
hollow fiber membrane and/or the hydrogel that is directing
contacting the tissue). In alternative embodiments, osmotic
pressure is controlled by (osmotic pressure is modified by changes
in): temperature, concentration, and solute. Because the osmotic
pressure is generated by the presence of the rejected species in
the hollow fiber or bundle/module lumen and not the ion species,
the process has the advantage of maintaining ionic equilibrium.
Furthermore, the system will operate in time scales on the order of
the swelling rate, ensuring system stability and allowing effective
feedback control. In one embodiment, scattering information from
optical coherence tomography (OCT) will be used to infer swelling
rate in the feedback process. The invention provides an integrated
system to detect and reverse cerebral edema and, thus, reduce a
CNS, a spinal or a brain damage and death in affected
individuals.
[0061] The invention provides a novel membrane transport device
designed to extract water from a CNS tissue, e.g., a CNS, a spinal
or a brain tissue. The invention provides a novel application of a
hollow fiber or bundle/module membrane transport device that can be
used to actively extract water from tissue in vivo and in vitro.
The invention also comprises establishing an "optical signature" of
early CNS, spinal or a brain tissue edema and, subsequently,
development of a feedback (closed-loop) paradigm for the device to
optimally detect and treat a CNS tissue, e.g., a spinal or a brain
tissue swelling in an integrated control system.
[0062] In one embodiment, the devices of the invention exploit the
inevitable osmotic pressure that is generated during transport of
concentrated rejected species (such as proteins or polymers) across
a semi-permeable membrane in the presence of aqueous systems.
Typically, membrane processes are used to separate or exchange
solutes in the media in contact with the membrane. In doing so, the
permeate flux is limited due to the osmotic pressure of the
rejected solutes due to concentration polarization [3,4]. As an
example, one of the most common models used to relate permeate
flux, J, to the transmembrane pressure driving force, .DELTA.P, is
the Kedem-Katchalsky model which states that [5]:
J = .DELTA. P - .sigma. .DELTA..pi. .mu. ( R m + R p ) ##EQU00001##
[0063] (1) The osmotic pressure, .DELTA..pi., is a function of the
solute concentration difference across the pores at the membrane
surface. The osmotic reflection coefficient, .sigma., provides a
measure of the membrane permselectivity, R.sub.m is the membrane
resistance during ultrafiltration, R.sub.p is the extra resistance
associated with any fouling, and .mu. is the solution viscosity.
The osmotic pressure in these processes is largely regarded as a
resistance to separation and must be overcome by increasing the
operating transmembrane pressure. For a hollow fiber or
bundle/module device, the transmembrane pressure is an average of
the hydraulic pressure in the lumen minus the pressure on the
outside of the fiber.
[0064] In one embodiment, the invention uses a model that takes
advantage of the fundamental physics of this process by operating
the process where .DELTA.P<.DELTA..pi.. This will result in a
flux of solvent into the fiber. In addition, we will examine the
controllability of the process by adjustments of .DELTA.P or feed
solution concentrations to the device. As mentioned above, this
process is amenable to stable process control since the reversal
process will operate on the same time scale as the swelling
phenomena. In one embodiment, the invention uses an OCT probe to
use as an indication of the dynamic state of tissue water infusion.
FIG. 1 illustrates the overall aspects of this embodiment of the
invention.
[0065] Although we will address a number of factors in determining
an effective design, perhaps one of the most critical factors in
developing this process is selection of solutes that will provide
the appropriate driving force to this therapeutic application. In
one embodiment, the invention uses protein and dextran solutions.
We have done extensive research on the osmotic pressure of protein
solutions and have developed the most rigorous free-solvent model
for osmotic pressure prediction available [6,7]. This invention
addresses the solution in terms of the protein-ion binding and
hydration, and, more specifically, changes in chemical
potential.
[0066] In particular, for a single protein with a monovalent salt,
the free-solvent model can be described as:
.DELTA..pi. = RT V _ 1 ln { ( N 1 II + ( 1 - v 12 - v 32 ) N 2 II +
N 3 II ) N 1 I ( N 1 II - v 12 N 2 II ) N I } ##EQU00002## [0067]
(2) where N.sub.j.sup.II denotes the moles of species j in the
lumen, N.sub.1.sup.I denotes the moles of water in the tissue,
N.sup.I denotes the total moles of solution in the tissue, and
v.sub.j2 is the net number of moles of solution component j (1 for
water, 3 for salt) that is interacting with protein (2) to make up
the new solvent-interacting protein. The model has been shown to
have excellent predictability of osmotic pressure for both single
and binary protein solutions [8,9]. We have also successfully
related this model to understanding the elusive limiting-flux
phenomena in membrane separations processes and the critical flux
problem using only physically relevant parameters [10,11]. We have
shown that this model has excellent agreement for uncharged
polymers provided their solvent accessible surface area (SASA) can
be determined [8]. In the dynamic membrane separation processes,
the ion binding contribution been shown to be insignificant
[10].
[0068] In one embodiment, the invention incorporates this
relationship to Eqn. (1) to couple solute concentration to the flux
of water across the hollow fiber. As shown in FIG. 2, many
concentrated solutes, and most globular proteins we studied, have
the advantage of producing non-linear osmotic pressures as
concentration is varied. However, flow resistance in the fiber
lumen, as measured by viscosity, also increases (FIG. 2).
[0069] In one embodiment, the invention provides an integrated
system to detect and reverse cerebral edema and, thus, reduce a
CNS, a spinal or a brain damage and/or death in affected
individuals, as illustrated e.g. in FIG. 1, which illustrates a
exemplary principle of using membrane transport device for edema
reversal.
