WO2012036697A1 - Micro devices biomedical applications and uses of the same - Google Patents

Micro devices biomedical applications and uses of the same Download PDF

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Publication number
WO2012036697A1
WO2012036697A1 PCT/US2010/049298 US2010049298W WO2012036697A1 WO 2012036697 A1 WO2012036697 A1 WO 2012036697A1 US 2010049298 W US2010049298 W US 2010049298W WO 2012036697 A1 WO2012036697 A1 WO 2012036697A1
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WO
WIPO (PCT)
Prior art keywords
micro
mechanical
chemical
micro device
electro
Prior art date
Application number
PCT/US2010/049298
Other languages
French (fr)
Inventor
Chris Chang Yu
He YU
Original Assignee
Chris Chang Yu
Yu He
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN201510770386.9A priority Critical patent/CN105403690A/en
Application filed by Chris Chang Yu, Yu He filed Critical Chris Chang Yu
Priority to BR112013006299A priority patent/BR112013006299B8/en
Priority to PCT/US2010/049298 priority patent/WO2012036697A1/en
Priority to KR1020137008453A priority patent/KR101761259B1/en
Priority to JP2013529116A priority patent/JP5917522B2/en
Priority to AU2010360764A priority patent/AU2010360764A1/en
Priority to EP10857394.0A priority patent/EP2615968A4/en
Priority to CN201080070042.2A priority patent/CN103237492B/en
Priority to CA2812189A priority patent/CA2812189C/en
Publication of WO2012036697A1 publication Critical patent/WO2012036697A1/en
Priority to IL225284A priority patent/IL225284B/en
Priority to ZA2013/02375A priority patent/ZA201302375B/en
Priority to AU2017200356A priority patent/AU2017200356A1/en

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Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82YSPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/24Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/001Preparation for luminescence or biological staining
    • A61K49/0063Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B81MICROSTRUCTURAL TECHNOLOGY
    • B81BMICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B7/00Microstructural systems; Auxiliary parts of microstructural devices or systems
    • B81B7/02Microstructural systems; Auxiliary parts of microstructural devices or systems containing distinct electrical or optical devices of particular relevance for their function, e.g. microelectro-mechanical systems [MEMS]
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00584Control arrangements for automatic analysers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/32Surgical cutting instruments
    • A61B17/3205Excision instruments
    • A61B17/3207Atherectomy devices working by cutting or abrading; Similar devices specially adapted for non-vascular obstructions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/32Surgical cutting instruments
    • A61B17/3205Excision instruments
    • A61B17/3207Atherectomy devices working by cutting or abrading; Similar devices specially adapted for non-vascular obstructions
    • A61B17/320758Atherectomy devices working by cutting or abrading; Similar devices specially adapted for non-vascular obstructions with a rotating cutting instrument, e.g. motor driven
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/34Trocars; Puncturing needles
    • A61B17/3478Endoscopic needles, e.g. for infusion
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017Electrical control of surgical instruments
    • A61B2017/00022Sensing or detecting at the treatment site
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017Electrical control of surgical instruments
    • A61B2017/00022Sensing or detecting at the treatment site
    • A61B2017/00084Temperature
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00234Surgical instruments, devices or methods, e.g. tourniquets for minimally invasive surgery
    • A61B2017/00345Micromachines, nanomachines, microsystems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/06Measuring instruments not otherwise provided for
    • A61B2090/064Measuring instruments not otherwise provided for for measuring force, pressure or mechanical tension
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02Details of sensors specially adapted for in-vivo measurements
    • A61B2562/028Microscale sensors, e.g. electromechanical sensors [MEMS]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles

