CN101132738A

CN101132738A - Systems and methods for detecting abnormal cells

Info

Publication number: CN101132738A
Application number: CNA2006800069547A
Authority: CN
Inventors: W·马尔茨曼; P·冈布里奇; G·迪蒙特; E·伊顿; E·拉森
Original assignee: Diamics Inc
Current assignee: Diamics Inc
Priority date: 2005-01-06
Filing date: 2006-01-04
Publication date: 2008-02-27
Also published as: CN101132737A

Abstract

A cell collector and cell collection method are provided for collecting clusters of cells for subsequent analysis of the cells to screen for abnormalities. The cell collector is designed to enhance the capability of the collector to pick-up clusters or clumps of cells, and to facilitate transfer of the collected clusters of cells onto a receiving . structure, for example a slide. In one embodiment, a combination of the material of the collector, the texture of the collection surface of the collector, and the use of expansion and rotation of the collector during collection facilitate the collection of the clusters of cells.

Description

Be used to detect paracytic system and method

The application requires the U.S. Provisional Application No.60/642 of submission on January 6th, 2005,008, the U.S. Provisional Application No.60/681 that submitted on May 17th, 2005,901, the U.S. Provisional Application No.60/686 that submitted on June 1st, 2005,150, the U.S. Provisional Application No.60/708 that submitted on August 15th, 2005,150, the U.S. Provisional Application No.60/729 that submitted on October 25th, 2005,854, the U.S. Provisional Application No.60/729 that submitted on October 25th, 2005, the priority of the U.S. Patent Application Serial Number (the unknown) of 857 and 2005 on Decembers submission in 23.Each application cited above in full with referring to mode include this paper in.

Technical field

Relate generally to of the present invention is used for the cell sample and the screening of (for example in the cervix uteri) abnormal structure in the detection bodies.More particularly, the present invention relates to the steric mode clusters of cells of the cell cluster that is collected with preservation and at the system and method for checking the biological characteristics of this cluster aspect the expression of two or more features.

Background technology

Usually be necessary that collecting various cell samples from patient screens, with detection and the final treatment that is used for multiple disease and abnormity.The one of the main reasons of collection of cellular samples is to be used to screen the cancer patient.For example, by cytotech and pathologist urine, saliva, nipple and fine needle aspiration thing and cervix uteri are peeled off cell and screen, check that there is the paracytic existence of solid tumor in prompting.In case find this suspicious cells, the sample by removing the tissue of suspecting the place that damage is arranged is also given the pathologist with sample and is checked and realize more definite diagnosis.

Any filler test, or the subject matter of tentative diagnosis test is, must be enough sensitive detecting disease, and enough special and can be with the high unaffected individuality of frequency categorization like this not present spirit or body burden.Especially true for some screening test, for example conventionally be used for large-scale groups and do not relate to cervical cell that doubtful index that disease exists raises and learn and check (being commonly referred to the Pap test).

Generally accepted is that the main chance of effective treatment can be provided in the diagnosis of cancer earliest period.The inference of this saying is that the early diagnosis of solid tumor is corresponding to being identified in the local anomaly that cellular level is different from surrounding tissue.This has proposed the challenge of screening cell sample under environment that does not have whole flanking cells and situation relatively.A kind of solution of this problem is to concentrate on tightr approximate complete unitary each unit, the i.e. groups of cells organized.In fact, can think that this cell cluster is therein or before the existence prompting cancer of itself or carcinous state.Yet the sample that also exists the normal structure unit to collect being used for cytological analysis shows as the situation of cell cluster.

