detection device

专利摘要:
APPARATUS TO DETECT A DISEASE IN A BIOLOGICAL MATERIAL Among others, the present invention provides an apparatus for detecting a disease, comprising a system for the administration of biological material to be detected and is capable of measuring at the microscopic level an electrical, magnetic, electromagnetic, thermal property , optical, biological, chemical, physical or mechanical acoustics of biological material.
公开号:BR112012033783B1
申请号:R112012033783-1
申请日:2011-06-30
公开日:2021-02-09
发明作者:Chris C. Yu；Xuedong Du；He Yu
申请人:Anpac Bio-Medical Science Co., Ltd.；
IPC主号:

专利说明:

Cross Reference for Related Applications
[001] This application claims priority for US Application No. 61 / 360,041, filed on June 30, 2010; US Application No. 61 / 389,960, filed on October 5, 2010; US Order No. 61 / 430,641, filed on January 7, 2011 US Order No. 61 / 467,097, filed on March 24, 2011 and US Application No. 61 / 498,954, filed on June 20, 2011, in which its contents are incorporated herein by reference in their entirety. Background of the Invention
[002] Many serious diseases with high morbidity and mortality, including cancer and heart disease, are very difficult to diagnose early and accurately. Current disease diagnosis technologies typically rely on macroscopic data and information such as body temperature, blood pressure, and scanned images of the body. For the detection of serious diseases such as cancer, many of the diagnostic devices commonly used today are based on imaging technologies, including x-rays, computed tomography and nuclear magnetic resonance (NMR). While they offer varying degrees of usefulness in diagnosing diseases, most of them cannot provide a completely accurate diagnosis that is safe and cost-effective in serious illnesses such as cancer at an early stage. In addition, many of the existing diagnostic techniques and related devices are invasive and are sometimes not easily accessible, especially in remote regions or rural areas.
[003] Even the recent DNA tests have not been shown to be effective, in a fast and reliable, accurate and economical way, in the diagnosis of a wide range of diseases. In recent years, there have been some efforts in the use of nano technologies for several biological applications, with most of the work focused on genetic mapping and moderate evolution in the field of disease detection. For example, Pantel et al. discussed the use of MicroElectromechanical Sensor Systems (MEMS) for the in vitro detection of cancer cells in the blood and bone marrow (see, for example, Klaus Pantel et al, Nature Reviews, 2008, 8, 329); Kubena et al. disclosed in US Patent Number 6,922,1 18 the implantation of MEMS to detect biological agents and Weissman et al. described in US patent number 6,330,885 using MEMS sensors for detecting the addition of biological material.
[004] However, to date, most of the technologies described above have been limited to isolated cases of detection, using relatively simple construction systems and large dimensions, but often with limited functions, and lack of sensitivity and specificity. In addition, some of the existing technologies, using nanoparticles and biological approaches, have the disadvantages of requiring complicated sample preparation procedures (such as the use of chemicals or biological markers), difficulty in interpreting the data, too much confidence in the visual alteration and color as a means of diagnosis (which is subjective and with limited resolution), making them unsuitable for the early detection of the disease stage, for example, for serious diseases such as cancer.
[005] These disadvantages demand new new solutions which not only overcome them, but also bring greater precision, specificity, efficiency, are non-invasive, and increase the detection of early stage diseases, at reduced costs. Summary of the Invention
[006] The present invention in general refers to an innovative device for disease detection that uses new microdevices (or functionalities) integrated in them to perform the diagnosis at the microscopic level in a single cell, in vivo or in vitro, a single biological molecule (for example, DNA, RNA or protein), a single biological material (for example, a virus), or another sufficiently small fundamental biological composition. These devices can be made using the state of the art of microdevice manufacturing technologies and new process flows, such as integrated circuit manufacturing technologies. As used herein, the term "disease detection device" can be interchanged with terms such as disease detection device or device integrated with microdevices, or any other similar terms with the same meaning. The apparatus of the present invention, containing several microdevices, can detect various parameters of a biological sample to be analyzed. These disease detection devices are capable of detecting diseases in their early stages with a high degree of sensitivity, specificity, speed, convenience (for example, the small size of the device), and accessibility (for example, reduced costs).
[007] A fundamental component of the detection device is to be a new class of microdevices and their inventive manufacturing processes that allow these new microdevices to operate at a much higher level than that of a conventional disease detection device or technologies due to greatly improved detection sensitivity, specificity and speed. Examples of manufacturing techniques that can be used to make the microdevices described herein include, but are not limited to, mechanical, chemical, physical-chemical, mechanical chemistry, biophysical-mechanical, electromechanical, bioelectromechanical, microelectromechanical, manufacturing techniques , electrochemistry-mechanics, electrobiochemistry-mechanics, nanofabrication techniques for integrated circuits, and semiconductor fabrication techniques and processes. For a general description of some of the applicable manufacturing technologies, see, for example, R. Zaouk et al, Introduction to Microfabrication Techniques, in Microfluidic Techniques (S. Minteer, ed.), 2006, Humana Press; Microsystem Engineering of Lab-on-a-chip Devices, 1st Ed. (Geschke, Klank & Tel Leman, eds.), John Wiley & Sons., 2004. The microdevice features that included at least feel, detect, measure, diagnose, monitor and analyze for the diagnosis of the disease. Several microdevices can be integrated in a detection device to make the device more advanced and more sophisticated for better measurement of sensitivity, specificity, speed and features, with the ability to measure the same parameter or even a set of different parameters.
[008] The optional components of the device include means to perform at least the function of directing, controlling, forcing, receiving, amplifying, or storing information from each probe. These means can be, for example, a central control unit, which includes a control circuit, an addressing unit, an amplifier circuit, a logic processing circuit, a memory unit, a specific application chip, a transmitter signal, a signal receiver, or a sensor.
[009] Specifically, one aspect of the present invention provides an apparatus for detecting a disease, each comprising a first microdevice and a first substrate supporting the microdevice, wherein the first microdevices contacts a biological material to be analyzed and is capable of measuring the microscopic level is a mechanical, electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical and mechanical, and physics of biological material property. Optionally, the device can also include a device for reading the data from the property measurement.
[0010] In some embodiments, the difference in the measured property of the biological material tested and that of a biological sample from a disease-free individual, is indicative of the possible occurrence of the disease at an early stage.
[0011] In some other embodiments, the electrical property is the surface charge, surface potential, oscillation in the electrical signal (eg, oscillation in the ions, pulsating electric field, pulsating surface charge, pulsating voltage), electric field, distribution electric field, electrical charge distribution, or impedance; the thermal property is the temperature, the chemical property is the p1-I value, ionic strength, bonding strength; physical property is density; and the mechanical property is hardness, shear strength, elongation force, fracture stress, adhesion, elasticity, and density.
[0012] In some other embodiments, each device further comprises at least one or more additional microdevice devices. In these embodiments, each of the microdevices contained in the apparatus comprises a conductive material, an electrically insulating material, or a semiconductor material; and each of the microdevices can comprise the same or different material (s) and can measure the same or different properties, at the same time, or at different times. These various microdevices can be spaced on the substrate, for example, with a distance of at least 10 angstroms. The various microdevices integrated in a disease detection device can sequentially and / or simultaneously measure various parameters in a biological material to be detected at macroscopic and / or microscopic levels. Sometimes, in a device with multiple microdevices, some microdevices can act as probes to disturb biological material and elicit a biological response from biological material, while other microdevices in the device can act as detection devices to measure the response triggered by the material biological.
[0013] In some other embodiments, each of the microdevices has a size ranging from about 1 angstrom (A) to about 5 millimeters (for example, between 5A to 1 millimeter).
[0014] In some other embodiments, the apparatus comprises one or more additional substrates on which the microdevices are placed. Each of the substrates can comprise the same or a different material (for example, a conductive or insulating material), and can present in the same or in a different form (for example, a plate or a tube), and each substrate can be an object two- or three-dimensional. They can take the form of cylinders, plates, or any other desired shapes and configurations, in order to further improve measurement sensitivity, specificity, speed, sample size, and reduce cost and size.
[0015] In terms of the detection device to integrate the microdevices, in a new design of the detection device to increase the measurement sensitivity, the microdevices mounted on two plates separated by a small distance with the sample to be measured between the two plates can be used to detect the disease with greater speed, the microdevices measuring cells, DNAs, and desired materials in the sample in parallel. The surface area of the plates can be maximized in order to have a maximum number of microdevices placed on the plates and to increase the measurement efficiency and speed. Optionally, several microdevices integrated into the surface of the plates can be spaced with their spacing corresponding to that of the cells, DNAs, and materials to be measured.
[0016] In another new configuration, a detection device integrated with the microdevices is molded in the form of a cylinder, with several microdevices with detection probes integrated / mounted on the interior surfaces of the cylinder and with the sample to be measured (for example, blood) flowing through the cylinder.
[0017] In yet another innovative configuration, an integrated detection device with microdevices is molded in the form of a rectangular tube, with several microdevices with detection probes integrated / mounted on the inner surfaces of the tube and with the sample to be measured (for example, blood) flowing through the rectangular tube.
[0018] In another aspect, the invention provides another set of apparatus for detecting a disease in a biological material, comprising a system for the administration of the biological material to be detected, and a probe and a probing device for detecting and probing of biological material.
[0019] The difference between the measured property of biological material and that of a standard biological sample is indicative of the possible occurrence of the disease.
[0020] In some embodiments, the probe and detection device comprises a first microdevice and a first substrate that supports the first microdevice, the first microdevice contacts the biological material to be detected and is capable of measuring the microscopic level, a electrical, chemical, magnetic, electromagnetic, thermal, optical, acoustic, biological, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biophysical-chemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical, mechanical, physical properties, or mechanical properties of biological material. For example, the electrical property can be the surface charge, the surface potential, the resting potential, the electric current, the electric field distribution, electric dipole, electric quadruple, three-dimensional electric cloud charge and distribution, the electrical properties in the telomere of DNA and chromosomes, or impedance; the thermal property can be the temperature, or the vibrational frequency of the material or biological molecules, the optical property can be the optical absorption, optical transmission, optical reflection, optical-electrical property, brightness, or fluorescent emission; the chemical property can be the pH value, chemical reaction, biochemical reaction, bioelectrochemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, or bonding strength; the physical property can be the density or the geometric size; the acoustic property is the frequency, the speed of acoustic waves, distribution of the intensity spectrum and acoustic distribution, acoustic intensity, acoustic absorption, or acoustic resonance; and the mechanical property is internal pressure, hardness, shear strength, elongation force, breaking stress, adhesion, frequency of mechanical resonance, elasticity, plasticity, and compressibility.
[0021] In some embodiments of the device, the detection and probe device is applied to biological material at a voltage ranging from 1 mV to about 10 V, or between I mV to about 1.0 V.
[0022] In some embodiments of the device, the first microdevice comprises a conductive material, an electrically insulating material, a biological material, and a semiconductor material
[0023] In some embodiments of the device, the first microdevice has a size ranging from about 1 angstrom to about 5 mm
[0024] In some embodiments of the apparatus, the detection and probing device further comprises one or more additional microdevices, each of which is also capable of measuring the microscopic level, the electrical, magnetic, electromagnetic, thermal, optical properties , acoustics, chemistry, biological, electromechanical, electrochemistry, electrochemistry-mechanics, biochemistry, biomechanics, bioelectromechanics, bioelectrochemistry, bioelectrochemistry-mechanics, physics or mechanics of the biological entity. The electrical property can be the surface charge, the surface potential, the resting potential, the electric current, the electric current distribution, electric dipole, electric quadripole, electrical three-dimensional cloud distribution and card, electrical properties in DNA telomeres and chromosome, or impedance; the thermal property can be the temperature, or the vibrational frequency of the biological material and molecules; the optical property can be optical absorption, optical transmission, optical reflection, electrical optical property, brightness or fluorescent emission; the chemical property can be the pH value, chemical reaction, chemical bioreaction, bioelectrochemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, or the binding force; the physical property can be the density or the geometric size; the acoustic property can be the frequency, the speed of acoustic waves, acoustic frequency and intensity distribution of the acoustic spectrum, acoustic absorption, or acoustic resonance; and the mechanical property can be internal pressure, hardness, shear strength, elongation force, stress fracture, adhesion, frequency of mechanical resonance, elasticity, plasticity, and compressibility.
[0025] In some embodiments of the apparatus, each of the other microdevices comprises a conductive material, an electrically insulating material, a biological material, or a semiconductor material. In addition, each of the other microdevices comprises a material that is the same or different from the material of the first microdevice, and is capable of measuring the same or a different property of the biological material that the first microdevice makes.
[0026] In some embodiments of the device, the first microdevice and each of the other microdevices are capable of measuring the surface charge, the surface potential, the resting potential, the electric current, the distribution of the electric field, electric dipole , electric quadruple, three-dimensional distribution of the electric cloud or charge, electrical properties in DNA telomeres and chromosomes, impedance, temperature, vibrational frequency, optical absorption, optical reflection, optical transmission, optical-electrical property, brightness, fluorescent emission, pH, reaction chemistry, chemical bioreaction, bioelectrochemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, binding force, density, geometric size, frequency, acoustic wave speed, frequency and spectrum distribution of acoustic intensity, acoustic intensity, acoustic absorption, acoustic resonance , internal pressure, hardness, shear force, elongation force, breaking stress, adhesion, frequency of mechanical resonance, elasticity, plasticity, and compressibility. They can measure the same and different properties, at the same time or at different times.
[0027] In some embodiments of the apparatus, the probing device and microdevices are placed at a desired distance from each other
[0028] In some embodiments of the device, each of the other microdevices has a size ranging from about 1 angstrom to about 5 millimeters.
[0029] In some embodiments of the apparatus, the microdevices are spaced out on the substrate by a distance of at least 10 angstroms (for example, from about 5 microns to about 100 microns).
[0030] In some embodiments of the apparatus, the substrate is in the form of a plate, a tube, or a set of tubes, or the substrate is a three-dimensional object.
[0031] In some embodiments of the apparatus, the probing and detection device further comprises a second substrate of the same or different material than the first substrate.
[0032] In some embodiments, the apparatus further comprises a device for reading data from the measurement of the property of the probing and detection device.
[0033] In some embodiments, each apparatus further comprises a fluid management system comprising a pressure generator, a pressure regulator, a throttle valve, a pressure gauge, and distribution kits. The pressure generator may include an engine piston system and a box containing compressed gas; the pressure regulator can regulate the pressure downwards and upwards to a desired value; the pressure gauge feeds back the measured value to the throttle valve, which then regulates the pressure to approach the target value.
[0034] The fluid to be administered in the device can be a liquid or gas. Examples of liquids include blood, urine, saliva, tears, saline, and sweat, while examples of the gas include nitrogen, argon, helium, neon, krypton, xenon, and radon.
[0035] In some embodiments of the apparatus, the detection and probing device further comprises a system controller comprising a preamplifier, a lock-in amplifier, an electrical meter, a thermal meter, a switching matrix, a system bus, a non-volatile storage device, a random access memory, a processor, and a user interface. The interface can include a sensor which can be, for example, a thermal sensor, a flow meter, and / or a piezo meter.
[0036] In some embodiments, the device may also include a biological interface, a controlling system, or at least a system for the recovery or treatment of hospital waste. The recovery and treatment of medical waste is carried out by the same system or through two different systems.
[0037] In some embodiments, the apparatus further includes a sample test delivery system, a test sample distribution system, a distribution channel, a pre-processing unit, a detection device, a detection system global positioning, a motion device, a signal transmitter, a signal receiver, a sensor, a memory storage unit, a logical processing unit, an application specific chip, a test sample recycling and recovery unit, a microelectromechanical device, a multifunctional device, or a microsurgical instrument to perform cleaning, maintenance or medical function. Such additional components can be manufactured by methods known in the art, for example, as described in PCT / US2011 / 024672, US Application No. 12 / 416,280, and PCT / US2010 / 041 00 1, all of which are incorporated herein. by reference in their entirety.
[0038] In some embodiments of the apparatus, the biological material administration system comprises at least one channel within which the biological material to be detected travels in a certain direction; the probe and detection device comprises at least one probe microdevice and at least one detection microdevice, wherein at least one probe microdevice is located before the detection microdevice in relation to the direction in which the biological material travels, and the probe microdevice and the detection microdevice can be attached to the inside or outside of the channel wall
[0039] In some embodiments of the apparatus, the shapes and sizes of different sections of the channel can be the same or different, the width of the channel ranges from about 1 nm to about 1 mm; the channel can be straight, curved, or angled; the inner wall of the channel defines a circular, oval, or polygonal space; the inner wall of the channel defines a circular or rectangular space, the channel is a circular carbon nanotube.
[0040] In some embodiments of the apparatus, the carbon nanotube has a diameter ranging from 0.5 nm to about 100 nm, and a length ranging from 5.0 nm to about 10 mm.
[0041] In some embodiments of the device, the inner wall of the channel has at least one hollow that can be in the same section as the probe or detection microdevice. The concave groove can be a cubic space or an angular space; the concave groove can have a depth ranging from 10 nm to about 1 mm.
[0042] In some embodiments of the device, a fluid is injected into the channel, either before or after the biological material passes through a probe micro-device, to assist the path, or for the separation of the biological material inside the channel. The delivery fluid can be injected into the channel through a fluid delivery channel connected to an opening in the channel wall.
[0043] The device can detect diseases of more than one biological material, and the channel comprises a device located inside it to separate or divide biological materials based on different levels of the same property of this biological material. The separation or dividing device can be, for example, a slit and separates or divides biological materials based on their properties, such as surface charges.
[0044] The device may also include a filtering device to remove irrelevant objects from biological material for detection.
[0045] The biological material can be DNA, DNA telomeres, RNA, chromosome, cell, cell substructure, protein, and virus.
[0046] In some embodiments, the apparatus may further include a unit for administering biological material, a channel, a detection unit, a data storage unit, a data analysis unit, a central control unit, a biological sample recirculation unit, a waste disposal unit, a pre-processing unit, a signal processing unit, or waste processing unit. All additional components can be integrated into a single device or board together with the distribution and sounding system and detection probe. The pre-processing unit may comprise a sample filtration unit; a distribution unit for delivering a desired ion, a biological component, or a biochemical component; a refill unit; a constant pressure supply unit; and a sample pre-polling disturbance unit. The sample filtration unit may comprise an inlet channel, a fluid distribution channel, an acceleration chamber, and a slit. The signal processing unit may comprise an amplifier, a lock-in amplifier, an A / D converter (analog to digital or an alternative to direct electric current), a microcomputer, a manipulator, a display, and the connections of network. The signal processing unit can collect more than one signal, and the signals can be integrated to cancel the noise or to increase the relationship between the signal and the noise.
[0047] In some embodiments of the apparatus, a biocompatible liquid is injected into the fluid distribution channel to separate the biological material, or the biocompatible fluid is injected into the entrance of the distribution fluid channel and administered to an opening in the wall of the fluid. input channel. The biocompatible fluid comprises water, saline, an oxygen-rich liquid, and plasma.
[0048] In some embodiments of the device, the angle between the inlet channel and the fluid distribution channel varies from 0 ° to about 180 °, from about 30 ° to about 150 °, to from about 60 ° to about 120 °, or from about 75 ° to about 105 °, or about 90 °; the width of each channel varies from about 1 nm to about 1 mm; and at least one of the channels comprises a sounding device connected to the side wall of the channel, in which the sounding device is capable of measuring the microscopic level an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical property , electrochemistry, electrochemistry-mechanics, biochemistry, biomechanics, bioelectromechanics, bioelectrochemistry, bioelectrochemistry-mechanics, physics and mechanics of biological material. The sample filtration unit may comprise an inlet channel, a biocompatible microfilter, and an outlet channel.
[0049] In some embodiments of the device, the biocompatible microfilter is capable of filtering a biological material based on at least one property selected from the physical size, hardness, elasticity, cut resistance, weight, surface characteristic, optics, acoustic, thermal, chemical, mechanical, biological, biochemical, electrical, electrochemical, magnetic, electromagnetic, electromechanical, electrochemical-mechanical and electrochemical-biological properties.
[0050] In some embodiments of the device, the refill unit carries nutrients or and breathing gas to the biological material. The nutrient may include a strong or weak biocompatible electrolyte, amino acid, mineral, ions, oxygen, oxygen-rich liquid, intravenous drip, glucose, or a protein, and the breathing gas may include oxygen.
[0051] In some embodiments, the biological material to be tested comprises blood, urine, saliva, tears, saline, or sweat
[0052] In yet another aspect, the invention provides an alternative apparatus for detecting a disease in a biological material. The apparatus comprises a launching chamber to launch a probe at a desired speed and direction, a detection unit, a probe object, a detection component, a channel for transporting the biological material to be tested, and the probe object .
[0053] In some embodiments of this device, the launching chamber comprises a piston to release the probe object and a channel to direct the probe object.
[0054] Yet another set of apparatus for detecting a disease in a biological material, as provided by the present invention, are those manufactured by a method which comprises: providing a substrate; sequentially depositing a first material and a second material as two layers on the substrate to form a pile of material; formatting the second material to form a desired first feature; depositing a third material on the material pile to cover the second material; optionally formatting the first material and third material to form a desired second characteristic, and optionally depositing a fourth material in the material pile; the detection device being able to interact with biological material to generate a response signal.
[0055] In some embodiments, in these methods used to manufacture the device, the second material can be standardized by microelectronic processes.
[0056] In some embodiments, in these methods used to manufacture the device, the first material and the third material can be the same or different
[0057] In some embodiments, in these methods used to manufacture the apparatus, the first material and the third material are standardized by lithography and chemical attack processes selective for the second material in order to form at least one type of characteristic in the layers of the third and first materials.
[0058] In some embodiments, in these methods used to manufacture the apparatus, the method of manufacture may further comprise capping the top of the material pile in order to form a closed ditch. The enclosed ditch can, for example, be used to observe and record characteristics and behaviors of biological material. The capping may comprise, for example, placing a second device on top of the material pile, and the second device may be a device identical to that of the detection device being enclosed, a piece of glass or crystal, or a selected functional device from the group consisting of an image forming device, an optical sensor, a memory storage device, a signal transmission, a logic processing component, a circuit for storing, transmitting and processing signals.
[0059] In some embodiments, in these methods used to manufacture the device, the first or second characteristic is selected from the group consisting of divided chambers, connected with channels, probe generator (probe), detection probes, electrical interconnection lines, optical transmission lines and piezoelectric lines. For example, the divided chambers can be for the pre-treatment of biological material ie the initial screening and reinforcement of the concentration of the biological material with disease for further tests, the chambers connected with channels are for pre-processing and detection, the channels can be for the flow of biological material, the probe generator (probe) can be for generating probes and disturbing the signal, in order to trigger a response signal from the biological material, the detection probe can be for the properties measurement of biological material and the response signal, the connective interconnecting electrical lines can be for the transmission of signals, the optical transmission lines can be for the transmission of signals, and the piezoelectric lines can be for the piezoelectric effect during probing of biological materials.
[0060] In some embodiments, in these methods used to manufacture the apparatus, the second material is standardized using lithography and chemical attack processes selective for the first material in order to form a desired component such as a detection probe
[0061] In some embodiments, in these methods used to manufacture the apparatus, the first and third materials are standardized using lithography and chemical attack processes selective for the second material, in order to form at least one type of gully in the layers of the third and first materials, in which the second material is reasonably aligned with the wall of the gully.
[0062] In some embodiments, in these methods used to manufacture the apparatus, the thickness of the fourth material is thinner than that of the third material.
[0063] In some embodiments, the second and fourth materials form detection probes.
[0064] In some embodiments, the second and fourth materials form a probe and a detector, respectively.
[0065] In some embodiments, the device may also include a device for creating images in order to observe and record the properties and behaviors of biological material.
[0066] In some embodiments, the apparatus may also include a pre-treatment unit with pre-sorting chambers and improving a biological material with disease for further testing, channels for transporting fluid samples, probes to probe and disturb the biological material to be tested in order to generate response signals, the detection probes for measuring the properties and response signals of the biological material, and an image forming device, a camera, a viewing station, a acoustic detector, a thermal detector, an ion emission detector, or a thermal recorder for the observation and recording of the properties and behaviors of biological material.
[0067] In some embodiments, the apparatus may further include a storage memory, a signal transmission, a logic processing component, or a circuit for storing data, transmitting the signal, or processing the signal. These additional devices can be manufactured using microelectronics processes on the substrate where the first material is deposited.
[0068] In some embodiments, the apparatus may have channel dimensions ranging from 2 microns x 2 microns to about 100 microns x 100 microns in cross-sectional area for a square-shaped channel, a radius ranging from about 1 micron to about 20 microns in cross-sectional area for a circular channel, and a typical probe dimension ranging from 0.5 microns x 0.5 microns to about 20 microns x 20 microns in cross-sectional area for a square-shaped probe.
[0069] In some embodiments, the apparatus may have typical channel dimensions ranging from 6 microns x 6 microns to about 14 microns x 14 microns in cross-section in a square-shaped channel, a radius that varies between about 3 microns and about 8 microns in cross-sectional area in a circular channel, and a typical probe size ranging from about 0.5 microns x 0.5 microns to about 10 microns x 10 microns in area cross section in a square-shaped probe.
