U.S. patent application number 13/506131 was filed with the patent office on 2012-07-26 for vasculature and lymphatic system imaging and ablation.
This patent application is currently assigned to The Invention Science Fund I, LLC. Invention is credited to Roderick A. Hyde, Edward K.Y. Jung, Nathan P. Myhrvold, Clarence T. Tegreene, Willard H. Wattenburg, Lowell L. Wood, JR., Richard N. Zare.
Application Number | 20120190964 13/506131 |
Document ID | / |
Family ID | 40523919 |
Filed Date | 2012-07-26 |
United States Patent
Application |
20120190964 |
Kind Code |
A1 |
Hyde; Roderick A. ; et
al. |
July 26, 2012 |
Vasculature and lymphatic system imaging and ablation
Abstract
Devices, methods, and systems related to imaging and ablation
are disclosed.
Inventors: |
Hyde; Roderick A.; (Redmond,
WA) ; Jung; Edward K.Y.; (Bellevue, WA) ;
Myhrvold; Nathan P.; (Medina, WA) ; Tegreene;
Clarence T.; (Bellevue, WA) ; Wattenburg; Willard
H.; (Walnut Creek, CA) ; Wood, JR.; Lowell L.;
(Bellevue, WA) ; Zare; Richard N.; (Stanford,
CA) |
Assignee: |
The Invention Science Fund I,
LLC
Bellevue
WA
|
Family ID: |
40523919 |
Appl. No.: |
13/506131 |
Filed: |
March 28, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11973010 |
Oct 3, 2007 |
8165663 |
|
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13506131 |
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Current U.S.
Class: |
600/407 |
Current CPC
Class: |
A61B 1/043 20130101;
A61B 1/3137 20130101; A61B 5/02007 20130101; A61B 5/7267 20130101;
A61B 8/56 20130101; A61B 1/041 20130101; A61B 5/412 20130101; A61B
18/20 20130101; A61B 2017/00106 20130101; A61B 5/0075 20130101;
A61N 7/02 20130101; A61B 5/053 20130101; A61B 5/0084 20130101; A61B
2018/1807 20130101; A61B 5/417 20130101; A61B 5/0071 20130101; A61B
5/418 20130101; A61B 8/12 20130101; A61B 18/18 20130101 |
Class at
Publication: |
600/407 |
International
Class: |
A61B 6/00 20060101
A61B006/00 |
Claims
1.-216. (canceled)
217. A method, comprising: eliciting image information responsive
to first energy output from one or more first energy source of one
or more untethered device disposed in or proximal to one or more
blood vessel or lymph vessel; locally capturing the image
information associated with the one or more blood vessel or lymph
vessel in a subject using the one or more untethered device;
analyzing the image information to at least partially identify one
or more targets in real time; selectively closing at least one
valve to trap the one or more identified targets in an insert of
the one or more untethered device responsive to the one or more
identified targets being identified; and locally providing second
energy, from one or more second energy source of the one or more
untethered device, to the one or more identified targets trapped in
the insert in real time, the energy having a magnitude selected to
at least partially ablate the one or more identified targets.
218. The method of claim 217, wherein the image information
includes spatial-temporal location information.
219. The method of claim 217, wherein the image information
includes velocity information.
220. The method of claim 217, wherein analyzing the image
information includes comparing the image information to one or more
of reference image information or target image information.
221. The method of claim 220, wherein comparing the image
information to one or more of reference image information or target
image information includes comparing one or more of cell shape or
cell outline with one or more of reference cell shape or cell
outline information or target cell shape or cell outline
information.
222. The method of claim 220, wherein comparing the image
information to one or more of reference image information or target
image information includes comparing one or more of intracellular
shape or intracellular outline with one or more of reference
intracellular shape or intracellular outline information or target
intracellular shape or intracellular outline information.
223. The method of claim 217, wherein analyzing the image
information includes performing one or more of pattern recognition
or shape recognition analysis.
224. The method of claim 217, wherein analyzing the image
information includes determining spatial-temporal information
associated with the image information.
225. The method of claim 224, wherein determining spatial-temporal
information associated with the image information includes
predicting future spatial-temporal locations associated with the
image information.
226. The method of claim 224, wherein determining spatial-temporal
information associated with the image information includes
determining velocity information associated with the image
information.
227. The method of claim 217, further comprising locally inhibiting
fluid flow associated with the one or more blood vessel or lymph
vessel.
228. A method of treating, ameliorating, or preventing a disease or
disorder in a subject, the method comprising: eliciting image
information responsive to first energy output from one or more
first energy source of an untethered device disposed in or proximal
to one or more blood vessel or lymph vessel; locally capturing the
image information associated with the one or more blood vessel or
lymph vessel in the subject using one or more sensors of the
untethered device; analyzing the image information to at least
partially identify one or more targets in real time; selectively
closing at least one valve to trap the one or more identified
targets in an insert of the untethered device responsive to the one
or more identified targets being identified; and with the one or
more identified targets trapped in the insert, locally providing
ablation energy, from one or more second energy sources, to the
target area in real time, the ablation energy having
characteristics appropriate to at least partially ablate the one or
more identified targets; wherein the one or more identified targets
are associated with the disease or disorder.
229. The method of claim 228, wherein the disease or disorder is an
infection.
230. The method of claim 228, wherein the disease or disorder is a
neoplasm.
231. The method of claim 228, wherein the image information
includes spatial-temporal location information.
232. The method of claim 228, wherein the image information
includes velocity information.
233. The method of claim 228, wherein analyzing the image
information includes performing one or more of a pattern
recognition or a shape recognition analysis.
234. The method of claim 228, wherein analyzing the image
information includes determining spatial-temporal information
associated with the image information.
235. The method of claim 234, wherein determining spatial-temporal
information associated with the image information includes
predicting future spatial-temporal locations associated with the
image information.
236. A method, comprising: eliciting image information responsive
to first energy output from one or more first energy source of one
or more untethered device disposed in or proximal to one or more
blood vessel or lymph vessel; locally capturing the image
information associated with the one or more blood vessel or lymph
vessel in a subject using one or more sensors of the one or more
untethered device; analyzing the image information using control
circuitry that is coupled to the one or more sensors to at least
partially identify one or more targets during an expected transit
time of the one or more targets through a detection area in the
lumen; selectively closing at least one valve to trap the one or
more identified targets in an insert of the one or more untethered
device responsive to the one or more identified targets being
identified by the control circuitry; and locally providing second
energy, from one or more second energy source of the one or more
untethered device, to the one or more identified targets trapped in
the insert in real time, the energy having a magnitude selected to
at least partially ablate the one or more identified targets.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is related to U.S. patent
application Ser. No. [To Be Assigned], entitled VASCULATURE AND
LYMPHATIC SYSTEM IMAGING AND ABLATION ASSOCIATED WITH A LOCAL
BYPASS, naming Roderick A. Hyde, Edward K. Y. Jung, Nathan P.
Myhrvold, Clarence T. Tegreene, Willard H. Wattenburg, Lowell L.
Wood, Jr. and Richard N. Zare as inventors, filed 4, Oct.,
2007.
[0002] The present application is related to U.S. patent
application Ser. No. [To Be Assigned], entitled VASCULATURE AND
LYMPHATIC SYSTEM IMAGING AND ABLATION ASSOCIATED WITH A RESERVOIR,
naming Roderick A. Hyde, Edward K. Y. Jung, Nathan P. Myhrvold,
Clarence T. Tegreene, Willard H. Wattenburg, Lowell L. Wood, Jr.
and Richard N. Zare as inventors, filed 5, Oct., 2007.
[0003] All subject matter of the Related Applications and of any
and all parent, grandparent, great-grandparent, etc. applications
of the Related Applications is incorporated herein by reference to
the extent such subject matter is not inconsistent herewith.
SUMMARY
[0004] The present application relates, in general, to devices and
methods for imaging and ablation of medical targets. Such devices
and methods are useful for ablating target cells and/or tissues as
well as treatment, prevention, and/or diagnosis of a variety of
diseases and disorders. Devices are configured to be used
internally and untethered. Various methods include using one or
more of the devices for ablating target cells within the vascular
or lymphatic systems. Illustrative examples include using one or
more of the devices or methods to treat and/or ablate blood-borne
pathogens and/or neoplasms.
[0005] The foregoing summary is illustrative only and is not
intended to be in any way limiting. In addition to the illustrative
aspects, embodiments, and features described above, further
aspects, embodiments, and features will become apparent by
reference to the drawings and the following detailed
description.
BRIEF DESCRIPTION OF THE FIGURES
[0006] FIG. 1 shows a schematic of an illustrative device in which
embodiments may be implemented.
[0007] FIG. 2 shows a schematic of illustrative embodiments of the
device of FIG. 1, with illustrative examples of an energy
source.
[0008] FIG. 3 shows a schematic of illustrative embodiments of the
device of FIG. 1, with illustrative examples of an optical energy
source.
[0009] FIG. 4 shows a schematic of illustrative embodiments of the
device of FIG. 1, with illustrative examples of a sensor.
[0010] FIG. 5 shows a schematic of illustrative embodiments of the
device of FIG. 1, with illustrative examples of an electromagnetic
energy sensor.
[0011] FIG. 6 shows a schematic of illustrative embodiments of the
device of FIG. 1, with illustrative examples of a power source.
[0012] FIG. 7 and FIG. 8 show schematics of an illustrative device
including a local bypass in which embodiments may be
implemented.
[0013] FIG. 9 and FIG. 10 show schematics of an illustrative device
including a reservoir in which embodiments may be implemented.
[0014] FIG. 11 shows a schematic of an illustrative embodiment of a
system including a device in use on a subject.
[0015] FIG. 12, FIG. 13, FIG. 14, FIG. 15, FIG. 16 and FIG. 17 show
schematics of illustrative embodiments of systems including devices
configured to function in a vessel lumen.
[0016] FIG. 18, FIG. 19, and FIG. 20 show schematics of
illustrative embodiments of systems including devices configured to
function proximal to a vessel lumen optionally including a
reservoir.
[0017] FIG. 21, FIG. 22, FIG. 23, and FIG. 24 show schematics of
illustrative embodiments of systems including devices including a
local bypass and optionally including a reservoir.
DETAILED DESCRIPTION
[0018] In the following detailed description, reference is made to
the accompanying drawings, which form a part hereof. In the
drawings, similar symbols typically identify similar components,
unless context dictates otherwise. The illustrative embodiments
described in the detailed description, drawings, and claims are not
meant to be limiting. Other embodiments may be utilized, and other
changes may be made, without departing from the spirit or scope of
the subject matter presented here.
[0019] The present application relates, in general, to systems,
devices, and methods for imaging and optionally ablating medical
targets in the vasculature and lymphatic systems for treatment,
prevention and/or diagnosis. Those having skill in the art will
appreciate that the specific devices and methods described herein
are intended as merely illustrative of their more general
counterparts.
[0020] In one aspect, FIG. 1 through FIG. 10 depict one or more
embodiments of one or more device 100, 200, and/or 300, configured
to image and optionally to ablate one or more targets or target
areas. Although one or more embodiments of one or more devices may
be presented separately herein, it is intended and envisioned that
one or more devices and/or embodiments of one or more devices, in
whole or in part, may be combined and/or substituted among the
devices to encompass a full disclosure of the one or more devices.
As disclosed below, one or more devices may be used in one or more
methods of treatment, prevention, and/or diagnosis as well as
methods for imaging and/or impairing targets as described
herein.
[0021] FIG. 1, FIG. 2, FIG. 3, FIG. 4, FIG. 5, and FIG. 6 depict
illustrative embodiments of one or more device 100 having one or
more sensors 130 configured to function in, or proximal to, one or
more blood vessel or lymph vessel and to capture one or more image
responses; and control circuitry 150 coupled to the one or more
sensors 130 and responsive to at least partially identify one or
more targets in real time at least partially based on the one or
more captured image responses. The one or more device 100
optionally includes one or more of one or more energy source 110,
one or more power source 160, one or more insert 170, one or more
vessel attachment units 180, and/or one or more vessel lumen
anchors 190.
[0022] FIG. 7 and FIG. 8 depict illustrative embodiments of one or
more device 200 having a local bypass 210 configured to function
in, or proximal to, one or more blood vessel or lymph vessel; one
or more sensors 130 configured to function in, or proximal to, the
local bypass and to capture one or more image responses; and
control circuitry 150 coupled to the one or more sensors 130 and
responsive to at least partially identify one or more targets in
real time at least partially based on the one or more captured
image responses. The one or more device 200 optionally includes one
or more of one or more energy source 110, one or more power source
160, one or more insert 170, one or more vessel attachment units
180, and/or one or more vessel lumen anchors 190.
[0023] FIG. 9 and FIG. 10 depict illustrative embodiments of one or
more device 300 having one or more reservoirs 310 responsive to
control circuitry 150, and configured to receive one or more
targets and to function in, or proximal to, one or more blood
vessel or lymph vessel; one or more sensors 130 configured to
function in, or proximal to, the one or more reservoirs and to
capture one or more image responses; and control circuitry 150
coupled to the one or more sensors 130 and responsive to at least
partially identify one or more targets in real time at least
partially based on the one or more captured image responses. The
one or more device 300 optionally includes one or more of one or
more energy source 110, one or more power source 160, one or more
insert 170, one or more vessel attachment units 180, and/or one or
more vessel lumen anchors 190.
[0024] The one or more devices 100, 200, and/or 300 in whole, or in
part, are configured for use in, or proximal to, one or more blood
vessels and/or lymph vessels of an organism. In illustrative
embodiments, the one or more device 100, 200, and/or 300, in part
or in whole, is an intra-lumenally sized device (e.g. small enough
to be placed in a blood vessel and/or lymph vessel while not
necessarily obstructing the flow). In illustrative embodiments, the
one or more device 100, 200, and/or 300, in part or in whole, is
configured for use proximal to a blood vessel or lymph vessel.
[0025] As used herein, the term "lumen" may include, but is not
limited to, part or all of the open interior of a blood vessel
(including e.g., arteries, veins, and capillaries), or of a lymph
vessel. As used herein, the term "proximal to" may include, but is
not limited to, a space and/or area near to a blood or lymph vessel
and/or vessel lumen. Locations that are proximal to a vessel may
include, for example, locations external to the vessel wall
optionally where there is space for implanting one or more devices
in whole or in part, and optionally to facilitate external access
to the devices in whole or in part. In some embodiments, "proximal
to" may include distances such as, but not limited to,
approximately 0.1, 1.0, 10, and/or 100 .mu.ms and/or 0.1, 1.0, 10,
and/or 100 mms, and may optionally include larger and/or smaller
distances depending on, for example, the availability of space, the
size of the device and/or the vessel, and the characteristics of
the energy (e.g. electromagnetic energy, particle beam, two-photon,
pulsed, etc.) and/or the sensors (e.g. sensitivity of detection).
Those of skill in the art would know (and/or are able to calculate)
the applicable distance for each form of energy.
[0026] The one or more devices 100, 200, and/or 300 are, in whole
or in part, untethered. As used herein, the term "untethered"
includes not required to be physically linked to one or more
external components and/or not physically linked to one or more
external components. In some embodiments, untethered may include
autonomous functioning, such that there is, for example, no
required external control circuitry link as well.
[0027] Embodiments of one or more device 100, 200, and/or 300 may
be configured as a self-contained unit that includes all
functionalities necessary for operation of the device, or
configured as one or more subparts in one or more locations
separate from one another (and optionally external to the subject),
wherein one or more of the subparts includes one or more essential
and/or non-essential functionalities. In illustrative examples, one
subpart may be placed within a lumen of, for example, a blood
vessel, and another subpart placed, for example, proximal to the
blood vessel optionally in a location more accessible from the
exterior of the subject, or where there is additional space. In
illustrative embodiments, a remote portion may provide for
monitoring of the lumen-based device, data collection, or data
analysis, and/or remote-control of one or more other functions such
as image capture, and energy use. The remote portion may be at a
separate location within the body of the subject, or outside the
body of the subject. Data and/or power signals may be transmitted
between the one or more subparts using electromagnetic signals, for
example, or electrical or optical links. Methods of distributing
functionalities of a system between hardware, firmware, and
software at located at two or more sites are well known to those of
skill in the art.
[0028] Embodiments of one or more device 100, 200, and/or 300 may
be described as having one or more subparts including, but not
limited to, one or more energy sources 110, one or more sensors
130, one or more control circuitry 150, one or more power sources
160, one or more insert 170, one or more vessel attachment units
180, and/or one or more vessel lumen anchors 190. In some
embodiments, one or more subpart may be a physically distinct unit.
In some embodiments, one or more subpart is combined with one or
more other subpart to form a single unit optionally with no
physically discernible separation. Some embodiments include a
first, second, third, fourth, fifth, etc. energy source 110, sensor
130, control circuitry 150, power sources 160, insert 170, vessel
attachment units 180, and/or vessel lumen anchors 190, for example.
One or more of the one, two three, four, five, etc. components may
be part of the same component and/or physical entity, or one or
more components may be a separate physical entity. For example,
there may be two lasers in a device, or there may be one laser able
to provide both excitation and ablation energy. For example, there
may be two sensors in a device, or there may be one sensor able to
detect a variety of energy wavelengths.
[0029] As used herein, the term "internal location" may include
locations within the body of a subject appropriate for the
placement of one or more device and/or part of one or more device.
In illustrative embodiments, one or more internal locations may be
proximal to one or more blood vessel and/or lymph vessel. Such
internal locations are known to those with skill in the art and/or
described herein. Methods for placing one or more devices in
internal locations are known to those in the medical profession,
for example. As used herein, the term "medical professional" may
include, but is not limited to, physicians, nurses, mid-wives,
and/or nurse practitioners, dental professionals, such as but not
limited to, dentists, orthodontists, dental hygienists, and
veterinary professionals, including but not limited to,
veterinarians during treatment optionally including surgery.
[0030] As used herein, the term "subject" may include, but is not
limited to, one or more living entities including, but not limited
to, animals, mammals, humans, reptiles, birds, amphibians, and/or
fish. The animals may include, but are not limited to,
domesticated, wild, research, zoo, sports, pet, primate, marine,
and/or farm animals. Animals include, but are not limited to,
bovine, porcine, swine, ovine, murine, canine, avian, feline,
equine, and/or rodent animals. Domesticated and/or farm animals
include, but are not limited to, chickens, horses, cattle, pigs,
sheep, donkeys, mules, rabbits, goats, ducks, geese, chickens,
and/or turkeys. Wild animals include, but are not limited to,
non-human primates, bear, deer, elk, raccoons, squirrels, wolves,
coyotes, opossums, foxes, skunks, and/or cougars. Research animals
include, but are not limited to, rats, mice, hamsters, guinea pigs,
rabbits, pigs, dogs, cats and/or non-human primates. Pets include,
but are not limited to, dogs, cats, gerbils, hamsters, guinea pigs
and/or rabbits. Reptiles include, but are not limited to, snakes,
lizards, alligators, crocodiles, iguanas, and/or turtles. Avian
animals include, but are not limited to, chickens, ducks, geese,
owls, sea gulls, eagles, hawks, and/or falcons. Fish include, but
are not limited to, farm-raised, wild, pelagic, coastal, sport,
commercial, fresh water, salt water, and/or tropical. Marine
animals include, but are not limited to, whales, sharks, seals, sea
lions, walruses, penguins, dolphins, and/or fish.
[0031] The dimensions and mechanical properties (e.g., rigidity) of
the one or more devices 100, 200, and/or 300, in part or in whole,
and particularly of the structural elements of the one or more
device (e.g. one or more inserts 170, one or more vessel attachment
units 180, one or more vessel lumen anchors 190, one or more local
bypass 210, one or more closable openings 213, one or more vessel
insertion unit 214, one or more bypass insert 216, one or more
intralumenal reservoir 311, and/or one or more self-sealing
aperture 313, among others), may be selected for compatibility with
the location of use in order to provide for reliable positioning
and/or to provide for movement of the device while preventing
damage to the vessel, the vessel lumen, and/or internal location
and its surrounding structure. In illustrative embodiments, part or
all of a device is configured for use within a blood vessel or
lymph vessel lumen. In illustrative embodiments, part or all of a
device is configured for use proximal to (i.e. at least partially
external to) a blood vessel or lymph vessel. In illustrative
embodiments, at least part of an untethered device is internal to a
subject. In illustrative embodiments, part of an untethered device
is external to a subject. In illustrative embodiments, part or all
of a device is immobile.
[0032] The choice of structural element size and configuration
appropriate for a particular blood or lymph vessel location may be
selected by a person of skill in the art, optionally a medical
professional. Structural elements may be constructed using a
variety of manufacturing methods, from a variety of materials.
Appropriate materials may include metals, ceramics, polymers, and
composite materials having suitable biocompatibility,
sterilizability, mechanical, and physical properties, as will be
known to those of skill in the art. Examples of materials and
selection criteria are described, for example, in The Biomedical
Engineering Handbook (Second Edition, Volume I, J. D. Bronzino,
Ed., Copyright 2000, CRC Press LLC, pp. IV-1-43-22). Manufacturing
techniques may include injection molding, extrusion, die-cutting,
rapid-prototyping, etc., and will depend on the choice of material
and device size and configuration. Sensing and energy-emitting
portions of the devices as well as associated control circuitry may
be fabricated on the structural elements using various
microfabrication and/or MEMS techniques (see, e.g., U.S. Patent
Applications 2005/0221529, 2005/0121411, 2005/0126916, and Nyitrai,
et al. "Preparing Stents with Masking & Etching Technology"
(2003) 26.sup.th International Spring Seminar on Electronics
Technology pp. 321-324, IEEE), or may be constructed separately and
subsequently assembled to the structural elements, as one or more
distinct components. See also, U.S. Patent Applications
2007/0066939 and 2007/0225633.
[0033] The choice of structural element size and configuration
appropriate for a device may be selected by a person of skill in
the art. Configurations for structural elements include, but are
not limited to, a substantially tubular structure, one or more
lumens in fluid communication with the body lumen, and/or an
adjustable diameter (see, e.g., U.S. patent application Ser. Nos.
11/403,230 and 11/645,357). Structural elements may have the form,
for example, of a short cylinder, an annulus, a cylinder, and/or a
spiral. A spiral structure is disclosed, for example, in Bezrouk et
al, ("Temperature Characteristics of Nitinol Spiral Stents" (2005)
Scripta Medica (BRNO) 78(4):219-226.
[0034] In illustrative embodiments, one or more structural elements
of one or more devices may be substantially cylindrical, and hollow
and tubular in configuration, with a single central opening,
optionally allowing the exterior of the cylindrical structural
element to contact and engage the wall of a vessel lumen, and the
interior of the structural element (within the single central
opening) to optionally form a fluid-contacting portion of the
structural element. Optionally, one or more structural elements of
one or more devices may be approximately hemi-spherical or
hemi-elliptoid, optionally allowing a portion of its cross-section
to contact and/or engage the wall of a lumen without significantly
and/or substantially obstructing the movement of fluid within the
body lumen. Optionally, one or more structural elements of one or
more devices may be pill- or capsule-shaped, and adapted to move
through a central portion of a body lumen. Lumen wall engaging
portions may include, but are not limited to, rotating wheels,
projections (e.g. arms), springs, hooks (e.g. claws), suction cups,
and/or tissue adhesives that are configured to engage wall portions
and optionally to provide mobility to one or more devices.
[0035] In additional to materials disclosed above, flexible
material having adjustable diameter, taper, and length properties
may be used as part of the structural material. For example, some
materials may change from a longer, narrower configuration, to a
shorter, wider configuration, or may taper over their length.
Structural elements that may exhibit this type of
expansion/contraction property may include mesh structures formed
of various metals or plastics, and some polymeric materials, for
example (see, e.g., "Agile new plastics change shape with heat" MIT
News Office (Nov. 20, 2006) pp. 1-4; MIT Tech Talk (Nov. 22, 2006)
p. 5; http://web.mit.edu/newsoffice/2006/triple-shape.html; and
Shanpoor et al., Smart Materials and Structures (2005) 14:197-214,
Institute of Physics Publishing).
[0036] In some embodiments, the structural element may include a
self-expanding material, a resilient material, or a mesh-like
material. Flexibility may also be conferred by configuration as
well as material; the structural element may include a slotted
structure and/or mesh-like material, for example. Structural
elements may be formed from various materials, including metals,
polymers, fabrics, and various composite materials, including ones
of either inorganic or organic character, the latter including
materials of both biologic and abiologic origin, selected to
provide suitable biocompatibility and mechanical properties. The
structural element may include a biocompatible material, and may
include a bioactive component (such as a drug releasing coating or
bioactive material attached to or incorporated into the structural
element).
[0037] Embodiments of one or more devices 100, 200, and/or 300
optionally include one or more insert 170 responsive to control
circuitry 150 and configured to modulate at least part of a vessel
lumen, optionally at least part of the circumference of the lumen.
In some embodiments, one or more insert 170 is configured to
controllably, reversibly, and/or programmably modulate at least
part of the circumference of the vessel lumen. In illustrative
embodiments, one or more insert 170 is configured to reduce the
diameter of at lest part of a vessel lumen responsive to a signal
from control circuitry 150 optionally once every 24 hours, or once
a week, or once a month, or once a year, for example. In
illustrative embodiments, one or more insert 170 is configured to
modulate at least part of the diameter of a vessel lumen responsive
to a signal from control circuitry 150 at a remote (e.g. external)
location, optionally in response to a medical professional for
screening and/or diagnosis.
[0038] In some embodiments, one or more insert 170 is configured to
modulate (optionally narrow, constrict, compress, and/or occlude,
or expand and/or enlarge) at least part of the inner (e.g.
interior) circumference of the vessel lumen. In some embodiments,
one or more insert 170 is configured to modulate (e.g. optionally
constrict and/or compress, or expand and/or enlarge) at least part
of the outer (e.g. exterior) circumference of the vessel lumen.
[0039] In some embodiments, one or more insert 170 is configured to
narrow (e.g. compress and/or occlude) at least part of the lumen
(e.g. the inner circumference and/or diameter) such that one or
more cells traverse the constriction in approximately single file
and/or such that one or more cells traverse a localized region. In
some embodiments, one or more insert 170 is configured to constrict
(e.g. compress and/or occlude) at least part of the lumen (e.g.
inner circumference and/or diameter) such that fluid flow is
modified and/or the movement of one or more cells (e.g. one or more
possible targets and/or one or more targets) is decreased.
[0040] In illustrative embodiments, one or more insert 170 is
configured to modify a vessel lumen such that one or more cells
traverse a localized region, such that the cells pass through an
imaging system. An imaging system may include one or more sensors
130, one or more energy sources 110 and/or control circuitry 150
optionally in association with the one or more insert 170. In
illustrative embodiments, one or more insert 170 is configured to
modify a vessel lumen such that one or more cells traverse a
localized region responsive to control circuitry 150, optionally
responsive to analysis of one or more image responses (e.g.
optionally identifying one or more possible targets and/or one or
more targets) from one or more sensors 130 upflow from the insert
170.
[0041] In some embodiments, one or more insert 170 is configured to
function proximal to the vessel lumen. In some embodiments, one or
more insert 170 is configured as a closable sleeve. In illustrative
embodiments, one or more insert 170 at least partial surrounds the
vessel wall, and optionally occludes fluid flow, by tightening
around the vessel wall, optionally in discrete locations.
[0042] In some embodiments, one or more insert 170 is configured to
function within the vessel lumen. In some embodiments, one or more
insert 170 is configured as an expandable tube. In some
embodiments, one or more insert 170 includes a movable valve. In
illustrative embodiments, one or more insert 170 includes a valve
that is open (e.g. not occluding fluid flow) until signaled by
control circuitry 150 to partially or completely stop fluid flow.
In illustrative embodiments, one or more insert includes an
expandable tube, that when expanded optionally enlarges the outer
circumference of the vessel wall and/or expands or narrows the
inner circumference of the vessel wall.
