CN105143435A - Diagnostic device for evaluating microbial content of a sample - Google Patents

Abstract

A diagnostic device evaluates microbial content of a sample. In some embodiments, the diagnostic device includes a plurality of sample cells in which the microbial content of a sample is evaluated. Electronic circuitry is used to apply electrical signals to electrodes that interact with the sample in the sample cells. The electronic circuitry also measures one or more characteristics of the sample. Using the measured characteristics, the diagnostic device performs one or more of: identifying microbes, counting microbes, and determining antimicrobial sensitivity of microbes within the sample.

Description

For assessment of the diagnostic device of the content of microorganisms of sample

the cross reference of related application:

Subject application is the pct international patent application case of filing an application on February 28th, 2014 and advocates the U.S. patent application case the 61/770th of filing an application on February 28th, 2013, the right of priority of No. 391, the full text of the disclosure of described application case is incorporated herein by reference.

Background technology

One of difficulty run into when processing and relating to the problem of microorganism is that microorganism is in continuous change.Microorganism comprises such as bacterium, fungi, virus, nematode, cell culture and tissue.Microorganism more and more has an antimicrobial drug resistance.Antimicrobial drug comprises microbiotic, antiviral agent, anti-mycotic agent or antiparasitic, and comprises and bite bacterial body, mycovirus, bite virosome, bite nematode body, and it is the virus of attack bacteria, fungi, nematode respectively.Such as, along with increasing of antibiotic-resistant bacteria, even if correctly identify the type of bacterium, think that the prior treatment effectively can resisting described bacterium may be also no longer valid.More particularly, concrete bacterial species may produce resistance to treatment, and therefore no longer responsive to this treatment.

Summary of the invention

In general, the present invention relates to the diagnostic device of the content of microorganisms of assessment sample.In a possible configuration and by limiting examples, diagnostic device performs one or many person in the following: the Antimicrobial susceptibility measuring microorganism, differentiate microorganism and to microorganism count.Describe many aspects in the present invention, it includes, but is not limited to following aspect.

An aspect is diagnostic device, and it comprises: at least one defines the sample block of sample cavity wherein; At least four are arranged in the electrode in sample cavity; With the electronic circuit being operably connected to electrode, wherein electronic circuit can operate in a first mode and a second mode, wherein when operating in a first pattern, electronic circuit operation is with the conductance of sample in working sample cavity, and wherein when operating in a second mode, electronic circuit operation is with the admittance of sample in working sample cavity.

Be antimicrobial drug divider on the other hand, it comprises: aseptic carrier materials; With carried by aseptic carrier materials bite bacterial body.

Be sample block on the other hand, it comprises: at least one substrate; At least four electrodes; With the sample cavity formed at least one substrate, described sample cavity comprises: comprising the transducing part of electrode, and described transducing part has and is configured in sample cavity, guide the electric field produced by electrode and the shape making it focus on; With riser (chimney) part, it extends from transducing part and has the cross section size of the cross section size being less than transducing part.

Be diagnostic device on the other hand, it comprises: multiple sample block; Be arranged in the electrode in sample block; Be arranged in the calibration solution in the calibration module of sample block; With the electronic package being coupled to electrode, wherein electronic package can operate with the temperature of the conductance measurement calibration solution of the specific conductivity of liquid in Measurement and calibration pond also measured by use.

Other side is disclosed in herein.

Accompanying drawing explanation

Fig. 1 is the perspective schematic view of exemplary diagnostics device.

Fig. 2 is the functional diagram of the exemplary reader of diagnostic device demonstrated in Figure 1.

Fig. 3 is the functional diagram of the exemplary diagnostics unit of diagnostic device demonstrated in Figure 2.

Fig. 4 is the perspective schematic view of the illustrative sensors system of diagnosis unit demonstrated in Figure 3.

Fig. 5 is the perspective schematic view in the exemplary sample pond of sensing system demonstrated in Figure 4.

Fig. 6 is the cross-sectional side view of sample pool demonstrated in Figure 5.

Fig. 7 is the vertical view of sample pool demonstrated in Figure 5, and it is the configuration of graphic extension electrode and exemplary antimicrobial drug divider also.

Fig. 8 is the cross-sectional plan view of another exemplary sample pond and the configuration of another exemplary electrode.

Fig. 9 is the cross-sectional plan view of another exemplary sample pond and the configuration of another exemplary electrode.

Figure 10 is the cross-sectional plan view of another exemplary sample pond and the configuration of another exemplary electrode.

Figure 11 is the cross-sectional plan view of another exemplary sample pond and the configuration of another exemplary electrode.

Figure 12 is the cross-sectional side view of exemplary sample pond and the exemplary electrode configuration shown in Figure 11.

Figure 13 is the state graph of the example of the operation of graphic extension diagnostic device demonstrated in Figure 1.

Figure 14 is the skeleton view of exemplary antimicrobial drug divider.

Figure 15 is the skeleton view of the exemplary antimicrobial drug divider shown in Figure 14, and antimicrobial drug is assigned in liquid by its graphic extension.

Figure 16 is the schematic block diagrams that graphic extension can be used for the exemplary architecture of the calculating device performing each side of the present invention.

Figure 17 graphic extension relates to another exemplary architecture of diagnostic device.

The experimental data that Figure 18 graphic extension uses diagnostic device to obtain.

Other experimental data that Figure 19 graphic extension uses diagnostic device to obtain.

Other experimental data that Figure 20 graphic extension uses diagnostic device to obtain.

Embodiment

With reference to the multiple embodiment of graphic detailed description, wherein in some views, identical reference numerals represents same parts and subassembly.Each embodiment of mentioning does not limit the scope of following claims.In addition, any example described in this specification sheets is not intended to have restricted, and for following claims only state many may some in embodiment.

In general, the present invention relates to the diagnostic device of the content of microorganisms of assessment sample.In certain embodiments, diagnostic device performs one or many person in the following: the Antimicrobial susceptibility measuring microorganism, differentiates microorganism and to microorganism count.

In certain embodiments, diagnostic device provides fast (such as one hour) Antimicrobial susceptibility to test.Along with increasing of antibiotic-resistant bacteria, Antimicrobial susceptibility test make medical professional can open the very first time correct antibiolics prescription reduce simultaneously antimicrobial drug resistant microorganism evolve chance.When the patient with septicemia sign arrives first-aid room, those patients starting effective antimicrobial regimen in the first hour have the result being better than the patient postponing treatment.In addition, in certain embodiments, diagnostic device can be differentiated and/or screen the bacterium (such as MRSA, vancomycin (vancomycin) tolerant bacteria and lethal bacteria described in other) needing special scheme, to help health care professional differentiate and select effective treatment plan, reduce the side effect for the treatment of simultaneously.Also by diagnostic device, severity with Grading of infection is counted to amount of bacteria.

In certain embodiments, diagnostic device operation is with the microbiological specimens produced from the mankind or the sample such as animal blood, urine by one or more Analysis of Electrical Characteristics of sample in measure sample pond.In addition, such as, some embodiments operation of diagnostic device is to detect harmful microorganism on food and detection is present in ducted harmful corrodibility microorganism in water drain, oil, Sweet natural gas and chemical plant.

For each bacteria types, there is the unique virulent bacteriophage only attacked and kill this specific bacteria.When bacterium be subject to through specific culture bite bacterial body attack time, bacterium can discharge ion when biting bacterial body and being expelled in bacterium by its DNA, thus the generation ionic flux that can electronically detect.In certain embodiments, some sample pools in array are loaded with nutrient medium, or be loaded with microorganism Ensure Liquid nutrient solution, or the different microbiotic be loaded with containing different virus phage or the microbiotic containing each in the microbiotic of a kind of unique phage or at least some of sample pool.Described bite bacterial body can be embedded in allow control bite in the material of the wash-out of bacterial body.Because each different virulent bacteriophage only attacks a kind of specific bacteria, therefore the identity of bacterium in test can be determined.In certain embodiments, bacterium identity is only containing nutrient medium according to analysis; Containing nutrient medium and microorganism; And the difference containing nutrient medium, specific conductivity feature between microorganism and the sample pool of virulent bacteriophage is determined.In other embodiments, bacterium identity can be determined according to biting the unlike signal produced when bacterial body attacks its target bacteria, and this carries out utilizing to bite in first 15 minutes that bacterium to be introduced sample pool by bacterial body impreg.Suppose to bite bacterial body can while impregnated in described material long-term cultivation.

By using the different microorganisms of concentration known to carry out calibration testing, the value of specific conductivity measured by the sample pool containing nutrient medium and microorganism can be used to carry out the concentration (such as, to the bacterial count in sample pool) of microorganism in assess sample pond.

Antimicrobial drug (such as microbiotic and bite bacterial body) makes metabolism slow down or stops, thus produces the testing mechanism of one or more specificity for the ability of given biocide the elimination of micro-organisms.After antimicrobial drug is attacked, first time period (such as a hour) period monitoring microorganism provides the good instruction of antimicrobial drug net result.Other sample pool in array can be loaded with the unique biocide array in each in nutrient medium, microorganism and multiple sample pool.Such as, biocide comprises microbiotic, antimicrobial peptide, bites bacterial body and small-molecule drug.In certain embodiments, different biocide kill the validity in microorganism (such as bacterium, fungi, virus, nematode, cell culture or tissue) by more different sample pool in only nutrient medium; Nutrient medium and microorganism; And nutrient medium, microorganism and antimicrobial drug electrical signal (conductance or admittance) feature determine.In other embodiments, different digital signal may be correlated with to the front of the resistance of different antimicrobial drug or negative effect to microorganism with it by antimicrobial drug different from each, and each coherent signal becomes numerical characteristic thus.The database of comparative figures feature and each numerical characteristic can determine the validity of antimicrobial drug.When bacterium identity can be determined, also optionally utilize this information to determine microbiotic validity.Such as, this produces β-lactamase bacterium (such as Staphylococcus (staphylococcusspp)) in discriminating or is even more important when detecting other extended spectrumβ-lactamase (ESBL) bacterium.

In certain embodiments, diagnostic device also can be used to detect the mixture of bacterium in sample.Such as, if bacteria samples contains two kinds of different bacteriums, then two kinds of bacteriums will grow in various kinds of cell, but will observe in more than one cell because making growth slow down caused by different each cracking of biting in the different bacterium of bacterial body.

Some embodiments of diagnostic device utilize simulated impedance formula/conductance type surveying instrument and technology to detect and quantize the bacterium that is present in culture.Some embodiments also relate to the method manufacturing impedance type measurement vessel.

Fig. 1 is the perspective schematic view of exemplary diagnostics device 100.In certain embodiments, diagnostic device comprises reader 102, diagnosis unit 104 and interface 106.

Diagnostic device 100 operates the content of microorganisms assessing sample.In certain embodiments, diagnostic device 100 is formed with single part.But in other embodiments, diagnostic device 100 is formed with at least two parts, and as demonstrated in Figure 1, it comprises reader 102 and diagnosis unit 104.Form the advantage with the diagnostic device 100 of at least two parts and be that reader 102 can be configured to recycling parts, diagnosis unit 104 can be configured to disposable unit simultaneously.Sample is all contained in disposable unit, and at least most of electron device is contained in reader.Interface 106 is allowed and is communicated between reader 102 with diagnosis unit 104.