[0070] In some embodiments, the first and fourth materials comprise an undoped oxide (Si02), silicon nitride, doped oxide, a polymeric material, glass or an insulating material.
[0071] In some embodiments, the second and third materials comprise an electrically conductive material, aluminum, an aluminum alloy, copper, copper alloy, tungsten, a tungsten alloy, gold, gold alloy, silver, a silver alloy, or a piezoelectric material. Examples of piezoelectric materials include, but are not limited to, quartz, berlinite, gallium, orthophosphate, GaPO4, tourmaline, ceramic, barium, titanate, BaTiO3, lead zirconate, PZT titanate, zinc oxide, aluminum nitride, and an polyvinylidene fluoride.
[0072] In still some other embodiments, the second and fourth materials comprise an electrically conductive material or a piezoelectric material. Examples of electrically conductive materials include, but are not limited to, aluminum, aluminum alloys, copper, copper alloy, tungsten, tungsten alloy, gold, gold alloy, silver, silver alloy; while examples of electric piezo material include, but are not limited to, quartz, berlinite, gallium, GaPO4 orthophosphate, tourmaline, ceramic, barium, titanate, BaTiO3, lead zirconate, PZT titanate, zinc oxide, aluminum nitride, and a polyvinylidene fluoride.
[0073] In some embodiments of the apparatus, the detection device comprises at least one probe, at least one detector, or at least one probe and detector, the probe generating a probe or disturbing signal for the biological material for the purpose of this give a response signal, while the detector measures the response signal generated in this way.
[0074] In some embodiments of the device, the second material is standardized by microelectronic processes in order to form a first desired characteristic; the first and third materials are optionally standardized through microelectronic processes to form a second desired feature; and the first and third materials can be the same, or be different.
[0075] In some embodiments, the methods for manufacturing the apparatus also include capping the top of the material pile to form a closed groove, in which such a gutter is used to transport the test sample or detection site.
[0076] One of the main innovative aspects of this patent application is the design and flows of the microdevices manufacturing process and methods for using microdevices to measure properties at the microscopic level and in a three-dimensional space, of a biological material (eg example, a single cell or a single biological molecule, such as DNA and RNA). The microdevices have microwaves arranged in a three-dimensional manner, with characteristic sizes as small as a cell, a DNA, an RNA and being able to capture, classify, probe, measure, and modify biological materials.
[0077] Another aspect of the present invention concerns methods for the manufacture of a microdevice. The methods include the deposition of various materials on a substrate and, in the interim of the deposit of two in two materials, configure the materials by microelectronic technology and associated processes, in which the microdevice is capable of measuring the microscopic level, the electrical, magnetic, electromagnetic, thermal, optical, acoustic, chemical, biological, physical, physical-chemical, biochemical, biophysical, mechanical, biomechanical, electrobiomechanical, bioelectromechanical-chemical, electromechanical-chemical, microelectromechanical of a biological material, with which the microdevice enters contact.
[0078] Yet another aspect of the present invention concerns methods for the manufacture of a microdevice, which includes the deposition of a first material on the substrate, configuring the first material by a microelectronics process to give rise to at least a residual part patterned and leaving the surface of the substrate uncovered by the first material, depositing a non-conductive material on the first processed material and the substrate, creating an opening in the second material and exposing part of the first standardized material, closing the opening in the second material with a third material . In some embodiments, the process comprises a microelectronic process with the deposition of a thin film, photolithography, engraving, cleaning and / or mechanical-chemical polishing.
However, in yet another aspect, the invention provides methods for the manufacture of a microdevice, which includes a first step of depositing a first material on a substrate; the second step, the deposition of a second material on the first material and, then, the standardization of the second material through a microtechnology or process; and repeating the second step, at least once, using a material that can be the same or different from the material of the first or second steps. The materials used in the repeated steps can be the same or different from the material of the first or second steps. In some embodiments, at least one of the materials used in the manufacture of the microdevices is a piezoelectric material or a conductive material.
[0080] In some embodiments, several microdevices manufactured, unified, and connected by physical or electrical methods can be coupled in order to constitute the most advanced devices
[0081] In some embodiments, the apparatus of the present invention can be integrated into a single device (for example, using semiconductor processing technology) or mounted on a board (for example, using computer packaging technology) .
[0082] In some embodiments, the standardization of a material is done by a microelectronics process (for example, chemical vapor deposition, physical vapor deposition, or atomic layer deposition in order to deposit various materials on a substrate such as an insulator or conductor; lithography or chemical attack to transfer patterns from design to structure; mechanical-chemical planarization, chemical cleaning to remove particles, thermal annealing peak to reduce crystal defects, diffusion or ion implantation to doping elements in specific layers). In some embodiments, planarization and standardization is done through chemical polishing, mechanical polishing, or mechanical-chemical polishing.
[0083] In some other embodiments, the methods further include the removal of a pile of several layers of materials by wet, dry chemical attack, or by chemical steam attack.
[0084] In some embodiments, the microdevice can move in any direction. For example, two microdevices can move in opposite directions
[0085] In some embodiments, the manufactured microdevice is standardized to be able to capture, classify, probe, measure, or modify a biological material; or that it can reconstitute through a cell's membrane.
[0086] Yet another aspect of the present invention relates to methods for manufacturing a device or apparatus for detecting disease in a biological material, which includes providing a substrate, sequentially depositing a first material and a second material as two layers. different on the substrate in order to form a pile of material, standardize the second material through microelectronics processes to form a desired first characteristic, depositing a third material on the material pile, optionally standardize the first and third materials through processes microelectronics to form a second desired feature, and optionally deposit a fourth material on the material pile.
[0087] In some embodiments, the methods further include the manufacturing steps (using processes that include, but are not limited to, depositing, standardizing, polishing, cleaning) additional components on the substrate before sequentially depositing the first material and the second material in the form of layers on the substrate, wherein the additional components comprise a data storage component, a signal processing component, a memory storage component, a signal transmission component, a logical processing component, and an RF (radio frequency) component.
[0088] In some other embodiments, the methods further include the steps of fabricating at least one circuit on the substrate before sequentially depositing the first material and the second layered material on the substrate, where the circuit comprises a data storage circuit, a signal processing circuit, a memory storage circuit, a signal transmission circuit, and a logical processing circuit.
[0089] In still some other embodiments, the methods of the present invention further include a planarization step, the third chemical material using a mechanical polishing process or a reverse chemical attack process, after the step of depositing the third material on the pile of material and before the standardization step of the first and the third materials.
[0090] Examples of suitable microelectronic processes include, but are not limited to, deposition of a thin layer, lithography, chemical attack, polishing, cleaning, ion implantation, diffusion, and packaging that is commonly used in microelectronics.
[0091] The first and third materials can be the same or different. They can be, for example, electrically insulating materials, such as oxide, doped oxide, silicon nitride, or a polymer.
[0092] The second material can be an electrically conductive material, a piezoelectric material, a semiconductor material, a thermal sensitive material, an optical material, a pressure sensitive material, a sensitive ion emission material, or any combination thereof. For example, the second material can be made of copper, aluminum, tungsten, gold, silver, glass, an aluminum alloy, copper alloy, a tungsten alloy, a gold alloy, a silver alloy, quartz, berlinite, orthophosphate, gallium, GaPO4, tourmaline, ceramic, barium titanate, BaTiO3, titanate, lead zirconate, PZT, zinc oxide, aluminum nitride, or a polyvinylidene fluoride.
[0093] In some embodiments, the first desired feature may be a probe, while the second desired feature may be a form of recess, or furrow in the layers of the first and third materials.
[0094] In yet another embodiment, the methods of the present invention further comprise depositing a fourth material on the material pile and then standardizing the fourth material to form a recess, such as a hole in a selected location .
[0095] In yet another embodiment, the methods of the present invention further comprise a step for removing the third material from the material pile by chemical wet or steam attack to form a detection chamber between the fourth material and the substrate. In addition, they may also include a step of removing the first material from the material pile by chemical attack on wet or steam to form a channel. The channel can connect the formed detection chamber with the additional cameras.
[0096] In yet another embodiment, the methods of the present invention further include a step for sealing or capping the top of the material pile to form a closed ditch. In an example of this step, the upper part of the material pile is sealed or covered with an additional device over the material pile. Examples of such an additional device include, but are not limited to, an imaging device and a detection probe. The aforementioned device at the top of the material stack comprises an optical device, an image forming device, camera, visualization station, acoustic detector, thermal detector, ion emission detector, and thermal recorder.
[0097] In yet another aspect, the present invention provides methods for manufacturing a device for detecting diseases in a biological material, which include providing a substrate, sequentially depositing a first and a second material as layers on the substrate to form a pile of material, standardize the second material through lithography and chemical attack to form a recessed area in the layer of the second material, depositing a third material on the material pile, removing a portion of the third material above the second material through chemical attack reverse or polishing process, standardizing the third material by lithography and chemical attack to form at least a portion of the recessed area in the layer of the third material, deposit a fourth material on the pile of material, and remove the portion of the fourth material above the third material through reverse chemical attack or polishing process in order to maintain at least one portion of the second and fourth materials in the same layer.
[0098] The first and third materials used in the methods of the present invention can be the same or different. In some embodiments, they are the same. They can be, for example, an electrically insulating material. Examples of the first and third materials include, but are not limited to, oxide, doped oxide, silicon nitride, or a polymer.
[0099] In some embodiments, after the deposition and processing of the third and fourth material, at least one more material is deposited and processed in order to form a top layer with the formation of a detection chamber or channels underneath from them.
[00100] Examples of the second material include, but are not limited to, electrically conductive materials, piezoelectric materials, semiconductor materials, thermal sensitive materials, a pressure sensitive material, an ion-sensitive material, optical material, or any combinations of these.
[00101] In some embodiments, a new detection device comprising a detection chamber and / or transport channels for the test sample is formed by methods that include the steps of: depositing a first material, standardizing the first material (“Material A”), to form at least one recessed area, depositing a second material (“material B”), the removal of the second material (“material B”) from the areas above the first material (“material A” ) using polishing and / or reverse chemical attack processes, leaving the second material (“material B”) in the recessed area of the first layer of material, deposition of a third material (“material C”) to cover the first material (“material A ”) And the second material (“ material B ”), standardization of the third material (“ material C ”) to form at least one hole smaller than the recess area (s) in the 3rd layer of material and above it, eliminating the second material (“material B”), optionally using chemical attack the vaporized or wet, forming a cavity enclosed in the first layer of material.
[00102] In still other embodiments, a new detection device can be integrated with at least one microinjector and at least one detector, in which the microinjector can inject a desired object in the biological material to be tested to generate a response from the biological material and the detector detecting the response thus generated by the biological material.
[00103] The invention further provides methods for detecting the dynamic response of a biological material to a signal. These methods include providing an apparatus comprising two microdevices of which one is a probe microdevice and the other is a detection microdevice positioned at a distance from the probe microdevice; contacting the biological material with the probe microdevice whereby the probe microdevices measures a biological property of the object at the microscopic level, or sends a stimulating signal to the biological material, and the detection microdevice measures the response of the biological material through the properties of biological material at the microscopic level. Optionally, the detection microdevice has contact with the biological material during measurements.
[00104] In some embodiments, the signal is electric, magnetic, electromagnetic, thermal, optical, acoustic, chemical, biological, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical, mechanical, physical, or mechanic.
[00105] In some other modalities, the property at the microscopic level is electric, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biochemical-physical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical or mechanical.
[00106] Examples of electrical properties include, but are not limited to, surface charge, surface potential, resting potential, electric current, electric field distribution, electric dipole, electric quadruple, three-dimensional distribution of the electric cloud and / or charge, electrical properties in DNA telomeres and chromosomes (also called the sticky end of DNA) or impedance. Examples of thermal properties include temperature, and frequency of vibration of biological material and molecules. Examples of optical properties include optical absorption, optical transmission, optical reflection, optical-electrical properties, brightness, and fluorescent emission. Examples of chemical properties include pH value, chemical reaction, chemical bioreaction, bioelectrochemical reaction, reaction speed, reaction energy, reaction speed, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior and bonding strength . Examples of physical properties include density and geometric size. Examples of acoustic properties include speed, frequency of acoustic waves, acoustic frequency and the distribution of the intensity spectrum, acoustic intensity, acoustic absorption and acoustic resonance. Examples of mechanical properties include internal pressure, hardness, shear strength, elongation force, tensile strength, adhesion, frequency of mechanical resonance, elasticity, plasticity and compressibility. Measurement data for one or more of the properties at the microscopic level can be used to detect diseases, for example, cancer in its early stage, or to estimate the life expectancy of the biological material carrier.
[00107] In some other embodiments, the apparatus also includes a third microdevice which is different from the probe microdevice and the detection microdevice; and the third microdevice measures the same or a different property of the biological material than the probing and detection microdevice probes do.
[00108] In still some other embodiments, the device also includes a microdevice clock that is different from the probe microdevice and the detection microdevice; and the clock type of the microdevice is placed at a fixed distance before the detection and probing microdevices, and detecting microdevices with a distinctive signal when a biological material passes and acts as a clock device.
[00109] Still in some embodiments, the data recorded by the detection microdevice are filtered through a phase lock-in technology to eliminate the noise not synchronized with the clock signal, and improve the signal-to-noise ratio and, therefore, , the sensitivity of the measurement.
[00110] Another aspect of the present invention relates to methods for detecting disease of a biological material, involving the provision of an apparatus comprising a channel, a detection probe, an image forming device, a memory storage component , a transmission signal component, or a logic processing component, pre-processing the biological material in order to increase its concentration, measuring the properties of the biological material, optionally contacting the biological material with the detection probe through the channel to generate a response signal, using the detection probe to detect the response signal from the biological material, optionally separating the biological material with disease from the healthy biological materials, based on the response signal, optionally sending the biological material, separated, suspicious of disease for new tests, and analyzing the response signal reaching a diagnostic conclusion. The biological material can be DNA, a substructure in a cell, a cell, or a protein.
[00111] In some embodiments, the methods of the present invention also include the detection of the response signal and the interaction or event behaviors that occur between at least two biological materials, or at least between a biological material with at least one non-biological material. biological. At least two biological materials can be different or the same, in type of composition. Examples of interactions or events occurring between at least two biological objects include, but are not limited to, a DNA colliding with another DNA, a cell colliding with another cell, a DNA colliding with a cell, a protein colliding with another protein, or a DNA colliding with a protein. Examples of interactions or events that occur between at least one biological material and at least one non-biological material include, but are not limited to, an inorganic particle colliding with a biological material, a biological particle that collides with a biological material, or a composite particle colliding with a biological material.
[00112] Examples of response signals include, but are not limited to, an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical, mechanical, biochemical, biochemical, physical, biomechanical signal , bioelectromechanical, bioelectrochemical, bioelectromechanical-chemical, physical and mechanical
[00113] Another aspect of the present invention concerns methods for detecting diseases of a biological material. Methods include providing an apparatus comprising a pretreatment unit, at least one detection device, a divided chamber with connecting channels between them, and an injection device (for example, for injecting a probe into the material to be tested), and measurement of response signals from biological material, where the probe material comprises an organic particle, an inorganic particle, a biological material, or a composite-based object.
[00114] Yet another aspect of the present invention concerns methods for detecting a disease in a biological material through interaction with a test object, which involves the provision of an apparatus comprising a launching chamber, a detection unit, and channels, launching a probe in the direction of the biological material, causing a collision between the probe and the biological material to give rise to a response signal, recording and detecting the response signal during and after the collision. The probe object can comprise an organic particle, an inorganic particle, a biological material, or a composite based object.
[00115] Yet another aspect of the present invention concerns methods for detecting a disease of a biological material in its early stage. These methods include the steps of collecting a first sample (including a cell or biological molecule) of tissue from biological material, or organs, potentially carrying the disease, collecting a second sample of the same tissue or organ from a second individual disease-free, separately contacting first and second samples, using a disease detection apparatus of the present invention, and comparing the measurement data of the first and second samples. As mentioned above, a disease detection apparatus of the present invention includes a microdevice and a substrate supporting the microdevice, wherein the microdevice is capable of measuring the microscopic level, electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological property , chemical, physical or mechanical of a biological sample.
[00116] Yet another aspect of the present invention relates to a method of cellular communication. The microdevice can generate artificial microscopic calcium (and other elements) whose oscillations stimulate intracellular biological communications. This artificial signal can be encoded to interact with cellular proteins, nuclei, and eventually regulate the cell's determination and fate.
[00117] Yet another aspect of the present invention concerns methods for determining the cellular or molecular response to a signal. The methods include the step of contacting a biological cell or molecule with a disease detection apparatus of the present invention, which includes a first microdevice, a second microdevice, and a first support substrate for the first and second microdevices. The first microdevice in the device is capable of measuring, at the microscopic level, an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical and bioelectrochemical content. mechanical, physical or mechanical of the cell, and the second microdevice contacts the cell or biological molecule and stimulates it with a signal.
[00118] In some embodiments of these methods, the device also comprises a third microdevice that is capable of measuring the same microscopic level, the same electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electromechanical-chemical property , biochemistry, biomechanics, bioelectromechanics, bioelectrochemistry, bioelectrochemistry-mechanics, physics or mechanics of the cell or biological molecule as the first microdevice is capable of doing.
[00119] In some other embodiments, the cell contacts the first, second and third microdevices in that order.
[00120] In some embodiments, the signal is electric, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical or mechanical.
[00121] In some embodiments of the apparatus of the present invention, the biological material delivery system includes at least one channel within which the biological material to be detected travels in a certain direction; the detection and probing device includes at least one probe microdevice and at least one detection microdevice, wherein at least the probe microdevice is located before the detection microdevice in relation to the direction the biological material travels, and the probing and detection microdevices can be attached to the inside or outside of the channel wall. In some other embodiments, multiple channels with different geometries are used.
[00122] In some examples of these embodiments, the detection and probing device includes at least two detection devices capable of measuring the same or different microproperties of the biological material. Examples of electrical properties include, but are not limited to, surface charge, surface potential, resting potential, electric current, electric field distribution, electric dipole, electric quadruple, three-dimensional distribution of the electric cloud and / or charge, electrical properties on the DNA telomere and chromosomes, and impedance; examples of thermal properties include temperature, frequency of vibration of biological material and molecules; examples of optical properties include optical absorption, optical transmission, optical reflection, optical-electrical properties, brightness, fluorescent emission; examples of chemical properties include pH value, chemical reaction, biochemical reaction, bioelectrochemistry, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, bond strength; examples of acoustic properties include frequency, speed of acoustic waves, acoustic frequency and intensity; distribution of spectrum intensity, acoustic intensity, acoustic absorption and acoustic resonance; examples of physical properties include density and geometric size; and examples of mechanical properties include internal pressure, hardness, shear strength, elongation force, fracture stress, adhesion, frequency of mechanical resonance, elasticity, plasticity, and compressibility. For example, detection microdevices are capable of measuring the microscopic level, surface charge, electrical potential, brightness, fluorescent emission, geometric size, shape, frequency, internal pressure, and the temperature of biological material.
[00123] In some other embodiments, the shapes and sizes of different sections of the channel can be the same or different, the width of the channel can be about 1 nm to 1 mm (for example, 1-750 nm, 1600 nm ; 100-800 nm, 200-750 nm, or 400-650 nm), the channel can be straight, curved, or angled, the inner wall of the channel defines a circular, oval, or polygonal (for example, rectangular) space .
[00124] An example of a suitable channel is a circular carbon nanotube, which can have a diameter of, for example, about 0.5 W- 100 nm, and a length of, for example, about 5.0 nm- 10 mm.
[00125] In some embodiments, the inner wall of the channel has at least one hollow that can be in the same section as the probe or detection microdevice. The concave groove can be, for example, a cubic space or an angular space. It can have a depth of, for example, about 10 nm to 1 mm.
[00126] In some other embodiments, a distribution fluid can be injected into the channel, either before or after the biological material passes through a probe microdevice, which will assist in traversing or separating the biological material inside of the channel. The suitable delivery fluid is a biocompatible liquid or solution, for example, water or saline. The delivery fluid can be injected into the channel through a fluid delivery channel connected to an opening in the channel wall. Using such a distribution fluid allows, among others, the preparation of the channel surface (in which biological material travels), the cleaning of the channel, the disinfection of the device, and increasing the measurement sensitivity of the device.
[00127] In still some other embodiments, the apparatus of the present invention can be for detecting diseases in more than one biological material, and the channel comprises a device located within it to separate or divide biological materials based on different levels of the same property. An example of such a separation or dividing device is a crack that can, for example, separate or divide biological materials based on their surface charges, density, size, or other properties, such as electrical, thermal, optical signals , chemical, physical, magnetic, electromagnetic and mechanical properties. Examples of electrical properties include, but are not limited to, surface charge, surface potential, resting potential, electric current, electric field distribution, electric dipole, electric quadruple, three-dimensional distribution of the electric cloud and / or charge, electrical properties in the DNA and chromosome telomeres, and impedance; examples of thermal properties include temperature, frequency of vibration of biological material and molecules; examples of optical properties include optical absorption, optical transmission, optical reflection, optical-electrical properties, brightness, fluorescent emission; examples of chemical properties include pH value, chemical reaction strength, biochemical reaction, bioelectrochemical reaction, reaction speed, reaction energy, reaction speed, oxygen concentration, oxygen consumption rate, ionic strength, catalytic and Link; examples of physical properties include density and geometric size; examples of acoustic properties include frequency, acoustic wave speed, acoustic frequency, intensity spectrum distribution, acoustic intensity, acoustic absorption, acoustic resonance; and examples of mechanical properties include internal pressure, hardness, fracture resistance, elongation force, stress fracture, adhesion, frequency of mechanical resonance, elasticity, plasticity, and compressibility.
[00128] In still some other embodiments, the apparatus of the present invention may further include a filtering device for removing objects irrelevant to biological material for detection
[00129] In another aspect, the invention provides methods for obtaining dynamic information from a biological material, comprising the contact of each biological material (for example, including, but not limited to, a cell, substructure of a cell, such as as a cell membrane, a DNA, an RNA, a protein or a virus), with an apparatus comprising a first microdevice, a second microdevice, and a first substrate supporting the first and second microdevices, in which the first microdevice is capable of measuring the microscopic level, an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical or mechanical property of biological material, and the second microdevice comes into contact with biological materials and stimulates them by means of a signal.
[00130] In yet another embodiment, the microdevice in the detection apparatus can communicate with biological materials such as cells, DNA, RNA, viruses, or proteins. In addition, the microdevice can capture, classify, analyze, treat and modify biological materials, such as cells, DNA, RNA, blood cells, proteins, and viruses. Specifically, an array of microdevices arranged in a desired shape can capture, classify, detect and modify DNA structures.
[00131] In some embodiments, the device also comprises a third microdevice that is capable of measuring the microscopic level the same electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, biochemical, physical or mechanical property of the cell , just like the first microdevice does. In some other embodiments, the cell contacts the first, second and third microdevices in that order. In still some other embodiments, the signal is an electrical signal, a magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical, or mechanical signal. electric.
[00132] In another aspect, this invention provides alternative methods for detecting dynamic information of biological material. Each method includes an apparatus comprising a clock microdevice, a probe microdevice, and a first detection microdevice, wherein the probe microdevice is placed between the clock microdevice and the detection microdevice; contacting the biological material with the device clock in which the microdevice clock records the arrival of the biological material, and optionally measures a property of the biological material at the microscopic level; contacting the biological material with the probe in which a periodic signal from the probe is sent to the biological material; using the detection microdevice to detect the response signal from biological material; and processing the signal detected by the detection microdevice using phase lock-in technology to filter signal components that are not synchronized with the probe signal frequency, and amplifying the signal synchronized with the probe signal.
