APPARATUS FOR DISEASE DETECTION

• US 20140342441A1
• Filed: 04/04/2013
• Published: 11/20/2014
• Est. Priority Date: 02/18/2013
• Status: Active Grant

• Current Assignee: Ningkasai Technology Company Limited
• Original Assignee: Anpac Bio-Medical Science Co., Ltd.
• Inventors: Yu, Chris C., Du, Xuedong, Yu, He
• Granted Patent: US 10,126,291 B2
• Time in Patent Office: Days
• US Class Current: 435/287.2
• CPC Class Codes: B01L 2200/0647 Handling flowable solids, e.g. microscopic beads, cells, particles
• CPC Class Codes: B01L 2200/0652 Sorting or classification of particles or molecules
• CPC Class Codes: B01L 2200/0663 Stretching or orienting elongated molecules or particles
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• CPC Class Codes: B01L 2400/0415 electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 2400/043 magnetic forces
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 3/502707 characterised by the manufacture of the container or its components by shaping or joining plastic parts B29C59/00, B29C65/00; by laminating B32B37/00; manufacture of microstructural devices in general B81C
• CPC Class Codes: B01L 3/502761 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: G01N 33/50 Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing measuring or testing processes involving enzymes or microorganisms, compositions or test papers therefor; processes for forming such compositions, condition responsive control in microbiological or enzymological processes C12Q

Abstract

The present invention provides, among others, apparatus for detecting a disease, comprising a system delivery biological subject and a probing and detecting device, wherein the probing and detecting device includes a first micro-device and a first substrate supporting the first micro-device, the first micro-device contacts a biologic material to be detected and is capable of measuring at the microscopic level an electric, magnetic, electromagnetic, thermal, optical, acoustical, biological, chemical, physical, or mechanical property of the biologic material.

Claims

1-85. -85. (canceled)

86. An apparatus for detecting a disease in a biological subject, comprising a detection device fabricated by a method comprising:

providing a substrate;

sequentially depositing a first material and a second material as two layers onto the substrate to form a material stack;

patterning the second material to form a first desired feature;

depositing a third material onto the material stack to cover the second material;

optionally polishing or etch back the third material to planarize the third material;

optionally patterning the first material and third material to form a second desired feature; and

optionally depositing a fourth material onto the material stack.

87. The apparatus of claim 86, wherein the detection device is capable of interacting with the biological subject to generate a response signal as an electric, magnetic, electromagnetic, thermal, optical, acoustical, biological, chemical, electro-mechanical, electro-chemical, electro-chemical-mechanical, bio-chemical, bio-chemical-physical, physical-chemical, bio-physical, bio-physical mechanical, bio-mechanical, bio-electro-mechanical, bio-electro-chemical, bio-electro-chemical-mechanical, physical, or mechanical property;

and the apparatus is capable of measuring the response signal at the microscopic level.

88. The apparatus of claim 87, wherein the electronic property is surface charge, surface potential, resting potential, action potential, electrical voltage, electrical current, electrical field distribution, electrical charge distribution, electric dipole, electric quadruple, three-dimensional electrical or charge cloud distribution, electrical properties at telomere of DNA and chromosome, dynamic changes in electrical properties, dynamic changes in potential, dynamic changes in surface charge, dynamic changes in current, dynamic changes in electrical field, dynamic changes in electrical voltage, dynamic changes in electrical distribution, dynamic changes in electronic cloud distribution, or impedance;

the thermal property is temperature or vibrational frequency;

the optical property is optical absorption, optical transmission, optical reflection, optical-electrical property, brightness, or fluorescent emission;

the chemical property is pH value, chemical reaction, bio-chemical reaction, bio-electro-chemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, or bonding strength;

the physical property is density or geometric size;

the acoustic property is frequency, speed of acoustic waves, acoustic frequency and intensity spectrum distribution, acoustic intensity, acoustical absorption, or acoustical resonance; and

the mechanical property is internal pressure, hardness, shear strength, elongation strength, fracture stress, adhesion, mechanical resonance frequency, elasticity, plasticity, or compressibility.

89. The apparatus of claim 86, wherein the second material is patterned by microelectronic processes, and optionally by using lithography and etch processes selective to the first material to form a detection probe.

90. The apparatus of claim 86, wherein the first material and third material can be the same or different, and are patterned by lithography and etch processes selective to the second material to form at least one type of trench feature in the layers of the third material and first material, optionally with the second material reasonably aligned with the wall of the trench.

92. The apparatus of claim 86, wherein the fabrication method further comprises capping the top of the material stack to form an enclosed trench.

93. The apparatus of claim 92, wherein the enclosed trench can be used to transport the biological subject, or to observe and record features and behaviors of the biological subject.

