Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
MICRO DEVICES FOR BIOMEDICAL APPLICATIONS AND USES OF THE SAM1
Background of the Invention
While in the last one to two decades, noted progresses have been made in the
area of
medicine and biology,, particularly in genomicsõ the conventional approach to
modern medicine,
including prevention, diagnosis and treatment of diseases such as cancer, has
fundamentally
remained the same, and it is still mainly focused on macroscopic
methodologies. For example,
current diagnosis of disease techniques use macroscopic data and information
such- as.
temperature, blood pressure, scanned images, measured chemical component
levels in the body,
etc. Even the effectiveness of newly emerged DNA tests in diagnosing-a wide
range of diseases
in a real-time, reliable, accurate, rapid, and cost efficient manner has not
been established. Many
diseases with great morbidity and mortality, including cancer and heart
disease, are very difficult
to diagnose early and accurately. Further, most of the existing diagnosis
techniques are invasive.
Relating to disease treatment, the situation is even worse. To. date, many
operations are
still highly invasive, have a high cost, carry a high risk of complications
and require a long
recuperation time.. Some treatments are even destructive of healthy cells or
tissue. One such
example would be cancer treatment using radiation, which kills not only cancer
cells; but normal,
healthy cells. Another example would be blood related disease treatment which
is often intrusive,
risky (e.g., open heart surgery), highly expensive and in many cases, post
surgical patients will
not be able to return to a normal active life style.
On the prevention side of the equation, beside the general guidelines of
eating healthy
and exercising regularly, the cause of many diseases, such as cancer, are
still unknown at this
point. This lack of knowledge relating to disease etiologies directly leads to
a. lack of
preventative drug development.
Most of the above stated issues in prevention, diagnosis, and treatment in
modern
medicine are, to a large extent, due to, e.g., lack of understanding of
pathology at the
microscopic level (cell biology level), lack of effective drag delivery and
efficient reaction
mechanisms, lack of non-invasive monitoring at the microscopic level as well
as preventive
mechanisms and approaches, and lack ()Ilion invasive, effective, targeted
disease treatment
approaches and technologies.
CA 02812189 2013-03-15
WO 2012/036697 PCT/1JS2010/049298
In recent years, there have been some efforts in the areas of using nano
technologies for
biological applications, mostly for use in vitro (outside the body). This in
vitro work has lead to
moderate developments in the field. Pantel et al. discussed the use of a micro
electromechanical
(MEMS) sensor for detecting cancer cells in blood and bone marrow in vitro.
See Klaus Parnel
et al., Nature Reviews, 2008, 8, 329. Wozniak and Chen used laser tweezers and
micro needles
for measuring forces generated by sample cells. See M.A. Wozniak et al.,
Nature Reviews, .2009,
10,34. Kubena etal. discussed in US Patent No. 6,922,118, the deployment of
MEMS for
detecting biological agents, while Weissman et at. discussed in US Patent No.
6,330,885,
utilizing MEMS sensor for detecting accretion of biological matter.
Due to the above stated limitations, at the fundamental level, many issues
facing modem
medicine remain unsolved, including sensing at the microscopic level in vivo
targeted treatments,
cancer prevention, early detection and non invasive treatment with minimum
damage to normal
tissues and organs. However, to date, most of the publications have been
limited to isolated
examples for sensing in vitro, using systems of relatively simple
constructions and large
dimensions and often with limited functions. There is no report of highly
integrated, multi
functional, micro devices (less than or equal to 5 millimeters) for advanced
biomedical
applications, particularly for applications in vivo (inside the body) and at
the microscopic level.
Summary of the Invention
The present invention generally relates to novel micro devices, and use
thereof, for
carrying out disease prevention, diagnosis, or treatment. at microscopic
levels, using a wide range
of novel functions achieved through their functionality integration at the
microscopic level and
using the state of the art micro device fabrication techniques such as
integrated circuit fabrication
techniques. Other fabrication techniques that may be suitable include, but are
not limited to,
mechanical, chemical, chemical mechanical, electro-chemical-mechanical,
electro-bio-chemical-
mechanical, bio-chemical, bio-chemical mechanical, optical, opto-electrical,
opto-electro-
mechanical, thermal chemical, thermal mechanical, thermal chemical mechanical,
and integrated
circuit and semiconductor manufacturing techniques and processes.
In one class of applications, a micro device includes multiple components,
with each
component typically of miniaturized sizes on the order of sub-biological cell
to typical full
biological cell sizes (or from one micron to a few hundred microns). Multiple
components of
2
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
diverse functions can be integrated onto a single micro device to perform a
range of functions
ineluding, e.g., disease detection, treatment, and cleaning, typically at a
microscopic level
Depending upon the intended application, the micro device of or used in the
present
invention can have a size ranging from I angstrom to 5 millimeters. Micro
device functionalities
would include sensing, detecting, measuring, diagnosing, monitoring,
analyzing, drug delivering,
selective absorption, selective adsorption, carrying out preventive procedures
and surgical
intervention, or any of their combinations.
In one aspect, the present invention provides micro devices fur medical
applications or
applications in live biological systems.