Preneoplastic lesion presents the unique biological feature.Abnormal development (tumor progression early stage) relates to individual minimum level ground and is different from the Normocellular cell that exists in the homologue.Abnormal development pathological changes and experience form change (metaplasia) or the interelement main difference of normal structure of propagation (hypertrophy) cell part unbalance that be to express the characteristic protein that relates to abnormal cell growth and turnover initiatively.The pathologist who checks complete tissue generally acknowledges, morphology of normal growth and function (for example mitosis image) or biochemistry (for example Ki-67 tissue antigen) label are dysplastic signs with the morphology of upgrading through the apoptotic process cell (for example, apoptotic body) or the mixing of biochemistry (for example activating caspase 3) indicator.

The routine sampling method that adopts in the current screening process is obtained cell from lesion, then these cells is dispersed in the common quantity obtained and wants the much bigger normal cell outside the pathological changes border.This dispersion causes assess sample to become the activity that detects rare event; That is, in the background that the normal cell of very large amount (for example 50,000-300,000) is formed, find one or several abnormal cell.And, and may be most important ground, disperse to have eliminated by the information that biological property obtained from the zonule of determining to represent preneoplastic lesion.Exist in the intercellular relation of this necessary information, and by check with tissue in the individual cells of adjacent cell separation be unconspicuous.Disperse also to hinder and use sample to determine diseased region on the patient.

Therefore, wish also that unique biological property with preneoplastic lesion is attached to the Collection and analysis cell cluster and in cell sample in the screening indication sampling tissue in the device of the existence of dysplastic cell cluster.

Summary of the invention

The present invention relates in cell sample, screen the system and method for the existence of dysplastic cell cluster in the indication sampling tissue.The searching cell mass concentrates on and does not exist between homocellular normal cell growth, growth and functional period or infrequent two or more biomarkers, is used for the indication formation and may exists before the tumor or the existence of the cell of the regional area part of tumor sexually transmitted disease (STD) change (hereinafter being called " abnormal development ").Keep intercellular relation, seek cell cluster simultaneously so that check and definite possible unusual existence of tissue development.

Can adopt in same cell not can or seldom coexpression but its are expressed in the biomarker that becomes unbalance in the abnormal development and implement notion described herein.Two or more labels of screening can derive from the unbalance of the cell part of expressing the characteristic protein relate to abnormal cell growth and generation.For example, the morphology of normal growth and function (for example, mitosis figure) or biochemistry (for example, Ki-67 breeds antigen) morphology that produces in label and the apoptotic process is (for example, apoptotic body) or the mixing of biochemistry (for example, activation caspase 3) cell sign be dysplastic feature.

Notion described herein is used in many body region screening abnormal development, for example from cervix uteri, bladder, pulmonary, colon, ovary and breast.Can analyze abiogenous cell cluster, perhaps with abiogenous form analysis they, perhaps use suitable catcher analysis from clusters of cells such as the saliva of tissue, urine, generation, breast secretion, ovary flushing cells.

Cell harvestor preferably is designed to improve the ability that catcher is kept the integrity of cell cluster or cluster, and the cell cluster of being convenient to collect is transferred to and accepted on structure such as the microscope slide.In one embodiment, the material of catcher, catcher are collected the collection that the combination that utilizes catcher to expand and rotate during surperficial texture and the collection helps cell cluster.Preferably, can during transfer expand catcher, cell cluster from interior Exocervix zone is terminated in basically on the common plane, to realize that subsequent transfer is to accepting structure.The mode of the spatial relationship that the iuntercellular before preferably, cell cluster can be kept and sample in the cell cluster exists is transferred to from catcher and is accepted structure.Catcher and the structural description point of acceptance help during transfer to keep spatial relationship.

Expand catcher during the collection and during the transitional cell.Expansion during collecting and shifting is by using air, by the mechanical expansion system, or realizes by the combination of air and mechanical system.

Description of drawings

Figure 1A-C has shown the general features that adopts the cervix uteri analytical system of notion of the present invention.

Fig. 2 A and 2B are respectively the cutaway views according to the side view of an embodiment of cell harvestor assembly of the present invention and A-A intercepting along the line.

Fig. 2 C is the detail drawing of the expandable collection tip of cell harvestor assembly.