94. The apparatus of claim 92, wherein the capping comprises placing a second device on the top of the material stack, and the second device can be a device identical to the detection device being capped, a piece of glass or crystal, or a functional device selected from the group consisting of an imaging device, an optical detector, a sensor, a memory storage, a signal transmission, a logic processing component, a circuit for data storage, signal transmission, and signal processing.

97. The apparatus of claim 86, wherein the thickness of the fourth material is thinner than that of the third material.

98. The apparatus of claim 86, further comprising an imaging device for observing and recording properties and behaviors of the biological subject, a pre-processing unit with chambers for pre-screening and enhancing the concentration of a diseased biological subject in the test sample for further testing, channels for carrying fluidic sample to flow through, probes for probing and disturbing the biological subject being tested for generating response signals, detection probes for measuring properties and response signals of the biological subject, and an imaging device, a camera, a viewing station, an acoustic detector, an optical detector, an electrical signal detector, a thermal detector, an ion emission detector, a thermal recorder for observing and recording properties and behaviors of the biological subject, a memory storage, a signal transmission, a logic processing component, a circuit for data storage, signal transmission, or a signal processing unit.

102. The apparatus of claim 86, wherein the first feature or second feature is selected from the group consisting of partitioned chambers, chambers connected with channels, channels, probe generator, detection probes, electrically connective interconnection lines, optical transmission lines, and piezo-electric lines.

103. The apparatus of claim 102, wherein the partitioned chambers are for pre-processing of the biological subject for initial screening and enhancement of concentration of diseased biological subject in the test sample for further testing, chambers connected with channels are for pre-processing and detection, channels are for biological subject to flow through, the probe generator (probe) is for generating probe and disturb signal onto the biological subject for triggering a response signal, the detection probe is for measuring properties of the biological subject and the response signal, the electrically connective interconnection lines are for transmitting signals, the optical transmission lines are for transmitting signals, and piezo-electric lines are for using piezo-electric effect to probe biological subjects.

104. The apparatus of claim 86, wherein the detection device has typical channel dimensions ranging from about 2 microns×

2 microns to about 100 microns×

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 shaped channel, and a typical probe dimension ranging from about 0.5 micron×

0.5 micron to about 20 microns×

20 microns in cross sectional area for a square-shaped probe;

or typical channel dimensions ranging from about 6 microns×

6 microns to about 14 microns×

14 microns in cross sectional area for a square-shaped channel, a radius ranging from about 3 microns to about 8 microns in cross sectional area for a circular shaped channel, and a typical probe dimension ranging from about 0.5 micron×

0.5 micron to about 10 microns×

10 microns in cross sectional area for a square shaped probe.

106. The apparatus of claim 86, wherein the first material and the third material each comprise un-doped oxide (SiO₂), doped oxide, silicon nitride, a polymer material, glass, or an insulating material.

107. The apparatus of claim 86, wherein the second material comprises an electrically conductive material, a thermal sensitive material, an optical material, an ion emission sensitive material, aluminum, an aluminum alloy, copper, a copper alloy, tungsten, a tungsten alloy, gold, a gold alloy, silver, a silver alloy, or a piezo-electric material.

108. The apparatus of claim 107, wherein the piezo-electric material is quartz, berlinite, gallium, orthophosphate, GaPO₄, tourmaline, ceramics, barium, titanate, BatiO₃, lead zirconate, titanate PZT, zinc oxide, aluminum nitride, or a polyvinylidene fluoride.

109. The apparatus of claim 86, wherein the detection device comprises at least one probe, at least one detector, or at least one pair of probe and detector, the probe generates a probing or disturbing signal onto the biological subject to result in a response signal, and the detector measures the response signal thus generated.

110. The apparatus of claim 86, wherein the second material is patterned by microelectronic processes to form a first desired feature;

the first material and third material are optionally patterned by microelectronic processes to form a second desired feature; and

the first material and third material can be the same or different.

111. The apparatus of claim 110, wherein the fabrication method further comprises capping the top of the material stack to form an enclosed trench.

112. The apparatus of claim 111, wherein the capping comprises sealing or capping the top of the material stack with an imaging device, a sensor, an optical detector, a camera, a viewing station, an acoustic detector, an optical detector, an electrical detector, a thermal detector, an ion emission detector, or a thermal recorder onto the material stack.

113. The apparatus of claim 110, further comprising a pre-processing unit (chambers) for pre-screening and enhancing the concentration of a diseased biological subject in the test sample for further testing, channels for carrying fluidic sample to flow through, probes for probing and disturbing the biological subject being tested for generating response signals, detection probes for measuring properties and response signals of the biological subject, or an imaging device for observing and recording properties and behaviors of the biological subject.