In some embodiments, each device comprising an outer membrane and a property
selected from the group consisting of micro mechanical, micro Chemical, micro
chemical
mechanical, micro optical, micro acoustical, micro biological, micro-bio-
chemical, micro-bio-
chemical-mechanical, micro-electro-bio-chemical-mechanical, micro-electro-
chemical-
mechanical, micro-electro-bio-chemical-mechanical, micro electro mechanical,
micro
electromagnetic mechanical, micro acoustic mechanical, and micro
superconducting mechanical
properties; and the micro device has a size ranging from approximately I
angstrom to
approximately 5 millimeters. For instance, a micro device with a micro
mechanical property can
also be called a mechanical device and generally means that the micro device
performs an
intended function due to this mechanical property. In some examples of these
embodiments, the
micro devices includes two properties selected from the group consisting of
micro mechanical,
micro chemical, micro chemical mechanical, micro optical, micro acoustical,
micro biological,
micro electro mechanical, micro electromagnetic mechanical, micro acoustic
mechanical, and
micro superconducting mechanical properties. In some other examples, the micro
devices may
further include a property selected from the group consisting of charged
surface, chemical
potential, geometrical matching, electro-magnetic, and electro-chemical
potential related
attraction. The one or more additional properties may allow for adsorption of
the micro device
onto a targeted biological organ or cell structure surfaces.
In some embodiments, the micro devices may be capable of differentiating
cancer cells
from normal cells. They may perform this function, e.g., by measuring
microscopic properties of
cells, including but not limited to, biochemical, physical, electrical,
electro-magnetic, bio-
chemical, mechanical, acoustical, thermal, and optical properties.
3
CA 02812189 2013-03-15
WO 2012/036697
PCT/US2010/049298
in some embodiments, the micro devices may be capable of measuring microscopic
properties of organ and cell structures (e.g., for having a detection probe),
diagnosing organ and
cell structures at a microscopic level, delivering desired chemistry to organ
and cell structures at
a microscopic level (e.g., for having a micro-injector or micro-container with
delivery
capabilities), delivering desired drug to organ and cell structures at a
microscopic level, and
manipulating selected organ and cell structure at 8, microscopic level. The
micro devices may
perform an intended function in a non invasive manner, or in real time.
In some embodiments, the micro devices may be capable of measuring at least
one.
property selected from the group consisting of surface charge, resting
potential, electro-chemical
potential, electrical potential, surface wettability, contact angle,
adhesion., temperature, density,
friction, hardness, surface tension, trace chemical concentration, hydrophobic
level, hydrophilic
level, pH, liquid flow rate, pressure, optical properties, absorption,
adsorption, and composition.
The micro devices of this invention may include a GPS, a signal transmitter, a
signal
receiver, a micro-motorizer, a micro-propeller, or a radio frequency (R.F)
communication chip.
As such, the micro devices may be capable of local positioning, location
identification, location
information communication and location positioning.
Insome other embodiments, the micro devices may further comprises a function
selected
from the group consisting of chemistry delivery function, controlled chemistry
delivery /Unction,
mechanical action, controlled mechanical action, selective absorption,
selective adsorption,
detection at microscopic level, timed electro mechanical action, controlled
electro mechanical
action, controlled electro-chemical-mechanical action, controlled electro-
biological action,
controlled electro-chemical-biological action, controlled electro-chemical-
biological action,
controlled dectro-chemical-biological-mechanical action, triggered action
based upon detected
signal and triggered action based upon external instruction. Such function may
be a result of a
property possessed by the micro device or a specific subunit of the micro
device.
In some other embodiments, the micro devices may have a pre-programmed trigger
function for actions selected front the group consisting of: chemistry
delivery, mechanical force
action, charge injection, light emitting, voltage application, cooling and
heating onto manic
structures. Such function may be programmed into an on-device chip which has
memory and
logic functions and may be triggered, e.g., when a sensed signal or a response
has reached a pre-
set value, an action or set of actions are initiated and taken. In some
instance, the trigger
4
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
function may be achieved by the employment from a group of parameters selected
from the
group consisting: charge, resting potential, electrical potential, electro-
chemical potential,
surface current., bulk current, surface wettability, adhesion property,
hydrophobic level,
hydrophilic level, flow property, electrical field, magnetic field, acoustic
field, temperature, light
wavelength and/or intensity, frictional force and coefficient, hardness,
pressure, and external
signal detected by the device.
In some embodiments, the micro devices may has a dissolution capability at a
targeted
pH range (e.g., from 6 to 8 or from 6.8 to 7.4) between 30 seconds and three
(3) days. It means
that the micro devices may dissolve in that targeted pH range within that time
period.
In some embodiments, the micro device includes a material selected from the
group
consisting of polymer, organic, and inorganic materials relatively compatible
with organic
systems. The term "relatively compatible" means that the material is generally
biocompatible
with a mammal body and does not cause infection, disorder, discomfort, and
other negative
effects (such as immunogenic effect). The micro devices can be fabricated
using a biornaterial,
or a biomaterial in combination with another material, or they can be
interfaced or coated with a
biomaterial. Biornaterials can include naturally occurring materials,
synthesized materials, or
composite of naturally occurring materials (including autograft, allograft or
xeriograft) and
synthesized materials. Examples of such materials include, but are not limited
to, silicon and
silicon dioxide, polysilicon, silicon nitride, silicon oxynitride, carbon
oxide, and carbon nitride,
polymers used in IC device packaging (which are expected to be compatible due
to their
inertness), lipids, peptides, hydroxyapatite (HA), calcium phosphate, calcium
carbonate,
magnesium phosphate, ammonium phosphate, silicates, and nautilus shell.