Fig. 3 is the cutaway view that is attached to the cell harvestor of catcher Handleset.

Fig. 4 person's of being to use hands grips the sketch map of the cell harvestor that is attached to the catcher Handleset.

The cutaway view of Fig. 5 A-C cell harvestor tip region has shown the expansion at cell harvestor tip during the cell cluster collection.

Fig. 6 A-C has shown the step of use cell harvestor from the cervix uteri clusters of cells.

Fig. 7 A-K has shown the process of using the cell harvestor transitional cell to troop, and what have cell cluster that simulation collects has color marker and a marked fluid.

Fig. 8 has shown the cell harvestor cell transfer equipment mounted thereto of the cell cluster that is used to shift collection.

Fig. 9 A-C is that view is prepared in the contact of cervical cell behind the label labelling.

Figure 10 is the axonometric chart of the hand scanner that uses in the cell cluster analytic process of collecting.

Figure 11 is the sketch map of the automatic scam equipment that uses in the cell cluster analytic process of collecting.

Figure 12 has shown another embodiment of cell harvestor.

Figure 13 A-C is the detailed view of Figure 12 cell harvestor tip region, has shown how to expand and rotate during collecting.

Figure 14 A-C has shown another embodiment at cell harvestor tip.

Figure 15 A-B has shown another mechanism that realizes the cell cluster transfer.

Figure 16 has shown how the cell harvestor of Fig. 2 A-B is attached to the installation pulley of another embodiment that is used to realize cell transfer mechanism.

Figure 17 has shown the cell harvestor of the installation pulley that is attached among Figure 16.

Figure 18 has shown the cell cluster of collecting is transferred to the cell harvestor during the turntable of tool microscope slide and pulley is installed.

Figure 19 is the cutaway view that is used to realize another embodiment of the installation pulley that cell cluster shifts.

Figure 20 A-C has shown the mechanism that rotates cell harvestor during collecting.

Figure 21 has shown another embodiment of catcher Handleset.

The specific embodiment

I. general introduction

Cancer is tissue but not cell disease.The pathologist is based on identification pathological changes architecture, specifically is how the pathological changes inner cell is different from every side that normal cell carries out the diagnosis of solid tumor.Used standard comprises that morphology, cytochemical staining come the identification of cell structure, and uses antibody and nucleic probe to determine cytogenetics expression of Substance pattern and composition.

Tumor progression corresponding to heredity and after the accumulation of changing, cause the cell in the newborn tumor more and more can hypertrophy and do not respond the normal regulating signal and the factor, invade the surrounding tissue element, formation blood vessel and transfer.Yet in the earliest period of this process, the abnormal development pathological changes derives from minimum level and is different from the clonal expansion of Normocellular precursor on every side.

Its earliest period screening cancer need discern as yet clonal expansion not to this cell quantity on health obviously or the minority abnormal development cell of clinical manifestation when being the degree of symptom.Because there are the character of minimum difference in these cells and adjacent normal cell, the method for discerning these cells is being restricted aspect morphology and the biologic criteria.

Notion of the present invention is, troops to seek in same cell seldom two or more biological markers of coexpression at any point of normal structure by analysis of cells, can divide dysplastic precancerous lesion from the normal structure element region.For example, can seek two or more biomarkers of cell cluster, indication is as the existence of the individual cells of the part that may have dysplastic regional area.Following explanation and example will be grown and apoptosis is regarded two or more biomarkers that are used to explain above-mentioned notion as.Yet it should be understood that two or more other the biomarkers that also can use in same cell coexpression seldom, perhaps can unite as label with cell growth and apoptosis.