[0070] In one embodiment, aqueous solutions are flowed or pumped or
passively flowed (such as by head pressure) across the edematous,
e.g., a burned or an injured, surface area through the
semi-permeable hollow fiber or bundle/module membrane lumen. In one
embodiment, the membrane is selected such that it completely
rejects the solute but allows easy passage of ions, electrolytes
and water, and also nutrients (such as oxygen or glucose) and small
molecules, proteins and other drugs. In one embodiment, the rate of
flowing or pumping or passively flowing will be controlled to allow
fluid from the tissue to flow up to the membrane device due to
osmotic pressure. In one embodiment, a hydrophilic gel or an
equivalent gel (e.g., a hydrophilic gel) with significantly large
permeability is used to maintain membrane-tissue contact. In one
embodiment, the OCT probe is appropriately placed to monitor the
rate of swelling. The probe signal can be sent to a feedback
control system that adjusts flow or pump speed or solution
concentrations to maintain appropriate tissue water and ion
content.
[0071] In one embodiment, devices of the invention are capable of
treating cerebral edema directly. In one embodiment, the invention
provides a novel membrane transport device to eliminate water from
edematous CNS, spinal or brain tissue directly and in a controlled
fashion. In one embodiment, the invention provides a novel device
for a clinically important syndrome.
[0072] FIG. 2 illustrates the relationship between osmotic pressure
and solution viscosity for bovine serum albumin for various
solution properties. This figure also shows the excellent
prediction of the free-solvent model (FSM) to the data. The
critical aspect of this figure relative to one embodiment of the
invention is balance pumping.
[0073] In one embodiment, the invention provides for the early
detection of cerebral edema with optical techniques; and provides a
reliable real-time method to detect cerebral edema in vivo. In one
embodiment, the invention provides a modality of detecting cerebral
edema directly. Real-time optical interrogation of brain tissue
with near-infrared fiberoptic probes can be capable of detecting
cerebral edema [12]. In particular, we have demonstrated that
reduction in NIR reflectance during early cerebral edema occurs
prior to ICP elevation [12], providing a clinically-relevant time
window for therapy. In one embodiment, the invention uses OCT with
high temporal resolution to detect early changes in NIR light
scattering during the development of cerebral edema. In one
embodiment, sensitive OCT imaging of the brain cortex during the
evolution of cerebral edema yields a clinically-relevant detection
algorithm that can then be incorporated into a closed-loop
treatment paradigm with our membrane transport device for
integrated detection and direct treatment of cerebral edema (FIG.
1).
[0074] In one embodiment, the invention provides membrane transport
devices designed to extract water from a CNS, a spinal or a brain
tissue. In one embodiment, the invention comprises: hollow fiber or
bundle/module membrane properties, solution properties, and gel
properties. Design criteria can be used to determine the most
appropriate choices for evaluation. Fractional factorial design
analysis will be used if necessary to maximize information from
each experiment and minimize the number of combinations for this
work. Factorial design analysis is a systematic method of
experimentally and quantitatively determining the effect of several
variables on system outputs [13,14]. In one embodiment, factorial
design analysis, analysis-of-variance (ANOVA) also is used to
determine if parameters are statistically significant in affecting
osmotic pressure and water flux [14]. In one embodiment, the
appropriate manipulated variable (i.e., pump speed, solute
concentration) for system control can be determined.
[0075] Membrane Selection. In one embodiment, hollow fibers from
commercially available dialyzer constructed with various hollow
fiber polymeric materials is used (e.g., Baxter dialyzers: XENIUM
XPH.TM. (polynephron), REVACLEAR.TM. (polyflux), OPTIFLUX.TM.
(polysulfone)). These systems have been selected because of their
proven clinical effectiveness and appropriate molecular weight
cutoff.
[0076] Protein/Polymer Selection, Preparation, Evaluation. In one
embodiment, proteins and dextrans are used. Table 1 (below)
summarizes the exemplary solutes for use in the invention. These
solutes have also been selected because of their variation in size,
which is coupled to their osmotic pressure. In one embodiment,
free-solvent models are used to predict their range of osmotic
pressure (using the solvent accessible surface area, and protein
charge, as categorized by their isoelectric points, pI) [8].
Solutions properties can be selected around the physiological range
of cerebrospinal fluid (in mmol/L: Na, 146.5; K, 27.7; Ca, 1.65;
Mg, 1.235; Cl, 213.5, P, 0.65) [15]. In one embodiment, viscosity
and density of solutions using Ostwald viscometers is determined
(e.g., Cannon Fenske Cat. Nos. 75 S560, 150 N956, 200 N843) and a
pycnometer (e.g., Kimble Kontes, Cat. No. 15123R-10),
respectively.
TABLE-US-00001 TABLE 1 Properties of Selected Proteins
Protein/Polymer (kD) pI PDB Ref. Dextrans .gtoreq.60 Hen egg
lysozyme (HEL) 14 11.0 1LZT [16,, 18] Bovine serum albumin (BSA) 67
4.7 -- [19] Rabbit transferrin 80 7.0 1JNF [20,, 22] Bovine
lactoferrin 80 9.0 1LFC [23, 24]
[0077] FIG. 3 illustrates the early detection of cerebral edema
with a fiberoptic NIRS system using a broadband halogen light
source. FIG. 3 A. Dual fiberoptic probe is passed into the right
cerebral cortex through a burr hole while the ICP monitor is placed
contralaterally. FIG. 3 B. Top: Intracranial pressure measurements
before and after the injection of distilled water (30% body weight,
i.p.; black arrows). Bottom: NIR reflectance measurements obtained
with fiberoptic probe. In this example, the optical trigger
(vertical blue line, for significant decline in baseline
reflectance) occurs 21.2 minutes prior to reaching a pathologically
increased ICP of 20 mmHg. FIG. 3 C. Latency between injection of
water (time point 0), optical trigger, and defined threshold ICP
values (n=3, mean.+-.SEM). Optical trigger for a decline in
reflectance occurs well before threshold rises in ICP to 10, 15, or
20 mmHg ** indicates p<0.02 compared to 10, 14 or 20 mm Hg.
[0078] The potential proteins listed in Table 1, are globular and,
as such, their physical structures are not expected to change
significantly with small changes in solution properties but can
denature [25,26,27,28,29]. We will take care to avoid these
solution properties of concern.
