U.S. patent application number 17/065510 was filed with the patent office on 2021-02-04 for implantable dissolved oxygen sensor and methods of use.
The applicant listed for this patent is Massachusetts Institute of Technology. Invention is credited to Michael J. Cima, Yibo Ling, Vincent Hok Liu, Christophoros Christou Vassiliou.
Application Number | 20210030321 17/065510 |
Document ID | / |
Family ID | 1000005150347 |
Filed Date | 2021-02-04 |
United States Patent
Application |
20210030321 |
Kind Code |
A1 |
Liu; Vincent Hok ; et
al. |
February 4, 2021 |
Implantable Dissolved Oxygen Sensor and Methods of Use
Abstract
A sensor is provided for measuring a dissolved oxygen
concentration in vivo when implanted at a tissue site and in ex
vivo applications. The sensor includes an article comprising a
sensing medium retained within the implantable article by an
oxygen-permeable material. The sensing medium comprises an MR
contrast agent for oxygen. The sensor is configured to indicate the
dissolved oxygen concentration of a fluid, e.g., in vivo at the
tissue site, when subjected to an MR-based method.
Inventors: |
Liu; Vincent Hok;
(Cambridge, MA) ; Vassiliou; Christophoros Christou;
(Cambridge, MA) ; Ling; Yibo; (Cambridge, MA)
; Cima; Michael J.; (Winchester, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Massachusetts Institute of Technology |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005150347 |
Appl. No.: |
17/065510 |
Filed: |
October 7, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13643707 |
Oct 26, 2012 |
10806383 |
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PCT/US2011/035146 |
May 4, 2011 |
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17065510 |
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61331236 |
May 4, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01R 33/448 20130101;
A61B 5/14503 20130101; A61K 49/10 20130101; G01R 33/5601 20130101;
A61B 5/055 20130101; A61B 5/415 20130101; A61B 5/418 20130101 |
International
Class: |
A61B 5/145 20060101
A61B005/145; A61B 5/00 20060101 A61B005/00; G01R 33/56 20060101
G01R033/56; A61K 49/10 20060101 A61K049/10 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under Grant
No. U54 CA119349 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A method of measuring a dissolved oxygen concentration in vivo
of a tissue site of a patient, comprising: (a) deploying a sensor
at the tissue site in the patient, the sensor comprising a sensing
medium, the sensing medium comprising a magnetic resonance (MR)
contrast agent for oxygen; and thereafter (b) subjecting the tissue
site to electromagnetic radiation and employing an MR-based
spectroscopy or other method to analyze the dissolved oxygen
concentration in vivo at the tissue site.
2. The method of claim 1, wherein the sensor comprises a reservoir
containing the sensing medium.
3. The method of claim 1, wherein the tissue site comprises a
tumor.
4. The method of claim 3, wherein the dissolved oxygen
concentration of the tissue site is analyzed to evaluate the state
of the tumor.
5. The method of claim 1, wherein the dissolved oxygen
concentration of the tissue site is analyzed to determine the
presence of hypoxia.
6. The method of claim 1, wherein the dissolved oxygen
concentration of the tissue site is analyzed to evaluate the
effectiveness of a treatment strategy on the patient.
7. The method of claim 1, wherein the dissolved oxygen
concentration of the tissue site is analyzed to schedule a therapy
on the patient.
8. The method of claim 1, wherein the tissue site is the brain of
the patient.
9. The method of claim 8, wherein the dissolved oxygen
concentration of the tissue site is analyzed in conjunction with a
functional magnetic resonance imaging (MRI) study.
10. The method of claim 1, wherein the dissolved oxygen
concentration of the tissue site is analyzed to monitor metabolic
activities in specific regions or organs of the body of the
patient.
11. The method of claim 1, wherein the MR-based spectroscopy
comprises .sup.1H nuclear magnetic resonance (NMR), .sup.19Fluorine
NMR or MRI.
12. The method of claim 1, wherein the dissolved oxygen
concentration of the tissue site is analyzed by measuring T1
relaxation.
13. The method of claim 1, wherein step (b) is repeated multiple
times over the course of a treatment.
14. A method of measuring a dissolved oxygen concentration in vivo
of a tissue site of a patient, comprising: (a) deploying a sensor
at the tissue site in the patient, the sensor comprising a sensing
medium, the sensing medium comprising a magnetic resonance (MR)
contrast agent for oxygen, wherein the sensor comprises a reservoir
containing the sensing medium; and thereafter (b) subjecting the
tissue site to electromagnetic radiation and employing an MR-based
spectroscopy or other method to analyze the dissolved oxygen
concentration in vivo at the tissue site, wherein the dissolved
oxygen concentration of the tissue site is analyzed by measuring T1
relaxation.