Can use notion described herein to screen dysplastic precancerous lesion from many body regions.For the purpose of explaining, below with reference to describing notion of the present invention with screen for cervical cancer from the cervix uteri clusters of cells.Yet will be appreciated that, notion of the present invention also can for example be collected to screen bladder cancer, collect to screen pulmonary carcinoma, collect to screen colon cancer, collect to screen ovarian cancer from ovary from colon from lung from bladder by screening abnormal development from other range check cell cluster of health.Can wash clusters of cells such as cell from saliva, the ovary of tissue, urine, generation.

Use the catcher clusters of cells, this catcher is designed to improve the ability that catcher is gathered cell cluster or cluster, and is convenient to the cell cluster of collecting transferred to and accepts on structure such as the microscope slide.In one embodiment, the combination of the application that catcher is expanded and rotated during the texture on the material of catcher, catcher collection surface, the collection helps the collection of cell cluster.Preferably, cell cluster is transferred to from catcher in the mode of the spatial relationship that exists between the cell that keeps the sampling pre-group and concentrate accepted structure.Catcher and accept spatial relationship during structural orientation mark helps to keep transfer.

Under the situation of abnormal development pathological changes on the cervix uteri, the cervix uteri analytical system of notion comprises according to the present invention: cell harvestor; Accept structure, the cell cluster of collection is transferred to from catcher and accepts structure; Reaction reagent and scanning device, they obtain cell cluster in (1) in the cervix uteri and Exocervix zone in Cervical together; (2) on the catcher and transferring to spatial relationship between the cell cluster of keeping collection when accepting structure; (3) check the molecular property of cell cluster is to set up whether there is unusual evidence in the cell; (4) so that can finding out, the clinicist where exist the mode of abnormal development pathological changes to move go the cervix uteri.

The cervix uteri analytical system is the cell cluster that exists in the screening sample with the embodiment of method that should be used for differentiating the abnormal development pathological changes according to the unbalance biomarker of the characteristic that can disclose the flanking cell biological property.

Figure 1A-C has shown from the notion of cervix uteri 50 clusters of cells.Figure 1A has shown the cervix uteri 50 that is formed by uterus 52, and cervix uteri comprises the transition region 58 from the inside cervix uteri extension of Exocervix of cervical canal 60, interior cervix uteri 56, Exocervix 62 and shadow representation.Show in the transition region 58 at exemplary pathological changes 54 cervix uteri 56 places in Cervical.

Figure 1B has shown the notion that can be used for from the cell harvestor 100 of cervix uteri 50 collecting cells and cell cluster.Catcher 100 has the surface 104 that adapts to the cervix uteri contour line, and this surface 104 has can be by it from interior cervix uteri and Exocervix 62, the 56 clusters of cells character with the spatial relationship between the cell cluster of guaranteeing to keep collecting from transition region 58 clusters of cells, simultaneously.

In addition, catcher 100 has observable orientation mark 106, so that the individual of clusters of cells can directional collector when cervix uteri is taken a sample, and cell cluster subsequently be transferred to have equally orientation mark 108 corresponding shown in Fig. 1 C accept structure 101 time keep this orientation.By surface 104 is contacted with the structure 101 of accepting that is constructed to be permeable to make cell cluster be transferred to structure 101 rather than keep being attached to surface 104, cell cluster can be transferred to accepts structure 101.During the transfer, orientation mark 106,108 alignment makes in case shift, and the cell cluster on the structure 101 has and they identical spatial relationships on catcher 100.But analysis of cells is trooped possible unusual to screen then.

Cell harvestor 100 can have many different configurations, as long as it can be from interior and Exocervix 56,62 clusters of cells to guarantee from transition region 58 clusters of cells.In one embodiment, the collection of cell cluster is convenient in the combination of the application that catcher is expanded and rotated during the texture of the material of collector surface 104, collector surface 104 and the collection.