[0079] Gel Properties: in alternative embodiments, concentrations
of agar (e.g., Agar, Sigma: A1296-1 kg, CAS: 9002-18-0) and NaCl
for our initial gels (e.g., 0.3% agar, 3% NaCl) are used. Hydraulic
permeability will be determined or checked.
[0080] In one embodiment, the device of the invention can actively
remove water from a CNS, a spinal or a brain tissue in vivo, which
can be demonstrated in animal models of cerebral edema.
[0081] Models of cerebral edema that can be used: water
intoxication and cortical freeze injury [12,30]. The water
intoxication model is a model of pure cytotoxic edema involving
intraperitoneal injection of distilled water (30% body weight).
This leads to a reproducible pattern of progressive cytotoxic edema
and increased ICP (FIG. 3). We will apply the membrane transport
device on the surface of the mouse brain after exposure via
atraumatic craniectomy. This will allow adequate contact of the
gel/fiber matrix to the brain surface for water efflux. Endpoints
will include brain water content, measured as described [12] by a
sensitive wet-dry weight method, and neurological outcome by direct
observation. The cortical freeze injury model is a model of pure
vasogenic edema. Cortical freeze injury disrupts the BBB and leads
to water influx from the bloodstream. Following cortical freeze
injury, we will immediately apply the membrane transport device to
the surface of the brain. Endpoints as before will include brain
tissue water content and neurological outcome.
[0082] In one embodiment, the devices of the invention provide
excellent surface contact between a CNS, e.g., a spinal or a brain
surface, and the membrane transport device. In one embodiment, the
appropriate gel concentrations are used to conform to the CNS
surface or tissue, e.g., spine or brain. In one embodiment, water
efflux from the CNS, spine or brain occur through the dura
(membrane covering the brain), and water can flow across the mouse
dura in response to osmotic gradients [31]. The water intoxication
and cortical freeze injury models can show a significant increase
in brain tissue water content in order to demonstrate that membrane
transport devices of the invention can reverse this. We have
demonstrated significant increases in brain water content using
these models in previous work [12,30].
[0083] The ability of optical coherence tomography (OCT) imaging to
detect cerebral edema can be tested. Previously reported results
demonstrate a reduction in NIR reflectance preceding ICP elevation
during early cerebral edema using a dual fiber optic reflectance
detector weighted toward measurement of scattering through a close
separation between fiber cores [12]. The ability of OCT to detect
these same changes with improved spatiotemporal resolution can be
tested. OCT can be thought of as an optical analog of ultrasound
imaging, in which the intensity and time delay of reflected light
is used to generate cross-sectional images of tissue microstructure
with micron-level resolution [32]. Second-generation instruments
utilize Fourier-domain, rather than time-domain, detection to
realize several orders of magnitude in system sensitivity that can
be used to increase acquisition speed and stability
[33,34,35,36,37]. Multi-functional versions of such systems can be
implemented using the unrestricted use of fiber-optic components
[38], and can be adapted for endoscopic application [39,40]. In
addition, it has been demonstrated that optical scattering and
reflectivity coefficients can be extracted from OCT images
accurately and with more than sufficient spatiotemporal resolution
[41,42]. The subsurface structure of the animal models can be
endoscopically probed, as described herein to determine the value
of various optical parameters from optical coherence tomography
(OCT) images. A similar reduction in tissue reflectivity with the
onset of cerebral edema, and an increase with the use of a membrane
transport device of this invention. These measurements can be used
for inferential prediction of tissue swelling and apply this to a
feedback control strategy.
[0084] To separate the effects of the reduction in NIR reflectance
inherent to the sample from changes in intensity caused by the
system, two methods are employed. The first is the introduction of
a small reference reflector of known reflectance within the field
of view of the probe but above the tissue sample surface. This will
allow normalization of the backscattered intensity from within the
tissue to yield directly comparable depth-resolved maps of absolute
tissue reflectivity, even between different imaging sessions.
Second, our analysis takes advantage of the fact that we obtain
depth-resolved information to extract optical parameters based on
depth-dependent changes in reflectivity. In basic principle, we
expect to see a roughly exponential reduction in the rate of
drop-off in the reflectivity profile of light intensity as a
function of depth below the tissue surface with the onset of
cerebral edema and a reversal with the application of the membrane
device. The relatively high degree of optical scatter typically
found in neural tissue now becomes advantageous, as it should be
easier to observe changes in a high depth-dependent rate of change
in back-reflected intensity.
[0085] FIG. 4A graphically illustrates data acquired from optical
coherence tomography (OCT) imaging of excised murine brain tissue.
A small section was cut and laid flat, with a buffer solution
applied topically at regular intervals to half the tissue. An image
composed of 2048 depth profiles (2 mm depth) spanning 5 mm in width
was acquired over the boundary between the two halves (indicated by
arrow). Signal to noise (SNR) profiles of backreflected intensity
as a function of depth beneath the tissue surface were determined
for each half Two effects should be noted in the resulting plots.
First, there is a significant difference in absolute backreflected
signal level at all depths between the two halves as a result of
the uncalibrated difference in their water content. Second, there
is a visible difference in the slopes of these intensity profiles
that are indicative of differences in scattering coefficients.
Reduction in Near-Infrared (NIR) Light Reflectance During Cerebral
Edema
[0086] Our previous results show that there is a reduction in NIR
optical reflectance during the early development of cerebral edema
(FIG. 3) [12]. These results, obtained in the water intoxication
model of cytotoxic edema, provide proof of principle for the early
detection of CNS, spinal or a cerebral (e.g., brain) edema with
optical methodologies.
Efficacy of Exemplary Membrane Transport Device of the Invention in
Removing Water
[0087] We performed two initial experiments. First, we place a
commercially available hollow fiber cartridge (Baxter CF15
Dialyzer) 25 cm above a container of water (that was in contact
with the fiber bundle shell) and pumped a solution (Sigma Cat. No.