In some embodiments, the micro devices can have a size ranging from about 1
angstrom
to about 100 millimeters (e.g., for cell structure, DNA, or bacteria related
applications, for
human cell tests and analysis), from about 1 angstrom to about 100 microns
(e.g., for selective
attachment applications), from about 0.01 micron to about 5 millimeters, from
about 10 microns
to about 2 millimeters, or from about 100 microns to about 1.5 millimeters.
In some embodiments, the micro devices include one material with multiple sub-
devices
integrated onto one unit with one or more functionalities. Examples of a
suitable material
include, but are not limited to, oreanic polymers, organic materials,
biological materials,
biochemical materials, inorganic conductors, inorganic semi conductors,
inorganic insulators and
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
ceramics. Examples of a suitable biological material, include, but are not
limited to, artificial
biological materials, natural biological materials, cultured biological
materials, and combinations
of natural biological materials and artificial biological materials.
In some embodiments, the micro device is an integrated micro device including
at least
one function selected from the group consisting of: sensing, detecting,
measuring, calculating,
analyzing, diagnosing, logic processing (decision making), transmitting, and
operating or
surgical functions.
In some other embodiments, the micro devices further include a hardware
selected from a
group consisting of voltage comparator, four point probe, calculator, logic
circuitry, memory unit,
micro cutter, micro hammer, micro shield, micro dye, micro pin, micro knife,
micro needle,
micro thread holder, micro tweezers, micro optical absorber, micro mirror,
micro shield, micro
wheeler, micro filter, micro chopper, micro shredder, micro pumps, micro
absorber, micro signal
detector, micro drilleronicm sucker, micro tester, micro container, micro-
puller, signal
transmitter, signal generator, friction sensor, electrical charge sensor,
temperature sensor,
hardness detector, acoustic wave generator, optical wave generator, heat
generator, micro
refrigerator, and charge generator. These terms are well known in the art and
their general
definitions apply to this invention. For instance, a filter can be a micro
device (or sub micro
device) which can separate various components by their sizes; a cleaner can be
a micro device
capable of washing, polishing, rubbing, and brushing an intended surface; a
pump can be a micro
device that can transport intended item from one location from the other; and
a shredder can be a
micro device with blades and sharp edges capable of making a larger item into
smaller pieces. In
some further embodiments, the micro devices include a cleaner, a filter, a
shredder, an injector,
and a pump: a cleaner, a filter, a shredder, and an injector; a polishing unit
with a polishing pad;
or a sensor, a micro tip for sample collection, a micro array for testing
collected sample, a data
analysis unit, and a signal transmitter.
In some embodiments, the micro devices can function be micro testers for
continued scan
and analysis of live biological system for early disease detection and
prevention.
Alternatively, the micro devices can be for in viiro applications outside a
biological
system, include an outer membrane and one or more properties selected from the
group
consisting of: micro mechanical, micro chemical, micro chemical mechanical,
micro optical,
micro acoustical, micro biological, micro electro mechanical, micro
electromagnetic mechanical,
6
micro acoustic mechanical, and micro superconducting mechanical properties;
and have a size
ranging from approximately 1. angstrom to approximately 5 millimeters.
The micro devices can also be used for medical applications such as artery
cleaning and
early cancer detection and prevention in vivo.
Accordingly, the invention also provides methods of using a micro device of
this
invention for cleaning a biological material. Each method include rising the
step of contacting
the micro device with the biological material, wherein the micro device
comprises an outer
membrane and a property selected from the group consisting of micro
mechanical, micro
chemical, micro chemical mechanical, micro optical, micro acoustical, micro
biological, micro-
bio-chemical, micro-blo-chemical-mechanical, micro-electro-bio-chemical-
mechanical, micro-
electro-chemical-mechanical, micro-electro-bio-chemieal-meehanical, micro
electro mechanical,
micro electromagnetic mechanical, micro acoustic mechanical, and micro
superconducting
mechanical properties; and the micro device has a size ranging from
approximately I angstrom
to approximately 5 millimeters. Examples of the biological material to be
cleaned include, but
are not limited to a vein or artery in a mammal. The cleaning can be carried
out, e.g., by
mechanical polishing, mechanical rubbing, chemical mechanical polishing,
chemical dissolution,
chemical passivation, chemical treatments, biological treatments, polishing
with chemical
dissolution, laser oblation, or a combination thereoff.
In somoembodiments, the method further includes the steps of delivering the
micro device to the general area of the biological material; optionally
measuring the local
temperature, local pressure, local frictional three, local surface charge,
loud resting potential,
local electrical potential, local surface property, local composition, or
local fluid flow rate;
optionally triggering the cleaning function; performing cleaning; optionally
collecting debris
from cleaning by a micro collector and transporting the debris away; and
optionally collecting
debris by a micro-filter and transporting the debris away.
In some other embodiments, the method further include the steps of delivering
a micro
device into the veins; optionally sensing and analyzing data being collected,
for instance local
pressure; optionally triggering cleaning functions when the targeted blood
vein location is
reached; cleaning plaque and deposits from the vein wall at the targeted
location; optionally
injecting desired chemistry into the blockage to be cleaned, to soften the
plaque being cleaned,
avoid formation of large debris from breakage from plaque, and minimize
possible damage to the
7
CA 2812189 2019-10-02
CA 02812189 2013-03-15
WO 2012/036697
PCT/US2010/049298
veins; optionally dissolving the micro device following completion of cleaning
or filtered out via
blood filtration; optionally filtering of the micro device and debris via
blood filtration during and
following completion of cleaning; and optionally carrying out post-cleaning
treatments by the
micro device.