114. The apparatus of claim 110, wherein the detection device has typical channel dimensions ranging from about 2 microns×

2 microns to about 100 microns×

100 microns or from about 6 microns×

6 microns to about 14 microns×

14 microns in cross sectional area for a square-shaped channel, a radius ranging from about 1 micron to about 20 microns or from about 3 microns to about 8 microns in cross sectional area for a circular shaped channel, and a typical probe dimension ranging from about 0.5 micron×

0.5 micron to about 20 microns×

20 microns or about 0.5 micron×

0.5 micron to about 10 microns×

10 microns in cross sectional area for a square-shaped probe.

116. The apparatus of claim 110, wherein the first and the third materials each comprises un-doped oxide (SiO₂), doped oxide, silicon nitride, a polymer material, glass, or an insulating material;

and the second material comprises an electrically conductive material, aluminum, an aluminum alloy, copper, a copper alloy, tungsten, a tungsten alloy, gold, a gold alloy, silver, a silver alloy, a piezo-electric material, a thermal sensitive material, an optical material, or an ion emission sensitive material; and

the piezo-electric material is quartz, berlinite, gallium, orthophosphate, GaPO₄, tourmaline, ceramics, barium, titanate, BatiO₃, lead zirconate, titanate PZT, zinc oxide, aluminum nitride, or a polyvinylidene fluoride.

119. The apparatus of claim 110, wherein the detection device comprises at least one probe, at least one detector, at least one pair of probe and detector in which the probe generates a probing or disturbing signal onto the biological subject to result in a response signal and the detector measures the response signal thus generated.

91. (canceled)

95. (canceled)

96. (canceled)

99. (canceled)

100. (canceled)

101. The apparatus of claim 100, wherein the additional device is fabricated by microelectronics processes on the substrate where the first material is deposited.

105. (canceled)

115. (canceled)

117. (canceled)

118. (canceled)

120. An apparatus for detecting a disease in a biological subject, comprising a detection device fabricated by a method comprising:

providing a substrate;

sequentially depositing a first material and a second material as two layers onto the substrate to form a material stack;

patterning the second material by microelectronic processes selective to the first material to create at least a portion of recessed area in the layer of the second material;

depositing a third material onto the material stack to cover the second material;

removing the portion of the third material above the second material by etch back or polishing process;

optionally patterning the third material by microelectronic processes to form at least a portion of recessed area;

depositing a fourth material onto the material stack;

optionally removing the portion of the fourth material above both the second and third materials by etch back or polishing process; and

optionally depositing a fifth material;

optionally patterning the fifth material to form trenches;

optionally covering the material stack with a plate or another device.

121. The apparatus of claim 120, wherein the second material and fourth material can be the same or different.

122. The apparatus of claim 120, wherein the third material is patterned by microelectronic processes to form at least a portion of recessed area;

the portion of the fourth material above both the second and third materials is removed by etch back or polishing process; and

the fifth material is deposited and then patterned to form trenches.

124. The apparatus of claim 120, wherein the second material is patterned using lithography and etch processes selective to the first material to create at least a portion of the recessed area in the layer of the second material;

or the second material is patterned to form a probe capable of probing or disturbing the biological subject.

126. The apparatus of claim 120, wherein the fourth material is patterned by a chemical mechanical polishing process or an etch back process to stop on the second and third materials to form a detector capable of detecting response signal from the biological subject;

or is patterned to form a second probe using polishing, etch back, or both polishing and etch back.

128. The apparatus of claim 120, wherein the fifth material is patterned to form a channel where a fluidic sample can flow through during disease detection with probes reasonably aligned along the bottoms of the channels.

129. The apparatus of claim 120, wherein the fabrication method further comprises placing another device on top of the above material stack to form an enclosed trench;

capping the top of the material stack to form an enclosed trench;

or fabricating a sensor, a memory storage, a signal transmission, a logic processing component, or a circuit for data storage, signal transmission, or signal processing on the substrate using microelectronics technologies.

132. The apparatus of claim 120, wherein the capping comprises placing an other device on the top of the material stack, and the other device can be a device identical to the device being capped, a piece of glass or crystal, or a functional device selected from the group consisting of an imaging device, a sensor, a memory storage, a signal transmission, a logic processing component, a circuit for data storage, signal transmission, and signal processing.

135. The apparatus of claim 120, wherein the microelectronic processes comprise thin film deposition, lithography, etch, polishing, cleaning, ion implantation, diffusion, or packaging.

136. The apparatus of claim 120, wherein the third material is patterned by a chemical or mechanical polishing process or by an etch back process to stop on the second material;

or by lithography and etch processes selective to the first and second materials to remove at least a portion of the third material, optionally while protecting the second material during the patterning processes.

139. The apparatus of claim 120, wherein the fourth material is patterned by a chemical or mechanical polishing process or by an etch back process to form a second detector.

