Integrated apparatus and methods for treating liquids
First Claim
1. A method of making an implement for use with treatment or analysis of a liquid, comprising:
- (a) devising a set of heuristic rules from the behavior of the liquid on a scale of the scale of the instrument to be made, (b) fabricating as a part of the instrument a liquid contacting device based upon at least one of the heuristic rules, and (c) providing a means of determination of a characteristic of the liquid based on the liquids behavior in contact with the liquid contacting device.
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Accused Products
Abstract
A passive self energized, liquid device operates entirely on capillary action. A microfilter fractionates nanoliter volumes of suspension such as whole blood into suspended particles or cells and liquid fractions. Blood, for example, is fractionated with minimal cell lysis, and the filtrate (plasma) flux is dependent upon design parameters similar to factors controlling blood filtration in microporous membranes, i.e. active filter area, fluid velocity and microfilter geometry. Weir-style filters communicate with a blood flow channel to separate plasma from blood moving by capillary action. An expanded downstream channel with multiple parallel capillary blood flow path provides continuing movement of blood past the filters. Lysing is controlled by the size of the filter pores and the duration of adherence of the red blood cells to the pores. The controlled lysis or prevention of lysis of red blood cells is accomplished by manipulating the significant capillary forces generated in the filters. Filtration, cell lysis and microchannel blood flow models are integrated into an overall microfilter design useful for fabricating microfilter devices for lab-on-a-chip clinical applications where they can be coupled with on-chip electrical and electro-optical devices.
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Citations
64 Claims
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1. A method of making an implement for use with treatment or analysis of a liquid, comprising:
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(a) devising a set of heuristic rules from the behavior of the liquid on a scale of the scale of the instrument to be made, (b) fabricating as a part of the instrument a liquid contacting device based upon at least one of the heuristic rules, and (c) providing a means of determination of a characteristic of the liquid based on the liquids behavior in contact with the liquid contacting device. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
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- 13. A blood separation instrument comprising an input opening to an input location for receiving whole blood, a first blood flow channel communicating with the input opening and being of a size to cause blood flow therein from the input location by capillary action, a filter opening into a side of the blood flow channel, the filter having at least one opening therethrough smaller than a red blood cell, a blood plasma collection location for receiving plasma from the filter, an expanded blood flow channel in communication with the first blood flow channel and having defined therein a plurality of parallel connected channels sized to draw blood therethrough by capillary action.
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17. An instrument for monitoring capillary pressure including:
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(a) an entrapped gas encapsulation, (b) a path of liquid flow of a cross-section that causes capillary action motivated flow of the liquid therein, (c) a tube in communication between the encapsulation and the path of liquid flow, (d) the tube having a diameter such that, under capillary pressure of a liquid moving in the path of liquid flow, capillary pressure in the liquid is indicated by a column of the liquid in the tube acting against and compressing the gas in the encapsulation, and (e) the tube being sufficiently transparent or translucent as to allow the meniscus level of the liquid therein to be detected. - View Dependent Claims (18, 19, 20, 21)
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22. A method of illuminating a substantially clear liquid specimen for observation comprising:
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(a) providing a substrate, (b) providing an at least partially light transmitting layer on the substrate to form a specimen support surface and having an interface with the substrate, (c) placing the liquid specimen on the specimen support surface, and (d) illuminating the specimen by;
(i) directing light onto the specimen support surface at an angle selected to cause partial reflection at the specimen support surface to divide illuminating light into refracted light and reflected light, (ii) reflecting the refracted light from the substrate at the interface of the layer and the substrate and through the layer to cause visible interference with reflected light that is reflected from the specimen support surface. - View Dependent Claims (23, 24, 25)
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26. A liquid specimen handling device, including:
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(a) a substrate, (b) a layer of at least partially light-transmitting material on the substrate and forming an interface therewith and having an upper specimen support surface, and (c) illumination means mounted to direct light into the specimen at an angle causing partial reflection at the specimen support surface, to divide illuminating light into refracted light and reflected light, and to cause interfering intersection of the refracted light reflected from the substrate-layer interface and the reflected light from the specimen-support surface. - View Dependent Claims (27, 28)
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29. A liquid specimen test device comprising:
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(a) a plurality of liquid flow channels defined in a substrate, (b) a plurality of filter openings communicating between the liquid flow channels and a plurality of filtrate collection regions, (c) at least one liquid input reservoir connected in liquid communication with the flow channels, (d) a plurality of expanded output flow channels downstream of the liquid flow channels, (e) a closure covering the flow channels, the filters, the collection regions and the expanded output flow channels, and (f) at least one vent line connecting the collection regions and the expanded flow channels to at least one opening to atmosphere. - View Dependent Claims (30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42)
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35. The device according to claim 35, wherein the flow channels comprise at least eight flow channels, each of the channels having a filter opening thereto and each flow channel leading to one of at least eight expanded output flow regions.