Still another aspect of this invention provides methods for delivering
multiple doses of
drug to a target location in vivo, each including the steps of transportation
of a micro device to
the target location; delivering the first drug to the target location; and
delivering a second dose of
the drug to the target location within a desired time interval from the
delivery time of the initial
delivery, wherein the micro device comprises an outer membrane and a property
selected from
the group consisting of micro mechanical, micro chemical, micro chemical
mechanical, micro
optical, micro acoustical, micro biological, micro-bio-chemical, micro-bio-
chemical-mechanical,
micro-electro-bio-chemical-mechanical, micro-electro-chemical-mechanical,
micro-electro-bio-
chemical-mechanical, micro electro mechanical, micro electromagnetic
mechanical, micro
acoustic mechanical, and micro superconducting mechanical properties; and the
micro device has
a size ranging from approximately I angstrom to approximately 5 millimeters.
In some embodiments, each dose delivers a different drug from another dose. In
some
other embodiments, the drugs are of different chemistries and delivering of a
first drug enhances
the attachment selectivity to the second drag.
Alternatively, the invention also provides methods of using a micro device for
a medical
purpose, wherein the micro device comprises an outer membrane and a property
selected from
the group consisting of micro mechanical, micro chemical, micro chemical
mechanical, micro
optical, micro acoustical, micro biological, micro-bio-chemical, micro-bio-
chemical-mechartical,
micro-electro-bio-chemical-mechanical, micro-electro-chemical-mechanical,
micro-electro-bio-
chemical-mechanical, micro electro mechanical, micro electromagnetic
mechanical, micro
acoustic mechanical, and micro superconducting mechanical properties; the
micro device has a
size ranging from approximately 1 angstrom to approximately 5 millimeters; and
the medical
purpose is selected from the group consisting of: drug delivery, cutting,
removing, polishing,
transporting, jointing, diagnosing, sensing, selective protection, targeted
removing, measuring,
treatment of cancer or blood related diseases, and assisting medical treatment
functions at cell
structure or micro-organ level in a target area (up to about 500 micron
scale).
8
CA 02812189 2013-03-15
WO 2012/036697
PCT/US2010/049298
In some embodiments, the method is for cancer treatment and includes the steps
of:
selectively attaching micro devices with drug delivery functions onto cancer
cells; triggering
injection function in the micro devices; and injecting drug into cancer cells.
Alternatively, the
method can include the steps of: selectively attaching micro devices with high
optical
reflectivity onto healthy cells; carrying out laser treatment to 'destroy
unhealthy cells; and
removing unhealthy cells in the treatment due to exposure to the laser.
In some embodiments, the micro device used for these methods can include a
property
selected from the group consisting of signal sensing unit, memory unit, logic
processing unit,
signal transmitter, and micro surgery; the micro device performs the function
of diagnosing,
sensingeor measuring; and the method can include the steps of delivering. the
micro device to a
targeted measuring site; performing measurement on the targeted site;
recording data in memory
unit; optionally triggering operations using the logic processing function;
optionally carrying out
surgery using the micro device; retrieving the micro device; and analyzing the
recorded data.
In some other embodiments, the micro device can perform the function of
diagnosing,
sensing, or measuring a target site: the micro device includes a signal
sensing unit., a memory
unit, a signal transmitter, a logic unit for on site decision making and micro
surgery; and the
method includes the steps of delivering the micro device to the target site
and performing the
diagnosing, sensing, or measuring function on the target site; reeording data
in memory unit;
analyzing the data performed by the micro device; deciding the course and type
of micro
operations based on data analysis and pre programmed logic decisions by the
micro device; and
performing micro operations on the target site.
In still some other embodiments, the micro devices include an electric
property
measurement unit and is capable of detecting cancer cells in a target site;
and the method
comprises the steps of: delivering the micro device to the target site;
measuring on the target site
one or more properties selected from the group consisting of: surface charge,
charge density,
resting potential, electrical potential, electro-chemical potential, surface
current, bulk current,
and current density. They may further include a voltage comparator, which,
e.g., has voltage
measurement sensitivity better than I mV.
In some other embodiments, the methods can be used for cancer cell detection
in a target
site and include the steps of delivering the micro device to the target site;
and measuring on the
target site one or more parameters selected from the group consisting of:
surface charge, resting
9
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
potential, electro-chemical potential, electrical potential, surface current,
bulk current, surface
wettability, contact angle, adhesion properties, temperature, density,
friction, hardness, surface
tension, trace chemical concentration, pH, liquid flow rate, pressure, optical
properties,
absorption, adsorption, and Composition.
The micro devices of this invention can be fabricated by methods known in the
art, e.g.,
one or more methods selected from the group Consisting of integrated circuit
manufacturing
method, semiconductor manufacturing method, mechanical manufacturing method,
Chemistry
processing method, synthesis method, electro chemistry processing method,
biological
processing method, bio-chemical processing method, mechanical manufacturing
method, and
laser processing method.
Thus, another aspect of the present invention is the use of micro devices for
obtaining
real time data and information at the cell structure level in a non-invasive
manner, such as using
a micro voltage comparator, four-point probe and other circuitry designs to
measure cell surface
charge. The cell surface charge differentiation can be an important factor in
deciding the healthy
or unhealthy status. of a cell and, if necessary, the proper treatment
thereof. One example would
be the use of such devices for measuring surface and/or bulk electrical
properties including
resting potential and surface charge for differentiating normal cells and
cancer cells.