A3059-100G, 60 g/L BSA solution, 40 mM KCl, pH 6.9) at 8 mL/min
through the lumen of the bundle fibers. We ran the system for 2 h
and removed 61.5.+-.4.95 mL from the container via the osmotic
pressure gradient. Next, we removed the hollow fibers from a
similar bundle and placed onto a 0.8% agar gel which was partially
submerged in a KCl solution (40 mM KCl). We pumped a solution of
(100 g/L BSA solution, 40 mM KCl, pH 7.1) through the lumen of the
bundles for approximately 3 h at a flowrate of 8 mL/min. The
contact area was approximately 243 mm.sup.2. The results showed
that 60% of the KCl solution was removed by osmotic pressure by the
fibers via the gel. We also performed a control study using a
similar gel (area of 206 mm.sup.2) partially submerged in a KCl
solution. For the control only 7.6% of the KCl solution was removed
through evaporation.
Efficacy of Prototype Membrane Transport Device in Removing Water
from Brain Tissue
[0088] FIG. 5 graphically illustrates the amount of water removed
(%) by each brain by each condition after 30 minutes of contact
with an exemplary product of manufacture of the invention, the
first column indicating fibers and gels, the second column
indicating fibers only, the third column indicating gel only, and
the fourth column (the right) the negative control. Contact areas
for non-control cases was held constant. Two brain halves were
studied using each condition (n=2). Flowrate: 8 mL/min.
[0089] In preliminary studies with postmortem dissected brain
tissue, we have applied the membrane transport device and verified
removal of water from the brain tissue. The dissected brains were
cut into half for use in one of the three conditions or as a
control. The three conditions tested were: 1) fibers were placed on
top of an agar gel which was in direct contact with the cerebral
cortex (fiber and gel); 2) fibers were placed directly onto the
cerebral cortex (fibers only), and; 3) gel was placed directly onto
the cerebral cortex (gel only). In all studies, the fibers had a
BSA solution (100 g/L BSA solution, 3% NaCl solution, pH 7.22)
passed through them, with a flowrate of 8 mL/min, to induce a flux
of water from the tissue. The gel was prepared using 0.3% agar and
3% NaCl solution. The gel thickness was .about.5 mm. The contact
area for all studies was 100 mm.sup.2. Initially, we immersed the
tissue in distilled water for 40 min to allow maximum uptake of
water (.about.13%). After the tissue had absorbed water, each of
the them was studied using one of the three conditions or the
control. In all studies, the brains were wrapped in polyvinylidene
chloride film to minimize evaporation and allowed 30 min for water
removal. The tissue was weighed before and after each experiment to
determine the amount of water removed. The results (FIG. 5) show
that all of the three conditions removed a significant amount of
water. From the combined observations, it is likely that further
time given to the experiment would result in larger fluid removal
using the combined hollow fiber/gel system.
Second-Generation Optical Systems
[0090] Two second-generation optical systems can be utilized. The
first is a higher resolution system in the near-infrared integrated
into an upright microscope. The second has been designed for wider
field imaging of structures that cannot be imaged with the upright
microscope system, and will utilize a source in the 1300 nm
wavelength range and has been adapted for use with a variety of
imaging probes.
[0091] One high resolution system has been optimally tuned for the
following objectives: UPlan S-Apo 20.times. (0.75NA, 0.65WD) for
detailed high-resolution images and the UPlan S-Apo 4.times.
(0.16NA, 13.0WD) for slightly lower resolution, wider-field of view
images.
[0092] FIG. 6 is a diagram of a high-resolution spectral-domain
optical coherence tomography system integrated into a fixed stage
upright microscope (pbs: polarizing beam splitter, Pol. Mod.:
polarization modulator, g: diffraction grating, lsc: line scan
camera, s: scanning galvanometers, um: upright microscope, e:
recording electrode, i: illumination source). A schematic of the
SD-OCT system is shown in FIG. 6: Light generated by a broadband
source Ti:Sapphire laser (INTEGRAL OCT.TM., FemtoLaser Inc.) is
split by a fiber-based 70/30 splitter. The source emits an average
power of 80 mW centered at 820 nm and a full-width-at-half-maximum
spectral bandwidth of .about.160 nm, resulting in an axial
resolution of .about.1-2 .mu.m in air. Light reflected from the
sample arm of the interferometer is combined with that reflected
from the static reference arm and directed into the detection arm.
This consists of a high-resolution polarization-sensitive
spectrometer in which the light is collimated, dispersed by a high
efficiency (>90%) transmission grating (1200 lines/mm), focused
and split via a lens and polarizing beam splitter cube onto two
synchronized line scan cameras. The line scan cameras (Basler
Sprint series) can acquire 140 k depth profiles per second. This
system is capable of shot-noise limited detection and an effective
spectral resolution of 0.14 nm, resulting in a ranging depth of
.about.2 mm in air. The sample arm beam path of the SD-OCT system
has been integrated into an Olympus BX61WI.TM. upright microscope
adapted for electrophysiology (FIG. 13). The microscope itself is
capable of motorized axial stepping with a resolution of 10 nm, and
is fitted with a Sutter Instruments MT78 motorized platform stage
for lateral stepping. The video port has been used to introduce the
SD-OCT beam into the microscope. An optical fiber port collimator
sends light to a galvanometer-based scanner set (Cambridge
Instruments XY-set customized with no differential controller for
lower stationary position jitter). The pivot points of the scanner
will be relayed to the back focal plane of the microscope objective
to minimize field curvature. This system has been optimally tuned
for the following objectives: UPlan S-Apo 20.times. (0.75NA,
0.65WD) for detailed high-resolution images and the UPlan S-Apo
4.times. (0.16NA, 13.0WD) for slightly lower resolution,
wider-field of view images.
[0093] The sample arm beam path of the SD-OCT system has been
integrated into an Olympus BX61WI.TM. upright microscope adapted
for electrophysiology. The microscope itself is capable of
motorized axial stepping with a resolution of 10 nm, and is fitted
with a Sutter Instruments MT78 motorized platform stage for lateral
stepping. The video port has been used to introduce the SD-OCT beam
into the microscope. An optical fiber port collimator sends light
to a galvanometer-based scanner set (Cambridge Instruments XY-set
customized with no differential controller for lower stationary
position jitter). The pivot points of the scanner will be relayed
to the back focal plane of the microscope objective to minimize
field curvature.