140. The apparatus of claim 120, wherein the fifth material is patterned using lithography and etch processes.

141. The apparatus of claim 140, wherein the fifth material is patterned to form at least a channel or at least a detection chamber where a fluidic sample can flow through during disease detection with probes reasonably aligned along the walls of the channels.

142. The apparatus of claim 120, wherein the fabrication method further comprises placing another device on top of the above material stack to form an enclosed trench, capping the top of the material stack to form an enclosed trench, or fabricating a memory storage, a sensor, a signal transmission, a logic processing component, or a circuit for data storage, signal transmission, or signal processing on the substrate using microelectronics technologies.

145. The apparatus of claim 142, wherein the capping comprises placing an other device on the top of the material stack, and the other device can be a device identical to the device being capped, a piece of glass or crystal, or a functional device selected from the group consisting of an imaging device, a sensor, a memory storage, a signal transmission, a logic processing component, a circuit for data storage, signal transmission, and signal processing.

147. The apparatus of claim 120, wherein the device is capable of measuring at the microscopic level an electric, magnetic, electromagnetic, thermal, optical, acoustical, biological, chemical, physical-chemical, bio-physical, bio-physical-chemical, electro-mechanical, electro-chemical, electro-chemical-mechanical, bio-chemical, bio-mechanical, bio-electro-mechanical, bio-electro-chemical, bio-electro-chemical-mechanical, physical or mechanical property of the biological subject.

148. The apparatus of claim 147, wherein the electrical property is surface charge, surface potential, resting potential, action potential, electrical voltage, electrical current, electrical field distribution, electrical charge distribution, electric dipole, electric quadruple, three-dimensional electrical or charge cloud distribution, electrical properties at telomere of DNA and chromosome, dynamic changes in electrical properties, dynamic changes in potential, dynamic changes in surface charge, dynamic changes in current, dynamic changes in electrical field, dynamic changes in electrical voltage, dynamic changes in electrical distribution, dynamic changes in electronic cloud distribution, or impedance;

the thermal property is temperature or vibrational frequency;

the optical property is optical absorption, optical transmission, optical reflection, optical-electrical property, brightness, or fluorescent emission;

the chemical property is pH value, chemical reaction, bio-chemical reaction, bio-electro-chemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, or bonding strength;

the physical property is density or geometric size;

the acoustic property is frequency, speed of acoustic waves, acoustic frequency and intensity spectrum distribution, acoustic intensity, acoustical absorption, or acoustical resonance; and

the mechanical property is internal pressure, hardness, shear strength, elongation strength, fracture stress, adhesion, mechanical resonance frequency, elasticity, plasticity, or compressibility.

123. (canceled)

125. (canceled)

127. (canceled)

130. (canceled)

131. (canceled)

133. (canceled)

134. (canceled)

137. (canceled)

138. (canceled)

143. (canceled)

144. (canceled)

146. (canceled)

149. An apparatus for detecting a disease in a biological subject, comprising a detection device and a channel or chamber fabricated by a method comprising:

providing a substrate;

optionally patterning the substrate to form at least a recessed area;

depositing material A onto the substrate to cover at least the substrate'"'"'s optional recessed area;

planarizing material A to remove at least part of it from above the substrate and leaving material A at least in the substrate'"'"'s optional recessed area;

depositing material B onto material A and optionally the recessed area of the substrate;

patterning material B to form at least a recessed area;

depositing material X onto material B to cover material B and its recessed area;

patterning material X to form at least a hole smaller than material B'"'"'s recessed area above material B'"'"'s recessed area;

removing at least part of material B and at least part of material A by wet etch, plasma etch, or vapor etch to form a channel or chamber between material X and the substrate or material A; and

depositing material Y to seal the at least one small hole in material X.

150. The apparatus of claim 149, wherein the detection device is capable of measuring at the microscopic level an electric, magnetic, electromagnetic, thermal, optical, acoustical, biological, chemical, physical-chemical, bio-physical, bio-physical-chemical, electro-mechanical, electro-chemical, electro-chemical-mechanical, bio-chemical, bio-mechanical, bio-electro-mechanical, bio-electro-chemical, bio-electro-chemical-mechanical, physical or mechanical property of the biological subject.