In an example, reader 102 contains with diagnosis unit 104 combine operations to assess the electronic package of the content of microorganisms of sample.In certain embodiments, reader 102 comprises the analog electronics producing alternating-current (AC) signal, and described signal is provided to diagnosis unit 104 for inquiring sample.In certain embodiments, reader 102 also comprises Sense Electronics, described electron device for one or more characteristic of sample during detecting inquiry to assess the content of microorganisms of sample.Some embodiments also comprise display unit 110 or other take-off equipment, and it is for carrying the result of the microbial assessment performed by diagnostic device 100.With reference to Fig. 2 more detailed illustration and example describing reader 102.

Diagnosis unit 104 comprises the sample pool 112 that one or more wherein carries out sample inquiry.In this example, diagnosis unit 104 also comprises sample input port 114 and lid 116.Sample is provided in input aperture 114, and lid 116 is fixed on sample input port 114 to be sealed in diagnosis unit 104 by sample.Sample is directed in one or more sample pool 112.In certain embodiments, sample is directed in sample pool 112 by the effect of fixed cap 116.The electrode 118 be arranged in sample pool is coupled to reader 102 by interface 106.Reader 102 operates to use the electrode 118 in sample pool to inquire sample.With reference to Fig. 3-12 more detailed illustration and example describing diagnosis unit 104.

In certain embodiments, at least one characteristic of diagnosis unit 104 measure sample.The example of described characteristic comprises electrical characteristic, such as admittance, conductance, susceptance etc.One or more characteristic of measure sample over time in certain embodiments.

In certain embodiments, diagnostic device 100 operates the one or many person performed in the following: differentiate the amount being present in microorganism in sample, differentiates that the type and determining of the microorganism be present in sample is present in whether (and to which kind of degree) the combating microorganisms susceptibility sense of microorganism in sample.The example of antimicrobial drug comprises microbiotic, bactericide, peptide, bites bacterial body, chemotherapeutic or its combination.The example of microorganism comprises bacterium, fungi, nematode, cell culture and tissue.

For determining microorganism whether combating microorganisms susceptibility sense, in certain embodiments, antimicrobial drug is included at least one sample pool 112.In certain embodiments, multiple sample pool 112 is separately containing different antimicrobial drugs.In certain embodiments, for the object of the redundancy of the accuracy of improvement diagnostic result, antimicrobial drug can be present in multiple sample pool 112.If be present in the microorganism combating microorganisms susceptibility sense in sample, then diagnosis unit 104 will detect the change of one or more characteristic of sample in respective sample pond 112, such as by comparing it and containing sample but do not carry out containing the compared with control cells of antimicrobial drug, this allows that diagnosis unit 104 determines that microorganism is responsive to the antimicrobial drug in sample pool 112.

In certain embodiments, such as, differentiate that microorganism contributes to following the trail of the source of infection, and microorganism count contributes to the severity of Grading of infection.

Fig. 2 is the functional diagram of the exemplary reader 102 of diagnostic device 100.In certain embodiments, reader 102 comprises shell 132, electronic package 134 and diagnosis unit interface 106A.Some embodiments comprise micro pump 136 further.In this example, electronic package 134 comprise power supply 142, comprise the analog electronics 144 of AC current source 146 and AC voltmeter 148, A/D converter 150, digital signal processor 160, central processing unit 162, computer-readable media 164, video-stream processor 166, display unit 168, communicator 170, heating controller 172 (and heating unit) and input unit 174.Some embodiments comprise clock and one or more voltmeter further.Other embodiment comprises more or less assembly.

Diagnosis unit interface 106A is a part for interface 106, and it is configured to reader 102 to be coupled to diagnosis unit 104.As an example, diagnosis unit interface 106A is configured to receive and the card slot be electrically connected with the reader interface 106B of diagnosis unit 104.In this example, be electrically connected to allow that numeral or analog electrical signal communicate between reader 102 with diagnosis unit 104 at reader 102 with setting up between diagnosis unit.Use electricity or the data corresponding of other type in other embodiments.Such as, some embodiments utilize RFDC, such as, use radio frequency, infrared or inductive communication device and signal.

Shell 132 provides protectiveness outer cover for reader 102.In certain embodiments, shell 132 is formed by plastics.Other embodiment is formed by other material.Shell 132 comprises the internal space of at least some assembly (such as micro pump 136 and electronic package 134) holding reader 102.In certain embodiments, one or more hole is formed in shell 132, such as to allow that the conduit being coupled to micro pump passes through, allow that diagnosis unit interface 106A is coupled to reader interface 106B (Fig. 3), and for the communication port of communicator 170.In certain embodiments, communicator 170 comprises multiple communications subcomponent.Such as, in certain embodiments, communicator 170 comprises RFID reader, and it is for communicate with sensing system 192 (and more particularly, communicate with data storage equipment 208, it is all discussed more in detail with reference to Fig. 3).Shell 132 can be formed by one or more material.In certain embodiments, shell 132 be transparent at least partially, such as with allow observe display unit 168.

Some embodiments comprise micro pump system 136.Micro pump system 136 passes through the flow control system 190 of tubes connection to diagnosis unit 104 of interface 106 (or independent interface), and generation pressure reduction moves in sample pool 112 to make the liquid in diagnosis unit.As discussed with respect to figure 3, some embodiments of diagnosis unit 104 do not comprise flow control system, and therefore do not need micro pump 136 in the described embodiment.Another is chosen as, and diagnosis unit 104 self produces pressure reduction when not utilizing micro pump 136 in certain embodiments.

Power supply 142 store power is also supplied to electronic package 134.In certain embodiments, power supply 142 is batteries.Some embodiments comprise battery charging electronics further.In other possibility embodiment, power supply 142 comprises powered electronic devices, it is configured to receive electric energy from external power source (such as trunk power supply), and convert electric energy to suitable form (such as converting relatively low voltage signal to, such as 3V, 12V or +/-15V direct current).

Analog electronics 144 is coupled to diagnosis unit interface 106A.In certain embodiments, analog electronics 144 comprises AC current source 146 and AC voltmeter 148.AC current source 146 produces AC signal, and it is provided to first group of electrode in the sample pool 112 of diagnosis unit 104 by diagnosis unit interface 106A.As an example, AC current source 146 produces and supplies continuous AC electric current.In certain embodiments, AC signal is the sine wave of frequency within the scope of about 100Hz to about 5kHz.In certain embodiments, AC signal is the sine wave of frequency within the scope of about 100Hz to about 10kHz.Some embodiments have the frequency of about 40kHz.Some embodiments have the frequency of about 3kHz.

AC voltmeter 148 is received in the simulating signal that second group of electrode in the sample pool 112 of diagnosis unit 104 produces by diagnosis unit interface 106A, and the AC voltage of measured signal.In certain embodiments, such as, AC voltmeter 148 measures the voltage of the second group of electrode crossed in sample pool 112.In certain embodiments, AC voltmeter 148 also can through operation with the voltage measuring leap first group of electrode and AC current source 146.

Some embodiments comprise the multiple AC current source 146 and/or multiple AC voltmeter 148 that are directly electrically connected to electrode 118, and in other embodiments, one or more multiplexer 143 is arranged between analog electronics 144 and electrode 118.Multiplexer 143 and analog electronics 144 are controlled by central processing unit 162.

In certain embodiments, analog electronics 144 control cycle, frequency, voltage and current, these through optimizing to measure and the admittance of sample in working sample pond 112, conductance and constant unit mutually, and over time.In certain embodiments, analog electronics 144 is controlled by central processing unit 162.Sensing value is converted to the further analysis of digital value for digital signal processor 160 by A/D converter 150.

Digital signal processor 160 execution algorithm to explain the signal on electrode 118, and is controlled by central processing unit 162.In certain embodiments, digital signal processor 160 is stored in the property data base in computer-readable storage medium 164, and comparison signal and described feature.In other embodiments, digital signal processor 160 directly explains signal based on recognizer or the combination of the two.Such as, the special algorithm that digital signal processor 160 uses is by the type decided of sample pool 112, and the type of sample pool 112 is determined by diagnosis unit 104 model.

Some embodiments comprise central processing unit 162.Central processing unit 162 is examples for the treatment of unit.In certain embodiments, central processing unit 162 controls the overall operation of diagnostic device 100.Such as, central processing unit 162 controls the operation of micro pump 136, in certain embodiments, select the operator scheme of electronic package 134, and control electronic package 134 according to selected operator scheme (as discussed in detail further with reference to Figure 12), and by communicator 170 and communication with external apparatus.

Computer-readable media 164 can be connected to the one or many person (such as, digital signal processor 160 and video-stream processor 166) in other treatment unit of central processing unit 162 or its part and/or reader 102 communicatedly.The example of computer-readable media is computer readable storage means, as discussed herein.

Video-stream processor 166 operates to control one or more display unit 168 so that information is transported to user with visual form.In certain embodiments, when display unit is touch-sensitive display, video-stream processor 166 is also used as input unit.In an example, display unit 168 is multiple light source, such as photodiode (LED).As another example, display unit 168 is two dimensional display, such as liquid-crystal display (LCD), light-emitting diode display etc.

Communicator 170 is provided to communicate between reader 102 with another device (such as calculating device, RFID storage media or data communication network) to allow in certain embodiments.In certain embodiments, communicator 170 comprises multiple communicator.In certain embodiments, communicator 170 comprises the communication port for being connected with telecommunication cable (such as USB cable or Ethernet cable).In other embodiments, communicator is radio communication device, such as RFID reader, Wi-Fi communicator, cellular communication devices or Bluetooth communication device.

Some embodiments comprise heating controller 172 further and are configured to heat to be applied to diagnosis unit 104 and realize and the heating unit maintaining the temperature contributing to microorganism growth.In certain embodiments, (namely heating unit is arranged in heating cushion, to heat cultivating container (incubatorwarmer)) in, it can in the housing exterior of reader 102 or part outside and through arrangement to make the adjacent at least partially heating cushion of diagnosis unit.In certain embodiments, heating cushion is silicone heating cushion.In certain embodiments, heating unit is formed by tungsten or nickel-cadmium line.In certain embodiments, in heating cushion, reader 102 or diagnosis unit 104, provide thermoelectricity occasionally other temperature-detecting device, to provide feedback to reader 102 thus to allow that reader 102 remains temperature required or temperature range in sample pool 112.In certain embodiments, thermopair directly inserts in electrolytic solution.

Some embodiments comprise one or more input unit 174.Input unit 174 can comprise button, switch, touch-sensitive display etc.Also can use other interface arrangement, such as audio frequency (such as voice) interface.Input unit can be used for opening or closing diagnostic device 100, and the operator scheme of setting device, such as, be adjusted to by device between first and second operational stage, as herein as described in reference Figure 11.Other is provided to input in other embodiments.

The example components of reader 102 only provides as an example.Other embodiment can comprise more or less assembly.In addition, in some implementations, some assemblies may be combined with into single component.

In certain embodiments, reader 102 is formed by two or more parts.Such as, in certain embodiments, reader 102 comprises integrated cellular formula phone.In another possibility embodiment, reader 102 is configured to receive and cooperate with cellular phone.In another embodiment, reader 102 comprises calculating device, such as mobile computing device (such as, smart mobile phone, laptop computer, tablet PC etc.), desk-top computer or other calculating device.Such as, calculating device can be incorporated in reader 102 or reader 102 outside and with its data corresponding.