Yet another aspect of the present invention is the use of a micro device to
deliver drugs to
targeted locations within the human body and with differentiation between
healthy cells and
unhealthy (cancer, for instance) cells. This can he achieved through selective
absorption or
adsorption of a micro device onto healthy or unhealthy cells (such as cancer
cells). For example,
to remove a part of an unhealthy organ with laser surgery, micro devices with
high optical
reflectivity can be used to selectively adsorb onto healthy cells, thereby
protecting good cells
from being removed and/or ablated via laser treatment.
As used herein, the term "or" is meant to include both "and" and "or."
As used herein, a term consisting of the word "a" or "one" and a single noun,
includes
the meaning of' the. noun in its plurality.
As used herein, a. "micro device" or "micro device"- can be any of a wide
ranee of
materials, properties, shapes, degree of complexity and integration, or their
combination as
appropriate. The term has a general meaning for an application from a single
material to a very
complex device comprising multiple materials with multiple sub units and
multiple functions.
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
The complexity contemplated in the present invention ranges from a very small,
single particle
with a set of desired properties to a fairly complicated, integrated unit with
various functional
units contained therein. For example, a simple micro device could be a single
spherical article of
manufacture of a diameter as small as 100 angstroms with a desired hardness, a
desired surface
charge, or a desired organic chemistry absorbed on its surface. A more complex
micro device
could be a 1 millimeter device -with a sensor, a simple calculator, a memory
unit, a logic unit, and
a cutter all integrated onto it. In the former case, the particle can be
formed via a fumed or
colloidal precipitation process, while the device with various components
integrated onto it can
be fabricated using various integrated circuit manufacturing processes.
A micro device of or used in the present invention can range in size (e.g.,
diameter) from
on the order of about 1 angstrom to on the order of about 5 millimeters. For
instance, a micro
device ranging in size from on the order of about 10 angstroms to on the order
of 100 microns
can be used in this invention for targeting biological molecules, entities or
compositions of small
sizes such as cell structures, DNA, and bacteria. Or, a micro device taming in
size from on the
order of about one micron to the order of about 5 millimeters can be used in
the present invention
for targeting relatively large biological matters such as a portion of. a
human organ. As an
example, a simple micro device defined in the present application can be a
single particle of a
diameter less than 100 angstroms, with desired surface properties (e.g., with
surface charge or a
chemical coating) for preferential absorption or adsorption into a targeted
type of cell.
The word "absorption" typically means a physical bonding between the surface
and the
material attached to it (absorbed onto it, in this case). On the other hand,
the word "adsorption"
generally means a stronger, chemical bonding between the two. These properties
are very
important for the present invention as they can be effectively used for
targeted attachment by
desired micro devices for (a) measurement at the microscopic level, (b)
targeted removal of
unhealthy cells, and (c) protection of healthy cells during a treatment such
as laser surgery.
As used herein, the term "chemistry" generally refers to a chemical material
of certain
activities(e.g., a large or small compound) or a compound that may react with
a substance in the
target delivery area).
Through novel micro devices, their novel combinations and integrations, and
integrated
operating process flow, many issues in today's medicine can be solved. In
particular, with the
present invention, a micro device can be used in "cleaning" biological organs,
e.g., cleaning
i
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
veins to prevent heart attack, strokes and blood clogging due to plaques and
fatty deposits in the
veins.
Brief Description of the Drawings
Fig. I is a perspective view of a micro device that can act as a micro
injector showing the
micro device before and then after the injection process has completed.
Fig. 2 is a perspective view of a micro device that acts as a micro polisher.
Fig. 3 is a perspective view of a micro device that acts as a micro polisher,
a micro-filter,
a micro injector, a micro sensor and micro shredder.
Fig. 4 is a perspective view of a micro device that acts as a micro knife.
Fig. 5 is a perspective view of a micro device that acts as a micro filter.
Fig. 6 is a perspective-view of a micro device that acts as a micro shield.
Fig. 7 is a perspective view of a. micro device in a blood vessel as it nears
a plaque in the
vessel wall.
Fig. 8 is a perspective view of a micro device in a blood vessel as it senses
a change in
pressure around a plaque, triggering, the micro device's cleaning function.
Fig. 9 is a perspective view of a micro device in a blood vessel after the
device has
cleaned a plaque from the vessel wall.
Fig. 10 is a perspective close up view of a group of healthy cells and a group
of unhealthy,
cancerous cells.
Fig. 11 is a perspective close up view of a group of healthy cells and a group
of unhealthy,
cancerous cells with micro devices acting as a voltage comparator on both sets
of cells.
Fig, 12 is a perspective close up view of a group of healthy cells and a group
of unhealthy,
cancerous cells.
Fig. 13 is a perspective close up view of a group of healthy cells and a group
of unhealthy,
cancerous cells with micro devices either adsorbed or absorbed onto the
healthy cells only.
Fig. 14 is a perspective close up view of an integrated micro device with
various sub-
units being a micro-cutter, a micro-needle, a memory unit, a unit for analysis
and logic
processing, a micro-sensor and a signal transmitter.
Fig. 15 is a perspective view of a micro device with a sensing unit, logic
unit and micro
injector.
12
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
Detailed Description of the Invention
The present invention provides novel micro devices for biological
applications, which are
expected to resolve a number of critical issues in the modern approach to
medicine. These issues
include lacks of, e.g., understanding in pathology and prevention for a number
of deadly diseases;
non invasive, microscopic and effective diagnosis of various disease states;
and an effective and
targeted drug delivery system and treatment for deadly diseases such as
cancer.