151. The apparatus of claim 150, wherein the electrical property is surface charge, surface potential, resting potential, action potential, electrical voltage, electrical current, electrical field distribution, electrical charge distribution, electric dipole, electric quadruple, three-dimensional electrical or charge cloud distribution, electrical properties at telomere of DNA and chromosome, dynamic changes in electrical properties, dynamic changes in potential, dynamic changes in surface charge, dynamic changes in current, dynamic changes in electrical field, dynamic changes in electrical voltage, dynamic changes in electrical distribution, dynamic changes in electronic cloud distribution, or impedance;

the thermal property is temperature or vibrational frequency;

the optical property is optical absorption, optical transmission, optical reflection, optical-electrical property, brightness, or fluorescent emission;

the chemical property is pH value, chemical reaction, bio-chemical reaction, bio-electro-chemical reaction, reaction speed, reaction energy, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, or bonding strength;

the physical property is density or geometric size;

the acoustic property is frequency, speed of acoustic waves, acoustic frequency and intensity spectrum distribution, acoustic intensity, acoustical absorption, or acoustical resonance; and

the mechanical property is internal pressure, hardness, shear strength, elongation strength, fracture stress, adhesion, mechanical resonance frequency, elasticity, plasticity, or compressibility.

153. The apparatus of claim 149, wherein all the recessed areas overlap;

and optionally material A comprises an electrically insulating material and material B comprises an electrically conductive material, a piezo-electric material, a semiconductor material, a thermal sensitive material, an optical material;

a pressure sensitive material, an ion emission sensitive material, or any combination thereof.

154. The apparatus of claim 149, where the fabricating method further comprises:

after patterning material B and before depositing material X, depositing material C onto material B to cover at least the recessed area of material B;

optionally planarizing material C; and

patterning material C to form at least a recessed area that overlaps with the recessed area of material B;

wherein material C can be the same or different from material A.

156. The apparatus of claim 154, wherein material C comprises an electrically insulating material, an electrically conductive material, a piezo-electric material, a semiconductor material, a thermal sensitive material, an optical material;

a pressure sensitive material, or an ion emission sensitive material.

157. The apparatus of claim 154, wherein all the recessed areas overlap;

and optionally material C comprises an electrically insulating material, an electrically conductive material, a piezo-electric material, a semiconductor material, a thermal sensitive material, an optical material, a pressure sensitive material, or an ion emission sensitive material.

158. The apparatus of claim 157, where the fabricating method further comprises:

after patterning material C and before depositing material X, depositing material D onto material C to cover at least the recessed area of material C; and

removing material D above material C and leaving material D in the recessed area of material C;

wherein material D can be the same or different from material B.

159. The apparatus of claim 157, wherein all the recessed areas overlap.

160. The apparatus of claim 154, wherein the fabricating method further comprises, after patterning material C and before depositing material X, depositing material E onto material D to cover at least the recessed area of material D;

and removing material E above material D and leaving material E in the recessed area of material D; and

optionally repeating the steps of depositing an additional material onto at least a recessed area and removing the additional material above the recessed area and leave the additional material in the recessed area.

161. The apparatus of claim 160, wherein all the recessed areas overlap.

162. The apparatus of claim 149, further comprising a micro-injector for injecting an object into the biological subject to generate a response, and a detector for detecting the response generated by the biological subject after the injection.

152. (canceled)

155. (canceled)

163. An apparatus comprising two micro-devices each fabricated by the method comprising:

providing a substrate,

depositing a first material onto a substrate;

depositing a second material onto the first material and then patterning the second material by microelectronic processes; and

repeating the second step at least once with a third material that can be the same as or different from the first or second material, wherein the micro-devices can pierce through the membrane of a cell and can move in different directions.

164. The apparatus of claim 163, wherein the micro-devices is capable of measuring at the microscopic level at least an electric, magnetic, electromagnetic, thermal, optical, acoustical, biological, chemical, physical-chemical, electro-mechanical, electro-chemical, electro-chemical-mechanical, bio-chemical, bio-physical, bio-physical mechanical, physical-chemical, bio-mechanical, bio-electro-mechanical, bio-electro-chemical, bio-electro-chemical-mechanical, physical, or mechanical property of the cell or cell membrane.

166. The apparatus of claim 163, wherein the fabricated micro-devices are physically or electrically coupled or integrated.

167. The apparatus of claim 163, wherein the microelectronic processes comprise thin film deposition, lithography, etch, polishing, cleaning, ion implantation, diffusion, or packaging.

168. The apparatus of claim 163, wherein the apparatus is integrated on a single device or assembled on a single board.

165. (canceled)

169-220. -220. (canceled)

221. A method for fabricating a micro-device, comprising depositing various materials on a substrate and, in the interims of depositing every two materials, patterning some or all of the deposited materials by a microelectronic process, wherein the micro-device is capable of measuring at the microscopic level an electric, magnetic, electromagnetic, thermal, optical, acoustical, biological, chemical, electro-mechanical, electro-chemical, electro-chemical-mechanical, bio-chemical, bio-physical, bio-physical-chemical, physical-chemical, bio-mechanical, bio-electro-mechanical, bio-electro-chemical, bio-electro-chemical-mechanical, physical, or mechanical property of a biologic subject with which the micro-device is to contact.