II. embodiment 1

A. collect

With reference now to Fig. 2 A-C,, shown the details that embodies the cervical cell collector assembly 150 of notion of the present invention.Collector assembly 150 comprises the removable hollow pipe 200 that is connected expandable collection tip 201.Pipe 200 is made by for example plastics or cardboard.Expandable tip 201 also is the cell harvesting zone of catcher 150, be the resilience elastic construction of being made by for example elastomeric material of thermoplastic elastomer alloy, described thermoplastic elastomer alloy is such as the Versaflex  CL30 for obtaining from GLS Corp. of Illinois McHenry.Expanding tip 201 preferably has can improve the texture of catcher from the ability of transition region 58 collecting cell clusters when most advanced and sophisticated 201 expansions and rotation.For example, tip 201 can have the texture of MT-11010.It is most advanced and sophisticated 201 that other elastomeric material also can be used for, for example microporous polyvinyl acetate, nitrile rubber, nitrile foam, urethane foam, silicone rubber, latex rubber, polyurethane and have low durometer, high elongation and suitably texture with other elastomer of the collection that promotes cell cluster.

Pipe 200 usually from an end 202 to the other end 204 hollows, pipe 200 end 202 openings.Concrete with reference to figure 2C, comprise the transition portion 212 that removable cervical region 206, the central authorities that are connected in the end 204 of pipe 200 expand shoulder 208, tip region 210 and extend under the initial condition of expandable tip 201 when forming between shoulder 208 and tip region 210.As shown in Figure 9, o ring 214 can be set, to help making most advanced and sophisticated 201 to remain on the pipe 200 around the cervical region 206 of collecting most advanced and sophisticated 201.

Fig. 3-5 has shown and has been arranged on the cervical cell collector assembly that is used to gather cell sample on the catcher Handleset 303.Assembly 303 comprises inner sleeve 308 and trocar sheath 307, and pipe 200 is provided with around trocar sheath 307, and trocar sheath 307 is slidably disposed on the inner sleeve 308.Probe 306 stretches into the inside of expandable tip 201 forward from the inside of inner sleeve 308.Expander probe 305 centers on the end that probe 306 is arranged on assembly 303, and the end 320 of probe 305 is arranged in the trocar sheath 307 in trocar sheath 308 ends.The opposite end 322 of probe is expanded and is comprised shoulder 324.

Probe 306 can have about 2 millimeters diameter, and projection exceeds the about 8-10 mm distance of end of expander probe 305.The expander probe 305 of shoulder 324 front sides can have about 6 millimeters diameter, and shoulder 324 diameters are about 10 millimeters.

Helical spring 326 is arranged between shoulder 324 and trocar sheath 307 ends, so that the left side biasing of expander probe 305 in Fig. 3 and 5A-C.In addition, helical spring 328 is in that to be arranged on the inner probe of inner sleeve 308 306 terminal and be arranged between the retainer ring 330 in the inner sleeve 308.Spring 328 makes the left side biasing of probe 306 in Fig. 3 and 5A-C.

Trocar sheath 307 also comprises pipeline locking piece 309.Pipeline locking piece 309 comprises the flexible member that is fixed in trocar sheath 307, and the hole 332 (seeing Fig. 2 B) that forms on the pipe 200 of catcher 150 is passed in its projection that makes progress.Pipeline locking piece 309 and hole 332 associations are equipped with the trocar sheath 307 that pipe 200 is locked in Handleset 303.

Again with reference to figure 3, back-moving spring 310 is arranged in the trocar sheath 307 and is terminal and be arranged between the spring compressor 311 of trocar sheath 307 ends at inner sleeve 308.Spring 310 is to the right side of Fig. 3 biasing trocar sheath 307, and the inner sleeve 308 of setovering to the left simultaneously is so that trocar sheath 307 and inner sleeve 308 return to initial position shown in Figure 3.

Handle 312 is fixed in the supporting member 313 that is connected to inner sleeve 308.Handle 312 rotatably is fixed in supporting member 313 by pivot 314, pivots so that handle 312 can be arranged essentially parallel to subsideing between the position of sleeve pipe 307,308 at position shown in Figure 3 and handle 312.Trocar sheath 307 is formed with slit 315, so that can slide relatively between trocar sheath 307 and the supporting member 313.In Fig. 3, slit 315 extends to medicated cap 311 places on support 313 right sides.