[0043] In some embodiments, one or more insert 170 is placed upflow
from at least one of the one or more sensors 130. In some
embodiments, one or more insert 170 is placed downflow from at
least one of the one or more sensors 130. In some embodiments, one
or more insert includes at least one of the one or more sensors
130. In some embodiments, one or more sensors 130 are configured to
capture one or more image responses within, downflow, and/or upflow
of the insert modulated part of the vessel lumen. In illustrative
embodiments, one or more insert 170 and one or more sensors 130
(and optionally one or more energy sources 110) are part of an
imaging (and/or sensing) system. For example, an insert 170 may
have one or more sensor 130 (and/or energy source 110) associated
upflow, optionally to screen for potential targets, one or more
sensor 130 (and/or energy source 110) positioned to detect images
within the insert 130, and/or one or more sensors (and/or energy
source 110) positioned to detect images downflow from the insert.
The one or more energy sources 110 are also optionally configured
to provide ablation energy to one or more targets.
[0044] In some embodiments, one or more insert 170 is placed upflow
from at least one of the one or more energy sources 110. In some
embodiments, one or more insert 170 is placed downflow from at
least one of the one or more energy sources 110. In some
embodiments, one or more insert includes at least one of the one or
more energy sources 110. In some embodiments, one or more energy
sources 110 are configured to function (optionally elicit one or
more image responses and/or provide ablation energy) within,
downflow, and/or upflow of the insert modulated part of the vessel
lumen. In some embodiments, one or more energy sources 110 are
placed upflow and/or downflow of the one or more insert.
[0045] As used herein, the term "fluid" may refer to liquids,
gases, and other compositions, mixtures, or materials exhibiting
fluid behavior. The fluid within the body lumen may include a
liquid, or a gas or gaseous mixtures. As used herein, the term
fluid may encompass liquids, gases, or mixtures thereof that also
include solid particles in a fluid carrier. Liquids may include
mixtures of two or more different liquids, solutions, slurries, or
suspensions. As used herein, lumen-related fluid refers to, blood
and/or lymph. Liquids present within vessel lumens may include
synthetic or introduced liquids, such as blood substitutes, or
drug, nutrient, fluorescent marker, or buffered saline solutions.
Fluids may include liquids containing dissolved gases or gas
bubbles, or gases containing fine liquid droplets or solid
particles. As used herein, the term "downflow" includes relative
locations that are in the expected subsequent path of the fluid
flow (e.g. the direction fluid is flowing towards). As used herein,
the term "upflow" includes relative locations that are in the
expected previous path of fluid flow (e.g. the direction fluid is
flowing from).
[0046] Embodiments of one or more devices 100, 200, and/or 300
optionally include one or more vessel attachment units 180.
Embodiments of one or more vessel attachment units 180 are
discussed herein optionally in relation to the local bypass 210 and
reservoirs 310 among others. In some embodiments, one or more
vessel attachment units 180 may also be used for attaching systems
and subparts of one or more devices 100, 200, and/or 300,
optionally including energy sources 110, sensors 130, control
circuitry 150, power sources 160, inserts 170, etc. proximal to a
vessel wall. In illustrative embodiments, one or more vessel
attachment unit 180 is configured to attach one or more insert 170
proximal to one or more vessel wall.
[0047] In illustrative embodiments, one or more vessel attachment
units 180 include mechanisms configured to allow affixation to a
vessel wall, either permanent or temporary. In illustrative
embodiments, configurations for affixing may include, but are not
limited to, one or more anchors configured to attach at least
temporarily to a vessel wall, one or more hooks and/or claws, one
or more adhesive materials and/or glues, one or more contracting
elements, and/or one or more suction-generating elements. In
illustrative embodiments, one or more vessel attachment units 180
include, but are not limited to, one or more of sleeves, straps,
clamps, Velcro (e.g. geckel), snaps, links, sutures, pins, staples,
and other appropriate medical closure devices.
[0048] Embodiments of one or more devices 100, 200, and/or 300
optionally include one or more vessel lumen anchors 190.
Embodiments of one or more vessel lumen anchors 190 are discussed
herein optionally in relation to the local bypass 210 and
reservoirs 310 among others. In some embodiments, one or more
vessel lumen anchors 190 may also be used for attaching systems and
subparts of one or more devices 100, 200, and/or 300, optionally
including energy sources 110, sensors 130, control circuitry 150,
power sources 160, inserts 170, etc. within a vessel lumen. In
illustrative embodiments, one or more vessel lumen anchors 190 are
configured to attach one or more insert 170 within one or more
vessel wall.
[0049] In illustrative embodiments, one or more vessel lumen
anchors include mechanisms configured to allow affixation to a
lumen wall, either permanent or temporary. In illustrative
embodiments, configurations for affixing may include, but are not
limited to, one or more anchors configured to attach at least
temporarily to a wall of the lumen, one or more hooks and/or claws,
one or more adhesive materials and/or glues, one or more expanding
elements, and/or one or more suction-generating elements.
[0050] In some embodiments, one or more configurations for affixing
one or more devices, in whole or in part, may be activated
responsive to control circuitry 150. In some embodiments, one or
more configurations for affixing one or more devices may be fixed
or movable. Movable structures may include, but are not limited to,
mechanical elements and/or materials that change shape or rigidity
in response to temperature, electric field, magnetic field, or
various other control signals. Affixation may be permanent, for
extended periods, and/or temporary. As used herein, the term
"extended periods" may include weeks to months to years and subsets
thereof. As used herein, the term "temporary" may include seconds,
to minutes, to hours, to days and subsets thereof.
[0051] Embodiments of one or more devices 200 include a local
bypass 210 (see, e.g., FIG. 7 and FIG. 8) configured to function
in, or proximal to, one or more blood vessel or lymph vessel. In
some embodiments, at least one location in the local bypass lumen
has a circumference and/or diameter such that one or more cells
traverse the location in single file and/or traverse a localized
region, optionally to facilitate sensing and/or ablation of one or
more possible targets and/or one or more targets. In illustrative
embodiments, the constriction in the bypass lumen is such that
cells larger than a certain size cannot pass (e.g. cells larger
than normal lymph cells and/or cells larger than normal
constituents of the blood). In illustrative embodiments, the
constriction in the bypass lumen is such that all cells can pass,
but at a restricted velocity depending on size (e.g. cell
deformation is required to allow passage of larger cells).
[0052] In illustrative embodiments, one or more local bypass 210 is
configured to receive fluid flow (and/or cellular flow) from a
vessel. The local bypass 210 is optionally configured for enhanced
imaging and/or sensing of one or more targets (e.g. funneling cells
through cooperative imaging and analysis units, optionally
sequential imaging and/or sensing units), facilitating treatment,
prevention, and/or diagnosis of one or more diseases and/or
disorders. The local bypass 210 is optionally configured for
enhanced ablation abilities, for example such that ablation energy
is provided within a confined area surrounded by bypass lumen walls
through which the energy does not penetrate (or does not penetrate
to collaterally damage the subject).
[0053] The local bypass is optionally configured as a system
optionally including, but not limited to, imaging and/or sensing
systems (e.g. one or more energy source 110, one or more control
circuitry 150, and/or one or more sensor 130), ablation systems
(e.g. one or more energy source 110, one or more control circuitry
150, and/or one or more sensor 130), and/or attachment/insertion
systems (e.g. one or more inserts 170, one or more bypass inserts
216, one or more vessel insertion units 214, one or more vessel
lumen anchors 190, one or more vessel attachment units 180, etc.).
In some embodiments, one or more of the systems are located within
the local bypass 210. In some embodiments, one or more systems are
configured to function upflow and.or downflow of the local bypass
210, optionally in a cooperative manner with one or more systems
within the local bypass 210. In some embodiments, the local bypass
210 is configured to function cooperatively with one or more device
100 and/or one or more device 300, and/or parts thereof.
[0054] In some embodiments, the local bypass 210 is configured to
function in a vessel lumen (e.g. an intralumenal bypass 211), and
is optionally configured with one or more vessel lumen anchors 190,
one or more bypass inserts 216, and/or one or more closable
openings 213 (e.g. one or more valves 215). In some embodiments,
the local bypass 210 is configured to function proximal to a vessel
lumen (e.g. an extralumenal bypass 212), and is optionally
configured with at least one vessel attachment unit 180 at each end
of the local bypass, one or more bypass insert 216, and/or one or
more vessel insertion unit 214 optionally including one or more
valves 215.
[0055] In some embodiments, one or more sensor 130 and/or one or
more control circuitry 150 (and optionally components such as but
not limited to one or more energy source 110, one or more power
source 160) are separate from or external to the local bypass. In
some embodiments, one or more sensor 130 and/or one or more control
circuitry 150 (and optionally components such as but not limited to
one or more energy source 110, one or more power source 160) are
part of or internal to the local bypass. In some embodiments, there
are one or more sensor 130 and/or one or more control circuitry 150
(and optionally components such as but not limited to one or more
energy source 110, one or more power source 160) external to the
local bypass as well as internal to the local bypass. Embodiments
in which one or more parts of the device 200 are not attached to
the local bypass 210, may also include one or more one or more
insert 170, and/or one or more vessel attachment units 180, and/or
one or more vessel lumen anchors 190.
[0056] Embodiments of the local bypass 210 are optionally
configured with one or more bypass insert 216 responsive to control
circuitry 150, and configured to modulate at least part of a local
bypass lumen, optionally at least part of the inner (e.g. interior)
and/or outer (e.g. exterior) circumference and/or diameter of the
lumen. Embodiments discussed in relation to the insert 170 herein,
are also applicable to the bypass insert 216 unless context
dictates otherwise.
[0057] In illustrative embodiments, the one or more bypass insert
216 is an integral part of the local bypass 210, optionally an
integral part of the intralumenal bypass 211 and/or the
extralumenal bypass 212. In illustrative embodiments, the one or
more bypass insert 216 is an attachable, insertable, and/or
additional part associated with the local bypass 210. In some
embodiments, one or more bypass insert 216 is configured as part of
the interior of (and/or to function within) the bypass lumen. In
some embodiments, one or more bypass insert 216 is configured as
part of the exterior of (and/or to function externally to) the
bypass lumen. In illustrative embodiments, one or more bypass
insert includes a valve, optionally responsive to control
circuitry.
[0058] In some embodiments, the one or more bypass insert 216 is
configured to modulate fluid and/or cellular flow, optionally such
that movement and/or velocity of one or more possible targets
and/or one or more targets is decreased, and/or optionally
increased. In illustrative embodiments, one or more bypass insert
216 is configured as one or more valves 215 within the lumen of the
local bypass 210. For example, the one or more valves are
configured to open to allow the influx of one or more possible
targets and/or one or more targets, and then to close trapping the
one or more possible targets and/or one or more targets in a target
area and/or a detection area for ablation and/or further imaging
and/or sensing, as appropriate.
[0059] In some embodiments, one or more bypass insert 216 is
configured to narrow, compress, constrict, and/or occlude at least
part of the bypass lumen. In some embodiments, one or more bypass
insert 216 is configured to expand and/or enlarge at least part of
the bypass lumen. In illustrative embodiments, one or more bypass
insert 216 is configured including an expandable material
configured to modulate the width of the inner circumference and/or
diameter of the bypass lumen, optionally decreasing the diameter
and/or circumference as the material expands. In illustrative
embodiments, one or more bypass insert 216 is configured as a
compression band that modulates the width of the bypass lumen
optionally from the exterior of the local bypass 210. For example,
the compression band is optionally configured with clamps and/or
ratchets designed to tighten (and/or to loosen) responsive to
control circuitry.
[0060] In some embodiments, one or more bypass insert 216 is
configured to modulate at least part of the local bypass 210 at
least partially based on one or more images captured by one or more
sensors 130. In illustrative embodiments, one or more bypass
inserts 216 constricts the bypass lumen trapping one or more
targets for ablation, and/or one or more possible targets from
further sensing. In some embodiments one or more bypass insert is
configured to remotely, wirelessly and/or programmably modulate at
least part of the bypass lumen. In illustrative embodiments, one or
more bypass inserts 216 occludes a portion of the bypass lumen
based on remote instructions from one or more external sources. In
illustrative embodiments, one or more bypass inserts 216 occludes a
portion of the bypass lumen based on a programmable protocol for
sensing and ablation at predetermined intervals.
[0061] Embodiments of the extralumenal bypass 212 are optionally
configured to function proximal to a blood vessel or lymph vessel
lumen. In illustrative embodiments, the extralumenal bypass 212 is
configured as a tubular structure optionally running parallel to
the vessel and optionally including porous material. In
illustrative embodiments, the extralumenal bypass 212 is configured
with an enlarged cavity optionally including one or more sensors
130, one or more energy sources 110, and/or one or more power
sources 160.
[0062] In some embodiments, the extralumenal bypass 212 is
configured with one or more vessel insertion units 214, optionally
responsive to control circuitry 150. In illustrative embodiments,
one or more vessel insertion units 214 are configured to pierce the
vessel wall to form an opening, optionally closable, through which
fluid and/or cells may enter the extralumenal bypass 212,
optionally by way of one or more valves 215. In illustrative
embodiments, fluid flow into the bypass lumen is a passive process
(e.g. the insertion sites are continually open), and/or an active
process (e.g. the insertion sites must be opened and/or closed by
an active mechanism). In illustrative embodiments, fluid flow
and/or cells are optionally sucked into the local bypass through
the one or more insertion units, and/or forced into the local
bypass 210 through the insertion units. Mechanisms for providing
suction and/or force are know in the art and/or described
herein.
[0063] In illustrative embodiments, there is at least one vessel
insertion unit 214 on each end of the extralumenal bypass 212,
optionally configured such that fluid flows in at one end and out
at the other end. In illustrative embodiments, the one or more
vessel insertion units are configured such that fluid and/or cells
enter the extralumenal bypass 212 through the downflow (in
reference to the fluid flow in the vessel lumen) insertion site and
exit the extralumenal bypass 212 through an upflow insertion site.
Vessel insertion units 214 and methods for implanting such devices
are known to those of skill in the art and/or are described
herein.
[0064] In illustrative embodiments, some configurations of the
extralumenal bypass 212 reduce fluid flow velocity including, but
not limited to, increased length compared to the distance between
insertion locations, baffling of local bypass lumen, changes in
direction of the local bypass lumen, enlargement of the local
bypass lumen as compared with the vessel lumen, and/or a path that
is partly or completely opposite to the vessel fluid flow and/or
gravity (e.g. fluid entry from the downflow insertion site and
return via the upflow insertion site).
[0065] In some embodiments, the one or more vessel insertion units
214 are configured to modulate fluid flow to, from, and/or within
the local bypass lumen (e.g. optionally through one or more valves
215), optionally at least partially based on one or more image
responses captured by the one or more sensors 130, and optionally
responsive to control circuitry 150. In illustrative embodiments,
one or more valves 215 in the one or more vessel insertion units
214 are configured to control fluid flow (and/or cellular flow)
into the local bypass lumen. The one or more valves are optionally
configured to open responsive to control circuitry 150 based at
least partially on the analysis of one or more image responses from
one or more sensors 130 at least partially identifying one or more
possible targets and/or one or more targets.
[0066] In illustrative embodiments, one or more valves 215 in the
one or more vessel insertion units 214 are configured to control
fluid flow (and/or cellular flow) out the local bypass lumen. The
one or more valves are optionally configured to open responsive to
control circuitry 150 based at least partially on the analysis of
one or more image responses from one or more sensors 130
(optionally internal to the local bypass lumen) at least partially
identifying one or more possible targets as not being one or more
targets. The one or more valves are optionally configured to open
responsive to control circuitry 150 following ablation (optionally
within the local bypass lumen) of the one or more possible targets
and/or one or more targets.
[0067] In illustrative embodiments, one or more valves 215 in the
one or more vessel insertion units 214 are configured to control
fluid flow (and/or cellular flow) within the local bypass lumen.
The one or more valves 215 are optionally configured to open and/or
close responsive to control circuitry 150 based at least partially
on an analysis of the velocity of movement of one or more possible
targets and/or one or more targets as they traverse the local
bypass lumen. In illustrative embodiments, the one or more valves
215 are optionally closed to reduce the velocity and optionally one
or more valves are opened to increase the velocity. In illustrative
embodiments, one or more valves 215 are located internal to the
local bypass lumen and are optionally configured to selectively
stop fluid and/or cellular flow in one or more parts of the local
bypass lumen. Selective modulation of fluid flow may be useful for
enhanced imaging, functioning of one or more physiological sensors
140, and/or for ablation, optionally targeted ablation, among other
reasons.
[0068] In some embodiments, the one or more vessel insertion units
214 and/or the one or more valves 215 are remotely controlled,
wirelessly controlled, and/or programmable. In illustrative
embodiments, the one or more vessel insertion units 214 are
configured for remote control, optionally by the subject, and/or a
medical professional such that the extralumenal bypass 212 is
connected to the vessel via the one or more vessel insertion units
214 optionally at an appropriate monitoring time by the subject,
and/or in the presence of a medical profession, optionally during a
routine exam for example. In illustrative embodiments, the one or
more valves 215 are configured as part of the one or more insertion
units and remotely controlled by one or more external source,
optionally the subject and/or a medical professional.
[0069] In illustrative embodiments, the one or more vessel
insertion units 214 and/or one or more valves 215 are optionally
programmed to insert in to the vessel wall and/or the one or more
valves 215 to open and/or close at pre-determined intervals. In
illustrative embodiments, the one or more vessel insertion units
214 and/or one or more valves 215 are optionally programmed to
insert in to the vessel wall and/or the one or more valves 215 to
open and/or close based at least partially on the occurrence of
some event, optionally a measurable event such as sensing of one or
more possible targets by the one or more sensors 130 and/or one or
more possible diseases and/or disorders optionally be one or more
physiological sensors 140.
[0070] Embodiments of the extralumenal bypass 212 are optionally
configured with one or more vessel attachment unit 180. In some
embodiments, the one or more vessel attachment unit 180 is
configured to attach to the external vessel wall. In some
embodiments, the one or more vessel attachment unit 180 is
configured to at least partially surround an external circumference
of a vessel. In some embodiments, the one or more vessel attachment
unit 180 is configured as a mesh sleeve.
[0071] In illustrative embodiments, one or more vessel attachment
unit 180 is configured to extend lengthwise down the extralumenal
bypass 212 and concurrently lengthwise down the exterior wall of
the vessel. In some embodiments, the one or more vessel attachments
unit 180 is configured to attach responsive to control circuitry
150. In illustrative embodiments, the one or more vessel attachment
unit 180 is configured to tighten and/or loosen based on control
circuitry 150, optionally remotely controlled and/or programmably
controlled.
[0072] In illustrative embodiments, one or more vessel attachment
unit 180 is configured as optionally a series of intermittent
connections between the extralumenal bypass 212 and the vessel
wall. In illustrative embodiments, one or more vessel attachment
unit 180 is configured to attach each end of the extralumenal
bypass 212 to the vessel wall. In illustrative embodiments, one or
more vessel attachment unit 180 is configured as part of and/or
including the one or more vessel insertion units 214. In
illustrative embodiments, the one or more vessel attachment unit
180 is configured to wrap partially and/or completely around the
external vessel wall. In illustrative embodiments, the one or more
vessel insertion units 214 are optionally configured to
concomitantly and/or automatically pierce the vessel wall (e.g.
during affixation).
[0073] In some embodiments, the one or more vessel attachment unit
180 is configured to include one or more vessel anchors and/or
vessel clamps. In illustrative embodiments, the one or more vessel
anchors optionally include one or more hooks and/or barbs
optionally configured to catch into the external wall of the lumen,
optionally without piercing through to the lumen. In illustrative
embodiments, one or more vessel clamps are configured to connect
part, or the entirety, of the vessel attachment unit 180 around the
vessel wall. In illustrative embodiments, the one or more clamps
are configured for optional tightening and/or loosening (e.g. for
constricting and/or compressing the vessel lumen as well as
attachment), optionally responsive to control circuitry 150. In
some embodiments, one or more vessel clamps include one or more
adhesives, optionally including geckel. Other mechanisms and
devices for affixation and/or closure are known in the art and/or
described herein.
[0074] In some embodiments, one or more vessel attachment unit 180
is configured to include one or more sensors 130 and/or one or more
energy sources 110, optionally configured to align cooperatively
during affixation of the vessel attachment unit 180 to the vessel
wall. In some embodiments, one or more vessel attachment unit 180
is configured to include one or more energy sources 110, optionally
configured to align to a target area during affixation of the
vessel attachment unit 180 to the vessel wall.
[0075] In some embodiments, the extralumenal bypass 212 is
configured with one or more bypass insert 216 responsive to control
circuitry and configured to modulate at least part of the bypass
lumen as described herein; those embodiments are also encompassed
for the bypass insert 216 associated with the intralumenal bypass
211 unless context dictates otherwise.
[0076] Embodiments of the intralumenal bypass 211 are optionally
configured to function in a blood vessel or lymph vessel lumen. In
illustrative embodiments, an intralumenal bypass 211 is a roughly
tubular shape sized for use within a vessel lumen, and optionally
including mesh to allow passage of fluid while retaining cells,
etc. In illustrative embodiments, an intralumenal bypass 211 is a
roughly oblong shape sized for use within a vessel lumen,
configured such that the length dimension is parallel to the length
dimension of the vessel lumen, and optionally open at both ends
(e.g. upflow and downflow). In illustrative embodiments, the
intralumenal bypass 211 is configured from optically pure material
optionally designed to enhance imaging and/or sensing. In
illustrative embodiments, one or more intralumenal bypass 211 is
configured such that ablation energy does not significantly
penetrate the lumen wall.
[0077] In some embodiments, the intralumenal bypass 211 is
configured with one or more vessel lumen anchors 190. In
illustrative embodiments, one or more vessel lumen anchors 190,
optionally hooks, are configured to affix the intralumenal bypass
211 to the internal wall of the vessel lumen. In some embodiments
one or more vessel lumen anchors 190 are expandable braces that
contact the lumen walls in opposition. In some embodiments, a
combination of anchors may be used, for example, braces at one or
more opening of the intralumenal bypass 211, and hooks along the
exterior bypass wall. In illustrative embodiments, the intralumenal
bypass 211 is affixed using geckel.
[0078] In some embodiments, the one or more vessel lumen anchors
190 are configured to attach to the vessel lumen responsive to
control circuitry 150. In illustrative embodiments, the
intralumenal bypass 211 is optionally configured to be placed in a
vessel lumen using some form of microsurgery, optionally an
endoscopic approach, where the vessel lumen anchors 190 are
triggered to attach to the lumen wall remotely, wirelessly, and/or
programmably. In illustrative embodiments, the vessel lumen anchors
190 can by controllably released to facilitate removal and/or
repositioning of the intralumenal bypass 211.
[0079] In some embodiments, the intralumenal bypass 211 is
configured with at least one closable opening 213 on an upflow end
and/or downflow end of the intralumenal bypass 211. In some
embodiments, the one or more closable openings 213 (e.g. one or
more valves 215) are responsive to control circuitry 150 and are
configured to modulate fluid flow to and/or from the local bypass
lumen. In illustrative embodiments, the intralumenal bypass 211 is
configured with closable openings 213 configured to allow fluid
flow to enter one end, traverse the bypass lumen and exit another
end. In illustrative embodiments, the closable openings 213 open
and close based on a pre-programmed pattern, optionally to allow
random sampling of cells in the fluid flow, and optionally the
bypass lumen is configured to include one or more sensors 130
and/or energy sources 110.
[0080] In illustrative embodiments, the closable openings 213 open
and close responsive to control circuitry 150 at least partially
based on image responses captured by sensors 130 associated with
one or more possible targets. For example, one or more sensors 130
and energy sources 110 are optionally cooperatively positioned
upflow from the intralumenal bypass 211, and following analysis of
one or more image responses by control circuitry 150 indicating the
presence of one or more possible targets, one or more valves 215 in
the upflow closable opening 213 open in response to the control
circuitry 150 to allow entry of the one or more possible targets.
One or more valves 215 in the downflow closable opening 213
optionally also sequentially close responsive to control circuitry
150 to temporarily trap the one or more possible targets in the
bypass lumen. Optionally, additional image responses may be
captured by the one or more sensors 130 (optionally different types
or quality of sensors) and analyzed to determine whether the one or
more possible targets are one or more targets. Optionally, ablation
energy is provided to the bypass lumen to ablate the one or more
possible targets and/or the one or more targets optionally in a
target area.
[0081] In some embodiments, the extraluminal bypass 212 is
configured with one or more bypass insert 216 responsive to control
circuitry and configured to modulate at least part of the bypass
lumen as described herein; those embodiments are also encompassed
for the bypass insert 216 associated with the intralumenal bypass
211 unless context dictates otherwise.
[0082] Embodiments of one or more devices 300 include one or more
reservoirs 310 (see e.g., FIG. 9 and FIG. 10) configured to receive
one or more targets from, and to function in, or proximal to, one
or more blood vessel or lymph vessel. In some embodiments, at least
one location in the reservoir lumen has a circumference and/or
diameter such that one or more cells traverse the location in
single file and/or traverse a localized region, optionally to
facilitate sensing and/or ablation of one or more possible targets
and/or one or more targets. In illustrative embodiments, the
constriction in the reservoir lumen is such that cells larger than
a certain size cannot pass (e.g. cells larger than normal lymph
cells and/or cells larger than normal constituents of the blood).
In illustrative embodiments, the constriction in the reservoir
lumen is such that all cells can pass, but optionally at a
restricted velocity depending on size (e.g. cell deformation is
required to allow passage of larger cells).
[0083] In some embodiments, one or more reservoirs 310 are
configured to function in a vessel lumen (e.g. intralumenal
reservoir 311), and optionally configured with one or more vessel
lumen anchors 190, one or more self-sealing apertures 313, and/or
one or more closable openings 213 optionally including one or more
valves 215. In some embodiments, one or more reservoirs 310 are
configured to function proximal to a vessel (e.g. extralumenal
reservoir 312), and optionally configured with one or more vessel
insertion units 214 (optionally including one or more valves 215),
one or more vessel attachment units 180, and/or one or more
self-sealing apertures 313.
[0084] In some embodiments, one or more sensor 130 and/or one or
more control circuitry 150 (and optionally components such as, but
not limited to, one or more energy source 110, one or more power
source 160, and/or one or more local bypass 210) are separate from
and/or external to the one or more reservoirs 310. In some
embodiments, one or more sensor 130 and/or one or more control
circuitry 150 (and optionally components such as but not limited to
one or more energy source 110, one or more power source 160, and/or
one or more local bypass 210) are part of, or internal to, the one
or more reservoirs 310. In some embodiments, there are one or more
sensors 130 and/or one or more control circuitry 150 (and
optionally components such as but not limited to one or more energy
source 110, one or more power source 160, and/or one or more local
bypass 210) external to the one or more reservoirs 310 as well as
internal to the one or more reservoirs 310. Embodiments in which
one or more parts of the device 300 are not attached and/or
internal to the one or more reservoirs 310, may also include one or
more of one or more insert 170, one or more vessel attachment units
180, and/or one or more vessel lumen anchors 190.
[0085] Embodiments of the one or more reservoirs 310 are optionally
configured with one or more reservoir inserts responsive to control
circuitry 150, and configured to modulate at least part of a
reservoir lumen, optionally at least part of the inner (e.g.
interior) and/or outer (e.g. exterior) circumference and/or
diameter of the lumen. Embodiments discussed in relation to the
insert 170 and/or bypass insert 216 herein, are also applicable to
the reservoir insert, unless context dictates otherwise.