15. The method of claim 14, wherein the tissue site comprises a
tumor.
16. The method of claim 15, wherein the dissolved oxygen
concentration of the tissue site is analyzed to evaluate the state
of the tumor.
17. The method of claim 14, wherein step (b) is repeated multiple
times over the course of a treatment.
Description
REFERENCES TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 13/643,707, filed Oct. 26, 2012, which is a
national phase entry of PCT Patent Application No.
PCT/US2011/035146, filed May 4, 2011, which claims priority to U.S.
Provisional Patent Application No. 61/331,236, filed May 4, 2010.
The content of these applications is incorporated by reference
herein.
BACKGROUND
[0003] The present invention is generally in the field of sensor
devices. More particularly, the present invention relates to a
sensor device that may be used to detect or measure the presence of
oxygen in a fluid, such as a gas or liquid.
[0004] The concentration of dissolved oxygen within biological
fluids may provide important information about biological systems.
As an essential nutrient and metabolite, the concentration of
dissolved oxygen in microenvironments is influenced by a number of
factors, such as cellular activity, and can possibly be used to
evaluate disease states. It is well known, for example, that the
hypoxic state of a tumor negatively affects the efficacy of
non-surgical therapies, especially with radiotherapy. Strategies to
mitigate hypoxia in tumors before therapy are thought to result in
improved outcomes for patients. Real-time knowledge of intratumoral
dissolved oxygen would allow a physician to schedule therapy at the
most opportune moment to improve outcome. Dissolved oxygen can, for
example, be used to estimate the required dose of radiation or the
appropriate regimen of chemotherapy. In addition, dissolved oxygen
measurements can be used to assess the stage of compartment
syndrome in trauma patients.
[0005] Current standard methods to measure intratumoral dissolved
oxygen in patients are invasive, as they rely on probes directly
linked to the measuring instruments. These instruments are not
suited for repeated measurements or measurement of non-superficial
tumors. The current standard for hypoxia measurement in tumors is
pO.sub.2 histography. This technique uses a polarographic needle
electrode to obtain an Eppendorf histograph, a frequency
distribution of oxygen partial pressures measured at several points
along a tumor. The needle is guided by computed tomography
fluoroscopy to allow physicians to visualize its location in real
time. This technique is limited to superficial tumors or metastatic
lymph nodes because of the invasiveness of the needle, and results
in significant patient discomfort. A number of non-invasive methods
have been developed to circumvent the limitations of pO.sub.2
histography, based on electron paramagnetic resonance (EPR)
oximetry, positron emission tomography (PET), single photon
emission computed tomography (SPECT) and MRI. However, improved
methods are needed. For example, some of these methods rely on the
administration of a contrast agent. The distribution of the
contrast agent within the tumor is not precisely known which limits
the ability to interpret the results.
[0006] It therefore would be desirable to provide a sensor that
provides the ability to take repeated measurements at the same
location over extended periods. This can be particularly valuable
where continual monitoring of in vivo dissolved oxygen levels is
required or beneficial.
SUMMARY
[0007] In one aspect, a sensor is provided for measuring a
dissolved oxygen concentration in vivo when implanted at a tissue
site. The sensor comprises an implantable article comprising a
sensing medium retained within the implantable article by an
oxygen-permeable material. The sensing medium comprises an MR
contrast agent for oxygen. The sensor is configured to indicate the
dissolved oxygen concentration in vivo at the tissue site when
subjected to an MR-based method. In one embodiment, an implantable
sensor includes a container having a reservoir and a reservoir
opening; an oxygen-permeable membrane covering the reservoir
opening; and a sensing medium contained in the reservoir, the
sensing medium comprising an MR contrast agent for oxygen. The
sensor is configured to indicate the dissolved oxygen concentration
of the fluid when subjected to an MR-based method. In another
embodiment, the implantable sensor includes one or more beads or
microspheres which comprise an agent having an MR relaxivity that
is sensitive to oxygen. The one or more beads or microspheres may
be injectable, for example in a fluid suspending media, and possess
a volume of the agent effective to indicate the dissolved oxygen
concentration of the tissue site in vivo when subjected to an
MR-based method.
[0008] In another aspect, a method is provided for measuring a
dissolved oxygen concentration in vivo of a tissue site of a
patient. The method includes deploying a sensor at the tissue site
in the patient, the sensor comprising a sensing medium, the sensing
medium comprising an MR contrast agent for oxygen; and thereafter
subjecting the tissue site to electromagnetic radiation and
employing an MR-based spectroscopy or other method to analyze the
dissolved oxygen concentration in vivo at the tissue site.