[00133] In some embodiments of these methods, there is a distance of at least 10 angstroms between the microdevice clock and the first detection microdevice.
[00134] In some other embodiments, the response signal is an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, electrobiomechanical, bioelectrochemical, bioelectrochemical, mechanical, physical or mechanical.
[00135] In some other embodiments, the first probe microdevice optionally measures the same property of biological material at the microscopic level as the first detection microdevice.
[00136] In still some other embodiments, the apparatus used in the methods further comprises a second probe microdevice capable of sending a stimulating signal to the biological material, which is different from the signal sent by the first probe microdevice.
[00137] In still some other embodiments, the apparatus used in the methods further comprises a second detection microdevice capable of measuring the same property of biological material at the microscopic level as the first detection microdevice.
[00138] In still some other modalities, the electrical property is the surface charge, the surface potential, resting potential, electric current, electric field distribution, electric dipole, electric quadruple, three-dimensional distribution of the electric cloud or charge, properties electrical in DNA telomeres and chromosomes, or impedance; the thermal property is the temperature, vibrational frequency of the biological material or molecule; the optical property is optical absorption, optical transmission, optical reflection, optical-electrical property, brightness or fluorescent emission; the chemical property is the pH value, chemical reaction, biochemical reaction, bioelectrochemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, binding force; physical property is density and geometric size; the acoustic property is the speed of frequency of acoustic waves, acoustic frequency and the distribution of the spectrum of intensity, acoustic intensity, acoustic absorption, acoustic resonance; and the mechanical property is the internal pressure, hardness, shear strength, elongation force, breaking stress, adhesion, frequency of mechanical resonance, elasticity, plasticity, and compressibility.
[00139] In some embodiments, the data recorded by the first detection microdevice is filtered using a phase lock-in technology to eliminate noise not synchronized with the data recorded by the first probe microdevice or with the clock microdevice. The filtered data may have a higher signal-to-noise ratio.
[00140] Another innovative aspect of the present invention is the obtaining of real-time data and information at the level of the cellular structure, such as the use of a voltage microcomparer, four-point probe and other circuit diagrams to measure the cell surface and crude electrical properties, including the resting potential and the surface charge to differentiate normal cells from cancer cells. Differentiating the charge of surface cells can be an important factor in deciding whether a cell is healthy or not and, consequently, its proper treatment.
[00141] For example, for a quick approach to obtain dynamic information about a biological material (for example, a cell, a substructure of a cell, a DNA or RNA molecule, or a virus), a first microdevice is used to send a signal that disturbs the biological material to be diagnosed and then a second microdevice is used to accurately measure the response of the biological material. in one arrangement, the first microdevice and the second device are positioned at a desired distance L, while biological material to be measured flows from the first microdevice to the second microdevice. When the biological sample passes, the first microdevice, the microdevice sends a signal to the biological sample in transit, then the second microdevice detects the response or retention of the disturbance signal in the entity. From the distance between the two microdevices, time interval, the nature of the disturbance by the first microdevice, and changes measured on the biological material during transit time, the microscopic and dynamic properties of the biological material can be measured and data can be obtained . in another arrangement, the first microdevice is used to probe the biological material, first by applying a signal (such as a charge) and then detecting the response of the biological material using a second microdevice as a function of time.
[00142] Another innovative area of this application is the invention of recoil and micro-probes to measure a variety of physical properties (such as mechanical properties) of biological materials. Examples of such physical properties include, but are not limited to, hardness, shear strength, elongation force, tensile strength, and properties related to cell membranes, as membranes can represent a critical component in the diagnosis of disease.
[00143] Yet another aspect of this invention is the design of the manufacture and the integration of the different components in the disease detection apparatus. These components include, for example, a sample containment and administration unit; a variety of sample distribution channels, a central disease detection unit comprising several detection probes, a central control unit comprising a logical processing unit, a memory unit, a sensor, a signal transmitter, a signal receiver and an application specific chip; and a waste treatment unit in which the sample used can be treated, recycled, transformed for reuse or disposed of.
[00144] Another innovative aspect of the current application is the design, integration and manufacturing process flow of microdevices capable of making highly sensitive and advanced measurements of very weak signals in biological systems to detect diseases in a complicated environment where the signals are very weak, and relatively high background noise. These innovative capabilities that use the class of microdevices disclosed in the present invention to detect diseases, for example, make dynamic measurements, measurements in real time (for example, the flight time of the measurements, and combining the response signals from the detection probe) , lock-in phase technique to reduce background noise, and 4-point probes to measure very weak signals, as well as unique and innovative probes to measure various electromagnetic, electronic signals and the magnetic properties of biological samples from a single cell , biological material (for example, virus) or molecule (for example, DNA or RNA).
[00145] Finally, another aspect of the present invention relates to an apparatus for detecting diseases in a biological material. The apparatus includes a detection device manufactured by a method which comprises: providing a substrate; sequentially depositing a first material and a second material in two layers on the substrate to form a pile of material; standardize the second material by means of microelectronic processes to form a desired first characteristic; depositing a third material on the material pile in order to cover the second material; optionally, standardization of the first and third materials through microelectronic processes in order to form a desired second characteristic; and, optionally, the deposition of a fourth material on the material pile. The first and third materials can be the same or different. The detection device is capable of probing a biological material to be detected, and giving rise to a response signal.
[00146] In some embodiments, the manufacturing method also includes capping the upper part of the material pile, in order to form a closed groove.
[00147] In some other embodiments, the capping comprises sealing or capping the top of the material pile with an image forming device on the material pile.
[00148] In still some other embodiments, the device also includes a pre-processing unit (chambers) for pre-sorting and improving a biological material with disease for additional tests, channels for transporting fluid samples, probes for probe and disturb the biological material to be tested in order to generate response signals, detection probes for measuring the properties and response signals of the biological material, and an imaging device to observe and record the properties and behaviors of biological material.
[00149] In still some other embodiments, the detection device has typical dimensions of square-shaped channels ranging from 2 microns x 2 microns to about 100 microns x 100 microns in cross-sectional area, and a radius ranging between about 1 micron to about 20 microns in cross-sectional area of a circular channel; a typical square probe size ranges from about 0.5 microns x 0.5 microns to about 20 microns x 20 microns in cross sectional area. Alternatively, the detection device in a square-shaped channel has typical dimensions of about 6 x 6 microns to about 14 microns x 14 microns in cross-sectional area, a radius ranging from about 3 microns to about 8 microns cross-sectional area (circular channel) and a typical square-shaped probe dimension between 0.5 microns x 0.5 microns to about 10 microns x 10 microns cross-sectional area.
[00150] In still some embodiments, the first and fourth materials comprise, non-doped oxide (Si02), doped oxide, silicon nitride, a polymeric material, glass or an electrically insulating material; and the second and third materials comprise an electrically conductive material, aluminum, an aluminum alloy, copper, copper alloy, tungsten, a tungsten alloy, gold, gold alloy, silver, a silver alloy, an optical material, a thermal sensitive material, a magnetic material, a pressure sensitive material, a material sensitive to mechanical stress, an ion sensitive material, and a piezoelectric material.
[00151] In still some other embodiments, the second and fourth materials can be manufactured at the same level as detectors, or as probes and detectors, the first and third materials comprise, non-doped oxide (SiO2), doped oxide, silicon nitride , a polymeric material, glass or an electrically insulating material, the second and fourth materials comprise an electrically conductive material (for example, aluminum, aluminum alloys, copper, copper alloy, tungsten, a tungsten alloy, gold, alloy of gold, silver, or a silver alloy), an optical material (for example, anisotropic optical material, glass, glass-ceramics, laser media, non-linear optical material, phosphor and scintillator, transparent material), a sensitive thermal material, a magnetic material, a pressure-sensitive material, a material sensitive to mechanical stress, an ion-sensitive material, and a piezoelectric material (eg quartz, berlinite, gallium, GaPO4 orthophosphate, tur malin, ceramics, barium, titanate, BaTiO3, lead zirconate, PZT titanate, zinc oxide, aluminum nitride, and a polyvinylidene fluoride).
[00152] In other embodiments, the detection device comprises at least one probe, a detector, a probe and sensor in which the probe generates a disturbing signal for biological material to emit a response signal, and in which the detector measures the response signal thus produced.
[00153] As used herein, the term "or" is intended to include both "and" and "or". Can be exchanged with “and / or”
[00154] As used here, a singular noun is intended to include its meaning in the plural. For example, a microdevice can mean either a single microdevice or several microdevices.
[00155] As used here, “patterning” means shaping a material into a particular physical shape or pattern, including a plane (in which case “patterning” also means “planarization”)
[00156] As used herein, the term "a biological material" or "a biological sample" for analysis or testing or diagnosis refers to the object to be analyzed by a disease detection apparatus. It can be a single cell, a single molecular biological entity (for example, DNA, RNA and proteins), a simple biological material (for example, a single cell or a virus), and any other small enough unit with fundamental biological composition, or an organ sample from a tissue that may have a disease or disorder.
[00157] As used herein, the term "disease" is interchangeable with "disorder" and generally refers to any abnormal microscopic property or condition (for example, a physical condition) of a biological material (for example, a mammal or species biological).
[00158] As used herein, the term "individual" generally refers to a mammal, that is, a human being
[00159] As used here, the "microscopic level" refers to the object to be analyzed by the disease detection apparatus of the present invention, being microscopic in nature and can be a single cell, a single biological molecular entity (for example, DNA, RNA and proteins), a single biological material (for example, a single cell or a virus), and another sufficiently small unit, or a fundamental biological composition.
[00160] As used herein, a "microdevice" or "microdevice" can be any of a wide variety of materials, properties, shapes and degree of complexity and integration. The term has a general meaning for an application from a single material to a very complex device that comprises several materials with multiple sub units and functions. The complexity contemplated in the present invention varies from a single small particle, to a set of desired properties for a relatively complicated unit, integrated with several functional units contained therein. For example, a simple microdevice could be a single spherical article with a diameter as small as 100 angstroms, with a desired hardness, a desired surface charge, or a desired organic chemical absorbed on its surface. A more complex device can be a 1mm microdevice with a sensor, a simple calculator, a memory unit, a logic unit, and a cutter, all integrated into it. In the first case, particles can be formed through a fumed colloidal precipitation process, while the device with several integrated components can be manufactured using various integrated circuit manufacturing processes.
[00161] The microdevices used in the present invention can vary in size (e.g., diameter) from about 1 angstrom to about 5 millimeters. For example, a microdevice ranging in size from about 10 angstroms to 100 microns can be used in the present invention to target small biological molecules, entities or compositions, such as cell structures, DNA, and bacteria. And, a microdevice ranging in size from about 1 to about 5 millimeters can be used in the present invention to target relatively large biological materials, such as a part of a human organ. As an example, a simple microdevice defined in the present patent application can be a single particle with a diameter of less than 100 angstroms, with desired surface properties (for example, with the surface charge or a chemical coating) for absorption or adsorption preferred in a target cell type.
[00162] The present invention further provides an apparatus for detecting a disease in a biological material, which comprises a pre-processing unit, a probing and detection unit, a signal processing unit, and a waste processing unit.
[00163] In some embodiments of the apparatus, the pre-processing unit includes a sample filtration unit, a refill unit, a constant pressure supply unit, and a disturbing pre-probe unit. This increases the rate of contraction of certain substances of interest (such as cancer cells) and therefore makes the device more effective and efficient for detecting the biological target object (such as cancer cells).
[00164] In some embodiments, the filter unit can filter an unwanted substance through physical filtration (ie based on the electronic charge or size of the substance), or via separation by chemical reaction (and thus completely remove unwanted substances ), biochemical reaction, electromechanical reaction, electrochemical reaction, or biological reaction.
[00165] In some embodiments, the sample filtration unit may include an inlet channel, a disturbing fluid channel, an acceleration chamber, and a slit. The slot and the inner walls of the entrance channel define two channels (ie, an upper channel and a lower channel) in which the biological material can be separated due to differences in its properties (for example, electrical or physical properties).
[00166] In some embodiments, a biocompatible fluid can be injected into the disturbing fluid channel to separate biological material. For example, biocompatible fluid can be injected from the inlet of the disturbing fluid channel and through an opening in the wall of the inlet channel. The biocompatible fluid can be liquid or semi-liquid, and can include water, saline, plasma, an oxygen-rich liquid, or any combination thereof.
[00167] In some other embodiments, the angle between the inlet channel and the boundaries of the disturbing fluid channel ranges from about 0 ° to about 180 ° (for example, from about 30 ° to about 150 °, from about 60 ° to about 120 °, or from about 75 ° to about 105 °, or about 90)
[00168] In some other embodiments, the width of each channel can vary from about 1 nm to about 1 mm (for example, from about 2 nm to about 0.6 mm or about 10 nm to about 0.2 mm.
[00169] In some other embodiments, at least one of the channels comprises a sounding device connected to the side wall of the channel, and the sounding device is capable of measuring the microscopic level, an electrical, magnetic, electromagnetic property or signal, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical and / or mechanical of biological material. Examples of electrical property include surface rate, surface potential, resting potential, electrical current and distribution, electrical dipole, electrical quadripole electrical, distribution of the three-dimensional electrical cloud or charge, electrical properties in DNA telomeres and chromosomes, and impedance. Examples of thermal properties include temperature and frequency of vibration. Examples of optical properties include optical absorption, optical transmission, optical reflection, optical-electrical properties, brightness and fluorescent emission. Examples of the chemical property include pH value, chemical reaction, chemical bioreaction, bioelectrochemical reaction, reaction speed, reaction energy, reaction speed, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, strength and adhesion . Examples of physical properties include density and geometric size. Examples of acoustic properties include frequency, acoustic wave velocity, acoustic intensity, intensity spectrum distribution, acoustic absorption and acoustic resonance. Examples of mechanical properties include internal pressure, hardness, shear strength, elongation force, tensile strength, adhesion, frequency of mechanical resonance, elasticity, plasticity and compressibility.
[00170] In some embodiments, at least one of the channels comprises two probing devices connected to the side walls of the channel, and the probing devices being able to measure the microscopic level or electrical, magnetic, electromagnetic, thermal, optical level , acoustic, chemical, biological, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, and the physical and mechanical properties of biological material. Drilling devices measure the same or different properties, at the same time or at different times.
[00171] The two or more sounding devices can be placed at a desired distance from each other (of at least 10 angstroms). Examples of the desired distance are from 10 nm to about 100 mm, from 100 nm to about 10 mm, from 1 mm to about 10 mm.
[00172] In some embodiments, the sample filtration unit may include an input channel, a biocompatible filter, an output channel, or any combination thereof. When a biological material passes through the inlet channel to the outlet channel, a biological material that is larger than the filter orifice will be blocked against the outlet channel, and that biological material will be washed into the outlet channel. A biocompatible fluid is injected from the outlet to transport the accumulated biological material around the filter and flush the channel. The biological material with a large size is then filtered for further analysis and detection in the device's detection component or unit.
[00173] In some embodiments, the disturbing pre-sounding unit may include a microdevice with a channel, a slot located inside the channel, and, optionally, two plates outside the channel. The two plates can apply a signal, for example, an electronic voltage, to the biological material that travels through the channel, and separate it, based on the electronic charge that the biological material carries. The slot and the inner channels of the channel define two channels, where separate biological materials enter and, optionally, their properties are detected at the microscopic level.
[00174] In some embodiments, the disturbing pre-sounding unit applies a biological, electrical, magnetic, electromagnetic, thermal, optical, acoustic, chemical, electromechanical, electrochemical, electrochemical-mechanical, biomechanical, bioelectromechanical, bioelectrochemical signal to the object , bioelectrochemical-mechanical, physical or mechanical. The signal can be applied, for example, with the two plates described above or by other means (depending on the nature of the signal). The signal applied as can be pulsed or constant
[00175] In some embodiments, the refill unit recharges nutrients or respirator gas (such as oxygen) for biological material. Alternatively, it can also clean up metabolites from biological material. With such a loading unit, the life stability of the biological material in the sample is maintained and its use is extended, thus giving more accurate and reliable detection results. Examples of nutrients include strong or weak biocompatible electrolytes, amino acids, minerals, ions, oxygen, oxygen-rich liquids, intravenous drip, glucose and proteins. Another example of nutrients is a solution containing nanoparticles that can be selectively absorbed by certain biological materials (for example, cells and viruses).
[00176] The charging system can be separated from outside the other components of the device. Alternatively, it can also be installed inside one of the other components, for example, in the detection probe unit or in the waste processing unit.
[00177] In some other embodiments, the signal processing unit comprises an amplifier (for example, a lock-in amplifier), an AID (alternating / direct or analog to digital current), converter, a microcomputer, a manipulator, a display and network connections.
[00178] In some examples, the signal processing unit collects more than one signal (ie, multiple signals), and the multiple signals can be integrated to cancel the noise or to improve the signal-to-noise ratio. The various signals can be signals from various locations or from various times.
[00179] The biological materials that can be detected by the device include, for example, blood, urine, saliva, tears, and sweat. The detection results can indicate the possible occurrence, or presence, of a disease (for example, an early disease) in the biological material.
[00180] As used here, the term "absorption" generally means a physical connection between the surface and the material attached to it (absorbed on it, in this case). On the other hand, the term "adsorption" means, generally, a stronger, chemical bond between the two. These properties are of great importance for the present invention since they can be effectively used for selective binding to targets, through microdevices that operate at the microscopic level.
[00181] As used here, the term “contact” (as in “the first microdevice contacts a biological entity”) is intended to include “direct” (or physical) contact and “non-direct” (or indirect or non-physical). When two individuals are in "direct" contact, there is usually no measurable space or distance between the contact points of the two objects; when they are in “indirect” contact, there is a measurable space or a distance between the contact points of the two objects
[00182] As used here, the term “probe” or “sounding”, in addition to its dictionary meaning, can mean the application of a signal (for example, electrical, acoustic, magnetic or thermal signals) to an object, and thus stimulating the object and making it have some kind of intrinsic response.
[00183] As used herein, the term "electrical property" refers to surface charge, surface potential, electric field, charge distribution, electric field distribution, resting potential, action potential, or impedance of a biological material to be analyzed.
[00184] As used herein, the term "magnetic property" refers to diamagnetic, paramagnetic or ferromagnetic.
[00185] As used herein, the term "electromagnetic property" refers to a property that has both electrical and magnetic dimensions.
[00186] As used herein, the term "thermal property" refers to temperature, freezing point, melting point, evaporation temperature, glass transition temperature, and thermal conductivity.
[00187] As used herein, the term "optical property" refers to reflection, optical absorption, optical scattering, wavelength-dependent properties, color, brightness, brightness, flickering, and dispersion
[00188] As used here, the term "acoustic property" refers to the characteristics found within a structure that determine the sound quality in its relevance to be heard. It can usually be measured by the sound absorption coefficient. See, for example, United States Patent No. 3,915,016, means and methods for determining a property of an acoustic material; TJ Cox et al., Acoustic Absorbers and Diffusers, 2004, Span Press
[00189] As used here, the term "biological property" is intended to include the chemical and physical properties of a biological material.
[00190] As used herein, the term "chemical property" refers to the pH value, ionic strength, or binding force within the biological sample
[00191] As used herein, the term "physical property" refers to any measurable property, the value of which describes a physical system, at any given time in time. The physical properties of a biological sample may include, but are not limited to, absorption, albedo, area, fragility, boiling point, capacitance, color, concentration, density, dielectric charge, electrical charge, electrical conductivity, electrical impedance, electrical field, electrical potential, emission, flow rate, fluidity, frequency, inductance, intrinsic impedance, intensity, irradiation, luminance, brightness, impedance, malleability, magnetic field, magnetic flux, mass, melting point, moment, permeability, permissiveness, voltage, luminosity, solubility, specific heat, strength, temperature, voltage, thermal conductivity, speed, viscosity, volume, and wave impedance.
[00192] As used herein, the term "mechanical property" means the strength, hardness, elasticity, plasticity, fragility, ductility, shear force, elongation force, stress, fracture and adhesion of the biological sample
[00193] As used here, the term "conductive material" (or its equivalent "electrical conductor") is a material that contains moving electrical charges. A conductive material can be a metal (for example, copper, silver, or gold) or non-metallic (for example, graphite, salt solutions, plasmas, or conductive polymers). In metallic conductors, such as copper or aluminum, the charged moving particles are electrons (see electrical conduction). Positive charges can also be mobile in the form of a lattice of atoms in which electrons are absent (known as holes), or in the form of ions, such as in the electrolytes of a battery.
[00194] As used herein, the term "electrical insulating material" (also known as "insulator" or "dielectric") refers to a material that resists the flow of electrical current. An insulating material has atoms with tightly bonded valence electrons. Examples of electrically insulating materials include glass, organic polymers (for example, rubber, plastic, and Teflon).
[00195] As used herein, the term "semiconductor" (also known as "semiconductor material") refers to a material with an electrical conductivity due to the flow of electrons (as opposed to ionic conductivity) in magnitude between a conductor and an insulator. Examples of inorganic semiconductors include silicon, materials based on silicon and germanium. Examples of organic semiconductors include aromatic hydrocarbons such as polycyclic aromatic compounds, pentacene, anthracene, and rubren; and organic polymeric semiconductors, such as poly (3-hexylthiophene), poly (p-phenylene-vinylene), polyacetylene and their derivatives. Semiconductor materials can be crystalline solids (eg, silicon), amorphous (eg, hydrogenated amorphous silicon and mixtures of arsenic, selenium and tellurium, in a variety of proportions), or even liquids.
[00196] As used here, the term "biological material" has the same meaning as "biomaterial", as understood by an expert in the art. Without limiting their meaning, biological or biomaterials can generally be produced either in nature or synthesized in the laboratory, using a variety of chemical approaches, using organic compounds (for example, small organic molecules or polymers) or organic compounds (for example, metallic or ceramic components). In general, they can be used and / or adapted for a medical application, and therefore comprise all or part of a biomedical structure or device that performs, enhances, or replaces a natural function. These functions can be benign, like those used for a heart valve, or they can be bioactive with more interactive functionality, such as hydroxyl-apatite-coated hip implants. Biomaterials can also be used every day in dental applications, surgery, and in drug administration. For example, a construction with impregnated pharmaceuticals can be placed inside the body, which allows the prolonged release of a drug over an extended period of time. A biomaterial can also be an autograft, allograft or xenograft, which can be used as a transplant material. All of these materials, which have found applications in other medical or biomedical fields, can also be used in the present invention.
[00197] As used herein, the term "microelectronic process or technology" generally includes the technologies or processes used for the manufacture of microelectronic and optical-electronic components. Examples include lithography, engraving (for example, wet chemical, dry or chemical vapor attack), oxidation, diffusion, implantation, annealing, film deposition, cleaning, direct implantation, polishing, planarization (for example, mechanical polishing -chemical), epitaxial growth, metallization, process integration, simulation, or any combination of these. Additional descriptions of microelectronic technologies and processes can be found, for example, Jaeger, Introduction to Microelectronic Fabrication, 2nd Ed., Prentice Hall, 2002; Ralph E. Williams, Modem GaAs Processing Methods, 2nd Ed., Artech House, 1990; Robert F. Pierret, Advanced Semiconductor Fundamentals, 2nd Ed., Prentice Hall, 2002; S. Campbell, The Science and Engineering of Microeletronic Fabrication, 2nd Ed., Oxford University Press, 2001, the contents of which are hereby incorporated by reference in their entirety.
[00198] As used herein, the term “selective” as it appears, for example, “material B standardized using a process a of microelectronics selective for material A”, means that the process is effective in the microelectronics of material B, but not on material A, or it is substantially more effective on material B than on material A (i.e., resulting in a much higher rate of removing material from B than material from A and thus removing much more material B than material A.
[00199] As used here, the term "carbon nanotube" generally refers to carbon allotropes with a cylindrical nanostructure. See, for example, Carbon Nanotube Science, by P.J.F. Harris, Cambridge University Press, 2009, for more details on carbon nanotubes.
[00200] Through the use of a single microdevice or a combination of microdevices integrated in a disease detection device, the disease detection capabilities can be significantly improved in terms of sensitivity, specificity, speed and cost, device size, functionality and ease of use, along with reduced invasiveness and side effects. A large number of types of microdevices capable of measuring a wide range of microscopic properties in biological samples to detect diseases can be integrated into a single detection device that uses manufacturing microtechnologies and new process flows disclosed here. On the other hand, for the purposes of demonstration and illustration, some new detailed examples have been shown here, illustrating how microelectronics and manufacturing nanotechniques and associated process flows can be used to manufacture very sensitive, multifunctional, miniaturized detection microdevices, in which the general principles and approaches of microelectronics that use the manufacture of nano technologies in the design and manufacture of high performance detection devices have been contemplated and taught, which can and should be expanded to various combinations of manufacturing processes, including, but not limited to, not limited to, thin layer deposition, standardization (lithography and chemical attack), planarization (including mechanical-chemical polishing), ion implantation, diffusion, cleaning, various materials, and various process sequences, flows and their combinations. Brief Description of the Figures