It is also possible that other reader 102 configures.Such as, another possible configuration comprising the reader 102 of multiple parts comprises first component and second component.The first component of reader comprises the shell containing at least some in electronic package 134.The second component of reader has the shell of himself and forms bearing of heating, and comprises the heating unit of at least heating controller 172.First component is connected with second component by first interface, and this allows and to communicate with heating between bearing at sensor.Second component is connected with diagnosis unit 104 by diagnosis unit interface 106A.

Fig. 3 is the functional diagram of the exemplary diagnostics unit 104 of diagnostic device 100 demonstrated in Figure 1.In this example, diagnosis unit 104 comprises shell 188, flow control system 190 and sensing system 192.

Also in this example, the input to flow control system 190 comprises sample input port 114 and lid 116.Exemplary fluidic system 190 comprises filtering system 202, and it comprises liquid source 203; With sample distribution system 204, it comprises manifold 206.Illustrative sensors system 192 comprises sample pool 112 and electrode 118.

In certain embodiments, diagnosis unit 104 receives sample by sample input port 114.In certain embodiments, diagnosis unit 104 comprises the sample input receptacle with the internal volume being suitable for the part or all of sample temporarily storing former state when receiving further.

Many several samples can be used in various embodiments.In certain embodiments, sample obtains from the individuality suspecting microbial infection, food or water sample, pedotheque or surface or other environmental sources.Such as, the sample obtained from individuality can comprise or can obtain from the following: urine, blood, sweat, mucus, saliva, seminal fluid, vaginal secretions, vomitus, tears, sebum, Pleural fluid, peritoneal fluid, gastric juice, earwax, celiolymph, breast milk, endolymph, perilymph, aqueous humor, vitreous humor, biomass, mucous membrane, faecal samples, infected cell or tissue, lung lavage, cell extract, biopsy and its combination.Sample can comprise the source of yeast, fungi, virus, nematode, cell culture or tissue further.

In certain embodiments, receive after in sample input port 114 at sample, the lid 116 that can be fixed on sample input port 114 is provided immediately.In certain embodiments, lid 116 is tightening covers, and it is included in the lock feature of resisting lid removal after lid has been fixed to sample input port 114.In this way, sample is contained in the shell 188 of diagnosis unit 104.In certain embodiments, shell 188 (comprising lid 116) forms sealing cover.In certain embodiments, sealed enclosure is allowed and is abandoned diagnosis unit 104, simultaneously in the sealing cover of shell 188 still containing the biomaterial that can be considered biological hazard.Therefore, in certain embodiments, diagnosis unit 104 is alone disposable units.

In certain embodiments, cover 116 driving device cams and be attached to piston and in diagnosis unit 104, produce different pressure, then this drive the automatization of flow control system 190.In other embodiments, the automatization of sample disposition device is driven by the micro pump 136 be contained in reader 102.

In certain embodiments, the sample received is delivered to sensing system 192 by flow control system 190.But, in other embodiments, omit flow control system 190, and manual handling is resuspended to through design with the sample in the nutrient medium worked together with sensing system 192, and can by the direct input pickup system 192 of user and antimicrobial drug divider 282.Embodiment described in some gives user the handiness for its application-specific customizing device.Such as, in certain embodiments, reader 102 comprises and allows that user differentiates the customized customized application of making diagnostic device 100.

In certain embodiments, to filter and after biased sample and nutrient medium from liquid source 203, received sample is transferred to sensing system 192 from sample input port 114 (or sample input receptacle) by flow control system 190.In certain embodiments, flow control system 190 is driven by the micro pump 136 of reader 102 demonstrated in Figure 2.In other embodiments, filtering system 202 is the pressure-driven of being originated by another, such as being formed by insertion and the rotation of tightening cover 116.In certain embodiments, lid 116 is attached to camming, and wherein rotatable cover makes piston produce pressure reduction to drive flow control system 190.

In certain embodiments, flow control system 190 comprise filter receive the filtering system 202 of sample.As an example, filtering system 202 is exclusively used in be disposed urine and comprises one or more filtration stage, such as, comprise first stage and subordinate phase.When urine sample, the first stage of filtering system 202 can be provided to remove blood and protein from urine sample.In subordinate phase, remove microorganism from urine sample.Then microorganism can be removed to be assessed further by diagnosis unit 104 from subordinate phase.Comprise wild residue urine of biting bacterial body and pass into waste liquid storage.

In certain embodiments, by filtering system 202 processing sample, then sample is placed in sample pool.In certain embodiments, such as, filtered sample is to remove comparatively macroparticle, cell and cell debris.In certain embodiments, the filtering system 202 making sample by strainer is provided.Such as, strainer can have the hole of measurement about 5 microns.Strainer allows microorganism to pass through, and retains comparatively macroparticle simultaneously.Filtering system can comprise secondary filter further.Secondary filter can be used for removing unwanted medium in sample (such as urine), such as use the strainer of less size (such as, there is the hole of measurement about 0.45 micron), thus make bacterium stay on filter surfaces, can be removed thus and be suspended in the further test for diagnostic device 100 in nutrient solution.In certain embodiments, another filtration stage is provided wildly to bite bacterial body to catch between first and second filtration stage discussed above.Such as, the strainer with 0.22 micron of hole can be used.Only attack bacterium alive owing to biting bacterial body, over time, then these wild phages can be introduced in the sample pool containing antimicrobial drug to detect residue bacterium alive again.In a sample in office, all bacteriums have a wild phage host.

Some embodiments of filtering system 202 also comprise liquid source and mixing device.Liquid source 203 provides can with sample mix for the liquid source in sensing system 192.Liquid can be the combination of single liquid or liquid.The example of liquid such as comprises electrolytical electrolytic solution.An example of electrolytic solution is nutrient solution.Another example is the combination of a kind of nutrient solution and one or more other nutrient solution or other liquid.Ionogen or nutrient medium should support the growth of institute's test microbes.Sample as used herein typically refer to containing in sample input port 114 receive biological liquid (or other liquid any, material or other input) liquid at least partially, comprise filter and/or with another liquid mixing before or after.

For obtaining repeatable result accurately, need ion supply to be strict controlled in pre-determined range.In addition, due to needs Real-Time Monitoring microbial life sign, electrolytic solution must support that it even stimulates microorganism growth.

Sample distribution system 204 is configured to received sample distribution to the sample pool 112 in sensing system 192.In certain embodiments, sample distribution system 204 comprises Homogeneous phase mixing and homogeneous samples is delivered to the manifold 206 of at least some in sample pool 112.Some embodiments comprise not by the manifold 206 of Sample delivery to all samples pond 112, to allow that one or many person in sample pool 112 is with comparing pond.In certain embodiments, sample distribution system 204 comprises the measuring apparatus of the sample providing substantial equal amount to sample pool 112.In another possibility embodiment, the filling level sensor operation on sample pool 112 is to provide feedback to obtain suitable sample load level in sample pool 112 to flow control system 190.

The electrode 118 that sensing system 192 comprises one or more sample pool 112 and is arranged in sample pool.With reference to Fig. 4 more detailed illustration and example describing sensing system 192.

In certain embodiments, sensing system 192 (or the other places in diagnosis unit) comprises the data storage equipment 208 for storing data (such as patient information, diagnostic result, diagnosis unit model, diagnosis unit sequence number or its combination).Such as, in certain embodiments, data storage equipment 208 is passive read-write RFID device.In certain embodiments, data storage equipment 208 can write the RFID reader of the communicator 170 (Fig. 2) of reader 102 and be read by it.

Reader interface 106B is provided between diagnosis unit 104 and reader 102, to carry out electricity or data corresponding (Fig. 2) to allow in certain embodiments.As an example, reader interface 106B comprises card-type interface, and it has the multiple electric contact pin in the corresponding card slot of the diagnosis unit interface 106A that can insert reader 102.Use other interface in other embodiments, such as data communication port (such as USB, serial etc.) or radio communication device.Reader interface 106B allows and to communicate for inquiring the sample in sample pool 112 between reader 102 with electrode 118.

In certain embodiments, diagnosis unit 104 is coupled to reader 102 (Fig. 2) and continues at least 1 minute or shorter, 5 minutes or shorter, 10 minutes or shorter, 15 minutes or shorter, 20 minutes or shorter, 30 minutes or shorter, 45 minutes or shorter or 60 minutes or shorter time period to implement diagnostic assessment.

Fig. 4 is the perspective schematic view of the illustrative sensors system 192 of diagnosis unit demonstrated in Figure 3.In this example, sensing system 192 comprises base substrate 222, multiple sample pool 112 (comprising sample pool 112A to 112X) and electrode 118.

In this example, sensing system 192 comprises base substrate 222.The example of base substrate 222 is circuit cards, such as printed circuit board (PCB).Another example of base substrate 222 is flexible substrate, such as flexible circuit.Base substrate can be formed by one layer or more and comprise at least one insulation layer.One or more conductive layer is provided in certain embodiments, such as ground plane or one or more comprise the layer of electric trace.In certain embodiments, base substrate 222 comprises the electric conductor between electrode and reader interface 106B (invisible in the diagram).

Sample pool 112 to be arranged in base substrate 222 and to be supported by it.In certain embodiments, sample pool 112 is formed by single piece of material, and in other embodiments, sample pool 112 is indivedual sheet.In other embodiments, the subgroup of sample pool 112 is formed (such as, every a line sample pool 112 can be formed by single piece of material) by monolithic.In one exemplary embodiment, sample pool 112 is obtained by plastics (such as molded plastics or injection molded).Sample pool 112 material can be formed by the insulation construction medically ratified.Described material does not preferably have a undesirable action to the microorganism in sample.Sample pool 112 is coupled to base substrate 222 by fastening piece (such as tackiness agent or other bonding coat or material).In addition, some embodiments comprise one or more material between sample pool 112 and base substrate 222, such as spacer layer.In certain embodiments, sample pool 112 is adhered to base substrate 222.One or more fastening piece connecting sample pool and base substrate 222 is preferably configured to suppress sample or other liquid to ooze and reveals outside sample pool 112 and between it.In certain embodiments, sample pool 112 is molded around the electrode in lead frame.

In certain embodiments, sensing system 192 comprises multiple sample pool 112.In the illustrated embodiment, sensing system 192 comprises the arrangement of 24 sample pool 112A-X.In certain embodiments, the grid that is arranged in rows and columns of sample pool.In this example, sample pool is arranged in four lines and six row.In other embodiments, sensing system 192 comprises the multiple sample pools 112 in 2 to 50 or 2 to 48 or 2 to 36 or 2 to 24 scopes.Sample pool can be arranged in one or multirow (such as, 1 row, 2 row, 3 row, 4 row, 5 row, 6 row, 7 row, 8 row or more row).Sample pool can have such as cubes, cylindrical or rectangle, and also can have other configuration, such as sexangle etc.In addition, in certain embodiments, sample pool 112 is formed by single piece of material.Such as, in certain embodiments, sample pool 112 is formed by the single plastics material molded around the lead frame forming electrode.