[0086] Embodiments of the one or more reservoirs 310 are optionally
configured with one or more closable openings 213 configured such
that one or more of the one or more closable openings are
externally accessible following implantation in the subject. In
illustrative embodiments, the one or more reservoirs 310 are
configured to be accessed externally, optionally by the subject
and/or by a medical professional. In illustrative embodiments, the
one or more reservoir 310 is accessible via a large bore needle
and/or via a portal configured for placement such that access is
close to the skin surface and/or the portal is able to be palpated
to determine the entry point. In illustrative embodiments, the
location of the access portal may be identified through X-ray
technology, MRI, imaging, or other methods known in the art. In
illustrative embodiments, the one or more reservoir 310 is
accessible via microsurgery, optionally through endoscopy or other
appropriate medical procedure. Methods of access are known to those
of skill in the art.
[0087] In some embodiments, one or more of the one or more closable
openings 213 and/or valves 215 are self-sealing (e.g. self-sealing
aperture 313). In illustrative embodiments, one or more reservoir
310 is configured with a self-sealing aperture 313 optionally
positioned to be accessible externally following placement in a
subject. Self-sealing apertures 313 are known in the art, for
example as used as part of the multiple use seal for dispensing
fluid pharmaceuticals from a vial. Self-sealing apertures 313 are
optionally configured to allow penetration of a needle (e.g. a
syringe needle and/or biopsy needle), withdrawal of part or all of
the contents of the reservoir 310 and/or one or more compartments
of the reservoir, and then to reseal (e.g. such that cells and/or
fluid cannot escape) following withdrawal of the needle from the
aperture.
[0088] Embodiments of one or more device 300 my optionally include
one or more local bypass 210. For example, although embodiments of
the one or more device 300 are described as they relate to one or
more blood vessel and/or lymph vessel, these embodiments are also
applicable to the one or more device 300 in association with the
local bypass 210, unless context dictates otherwise. In some
embodiments, the one or more reservoir 310 is configured as an
integral part of one or more local bypass 210, optionally
intralumenal or extralumenal. In some embodiments, the one or more
reservoir 310 is configured as an additional part of the local
bypass 210, optionally attachable externally and/or internally. In
some embodiments, the one or more reservoir 310 is configured as
part of a system including the one or more local bypass 210.
[0089] In illustrative embodiments, the local bypass 210 is
configured to receive fluid flow from a vessel lumen, which fluid
passes through a sensing system (optionally including one or more
energy source 110, one or more sensors 130, one or more control
circuitry 150, and/or one or more bypass insert 216) configured to
identify one or more targets and/or possible targets, and then to
one or more reservoirs or reservoir compartments optionally through
one or more closable openings 213 and/or valves 215.
[0090] Embodiments of the one or more reservoirs 310 are optionally
configured with one or more compartments within the one or more
reservoirs 310. In some embodiments, one or more reservoir inserts
optionally including one or more valves 215 direct fluid and/or
cellular flow to one or more of the compartments optionally based
on control circuitry 150. In illustrative embodiments, one or more
targets and/or one or more possible targets are directed to
different compartment at least partially based on space
availability and/or at least partially based on the time of
collection, for example. In some embodiments, one or more reservoir
inserts, optionally including one or more valves 215, direct fluid
and/or cellular flow to one or more of the compartments optionally
at least partially based on analysis by control circuitry 150 of
one or more image responses captured by one or more sensors
130.
[0091] In illustrative embodiments, one or more possible targets
and/or one or more targets are segregated into one or more
different compartments depending on one or more criteria,
optionally disease and/or disorder associated criteria. For
example, putatively cancerous cells may be directed to one
compartment and putatively infectious agents may be directed to
another compartment. The one or more compartments may be configured
for additional analysis of the one or more putative targets by one
or more sensing systems (optionally including one or more energy
sources 110, one or more sensors 130 and one or more control
circuitry 150).
[0092] Embodiments of the extralumenal reservoir 312 are optionally
configured to function proximal to a blood vessel and/or lymph
vessel lumen. In illustrative embodiments, the extralumenal
reservoir 312 is configured as a roughly bag-like structure,
optionally including porous and/or mesh-like material. In
illustrative embodiments, the extralumenal reservoir 312 is
configured as an expandable structure, optionally including a
reservoir relief valve (e.g. purge valve) optionally configured for
releasing excess pressure, and/or fluid (optionally cellular) flow,
optionally following at least partial ablation and/or modification
of one or more targets and/or possible targets. In illustrative
embodiments, at least part of the reservoir is configured for
enhanced imaging and/or sensing. In illustrative embodiments, at
least part of the reservoir is configured for ablation, optionally
with limited collateral damage to surrounding subject tissues. In
illustrative embodiments, the extralumenal reservoir 312 is
configured with one or more cavity optionally including one or more
sensors 130, one or more energy sources 110, one or more reservoir
inserts, and/or one or more power sources 160.
[0093] In some embodiments, the extralumenal reservoir 312 is
configured with one or more vessel insertion units 214, optionally
responsive to control circuitry 150. Embodiments of the one or more
vessel insertion units 214 discussed in relation to the
extralumenal bypass 212 herein, are also applicable to the
extralumenal reservoir 312, unless context dictates otherwise.
[0094] In illustrative embodiments, one or more extralumenal
reservoirs 312 are configured with one vessel insertion unit 214
configured such that fluid (and/or cells) from a vessel lumen flow
in to the one or more extralumenal reservoirs 312. In some
embodiments, the one or more vessel insertion units 214 are
configured to modulate fluid flow to, from, and/or within the
reservoir lumen (e.g. optionally through one or more valves 215),
optionally at least partially based on one or more image responses
captured by the one or more sensors 130, and optionally responsive
to control circuitry 150.
[0095] In illustrative embodiments, one or more valves 215 in the
one or more vessel insertion units 214 are configured to control
fluid flow (and/or cellular flow) into the reservoir lumen. The one
or more valves are optionally configured to open responsive to
control circuitry 150 based at least partially on the analysis of
one or more image responses from sensing systems (optionally
including one or more sensors 130, one or more coordinating energy
sources 110, and one or more control circuitry 150), and optionally
external to the extralumenal reservoir 312 and/or configured to
image the vessel lumen) at least partially identifying one or more
possible targets and/or one or more targets.
[0096] In illustrative embodiments, the one or more vessel
insertion units 214 and/or valves 215 are configured to be
programmable, optionally remotely and/or wirelessly, optionally to
screen for the presence and/or absence of one or more targets,
and/or to count numbers of one or more targets. In illustrative
embodiments, the one or more sensing systems are configured
remotely (by the subject and/or a medical professional) to detect
image responses associated with one or more diseases or disorders
for which the subject is considered at risk (e.g. due to genetics,
health care, lifestyle, and/or symptoms) and to trigger the one or
more valves 215 to open in the presence of one or more possible
targets, and/or to open at designated sensing times (e.g. hourly,
2.times. per day, 4.times. per day, daily, weekly, monthly,
etc.).
[0097] Embodiments of the extralumenal reservoir 312 are optionally
configured with one or more vessel attachment unit 180. Embodiments
of the one or more vessel attachment units 180 discussed herein,
optionally in relation to the extralumenal bypass 212, are also
applicable to the extralumenal reservoir 312, unless context
dictates otherwise.
[0098] Embodiments of the extralumenal reservoir 312 are optionally
configured with one or more reservoir insert responsive to control
circuitry and configured to modulate at least part of the reservoir
lumen. Embodiments of the one or more inserts 170 and/or one or
more bypass inserts 216 discussed herein, are also applicable to
one or more reservoir inserts in the extralumenal reservoir 312,
unless context dictates otherwise.
[0099] Embodiments of the intralumenal reservoir 311 are optionally
configured to function in a blood vessel or lymph vessel lumen. In
illustrative embodiments, an intralumenal reservoir 311 is a
roughly tubular shape sized for use within a vessel lumen, and
optionally including mesh to allow passage of fluid while retaining
cells, etc. In illustrative embodiments, an intralumenal reservoir
311 is a roughly oblong shape sized for use within a vessel lumen,
configured such that the length dimension is parallel to the length
dimension of the vessel lumen, and optionally includes one or more
relief valve (e.g. pressure relief valve and/or fluid (cellular)
flow release valve, optionally following ablation). In illustrative
embodiments, the intralumenal reservoir is configured for enhanced
sensing and/or imaging, and is designed to quantify numbers of
targets, and/or percentages of targets based on control
circuitry.
[0100] In some embodiments, the intralumenal reservoir 311 is
configured with one or more vessel lumen anchors 190 optionally
associated with one or more vessel insertion units 214 and/or one
or more sensing systems. Embodiments of the one or more vessel
lumen anchors 190 discussed herein are also applicable to one or
more intralumenal reservoirs 311, unless context dictates
otherwise.
[0101] Embodiments of the intralumenal reservoir 311 are configured
with at least one closable opening 213 and/or one or more valves
215 providing a conduit from the vessel lumen to the reservoir
lumen. In some embodiments, one or more closable opening is
configured to be located on an upflow part of the reservoir 310. In
some embodiments, one or more closable opening is configured to be
located on a downflow part of the reservoir 310. Embodiments of the
one or more closable opening 213 and/or one or more valves 215
discussed herein are also applicable to one or more intralumenal
reservoirs 311, unless context dictates otherwise.
[0102] In illustrative embodiments, the intralumenal reservoir 311
is configured with closable openings 213 configured to allow fluid
flow or optionally cellular flow to enter, optionally flow pass one
or more sensing systems, and then enter one or more reservoir
compartments optionally for storage, be ablated, and/or pass
through another closable opening back into the subject. In
illustrative embodiments, the closable openings 213 open and close
to selectively receive and/or contain one or more identified
targets.
[0103] In some embodiments, the intraluminal reservoir 311 is
configured with one or more reservoir insert responsive to control
circuitry and configured to modulate at least part of the reservoir
lumen. Embodiments described for one or more insert 170 and/or one
or more bypass insert 216 also encompassed for the reservoir insert
associated with the intralumenal reservoir 311, unless context
dictates otherwise.
[0104] It is contemplated that components, such as energy sources
110, sensors 130, control circuitry 150, and/or power sources 160,
for example, will optionally be attached, connected to, place
within, manufactured on or in, and/or formed integrally with one or
more structural element. Methods for manufacture and/or assembly
are known in the art and/or described herein.
[0105] Embodiments of one or more device 100, 200, and/or 300 may
include one or more energy sources 110 (see e.g. FIG. 2 and FIG.
3). In some embodiments, one or more device 100 may include a first
energy source configured to function in, or proximal to, one or
more blood vessel or lymph vessel, and to provide energy configured
to elicit one or more image responses associated with one or more
blood vessel or lymph vessel; and one or more second energy source
responsive to control circuitry and configured to provide ablation
energy to a target area during the expected transit time of one or
more targets through the target area.
[0106] In some embodiments, one or more device 200 may optionally
include a first energy source configured to function in, or
proximal to, a local bypass lumen, and to provide energy configured
to elicit one or more image responses associated with a local
bypass lumen; and optionally one or more second energy source
responsive to control circuitry and configured to provide ablation
energy to a target area during the expected transit time of one or
more targets through the target area. In some embodiments, the
first energy source 110 is configured to provide energy to elicit
one or more image responses associated with fluid (and/or cellular)
flow in, or proximal to (optionally upflow and/or downflow), the
local bypass 210. In some embodiments, the first energy source 110
is configured to provide energy to elicit one or more image
responses associated with fluid flow in the local bypass lumen. In
some embodiments, the second energy source 110 is configured to
emit ablation energy within, or proximal to, the local bypass 210,
optionally with the local bypass lumen.
[0107] In some embodiments, one or more device 300 may include a
first energy source configured to function in, or proximal to, one
or more reservoirs, and to provide energy configured to elicit one
or more image responses associated with the one or more reservoirs;
and optionally one or more second energy source responsive to
control circuitry and configured to provide ablation energy to a
target area during the expected transit time of one or more targets
through the target area. In some embodiments, the first energy
source 110 is configured to provide energy to elicit one or more
image responses associated with fluid (and/or cellular) flow in, or
proximal to (optionally upflow and/or downflow), the one or more
reservoirs 310. In some embodiments, the first energy source 110 is
configured to provide energy to elicit one or more image responses
associated with fluid flow in the lumen of the one or more
reservoirs 310. In some embodiments, the second energy source 110
is configured to emit ablation energy within, or proximal to, the
one or more reservoirs 310, optionally within the lumen of the one
or more reservoirs. In some embodiments, the target area is in the
lumen of a blood and/or lymph vessel, upflow and/or downflow of one
or more reservoirs, and/or in the reservoir lumen.
[0108] One or more energy sources 110 may include, but are not
limited to, one or more electromagnetic energy sources 111, one or
more acoustic energy sources 120 (e.g. one or more ultrasonic
energy sources 121), and/or one or more charged particle energy
sources 125. One or more electromagnetic energy sources 111 may
include, but are not limited to, one or more optical energy sources
112, one or more radio frequency sources 113, one or more magnetic
energy sources 114, one or more thermal energy sources 115, and/or
one or more X-ray energy sources 116. One or more optical energy
sources 112 may include, but are not limited to, one or more visual
energy sources 117, infrared energy sources 118, and/or one or more
ultraviolet energy sources 119. In some embodiments, one or more
energy sources described herein and/or known in the art may be
specifically excluded, e.g. one or more electromagnetic energy
source not including one or more X-ray energy source. In some
embodiments one or more electromagnetic energy source 111 is one or
more laser. In some embodiments, the optical energy is provided
through fiber optic lines and/or a web of fiber optic lines. In
some embodiments, one or more energy sources 110 are programmable,
remote-controlled, wirelessly controlled, and or
feedback-controlled.
[0109] One or more energy sources 110 (e.g. electromagnetic 111
and/or acoustic 120) are configured to elicit one or more image
responses such as, but not limited to, electromagnetic image
responses including, but not limited to, optical image responses
(e.g. visible light image responses, infrared image responses,
ultraviolet image responses, and/or fluorescent image responses,
among others), radiofrequency image responses, and/or magnetic
image responses. One or more energy sources 110 are configured to
elicit one or more image responses including a scattering response
and/or an absorptive response from the one or more targets. One or
more image responses may include, but are not limited to, acoustic
image responses, such as, but not limited to, ultrasonic image
responses. One or more image responses may include, but are not
limited to, thermal image responses, and/or color image responses.
One or more image responses may include, but are not limited to,
light scatter and/or light absorption. Characteristics of the
energy appropriate for generating one or more image responses are
known in the art and/or described herein.
[0110] One or more energy sources 110 (e.g. electromagnetic 111,
acoustic 120 and/or particle beam 125) are configured to provide
ablation energy to one or more targets or to a target area. In some
embodiments, the electromagnetic energy source is an optical energy
source and/or an X-ray energy source. In some embodiments, the
electromagnetic energy is provided by one or more lasers. In some
embodiments, one or more energy source 110 is configured to
function within the one or more blood vessel and/or lymph vessel.
In some embodiments, one or more energy source 110 is configured to
function proximal to the one or more blood vessel and/or lymph
vessel.
[0111] In some embodiments, different energy sources 110 provide
energy to elicit an image response and to ablate one or more
targets. In some embodiments, one energy source 110 provides energy
to elicit an image response and to ablate one or more targets. In
some embodiments, more than one energy source 110 provides energy
to elicit an image response. In some embodiments, more than one
energy source provides energy to ablate one or more targets. In
some embodiments, a first energy source and a second energy source
are the same energy source. In some embodiments, one or more of the
one or more second energy source is separate from the one or more
first energy source and/or the one or more sensors.
[0112] As used herein, the term "electromagnetic energy" may
include, but is not limited to, radio waves, microwaves, terahertz
radiation, infrared radiation, visible light, X-rays, and gamma
rays. In some embodiments, one or more of these frequencies may be
explicitly excluded from the general category of electromagnetic
energy (e.g. electromagnetic energy sources, but not including
X-ray energy sources). Electromagnetic energy (or radiation) with a
wavelength between approximately 400 nm and 700 nm is detected by
the human eye and perceived as visible light. Optical light may
also include near infrared (longer than 700 nm) and ultraviolet
(shorter than 400 nm).
[0113] As used herein, the term "charged particle" may include
particles generated using one or more particle beams. A particle
beam is optionally an accelerated stream of charged particles or
atoms that may be directed by magnets and focused by electrostatic
lenses, although they may also be self-focusing. Particle beams may
be high energy beams (e.g. created in particle accelerators),
medium and/or low energy beams.
[0114] Electromagnetic or optical energy is made up of photons.
Electromagnetic energy includes, but is not limited to, single
photon electromagnetic energy, two photon electromagnetic energy,
multiple wavelength electromagnetic energy, and extended-spectrum
electromagnetic energy. Electromagnetic energy may be used for
eliciting image responses and/or for ablation of one or more
targets.
[0115] As used herein, the term "fluorescence" may include the
production of light (emission) following excitation by
electromagnetic energy. Fluorescence may result from an inherent
response of one or more targets to excitation with electromagnetic
energy. As used herein, the term "auto-fluorescence" may include an
inherent fluorescent response from one or more targets.
[0116] Electromagnetic energy sources 111 may be configured to emit
energy as a continuous beam or as a train of short pulses. In the
continuous wave mode of operation, the output is relatively
consistent with respect to time. In the pulsed mode of operation,
the output varies with respect to time, optionally having
alternating `on` and `off` periods. In illustrative examples, one
or more energy sources are configured to emit pulsed energy to
specifically ablate a limited area and/or a limited number of
target cells. In illustrative examples, one or more energy sources
are configured to emit continuous energy to excite endogenous
fluorophores to emit fluorescence.
[0117] One or more electromagnetic energy sources 111 may include
one or more lasers having one or more of a continuous or pulsed
mode of action. One or more pulsed lasers may include, but are not
limited to, Q-switched lasers, mode locking lasers, and
pulsed-pumping lasers. Mode locked lasers emit extremely short
pulses on the order of tens of picoseconds down to less than 10
femtoseconds, the pulses optionally separated by the time that a
pulse takes to complete one round trip in the resonator cavity. Due
to the Fourier limit, a pulse of such short temporal length may
have a spectrum which contains a wide range of wavelengths.
[0118] In some embodiments, the energy (optionally electromagnetic)
is focused at a depth of approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4
mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm,
1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1
mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm,
or 3.0 mm within a vessel lumen, a bypass lumen, and/or a
reservoir. In some embodiments, the electromagnetic energy is
focused at a depth of approximately 0.1 to 3 mm, 0.1 to 2.5 mm, 0.1
to 2.0 mm, 0.1 to 1.5 mm, 0.1 to 1.0 mm, 0.1 to 0.5 mm, 0.5 to 3.0
mm, 0.5 to 2.5 mm, 0.5 to 2.0 mm, 0.5 to 1.5 mm, 0.5 to 1.0 mm, 1.0
to 3.0 mm, 1.0 to 2.5 mm, 1.0 to 2.0 mm, 1.0 to 1.5 mm, 1.5 to 3.0
mm, 1.5 to 2.5 mm, 1.5 to 2.0 mm, 2.0 to 3.0 mm, 2.0 to 2.5 mm, or
2.5 to 3.0 mm within a vessel lumen, a bypass lumen, and/or a
reservoir.
[0119] In some embodiments, the electromagnetic energy is generated
by two photons having the same wavelength. In some embodiments, the
electromagnetic energy is generated by two photons having a
different wavelength. Electromagnetic energy generated by two
photons is optionally focused at a depth within a vessel lumen, a
bypass lumen, and/or a reservoir, optionally at one or more depths
as described above and/or herein.
[0120] As used herein, the term "two-photon" may include excitation
of a fluorophore by two photons in a quantum event, resulting in
the emission of a fluorescence photon, optionally at a higher
energy than either of the two excitatory photons, optionally using
a femtosecond laser. In some embodiments, two photon
electromagnetic energy is coupled through a virtual energy level
and/or coupled through an intermediate energy level.
[0121] As used herein, the term "extended-spectrum" may include a
range of possible electromagnetic radiation wavelengths within the
full spectrum of possible wavelengths, optionally from extremely
long to extremely short. One of skill in the art is able to select
appropriate ranges for the devices and methods disclosed herein
based on information publicly available and/or disclosed
herein.
[0122] In some embodiments, the energy (optionally electromagnetic)
may be defined spatially and/or directionally. In some embodiments,
the electromagnetic energy may be spatially limited, optionally
spatially focused and/or spatially collimated. In illustrative
embodiments, the electromagnetic energy optionally contacts less
than less than an entire possible area, or an entire possible
target, and/or is limited to a certain depth within a vessel lumen,
a bypass lumen, and/or a reservoir.
[0123] In some embodiments, the energy (optionally electromagnetic)
may be directionally limited, directionally varied, and/or
directionally variable. In illustrative embodiments, the energy may
be provided only in a single direction, for example 90 degrees from
the horizontal axis of a device, or toward a lumen wall, a bypass
wall, and/or a reservoir wall. In illustrative embodiments, the
energy may be provided over a range of directions for example,
through movement of the energy source 110, through movement of the
entire device, and/or through illumination from a variety of energy
sources 110 in the device.
[0124] Electromagnetic energy and/or acoustic energy configured to
induce an image response in a target may be selected, optionally
manually, remotely, programmably, wirelessly, and/or using feedback
information. Frequencies that induce an image response in one or
more targets are known in the art and/or discussed herein. In some
embodiments, selection of excitation energy may be performed in
advance, or as a result of information received, optionally
including feedback information, optionally from one or more sensors
130 or provided by one or more external sources.
[0125] Electromagnetic energy, acoustic energy, and/or particle
beam energy configured to ablate one or more targets may be
selected, optionally manually, remotely, programmably, wirelessly,
and/or using feedback information. Frequencies useful to at least
partially ablate one or more targets are known in the art and/or
discussed herein. In some embodiments, selection of ablation energy
may be performed in advance, or as a result of information
received, optionally including feedback information, optionally
from one or more sensors 130 or provided by one or more external
sources.
[0126] In addition to electromagnetic energy described herein, the
ablation energy may be supplied by energetic charged particles,
such as electrons, protons, or other ions. In one embodiment, the
charged particles are directed towards the one or more targets
and/or target area in the form of particle beams. In another
embodiment, the charged particles are emitted over relatively wide
solid-angles, and address the designated autofluorescent target by
virtue of spatial proximity.
[0127] In one embodiment, particle beams are generated outside the
body by beam generators such as particle accelerators, cathode ray
tubes, electrostatic accelerators, voltage-multiplier accelerators,
Cockcroft-Walton accelerators, Van de Graaff accelerators, Alvarez
accelerators, linear accelerators, circular accelerators, wakefield
accelerators, collimated radioactive emitters, etc. The beams from
these sources can be directed towards the one or more targets
and/or target area by mechanical, electrical, or magnetic methods.
In some embodiments, the particle beams may be generated and
directed from locations separate from the energy source 110 used to
induce the image response. In other embodiments, the particle beam
may be generated in proximity to the energy source for eliciting
the image response, by using compact particle sources such as
electrostatic accelerators, Alvarez accelerators, linear
accelerators, voltage-multiplier accelerators, Cockcroft-Walton
accelerators, wakefield accelerators, collimated radioactive
emitters, etc.
[0128] In some embodiments, particle beams are generated and
delivered from inside the body. Compact particle beam generators
such as electrostatic accelerators, Alvarez accelerators, linear
accelerators, voltage-multiplier accelerators, Cockcroft-Walton
accelerators, or wakefield accelerators can be used. In one
embodiment of a voltage-multiplier accelerator, the staged voltage
elements can use high-field-strength capacitors. In another
embodiment, the staged voltages can be generated in an array of
photocells by photogeneration using on-board or off-board light
sources. In another embodiment of an in-vivo particle source, a
radioactive emitter can be used to provide a charged particle
source. One example of such a source is the Beta-Cath.TM. System,
developed by Novoste Corp.
[0129] In one embodiment, in-vivo radioactive sources can be
encapsulated within shielding which can be used to control charged
particle exposure to nearby tissue. The shielding can have one or
more portals, allowing for collimated emission. The shielding can
be movable, either across all or part of its extent, or across one
or more portal openings, in order to provide switchable particle
sources. Shielding can be controllably moved by mechanical
techniques such as valves, shutters, or similar devices, can
utilize movable liquids, such as Hg, or utilize other methods. The
particles from these in-vivo sources can be directed towards the
one or more targets and/or target area by mechanical, electrical,
or magnetic methods, or may rely upon proximity.
[0130] Embodiments of one or more devices 100, 200, and/or 300
include one or more sensors 130 (see, e.g., FIG. 4 and FIG. 5). In
some embodiments, one or more sensors 130 are the same sensor. In
some embodiments, one or more sensors 130 are different sensors. In
some embodiments, one or more sensors are in the same unit and/or
are physically connected. In some embodiments, one or more sensors
130 are in separate units and/or not physically connected. In some
embodiments, one or more sensors 130 are in the same and/or
different units than one or more energy sources 110. In some
embodiments, the one or more sensors 130 are configured to align
with the one or more energy sources 110 and cooperatively elicit
and capture image responses. In some embodiments, the one or more
sensors 130 are configured to orient to the one or more energy
sources 110 to cooperatively elicit and capture image responses.
One or more sensors 130 may include, but are not limited to, one or
more imaging sensors 131 and/or one or more physiological sensors
140.
[0131] Embodiments of one or more device 200 include one or more
sensors 130 configured to function in, or proximal to, a local
bypass 210, optionally the local bypass lumen. In some embodiments,
the one or more sensors 130 are configured to capture one or more
image responses associated with fluid (and/or cellular) flow in, or
proximal to (optionally upflow and/or downflow), the local bypass
210. In some embodiments, the one or more sensors 130 are
configured to capture one or more image responses associated with
fluid (and/or cellular) flow in the local bypass lumen.
[0132] Embodiments of one or more devices 100, 200, and/or 300
include more then one sensor 130, optionally several sensors of the
same or different types, optionally configured to function
independently and/or in sequentially. In illustrative examples, one
or more device 200 includes one or more sensors 130 upflow (e.g. in
the vessel lumen) from the local bypass 210 (optionally configured
to identify one or more possible targets for entry into the local
bypass 210), one or more sensors within the local bypass lumen
optionally configured to further image the one or more possible
targets, one or more sensors 130 configured to capture images
associated with ablation energy and modification of the one or more
possible targets and/or one or more targets, and/or one or more
sensors 130 downflow (e.g. configured to image the fluid flow
re-entering the vessel lumen) from the local bypass 210.
[0133] In illustrative examples, one or more device 300 includes
one or more sensors 130 upflow (e.g. in the vessel lumen) from the
reservoir 310 (optionally configured to identify one or more
possible targets for entry into the reservoir 310), one or more
sensors within the reservoir lumen optionally configured to further
image the one or more possible targets, one or more sensors 130
configured to capture images associated with ablation energy and
modification of the one or more possible targets and/or one or more
targets, and/or one or more sensors 130 downflow (e.g. configured
to image the fluid flow re-entering the vessel lumen) from the
reservoir 310. In some embodiments, the detection area is in the
one or more reservoirs 310, upflow and/or downflow from the one or
more reservoirs 310, proximal to the one or more reservoirs 310,
proximal to the one or more blood and/or lymph vessels, and/or in a
vessel lumen.
[0134] One or more imaging sensors 131 may include, but are not
limited to, one or more electromagnetic energy sensors 132 and/or
one or more acoustic sensors 133 (e.g. ultrasonic sensors 134). One
or more electromagnetic energy sensors 132 may include, but are not
limited to, one or more photodetectors 135, one or more
radiofrequency antennae 136, one or more magnetic energy sensors
137, one or more thermal sensors 138, and/or one or more electrical
energy sensors 139. One or more electromagnetic energy sensors 132
may include one or more optical sensors such as, but not limited
to, sensors configured to detect near IR, UV, fluorescence, and/or
visual light.
[0135] One or more imaging sensors may include, but are not limited
to, charge-coupled device cameras and/or complementary metal oxide
semiconductor (CMOS) cameras. One or more imaging sensors may
include, but are not limited to, one or more piezo transducers, one
or more MEMS devices, one or more cavity resonators, one or more
magneto resistive sensors, one or more magnetic field sensors,
and/or one or more thermal sensors.