[00201] Figure 1 (a) is a perspective illustration of a disease detection apparatus of the present invention in which a biological sample is set in motion through it. Figure 1 (b) and Figure 1 (c) illustrate the apparatus comprising the multiple detection of individual microdevices.
[00202] Figure 2 (a) is a cross-sectional illustration of a disease detection apparatus of the present invention with several microdevices. The biological sample is placed in, or moving through, the device, while one or more microscopic properties of this biological sample are measured with the various microdevices. Figures 2 (b) -2 (l) are perspective illustrations of the new process flow for the manufacture of the microdevice. Figures 2 (m) -2 (n) are a cross-sectional view of an apparatus comprising multiple individual microdevices
[00203] Figure 3 is a cross-sectional illustration of a disease detection apparatus of the present invention with several different detection probe microdevices. The biological sample is placed in, or moving through, the device, and one or more microscopic properties of this sample are measured with the multiple microdevice.
[00204] Figure 4 is a perspective illustration of a disease detection apparatus of the present invention. It includes two plates separated by a narrow spacing with a biological sample to be analyzed placed between the plates, with several microdevices placed on the inner surfaces of the plates to measure one or several desired parameters of the sample at the microscopic level.
[00205] Figure 5 illustrates a new process flow for the manufacture of a disease detection apparatus of the present invention, using microelectronics technologies.
[00206] Figure 6 is a perspective illustration of a disease detection apparatus manufactured by a method of the present invention. The device is able to probe a single cell and measure and its microscopic properties.
[00207] Figure 7 is a cross-sectional illustration of a disease detection apparatus of the present invention with several microdevices placed at a desired distance during transit time, and whose measurements have greater sensitivity, specificity and speed, including information dynamic that varies with time.
[00208] Figure 8 is a perspective illustration of a new set of microscopic probes, included in a disease detection apparatus of the present invention, to detect various electronic or magnetic states, configurations, or other properties of a biological sample (for example, example, a cell, a DNA or RNA molecule, a DNA or chromosome telomere, a virus, or a tissue sample)
[00209] Figure 9 is a perspective illustration of a new four-point probe, included in a disease detection apparatus of the present invention, which is intended for the detection of weak electronic signals in a biological sample (for example, a cell , a DNA or RNA molecule, a DNA or chromosome telomer, a virus, or a tissue sample).
[00210] Figure 10 illustrates a new flow of processes for the manufacture of a class of microdevices, capable of capturing, classifying, probing, measuring, and modifying a biological material (for example, a cell, a DNA or RNA molecule, a DNA telomere or chromosome, a virus, or a tissue sample) at the microscopic level and in a three-dimensional space.
[00211] Figure 11 illustrates a new flow of processes for the manufacture of a class of microdevices capable of measuring the physical properties of a biological material (for example, a cell, a DNA or RNA molecule, a DNA telomere or chromosome , a virus, or a tissue sample), such as its mechanical properties (for example, hardness, shear strength, tensile strength at break, elongation) and other properties related to the cell membrane.
[00212] Figure 12 illustrates how a microdevice with two microwaves is able to move in opposite directions, when an applied force can be used to probe the properties of a biological material (for example, the mechanical properties of a cell membrane).
[00213] Figure 13 illustrates a new arrangement for disease detection applications, in which both the clock signal generator and signal detection probes are used, together with the schematically recorded clock signal, the probe signal (signal detected by the microdevice probe), the signal processed and improved after filtering using the lock-in phase processing technique to increase the detected signal.
[00214] Figure 14 further illustrates a new arrangement for disease detection applications in which clock signal generators, a probe signal generator and signal detection probes are used, together with the clock signal schematically recorded , the signal detected by the probe of the microdevice in response to the probe signal, and processing and reinforcing the signal after filtering through the processing technology using lockin phase to increase the detected signal, and showing the detected signal as a function of time (response delay signal over time, in this case)
[00215] Figure 15 illustrates a new arrangement for disease detection applications, in which a new set of microfilters are used to detect biological materials by separating biological materials by their different specific properties, such as size, weight, shape , electrical properties and surface properties.
[00216] Figure 16 illustrates a fluid distribution system, which is a part of the pre-treatment for the disease detection apparatus, and which releases a sample or auxiliary material to a device, at a desired pressure and speed.
[00217] Figures 17 (b) -17 (c) illustrate a new device that can engage in cellular communications at the level of the individual cell, simulating cellular signals, and receives responses from the cell that may be an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical, or mechanical. Figure 17 (a) illustrates how the signal is processed and responded to in a single cell.
[00218] Figure 18 illustrates a diagram of a disease detection apparatus, comprising several functional modules.
[00219] Figure 19 illustrates a microdevice capable of communicating, capturing, classifying, treating, and modifying a DNA and measuring various properties of the DNA (for example, electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical properties electromechanical, electrochemistry, electrochemistry-mechanics, biochemistry, biomechanics, bioelectromechanics, electrobiochemistry, bioelectrochemistry-mechanics, physics and mechanics.
[00220] Figure 20 illustrates an apparatus of the present invention, which can detect the surface charge in biological materials and separate them by a slot based on the charge.
[00221] Figure 21 illustrates another device according to the present invention, which can detect the optical properties of biological material through a set of optical sensors
[00222] Figure 22 illustrates another apparatus of the present invention, which can separate biological materials of different geometric size, and detect their respective properties.
[00223] Figure 23 illustrates an apparatus of the present invention that can measure the acoustic property of a biological material.
[00224] Figure 24 illustrates an apparatus of the present invention that can measure the internal pressure of a biological material.
[00225] Figure 25 illustrates an apparatus of the present invention that has concave between the pairs of probes, on the bottom and on the roof of the channel.
[00226] Figure 26 illustrates another apparatus according to the present invention that has concave differently from those illustrated in Figure 25.
[00227] Figure 27 illustrates an apparatus of the present invention that has a stepped channel.
[00228] Figure 28 illustrates an apparatus of the present invention that has a set of thermal meters.
[00229] Figure 29 illustrates an apparatus of the present invention that includes a carbon nano tube as the channel with the DNA contained therein.
[00230] Figure 30 illustrates an integrated apparatus of the present invention that includes a detection device and an optical sensor
[00231] Figure 31 illustrates an integrated apparatus of the present invention that includes a detection device and a logic circuit system
[00232] Figure 32 illustrates an apparatus of the present invention that includes a detection device and a filter
[00233] Figure 33 illustrates how the microdevices of the present invention can be used to measure the geometric factors of DNA.
[00234] Figure 34 illustrates a process for the manufacture of a microdevice of the present invention with a lid on top of the furrow, to form a channel.
[00235] Figure 35 is a diagram of an apparatus of the present invention to detect a disease in a biological material
[00236] Figure 36 shows an example of a sample filtration unit
[00237] Figure 37 shows another example of a sample filtration unit
[00238] Figure 38 is a diagram of a pre-processing unit for an apparatus of the present invention
[00239] Figure 39 is a diagram of an information processing unit of an apparatus of the present invention.
[00240] Figure 40 shows the integration of multiple signal results in noise cancellation and in improving the signal / noise ratio.
[00241] Figure 41 shows an embodiment of the process of the present invention for the manufacture of a detection device of at least one detection chamber and at least one detector.
[00242] Figure 42 shows another embodiment of a process of the present invention for the manufacture of a detection device with closed detection chambers, detectors, and channels for the transport of biological samples, such as fluid samples.
[00243] Figure 43 shows a new disease detection method in which at least one probe is launched into a biological material at a desired speed and direction, resulting in a collision.
[00244] Figure 44 illustrates a new manufacturing process of this invention for the formation of multiple components with different materials at the same level as the device.
[00245] Figure 45 shows a process of the present invention for detecting a biological material using a disease detection device.
[00246] Figure 46 shows another embodiment of the detection process, in which healthy materials and biological materials with disease are separated, in which biological materials with disease are administered for further testing.
[00247] Figure 47 is a biological matrix detection device, in which a series of detection devices are manufactured in an apparatus.
[00248] Figure 48 shows another embodiment of a disease detection device of the present invention, including the inlet and outlet of the device, the channel through which the biological material passes, and the detection devices aligned along the walls of the device. channel. Detailed Description of the Invention
[00249] One aspect of the present invention relates to an apparatus for the detection, in vivo or in vitro, of diseases in a biological material (for example, the human being, of an organ, tissue or cells of a culture). Each device includes a biological fluid delivery system and a probing and detection device. The device is capable of measuring the microscopic properties of a biological sample. Through the system of constant administration of fluid pressure, microscopic biological materials can be administered inside or on the device's diagnostic microdevice. In comparison with traditional detection devices or technologies, the device of the present invention is advantageous in providing an increased detection sensitivity, specificity and speed, with reduced costs and size. The device can also include a biological interface, a control probe and a data analysis circuit, or a system for the recovery or treatment of medical waste. Additional microdevices, for example, a second detection device can also be included, or integrated, in the device to enhance the detection capability.
[00250] As an essential component of the device, the microdevice must include means to perform, at least, the function of directing, controlling, forcing, receiving, expanding and storing the information of each polling address. As an example, such means can be a central control unit, which includes a control circuit, an addressing unit, an amplifier circuit, a logic processing circuit, a memory unit, an application-specific chip, a signal transmitter , a signal receiver and a sensor.
[00251] In some embodiments, the fluid supply system comprises a pressure generator, a pressure regulator, a throttle valve, a pressure gauge, and distribution kits. As examples of these embodiments, the pressure generator may include a motor piston system and a box containing compressed gas; the pressure regulator (which can be composed of several regulators) can regulate the pressure to a desired value; the pressure gauge re-launches the measured value for the throttle valve, which then regulates the pressure to approach the target value.
[00252] The biological fluid to be administered can be a biological sample from an individual to detect a disease, or something not necessarily related to the disease. In some embodiments, the fluid to be administered is a liquid (for example, a blood sample, a urine sample, or a saline solution) or a gas (for example, nitrogen, argon, helium, neon, krypton, xenon, or radon). The pressure regulator can be a single pressure regulator or several pressure regulators, which are placed in succession, either to set a low or high value to a desired level, especially when the initial pressure is too high or too low for a single regulator adjust to the desired level, or up to a level that is acceptable for a device or final destination.
[00253] In some other embodiments, the system controller includes a preamplifier, a lock-in amplifier, an electrical measuring device, a thermal meter, a switching matrix, a system bus, a storage device non-volatile, a random access memory, a processor, and a user interface. The interface can include a sensor which can be a temperature sensor, a flow meter, a piezo meter, or another sensor.
[00254] In still some other embodiments, the apparatus of the present invention further includes a biological interface, a system controller, a system for the recovery or treatment of medical waste. The recovery and treatment of medical waste can be carried out through the same system or through two different systems.
[00255] Another aspect of the present invention provides an apparatus for interacting with a cell, which includes a device for sending a signal to the cell and, optionally, receiving a response to the signal emitted from the cell.
[00256] In some embodiments, the interaction with the cell can be probing, detection, communication, treatment, or modification of a coded signal, which can be electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical, mechanical, or a combination thereof.
[00257] In some other embodiments, the device contained in the apparatus may include several surfaces coated by one or more elements or combinations of elements, and a control system for the release of the elements. In some cases, the control system can cause the release of elements from the device's surface through thermal energy, optical energy, acoustic energy, electrical energy, electromagnetic energy, magnetic energy, radiation energy, and / or mechanical energy in a manner controlled. The energy can be in the form of pulses with desired frequencies.
[00258] In some other embodiments, the device contained in the apparatus includes a first component for storing or releasing an element or a combination of elements to the cell surface or within the cell; and a second component to control the release of the elements (for example, a circuit to control the release of the elements). The elements can be a component, a chemical compound, Ca, C, Cl, Co, Cu, H, I, Fe, Mg, Mn, N, 0, P, F, K, Na, S, Zn, or a combination of the same. The pulsed, or constant, signal can be in the form of a released element or a combination of elements, and can be carried out in solution in a liquid, gas or a combination of them. In some cases, the signal may have a frequency that ranges from about 1 x 10-4 Hz to about 100 MHz or that ranges from about 1 x 10-4 Hz to about 10 Hz, or an oscillation concentration that varies between about 1.0 nmol / L to about 10.0 mmol / L. Likewise, the signal comprises the oscillation of a biological component, a chemical compound, Ca, C, Cl, Co, Cu, H, I, Fe, Mg, Mn, N, 0, P, F, K, Na, S, Zn, or a combination thereof, for example, at desired oscillation frequencies.
[00259] In some embodiments, the signal to be sent to the cell can be in the form of an oscillating element, compound, or an oscillating density of a biological component, and a response to the signal from the cell takes the form oscillating element, compound, or oscillating density of a biological component.
[00260] In some embodiments, the device can be coated with a biological film, for example, to improve compatibility between the device and the cell.
[00261] In some other embodiments, the device may include components for generating a signal to be sent to the cell, receiving a response to the signal from the cell, analyzing the response, processing the response, and interfacing between the device and the cell.
[00262] Yet another aspect of the present invention provides devices each including a microfilter, a plug, a cell counter, a selector, a microsurgical kit, a timer, and a data processing circuit. The microfilter can discriminate abnormal cells through a physical property (for example, size, shape or speed), a mechanical property, electrical property, magnetic properties, electromagnetic properties, thermal (for example, temperature), optical properties, acoustic properties, properties biological, chemical, and biochemical properties. The devices may also include one or more microfilters. Each of these microfilters can be integrated with two cellular markers, one of which is installed at the entrance to each filter, while the other is installed at the filter exit of each well. The shape of the microfilter is a rectangle, an ellipse, a circle or polygon, and the dimensions of the microfilter are about 0.1 μm until about 500 pm, or from about 5 µm to about 200 µm. As used herein, the term "dimension" designates the physical size or characteristic of the aperture filter, that is, length, diameter, width or height. The filter can be coated with a biological film or biocompatible film in order to increase the compatibility between the device and the cell.
[00263] In some embodiments of these devices, the shutter sandwiched by two filter membranes can be controlled by a timer (thus time shutter). The timer can be triggered by the cell counter. For example, when a cell passes through the cell counter at the filter inlet, the clock is triggered to reset the shutter to the home position, and moves at a preset speed for the cell's path, and the timer records the time. the passage of cells through the cell counter, which is at the exit.
[00264] Yet another aspect of the present invention provides methods for manufacturing a microdevice with a ditch and probe embedded in the side walls of the ditch. A ditch is an unfinished tunnel (see, for example, Figure 2 (i), (2030), which can be coupled to another symmetrical ditch (see, for example, Figure 2 (k), 2031) of to form a closed channel (see, for example, Figure 2 (1), 2020) .The method may include chemical vapor deposition, physical vapor deposition, or atomic layer deposition to deposit various materials on a substrate; lithography or chemical attack to transfer design patterns to the structure; mechanical-chemical planarization to planarize the surface, chemical cleaning to remove particles, ion diffusion or implantation to dose elements in specific layers; or annealing thermals to reduce defects in crystal and activate diffuse ions. An example of such a method includes: depositing a first material on a substrate; depositing a second material on the first material and standardizing the second material via a microelectronics process (for example, lithography, chemical attack) to form a detection tip; depositing a third material on the second material and then standardizing the second material by a planarization process; deposition of a fourth material on the third material and standardization of the fourth material by a microelectronics process (for example, lithography, chemical attack) and then by a microelectronics process (for example, another chemical attack) in which the material serves as a fourth hard mask. A hard mask generally refers to a material (for example, dielectric, or an inorganic metallic compound) used in semiconductor processing as a chemical attack mask instead of polymers and other "soft" organic materials.
[00265] In some embodiments, the method further includes two coupling devices that are therefore manufactured and symmetrical (i.e., an inverted mirror) to form a detection device with channels. The entrance to each channel can optionally be bell-shaped, for example, in such a way that the size of the opening of the channel (entrance) is larger than the body of the channel, thus making it easier for a cell to enter the channel. The shape of the cross section of each channel can be a rectangle, ellipse, circle or polygon. The trenches of the two coupled microdevices can be aligned by the alignment marks projected on the microdevice layout. The trench size can vary from about 0.1 μm to about 500 μm.
[00266] Alternatively, the method may also include covering the ditch of the microdevice through a flat screen. Such a panel may include, or be made with, silicone, SiGe, SiO2, Al2O3, or other optical materials. Examples of other potentially suitable optical materials include acrylate polymer, AgInSbTe, synthetic alexandrite, arsenic triselenide, arsenic trisulfide, barium fluoride, CR-39, cadmium selenide, cadmium chloride, cesium, calcium carbonate, calcium fluoride , chalcogenide glass, gallium phosphide, GeSbTe, germanium, germanium dioxide, glass code, hydrogen silsesquioxane, Iceland stringer, liquid crystal, lithium fluoride, lumicera, METATOY, magnesium fluoride, magnesium oxide, metamaterials, super neutrons mirror, phosphorus, picarine, poly (methyl methacrylate), polycarbonate, potassium bromide, sapphire, scotophor, spectralon, metal specula, split ring vibrator, strontium fluoride, aluminum yttrium grenade, yttrium lithium fluoride, yttrium orthovanadate , ZBLAN, zinc selenide, zinc sulfide.
[00267] In other embodiments, the method may also include the integration of three or more microdevices manufactured to produce an advanced device with an array of channels.
[00268] However, yet another aspect of the present invention relates to microdevices, each including a trench, a probe incorporated into the walls or base of the trench, a support structure for moving the probe, and a set of circuitry. control, in which the microdevice is able to capture, classify and modify a DNA and measure its properties (for example, electrical, thermal or optical properties). The ditch can be used to wrap the DNA double helix.
[00269] In some embodiments, the width of the ditch bands is from about 1 nm to about 10 nm, the depth of the ditch is between about 1 nm and about 10 µm, and the length is about 1 nm up to about 10 mm. The probe can include, or be made of, a conductive material and, optionally, a flexible support structure for extending or retracting the probe. The probe can also have a tip next to the ditch and the tip corresponds spatially to either a larger groove or a smaller DNA groove. The tip can correspond spatially to the interwoven grooves of DNA, which can be variable. The tip can also match the end of each strand of the DNA helix. In some examples, the tip diameter can vary from about 1 angstrom to about 10 μm.
[00270] In some other embodiments, the microdevice may also include a set of trenches, for example, to improve efficiency.
[00271] Another aspect of the present invention concerns a set of new process flows for the manufacture of microdevices (including microwaves and microwaves indentation) for their applications in the detection of diseases through the determination of the microscopic properties of a biological sample . The microdevices can be integrated into a disease detection apparatus of the present invention to measure one or more properties at the microscopic level.
[00272] Yet another aspect of the present invention is to engage in cellular communications and regulate cellular decision or response (such as cell division, differentiation, differentiation and cell death) through fabricated signals. This could also be used to detect and treat disease.
[00273] To further increase the measurement capacity, several microdevices can be implemented in a piece of detection equipment employing the flight time technique, in which at least one probe microdevice and a microsensor are placed at a pre- known. The probe micro-device can apply a signal (for example, a voltage, a charge, an electric field, a laser beam, or an acoustic wave) to a biological sample to be measured, and the detection micro-device can measure the response from the biological sample, after the sample has traveled a known distance and a desired period of time. For example, a probe microdevice can apply an electrical charge to a first cell, and then a detection microdevice and subsequently measure the surface charge after a desired period of time (T) has passed and the cell has traveled one certain distance (L).
[00274] The microdevices contained in the apparatus of the present invention can have a wide variety of designs, structures, functionalities, and applications due to their different properties, the high degree of flexibility and the ability to integrate and miniaturize. They include, for example, a voltage comparator, a four-point probe, a calculator, a logic circuit, a memory unit, a micro-cutter, a micro-hammer, a micro-shield, a micro-dye, a micro-pin, a micro-chip, a microneedle, microwire, microwire, micro-absorber of optics, micro-mirror, micro-wave, micro-helicopter, micro-helicopter, micro-crusher, micro-pumps, micro-absorber, micro-detector of signals, micro-drill, micro-tester, micro-tester, a micro-container, a signal transmitter, a signal generator, a friction sensor, an electric charge sensor, a temperature sensor, a hardness detector, an acoustic wave generator, an optical wave generator, a generator of heat, a refrigerator and a micro-generator of charge.
[00275] In addition, it should be noted that advances in manufacturing technology have already made manufactures of a wide variety of microdevices and integration of various functions for the same device that are highly viable and cost effective. The size of the typical human cell is about 10 microns. Using the state of the art of integrated circuit manufacturing techniques, the minimum dimension defined in a microdevice can be as small as 0.1 micron or less. Thus, it is ideal for using the microdevices disclosed for biological applications.
[00276] In terms of materials for microdevices, the general principle or consideration is the compatibility of the material with a biological material. Because the time when a microdevice is in contact with a biological sample (for example, a cell, a biological molecule, such as DNA, RNA, or protein, or a tissue or organ sample) can vary, depending on its application to intended, a different material or a different combination of materials can be used to make the microdevice. In some special cases, materials can dissolve at a given pH in a controlled manner and therefore can be selected as an appropriate material. Other considerations include cost, simplicity, ease of use and practicality. With significant advances in microfabrication technologies, such as integrated circuit manufacturing technology, highly integrated devices with a minimum size as small as 0.1 micron can now be built in a commercially cost-effective manner. A good example is the design and manufacture of electromechanical microdevices (MEMS), which are now being used in a wide variety of applications in the integrated circuit industry.
[00277] Described below are several examples of apparatus of the present invention that contain a class of innovative microdevices that are integrated into the disease detection apparatus of the present invention, and its manufacturing process.
[00278] Figure 1 is a perspective illustration of a disease detection apparatus 111 of this invention in which a biological sample 211, such as a blood sample, placed in or moving through it, is tested. In this figure, an example of a disease detection apparatus 111 is in the form of a cylinder, in which a biological sample 211 flows through it (from the left side to the right side in the figure) and can be tested for one or more properties at microscopic levels.
[00279] To increase detection speed and sensitivity, a large number of microdevices can be integrated into a single disease detection device of the present invention, such as the device illustrated in Figure 1 (b) and Figure 1 (c) with microdevices spaced to measure a large number of desired entities (such as cells, DNAs, RNAs, proteins, etc.) in the biological sample. To achieve the above requirements, the detection apparatus must be optimized with its maximum contact surface area in relation to the biological sample, and with a large number of microdevices integrated into the maximized surface.
[00280] Figure 2 (a) is a cross-sectional view of a disease detection apparatus of the present invention 122 with multiple identical microdevices 311. A biological sample, such as a blood sample 211 is set in motion through it or can be tested for one or more properties at the microscopic level, including, for example, electrical properties (eg surface charge, surface potential, current and impedance, other electrical properties), magnetic properties, electromagnetic properties, mechanical properties (such as density, hardness, shear strength, strength, elongation, fracture stress, adhesion), biological characteristics, chemical properties (for example, pH, ionic strength), biochemical properties, thermal properties (for example, temperature) , And optical properties.
[00281] Instead of measuring a single property of a biological material to diagnose diseases, several microdevices can be integrated in a detection device to detect various properties. Figure 3 is a cross-sectional illustration of a disease detection apparatus of the present invention 133 with various microdevices 311, 312, 313, 314, and 315, with different detection probes, in which a sample 211, such as a sample of blood is placed, or moving through it. can be tested for various properties including, but not limited to, electrical properties (eg surface charge, surface potential, and impedance), magnetic properties, electromagnetic properties, mechanical properties (eg density, hardness and adhesion), thermal properties (ie temperature), biological properties, chemical properties (eg, pH), physical properties, acoustic properties, and optical properties.
[00282] Figures 2 (b) -2 (n) illustrate a process flow of the present invention for the manufacture of microdevices for the capture, classification, probing, measurement and modification of biological materials (for example, a single cell, a DNA and RNA molecule). First, a 2002 material (for example, a non-conductive material) and another 2003 material (for example, a conductive material) are sequentially deposited on a 2001 substrate (see Figure 2 (b) and Figure 2 (c)) . The first material 2003 is then subsequently standardized by lithography and chemical attack processes (see Figure 2 (d)). Another 2004 material is then deposited (as shown in Figure 2 (e)) and planarized (as shown in Figure 2 (f)). Another layer of material 2005 is deposited (as shown in Figure 2 (g)) and patterned as a hard mask (as shown in Figure 2 (h)), followed by chemical attack (as shown in Figure 20)), which is stopped on the substrate 2001. Figure 2 (i) is a perspective illustration of the device, while Figure 2 (j) is a vertical illustration of the device.
[00283] As shown in Figure 2 (k), the device 2080 and a symmetric mirror device 2081 can be coupled together (as shown in Figure 2 (l)). As such, the device is manufactured having the track with the probe embedded in the side wall.
[00284] As illustrated in Figure 2 (m) and Figure 2 (n), a large number of microorganism detection devices can be integrated together to improve detection efficiency.
[00285] As illustrated here, it is desirable to optimize the design of the detection device to maximize the measurement surface area, since the larger the surface area, the greater the number of microdevices, which can be placed on the detection device. detection to simultaneously measure the sample, thereby increasing the detection speed and also minimizing the amount of sample required for testing. Figure 4 is a perspective illustration of a disease detection apparatus of the present invention 144. It includes two plates separated by a narrow spacing with a sample, such as a blood sample, to be measured placed between the plates, with several microdevices placed inside.
