CN101365381A - Configurable, flexible apparatus and method for personal health monitoring and delivery - Google Patents

Abstract

The present invention generally relates to a system and method that co-locates in a small flexible, configurable system and multi-level substrate sampling, rapid analysis, bio-sample storage and delivery functions to be performed on living tissues or matter obtained from living organisms. The types of the sampling may include chemical, biochemical, biological, thermal, mechanical, electrical, magnetic and optical sampling. In general, the analysis performed at the point of sampling measures the sample taken and records its value. The bio-sample storage function encapsulates a small sample of analyte and preserves it for subsequent examination or analysis, either on the organism by the system or at a remote location by an independent analysis system. Once stored, the sample can provide a record of a biological state at the precise time of sampling. The delivery at the point of sampling can include chemical, biochemical, biological, thermal, mechanical, electrical, magnetic and optical stimuli.

Description

Be used to the flexible apparatus and the method for monitoring and sending

The cross reference of related application

[0001] the application relates to and requires the priority of international patent application No.PCT/US 2005/044287, it was filed in December in 2005 9, name is called " Apparatus and Methodfor Continuous Real-Time Trace Biomolecular Sampling; Analysis andDelivery ", it requires the priority of U.S. Provisional Patent Application No.60/634783, this provisional application was filed in December in 2004 9, name is called " Systems and Methods forMonitoring Health and Delivering Drugs Transdermally ", and the full text that is incorporated herein two pieces of documents as a reference.

Invention field

[0002] the present invention relates to portable biometric medical treatment and biomolecule monitoring, remote diagnosis and relevant healthcare field.More particularly, the present invention relates to be used for the method, apparatus and system of configurable flexible personal health monitoring and material delivery system.

Background of invention

[0003] percutaneous of Noninvasive sampling body fluid is the target of medical research for a long time.Attempting realizing that the prior art of this target is recorded in, the United States Patent (USP) of authorizing on May 3rd, 2,005 6887202 for example to people such as Currie, name is called " Systems and Methods for MonitoringHealth and Delivering Drugs Transdermally ", is incorporated herein its content as a reference.

[0004] prior art of trial percutaneous sampling is characterised in that usually at the outermost layer of epidermis, promptly open some bigger holes in the horny layer, described horny layer is the active surface of skin, and mainly the dead cell by acellular nuclear constitutes.These holes usually form through following growth epidermis by scorching hot or laser ablation or with fine needle aspiration.Usually will below skin, aspirate or be expressed to the transcutaneous device from the interstitial fluid of this epidermis of growing or from the fluid of vascular system end then, and utilize little processing channel and light-guiding system that it is carried out spectrum analysis at this.

[0005] this system has many defectives, comprises hole dimension usually in tens of micron number magnitudes, and it is enough to cause local pain.This can cause inflammation usually, has hindered described passage to keep open a few hours to more than a couple of days usually usually.

[0006] and, little processing of complication system need be used silicon chip usually, it is not flexible relatively, thereby makes and to be difficult to realize surface contact closely, and causes the percutaneous carbon dioside monitoring device and pass between the cuticular hole lateral movement takes place.Since through the size of hole skin usually at the tens of microns of diameter, so even the lateral movement of small quantity can make that all this device is malfunctioning.

[0007] be desirable to provide configurable flexible personal health monitoring and delivery system, it can be through structure to be used for range of application more widely.It would also be desirable to provide sampling apparatus, it can be used for the operation that relates to percutaneous and the sampling of non-percutaneous of invasive, minimally-invasive and Noninvasive.

The invention summary

[0008] the present invention relates generally to system and method, and it has multilevel substrate sampling, rapid analysis, biological sample storage and sends in the configurable system of small-sized flexibility function is to implement on living tissue or the material from Living Organism.In described below a plurality of applications, the sampling type can comprise chemistry, biochemistry, biology, calorifics, machinery, electricity, magnetic and optical sampling.In general, the sample of obtaining at the analysis to measure that carries out of sampling site and write down its value.The small amounts of analyte sample is encapsulated and deposits the biological sample memory function so that detection afterwards or analysis, this detection or analyze by described system and carry out on organism or carry out at remote location by analytical system independently.In case after storing, the biological aspect record when described sample just can provide accurate sampling time.Can comprise chemistry, biochemistry, biology, calorifics, machinery, electricity, magnetic and optical stimulation sending of site of sampling.

[0009] measurement result can provide tested tissue or the quantitative snapshot of monitored organic health degree in sampling and the moment of measuring.In the time of outside the value that records is in normal biomedical scope, can report out possible morbid state, and can take the intervention means to make organism recover its health status.

[0010] generalized monitoring definition (for example is meant periodic measurement bioprocess, physiological, biochemical or metabolic process) activity, it attempts to set up a kind of scope, the biological function of input is in normally, in functionalization and the healthy boundary, proofreaies and correct the defective that records so that can carry out periodic action.Closely-related with monitoring is assessment.Assessment is a kind of process of analyzing and pass judgment on measurement result at individual and colony's standard clearly.Similarly, can monitor people, animal tissue or organic biotic environment (comprising air, food, water, medicine, temperature etc.), as its input value to bioprocess.The specified monitoring type instance of this system comprises: the safety of monitoring bio and chemical environment; Monitoring is to explain and to keep the healthy baseline behavior of individuality; Monitoring at early stage disease detection; Monitoring of diseases progress degree comprises secondary action (disease burden); Medical treatment gets involved and comprises administration; Monitor therapy is renderd a service; The monitor therapy compliance; And/or monitoring recurrence probability.

[0011] monitoring under these states can be acute or chronic.Can only carry out one-shot measurement in an expection, ready or controlled moment.The time scale of repeated measure can be different, from several minutes to several weeks, perhaps from hour to many decades.The scale of biochemical concentration changes can be from the 1pg/dl of trace to spissated 1g/dl, perhaps at 12 more than the order of magnitude.

[0012] the disposable sample unit of described system can have mechanical flexibility, is made of the thin layer of a plurality of 26S Proteasome Structure and Function films, adapts to the shape of monitored tissue and attached to it so that deformation takes place.As described below, the contact that is realized is a minimally-invasive, i.e. the active function that it can disrupt tissue or owing to its existence is disturbed the measurement target thing.Similarly, described flexible sample unit can be installed in the suitable packing with analyzing biologic fluids and biological or chemical sample.Pick off can be connected to different sampling sites, for example buccal, gingiva, nose, pharynx, nasal sinuses, ear and part tissue of eye.Each position can have unique sampling characteristic.For example, eye and internal ear have the approach of the central nervous system in the blood brain barrier.

[0013] described system and all its building blocks can be constructed at the value volume and range of product of the sampling location on organism, measurement target and frequency, amount of redundancy, record and the report of each measurement.Structural type can be divided into: the identification of measurement target; The size of measurement target; The position of sample; The kind of sampling mechanism, as Noninvasive, minimally-invasive, or invasive; The sample type of obtaining; Depositing of sample; The modification of sample; And single measurement target quantity is definite.In addition, the details of structure should change in time to adapt to the target of health monitoring.

[0014] system that describes in further detail below can be used for very application fields, includes but not limited to: diabetes monitoring and treatment; The recovery medical treatment comprises hemorrhagic shock, wound, burn or the like; The detection of infantile jaundice and treatment; Endurance, health performance, fatigue strength and Alertness monitoring; The organizational vitality test; Implement biopsy; The earlier detection of disease, as cancer and infectious disease, and to the response of this disease treatment; The detection of gum disease and treatment are as antibacterial, virus, microbial film, inflammation and dental caries and normal hormone, protein and metabolite, in order to estimate whole body health; The management that monitoring obesity, diet, exercise, body weight and whole body are formed; Detect cardiovascular function and apoplexy; Drug discovery and exploitation screening; The pharmacokinetics of medicine, individual dose is renderd a service safety, toxicity, side effect, interference and pharmaceutical research and clinical trial; Detect and the treatment infectious disease, include but not limited to influenza, malaria and dengue fever; At the neural interface of short-term or long-term interface, as responding at prosthese control and treatment; The monitoring nerve problems is as dejected, anxiety, multiple sclerosis; Monitoring animal, crops, water, food supply or the like; Monitoring material and drug use and abuse are as cigarette, ethanol, tranquilizer or the like; The drug dose clinical practice is as anticoagulant.In addition, described system also can be used in combination with biomedical instrument, so that the direct feedback to radiotherapy, chemotherapy, exercise, dialysis, respiratory organ, tissue and organ aid system curative effect to be provided.Described system can also be used for all can with postoperative before art at being removed or the activity and the function of implanted tissue being carried out the implanting tissue monitoring.

[0015] one aspect of the present invention is to be provided for monitoring the method for the biological situation of experimenter.In embodiments, described method comprises that the pick off with sampling, analysis and delivery apparatus is exposed to the material that comprises target biological molecules, provides the signal of telecommunication to described pick off; Measure the electrical property that described pick off place responds the described signal of telecommunication; Measured electrical property is associated with biological situation; Determine that measured biological situation is normally or undesired; And when the biological situation that records is undesired, generate signal.

[0016] in one embodiment, described target biological molecules is selected from the group of being made up of following material: glucose, lactic acid, bilirubin, ethanol, acetone acid and cytochrome P-450 2A6 enzyme.

[0017] in one embodiment, target biological molecules is selected from the group of being made up of following material: glucosylation hemoglobin and protein, insulin, cholesterol, c reactive protein, homocysteine, the appetite peptide, Plasmodium falciparum histatins 2, the parasite lactic acid dehydrogenase, prostate specific antigen, prostate film specific antigen, estrogen, epidermal growth factor, insulin-like growth factor, hemagglutinin, neuraminidase, the 17kDa subunit of splitted Caspase-3, protein such as p54, immunoglobulin, anesthetis, leptin, ghrelin, vitamin, folic acid, creatine kinase (CK and CK-MB), troponin, c reactive protein, Tumor Necrosis Factor Receptors 1 and 2, creatine phosphokinase (CK and CK-MB), sarcosine, troponin, interleukin 1,2 and 6, the interleukin II receptor, tumor necrosis factor, the n-nitrosamine, nicotine, but ferrum is peaceful, Opium class medicine, cocaine, and spore metabolite.

[0018] in one embodiment, target biological molecules is selected from the group of being made up of following material: influenza virus, multiple sclerosis syndrome virus, dengue fever, malaria, HIV and pulmonary tuberculosis.

[0019] another aspect of the present invention is to provide a kind of method that is used for the biomolecule monitoring.In one embodiment, described method comprises samples to the material that comprises biochemical product, and utilizes pair of electrodes to analyze described material.Described electrode pair is placed on the support substrate.Described method also comprises to be utilized controller control sampling and analyzes, and between controller and remote-control device communication information.

[0020] one aspect of the present invention system of being to be provided for sampling, analyzing and/or send at least a biochemical product (biochemical).In one embodiment, described system comprises support substrate and a plurality of by described support substrate support and be arranged to the cell (cell) of multiple lines and multiple rows.Each of described a plurality of cells is through constructing with sampling, analyzing and/or send described biochemical product.Described system also comprises controller, its through structure to control the interaction between each and the material relevant in described a plurality of cell with described biochemical product.Described controller is connected with described a plurality of cells by a plurality of column address conductive paths, a plurality of row address conductive path and a plurality of zero-force connectors.Described system further comprises communication device, and it is through constructing to communicate with described controller and external device (ED).

[0021] another aspect of the present invention is to provide a kind of system that is used for amalyzing substances character.In one embodiment, described system comprises support substrate and a plurality of pick off of being supported by described support substrate.Each pick off comprises the pair of electrodes of being supported by described substrate.Described electrode pair comprises working electrode and reference electrode.Described working electrode activate by electrochemistry and through structure with described substance reaction.When on described electrode, applying voltage and described at least working electrode and be exposed to described material, produced electrical property corresponding to described physical property.Described system also comprises controller, is used to control to the series of electrical signals of described electrode, and receives the electrical property of its generation.

[0022] another aspect of the present invention is to be provided for detecting the pick off of the Substance Properties that comprises biomolecule.In embodiments, described pick off comprises a pair of electrode of being supported by substrate.Described electrode pair comprises working electrode and reference electrode.Described working electrode activate by electrochemistry and through structure with described substance reaction.When on described electrode, applying voltage and described at least working electrode and be exposed to described material, produced electrical property corresponding to described physical property.

[0023] and another aspect of the present invention be to be provided for the sampling sampling apparatus of the material that comprises biochemical product.In one embodiment, described sampling apparatus comprises support substrate, and a pair of electrode of being supported by described support substrate.Described electrode pair is through constructing to interrupt (disrupt) protecting film between described support substrate and described material.

[0024] one aspect of the present invention is to be provided for the method for the biochemistry product in the amalyzing substances.In one embodiment, described method comprises that the working electrode at least with pick off is exposed to described material, on working electrode and reference electrode, apply voltage, measure the electrical property conduct that is generated applies described voltage on described electrode result, and measured electrical property is associated with described Substance Properties.

[0025] another aspect of the present invention is to provide the method for filling the chamber (cavity) in the delivery apparatus supporting layer.In embodiments, described method comprises the foraminous sealant of tool wherein is placed on the described supporting layer, make described hole be positioned on the described chamber, fill described chamber with material, the described relatively supporting layer of described sealant is placed, make described hole remove and make described sealant to cover described chamber, and described sealant is combined on the described supporting layer from described chamber.

[0026] one aspect of the present invention is to provide a kind of manufacturing to be used for the method for the device of amalyzing substances character.In one embodiment, described method is included between a plurality of adapters on the described support substrate and a plurality of electrode and connects with lead, make described a plurality of electrodes exposed in polymeric matrix, provide relatively electrochemistry potential energy from described a plurality of electrodes, selecting electrode, and be coated with selected electrode with described polymeric matrix.

[0027] these and others of described system are described referring now to accompanying drawing.

Brief Description Of Drawings

[0028] in order to understand inventive concept of the present invention, be usefulness very with reference to the accompanying drawings, wherein represent identical parts with identical Reference numeral as far as possible, wherein:

[0029] Fig. 1 is the sketch map of a kind of embodiment of expression biomolecular sampling and delivery system;

[0030] Fig. 2 is the sketch map of functional parts embodiment of sampling, analysis and the delivery apparatus of presentation graphs 1 system;

[0031] Fig. 3 is the schematic top view of sampling, analyzing and sending the geometry part of cell according to embodiments of the present invention;

[0032] Fig. 4 A samples according to embodiments of the present invention and analyzes the geometry schematic top view of cell;

[0033] Fig. 4 B is the geometry schematic top view of sending cell according to embodiments of the present invention;

[0034] Fig. 5 has represented the cross section of the embodiment of Fig. 3 along the A-B line;

[0035] Fig. 6 is the cross sectional representation of the mode of texturing of the design described among Fig. 3;

[0036] Fig. 7 has represented the cross section identical with Fig. 6, has a breach in the thin film of substrate;

[0037] Fig. 8 has represented the cross section of Fig. 6, has the chamber that is filled with material, is used for sending at the sample sites place;

[0038] Fig. 9 has represented the cross section of Fig. 6, has wherein increased the effective surface area of analyzing electrode;

[0039] Figure 10 has represented the cross section of Fig. 6, has wherein increased the effective surface area of analyzing electrode;

[0040] Figure 11 has represented and has organized for example cell of the contacted Fig. 6 of skin, and this tissue has carried out simplifying to schematically show squamous horny layer and growth epidermal tissue;

[0041] Figure 12 is that the cell of representing Figure 11 is interrupting the sketch map behind the barrier tissue;

[0042] Figure 13 has represented and the cell of organizing contacted Fig. 8;

[0043] Figure 14 has represented that the cell of Figure 11 is interrupting the sketch map behind the barrier tissue;

[0044] Figure 15 has represented to be used to sample fluidic cell;

[0045] Figure 16 has represented the cell of Figure 15, and it is opened so that fluid enters the described chamber that is placed with analyzing electrode;

[0046] Figure 17 cell of solid or powder of having represented to be used to sample;

[0047] Figure 18 has represented the cell of Figure 17, and it is opened so that the fluid wets of holding and dissolve described drying sample, makes to exist at described analyzing electrode place to concentrate;

[0048] Figure 20 is the structure chart of some parts of expression controller and wireless telecommunications;

[0049] Figure 21 is the side schematic view of a device cell part, and it has represented to fill and sealed the embodiment of the chamber of Fig. 8;

[0050] Figure 22 is the schematic top view of interface embodiment that is used to fill the single chamber of described device;

[0051] Figure 23 is the schematic top view of interface embodiment that is used for filling simultaneously five chambers of described device;

[0052] Figure 24 is the schematic top view of interface embodiment that is used for filling simultaneously 25 chambers of described device;

[0053] Figure 25 is the flow chart of the method embodiment of the expression undesired biochemical situation that is used to monitor and treat the experimenter;

[0054] Figure 26 is the sketch map for preparing the method embodiment of the electrode that is used for described device;

[0055] Figure 27 is the sketch map of the nano-tube array embodiment that is prepared on the electrode of described device;

[0056] Figure 28 is the applied nano-tube array sketch map afterwards of described nanotube;

[0057] Figure 29 is the schematic top view of described device embodiment;

[0058] Figure 30 is the viewgraph of cross-section along the XXX-XXX line of Figure 29;

[0059] Figure 31 is the multiple arrangement schematic top view in process of production of Figure 29;

[0060] Figure 32 is the sketch map that can be used for the hand-held sampler embodiment in the dental applications;

[0061] Figure 33 is the sketch map of a pair of plug embodiment that can be used for the hand-held sampler of Figure 32;

[0062] Figure 34 is based on the embodiment sketch map of the dental explorer device of microcapillary.