[0136] One or more physiological sensors 140 may include, but are
not limited to, one or more chemical and/or biological molecule
sensors 141 (e.g. blood chemistry, chemical concentration,
biosensors), one or more pH sensors 142, one or more time sensors
143 (e.g. timers, clocks), and/or one or more temperature sensors
144. One or more physiological detectors 140 may include, but are
not limited to blood pressure detectors, pulse detectors,
peristaltic action sensors, pressure sensors, flow sensors,
viscosity sensors, and/or shear sensors.
[0137] One or more sensors may be configured to measure various
parameters, including, but not limited to, the electrical
resistivity of the fluid, the density or sound speed of the fluid,
the pH, the osmolality, or the index of refraction of the fluid at
least one wavelength. The selection of a suitable sensor for a
particular application or use site is considered to be within the
capability of a person having skill in the art. One or more of
these and/or other sensing capabilities may be present in a single
sensor or an array of sensors; sensing capabilities are not limited
to a particular number or type of sensors.
[0138] One or more biosensors may detect materials including, but
not limited to, a biological marker, an antibody, an antigen, a
peptide, a polypeptide, a protein, a complex, a nucleic acid, a
cell (and, in some cases, a cell of a particular type, e.g. by
methods used in flow cytometry), a cellular component, an
organelle, a gamete, a pathogen, a lipid, a lipoprotein, an
alcohol, an acid, an ion, an immunomodulator, a sterol, a
carbohydrate, a polysaccharide, a glycoprotein, a metal, an
electrolyte, a metabolite, an organic compound, an organophosphate,
a drug, a therapeutic, a gas, a pollutant, or a tag. A biosensor
may include an antibody or other binding molecule such as a
receptor or ligand.
[0139] One or more sensors optionally include, in part or whole, a
gas sensor such as an acoustic wave, chemiresistant, or
piezoelectric sensors, or an electronic nose. One or more sensors
are optionally small in size, for example a sensor or array that is
a chemical sensor (Snow (2005) Science 307:1942-1945), a gas sensor
(Hagleitner, et al. (2001) Nature 414:293-296.), an electronic
nose, and/or a nuclear magnetic resonance imager (Yusa (2005),
Nature 434:1001-1005). Further examples of sensors are provided in
The Biomedical Engineering Handbook, Second Edition, Volume I, J.
D. Bronzino, Ed., Copyright 2000, CRC Press LLC, pp. V-1-51-9, and
U.S. Pat. No. 6,802,811) and/or known in the art.
[0140] In some embodiments, one or more sensors 130 are configured
to capture one or more image responses including, but not limited
to, electromagnetic image responses including, but not limited to,
optical image responses (e.g. visible light image responses,
infrared image responses, ultraviolet image responses, and/or
fluorescent image responses, among others), radiofrequency image
responses, and/or magnetic image responses. One or more image
responses may include, but are not limited to, acoustic image
responses, such as, but not limited to, ultrasonic image responses.
One or more image responses may include, but are not limited to,
thermal image responses, and/or color image responses. In some
embodiments, one or more sensors 130 are configured to capture one
or more image responses at one or more wavelengths. In some
embodiments, one or more image responses described herein and/or
known in the art may be specifically excluded from an embodiment,
e.g. image responses not including fluorescent image responses.
[0141] In some embodiments, one or more image responses include,
but are not limited to, actual images of, for example, cells within
the vessel lumen. In some embodiments, one or more image responses
include image information such as cell shape, cell outline, and/or
cell periphery, among others. In some embodiments, one or more
image responses include image information such as intracellular
shapes, intracellular outlines, and/or intracellular peripheries,
among others. In some embodiments, one or more sensors 130 are
configured to capture light scattering. In some embodiments, one or
more sensors 130 are configured to capture fluid and/or cell
velocity.
[0142] One or more electromagnetic energy sensors 132 may be
configured to measure the absorption, emission, fluorescence, or
phosphorescence of one or more targets. Such electromagnetic
properties may be inherent properties of all or a portion of one or
more targets (e.g. auto-fluorescence), or may be associated with
materials added or introduced to the body, surface, lumen,
interior, and/or fluid, such as tags or markers for one or more
targets. One or more targets may include, but are not limited to,
one or more cells.
[0143] In some embodiments, one or more sensors 130 are configured
to detect a fluorescent response at a single wavelength of
electromagnetic energy, at two wavelengths of electromagnetic
energy, at multiple wavelengths of electromagnetic energy, or over
extended-spectrum electromagnetic energy. In some embodiments, one
or more sensors 130 are configured to detect excitation energy
and/or ablation energy.
[0144] In some embodiments, one or more sensors 130 are configured
to detect a cumulative (optionally fluorescent) response over a
time interval. In some embodiments, one or more sensors 130 are
configured to detect a (optionally fluorescent) response at a
specific time interval and/or at a specific time. In some
embodiments, one or more sensors 130 are configured to detect a
time-dependent (optionally fluorescent) response. In illustrative
embodiments, the cumulative response is determined over
milliseconds, seconds, and/or minutes following excitation. In some
embodiments, the response is detected over millisecond, second,
and/or minute time intervals following excitation. In some
embodiments, the response is detected approximately femtoseconds,
picoseconds, nanoseconds, milliseconds, seconds, and/or minutes
after excitation.
[0145] In some embodiments, one or more sensors 130 are configured
to be calibrated optionally at least partially based an expected
baseline image response (e.g. normal image response) for the fluid,
tissue, cells, and/or lumen. As used herein, the term "normal image
response" may include the detected intrinsic image response of one
or more fluid, tissue, cells, and/or lumen as determined by
researchers and/or medical or veterinary professionals for subjects
of a certain age, ethnicity, etc. who do not have pathological
conditions (e.g. control subjects). "Normal image response" may
include the intrinsic detected image response of fluid, tissue,
cells, and/or lumen of a subject prior to a pathological condition
and/or of a comparable location not affected by the pathological
condition.
[0146] In some embodiments, one or more sensors 130 may be
configured to detect a condition of interest including, but not
limited to, a temperature, a pressure, a fluid flow, an optical
absorption, optical emission, fluorescence, or phosphorescence, an
index of refraction at least one wavelength, an electrical
resistivity, a density or sound speed, a pH, an osmolality, the
presence of an embolism, the presence (or absence) of an object
(such as a blood clot, a thrombus, an embolus, a plaque, a lipid, a
gas bubble, an aggregate, a cell, a specific type of cell, a
cellular component or fragment, a collection of cell, a gamete, a
pathogen, or a parasite), and/or the presence (or absence) of a
substance such as a biological marker, an antibody, an antigen, a
peptide, a polypeptide, a protein, a complex, a nucleic acid, a
cell and/or a cell of a particular type, a cellular component, an
organelle, a pathogen, a lipid, a lipoprotein, an alcohol, an acid,
an ion, an immunomodulator, a sterol, a carbohydrate, a
polysaccharide, a glycoprotein, a metal, an electrolyte, a
metabolite, an organic compound, an organophosphate, a drug, a
therapeutic, a gas, and/or a pollutant, for example.
[0147] As used herein, the term "target" may include a material of
interest, optionally cells of interest such as, but not limited to
blood cells and/or lymph cells. As used herein the term "possible
and/or potential targets" includes entities having characteristics
suggestive of targets, but not yet confirmed as targets. Materials
of interest may include, but are not limited to, materials
identifiable by one or more captured image responses (individually
or as an aggregate signal). Such materials may include, but are not
limited to, a blood clot, a thrombus, an embolus, an aggregate, a
cell, a specific type of cell, a cellular component, an organelle,
a collection or aggregation of cells or components thereof, a
pathogen, an infected cell (e.g. virally-infected and/or
parasite-infected), or a parasite.
[0148] One or more targets may include, but are not limited to,
cancer cells, microbial cells, and/or infected cells. One or more
cancer cells may include, but are not limited to, neoplastic cells,
metastatic cancer cells, precancerous cells, adenomas, and/or
cancer stem cells. Cancer types may include, but are not limited
to, bladder cancer, breast cancer, colon cancer, rectal cancer,
endometrial cancer, kidney (renal) cancer, lung cancer, leukemia,
melanoma, non-Hodgkin's Lymphoma, pancreatic cancer, prostate
cancer, skin (non-melanoma) cancer, and thyroid cancer. Cancers may
include, but are not limited to, bone, brain, breast, digestive,
gastrointestinal, endocrine, eye, genitourinary, germ line,
gynecological, head and neck, hematologic/blood, leukemia,
lymphoma, lung, musculoskeletal, neurologic, respiratory/thoracic,
skin, and pregnancy-related.
[0149] Microbial cells (microorganisms) may include, but are not
limited to, bacteria, protists, protozoa, fungi, and/or amoeba.
Pathogens may include, but are not limited to, bacteria, viruses,
parasites, protozoa, fungi, and/or proteins. Bacteria may include,
but are not limited to, Escherichia coli, Salmonella, Mycobacterium
spp., Bacillus anthraces, Streptococcus spp., Staphylococcus spp.,
Francisella tularensis, and/or Helicobacter pylori. Viruses may
include, but are not limited to, Hepatitis A, B, C, D, and/or E,
Influenza virus, Herpes simplex virus, Molluscum contagiosum,
and/or Human Immunodeficiency virus. Protozoa may include, but are
not limited to, Cryptosporidium, Toxoplasma spp., Giardia lamblia,
Trypanosoma spp., Plasmodia spp. and/or Leishmania spp. Fungi may
include, but are not limited to, Pneumocystis spp., Tinea, Candida
spp., Histoplasma spp., and/or Cryptococcus spp. Parasites may
include, but are not limited to tapeworms, helminthes, and/or
roundworms. Proteins may include, but are not limited to,
prions.
[0150] Embodiments of one or more device 100, 200, and/or 300 may
include control circuitry 150 coupled to one or more sensors, and
responsive to at least partially identify one or more targets
during an expected transit time (optionally residence time) of the
one or more targets through a detection area in one or more blood
vessel or lymph vessel at least partially based on one or more
captured image response. In some embodiments, the control circuitry
150 is responsive to identify one or more predicted future
locations of the one or more targets at least partially based on
the one or more image responses. In some embodiments, the control
circuitry 150 is responsive to identify the effect of the ablation
energy on the one or more targets at least partially based on the
one or more image responses.
[0151] Embodiments of one or more device 200, include control
circuitry 150 coupled to the one or more sensors 130, and
responsive to at least partially identify one or more targets
during an expected transit time (optionally residence time) of the
one or more targets through a detection area in, or proximal to,
the local bypass 210. Embodiments of one or more device 300,
include control circuitry 150 coupled to the one or more sensors
130, and responsive to at least partially identify one or more
targets during an expected transit time (optionally residence time)
of the one or more targets through a detection area in, or proximal
to, one or more reservoirs 310.
[0152] As used herein the term "expected transit time" includes,
but is not limited to, the amount of time calculated and/or
predicted to elapse while one or more possible targets are within
the approximate boundaries of the detection area. Methods and
calculations for predicting this time are described herein and/or
known in the art. As used herein, the term "detection area"
includes, but is not limited to, an area from which one or more
sensors receive image responses and/or image information.
[0153] In some embodiments, the control circuitry 150 is configured
to control one or more of one or more energy sources 110, one or
more sensors 130, and/or one or more power sources 160. In some
embodiments, the control circuitry is configured to control one or
more of one or more insert 170, one or more vessel attachment units
180, and/or one or more vessel lumen anchors 190. In some
embodiments, the control circuitry 150 may be directly coupled,
indirectly coupled, and/or wirelessly coupled to one or more energy
sources 110, one or more sensors 130, and/or one or more power
sources 160. In some embodiments, the control circuitry 150 may be
directly coupled, indirectly coupled, and/or wirelessly coupled to
one or more of one or more insert 170, one or more vessel
attachment units 180, and/or one or more vessel lumen anchors
190.
[0154] Control circuitry 150 may be electrical circuitry and/or
other types of logic/circuitry including, for example, fluid
circuitry, chemo-mechanical circuitry, and other types of
logic/circuitry that provide equivalent functionality. The control
circuitry 150 may include at least one of hardware, software, and
firmware; in some embodiments the control circuitry may include a
microprocessor. The control circuitry 150 may be located in or on
the structural element of a device and/or at a location separate
from the structural element. Control circuitry may be internal
and/or external to the subject.
[0155] There is little distinction left between hardware and
software implementations of aspects of systems; the use of hardware
or software is generally (but not always, in that in certain
contexts the choice between hardware and software can become
significant) a design choice representing cost vs. efficiency
tradeoffs. There are various vehicles by which processes and/or
systems and/or other technologies described herein can be effected
(e.g., hardware, software, and/or firmware), and that the preferred
vehicle will vary with the context in which the processes and/or
systems and/or other technologies are deployed. For example, if an
implementer determines that speed and accuracy are paramount, the
implementer may opt for a mainly hardware and/or firmware vehicle;
if flexibility is paramount, the implementer may opt for a mainly
software implementation; or, yet again alternatively, the
implementer may opt for some combination of hardware, software,
and/or firmware.
[0156] In some embodiments, the control circuitry 150 is responsive
to at least partially and/or completely identify one or more
targets at least partially based on one or more of pattern
recognition and/or shape recognition. In illustrative embodiments,
amoeba, fungi, and/or protists may be identified through pattern
and/or shape recognition. In some embodiments, the control
circuitry 150 is responsive to at least partially and/or completely
identify one or more targets at least partially based on an actual
image optionally of one or more possible targets, optionally one or
more cells. In illustrative embodiments, one or more amoeba and/or
malaria-infected red blood cells may be identified by actual image.
In some embodiments, the control circuitry 150 is responsive to at
least partially and/or completely identify one or more targets at
least partially based on relative and/or absolute size, optionally
of one or more possible targets, optionally of one or more cells.
In illustrative embodiments, one or more cancer cells may be
identified at least partially based on size, either absolute, or
compared with other cells. In some embodiments, the control
circuitry 150 is responsive to at least partially and/or completely
identify one or more targets at least partially based on surface
features. In illustrative embodiments, one or more virally-infected
cells and/or pathogen-infected cells may be identified based on
changes in membrane morphology and shape, including for example
blebs and knobs.
[0157] In some embodiments, the control circuitry 150 is responsive
to identify select one or more characteristics of energy for
eliciting an image response (e.g. excitation energy). In some
embodiments, the control circuitry 150 selects one or more
characteristics of energy for eliciting an image response
responsive to one or more characteristics of a prior the image
response and/or the energy selected to elicit the prior image
response. In some embodiments, the control circuitry 150 selects
one or more characteristics of energy for eliciting an image
response responsive to input from external control circuitry. In
some embodiments, the control circuitry 150 selects one or more
characteristics of energy for eliciting an image response
responsive to one or more characteristics of a known target, for
example characteristics designed specifically identify the presence
or absence of a particular cell and/or pathogen. In some
embodiments, the control circuitry 150 selects one or more
characteristics of energy for eliciting an image response in a
pre-programmed manner.
[0158] In some embodiments, the control circuitry 150 is responsive
to at least partially and/or completely identify one or more
targets and/or target area at least partially based on one or more
of one or more temporal locations, one or more spatial locations,
and/or one or more temporal-spatial locations of the one or more
identified targets. In some embodiments, the control circuitry 150
is responsive to at least partially and/or completely identify one
or more targets and/or target area at least partially based on one
or more of the velocity, the vibratory dynamic response, the
angular response, and/or the inertial response of the one or more
targets. In some embodiments, the control circuitry 150 is
responsive to at least partially and/or completely identify one or
more targets and/or target area at least partially based on
predicting one or more future locations of the one or more
targets.
[0159] In some embodiments, the control circuitry 150 identifies a
target, target area, and/or target cells by determining one or more
of the direction, the distance, the lumen depth, the time, and/or
the coordinates from which an image response originated, optionally
in relation to the energy used to elicit the one or more image
response. In some embodiments, the control circuitry 150 identifies
a target, target area, and/or target cells by analysis of one or
more characteristics of an image response (e.g. presence and/or
absence of an image response and/or density of a image
response--grouping of cells that if non-grouped would not be
considered a target), optionally including but not limited to, the
electromagnetic spectrum, or parts thereof. In some embodiments,
the control circuitry 150 identifies a target, target area, and/or
target cells in real time.
[0160] As used herein, the term "target area" includes, but is not
limited to, an area identified, determined, and/or predicted for at
least partially ablating (optionally damaging, destroying, making
non-viable, among others) one or more targets. In some embodiments,
a target area is an approximately fixed location through which one
or more targets are predicted to pass and/or actively moved toward
(e.g. funneled, passed through a narrowing insert, passed through a
valve, etc.). In some embodiments, a target area is determined by
the presence (or predicted presence) of one or more targets.
[0161] In some embodiments, the control circuitry 150 is responsive
to select one or more characteristics of ablation energy for at
least partially ablating a target, target area, and/or target
cells. In some embodiments, the control circuitry 150 selects one
or more characteristics of ablation energy for at least partially
ablating a target, target area, and/or target cells responsive to
one or more characteristics of the image response and/or the energy
selected to elicit the image response. In some embodiments, the
control circuitry 150 increases the ablation energy responsive to
an increase in the image response, and/or decreases the ablation
energy responsive to a decrease in the image response. In some
embodiments, the control circuitry 150 selects one or more
characteristics of the ablation energy at least partially
responsive to detection of one or more wavelengths of the image
response.
[0162] In some embodiments, the control circuitry 150 is responsive
to update targeting information on the basis of movement of part or
all of a device 100, 200, and/or 300 and/or a target and/or target
area. In illustrative embodiments, such target updating may be
useful when the ablating energy may be delivered at a time
(optionally substantially) later than the time at which an image
response is detected, or when the target is moving in relation to
the ablation energy source. In this case, the detected location may
be updated to take into account possible motion of the target area
and/or the device.
[0163] Motion of the image response location can be updated by
registering the detected image response location relative to other,
updatable, location information. In one example, the detected image
response location is registered relative to fiducials within the
individual. Then, the location of the fiducials is updated, and the
site of the image response location at such time can be predicted
based upon its known registration relative to the fiducial
locations. In another example, the detected image response location
is registered relative to features within an image of a related
portion of the individual. Then, the image is updated and the
location of the image response location at such time can be
predicted based upon its known registration relative to the image
features.
[0164] Motion, which may include location and/or orientation, of
the device can be updated by a variety of methods, including
inertial navigation, measurements based on beacons or fiducials,
measurements based on orientation sensors, or combinations of such
techniques. Inertial navigation can be performed with the support
of accelerometers on the device, and may also incorporate use of
gyroscopic sensors on the device. Beacons and/or fiducials can be
used to measure the device's motion; the beacons or fiducials may
be on the device and their location or direction measured by remote
sensors. Alternatively, measurements of remote beacons or fiducials
may be made by sensors on the device. Combined systems may be used,
with mixtures of remote and on-board sensors, measuring the
location or direction of remote or on-board beacons or fiducials.
Orientation sensors, such as tilt sensors may be used to provide
information of one or more aspects of the device's orientation.
Motion information obtained from different sources or methods can
be combined together to give improved motion estimates, using
techniques such as nonlinear filtering, least-squares filtering,
Kalman filtering, etc.
[0165] The updated image response location may then be combined,
via a coordinate translation and rotation, with the updated
position and location of the device. This results in updated
coordinates or directions of the image response location with
respect to the device, and can be used to direct the delivery of
ablation energy.
[0166] In some embodiments, control circuitry 150 receives
information from one or more sensors 130 and/or one or more
external sources. Information may include, but is not limited to, a
location of an untethered device, allowable dose limits (e.g. of
energy for excitation and/or ablation), release authority (e.g. for
release of energy for excitation, ablation, and/or release from an
affixed and/or stationary location), control parameters (e.g. for
energy release, for motion, for power, for sensors, etc.),
operating instructions, and/or status queries.
[0167] In some embodiments, control circuitry 150 is feedback
controlled, optionally from information from one or more sensors
130, and/or one or more external sources. In some embodiments,
control circuitry 150 is monitored by one or more external sources,
provides outputs to one or more sources, and/or sends outputs to
one or more sources. In some embodiments control circuitry is
remote-controlled, wirelessly controlled, programmed, and/or
automatic. Equipment, methods, and software associated with control
circuitry are described herein and/or known in the art (see e.g.,
U.S. Patent Applications 2007/0066939, 2007/0225633, 11/414,164 and
11/414,149).
[0168] Embodiments of one or more device 100, 200, and/or 300
optionally include a power source 160 (see e.g., FIG. 6). One or
more power sources 160 may be configured to provide power to one or
more of one or more control circuitry 150, one or more sensor 130,
and/or one or more energy source 110. One or more power sources 160
may be configured to provide power to one or more of one or more
inserts 170, one or more vessel attachment units 180, and/or one or
more vessel lumen anchors 190. One or more power sources 160 may be
configured to provide power to one or more of one or more local
bypass 210 and/or one or more reservoirs 310.
[0169] Power sources 160 may include, but are not limited to, one
or more batteries 161, fuel cells 162, energy scavenging 163,
electrical 164, and/or receivers 165 located on and/or in one or
more parts of the one or more devices or separately from the one or
more devices. The one or more batteries may include a microbattery
such as those available from Quallion LLC
(http://www.quallion.com), may be designed as a film (U.S. Pat.
Nos. 5,338,625 and 5,705,293), or may be a nuclear battery. The one
or more fuel cells may be enzymatic, microbial, or photosynthetic
fuel cells or other biofuel cells (US2003/0152823A1; WO03106966A2
Miniature Biofuel cell; Chen T et al. J. Am. Chem. Soc. 2001, 123,
8630-8631, A Miniature Biofuel Cell), and may be of any size,
including the micro- or nano-scale.
[0170] The one or more energy-scavenging devices may include a
pressure-rectifying mechanism that utilizes pulsatile changes in
blood pressure, for example, or an acceleration-rectifying
mechanism as used in self-winding watches, or other types of flow
rectifying mechanisms capable of deriving energy from other flow
parameters. The one or more electrical power sources may be located
separately from the structural element of the device and connected
to the structural element by a wire, or an optical power source
located separately from the structural element and connected to the
structural element by a fiber-optic line or cable. The one or more
power receivers may be capable of receiving power from an external
source, acoustic energy from an external source, and/or a power
receiver capable of receiving electromagnetic energy (e.g.,
infrared energy) from an external source.
[0171] In illustrative embodiments, one or more power sources 160
are optionally part of and/or are configured to open and/or close
one or more valves, to attach or detach one or more anchors, to
insert or remove one or more local bypass couplings, or to change
conformations of one or more inserts. One or more of the mechanisms
may include mechanical or micromechanical structures driven by at
least one motor, micromotor, or molecular motor, or by expansion or
change in configuration of a shape change polymer or metal. A
molecular motor may be a biomolecular motor that runs on a
biological chemical such as ATP, kinesin, RNA polymerase, myosin
dynein, adenosinetriphosphate synthetase, rotaxanes, or a viral
protein.
[0172] In some embodiments, the power source 160 optionally
includes a power transmitter capable of transmitting power from one
or more device to a secondary location or vice versa. The power
transmitter may be capable of transmitting at least one of acoustic
power, electrical power, or optical power, among others. The
secondary location may be, for example, another device within the
body, either in a body lumen or elsewhere that includes a power
receiver and structures for using, storing and/or re-transmitting
the received power.
[0173] In some embodiments, the power source 160 optionally
includes a power receiver optionally configured to receive power
from one or more external sources. Power may be received wirelessly
or through a wired connection, for example. Power may be received
from a battery pack or other power source (optionally continually
renewable, such as motion re-charged) that can be worn or attached
to a subject, and/or received from chargers present in buildings,
homes, and/or care-giving settings (e.g. clinic and/or
hospital).
[0174] In one aspect, the disclosure is drawn to one or more
methods for imaging and optionally ablating one or more targets,
optionally using one or more device 100, 200, and/or 300 described
herein. Although one or more methods may be presented separately
herein, it is intended and envisioned that one or more methods
and/or embodiments of one or more methods may be combined and/or
substituted to encompass the full disclosure. In some embodiments,
one or more methods may include one or more operations, and be
implemented using one or more computing devices and/or systems.
[0175] Embodiments of one or more methods for screening for, or
against, one or more targets, optionally using a system including
one or more device 100, 200, and/or 300, include locally capturing
image information associated with one or more blood vessel or lymph
vessel in a subject; analyzing the image information to at least
partially identify one or more targets in real time; and optionally
determining the absolute numbers and/or ratio (as compared to a
control population of cells, for example) of one or more targets
over a time interval.
[0176] Embodiments of one or more methods for imaging and
optionally ablating one or more targets, optionally using a system
including one or more device 100, 200, and/or 300, include locally
capturing image information associated with one or more blood
vessel or lymph vessel in a subject; analyzing the image
information to at least partially identify one or more targets in
real time (e.g. during residence time in the detection and/or
destruction areas); selecting a target area at least partially
based on the one or more identified targets; and locally providing
energy to the target area in real time (e.g. during residence time
in the detection and/or destruction areas), the energy having a
magnitude selected to at least partially ablate the one or more
targets.
[0177] Embodiments of one or more methods for modulating the
biological activity of one or more targets in a subject, optionally
using a system including one or more device 100, 200, and/or 300,
include locally capturing image information associated with one or
more blood vessel or lymph vessel in the subject; analyzing the
image information to at least partially identify one or more
targets; and locally providing energy in an amount sufficient to at
least partially impair the biological activity (e.g. at least
partially inactivate) of the one or more identified targets.
[0178] Embodiments of one or more methods of treating,
ameliorating, and/or preventing a disease or disorder in a subject
in need of such treatment, optionally using a system including one
or more device 100, 200, and/or 300, include locally capturing
image information associated with one or more blood vessel or lymph
vessel in a subject; analyzing the image information to at least
partially identify one or more targets in real time (e.g. during
residence time in the detection and/or destruction areas);
selecting a target area at least partially based on the one or more
identified targets; and locally providing energy to the target area
in real time (e.g. during residence time in the detection and/or
destruction areas), the ablation energy having characteristics
appropriate to at least partially ablate the one or more identified
targets, wherein the one or more identified targets are associated
with the disease or disorder.
[0179] Embodiments of one or more methods include affixing one or
more devices 100, 200, and/or 300 to a location in, or proximal to,
a blood vessel or lymph vessel. As used herein, the term "affixing"
may include, but is not limited to one or more processes by which
the one or more devices may be held stationary in the lumen or
internal location. The affixation may be temporary and/or permanent
as described herein. Mechanisms by which one or more device may
become affixed are known in the art and/or described herein.
[0180] Embodiments of one or more methods include locally and/or
externally (e.g. external to the subject) providing energy,
optionally electromagnetic energy and/or acoustic energy (e.g.
ultrasonic energy) selected to induce an image response (e.g.
elicit image information), to a target, target area, target cell,
target tissue, internal location, and/or blood or lymph vessel,
optionally the vessel lumen. Electromagnetic energy optionally
includes, but is not limited to, optical energy (e.g. visible
light), infrared energy, ultraviolet energy, and/or radiofrequency
energy. Providing electromagnetic energy optionally includes using
a laser or other device to provide optical energy to a target.
[0181] Parameters associated with the selection of energy to induce
an image response (and/or elicit image information) include, but
are not limited to, the target, the environment associated with the
target, the characteristics of the energy source 110, optionally an
electromagnetic energy source 111, and/or an acoustic energy source
120, and/or the characteristics of the one or more sensors 130.
[0182] The parameters associated with the target include, but are
not limited to, the distance of the target from the energy source
110, the depth of the target beneath a surface (e.g. a lumen wall),
the inherent characteristics of the target (e.g. fluorescence), the
size of the target, and/or the movement of the target (e.g.
stationary, steady movement, variable movement, predictable
movement, etc.).