[00286] Yet another aspect of the present invention concerns a set of manufacturing process flows for making new microdevices for the purpose of disease detection. Figure 5 illustrates a flow of a new process for the manufacture of a disease detection device, using microelectronic technologies and processes. First, the 412 material is deposited on a 411 substrate (Figure 5 (a)). Then, it is standardized by photolithography and chemical attack processes (Figure 5 (b)). After deposition, material 413 is planarized using mechanical-chemical polishing as shown in Figure 5 (d). Then, 413 recessed areas are formed in the material in the form of an orifice pattern, using photoprocesses of chemical attack and lithography, as shown in Figure 5 (e), followed by the deposition of material 414 (Figure 5 (f) ). Material 414 above the surface of material 413 is removed by mechanical-chemical polishing (Figure 5 (g), followed by deposition of material 415. Then, material 415 is standardized using chemical attack and lithography photoprocesses (Figure 5 ( i)). Then, the material 414 is deposited and its excess above the substrate 415 is removed by mechanical-chemical polishing (Figures 5 (j) and (k)). Finally, an attack process is carried out short-term chemical or chemical-mechanical polishing to excess material 415 and selective to material 414 (Figure 5) (1), resulting in a slight protrusion of material 414. Material 412 can be a piezoelectric material. applied to it in the right direction, it will expand and push upwards, resulting in upward movement at the middle tip of material 414. Thus, a two microwaves microdevice capable of measuring a range of properties (including mechanical and of biological samples, using a new flow of manufacturing processes.
[00287] The detection apparatus integrated with the microdevices disclosed in the present application are fully capable of detecting properties previously chosen in a single cell, a single-stranded DNA, an individual RNA, or the small biological content of a individual. Figure 6 is a perspective illustration of a 555 microdevice manufactured by a new flow process disclosed in this patent application (for example, the new process flow illustrated in Figure 5 above), and as such, a device is able to probe a single 666 cell and measure the cell to collect the desired parameters. Figure 6 (a) illustrates a cross-sectional view of a micro device 555 with a pair of micro probes 531 and 520, where the micro probe 531 is shaped like a tip and the micro probe 520 is shaped like a ring. Both micro531 and 520 probes can be conductive and can serve as a pair of probes to measure the electrical properties of a biological sample. Microsonde 531 is in contact with a base 518 which can be a piezoelectric material. When a voltage is applied to the base 518 made of a piezoelectric material, the base 518 can expand and push the tip of the microprobe 531 upwards, which can be useful for measuring various properties of a biological sample, such as a single cell. In Figure 6 (b), microdevice 555 is shown to measure a single cell 666, using the tip of probe 531 that penetrates through the membrane of cell 611 and into the interior space of cell 622, while ring probe 520 enters in contact with cell membrane 611 on the outside of the membrane surface. In this way, the 555 microdevice can take various measurements of the cell, including its electrical properties (eg electrical potential, current across the cell membrane, surface charge on the membrane, and impedance), mechanical properties (eg hardness, when the tip of probe 531 is designed as a micro-indentation probe), thermal properties (for example, temperature), physical and chemical properties (for example, pH).
[00288] In another aspect, the invention provides the design, integration and flow of the microdevices manufacturing process capable of making highly sensitive and advanced measurements on very weak signals in biological systems to detect diseases in a complicated environment with very weak signal and noise relatively high background. Those innovative capabilities that use the class of microdevices described in the present invention to detect diseases include, but are not limited to, making dynamic measurements, real-time measurements (for example, flight measurement time, and combining the probe signal using the detection of the response signal) lock-in phase technique to reduce background noise, and the 4-peak probe techniques to measure very weak signals, and unique and innovative probes to measure various electronic, electromagnetic and magnetic properties of samples biological in a single cell (for example, one of the DNA and chromosome telomeres), single molecule (for example, DNA, RNA and protein), single biological material (for example, virus).
[00289] For example, in a time-of-flight approach to obtain dynamic information about the biological sample (for example, a cell, a substructure of a cell, a DNA, an RNA, or a virus), a first microdevice is used to send a signal to disturb the biological material to be diagnosed and then a second microdevice is used to accurately measure the response of the biological material. in one embodiment, the first microdevice and the second microdevice are positioned at a desired or predetermined distance L, and a biological material that flows from the first microdevice to the second microdevice to be measured. When the biological material passes the first microdevice, the first microdevice sends a signal to the biological material, and then the second microdevice detects the response or retention of the disturbance signal in the biological material. From the distance between the two microdevices, time interval, nature of the disturbance by the first microdevice, and changes measured on the biological material during the flight time, the microscopic and dynamic properties of the biological material can be obtained. In another embodiment, a first microdevice is used to probe the biological material through the application of a signal (for example, an electronic charge) and the response of the biological material is detected by a second microdevice, as a function of time.
[00290] To further increase the detection sensitivity, a new disease detection process is used, in which the flight time technique is used. Figure 7 is a cross-sectional view of the detection apparatus 155 with several microdevices 321 and 331 placed at a desired distance 700 for time measurements to achieve dynamic information about a biological sample 211 (for example, a cell), shown greater sensitivity, specificity and speed of measurement. At this flight measurement time, one or more properties of biological sample 211 are first measured when sample 211 passes the first microdevice 321. The same properties are then measured again when sample 211 passes the second microdevice 331, after having traveled through distance 700, The modification of the properties of sample 211 from microdevice 321 to microdevice 331, indicates how it reacts with the surrounding environment (for example, a particular biological environment) during this period. It can also reveal and provide information about how its properties evolve over time. Alternatively, in the configuration shown in Figure 7, the microdevice can first be used as a probe to provide a probe signal (for example, an electrical charge) to sample 211 while this sample passes through microdevice 321. Subsequently, the sample response to probe signal, can be detected by the 331 microdevice as the sample passes through it (for example, alteration of the electrical charge on the sample during the journey). Measurements can be made on the biological sample 211 through contact or non-contact measurements. In one embodiment, a series of microdevices can be implanted at a desired spacing to measure the properties of biological material over time.
[00291] The use of microdevices (for example, through the manufacturing process flows of the present invention) as discussed above and illustrated in Figure 7, can be useful for detecting a set of new microscopic properties of a biological sample (for example , a cell, a cellular substructure or a biological molecule, such as DNA, RNA or protein) that have not been considered in existing detection technologies. Such microscopic properties can be electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, chemical, biobiomechanical, bio-electromechanical, deposit-electrochemical, bio-electrochemical-mechanical, physical, and mechanical properties of a physical, and mechanical properties biological sample that is a single biological material (such as a cell, a cellular substructure, a biological molecule-for example, DNA, RNA, protein or a sample of a tissue or organ). Biological materials are known to include bonds such as OH, CO, CH, to complex three-dimensional structures such as DNA and RNA. Some of them have a single signature in terms of their electronic configuration.
[00292] Some of them may have unique configurations and electrical, magnetic, electromagnetic, thermal, optical, acoustic, chemical, biological, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bio-electromechanical, bio-electrochemical, bio-mechanical and mechanical, physical and mechanical properties . The normal biological material and biological material with disease can carry different signatures, in relation to the properties mentioned above. However, none of the above parameters or properties have been used routinely as a disease detection property. Using a disease detection apparatus that includes one or more microdevices of the present invention, properties can be detected, measured, and used as useful signals for detecting diseases, especially during the initial stage of detecting serious diseases such as cancer.
[00293] Figure 8 is a perspective illustration of a new set of microscopic probes 341, 342, 343, 344, 345, 346, and 347 designed and configured to detect various electronic, magnetic, or electromagnetic states, configurations or other properties at the microscopic level in biological samples 212, 213, 214, and 215, which can be single cell, DNA, RNA, and tissue or sample. As an example, in terms of determining electronic properties, the shapes of biological samples 212, 213, 214, and 215 in Figure 8 can represent electronic monopole (sample 212), dipole (samples 213 and 214), and quadruples (sample 215 ). The microdevices 341, 342, 343, 344, 345, 346, and 347 are optimized to maximize the measurement sensitivity of these parameters, including, but not limited to, electronic states, electronic charge, electronic cloud distribution, electric field, magnetic and electromagnetic properties, and microdevices can be designed and arranged in three three-dimensional configurations. For some diseases such as cancer, electronic states and corresponding electronic properties are likely to differ between normal and cancerous cells, DNA, RNA, and tissues. Therefore, disease detection can be increased by determining electronic, magnetic and electromagnetic properties at microscopic levels, including in the cell, DNA, and RNA levels, sensitivity and specificity.
[00294] In addition to the previous examples of measurement of electrical properties (for example, charge, electronic states, electronic charge, distribution of the electronic cloud, electric field, electric current and potential, and impedance), mechanical properties (for example, hardness, density, shear strength and fracture strength) and chemical properties (for example, pH) in a single cell, and in Figure 8 to measure electrical, magnetic or electromagnetic states or biological sample configurations in cells and molecules (for example, DNA , RNA and proteins), other microdevices are disclosed in this patent application for sensitive electrical measurements.
[00295] Figure 9 is a perspective illustration of a four-peak probe to detect a weak electronic signal in a biological sample, such as a cell, in which a four-peak probe 348 is designed to measure electrical properties (impedance and weak electric current) of a biological sample 216.
[00296] One of the main aspects of the present invention is the microdevice design and manufacture process flow and methods of using the microdevices for the capture and / or measurement of biological materials (eg cells, cellular structures, DNA and RNA) at microscopic levels and in three-dimensional space, in which microdevices have microwaves arranged in three dimensions with characteristic shapes and sizes as small as a cell, DNA, or RNA, and capable of capturing, classifying, probing, measuring and modifying biological materials. Such microdevices can be manufactured using the state of the art of microelectronics processing techniques, such as those used in the manufacture of integrated circuits. Using thin film deposition technologies, such as epitaxy molecular beam (MEB) and atomic layer deposition (ALD), film thickness in a few monolayers can be achieved (for example, 4 A to 10 A). In addition, using electronic beams and / or x-ray lithography, the size of the device can be obtained as a function of the nanometer sequence, making the microdevice capable of capturing, probing, measuring, and modifying biological material (for example, a single cell, single-stranded DNA or an RNA molecule).
[00297] Figure 10 illustrates a process flow of the present invention for the manufacture of microdevices for the capture, classification, probing, measurement and modification of biological subjects (for example, a single cell, a DNA or RNA molecule). In this process flow, microelectronics processes are used to manufacture microdevices designed to achieve the aforementioned unique functions. Specifically, a first material 712 (typically a conductive material) is first deposited on a substrate 711 (Figure 10 (a) and Figure 10 (b)). The first material 712 is subsequently standardized using chemical attack and lithography process techniques (Figure 10 (c)). A second material 713 is then deposited and planarized using the chemical-mechanical polishing process to remove excess second material 713 over the first material 712 (as shown in Figure 10 (e)). Another layer of material 714 is deposited and standardized, followed by deposition and planarization by mechanic-chemical polishing of another layer 712 (Figure 10 (f)). Then, a third material 715 is deposited and standardized, using lithography and chemical attack processes (Figure 10 (g) and Figure 10 (h)), followed by the deposition and planarization of a fourth material 716, typically a material of sacrifice (Figure 10 (i) and Figure 10 (j)). The flow of the deposition and standardization process of material 712 and 715 is repeated alternately, followed by the deposition of material 716 and planarization by mechanical-chemical polishing (Figure 10 (k) - (m)), and a pile is formed of films with several layers alternated with material 712 (for example, a conductive material) and material 715 (for example, an insulator). Finally, material 716 between the layers of film 771 and 772 is removed by wet chemical attack, dry chemical attack (which may require lithography processes) or chemical vapor attack, selective for all other materials (Figure 10 (n)). As illustrated in Figure 10 (o), if 712 is a conductive material connected to an electrical circuit or an electrical source (for example, a load source), each probe tip formed by 712 in the layer (for example, 781 and 782) can have a charge or an electric field on the surface (for example, 781 and 782), which (each end of the probe) can be selected to have a positive charge or a negative charge, or a positive electric field or negative. On the other hand, the probe tip may also be sensitive to the properties of biological material to be measured (for example, electronic cloud, electric field, and temperature when the probe tip is a thermal detector, or the emission of light when the probe tip is an optical sensor). Using the source of the electrical circuit or electrical source, various combinations of electrical charge distribution or electrical field can be placed on the microdevice, as shown in Figure 10 (o) and Figure 10 (p), which can be used to separate and classify various biological materials such as a cell or a DNA molecule. For example, a biological material with an inverse charge distribution from that in Figure 10 (p) can be retained by the microdevice shown in Figure 10 (p). A matrix of microdevices with different charge or electric field distributions can trap the respective biological materials at high speed, which can serve as a sorting device. Figure 1 O (q) illustrates the use of a microdevice capable of capturing DNA and measuring different properties (for example, electrical, thermal or optical properties) of a DNA, where the tip of the probe corresponds spatially to a large groove or small amount of double-stranded DNA. Figure 10 (r) illustrates how the probe tips are connected to the electrical circuit, in which only the electrical cables are shown. It should be noted that the microdevice shown in this example can be integrated on a single chip with a billion or more of such microdevices to capture and / or screen cells, DNAs, RNAs, proteins, and other biological objects, at high speed.
[00298] Another aspect of the present invention relates to recoil and micro-probes for measuring a range of physical properties (such as mechanical properties) of biological materials. Examples of mechanical properties include hardness, shear strength, elongation strength or fracture stress and other properties related to the cell membrane, which are believed to be a critical component in the diagnosis of diseases.
[00299] Figure 11 illustrates a new flow of microdevice manufacturing processes capable of probing a variety of biological properties of objects, such as mechanical properties of a cell membrane (for example, mechanical strength of a cell membrane). In this process flow, a material 812 is first deposited on a substrate 811, followed by the deposition of another material 813 (Figure 11 (a)). It follows the standardization of material 813 using lithography and chemical attack processes, and a material 814 is deposited (Figure 11 (b)) and planarized (Figure 1 l (c)). Then, another layer of material 813 is deposited and standardized using lithography techniques and chemical attack processes to remove portions of the material 813, followed by the deposition and planarization of an 815 material (which can be a piezoelectric material and can serve as a conductor) (Figure 1 l (d)). A layer of material 813 is then deposited, followed by the deposition and standardization of an additional layer 813, deposition and planarization of material 816 (Figure 11 (e)). Then, the material 816 is placed back to a reduced thickness, and standardized, following the standardization of the triple layer of material 813 (Figure 11 (f)). Another layer 814 is deposited (Figure 11 (g)) and planarized through mechanical-chemical polishing (Figure 1 l (h)), and standardized (Fig. 11 (i)). Finally, the multiple layers 813 are removed by chemical attack, wet or dry, or by steam (Figure 11 (j)) Figure 11 (k) is a sectional sectional view of the microdevice in a plane perpendicular to that of Figure 11 (j) (90-degree rotation of Figure 110, Figure 11 (1) illustrates a microdevice with two micro-points 871 and 872, which can move in opposite directions, when a voltage is applied to the piezoelectric conductors 881 and 882, which can be used to probe biological materials such as cells.
[00300] Figure 12 is an illustration of how microdevices are manufactured using the new manufacturing process shown in Figure 1 1. In Figure 12, an 850 microdevice with two 866 and 855 microwells can move in opposite directions over the force to be applied (Figure 12 (a)). When the tips of the two probes pierce an 870 cell, as the distance between the two micro probes is increased with increasing force applied, the cell is stretched. Finally, as the applied force reaches a critical value, the cell is divided into two parts (Figure 12 (b)). The cell's dynamic response to the applied force provides information about the cell, particularly about the mechanical properties (for example, elasticity) of the cell membrane. The force at the point where the cell is torn reflects the resistance of the cell and can be called a breaking point: the greater the mechanical resistance of the cell membrane, the greater the force at the breaking point.
[00301] Another new approach provided by the present invention is the use of phase lock in the measurement to detect diseases, which reduces background noise and effectively increases the signal-to-noise ratio. In general, in this measurement method, a periodic signal is used to probe the biological sample and the coherent response to the frequency of this probe's periodic signal is detected and amplified, while other signals not coherent with the frequency of the signal are filtered. probe, and thus effectively reduces background noise. In one embodiment of this invention, a probe microdevice can send a periodic signal from the probe (for example, a pulsed laser group, a pulsed thermal wave, or an alternating electric field) to a biological material, and the response to probe signal by biological material can be detected using a micro detection device. The phase blocking technique can be used to filter out unwanted noise and improve the response signal that is synchronized with the frequency of the probe signal. The following two examples illustrate the new features of the flight detection time system, in combination with the lock-in phase detection signal technique to increase sensitivity to weak signal detection and therefore in disease detection measurement .
[00302] Figure 13 is an illustration of a new time of the flight detection system for disease detection applications. Specifically, Figure 13 (a) shows a configuration for measuring a biological material 911 using the detection probe 933 and the clock generator 922, and Figure 13 (b) contains the recorded signal 921 due to structure 922, the signal 931 recorded by probe signal 933, and processed signal 941, using the phase blocking technique to filter out noise in recorded signal 931, in which only a response synchronized with clock signal 921 is maintained. In the configuration shown in Figure 13 (a), when a biological material, such as a 911 cell passes through a 922 structure, triggers a clear signal (for example, a light scattering signal if 922 is a light source, or a sharp increase in tension if 922 is an orifice structure in a resistor). Therefore, 922 can be used to register the arrival of biological material, and as a clock when multiple structures 922 are placed at a periodic distance, as shown in the trace of the recorded signal 921 in Figure 13 (b). In addition, when 922 is placed at a known distance in front of a probe 933, it signals the arrival of biological material coming in the direction of 933, and the response of the signal recorded in 933 is delayed by a time t in relation to the signal triggered by 922, where t equals the distance between 922 and 933 divided by the speed of travel of biological material. As illustrated in Figure 13 (b), signal 921, due to structure 922, is clear and periodic with a periodicity that is proportional to the distance between structure 922, while the signal measured by sensor 933 has a high noise level and relatively weak signal related to biological material. By using the phase locking technique to filter out the noise in the recorded signal 931, by the non-synchronized detection probe 933 and by the clock signal 921, the signal-to-noise ratio can be greatly improved, as shown in signal 941 in Figure 13 (B).
[00303] Figure 14 illustrates yet another flight time arrangement for disease detection in which a clock signal generator 922, a probe signal generator 944 and a signal detection probe 955 are used, together with the schematically recorded clock signal 921, recorded total response signal 951 (with the exception of the clock signal), and signal 950 processed using the phase lock technique. In this arrangement, a probe signal generator 944 is used to disturb biological material 911 (for example, heating 911 using an optical beam, or adding an electrical charge to 911), and a response to the probe signal is subsequently measured in function of time, using a variety of detection probes 955. The filtered signal at 952 shows the dynamic response to the probe signal by 944, as it decreases with time. Since the normal and abnormal cell can respond differently to the probe signal, this array with suitable microwaves can be used to detect diseases such as cancer. In another embodiment that uses this configuration (shown in Figure 14), probe signal generator 944 can send a periodic signal to biological material 911, and the signal detected from the response of biological material by detection probe 955 can be processed based on the phase blocking technique, in which noise not synchronized with the frequency of the probe signal is filtered and the signal that is synchronized with the frequency of the probe signal is amplified.
[00304] Figure 15 is a perspective illustration of the new multi-function microfilter. A timed shutter 1502 is sandwiched between two pieces of filter membrane 1501 with grooves. When a biological material 1511 moves through the gutter, it is detected for the first time by the counter 1512, which triggers the barrier panel 1502 clock. Then, the larger cells will be filtered or blocked by the holes in the filter 1001, while only the specific objects with enough speed will be able to cross path 1503 before timed shutter 1502 closes the filter path (see Figure 15 (b)). Otherwise, it will be retained as the timed shutter 1502 moves to block the path as shown in Figure 15 (c).
[00305] Figure 16 illustrates a fluid distribution system, which includes a pressure generator, a pressure regulator, a throttle valve, a pressure gauge, and distribution kits. The fluid pressure generator 1605 holds the fluid to the desired pressure, and the pressure is further regulated by regulator 1601 and then precisely manipulated by the choke valve 1602. At the same time, the pressure is monitored in real time and fed back through the pressure gauge 1603 to the choke valve 1602. The regulated fluid is then conducted in parallel to the various devices where a constant pressure is required to conduct the fluid sample.
[00306] Figure 17 illustrates how a microdevice in a disease detection apparatus of the present invention can communicate, investigate, detect and, optionally, treat and modify biological materials at a microscopic level. Figure 17 (a) illustrates the sequence of cellular events from the recognition of the signal to determine the destinations of the cells. First, as the 1701 signals are detected by the 1702 receptors on the cell surface, the cell will integrate and encode the signals in a biologically intelligible message, such as the 1703 calcium oscillation. Therefore, what corresponds to the corresponding proteins 1704 in the cell will interact with the message, and then be modified and become proteins interacted by 1705 ions. Through translocation, these 1705 modified proteins will pass on the message transmitted to the nuclear proteins, and the controlled modification in the nuclear proteins will modulate the expression of the 1707 gene which includes transcription, translation, hypergenetic processes, and chromatin modifications. Through messenger RNA 1709, the message is, in turn, passed to specific 1710 proteins, thus changing its concentration that will determine or regulate the cell's decision or activities, such as differentiation, division, or even its death .
[00307] Figure 17 (b) illustrates an apparatus of the present invention that is capable of detecting, communicating, treating, modifying and probing a single cell, by means of contact or without contact. The device is equipped with micro probes and micro injectors that are directed and modulated by the 1720 control circuit. Each individual micro injector is supplied with a separate microcarrier, which carries the designed chemicals or compounds.
[00308] To illustrate how an apparatus of the present invention can be used to simulate an intracellular signal, calcium oscillation is considered as an example mechanism. First, a Cat-release-activation channel (CRAC) must be opened to its maximum extent, which can be achieved in several ways. In an example of the applicable methods, a biochemical material (for example, tapsigargine) stored in the 1724 cartridge is released through an injector 1725 into the cell, and the CRAC will open to stimulating the biological material. In another example of the applicable methods, the 1724 injector forces a specific tension on the cell membrane, which also causes the CRAC to open.
[00309] The Ca + 2 concentration of a solution in the 1728 injector can be regulated, since it is a desirable combination of a solution containing Ca + 2 1726, and a solution free of Ca + 2 1727. While the injector 1730 contains a solution free of Ca + 2 *, injectors 1728 and 1730 are alternately turned on and off at a desired frequency. As such, a Ca + 2 oscillation is achieved and the contents inside the cell membrane are then exposed to a Ca + 2 oscillation. Therefore, the activities or destination of the cell is being manipulated by the regulated signal generated by the device.
[00310] At the same time, the cell response (for example, in the form of an electrical, magnetic, electromagnetic, thermal, optical, acoustic or mechanical property) can be monitored and recorded by the probes integrated in this device.
[00311] Figure 17 (c) illustrates another conception of an apparatus that is capable of configuring communication with a single cell. The device is equipped with microwaves that are coated with biologically compatible compounds or elements, for example, Ca, C, Cl, Co, Cu, H, I, Fe, Mg, Mn, N, 0, P, F, K, Na , S, or Zn. These probes can generate oscillating chemical signals with such an element or compound to interact with the cell, resulting in a response that affects the activities of the cell or final destination, as described above. Likewise, this device can also probe and record the cell's response (for example, in the form of an electrical, magnetic, electromagnetic, thermal, optical, acoustic, chemical, biological, electromechanical, electrochemical, electrochemical-mechanical, biochemical property , biomechanics, bioelectromechanics, bioelectrochemistry, bioelectrochemistry-mechanics, physics, or mechanics).
[00312] Figure 18 shows the block diagram of the system of a disease detection apparatus of this invention. This example includes a fluid delivery system 1801, a biological interface 1802, a detection and probing device 1803, a system controller 1805, a medical waste treatment system 1804. The biological sample or material is transported to the interface 1802 through the fluid distribution system 1801, however, the liquid parameters (or properties) are communicated to the system controller 1805 which comprises a logic processing unit, a memory unit, an application-specific chip, a sensor , a signal transmitter, and a signal receiver; and then the 1805 system controller can give additional command to the system. The 1802 interface is an assembly that bridges a fluid sample and the detection device, and monitors the parameters or properties of the biological sample (for example, pressure, temperature, viscosity, or flow rate) and then communicates the data to the 1805 system controller while distributing the biological sample to the probe and probe detection device, and at a certain speed or pressure (which can be controlled by the 1805 system controller).
[00313] The 1805 system controller is the central commander and monitor of the entire system (or device), where all parameters and information from various modules are processed and exchanged and where instructions are given, and where the command is issued. The 1805 system controller can include, for example, a preamplifier, an electrical meter, a thermal meter, a switching matrix, a system bus, a non-volatile storage device, a random access memory, a processor, and a user interface through which the user of the device can manipulate, configure the device, read the operating parameters, and the final result. The preamplifier can process the raw signal to a recognizable signal for the meters. Meters can force and measure corresponding signals that can be, for example, electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical , physical, mechanical, and their combinations. The switching matrix can change the test leads of different probe arrays. The user interface includes inlet and outlet mounts, which seal the fluid distribution system and the probing and detection device.
[00314] The 1803 detection and probing device is the core functional module of the disease detection apparatus of the present invention, since it is the unit that probes the biological sample and collects the related cellular signals (or responses). The 1804 waste recovery and treatment system retrieves the biological waste sample to protect the privacy of its biological host, and avoids polluting the environment.
[00315] Figures 19 (b) - (n) illustrate a process flow for the manufacture of a microdevice to trap, screen, probe, measure, treat, and modify a biological material (for example, a single cell, a molecule of DNA or RNA). A first material 1902 (for example, a conductive piezoelectric material) and a second material 1903 (for example, a conductive material) are sequentially deposited on a substrate 1901 (see Figures 19 (b) and 19 (c)). The second material 1903 is subsequently standardized by lithography and chemical attack processes (see Figure 19 (d)). Then, a third material 1904 is deposited (as shown in Figure 19 (e)) and planarized (see Figure 19 (f)). A layer of a fourth material 1905 is subsequently deposited (see Figure 19 (g)) and patterned as a rigid mask (see Figure 19 (h)), followed by chemical attack to remove the third and first materials from desired areas, which accumulate on substrate 1901. Figure 19 (i) is a perspective illustration of the device, while Figure 19 (j) is a vertical illustration of the same device.