Sample pool 112 comprises sample chamber.Electrode 118 is arranged in sample pool 112, carrys out one or more characteristic of working sample to interact with sample, as discussed in detail further herein.Herein with reference to Fig. 5-10 more detailed illustration and more particular instances describing sample pool 112.

In certain embodiments, the shape of adjustment sample chamber, to provide the more Measurement accuracy of characteristic, comprises keeper electrode, makes the shape of the electric field produced by the electrical signal being applied to electrode for signal-to-noise performance optimizing.

In certain embodiments, sample pool 112 is through manufacturing to make the size and shape of sample chamber identical in fact.In this way, sample pool has and similar has dimensional constant, and this allows and is comparing between characteristic measured by one or more sample pool, as hereafter discussed in detail further compared with characteristic measured by other pond of diagnostic device and one or more.

In certain embodiments, electrode 118 is formed in base substrate 222.For the sealing between improvement sample pool 112 and base substrate 222, formed in the depressed area that electrode can be formed in the surface of base substrate 222, the surface of electrode is flushed with the surface of base substrate 222.In certain embodiments, depressed area is nanoporous.In another possibility embodiment, electrode is formed on the surface of substrate 222.In other possibility embodiment, electrode can be arranged in other position, such as, be arranged on the wall of the sample chamber of sample pool 112.In another embodiment, sample pool 112 comprises lower surface, and on electrode 118 inner side that is arranged in lower surface or sidewall bottom the sample pool 112.

Electrode 118 can be obtained by one or many person in multiple material, such as any precious metal, through Graphene or the metal of graphite alcohol sample material coating or the combination (such as, metal alloy) of one or many person in these.As an example, electrode 118 is formed by metallic pin.In another possibility embodiment, electrode 118 is gold-plated.In certain embodiments, electrode is that patterning is to the gold-plated electrode in base substrate 222.In certain embodiments, electrode 118 is through the coating of graphite alcohol sample material, and described graphite alcohol sample material (when such as, at printed circuit board (PCB)) before or after applying solder mask is applied directly to the copper tracing wire in base substrate 222.Other embodiment utilizes the gold that is directly printed onto in flexible plastic substrate or Graphene to carry out manufacturing flexible circuit.Other embodiment utilizes the electrode formed from the exposed tip of the lead frame be molded to plastics diagnosis unit 104.

In certain embodiments, the size of each electrode and the distance apart from each electrode is accurately controlled.In an embodiment, the size of electrode is identical in fact, that is, electrode has the difference in size being less than 5%, 1%, 0.1%, 0.01% or .001%.In certain embodiments, the distance in different sample pool between electrode is identical in fact, that is, have the distance difference being less than 5%, 1%, 0.1%, 0.01% or 0.001% between electrode.In certain embodiments, the difference of the distance between electrode size and electrode is controlled 1% or less.

In certain embodiments, sample pool comprises antimicrobial drug divider 282 further, as reference Fig. 7 and 12-13 more detailed illustration and description.

The example of Fig. 5-7 graphic extension sample pool 112.

Fig. 5 is the perspective schematic view in exemplary sample pond 112.The each several part of sample pool 112 illustrates as transparent with the internal structure of graphic extension sample pool 112.In this example, sample pool 112 comprises body 240, feed opening 242, sample chamber 244 and electrode 118.In certain embodiments, sample chamber 244 comprises riser 246 and interrogation zone 248.

Sample is received by opening 242.In certain embodiments, feed opening 242 is coupled to the manifold 206 of sample distribution system 204 demonstrated in Figure 3.In certain embodiments, opening 242 comprises the coupling port being such as configured to be connected to liquid delivery conduit (such as pipeline), with connection opening 242 and manifold 206.Sample delivery to be delivered in feed opening 242 by manifold by sample distribution system 204.In another possibility embodiment, such as use suction pipe or other sampling receptacle or liquid delivery conduit, be directly provided to sample in feed opening 242 by user or another device.

At sample by after feed opening 242, then make sample by the riser 246 of sample chamber 244, and then enter in interrogation zone 248.

The electrode 118 be arranged in the interrogation zone 248 of sample chamber 244 is electrically coupled to electronic circuit, the analog electronics 144 (being showed in Fig. 2) of such as reader 102, its operation is located to produce electrical signal with one or many person in electrode 118, and detects the electrical signal at one or many person place in other electrode 118.Then use detect electrical signal to assess one or more characteristic of sample.

Fig. 6 is the schematic side view elevation view in exemplary sample pond 112 demonstrated in Figure 5.In this example, sample pool 112 comprises body 240, feed opening 242, sample chamber 244 and electrode 118.

In this example, sample chamber 244 comprises both interrogation zone 248 and riser 246.To interrogation zone 248 sizing to hold the sample of precise volumes.Preferably interrogation zone was filled completely, with the homogeneous result between sampling pond 112 before inquiry sample.When electrical signal being applied to one or many persons in electrode 118, generation current and electric field in sample.If interrogation zone is not completely filled, then the electric current produced in sample and electric field change, this may cause sample one or more measured by characteristic change.Therefore, for the sample (such as blood, urine etc.) of given type, the volume of interrogation zone 248 can by the sample load based on the usual obtainable sample volume of sample of given type for this reason to be small enough to it through selection.In certain embodiments, the volume of interrogation zone 248 is within the scope of about 0.1mL to about 10mL or about 0.5mL to about 2mL or about 1mL to about 1.5mL.

Riser 246 is from interrogation zone extension and in certain embodiments through providing with the sample containing additional volumes except the volume of interrogation zone 248.In this way, need not the volume of accurately measure sample just to mate the volume of interrogation zone 248, but can slightly larger than the combined volume of the volume of interrogation zone 248-be to the maximum the volume of interrogation zone 248 and riser 246.In certain embodiments, the volume of riser is within the scope of about 0.01mL to about 2mL or about 0.1mL to about 0.2mL or about 0.14mL.In certain embodiments, the volume of riser is in about 5% to about 20% or about 1% to about 10% or about 10% scope of interrogation zone volume.

The configuration of riser 246 allows that sample volume changes a lot and the measured characteristic of not remarkably influenced sample.Such as, riser 246 has the cross-sectional dimension (W2) of the cross-sectional dimension (W1) much smaller than interrogation zone 248.In addition, riser 246 extends away from interrogation zone 248, and not for electric current provides the return path flowing through riser 246.Therefore, when electrical signal being applied to one or many persons in electrode 118, few conduction of current is by any part of sample in riser.Therefore, no matter the liquid level of sample be in or near the top (namely at opening 242 place) of riser 246, to be in or near the bottom of riser 246 or the somewhere between it, measured by one or more of sample, characteristic there is no noticeable change.Therefore, riser 246 provides the volume change of allowing sample mostly to be the sample volume damping fluid of the cumulative volume of riser 246 most.

In this example, riser has width (W2) and even depth (D2 does not show) and height (H2).The volume of riser is W2 × D2 × H2.Therefore, adjusted volume is carried out by increase or any one reduction in these sizes.Such as, by regulating the height (H2) of riser increase or reduce volume.In an example, width W 2 is within the scope of about 1mm to about 20mm or about 2mm to about 6mm or about 4mm to about 5mm or about 4.5mm.In this example, height H 2 is within the scope of about 1mm to about 50mm or about 5mm to about 10mm or about 6mm to about 8mm or about 7mm.

In certain embodiments, interrogation zone 248 comprises central area 262 and radial extension arm 264 (comprising arm 264A to 264D).As shown best in Fig. 7, in certain embodiments, interrogation zone 248 has the shape of cross section of plus sige, cross or " X ".

In this example, central area 262 has square horizontal cross-section and rectangular vertical cross section.Such as, central area 262 has width (W2), even depth (D2) (not being showed in Fig. 6) and height (H3+H4).In certain embodiments, described width (W2) is identical with the width (W2) of riser.In other embodiments, the width of central area 262 is different with the width of riser.In an example, the height (H3+H4) of central area 262 is within the scope of about 2mm to about 35mm or about 5mm to about 20mm or about 10mm to about 14mm or about 12mm.

Four arms 264 extend from central area 262 radial direction.Each arm all has linearity sector 266 and ends in semi-cylindrical region 268.Linearity sector 266 has the cone height changed to (H3+H4) from H4.Semi-cylindrical region 268 has diameter and the height (H4) of the degree of depth (D3 does not show) equaling linearity sector 266.In an example, the length of linearity sector 266 is within the scope of about 1mm to about 20mm or about 2mm to about 6mm or about 4mm to about 5mm or about 4.5mm.Described length can be greater than or less than the length W2 of central area 262.In this example, the diameter in semi-cylindrical region 268 is within the scope of about 1mm to about 20mm or about 2mm to about 6mm or about 4mm to about 5mm or about 4.5mm.The height (H4) in semi-cylindrical region is within the scope of about 2mm to about 30mm or about 5mm to about 20mm or about 8mm to about 12mm or about 9.6mm.

In certain embodiments, upper part 250 of interrogation zone 248 has conical by its shape.If there is bubble in the sample in interrogation zone 248, then described bubble can change potentially sample one or more measured by characteristic.The conical by its shape of upper part 250 collects bubble when bubble rises to the top of interrogation zone 248, and is guided to by bubble and be directed in riser 246.Then bubble rises through riser 246 and arrives the surface of sample and leave sample.Improve the accuracy of sample measurement thus.In this example, upper part 250 has cone angle A1.In certain embodiments, cone angle A1 is within the scope of about 10 ° to about 80 ° or about 10 ° to about 45 ° or about 10 ° to about 20 °.Some embodiments have the angle A1 of about 15 °.Although this example graphic extension tapered upper portion 250 stopped before semi-cylindrical region 268, in other possibility embodiment, tapered upper portion 250 extends to the end of arm 264.

Exemplary dimensions as herein described only provides as an example.Other embodiment can have be greater than or less than herein discuss the size of size.In addition, the overall size of sample pool 112 can be any desired size of the size being greater than (or equaling) sample chamber 244.

Fig. 7 is the schematic top plan view in exemplary sample pond 112 demonstrated in Figure 5.Fig. 7 is the AC current source 146 of graphic extension base substrate 222, electric conductor 280 (comprising conductor 280A-D) and exemplary antimicrobial drug divider 282 and reader 102 and AC voltmeter 148 (being showed in Fig. 2) also.

As mentioned before, this example of sample pool 112 comprises body 240 and sample chamber 244.Sample chamber 244 comprises opening 242, riser 246 and interrogation zone 248.Interrogation zone 248 comprises central area 262 and arm 264 (comprising arm 264A-D).In certain embodiments, sample pool 112 is arranged in base substrate 222, and electrode 118 (comprising electrode 118A-D) and antimicrobial drug divider 282 arrange thereon.

The shape of cross section of example room 244 is showed in Fig. 7, and it has the general shape of plus sige, cross or " X ", and wherein arm 264 extends from central area 262 radial direction and extends to right angle and adjoins arm.Such as, arm 264A with 264C extends vertical to arm 264B and 264D, and arm 264A and arm 264C extends in parallel simultaneously, and arm 264B and arm 264D extends in parallel.