Detailed Description Of The Invention

The system and method general introduction

[0063] the present invention relates generally to the method, apparatus and system that are used for configurable flexible personal health monitoring and delivery system.More particularly, the present invention relates to a kind of selective sampling material that is used for, include but not limited to a matter and biofluid,, include but not limited to be present in the biomolecule in the sample in order to measurement target character optionally, system and method.In addition, described system and method can provide storage material, includes but not limited to the release on request of chemicals, biochemical product and medicine.

[0064] Fig. 1 is the embodiment sketch map of expression configurable flexible personal health monitoring of the present invention and delivery system 10.In the illustrated embodiment, system 10 comprises three collaborative devices, comprise sampling, analysis and delivery apparatus 12, the control device or the controller 14 that link to each other with described sampling, analysis and delivery apparatus 12, and make data come and go to be sent to remote logging instrument, controller or any other through structure to transmit and/or to accept the communication device 16 of the device of data.

[0065] as below with discussed in detail, described sampling, analysis and delivery apparatus 12 can through structure with sampling substance and/or, analyze this material and/or delivery materials, as chemicals, biochemical product or medicine, to the described material that is sampled and/or analyzes.Here, phrase " sampling, analysis and delivery apparatus " is not appreciated that needs this device that three kinds of all functions all are provided in all embodiments.On the contrary, in some embodiments, described device 12 can be through structure with sampling substance and amalyzing substances, perhaps only sampling substance or only amalyzing substances.The combination in any of these three kinds of functions is all thought within the scope of the present invention.As below will going through, in embodiments, described device 12 can be the aseptic disposable microfluid electrochemistry chip of flexible adaptation that comprises a plurality of electrochemical sensor cells.

[0066] in embodiments, controller 14 can comprise flexible cable and the adapter that is connected to device 12, makes controller 14 link to each other with described a plurality of electrochemical sensor cells.Described controller 14 can also comprise controlled in wireless and message elements, its through the structure with described communication device 16 communications, described communication device 16 can through the structure with computer long-range, preferred wireless or any other through the structure to accept the device communication of data.For example, described remote-control device can comprise the device of memorizer for mobile phone, photographing unit, music player or any other.Controller 14 and communication device 16 also will illustrate in greater detail hereinafter.

It will be appreciated by those skilled in the art that [0067] embodiment of system 10 can be used for the extensive use field of the predetermined state of needs monitoring material.In general, system 10 can be used for monitoring specific undesired biochemical situation, disease for example, and treat this situation according to testing result.

[0068] as shown in Figure 25, in embodiments, provide and utilized system 10 as herein described to monitor the biochemical situation of experimenter, as the method 200 of disease.The experimenter can be people, animal, living tissue, organ or non-lived material, as food or water.The method 200 of this embodiment begins with step 202.In step 204, be placed on experimenter's the suitable position and can make the pick off of sampling, analysis and delivery apparatus 12 be exposed to the material that comprises target biological molecules by installing 12.Device 12 can link to each other with monitoring system with communication device 16 by controller 14.In case the 12 in place and systems 10 of installing play a role, just can be preset time section monitoring experimenter to set up this experimenter's normal health baseline habit.For example, by the biomolecule in sampling experimenter's the detectable experimenter's blood flow of interstitial fluid, can be analyzed to determine " normally " concentration in this particular subject.Can be by in step 206, providing the signal of telecommunication to pick off, and the electrical property of measuring this pick off place in step 208 analyzes described sample, described electrical property generates as the response to the described signal of telecommunication.In step 210, measured electrical property can be associated with biological situation then.In some embodiments, experimenter's normal health baseline habit may be programmed in the system 10 known and.After baseline is set up, adopt identical step 206,208 and 210 can continue to monitor with 10 couples of experimenters of system, detect abnormal state up to system in step 212, for example the rising of target biological molecules concentration or reduction.

[0069] in case monitors abnormal state, just can step 214 generate signal and can with controller 14 communications, at this moment, in step 216, controller 14 can determine to continue monitoring, this moment, this method turned back to step 206, perhaps can determine to signal to device 12 so that delivery materials is to described material in 12 the chamber from installing in step 218, and this method can turn back to step 206 afterwards.Can carry out continuous monitoring to the experimenter, can monitor the effectiveness and the adaptability of described material like this.In addition, controller 14 can signal to device 12, detects any second order effect that is caused by described abnormal condition so that another pick off is exposed to described material.If determine that described abnormal condition disappears, then system 10 can be through structure to stop to send described material.Then can be with the probability of described system monitoring experimenter's abnormal state recurrence.When having detected the recurrence generation, described material can be delivered to the experimenter once more, perhaps can provide another kind of material, and can proceed monitoring described experimenter.At any time, if determine to stop monitoring, described method can end at step 222.Particularly, if in step 212, determining does not have abnormal state, controller 14 just can provide the signal of telecommunication with identical or another pick off on device 12 at step 220 relaying supervention signal, and perhaps controller 14 can stop to provide signal and described method can end at step 222 to pick off.

[0070] interval of above-mentioned monitoring can be different, perhaps can set predetermined interval, the scope from several minutes to several weeks.Pick off in the cell 18 of device 12 can be through structure with in very large range, and approximately 1pg/dl (trace) detects target biological molecules concentration to about 1g/dl (concentrating amount).

[0071] device 12 can comprise outside and inner portion through structure to be placed on the many tissue sites on experimenter's health.For example, outer portion can comprise experimenter's arm, lower limb, cervical region, hands, foot and facial skin.The example of inner portion comprises mouth (comprising buccal, gingiva and tongue), nose and Dou Tongdao, pharynx, ear and part tissue of eye or the like of experimenter.On a part that device is installed to eye or internal ear, can obtain relevant central nervous system's information.

[0072] system 10 can also be through structure to monitor at the whole chemical instruments plate that is in individuality, patient or colony in the disease risks.In one embodiment, described system can be through structure with patient, the shock patients that is used for the instant Intensive Care Therapy of needs, the recovery of suffering from the patient or even the senseless patient of certain wound.By giving patient's application apparatus 12, can implement real-time analysis, so that relevant patient's out of Memory to be provided to the care-giver, even under the situation that the patient can not talk to target molecule.In embodiments, system 10 can provide the earlier detection of disease, and/or monitoring be to the response of treatment through structure to monitor and to treat chronic seriously disease.

Sampling, analysis and delivery apparatus

[0073] Fig. 2 is the sketch map of the functional parts of indication device 12.As shown in the figure, device 12 comprises a plurality of samplings, analyzes and sends cell 18.Term " is sampled, is analyzed and send cell " and need not should be understood to this cell that all three kinds of functions are provided in all embodiments.On the contrary, in some embodiments, cell 18 can be through structure with sampling substance and amalyzing substances, and cell 18 can be through structure with sampling substance only or amalyzing substances or only provide material delivery to arrive material only.The combination in any of these three kinds of functions all is considered as within the scope of the present invention in a cell.

[0074] in the embodiment illustrated, cell 18 is arranged to a plurality of row and row.Consider other set-up mode, shown embodiment does not mean that the restriction of any way.Device 12 also comprises a plurality of electrical contact pads 20, its through structure linking to each other with controller 14, and a plurality of conductive vias 22, it is connecting cell 18 and contact mat 20.Cell 18 is positioned at and is placed to and analyzed sample, as tissue, in contacted regional 24.Device 12 can randomly comprise electric installation identified region 26, and when this device 12 was connected with it, it can make this specific device 12 controlled devices 14 discern.

[0075] be present in therein in the embodiment of biomolecule by percutaneous sampling in the interstitial fluid, device 12 is placed on the position that closely contacts with experimenter's skin, and pass through pressure or adhesive in place.Can be to a pair of or several series of pulses that a plurality of selectable electrode that is arranged in cell 18 applied accurately predetermined and control, producing heat and internal field, wherein disconnected cuticular dead Skin Cell and do not damage the living cells of the growth epidermis of its below of next-door neighbour.This make interstitial fluid to flow to and damping device 12 on the surface in this site, and the concentration balance of maintenance and bottom tissue reaches many hours, that is, form again up to horny layer.

[0076] at the interrupted accurate position of horny layer, can place one or more pairs of electrochemical electrodes, and can adopt one of several means to prepare described electrode, so that optionally measure one or more character of described interstitial fluid.These character include but not limited to the concentration of biomolecule, as the concentration of biochemical analyte, and/or physicochemical property, as the concentration of pH value or dissolved gas.This measurement can be successive in essence, and can follow the trail of any time variation of these concentration reliably, up to the horny layer reparation.As following further discussion, the preparation of each cell place counter electrode can comprise encapsulation with beginning expection measure before the protective reaction surface.Described encapsulation can be by impervious and reactive, for example viscosity, associativity, charging property, electric conductivity etc., and perhaps the film of selective permeation provides, and described film is used for various application through selection, specifically depends on target biological molecules.

[0077] in one embodiment, the described material that contains biofluid to be analyzed can be collected from various samples, and described sample includes but not limited to food, water, air, whole blood, urine, saliva, chemical reactant and culture.In this embodiment, can be statically or the small amount of matter that will contain described biofluid of the mode by Continuous Flow on described surface be applied to the surface of device 12.Controller 14 can be through structure to open one or several selectivity sensing cells 18 and to begin to monitor the specific concentrations of described biofluid.For example, can analyze at once blood drainage in when nursing, perhaps can the continuous monitoring air and the chemistry and the biological pollution-free purity of water sample.In addition, use up or when detecting new pollution threat,, can replace described cell 18 when described cell by opening new cell 18 at suitable position.Described system 10 can be through structure to provide application specific analysis and monitoring system.

Sampling

[0078] Fig. 3 is the part schematic top view of single cell 18 embodiments, and it can be in many cells on the device 12.In this embodiment, cell 18 through structure with sampling, analyze and send, and be used to simultaneously to sample and the component exposed analyzed in the surface of adaptability substrate 40.12 be connected in the application of non-flat surface for device, described substrate can be flexible, makes surperficial conformal that device 12 can be with this non-flat surface.Represented encapsulation or the chamber 28 imbedded in the sketch map, it can contain and is useful on the material of sending.The conductive vias 30 that finally is connected on the conductive vias shown in Figure 2 is covered by thin dielectric layer, and has constituted the part of selectivity working electrode 32 and reference electrode 34.As shown in Figure 3, the resistance element part 36 of exposure is connecting the expose portion 38 of other conductive vias 39.

[0079] Fig. 4 A is sampling and the schematic top view of analyzing the embodiment of cell 18.In this layout, selectivity working electrode 32 is connected with the expose portion of reference electrode 34 by the conductive vias 38 of second conductive vias, can interrupt horny layer and analysis to measure timing electric current or other electrical properties by identical electrode 32,34 like this.

[0080] Fig. 5 has represented in Fig. 3 embodiment the cross section along the A-B line.This cross section has been represented the resistance element 36 of contiguous analyzing electrode, and described analyzing electrode can be the selectivity working electrode 32 on flexible substrate 40 parts.

[0081] Fig. 6 is the mode of texturing cross sectional representation of the design described among Fig. 3, and wherein analyzing electrode 32 and 34 is encapsulated in the chamber in the substrate 40, and is positioned on the thin film of substrate material at sampling position.Chamber 28 can be filled with the material that will be delivered to the sampling site, and perhaps chamber 28 can be empty.

[0082] Fig. 7 has represented the cross section identical with Fig. 6, and wherein the breach in the substrate membrane 42 is that driving by resistive element causes.This breach 42 causes analyzing electrode 32,34 to be exposed to material to be analyzed, can also make the delivery materials of any encapsulation be delivered to the sampling site from chamber 28.

Interrupt

[0083] among a kind of in multiple analytical applications, device 12 adhesions are fixing to contact with skin or some other tissues or film on the target subject.Figure 11 has represented the cell of Fig. 6 and has organized for example contact skin, described tissue to be simplified as to schematically show squamous horny layer 48 and following growth epidermal tissue 50, and interstitial fluid is arranged in this growth epidermal tissue.

[0084] in one embodiment, by applying the potential pulse of a series of about 2V, the persistent period can be interrupted experimenter's horny layer less than a second.Required accurate order and voltage must and want the interrupted person's character of organizing to regulate at specific experimenter and position.Heat and voltage drop between the sampling electrode can not removed cuticular dead cell, but can cut off connection therebetween, thereby form the capillary tube opening, be used for upwards wicking into interstitial fluid on the sampling electrode and making enough fluid transfer with balance with dynamically keep below horny layer the fluidic balance of matter in the middle of the growing tissue from the growth epidermis.

[0085] interruption to barrier tissue is different from the prior art normally used such as the process of ablating and puncturing by mechanical means (for example pin).Ablation is meant removes some target cell.The barrier cell is not living cells usually, and is to be formed with evening up by its shape scaleization that lives sometimes, and it closely and conformally is crowded together, and is attached to each other by the chemical bond between the biomolecule of forming cell wall.Interrupt procedure is the process of instigating the key between the barrier cell that is crowded together to rupture gradually, makes narrow capillary tube opening form at iuntercellular.Described cell itself is kept perfectly mostly.When capillary dimensions increases, conductive path is arranged, interstitial fluid can be drawn to described surface by it.We observe mobile speed and character for example depends on, the basal metabolism blood pressure, and the pressure inside head does not force interstitial fluid outwards to flow out.Flowing of interstitial fluid can be by carrying out specific hydrophilic surface and handle and strengthen sampling apparatus up-sampling position and patterning capillary structure or the little obturator in the sampling apparatus surface.

[0086] this unique technique that is used for interrupting reliably barrier tissue comprises the particular order on the sampling electrode of independent addressing and the electrical energy pulse of combination.Particularly, at people's skin of forearm, the one or more conductive film resistors between the sampling electrode have been adopted.For a plurality of resistors, select by high (for example 200Ohm) in to the cascade resistance value of low (50Ohm).The big I of each resistor is equivalent to the size of the barrier cell that will remove from its flanking cell.For 50 microns corneocyte, this means that gaps between electrodes should be less than 100 microns.Can apply from 0 to 2V voltage step to described electrode with the short burst less than 1 second, each pulse increment is 0.2V usually.Described device can be through making so that from the adapter to the electrode conductive trace except that resistor, all being got up by embedding.

[0087] in one embodiment, can apply the moderate electric field of maximum 4MV/m.Then, by 2.2V, the temperature of minimum resistance element can reach 140 ℃ in the very short time, and resistance can be opened then.Described opening by the accurate making material of resistance, size and order and following sampling apparatus material (being generally the polymeric film of low melting temperature) as polyethylene or polymethacrylates decision.Along with distortion of materials, the conductive trace fracture.Calorifics distribution measuring value shows that on 50 micron thickness horny layer, temperature can drop to and be lower than 80 ℃.If have only a resistance, then electrode forms open electric circuit, still can apply the electric field of impulse form between described electrode.For a plurality of resistance, voltage step can be continuous, fragments into open electric circuit up to all resistance.Can stay electrode separately now and allow between sensing and reference electrode, to carry out electrochemical measurement.