[00316] Figure 19 (k) illustrates the use of a microdevice capable of capturing 1920 DNA and measuring different properties (for example, chemical, electrical, magnetic, physical, thermal, biological, biochemical, and optical properties) of a DNA . Each tip of the 1912 probe corresponds spatially with either a larger or smaller groove of a double-stranded DNA. Meanwhile, two probes (1911 and 1910), configured at the end of the groove, can force or measure the signals at each end of the double-stranded DNA chain. The probes can be made of a conductive material, optionally with a piezoelectric support structure, which can stretch back and forth at a desired distance. All probes are enumerated, directed and controlled by a control circuit.
[00317] Figure 19 (1) shows a simplified shape of the device represented in Figure 19 (k). In this device, the probe tips correspond spatially to the interlaced grooves of a double helix DNA. The number of slot intervals between adjacent probes is variable. If necessary, the DNA can be moved (for example, by pulling through probes 1910 and 1911), and the probes can move along the ditch direction, mapping the total and / or partial properties of a DNA.
[00318] Figure 20 illustrates an apparatus of the present invention that is capable of detecting or measuring the surface load of a biological material 2010, It includes a channel, a pair of plates 2022, and a slot 2030 that separates the channel in one upper channel 2041 and a lower channel 2051. When a biological material 2010 carrying a surface charge (positive charge shown in Figure 20 (a)) passes through the channel, under the influence of the applied voltage on the 2022 plates (with positive voltage in the top and negative plate on the bottom plate), it will move towards the bottom plate, as shown in Figure 20 (b). Thus, the biological material 2010 will pass through the lower channel 2051 when it reaches the gap 2030, (If the biological material 2010 carries a negative charge, it would pass through the upper channel 2041.) In this way, a biological material with the type of charge unknown (negative or positive) can be measured using this device.
[00319] This device comprises at least two channel parts, one of which is channel 2060, where the biological material is loaded or modified, and the other comprising is a plate or crack to separate biological materials (ie, where the biological materials are separated).
[00320] As the surface load will affect the shape of a biological material, using the new and multiple plates, information on the shape and load distribution of biological materials can be obtained. The general principle and design of the microdevice can be extended to a broader scope, thus making it possible to obtain other information about the biological material through separation by applying other parameters such as the ionic gradient, thermal gradient, optical beam, or another form of energy.
[00321] Figure 21 illustrates another apparatus of the present invention for the detection or measurement of microscopic properties of a biological material 2110, using a microdevice that includes a channel, a set of probes 2120, and a set of optical sensors 2132 (see Figure 21 (a)). The signals detected by the 2120 probes can be correlated with information that includes images collected by the 2132 optical sensors to increase the detection sensitivity and specificity. Optical sensors can be, for example, a CCD camera, a fluorescence light detector, a CMOS image sensor, or any combination thereof.
[00322] Alternatively, a 2120 probe can be designed to cause optical emission, such as the emission of fluorescence light 2143 from the biological target biological material, such as cells with disease, which can then be detected by an optical probe 2132, as shown in Figure 21 (c). Specifically, biological materials can first be treated with a labeling solution, which can react selectively on cells with disease. Subsequently, after the reaction (contact or non-contact) with the 2120 probe, the optical emissions of cells with disease occur and can be detected using the 2132 optical sensors. This new process using microdevices is more sensitive than conventional methods such as fluorescence spectroscopy as the emission trigger point next to the optical probe, and the triggered signal 2143 can be recorded in real time and on site, with minimal signal loss.
[00323] Figure 22 illustrates another embodiment of the apparatus of the present invention, which can be used to separate biological materials of geometrically different size and detect their properties. It includes at least one input channel 2210, a fluid disturbing channel 2220, an acceleration chamber 2230, and two channels for selection 2240 and 2250. The angle between 2220 and 2210 is between 0 ° and 180 °. Biological material 2201 flows in the x direction between 2210 and 2230, Biocompatible distribution fluid 2202 flows between 2220 and 2230, Then liquid 2202 will accelerate 2201 in the y direction. However, the acceleration correlates with the radius of the biological materials and the larger ones are less accelerated than the smaller ones. Thus, the major and minor objects are separated into different channels. Meanwhile, the probes can optionally be mounted sideways on the side wall of 2210, 2220, 2230, 2240, and 2250, They could detect electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical and mechanical properties, the microscopic level.
[00324] The channel included in the apparatus of the present invention can have a width, for example, from 1 nm to 1 mm. The device must have at least one input channel and at least two output channels.
[00325] Figure 23 shows another apparatus of the present invention with an acoustic detector 2320 for measuring the acoustic property of a biological material 2301. This apparatus includes a 2310 channel, and at least one ultrasound emitter and an ultrasound receiver installed along the side wall of the channel. When biological material 2301 passes through channel 2310, the ultrasound signal emitted from 2320 will be received after the information in 2301 is carried by the 2330 receiver. The frequency of the ultrasound signal can be, for example, between 2 MHz and 10 GHz, and the channel ditch width can be, for example, from 1 nm to 1 mm. The acoustic transducer (ie, the ultrasound emitter) can be manufactured using a piezoelectric material (for example, quartz, berlinite, orthophosphate, gallium, GaPO4, tourmalines, ceramics, barium, titanate, BaTiO3, lead zirconate, PZT titanate, zinc oxide, aluminum nitride and polyvinylidene fluorides).
[00326] Figure 24 shows another apparatus of the present invention that includes a pressure detector of biological material 2401. It includes at least one channel 2410 and at least one piezoelectric detector 2420, When biological material 2401 passes through the channel, the piezoelectric detector 2420 will detect the pressure of 2401, transforming the information into an electrical signal, and send it to a signal reader. Likewise, the trench width in the apparatus can be, for example, from 1 nm to 1 mm, and the piezoelectric material can be, for example, quartz, berlinite, orthophosphate, gallium, GaPO4, tourmalines, ceramics, barium , titanate, BaTiO3, lead zirconate, PZT titanate, zinc oxide, aluminum nitride or polyvinylidene fluorides).
[00327] Figure 25 shows another apparatus of the present invention that includes a 2530 concave groove between a pair of probes, at the bottom or in the roof of the channel. When a biological material 2510 passes, the concave 2530 can selectively capture the biological material with special geometric characteristics and makes the probing more efficiently. The shape of the projection of the concavity can be rectangular, polygonal, ellipse or round. The probe can detect electrical, magnetic, electromagnetic, thermal, optical, acoustic, chemical, biological, physical and mechanical properties. Likewise, the width of the microwall can be, for example, from 1 nm to 1 mm. Figure 25 (a) is a top-to-bottom view of this apparatus, Figure 25 (b) is a side view, while Figure 25 (c) is a perspective view.
[00328] Figure 26 is another apparatus of the present invention that also includes concave grooves 2630 (in a different way than shown in Figure 25) at the bottom and on the roof of the channel. When a biological material 2610 passes through, the concave grooves 2630 will generate a turbulent fluidic flow, which can selectively capture microbiological objects that have certain geometric characteristics. The probe can detect electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical and mechanical properties. The depth of the concave groove can be, for example, from 10 nm to 1 mm, and the width of the channel can be, for example, from 1 nm to 1 mm.
[00329] Figure 27 illustrates an apparatus of the present invention, with a cascade channel 2710. When a biological material 2701 passes through channel 2710, pairs of probes of different distances can be used to measure different microscopic properties, or even or even the same microscopic property in several stages (2720, 2730, 2740) with the probe aside at each step. This mechanism can be used in the phase block, so that the signal for the same microscopic property can be accumulated. The probes can detect or measure microscopic electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical and mechanical properties.
[00330] Figure 28 illustrates another apparatus of the present invention with 2830 thermal meters, It includes a channel, a set of 2820 probes, and a set of 2830 thermal meters, The 2830 thermal meters can be an infrared sensor, a tester subliminal leakage transistor, or a thermistor.
[00331] Figure 29 illustrates a specific apparatus of the present invention that includes a carbon nanotube 2920 with a channel inside it 2910, probes 2940 that allow the detection of the electric microscopic field, and the magnetic, electromagnetic, thermal, optical, acoustic properties , chemical, biological, physical and mechanical. As shown, the 2920 carbon nanotube contains a 2930 double helix DNA molecule. The carbon nanotube can force and sense electrical signals through the 2940 side probes. The diameter of the carbon nanotube can be, for example, from from 0.5 nm to 50 nm, and their length can vary, for example, from 5 nm to 10 mm.
[00332] Figure 30 shows an integrated apparatus of the present invention, which includes a detection device (shown in Figure 30 (a)) and an optical sensor (shown in Figure 30 (b)), which can be, for example, a CMOS image sensor (CIS), a Charged Coupled Device (CCD), a fluorescence light detector, or another image sensor. The detection device comprises at least one probe and a channel, and the image forming device comprises at least 1 pixel. Figure 30 (c-1) and Figure 30 (c-2) illustrate the device with the integrated detection and optical sensor device. As illustrated in Figure 30 (d), when biological materials 3001, 3002, 3003 pass through the passage, probe 3010 on channel 3020 can measure its electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical properties and the mechanical properties (see Figure 30 (e)), while the image could be recorded synchronously by the optical sensor (Figure 30 (f)). Both the image signal and the probe signal are combined together to provide improved diagnosis and detection as well as their sensitivity and specificity. Such a detection device and an optical detection device can be designed on a chip system or be packaged on a chip.
[00333] Figure 31 shows an apparatus with a micro detection device (Figure 31 (a)) and a logic circuit (Fig. 31 (b)). The detection device comprises at least one probe and a channel, and the logic circuit comprises an address, an amplifier and a RAM. When a biological material 3101 passes through the channel, its property can be detected by probe 3130, and the signal can be treated, analyzed, stored, processed and plotted in real time. Figure 31 (c-1) and Figure 3 I (c-2) illustrate the device with the detection device and the integrated circuits. Likewise, the detection device and the integrated circuit can be designed on a chip system or be packaged on a chip.
[00334] Figure 32 shows an apparatus of the present invention comprising a detection device (Figure 32 (a)) and a filter (Figure 32 (b)). When a biological material 3201 passes through the device, filtration is performed on the filter, and irrelevant objects can be removed. The remaining property of the objects can then be detected by the sensor device (Figure 31 (a)). Filtration before polling will improve the accuracy of the device. The width of the channel can also vary, for example, from 1 nm to 1 mm.
[00335] Figure 33 shows the geometric factors of DNA 3330 such as the spacing in the minor DNA groove (3310) has an impact on the spatial distribution of electrostatic properties in the region, which in turn can affect biochemical or chemical reactions in the segment of the DNA. By probing, measuring and modifying the spatial properties of DNA (such as the spacing of the smallest space), using the detector described and the probe 3320, it is possible to detect the properties, such as DNA defects, predict reactions / processes for the DNA segment, and repair or manipulate the geometric properties and thus the spatial distribution of the electrostatic field / charge, with biochemical impacts or chemical reactions in the DNA segment. For example, the tip 3320 can be used to increase the spacing of the minor groove 3310,
[00336] Figure 34 shows the process of making a microdevice of this invention that has a flat surface on the lid to form a channel. This will eliminate the need for coupling two ditches to form a channel, which can be tedious to require perfect alignment.
[00337] The cover can be transparent and allow observation with a microscope. It can include, or be made of silicone, SiGe, SiO2, various types of glass, and Al203.
[00338] While, for the purposes of demonstration and illustration, the aforementioned novel, detailed examples show how microelectronics and / or nanofabrication techniques and associated process flows can be used to manufacture highly sensitive, multifunctional and miniaturized detection devices powerful, the principles and general approaches of employing microelectronics and nano manufacturing technologies were contemplated and taught in the design and manufacture of high performance detection devices, which can, and should, be expanded with a view to various combinations of manufacturing processes , including but not limited to, deposition of thin films, standardization (lithography and chemical attack), planarization (including mechanical-chemical polishing), ion implantation, diffusion, cleaning, various materials, combination of processes and steps and various process sequences and flows. For example, in the alternative design of the detection device and the manufacturing process flows, the number of materials involved can be less than or greater than four materials (which have been used in the example above), and the number of process steps can be lower or higher those demonstrated process sequences, depending on the specific needs and performance goals. For example, in some disease detection applications, a fifth material, such as a film based on thin biomaterial, can be used to coat a metal detection tip in order to increase the contact between the detection tip and a biological material. to be measured, thereby improving the measurement sensitivity.
[00339] Applications for the detection apparatus and methods of the present invention include the detection of diseases (for example, in their early stages), particularly serious diseases such as cancer Since cancer cells and normal cells differ in a number of ways, including differences in possible microscopic properties, such as electrical potential, surface charge, density, adhesion and pH, the new microdevices described here are capable of detecting these differences and are therefore applicable, having a greater ability to detect diseases (eg cancer), particularly in its early stages. In addition, microdevices for measuring electrical potential and microdevice electrical charge parameters capable of performing measurements of mechanical properties (eg density) can also be manufactured and used as disclosed herein. In measuring mechanical properties for the early detection of disease, the focus will be on the mechanical properties that are likely to differentiate cancer cells or those with disease from normal cells. As an example, one can differentiate cancer cells from normal cells, using a detection apparatus of the present invention, which is integrated with microdevices capable of performing microindentation measurements.
[00340] Figure 35 is a diagram of an apparatus of the present invention for detecting a disease in a biological material. This apparatus includes a pre-processing unit, a probe and detection unit, signal processing, and a waste processing unit.
[00341] Figure 36 shows an example of a sub sample filtering unit in the pre-processing unit, which can separate cells of different dimensions or sizes. This device comprises at least one input channel 3610, a fluid disturbing channel 3620, an acceleration chamber 3630, and two selection channels (3640 and 3650). The angles 3620 between 3660 and 3610 vary from 0 ° to 180 °.
[00342] The biological material 3601 flows in the x direction from the input channel 3610 to the acceleration chamber 3630, A biocompatible fluid 3602 flows from the disturbing fluid channel 3620 to the acceleration chamber 3630, which then accelerates the biological material 3601 in the y direction. The acceleration correlates with the radius of the biological material and the larger ones are less accelerated than the smaller ones. The larger and smaller objects are then separated into different selection channels. Meanwhile, the probes can be optionally mounted on the side walls of channels 3610, 3620, 3630, 3640 and 3650. The probes can detect, at the microscopic level, the electrical, magnetic, electromagnetic, thermal, optical, acoustic properties, biological, chemical, biochemical, electromechanical, electrochemical, electrochemical-mechanical, physical, and mechanical.
[00343] Figure 37 is a diagram of another example of a sample filtration unit in the apparatus of the present invention. 3701 represents small cells, while 3702 represents large cells. When a 3704 valve is open and another 3703 valve is closed, biological materials (3701 flow 3702) to outlet A. Large cells, larger than the filtration hole are blocked against outlet A, while small cells are released via outlet A. Inlet valve 3704 and outlet valve 3707 are then closed, and a biocompatible fluid is injected through fluid inlet valve 3706. The fluid carries large cells that are drained out through the outlet B. Next, the larger cells are analyzed and detected in the detection part of the invention.
[00344] Figure 38 is a diagram of a pre-processing unit in an apparatus of the present invention. This unit includes a sample filtration unit, a refill unit or system for refilling nutrient or gas for biological material, a constant pressure supply unit, and an example of a disturbing pre-probe unit
[00345] Figure 39 is a diagram of an information processing unit, or signals, of an apparatus of the present invention. This unit includes an amplifier (such as a lock-in amplifier) to amplify the signal, an AID converter, and a microcomputer (for example, a device containing a computer chip or a sub-device for processing information), a manipulator, a display, and network connections.
[00346] Figure 40 shows the integration of multiple signals that result in noise cancellation and increased signal / noise ratio. In this figure, a biological material 4001 is tested by Probe I between T1 and T2, and by probe 2 between T3 and T4. 4002 is 4001 tested signal from probe 1, and 4003 is from probe 2. 4002 is the tested signal from 4001 from S and 4003 is from probe 2. One noise cancels the other to some extent, and results in an intensity of signal or improved signal-to-noise ratio. The same principle can be applied to data collected from more than 2 microdevices or polling units.
[00347] Figure 41 shows an embodiment of the flow of the manufacturing processes of the present invention for the production of a detection device with at least one detection chamber and at least one detector. In this example, following an optional manufacturing process flow of data storage, data processing and component analysis (including transistors, memory devices, logic circuits and RF devices), a 4122 material is first deposited on a 4111 substrate, following deposition of another material 4133 (material for future detectors). Material 4133 can be selected from electrically conductive materials, piezoelectric materials, semiconductor materials, thermal sensitive materials, ion-sensitive emission materials, pressure-sensitive materials, materials sensitive to mechanical stress or optical materials. Optionally, it can also consist of composite materials or a stack of desired material. If necessary, an integrated detector with a set of subcomponents can be placed at this level. Then, material 4133 is standardized through lithography and chemical attack processes, forming a set of desired characteristics indicated in Figure 41 (c). Another material 4144 is subsequently deposited, which can be the same or different from material 4122. Material 4122 can be an electrically insulating material, such as oxide (SiO2), doped oxide, silicon nitride, or a polymeric material. Then, material 4144 is optionally planarized, using polishing (for example, using mechanical-chemical polishing) or the reverse process involving chemical attack. The material pile is then standardized using lithography and chemical attack processes, reaching substrate 4111. Finally, as shown in Figure 41 (g), a leveling layer, or the surface of another component 4155 is placed on top of the pile of material (and thus seal or cap), forming a closed detection chamber 4166 with detector 4177 for the detection of the biological sample
[00348] Figure 42 illustrates another embodiment of the manufacturing method of the present invention for a detection detection device with closed chambers, detectors, and channels for the transport of biological samples, such as fluid samples. In this embodiment, following an optional process flow of manufacturing data storage, processing and component analysis (including transistors, memory devices, logic circuits, and RF devices), a 4222 material is first deposited on a 4211 substrate, followed by the deposition of another material 4233 (material of future detectors). The 4233 material can be selected from electrically conductive materials, piezoelectric materials, semiconductor materials, thermal sensitive materials, ion sensitive materials, pressure sensitive materials, materials sensitive to mechanical stress and optical materials. Optionally, it can also include composite materials or a stack of desired material. If necessary, an integrated detector with a set of subcomponents can be placed at this level.
[00349] Then, materials 4222 and 4233 are standardized using lithography and chemical attack processes (Figure 42 (c)). These two layers (4222 and 4233) can be standardized through separate processes, sequentially, or can be standardized in the same process, depending on the design of the device, the types of materials and the chemicals. Substrate 4211 is then chemically attacked as shown in Figure 42 (d), forming a recessed zone (cavity), 4211, in which stacks 4222 and 4233 can be used as a rigid mask during the chemical attack process.
[00350] A material 4244 is deposited in the recess area, and the portion of material 4244 above material 4233 is removed using a polishing (chemical or mechanical) or a reverse chemical attack process. 4244 material can be selected from oxides, doped oxides, silicon nitride, and polymeric materials. The 4255 layer is then deposited on a 4244 material, and patterned to form small holes in selected positions. Then, the chemical wet or steam attack technique is used to remove material 4244, forming a closed detection chamber 4266.
[00351] Optionally, as shown in Figure 42 (i), material 4233 can also be removed using wet or steam chemical attack processes, forming 4288 channels that connect the different detection chambers, thus forming detection chambers with a detector 4277 aligned with the walls of the detection chamber, and in which biological samples gaseous or fluidic through the chambers. Finally, the upper surface of the detection chamber is sealed with another layer of material (for example, 4255).
[00352] Figure 43 shows a new disease detection method of the present invention in which at least one probe is launched at a desired speed and direction in the direction of a biological material, resulting in a collision. The response given by the biological material, during and / or after the collision is detected and recorded, which can provide detailed and microscopic information on the biological material, such as weight, density, elasticity, stiffness, the connection structure ( between different components of biological material), electrical properties, such as electric charge, magnetic properties, structural information and surface properties. For example, for the same type of cell, it is expected that a cancer cell will experience a shorter traveling distance after collision than that of a normal cell, due to its greater density, greater weight, and possibly greater volume. As shown in Figure 43 (a), a 4311 probe is launched for a 4322 biological material. After colliding with the 4311 probe, the 4322 biological material can be pushed (dispersed) to a distance according to its properties, as shown in Figure 43 (b).
[00353] Figure 43 (c) shows a schematic diagram of a new disease detection device with a 4344 probe launching camera, a set of 4333 detectors, a 4322 probe object and a biological material to be tested 4311. In general, the test object can be an inorganic particle, an organic particle, a composite particle, or a biological material itself. The launch chamber comprises a piston to launch the object, a control system with an interface connected to an electronic circuit or a computer for instructions, and a channel to direct the object.
[00354] Figure 44 illustrates a new manufacturing process that forms multiple components with different materials, at the same device level. First, a first material 4422 is deposited on a substrate 4411 (see Figure 44 (a)), followed by the deposition of a second material 4433. Then, the second material 4433 is standardized to form at least a portion of lowered area in layer 4433, using techniques of chemical attack and lithography processes (see Figure 44 (c)). A third material 4444 is subsequently deposited. The third material can be the same or different from the second material 4422.
[00355] The third material directly above the second material is removed by means of reverse chemical attack processes and / or polishing processes (such as mechanical-chemical polishing) (see Figure 44 (e)). Optionally, the third material is then standardized to form at least a portion of the recessed area in layer 4444 (Figure 44 (f)). A fourth 4455 material is then deposited. Optionally, the portion of the fourth material 4455 directly above the third material 4444 or above the second and third materials is removed by means of reverse chemical attack and / or polishing (such as mechanical-chemical polishing). The above process can continue to be repeated to form several characteristics using the same or different materials at the same device level. Thus, this process flow forms at least two components 4466 and 4477 with different materials or, with the same materials, at the same device level. For example, in one embodiment, one component can be used as a probe and the other can be used as a detector.
[00356] Figure 45 illustrates a method for detecting a disease in a biological material. A biological material 4501 passes through channel 4531 at speed v, and probe 4511 is able to grossly detect the properties of biological material at high speed.
[00357] The 4512 probe is a fine probing device that is coated with a piezoelectric material. There is a distance A L between probe 4511 and probe 4512.
[00358] When biological materials are tested to cross 4511, if the entity is identified as being an abnormal suspect, the system would cause the piezoelectric probe 4512 to extend into the channel and measure specific properties after a time delay of t . Probe 4512 retracts after the suspect entity has crossed.
[00359] The probing device is capable of measuring the microscopic level, an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical and biochemical characteristics mechanics, physics and mechanics of biological material.
[00360] The width of the microchannel can vary from about 1 nm to about 1 mm.
[00361] Figure 46 shows a process for detecting a disease in a biological material. A biological material 4601 passes through channel 4631 at speed v. The 4611 probe is a probe that can roughly detect the properties of biological material at high speed. 4621 and 4622 are piezoelectric valves for controlling the 4631 and 4632 microchannels. 4612 is a fine probing device that can probe the biological properties in more detail. 4631 is the discharge channel for draining normal biological objects. 4632 is the detection channel where suspicious entities are detected in detail.
[00362] When a biological material is tested while crossing 4611, if normal, the discharge channel valve 4621 is opened while the 4622 detection channel valve is closed, the biological material is then drained without detailed detection. When the biological material is tested while passing through 4611, if it is suspected to be abnormal or diseased, the discharge channel valve 4621 is closed, while the 4622 detection channel valve is open, the biological material is then conducted to the detection channel for more detailed probing.
[00363] The width of the microchannel can vary from about 1 nm to about 1 mm.
[00364] The probing device is capable of measuring the microscopic level, an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, biochemical electrochemical - mechanics, physics and mechanics of biological material.
[00365] Figure 47 illustrates a biological matrix detection device. 4701 are microchannels that can reach biological fluids and materials. 4702 are built-in probes on the side of the channels. The sensors are connected by bit lines 4721 and text lines 4722. The signals are applied and collected by the decoder R select line 4742 and the selector of the column decoder 4741. As illustrated in Figure 47-b, the biological detection device -microchannel matrix 4700 can be incorporated in a microchannel 4701. The dimension of the microchannel varies from about 1 μm to about 1 mm. The shape of the microchannel can be rectangular, ellipse, circular or polygonal.
[00366] The probing device is capable of measuring at the microscopic level electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, biomechanical, bio-electrochemical, bio-electro-chemical, bio-electro-chemical, bio-electrochemical characteristics physical and mechanical properties of biological material.
[00367] Figure 48 illustrates a device of the present invention for detecting disease. 4801 is the input of the detection device, and 4802 is the output of the device. 4820 is the channel through which biological material passes. 4811 is the optical component of the detection device.
[00368] As illustrated in Figure 48 (b), the optical component 4811 consists of an optical emitter 4812 and an optical receiver 4813. The emitter emits an optical pulse (for example, pulse laser beam) and, when biological material 4801 passes through the optical component, the optical sensor detects the diffraction of the optical pulse, then identifies the entity's morphology.
[00369] The width of the microchannel can vary from 1 nm to about 1 millimeter.
[00370] Although the specific embodiments of the present invention have been illustrated herein, it will be appreciated by those skilled in the art that modifications and variations can be made without departing from the spirit of the invention. The above examples and illustrations are not intended to limit the scope of the present invention. Any combination of the detection apparatus, microdevices, manufacturing processes, and applications of the present invention, together with any obvious extension or the like, are within the scope of the present invention. Furthermore, it is intended that this invention encompasses any arrangement that is calculated to achieve the same purpose, and all such variations and modifications fall within the scope of the appended claims.
[00371] All publications referred to above are hereby incorporated by reference in their entirety. All features described in this specification (including any attached claims, abstracts and figures) may be replaced by alternative features that serve the same, or equivalent purpose, unless expressly stated otherwise. Thus, unless expressly stated to the contrary, each feature revealed is an example of a generic series of equivalent or similar features. Other Forms of Realization
[00372] It is to be understood that although the invention has been described in conjunction with its detailed description, the above description is intended to illustrate, and not to limit, the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the claims that follow. All publications referenced herein are incorporated by reference in their entirety.