Definitions

  • 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.
  • a micro device in one class of applications, 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 diverse functions can be integrated onto a single micro device to perform a range of functions including, e.g., disease detection, treatment, and cleaning, typically at a microscopic level.
  • the micro device of or used in the present invention can have a size ranging from 1 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.
  • the present invention provides micro devices for medical applications or applications in live biological systems.
  • 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-biochemical-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 1 angstrom to approximately 5 millimeters.
  • 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.
  • 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.
  • 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.
  • 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, biochemical, mechanical, acoustical, thermal, and optical properties.
  • 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 a microscopic level.
  • the micro devices may perform an intended function in a non invasive manner, or in real time.
  • 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 (RF) communication chip.
  • the micro devices may be capable of local positioning, location identification, location information communication and location positioning.
  • the micro devices may further comprises a function selected from the group consisting of chemistry delivery function, controlled chemistry delivery function, 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 electro-chemical-biological-mechanical action, triggered action based upon detected signal and triggered action based upon external instruction.
  • a function selected from the group consisting of chemistry delivery function, controlled chemistry delivery function, 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-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
  • the micro devices may have a pre-programmed trigger function for actions selected from the group consisting of: chemistry delivery, mechanical force action, charge injection, light emitting, voltage application, cooling and heating onto organic structures.
  • a pre-programmed trigger function for actions selected from the group consisting of: chemistry delivery, mechanical force action, charge injection, light emitting, voltage application, cooling and heating onto organic 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 preset value, an action or set of actions are initiated and taken.
  • the trigger 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.
  • 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.
  • a targeted pH range e.g., from 6 to 8 or from 6.8 to 7.4
  • 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 biomaterial, or a biomaterial in combination with another material, or they can be interfaced or coated with a biomaterial.
  • Biomaterials can include naturally occurring materials, synthesized materials, or composite of naturally occurring materials (including autograft, allograft or xenograft) and synthesized materials.
  • 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.
  • 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.
  • the micro devices include one material with multiple sub-devices integrated onto one unit with one or more functionalities.
  • a suitable material include, but are not limited to, organic polymers, organic materials, biological materials, biochemical materials, inorganic conductors, inorganic semi conductors, inorganic insulators and ceramics.
  • 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.
  • 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.
  • 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 driller, micro 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.
  • 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 c
  • 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.
  • 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.
  • the micro devices can function be micro testers for continued scan and analysis of live biological system for early disease detection and prevention.
  • the micro devices can be for in vitro 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, micro acoustic mechanical, and micro superconducting mechanical properties; and have a size ranging from approximately 1 angstrom to approximately 5 millimeters.
  • micro devices can also be used for medical applications such as artery cleaning and early cancer detection and prevention in vivo.
  • 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-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 1 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 thereof.
  • the method of claim 38 further include the steps of delivering the micro device to the general area of the biological material; optionally measuring the local temperature, local pressure, local frictional force, local surface charge, local 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.
  • 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 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-biochemical-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 1 angstrom to approximately 5 millimeters.
  • each dose delivers a different drug from another dose.
  • the drugs are of different chemistries and delivering of a first drug enhances the attachment selectivity to the second drug.
  • 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-mechanical, micro-electro-bio-chemical-mechanical, micro-electro-chemical-mechanical, micro-electro-biochemical-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).
  • the micro device comprises an outer membrane and a property selected
  • 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.
  • 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.
  • 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, sensing, or 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.
  • 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; recording 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.
  • 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 1 mV.
  • 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 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.
  • 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.
  • 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 be achieved through selective absorption or adsorption of a micro device onto healthy or unhealthy cells (such as cancer cells).
  • healthy or unhealthy cells such as cancer cells.
  • 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.
  • a term consisting of the word "a” or “one” and a single noun includes the meaning of the noun in its plurality.
  • a "micro device” or “micro device” can be any of a wide range 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a micro device ranging 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.
  • 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.
  • absorption typically means a physical bonding between the surface and the material attached to it (absorbed onto it, in this case).
  • the word “adsorption” generally means a stronger, chemical bonding between the two.
  • 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).
  • a micro device can be used in "cleaning" biological organs, e.g., cleaning veins to prevent heart attack, strokes and blood clogging due to plaques and fatty deposits in the veins.
  • Fig. 1 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. 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 5 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
  • a larger micro device e.g., from about 100 microns to about 5 millimeters
  • micro device can mean a wide range of materials, properties, shapes, degree of complexity and integration, or combination thereof.
  • 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.
  • 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, 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.
  • a voltage comparator e.g
  • 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.
  • micro devices of this invention are ideal for biological applications.
  • 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.
  • MEMS micro electro mechanical devices
  • novel micro devices can measure cell properties in living organs. It is expected that the information from the measurement can be retrieved in real time for use as a diagnostic tool.
  • a micro device of this invention can be utilized to detect a cancer cell in a living organ 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.
  • the micro device with a voltage comparator is calibrated by measuring surface charge (or voltage) at known healthy cells.
  • a micro device 41 with voltage comparators 42 is used to scan the area.
  • 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.
  • 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.
  • 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.
  • the micro device 64 Once the micro device 64 is attached to the unhealthy cell, it will inject one or more cancer killing agents into the cancer cell through a micro-injector 61.
  • a logic 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.
  • 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 P2 35.
  • 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.
  • 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.
  • 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 pressure 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.
  • a micro device disclosed in this application can be used as a "smart" device for biological applications in a non invasive, real time manner.
  • 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 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.
  • the cleaning unit can be a polishing pad 9 made of polymer material(s) with desired roughness for polishing or rubbing.
  • a polishing solution can be applied at the point of micro polishing, with the use of an injector 16.
  • 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.
  • 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.
  • 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.
  • the size for a micro device for this type of cleaning application can range from about 10 microns to less than 2 millimeters, e.g., from about 100 microns to about 1.5 millimeters.
  • 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.
  • healthy cells 39 are first covered with micro devices 43 (called micro shields) with a high optical reflectivity.
  • unhealthy cells 40 such as cancer cells are removed via optical oblation, while healthy cells 39 are protected by the micro shields 43.
  • 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 and/or desired micro device properties such as charge attraction.
  • 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. 11 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.
  • the micro device injects cancer killing agent(s) into the cancer cell.
  • 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. 1 through 6.
  • Fig. 1 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 5 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. 1 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 5 which is empty once the floor 3 is
  • 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.
  • 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 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.
  • 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.