[0183] The parameters associated with the environment include, but
are not limited to, location, milieu (e.g. many cells, few cells),
movement (e.g. stationary, steady movement, intermittent movement,
predictable movement, etc.), physiologic parameters (e.g. pH,
temperature, etc.), and/or non-target image responses (e.g.
background fluorescence, non-specific fluorescence, intrinsic
non-target fluorescence, etc.).
[0184] The parameters associated with the characteristics of the
electromagnetic energy source 111 include, but are not limited to,
the wavelengths available for selection (e.g. single, two-photon,
multiple, extended-spectrum, etc.), the strength of the emitted
electromagnetic energy (e.g. limitations on distance and/or depth,
etc.), the type of output (e.g. pulsed, two-photon, etc.),
directionality (e.g. limited, variable, varied, etc.), and/or
spatial parameters (e.g. limited, focused, collimated, etc.).
[0185] The parameters associated with the characteristics of the
sensor 130 include, but are not limited to, the detection limits
associated with wavelength (e.g. single, two-photon, multiple,
extended-spectrum, etc.), signal strength (e.g. sensitivity of
detection, level above background, etc.), and/or time (e.g. detects
cumulative readings over time, detects readings at certain time
intervals, or at a certain time post excitation, etc.). Parameters
associated with the characteristics of the sensor 130 include, but
are not limited to, the type of image response and/or image
information captured by the sensor 130.
[0186] In some embodiments, image information includes, but is not
limited to, one or more of acoustic image information (e.g.
ultrasonic image information), thermal image information, and/or
electromagnetic image information, optionally radiofrequency image
information and/or optical image information (e.g. visible light
image information, infrared image information, ultraviolet image
information, and/or color image information). In some embodiments,
image information includes scattering response information (e.g.
light scatter, but optionally other energy scatter responses)
and/or absorptive response information (e.g. lack of back scatter
from energy excitation). In some embodiments, image information
includes, but is not limited to, one or more of spatial and/or
temporal information, and/or velocity information relating to fluid
and/or cellular flow (e.g. one or more possible targets in the
lumen). Appropriate sensors 130 for capturing image information and
their selection are known to one of skill in the art and/or
described herein.
[0187] Embodiments of one or more methods include selecting the
energy to induce the image response. Methods for selecting include,
but are not limited, manually, remotely, automatically,
programmably, wirelessly, and/or using control circuitry. Manually
selecting includes, but is not limited to, manually operating one
or mechanism (e.g. a switch, dial, button, setting, etc.) on one or
more device 100, 200, and/or 300 that controls the characteristics
of the energy emitted from one or more energy source 110. Remotely
selecting includes, but is not limited to, optionally wirelessly
interacting with circuitry on one or more device 100, 200, and/or
300 that controls the characteristics of the energy emitted from
one or more energy source 110. Programmably selecting includes, but
is not limited to, optionally using control circuitry 150,
optionally part of one or more device 100, 200, and/or 300 (e.g.
internal and/or external to the subject), programmed, optionally
manually, remotely, and/or wirelessly, to select the
characteristics of the energy emitted from one or more energy
source 110. Methods for programming control circuitry and
applicable control circuitry are well-known to one of skill in the
art and/or described herein.
[0188] Embodiments of one or more methods include monitoring the
energy selected to induce an image response and/or elicit image
information, monitoring the energy selected to ablate the target,
optionally electromagnetic energy, acoustic energy, and/or particle
beam energy. Methods of monitoring electromagnetic energy, acoustic
energy. and/or particle beam energy are known in the art and/or
described herein. Methods include, but are not limited to, using
sensors able to detect one or more characteristics of the
energy.
[0189] Embodiments of one or more methods include capturing,
optionally locally (e.g. using one or more sensors 130), image
information associated with one or more blood vessel and/or lymph
vessel, optionally the vessel lumen. In some embodiments, image
information is captured sequentially. In illustrative embodiments,
image information is captured by a first sensing system (e.g.
sensor 130, energy source 110, and/or control circuitry 150), of
fluid and/or cellular flow in a blood or lymph vessel lumen. If
analysis optionally by control circuitry 150 of the image
information indicates the presence of one or more possible targets,
then additionally image information is captured, optionally by a
second sensing system (e.g. sensor 130, energy source 110, control
circuitry 150 and/or insert 170) further downflow from the first
sensing system. This second sensing system may optionally include
an insert to direct the one or more possible targets to a detection
area for sensing using one or more optionally different types of
sensors 130.
[0190] Embodiments of one or more methods include detecting an
image response. Methods of detecting an image response include, but
are not limited to, detecting an image response using one or more
sensors 130, detectors, and/or monitors. Sensors 130, detectors,
and/or monitors appropriate for detection and/or monitoring of the
image response are known in the art and/or described herein. As
used herein, the term "detecting" may include any process by which
one or more characteristics of an image response may be measured
and/or quantified.
[0191] Embodiments of one or more methods include identifying a
target for ablation (e.g. target area, target cells, and/or target
tissues). As used herein, the term "identifying a target" may
include, but is not limited to, processes including selecting a
target and/or determining a target. One or more methods for
identifying a target for ablation optionally include analyzing an
image response, image information, and/or other information,
optionally using control circuitry 150, optionally in real
time.
[0192] Embodiments of one or more methods include analyzing image
information, optionally using control circuitry 150. In some
embodiments, analyzing the image information includes comparing the
image information to one or more of reference image information
and/or target image information (see e.g. U.S. Patent Applications
2007/0066939 and 2007/0225633). In some embodiments, this
comparison includes comparing one or more of cell shape and/or cell
outline information with reference and/or targets cell shapes
and/or cell outline information. In some embodiments, this
comparison includes comparing one or more of intracellular shape
and/or intracellular outline information with reference and/or
target intracellular shape and/or intracellular outline
information. In some embodiments, analyzing the image information
includes performing one or more of pattern recognition or shape
recognition analysis. Software, systems, and/or firmware, for
example, for performing these calculations and analyses is known in
the art and/or described herein.
[0193] In some embodiments, analyzing the image information
includes determining temporal and/or spatial information associated
(and/or correlated) with the image information. In some
embodiments, analyzing the image information includes determining
velocity of the fluid and/or cellular flow (e.g. velocity of target
movement) associated (and/or correlated) with the image
information. In some embodiments, analyzing the image information
includes predicting future spatial and/or temporal locations
associated with the image information. Software, systems, and/or
firmware, for example, for performing these calculations and
analyses is known in the art and/or described herein.
[0194] In illustrative embodiments, image information is analyzed
either by control circuitry in the subject and/or by control
circuitry external to the subject, optionally transmitted
wirelessly. The control circuitry analyzes the image information in
real time and/or within the expected transit time through the
detection area and/or to the destruction area (e.g. target area).
If one or more targets is identified for ablation the target may be
ablated in real time, and/or its arrival in a destruction area may
be predicted using control circuitry. In this event, control
circuitry optionally uses information relating to measurements of
fluid and/or cellular for determined from the image information to
predict the time for ablation and/or the location for ablation.
Software, systems, and/or firmware, for example, for performing
these calculations and analyses is known in the art and/or
described herein
[0195] Analyzing an image response to at least partially identify a
target for ablation may include, but is not limited to, evaluating
an image response at least partially in reference to baseline,
background, and/or non-specific image responses, as well as
expected, reference, and/or normal image responses (e.g. baseline
fluorescence, background fluorescence, expected fluorescence,
normal fluorescence, reference fluorescence, non-specific
fluorescence, and/or intrinsic non-target fluorescence, etc.).
Analyzing an image response may include, but is not limited to,
subtractively determining an image response, optionally a target
fluorescent response (e.g. subtracting the non-target fluorescence
from the total fluorescence to determine the target fluorescence).
Analyzing an image response may include, but is not limited to,
evaluating an image response at least partially based on detection
at one or more wavelengths (e.g. single, multiple,
extended-spectrum, etc.), based on time (e.g. one or more times,
time intervals, and/or over time, etc.), based on direction (e.g.
of origination of the emission, etc.), based on strength, and/or
based on distance (e.g. of origination of emission from a sensor).
In illustrative embodiments, analyzing an image response may
include, but is not limited to, identifying "clumps" and/or
"groups" of cells that in another context might be considered
"normal", but that are not normally grouped and so may be a target
for ablation (see e.g. U.S. Patent Applications 2007/0066939 and
2007/0225633).
[0196] In illustrative embodiments, an analyzed target image
response is used to determine the direction from which the response
originated in order to provide ablation energy to the location
and/or general area. In illustrative embodiments, an analyzed
target image response is used to determine the coordinates from
which the response originated in order to provide ablation energy
to the location and/or general area.
[0197] As used herein, the term "location" may include, but is not
limited to, one or more of a direction, an area, a depth, a site,
or a size, etc. A location may be defined by spatial coordinates
and/or temporal coordinates. A location may be defined as precisely
as the cellular level, for example, or as broadly as a general
area, or a general direction. Methods of determining a location
based on the detection of a image response are known in the art
and/or described herein. In illustrative embodiments, a target
location may be the lumen of a blood vessel following detection of
a target image response.
[0198] Analyzing other information to at least partially identify a
target for ablation may include, but is not limited to, analyzing
information optionally provided by one or more sensors 130 (e.g.
intrinsic and/or extrinsic to one or more device 100, 200 and/or
300) and/or provided by one or more external sources (e.g. remotely
and/or wirelessly, etc.). Analyzing information optionally provided
by one or more sensors may include analyzing information including,
but not limited to, environmental information such as, but not
limited to, pH, temperature, pressure, chemistry, physiological
measurements, dietary measurements, biological measurements, etc.
In illustrative embodiments, identifying a target fluorescent
response is a least partially based on identifying the pH of the
environment, optionally detecting an acidic pH. Analyzing
information optionally provided by one or more external sources may
include analyzing information including, but not limited to,
environmental information and/or medical and/or veterinary
professional information.
[0199] Analyzing an image response to at least partially identify a
target for ablation may include, but is not limited to, evaluating
an image response in real time. As used herein, the term "in real
time" may include, but is not limited to, immediate, rapid, not
requiring operator intervention, automatic, and/or programmed. In
real time may include, but is not limited to, measurements in
femtoseconds, picoseconds, nanoseconds, milliseconds, as well as
longer, and optionally shorter, time intervals. In illustrative
embodiments, analysis in real time is sufficiently rapid such that
the target and the device have not moved and/or changed
positions/locations significantly with respect to each other such
that ablation energy sent along the path of the initial excitation
energy will cause damage to the one or more identified targets. In
illustrative embodiments, an image response is detected and
analyzed, and a target is identified without operator intervention
and the target ablation information is provided to an energy
source.
[0200] In some embodiments, in real time may include during a
period of residence of the one or more targets in a detection area
and/or an ablation area. One or more of the diction area and/or the
ablation area may be in the local bypass 210 and/or in a reservoir
310. In some embodiments, on or more of analyzing image information
and/or providing ablation energy may be performed during a period
of residence of the one or more targets.
[0201] Embodiments of one or more methods include providing energy
to at least partially ablate a target, optionally from one or more
local energy sources 110 and/or from one or more external energy
sources (e.g. external to the subject). One or more methods include
providing energy to at least partially ablate a target in real
time. As used herein the term "ablation or ablate" may include, but
is not limited to, processes including destroying, modifying,
removing, inactivating, and/or eliminating, in part or in whole, a
target and/or a material of interest. As used herein, ablation may
include the process of removing material and/or damaging and/or
inactivating a biological entity by irradiating it, optionally with
a laser beam, optionally with a pulsed laser, or a continuous wave
laser. As used herein, the term "inactivating" includes but is not
limited to, damage such that the biological entity is no longer
viable, cannot reproduce, and/or is no longer infectious.
[0202] Energy for ablation may include, but is not limited to,
electromagnetic energy, acoustic energy (e.g. ultrasonic energy),
X-ray energy, and particle beam energy. Electromagnetic energy such
as light may cause, for example, a photoreaction, molecular bond
breakage, heating, or other appropriate effect. Electromagnetic
energy sources 110 may include, but are not limited to, light
sources such as light emitting diodes and laser diodes, or sources
of other frequencies of electromagnetic energy, radio waves,
microwaves, ultraviolet rays, infra-red rays, optical rays, thermal
energy, terahertz beams, and the like.
[0203] As used herein, the term "at least partially ablate" may
include partially and/or completely ablating a target. As used
herein, the term "completely ablate" may include ablation of a
target up to the applicable limits of detection (e.g. no longer
detectable by the sensors used to detect the image response, no
longer detectable over background, and/or no longer statistically
significant). As used herein the term "partially ablate" may
include ablation less than complete ablation, but where at least
some detectable ablation occurs. At least some detection ablation
includes, but is not limited to, ablation detectable by the sensors
used to detect the image response, statistically significant
ablation, detection by external sensors, and/or detection by
inference from other measurements and/or sensor readouts.
[0204] Embodiments of one or more methods include locally
inhibiting fluid and/or cellular flow associated with one or more
blood vessel or lymph vessel, optionally associated with a vessel
lumen. In some embodiments, locally inhibiting fluid flow includes
locally restricting cellular flow in the lumen. In some
embodiments, locally inhibiting fluid flow includes modifying
cellular flow such that one or more cells traverse the lumen in
single file and/or traverse a localized region of the lumen. In
some embodiments, locally modifying fluid flow includes at least
partially reducing and/or constricting an internal and/or external
circumference of the vessel lumen. In some embodiments, locally
modifying fluid flow includes locally compressing and/or at least
partially occluding the lumen. In some embodiments, locally
modifying fluid flow includes activating a local compression
mechanism and/or local occlusion mechanism associated with the
lumen.
[0205] As used herein the term "modifying" includes, but is not
limited to, changes made to the referent which may be partial
and/or complete. For example, modifying fluid flow may include
increasing and/or decreasing fluid flow and/or inhibiting and/or
enhancing fluid flow. Modifying fluid flow may refer to increasing
and/or decreasing the speed of the fluid flow and/or the amount of
the fluid flow. Modifying fluid flow may refer to changing the
direction and/or path of the fluid flow. These changes may be
partial (e.g. less than complete inhibition, but yet measurable)
and/or complete (e.g. no detectable fluid flow can occur, and/or a
non-significant amount of fluid flow occurs). Unless indicated
otherwise, generally modification refers to partial, not complete
modification (e.g. partial, not complete inhibition). Methods for
detecting changes in fluid and cellular flow are known in the art
and/or described herein. To be considered modified, changes are
measurable, and optionally statistically significant differences as
compared to the previous, calculated, and/or reference amounts of
fluid flow.
[0206] In illustrative embodiments, locally modifying fluid and/or
cellular flow may occur using one or more insert 170 and/or one or
more valve. In illustrative embodiments, image information is
optionally captured of the modified fluid flow, and optionally
analyzed by control circuitry 150. In some embodiments, ablation
and/or modification (inactivation energy) is provided to the
modified fluid flow. For example, image information may be enhanced
when captured from fluid and/or cells moving at a reduced speed, or
reduction in speed may permit more time for analysis by control
circuitry 150 of the image information, or permit additional or
different types of sensors to capture image information. In
illustrative embodiments, inhibition and/or reduction in speed of
fluid flow (or capture of one or more targets) my facilitate
ablation of one or more targets, either through prediction and/or
calculation of a predicted future location or time of passage
through a known location, or through directing the one or more
targets to a destruction area.
[0207] Embodiments of one or more methods optionally include at
least partially (optionally completely) diverting fluid flow from
and at least partially returning fluid to a lumen of one or more
blood vessel and/or lymph vessel, optionally through a local
bypass. In some embodiments, this process of diversion and return
of fluid flow is controllable and/or programmable. In illustrative
embodiments, fluid is diverted from a vessel lumen optionally
through a valve leading to a local bypass (e.g. an optionally
optically pure channel) in which additional image information can
be captured and optionally ablation can occur. The local bypass may
be in line with the vessel lumen, internal to the vessel lumen, and
or an off-branch from the vessel lumen. Illustrative examples are
provided herein.
[0208] In some embodiments, the methods include controllably
attaching the local bypass to the one or more vessel. In
illustrative embodiments, the insert may be provided to (and
removed from) the appropriate location via some form of
microsurgery. The connections attaching the local bypass in local
may optionally be remotely and/or wirelessly and/or programmably
activated and de-activated to facilitate this process.
[0209] In some embodiments, image information is captured
associated with the local bypass. In some embodiments, the image
information is captured in the vessel lumen upflow and/or downflow
of the local bypass, and/or in the local bypass lumen. In
illustrative embodiments, image information is captured upflow of
the local bypass, analyzed by control circuitry and then the valve
leading to the local bypass is opened or closed depending, for
example, on whether any possible targets are detected. Once in the
local bypass, additional sensing may be performed (or this may be
where all sensing takes place and the bypass opens and closes
according to a program or parameters other than the presence or
absence of possible targets in the vessel lumen). The local bypass
is optionally designed for optical imaging such that better
measurements are optionally available. More than one sensor system
is optionally present in the local bypass, and more than one type
of imaging may be done on all cells, done randomly on a subset of
cells, and/or done sequentially on cells depending on earlier
sensing results. In illustrative embodiments, image information is
captured downflow of the local bypass (or downflow of the upflow
bypass valve) in the vessel lumen, optionally to document cells
that do not enter the bypass lumen, and/or to document cells
exiting the bypass lumen.
[0210] In some embodiments, the target area is selected in the
local bypass. In some embodiments, selection of the target area is
based at least partially on a predicted future path of the one or
more targets, and/or on a predicted time of arrival of the one or
more identified targets at an identified location in the local
bypass.
[0211] Some embodiments include locally modulating fluid flow in
the local bypass (optionally using a bypass insert 216), optionally
reducing fluid flow and/or increasing fluid flow in the local
bypass. In some embodiments modulating fluid flow in the local
bypass includes modulating the lumen of the local bypass. Methods
relating to modulating fluid flow in a vessel are discussed herein,
and are applicable to the local bypass unless context dictates
otherwise.
[0212] Embodiments of one or more methods include locally
collecting one or more identified targets in one or more reservoirs
310. In some embodiments, image information is captured from the
lumen of the one or more reservoirs. In some embodiments, energy is
provided to the lumen of the one or more reservoirs to elicit the
image information and/or to ablate one or more targets. In
illustrative embodiments, one or more reservoirs are configured to
receive one or more targets (or possible targets) identified by one
or more sensing systems upflow from the reservoir. Within the
reservoir, the one or more targets (or possible targets) optionally
undergo additional tests and analysis from one or more sensing
systems optionally including counting the numbers of one or more
targets optionally during a defined time period) and/or are simply
collected for further analysis ex vivo. Information relating to the
targets may be provided to one or more external control circuitry,
and/or accessible to one or more external sources through wireless
technology.
[0213] In some embodiments, the reservoir lumens are accessed from
the exterior of the subject, optionally so that the one or more
possible targets and/or one or more targets can undergo additional
tests and analysis ex vivo. In illustrative embodiments, the
reservoirs are placed to facilitate external access from the
subject and/or medical professionals. Optionally a permanent or
semi-permanent conduit may be in place to allow easy access.
Optionally access is through a large bore needle (e.g. biopsy
needle).
[0214] Embodiments of one or more methods may include combinations
including one or more bypass, one or more insert, one or more
reservoir, etc in a variety of combinations and configurations, as
well as one or more sensors 130, energy sources 110, control
circuitry 150, and power sources 160.
EXAMPLES
[0215] The following Examples are provided to illustrate, not to
limit, aspects of the present invention. Materials and reagents
described in the Examples are commercially available unless
otherwise specified.
Example 1
Detection of Biological Targets in Vessels Using Light
Scattering
[0216] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based on differential scattering of light. As
such, a cell or cells in the vessel circulation may pass through an
examination zone either incorporated within the device or in close
proximity to the device. A cell or cells may be, for example, a
bacterium, a protozoan, a platelet, a red blood cell, a lymphocyte,
a monocyte, a neutrophil, an eosinophil, a circulating tumor cell
or a combination thereof.
[0217] For imaging through use of differential scattering, the cell
or cells are illuminated in an examination zone with a focused beam
of energy. The beam may be a form of electromagnetic energy such
as, for example, white light, laser light, X-rays, or infrared
radiation. The device measures the optical interactions of the
electromagnetic energy with the cell or cells, such as multiple
wavelength absorption, scatter as a function of angle, or
fluorescence as a function of either wavelength or polarization.
The information regarding the optical interactions may be captured
by a photosensor such as, for example, a CCD (charge coupled
device) and/or a CMOS (complementary metal oxide semiconductor)
sensor.
[0218] The captured information is processed internally by the
device or sent wirelessly to an external processor. In real time,
the captured information is compared with preset algorithms
defining, for example, the light scattering properties of cells
normally found in the circulation. For example, forward light
scattering may provide a rough indication of cell size while side
light scattering may provide a rough indication of cellular
granularity, membrane complexity, and number of organelles.
Alternatively (or additionally), the captured information is
compared with preset algorithms defining, for example, the light
scattering properties of abnormal blood cells or cells foreign to
the circulation such as bacteria or circulating neoplastic cells,
for example.
[0219] Upon identification of an abnormal cell or cells, the
information may be provided to an external source through control
circuitry, additional sensing parameters may be instigated, the
cells may be provided to a reservoir for storage and optional
retrieval, and/or the device may emit radiation sufficient to at
least partially modify (or render non-viable or at least of reduced
viability) the targeted cell. Alternatively, the device triggers
emission of radiation from a second component of the device
positioned downstream from the first detecting device.
[0220] Lymphocytes, monocytes, and granulocytes may be
differentiated from one another under conditions of flow using, for
example, a four-parameter light scattering technique used, for
example, in flow cytometry (Terstappen et al. (1988) Cytometry
9:39-43). Electromagnetic energy emitted from a laser at
wavelengths from 400 nm to 700 nm, for example, is differentially
scattered by a cell or cells in the examination zone. The light
scattering intensity may be simultaneously measured, for example at
angles between 1.0 and 2.6 degrees and 3.0 and 11.0 degrees.
Eosinophilic granulocytes may be differentiated from neutrophilic
granulocytes by simultaneous measurement of the orthogonal and
depolarized orthogonal light scattering. Platelets and red blood
cells exhibit minimal light scattering at the angles described
above and are consequently excluded from the analysis.
Alternatively, red and white blood cells may be distinguished by
simultaneously observing forward and orthogonal light scatter at a
wavelength of 413.1 nm, for example (Ost et al. (1998) Cytometry
32:191-197). Alternatively, a diode laser emitting, for example, at
either 670 nm or 780 nm may be used to distinguish lymphocytes,
monocytes, neutrophils, and eosinophils using a combination of
forward, orthogonal, and depolarized orthogonal scatter (Doornbos
et al. (1993) Cytometry 14:589-594).
[0221] Lymphocytes, granulocytes, and red blood cells may also be
differentiated from one another based on forward and side light
scattering under conditions of flow in an in vivo analysis, for
example, of a surgically exposed mesentery artery (see, e.g., U.S.
Pat. No. 7,264,794 B2).
[0222] An abnormal white blood cell associated with, for example,
acute myeloblastic leukemia (AML), may be differentiated by light
scatter. AML is characterized by uncontrolled proliferation of
malignant myeloid progenitors in the bone marrow, at the expense of
normal proliferation of white blood cells, red blood cells, and
platelets. These immature white blood cells or blasts are arrested
in their maturation process and can easily egress from the bone
marrow into the circulation. Sarcomas found in various solid
tissues may arise from metastasis of AML (Konoplev &
Bueso-Ramos (2006) Ann. Diag. Path. 10:39-65).
[0223] AML blast cells may be differentiated from T-lymphocytes,
for example, by measuring low angle forward light scatter and
orthogonal light scatter (Vidriales et al. (1995) J. Clin. Pathol.
48:456-462). As such, the device may be used to induce and detect
the patterns of forward and orthogonal light scatter of AML blast
cells, for example, in the circulation. These patterns may be
compared with those of normal white blood cells using preset
algorithms.
[0224] Differential light scattering may also be used to detect
circulating tumor cells derived from metastasis of solid tumors. In
general, a circulating tumor cell is characterized by its large
size, immature appearance, increased nuclear to cytoplasmic ratio,
abnormally shaped nuclei, and disproportionately large nucleolus or
multiple nucleoli (Moore et al. (1960) Cancer 13:111-117).
[0225] The size differential between a circulating tumor cell and
components of the blood may be used to specifically detect the
cancerous cells. For example, the average diameter of neutrophils,
red bloods cells, and platelets is 10.5-12.5 microns, 7-8 microns,
and 3 microns, respectively. In contrast, the average size of
circulating tumor cells isolated from patients with breast, colon,
stomach and lung cancers range from 18.3 to 20.6 microns in
diameter (Moore et al. (1960) Cancer 13:111-117). Similarly,
circulating neuroblastoma tumor cells are greater than 20 microns
in diameter (Mohamed et al. (2004) IEEE Transactions on
Nanobioscience, 3:251-256).
[0226] While neuroblastoma is a radiosensitive tumor, long-term
control is difficult due to metastasis. Therefore, the ability to
detect and ablate circulating tumor cells, such as neuroblastoma
cells, may aide in the treatment of this cancer. As such, the size
of a cell or cells passing through the examination zone is
determined using forward light scattering. The size, as measured
for example in diameter, is compared with known parameters
regarding the size of normal blood components. Detection of an
abnormally large cell may signal the presence of a circulating
tumor cell and may trigger an ablation response.
[0227] An untethered device configured to function in or proximal
to a blood vessel or lymph vessel may also be used to detect
circulating bacteria relative to other cellular components of the
circulation based on size analysis using light scattering. Bacteria
are on average 0.2 to 1.0 microns in diameter as compared to 1.5 to
3.0 microns for platelets, for example. Staphylococcus aureus
bacteria, for example, are perfectly round and approximately 1
micron in diameter. As such, a bacterium may be distinguished from
platelets and other larger blood cell components based on size as
described herein. The diameter as well as the length of the
rod-shaped Escherichia coli bacteria, for example, may be
determined using polarized light scattering, as described by Bronk
et al. ((1995) Biophysical J. 69:1170-1177).
[0228] Other pathogens may be detected in the circulation based on
size analysis and light scattering. For example Trypanosoma brucei
gambiense, a blood borne protozoan associated with African sleeping
sickness, has a unique elongated cellular shape relative to the
predominantly spherical shape of normal cellular components of the
blood. It is 25-40 microns in length, with a flagellum. As such, is
anticipated that the light scattering properties of trypanosomes
will be readily distinguished from those of normal components of
the vasculature.
[0229] Blood cells infected with the parasite Plasmodium falciparum
may be differentiated from other cells in the vasculature using
differential light scatter at 10 degrees (complexity) and polarized
light scatter at 90 degrees (lobularity) based on the pigmentation
of the parasite (Mendelow et al. (1999) Br. J. Haematology
104:499-503).
Example 2
Detection of Biological Targets in Vessels Using Electrical
Impedance and Dielectric Properties
[0230] An untethered device configured to function in or proximal
to a blood vessel or lymph vessel may be used to detect specific
biological targets based on changes in electrical impedance
relative to cell size. As such, a cell or cells in the vessel
circulation may pass through an examination zone either
incorporated within the device or in close proximity to the
device.
[0231] The examination zone may contain two or more electrodes
between which an electric current flows. As each cell passes
through the electric current in the examination zone, it displaces
its own volume of conducting fluid (i.e. plasma), momentarily
increasing the impedance within the examination zone. This change
in impedance produces a tiny but proportional current fluctuation
that can be converted into a voltage pulse. The amplitude of this
pulse is directly proportional to the volume of the cell that
produced it. As such, the device may detect changes in electrical
impedance and convert this information into volume information that
may be compared with preset algorithms defining, for example, the
volume of normal blood cells or cells foreign to the circulation
such as bacteria or circulating neoplastic cells.