[0009] In yet another aspect, uses for a dissolved oxygen sensor
are provided. For example, the sensor may be used to evaluate the
state of a tumor, to determine the presence of hypoxia, to evaluate
the effectiveness of a treatment strategy on a patient, to schedule
therapies at an opportune time to achieve an improved patient
outcome, to monitor metabolic activities in specific regions or
organs of the body.
[0010] In still another aspect, sensor devices and methods for ex
vivo applications are provided for measuring oxygen concentration.
The method may include placing a sensor at a location, e.g., in a
process stream, in which the sensor is exposed to a fluid to be
analyzed, the sensor comprising a sensing medium, the sensing
medium comprising an MR contrast agent for oxygen; and thereafter
subjecting the sensor to electromagnetic radiation and analyzing
the dissolved oxygen concentration by measuring a change in
relaxivity of the sensing medium while the sensor is exposed to the
fluid to be analyzed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is an exploded perspective view, illustrating an
embodiment of a sensor having a reservoir for containing an MR
contrast agent for oxygen.
[0012] FIG. 2 is a perspective view, illustrating the embodiment of
FIG. 1 in an assembled state.
[0013] FIG. 3 is a chart, illustrating spin lattice relaxation time
(T1) as a function of oxygen concentration for HMDSO.
[0014] FIG. 4 is a chart, illustrating a sensor's response to an
oxygenated environment over time.
[0015] FIG. 5 is a chart, illustrating spin lattice relaxation time
(T1) as a function of oxygen concentration in a sensor comprising a
DDMPS/PDMS composite body.
[0016] FIG. 6 is a perspective view, illustrating a sensor having a
composite polymeric body.
[0017] FIG. 7 is a section view, illustrating one embodiment of a
sensor in a bead form.
DETAILED DESCRIPTION
[0018] In one aspect, an implantable sensor is provided for
measuring the dissolved oxygen concentration of a fluid in vivo.
The implantable sensor may be wholly deployable and implantable
within a patient and may include a sensing material that is a
magnetic resonance (MR) contrast agent for oxygen. The term
"implantable" as used herein refers to a device that is configured
for implantation. That is, the device is to be introduced into a
subject's body by a surgical or medical procedure and remain there
after the procedure. The term "wholly deployable" or "wholly
deployed" and "wholly implanted" or "wholly implantable" means that
there is not a portion of the sensor device that extends out of the
patient transcutaneously or from an anatomical orifice. For
example, the device may be sized and shaped to be wholly deployed
in the body of a human or animal and to remain deployed for a
period of time, such as 30 days or more. The device also may have
suitable sterility, biocompatibility, and physical and/or chemical
integrity to be implanted and remain implanted over the intended
duration of use of the device.
[0019] Advantageously, in some embodiments, the sensor may be
wholly deployed in vivo and subjected to repeated measurements
thereby overcoming the problems associated with repetitive invasive
measurement procedures. Moreover, in some embodiments, the sensor
may be wholly deployed to a specific target tissue site of interest
to allow for site-specific measurement and analysis. Furthermore,
the sensor, which comprises an MR contrast agent for oxygen, may
provide a higher degree of measurement sensitivity, accuracy, and
precision with respect to oxygen concentration than other
measurement techniques. The sensor may be employed in various
patients or subjects including human or other mammals.
[0020] In one embodiment, the implantable sensor may include a
container having a reservoir and a reservoir opening, an
oxygen-permeable membrane covering the reservoir opening, and a
sensing medium contained in the reservoir. The sensing medium may
comprise a MR contrast agent for oxygen, and the sensor may be
configured to indicate the dissolved oxygen concentration of the
fluid when subjected to MR-based methods. In another embodiment,
the implantable sensor may comprise a solid polymeric article that
has an MR contrast agent for oxygen integrated with the polymeric
structure of the article. In certain embodiments, the implantable
sensor may be in the form of beads or microspheres which have an MR
contrast agent for oxygen incorporated within the bead or
microsphere.
[0021] In another aspect, a method is provided for measuring a
dissolved oxygen concentration of a fluid in vivo. The method may
include deploying a sensor at a tissue site, and thereafter
subjecting the tissue site to electromagnetic radiation and
employing MR-based methods to analyze the dissolved oxygen
concentration of the fluid. The sensor may comprise a sensing
medium that comprises an MR contrast agent for oxygen. The MR
contrast agent may be contained in a reservoir provided with the
sensor. Sensing media is prevented from escaping the device with
the use of an impermeable membrane (impermeable to the sensing
media, but permeable to dissolved oxygen).
[0022] In other aspects, sensors and methods are provided for
measuring oxygen concentrations in ex vivo environments. Such
sensors and methods may utilize the direct measurement of the NMR
relaxivity of a sensing medium in contact with the liquid or gas of
interest. The oxygen sensors may have advantages over conventional
oxygen sensors that are based on a surface reaction such as the
automotive oxygen sensor which requires oxygen to react at a
precious metal electrode in contact with a solid electrolyte. The
present sensors may absorb oxygen throughout the bulk of the
material and may therefore be less sensitive to contamination.