[0094] A schematic of the wide field imaging system is shown in
FIG. 7. The output of a custom-built fiber-coupled source powered
by 8 SLEDs with an overall power of 68 mW and a FWHM bandwidth of
213 nm centered in the 1300 nm range is aligned with a polarizing
beam splitter and an electro-optic polarization modulator such that
transmitted light can be toggled between polarization states that
are perpendicular in a Poincare sphere representation. This light
is sent into an interferometer composed of a fiber circulator and a
90/10 fiber splitter for efficient sample arm illumination and
collection. The reference arm is composed of a lens, polarizer,
variable neutral density filter, and a stationary mirror. Light
returning from both arms passed back through the fiber splitter and
circulator and was directed to a polarization-sensitive
spectrometer. In the spectrometer, the optical spectrum was
dispersed by a transmission grating, focused with a planoconvex
lens, and split with a polarizing beam splitter cube onto two
Goodrich line scan cameras (SU1024LDH, 1024 pixel InGaAs 14-bit
CAMERALINKT.TM. A=.pi.r.sup.2 output at 45 kHz). A polarizer is
introduced between the polarizing cube and one camera to improve
rejection of horizontally polarized light from the vertical
polarization channel.
Other Applications for Use of Exemplary Edema Reduction Devices of
the Invention
[0095] In alternative embodiments, devices of the invention are
portable, and advantages of this portable design, or "portability",
is its use in the event of a catastrophic event or in the warfare
theatre during active combat.
[0096] In alternative embodiments, the design for flow-through the
lumen (the protein solution) can be achieved with very low flow
including gravity feed. In alternative embodiments, a CerebroSpinal
Fluid (CSF) solution can be stored in flexible bags (just as
lactated ringer's solution or saline solutions used in hospitals
and temporary combat emergency facilities such as MASH (Mobile Army
Surgical Hospital).
[0097] In alternative embodiments, these bags are connected to
transfer tubing and the device and hung over the patient's injury,
the resulting flow will be sufficient to induce the osmotic
pressure effect. In the field, the device design will be effective
for first responders, and can be carried in a small kit that
supplies the tubing, hollow fiber device and the associated gel.
The kit can be rapidly deployed and the flexibility of the fibers,
as well as the efficacy of the device (it does not need to cover
the entire edematous, e.g., burned or injured area), allows for its
use in a number of emergency applications were skull fracture,
skull removal or craniotomies have taken place or for use with
reducing swelling in other areas of the body were contact with the
device is assessable such as spinal swelling.
[0098] FIG. 8 is a schematic of an exemplary, optionally portable,
device of the invention, and this exemplary application for a
device, e.g., a portable device, of the invention. The gravity feed
of the solution is an alternative embodiment, as is the retentate
collection device illustrated.
Kits and Instructions
[0099] The invention provides kits comprising compositions and
methods of the invention, including instructions for use thereof.
In alternative embodiments, the invention provides kits comprising
a composition, product of manufacture, or mixture or culture of
cells of the invention; wherein optionally the kit further
comprises instructions for practicing a method of the
invention.
[0100] In alternative embodiments, the invention provides portable,
movable and/or small kits that can comprise tubing, a hollow fiber
device and the associated gel.
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[0149] The invention will be further described with reference to
the following examples; however, it is to be understood that the
invention is not limited to such examples.
EXAMPLES
Example 1
Hollow Fiber-Hydrogel Devices of the Invention Improve Survival
Following Cerebral Edema
[0150] The data presented herein demonstrates that embodiments of
hollow fiber-hydrogel devices of the invention effectively improve
survival following cerebral edema. In alternative embodiments of
the invention provides hollow fiber-hydrogel devices (HFHD) for
direct surface contact-based treatment of severe cerebral edema. In
alternative embodiments the invention provides direct
surface-contact-based treatments using an exemplary hollow
fiber-hydrogel devices (HFHD) of the invention. Using devices of
the invention, tissue water extraction and survival is successfully
enhanced in mice with severe cerebral edema.
SUMMARY
[0151] Methods:
[0152] Brain edema was induced in adult mice via water intoxication
by intraperitoneal water administration (30% body weight, i.p.).
Control mice received no treatment. A distinct group of mice were
treated with craniectomy but no device application. A third
experimental group was treated with craniectomy and the exemplary
HFHD of the invention. This exemplary HFHD contained a lumen
solution of 350 g/L BSA in artificial cerebrospinal fluid at pH 7.4
and room temperature. Brain water content and survival were
assessed as endpoints.
[0153] Results:
[0154] Craniectomy and application of the HFHD enhanced survival in
mice with severe cerebral edema. Mice treated with a craniectomy
and HFHD (n=5) survived up to five hours longer than mice treated
with craniectomy only (n=5) (p<0.0001) or no treatment (n=5)
(p<0.0001). Mice treated with a craniectomy and HFHD (n=5) had a
survival rate of 80% within the observation period (360 minutes),
whereas no mice treated with craniectomy only (n=5) or no treatment
(n=5) survived longer than 53 and 35 minutes, respectively.
Statistical significance was observed for survival rate between the
animals treated with HFHD (n=5) vs. craniectomy only (n=5)
(p<0.0001), and HFHD vs. no treatment (n=5) (p<0.0001).
[0155] Conclusions:
[0156] Here we demonstrate the feasibility of an exemplary HFHD of
the invention to treat a cerebral edema using this art-accepted
animal model. Advantages of this exemplary HFHD of the invention
includes modifiability in terms of rate of water removal based on
alterations in lumen solution properties; and modifiability in
terms of size and contact area to the brain surface. These results
indicate that controlled water extraction from edematous brain
tissue can be performed and lead to increased survival compared to
craniectomy only. In alternative embodiments, exemplary HFHD of the
invention is used to treat traumatic CNS, spinal or brain
injuries.