权利要求:
Claims (44)
[0001]
1. Detection apparatus, characterized by the fact that it comprises a system to administer a biological material to be detected, and a probe and detection device to probe and detect the biological material; wherein the system for delivering biological material comprises a channel or chamber; wherein the probe and detection device comprises a first probe microdevice and a first detection microdevice; at least one of the first probe microdevice and first detection microdevice is supported by a first substrate that forms a part of the channel or chamber; and the first probe microdevice and the first detection microdevice are attached to an inner or outer wall of the channel or chamber; wherein at least one probe microdevice is capable of applying a signal to the biological material, thereby stimulating the biological material and causing it to have an intrinsic response; wherein the biological material comprises a liquid sample of blood, urine, sweat or saliva, which additionally comprises one or more cells, proteins or DNAs; in which at least one detection microdevice comprises a sensor configured to contact the biological sample to be detected and directly measures, at the microscopic level, the intrinsic response of the biological sample, in which when the biological sample travels in a certain direction in the system, the detection occurs after the biological sample travels a distance from the probe function.
[0002]
2. Apparatus, according to claim 1, characterized by the fact that each detection microdevice is optionally capable of measuring, at the microscopic level, a property of the biological sample; the property measured by each detection microdevice or the response signal measured by each detector microdevice comprises the electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical, electrochemical, electrochemical-mechanical, biophysical, physical-chemical properties , biochemical, biophysical-chemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical and mechanical biological material.
[0003]
3. Apparatus according to claim 2, characterized by the fact that the electrical property is the surface charge, surface potential, resting potential, action potential, electrical voltage, electric current, distribution of the electric field, distribution of the electric charge , electric dipole, electric quadruple, three-dimensional distribution of electric cloud or charge, electrical properties in DNA telomeres and chromosomes, dynamic changes in electrical properties, dynamic changes in potential, dynamic changes in surface charge, dynamic changes in current, dynamic changes in the electric field, dynamic changes in electrical voltage, dynamic changes in the distribution of electrical energy, dynamic changes in the distribution of the electronic cloud, and / or impedance; the thermal property is the temperature, or the vibrational frequency of the biological material or molecules; the optical property is optical absorption, optical reflection, optical transmission, optical-electrical property, brightness or fluorescent emission; the chemical property is the pH value, chemical reaction, biochemical reaction, bioelectrochemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, and binding strength; physical property is density or geometric size; the acoustic property is the frequency and speed of the acoustic waves, the frequency and intensity of the spectrum, acoustic distribution, acoustic intensity, acoustic absorption, and acoustic resonance, and the mechanical property is the internal pressure, hardness, cut resistance, elongation force fracture resistance, adhesion, frequency of mechanical resonance, elasticity, plasticity and compressibility.
[0004]
Apparatus according to claim 2, characterized by the fact that the probe detection device and a voltage between about 1 mV and about 10 V or between about 1 mV and about 1 applies to biological material , 0 V.
[0005]
Apparatus according to claim 2, characterized by the fact that each detection microdevice comprises an electrically conductive material, an electrically insulating material, a biological material, or a semiconductor material.
[0006]
Apparatus according to claim 2, characterized by the fact that each detection microdevice has a size ranging from about 11 angstroms to about 5 millimeters.
[0007]
Apparatus according to claim 2, characterized in that the detection microdevices are spaced out over the substrate, by a distance of at least 10 angstroms or in which the distance between 2 adjacent microdevices varies between about 5 microns and about 100 microns.
[0008]
Apparatus according to claim 2, characterized by the fact that the substrate is a three-dimensional object or is in the form of a slab, a tube, an array of tubes, a rectangle, or an array of rectangles.
[0009]
Apparatus according to claim 2, characterized in that the probe and detection device additionally comprises a second substrate of the same or different material than the first substrate.
[0010]
Apparatus according to claim 2, characterized by the fact that it additionally comprises a device for reading the data from the measurement of the property of the probing and detection device.
[0011]
11. Apparatus according to claim 1, characterized in that it additionally comprises a fluid supply system, which comprises a pressure generator, a pressure regulator, a throttle valve, a pressure gauge, and a pressure kit. distribution; a system controller comprising a preamplifier, a lock-in amplifier, an electrical meter, a thermal meter, a switching matrix, a system bus, a non-volatile storage device, a random access memory, a circuit logic, a signal receiver, a signal transmitter, a processor, or a user interface; a biological interface, a system controller, or at least one system for the recovery or treatment of medical waste; a sample test administration system, sample test distribution system, a distribution channel, a detection device, a global positioning system, a movement device, a signal transmitter, a signal receiver, a sensor , a memory storage unit, a logical processing unit, an application-specific chip, a sample test recovery and recycling unit, an electromechanical microdevice, a multifunctional device, or a microinstrument for performing surgery, cleaning, or function doctor; a unit for administering biological material, a channel, a detection unit, a data storage unit, a data analysis unit, a central control unit, a biological sample recirculation unit, or a waste disposal unit ; or a pre-processing unit, a signal processing unit, or an elimination processing unit.
[0012]
Apparatus according to claim 11, characterized in that the pressure generator comprises a piston engine system or a tank containing compressed gas; or where the pressure gauge relaunches the measured value for the throttle valve, which then regulates the pressure to approach the target value; the interface comprises a sensor; the recovery and treatment of medical waste is carried out by the same or two different systems; the pre-processing unit comprises a sample filtration unit, a refill unit, a constant pressure supply unit, or a sample pre-probe disturbance unit; the signal processing unit comprises an amplifier, a lock-in amplifier, an A / D converter, a microcomputer, a manipulator, a monitor, or a network connection.
[0013]
13. Apparatus according to claim 11, characterized by the fact that the fluid to be administered is a liquid or gas.
[0014]
14. Apparatus according to claim 13, characterized by the fact that the liquid is blood, urine, saliva, tears, saline, or sweat; and where the gas is nitrogen, argon, helium, neon, krypton, xenon, or radon.
[0015]
Apparatus according to claim 12, characterized by the fact that the sensor is a thermal sensor, a flow meter, an optical sensor, or a piezo meter.
[0016]
16. Apparatus according to claim 1, characterized by the fact that the system for administering biological material comprises at least one channel within which the biological material to be detected travels in a certain direction; the probe and detection device comprises at least one probe microdevice and at least one detection microdevice, at least one probe microdevice is located before the detection microdevice in relation to the direction of passage of biological materials, and the probe microdevice and the detection microdevice can be connected to the inside or outside of the channel wall.
[0017]
Apparatus according to claim 16, characterized by the fact that the probing and detection device comprises at least two detection devices capable of measuring at the microlevel, the same or different properties of the biological material.
[0018]
18. Apparatus according to claim 17, characterized by the fact that the detection microdevices are capable of measuring the microscopic level, the surface charge, the surface potential, the resting potential, the action potential, the electrical voltage , electric current, electric field distribution, electric charge distribution, electric dipole, electric quadruple, three-dimensional distribution of the cloud or electric charge, electrical properties in DNA telomeres and chromosomes, dynamic changes in electrical properties, potential dynamic changes , dynamic changes in surface charge, dynamic changes in current, dynamic changes in the electric field, dynamic changes in electrical voltage, dynamic changes in electrical distribution, dynamic changes in the distribution of the electronic cloud, impedance, temperature, vibrational frequency, optical absorption, transmission optics, optical reflection, optical-electrical property, brightness, fluorescent emission e, pH, chemical reaction, biochemical reaction, bioelectrochemical reaction, reaction speed, reaction energy, reaction speed, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, binding strength, density, size geometry, frequency and speed of acoustic waves, distribution of frequency and intensity spectrum, acoustic intensity, acoustic absorption, acoustic resonance, internal pressure, hardness, shear strength, elongation force, tensile strength, adhesion, mechanical resonance frequency, elasticity, plasticity or compressibility.
[0019]
An apparatus according to claim 16, characterized in that the channel can be straight, curved, or angular or in which the width of the channel varies from about 1 nm to about 1 mm; or the inner wall of the channel defines a circular, oval, rectangular, or polygonal space, or has at least one hollow that can be in the same section of the probe or detection microdevice.
[0020]
20. Apparatus according to claim 19, characterized by the fact that the channel is a circular carbon nanotube.
[0021]
21. Apparatus according to claim 20, characterized in that the carbon nanotube has a diameter ranging from about 0.5 nm to about 100 nm, and a length ranging from about 5.0 nm to about 10 mm.
[0022]
22. Apparatus according to claim 19, characterized by the fact that the concave groove has a cubic or angular space or in which the concave groove has a depth ranging from about 10 nm to about 1 mm.
[0023]
23. Apparatus according to claim 16, characterized in that a distribution fluid is injected into the channel, optionally through a fluid distribution channel connected to an opening in the channel wall, either before or after the material pass through the probe microdevice, to help traverse or separate from the biological material inside the channel.
[0024]
24. Apparatus according to claim 16, characterized in that the apparatus serves to detect diseases in more than one biological material, and the channel comprises a device located inside it to separate or divide biological materials based on different levels of the same property.
[0025]
25. Apparatus according to claim 24, characterized by the fact that the separating or dividing device is a slit and separates or divides biological materials based on their surface loads.
[0026]
26. Apparatus according to claim 16, characterized in that it additionally comprises a filtering device for removing objects irrelevant to the biological material for detection.
[0027]
27. Apparatus according to claim 1, characterized by the fact that the biological material is a DNA telomere or chromosome.
[0028]
28. Apparatus according to claim 11, characterized by the fact that the apparatus is integrated into a single device or panel.
[0029]
29. Apparatus according to claim 12, characterized in that the sample filtration unit comprises an inlet channel, a disturbance fluid channel, an acceleration chamber, or a crack, or comprises an inlet channel, a biocompatible microfilter, or an outlet channel; the disturbing sample pre-polling unit comprises a microdevice with a channel, a pair of plates, or a slot located in the channel to separate the channel into an upper channel and a lower channel; the refill unit recharges nutrient or respirator gas for biological material; the signal processing unit comprises an amplifier, a lock-in amplifier, an A / D converter, a microcomputer, a manipulator, a monitor, or a network connection.
[0030]
30. Apparatus according to claim 29, characterized by the fact that a biocompatible fluid is injected into the fluid's disturbing channel, optionally from the inlet of the fluid's disturbing channel and administered to an opening in the wall of the inlet channel, to separate biological material.
[0031]
31. Apparatus according to claim 30, characterized by the fact that the biocompatible fluid comprises water, saline, an oxygen-rich liquid, and plasma.
[0032]
32. Apparatus according to claim 29, characterized in that the angle between the inlet channel and the disturbing fluid channel varies between about 0 ° -180 °, or between 30 ° -150 °, or between 60 ° -120 °, or between 75 ° -105 °, or about 90 °.
[0033]
33. Apparatus according to claim 29, characterized in that the width of each channel varies from about 1 nm to about 1 mm.
[0034]
34. Apparatus according to claim 29, characterized in that at least one of the channels comprises one or more sounding devices connected to the side wall of the channel, in which each sounding device is capable of measuring the microscopic level, a bioelectric property, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical-chemical, biophysical, biophysical-chemical, electromechanical, electrochemical, electrochemical-mechanical, biochemical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical and mechanical biological material .
[0035]
35. Apparatus according to claim 29, characterized by the fact that the biocompatible microfilter is capable of filtering biological material based on at least one electrical, magnetic, electromagnetic property, physical size, hardness, elasticity, cut resistance, weight , surface characteristic, optical, acoustic, thermal, chemical, mechanical, biological, biochemical, physical-chemical, biophysical, biophysical-chemical, electrical, electrochemical, magnetic, electromagnetic, electromechanical, electrochemical-mechanical and electrochemical-biological.
[0036]
36. Apparatus according to claim 34, characterized by the fact that the electrical property is the surface charge, surface potential, resting potential, action potential, electrical voltage, electric current, distribution of the electric field, distribution of the electric charge , electric dipole, electric quadruple, three-dimensional distribution of the electric cloud or charge, electrical properties in DNA and chromosome telomeres, dynamic changes in electrical properties, dynamic changes in potential, dynamic changes in surface charge, dynamic changes in current, dynamic changes in the electric field, dynamic changes in electrical voltage, dynamic changes in the distribution of electrical energy, dynamic changes in the distribution of the electronic cloud and impedance; the thermal property is the temperature and frequency of vibration; the optical property is optical absorption, optical transmission, optical reflection, optical-electrical property, brightness and fluorescent emission; the chemical property is the pH value, chemical reaction, biochemical reaction, bioelectrochemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, binding force; physical property is density or geometric size; the acoustic property is frequency, speed of acoustic waves, acoustic frequency and distribution of the intensity spectrum, acoustic intensity, acoustic absorption, and acoustic resonance; and the mechanical property is internal pressure, hardness, shear strength, elongation force, tensile strength, adhesion, frequency of mechanical resonance, elasticity, plasticity and compressibility.
[0037]
37. Apparatus according to claim 34, characterized by the fact that the two or more sounding devices are placed at a desired distance from each other.
[0038]
38. Apparatus according to claim 29, characterized by the fact that the sample pre-probing disturbing unit applies an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, physical, chemical signal to the biological material , electromechanical, electrochemical, electrochemical-mechanical, biochemical, biophysical, biophysical-mechanical, biomechanical, bioelectromechanical, bioelectrochemical, bioelectrochemical-mechanical, physical or mechanical, and optionally the signal is pulsed or constant.
[0039]
39. Apparatus according to claim 29, characterized in that the nutrient comprises a strong or weak biocompatible electrolyte, amino acid, mineral, ions, oxygen, oxygen-rich liquid, intravenous drip, glucose, or a protein; and the breathing gas comprises oxygen.
[0040]
40. Apparatus according to claim 1, characterized by the fact that the biological material comprises blood, urine, saliva, lacrimal, saline, and sweat.
[0041]
41. Detection apparatus, characterized by the fact that it comprises a launching chamber to launch a probe object at a desired speed and direction, a detection unit, a probe object, a detection component, a channel for the transport of material biological to be tested, and the probe object, in which the probe object is launched to apply a signal to the biological material, thus stimulating the biological material and causing it to have an intrinsic response; wherein the biological sample comprises a liquid sample of blood, urine, sweat or saliva, which additionally comprises one or more cells, proteins or DNAs; where the detection unit comprises a sensor configured to contact the biological material to be detected and directly measure, at the microscopic level, the intrinsic response of the biological material, where when the biological material travels in a certain direction in the system, the detection occurs after the biological material travels a distance from the probe function.
[0042]
42. Apparatus according to claim 41, characterized in that the launching chamber comprises a piston for releasing the probe object, and a channel for directing the probe object.
[0043]
43. Apparatus according to claim 41, characterized by the fact that the detection unit or the detection component is capable of measuring at an microscopic level an electrical, magnetic, electromagnetic, thermal, optical, acoustic, biological, chemical, electromechanical property , electrochemistry, electrochemistry-mechanics, biochemistry, physicochemistry, biophysics, biophysics-mechanics, biomechanics, bioelectromechanics, bioelectrochemistry, bioelectrochemistry-mechanics, physics and mechanics of biological material.
[0044]
44. Apparatus according to claim 44, characterized by the fact that the electronic property is the surface charge, surface potential, resting potential, action potential, electric voltage, electric current, electric field distribution, charge distribution electrical, electrical dipole, electrical quadruple, three-dimensional distribution of the electric cloud or charge, electrical properties in DNA and chromosome telomeres, dynamic changes in electrical properties, dynamic changes in potential, dynamic changes in surface charge, dynamic changes in current, changes dynamics in the electric field, dynamic changes in electrical voltage, dynamic changes in the distribution of electrical energy, dynamic changes in the distribution of the electronic cloud, and impedance; the thermal property is the temperature or frequency of vibration; the optical property is optical absorption, optical transmission, optical reflection, optical-electrical property, brightness or fluorescent emission; the chemical property is the pH value, chemical reaction, biochemical reaction, bioelectrochemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, binding force; physical property is density or geometric size; the acoustic property is frequency and speed of acoustic waves, acoustic frequency and distribution of the intensity spectrum, acoustic intensity, acoustic absorption, acoustic resonance; and the mechanical property is the internal pressure, hardness, shear strength, elongation force, tensile strength, adhesion, frequency of mechanical resonance, elasticity, plasticity and compressibility.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4737268A|1986-03-18|1988-04-12|University Of Utah|Thin channel split flow continuous equilibrium process and apparatus for particle fractionation|