Sensors
[0023] Implantable sensors are provided for measuring the dissolved
oxygen concentration of a fluid in vivo. Advantageously, the
sensors may be wholly implanted at a tissue site and may be used to
take repeated measurements of dissolved oxygen levels at the tissue
site without the need for repeated invasive measurement procedures.
Specifically, the sensors may be configured to be utilized with
standard MR-based spectroscopy. As used herein, the terms "MR-based
spectroscopy" and "MR-based methods" broadly refer to analytical
and measurement techniques in which a material, such as a material
present at a tissue site, is subjected to electromagnetic radiation
for purposes of characterization. In particular, the term
encompasses analytical techniques in which a magnetic field is
applied to a material and the effect of the applied magnetic field
on the material is measured or observed such as H1 NMR (hydrogen-1
nuclear magnetic resonance), Flourine-19 NMR, and MRI (magnetic
resonance imaging). Although not limited to H1 NMR based
techniques, this is a convenient approach because of the ready
access to equipment, appropriate pulse sequences, and software.
[0024] One embodiment of an implantable sensor 10 is illustrated in
FIG. 1. The implantable sensor 10 may include a container 14 having
a reservoir 30 that contains a sensing medium. The container 14 may
include a mouth portion 22 and a base portion 28. The container 14
may further include a reservoir opening 24 within the mouth portion
22 above the reservoir 30. An oxygen-permeable membrane 16 may be
in register with the reservoir opening 24 so as to allow oxygen to
diffuse through the membrane 16 and the reservoir opening 24. For
example, the membrane 16 may be attached to the container 14 across
the reservoir opening 24. The implantable sensor 10 may further
include a cap 12 that may be attached to the mouth portion 22 of
the container 28 to secure the membrane 16 to the implantable
sensor 10 in a position over the reservoir 30. The cap 12 may
include a cap opening 18 that is completely or at least partially
aligned with the reservoir opening 24 of the container 14 when the
cap 12 is secured to the container 14. The cap opening 18 need not
occupy the entire width of the cap but may be adjusted to a size
sufficient to allow chemical diffusion of oxygen into and out of
the reservoir. Alternatively, there may be a plurality of smaller
openings on the cap to insure mechanical stability of the
device.
[0025] The mouth portion 22 of the container 14 may include an
external flange 26 which engages a partial internal flange 20 of
the cap 12 when the cap 12 is pressed over the mouth portion 22 of
the container 14, thereby securing the cap 12 to the container 14
and securing the membrane 16 in place over the reservoir 30.
Alternatively, other fastening features may be used for attaching
the cap 12 to the container 14, e.g., male and female threading,
tabs, snap fingers, quarter-turn fastening structures and the like.
In other embodiments, the membrane 16 may be secured over the
reservoir 30 with an adhesive. It is possible that the oxygen
permeable membrane 16 may be replaced entirely by a fully solid cap
which is thin enough to allow permeability of oxygen into and out
of the reservoir. In one embodiment, for example, the cap could
achieve the necessary thin cross section by having one or a
plurality of blind holes or dimples in its surface.
[0026] The implantable sensor 10 of FIG. 1 is shown in an assembled
state in FIG. 2. When assembled, the implantable sensor 10 may
assume a low-profile shape suitable for wholly deploying at a
tissue site of a patient. The oxygen-permeable membrane 16 is
exposed to fluids at the tissue site via the cap opening 18 of the
cap 12. As such, oxygen dissolved in the biological fluid at the
tissue site may pass through the oxygen-permeable membrane 16 into
the sensing medium.
[0027] Although the implantable sensor 10 is shown as being
substantially cylindrical in shape in FIGS. 1 and 2, the
implantable sensor 10 may be formed into many different shapes.
Advantageously, the implantable sensor 10 may be shaped and
dimensioned for minimally invasive implantation, for example
through a needle or trocar. In some embodiments, the implantable
sensor 10 may have a diameter, or width in the plane of the
membrane 16, of about 10 mm or less, or more preferably about 1 mm
to about 5 mm. In certain embodiments, the implantable sensor 10
may have a diameter less than about 1 mm in diameter. In some
embodiments, the implantable sensor 10 may have a depth, measured
in a direction substantially perpendicular to the plane of the
membrane 16 of about 0.5 mm to about 3 mm, or more preferably about
0.5 mm to about 1 mm. In certain embodiments, the implantable
sensor 10 may have a depth less than about 0.5 mm. Other convenient
dimensions are those compatible with biopsy tools such as a needle
biopsy device.