A micro device of the present invention can range in size from about 1
angstrom to about
millimeters (e.g., from about 1 angstrom to about .100 microns; or from about
100 microns to 5
millimeters). A smaller micro device (e.g., from about 1 angstrom to about 100
microns) can be
used for sensing, measuring, and diagnostic purposes, particularly for
obtaining information and
data at the cell structure level or molecular (e.g., DNA, RNA, or protein)
level; whereas a larger
micro device (e.g., from about 100 microns to about 5 millimeters) can be used
in mechanical or
surgical operations of a human organ or a human tissue except for manipulation
at the cell
structure level.
As stated herein, the general term "micro device" can mean a wide range of
materials,
properties, shapes, degree of complexity and integration, or combination
thereof. The
complexity contemplated in the present invention ranges from a very small,
single particle with a
set of desired properties to a fairly complicated, integrated unit comprising
various functional
subunits. For example, a simple micro device could be a single spherical
article of manufacture
of a diameter as small as 100 angstroms with a desired hardness, a desired
surface charge, or a
desired organic chemistry absorbed on its surface. A more complex micro device
could be a 1
millimeter device with a sensor, a simple calculator, a memory unit, a logic
unit, and a cutter all
integrated onto it. In the former case, the particle can be formed, e.g., by a
fumed or colloidal
precipitation process, while the device with various components integrated
onto it can be
fabricated using various integrated circuit manufacturing processes.
The micro devices of the present invention can have a wide range of designs,
structures
and functionalities. They include; e.g., a voltage comparator, a four point
probe, a calculator, a
logic circuitry, a memory unit, a micro cutter, a micro hammer, a micro
shield, a micro dye, a
micro pin, a micro knife, a micro needle, a micro thread holder, micro
tweezers, a micro optical
absorber, a micro mirror, a micro wheeler, a micro filter, a micro chopper, a
micro shredder,
13
CA 02812189 2013-03-15
WO 2012/036697
PCT/US2010/049298
micro pumps, a micro absorber, a micro signal detector, a micro driller, a
micro sucker, a micro
tester, a micro container, a signal transmitter, a signal generator, a
friction sensor, an electrical
charge sensor, a temperature sensor, a hardness detector, an acoustic wave
generator, an optical
wave generator, a heat generator, a micro refrigerator, and a charge
generator.
As disclosed herein, the range of functionalities and applications using the
micro devices
can be made extremely powerful due to their diverse properties, high degree of
flexibility, and
ability of integration and miniaturization.
Further, it should be noted that advancements in manufacturing technologies
have now
made it highly feasible and cost effective to fabricate a wide range of micro
devices and integrate
various functions onto a micro device. The typical human cell size is about 10
microns. Using
the state of the art integrated circuit fabrication techniques, the minimum
feature size defined on
a micro device can be as small as 0.1 micron. Thus, the micro devices of this
invention are ideal
for biological applications.
In terms of materials for the micro devices, the general principle will be a
material's
compatibility with biological materials. Since the time in contact with a
biological material (e.g.,
biological molecules such as DNA, RNA, or protein; cell; a group of cells;
tissue; or organ) may
vary, depending on its applications, different materials may be selected for
fabricating the micro
devices of this invention or any subunits thereof. In some cases, the
materials may dissolve in a
given pH in a controlled manner and thus may be selected as an appropriate
material. Other
considerations include cost, simplicity, ease of use, and practicality. With
the significant
advancements in micro fabrication technologies such as integrated circuit
manufacturing
technology, highly integrated devices with minimum feature size as small as
0.1 micron can now
be made cost effectively and commercially. One example is the design and
fabrication of micro
electro mechanical devices (MEMS), which now are being used in a wide variety
of applications
in the integrated circuit industry.
The following sections include several examples of the use of various types of
micro
devices of the present invention that can be used for novel biological
applications.
Sensing, Measuring, and Diagnosis
It is believed that before the present invention, there had been no probe to
measure
microscopic properties, in real time, at the cellular level in living organs
(in vivo). The novel
micro devices provided by the present invention can measure cell properties in
living organs. it
14
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
is expected that the information from the measurement can be retrieved in real
time for use as a
diagnostic tool.
For example, a micro device of this invention can be utilized to detect a
cancer cell in a
living omen in a non invasive manner. Fig. 10 illustrates an area in the human
body with a
number of healthy (or normal) cells "a" 39 and a number of unhealthy (or
abnormal) cells "b" 40.
The electrical properties such as electrical charge and resting potential of
healthy cells "a" 39 are
different from those of unhealthy cells "b" 40. First, the micro device with a
voltage comparator
is calibrated by measuring surface charge (or voltage) at known healthy cells.
Next, as shown in
Fig. 11, for an area containing both healthy cells 39 and unhealthy cells 40,
a micro device 41
with voltage comparators 42 is used to scan the area. By comparing voltages at
the cell surface
the difference in charges or potential), unhealthy cells 40 can readily be
differentiated from the
healthy cells 39. Such micro devices 41 can be easily extended to perform
functions of
identifying, measuring and treating of cancer cell by integrating a voltage
comparator, a logic
circuitry unit, and a micro injector (needle) which can deliver, e.g., cancer
killing agents
specifically to a cancer cell.