Methods
[0157] Hollow Fiber-Hydrogel Devices
[0158] The exemplary hollow fiber-hydrogel device (FIG. 1)
(hereafter HFHD) comprises or consists of a hollow fiber
semi-permeable membrane system embedded in a moldable, soft
hydrogel that is placed directly on the exposed edematous, e.g.,
burned or injured, tissue and will conform to the edematous, e.g.,
burned or injured, area to maximize contact area. In addition, the
hydrogel will ensure that the contact between fiber and tissue is
maintained. An aqueous fluid containing concentrated, fully
rejected species (such as proteins) is passed through the lumen of
the fibers. The hydrogel contact is continuous through the moldable
gel and the tissue resulting in an inevitable osmotic pressure.
This pressure gradient will gently remove fluid from the tissue
through the gel and ultimately through the fibers and away from the
subject.
[0159] In one embodiment, a major advantage of using the HFHD lies
in its intrinsic nature. The water removal rate can be controlled
and modified as treatment requires based on alterations in the
lumen solutions properties. A few of the possibilities are changes
in the impermeable solute concentration to alter the osmotic
pressure of the lumen solution, altering the flow properties (e.g.
flow rate or viscosity), and increasing the number of hollow fibers
or treatment contact area.
[0160] In alternative embodiments, the choice of hollow fibers
requires flexibility and knowledge of the lumen solution
properties. The smaller the hollow fiber outer diameter is, as well
as the hollow fiber material, will determine the flexibility and,
more importantly, the range of surface area which can be treated.
Flexible hollow fibers with a relatively small outer diameter (200
.mu.m) will be able to mold to brain gyrations while the hydrogel
ensures that fiber-tissue contact is maintained.
[0161] In this study, the exemplary HFHD was developed using
regenerated cellulose fibers with a molecular weight cut-off of 13
kDa (Spectrum Laboratories, Inc. 132294). The contact area between
the hollow fibers and the cerebral cortex was 17.8.+-.2.2 mm.sup.2
The solution passing through the hollow fibers (lumen solution)
operated at a flowrate with a Reynolds number (Re) between 50 and
100.
[0162] Treatment with the exemplary HFHD consisted of the fibers
being placed directly onto the mouse cerebral cortex following
craniectomy, with a hydrogel covering the fibers and the exposed
tissue (FIG. 2). The hydrogel was created by dissolving agar into
the same solution properties as the lumen solution without the
impermeable solute (0.3% agar, artificial CSF, pH 7.4 gel).
[0163] Lumen Solution
[0164] The lumen solution consisted of concentrated bovine serum
albumin (BSA) (impermeable solute) in a saline solution at pH 7.4.
BSA was used because the osmotic pressure of concentrated BSA
solutions has been extensively studied for various solution
properties.sup.15,16 and because it is completely rejected by the
hollow fiber membrane. The BSA solution was made by dissolving BSA
(Research Products International Corp. A30075) into the saline
solution. The BSA was mixed using a stir-plate at room temperature
and the pH was adjusted using 1 M NaOH or 1 M HCl. In these
experiments, a BSA concentration of 350 g/L in a CSF at pH 7.4 was
used. This BSA concentration has an osmotic pressure of
approximately 28 psi..sup.15
[0165] The saline solution used in this study was isotonic saline
mimicking the CSF (artificial CSF, a CSF). A CSF was prepared by
dissolving the salts in nanopure (ddH.sub.2O) water following the
protocol described for a CSF..sup.4
[0166] Animals:
[0167] all experiments were conducted under protocols (A-20100018)
approved by the University of California, Riverside Institutional
Animal Care and Use Committee (IACUC). Adult female ten- to
twelve-week-old mice were used in all experiments.
[0168] Surgical Technique:
[0169] Prior to induction of water intoxication, animals were
anesthetized with an 80 mg/kg ketamine, 10 mg/kg xylazine mixture.
Surgical procedures began only after determining that an adequate
plane of anesthesia had been reached with the loss of paw pinch
reflex. Reflex activity was continuously monitored throughout the
procedure and supplemental doses of half of the initial dose were
provided as needed.
[0170] After anesthesia, the animals were placed into a standard
rodent stereotatic frame. A midline skin incision was made and
reflected. A right-sided craniectomy was performed (anterior
border: coronal suture, posterior border: lambdoid suture, medial
border: midline, lateral border: temporalis attachment). The dura
was carefully and atraumatically opened with microdissection.
[0171] Water Intoxication Model
[0172] Cytotoxic cerebral edema from water intoxication was
produced as previously described..sup.5 Mice were injected with
distilled water (30% body weight, i.p.). Approximately five minutes
post-injury, treatment began. The three experimental groups were:
(1) no treatment (water intoxication only); (2) craniectomy-only;
and (3) craniectomy+HFHD.
[0173] Endpoints included survival time and brain water content
analysis. Survival was assessed over the course of 360 minutes
following water intoxication in all mice. After the treatment
procedure, brains were dissected out post-mortem and subjected to
wet-dry weight comparisons to determine % water content as
previously described..sup.5,17
[0174] Histology
[0175] In order to determine the tissue damage caused by treatment
using the exemplary HFHD, three animals were used. For these
animals, the surgical procedure was completed but water
intoxication was not induced. The HFHD was applied directly to the
brain tissue for three hours. The animals were then euthanized. The
brain tissue was then dissected and frozen for post-mortem
histology. 50 .mu.m coronal cryostat sections were prepared,
stained with
[0176] Data Analysis
[0177] Intergroup comparisons of survival times and brain tissue
water content were done using one-way ANOVAs and post-hoc
Bonferroni tests.