In this example, electrode 118 is arranged in the end of each in base substrate 222 upper arm 264.Each in electrode 118A-D is electrically coupled to electric conductor 280A-D respectively.Electric conductor 280 is coupled to the analog electronics 144 of reader 102.Such as, electrode 118A and 118B is electrically coupled to AC current source 146, and electrode 118C and 118D is electrically coupled to AC voltmeter 148.Electrode 118A is with low current (L _cUR) end formal operations.Electrode 118B is with high electric current (H _cUR) end operation.Electrode 118C is with noble potential (H _pOT) end operation.Electrode 118D is with low potential (L _pOT) end operation.In certain embodiments, such as, by using multiplexer, other electrical connection is possible, as discussed herein.In certain embodiments, AC voltmeter 148 can read the voltage of other combination of crossing over electrode 118A and 118B and crossing over electrode 118C and 118D or electrode.

In certain embodiments, the measurement of conductance is insensitive to driving or force the capacitive reactance at electrode (i.e. 118A-B) place.Described measurement is also insensitive to the capacitive reactance at voltage-sensing electrode (i.e. 118C-D) place, this is because under the frequency being equal to or greater than hundreds of Hz compared with the input resistance of voltage sensor instrument reactance not remarkable.Low frequency performance is improved by the more bulky capacitor using larger electrode 118 to produce from polarization of electrode.

In certain embodiments, four electrode sample ponds (to comprise in Fig. 5-12 show in example any one) provide the direct measurement of the specific conductivity of being measured by geometric constant.Conductance measured by being produced by the specific conductivity of geometric constant tolerance sample pool 112 content.

Geometric constant as herein defined (ζ) makes the relation of conductance (G) and specific conductivity (κ) as follows:

$\mathrm{\ξ}\≡\frac{G_0}{{\mathrm{\κ}}_0}$

Wherein G ₀and κ _oit is the reference value under actual temp.

Geometric constant can utilize the knowledge of temperature factor (ζ) to calculate as follows according to the conductance under temperature G (T):

$\mathrm{\ξ}=\frac{G\left(r\right)}{{\mathrm{\κ}}_0(1+\mathrm{\ζ}(T-T_0\left)\right)}.$

Therefore, the mean value of the group of indivedual geometric constant is:

If multiple electrolysis content is contained in the group in each pond, under the hypothesis of so reasonably mating in specific conductivity and temperature factor, average geometric constant can be designated as virtual value then, unique scaling constant that each conductance plots can be derived over time, looking to make measured curve when as each pond there is the geometric constant of the matched well of the mean value close to actual geometric constant value.Scaling constant set can be obtained as follows according to above-mentioned geometric constant:

Under above-mentioned hypothesis, κ ₀balance out scaling constant.Such as:

Be applied to the C of these equatioies generation for each time point of whole data acquisition _nset.

Cannot obscure and calculate G accurately by measuring tempeature exactly during the period that is rapidly heated under thermal gradient exists, such as _n(T ₀) value and the ability of therefore above-mentioned scaling constant.But the scaling constant of each pond within for some time produces single useful value after equalization heats up.At the temperature G of the function about the time _n(T) each conductance under can be multiplied by corresponding scaling constant (C _n) to obtain metric function:

G _ξ(T) _n＝C _nG _n(T).

For the situation using all test pools at the same temperature, the scaling constant equation from above-mentioned example is simplified to

$C_1=\frac{1+\frac{G_2}{G_1}+...+\frac{G_N}{G_1}}{N}.$

The accurate conductivity measurement of electrolytic solution contributes to the ion content in the multiple sample pool 112 of quantitative comparison.If electrolytic solution comprises the nutritional medium (sometimes in this article also referred to as nutrient solution) being added with live microorganism, then due to the metabolic activity of microorganism on nutrient solution component, can increase according to the effective of ion content the existence detecting microorganism.The specific conductivity increase caused by the existence of bacterium of living can be expressed as the difference of the conductivity measurement that the sample pool (pond 0) that uses the sample pool (pond 1) containing nutrient solution and bacterium and only contain nutrient solution obtains.In this example, sample pool has four electrodes (118A-D) separately, a pair (118A-B) sends the electric current (" pressure electrode ") from AC current source 146, and a pair (118C-D) senses the voltage (" sensing electrode ") that the inner response current of sample pool produces, as passed through measured by AC voltmeter 148.If the size of two sample pools is mated well, then obtain the metric difference of specific conductivity as follows according to the difference of conductance measurement:

$\mathrm{\ξ}\·{\mathrm{\κ}}_B=G_1-G_0=\frac{{\mathrm{If}}_1}{{\mathrm{Vs}}_1}-\frac{{\mathrm{If}}_0}{{\mathrm{Vs}}_0}$

Wherein κ _bthe ratio of the specific conductivity being attributable to bacterial activity in pond 1, G ₁the conductance in pond 1, G ₀the conductance in pond 0, ξ ₁and ξ ₀be pond 1 and pond 0 should have dimensional constant mutually, If ₁and If ₀the phase induced current flowing into pond 1 and pond 0, and Vs ₁and Vs ₀the corresponding sense voltage in pond 1 and pond 0.If each pond is not mated well, then by analog value ξ ₁and ξ ₀be applied to pond 1 and pond 0:

${\mathrm{\κ}}_B=\frac{G_1}{{\mathrm{\ξ}}_1}-\frac{G_0}{{\mathrm{\ξ}}_0}={\mathrm{\κ}}_1-{\mathrm{\κ}}_0$

Wherein κ _aand κ ₀it is the corresponding specific conductivity of electrolytic solution in pond 1 and pond 0.

Due to ^κthe value of B increases monotonously along with the bacterial colony be present in sample pool 1 forms unit (CFU) number, thus its for counting (or quantification) bacterial concentration and Real-Time Monitoring, it provides basis over time.

By with acquisition ^κb use identical method, another sample pool (pond 3) containing nutrient solution, bacterium and biocide has the specific conductivity (κ of the bacterial activity that the biocide provided by antimicrobial drug divider 282 that is attributable to is offset _a) a part:

${\mathrm{\κ}}_A=\frac{G_3}{{\mathrm{\ξ}}_3}-\frac{G_0}{{\mathrm{\ξ}}_0}={\mathrm{\κ}}_3-{\mathrm{\κ}}_0$

Can real-time analysis κ _o, κ _bwith κ _abetween relation with the increase of bacterial detection metabolic activity and reduction.From these data relationships, the validity of given biocide can be assessed.

In certain embodiments, when quantizing the conductance measurement of microorganism culturing solution maybe when the result of test relatively separately, temperature compensation is useful.Some nutrient solution formulas produce the specific conductivity that linear temperature coefficient is generally about 20,000ppm/ DEG C.Rapid test conclusion needs mixed culture and to be transferred in sample pool and without the need to waiting for thermal equilibrium condition before starting test.Microorganisms cultures is cultivated normal people's body temperature, such as 35 DEG C, 37 DEG C or between about 35 DEG C to (normal people's body temperature) within the scope of 37 DEG C with growth promoting effects, therefore need control temperature to a certain extent, but cultivating container temperature fast and the feedback control of pin-point accuracy will increase cost and the complicacy of measuring system.If monitor the temperature of nutrient solution at test period, but accurately direct monitoring may increase to the especially unwanted cost of alone disposable sensor and complicacy, then compensation can be applied to test data.Without the need to control or monitor temperature indirect temperature equalising means will in cost and aspect of performance favourable.Hereafter describe this method to be applicable to test the multiple sample pools in some embodiments simultaneously.

If the specific conductivity at known reference temperature and temperature factor, then can use and only carry out indicated temperature containing the contrast pond (above-mentioned pond 0) of nutrient solution:

$T=T_0+\frac{{\mathrm{\κ}}_0\left(T\right)-{\mathrm{\κ}}_0\left(T_0\right)}{\mathrm{\ζ}}$

Wherein T measures specific conductivity x _o(T) culture-liquid temp time, T ₀known nutrient solution specific conductivity x _o(T ₀) time reference temperature, and ζ is temperature factor.

If measure another pond (above-mentioned pond 1) containing nutrient solution and bacterium under the temperature T identical with pond 0, then the specific conductivity under reference temperature can be expressed as:

κ ₁(T ₀)＝κ ₁(T)-ζ(T-T ₀)

Described in combination, latter two equation provides:

κ ₁(T ₀)＝κ ₁(T)-κ ₀(T)+κ ₀(T ₀)

The hypothesis of use this method is: the microorganism concn added in nutrient solution has insignificant effect to temperature factor, and sample pool has the temperature contrast of negligible quantity.It should be noted that at test period without the need to measuring tempeature, and without the need to known temperature coefficient.

Alternative method can be used represent the conductance of the sample pool under the arbitrary temp value in temperature range of carrying out in test time, or the specific conductivity of its content.Re-use pond 0 as hereinbefore defined and pond 1 and identical hypothesis, the nutrient solution conductance in pond 0 measured under any test point may be defined as G _0A.One group of correct ratio (Rn) that then can produce under each test point is as follows:

R _n＝G _0A/G _0n

Then, if the electric conductivity value G measured by each _0nbe multiplied by suitable R _nvalue, then all G _0nconductivity value will be corrected to G _0nvalue.

Such as, this same group of correct ratio R of pond 1 conductance is applied to _nthe temperature dependency of bacterium electric conductivity value removal nutrient solution will be added according to nutrient solution.

The G of temperature compensation _1n=G _{1 compensates}=R _n* G _1n

Then, only nutrient solution conductance and nutrient solution add residue difference between bacterium conductance by the complete existence owing to bacterium.

It should be noted that G _0Awithout the need to being real data point measurement.In a preferred embodiment, G _0Amay be defined as measured G _0nthe mean value of data set.Then, G _{1 compensates}represent as synthermal in test time keep constant data under the mean value that reaches.

When bacterium bitten bacterial body attack time, even if allow that background conductance rate for substratum is also by ionic weight that this measuring technology detects.Biting bacterial body can through cultivating to make it attack one and only a kind of bacterial species or subspecies.In addition, biting bacterial body can through selecting to make bacterium discharge ion during initial attack.When use attack a kind of and only a kind of bacterium bite bacterial body time, final minimizing by observing ion surge and the bacterium that lives carrys out discriminating bacteria, its be introducing cultivate the period after biting bacterial body and target bacteria during (namely first 5 to 15 minutes) carry out, to make it possible to quick discriminating bacteria.

Finally, the microbiotic of antimicrobial drug-in particular and bite bacterial body-metabolism is slowed down or stops, thus produce the testing mechanism of one or more specificity for the ability of given biocide the elimination of micro-organisms.Period period (namely first hour) monitoring microorganism after antimicrobial drug is attacked provides the good instruction of the net result of antimicrobial drug.

The algorithm of discriminating bacteria comprises monitors electrical property and thermal properties when bacterium is under the existence of antimicrobial drug (comprise and bite bacterial body), and in certain embodiments simultaneously in independent test pool bacteria tested to antibiotic reaction.The combinatory analysis of whole sample pool is provided to the accuracy of increase.In addition, add redundancy differential test pond and increase the accuracy differentiated.

Discriminating bacteria susceptibility also can comprise antibiotic algorithm considers that the result of discrimination of bacteria test monitors the accuracy that electricity and thermal properties and use redundancy statistically improve Antimicrobial susceptibility test result.

In this embodiment, antimicrobial drug (comprise microbiotic or bite bacterial body) be impregnated in fibrous substrate, described fibrous substrate through design with the antimicrobial drug of premeasuring concentration to be stored in water-less environment and further through design with when both contact with each other time antimicrobial drug is eluted in nutrient solution.