[0028] The container 14 and the cap 12 can be made of various
biocompatible materials. The container 14 and the cap 12 may
comprise the same material or they may comprise different
materials. Preferably, the container 14 and the cap 12 comprise a
biocompatible polymeric material, such as a polyethylene polymeric
blend, that does not interfere with the detection of dissolved
oxygen in the sensing medium. In some embodiments, the container 14
and/or the cap 12 comprise a material that contrasts with the
surrounding tissue when subjected to MR-based spectroscopy.
[0029] In some embodiments, the sensor 10 comprises a sensing
medium in the reservoir 30 that comprises an MR contrast agent for
oxygen. The term "MR contrast agent for oxygen" as used herein
refers to material suitable for indicating the dissolved oxygen
concentration within the material when employing MR-based
spectroscopy by enhancing the desired signal beyond that which is
provided by background molecules (i.e., molecules naturally present
at the site of implantation), such as water molecules. For example,
the MR contrast agent for oxygen may comprise a material having a
spin-lattice relaxation time (T1) that is dependent on dissolved
oxygen concentration. In certain embodiments, the sensing medium
may exhibit sufficient sensitivity to resolve oxygen concentration
at low oxygen concentrations, particularly between about 0% and 2%
oxygen. These sensing mediums include certain liquid or solid
compounds having MR properties that are sensitive to oxygen
concentration. Particulate suspensions or emulsions of such
materials are contemplated.
[0030] Proton spins can be flipped into different planes and axis
of rotation when protons are irradiated with a radio frequency (RF)
pulse. This change in rotation is temporary and the direction in
magnetic moment eventually returns to the original configuration.
In particular, the restoration of magnetic moments to the original
axis can be characterized by T1. As T1 is a material property, it
can provide a reliable source of contrast in MRI images; T1 maps
are frequently used in imaging applications to distinguish between
different anatomical structures. Paramagnetic molecules or
particulates that decrease the relaxation time of surrounding
molecules can be used to enhance contrast of T1 maps. They can also
provide a mechanism for sensing. For example, dissolved oxygen
molecules are paramagnetic and can decrease the T1 relaxation time
of water protons (or other spin bearing atoms) surrounding it.
Thus, the T1 value of these mixtures would depend on the
concentration of dissolved oxygen and thus dissolved oxygen
concentration can be determined by averaging the T1 of the
area.
[0031] Instead of using water protons, other materials can also be
read using MR-based spectroscopy (e.g., H1 NMR, Fl19 NMR, or MRI)
and some of these materials are more sensitive to concentrations of
dissolved oxygen. Indeed, using materials other than water has the
advantage that the sensing medium can give a different MR signature
and can be more easily distinguished from the background water
molecules inside the body. Siloxanes may be particularly useful in
sensors as MR contrast agents for oxygen. One particularly useful
siloxane is hexamethyldisiloxane (HMDSO), which is a highly
hydrophobic and non-polar molecule. This molecule has a high
solubility for oxygen, and has a single peak for hydrogen NMR. FIG.
3 illustrates the dissolved oxygen dependent T1 relaxation of HMDSO
as measured with a Bruker Minispec. Other potentially useful
siloxanes include octamethyltrisiloxane, decamethyltetrasiloxane,
dodecamethylpentasiloxane, hexamethylcyclotrisiloxane,
octamethylcyclotetrasilane, decamethylcyclopentasiloxane,
dodecamethylcyclohexasiloxane, and PDMS.
[0032] FIG. 4 illustrates magnetic relaxation properties of HMDSO
loaded in an implantable sensor. The T1 measurements were taken
using a single sided magnet (a modified version of an
NMRMouse.TM.). The data demonstrates that the sensor is capable of
distinguishing between different concentrations of dissolved oxygen
in a surrounding environment of aqueous solution. In these
measurements, T1 of devices are measured before and after complete
deoxygenation of the surrounding environments, and can be seen to
reflect increasing levels of oxygen in the surrounding medium. FIG.
4 illustrates the sensor's response to changes in oxygenation
conditions. The "closed" data series represent a device that has
been left in the deoxygenated environment, whereas the "open" data
series represent a device that has been exposed to atmospheric air
after the first data point. The sensors may be fully reversible,
which would allow for repeated sampling of the same area with
changing oxygen content over time.
[0033] Other potentially useful materials that may be employed in
sensors as a sensing medium include, but are not limited to,
compounds that have a high oxygen solubility. For example,
perfluorocarbons, a class of highly fluorinated and inert organic
compounds, may be used in place of siloxanes as oxygen sensitive
agents for use in Fluorine-19 MR systems. Exemplary
perfluorocarbons include perfluoro-15-crown-5-ether,
hexafluorobenzene, and perfluorotributylamine.