Drug Delivery
To date, many cancer treatment drugs have not shown their expected promising
results in
human trials, even though laboratory tests on mice may have been successful.
It is believed that
there may be major problems relating to the successful and effective drug
delivery to the targeted
cancer cells. Since such drugs are often taken in pill form or by injection
into the body, there
may be serious issues in the drug reaching the targeted cancer sites. Even if
a drug can reach its
tareeted site, its strength (concentration) and chemical composition may have
been altered,
rendering it either partially or entirely ineffective. An increase in the
amount of drug delivered
in this fashion will increase side effects and possibly cause an increase in
mortality.
In the present invention, the novel, effective and targeted drug delivery
system hopes to
correct the above stated problems. As shown in Fig. IS, a micro device 64 with
a sensing unit 62,
a logic unit 63 and a micro injector 61 is utilized. The micro device 64 is
designed in a way that
it will preferentially absorb (or adsorb) only onto unhealthy cells.
Alternatively, the sensor 62
can detect unhealthy cells through measurements of desired physical, chemical,
electrical and
biological properties of cells being scanned and attached onto detected
unhealthy cells. Once the
micro device 64 is attached to the unhealthy cell, it will inject one or more
cancer killing agents
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
into the cancer cell through a micro-injector 61. To make sure that healthy
cells are not injected
due to error in attachment, a loaic unit 63 may be used to make a correct
decision based on the
sensor data received by the sensing unit 62 from the attached cell. Since this
approach is a
targeted approach with a cancer killing drug directly delivered to the
unhealthy cells, it is
expected that its effectiveness can be greatly improved over the standard
therapies that are used
conventionally for the current treatment of cancer.
Cleaning
Another major area of ibctis for this invention is a novel type of micro
device for
biological "cleaning" purposes, in particular, for the "cleaning" of human
arteries and veins. Fig.
7 illustrates a blood vessel wall 30, a micro device 32 traveling in a
direction 33, a blood clot 36,
lower blood pressure PI 34 and a lower blood pressure P235. In this type of
applications, the
present invention is a micro device 32 with at least one cleaner attached
thereto. A more
complete micro device will be comprised of at least one sensor, one cleaner,
one micro filter, one
injector, one shredder and one pump.
As shown in Fig. 8, a micro device 32 with integrated functions of sensing
(for local
pressure measurement) and cleaning 37 can be used. for arteries and vein
cleaning applications.
In this case, local pressure is higher where a plaque 36 is located at P2 35
within the blood vessel
wall 30. The device is moving within the vessel walls 30 in direction 33
toward the plaque 36.
The device 32 senses this increase in local press= as it approaches the
plaque, triggering the
cleaning function 37 to be deployed.
Fig. 9 illustrates the blood vessel wall 30 after the micro device 32 with
cleaning function
37 has cleaned the plaque from an area 38 within the blood vessel wall 30.
This is just one of the
many examples where a micro device disclosed in this application can be used
as a "smart"
device for biological applications in a non invasive, real time manner.
In Fig. 3, a more refined micro device 17 is disclosed, Which is comprised of
cleaner
arms 8 and cleaners 9, sensors 15, micro filters 13 and 14, micro shredders
11, and micro
injectors 16. This design is aimed to facilitate the cleaning process and to
make sure that
cleaning debris is reduced to much smaller pieces so that it is completely
removed and will not
cause a clot in other areas of the human body. The cleaner typically has a
polishing or rubbing
capability, while filters are used to filter debris from cleaning and prevent
them from moving to
other parts of the body and cause clogging problems. The injector is used to
dispense a
16
CA 02812189 2013-03-15
WO 2012/036697
PCT/US2010/049298
dissolution agent to dissolve the debris from the cleaner portion of the micro
device; it can also
deliver agents to facilitate the "cleaning" (polishing) process. A micro
shredder 11 can be used
to shred the relatively large debris from the cleaning (if any) activity. More
specifically, the
cleaning unit can be a polishing pad 9 made of polymer material(s) with
desired roughness for
polishing or rubbing. To reduce mechanical force and avoid breakage of the
plaque into large
pieces, a polishing solution can be applied at the point of micro polishing,
with the use of an
injector 16. In a preferred method, the plaque is polished off in a layer-by-
layer (a few mono
layers of about 10 angstroms in thickness) process, with a controlled removal
rate. A balanced
chemical mechanical polishing process is preferred where both surface chemical
reaction and
mechanical abrasion is present, with the mechanical abrasion controlled to a
low enough level
not to cause breakage in plaque. In the meantime, micro filters 13 and 14 are
used to insure that
no large debris can leave the area of cleaning and causing damage to other
portions of the human
body. For patients with a propensity for deposits building up in their veins,
cleaning using the
disclosed method should be carried out on a regular basis to reduce .the risks
of heart attack and
stroke, and to reduce the degree of difficulty in subsequent cleaning
processes.
Since the diameter for major arteries is typically a few millimeters (about 2
mm to 4 mm
in diameters), the size for a micro device for this type of cleaning
application (for cleaning of
major arteries) can range from about 10 microns to less than 2 millimeters,
e.g., from about 100
microns to about 1.5 millimeters.
Targeted Treatment
The micro devices disclosed in this invention are ideally suited for targeted
medical
treatment to remove or destroy unhealthy cells or organ portions while
minimizing damage to
healthy cells or organ parts. This can be carried out with a high degree of
selectivity, can be non
invasive and can be done in a microscopic manner.