[0088] in the embodiment of hope ablation cell rather than interruption cell, can on apparatus surface, provide heater.This heater can be through structure so that for example, and the heat energy of 50mJ pulse can be applied on the corneocyte with the described cell of ablating.This set for example is recorded in the U.S. Patent No. 6887202, is incorporated herein it as a reference.

[0089] Figure 12 is barrier tissue afterwards the sketch map of cell in having interrupted zone 52 of expression Figure 11.Set up the diafiltration fluid passage so that interstitial fluid 54 flows out by capillary force and moistening sampling position from growth epidermal tissue 50.Can analyze the interstitial fluid 54 that has wet electrode by electrodes selective 32 and 34, as mentioned below.

[0090] in one embodiment, interrupt electrode itself and can be used for electrochemical measurement, it can provide compact economic manufacturing, higher packed bulk density, and simplify connection and control circuit.

[0091] in some applications, when material particularly to be sampled has been positioned on the target subject upper surface, described device even can not comprise the mechanism that is used to interrupt cell.

Analyze

[0092] In one embodiment of the present invention, two sampling electrodes connect by substrate 40 supports and by resistive element.Electric conductivity enzyme fixed layer has covered in the sampling electrode part of at least one, but whole device protected seam be covered with, near the sampling electrode.

[0093] analyzes in the embodiment of interstitial fluid being intended to, be drawn onto any target biological molecules near the interstitial fluid the electric conductivity enzyme fixed layer, with fixed enzyme interacting.This interaction can record by for example timing current measurement method, and the voltage that its utilization is applied on the sampling electrode is realized.Certainly, described electrode can be through structure so that can record the electrical property of other type, as resistance, electric capacity or the like.

[0094] Fig. 9 has represented the cross section part of Fig. 6, and the effective surface area that has wherein increased analyzing electrode 32 and 36 is with the corresponding increase of the realization signal of telecommunication and the minimizing of signal to noise ratio.The increase of area can both realize by the other area on the covering chamber wall and by adopting shielded spongy porous electrode material.

[0095] Figure 10 has represented the cross section part of Fig. 6, and the effective surface area that has wherein increased analyzing electrode 32 and 34 is with the corresponding increase of the realization signal of telecommunication and the minimizing of signal to noise ratio.The increase of area can realize by the surface that covers working electrode 32 with shielded compact nanometer material 46, the chemical production of the desirable selection of described nano material 46 usefulness.The preparation of this nano material will discuss in more detail hereinafter.

[0096] Figure 15 has represented to be used to sample and has not been positioned at fluidic cell on the protecting film reverse side.The cell of Fig. 6 directly contacts with delay to be analyzed or streaming flow 56.Figure 16 has represented the cell of Figure 15, and it is opened so that fluid enters chamber 28, is provided with analyzing electrode 32 and 34 in this chamber.In case electrode 32 and 34 is exposed to fluid and to described electrode application voltage, just can measures resulting electrical property.

[0097] Figure 17 cell of solid or powder of having represented to be used to sample.In the cell among Fig. 8, apply or collect drying sample to be analyzed 58.Figure 18 has represented the cell of Figure 17, its be opened so that the fluid wets that comprises and the dissolving exsiccant sample 58, thereby make concentration be present on the analyzing electrode.

[0098] embodiment of represented above-mentioned cell and electrode and be not intended to restriction by any way, but for the example that may construct is provided.

[0099] for example, in needing the embodiment of measure gas concentrations, described gas includes but not limited to be dissolved in oxygen, carbon dioxide, carbon monoxide (deleterious) and the nitrogen oxide in biofluid such as the interstitial fluid, and device 12 can have following structure.In one embodiment, device 12 can be placed on the health to obtain interstitial fluid.In another embodiment, device 12 can be placed in experimenter's pulmonary respiration passage, for example be arranged in nasal passage or near, expose in the air of breathing will install 12, thereby can carry out the gas component measurement.

[0100] have sensing electrode that multiple mode can make device 12 delicately selectivity accurately measure these gases, for example be recorded in U.S. Patent No. 6270651 and 7001495, and among the open No.20010052459 of U. S. application those, introduce it here in full as a reference.The sensing electrode of device 12 can form with particulate metal and electrolytical film preparation, and it optionally generates and the proportional electrochemical voltage of the logarithm of described partial pressure when being exposed to gas.Some electrolytes that can adopt can be water-soluble slightly, and can be by hydrophobic but allow the gas molecule infiltration and by this layer and arrive the polymer coating thin film protection of sensing electrode, shown in the layer 58 among Figure 18.

[0101] in the another kind of method of detected gas such as oxygenated blood fluid gas, the sensing electrode of device 12 can connect by thin multichip semiconductor crystal material layer, for example stannum oxide or tin indium oxide.Can be adsorbed onto in the described polycrystal semi-conducting material from the interstitial fluid or the airborne oxygen of breathing out, and change electric conductivity between the described electrode according to described partial pressure.In addition, can adopt quasiconductor or the insulator thin film of (comprising polymer), it optionally adsorbs the purpose gas molecule, and because the electric capacity between the electrode 32,34 in the cell 18 of device 12 changes, described adsorbance can electrical measurement obtain.

[0102] In one embodiment of the present invention, in the chamber 28 of device 12, can form the piezoelectric detection device and detect Ag-Ab with permission, or Ab-Ag.The resonant frequency change of following binding events to take place by monitoring can help Ab-Ag to detect.In one embodiment, piezo-electric device comprises cantilever beam and the membrane structure that has added piezoelectric, to detect and the bonded analyte of its specific receptor.For cantilever beam, can adopt two kinds of sensing patterns.First kind, when binding events takes place, can record caused surface stress by measuring the voltage that produces by the piezoelectric film that is subjected to stress.Second kind, can detect the change of cantilever beam resonant frequency, described change is as the result of the mass change that is produced by binding events.For the membrane structure that adds piezoelectric, the complexation of Ab-Ag is determined in the change that can measure resonant frequency.

[0103] in one embodiment, described device can be equipped with piezoelectric film to form electric current in apparatus structure, and it can be stored on the capacity cell.This device can be worn over (forearm, wrist, buttocks etc.) on the health, and here Zi Ran body kinematics causes the bending action of paster.By adopting piezoelectric element, can convert any bending stress to electric energy.Solid depends on uneven CHARGE DISTRIBUTION in the solid with the ability that mechanical stress converts the signal of telecommunication and reverse transformation to.Although it is neutral that whole material keeps being, many internal dipole squares that can form detectable inner potential energy are arranged wherein.When piezoelectric at first experiences when being called as polar polarization process this signal of telecommunication maximum.Before polarization process, dipole, be randomly dispersed on the whole solid, yet when by external electrical field and temperature polarization, dipole makes internal dipole to redirect with the approximate state that aligns in order.Mechanical compress has reduced the size of dipole moment, thereby has reduced voltage, and drawing process has increased the size of dipole moment and the signal of telecommunication that raise.

[0104] in a similar fashion, with the piezoelectric identical polar apply the voltage described material that stretches, and the voltage that applies of opposite polarity compresses described material.In a kind of structure of described device, one layer of polymeric piezoelectric such as polyvinylidene fluoride or PVDF add or are deposited on the substrate.A kind of purposes of this device is to measure electromotive force also with its metric as sampling apparatus deformation.Second kind of independent and reconcilable purposes relates to control and communication device 14,16.Described electromotive force produces electric current, and controller 14 can and be used for to the chargeable flexible polymer lithium cell charging on capacitor or the plate this current commutates.

Send

[0105] Fig. 4 B is the schematic top view of the embodiment of cell 18, and it gives described material through structure with delivery materials.In this layout, the back of the expose portion 38 that encapsulation that containing of imbedding is useful on the material of sending or chamber 28 are positioned at the pair of conductive path, described expose portion is partly connected by the exposure resistive element of this conductive path.In this way, cuticular interruption also can be used for providing and will imbed material delivery in the encapsulation 28 to interstitial fluid.Described material can be the form of gas, liquid or solid, and can comprise medicine, chemicals, cell, biochemical product, biomolecule, protein, peptide, genetic stocks or the like.

[0106] Fig. 4 C has represented the schematic top view of a part of the another embodiment of cell 18, and it can be in many on the device 12 one.In this embodiment, sampling and analyzing unit all is exposed on the surface of adaptability substrate 40, and electrode 32,34 is positioned at the expose portion place of conductive path, thereby has formed less conductive path, and it can cause needs to improve the control function.

[0107] in independently a plurality of encapsulation of measuring site, gas phase biochemical product, dried powder or aqueous solution can store and discharge by the control diffusion process, described diffusion process be by the enclosure wall material or by splitting of sequential control part enclosure wall carry out so that the chemicals of desired concn is dissolved in the interstitial fluid and horny layer by local interruption arrives health.As the analytical chemistry instrument, described chemicals can be selected to make itself and local interstitial fluid to react and its composition is changed, and product can record by described a plurality of electrodes.Perhaps, the chemical example of encapsulation can be the calibration standard thing.Measurement electrode selected or new selection is used for following continuously the experimenter discriminably to applying the reaction of chemicals, thus quantitatively effect and being adapted to a plurality of side reactions of detecting safely and preventing with minimum dosage.

[0108] Fig. 8 has represented the cross section of Fig. 6, and its middle chamber 28 is filled with and is used at the material 44 sent of sampling site.How the embodiment of filled chamber will discuss in more detail hereinafter.Working electrode 32 and 34 can be through structure setting delivery materials 44 concentration, and measured how many materials thus and stayed the chamber neutralization what have be delivered to the sampling site.

[0109] Figure 13 has represented and the cell of tissue as the contacted Fig. 8 of skin, and described tissue is simplified to schematically show squamous horny layer 48 and the following growth epidermal tissue 50 with interstitial fluid.

[0110] Figure 14 has represented the sketch map of cell after the thin film that has interrupted barrier tissue and sealed chamber 28 of Figure 13.Set up the osmotic fluid passage, thereby allowed interstitial fluid 54 to flow to and moistening sampling site by capillary force.Delivery materials 44 mixes or is dissolved in the interstitial fluid and because the high concentration gradient that obtains and be diffused into growing tissue 50 backward and arrive the remainder of health thus by the horny layer 48 that interrupts.

[0111] by making the single sampling site on the device 12 be amplified to 10 microns or littler size, can analyze born of the same parents' inner fluid of each cell by the local interruption cell membrane, and can before it is discharged from the sampler surface, will treat material and inject this cell.

[0112] as mentioned above, in one embodiment, can realize wherein disconnected horny layer to the destruction of the thin film of sealed chamber by the heat that electrode and/or resistive element produce.In this embodiment, breaking basically by this film melts was realized to the moment that wherein forms breach in film of thin film broken so that form hot melt.In another embodiment, the thin film of chamber can interrupt by the mechanical force that is applied on the thin film, so that explosion, tear and/or cut off this thin film.The generation of this mechanical force can be by for example, carries out electrolysis via the electrode that is positioned at this chamber and form bubble and carry out in chamber.Because can becoming enough high, the pressure that bubble formation produces also make the material 44 that is encapsulated in the chamber 28 flow out chamber 28 in the chamber from fracture site with this thin film of explosion.To flow out that example that chamber or material enter the flow passage of chamber should not be considered as be the restriction of any way to this breakable to form material.

Make

[0113] in manufacture process, the conductive layer on the electrode 32 can utilize the fixed enzyme that changes target biological molecules to come electrochemical activation.For example, if glucose is a target biological molecules, then described enzyme can be but be not limited to be, glucoseoxidase, if lactose is a target biological molecules, then described enzyme can be a galactoseoxidase, if bilirubin is a target biological molecules, then described enzyme can be a Bilirubin oxidase.In some embodiments, conductive layer can utilize the antibody electrochemical activation.By utilizing the optionally described electrode of electrochemical activation of specific enzyme and antibody, can be positioned at different cells 18 on the same device 12 through structure with the sensing different biological molecules.

[0114] in one embodiment, device 12 can be the chip of flexible patch sample, it has the metal laminated structure of multiple layer polymer, and can utilize SU-8, Teflon-AF releasing layer, polymethyl methacrylate (PMMA), polypyrrole (PPy) and glucoseoxidase (GOD) as structure sheaf to make.For for simplicity, we wherein for the sake of clarity, have not had the disruptive feature of packing and protecting film with the special embodiment of tracing device, and wherein we have selected to be used to interrupt cuticular electrode and combine with sensing and reference electrochemical electrode.

[0115] in one embodiment, sampling, analysis and chemical delivery apparatus manufacture process utilize SU8 as main structural material, and are made of five steps usually.This process is the part in the technology that develops for polymeric material polydimethylsiloxane (PDMS) previously.The first step is a deposition Teflon releasing layer on glass substrate, and it makes described multiwalled heteropolymer device be easy to remove from glass after making.The SU8 thin layer is made by spin-coating method, plays the basal layer (10 μ) of auto levelizer remainder, and provides viscosity to Teflon.In the manufacture process the 3rd step is made of thick (150 μ) the SU8 layer of spin coating.This thick-layer provides the structural support to device.Make chromium/gold electrode/heating of metalization (0.5 μ) sputtering sedimentation and form pattern at described thick SU8 (150 μ) layer top.The PMMA of spin coating 10 μ is as the protective layer to selective deposition PPy and enzyme then.In order to prevent that electronic pads from being covered by PMMA, remove before the PMMA spin coating adhesive tape being placed on the electronic pads and before the PMMA bake process.Described PMMA layer further optionally carries out plasma etching by this way: promptly have only an electrodes exposed and another covering electrodes covers.Described metal adopts positive photoetching rubber and wet chemical etch to form pattern.Before sputtering sedimentation, the employing Surface Treatment with Plasma improves the viscosity between SU8 and the metal level.With razor described device is taken off from glass substrate then.Described releasing layer forms by the amorphous fluoropolymer solution of spin coating with the perfluorinated solvents dilution.

[0116] utilize the permanent electrolyte of putting the position instrument and being made up of PPy and each 0.1M of KCl to carry out under 0.8V 2 minutes, with glucoseoxidase (GOD), proenzyme type, electrochemistry are adsorbed onto on polypyrrole (PPy) layer.The iron cyanide of further interpolation 0.1M and the GOD (the 18 μ l GOD and the 48 μ l potassium ferricyanides (K3FeCN6) are in the phosphate buffer of 10ml) of 8001 unit/ml deposit GOD in electrolyte.The oxidoreduction electronic media, as the potassium ferricyanide, can be by maximizing the sensitivity that the current conversion rate improves resulting electrical properties measured value.On one of exposed electrode of described sampling, analysis and chemical delivery apparatus cell, optionally deposit PPy+GOD (Fig. 3) then.Electric current dose response during recording gauge, its result shows that this pick off has favorable linearity in 0 to 10mM glucose range, sensitivity is 2.9mA/mM.For our lactose sensor chip, we have adopted identical process, and only we have replaced GOD with galactoseoxidase.

[0117] above-mentioned embodiment does not mean that the restriction of any way, but provides as an example.Can expect that other material and method also can be used for making device 12.In addition, when thick supporting layer formed, chamber 28 and microcapillary can be formed in the thick supporting layer.

[0118] microcapillary can be used for operating the material that is sampled, and for example the material in interstitial fluid and/or the chamber is decided according to the position of microcapillary.Plasma and/or chemical surface treatment can optionally be passed through so that the accurate controlled site in device 12 forms hydrophobicity or hydrophilic surface in the surface of the device 12 of material that may no matter be sampled and/or analyze with fluid or the material interfaces of being sent from chamber 28.For example,, can handle this surface, and, can handle this surface with alkyl hydrosulfide in order on gold, silver or copper, to form hydrophilic surface with low contact angle with silane derivative in order on SU-8, PDMS, silicon or aluminum surface, to form hydrophilic surface.The example of the wetting property of this change certain material and the mode of delivery capability is not represented the restriction of any way.

[0119] in one embodiment, the cell of device comprises three layers of PDMS, its carried out molded and shaped, metallize and bond together.A cell of device only is discussed here, but is understood that other cell of device can make in substantially the same mode.The middle supporting layer of PDMS comprises chamber and a pair of microcapillary.The upper strata of PDMS seals up this chamber, but comprises a pair of microcapillary that aligns with microcapillary in the intermediate layer basically.The bottom of PDMS seals up the bottom of chamber, and can comprise electrode and the resistive element that is used to interrupt corneocyte, perhaps use at interstitial fluid through structure with the heating element heater in the cuticular embodiment of ablating.Described bottom can also comprise a pair of microcapillary that aligns with the microcapillary of other layer basically.