As Fig. 3 and 4 best image, the diameter of trocar sheath 307 from the smaller diameter portion of the pipe 200 that is designed to admit catcher 150 change to contiguous handle 213 and among Fig. 3, extend to supporting member 313 right sides than the major diameter part.Smaller diameter portion and form shoulder 216 (Fig. 4) than the transition between major diameter part, the end of pipe 200 abuts against shoulder 216.When needing, the angle (referring to Figure 16-18) that end 202 tiltables of pipe 200 form with coupling shoulder 216.When collector assembly 150 cunnings installed on the Handleset 303, the angle on the angle of shoulder 216 and the pipe 200 can be alignd, to help to guarantee collector assembly 150 correct orientation on Handleset 303.

Fig. 4 is the sketch map with thumb press hand-held handle 312 on spring compressor 311.Fig. 5 A-C and Fig. 6 A-C have shown the collection process of using cell harvestor assembly 150 with Fig. 4.User at first is inserted into cell harvestor assembly 150 on the Handleset 303.Like this, the tip region 210 of probe 306 tip engages expandable tip 201 makes expandable tip flatten and the shoulder 208 of reduction temporarily most advanced and sophisticated 201, shown in Fig. 5 A and 6A.This has improved the sight line that is used for catcher is inserted Cervical user.

Then, user pushes spring compressor 311 with thumb or other finger, as shown in Figure 4.This makes trocar sheath 307 along with expander probe 305 moves forward together, shown in Fig. 5 B.When probe 305 when moving forward, the shoulder 208 of expandable tip 201 is expanded outwardly, shown in Fig. 5 B and 6B from flat form.After advancing about 8-10 millimeter expander probe 305 with pop one's head in 306 terminally when concordant, the 305 spy ends of expander probe, are shown in Fig. 5 B.Cervical canal is extremely about 6 millimeters in expander probe 305 expansions, expandable tip 201 contact shoe cervical canals.305 visit the end in case pop one's head in, and continue to push with thumb to make trocar sheath 307 continue to move about 3-4 millimeter again, promote pipe 200 simultaneously forward.As a result, the shoulder 208 of expandable tip 201 and/or transition portion 212 compressions are resisted against on the Exocervix 62, shown in Fig. 6 C.

During it moved, expander probe 305 expanded into and the cooperating of interior cervix uteri 56 tip region 210 of expandable tip 201.In addition, the shoulder 208 of expandable tip 201 and/or transition portion 212 compressions are against the outer surface of cervix uteri 50.As a result, can collect interior cervix uteri and Exocervix cell, comprise the cell of transition region 58.

Also rotatable expandable tip 201 during the collection, with under the help of most advanced and sophisticated 201 texture by shearing cell clusters from transition region 58 from the transition region clusters of cells.Most advanced and sophisticated 201 rotate for example 20-30 degree.Can rotate most advanced and sophisticated 201 by manual rotary handle assembly 303 of user and connected collector assembly 150.Perhaps, it is most advanced and sophisticated 201 to use suitable mechanical rotating mechanism to rotate, and this rotating mechanism just makes most advanced and sophisticated 201 rotations when contacting with interior cervix uteri and Exocervix in case Handleset 303 expands into most advanced and sophisticated 201 tip region 210, shoulder 208 and transition portion 212.

The example that has shown mechanical rotating mechanism as Figure 20 A-C.Figure 20 A has shown the collector assembly 150 that is arranged on the Handleset 250.Assembly 250 comprises U-shaped end portion 252, thereby and is rotatably connected to U-shaped end portion 252 and makes the part 254 can be with respect to the expansion and the rotating part 254 of end portion 252 rotation.Construct the end of most advanced and sophisticated 201 parts that center on 254 to be similar to the mode shown in Fig. 5 A-C.The opposite end of part 254 is provided with helical tooth 256 on its outer surface.