Fig. 12 illustrates an area in the human body with a number of healthy cells
39 and a
number of unhealthy cells 40. In Fig. 13, for use in laser surgery using an
optical oblation
process, healthy cells 39 are first covered with micro devices 43 (called
micro shields) with a
high optical reflectivity. Next, unhealthy cells 40 such as cancer cells are
removed via optical
oblation, while healthy cells 39 are protected by the micro shields 43. This
selective attachment
of the micro-shields 43 to healthy cells is made possible through surface
adsorption (or
absorption) between the micro devices and healthy cells through micro device
sensing process
I7
CA 02812189 2013-03-15
WO 2012/036697 PCT/US2010/049298
and/or desired micro device properties such as charge attraction. For example,
micro devices can
be designed or programmed such that they only attach to healthy cells through
surface charge
measurement and subsequent logic decision and action as set forth in Fig. Ii
described above.
Another embodiment of the present invention for targeted treatment is the use
of an
integrated micro device with sensing, logic processing, and injection
functions. The micro
device first uses a sensing function to locate its target. The micro device
then attaches itself to
the target. Finally, the micro device injects cancer killing agent(s) into the
cancer cell.
Micro Surgery
As disclosed herein, various micro devices capable of performing a wide range
of
surgical functions can be employed to accomplish specific goals. Some examples
of the micro
devices capable of carrying out micro surgeries are shown in Figs. I through
6.
Fig. I illustrates a micro device 6 before it is triggered and a micro device
7 after it is
triggered. The device 6 is comprised of an outer membrane 1, a sensing unit 2,
a floor 3 and an
area 4 in which various agents can be held prior to triggering. The triggered
device 7 has an area
which is empty once the floor 3 is pushed vertically to expel the contents of
the area 4. Fig. 2
illustrates a micro device 10 with a polisher/scrubber function 9 attached to
an extension arm 8
outside of the outer membrane 1. Fig. 4 illustrates a micro device 20 with an
outer membrane 1,
a vertical attachment 19 with a cutting knife end 18. Fig. 5 illustrates a
micro device 25 with a
top side 24, an outer membrane 21, a series of openings 22 in the top side 24
with the openings
22 extending through passage 23 entirely through micro device 25 to the bottom
side 26. Fig. 6
illustrates a micro device 29 having a body 27 with a reflective portion 28
attached to the top of
the body 27.
It should be emphasized that for practical surgical applications, integrated
micro devices
with multiple functional components and functionalities will be the preferred
choices, and they
will be the most effective and versatile instruments for surgeries. The clear
advantages of those
"smart" devices disclosed in this invention, will be to carry out surgery in a
minimally invasive
and at a microscopic level with high precision, high selectivity, with minimum
damage U.)
healthy cells and organs.
One example of an integrated micro device includes at least one sensor, one
memory unit,
one logic processing unit, one signal transmitter, one signal receiver, at
least one micro injector,
multiple micro knives, multiple micro needles, at least one pair of micro
tweezers, and at. least
18
CA 02812189 2013-03-15
WO 2012/036697
PCT/US2010/049298
one micro thread holder. Such integrated micro device will be capable of
performing some basic
surgical operations. One such example of integrated micro devices is shown in
Figure 14. Fig.
14 illustrates an integrated micro device 43 with an outer membrane 44, a
sensing unit 47
attached to a sensing arm 48 linked to a memory unit 50 via pathway 49, the
memory unit 50
linked via pathway 51 to an analysis/logic unit 52 attached via pathway 46 to
a signal transmitter
45, the unit 52 attached via pathway 53 to a micro-needle unit 55 reaching
externally via a needle
54 extending past the outer membrane 44 and the unit 52 attached via pathway
56 to a micro-
cutter unit 57 with an extending arm 58 having a cutting end 59.
Thus it is apparent that there has been provided, in accordance with the
invention
disclosed herein, a micro device for biological applications, particularly for
disease detection,
treatment, and prevention in live biological systems at a microscopic level,
that fully meets the
needs and advantages set forth herein. Although specific embodiments have been
illustrated
herein, it will be appreciated by those skilled in the art that any
modifications and variations can
be made without departing from the spirit of the invention. Therefore, it is
not intended that the
invention be limited by the description herein. Any combination of the micro
devices disclosed
in this invention and any obvious extension of the micro devices for
biological applications
would be covered by this invention. Additionally, any integration of disclosed
micro devices for
disease detection, prevention and treatment including surgical operations in
live human body
disclosed herein. Therefore, it is intended that this invention encompass any
arrangement, which
is calculated to achieve that same purpose, and all such variations and
modifications as fall
within the scope of the appended claims.
The reader's attention is directed to all papers and documents which are tiled
concurrently
with this specification and which are open to public inspection with this
specification, and the
contents of all such papers and documents are incorporated herein by
reference. All the features
disclosed in this specification (including any accompanying claims, abstract
and drawings) may
be replaced by alternative features serving the same, equivalent or similar
purpose, unless
expressly stated otherwise. Thus, unless expressly stated otherwise, each
feature disclosed is one
example of a generic series of equivalent or similar features.
Any element in a claim that does not explicitly state "means for" performing a
specific
function, or "step for" or "step of' performing a specific function, is not to
be interpreted as a
"means" or "step" clause as specified in 35 U.S.C. 112 paragraph 6.
19
CA 02812189 2013-03-15
WO 2012/036697
PCT/US2010/049298
All publications referred to above are incorporated herein by reference in
their entireties.