222. The method of claim 221, wherein the microelectronic process comprises deposition, lithography, etch, cleaning, direct-writing, diffusion, ion implantation, cleaning, polishing, planarization, or packaging.

223. The method of claim 221, wherein the electrical property is surface charge, surface potential, resting potential, action potential, electrical voltage, electrical current, electrical field distribution, electrical charge distribution, electric dipole, electric quadruple, three-dimensional electrical or charge cloud distribution, electrical properties at telomere of DNA and chromosome, dynamic changes in electrical properties, dynamic changes in potential, dynamic changes in surface charge, dynamic changes in current, dynamic changes in electrical field, dynamic changes in electrical voltage, dynamic changes in electrical distribution, dynamic changes in electronic cloud distribution, or impedance;

the thermal property is temperature, or vibrational frequency of biological item or molecules;

the optical property is optical absorption, optical transmission, optical reflection, optical-electrical property, brightness, or fluorescent emission;

the chemical property is pH value, chemical reaction, bio-chemical reaction, bio-electro-chemical reaction, reaction speed, reaction energy, speed of reaction, oxygen concentration, oxygen consumption rate, ionic strength, catalytic behavior, or bonding strength;

the physical property is density or geometric size;

the acoustic property is frequency, speed of acoustic waves, acoustic frequency and intensity spectrum distribution, acoustic intensity, acoustical absorption, or acoustical resonance; and

the mechanical property is internal pressure, hardness, shear strength, elongation strength, fracture stress, adhesion, mechanical resonance frequency, elasticity, plasticity, or compressibility.

224. A method for fabricating a micro-device, comprising:

providing a substrate;

depositing a first material onto the substrate;

depositing a second material onto the first material and then patterning the second material by a microelectronic process; and

repeating the second step at least once with a material that can be the same as or different from any of the previously deposited materials.

225. The method of claim 224, wherein the microelectronic process comprises lithography, etch process, direct writing, molecular self assembly, laser oblation, electron beam writing, x-ray writing, diffusion, ion implantation, cleaning, polishing, planarization by chemical mechanical polishing, and packaging.

226. The method of claim 224, further comprising removal of a stack of multiple layers of materials by wet etch, dry etch, or vapor etch.

227. The method of claim 224, wherein the materials used in the repeated steps can be the same as or different from the first or second material.

228. The method of claim 224, wherein the micro-device can move in any direction.

229. The method of claim 224, wherein at least one of the materials used in fabricating the micro-device is a biological material, a polymer, a piezo-electric material, a semiconductor material, an electrically insulating material, or an electrically conductive material.

230. The apparatus of claim 229, wherein the piezo-electric material is quartz, berlinite, gallium, orthophosphate, GaPO₄, tourmaline, ceramics, barium, titanate, BatiO₃, lead zirconate, titanate PZT, zinc oxide, aluminum nitride, or a polyvinylidene fluoride.

231. The method of claim 224, wherein the micro-device is capable of sorting, probing, measuring, communicating, or modifying a biological subject.

232. The method of claim 224, wherein the micro-device comprising a micro-trench having side-walls and a probe embedded in the micro-trench'"'"'s sidewalls, and the method comprises:

providing a substrate;

depositing a first material onto the substrate;

depositing a second material onto the first material and then patterning the second material by microelectronic processes to form a detecting tip;

depositing a third material on the second material and then patterning the third material by a planarization process;

depositing a fourth material on the third material and patterning the fourth material by microelectronic processes;

patterning the third material using a microelectronic process with the fourth material serving as a hardmask.

233. The method of claim 232, wherein the microelectronic processes comprise thin film deposition, lithography, etch, polishing, cleaning, ion implantation, diffusion, or packaging.

234. The method of claim 232, further comprising coupling two devices that are thus fabricated and symmetric to form a detecting device with channels or to form a probing device capable to sending a signal to a biological subject and result in a response.

236. The method of claim 234, wherein the shape of each channel'"'"'s cross-section is rectangle, ellipse, circle, or polygon, and each channel'"'"'s entrance is optionally bell-mouthed.

237. The method of claim 234, wherein the micro-trenches of the coupled two micro-devices are aligned by the module of alignment marks designed on the layout of the micro-device.

238. The method of claim 232, wherein the dimension of the micro-trench ranges from about 0.1 um to about 500 um.

239. The method of claim 232, further comprises integrating three or more micro-devices to give an enhanced device with an array of the channels, or capping the micro-trench of the micro-device with a flat panel or coupling two micro-trenches to form one or more channels.