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43. A method of cell lysis comprising:
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(a) moving a liquid suspension of cells in a flow path by capillary action, (b) providing a filter opening into the flow path, the filter having one or more pores sized to engage and retain cells in the suspension and having a length in the direction of liquid flow through the filter sufficiently long to cause lysis of at least some retained cells in the suspension as a function of the stress on the cell and the duration of its retention at the filter pore. - View Dependent Claims (44, 45, 46, 47, 48, 49, 50, 51, 52)
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53. A method of fabricating a passive, liquid specimen handing device including:
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(a) providing a semiconductor substrate;
(b) applying a photoresist to the substrate;
(c) providing a mask defining liquid flow channels of cross-sectional dimensions suitable to induce capillary action flowing of the liquid therein;
(d) exposing the photoresist to U.V. light through the mask;
(e) removing the photoresist in locations exposed to light through the mask;
(f) etching the semiconductor in areas revealed by removing the photoresist to form the liquid flow channels and other features of the device; and
(g) securing a closure layer to the semiconductor substrate over the etched channels and other features of the device. - View Dependent Claims (54, 55, 56, 57)
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58. A micro-engineered blood separation device including:
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(a) a substrate, (b) a cover plate, (c) a blood inlet reservoir, (d) a blood outlet reservoir, (e) a blood flow channel etched into the substrate and connecting the blood inlet reservoir and the blood outlet reservoir (f) an area of microfilter etched into the surface, pores of the microfilter having an opening into the blood flow channel, the pores having a cross-sectional dimension less than 10 μ
m,(g) a plasma outlet channel etched in the surface of the substrate in communication with the pores at ends thereof opposite the ends opening into the blood flow channel, and (h) a plasma outlet reservoir connected with the plasma outlet channel.
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59. A blood separation instrument comprising:
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(a) a blood inlet opening;
(b) a first reservoir connected with the blood inlet opening;
(c) a blood outlet opening;
(d) a second reservoir connected with the blood outlet opening;
(e) a blood flow path from the first to the second reservoir;
(f) a plurality of micro-channel blood filters communicating with the channel between the first and second reservoirs;
(g) each of the micro-channel blood filters comprising;
(i) a plurality of micro-channels having at least one cross-sectional dimension less than 1.0 μ
m in communication with the channel; and
(h) the length of the micro-channel of each filter differing in length from the length of the micro-channels of each other filter.
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60. A method of measuring % hematocrit of a blood specimen including:
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(a) providing a substrate having a blood flow channel thereon leading away from an input region and having a serpentine path to a vented location, (b) the blood flow channel being of a cross-dimensional size to effect flow of the blood sample by capillary action therein, (c) introducing a blood specimen to the input region; and
(d) determining how far along the blood flow channel the blood from the specimen flows by capillary action as a function of % hematocrit.
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61. A % hematocrit testing device for use with a blood specimen including:
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(a) a substrate;
(b) an input region, (c) a blood flow channel formed in the substrate and communicating with the input region, (d) the blood flow channel being of a cross-sectional dimension that will effect blood flow by capillary action, (e) a vent opening to the blood flow channel remote from the input region, whereby the distance along the blood flow channel that blood from a specimen travels from the input region is a function of the % hematocrit of the blood of the specimen. - View Dependent Claims (62, 63)
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64. A method of designing a device including:
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(a) operational modeling the device by applying known relationships of theoretical operations features of the device to define a design space, (b) fashioning the actual operational features of the device from within the constrained design space.
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Specification