---

AU6354190A|1989-08-21|1991-04-03|Board Of Regents Of The University Of Washington, The|Multiple-probe diagnostic sensor|

---

JP2832117B2|1991-11-29|1998-12-02|キヤノン株式会社|Sample measuring device and sample measuring system|

---

DE69610926T2|1995-07-25|2001-06-21|Horus Therapeutics Inc|COMPUTER-AIDED METHOD AND ARRANGEMENT FOR DIAGNOSIS OF DISEASES|

---

FR2777293B1|1998-04-10|2000-05-19|Bio Merieux|ELECTRO-SEPARATION PROCESS OF A BIOLOGICAL SAMPLE AND IMPLEMENTATION DEVICE|

---

AU763433B2|1998-05-22|2003-07-24|California Institute Of Technology|Microfabricated cell sorter|

---

CN1122499C|1999-06-17|2003-10-01|曾金铃|Disease diagnosing and predicting system|

---

WO2001018246A1|1999-08-26|2001-03-15|The Trustees Of Princeton University|Microfluidic and nanofluidic electronic devices for detecting changes in capacitance of fluids and methods of using|

---

US8323564B2|2004-05-14|2012-12-04|Honeywell International Inc.|Portable sample analyzer system|

---

US7351376B1|2000-06-05|2008-04-01|California Institute Of Technology|Integrated active flux microfluidic devices and methods|

---

WO2002086162A1|2001-04-23|2002-10-31|Samsung Electronics Co., Ltd.|Molecular detection chip including mosfet, molecular detection device employing the chip, and molecular detection method using the device|

---

EP1460415B1|2001-11-19|2011-01-12|Panasonic Corporation|Measurement device for measuring electric signal emitted by biological sample|

---

US7252987B2|2001-12-06|2007-08-07|Islet Technology, Inc.|System for analysis and selection of encapsulated cellular materials|

---

ES2217208T3|2002-02-01|2004-11-01|Leister Process Technologies|MICROFLUID COMPONENT AND PROCEDURE FOR CLASSIFICATION OF PARTICLES IN A FLUID.|

---

US20050009004A1|2002-05-04|2005-01-13|Jia Xu|Apparatus including ion transport detecting structures and methods of use|

---

US7667010B2|2003-11-18|2010-02-23|Phynexus, Inc.|Open channel solid phase extraction systems and methods|

---

JP2004069395A|2002-08-02|2004-03-04|Nec Corp|Microchip, method for manufacturing the same, and constituent detection method|

---

WO2004036202A1|2002-10-16|2004-04-29|Cellectricon Ab|Nanoelectrodes and nanotips for recording transmembrane currents in a plurality of cells|

---

JP2004249674A|2003-02-21|2004-09-09|Riso Kagaku Corp|Plate discharge box and stencil printing equipment|

---

DK1608963T3|2003-03-28|2010-04-06|Inguran Llc|Apparatus and methods for providing sex-sorted animal sperm|

---

CN1240994C|2003-04-10|2006-02-08|北京大学|Microcantilever sensor and its making method|

---

JP3913189B2|2003-04-17|2007-05-09|キヤノン株式会社|Fine particle separation and recovery equipment|

---

US7309467B2|2003-06-24|2007-12-18|Hewlett-Packard Development Company, L.P.|Fluidic MEMS device|

---

AT427496T|2003-07-02|2009-04-15|Canon Kk|Method for obtaining information and method for diagnosing disease by means of secondary mass spectrometry|

---

KR101165102B1|2003-09-03|2012-07-12|라이프 패치 인터내셔널, 인크.|Personal diagnostic devices and related methods|

---

WO2005033263A1|2003-10-01|2005-04-14|Athena Capital Partners, Llc|Circulating flow device for assays of cell cultures, cellular components and cell products|

---

JP4735119B2|2004-08-09|2011-07-27|日本精工株式会社|Reactor and production method thereof|

---

JP4466308B2|2004-10-06|2010-05-26|富士電機ホールディングス株式会社|Fine particle measuring device|

---

US20060275779A1|2005-06-03|2006-12-07|Zhiyong Li|Method and apparatus for molecular analysis using nanowires|

---

US7757568B2|2005-09-06|2010-07-20|Arkray, Inc.|Flowmeter for fine channel, analyzer using the same, and cartridge for analyzer|

---

US20070178507A1|2006-01-31|2007-08-02|Wei Wu|Method and apparatus for detection of molecules using nanopores|

---

US9149564B2|2006-06-23|2015-10-06|The Regents Of The University Of California|Articles comprising large-surface-area bio-compatible materials and methods for making and using them|

---

CN101669025B|2007-04-27|2013-09-25|Nxp股份有限公司|A biosensor chip and a method of manufacturing the same|

---

EP2160220A4|2007-06-14|2012-07-04|Advanced Neuromodulation Sys|Microdevice-based electrode assemblies and associated neural stimulation systems, devices, and methods|

---

US20100181195A1|2007-07-03|2010-07-22|Nxp B.V.|Microfluidic chip for and a method of handling fluidic droplets|

---

WO2009018467A2|2007-07-31|2009-02-05|Massachusetts Institute Of Technology|Bio-sensing nanodevice|

---

US7952705B2|2007-08-24|2011-05-31|Dynamic Throughput Inc.|Integrated microfluidic optical device for sub-micro liter liquid sample microspectroscopy|

---

US20090116207A1|2007-11-05|2009-05-07|Samuel Long Yak Lim|Method for micro component self-assembly|

---

US20090181361A1|2008-01-14|2009-07-16|Weidong Xu|Rapid test for detecting infection|

---

KR100975010B1|2008-02-29|2010-08-09|성균관대학교산학협력단|Physical sensor using piezoelectric microcantilever and manufacturing method thereof|

---

US10670559B2|2008-07-11|2020-06-02|Cornell University|Nanofluidic channels with integrated charge sensors and methods based thereon|

---

US8387803B2|2008-08-26|2013-03-05|Ge Healthcare Bio-Sciences Ab|Particle sorting|

---

TWI383144B|2008-09-23|2013-01-21|Univ Nat Chiao Tung|Sensing element, manufacturing method and detecting system thereof|

---

US8169006B2|2008-11-29|2012-05-01|Electronics And Telecommunications Research Institute|Bio-sensor chip for detecting target material|

---

KR101518858B1|2008-12-03|2015-05-13|삼성전자주식회사|Semiconductor light emitting device and manufacturing method of the same|

---

CN101561446A|2009-06-04|2009-10-21|大连理工大学|Glass micro-nano-fluidic control chip, preparation and assembly method and auxiliary assembly device thereof|

---

US8685251B2|2009-12-05|2014-04-01|Home Dialysis Plus, Ltd.|Ultra-pasteurization for dialysis machines|

---

CN101630946A|2009-08-27|2010-01-20|浙江大学|Film bulk acoustic resonator and preparation method thereof|

---

CN101696449B|2009-11-10|2017-05-17|苏州吉玛基因股份有限公司|Nucleic acid chip, preparation method and application thereof|US9885644B2|2006-01-10|2018-02-06|Colorado School Of Mines|Dynamic viscoelasticity as a rapid single-cell biomarker|

---

US10722250B2|2007-09-04|2020-07-28|Colorado School Of Mines|Magnetic-field driven colloidal microbots, methods for forming and using the same|

---

US9878326B2|2007-09-26|2018-01-30|Colorado School Of Mines|Fiber-focused diode-bar optical trapping for microfluidic manipulation|

---

US9651542B2|2011-03-24|2017-05-16|Anpac Bio-Medical Science Co., Ltd|Micro-devices for disease detection|

---

BR112013024764A2|2011-05-05|2019-05-21|Anpac Bio-Medical Science Co., Ltd.|apparatus, device and microdevice for detection of tumor cells and for interaction with biological matter|

---

US9487812B2|2012-02-17|2016-11-08|Colorado School Of Mines|Optical alignment deformation spectroscopy|

---

WO2013126412A1|2012-02-20|2013-08-29|Advanced Tactical Ordnance LLC|Chimeric dna identifier|

---

TWI618932B|2012-03-08|2018-03-21|上海新申派科技有限公司|Micro-devices for improved disease detection|

---

TWI630385B|2012-07-16|2018-07-21|昌和生物醫學科技（揚州）有限公司|Devices and methods for enhanced detection and identification of diseases|

---

US8802568B2|2012-09-27|2014-08-12|Sensirion Ag|Method for manufacturing chemical sensor with multiple sensor cells|

---

CN105164530B|2013-01-07|2017-04-12|安派科生物医学科技（丽水）有限公司|Apparatus for improved disease detection|

---

US10266802B2|2013-01-16|2019-04-23|OrteronLtd.|Method for controlling biological processes in microorganisms|

---

IL226105A|2013-01-16|2014-05-28|Orteron T O Ltd|System and method for generating modified plasma|

---

CN104969063B|2013-02-08|2018-05-22|索尼公司|Particulate analysis equipment and particulate analysis system|

---

US10012642B2|2013-03-15|2018-07-03|Anpac Bio-Medical ScienceCo., Ltd.|Methods and apparatus for enhanced detection of diseases|

---

US10272428B2|2013-04-30|2019-04-30|Hewlett-Packard Development Company, L.P.|Microfluidic sensing device and system|

---

CN104162457B|2013-05-16|2020-08-04|昌微系统科技有限公司|Microfluidic device and manufacturing method thereof|

---

EP3060124B1|2013-10-23|2020-04-15|Verily Life Sciences LLC|Spatial modulation of magnetic particles in vasculature by external magnetic field|

---

CN106232526B|2014-04-24|2019-07-30|第一稀元素化学工业株式会社|The manufacturing method of garnet type compound|

---

KR101528773B1|2014-05-16|2015-06-15|연세대학교 산학협력단|Apparatus for Real Time Detecting Bio Particle and Non-Bio Particle in Atmospheric Air, and Method for Detecting Bio Particle and Non-Bio Particle Using the Same|

---

EP2952885B1|2014-06-02|2016-07-27|Sensirion AG|Gas sensor|

---

EP3198257B1|2014-09-23|2020-08-12|Tearlab Research, Inc.|System for integration of microfluidic tear collection and lateral flow analysis of analytes of interest|

---

USD765215S1|2015-01-22|2016-08-30|United Tactical Systems, Llc|Non-lethal projectile|

---

US10705012B2|2015-04-23|2020-07-07|Singapore University Of Technology And Design|Device and method for analysing and controlling cell motility|

---

US10379131B2|2015-11-18|2019-08-13|Elbit Systems Of America/Kmc Systems, Inc.|Systems and methods for detecting a liquid level|

---

US10030961B2|2015-11-27|2018-07-24|General Electric Company|Gap measuring device|

---

WO2017195692A1|2016-05-13|2017-11-16|株式会社村田製作所|Swallowing sensor and swallowing function analysis system equipped with same|

---

CN106357741A|2016-08-28|2017-01-25|武汉山不厌高科技有限公司|Cloud platform for analyzing urine data|

---

CN106353702B|2016-09-14|2018-11-13|广东顺德中山大学卡内基梅隆大学国际联合研究院|A kind of MEMS magnetic field sensors and preparation method based on the modal resonance device that stretches in face|

---

WO2018165625A1|2017-03-10|2018-09-13|Shanghai Xinshenpai Technology Co., Ltd.|New apparatus and methods for disease detection|

---

KR102130622B1|2017-09-28|2020-07-06|주식회사 네오펙트|Pegboard, rehabilitation training system and rehabilitation training method|

---

CN108846896A|2018-06-29|2018-11-20|南华大学|A kind of automatic molecule protein molecule body diagnostic system|

---

EP3821230A1|2018-07-09|2021-05-19|PreSens Precision Sensing GmbH|System for analysis of a fluid sample|

---

CN109044411B|2018-09-06|2021-04-23|清华大学深圳研究生院|Tear detection contact lens based on capillary force driving|

---

CN109540969B|2018-11-13|2021-01-05|中国科学院微电子研究所|Method for measuring types and position distribution of SiC-SiO2 interface carbon impurities in SiC oxidation|

---

US20200161485A1|2018-11-16|2020-05-21|NeuroSilica, Inc.|Novel multilayered composite material utilizing quantum dot based photovoltaic effect for bi-directional brain-computer interface|

---

US10665581B1|2019-01-23|2020-05-26|Sandisk Technologies Llc|Three-dimensional semiconductor chip containing memory die bonded to both sides of a support die and methods of making the same|

---

US10879260B2|2019-02-28|2020-12-29|Sandisk Technologies Llc|Bonded assembly of a support die and plural memory dies containing laterally shifted vertical interconnections and methods for making the same|

---

CN109975411B|2019-04-17|2021-09-24|江苏至上检测科技有限公司|Axle part is phased array ultrasonic detection assembly line in batches|

---

CN110772247A|2019-09-19|2020-02-11|北京航空航天大学|Sensing device for synchronous and apposition detection of bioelectric signals and pressure signals|

---

CN111060170B|2019-11-20|2021-03-02|郑州大学|Flexible microflow pipeline gas flow sensor and preparation method and use method thereof|

---

KR20210132476A|2020-04-27|2021-11-04|한국식품연구원|Meta-structure sensor for detecting food quality|

---

CN111337469B|2020-04-27|2021-06-08|中国科学院化学研究所|Method for acquiring microscopic motion information under shear field by utilizing fluorescence wide field imaging|

法律状态:
2017-02-07| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|

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2017-03-28| B08G| Application fees: restoration [chapter 8.7 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-06-09| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-12-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-09| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 30/06/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US36004110P| true| 2010-06-30|2010-06-30|

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US61/360041|2010-06-30|

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US38996010P| true| 2010-10-05|2010-10-05|

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US61/389960|2010-10-05|

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US201161430641P| true| 2011-01-07|2011-01-07|

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US61/430641|2011-01-07|

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US201161467097P| true| 2011-03-24|2011-03-24|

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US61/467097|2011-03-24|

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US201161498954P| true| 2011-06-20|2011-06-20|

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US61/498954|2011-06-20|

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PCT/US2011/042637|WO2012003348A2|2010-06-30|2011-06-30|Apparatus for disease detection|

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