241. The method of claim 239, wherein the flat panel comprises silicon, SiGe, SiO₂, Al₂O₃, acrylate polymer, AgInSbTe, synthetic alexandrite, arsenic triselenide, arsenic trisulfide, barium fluoride, CR-39, cadmium selenide, caesium cadmium chloride, calcite, calcium fluoride, chalcogenide glass, gallium phosphide, GeSbTe, germanium, germanium dioxide, glass code, hydrogen silsesquioxane, Iceland spar, liquid crystal, lithium fluoride, lumicera, METATOY, magnesium fluoride, magnesium oxide, negative index metamaterials, neutron super mirror, phosphor, picarin, poly(methyl methacrylate), polycarbonate, potassium bromide, sapphire, scotophor, spectralon, speculum metal, split-ring resonator, strontium fluoride, yttrium aluminum garnet, yttrium lithium fluoride, yttrium orthovanadate, ZBLAN, zinc selenide, or zinc sulfide.

242. The method of claim 224, further comprising:

before depositing the second material, patterning the first material by a microelectronic process to give rise to at least one patterned residual and leaving part of the substrate surface uncovered by the first material;

creating an opening in the second material to expose part of the patterned residual of the first material; and

filling up the opening in the second material with a third material;

wherein the second material is a non-electrically conductive material.

243. The apparatus of claim 242, wherein the microelectronic processes comprise thin film deposition, lithography, etch, polishing, cleaning, ion implantation, diffusion, or packaging.

235. (canceled)

240. (canceled)

244. A method for fabricating a micro-device for detecting a disease in a biological subject, comprising:

providing a substrate;

sequentially depositing a first material and a second material as two layers onto the substrate to form a material stack;

patterning the second material by microelectronic processes to form a first desired feature;

depositing a third material onto the material stack to cover the second material and optionally the first material;

optionally patterning the first and third materials by microelectronic processes to form a second desired feature; and

optionally depositing a fourth material onto the material stack.

245. The method of claim 244, further comprising fabricating at least an additional component onto the substrate before sequentially depositing the first material and the second material as layers onto the substrate, wherein the additional component comprises a data storage component, a signal processing component, a memory storage component, a signal receiver, a signal transmitting component, a logic processing component, or an RF component;

fabricating at least a circuit onto the substrate before sequentially depositing the first material and the second material as layers onto the substrate, wherein the circuit comprises a data storage circuit, a signal processing circuit, a memory storage circuit, a signal transmitting circuit, or a logic processing circuit;

or capping the top of the material stack to cover the third material and form an enclosed trench.

247. The method of claim 244, wherein the microelectronic processes comprise thin film deposition, lithography, etch, polishing, cleaning, ion implantation, diffusion, or packaging.

248. The method of claim 244, wherein the first material and the third material are the same.

249. The method of claim 248, wherein the first material and the third material are electrically insulating.

250. The method of claim 248, wherein the first material or the third material is oxide, doped oxide, silicon nitride, or a polymer.

251. The method of claim 244, wherein the second material is an electrically conductive material, a piezo-electric material, a semiconductor material, a thermal sensitive material, a magnetic material, a pressure sensitive material, a mechanical stress sensitive material, an ion emission sensitive material, a optical material, or a combination thereof.

252. The method of claim 251, wherein the second material comprises copper, aluminum, tungsten, gold, silver, the alloys thereof, or glass.

253. The method of claim 244, wherein the first desired feature is a detection probe capable of probing or disturbing a biological subject to be measured.

254. The method of claim 244, wherein the second desired feature is a recessed form, or a trench form in the layers of the third and first materials.

255. The method of claim 254, wherein the second material is aligned with the wall of the trench form in the layers of the third and first materials.

256. The method of claim 244, further comprising capping the top of the material stack to cover the third material and form an enclosed trench.

257. The method of claim 245, wherein the capping comprises sealing or capping the top of the material stack with a layer of material, an imaging device, a camera, a viewing station, an acoustic detector, a thermal detector, an ion emission detector, or a thermal recorder onto the material stack.

258. The method of claim 244, wherein the second material can be the same as or different from the third material, the second material is patterned by microelectronic process to form at least a portion of the recessed area in the layer of the second material;

and the method further comprises;

optionally planarizing the third material by chemical mechanical polishing process, an etch process, or a combination thereof to stop on the second material;

patterning the third material by microelectronic processes to remove at least a portion of the third material;

depositing a fourth material onto the material stack; and

patterning the fourth material and first material by microelectronic processes to form a channel;

wherein the channel is used to deliver the biological subject passing through.

259. The method of claim 258, further comprising fabricating at least an additional component onto the substrate before sequentially depositing the first material and the second material as layers onto the substrate, wherein the additional component comprises a data storage component, a signal processing component, a memory storage component, a signal transmitting component, a logic processing component, or an RF component;

or fabricating at least a circuit onto the substrate before sequentially depositing the first material and the second material as layers onto the substrate, wherein the circuit comprises a data storage circuit, a signal processing circuit, a memory storage circuit, a sensor, a signal transmitting circuit, or a logic processing circuit.