[0034] In another embodiment, the implantable sensor may be in the
form of a solid polymeric article that has an MR contrast agent for
oxygen integrated with the polymeric structure of the article,
e.g., by the direct incorporation of MR-readable, oxygen sensitive
materials into a polymeric matrix. In a certain embodiment, the
implantable sensor may be a cured composite article comprising an
MR contrast agent for oxygen dispersed throughout a polymeric
matrix. The polymeric matrix material may be permeable to oxygen
and may be configured to prevent the diffusion of MR contrast agent
for oxygen from the structure at least over the period the sensor
device is deployed in vivo, e.g., 1 to 6 months. An exemplary
polymeric matrix material is polydimethylsiloxane ("PDMS"). Other
polymers that can serve as the matrix material include various
UV-curable epoxies and silicones.
[0035] An exemplary polymeric composite sensor 30 is illustrated in
FIG. 6. The sensor 30 is formed of a cured polymeric body 32 that
may be substantially uniform in composition throughout the body 32.
The cured polymeric body 32 may be in the form of a polymeric
matrix having an MR contrast agent for oxygen dispersed throughout
the body 32. In some embodiments, the MR contrast agent for oxygen
is dispersed substantially uniformly throughout the body 32. The MR
contrast agent for oxygen may be, for example, a siloxane such as
HDMSO or dodecamethylpentasiloxane (DDMPS). In the present example,
the body 32 includes corner or portions 34, which may be used as
attachment points for securing the sensor 32 to a specific tissue
site or otherwise facilitate the embedding of the sensor 32 at the
specific tissue site. The body 32 may be formed in any regular or
irregular shape as desired.
[0036] To fabricate such sensors, an MR contrast agent for oxygen,
such as a siloxane, may be added to an uncured liquid polymer base,
such as SYLGARD.RTM. 184 elastomer base from Dow Corning, and mixed
thoroughly. An appropriate curing agent may then may be added, and
the mixture/solution may be cured, e.g., with heat treatment, to
form a solid composite article. These solid composite articles may
be directly used in oxygen sensing applications without further
modification or can be coated with other materials to enhance
biocompatibility, stability, and/or containment of the MR contrast
agent for oxygen. For example, the polymeric body may further
include PDMS or another oxygen permeable material that is
completely or substantially impermeable to the MR contrast agent
for oxygen.
[0037] Polymeric composite sensors may be made in various shapes
and sizes. In certain embodiments, the sensor is about 1 mm or more
in size. Such a size is suitable for imaging based on the
resolution of most clinical scans. The shape of devices may be
negative impressions of the mold forms in which they are cured. The
mold forms and sensor shapes can be designed in shapes that
facilitate implantation. They can also be designed to impact
particular features on molded devices, such as anchor points for
attaching the device to implantation site.
[0038] In another embodiment, the implantable sensor may be in the
form of a beads or microspheres. For example, in one embodiment,
the sensor is composed of a single or a plurality of fine beads or
microspheres each containing an agent whose MR relaxivity is
sensitive to oxygen. The beads or microspheres may consist of a
core of the MR contrast agent encapsulated by the oxygen permeable
material. The beads may be spherical or non-spherical (e.g.,
elongated, like grains of rice). One advantage of such an
embodiment is that the sensor(s) may be injected through a
conventional hypodermic needle/syringe into one or more tissue
sites in the patient, providing a minimally invasive route to
deploy the sensor into the patient's body. In some embodiments, the
beads or microspheres may have a volume average diameter of about
100 microns or less. In certain embodiments, the beads or
microspheres may have a volume average diameter of about 20 microns
or less. The beads or microspheres may be provided in an injectable
formulation, for example, as a colloidal or other suspension with
pharmaceutically acceptable liquid known in the art.
[0039] In one example, each bead is composed of a shell that has a
primary purpose of providing mechanical stability and permeability
to oxygen and an interior volume in which the MR sensitive material
resides. The shell and interior volume materials may be very
similar to one another in their chemistry, but they may differ in
their mechanical properties. The interior may, for example, be a
low molecular weight or liquid silicone derived material but the
shell may be a high molecular weight or cross linked silicone
material in such a way that it provides sufficient strength to the
bead. In another example, the core and the shell are comprised of
the same material and substantially indistinguishable.
[0040] An exemplary embodiment of a bead sensor 40 is illustrated
in FIG. 7. The sensor 40 includes an oxygen permeable shell 42 that
surrounds a sensing medium core 44. The sensing medium core 44 more
comprise an MR contrast agent for oxygen, such as a siloxane.