[0120] for every layer of PDMS, can form described chamber and microcapillary with the mould of making by SU-8.The manufacturing of SU-8 mould usually can be by being spin-coated on SU-8 on the substrate such as glass, and exposure and the negative photoresist SU-8 that develops are formed at wherein feature (corresponding to described chamber and microcapillary).In case formed mould, this mould just can be used in the press, and PDMS just can be applied on the mould in the described press, solidifies in stove then.In case after solidifying, PDMS just can remove from press and mould.The further feature of cell, for example electrode can be formed in the suitable layer of PDMS by metallization processes afterwards.After each layer PDMS has suitable feature, described layer can be bonded to together, make microcapillary be in alignment with each other basically.

[0121] in addition, for each layer of polymeric material, as SU-8 and PDMS, in making the process of these layers on glass or the similar substrate undeformed discharging, can use various sacrificial layer material.For example, for SU-8, can adopt polystyrene and PDMS together positive photoetching rubber and aluminum as releasing layer.Polystyrene can be dissolved in toluene, thereby the SU-8 layer is discharged from glass or similar substrate.Positive photoetching rubber can be dissolved in acetone, and PDMS can help photoresist to absorb acetone to discharge the SU-8 layer.Aluminum can be etched to discharge the SU-8 layer.For PDMS, can be used for the possible sacrificial release layers that PDMS discharges from above-mentioned SU-8 mould can be comprised photoresist (being etched with release with acetone), aluminum (using phosphoric acid etch), silver (the KI2 etchant is to discharge), and copper (the KI2 etchant is to discharge).In addition, fluoropolymer polymer is as CYTOP

, also can be used for regulating the surface that receives the polymer architecture layer, thereby strengthen the release characteristics of polymer and minimize deformation.By using sacrificial layer material and/or regulating described surface, can minimize the deformation of object construction layer.

[0122] certainly, can adopt other mode of texturing of manufacturing installation cell, and above-mentioned embodiment is not represented the restriction of any way yet.For example, can expect, other polymeric material can be used for any layer of described device, include but not limited to have the polymeric material of relatively low flexible modulus, for example polyolefin, polyester, methacrylate and polyimides, and more inflexible polymeric material, as Merlon and polystyrene.

[0123] in addition, can adopt except that above-mentioned technology the sort of and form working electrode.For example, in case formed the supporting layer of device, then can be with this supporting layer by connecting (by metallization) particular desired position to electrode from ZIF (ZIF) the electric wiring lead that adapter extended out that is positioned at this supporting layer front, edge or back.The hardware of electrode also can be before forming electric wiring, among or carry out electro-deposition afterwards.The ZIF adapter that is positioned at supporting layer front, edge or back can be connected on the controller then, described controller is programmed with the special design and the structure of described device cell.In the time of the particular polymer substrate that working electrode is exposed to may comprise enzyme or antibody, described controller provides signal to selected cell, and described cell is used for receiving specific polymers substrate at the specific part of electric wiring end.For example, described controller can provide the selected electrode that has certain electrochemical potential with respect to ground, to form the site of anode or positively charged.Selected then electrode can grow coating or thin film from electrochemistry on the polymeric matrix, thereby encapsulates described working electrode.Described process can repeat with different polymeric matrixs, and is coated up to all working electrodes.According to whole Design of device, this makes each cell all have the electrode that is coated with special sensing coating.The sensing coating can be designed to the sensing electrical properties, includes but not limited to electrochemical source of current, electric capacity, impedance, voltage class electromotive force, or electromotive force.In some embodiments, all working electrode on the single assembly all can have identical coating.In some embodiments, the working electrode of half can have a kind of coating, and second half can have second kind of coating, or the like.

[0124] after in a single day whole device was made, when described material existed, the same electrical wiring that is used to form electrode also was used on sensing and the reference electrode and applies voltage potential, and can record the electrical properties of described material.Described electrical properties can comprise electric current, electric capacity, impedance, voltage class electromotive force, or electromotive force, decides according to the polymeric matrix that is used to be coated with electrode.Described electrical properties can be associated with the special properties of material, the level of biomolecule in the material for example, and perhaps physicochemical property is as pH value.

[0125] in one embodiment, sensing electrode can be grown to comprise that in its surface nanostructured is to improve the electric conductivity of electrode.Conducting polymer polypyrrole (PPy) is current being used to based on the electrochemica biological sensor of nm-class conducting wire and nanotube and the material of nanostructured, because it has high environmental stability, electric conductivity, ion-exchange capacity and biocompatibility.By utilizing, formed the thin film of the nanostructured of similar nanometer grass by single nanotube or the already provided high surface volume ratio of nm-class conducting wire structure.Ppy can electro-deposition in by the hole 250 of sacrificing the template 252 that the template intermediate layer material makes, described material is aluminium oxide (aluminium oxide) for example, as shown in figure 26.In case nm-class conducting wire array 254 is formed by PPy, just can sacrifice template 252 by etching or any other suitable method removal, thereby PPy nanotube 256 be stayed on the basal layer of electrode.Shown and utilized this nanometer texture method, polypyrrole can obtain than the higher better electric conductivity of integral type PPy film because the alignment thereof of polymer chain be as one man along traverse shaft to.

[0126] thin film of nanostructured can be by being similar to method manufacturing recited above, and simple effectively biocompatibility environment can be provided for the controlled substrate that protein is added formed PPy nm-class conducting wire.The described conduction living polymer that contains bioactive molecule (for example enzyme, antibody, cell and DNA) can be widely used in biosensor application and the signal generting machanism.For conducting polymer, find that pulse current detects and impedance spectrum is best suited for being used for producing and analysis antibody-antigen (Ab-Ag) signal.By on Pt that polishes or Au electrode, preparing the PPy electrode from the aqueous solution constant current ground electropolymerization monomer pyrroles of containing AHS's albumin (anti-HSA).Utilize cyclic voltammetry (CV), shown certain and these the anti-HAS sensing layers interactions of HSA, and do not obtained response with the contrast polypyrrole that does not add antibody.Adopt nanostructured to make relatively large enzyme or receptor be fixed, thereby improved sensitivity.

[0127] designed a kind of mode of texturing of isolated PPy nano-tube array shown in Figure 26, as the means of three problems avoiding to cause with pure Ppy nm-class conducting wire array.The first, because its length (reaching 50000nm) and by the field effect that causes with the bonded sessile antibody of antigen may be observed big series resistance in nm-class conducting wire, the gold nano wire stylet is not influenced by this then can.The second, the elastic modelling quantity of PPy (approximately 80MPa) becomes the little of the order of magnitude than gold (1.6GPa) at least, so golden cored structure rigidity and be not easy in the course of processing or subside when sampling or stick together comparatively.The 3rd, described series impedance also may cause compiling electric current and reduce, and thereby reduce detection sensitivity, in the course of processing, may make simultaneously in electrochemical deposition process the PPy nanostructured endways with comparing reception antibody still less near conduction basic electrode place.

[0128] the replaceability fabrication scheme has utilized metal (Au) core, can be described as four steps: 1) form anodic oxidation aluminium formwork on golden film, be similar to the template shown in Figure 26; 2) from following golden flat film electrode with golden electro-deposition to the hole of alumina pore; 3) optionally the etching oxidation aluminum alloy pattern plate with the exposed gold nm-class conducting wire, thereby stay all-metal nanostructured 258, as shown in Figure 27, and 4) some Ppy film 260 monolayers of electro-deposition on the gold surface of all exposures, as shown in Figure 28.This method can reduce the resistance via that offers electron stream in the nanotube, comes in parallel with electric conductivity PPy nanotube electricity because added the gold nano lead effectively.When comparing with nanotube, this effect can be the impedance path of the nm-class conducting wire that reduces, and applies for identical that should there be bigger signal in nm-class conducting wire for the voltage.And bigger signal has improved sensitivity and the overall performance that installs biosensor in 12.The another kind of mode of texturing of this method is that at on-chip carbon based nanotube replacement Au, it can adopt the formation method of standard with vertical deposition.Then can be coated with Ppy.A kind of possible advantage of this method is that CNT has had electric conductivity, for its vertical formation without any need for template.

[0129] other manufacturing technology that can be used for producing the nano-pattern polarizing electrode is based on relevant but different technology, described technology is compatible mutually with the sensing chip device fabrication, include but not limited to two-dimensional electrophoresis method (dielectrophoresis) (between two electrodes on the device or between electrode on the device and outer counter electrode), electrostatic deposition and vapour deposition process.Normally polarizable nanotube of sedimentary like this material or nm-class conducting wire.In one embodiment, CNT can be deposited on the sensing electrode, and aligns with the mode on sensing electrode surface to be parallel between the sensing electrode or vertically.These nano-pattern formed materials that are deposited on the sensing electrode may show very big electric conductivity variation between two probe electrodes when utilizing specific receptor absorption/absorption special analysis thing.

[0130] in the aforesaid associated fabrication techniques that is used for molded PPY nanometer rods, extremely thin tinsel includes but not limited to aluminum, can make the pattern at a tip, to form the mould of PPY nanometer rods, perhaps is used for deposition of carbon nanotubes.Resulting metal tip by towards the compact nanometer structural material consistent bunch with lead itself cover.Another section of lead connecting the control and the communication part of device.From machinery in nature, described material softness and yielding.Described material conducts electricity very much on the electrical property.For the following neurological of discussing was used, described nano-patterning electrode material had been simulated the ciliary structures of the most advanced and sophisticated natural formation in place of aixs cylinder.Really, described nano-pattern formed material can be coated with the PPY thin layer of having fixed nerve growth factor.Nervous tissue can be connected towards the growth of described nano-pattern formed material and with it, makes cell growth and infinitely suitably working, and keeps splendid electrically contacting.

Chamber is filled

[0131] Figure 21 has represented to be used for the equipment of filled chamber 28 and the embodiment of method at the cell that comprises chamber 28.Chamber 28 can form by above-mentioned molding process, perhaps be spun to the another kind of material layer of formation thin film 82 when thick supporting layer (for example SU8) 80, when going up as PDMS, and can form at least one capilar bore 84, preferred two capilar bores make it to be parallel to described chamber 28 and to extend by the mode of described supporting layer 80.Thin film 82 can also comprise with support substrate 80 in the capilar bore of capilar bore 84 substantial alignment, as shown in figure 21.After this chamber 28 was filled with material from material supply 88, another polymeric material can be come the top of sealed chamber 28 as sealant 86 as PDMS.Sealant 86 is preferably thick than thin film 82, if come breakable 82 so that the approach that leads to chamber 82 to be provided in the use with aforesaid foaming technology like this, sealant 86 will can not break yet.

[0132] in embodiments, sealant 86 also comprises at least one capilar bore 90, and it aligns with chamber 28 at first, makes that the material be provided for chamber 28 can be by wherein and enter chamber 28.In embodiments, sealant 86 comprises two capilar bores, as shown in figure 22, and the distance that two capillary tubies of its spaced apart and supporting layer 80 84 are same.Two capilar bores that exist in the sealant 86 provide the selectivity that uses push-and-pull mechanism in the process of filled chamber 28.One of two capilar bores can be as the inlet of material, and another capilar bore can be used for removing any surplus air of chamber 28.In order to come filled chamber 28, can between material supply and capilar bore, form interface with the material that will be delivered to material.

[0133] as shown in figure 21, can provide interface 92 to help to use material filled chamber 28 from material supply 88.Interface 92 can comprise the glass carrier 94 that wherein has reservoir 96 and capilar bore 98, polymer material layer 100, as PMDS, be positioned on described glass carrier 94 1 sides through constructing to supply 88 interfaces with material, with releasing layer 102, its be positioned on described glass carrier 94 opposite sides through structure with sealant 86 interfaces of described sampling, analysis and delivery apparatus.As shown in the figure, releasing layer 102 also comprises at least one capilar bore that therefrom passes through 104, its through structure with hole 90 substantial alignment of 86 kinds of sealants.

[0134] but glass carrier 94 can be the glass of photoetch, reservoir 96 wherein and hole 98 can etching form.In one embodiment, reservoir in the glass carrier 96 and hole 98 form by the technology of dusting.The polymer material layer 100 that is positioned at glass carrier 94 tops comprises the hole 106 by wherein, and its shape can receive the stopper 108 with material supply 88 flexible pipes that are connected 110 ends, as shown in Figure 21 part A.When chamber 28 was filled a vacancy, this can help to make stopper 110 to locate and remain on the appropriate location definitely.

[0135] polymer material layer 100 can be bonding with the one side of the glass carrier 94 that comprises reservoir 96, so that align with reservoir 96 in the glass carrier 94 in the hole 106 in the polymer material layer 100.This feasible material that provides by material supply 88 is filled reservoir 96, and reservoir 96 can be discharged in the chamber 28 by the hole 98,104,90 that lays respectively in each layer 94,102,86.

[0136] in case material is offered chamber 96, the sealant 86 of device can move (as sliding) with respect to supporting layer 80 with chamber 28 as described in sealing, shown in Figure 21 part B.Move on to the position of guaranteeing that chamber 28 is sealed really in order to ensure sealant 86, the capilar bore 90 in the sealant 86 can align with the capilar bore 84 in the supporting layer 82, shown in the part B among Figure 21.Be in correct position (for example with chamber 28 sealings) in case determine sealant 86, just can sealant 86 and supporting layer 80 is bonding, discharge from interface 92 then, shown in portion C among Figure 21.

[0137] as mentioned above, the chamber 28 of a cell 18 can be filled and sealed.In one embodiment, described glass carrier can be through structure to comprise that to all the cell 18 on the same device 12 of being positioned at of chamber 28 provides passage.Like this, chamber 28 can fill and seal simultaneously.Figure 22-24 has represented the schematical top view of this structure.Especially, Figure 22 represents to have the single chamber 28 in reservoir 96 and hole 106, and described reservoir is expressed as square, and described hole 106 is expressed as circle in polymer material layer, thereby has represented that stopper 108 will be with respect to chamber 28 location when having filled chamber 28.Similarly, Figure 23 has represented five chambers 28 of filling simultaneously, and Figure 24 has represented 25 chambers 28 of filling simultaneously.In each width of cloth of these figure, in the glass carrier (not shown among Figure 22-24) with reservoir 96 and through hole 98 between the passage 112 that is connected of material just in time end at chamber 28 tops.Represented two capilar bores 84 equally in Figure 22 and 23, it is arranged in supporting layer and is parallel to each chamber 28.Although represented among each figure that 96, one reservoirs of two reservoirs can be used for receiving the air that displaces when material enters chamber 28 as mentioned above.Described embodiment not will be understood that it is the restriction of any way, and is that as how to fill also with material the example of sealed chamber provides.

[0138] for example, can expect that supporting layer 80 can be directly and releasing layer 102 interfaces, and be deposited on the supporting layer 80 without sealant 86.In this embodiment, can filled chamber 28, and sealant 86 can seal up chamber 28 like this in that supporting layer 80 is applied on the supporting layer 80 after interface 92 discharges.

Adapter

[0139] for brevity, the prototype that the control function in simplified system will be discussed now realizes.The design of sampling, analysis and chemical delivery apparatus 12 is improved so that it meets ZIF (ZIF) adapter.Chip thickness is adjusted into 150 μ m+/-10 μ m so that can repeat to insert, moves described adapter pad union joint (pin-out) to 300 pins (pitch) alternating expression connector position place.Desirable is that feasible " bottom " chip contacts allows flat adapter and chip surface can be pressed against in experimenter's the health.That is to say on connector body, there is not to hinder the step that contacts with the skin excellent planar.In other embodiments, chip contacts can be made on the front of described device or side surface.The main body of adapter is the 1.8mm height, is arranged in surface-mountable dual-in-line package, in case and the correct back of inserting is installed just with the ZIF slide mechanism of chip locks in place.We see, this made us can repeat to change the sensor chip of sampling, analysis and chemical delivery apparatus in one minute, and enough firmly accept repeatedly to insert and resist stay in the experimentation meeting that the proper motion owing to animal causes is withdrawn chip from socket active force.Described parts can be made different width, corresponding to 17 to 91 pin contact scopes.We once used the parts of 31 and 61 pins in development.For example, the adapter of 61 pins can be soldered on the electric wire, and perhaps described adapter can use with many conductors of flexibility Kapton adhesive tape (multi-conductor KaptonTape).In integrated system, adapter can be rigidly connected on the main body of controller.Described adapter can obtain with adhesive tape and coil type packing forms, is applicable to economical automatization's assembling and manufacturing.