[0178] Results
[0179] Improved Survival Following Treatment with the Exemplary
Hollow Fiber-Hydrogel Device of the Invention:
[0180] Mean survival times following water intoxication were
determined for untreated, craniectomy-only treated, and
craniectomy+HFHD-treated mice (FIG. 3A). Survival time for the no
treatment group was 31.+-.3.1 minutes (n=5). Treatment with
craniectomy only slightly increased survival time to 48.+-.4
minutes (n=5). Treatment with craniectomy+HFHD markedly improved
survival time to 333.+-.28 minutes (n=5). Four of five (80%) of the
HFHD-treated mice actually survived throughout the entire
360-minute observation period (and then were sacrificed to obtain
brain water content data). Thus, mice treated with a
craniectomy+HFHD survived approximately five hours longer, before
termination, than mice receiving no treatment or craniectomy only
(FIG. 3B). Significant differences in survival were observed
statistically between the craniectomy+HFHD vs. craniectomy only
group (p<0.0001); and significant difference in survival was
observed between the craniectomy+HFHD vs. no treatment group
(p<0.0001).
[0181] Brain Water Content:
[0182] In addition to enhancing survival, the HFHD was able to
remove a significant amount of water from brain tissue. Using
wet-dry brain weights, % brain water content was determined for
control non-water intoxicated mice (n=5), untreated
water-intoxicated mice (n=5), water-intoxicated mice treated with
craniectomy only (n=4), and water-intoxicated mice treated with
craniectomy+HFHD (n=5) (FIG. 4). No significant differences were
found between the water content of the left and right hemispheres
for any treatment group, so the water content of both hemispheres
is shown. Of course, based on survival differences, there was a
different time of sacrifice for brain water content analysis. The
untreated non-water intoxicated control mice were sacrificed;
untreated water-intoxicated mice all expired within 35 minutes
following injection; water-intoxicated mice treated with
craniectomy only all expired within 53 minutes following injection;
and 80% of the water intoxicated mice treated with craniectomy+HFHD
were sacrificed at the end of the observation period.
[0183] The brain water content for the untreated water-intoxicated
animals (W), water-intoxicated animals treated with a craniectomy
only (W+C), and water-intoxicated animals treated with a
craniectomy and the HFHD (W+C+D) was higher, in all cases, than the
brain water content for the untreated control animals. Brain water
content of untreated control mice without water intoxication was
64.2.+-.1.4%. The percent increase of the brain water content of
untreated mice with water intoxication was 5.4.+-.5.8%, which was
significantly elevated compared to non-water intoxicated animals
(p<0.05). Mice treated with water intoxication and craniectomy
only had a percent increase in brain water content of 10.3.+-.3.1%,
which was significantly higher than both the untreated
water-intoxicated mice (p<0.05) and the untreated non-water
intoxicated mice (p<0.0001). However, water-intoxicated mice
treated with a craniectomy+HFHD had a percent increase in brain
water content of 4.3.+-.2.3% which is significantly lower than the
craniectomy only group (p<0.01). Indeed, water-intoxicated mice
treated with craniectomy+HFHD have brain water content similar to
non-water intoxicated untreated mice (no statistical significance
is observed, p>0.05).
[0184] Tissue Damage Caused by HFHD Treatment:
[0185] To further validate the use of an exemplary HFHD of the
invention to treat water intoxication and general edema, histology
staining of the brain for non-water intoxicated mice treated with a
craniectomy and the HFHD was performed. Histology was performed to
determine the extent of tissue damage caused by the HFHD treatment
protocol, which included the craniectomy, HFHD placement, and water
removal via the HFHD (FIG. 5).
[0186] Discussion
[0187] We have developed a novel device to directly remove water
from a CNS, e.g., a spinal or a brain tissue, in a controlled
fashion to treat CNS or cerebral edema. The invention provides a
HFHD for removing water from in vivo tissues, as validated using ex
vivo tissue samples. Second, in the studies reported here, we
validated the use of the exemplary HFHD of the invention, with the
correct lumen solution properties, in conjunction with a
craniectomy for enhancing survival in mice in vivo following
cytotoxic cerebral edema. Third, we demonstrated that the HFHD is
able to remove water from brain tissue and normalize CNS (brain)
tissue water content.
[0188] Device Design:
[0189] Developing a HFHD to treat cerebral edema presents several
technical challenges.
[0190] First, lumen solution and concentration need to be selected
carefully. Although there are many possibilities for the lumen
solution, we chose to use BSA in a CSF solution at physiological
pH. BSA was chosen because its physical properties are known and
because at high solution concentrations, it exhibits high osmotic
pressure effects with moderate viscosity increases..sup.15,16
[0191] Second, contact with the brain tissue and the liquid-liquid
interface, if not maintained, could severely limit the removal of
water and success of the treatment. In order to better maintain the
liquid-liquid interface and contact with the brain tissue, we
utilized a hydrogel. One advantage of the hydrogel is that it
allows for the exemplary HFHD to conform to brain sulci and gyri.
The moldability of the hydrogel will be a significant
advantage.
[0192] Third, another design parameter of importance is the
flexibility of the hollow fibers. We carefully chose very flexible
hollow fibers so as to allow moldability through smaller openings
in future applications (e.g. application through a burr hole and
obviating the need for craniectomy).
[0193] The components of the exemplary HFHD allow for easy scale
up. The number of the hollow fibers can be increased to increase
treatment area to the maximum desired surface area. In alternative
embodiments, a larger hydrogel can be used to cover a desired
surface area. Further, increasing the amount of hollow fibers will
allow for the HFHD to fully conform to the brain surface
topography, including brain gyrations.
[0194] Device Efficacy:
[0195] In the present study, use of the exemplary HFHD of the
invention to treat induced cytotoxic edema resulted in markedly
improved survival compared to no treatment or craniectomy only.
These results provide proof-of-principle for direct controlled
water extraction as a novel form of treatment for cerebral edema.
The device-brain surface contact is gentle and simple application
of the device is not associated with any histological damage.
[0196] One important finding is that device application to one
small quadrant of the brain over the right hemisphere (based on
atlas calculations, we estimated contact of the device with
approximately 17% of cortical surface area on the right hemisphere
only) led to uniform reduction in water content throughout the
brain and even in the contralateral hemisphere. These results
suggest that even for large areas of hemispheric edema the area of
contact may not need to be so extensive to attain adequate water
extraction. This interesting result is likely due to rapid osmotic
water flux via aquaporin-rich astrocyte networks.sup.14 which will
be investigated in future studies.