Abstract

The present invention provide micro devices for biological applications and methods of using them, wherein each micro device comprises an oater membrane and a property and has a size ranging from approximately 1 angstrom to no greater than approximately millimeters.

Description

MICRO DEVICES FOR BIOMEDICAL APPLICATIONS AND USES OF THE SAME
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 genomics, 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 drug delivery and efficient reaction mechanisms, lack of non-invasive monitoring at the microscopic level as well as preventive mechanisms and approaches, and lack of non invasive, effective, targeted disease treatment approaches and technologies. 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 Pantel 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 et al. discussed in US Patent No. 6,922,118, the deployment of MEMS for detecting biological agents, while Weissman et al. 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 modern 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 diverse functions can be integrated onto a single micro device to perform a range of functions including, 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 1 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 for 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-biochemical-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 1 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, biochemical, mechanical, acoustical, thermal, and optical properties. 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 a 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 (RF) communication chip. As such, the micro devices may be capable of local positioning, location identification, location information communication and location positioning.
In some other embodiments, the micro devices may further comprises a function selected from the group consisting of chemistry delivery function, controlled chemistry delivery function, 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 electro-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 from the group consisting of: chemistry delivery, mechanical force action, charge injection, light emitting, voltage application, cooling and heating onto organic 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 preset value, an action or set of actions are initiated and taken. In some instance, the trigger 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 biomaterial, or a biomaterial in combination with another material, or they can be interfaced or coated with a biomaterial. Biomaterials can include naturally occurring materials, synthesized materials, or composite of naturally occurring materials (including autograft, allograft or xenograft) 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, organic polymers, organic materials, biological materials, biochemical materials, inorganic conductors, inorganic semi conductors, inorganic insulators and 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 driller, micro 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 vitro 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, 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-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 1 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 thereof.
In some embodiments, the method of claim 38 further include the steps of delivering the micro device to the general area of the biological material; optionally measuring the local temperature, local pressure, local frictional force, local surface charge, local 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 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-biochemical-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 1 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 drug.
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-mechanical, micro-electro-bio-chemical-mechanical, micro-electro-chemical-mechanical, micro-electro-biochemical-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). 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, sensing, or 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; recording 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 1 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 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 be 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 range 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. 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 ranging 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 veins to prevent heart attack, strokes and blood clogging due to plaques and fatty deposits in the veins.
Brief Description of the Drawings
Fig. 1 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. 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 5 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, 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 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 organ 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 targeted 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. 15, 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 into the cancer cell through a micro-injector 61. To make sure that healthy cells are not injected due to error in attachment, a logic 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 focus 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 P2 35. 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 pressure 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 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 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. 11 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. 1 through 6.
Fig. 1 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 5 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 to 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 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 filed 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. All publications referred to above are incorporated herein by reference in their entireties.