[0140] in one embodiment, described adapter can form by following mode.Described method can start from core substrate, is made by flexible material, and as polyimides or Kapton, its thickness is generally 0.001 " (1mil=25 micron), there is thin electric conductivity copper film (9 microns) its end face and bottom surface all lamination.Shown in Figure 29 and 30, described device 12 in the bottom or skin side can have micro-heater 270, its trace is wide to be 1mil.Being expressed as 272 electrochemical detection electrode among Figure 29 and 30 can separate with heater 270, but tightly is positioned near it.Interrupt horny layer for micro-heater 270 can to produce about 130 ℃ temperature by applying current impulse, this is enough to cause one corneocyte separation, thereby makes interstitial fluid emit skin surface when continuing about 30 milliseconds.Two electrochemical electrode 272 next-door neighbours, one is gold electrode, and in some embodiments, another electro-deposition has polypyrrole and is embedded with biomolecule enzyme and redox mediator, perhaps be embedded with antibody in other embodiments, allow to detect specifically target biological molecules.Bottom dielectric layer 274 is being supported support substrate 278, and it can have a plurality of capillary tubies 276 that extend through wherein.Layer of copper 280 can be deposited on the end face of support substrate 278, and before dielectric layer 274, other layer of copper 282 can be deposited on the bottom surface of support substrate 278.Top layer flexible circuit 280 can have pad (bonding pad) 284, and it can electroplate projection or boss so that rising to be provided with copper.Projection 284 can be used for providing and the more reliable electrical connectivity of testing circuit, and described testing circuit can be integrated on the second flexible circuit (not shown) that can be complementary with the end face projection 284 on the device 12.Array format (for example, the 4x4 shown in Figure 29) can be arranged in the sampling site, and wherein the connectivity trace (is processed the back) in sampling process and in Electrochemical Detection and the deposition process suitable voltage is provided.In the embodiment illustrated, the bottom surface of double-faced flexible substrate has functional pick off and commissure formula trace, and top layer contains strap and the contact that mates with another flexible substrate.It is how can be laid on the large-scale substrate region that Figure 31 has represented to install 12, and it can record and be approximately 10 " x 12 ".Thick line between the device 12 will be joined together to form device and separate the common point that will apply electromotive force before.Also expressed the strap that is used for special post-treatment process, it may relate to the electric conductive polymer that is fixed with enzyme, and is used for applying suitable electromotive force in the Electrochemical Detection process.

Control and communication device

[0141] controller 14 is made of two parts usually.First is the wireless data acquisition system of computer interface, and it can addressing reach 64 distance sensor nodes, manages the identity of each, and the cache contents of inquiring each.Second portion is a sensor node.It can be made up of five functional parts, RF communicator (have unique identity) for example, microprocessor controller, multiplexer, analog circuit source and A/D converter, and a plurality of pick off input.Described microprocessor can be at specific application programming.The specific device that analog circuit, multiplexer and input line can use in constructing with described system especially.Communication context can reach about 300m or even longer.In real-time process, controller 14 calculates implements sampling, electro chemical analysis and continuous record result and the required essential sequence of the signal of telecommunication of chemistry release.

[0142] communication device 16 allows external device (ED) inquiry control device 14 so that implement various operations, comprises the described system of identification, sets up the interrogator identity, sends canned data, allows reconfiguring of control sequence.The process of reconfiguring can comprise device for opening 12 lip-deep several sampling cells 18, to test same or multiple different analyte simultaneously, perhaps selecting to increase, reduce or stop chemicals discharging, perhaps change sample frequency owing to measuring the stability that records in the concentration or changing rapidly, perhaps conciliation is used to interrupt cuticular pulse details.May detect after several weeks, electrochemical sensing cell 18 may all be used up, and perhaps encapsulation may all be opened, disposable like this sampling, analysis and delivery apparatus 12 should be dropped and structure insertion system 10 that can another is same or different in.

[0143] Figure 20 is the structure chart of some parts of expression controller 14 and communication device 16.In the system 10, the material in the test, fluid or tissue and sampling, analysis and delivery apparatus 12 disposable, separable and that can make configuration interact.The parts of control device 14 can comprise electrical connector, multiplexor, electrochemistry constant pressure and constant flowmeter, interruptive current sensing ﹠ drive circuit, controller, be used to measure, logic, adaptability serialization, data storage, dynamically reconfigure and provide the microprocessor of interface driver, and at the power manager of regulating and controlling voltage and battery charging and discharging.The parts of communication device 16 can comprise reception antenna, wireless communication module, RF power manager and energy content of battery memorizer.

Can expect that [0144] controller 14 and communication device 16 can be integrated systems that is positioned at same device, perhaps described controller and communication device can be independent devices, and it is by hardwired or wireless interaction.Above-mentioned embodiment does not also mean that the restriction of any way.

[0145] Figure 19 has represented to adopt the randow addressing process of the cell element of row and column addressing.Described addressing method comprise column address conductive path 60, row address conductive path 62 and single addressing sample, analyze and send cell 64.This method is used to replace parallel addressing method, and wherein each cell has its oneself the conductive path that links to each other with controller, as shown in Figure 2.For example, 1024 cells forming 32 row and 32 column matrix forms can be by 64 adapter sequential addressings to controller, and 32 wiring of described controller are used for row address, and 32 are used for column address.In order to implement sampling simultaneously and to analyze, controller must be continuously at sample analysis with send between the cell and switch.

Adopt the application example of the embodiment of described system

[0146] in one embodiment, aforesaid system 10 can be through structure to detect and the treatment diabetes.Type 1 diabetes (T1DM) is a kind of autoimmune imbalance, and it is because the interruption of the insulin of generation pancreatic beta cell causes.For blood sugar control, the experimenter who suffers from T1DM must accept multiple injection every day (multiple daily injection) insulin or use insulin pump, and checks its glucose level every day for several times.Although novel and improved therapeutic modality and studies show that, strict glycemic control has reduced the generation of diabetes secondary complication, and it is normal to be difficult to reach blood glucose.One of stable orthoglycemic restriction is the technology of current measurement patient glucose level.Multiple collection of body fluids (for example blood, perspiration, tear) is arranged and analyze its competitive technology, be used for carrying out glucose monitoring according to optics, electrochemistry and spectrographic technique.Yet all technology all have in various degree the invasive with type.Form sharp contrast with the existing method of having developed, the method that we describe in this application only needs prima facie and highly controlled invasive (mild heat and electric field help to interrupt the micro-segment of skin), and combines with the dynamic sampling of interstitial fluid.

[0147] main measurement target is a glucose, and second target is glycosylated hemoglobin and protein, insulin and cholesterol.The skin interrupt procedure allows about 10 interstitial fluids of receiving liter to be diffused into the horny layer surface under the help of capillary force.Concentration of glucose in blood and the interstitial fluid changes about the meansigma methods of 90mg/dl, and dangerous is low to 40mg/dl, high to 600mg/dl: surpassed 10 years in diabetes and very unsound people.Carry out on interstitial fluid sampling any one in several sites of human body of minimally-invasive: inboard arm or lower limb and torso portion most convenient.Can flexible apparatus 12 be kept contacting with the zone that will sample with binding agent.A spot of interstitial fluid can be encapsulated in the chamber 18 and be kept at the there to be used for subsequent analysis.Need not carry out modification to sample.Finish each electro chemical analysis and want about 10 seconds.Can parallelly carry out three or more analyzes to improve accuracy and to set up the statistical measurement uncertainty.Can utilize periodic heating and potential pulse to keep horny layer to interrupt a few hours, and during this period of time can arbitrarily measure.Because about several seconds of time of extracellular concentration in the very short the evolving path (＜50 microns), balance horny layer.

[0148] in another embodiment, monitoring device 12 can be through structure to deposit gauged tested analyte sample in device chamber 18, and described sample can discharge according to the requirement of control and communication system and measure, with further raising measurement accuracy.

[0149] in another embodiment, monitoring device 12 can be through structure to deposit the medicine of dry powdered form or water dissolution form in multiple arrangement chamber 18, described medicine is insulin (dosage is approximately 1 unit) for example, and it can once discharge one according to the requirement of control and communication system.Determining and can being made by fitness guru or patient individual of administration or delivering drugs perhaps can be made automatically.Back one structure is called closed loop control.When order and control system 14 through structure so that glucose maintenance within certain limit and described glucose monitoring device when detecting hyperglycemia, can apply insulin in proper order.At first, by opening a specific chamber applying portion dosage, discharge the insulin of 1 unit.After a few minutes,, then apply second portion dosage or the like, up to having given complete dosage if hyperglycemia also exists.This pulsating mechanism has been simulated the process of healthy pancreas uelralante in the blood flow of the concentration of glucose with rising.The amount of dosage can change according to the viewed response that the pulsating medicine is sent fully, and extraordinary image is worked as response every day simultaneously not autonomous the treat property diabetes compulsory thing of its individuality to insulin.

[0150] in one embodiment, described system can be through structure with the monitoring neonatal bilirubin.Bilirubin is the toxicity refuse of the Lock-in that forms in the conventional catabolic process of hemoglobin of human body, and it is a ferruginous commentaries on classics oxygen respiratory protein in the erythrocyte.For neonate, there is the erythrocyte of rising speed to decompose usually, especially in several leading day of birth.What the speed of this rising may exceed the neonate organ goes back the good metabolic capacity of incomplete development.The erythrocyte of higher rate decomposes the bilirubin that has produced higher level usually, and it can make neonate suffer from jaundice easily.Unusual high-level bilirubin may cause middle cerebral artery aneurysm, hearing loss and other body abnormality in the neonate.Under opposite extreme situations, the high-level bilirubin of not treating even may cause death.Thereby, wish to detect as early as possible and treat bilirubinic abnormal level.At present, by coming blood sampling to measure bilirubin from vein or by the tying-up heel.This is undesirable to the neonatal invasive method of sampling, because they may cause tangible discomfort.By the structure said system measure neonatal bilirubin concentration, the method for Noninvasive can be provided, itself in addition can after neonate is left hospital, implement by the neonate father and mother.

[0151] in this system, target biological tested in the material is a bilirubin, and the work conductive electrode of device through structure to comprise the fixed biological identification molecule among polymeric matrix such as the conductive poly pyrroles (Ppy), Bilirubin oxidase for example.Because Bilirubin oxidase is an oxidant, it causes that cation generates when being exposed to bilirubin, thereby will form the variation of local potential.This variation will be proportional with existing bilirubin level in the material that is contacted working electrode.As mentioned above, the electrochemistry cell can detect this potential change, and can provide signal to controller.In case proofreaied and correct pick off, described controller just can be according to from the described material of the signal measuring of cell how many bilirubin being arranged.

[0152] in one embodiment, system's 10 structures come monitoring human effectively to utilize the ability of its fuel source.The actual energy of muscle utilization source is ATP (adenosine triphosphate) in any activity, its can be under aerobic conditions or anaerobic condition produce down, promptly respectively have or the condition of no oxygen under.The anaerobism energy source usually take exercise initial period and when exercise intensity greater than utilize aerobic source by obtainable oxygen supply can support intensity the time adopt.This situation is called " anaerobic threshold " when taking place, it limits by tempering intensity of performance, and when surpassing this intensity, because health can not provide its all oxygen needs, blood lactic acid concentration sharply increases.The phosphate-based lactate system that unifies be in the anaerobic system two kinds of energy sources---phosphate is used for the energy burst of short-term, lactate is used for strong and secular behavior.The utilization of lactic acid system is stored in the sugar in muscle and the blood, yet the former adopts prior to the latter usually.The anaerobic digestion of glucose has caused the formation of lactic acid in the muscle, yet when having oxygen, it is easy to just to change into ATP becomes fuel.Thereby, produce more ATP if exercise intensity is low to enough its complete oxidations, then lactic acid just can not be accumulated.Exceeded clearance rate when producing speed, then lactic acid begins to gather and blood pH level (acidity) rising, and muscle can not correctly work and begin to present known " burning ".For the athlete of highly training or for more idle fan, may wish to monitor endurance and the behavior that do not reduce peak value.

[0153] comprise the embodiment of the device 12 in glucose and lactate sensing site by employing, system 10 can be used for the maximum output of monitor user ', and does not exceed anaerobic threshold.Control that links to each other with described device and communication device 14,16 (referring to Fig. 1) can pass to it with glucose and lactate concentration information with individuality through structure

PDA(Personal Digital Assistant) or mobile phone, and provide the curve chart of the energy output of the relevant anaerobic threshold of track user.Described device 12 can provide the monitoring of successive Noninvasive and non-insertion, be used for taking exercise and the diet industry, by using of specialty with Olympic Games mass motion person, be used for the occupation (for example fireman, builder etc.) of the violent energy output of needs, even can be used for animal, contest animal (horse racing and dog race) and work animal.Utilize said apparatus 12, it comprises the pick off cell that is dissolved in the gas in the interstitial fluid with detection through constructing, directly monitoring pO ₂Concentration.Can also combine with oximeter independently from the output signal of this pick off cell, this oximeter is given controller 14 and communication device 16 with its outputting communication in real time.In addition, the coronary artery sign (by monitoring for example c reactive protein and/or homocysteine) among the monitoring athlete can make coach and doctor be concerned about unsafe situation.The team doctor can be on your toes to avoid its death or to take place seriously injured to the entrant.And, to medicine for example steroid test can be also beneficial to athletic health.

[0154], finds to have direct dependency between individual Alertness and the fatigue strength according to the measured value of individual concentration of glucose.Really, this viewpoint is characterized in that taking place physical weakness, lasting fatigue and energy loss and reaches more than six months, and be not because any other health or mental sickness cause about chronic fatigue syndrome (CFS).Shown that glucose has suppressed to produce the small proteinic particular types glucose sensing neuron that is called the appetite peptide, it is the maincenter governor motion of state of consciousness.If the percussion mechanism of appetite peptid neuron is affected, even mainly be because the delicate variation of glucose, this also will cause the change of state of Alertness, the lethargy, in addition fat.This has improved the probability that has greatly extensive effect by glucose modulation of appetite polypeptide cell, helps daily continuous re-adjustments awakening and Alertness level.Can expect that by monitoring glucose concentration non-invasively, the embodiment of device 12 discussed above can provide the clinical observation to CFS, can also be used for the public being on the verge of tired early warning indicator.This is used in the occupation with importance very on your toes, wherein for example military personnel, commercial pilot, school bus driver, truck driver, air traffic controller etc.In one embodiment, said system 10 can also comprise the sounding warning, sense individual concentration of glucose and reached the level that shows that this individuality becomes tired if be used to monitor individual device 12, then it can be triggered to keep individuality to be in ready state.

[0155] probability of successfully recovering from serious traumatic hemorrhage shock for the antagonism accident casualty and because wound is lost blood dead wound to be injured the public all be it is pressed for time.A plurality of research fields are arranged, and wherein quasi-continuous the deployable property monitor (non-intrusivequasi-continuous field deployable monitor) of Noninvasive can increase the successfully chance of recovery.At first, for the treatment taxonomy with for effectively treating, when the doctor finds accident casualty, determine that accurately the accurate moment of shock time is very favourable.Observed typical hematocrit value, plasma glucose and lactic acid value are known in the hemorrhagic shock process, and see four progressive phases as: 1) the early stage compensatory phase (homeostatic mechanism), 2) the maximum compensatory phase, 3) lose the compensatory phase in early days (during the blood recovery, near irreversible) and 4) lose late period (causing death) compensatory phase.If the recovery fluid can when organ for example kidney and hepatic necrosis and occur losing the compensatory phase in serious acidosic late period before apply, chance of surviving then can increase greatly.The second, by adding the very ethanol of low concentration, blood plasma ethanol and metabolite thereof can be by monitoring in real time with the labels as recovery liver function degree in the recovery fluid.From the research angle, quasi-continuity (for example per two minutes carry out single reading) also will clearly reveal fluidic volume of the recovery of being adopted and component effect.Evidence suggests that a spot of glucose infusion liquid (non-blood) can the mitigation system acidosis and delay the outbreak that mortality is lost the compensatory phase.The 3rd, for in addition know that stage that body one by one is in compensatory phase/compensatory phase time course of mistake more accurately, it must have " baseline " before individual plasma glucose and lactic acid (even ethanol) concentration are hurt, it is owing to be subjected to pressure and effect extremely, for example in fight, run into, the significant change can be taken place on normal static value.