261. The method of claim 258, further comprising planarizing the third material using a chemical mechanical polishing process or an etch back process after depositing the third material onto the material stack and before patterning the first and the third materials.

262. The method of claim 258, further comprising planarizing the third material using a chemical mechanical polishing process or an etch back process to form a detector capable of detecting a response signal from the biological subject.

263. The method of claim 258, wherein the microelectronic processes comprise thin film deposition, lithography, etch, polishing, cleaning, ion implantation, diffusion, or packaging.

264. The method of claim 258, wherein the first material and the fourth material are the same and are optionally electronically insulating.

266. The method of claim 264, wherein first material or fourth material is un-doped oxide, doped oxide, silicon nitride, polymer material, or glass.

267. The method of claim 258, wherein the second material and the third material are the same.

268. The method of claim 267, wherein the second material or the third material is an electrical conductive material, a magnetic material, an electro-magnetic material, an optical material, a thermal sensitive material, a pressure sensitive material, an ion emission sensitive material, or a piezo-electric material.

269. The method of claim 268, wherein the second material or the third material is aluminum, copper, tungsten, gold, silver, the alloys thereof, quartz, berlinite, gallium, orthophosphate, GaPO₄, tourmalines, ceramics, barium, titanate, BatiO₃, lead zirconate, titanate PZT, zinc oxide, aluminum nitride, or polyvinylidene fluoride.

270. The method of claim 258, wherein the probe is aligned with the wall of the channel.

271. The method of claim 268, further comprising patterning the fourth material to form a hole at a selected location after depositing the fourth material onto the material stack.

272. The method of claim 258, further comprising removing the third material from the material stack by wet or vapor etch to form a detection chamber between the fourth material and the substrate, or removing the first material from the material stack by wet or vapor etch to form a channel.

274. The method of claim 272, wherein the channel connects the detection chamber with at least an additional detection chamber.

275. The method of claim 258, further comprising capping the top of the material stack to form an enclosed trench or channel;

sealing or capping the top of the material stack with a fifth material to form an enclosed channel capable of observing and recording the biological subject;

or sealing or capping the top of the material stack with an imaging device, a detector, an optical sensor, a camera, a viewing station, an acoustic detector, a thermal detector, an electrical detector, an ion emission detector, or a thermal recorder onto the material stack.

246. (canceled)

260. (canceled)

265. (canceled)

273. (canceled)

276. (canceled)

277. (canceled)

278. A method for fabricating a device for detecting disease in a biological subject, comprising:

providing a substrate;

sequentially depositing a first and a second materials as layers onto the substrate to form a material stack;

patterning the second material by microelectronic processes to form at least a portion of a recessed area in the second material depositing a third material onto the material stack to cover the second material, and removing the portion of the third material above the second material by etch back or polishing process;

patterning the third material by lithography and etch processes to remove at least a portion of the third material; and

depositing a fourth material onto the material stack to cover the second and third material, and removing the portion of the fourth material above the second and third material by etch back or polishing process; and

optionally, depositing a fifth material and repeating the above process sequence used for the third material.

279. The method of claim 278, further comprising fabricating at least an additional component onto the substrate before sequentially depositing the first material and the second material as layers onto the substrate, wherein the additional component comprises a data storage component, a signal processing component, a memory storage component, a signal transmitting component, a logic processing component, or an RF component;

or fabricating at least a circuit onto the substrate before sequentially depositing the first material and the second material as layers onto the substrate, wherein the circuit comprises a data storage circuit, a signal processing circuit, a memory storage circuit, a signal transmitting circuit, or a logic processing circuit.

281. The method of claim 278, wherein the substrate is silicon, polysilicon, silicon nitride, or polymer material.

282. The method of claim 278, wherein the first material is oxide, doped oxide, silicon nitride, or polymer material.

283. The method of claim 278, wherein patterning of the second material forms a probe, a detector or an integrated unit with sub-component for detection.

284. The method of claim 278, wherein the fourth material forms a probe, a detector or an integrated unit with sub-component for detection.

285. The method of claim 278, wherein the second and the fourth material are the same, and optionally are electrical conductive material, semiconductor material, piezo-electric material, thermal sensitive material, an ion emission sensitive material, a magnetic material, a pressure sensitive material, a mechanical stress sensitive material, or optical material.

287. The method of claim 285, wherein the second or the fourth material is aluminum, copper, tungsten, gold, silver, the alloys thereof, quartz, berlinite, gallium, orthophosphate, GaPO₄, tourmalines, ceramics, barium, titanate, BatiO₃, lead zirconate, titanate PZT, zinc oxide, aluminum nitride, or polyvinylidene fluoride.

280. (canceled)

286. (canceled)

288-319. -319. (canceled)