[0041] In another embodiment, the beads may be in the form of
composite polymeric particles comprising an MR contrast agent for
oxygen dispersed throughout a polymeric matrix. For example, the
particles may comprise a PDMS matrix and a siloxane, such as DDMPS
or HMDSO, dispersed throughout the polymeric matrix. In some
embodiments, no shell is provided around the composite polymeric
particles. In other embodiments, an oxygen-permeable shell material
may be provided around each of the beads for improved
biocompatibility or stability.
[0042] The beads may be formulated into an injectable suspension
using one or more liquid vehicles or pharmaceutically-acceptable
excipients known in the art. In a particular embodiment, it may be
advantageous to incorporate a gel in the formulation of such beads
so that they remain in one location within the body after
injection, e.g., proximate to the injection site. Suitable gels and
gelling materials for parenteral use are known in the art. The
volume of the formulation (and beads) administered in a given
injection is adjustable. Thus, one may insure that the total volume
of oxygen sensitive material is sufficient to image in any given
MRI instrument.
[0043] The sensor may be packaged for shipping and storage. It may
be sterilized before or after packaging. For example, sterilization
may be achieved by ionizing radiation (gamma or electron beam) or
ethylene oxide (EtO) as known in the art. In one embodiment, the
container is made from a gamma-irradiation stable, biocompatible
polymer known in the art.
Methods of Use
[0044] In another aspect, a method is provided for measuring the
dissolved oxygen concentration of the extracellular environment in
vivo. The method may include deploying a sensor at a tissue site,
and thereafter subjecting the tissue site to electromagnetic
radiation and employing MR-based spectroscopy to analyze the
dissolved oxygen concentration of the fluid. The sensor may
comprise a sensing medium that comprises an MR contrast agent for
oxygen contained in a reservoir.
[0045] In some embodiments, the implanted device may be used to
analyze the dissolved oxygen concentration of a tissue site at the
same location(s) over time. Because of the non-invasive nature of
the "sampling" analysis, the "sampling" may advantageously be
performed more frequently or over a shorter sampling interval.
Compared to the injection of HMDSO directly into tissue, the
implantable devices may also offer the advantage of confining the
molecules to a known space and also keeping the amount of HMDSO
sampled constant. In injection methods, it may be difficult to
ascertain a specific amount of contrast agent in a specific area;
as the contrast agent is cleared from the body, the exact amount of
contrast agent remaining can also be difficult to determine. The
use of the sensor devices may alleviate these problems, as the
molecules are prevented from escaping by the oxygen permeable
membrane.
[0046] In some embodiments, one or more sensors are implanted in a
patient. For example, the sensors may be placed at or adjacent to
or within an organ or tissue site of interest in the patient, such
as the brain, the heart, or other vital organ. The sensors may also
be placed at or around the site of a tumor. The sensors may be
subjected to MR-based spectroscopy for analysis or imaging. In some
embodiments, the sensors and tissue site may be analyzed by
measuring T1 relaxation times using MRI. These measurements may be
taken repeatedly, such as over the course of a patient's treatment
for a disease.
[0047] In some embodiments, one or more sensors are used to monitor
hypoxia within solid tumors. The one or more sensors may be
implanted in or around the tumor tissue. For example, the one or
more sensors may be implanted during a resection surgery or a
biopsy procedure. Thereafter, the tumor site may be analyzed or
imaged using MR-based spectroscopy, such as H1 NMR or MRI. The
measurements may be repeated regularly and non-invasively as
needed. A physician or other health care professional may use the
dissolved oxygen data obtained from the sensors to manage the
treatment of the patient. For example, the physician or health care
professional may used the dissolved oxygen data from the sensor to
evaluate the state of the tumor, to identify hypoxia conditions in
tumors, to evaluate the effectiveness of a treatment strategy on
the patient, and to schedule therapies, such as radiotherapy, at
the most opportune times to achieve improved outcomes.
[0048] Other applications for measurement of dissolved oxygen
include the monitoring of metabolic activities in specific regions
or organs of the body. One highly investigated area is the use of
MRI techniques to probe oxygen usage in the brain in functional MRI
studies. Biologists studying neural activities can glean
information on the functions of those areas by monitoring the usage
of oxygen in different regions of the brain. Oxygen depletion in
parts of the body can be detected with implanted sensors,
specifically, detecting oxygen depletion in vital organs such as
the heart or brain can potentially inform physicians of problems
(e.g., minor myocardial infarction or stroke) that can otherwise go
unnoticed.
[0049] Another application is the staging of compartment syndrome
in trauma patients and whether a fasciotomy is indicated. The
swelling that occurs in an injured limb of a trauma patient can
dramatically reduce blood flow to the limb which can ultimately
lead to necrosis of the tissue. A surgical procedure where the
fascia is cut to reduce such pressure (a fasciotomy) is called for
when there is insufficient circulation in the limb. One indicator
of that circulation is interstitial dissolved oxygen. An oxygen
sensitive device placed in the limb and monitored over time will be
very helpful in quantitative assessment of the level of compartment
circulation.