[0156] in this article, wish very in whole fight that (from static to dropping into and possible injury taking place) utilizes said apparatus 12 and each individual lactic acid of system's 10 non-invasive monitorings, glucose, bilirubin, pyruvate and ethanol (as label).To bilirubin concentration with ethanol by the speed of hepatic clearance the time understanding can provide the precise information of relevant hepatic ischemia.When monitoring device during, has only sample frequency along with frequency, quasi-continuity in accident change as treatment classification method and critical monitor.When being used in combination with other physiology instrument, commanding officer, doctor or medical officer can obtain complete photo.Health is very similar to the reaction of hemorrhagic shock to the reaction of wound and large-area burns, so the sensor performs well in assessing the seriousness of injury, with recovery and response treatment, particularly for the correct function of liver.

[0157] in one embodiment, said system 10 can be through structure to be used to monitor a plurality of experimenters that are under the same condition.For example, a row soldier can connect said apparatus 12 on everyone skin, and installs 12 and can be connected with central command center.Like this, can monitor each soldier's multiple unusual condition separately.For example, can monitoring glucose and lactic acid concn.If the soldier is healthy, then can measure and store individual static baseline.When the soldier puts forth one's strength, can monitor blood glucose and lactate level.Extremely firmly can be reflected at the rising of hyperglycemia and lactate level.This physiological status can influence the soldier in put forth one's strength executive capability under the condition of fight or follow-up height.Therefore, command centre can determine to convene the soldier to have a rest for a moment, up to recording glucose and lactate level is got back to normal level.In addition, if the soldier is injured in accident, can carry out quasi-continuous measurement by activated sensors, system 10 can be used as the instrument of critical monitoring and treatment classification in can be in the above described manner.

[0158] in one embodiment, the experimenter can be the animal in herds or the conventional environment.For example, said apparatus 12 can be connected in the herds on the some or all of animal ears.Described device can be through structure to measure glucose level in time in the animal.Central authorities' command node can be positioned on the door of distant place, and is for example far away from 0.25 mile of herds.Described command node can be through structure to send signal, to inquire all devices in its scope so that locate those may be owing to infect uncomfortable animals.By the glucose level of monitoring animal, (when monitoring the level of rising, it is not moderate to indicate this animal to be in thus) can isolate uncomfortable animal and herds, and inspection and test are to determine its disease cause type more accurately.Described device can be through structure adopting antibody or enzyme coating, and its target is among the experimenter that by the special abnormality state of special disease label reflection, described label may reside in blood, milk, urine or the like.In this way, described system can be used as wireless sampled point monitor, and it can pass to its test result the existence of command node and signaling infection immediately in real time.In one embodiment, described system is used in milk and is loaded into before the refrigerated cylinder, analyzes milk sample to guarantee that described milk is that safety is for drinking in each collection point.

[0159] in one embodiment, described system can implant and preparation and the organ of depositing and the activity and the function of tissue in order to perform the operation with monitoring through structure.For example, can monitor the specific biological molecule that may be present in described organ and the tissue and still be suitable for implantation to guarantee described organ or tissue.These biomolecule can be desired existence or can not wish to exist.

[0160] the simple test of most of tissue activities is assessment glucose, lactic acid, blood oxygen gas, carbon dioxide and pH value.As long as these concentration fall within the boundary, histiocyte just can keep normal metabolic.The more function of complex organization, for example liver, heart, lung, kidney and neural system tissue can be suitably estimated in other test.For example, as mentioned above, can monitor liver function by the ability of analyzing bilirubin concentration and hepatic clearance such as alcoholic acid molecule.For the device 12 of these application constructions is similar to foregoing geometry, possible exception be if organ or tissue in operation for example when exposing, described device 12 can be applied directly to tissue does not have complicated barrier with the evaluation and test interstitial fluid, as horny layer.Some organ has the peplos tissue, and it also plays a part barrier.In this case, can realize the interruption of described barrier at peplos property adjustments temperature and voltage levvl.For the organ that is in the stasis state, wherein keep its function with artificial circulation, can monitor input and output circulation of fluid with alcoholic acid ability in evaluation and test some molecule of removing such as the liver by operative installations 12.Neural system tissue may need the special structure of device 12, and is as described below, so that measure accurately the signal of telecommunication for a long time and do not injure neuron itself.

[0161] similarly, the tissue of little quality can excise from health by the probe of operation or minimally-invasive.The top that described little quality organization can be placed on device 12 easily is used to analyze the inclusions of interstitial fluid.Described device 12 can be before described tissue deterioration measuring samples (for example in the several seconds) apace, and can measure the biomolecule of trace concentration.It is any disease that accurately measuring in groups of carrying out on biopsy samples will depend on what be studied.Even not all, also be under the most situation, the analyzed very interstitial fluid of trace (nl) should not can disturb the biopsy biological aspect.

[0162] in embodiments, said system 10 can include but not limited to cancer and infectious disease, for example influenza, malaria and dengue fever through structure to be used for the earlier detection of disease.In these embodiments, device 12 (for example Zhuan Zhi sensing electrodes) can be used and the bonded Antibody Preparation of specific antigen, described antigenic abnormal concentrations is relevant with the high risk degree of disease or infection, and perhaps only the existence with growing tumors piece or infection is relevant.For numerous disease, increasing biochemical marker and disease association connection is arranged.Under the situation of prostate and breast carcinoma, the specific antigen of testing usually has prostate specific antigen (PSA) and prostate film specific antigen (PMSA), estrogen, epidermal growth factor (EGF), and insulin-like growth factor (IGF).All these antigens are all had antibody, and described antibody can be fixed on optionally on the electrode of device 12.All antigens are less than 60kDa, and are present in the interstitial fluid.Thereby the test that can carry out at these cancer markers is percutaneous, but also can make urine and chest breathe fluid.In order under least concentration, to obtain maximum sensitivity, can adopt the method for above-mentioned nano-pattern polarizing electrode.For the infectious disease that causes by virus or spore, may need the device 12 of two kinds of structures.First kind of measurement is exposed to virus or spore down and adopt and have target viral, H5N1 virus for example, the electrode of the antibody of developing.Detect spore by externally seeking specific metabolite.Described electrode can be a nano-patterning, as mentioned above, so that obtain least concentration and provide the earliest period warning that individuality is exposed to infectious agent.Individuality can be not sick immediately once exposing.Have only when influenza virus outside dense, virus just can begin to circulate in blood.Described virus and spore are difficult to exist in interstitial fluid too greatly, but viral fragment (hemagglutinin and neuraminidase) is present in the interstitial fluid.Under every ml interstitial fluid 1,000,000 segmental concentration levels, to detect antibody be possible to this structure of use device 12 in several minutes, and described concentration level is enough low with the medical treatment of response antiviral.

[0163] in one embodiment, device 12 can be through structure with monitoring and the parasitic disease malaria of treatment infectiousness.In one embodiment, device 12 can be through structure existing with the label of monitoring parasite and the function of relevant organ such as liver, kidney, brain and lung.Particularly, the characteristic metabolite sensitivity of utilizing antibody and enzyme that described device is discharged parasitic protozoal animal (plasmodium), described metabolite is Plasmodium falciparum histidine rich protein 2 (PfHRP2) for example, parasite lactic acid dehydrogenase (pLDH) etc.Malaria influence and final these organs of infringement cause further healthy the deterioration, are called as the disease burden.The label of measuring each organ is determined how far pressure or the infringement to infer organ of concentration from normal value.In another embodiment, device 12 send chamber 18 can through structure with order or unite send arteannuin and primaquine and now parasite have morning of medicine than multiresistance, this is determined automatically by health care professionals, individuality or control and communication part by device.In one embodiment, described device can be similarly through structure with monitoring with treat other disease, for example HIV and pulmonary tuberculosis, described like this device can monitoring of diseases and burden thereof, and applies medicine or drug regimen.

[0164] in embodiments, described system can also be through structure with treatment cancer and infectious disease.Although that has developed, tested and used multiple routine treats cancer with gene therapy, Noninvasive and the measuring technique or the system of the trace biology label of Quantitative Monitoring in the process of individuality response therapeutic scheme are in high sensitivity arranged seldom.Wherein, have only minority based on to nearly all radiotherapy and/or the general biomolecule approach of chemotherapeutics, and do not have in them continuous monitoring can all be provided in clutch and therapeutic process.Utilize said method to make the polymer of nano-patterning on the sensing electrode of described device, targeting is present in the protein in the apoptotic programmed cell death biotic succession specifically.This includes but not limited to, biological related concentrations, and promptly 1ng/ml is to the splitted Caspase-3 of the 17kDa between 0.1mg/ml subunit.Shown some protein in the apoptosis, can be as p54 and 17kDa albumen as most of surrogate markers things that cause apoptotic treatment of cancer effect.

[0165] in embodiments, described system can through structure with sampling experimenter mouth in fluid.For example, described system can be through structure with bacterial detection, virus, microbial film, inflammation and dental caries, and normal hormone, protein and metabolite, with assessment experimenter's whole body health degree.Contain many target analytes that are used to screen, diagnose and monitor application in the composition of people's saliva and other mouth cavity fluid, and utilize the method for various Noninvasive low-risk degree can be easy to obtain sample.Saliva is produced by blood plasma and body of gland, thereby plasma proteins and medicine enter interstice based on Starling active force and tremulous pulse permeability.Matter albumen, low molecular weight substance, medicine, ion and water were by the flow of oral cavity and gingival mucosa between similarly active force was regulated and control.Oral mucosa provides the position that arrives the easy visit of matter and sampling interstitial fluid between tissue.The relative transfer rate that strides across oral film from blood plasma to the saliva can be determined by the concentration of measuring two kinds of medicine, plasma proteins and other analytes in the liquid simultaneously.In general, said system can have pharmacokinetics, unauthorized substances detect and the application possibility of a monitoring blood plasma/matter medicine or medium level.And well-known, the various potentiation of microorganism interact and have activated inflammation mechanism in the gingiva seam, and it may cause dental caries, gingivitis and other oral pathology.Can identify the specific protein of microorganism, metabolite, the specific form of the catabolite of host protein and gap connective tissue (interstitial connective), tooth and osseous tissue.By sampling gingival sulcus fluid, standard protein analysis afterwards (liquid spectrum/mass spectrum/mass spectrum, or LC-MS-MS), unique or change after the product form can limit the biological marker of disease specific.Given this, we have adopted sampling this fluid that three kinds of micro-processing technologies come Noninvasive and biomembrane to obtain the information of state before the disease.

[0166] in a kind of special structure, described sampling apparatus can enlarge by near the micro-flow channels electrode and the sampling chamber, in wherein carrying out isoelectrofocusing and capillary electrophoresis (2-D separates).Separating resulting can record by electrical method, as mentioned above, perhaps isolating sample preservation can be used in chamber in the outside subsequent analysis that adopts mass spectrography of device.

[0167] can realize the saliva diagnosis with microcapillary " toothpick " from the area sampling between gingiva and the buccal, to detect cariogenic bacteria, medicine effect, forbidden drug abuse and HIV or the herpesvirus in oral cancer, dental caries (cavity) formation.Oral biological film (dental plaque bits) and utilize the microcapillary be connected on the tooth probe unit fluidic collection can help to detect periodontal, helicobacter pylori and halitosis to gingival sulcus.Utilize the sample collecting apparatus 12 of above-mentioned Noninvasive, the interstitial fluid of can from the mucosa of porous relatively oral cavity inwall, sampling, thus can measure systemic disease and carry out drug test.Can as the quick clinical diagnosis test of gingivitis or other disease, can utilize domestic or office to realize through structure with machine-processed with state before determining certain disease as screening with the system implementation plan of diagnosis " cream rod " form based on saliva.

[0168] described tooth system can be used for but is not limited to two kinds of special diagnostic fields: the firstth, and sampling interstitial fluid, saliva and other mouth cavity fluid are so that determine the molecular biosciences sign, perhaps " fingerprint " of saliva, itself and many clinical conditions be the susceptibility and the conventional health status of risks and assumptions, disease for example, is associated.Second diagnostic field is directly at oral disease, pays close attention to the influence to cariogenic bacteria and the dental caries that develops into afterwards of saliva and salivary component, comprises that immunoglobulin A (IgA) is preventing the effect of acidogenic bactria aspect trooping.

[0169] can use little sampling apparatus of three types, wherein every kind of device is specific to analyzed mouth cavity fluid kind.First kind, the microcapillary bundle saliva between buccal and the gingival areas of can sampling, gingival sulcus fluid and a plurality of microcapillary that is connected on the tooth probe can be used for sampling.The third little sampling apparatus is the improvement to the system that is used for the glucose sampling as mentioned above, is used for by mucosa sampling interstitial fluid.This sampler, with preceding two different, comprise compact battery, and be installed on the device of similar depressor.Sampling process is by pressing the button beginning, and at this moment described device is pushed towards buccal.Described sample can be stored behind the release-push.This structure can be used for gathering the fluid of saliva and transmucosal in order to detect the whole body label.Multiple studies show that has dependency highly between serum composition (whole body indicator) and the mouth cavity fluid from buccal mucosa.

[0170] microcapillary bundle sampler device comprises the microcapillary assembly, can be used for gathering the saliva sample between buccal and the gingival areas.Utilization is similar to the hand-held device of a dropper, described microcapillary collecting unit a large amount of saliva of can sampling in the zone of specific distribution.One microcapillary is available and made by the micro glass pipe that is coated with the polyimides outer sheath on market, so that rigidity and ruggedness to be provided.The size of interior external diameter can be different in these microcapillarys each, and wherein internal diameter is minimum 30 microns, maximum 350 microns of external diameter.

[0171] for the convenient hand-held sampler of using 300, in embodiment shown in Figure 32, the bundle 304 of one microcapillary can insert in the ball bubble pipette 302 that an end has flexible ball bubble 303, and by with its " potting " fix in position in the silicone elastomer that is called polydimethylsiloxane or PDMS 306.In the illustrated embodiment, sampling bundle 304 is loaded onto in the molded pipette (not shown), and it is similar to the pipette 302 shown in Figure 32, pours into a mould afterwards and solidifies described silicones PDMS potting material 306.Described PDMS 306 does not cover two ends of microcapillary 304, can aspirate and be distributed on chip lab (lab-on-a-chip) device and utilize described ball to steep by this capillary tube sampling like this.In case after solidifying, described silicones and microcapillary structure 308 or the PDMS stopper of meeting, the two is shown among Figure 33, can remove from molded pipette, can make other the similar tube bank that is contained among the PDMS like this.For the purpose of sampling, the user can adopt ball bubble pipette 302, and after removing ball bubble 303, PDMS stopper 308 can be inserted in the pipette 302 as far as possible.The tapered feature of ball bubble pipette 302 will guarantee that microcapillary 304 is in suitable position in sampling process, and the opening of sealing pipette 302.Ball bubble 303 can reconnect and can carry out the saliva sampling between buccal and tooth.PDMS stopper 308 can remove and preserve analysis after being used for, perhaps can directly described sampling fluid be assigned in the separation equipment.The purpose of PDMS stopper 308 provides new support or the bottle that is used for each sampling step.Shown in embodiment do not represent the restriction of any way.

[0172] in one embodiment, provide tooth probe unit 400, as shown in figure 34 based on microcapillary.Clinical when being connected degree what determine periodontal disease and gingiva and tooth, it is method in common that periodontal probe obtains.In general, approximately the depth of interstices of 1-3mm is considered to acceptable.The purpose of described device 400 based on microcapillary be in standard periodontal checking process sampling gingival sulcus fluid to determine the depth of pocket of connective tissue.In a kind of embodiment of described system, can construct platform and accept the deserted convenient periodontal probe 402 that uses commercially available, that make by the flexible polymer plastics as the substrate of described device.Periodontal probe 402 can improve by using microcapillary 408, described microcapillary 408 has very little external diameter (about 100 microns) and can be connected on the horizontal edge of tapered probe 402, and can be held in place by 25 microns thin layer curing PDMS silicone rubber 410.Because far-end 406 nominal diameters of probe 402 are 0.5mm (perhaps 500 microns), so microcapillary 408 that is connected and PDMS layer 410 will make the lateral dimension of described device only increase 0.25mm.By using PDMS, the whole flexibility of probe can be kept, and negative reaction can not take place when the short time is incorporated in the body.The gingival sulcus fluid can be transported in described two microcapillarys 408 by capillarity is passive.In the another kind structure, microcapillary 408 can be connected to aspirator (generally common in dental clinic) gently to aspirate the gingival sulcus fluid along microcapillary 408.In another embodiment, can single microcapillary be arranged in the handle of probe by the molding program, to form the probe of the described microcapillary of meat.Shown embodiment is not intended to limit by any way.