[0197] Study Limitations and Possible Implications for
Treatment:
[0198] While this study used a model of "pure" cytotoxic edema
(water intoxication), in alternative embodiments, devices of the
invention also can be used for post-stroke edema (which is thought
to be largely cytotoxic in nature), brain tumor edema and
post-infectious edema (these two are largely vasogenic in nature),
and posttraumatic edema (which is mixed cytotoxic and vasogenic in
nature)..sup.9 Therefore, in alternative embodiments, devices of
the invention are used to treat vasogenic edema and posttraumatic
edema, and any type of cerebral edema. For example, in alternative
embodiments, devices of the invention are used to treat "malignant"
cerebral edema that cannot be adequately treated by other methods,
including osmolar therapy, ventriculostomy, craniectomy only. In
alternative embodiments the flexibility of application and
titratability of duration of contact and rate of water removal are
all user-defined parameters that can be tailored to a given
clinical situation.
CONCLUSIONS
[0199] In summary, we have validated the use of an exemplary HFHD
directly applied to the brain surface to treat and reverse severe
cerebral edema. This therapy improved survival and reduced elevated
brain tissue water content. In alternative embodiments, devices of
the invention are used to treat e.g. any cerebral edema, such as
controlled cortical impact (CCI), a model of traumatic brain
injury. In alternative embodiments, devices of the invention are
used flexibly to treat any anatomic extent and severity of edema
given that the appropriate device parameters (lumen solution and
concentration, flow rate, contact surface area) are chosen to
provide the therapeutically appropriate water removal rate.
[0200] Figure Legends
[0201] FIG. 1: Concept of an Exemplary Hollow Fiber-Hydrogel Device
of the Invention For Treating a Cerebral Edema.
[0202] In alternative embodiments, aqueous proteinaceous solution
is flowed or pumped or passively flowed across the edematous, e.g.,
a burned or an injured, area through the semi-permeable hollow
fiber membrane lumen. The membrane is selected such that it
completely rejects the solute but allows easy passage of ions,
electrolytes and water, and also nutrients (such as oxygen or
glucose) and small molecules, proteins and other drugs. The lumen
solution induces an osmotic pressure driving force for water
removal. The rate of pumping is controlled to allow fluid from the
tissue to flow up into the membrane device due to osmotic pressure.
In alternative embodiments, a hydrogel or an equivalent gel (e.g.,
a hydrophilic gel) with significantly large permeability is used to
maintain membrane-tissue contact.
[0203] FIG. 9. Application of an Exemplary Hollow Fiber-Hydrogel
Device.
[0204] The left image of FIG. 9 illustrates an exemplary hollow
fiber attached to inlet and outlet ports (of an exemplary device of
the invention; and the right image of FIG. 9 illustrates
application of an exemplary device with multiple parallel hollow
fibers embedded in hydrogel to brain surface. Point A is the inlet
of the fiber bundle. Point B is the gel that is placed directly on
the tissue surface at the injury location. As can be seen, the gel
also molds around the fiber bundle. Point C is the outlet for the
fiber bundle. Fluid passing through the fiber at Point A
osmotically drives excess fluid from the tissue under the gel at
Point B into the walls of the hollow fibers. The excess fluid
associated with edema is subsequently carried away from the brain
at Point C.
[0205] FIG. 10. Hollow Fiber-Hydrogel Device Improves Survival in a
Mouse Model of Cytotoxic Cerebral Edema.
[0206] FIG. 10A.
[0207] Time to expiration (min.) for three treatment groups. W,
water-intoxicated mice with no treatment (time to expiration:
31.+-.3.1 min) W+C, water-intoxicated mice treated with craniectomy
only (time to expiration: 48.+-.4 min) W+C+D, water-intoxicated
mice treated with craniectomy and HFHD (time to expiration:
333.+-.28 min). Significant increase in time to expiration was seen
in the mice treated with HFHD (***, p<0.001 vs. W or W+C
groups).
[0208] FIG. 10B.
[0209] Kaplan-Meier survival curve. Comparison of the survival
curves for W, W+C, and W+C+D groups. Individual mice are depicted
as closed ovals.
[0210] FIG. 11 and FIG. 12. Hollow Fiber-Hydrogel Device Limits
Increase in Brain Tissue Water Content.
[0211] FIG. 11:
[0212] Percent (%) increase in brain water content is shown for
water-intoxicated mice with no treatment (W), water-intoxicated
mice treated with craniectomy only (W+C), and water-intoxicated
mice treated with craniectomy+HFHD (W+C+D). The % increase in brain
water content was determined by subtracting the water content of
the control animals (64.2.+-.1.4%). The percent increase in brain
water content of untreated water-intoxicated mice was significantly
higher than control mice (*, p<0.05). The percent increase in
brain water content of water-intoxicated mice treated with
craniectomy only was significantly higher than that of control mice
(***, p<0.001), untreated water-intoxicated animals (p<0.05),
and water-intoxicated mice treated with craniectomy+HFHD
(p<0.05). The percent increase in brain water content of
water-intoxicated mice treated with craniectomy+HFHD was higher but
not statistically significantly different from control mice.
[0213] FIG. 12A:
[0214] Percent (%) increase in brain water content is shown for
water-intoxicated mice with no treatment (W), water-intoxicated
mice no treatment, water-intoxicated craniectomy only ("C"), and
water-intoxicated mice treated with craniectomy+HFHD (W+C+D).
[0215] FIG. 12B:
[0216] Percent (%) increase in brain water content is shown for no
water-intoxicated mice with no treatment (W), no water and treated
with craniectomy only (C), craniectomy only ("C"), and no
water-intoxication with the exemplary device of the invention only,
the "HFHD" ("D").
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[0234] A number of embodiments of the invention have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the invention. Accordingly, other embodiments are within
the scope of the following claims.
* * * * *