Carry out Setup Experiments.The workflow of use standard tiling technique to bacterial count carrys out the performance that test experiments is arranged.Before testing begins to bacterial count (by for the preparation of the bacterium in experiment or the culture plate of three kinds of basket dilutions carrying out derived bacterium).The opposing of incubated overnight technical testing is used to carry out the source antimicrobial drug of derived bacterium.Tiling experiment after each hole be illustrated in experimental session nutrient solution by/not contaminated; Antimicrobial drug plays/does not play to antibacterial effect; And the definite growth of contrast bacterium (culture plates of the two kinds of basket dilutions prepared according to the content in only bacterium pond by preparation).In general, each experiment use four pond: the only antimicrobial drug of nutrient solution, only microorganism, the antimicrobial drug producing true positives, generation true negative.

Fig. 8 is the cross-sectional plan view of another exemplary sample pond 112 and the configuration of another exemplary electrode.Sample pool 112 comprises the body 240 being wherein formed with the sample chamber 244 comprising interrogation zone 248.Electrode 118A-D is arranged in sample chamber 244 and antimicrobial drug divider 282.Electric conductor 280A-D is provided to the electrical connection of electrode 118A-D, with the analog electronics 144 of coupling electrode 118A-D and reader 102.

Electrode 118 comprises electrode 118A, and it is with low current (L _cUR) end operation, and be coupled to AC current source 146 by electric conductor 280A.Electrode 118B is with high electric current (H _cUR) end operation, and be coupled to AC current source 146 by electric conductor 280B.Electrode 118C is with noble potential (H _pOT) end operation, and be coupled to AC voltmeter 148 by electric conductor 280C.Electrode 118D is with low potential (L _pOT) end operation, and be coupled to AC voltmeter 148 by electric conductor 280D.

Sample chamber 244 comprises the interrogation zone 248 of wherein carrying out sample inquiry.In this example, interrogation zone 248 has the elongated shape comprising longitudinal side wall 302 and 304 and semicircle end 306 and 308.In certain embodiments, the interrogation zone 248 of prolongation is included in the recess 310 and 312 that sidewall 302 and 304 place is formed, its in interrogation zone 248 for antimicrobial drug divider 282 provides exceptional space.

Drive or force electrode 118A and 118B to be arranged in the interrogation zone of prolongation, described electrode is being flow to the AC electric current of low current electrode 118A from high galvanic electrode 118B by the interrogation zone produced during 146 energy supply of AC current source by extending.

Sample chamber 244 also comprises sensing area 314 and 316.Sensing area 314 and 316 all extends from the common sidewall 304 of the interrogation zone 248 extended.Sensing area 314 comprises narrow arm section, and it extends perpendicular to sidewall 304 and ends in the larger border circular areas of narrow arm section end.Sensing electrode 118C and 118D is arranged in the larger border circular areas of sensing area 314 and 316 respectively.In certain embodiments, sample chamber 244 is symmetrical in the axis of centres extended between recess 310 and 312.

Fig. 9 is the cross-sectional plan view of another exemplary sample pond 112 and the configuration of another exemplary electrode.Sample pool 112 comprises body 240 and comprises the sample chamber 244 of interrogation zone 248.

Interrogation zone 248 comprises the prolongation linearity sector with longitudinal side wall 322 and 324 and planar end wall 326 and 328.In certain embodiments, recess 330 and 332 is formed at sidewall 322 and 324 place, adjoins the position of antimicrobial drug divider 282.

District 334 and 336 is forced to extend from the opposing end portions of sidewall 322 on common direction.District 334 and 336 is forced to comprise the narrow arm section extended from sidewall 322.A part for each in the crevice in district 334 and 336 is forced to share common wall with planar end wall 326 and 328 respectively.District 334 and 336 is forced to end at larger circular stub area.

Electrode 118B and 118A is forced to be arranged in the larger circular stub area of forcing district 334 and 336.Such as, high galvanic electrode 118B is arranged in and forces in district 334 and low current electrode 118A is arranged in and forces in district 336.High galvanic electrode 118B and low current electrode 118A is coupled to AC current source 146 respectively by electric conductor 280B and 280A.

Sensing area 338 extends from the opposing end portions of sidewall 324 on common direction (district 334 is parallel but not contrary with the direction of 336 with pressure) in a similar manner with 340.Sensing area 338 and 340 comprises the narrow arm section extended from sidewall 324.A part for each in the crevice of sensing area 338 and 340 shares common wall with planar end wall 326 and 328 respectively.Sensing area 338 and 340 ends in larger circular stub area.

Sensing electrode 118C and 118D is arranged in the larger circular stub area of sensing area 338 and 340.Such as, high-potential electrode 118C to be arranged in sensing area 338 and low-potential electrode 118D is arranged in sensing area 340.High-potential electrode 118C and low-potential electrode 118D is coupled to AC voltmeter 148 respectively by electric conductor 280C and 280D.

In this example, interrogation zone 248 is symmetrical in and extends through end wall 326 and 328 and the axis of centres extending through recess 330 and 332.Therefore, under the operation not changing sample pool 112, correspondingly can exchange the function of electrode.

Figure 10 is the cross-sectional plan view of another exemplary sample pond 112 and the configuration of another exemplary electrode.Sample pool 112 comprises the sample chamber 244 with interrogation zone 248.

In this example, interrogation zone 248 has the cylindrical shape of the single sidewall 342 of tool.All electrode 118A-118D are arranged in the cylindrical interrogation zone 248 bottom sample pool 112.Antimicrobial drug divider 282 is also arranged in sample pool 112.

Figure 11 and another exemplary sample pond 112 of 12 graphic extensions configure with another exemplary electrode.Figure 11 is cross-sectional plan view and Figure 12 is cross-sectional side view.This exemplary sample pond 112 comprises the sample chamber 244 (Figure 12) with interrogation zone 248.

In this example, interrogation zone 248 has the cylindrical shape of the single sidewall of tool.All electrode 118A-118D are arranged in the cylindrical interrogation zone 248 bottom sample pool 112.The riser 246 with cylindrical shape extends to interrogation zone 248 from feed opening 242.Antimicrobial drug divider 282 is arranged in the level attitude at the top of antimicrobial drug divider upholder 284, and it extends across riser 246, has the shape of cross or X-shaped.

Figure 13 is the state graph 350 of the example of the operation of graphic extension diagnostic device 100, and goes back the method for graphic extension operation diagnosis device 100.In this example, diagnostic device 100 operates with state 352,354 and 356.

When opening diagnostic device 100, diagnostic device 100 starts at state 352 place.Before unlatching, diagnostic device 100 such as by preparation in the sample input port 114 (Fig. 3) that the sample of sufficient quantity added to diagnosis unit 104 for inquiring sample.After unlatching, namely diagnostic device 100 is converted to the one in state 354 or 356.

When diagnostic device operates with state 352, diagnostic device utilizes all four electrodes 118 to carry out the measurement of sample.In certain embodiments, electrode (such as, 118B and 118A) is forced by AC current source 146 energy supply to produce the electric current by sample for first group.Then use second group of sensing electrode (such as, 118C and 118D) to detect one or more characteristic of sample by AC voltmeter 148.

Such as, in certain embodiments, diagnostic device 100 operates the conductance with measure sample.Then use conductance measurement to the amount of bacteria counting be present in sample.In certain embodiments, the amount of bacterium is determined according to the amount of colony-forming unit (CFU).

As another example, in certain embodiments, diagnostic device 100 operates the bacteria types differentiating to be present in sample.For the type of discriminating bacteria, diagnostic device 100 monitors the sample conductance of crossing over multiple sample pool in time.At least some sample pool comprises the antimicrobial drug divider comprising different antimicrobial drug.Such as, final minimizing (with the corresponding reduction of conductance) by observing ion surge (with the corresponding increase of conductance) and bacterium alive carrys out discriminating bacteria, and this is that (namely first 5 to 15 minutes) carry out during introducing the period after can effectively attacking the antimicrobial drug of the bacterium be present in sample pool 112.Therefore, diagnostic device 100 can be monitored in the change with the conductance occurred in the sample pool of effective antimicrobial drug, and can determine in a similar manner to exist in other sample pool without effect antimicrobial drug seldom to change to the conductance of nothing.In addition, pond can be contrasted with one or more other and compare conductance, described contrast pond be such as containing contrast liquid, do not exist arbitrary sample contrast pond and/or containing contrast liquid and sample but not containing the contrast pond of antimicrobial drug.

When diagnostic device in a second mode 356 operation time, one or more characteristic of two or more electrode measurement samples in sample pool 112 in one or many person.Such as, in certain embodiments, diagnostic device 100 operates the admittance with measure sample.Admittance can be calculated as such as impressed current divided by the voltage forced between electrode.

In certain embodiments, the second mode 3 56 only utilizes both in sample pool in electrode 118.Another is chosen as, and can operate electrode in pairs and carry out admittance measurement to utilize four electrodes.

In certain embodiments, electrode uses the electronic package of reader 102 (being showed in Fig. 2) to control.

The impedance type that the second state 356 can be used to carry out sample is measured to monitor chemical process and biological activity.Specifically, in certain embodiments, reader 102 comprises and comprising for detecting and Real-Time Monitoring and quantize the electronic package of the electron device based on impedance of the bacterium in nutrient solution (culture).Impedance type electron device depends on the admittance change in microorganisms cultures, and described change is derived from the change of ion content, and it is produced the metabolism of compound by the microorganism in substratum.Impedance type measurement provides and is better than the convenience of other technology (such as the tiling technique of microbe colony counting) and the advantage of fast results.

Admittance measurement can utilize AC signal to carry out.In general, the admittance of sample pool 112 is complicated.The susceptible component of admittance is apparent because the electric capacity (being also called polarization of electrode) that produces from the charge double layer formed at each electrode-example interface is caused.The cubic conductance being contained in the electrolytic solution in the concrete geometry of sample pool 112 determines the conduction component of admittance.The concentration of electrolytic solution intermediate ion and or the change of type produce the change of susceptible and conduction component.For admittance/impedance modeling, pond can be expressed as the electrical condenser and resistor that are connected in series.More high level model (such as applying constant unit mutually to comprise those of distribution effect) is of value to detailed analysis.

Constant unit mutually can indicate the distribution in pond of relaxation time or ionization energy to the validity in the pond admittance modeling of change of frequency, thus produces the random electrical noise changed on the contrary with the power of frequency.Constant unit mutually also provides owing to the obscured pond of electrode surface roughness and the variable understanding of pond repeatability.Embody pond electric capacity and according to the charge double layer also response problem impact of ionic concn and ionic type and temperature variation, the precipitation at such as electrode place, microbial film or bubble.

In addition, Van der Waals force (VanderWaalsforce) support of electrode surface reduces the film growth of the electric capacity response to the ionic concn change in electrolytic solution.This causes admittance during measurement sequence additionally to change in time and responsiveness reduces in time.Stochastic variable, noise and film growth limitation can be used for the signal to noise ratio of microbe colony formation unit (CFU) measuring per unit volume electrolytic solution.