[0173] in embodiments, device 12 and system 10 can through structure be used to help continuous long-period of management heat and take in and heat exhaustion between balance, this causes owing to basal metabolism and physical motion.Installing 12 in this case can be through structure to measure physiology and the biochemical process in a whole day each several weeks.In a kind of example, can set up basal metabolism by muscle bending, heart rate, skin temperature, skin conductivity, interstitial fluid oxygen and carbon dioxide gas concentration and interstitial fluid glucose, lactate, insulin, ghrelin, leptin concentration under monitoring motion, the skin.In the circuit of device 12 order and control section, preferably by adding list or the multiaxis accelerometer is measured motion.When the device 12 on adhering to skin is out of shape with skin, the voltage measurement that utilization is produced by the piezoelectric layer in the substrate that is embedded in device 12 (ceramics polymer) is positioned at motion below the device flexible sensing part and muscle bending and by tremulous pulse and the little blood the felt pulse (measuring heart rate thus) of venous.The mode of impedance variation that has the material of known temperature coefficient impedance by measurement can be measured temperature, and described material is deposited between the measurement electrode, for example perhaps can adopt the heater material shown in Figure 29 to measure.

[0174] also can measure Skin Resistance easily by two or four electrode technologies.In the technology of two electrodes, can be according to calculating impedance by the characteristic frequency DC between the open electrode of two and contact skin or AC electric current and the known voltage that applies.Measure, the electrode in the electrode in can 12 1 cells of operative installations and the different cells of same device 12 is realized several millimeters separation, so that remove the influence of local skin texture, feature or variable constituents for this reason.In the technology of four electrodes, each that it is desirable in four corners of device 12 adopts single electrode, and known DC or AC electric current are passed through to measure electric current between the corner electrode of two vicinities between two electrode of opposite via skin.This technology can be removed the common uncertainty seldom of contact impedance between electrode and the skin, and produces the unique value of this skin.Causing under the serious motion of perspiring, the perspiration of conduction may shunting impedance be measured.Carrying out the AC measurement under different frequencies of oscillation can be used for and will separate the influence of perspiration to the skin of influence below the cortex mesocuticle of electric conductivity and fatty tissue.Biochemical measurement can be provided in the metabolic continuous measurement of carrying out in the body, and this is relevant with the total amount of heat expenditure that reaches 60%.Described measurement is not only all gathered and is stored separately by controller 14, also can be considered to provide the preferably estimation that total amount of heat is taken in.This total amount can show to tell the heat expenditure of described individual accumulation in the analog or digital mode.

[0175] heat absorption, appetite control, satiety, fat generation and consumption also can be quantitative with measured value.The glucose and the insulin concentration that record when picked-up and digestion can provide the qualitative assessment that a meal has been absorbed how many heats.The actual quantity of the heat that absorbs with by treating that the heat estimated value that edible food calculates has a great difference.The following concentration of ghrelin has after meal shown the satiety state.By measuring the increase of ghrelin concentration, can feel that health detects the generation of satiety state before satiating, thereby avoid excessively edible.By following glucose before the meal and insulin level, can record the physiological signal of appetite.When feeling hungry,, can make what the wisdom decision of whether having meal and have meal by relatively heat expenditure and intake.

[0176] well-known, the heat that consumes when health in time several weeks more than its absorption the time, body weight just reduces.By close monitoring heat balance, the picked-up deficiency that can keep fit every day is so that reduce fat weight.Leptin is a kind of in many peptides in the biosystem, and it is by sending signal and produce, keep and eliminating fatty to hypothalamus.Measure leptin the direct scale of how human body being managed its fat mass is provided.When conducting electricity under various AC frequencies, four point probe resistivity (impedance) also can be associated with the adipose tissue mass in the current path.This making with the bonded electroanalysis of leptin concentration also disclosed the speed that increases or reduce quality at the control of system and the fatty tissue state that gathers that communication device 14,16 has not only disclosed the analysis site place.These all are that current individual is difficult to obtain valuable instrument, in order to come closely by conscious interference and non-invasively controlling body weight and health are formed to help the autonomous mechanism of energy storage and use.

[0177] although diet comprises rich in protein, fat and carbohydrate to be supplied with, food intake lacks some essential mineral, vitamin and acid usually.In a kind of nonrestrictive structure, the cell 18 of device 12 can be through preparation to measure the available concentration of these materials in the interstitial fluid.These molecules are little and be present in the interstitial fluid easily.In one embodiment, the cell 18 of device 12 can be made by electrochemistry, enzyme and antibody mechanism and measure mineral ion such as calcium and potassium, vitamin such as vitamin A, and acid is as the concentration of folic acid.These nutraceutical shortages can not be reflected as obesity inevitably or lose weight, but think the consequence that can have osteoporosis and nervous disorder.

[0178] in embodiments, said system 10 can be used for heart, blood vessel and apoplexy detection usually.Past changes according to the characteristic of the existence of chest pain or historical and electrocardiogram (ECG) waveform comes diagnostic techniques term myocardial infarction or M1, heart disease.Recently, creatine kinase (CK and CK-MB) blood testing result is used to diagnosis, brings into use cardiac troponin simultaneously.The major advantage of troponin is that it is all very sensitive for heart even very small infringement.Troponin is a kind of protein with three kinds of isotypes (I, T and C), discharge from the dead and injured cell of cardiac muscle, thereby the level of its rising can show that damage is arranged, for example can generation in heart disease, even very slight.In CK-MB test troponin particularly other advantages of TnI and TnT be, after heart disease, it can keep a couple of days in blood flow, allow more Diagnostic Time, although and CK and CK-MB only discharge from the myocyte of dead (definition of infraction), troponin discharges from dead and serious injured myocyte.Studies show that to have the troponin of rising but the physiognomy ratio of the normal people of CK and CK-MB and the diagnostic criteria of satisfying more traditional diagnosis of heart disease has similar consequence.

[0179] it is relevant with apoplexy blood to be brought into the existence of speckle in the carotid artery in the brain, and it is by being sent to sludged blood in brain or by stopping blood flow and causing that apoplexy works.The people of trouble carotid arterial atherosclerosis is also easier to have atherosclerosis in coronary artery and whole circulation system, thereby makes its easier heart disease that gets.Tumor necrosis factor and receptor thereof are the labels of inflammation, and its blood middle concentration in various infection, inflammation and autoimmune disease raises.Experimental evidence shows that immunologic process and inflammation have effect in the development that tremulous pulse thickens.The Tumor Necrosis Factor Receptors of elevated levels can reflect that speckle forms the middle inflammatory process that takes place.

[0180] in order to be used for this monitoring, system 10 can indicate the analyte set of healthy heart and circulatory function with monitoring through structure, and the early stage indication of the abnormal phenomena that can cause heart disease, blood circulation problem and apoplexy can be provided.In one embodiment, the cell 18 of device 12 can be through preparation to measure analyte concentration in the interstitial fluid simultaneously, and described analyte includes but not limited to c reactive protein, Tumor Necrosis Factor Receptors 1 and 2, creatine phosphokinase (CK and CK-MB), kreatinin, troponin, interleukin 1,2 and 6, interleukin 2 receptor and tumor necrosis factor.

[0181] in one embodiment, system 10 can for example monitor smoking, ethanol use, anesthetis or the like through structure with monitoring material and drug dependence.But utilize said system 10 can the percutaneous carbon dioside monitoring nicotine and metabolite ferrum peaceful.But nicotine to the peaceful oxidizing process of ferrum by being arranged in the cytochrome P-450 2A6 enzyme catalysis of cell mitochondrial.But ferrum rather is generally used for distinguishing smoker and non smoker, that is to say the people who is subjected to second hand smoking, is commonly referred to environment Yan cigarette (ETS).Compare with mainstream smoke, passive smoking contains more substantial ammonia, benzene, carbon monoxide, nicotine and carcinogen, as positive nitrosamine.The more important thing is that the doctor can monitor the ready-to-be mother after phenolics and birth, thus these two kinds of activities be sudden infant death syndrome (SIDS) mainly with risks and assumptions independently.Recent research points out that also Shi Bie second hand smoking composition can influence the neuromodulation of breathing so far, and this can cause sleep apnea incident and SIDS.Studies show that the baby pulmonary that dies from SIDS has apparently higher than contrast experimenter's nicotine level.Utilize our Noninvasive mount technology to use by the continuous monitoring Nicotiana tabacum L..Described system 10 can add anti-tamper contrast, and it is taken away indicating device 12 a period of time on one's body from user, in the chances are the smoking process.Device 12 can also be used as at the outer instrument of the separate component of urine sample, but the peaceful place of the ferrum that described urine sample is normally discharged from health is introduced into the sampling site on the device 12.

[0182] in embodiments of the invention, device 12 can be used for monitoring unauthorized substances, comprise analeptic, Drug abuse (Opium, cocaine, anesthetis) and abuse of alcohol, described device 12 uses the enzyme that utilizes electrochemical reaction to carry out to detect, the specificity sessile receptor site that the antigen-antibody that perhaps utilizes the resonant frequency shift that uses the unsettled film of vibration to carry out detects.Described device 12 can comprise that some detect the cell set to monitor individual various unauthorized substances, perhaps can be at certain special material.

[0183] in one embodiment, the microcapillary that described system 10 is vertically oriented with utilization through structure, as discussed above, it is vertical with skin surface.By capillarity, the interstitial fluid of sampling upwards can be drawn and pass through capillary tube.Same capillary tube can be filled with gel, for example polyacrylamide or agarose, half porous medium that it provides the sampling interstitial fluid to flow through.Yet capillarity may lose efficacy, and therefore can utilize the electrode application voltage that is positioned at described capillary tube top and bottom.Because the described size capillaceous of gel that is filled with is only for hundreds of microns, so by applying low-level voltage, just can drive described interstitial fluid by electrophoresis.Like this, low-voltage still can produce high electric field, because E=V/d, thereby biotic component is separated in gel according to electric charge/mass ratio.Then, remove on one's body, effective 1-D can be separated and further analyze in case will install from the user.

[0184] in one embodiment, described system can be used for short-term or secular interface (for example prosthese control, treatment response) through structure to be used for neural interface.In addition, described system can be through structure to monitor and to treat possibly sacred disease, for example depression, anxiety and multiple sclerosis.By on thin lead electrode, using the deformable nano-pattern formed material of compliance, as mentioned above, wherein be coated with the nerve growth factor among the PPY that is fixed on electrochemical deposition, described device can obtain the neuronic good biocompatibility of living is connected.Described connection may be that electric current passes through described nanoscale conductor under the help of tunneling mechanism owing to the intimate and secular bonding formation between neuron and the fibrous nano yardstick conductor.

[0185] in one embodiment, described system can be through structure to guarantee environmental organism safety by detecting animal, crop, water and food supply.The entering of U.S.'s hand-foot-mouth disease represented in next two decades maximum biological a threat to trillion dollars of agro-industries in our country.But described system can be through structure to provide the platform of the bi-directional scaling of determining that disease distributes in country or specific region.Carry out each body supervision if desired in real time, then the assessment of high flux Noninvasive can be attached in (onboard) test of boarding, determine in order to the hypothesis that infects.If particular individual is positive, then can carry out the follow-up effort of each body level.

[0186] in relevant bio-safety field, described device can be through structure with at particular chemicals, for example specific insecticide.The disease that environment causes is affecting everyone in varying degrees, yet individual susceptibility can be according to another colony of toxic reaction degree pretreatment of a colony.Particularly, in the stage of development of individuality, from period of embryo to the adolescence, special susceptible is in this ambient pressure because crucial body function also immaturity can bear, tackle and handle the level of this exposure to it.Use is added in biomarker in the described device can provide continuous monitoring to child's Environmental Health, and be used for the earlier detection of toxin, prevent to damage its health, and determine the treatment policy at being exposed to the child who contains under the toxicity of pesticides environment for example.Have many different insecticides, but as if great majority by disturbing neurotransmitter---the enzyme of the acetylcholine system that affects the nerves.The insecticide monitoring can also be used for crop for various reasons, and described reason includes but not limited to optimize the chemical treatment of relevant output; Guarantee that crop is not by excess processes; And monitoring is from the agricultural product of claiming the supplier who does not have use of insecticide.Described device can be used as independent device, wherein pedotheque can be placed on the sensor site.The water that contains in the sample can arrive the pick off of the suitable receptor set that contains promising various insecticide settings, and indicator can provide the information of insecticide concentration in the relevant environment.

It will also be appreciated that [0187] said system can be through structure not to be used for detecting and treatment in the various application of record in this article.

[0188] it will be appreciated by those skilled in the art that, a lot of and unlimited at the application that said system is expected.It is the restriction of any way that above-mentioned application example should not be considered as.On the contrary, it is that the example of the extensive use that can provide as embodiment of the present invention provides.

[0189], is understood that invention defined in the appended claims and necessarily is limited to described specific feature or method although the present invention is described by the literal at architectural feature and/or method.On the contrary, described specific characteristic and method are disclosed as the example forms of implementing claimed invention.

Claims (132)

1. method that is used to monitor the biological situation of experimenter, described method comprises:

The pick off of sampling, analysis and delivery apparatus is exposed to the material that comprises target biological molecules;

Provide the signal of telecommunication to described pick off;

Measure the electrical property that described pick off place responds the described signal of telecommunication;

Measured electrical property is associated with described biological situation;

Determine that normally whether measured biological situation; And

When the biological situation that records is undesired, generate signal.

2. according to the method for claim 2, further comprise:

Chamber delivery materials in described sampling, analysis and delivery apparatus gives described material to respond the signal of described generation.

3. according to the method for claim 3, further comprise at the described material of the efficiency analysis of described material.

4. describedly determine that the measured whether normal process of biological situation comprises that the biological situation that will record compares with the normal healthy baseline condition according to the process of claim 1 wherein.

5. according to the process of claim 1 wherein that described target biological molecules is selected from the group of being made up of following material: glucose, lactate, bilirubin, ethanol, pyruvate and cytochrome P-450 2A6 enzyme.

6. according to the process of claim 1 wherein that described target biological molecules is selected from the group of being made up of following material: glucosylation hemoglobin and protein, insulin, cholesterol, c reactive protein, homocysteine, the appetite peptide, Plasmodium falciparum histatins 2, the parasite lactic acid dehydrogenase, prostate specific antigen, prostate film specific antigen, estrogen, epidermal growth factor, insulin-like growth factor, hemagglutinin, neuraminidase, the 17kDa subunit of splitted Caspase-3, protein such as p54, immunoglobulin, anesthetis, leptin, ghrelin, vitamin, folic acid, creatine kinase, troponin, c reactive protein, Tumor Necrosis Factor Receptors 1 and 2, creatine phosphokinase, sarcosine, troponin, interleukin 1,2 and 6, the interleukin II receptor, tumor necrosis factor, the n-nitrosamine, nicotine, but ferrum is peaceful, Opium class medicine, cocaine, and spore metabolite.

7. according to the process of claim 1 wherein that described target biological molecules is selected from the group of being made up of following material: influenza virus, multiple sclerosis syndrome virus, dengue fever, malaria, HIV and pulmonary tuberculosis.

8. according to the process of claim 1 wherein that described electrical properties is selected from following group: electric current, electric capacity, resistance, voltage class electromotive force and electromotive force.

9. method according to Claim 8, wherein said electrical properties is an electric current.

10. one kind is used for the method that biomolecule is monitored, and described method comprises:

To comprising the material sampling of biochemical product;

Utilize pair of electrodes to analyze described material, described electrode pair is placed on the support substrate;

Utilize controller to control described sampling and described analysis; And

Communication information between controller and remote-control device.

11. according to the method for claim 10, wherein said sampling comprises and utilizes described electrode pair to interrupt protecting film.

12. according to the method for claim 10, wherein said sampling comprises and utilizes another counter electrode to interrupt protecting film.

13. according to the method for claim 12, wherein said protecting film comprises barrier tissue.

14. according to the method for claim 12, wherein said protecting film comprises horny layer.