[0232] Cellular components of the blood may be differentiated based
on volume using electrical impedance as described herein and/or
commonly practiced using a Coulter counter. For example, platelets
range in volume from 2 to 20 femtoliters (fL) whereas red blood
cells range in volume from 70-90 ft, (Hauser (2001) International
Waldenstrom's Macroglobulinemia Foundation). Neutrophils and
eosinophils range in volume from 160 to 450 fL while monocytes
range in volume from 90 to 160 fL. By comparison, bacteria may be
as small as 1 fL whereas a circulating tumor cell may be as large
as 2000 fL. As such, changes in the electrical impedance in the
examination zone may be used to differentiate between various
components of the blood.
[0233] A MEMS resembling a miniaturized Coulter counter may be
incorporated into the device described herein and may be
constructed using thin platinum electrodes with a sensing zone of,
for example, 20-100 microns (see, e.g., Zheng et al. (2006)
Proceedings of 2006 International Conference on Microtechnologies
in Medicine and Biology, IEEE, Okinawa, Japan, 9-12 May, 2006; Gao
et al. (2003) Proceedings of the 25.sup.th Annual International
Conference of the IEEE EMBS, Cancun, Mexico, Sep. 17-21, 2003).
[0234] Alternatively, cellular components of the blood may be
differentiated using electrical impedance spectroscopy. In this
instance, the electrical impedance of a given cell is obtained by
applying impulses over a range of frequencies from, for example, 10
Hz to 10 MHz and measuring the impulse response. The resulting
spectrum is characteristic of a given cell type. For example, T
lymphocytes exhibit resonance at 1.0 MHz, 2.9 MHz, 3.6 MHz, 4.5
MHz, 5.5 MHz, and 6.3 MHz while B lymphocytes exhibit resonance at
0.6 MHz, 1.7 MHz, 4.3 MHz, 5.0 MHz, 5.8 MHz, and 6.3 MHz (Liu et
al. (1998) IEEE: Proceedings of the 20.sup.th Annual International
Conference of the IEEE Engineering in Medicine and Biology Society,
Vol. 20, No. 4, 1881-1884).
[0235] A component capable of micro electrical impedance
spectroscopy may be generated using MEMS and/or Lab-on-a-chip
technology and incorporated into the untethered device described
herein (see, e.g., Sun et al. (2007) Meas. Sci. Technol.
18:2859-2868; Mohanty et al., Microtechnologies in Medicine and
Biology 485-488).
[0236] Normal and cancerous lymphocytes may be distinguished by
differences in the relative capacitance and conductivity of their
respective cell membranes using dielectric spectroscopy (Feldman et
al. (2003) IEEE Transactions on Dielectrics and Electrical
Insulation 10:728-753).
Example 3
Detection of Biological Targets in Vessels Using Infrared
Spectroscopy
[0237] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based on infrared spectroscopy imaging. As such,
a cell or cells in the vessel circulation may pass through an
examination zone either incorporated within the device or in close
proximity to the device. The cell or cells are illuminated in the
examination zone by an electromagnetic energy source emitting
radiation at infrared wavelengths. The device measures the optical
interactions of the electromagnetic energy with the cell or cells,
such as absorbance as a function of wavelength. The absorbance
information is captured by the device and either processed
internally or sent wirelessly to an external processor. In real
time, the captured information is compared with preset algorithms
defining, for example, the infrared absorbance properties of normal
blood cells and circulating tumor cells.
[0238] Infrared spectroscopy is a nondestructive photonic technique
that provides a rapid measure of sample chemistry. A tissue or cell
contains various chemical components with characteristic infrared
spectra, including proteins, nucleic acids, carbohydrates and
lipids. These spectra are created when a molecule converts infrared
radiation into molecular vibrations. These vibrational movements
create bands in a spectrum that occur at specific wavelengths
(cm.sup.-1). Subtle differences in the chemical composition of a
tissue or cell can be distinguished by subtle changes in the
spectra. Chemical concentrations may be quantified by spectral
absorbance properties at specific wavelengths, while subtle
molecular structural changes may be indicated by spectral peak
shifts, band shapes and relative intensity changes occurring across
the spectrum.
[0239] Infrared covers the electromagnetic spectrum from
wavelengths of 0.78 to 1000 .mu.m. In the context of infrared
spectroscopy, wavelength may be expressed as wavenumber with units
of cm.sup.-1, such that the wavenumber is equal to the reciprocal
of the wavelength in centimeters. For analysis of tissue and cells,
for example, spectral data may be taken at wavenumbers between 3500
and 1000 cm.sup.-1, corresponding to wavelengths between 2.8 .mu.m
and 10 .mu.m.
[0240] Infrared spectroscopy has been used, for example, to
distinguish normal epithelial cells from cancerous epithelial cells
in the prostate. Glandular epithelial cells in the prostate are the
primary cell type involved in prostate adenocarcinoma and can be
found in the circulation as a result of tumor metastasis. The
infrared spectra of malignant prostate epithelial cells can be
distinguished from normal epithelial cells at a variety of
different wavenumbers or spectral biomarkers ranging from 966 to
3290 cm.sup.-1 and can be further distinguished from, for example,
lymphocytes (Fernandez et al. (2005) Nat. Biotech. 23:469-474). As
such, the device may contain an electromagnetic energy source
capable of emitting infrared radiation at wavelengths/wavenumbers
in the range described above and may be a laser diode or diodes
emitting at a specific wavelength or a type of tunable lead salt
laser, for example.
[0241] Infrared spectroscopy may also be used to detect bacteria in
the blood. For example, Fourier Transfer Infrared (FT-IR)
Spectroscopy may be used to distinguish Streptococcus pneumoniae,
Haemophilus influenzae, and Morazella catarrhalis bacteria in serum
using a spectral range of wavenumbers from 4000 to 800 cm.sup.-1
(U.S. Pat. No. 6,379,920 B1). H. influenzae, for example, exhibits
increased absorbance at 1077 cm.sup.-1 relative to serum alone or
other bacteria tested. Alternatively, FT-IR data may be obtained at
various frequency ranges, such as, for example, 3000-2800
cm.sup.-1, 1800-1500 cm.sup.-1, 1500-12000 cm.sup.-1 1200-900
cm.sup.-1 and 900-700 cm.sup.-1 and spectra obtained in these
various ranges compared with known spectra of various bacteria
(see, e.g., Oberreuter et al. (2002) Int. J. Syst. Evol. Microbiol.
52:91-100).
Example 4
Detection of Biological Targets in Vessels Using Acoustic
Imaging
[0242] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based on ultrasound. As such, a cell or cells in
the vessel circulation may pass through an examination zone either
incorporated within the device or in close proximity to the device.
The cell or cells in the examination zone are exposed to acoustic
waves. The device measures the interactions of the acoustic waves
with the cell or cells.
[0243] Acoustic imaging uses sound waves rather than light waves to
generate an image. As such, a sound wave may be sent through a
piece of quartz or glass coated with a thin layer of piezoelectric
material that resonates at a specific frequency, for example, 1
GHz, and through a lens to scan a cell or cells (Ouellette (2004)
The Industrial Physicist June/July:14-17). The sound waves are
reflected back up through the lens and piezoelectric material which
serve as detector and amplifier. The reflected sound waves are
recorded electronically and may be used directly to compare
cellular profiles. Alternatively, the recorded sound waves may be
converted into an image.
[0244] The resolution of acoustic imaging is dependent upon the
frequency of sound used for imaging. As such, standard ultrasound
imaging uses sound waves ranging in frequency from 3-10 MHz, but
does not provide cellular detail. Higher frequency ultrasound in
the range of 20-100 MHz may be used to detect changes in cellular
structures in tissues and cells, although individual cells are
still not easily resolved. For example, cells undergoing mitosis
and cells undergoing apoptosis in response to a chemotherapeutic
agent, for example, exhibit increased backscattered signal relative
to normal cells (Baddour et al. (2002) Ultrasonics Symposium IEEE
2:1639-1644). Cellular resolution may be attained using sound waves
ranging in frequency from 100 MHz to 2 GHz, comparable to the range
used for acoustic microscopy, for example (Schenk et al. (1988) J.
Histochem. Cytochem. 36:1341-1351). The latter corresponds to
wavelengths of 15 to 0.75 microns in water, the medium through
which ultrasound and acoustic imaging are done.
[0245] Photoacoustic imaging, in which ultrasound detection is
combined with optical stimulation, may also be used to image
objects (see, e.g. Wygant et al. (2005) IEEE Ultrasonics Symposium
1921-1924). In this process, the optical absorption properties of a
material are imaged by detecting the ultrasound emitted when a cell
is illuminated with a laser. The emitted ultrasound is due to the
brief thermal expansions that occur when the laser energy is
absorbed by the cell. Those regions that are more optically
absorbent will generate a stronger acoustic signal. Laser pulse
widths, for example, of 10 ns and wavelengths between 600 nm and
1000 nm may be used for photoacoustic imaging of cells. A single
mechanically scanned piezoelectric transducer or a capacitive
micromachined ultrasonic transducer array, for example, may be used
to detect the laser generated ultrasound (see, e.g. Wygant et al.
(2005) IEEE Ultrasonics Symposium 1921-1924).
[0246] Photoacoustic imaging may also be used to detect flowing
cells in vivo (see, e.g. Zharov et al. (2006) SPIE Newsroom
10.1117/2.1200609.0391). As such, a cell or cells are irradiated
with one or several focused laser beams operating at different
wavelengths ranging, for example, from 415 to 2300 nm. An
ultrasound transducer is used to record laser-induced acoustic
waves.
Example 5
Detection of Biological Targets in Vessels Using Thermal
Imaging
[0247] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based on thermal imaging. As such, a cell or
cells in the circulation may pass through an examination zone
either incorporated within the device or in close proximity to the
device. Thermal energy or infrared radiation emitted from a cell or
cells in the examination zone is detected by the device using
infrared photosensors made of, for example, indium gallium arsenide
or mercury cadmium telluride. The thermal information is captured
by the device and either processed internally or sent wirelessly to
an external processor. In real time, the captured information is
compared with preset algorithms defining, for example, the thermal
properties of normal blood cells and circulating tumor cells.
[0248] Infrared thermography may be used to characterize tissues
and cells. For example, infrared thermography has been used to
monitor mitochondrial heat production of human adipocytes and yeast
in response to agents that either activate or inhibit cellular
thermogenesis (see, e.g., U.S. Pat. No. 6,881,584). As such,
infrared thermography may enable differentiation between normal and
abnormal cells. For example, highly proliferative malignant tumor
cells often have decreased mitochondria but higher metabolic
activity due to compensatory increases in glycolytic ATP production
in place of normal, more efficient oxidative phosphorylation
(Gourley et al. (2005) Biomed. Microdevices 7:331-339). In
contrast, benign or low grade malignant cells may have an increased
number of mitochondria. Differences in mitochondrial number and
function may be distinguishable using infrared thermography.
Example 6
Detection of Biological Targets in Vessels Using Photothermal
Imaging
[0249] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based on photothermal imaging. As such, a cell
or cells in the circulation may pass through an examination zone
where they are illuminated by an electromagnetic energy source. The
device measures the thermal response and related effects taking
place directly in a cell or cells as a result of non-radiative
relaxation of the absorbed electromagnetic energy in heat. The
thermal information is captured by the device and either processed
internally or sent wirelessly to an external processor. In real
time, the captured information is compared with preset algorithms
defining, for example, the photothermal properties of normal blood
cells and circulating tumor cells.
[0250] Photothermal imaging may be used to distinguish between a
white blood cell, a red blood cell, and a circulating tumor cell in
vivo (see, e.g. Zharov et al. (2006) J. Cell. Biochem. 97:916-932).
Basic informative parameters provided by photothermal spectroscopy
include an absorption coefficient similar to those in conventional
absorption spectroscopy, but several orders of magnitude more
sensitive. Light absorbed into cells is measured directly through
thermal phenomena.
[0251] A cell or cells may be irradiated, for example, with a
short, focused pump laser pulse (415-2300 nm) leading to an
increase in temperature of local cellular absorbing structures. The
temperature distribution is transformed into a refraction
distribution. Time-resolved monitoring of temperature-dependent
variations in the cells refractive index is realized with
thermolens or phase contrast imaging with a CCD camera and a second
collinear laser pulse at 639 nm (Zharov et al. (2006) J. Cell.
Biochem. 97:916-932).
[0252] As such, correlations between specific photothermal imaging
parameters, such as cell shape, and photothermal response
parameters, such as amplitude, shape and duration, and morphologic
cell type may be used to differentiate between, for example,
"rigid` red blood cells versus "flexible" red blood cells or
circulating tumor cells versus normal white blood cells. As such,
photothermal imaging may differentiate between flexible normal red
blood cells and rigid Plasmodium-infected red blood cells. Red
blood cells may be differentiated from white blood cells based on
the amplitude of the integral photothermal responses, which are
proportional to the cells' average absorption and differ
.about.30-40 fold for red blood cells and white blood cells (Zharov
et al. (2006) J. Cell. Biochem. 97:916-932).
[0253] In addition, photothermal imaging is able to reveal the
subcellular structures of a red blood cell versus a white blood
cell based on specific distribution of chromophores (Galanzha et
al. (2007) World J. Gastroenterol. 13:192-218). For example,
hemoglobin associated with red blood cells has a smooth
distribution whereas cytochromes or other absorbing biomolecules in
white blood cells have a localized distribution.
[0254] Photothermal imaging associated with an untethered device
may also be used to detect red blood cells that have been infected
with the malaria parasite, Plasmodium falciparum. Red blood cells
infected with P. falciparum accumulate light-absorbing hemozoin
granules in the digestive vacuole of the parasite (Cowman et al.
(1991) J. Cell. Biol. 113:1033-1042). Hemozoin is the chemically
inert crystalline substance that is visible using standard light
microscopy in stages that are actively degrading hemoglobin, such
as trophozoites, schizonts and gametocytes. The monomeric,
potentially toxic heme is released during proteolysis of red blood
cell hemoglobin and, as the parasite is unable to cleave the
porphyrin ring, it is `detoxified` by conversion to the insoluble
hemozoin polymer. As such, it is anticipated that the increased
sensitivity of photothermal imaging over standard absorbance
spectroscopy will enable differentiation of normal and
malaria-infected red blood cells.
Example 7
Detection of Biological Targets Using Visible Light Absorption and
Refraction
[0255] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based on visible light absorption. As such, a
cell or cells in the circulation may pass through an examination
zone where they are illuminated by visible light. The device
captures the image of a cell or cells in the examination zone using
a photosensor such as, for example, a CCD or CMOS camera. The image
is captured by the device and either processed internally or sent
wirelessly to an external processor. In real time, the captured
information is compared with preset algorithms defining, for
example, image and shape characteristics of normal circulating
cells and abnormal or foreign cells.
[0256] Red blood cells infected with the malaria parasite may be
detected using visible light and phase imaging (Cowman et al.
(1991) J. Cell. Biol. 113:1033-1042). The parasite survives by
digesting hemoglobin in the red blood cell and converts the toxic
heme to hemozoin, the later of which forms brown crystalline
structures that are readily detected by light microscopy. As such,
a device emitting visible light may detect and distinguish infected
red blood cells from normal red blood cells based on absorbance
properties of the hemozoin. In addition, red blood cells in general
may be detected based on light absorption and scattering using
conventional bright field imaging under the conditions of flow
using high speed data capture with a CCD or CMOS sensor (see, e.g.,
Zharov et al. (2006) J. Biomed. Opt. 11:054034-1-4; U.S. Pat. No.
5,934,278).
[0257] Trypanosomes may be distinguished from other components of
the blood using visible light and phase imaging (Nolan et al.
(1997) J. Biol. Chem. 272:29212-29221). The morphology of the
protozoan is very distinct from that of normal blood cells. The
protozoan is elongated, from 25 to 40 um in length with a flagellum
while normal blood cells are predominantly spherical in shape. As
such, the shape of a trypanosome as determined by visible light
imaging can be readily distinguished from normal cells.
[0258] Similarly, cells may be imaged using quantitative phase
contrast mapping which can reveal an objects surface with vertical
resolution at the nanometer scale (Emery et al. (2007) J. Physics
61:1317-1321).
[0259] Cells may also be imaged using refractive index tomography
(see, e.g. Choi et al. (2007) Nature Methods; advance online
publication Aug. 12, 2007). In this instance, quantitative phase
images from time-dependent interference patterns by the frequency
shifting of a reference beam relative to the sample beam. A laser
beam with a wavelength, for example, of 633 nm is divided into a
sample and a reference path with a beamsplitter. A tilting mirror
is used to vary the angle of illumination of the sample. The
reference beam passes through a modulator shifting the frequency to
a longer wavelength. When the reference beam and the sample beam
are recombined, an interference pattern forms at the image plane.
The interference pattern is captured with a CCD or CMOS sensor and
the phase images are them calculated by applying phase-shifting
interferometry.
Example 8
Detection of Biological Targets Using Autofluorescence
[0260] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based on autofluorescence. As such, a cell or
cells in the vessel circulation may pass through an examination
zone incorporated within part of the device or in close proximity
to the device, such as the local bypass or reservoir described
herein. The cell or cells are illuminated in the examination zone
with a focused beam of light. The beam may be a form of
electromagnetic energy such as, for example, white light, laser
light, X-rays, or infrared radiation. The device detects cellular
autofluorescence induced by the electromagnetic energy. The
autofluorescence information may be captured by a photosensor such
as, for example, a CCD (charge coupled device) and/or a CMOS
(complementary metal oxide semiconductor) sensor. Disclosure of
autofluorescence methods and related devices and systems is found
in U.S. Application Ser. Nos. 11/895,563, 11/895,564, 11/895,562,
11/895,565, 11/895,566, 11/895,567, 11/895,560, and 11/895,561.
[0261] A pathogen or pathogens may be detected in the vasculature
via autofluorescence induced, for example, by electromagnetic
energy. Naturally occurring autofluorescence in bacteria, for
example, is derived from biomolecules containing fluorophores, such
as porphyrins, amino acids tryptophan, tyrosine, and phenylalanine,
and the coenzymes NADP, NADPH, and flavins (Koenig et al. (1994) J.
Fluoresc. 4:17-40; Kim et al. (2004) IEEE/EMB Magazine
January/February 122-129). The excitation maxima of these
biomolecules lie in the range of 250-450 nm (spanning the
ultraviolet/visible (UV/VIS) spectral range), whereas their
emission maxima lie in the range of 280-540 (spanning the UV/VIS
spectral range; Ammor (2007) J. Fluoresc. published on-line ahead
of publication).
[0262] An untethered device may be used to detect pathogens
associated with blood infections or septicemia, for example.
Gram-negative enteric bacilli, Staphylococcus aureus, and
Streptococcus pneumoniae are the most common pathogens in the
United States associated with micronemia and sepsis. Staphylococcus
aureus may be detected by autofluorescence using a device emitting
electromagnetic energy at a wavelength, for example, of 488 nm
(Hilton (1998) SPIE 3491:1174-1178). Optionally, Staphylococcus
aureus may be distinguished from, for example, Escherichia coli and
Enterococcus faecalis based on emission spectra induced by
excitations at 410-430 nm (Giana et al. (2003) J. Fluoresc.
13:489-493; Ammor (2007) J. Fluoresc. published on-line ahead of
publication). Similarly, Streptococcus pneumoniae, may be detected
using fluorescence spectroscopy at excitation wavelengths of 250
and 550 nm and emission wavelengths of 265 and 700 nm (Ammor (2007)
J. Fluoresc. published on-line ahead of publication).
[0263] A number of other bacteria may be identified based on
autofluorescence. For example, bacteria associated with community
acquired pneumonia, Legionella anisa and Legionella dumoffii,
autofluoresce blue-white when exposed to long-wave (365-nm) UV
light (Thacker et al. (1990) J. Clin. Microbiol. 28:122-123).
Bacillus spores will autofluoresce when excited by UV irradiation
at a wavelength of 352 nm (Laflamme et al. (2006) J. Fluoresc.
16:733-737). Clostridium sporogenes, Pseuodomonas aeruginose,
Pseudomonas fluorescens, Kocuria rhizophila, Bacteroides vulgaris,
Serratia marcescens, and Burkholderia cepacia emit yellow-green
fluorescent signal when illuminated with blue light (Sage et al.
(2006) American Biotechnology Laboratory 24:20-23). Enterococcus
faecalis and Staphylococcus aureus may be differentiated based on
their respective autofluorescence in response to excitation spectra
of 330-510 nm and emission spectra of 410-430 nm (Ammor (2007) J.
Fluoresc. published on-line ahead of publication). P. aeruginosa
may be detected by autofluorescence using a device emitting
electromagnetic energy at a wavelength, for example, of 488 nm
(Hilton (1998) SPIE 3491:1174-1178). P. aeruginosa contains a
pigment called pyocyanin which appears blue in visible light and
may also be used for detection.
[0264] Autofluorescence of endogenous porphyrins may also be used
to detect bacteria. A number of bacteria produce protoporphyrins,
including Propinibacterium acnes, Bacillus thuringiensis,
Staphylococcus aureus, and some strains of Clostridium,
Bifidobacterium, and Actinomyces (Koenig et al. (1994) J. Fluoresc.
4:17-40). Bacteria may also be detected using fluorescence
lifetimes measured at 430, 487, and 514 nm after selective
excitation at 340, 405, and 430 nm (Bouchard et al. (2006) J.
Biomed. Opt. 11:014011, 1-7).
[0265] Autofluorescence may also be used to detect members of the
fungi family. For example, Candida albicans irradiated with
electromagnetic energy at wavelengths of 465-495 nm autofluoresces
at an emission wavelength of 515-555 nm (Mateus et al. (2004)
Antimicrob. Agents and Chemother. (2004) 48:3358-3336; Graham
(1983) Am. J. Clin. Pathol. 79:231-234). Similarly, Aspergillus
niger and Aspergillus versicolor may be detected using
autofluorescence in response to excitation at 450-490 nm and
emission at 560 nm (Sage et al. (2006) American Biotechnology
Laboratory 24:20-23; Graham (1983) Am. J. Clin. Pathol.
79:231-234).
[0266] An untethered device may be used to detect and ablate
parasites in the blood stream. For example, autofluorescence
associated with the food vacuole of the malaria parasite Plasmodium
spp. may be used to detect infected red blood cells with in the
blood stream (Wissing et al. (2002) J. Biol. Chem.
277:37747-37755). As such, an untethered device may induce
autofluorescence of parasites at a wavelength, for example, of 488
nm (Wissing et al. (2002) J. Biol. Chem. 277:37747-37755).
Example 9
Detection of Biological Targets Using Properties of
Mitochondria
[0267] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect specific
biological targets based the properties of intracellular
mitochondria.
[0268] A biocavity nanolaser may be used for optical phenotyping of
human mitochondria (see, e.g. Gourley & Naviaux (2005) IEEE: J.
Selected Topics in Quantum Electronics 11:818-826). This method may
be used to detect submicrometer particles by nanosqueezing light
into photon modes imposed by the ultrasmall dimensions of the
submicrometer laser cavity. As such, mitochondria from normal and
abnormal cells may be differentiated.
[0269] For example, the mean diameter of a normal mitochondria
ranges from 680 to 730 nm while diseased mitochondria from a cancer
cell, for example, exhibit a larger mean diameter in the range of
750 to 830 nm. In addition, the mitochondria in the cancer cell
have a very chaotic, unorganized and random distribution within the
cytosol as compared with normal cells. As such, the lasing spectra
of mitochondria may be used to differentiate between normal and
abnormal cells flowing in the circulation (see, e.g. Gourley et al.
(2005) Biomedical Microdevices 7:331-339).
[0270] Optionally, autofluorescence may be used to detect and image
mitochondria (see, e.g., Sikder et al. (2005) Photochem. Photobiol.
81:1569-1571). Redox fluorometry may be used to measure the levels
of pyridine nucleotides in the mitochondria, which may reflect
differences in cellular metabolic state and activity. As such,
autofluorescence associated with reduced pyridine nucleotides
(nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine
dinucleotide phosphate (NADPH) may be measured in the region of 450
nm after excitation at 366 nm.
Example 10
Pattern and Cell Shape Recognition
[0271] The untethered device captures information regarding the
properties of cells in a blood vessel or a lymph vessel. The
information is either processed internally by the device or sent
wirelessly to an external processor. The information processing
results in identification of a cell as normal or abnormal, leading
to a decision regarding the need for initiation of the ablation
process.
[0272] Pattern recognition and cell shape algorithms may be used in
the information processing. Various methods have been described for
image and shape analysis of cells and subcellular components of
cells (see, e.g., U.S. Pat. No. 5,107,422; U.S. Pat. No. 5,790,691;
U.S. Pat. No. 6,956,961 B2; U.S. Pat. No. 7,151,847 B2; U.S. Patent
Application 2005/0251347 A1; U.S. Patent Application 2006/0039593
A1; Fei-Fei et al. (2006) IEEE Transactions on Pattern analysis and
Machine Intelligence 28:594-611; Martin et al. (2004) IEEE
Transactions on Pattern analysis and Machine Intelligence
26:530-549; Olson et al. (1980) Proc. Natl. Acad. Sci. USA
77:1516-1520; Schneider, et al (1995) Biorheology 32:237-238).
[0273] Pattern recognition classifies patterns based on either
prior knowledge or on statistical information extracted from the
patterns. The patterns to be classified may be groups of
measurements or observations, defining points in an appropriate
multidimensional space. As such, a pattern recognition system may
consist of a sensor that gathers information or observations to be
classified or described; a feature extraction mechanism that
computes numeric or symbolic information from the observations; and
a classification or description scheme that does the actual work of
classifying or describing the observations, based on extracted
features. The classification or description scheme may be based on
a set of patterns or a training set that have already been
classified or described. The resulting learning strategy is
characterized as supervised learning. Alternatively, the system may
engage in unsupervised learning in that the system is not given
prior labeling of patterns, but instead establishes the classes
itself based on the statistical regularities of the patterns.
[0274] A Texture Analyzing System may be used to distinguish
various cells in the vasculature based on the granularity of the
cell or cells (Bins et al. (1981) Cytometry 1:321-324). As such,
the imaged components of the cells are measured with a gray scale
with 33 intervals ranging from black (level 0) to white (level 99)
and a histogram is generated.
[0275] For example, mature WBC (neutrophils, eosinophils, basophils
and lymphocytes) have a dense nuclear structure and therefore low
counts. In contrast, monocytes have a looser, less dense nuclear
structure and high counts. The cytoplasm of eosinophils and
neutrophils is very granular and is reflected in the combination of
high positive and low negative counts. Smaller values are seen in
the cytoplasm of lymphocytes, monocytes and basophils. Similarly,
granulometries may be used to identify red blood cells infected
with the malarial parasite (Dempster & DiRuberto (2001) IEEE
5:V291-V294).
[0276] A neural network algorithm may be used to classify normal
and abnormal components of the vasculature. For example, a neural
network based fuzzy classifier may be used to automatically
distinguish mature and immature white blood cells with a
recognition rate of 90-92% (Uebele et al. (1995) IEEE Transactions
on Systems, Man, and Cybernetics 25:353-361). In this instance,
optically screened white blood cells may be classified into 12
categories of mature and immature white blood cells using features
such as area and perimeter. A neural network based shape
recognition algorithm using nuclear radius and curvature features
may be also be used to automatically distinguish mature and
immature white blood cells (He & Wilder (2002) IEEE:
Proceedings of the Second Joint EMBS/BMES Conference, Houston,
Tex., USA Oct. 23-26, 2002). Similar approaches may be used to
classify and recognize lymphocytes, monocytes, neutrophils,
eosinophils and basophils (see, e.g. Kovalev et al. (1996) IEEE:
Proceedings of ICPR 1996 371-375). Alternatively, data regarding,
for example, the infrared or light scattering properties of mature
and immature cells may be the basis for the neural network based
pattern recognition.
[0277] Subcellular phenotypes of a cell, for example, nuclei or
mitochondria, may be automatically identified using different
machine learning methods, including Support Vector Machines (SVMs),
Artificial Neural Networks (ANN) or a combination of ANN and
Bayesian learning (Conrad et al. (2004) Genome Res. 14:1130-1136).