[0050] These sensor devices may be used in other clinical and
research applications. The sensor devices may provide physicians
and researchers unprecedented access to real-time pO.sub.2 data
without affecting patients' quality of life.
[0051] These sensor devices may also be employed in ex vivo
applications. For example. the sensors may be used in ex vivo
applications in which it is desirable to determine the oxygen
concentration of a fluid, such as a liquid or a gas. In some
embodiments, an electromagnet, such as an electromagnet comprising
a coil and a rare-earth magnet, may be used to measure the
relaxivity of a sensing medium when it is in contact with the
fluid. The sensing medium may be an MR contrast agent for oxygen.
As the oxygen content of the fluid changes, the relaxivity of the
sensor medium will also change, and the change in the relaxivity of
the sensing material may be detected by a sensing circuit that is
electrically connected to the electromagnet. The sensing circuit
may be calibrated to detect changes in the relaxivity of the sensor
material that are of significance to the particular sensing
application. For example, in sensing application in which a 1%
change in oxygen concentration from a set point of 10 volume
percent oxygen concentration would be of significance, the sensor
may be calibrated by employing the appropriate amount of sensing
medium with an appropriately-sized electromagnet and an
appropriately-calibrated sensing circuit to detect changes of the
magnitude of concern in the sensing application. Of course, the
foregoing percentages are only intended to be illustrative, and one
of ordinary skill in the art will appreciate that, consistent with
the present disclosure, the actual control set points and degree of
change in concentration that is of significance may vary depending
on the particular application and the disclosed sensors and methods
may be calibrated to the particular application.
[0052] In a certain embodiment, the sensor may be employed in an
automobile to determine oxygen concentration in an exhaust stream.
For example, a sensor may be placed in the exhaust stream flow
path, such as downstream and/or upstream of a catalytic converter
in a location in the exhaust stream flow path that exposes the
sensing medium to the exhaust stream. The sensing medium may be
positioned and arranged with respect to an electromagnet such that
changes in the relaxivity of the sensing medium may be detected by
a sensing circuit that is electrically coupled to the
electromagnet. The sensing circuit may detect the oxygen
concentration of the exhaust gas at the location of the sensor. The
oxygen concentration may be an absolute oxygen concentration or it
may be change in concentration from a pre-designated control set
point. The sensor may communicate with a controller, e.g., via an
electrical connection between the sensor and controller or via
telemetry. The controller may then control an actuation function
when the measured oxygen concentration meets, exceeds, or is less
than a set point. For example, the controller may control the
actuation of a change in fuel injection, e.g., by injector
pulse-width modulation or by altering pulse frequency, to achieve a
desired air-fuel ratio, such a stoichiometric air-fuel ratio.
[0053] In addition to automotive sensing applications, other ex
vivo applications are envisioned for the present sensors. For
example, the sensors may be used to measure dissolved oxygen in
bodies of water such as lakes, rivers, and oceans. In such
applications, the sensing medium may be submerged into the body of
water, and a sensing circuit that is coupled to an electromagnet
may detect changes in relaxivity of the sensing medium as the
concentration of dissolved oxygen around the sensor changes.
Example
[0054] Three composite sensors having different concentrations of
contrast agent in a matrix material were produced. Each sensor was
produced by adding dodecamethylpentasiloxane (DDMPS) to
SYLGARD.RTM. 184 elastomer base from Dow Corning. The liquid
mixture was then mixing thoroughly, poured into a mold, and then
cured to produce solid composite sensors. The three samples were
75% DDMPS, 50% DDMPS, and 25% DDMPS (percentages expressed in
volume percent).
[0055] Spin-lattice relaxation time (T1) data has been collected
for each device. Each of the three molded PDMS/siloxane devices
were placed in a 10 mm NMR tube and then inserted into a Bruker
Minispec TD-NMR system for measurements. Gas composition in the
tube was altered with the use of a gas mixer that outputs gas
mixtures at different oxygen concentrations. The T1 data for three
samples is illustrated in FIG. 5. The numbers at the top of the
graph indicate the oxygen concentration around the sample when
measurements were taken. As shown in FIG. 5, the measured T1 for
each sample correlate strongly with oxygen concentration and
therefore provide a good indicator for dissolved oxygen
concentration.
[0056] While the present invention may be embodied in many
different forms, disclosed herein are specific illustrative
embodiments thereof that exemplify the principles of the invention.
It should be emphasized that the present invention is not limited
to the specific embodiments illustrated.
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