15. according to the method for claim 10, wherein said support substrate comprises chamber, and described sampling comprises described material is wicked in the described chamber.

16. according to the method for claim 15, wherein said electrode to small part is arranged in the described chamber.

17., comprise that further delivery materials arrives described material according to the method for claim 10.

18. according to the method for claim 17, wherein said material comprises at least a following material: chemicals, medicine, biomolecule, protein, peptide and genetic stocks.

19. according to the method for claim 17, wherein said material has reactivity to described material.

20. according to the method for claim 17, wherein said support substrate comprises chamber, described method further comprises described material is stored in the described chamber sends up to described.

21. according to the method for claim 10, wherein said communication comprises the wireless telecommunications with described remote-control device.

22. according to the method for claim 10, wherein said information comprises the result of the described analysis from described controller to described remote-control device.

23. according to the method for claim 10, wherein said information comprises the instruction from described remote-control device to described controller.

24. a sampling, the system that analyzes and/or send at least a biochemical product, described system comprises:

Support substrate;

A plurality of by described support substrate support and be arranged to the cell of multiple lines and multiple rows, each of described a plurality of cells through structure with sampling, analyze and/or send described biochemical product;

To control the interactional controller between each and the material relevant with described biochemical product in described a plurality of cell, described controller is connected with described a plurality of cells by a plurality of column address conductive paths, a plurality of row address conductive path and a plurality of zero-force connectors through structure; And

Communication device, it is through constructing to communicate with described controller and external device (ED).

25. according to the system of claim 24, wherein each cell comprises a pair of electrode of being supported by described support substrate.

26. according to the system of claim 25, at least some in the wherein said electrode pair are through constructing to interrupt the protecting film between described support substrate and described material.

27. according to the system of claim 26, wherein resistive element be arranged between described at least some electrode pairs and through structure to interrupt described protecting film.

28. according to the system of claim 25, wherein each at least some described cells comprises pick off, described pick off comprises working electrode and reference electrode, described working electrode activate by electrochemistry and through structure with described substance reaction; Wherein when on described electrode, applying voltage and described at least working electrode and be exposed to described material, produced electrical property corresponding to described Substance Properties; And wherein said controller controlling to the series of electrical signals of described electrode, and receives the described electrical property that generates through structure.

29. according to the system of claim 28, wherein said electrical property is the electric current that generates between described electrode.

30. according to the system of claim 28, the described character of wherein said material is the biochemical analyte level in the described material.

31. according to the system of claim 28, the described character of wherein said material is physicochemical property.

32. according to the system of claim 24, wherein said support substrate be flexible and through structure to be connected on the protecting film.

33. according to the system of claim 32, wherein said support substrate comprises polymer.

34. according to the system of claim 32, wherein said protecting film is a horny layer, and described material is the interstitial fluid that is positioned at below the described horny layer.

35. according to the system of claim 32, wherein said protecting film is a barrier tissue.

36. according to the system of claim 24, wherein at least some described a plurality of cells are included in the chamber in the described support substrate.

37. according to the system of claim 36, wherein said chamber is through constructing to receive the sample of described material.

38. according to the system of claim 36, wherein said chamber comprises material below at least a through structure with storage: chemicals, medicine, biomolecule, protein, peptide and genetic stocks.

39. according to the system of claim 38, wherein said material has reactivity to described material.

40. according to the system of claim 38, wherein said material is to proofread and correct standard specimen.

41. according to the system of claim 38, wherein said material is gas, liquid or solid.

42. according to the system of claim 24, wherein said controller is applied in described a plurality of cell voltage on each through structure with control.

43. according to the system of claim 42, wherein said controller through structure once to apply voltage in described a plurality of cells.

44. according to the system of claim 42, wherein said controller through structure with once apply voltage in described a plurality of cells more than one.

45. according to the system of claim 24, further comprise power supply, wherein said controller is through constructing to manage described power supply.

46. according to the system of claim 45, wherein said power supply is a battery.

47. according to the system of claim 24, wherein said communicator comprises at least one wireless communication module, its through the structure with described external device (ED) wireless connections.

48. according to the system of claim 24, wherein said external device (ED) is a computer.

49. a system that is used for amalyzing substances character, described system comprises:

Support substrate;

A plurality of pick offs of supporting by described support substrate, each pick off comprises:

By the electrode pair that described substrate is supported, described electrode pair comprises working electrode and reference electrode, described working electrode activate by electrochemical reaction and through structure with described substance reaction;

Wherein when on described electrode, applying voltage and described at least working electrode and be exposed to described material, produced electrical property corresponding to described Substance Properties; And

Controller is used to control to the series of electrical signals of described electrode, and receives the described electrical property of its generation.

50., further comprise the communicator that is used for described controller and external device (ED) communication according to the system of claim 49.

51. according to the system of claim 50, wherein said communicator comprises at least one wireless communication module, its through the structure with described external device (ED) wireless telecommunications.

52. according to the system of claim 50, wherein said external device (ED) is a computer.

53. according to the system of claim 49, wherein said electrical property is the electric current that generates between described electrode.

54. according to the system of claim 49, the described character of wherein said material is the biochemical analyte level in the described material.

55. according to the system of claim 54, wherein said biochemical analyte is a glucose.

56. according to the system of claim 54, wherein said biochemical analyte is a lactate.

57. according to the system of claim 54, wherein said biochemical analyte is a bilirubin.

58. according to the system of claim 49, the described character of wherein said material is physicochemical property.

59. according to the system of claim 58, wherein said physicochemical property is the pH value of described material.

60. according to the system of claim 58, wherein said physicochemical property is the level of dissolved gas in the described material.

61. according to the system of claim 49, wherein said support substrate be flexible and through structure to be bonded on the protecting film, described material is positioned on the described protecting film one side relative with described support substrate.

62. system according to claim 61; wherein each pick off further comprises the resistive element that is arranged between the described electrode; interrupting and the contacted protecting film of each pick off, and the described material that allows to be positioned at described protecting film opposite face contacts with described at least working electrode through structure for wherein said electrode and resistive element.

63. according to the system of claim 61, wherein said protecting film is a horny layer, described material is the interstitial fluid that is positioned at below the described horny layer.

64. according to the system of claim 61, wherein said protecting film is a barrier tissue.

65. system according to claim 61; wherein each pick off further is included in the chamber in the described support substrate; at least a portion of wherein said electrode is positioned at described chamber; and wherein said chamber through structure opening by described resistive element, thereby allow to link with the described material that is positioned at described protecting film opposite face.

66. according to the system of claim 65, wherein said chamber is through constructing to receive the sample of described material.

67. system according to claim 49, wherein each pick off further is included in the chamber in the described support substrate, and wherein said chamber comprises the material of at least a following material with storage through structure: chemicals, medicine, biomolecule, protein, peptide and genetic stocks.

68. according to the system of claim 67, wherein said material has reactivity to described material.

69. according to the system of claim 67, wherein said material is to proofread and correct standard specimen.

70. according to the system of claim 67, wherein said material is gas, liquid or solid.

71. according to the system of claim 49, wherein said controller is applied in described a plurality of pick off voltage on each through structure with control.

72. according to the system of claim 71, wherein said controller through structure once to apply voltage in described a plurality of pick offs.

73. according to the system of claim 71, wherein said controller through structure with once apply voltage in described a plurality of pick offs more than one on.

74. according to the system of claim 49, further comprise power supply, wherein said controller is through constructing to manage described power supply.

75. according to the system of claim 74, wherein said power supply is a battery.

76. system according to claim 49, wherein said a plurality of pick off is arranged to comprise the clathrate of multiple row and multirow on described support substrate, and wherein said system further comprises a plurality of column address conductive paths and a plurality of row address conductive path, and it is connected to described a plurality of pick offs on the described controller.

77. according to the system of claim 49, further comprise a plurality of zero-force connectors, it is through constructing so that described a plurality of pick offs are connected on the described controller.

78. be used to detect the pick off of the Substance Properties that comprises biomolecule, described pick off comprises:

By the electrode pair that substrate is supported, described electrode pair comprises working electrode and reference electrode, described working electrode activate by electrochemistry and through structure with described substance reaction;

Wherein when on described electrode, applying voltage and described at least working electrode and be exposed to described material, produced electrical property corresponding to the described character of described material.

79. according to the pick off of claim 78, wherein said working electrode is activated by enzyme electrochemistry.

80. according to the pick off of claim 79, wherein said biomolecule is selected from the group of being made up of following material: glucose, lactate, bilirubin, ethanol, pyruvate and cytochrome P-450 2A6 enzyme.

81. according to the pick off of claim 78, wherein said working electrode is activated by antibody electrochemistry.

82. 1 pick off according to Claim 8, wherein said biomolecule is selected from the group of being made up of following material: glucosylation hemoglobin and protein, insulin, cholesterol, c reactive protein, homocysteine, the appetite peptide, Plasmodium falciparum histatins 2, the parasite lactic acid dehydrogenase, prostate specific antigen, prostate film specific antigen, estrogen, epidermal growth factor, insulin-like growth factor, hemagglutinin, neuraminidase, the 17kDa subunit of splitted Caspase-3, protein such as p54, immunoglobulin, anesthetis, leptin, ghrelin, vitamin, folic acid, creatine kinase, troponin, c reactive protein, Tumor Necrosis Factor Receptors 1 and 2, creatine phosphokinase, sarcosine, troponin, interleukin 1,2 and 6, the interleukin II receptor, tumor necrosis factor, the n-nitrosamine, nicotine, but ferrum is peaceful, Opium class medicine, cocaine, and spore metabolite.

83. 1 pick off according to Claim 8, wherein said biomolecule is selected from the group of being made up of following material: influenza virus, multiple sclerosis syndrome virus, dengue fever, malaria, HIV and pulmonary tuberculosis.

84. according to the pick off of claim 78, wherein said electrical properties is selected from following group: electric current, electric capacity, resistance, voltage class electromotive force and electromotive force.

85. pick off according to claim 78; further comprise the resistive element that is arranged between the described electrode; interrupting at the protecting film between working electrode and the described material at least, described so at least working electrode is exposed to described material through structure for wherein said electrode and resistive element.

86. 5 pick off according to Claim 8, wherein said protecting film comprise the dead Skin Cell of the horny layer that contacts with described pick off, described material comprises the interstitial fluid that is positioned at below the described horny layer.

87. 5 pick off according to Claim 8, wherein said substrate are the flexible substrates that one side has binding agent, described binding agent through structure to be attached on the described protecting film.

88. 7 pick off according to Claim 8, wherein said substrate comprises polymer.

89. 8 pick off according to Claim 8, wherein said polymer is SU-8.

90. 8 pick off according to Claim 8, wherein said polymer is a polymethyl methacrylate.

91. 8 pick off according to Claim 8, wherein said polymer is a polydimethylsiloxane.

92. 5 pick off according to Claim 8, further be included in the chamber in the described support substrate, at least a portion of wherein said electrode is positioned at described chamber, and wherein said chamber through structure opening by described resistive element, thereby allow described chamber and described material UNICOM.

93. according to the pick off of claim 92, further comprise the material that is included in the described chamber, described chamber through structure with after opening at described chamber, with the position of described material delivery to the described protecting film opposing face as working electrode.

94. according to the pick off of claim 93, wherein said material comprises at least a following material: chemicals, medicine, biomolecule, protein, peptide and genetic stocks.

95. according to the system of claim 93, wherein said material has reactivity to described material.

96. according to the system of claim 93, wherein said material is to proofread and correct standard specimen.

97. according to the system of claim 93, wherein said material is gas, liquid or solid.

Comprise the sampling apparatus of the material of biochemical product 98. be used to sample, described sampling apparatus comprises:

Support substrate; And

By the electrode pair that described support substrate is supported, described electrode pair is through constructing to interrupt the protecting film between described support substrate and described material.

99. according to the sampling apparatus of claim 98, further be included in the chamber in the described support substrate, wherein said chamber is through constructing to receive the sample of described material.

100. according to the sampling apparatus of claim 99, wherein the described electrode pair of at least a portion is exposed in the described chamber.

According to the sampling apparatus of claim 98, further comprise the resistive element that is arranged between the described electrode, wherein said resistive element is through constructing to interrupt described protecting film.

According to the sampling apparatus of claim 98, wherein said protecting film is a barrier tissue.

According to the sampling apparatus of claim 98, wherein said protecting film is a horny layer.

According to the sampling apparatus of claim 98, wherein said support substrate is flexible.

According to the sampling apparatus of claim 104, wherein said support substrate comprises polymer.

According to the sampling apparatus of claim 98, further comprise zero-force connector, it is through constructing so that described electrode pair is connected on the controller.

According to the sampling apparatus of claim 106, wherein said controller is applied to voltage on the described electrode through structure with control by power supply.

According to the sampling apparatus of claim 107, wherein said power supply comprises battery.

Be used for the method for the biochemistry product of amalyzing substances, described method comprises:

At least the working electrode of pick off is exposed to described material;

On working electrode and reference electrode, apply voltage;

Measure the electrical property conduct that is generated applies described voltage on described electrode result; And

Measured electrical property is associated with described Substance Properties.

110. according to the method for claim 109, wherein said Substance Properties is the biochemical analyte level in the described material.

111. according to the method for claim 109, wherein said Substance Properties is a physicochemical property.

112. according to the method for claim 109, wherein said electrical properties is selected from following group: electric current, electric capacity, resistance, voltage class electromotive force and electromotive force.

113. according to the method for claim 112, wherein said electrical properties is an electric current.

114. according to the method for claim 109, further be included in before the described exposure, by applying a series of potential pulses to described electrode be arranged at the capillary tube that forms on the resistive element between the described electrode by protecting film.

115., further comprise by described capillary tube described material of wicking below described protecting film according to the method for claim 114.

116. according to the method for claim 114, wherein said protecting film comprises barrier tissue.

117. according to the method for claim 114, wherein said protecting film comprises horny layer.

118., further comprise material is discharged to described material according to the method for claim 109.

119. according to the method for claim 118, wherein said material comprises at least a following material: chemicals, medicine, biomolecule, protein, peptide and genetic stocks.

120. according to the method for claim 119, wherein said material has reactivity to described material.

121., further comprise and give remote-control device with the described character wireless telecommunications of described material according to the method for claim 109.

122. fill the method for the chamber in the delivery apparatus supporting layer, described method comprises:

Wherein the foraminous sealant of tool is placed on the described supporting layer, makes described hole be positioned at described chamber top;

Fill described chamber with material;

The described relatively supporting layer of described sealant is placed, made described hole remove and make described sealant to cover described chamber from described chamber; And

Described sealant is bonded on the described supporting layer.

123. method according to claim 122, wherein said filled chamber comprises that the glass carrier that will wherein have reservoir and hole places with respect to described sealant, make hole in the described glass carrier and the hole substantial alignment in the described sealant, fill described reservoir with described material and make described material moving and fill described chamber by the orifice flow in hole the described glass carrier and the described sealant from described reservoir.

124. method according to claim 122, wherein said supporting layer comprises the capilar bore that at least one is parallel with described chamber, and places described sealant with respect to described supporting layer and comprise that moving described sealant makes and alignd with capilar bore in the supporting layer in the hole in the sealant.

125. make the method for the device that is used for amalyzing substances character, described method comprises:

Between a plurality of adapters on the support substrate and a plurality of electrode, connecting with lead;

Make described a plurality of electrodes exposed in polymeric matrix;

Provide relatively electrochemistry potential energy from described a plurality of electrodes, to select electrode; And

Be coated with selected electrode with described polymeric matrix.

126. the method according to claim 125 further comprises:

With described a plurality of electrodes exposed in second polymeric matrix that is different from described first polymeric matrix;

Other selection electrode in described a plurality of electrodes provides the electrochemical potential with respect to ground; And

Apply described selection electrode with described second polymeric matrix.

127. according to the method for claim 125, wherein said adapter is a zero-force connector.

128. according to the method for claim 127, wherein said zero-force connector is positioned at front surface, rear surface and/or the side surface of described support substrate.

129. according to the method for claim 125, wherein said polymeric matrix comprises the antibody with described substance reaction.

130. according to the method for claim 125, wherein said polymeric matrix comprises the enzyme with described substance reaction.

131. according to the method for claim 125, wherein said polymeric matrix comprises the oxidoreduction electronic media.

132. according to the method for claim 129, wherein when described device was used to analyze the described character of described material, described connection also was used for providing voltage to described electrode.

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