As such, image or spectral information regarding a subcellular
component of a cell may be processed and used to distinguish
various cell types.
Example 11
Methods for Capturing and Sequestering Biological Targets in
Vessels
[0278] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may include the capacity to
capture and sequester specific biological targets from the
vasculature optionally into a reservoir (and/or local bypass) for
future analysis. As such, the device may have the capacity to
capture a biological target before analysis in the examination
zone, at which point the biological target is identified as normal
or abnormal and either released back into circulation or
sequestered into a reservoir or holding chamber. Alternatively, the
device may have the capacity to analyze the biological target as it
passes through the examination zone, at which point the biological
target is identified as normal or abnormal and either allowed to
keeping moving or is captured and sequestered in a reservoir.
[0279] A specific cell or cells may be captured and moved into a
reservoir (and/or local bypass) of the device using the natural
fluid flow within the vessel. As such, the opening and closing of
strategically placed valves within the device may be used to
manipulate the flow of cells, allowing for selective sequestration
of targeted cells into the reservoir.
[0280] Size exclusion may be used to detect and capture circulating
tumor cells (see, e.g., Mohamed et al. (2004) IEEE Transactions on
Nanobioscience, 3:251-256). As such, the device may have a fixed
diameter or sieve, for example, through which normal blood
components may pass but larger cells such as, for example,
circulating tumor cells, are retained and either immediately
ablated or shunted to a reservoir. Alternatively, the device may
have a moveable aperture that allows for controlled changes in
device diameter to capture and release or sequester a cell or cells
as appropriate.
[0281] Alternatively, a cell or cells may be captured and
sequestered based on intrinsic magnetic properties. For example,
red blood cells infected with the malaria parasite P. falciparum
may be captured based on the magnetic properties of the infected
cells (Moore et al. (2006) FASEB J. 20:747-749). During development
in the red blood cell, the malaria parasite digests hemoglobin
leading to the accumulation of toxic heme. In the process of
incorporating the heme into hemozoin crystals, the heme is
converted to a high-spin ferriheme with increased magnetic
properties. P. falciparum infected red blood cells may be enriched
40-fold relative to other blood components using a magnetic field
intensity of 1.426 T (Zimmerman et al. (2006) Am. J. Trop. Med.
Hyg. 74:568-572). As such, malaria-infected cells may be identified
using the methods described here in and subsequently captured
relative to other blood components, for example, using net volume
magnetic susceptibility.
[0282] Optionally, a cell or cells may be captured and sequestered
using suction. For example, cells along the surface of a lumen may
be pulled away from the surface using a plunger system that sucks
the cells into a suction chamber (see, e.g. U.S. Patent Application
2005/0272972 A1). As such, the device may include a plunger that
when retracted causes a cell or cells to be sucked directly into a
reservoir or into a tube (e.g. local bypass) that optionally leads
to a reservoir.
[0283] Optionally, a form of optical trapping or optical tweezers
may be used to move or sort a cell or cells into a reservoir. For
example, red blood cells may be moved using a focused laser beam
from, for example, a He--Ne laser (Grover et al. (2000) Optics
Express 7:533-538). A focused laser exerts both a scattering force
and a gradient force on a cell in its path and these forces can be
manipulated to move an object. Optical tweezers may also be used to
differentiate between normal and Plasmodium-infected red blood
cells (Dharmadhikari et al. (2004) Optics Express
12:1179-1184).
[0284] Alternatively, dielectrophoresis may be used to move or sort
a cell or cells in a microdevice (see, e.g. Chiou et al. (2005)
Nature 436:370-372; Holmes & Morgan (2002) European Cells
Materials 4:120-122). Dielectrophoresis (DEP) refers to the force
on a cell in a non-uniform electrical field produced by an array of
microelectrodes. Depending upon how negative and positive DEP
forces are manipulated, a specific cell or cell type may be
concentrated from a heterogeneous mix. Alternatively, different
cell types may be sorted along the path of a device based on size
and dielectric properties of the cellular membrane.
Example 12
Surveillance of Biological Targets in the Vasculature
[0285] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used over a period of
time to monitor specific biological targets in the vasculature
using the detection methods described herein. As such, a cell or
cells in the vessel circulation may pass through an examination
zone either incorporated within the device or in close proximity to
the device. A cell or cells may be, for example, a bacterium, a
platelet, a red blood cell, a white blood cell, a circulating tumor
cell or a combination thereof. The cell or cells are analyzed in
the examination zone using one or more of the methods described
herein. The device captures information regarding the cell or cells
and either processes the information internally or sends the
information wirelessly to an external processor. The captured
information is compared with preset algorithms defining, for
example, the properties of a normal versus an abnormal or foreign
cell. The device may keep track of or count the number of normal,
abnormal and/or foreign cells, for example, over a period of time.
Optionally, the device may monitor changes in cell morphology or
chemistry over a period of time.
[0286] The untethered device may be used, for example, to monitor
the relative numbers of normal biological components of blood or
lymph vessels. Changes in the normal cell counts may be indicative
of disease. For example, a normal white blood cell count ranges
from 4,500 to 10,000 cells per microliter of blood. Leukopenia, a
dangerously low white blood cell count below 2,500 cells per
microliter, may be indicative of HIV or other viral infection, an
autoimmune disorder such as lupus, or a bone marrow disease, such
as leukemia or myelodysplastic syndromes (Mayo Clinic (2006) Low
white blood cell count (leukopenia)).
[0287] As another example, the normal level of platelets in the
blood ranges from 150,000 to 350,000 per microliter. As the
platelet count decreases below a normal level, the ability of the
body to prevent bleeding decreases. As such, tiny red dots may
appear in the skin, bruising may occur more easily, the gums may
bleed, and blood may appear in the stool or urine. When the
platelet count falls to 10,000 to 5,000, life threatening bleeding
in the digestive tract or brain may occur even when there is no
injury (Merck Manual (1997) p. 755; Berkow et al, eds).
[0288] The surveillance information acquired by the untethered
device may be used to monitor disease progression. For example, the
device may be used in a patient or patients with cancer to monitor
for the appearance of circulating tumor cells in the vasculature.
Circulating tumor cells may be indicative of metastasis and may
suggest a need for changes in the treatment regime. For example,
the detection of circulating tumor cells in melanoma patients who
are clinically "disease-free" indicates disease recurrence, tumor
cell spreading, and a high potential for distant metastasis, and
enables identification of high-risk melanoma patients (Hoon (2004)
Nat. Clin. Pract. Oncol. 1:74-75).
[0289] The appearance of circulating tumor cells may also be
indicative of long term prognosis for the patient. For example,
breast cancer patients with levels of circulating tumor cells equal
to or higher than 5 cells per 7.5 milliliters of blood have a
shorter median progression-free survival (2.7 months vs. 7.0
months) and shorter overall survival (10.1 months versus greater
than 18.0 months) as compared with breast cancer patients with less
than 5 cells per 7.5 milliliters of blood (Cristofanilli et al.
(2004) N. Engl. J. Med. 351:781-791).
[0290] The untethered device may also be used to monitor the
effectiveness of a treatment regime. For example, the device may be
used to monitor the titer of bacteria in the vasculature in
response to antibiotic treatment. Similarly, the device may be used
to monitor the white blood cell count of an HIV-AIDS patient in
response to anti-viral treatments.
[0291] Alternatively, the device may be used to monitor side
effects associated with a specific treatment regime. For example,
treatment of HIV-AIDS with anti-viral nucleoside reverse
transcriptase inhibitors (NRTIs) induces severe changes in
lymphocyte mitochondrial morphology and function (Tolomeo et al.
(2003) J. Clin. Pathol. 56:147-151). As such, the device may
monitor lymphocyte mitochondria using the methods described herein
to monitor the toxic effects of HIV treatment.
[0292] In another example, the device may monitor the effects of
cancer therapy on normal blood components. Both chemotherapy and
radiotherapy reduce white blood cell counts, making an individual
more prone to infection. Similarly, red blood cell and platelet
counts may be lowered in response to chemotherapy (Mayo Clinic
(2005) Low blood cell counts: Side effect of cancer treatment). As
such, the device may monitor the blood in real time and provide
feedback to the physician and/or patient as to the blood cell
counts, allowing for prompt treatment.
Example 13
Methods for at Least Partially Inactivating Biological Targets in
Vessels
[0293] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to at least
partially inactivate a biological target in response to detection
and recognition of the biological target as abnormal, for example.
Alternatively, a second component downstream of the untethered
device, for example, may be used to at least partially inactivate a
biological target in the vessels and/or in a local bypass and/or
reservoir. As such, once the abnormal cell has been detected and
recognized by the untethered device, the untethered device may
nearly simultaneously initiate an inactivation process while the
cell is still effectively in the examination zone. Alternatively,
once the abnormal cell has been detected and recognized by the
untethered device, a downstream component may be signaled to
initiate inactivation at a future time consistent with passage of
the abnormal cell in proximity to the downstream component based,
for example, on the measured flow rate within the vessel. In some
instances, focused energy sufficient to at least partially
inactivate an abnormal cell may be directed only at the cell of
interest. Alternatively, a segment of the vessel lumen containing
at least the abnormal cell may be targeted.
[0294] An untethered device configured to function in or proximal
to a blood vessel or lymph vessel may use ultraviolet radiation to
at least partially inactivate a biological target. For example,
many pathogens are inactivated or killed by UV germicidal
irradiation (Anderson et al. (2000) IEEE Transactions on Plasma
Science 28:83-88; Hancock et al. (2004) IEEE Transactions on Plasma
Science 32:2026-2031). UV light ranges from UVA (400-315 nm), also
called long wave or `blacklight`; UVB (315-280 nm), also called
medium wave; and UVC (<280 nm), also called short wave or
`germicidal`." Escherichia coli may be partially or completely
inactivated, for example, by exposure to a UV electromagnetic
energy source at wavelengths of 100-280 nm (Anderson et al. (2000)
IEEE Transactions on Plasma Science 28:83-88). Alternatively,
Escherichia coli as well as Salmonella enteritidis, for example,
may be inactivated using pulsed broad-spectrum electromagnetic
energy with high UV content from, for example, a Xenon lamp
(Anderson et al. (2000) IEEE Transactions on Plasma Science
28:83-88). In this instance, targeted bacteria are subjected to
100-1000 pulses of broad-spectrum light with each pulse lasting,
for example, 85 ns and having, for example, a power output of 10
MW. Viruses may be inactivated using UV irradiation (Tseng &
Li, (2007) J. Occup. Envirn. Hyg. 4:400-405). Fungi, such as
Aspergillus flavus and Aspergillus fumigatus, may also be
inactivated using UV germicidal irradiation at, for example, 12-98
mJ/cm.sup.2 (Green et al. (2004) Can. J. Microbiol.
50:221-224).
[0295] Optionally, the device may emit electromagnetic energy at a
wavelength or wavelengths within the visible spectrum to at least
partially inactivate a biological target. For example,
Staphylococcus aureus and Pseudomonas aeruginosa may be inactivated
using a wavelength of 405 nm at doses ranging, for example, from
1-20 J/cm.sup.2 (Guffey et al. (2006) Photomed. Laser Surg.
24:680-683). Pseudomonas aeruginosa as well as Escherichia coli may
be partially inactivated using, for example, a wavelength of 630 nm
at 1-20 J/cm.sup.2 (Nussbaum et al. (2002) J. Clin. Laser Med.
Surg. 20:325-333). Similarly, a number of oral bacteria, including
Acinobacillus actinomycetemcomitans, Fusobacterium nucleatum,
Porphromonas gingivalis, Pnevotella intermedia, and Streptococcus
sanguis, may be partially inactivated using a diode 665 laser at
100 mW at energy densities ranging from 10 J/cm.sup.2 to 22
J/cm.sup.2 (Chan et al. (2003) Lasers Surg. Med. 18:51-55).
Alternatively, a pathogen, for example Escherichia coli, may be at
least partially inactivated or killed using a 810 nm diode laser
with doses ranging from 130-260 J/cm.sup.2 (Jawhara et al. (2006)
Lasers Med. Sci. 21:153-159).
[0296] Similarly, visible light may be used to at least partially
inactivate a virus. For example, a virus may be at least partially
inactivated using a very low power laser emitting 80 femtosecond
pulses at a wavelength of 425 nm and frequency of 80 MHz (Tsen et
al. (2007) Virol. J. Vol. 4, published on line ahead of
publication; Tsen et al. (2007) J. Physics: Condensed Matter Vol.
19, published on line ahead of publication). Under these
conditions, the viruses are inactivated through impulsive
stimulated Raman scattering, which induces vibrations within the
microorganism sufficient to disrupt normal function.
[0297] Alternatively, energy may be used that disrupts the function
of heme iron porphyrins associated with iron uptake and
utilization, inactivating iron dependent bacteria such as
Escherichia coli and Salmonella (U.S. Pat. No. 6,030,653).
Pathogens may be inactivated by irradiating the surface with
visible and near infrared light having wavelengths of approximately
465 nm, 600 nm, and 950 nm, respectively.
[0298] Optionally, visible light energy emitted from an untethered
device may be combined, for example, with systemic administration
of a photosensitive agent (Maisch (2007) Lasers Med. Sci. 22:83-91;
Jori et al. (2006) Lasers Surg. Med. 38:468-481). For example,
Staphylococcus aureus and Pseudomonas aeruginosa may be inactivated
using either a 0.95-mW helium-neon laser (632 nm) or a 5-mW
indium-gallium-aluminum-phosphate laser (670 nm) with exposure
doses ranging from 0.1 to 10.0 J/cm.sup.2 in combination with the
bacterial sensitizing agent, toluidine blue 0 (DeSimone et al.
(1999) Phys. Ther. 79:839-846). Similarly, inactivation of bacteria
by a diode 665 laser may be enhanced, for example, by prestaining
the bacteria with methylene blue (Chan et al. (2003) Lasers Surg.
Med. 18:51-55). Alternatively, a fluorescing dye, for example,
indocyanine green (ICG) may be used in combination with a diode
laser with an emission wavelength, for example, of 808 nm, to
inactive a pathogen or pathogens (Bartels et al. (1995) SPIE
2395:602-606). Optionally, a polycationic photosensitizer
conjugated between, for example, poly-L-lysine and
chlorin.sub..di-elect cons.6, may be administered and subsequently
irradiated with a diode laser at 665 nm at doses ranging from, for
example, 40-160 J/cm.sup.2 to kill bacteria (Hamblin et al. (2002)
Photochem. Photobiol. 75:51-57). Optionally, pathogens in the
vasculature, such as, for example, Staphylococcus aureus and
Staphylococcus epidermidis, may be at least partially inactivated
using energy from, for example, an argon-ion pumped dye laser
(wavelength of 630 nm with total light dose of 180 J/cm2) in
combination with 5-aminolevulinic acid or Photofrin (Karrer et al.
(1999) Lasers Med. Sci. 14:54-61; Nitzan et al. (1999) Lasers Med.
Sci. 14:269-277).
[0299] An untethered device configured to function in or proximal
to a blood vessel or lymph vessel may use laser-induced thermal
energy to at least partially inactivate a biological target. For
example, lasers are commonly used to treat cancers, such as basal
cell skin cancer and the very early stages of some cancers, such as
cervical, penile, vaginal, vulvar, and non-small cell lung cancer
(National Cancer Institute (2004) Laser in Cancer Treatment
FactSheet). As such, circulating tumor cells, for example, may be
at least partially inactivated by laser-induced thermal energy.
[0300] A variety of lasers with varied excitation wavelengths and
penetration potential may be used to generate electromagnetic
energy sufficient to at least partially inactivate, for example, a
circulating tumor cell or cells (Burr et al. (2004) Interventional
Technologies for Tissue Volume Reduction, October 2004). For
example, circulating tumor cell or cells may be ablated using a
carbon dioxide (CO.sub.2) laser (10,600 nm, 0.1-0.2 mm penetration
depth). Melanoma and cervical cancer cells may be ablated with a
CO.sub.2 laser using a power output ranging, for example, from 40 W
to 80 W (Gibson, et al (2004) Br. J. Surg. 91:893-895; Bekassy et
al. (1997) Lasers. Surg. Med. 20:461-466). Alternatively, cancer
cells may be ablated by a Yttrium-Aluminium-Garnet (YAG) laser with
Neodymium (Nd, 1064 nm or 1320 nm, 3-4 mm penetration depth),
Erbium (Eb, 2940 nm, with <0.1 mm penetration depth), or Holmium
(Ho, 2070 nm). For example, colorectal adenoma cells and lung
cancer cells may be ablated using an Nd:YAG (1064 nm) with maximal
power output of 100 W (Norberto et al. (2005) Surg. Endosc.
19:1045-1048; Hansen et al. (2006) Minim. Invasive Ther. Allied
Technol. 15:4-8). Alternatively, cancer cells may be ablated by
diode lasers (600-1600 nm), argon laser (488 nm and 514 nm, 1-1.5
mm penetration depth), or an excimer laser (180-350 nm, cell/tissue
disintegration). As such, the untethered device may contain one or
more of the lasers described herein as an optical energy source for
use in at least partially inactivating a biological target such as,
for example, a circulating tumor cells.
[0301] Alternatively, a circulating tumor cells or cells, for
example, may be ablated by electromagnetic energy emitted from a
laser in combination with a photosensitizing agent in a process
termed photodynamic therapy (PDT; National Cancer Institute (2004)
Laser in Cancer Treatment FactSheet). For example, a patient may be
injected with a photosensitizing agent such as, for example,
Photofrin or 5-aminolevulinic acid, which after a few days
concentrates in the cancerous cells. Electromagnetic energy from,
for example, a laser is then used to activate the photosensitizing
agent which has a subsequent toxic effect on the cancer cell or
cells and results in cell death.
[0302] Laser-induced thermal energy generated by a CO.sub.2 or
Nd:YAG laser may also be used to at least partially inactivate a
pathogen in the vasculature (see, e.g. Bartels et al. (1995) SPIE
2395:602-606). Escherichia coli 0157:H7, for example, is extremely
sensitive to heat with a maximum tolerance of approximately 35
degrees centigrade (U.S. Pat. No. 6,030,653). Staphylococcus aureus
may be partially inactivated or killed using high-power Nd:YAG
laser radiation between 50 and 300 W with laser pulse frequencies
of 5 to 30 Hz and pulse energies from 2 to 30 J, resulting in a
range of energy densities from 800 to 270 J/cm.sup.2 (Yeo et al.
(1998) Pure Appl. Opt. 7:643-655). Similarly, Staphylococcus
epidermidis, may be killed using pulsed radiation from a Nd:YAG
laser with an exposure of 1000-2000 J/cm.sup.2 (Gronqvist et al.
(2000) Lasers Surg. Med. 27:336-340).
[0303] The untethered device may use electromagnetic energy in the
form of x-rays to at least partially inactivate biological targets
in the vasculature. As such, the device may contain a miniature
X-ray emitter, such as that described in U.S. Patent Application
2004/0218724 A1. Alternatively, the device may contain
radioisotopes such as cobalt 60, cesium 137, or europium 152, for
example, that emit strong gamma rays and may be used to ablate
cancerous cells. Optionally, the device may contain other
intrinsically radioactive isotope such as those that might be used
for brachytherapy, including, for example, iodine 125, iodine 131,
strontium 89, phosphorous, palladium, or phosphate (National Cancer
Institute (2004) Radiation Therapy for Cancer FactSheet).
[0304] X-ray therapy or radiotherapy is routinely used to treat
almost every type of solid tumor, including cancers of the brain,
breast, cervix, larynx, lung, pancreas, prostate, skin, spine,
stomach, uterus, or soft tissue sarcomas (National Cancer Institute
(2004) Radiation Therapy for Cancer FactSheet). For example, breast
cancer cells may be ablated using a miniature electron beam-driven
x-ray source at doses of 5 to 20 Gy (Ross et al. (2005) Breast
Cancer Res. 7:110-112). As such, radiotherapy may be used to at
least partially inactivate circulating tumor cells derived from,
for example, these solid tumors.
[0305] Pathogens may also be at least partially inactivated by
x-ray electromagnetic energy. For example, pathogens such as
Escherichia coli 0157:H7, Salmonella, and Campylobacter jejuni may
be at least partially inactivated or killed using cobalt-60 gamma
radiation at doses of 0.5 to 3 kGy (Clavero et al. (1994) Applied
Environ. Microbiol. 60:2069-2075).
[0306] Alternatively, particle beam energy may be used to at least
partially inactivate a biological target. For example, Salmonella,
Yersinia, and Campylobacter may be at least partially inactivated
using accelerated electrons with doses of irradiation ranging from
1-3 kGy (Sarjeant et al. (2005) Poult. Sci. 84:955-958). Similarly,
Bacillus endospores may be at least partially inactivated using
electron beam irradiation with doses ranging from 5 to 40 kGy
(Helfinstine et al. (2005) Applied Environ. Microbiol.
71:7029-7032).
[0307] Alternatively, a cancer cell or cells may be ablated by
using particle beam energy using a type of linear accelerator.
Medical LINAC (linear accelerator-based external beam
radiotherapy), for example, accelerates electrons to kinetic
energies from 4 to 25 MeV using microwave radiofrequency waves at
10.sup.3 to 10.sup.4 MHz (Podgorsak Chapter 5). A LINAC may provide
X-rays in the low megavoltage range (4 to 6 MV). Alternatively, a
LINAC may provide both X-rays and electrons at various megavoltage
energies, for example, two photon energies (6 and 18 MV) and
several electron energies (6, 9, 12, 16, and 22 MeV; Podgorsak
Chapter 5).
[0308] The untethered device may use electromagnetic energy in the
form microwave or radiofrequency waves to at least partially
inactivate biological targets in the vessels. The microwave range
includes ultra-high frequency (UHF) (0.3-3 GHz), super high
frequency (SHF) (3-30 GHz), and extremely high frequency (EHF)
(30-300 GHz) signals. Microwave radiation at a frequency of 29.8
GHz (Ka-band), for example, may be used to at selectively kill
bacteria with minimal damage to healthy human cells (Ardnt et al.
Microwave radiation--Therapeutic application for cure of
subcutaneous bacterial infections. Space Life Sciences).
[0309] The untethered device may alternatively use the heating
properties of focused ultrasound to at least partially inactivate
biological targets in the vasculature. Ultrasound causes tissue
damage through conversion of mechanical energy into heat and
through cavitation. Above a threshold of 56 degrees centigrade, for
example, rapid thermal toxicity is achieved and cells are
irreversibly inactivated or killed. High-intensity focused
ultrasound (HIFU) uses short exposures of focused ultrasound that
rapidly increases cellular temperature above 80 degrees centigrade
and is used for ablation, for example, of hepatocellular carcinoma,
prostate carcinoma, bladder and kidney cancers (see, e.g., Kennedy
et al. (2003) Br. J. Radiology 76:590-599). As such, it is
anticipated that short exposures to high-intensity focused
ultrasound may be used to at least partially ablate targeted cells
within the vessels.
[0310] Optionally, an untethered device may emit a laser-generated
stress wave sufficient to disrupt a biological target. For example,
stress waves sufficient to disrupt cell membranes may be generated
with an ArF (193 nm) or a KrF (248 nm) eximer laser. Peripheral
blood mononuclear cells and red blood cells may be damaged using,
for example, 5 pulses of pressure ranging from 700 to 1000 bar (Lee
et al. (1999) IEEE Journal of Selected Topics in Quantum
Electronics 5:997-1003). As such, the device may use a laser to
generate a stress wave sufficient to at least partially ablate a
targeted cell.
[0311] An untethered device may emit electrical energy in a focused
area in the vasculature sufficient to ablate a biological target.
For example, cancer cells in suspension may be at least partially
ablated using electrical pulses sufficient to induce irreversible
electroporation of the cells (Miller et al. (2005) Technol. Cancer
Res. Treat. 4:699-705). As such, a cell or cells may be exposed,
for example, to 10-30, 0.3 millisecond pulses at 500 to 2500 V/cm
to induce at least partial inactivation.
Examples 14
Devices for Detection and Ablation of Biological Targets in
Vessels
[0312] An untethered device configured to function in or proximal
to a blood vessel or a lymph vessel may be used to detect, register
and at least partially inactivate a biological target. FIG. 11
shows an illustrative diagram of a system including a device 400.
The device 400 is placed in or proximal to a vessel 410 of a
patient 420. The device 400 may work autonomously, containing all
of the components necessary to detect, register and/or inactive a
biological target. Alternatively, the device 400 may be linked
wirelessly to a remote (optionally portable), processor and/or
power supply 430 and/or external computer processor 450 and/or
power supply.
[0313] In one configuration, the processor and/or power supply 430
is worn externally by the patient 420 on, for example, a belt 440.
Optionally, the processor and/or power supply 430 may be held by
the patient 420 in, for example, a pocket, a backpack or a purse.
Alternatively, the processor and/or power supply 430 may be
surgically implanted in the patient 420 (see, e.g., U.S. Pat. No.
6,409,719). Optionally, the processor and/or power supply 430 may
be linked to the device 400 via a wire or wires.
[0314] FIG. 12, FIG. 13, FIG. 14, and FIG. 15. show illustrative
configurations of systems including one or more untethered devices
configured to function in the lumen of a blood vessel or lymph
vessel to detect, register and optionally at least partially
inactivate a biological target.
[0315] FIG. 12A shows an illustrative configuration of an
untethered device 460 for the detection and at least partial
inactivation of a biological target in the lumen of a vessel 410.
In this configuration, the untethered device 460 may be a hollow
cylinder that when placed in a lumen of a vessel 410 allows for the
flow of fluid and cells 500 and 510 through the central core 470 of
the cylinder. The cylinder may be reversibly positioned in the
vessel using inflatable pouches 480. Alternatively, the cylinder
may be positioned in the vessel using one or more retractable hooks
or barbs, for example, that latch on to the lumen of the vessel
410. The hollow cylinder contains a detection and/or ablation unit
490, which optionally contains one or more of a power source,
control circuitry, one or more energy sources, one or more sensors
and a processor. Control of the device may be completely
self-contained or at least partially controlled wirelessly by an
external user.
[0316] As normal cells 500 and abnormal cells 510 pass through the
central core 470 of the untethered device 460, the detection and/or
ablation unit 490 emits a first energy beam, such as, for example,
an electromagnetic or acoustic energy which interacts with the cell
in a characteristic manner. In this context, abnormal cells 510 may
be, for example, pathogens, pathological cells or cancerous cells
as described herein. The detection and ablation unit 490 processes
the information regarding the interaction of the normal cell 500
and abnormal cell 510 with a first energy beam and analyzes whether
the cell is normal or abnormal and almost simultaneously emits a
second energy beam sufficient to at least partially inactivate the
abnormal cell 510.
[0317] As illustrated in FIG. 12B, the system may include a second
untethered device 465 positioned downstream from the first device
460. As such, the first device 460 emits an energy beam from the
detection and/or ablation unit 490 to analyze a passing biological
target, and determines whether the biological target is normal or
abnormal. The first device 460 may send a signal to the second
device 465 to initiate emission of an energy beam from a second
detection and/or ablation unit 495 sufficient to at least partially
inactivate a biological target at a time in the future consistent
with the passage of an abnormal target through the second device
465.
[0318] FIG. 13 shows an illustrative configuration of a system
including an untethered device 460 with the capability of
controlling fluid and cell flow in the lumen of a vessel 410 for
the detection and optionally at least partial inactivation of a
biological target. In this configuration, the device 460 is a
hollow tube with an exit aperture 520 that may be opened or closed
to control the flow of fluid and cells in the vessel. As such, the
exit aperture 520 of the device 460 may be in an open position 525
allowing for free flow of fluid and cells, as shown in FIG. 13A.
Cells pass through the device 460 unabated and are monitored and
optionally destroyed by the detection and/or ablation unit 490.