Claims

What Is Claimed Is:
1. A micro device for applications in a biological system, 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-electrochemical-mechanical, micro-electro-bio-chemical-mechanical, micro electro mechanical, micro electromagnetic mechanical, micro acoustic mechanical, micro thermal mechanical, micro thermal electrical, micro thermal electro-mechanical, and micro superconducting mechanical properties; wherein the micro device has a size ranging from approximately 1 angstrom to approximately 5 millimeters.
2. The micro device of claim 1, comprising 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, micro thermal mechanical, micro thermal chemical mechanical, micro thermal electrical, micro thermal electro-mechanical, and micro superconducting mechanical properties.
3. The micro device of claim 1, further comprising a property selected from the group consisting of charged surface, electrical potential, chemical potential, geometrical matching, electro-magnetic, ion gradient, thermal gradient, surface tension, mechanical force, electrochemical potential, and physical force related attraction.
4. The micro device of claim 1, wherein the micro device is capable of differentiating cancer cells from normal cells.
5. The micro device of claim 1, wherein the micro device is capable of measuring microscopic properties of organ and cell structures, diagnosing organ and cell structures at a microscopic level, delivering desired chemistry to organ and cell structures at a microscopic level, delivering desired drug to organ and cell structures at a microscopic level, and
manipulating selected organ and cell structure at a microscopic level.
6. The micro device of claim 5, wherein the micro device performs the function in a non invasive manner.
7. The micro device of claim 5, wherein the micro device performs the function in real time.
8. The micro device of claim 5, wherein the micro device is capable of measuring at least one property selected from the group consisting of surface charge, resting potential, electrochemical 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.
9. The micro device of claim 1 , further comprising a global positioning system (GPS), a signal transmitter, a signal receiver, a micro-motorizer, a micro-propeller, an RF communication chip, logic circuits, and memory circuits.
10. The micro device of claim 1 , further comprising a function selected from the group consisting of chemistry delivery function, controlled chemistry delivery function, 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 electro-chemical-biological-mechanical action, triggered action based upon detected signal and triggered action based upon external instruction.
11. The micro device of claim 1 , wherein the micro device has a pre-programmed trigger function for actions selected from the group consisting of: chemistry delivery, mechanical force action, charge injection, light emitting, voltage application, cooling and heating onto organic structures.
12. The micro device of claim 11 , wherein the trigger function is achieved by the employment from a group of parameters selected from the group consisting of: 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.
13. The micro device of claim 1, wherein the micro device optionally has a dissolution capability at a targeted pH range between 30 seconds and 3 days.
14. The micro device of claim 1 , wherein the micro device comprise a material selected from the group consisting of polymer, organic, and inorganic materials relatively compatible with organic systems.
15. The micro device of claim 1, wherein the micro device has a size ranging from about 1 angstrom to about 100 millimeters.
16. The micro device of claim 1 , wherein the micro device has a size ranging from about 1 angstrom to about 100 microns.
17. The micro device of claim 1 , wherein the micro device comprises one material with multiple sub-devices integrated onto one unit with at least one functionality.
18. The micro device of claim 1 , further comprising a material selected from the group consisting of polymers, organic materials, biological materials, biochemical materials, inorganic conductors, inorganic semi conductors, inorganic insulators and ceramics.
19. The micro device of claim 18, wherein a biological material is selected from the group consisting of: artificial biological materials, natural biological materials, cultured biological materials, and combinations of natural biological materials and artificial biological materials.
20. The micro device of claim 17, wherein the micro device has a size ranging from about 0.01 micron to about 5 millimeters.
21. The micro device of claim 1 , wherein the micro device is an integrated micro device comprising one function selected from the group consisting of: sensing, detecting, measuring, calculating, analyzing, diagnosing, logic processing (decision making), transmitting, and operating or surgical functions.
22. The micro device of claim 1, further comprising 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 driller, micro 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, thermal mechanical device, thermal chemical mechanical device, thermal electro-mechanical device, heat generator, micro refrigerator, micro signal transmitter, micro signal receiver, and charge generator.
23. The micro device of claim 1 , wherein the micro device is fabricated by a method 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, biochemical processing method, mechanical manufacturing method, and laser processing method.
24. The micro device of claim 1, further comprising a cleaner, a filter, a shredder, an injector, or a pump.
25. The micro device of claim 1, further comprising a cleaner, a filter, a shredder, or an injector.
26. The micro device of claim 1 , further comprising a polishing unit with a polishing pad.
27. The micro device of claim 1, wherein the micro device has a size ranging from 10 microns to 2 millimeters.
28. The micro device of claim 1, wherein the micro device has a size ranging from 100 microns to 1.5 millimeters.
29. The micro device of claim 1, wherein the micro device is a micro tester for continued scan and analysis of live biological system for early disease detection and prevention.
30. The micro device of claim 1, further comprising a sensor, a micro tip for sample collection, a micro array for testing collected sample, a data analysis unit, or a signal transmitter.
31. The micro device of claim 1 , wherein the micro device has a size ranging from about 1 micron to about 100 microns.
32. The micro device of claim 1, wherein the micro device has a size ranging from about 10 microns to about 5 millimeters.
33. The micro device of claim 1 , wherein the micro device has a size ranging from about 2 angstroms to about 500 microns.
34. The micro device of claim 1, wherein the micro device is used for artery cleaning.
35. The micro device of claim 1, wherein the micro device is employed for early cancer detection and prevention in vivo.
36. A method of using a micro device for cleaning a biological material, comprising 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-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, micro thermal mechanical, micro thermal chemical mechanical, micro thermal electrical, micro thermal electromechanical, and micro superconducting mechanical properties; and the micro device has a size ranging from approximately 1 angstrom to approximately 5 millimeters.
37. The method of claim 36, wherein the biological material is a vein or artery in a mammal.
38. The method of claim 36, further comprising the steps of: delivering the micro device to the general area of the biological material; optionally measuring the local temperature, local pressure, local frictional force, local surface charge, local 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.
39. The method of claim 36, further comprising 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 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.
40. The method of claim 36, wherein the cleaning is carried out 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 thereof.
41. A method for delivering multiple doses of drug to a target location in vivo, comprising: 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, micro thermal mechanical, micro thermal chemical mechanical, micro thermal electrical, micro thermal electro-mechanical, and micro superconducting mechanical properties; and the micro device has a size ranging from approximately 1 angstrom to approximately 5 millimeters.
42. The method of claim 41, wherein each dose delivers a different drug from another dose.
43. The method of claim 41 , wherein the drugs are of different chemistries and delivering of a first drug enhances the attachment selectivity to the second drug.
44. A method 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-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; 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, and assisting medical treatment functions at cell structure or micro-organ level in a target area.
45. The method of claim 44, wherein the method is used for cancer treatment and comprises 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.
46. The method of claim 44, comprising 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.
47. The method of claim 44, wherein the micro device comprises 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, sensing, or measuring; and the method comprises 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.
48. The method of claim 44, wherein the micro device performs the function of diagnosing, sensing, or measuring a target site; the micro device comprises a signal sensing unit, a memory unit, a signal transmitter, a logic unit for on site decision making and micro surgery; and the method comprise the steps of: delivering the micro device to the target site and performing the diagnosing, sensing, or measuring function on the target site; recording 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.
49. The method of claim 44, wherein the micro device comprises 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.
50. The method of claim 49, wherein the micro device further comprises a voltage comparator.
51. The method of claim 50, whereby the voltage comparator has a voltage measurement sensitivity better than 1 mV.
52. The method of claim 44, wherein the method is used for cancer cell detection in a target site and comprises 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 potential, electro-chemical potential, electrical potential, surface current, bulk current, surface wettability, contact angle, adhesion properties, temperature, density, friction, hardness, compressibility, shear modulus, acoustical properties, surface tension, trace chemical concentration, pH, liquid flow rate, pressure, optical properties, absorption, adsorption, and composition.
53. A micro device for application outside a biological system, comprising an outer membrane and one property 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; wherein the micro device has a size ranging from approximately 1 angstrom to approximately 5 millimeters.
PCT/US2010/049298 2010-09-17 2010-09-17 Micro devices biomedical applications and uses of the same WO2012036697A1 (en)