For avoiding, because of main many restrictions of measuring electric capacity at low frequencies and causing, can carrying out at higher frequencies measuring to make the contribution of capacitive susceptance to resultant admittance less.The electrolytical conductance of body then manipulates measured pond admittance.But the distribution property of pond admittance is obscured application and will be allowed fully to be separated by means of only change frequency lump type resistor-capacitor circuit (series connection RC) model of these parameters.In fact, this change through the conductance of measurement is observed relevant to electric capacity.And, for the given mark change of ionic concn, observe the more than one greatly order of magnitude of the usual change of the mark than conductance of the obatained score change showing electric capacity.Therefore, " conductance " parameter represents noise less compared with " electric capacity " parameter, but also has and change less response to ionic concn.

Therefore, although the second state 356 can be used to measure admittance and to assess microbe-sensitive, but still the first state 354 acquisition can be used to exceed accuracy and the dynamicrange of the extension obtained by the second state 356.

In certain embodiments, the application of the four end technology used during the first state 354 relates to the two ends fallen by the test two ends of sample and the subsequent voltage for sensing wherein for induced current.It is responsive when the embodiment of four end pond operations during state 354 is not so good as pass through to get rid of the effect of polarization of electrode with the second state 356 but not only get rid of the series impedance operation of each end and cross tie part to the effect at pressure/drive electrode place.In addition, the first state also can provide the direct measurement of the electrolytic solution specific conductivity of being measured by geometrical dependence sample pool factor.

Diagnostic device 100 can utilize admittance measurement, such as, measure the antibiotics sensitivity of the microorganism be present in sample.Such as, diagnostic device 100 can determine that microorganism has low, medium or high susceptibility to the antimicrobial drug be present in sample pool.

Some embodiments comprise the additional state of not showing in one or more Figure 11.Such as, some embodiments comprise liquid treatment state, activate flow control system 190 during this period to process the sample that receives and to be distributed in sample pool 112.

The example of Figure 14-15 graphic extension antimicrobial drug divider 282.

Figure 14 is the skeleton view of exemplary antimicrobial drug divider 282.In this example, antimicrobial drug divider 282 comprises carrier materials 370 and antimicrobial drug 372.

Carrier materials 370 is one piece materials, such as paper, cloth etc.In certain embodiments, carrier materials 370 comprises the fastening piece of the carrier materials 370 (such as, be attached to the inside of sample pool 112 self or be attached to base substrate 222, be such as demonstrated in Figure 4) be configured for being attached sample pool 112 inside.

In certain embodiments, carrier materials 370 is sheetings, and it has the thickness much smaller than its length and width (such as, <10% or <1%).This provides the surface-area interactional with sample of increase.

Antimicrobial drug 372 is carried by carrier materials 370.In certain embodiments, antimicrobial drug 372 is applied to the outside of carrier materials 370.In certain embodiments, antimicrobial drug 372 is also contained in carrier materials 370.Antimicrobial drug divider (comprising antimicrobial drug 372 and carrier materials 370) is dry before the use.

This antimicrobial drug divider 282 can have multiple possible shape in different embodiments, comprises rectangle, circle, cylindrical, square, trilateral or other shape.In certain embodiments, the front surface of the carrier materials 370 of antimicrobial drug divider 282 is slightly through hardening to resist moisture, and edge allows the filamentary material being easy to absorb moisture to enter, and forces the antimicrobial drug 372 of premeasuring to be eluted in surrounding liquid thus.Embodiment of antimicrobial drug divider 282 uses specifically bites bacterial body maybe will to bite bacterial body mixture particular design is antimicrobial drug.

An example of antimicrobial drug divider is the SENSI-DISC of the Bi Di Medical Devices Co., Ltd. (Becton, DickinsonandCompany) purchased from Franklin, New Jersey lachs ^tMsusceptibility test panel, it contains antibiotic medicine.

In other possibility embodiment, antimicrobial drug divider 282 comprises to be bitten bacterial body or bites bacterial body mixture.Biting bacterial body is infect in bacterium and the virus copied.Such as, for detecting urinary tract infection, select specificity for can comprise intestinal bacteria (E.coli), streptococcus aureus (Staphylococcusaureaus), Klebsiella (Klebsiella), proteus (Proteus), Rhodopseudomonas (Pseudomonas) and enterobacter (Enterobacter) this organize bacterium bite bacterial body.The spendable example biting bacterial body comprise phage T1, T457, VD13,92, PB-1 or other specific cultivation pay close attention to and bite bacterial body separately or its combination.The concentration of biting bacterial body is differentiated by every milliliter of plaque forming unit (PFU).

In certain embodiments, bite bacterial body and have one or many person in following characteristics or all: through cultivating and being separated, it attacks one and only a kind of bacterium thus; Insert DNA by the hole in bacteria cell wall, discharge potassium ion fast thus; The long half-lift of having when freeze-drying (such as, the dry transformation period of 2 years or longer); Fast quick-recovery when rehydrated; If target subspecies, then coexist in the mixture of kind described in target; Whether attack bacteria is in initial bacterial concentration and bacterium and has nothing to do exponential phase of growth; There is quick life cycle (such as, cracking is less than 30 minutes or shorter); And cover any tolerant bacteria of effectively attacking-there is the enough different phage of multiple subspecies of target single kind to eliminate bacteriums in fact all in sample to minimize for the extensive adulterant of phage, such as, these features can see Caudoviradles phage (Caudoviralesphages).

Figure 15 be in the Figure 14 of the inside, sample chamber 244 being arranged in sample pool 112 show the skeleton view of exemplary antimicrobial drug divider 282.Sample chamber 244 comprises sample 380.Antimicrobial drug 372 is assigned in sample 380 by Figure 15 also graphic extension.

In this example, antimicrobial drug divider 282 is arranged in the sample chamber 244 of sample pool 112.In certain embodiments, it is inner that antimicrobial drug divider 282 is fixed on sample chamber 244 with vertical orientation, as demonstrated.Vertical orientation increase is exposed to the surface-area of the carrier materials 370 in sample chamber 244.In other possibility embodiment, antimicrobial drug divider 282 is fixed through level.In certain embodiments, antimicrobial drug divider 282 is positioned in the riser 246 (Fig. 5 and Figure 11-12) of sample pool.

When being provided in sample chamber 244 or riser 246 by sample 380, sample makes antimicrobial drug divider 282 soak.When moistened, antimicrobial drug 372 discharges from carrier materials and is assigned to sample 380.Due to high surface area and relatively little internal volume, the antimicrobial drug 372 of vast scale by fast allocation in sample 380.

In certain embodiments, multiple sample pool 112 comprises the different antimicrobial drug dividers 282 containing different antimicrobial drug.Such as, in certain embodiments, at least 10 sample pools 112 are separately containing the antimicrobial drug divider 282 for distributing different antimicrobial drug.As an example, antimicrobial drug be at least 10 kinds of a certain bacterium of cracking different bite bacterial body.Such as, then can determine to be present in microorganism in sample pool whether by the impact of antimicrobial drug to monitor 10 sample pools by operation diagnosis device 100, and if influenced, then can determine the identity of microorganism.In certain embodiments, at least one or many person in sample pool 112 comprises and distributes antibiotic antimicrobial drug divider 282.Usually, at least two sample pools 112 are with comparing, and sample pool 112 can not comprise antimicrobial drug divider 282 in this case, or another is chosen as antimicrobial drug divider 282 carrier materials 370 that can comprise and not contain antimicrobial drug 372.In certain embodiments, the first control sample pond is contained electrolyte solution and is not contained sample 380 (and wherein containing microorganism) or antimicrobial drug 372.Electrolyte solution and sample (and wherein containing microorganism) are contained in second control sample pond, but do not comprise antimicrobial drug 372.There is other control sample pond in certain embodiments, such as, contain ionogen and comprise the antimicrobial drug divider or ionogen of biting bacterial body and the antimicrobial drug divider comprising the antimicrobial drug except biting bacterial body.Carry out different Antimicrobial susceptibility test, the many different embodiment with the sample pool of different quantities of microorganism differential test or microorganism count is possible.

Figure 16 is the schematic block diagrams that graphic extension can be used for the exemplary architecture of the calculating device 410 performing each side of the present invention.Such as, calculating device 410 is coupled to diagnostic device 100 by the communicator 170 (Fig. 2) of reader 102, in another possibility embodiment, calculating device 410 is parts (such as to provide CPU162, computer-readable media 164, video-stream processor 166, display unit 168, communicator 170 and power supply 142) of reader 102.For example, calculating device will be described below as independent calculating device 410.

In certain embodiments, calculating device 410 comprises at least one treatment unit 420, such as central processing unit (CPU).Multiple treatment unit can from multiple manufacturers, such as Intel (Intel) or advanced micro devices company (AdvancedMicroDevices).In this example, calculating device 410 also comprises the system bus 424 of system memory 422 and coupling multiple systems assembly (comprising system memory 422) and treatment unit 420.System bus 424 is the one in the bus structure of arbitrary quantity type, comprises memory bus or Memory Controller; Peripheral bus; With the local bus of any one used in multiple bus architecture.

The example being applicable to the calculating device of calculating device 410 comprise desk-top computer, laptop computer, tablet PC, mobile computing device (such as smart mobile phone, or mobile digital devices or other running gear) or be configured to other device processing digital command.

System memory 422 comprises read-only storage 426 and random access memory 428.Usually be stored in read-only storage 426 containing the basic input/output 430 for the basic routine of the information such as between the starting period in transfer computing device 410.

In certain embodiments, calculating device 410 also comprises the auxilary unit 432 for storing numerical data, such as hard disk drive.Auxilary unit 432 is connected to system bus 424 by auxiliary storage interface 434.Auxilary unit 432 and its associated computer readable media provide the non-volatile memories of computer-readable instruction (comprising application program and programmodule), data structure and other data for calculating device 410.

Although exemplary environments as herein described adopts hard disk drive as auxilary unit, use the computer-readable storage medium of other type in other embodiments.The example of the computer-readable storage medium of these other types comprises magnetic holder, flash memory cards, digital video disk, Bernoulli cartridges (Bernoullicartridge), cd-rom, digital universal disc read-only storage, random access memory or read-only storage.Some embodiments comprise non-transitory media.In addition, described computer-readable storage medium can comprise local storage or the storage based on cloud.

Multiple programmodule can be stored in auxilary unit 432 or storer 422, comprises operating system 436, one or more application program 438, other programmodule 440 (such as software engine as herein described) and routine data 442.Calculating device 410 can utilize any suitable operating system, such as MicrosoftWindows ^tM, GoogleChrome ^tM, apple OS (AppleOS), GoogleDroid ^tM, GoogleIceCream ^tMwith other operating system any being applicable to calculating device.

In certain embodiments, user provides input by one or more input unit 444 to calculating device 410.The example of input unit 444 comprises keyboard 446, mouse 448, microphone 450 and touch sensor 452 (such as touch-screen or touch-sensitive display).Other embodiment comprises other input unit 444.Input unit is connected to treatment unit 420 by the input/output interface 454 being coupled to system bus 424 usually.These input units 444 connect by the input/output interface of arbitrary quantity, such as parallel port, serial port, game port or USB.May in embodiments at some, the radio communication between input unit and interface 454 is also possible, and comprise infrared, wireless technology, 802.11a/b/g/n, honeycomb fashion or other RF communication system.