Alternatively, as shown in FIG. 13B, the exit aperture 520 may
periodically shift to the closed position 530 providing more time,
for example, for the analysis of cells in the device 460 and/or
opportunity for targeted inactivation. The device may automatically
open and close the exit aperture 520 at a fixed rate.
Alternatively, the exit aperture 520 may open and close depending
upon signals sent from the detection and/or ablation unit 490 in
response to detecting an abnormal cell, for example. Optionally,
opening and closing of the exit aperture 520 may be dictated
externally by the patient, physician, or other medical
practitioner.
[0319] FIG. 14 shows an illustrative configuration of an untethered
device 540 with the capability of temporarily trapping and at least
partially inactivating abnormally large biological targets in the
lumen of a vessel 410. In this configuration, size exclusion may be
used to trap an abnormally large cell 560 such as, for example, a
circulating tumor cell. As such, cells pass through the hollow tube
of the device 540. Within the device 540 is a choke point 545 which
narrows the diameter of the hollow tube. As such, smaller cells 510
and 550, such as, for example, red and white blood cells, may pass
through the device whereas an abnormally large cell 560 will slowed
down or become trapped, at which point the cell is bombarded with
an energy beam sufficient to at least partially inactivate the
target.
[0320] FIG. 15A and FIG. 15B show alternative illustrative
configurations of systems including an untethered device for the
detection and at least partial inactivation of a biological target
in the lumen of a vessel 410.
[0321] FIG. 15A shows an illustrative configuration of an
untethered device 570 in the lumen of a vessel 410 in which the
main body of the device is a hollow tube configured using a
diamond-patterned mesh structure similar to, for example, a stent
(see, e.g. Lally et al. (2005) J. Biomechanics 38:1574-1581; U.S.
Patent Application 2006/0074479 A1). In this configuration, one or
more detection and/or ablation units 575 are distributed around the
hollow tube. Each detection and/or ablation unit 575 may have the
capability of emitting energy, sensing a response, inducing
ablation, or a combination thereof. Optionally, the system may
include an exterior (to the vessel lumen) unit 580 which may
provide processing and/or power capabilities. The exterior unit 580
may be attached to the outer surface of the vessel with one or more
hooks or barbs 585, for example.
[0322] FIG. 15B shows an illustrative configuration of system
including an untethered device 590 in the lumen of a vessel 410 in
which the main body of the device is a hollow tube configured from
one or more parallel rings 595. Alternatively the hollow tube may
be formed from a spiral, for example, of a single or multiple
pieces of material. As shown, each ring 595 of the device 590 may
include an energy emitting unit 600 and a sensing unit 610.
Alternatively, units 600 and 610 may have both energy emitting and
sensing capabilities. In this configuration, the device may have an
ablating unit 620 downstream from the energy emitting units 600 and
the sensing units 610. As such, a cell may pass through the hollow
tube where the energy emitting unit 600 and the sensing unit 610
register the cell as normal or abnormal. If the cell is abnormal a
signal is sent to the ablating unit 620 to initiate cell
inactivation at a time in the future consistent with the time
needed for a cell to move from one end of the tube to the other.
The device 590 may be used in conjunction with an exterior unit 630
which optionally surrounds the exterior of the vessel 410 like a
sleeve and provides, for example, additional processing and/or
power capabilities.
[0323] FIG. 16 and FIG. 17 show illustrative configurations of
systems including one or more untethered devices configured as
units to function alone or together in the lumen of a blood vessel
or lymph vessel to detect, register and optionally at least
partially inactivate a biological target.
[0324] FIG. 16A shows an illustrative configuration of a device 640
which is attached to the interior surface of a vessel 410 by virtue
of a hook or barb 650. The untethered device 640 may be configured
to act autonomous or be controlled by an external user. The
untethered device 640 may monitor the flow of fluid and normal
cells 500 and abnormal cells 510. The device 640 detects abnormal
cells 510 based on the characteristic response of normal cells 500
and abnormal cells 510 to a beam of energy 660. On detection of one
or more abnormal cells, the device 640 emits a second beam of
energy 660 sufficient to at least partially ablate the detected
abnormal cell 510 before the cell exits the inactivation area.
[0325] In an alternative illustrative configuration of the system,
an energy emitting unit 670 may be paired with a sensing unit 680,
as shown in FIG. 16B. In this configuration, the energy emitting
unit 670 and sensing unit 680 are each attached to the interior
surface of a vessel 410 by virtue of one or more hook or barb 650.
The energy emitting unit 670 emits a beam of energy 660 which
irradiates, for example, an abnormal cell 510. The sensing unit 680
measures the response of the abnormal cell 510 to the beam of
energy 660 and sends a signal back to the energy emitting unit 670
to initiate cell inactivation, whereupon the energy emitting unit
670 emits a second beam of energy 660 sufficient to at least
partially inactivate a biological target.
[0326] Alternatively, one or more illustrative system may include
an energy emitting and sensing unit 690 paired with a downstream
ablating unit 700 as shown in FIG. 16C. The energy emitting and
sensing unit 690 and the ablating unit 700 are optionally attached
to the interior surface of a vessel 410 by virtue of one or more
hook or barb 650. An abnormal cell 510 is irradiated by a beam of
energy 660 emitted from the energy emitting and sensing unit 690
and registered as abnormal. A signal is sent to the ablating unit
700 to initiate cell inactivation at a time in the future
consistent with the time needed for a cell to move from the energy
emitting and sensing unit 690 to the ablating unit 700. The
ablating unit 700 emits a second energy beam 710 sufficient to at
least partially inactivate a biological target.
[0327] FIG. 17A shows an illustrative configuration of a system
including three separate units; an energy emitting unit 720, a
sensing unit 680, and a downstream ablating unit 700, all of which
are attached to the interior surface of a vessel 410 by virtue of
one or more hook or barb 650. In this configuration, an abnormal
cell 510, for example, is irradiated by an energy beam 660 from an
energy emitting unit 720. The response of the abnormal cell 510 to
the energy beam 660 is detected by the sensing unit 680 which may
relay information to the ablating unit 700 as to whether cell
inactivation should be initiated. The ablating unit 700 emits an
energy beam 710 at a time in the future consistent with the time
needed for a cell to move from the sensing unit 680 to the ablating
unit 700. The energy emitting unit 720, the sensing unit 680, and
the downstream ablating unit 700 may be used in conjunction with an
exterior unit 630 which optionally surrounds the exterior of the
vessel 410 like a sleeve and provides, for example, processing
and/or power capabilities.
[0328] FIG. 17B shows an alternative illustrative configuration of
a system in which an energy emitting and sensing unit 690 is paired
with a downstream ablating unit 730. In this configuration, the
ablating unit 730 is a hollow tube positioned within a vessel 410
using inflatable pouches 480, for example. The ablating unit 730
has an aperture 740 which may be closed to trap biological targets
identified for inactivation, and/or for additional sensing
optionally prior to inactivation, for example. An abnormal cell
510, for example, is identified by the energy emitting and sensing
unit 690 as abnormal and a signal is sent to the ablating unit 730.
The downstream ablating unit 730 initiates closure of the aperture
740 at a time in the future consistent with the time needed for the
abnormal cell 510 to reach the ablating unit 730. Once the abnormal
cell 510 is trapped, the ablating unit 730 emits an energy beam 710
sufficient to at least partially inactive a biological target.
[0329] FIG. 18, FIG. 19, and FIG. 20 show illustrative
configurations of systems configured to function proximal to a
blood vessel or lymph vessel to detect, register and optionally at
least partially inactivate a biological target. In these examples,
the system may incorporate device including a sleeve which at least
partially encircles a vessel.
[0330] FIG. 18A shows an illustrative configuration of a device 750
which at least partially encircles the exterior of a vessel 410
(see, e.g., U.S. Pat. No. 6,106,477). FIG. 18B shows an
illustrative configuration of optional components of the device
750. A hinge 760 may be used to open the device 750 to enable it to
at least partially encircle a vessel 410. The device may have an
energy emitting unit 780 coupled with a sensing unit 770 which
scans cells through the wall of a vessel 410. Methods have been
described for imaging cells in vivo from the exterior of a vessel
(see, e.g., Galanzha et al. (2007) World. J. Gastroenterol.
13:192-218; U.S. Pat. No. 7,264,794 B2). The device 750 may also
contain a processing and/or power supply unit 790.
[0331] FIG. 19 shows various illustrative configurations of one or
more systems including a device configured to function proximal to
a blood vessel or lymph vessel. In these examples, a sleeve 810
constructed from a mesh-like, breathable, biocompatible material is
used to encircle the exterior of a vessel 410 (see, e.g., U.S.
Patent Application 2006/0149348 A1). Various components are
optionally attached to this sleeve. In FIG. 19A, a device 800
consists of a sleeve 810 that is attached along a seam 820 to
itself and/or the vessel 410 using a reversible wet/dry adhesive
such as that derived from gecko and mussel (e.g. geckel), for
example (see, e.g., Lee et al. (2007) Nature 448:338-342).
Alternatively, a magnetic strip or Velcro-like material may be used
to close the sleeve. Attached to the sleeve 810 is an energy
emitting unit 830 and a sensing unit 840. Alternatively, a single
unit capable of energy emitting and sensing may be attached to the
sleeve 810.
[0332] In FIG. 19B, a device 801 may have a sleeve 810 attached to
itself and/or to the vessel 410 using, for example, sutures 850
(optionally staples and/or another kind of medical closure known to
those of skill in the art). In this configuration, a constrictor
(e.g. compression) band 860 is positioned downstream from the
sleeve 810. The constrictor band 860 may be used to restrict the
flow of fluid and cells through the vessel 410 optionally for brief
periods of time. The constrictor band 860 may be an inflatable tube
that upon inflation closes down the diameter of the vessel 410.
Alternatively, the constrictor band 860 may constitute a band of
biocompatible material that may be controllably tightened and
loosened, optionally using one or more ratchets, for example.
[0333] The constrictor band 860 may be activated by inputs from a
wire 870 connected, for example, to the sensing unit 840.
Alternatively, the constrictor band 860 may be activated by a
wireless signal form the sensing unit 840, and/or from one or more
external sources. The constrictor band 860 may be used to slow down
cells to facilitate analysis by the energy emitting unit 830 and
the sensing unit 840. Alternatively, the constrictor band 860 may
be activated after an abnormal cell has been identified to trap the
cell prior to inactivation from an energy beam emitted, for
example, from the energy emitting unit 830.
[0334] In FIG. 19C, a device 802 is configured with a first sleeve
810 and a second sleeve 890 which is positioned downstream of the
first. Attached to the second sleeve 890 is an ablating unit 900
that is optionally attached by a wire 870 to the sensing unit 840.
In this configuration, the sleeve 810 is attached to itself and/or
the vessel 410 using a closure device 880. A closure device may
include, for example, a snap, a hook, or Velcro-like material. A
cell or cells in the vessel 410 are analyzed, for example, by the
energy emitting unit 830 and the sensing unit 840. When an abnormal
cell is registered by the sensing unit 840, a signal is sent to the
downstream ablating unit 900 by a wire 870. Alternatively, a
wireless signal may be sent to activate the ablating unit 900. The
ablating unit 900 emits an energy beam sufficient to at least
partially inactivate a biological target at a time in the future
consistent with the passage of the cell into the target zone of the
ablating unit 900.
[0335] FIG. 20 shows various illustrative configurations of systems
including a device configured to function proximal to a blood
vessel or lymph vessel and optionally to sequester a biological
target into a reservoir, for example, for future analysis. In FIG.
20A, a device 803 is configured with a sleeve 810 constructed from
a breathable, biocompatible material. The sleeve 810 is used to
encircle the exterior of a vessel 410. An expandable reservoir 930,
for example, a sack constructed from biocompatible material, is
attached to the sleeve 810 by a tube-like structure 920. The tube
920 opens into the vessel 410 through an adjustable valve 910. In
this configuration, a constrictor band 860 may be positioned
downstream of the sleeve 810 to restrict the flow of fluid and
cells for brief periods of time. A cell in the vessel 410 is
analyzed by the energy emitting unit 830 and the sensing unit 840.
If a cell or cells is identified that should be sequestered, a
signal is sent to the constrictor band 860 via a wire 870, for
example. The constrictor band 860 closes down the diameter of the
vessel 410, trapping cells in the vicinity of the valve 910. The
valve 910 is triggered to open, allowing a cell or cells to flow
into the tube 920 and into the reservoir 930. The movement of cells
into the reservoir 930 may be passive, optionally driven by the
flow pressure of the vessel 410.
[0336] FIG. 20B shows an alternative configuration in which device
804 includes a reservoir 940 located in a remote position relative
to the vessel 410. For example, the remote reservoir 940, made from
silicon or other biocompatible material, may be positioned on or
near the surface of the skin, for example, allowing for easy access
by a physician, veterinarian, or other medical practitioner using a
syringe, for example (see, e.g. Diegelmann et al. (1987) J.
Leukocyte Biol. 42:667-672). The remote reservoir 940 is attached
to the sleeve 810 through a tube 920 that traverses the length
between the position of the sleeve 810 on a vessel 410 and the
position of the reservoir 940. As such, a cell or cells is analyzed
by an energy emitting unit 830 and a sensing unit 840. If a cell or
cells is identified that should be sequestered, a wireless signal
is sent to the constrictor band 860. The constrictor band 860
closes down the diameter of the vessel 410, trapping cells in the
vicinity of a valve 910. The valve 910 is triggered to open,
allowing a cell or cells to flow into the tube 920 and down its
length to the reservoir 940. The movement of cells into the remote
reservoir 940 may be passive, optionally driven by the flow
pressure of the vessel 410. Alternatively, a type of peristaltic
motion, for example, may be used along the length of the tube 920
to move cells into the remote reservoir 940.
[0337] FIG. 21, FIG. 22, FIG. 23, and FIG. 24 show illustrative
configurations of systems including a device configured to function
proximal to a blood vessel or lymph vessel to detect, register and
optionally at least partially inactivate a biological target. In
these examples, the device may incorporate a shunt (e.g. local
bypass), allowing for analysis of all or part of the cells flowing
through a vessel 410.
[0338] FIG. 21 shows an illustrative configuration of a device 805
in which a sleeve 810 is combined with a shunt 960. FIG. 21A shows
an exterior view of the device 805 encircling a vessel 410. The
sleeve 810 is reversibly attached to itself and/or the vessel 410
along the seam 820 using the methods described herein. The shunt
960 may have sharp, optionally scalpel-like and/or large-bore
needle-like ends 970 that pierce the vessel 410 as the sleeve 810
is closed around the vessel 410. In this manner, openings are
created in the wall of the vessel 410 allowing for passage of some
or all of the vessel contents into the shunt 960. Attached to the
shunt may be an energy emitting unit 980 and a sensing unit 990.
The shunt 960 itself may be made of clear, optically compatible
material, allowing for unobstructed imaging of a cell or cells from
the outside surface of the shunt 960. Alternatively, a portion of
the energy emitting unit 980 and/or the sensing unit 990 may be
incorporated into the inner surface of the shunt.
[0339] FIG. 21B shows an illustrative configuration of the interior
view of a device 805 in which a sleeve 810 is combined with a shunt
960. As such, a subset of cells in vessel 410 may enter the shunt
960 through an opening 1000 generated by piercing the surface of
the vessel 410 optionally as described in FIG. 21A and/or known in
the art. An abnormal cell 510, for example, may be targeted with an
energy beam 660 emitted from the energy emitting unit 980. The
cellular response is detected by the sensing unit 990. The sensing
unit 990 sends a signal to the energy emitting unit 980 to activate
a second energy beam 660 configured to at least partially
inactivate the abnormal cell 510. Untargeted cells pass through the
shunt 960 and back into the flow of vessel 410.
[0340] FIG. 22A and FIG. 22B show illustrative configurations of
systems showing the interior view of devices 950 and 955 configured
with a shunt 960 (e.g. local bypass) to analyze all or a subset of
cells in a vessel 410. In FIG. 22A, a device 950 includes a shunt
960 attached to a vessel 410 and contains an energy emitting unit
980 and a sensing unit 990. Access to and from the vessel 410 to
the shunt 960 is controlled by valves 1005 at either end of the
shunt 960. As such, when the valve 1005 is opened, a cell or cells
may pass into the shunt 960. The cell, for example an abnormal cell
510, may pass through an examination zone 965 within the shunt
960.
[0341] Within the examination zone, the abnormal cell 510 is
irradiated, for example, with electromagnetic energy from a laser
unit 1010. The laser unit 1010 may be comprised of one or more
quantum dot lasers or nanolasers, for example (see, e.g., PHYSORG
(2007) news95617101; Nozaki et al. (2007) Optics Express
15:7506-7514). Alternatively, acoustic energy may be emitted from
laser unit 1010. A specific sensing device 1020, such as, for
example, a CCD or CMOS sensor, captures information regarding the
interaction of the abnormal cell 510 with the electromagnetic
energy emitted by a laser unit 1010. Methods have been described,
for example, for the scaling of CMOS sensor technology down to the
nanometer scale (Chang et al. (2003) Proceedings of the IEEE
91:1860-1873). The shunt 960 may also contain a processor and/or
power unit 1030. Alternatively, the shunt 960 may be connected
wirelessly or by wire to a remote or external processor and/or
power supply.
[0342] Once the abnormal cell 510 has been identified as abnormal,
a signal is optionally sent to initiate cell inactivation. As such,
the laser unit 1010 may emit a second energy beam sufficient to at
least partially inactivate the abnormal cell 510. Optionally a
second energy emitting unit 1040 may be used to emit energy
sufficient to at least partially inactivate the abnormal cell
510.
[0343] In FIG. 22B, a device 955 includes a shunt 960 configured to
allow for sequestering of specific biological targets into a
reservoir. The shunt 960 is attached to a vessel 410 and contains
an energy emitting unit 980 and a sensing unit 990. Access to and
from the vessel 410 to the shunt 960 is controlled by valves 1005
at either end of the shunt 960. As such, when the valve 1005 is
opened, a cell or cells may pass into the shunt 960. Additional
valves 1005 may be placed at either end of the examination zone
965. The cell, for example an abnormal cell 510, may pass through
an examination zone 965 within the shunt 960. The abnormal cell 510
is analyzed by the laser unit 1010 and the sensing unit 1020 as
described in FIG. 22A.
[0344] The abnormal cell 510 may be targeted for sequestration. As
such an additional valve 1005 may open into tube 1070 connected to
a reservoir. The reservoir may be proximal or remote relative to
the analysis device as described herein. The cell or cells may
passively move into the tube 1070 based on flow pressure.
Alternatively, a cell or cell may be specifically moved into the
tube 1070 by a force 1060 emitted from a force unit 1050. The force
may be part of an optical trap, a DEP trap or magnetic in nature,
as described herein. Once the appropriate cell or cells have been
sequestered, the valve 1005 associated with the tube 1070 may be
closed and other valves 1005 downstream opened to allow untargeted
cells in the shunt 960 to rejoin the flow in vessel 410.
[0345] FIG. 23 and FIG. 24 show illustrative configurations of
systems including an artificial vessel shunt which is secured
between the ends of a vessel 410. FIG. 23A shows an exterior view
of this configuration in which the artificial vessel shunt 1080 is
attached to the free ends of a vessel 410 by a connector 1090, such
as, for example, a cinch. Alternatively, the artificial vessel
shunt 1080 may be attached to the vessel 410, for example, by a
tight fitting with the lumen of the vessel 410 and barbs on the end
of the artificial vessel shunt 1080 (see, e.g. U.S. Pat. No.
7,175,637). The artificial vessel shunt 1080 has an energy emitting
unit 980 and a sensing unit 990 associated with it.
[0346] FIG. 23B shows an illustrative configuration of the interior
of an artificial vessel shunt 1080 attached to both ends of vessel
410 using connectors 1090. The artificial vessel shunt 1080 may
have one or more valves 1005 to control the flow of fluid and
cells. Within the examination zone, an abnormal cell 510 as
referenced in FIG. 22 is irradiated, for example, with
electromagnetic energy from a laser unit 1010. A specific sensing
device 1020 captures information regarding the interaction of the
abnormal cell 510 with the electromagnetic energy emitted by a
laser unit 1010. Once the abnormal cell 510 has been identified as
abnormal, a signal is sent to initiate cell inactivation. As such,
the laser unit 1010 may emit a second energy beam sufficient to at
least partially inactivate the abnormal cell 510. Optionally a
second energy emitting unit 1040 may be used to emit energy
sufficient to at least partially inactivate the abnormal cell 510.
Optionally, the abnormal cell is targeted for sequestration and is
moved through a valve 1005 into a tube 1070 for removal to a
reservoir.
[0347] FIG. 24A and FIG. 24B show alternative configurations of
systems including an artificial vessel in which all or a subset of
the cells in the vessel flow are analyzed. For example, in FIG.
24A, a device 1100 is inserted between the two ends of a vessel 410
using connectors 1090. Associated with the device is a shunt 960. A
cell or cells passing through the shunt may be analyzed by an
energy emitting unit 980 and a sensing unit 990. If appropriate, a
cell may be at least partially inactivated within the shunt 960.
FIG. 24B shows an illustrative configuration of a device 1110 which
is similar to that of device 1100 with the addition of a tube 1070
which allows for sequestration of targeted cells to a reservoir
940.
[0348] The foregoing detailed description has set forth various
embodiments of the devices and/or processes via the use of block
diagrams, flowcharts, and/or examples. Insofar as such block
diagrams, flowcharts, and/or examples contain one or more functions
and/or operations, it will be understood by those within the art
that each function and/or operation within such block diagrams,
flowcharts, or examples can be implemented, individually and/or
collectively, by a wide range of hardware, software, firmware, or
virtually any combination thereof. In one embodiment, several
portions of the subject matter described herein may be implemented
via Application Specific Integrated Circuits (ASICs), Field
Programmable Gate Arrays (FPGAs), digital signal processors (DSPs),
or other integrated formats. However, those skilled in the art will
recognize that some aspects of the embodiments disclosed herein, in
whole or in part, can be equivalently implemented in integrated
circuits, as one or more computer programs running on one or more
computers (e.g., as one or more programs running on one or more
computer systems), as one or more programs running on one or more
processors (e.g., as one or more programs running on one or more
microprocessors), as firmware, or as virtually any combination
thereof, and that designing the circuitry and/or writing the code
for the software and or firmware would be well within the skill of
one of skill in the art in light of this disclosure. In addition,
those skilled in the art will appreciate that the mechanisms of the
subject matter described herein are capable of being distributed as
a program product in a variety of forms, and that an illustrative
embodiment of the subject matter described herein applies
regardless of the particular type of signal bearing medium used to
actually carry out the distribution. Examples of a signal bearing
medium include, but are not limited to, the following: a recordable
type medium such as a floppy disk, a hard disk drive, a Compact
Disc (CD), a Digital Video Disk (DVD), a digital tape, a computer
memory, etc.; and a transmission type medium such as a digital
and/or an analog communication medium (e.g., a fiber optic cable, a
waveguide, a wired communications link, a wireless communication
link, etc.).
[0349] Those skilled in the art will recognize that it is common
within the art to describe devices and/or processes in the fashion
set forth herein, and thereafter use engineering practices to
integrate such described devices and/or processes into data
processing systems. That is, at least a portion of the devices
and/or processes described herein can be integrated into a data
processing system via a reasonable amount of experimentation. Those
having skill in the art will recognize that a typical data
processing system generally includes one or more of a system unit
housing, a video display device, a memory such as volatile and
non-volatile memory, processors such as microprocessors and digital
signal processors, computational entities such as operating
systems, drivers, graphical user interfaces, and applications
programs, one or more interaction devices, such as a touch pad or
screen, and/or control systems including feedback loops and control
motors (e.g., feedback for sensing position and/or velocity;
control motors for moving and/or adjusting components and/or
quantities). A typical data processing system may be implemented
utilizing any suitable commercially available components, such as
those typically found in data computing/communication and/or
network computing/communication systems.
[0350] The herein described subject matter sometimes illustrates
different components contained within, or connected with, different
other components. It is to be understood that such depicted
architectures are merely exemplary, and that in fact many other
architectures can be implemented which achieve the same
functionality. In a conceptual sense, any arrangement of components
to achieve the same functionality is effectively "associated" such
that the desired functionality is achieved. Hence, any two
components herein combined to achieve a particular functionality
can be seen as "associated with" each other such that the desired
functionality is achieved, irrespective of architectures or
intermedial components. Likewise, any two components so associated
can also be viewed as being "operably connected", or "operably
coupled", to each other to achieve the desired functionality, and
any two components capable of being so associated can also be
viewed as being "operably couplable", to each other to achieve the
desired functionality. Specific examples of operably couplable
include but are not limited to physically mateable and/or
physically interacting components and/or wirelessly interactable
and/or wirelessly interacting components and/or logically
interacting and/or logically interactable components.
[0351] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations may be expressly set forth
herein for sake of clarity.
[0352] For ease of reading, all values described herein, and all
numerical ranges described herein are approximate and should be
read as including the word "about" or "approximately" prior to each
numeral, unless context indicates otherwise. For example, the range
"0.0001 to 0.01" is meant to read as "about 0.0001 to about
0.01."
[0353] It will be understood by those within the art that, in
general, terms used herein, and especially in the appended claims
(e.g., bodies of the appended claims) are generally intended as
"open" terms (e.g., the term "including" should be interpreted as
"including but not limited to," the term "having" should be
interpreted as "having at least," the term "includes" should be
interpreted as "includes but is not limited to," etc.). It will be
further understood by those within the art that if a specific
number of an introduced claim recitation is intended, such an
intent will be explicitly recited in the claim, and in the absence
of such recitation no such intent is present. For example, as an
aid to understanding, the following appended claims may contain
usage of the introductory phrases "at least one" and "one or more"
to introduce claim recitations. However, the use of such phrases
should not be construed to imply that the introduction of a claim
recitation by the indefinite articles "a" or "an" limits any
particular claim containing such introduced claim recitation to
inventions containing only one such recitation, even when the same
claim includes the introductory phrases "one or more" or "at least
one" and indefinite articles such as "a" or "an" (e.g., "a" and/or
"an" should typically be interpreted to mean "at least one" or "one
or more"); the same holds true for the use of definite articles
used to introduce claim recitations. In addition, even if a
specific number of an introduced claim recitation is explicitly
recited, those skilled in the art will recognize that such
recitation should typically be interpreted to mean at least the
recited number (e.g., the bare recitation of "two recitations,"
without other modifiers, typically means at least two recitations,
or two or more recitations). Furthermore, in those instances where
a convention analogous to "at least one of A, B, and C, etc." is
used, in general such a construction is intended in the sense one
having skill in the art would understand the convention (e.g., "a
system having at least one of A, B, and C" would include but not be
limited to systems that have A alone, B alone, C alone, A and B
together, A and C together, B and C together, and/or A, B, and C
together, etc.). In those instances where a convention analogous to
"at least one of A, B, or C, etc." is used, in general such a
construction is intended in the sense one having skill in the art
would understand the convention (e.g., "a system having at least
one of A, B, or C" would include but not be limited to systems that
have A alone, B alone, C alone, A and B together, A and C together,
B and C together, and/or A, B, and C together, etc.). It will be
further understood by those within the art that virtually any
disjunctive word and/or phrase presenting two or more alternative
terms, whether in the description, claims, or drawings, should be
understood to contemplate the possibilities of including one of the
terms, either of the terms, or both terms. For example, the phrase
"A or B" will be understood to include the possibilities of "A" or
"B" or "A and B."
[0354] All references herein, including but not limited to patents,
patent applications, and non-patent literature are hereby
incorporated by reference herein in their entirety.
[0355] While various aspects and embodiments have been disclosed
herein, other aspects and embodiments will be apparent to those
skilled in the art. The various aspects and embodiments disclosed
herein are for purposes of illustration and are not intended to be
limiting, with the true scope and spirit being indicated by the
following claims.
* * * * *
References