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BR112013006299A BR112013006299B8 (en) 2010-09-17 2010-09-17 microdevice for applications in a biological system, and microdevice for application outside the biological system
PCT/US2010/049298 WO2012036697A1 (en) 2010-09-17 2010-09-17 Micro devices biomedical applications and uses of the same
KR1020137008453A KR101761259B1 (en) 2010-09-17 2010-09-17 Micro devices for biomedical applications and uses of the same
JP2013529116A JP5917522B2 (en) 2010-09-17 2010-09-17 Microdevices for biomedical applications and uses thereof
CN201510770386.9A CN105403690A (en) 2010-09-17 2010-09-17 Micro-device applied to biomedicine and use method thereof
EP10857394.0A EP2615968A4 (en) 2010-09-17 2010-09-17 Micro devices biomedical applications and uses of the same
CN201080070042.2A CN103237492B (en) 2010-09-17 2010-09-17 Be applied to microdevice in biomedicine and using method thereof
CA2812189A CA2812189C (en) 2010-09-17 2010-09-17 Micro devices for biomedical applications and uses of the same
IL225284A IL225284B (en) 2010-09-17 2013-03-17 Micro devices biomedical applications and uses of the same
ZA2013/02375A ZA201302375B (en) 2010-09-17 2013-04-02 Micro devices biomedical applications and uses of the same
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CA2812189A1 (en) 2012-03-22
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BR112013006299B8 (en) 2021-07-27
KR101761259B1 (en) 2017-07-25
KR20130124484A (en) 2013-11-14
IL225284A0 (en) 2013-06-27
IL225284B (en) 2018-11-29
CA2812189C (en) 2021-09-21
JP5917522B2 (en) 2016-05-18
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AU2010360764A8 (en) 2013-04-18
JP2013539669A (en) 2013-10-28

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