In the exemplary embodiment, display unit 456 (such as watch-dog, liquid crystal indicator, projector or touch quick display unit) is also connected to system bus 424 by interface (such as video adapter 458).Except display unit 456, calculating device 410 can comprise multiple other peripheral unit (displaying), such as loud speaker or printer.

Time in for LAN environment, wan environment (such as Internet) or individual territory net, calculating device 410 is usually by network interface 460 (such as Ethernet interface) or wirelessly (such as use the arbitrary or many person in above-mentioned radio communication device) and be connected to network 462.In certain embodiments, network interface 460 can be situated between with many different types of networks and connects.Other embodiment may use other communicator.Such as, some embodiments of calculating device 410 comprise the modem communicated for spanning network 462 (such as Internet or such as cellular network).

Such as, in certain embodiments, application program 438 operates to shift the patient information be stored in data storage medium 208 (Fig. 3), and in a similar manner receive come self-diagnosis system 100 diagnostic result and described result is transferred to another calculating device by spanning network.

In certain embodiments, the diagnostic result of calculating device 410 self-diagnosis system 100 in future transfers to the network be stored in cloud data-storage system.Similarly, in certain embodiments, calculating device 410 operate that numerical data is transferred to cloud data storage equipment and such as when required analyzing and processing for calculating device 410 or diagnostic device 100 too intensive time, for further analyzing and processing.

Calculating device 410 generally includes at least certain form of computer-readable media.Computer-readable media comprises any useable medium accessed by calculating device 410.For example, computer-readable media comprises computer-readable storage medium and computer-readable communication medium.

Computer-readable storage medium be included in the volatibility that performs in any device of the storage information that is configured to (such as computer-readable instruction, data structure, programmodule or other data) and non-volatile, can load and unload and can not media be loaded and unloaded.Computer-readable storage medium includes, but is not limited to random access memory, read-only storage, electric erasable programmable read-only memory, flash memory or other memory technology, cd-rom, digital universal disc or other optical storage, magnetic holder, tape, disk storage or other magnetic storage device or can be used for storing information needed and other media any accessed by calculating device 410.Computer-readable storage medium does not comprise computer-readable communication medium.

Computer-readable communication medium usually embodies computer-readable instruction, data structure, programmodule or other data in modulated data signal (such as carrier wave or other conveyer mechanism) and comprises any information delivery media.Term " through modulated data signal " refers to following signal: one or many person in its characteristic makes the mode of coded message in described signal set or change.For example, computer-readable communication medium comprises wired media (such as, cable network or directly wired connection) and wireless medium (such as acoustics, radio frequency, infrared and other wireless medium).Any one combination above-mentioned is also included within the scope of computer-readable media.

Calculating device illustrated in Figure 16 is also the example of sequencing electron device, it can comprise calculating device described in one or more, and when comprising multiple calculating device, described calculating device can be coupled jointly to perform various functions disclosed herein, method or operation with suitable data communication network.

Figure 17 graphic extension relates to another exemplary architecture of diagnostic device 100.In this example, diagnostic device 100 comprises flow control system 190, sensing system 192, reader computing unit 102A, reader analogue unit 102B, the calculating device 410 comprising Application of Interface 438, data communication network and Cloud Server calculating device 510.

In this example, flow control system 190 receives the sample from health care worker.Reader computing unit 102A receives from the input of health care worker, such as to select the operating mode or other input.

Flow control system 190 and sensing system 192 operate under the control of reader computing unit 102A, and assess sample by sensing system 192 and reader analogue unit 102B.

Data corresponding is carried out between reader computing unit 102A and calculating device 410.Data corresponding is also crossed over data communication network and is carried out between calculating device 410 and Cloud Server 510.The example of described data corresponding is discussed in herein.

The experimental data that Figure 17-20 graphic extension uses diagnostic device 100 to obtain.

The present invention uses word " cell (cell, pond) " under at least two backgrounds.Background is biological " cell (cell) " and another background is " sample pool (cell) ".For avoiding confusion, another is chosen as, and sample pool can be described as sample unit, test pool, test cell, sample block etc.

Some embodiments comprise following in one or many person:

For monitoring an impedance type measuring apparatus for the microorganism be present in liquid nutrient medium, it comprises: electrolytic solution, hold the electrode (sensing electrode) of vessel, two electrodes utilizing electric stimulus to drive (pressure electrode) and two sensing electric signals: a. is for monitoring the counting of live microorganism over time; B. for measuring the antibiotics sensitivity of microorganism; And/or c. differentiates microorganism for using selected antimicrobial drug.

A kind of device, it uses electric stimulus as ac voltage or electric current.

A kind of device, it uses sensing electric signals as ac voltage.

A kind of device, it has the sensing electrode of the path orientation along the quiescent current flowed between pressure electrode.

A kind of device, it has with the electrode of corner geometric arrangements, to adjoin and sensing electrode is adjoined along geometrical shape border to make to force electrode along geometrical shape border.

A kind of device, it has through generalization to contain electrode, simultaneously for the shape on the ionogen accommodation vessel border of optimum performance guide field.

A kind of device, it has and is comprising the electrode that the flat substrate bottom electrolyzer manufactures.

A kind of device, it has the printed circuit board (PCB) comprising flat substrate.

According to the device of technical scheme 6, its have be arranged on electrolyzer sidewall in and bottom electrolyzer or the electrode that adjoins bottom it.

A kind of device, wherein when filling pond with electrolytic solution, defines volume, to locate antimicrobial drug impreg for the object introduced in pond by one or more biocide of measuring vol.

A kind of device, it is through calibrating with the instruction providing microorganism concn.

A kind of algorithm, it is for detecting microorganism concn increase in time and minimizing.

A kind of algorithm, it uses temperature compensation from the take off data in multiple pond and with reference to the pond only containing electrolytic solution.

A kind of algorithm, they can the data in more indivedual pond, are used to indicate the object of the Relative biological activity in described pond.

A kind of algorithm, it can distinguish the validity of the biocide be present in concrete pond.

According to any one in algorithm described herein, wherein said algorithm be by or use calculating device perform.

A kind of device, it has through defining to hold the volume biting the material of bacterial body dipping through one or more of measured concentration, and described material will be bitten bacterial body and be discharged in electrolytic solution when wetting.

A kind of device, it has the volume through defining to hold the material flooded through one or more antimicrobial drug, and antimicrobial drug is discharged in electrolytic solution by described material when wetting.

One method, wherein uses sensing voltage to calculate conductance or admittance.

A kind of device, its shape alleviates pond factor to the dependency holding vessel fill factor.

Have the device holding vessel, it comprises: at least one substrate of a.; B. at least four electrodes; With the sample cavity that c. is formed at least one substrate, described sample cavity comprises: i. is comprising the transducing part of electrode, and described transducing part has and is configured in sample cavity, guide the electric field produced by electrode and the shape making it focus on; Extending from transducing part with ii. and have the shape of the cross section size being less than transducing part cross section size, described shape extends and has certain volume, and wherein the volume of extension is allowed sample volume change and do not affect in fact the electrical measurement of electrode.

One method, it uses the conductance of only nutrient solution sample cavity to carry out all features of adjusting pin to the temperature variation during test time.

A kind of component, it keeps at the same temperature for making the liquid in test period all samples cavity.

A kind of component, if realize needed for the most sane admittance and conductance feature, then its temperature for sample holder being heated to 35 DEG C.

Use A/D converter that simulation AC electric current and voltage are reduced to digital format, it can be used for more easily calculating and compare admittance and conductance feature.

A kind of diagnostic device, it comprises the one in the following: multiple possibility sample cavity and geometric electrode structure, with electrode size and spacing needed for mechanical tolerance, and the degree of the change of the calibration factor of above-mentioned every multiple sample cavity affected in sample holder.

One method, it utilizes the four-terminal measurement of conductance to realize the temperature compensation of only nutrient solution sample cavity and avoids the negative effect of biofilm development on electrode.

One method, it carrys out operation diagnosis device to avoid plating action and the electrolysis at electrode surface place by the limit value defining applied alternative current and/or voltage.

One method, it defines the biocompatible materials for constructing antimicrobial drug divider.

One method, it provides specificity for the virulent bacteriophage of each type bacterium and uses virulent bacteriophage to carry out discriminating bacteria.

One method, it utilizes the conductance feature of the uniqueness of effective bacteriophage attack.

A kind of diagnostic device, it utilizes and promotes bacterial growth and can the nutrient medium of controlled specific conductivity and temperature factor.

Discriminating is present in the method for microorganism in sample, and it relates to the ratio of admittance between discriminating nutrient solution+bacterium and nutrient solution+bacterium+virulent bacteriophage sample cavity and/or conductance feature.

Differentiate for the method for the effective antimicrobial drug through discriminating bacteria, it relates to the ratio of admittance between mensuration nutrient solution+bacterium and nutrient solution+bacterium+antimicrobial sample cavity and/or conductance feature.

A method for the CFU concentration of bacterium in working sample, it relates to the conductance feature of discriminating nutrient solution+bacteria samples cavity.

A kind of component, its temperature for sample holder being heated to 35 DEG C.

Various embodiments mentioned above only provide by way of illustration and should not be construed as restriction appended claims.Those skilled in the art by be easy to identification can when do not follow herein illustrated and describe exemplary embodiment and application and the various amendment made when not deviating from true spirit and the scope of appended claims and change.

Claims (8)

1. a diagnostic device, it comprises:

At least one defines the sample block of sample cavity wherein;

At least four electrodes be arranged in described sample cavity; And

Be operably connected to the electronic circuit of described electrode, wherein said electronic circuit can operate in a first mode and a second mode, wherein when with described first mode operation, described electronic circuit operation is with the conductance measuring the sample in described sample cavity, and wherein when with described second pattern operation, described electronic circuit operation is with the admittance measuring the described sample in described sample cavity.

2. diagnostic device according to claim 1, wherein said diagnostic device operation is to differentiate the microorganism in described sample.

3. diagnostic device according to claim 1, the operation of wherein said diagnostic device is with to the microorganism count in described sample.

4. diagnostic device according to claim 1, wherein said diagnostic device measures the Antimicrobial susceptibility of the microorganism in described sample.

5. an antimicrobial drug divider, it comprises:

Aseptic carrier materials; And

What carried by described aseptic carrier materials bites bacterial body.

6. a sample block, it comprises:

At least one substrate;

At least four electrodes; And

The sample cavity formed at least one substrate described, described sample cavity comprises:

Comprising the transducing part of described electrode, described transducing part has and is configured in described sample cavity, guide the electric field produced by described electrode and the shape making it focus on; And

Riser part, it extends from described transducing part and has the cross section size of the cross section size being less than described transducing part.

7. sample block according to claim 6, the described shape of wherein said riser part and position allow that the volume of described sample changes, the excessive portion of described sample is stored in the outside of described sample cavity, the described change of the described volume of described sample does not affect in fact the electrical measurement at described electrode place thus simultaneously.

8. a diagnostic device, it comprises:

Multiple sample block;

Be arranged in the electrode in described sample block;

Be arranged in the calibration solution in the calibration module of described sample block; And

Be coupled to the electronic package of described electrode, wherein said electronic package can operate to measure the specific conductivity of liquid described in described calibration pool and use the temperature of calibration solution described in the described conductance measurement through measuring.