Grip sleeve 258 is slidably disposed on part 252 and the part 254 in the position that part 252,254 links to each other.The helical tooth (not shown) is arranged on the inner surface of grip sleeve 258, with tooth 256 engagement on part 254.

Between the operating period of assembly 250, be installed to catcher 150 on the Handleset 250 after, when user inserted probe, probe 305 (shown in Figure 20 A-C) moved forward, and caused most advanced and sophisticated 201 expansions (Figure 20 B).User continues to push, and makes most advanced and sophisticated 201 further to expand to cooperate against Exocervix (Figure 20 C).Can stop further insertion with Exocervical the cooperation, cause that grip sleeve 258 moves forward along the direction of arrow among Figure 20 C.Grip sleeve 258 final moving enough far to contact with helical tooth 256.Continue to advance grip sleeve 258 and meshing spiral tooth that part 254 is rotated shown in arrow among Figure 20 C with catcher 150.

Inserting, expanding and rotating with after realizing cell cluster collection, release pressure and back-moving spring make mechanism get back to initial position.Pipeline locking piece 309 is depressed, and removes cervical cell collector 150 then.

Figure 21 has shown another embodiment of the catcher Handleset 400 that cell harvestor assembly 150 is installed on it.Assembly 400 comprises front tube 402, and the front end of front tube is connected with deflector 404.Handleset 400 is designed so that the pipe 200 of collector assembly 150 slips into pipe 402 so that collector assembly 150 to be installed.When collector assembly 150 was installed on the assembly 400, deflector 404 flattened the shoulder 208 on most advanced and sophisticated 201, to improve the insertion sight line during collecting.Pipe 402 also is included near the slit 406 its rear end.Similar Fig. 5 A-C ground structure pipe 200 is around the inside of the pipe 402 of its setting.

Assembly 400 also comprises rear end pipe 408, and its front end is received within the rear end of pipe 402.Form slit 410 in the rear end pipe 408, button 412 is slidably disposed in the slit 410.Button 412 is connected in the projection 414 in the following groove 406 that is arranged on front tube 402.

Being in the home position at Figure 20 the Show Button 412, also is the on position of assembly 400.After suitably inserting, user is button push 412 backward, and button 412 moves to the rear button position to the end of groove 410.Because button 412 414 is connected with projection, projection 414 also moves backward, pulls back the deflection at the collection tip 201 that front tube 402 causes with release deflector 404 with respect to collector assembly 150.Then, user promotes button 412 forward and collects most advanced and sophisticated 201 with expansion.Button 412 is connected in the expanding mechanism shown in Fig. 5 A-C, makes button the most forward position from the home position of button to button in groove 410 can cause expansion.

Push button 412 in case go ahead and collect after the tip expanded most advanced and sophisticated then just rotation.Can manually rotate most advanced and sophisticated as mentioned above by manual rotation rear end pipe 408.Perhaps, suitable mechanical rotating mechanism can be set and rotate the collection tip.

B. shift

After the collection, cell harvestor assembly 150 is installed on the transfer device, is used for and transfers to collection structure to carry out the subsequent analysis of cell cluster from most advanced and sophisticated 201 cell cluster.The suitable example of structure of accepting comprises: microscope slide, culture dish and cell cluster can be shifted to carry out other structure of cell cluster subsequent analysis.Transfer device is configured such that from accepting structure and shifts with the pressure that equates to accepting structure.And the surface that the surface ratio of accepting structure contains the tip 201 of cell cluster has bigger adhesiveness, with promote cell cluster from the tip to the transfer of accepting structure.When accepting structure and be microscope slide, this microscope slide can have the bigger adhering coating of generation.

Preferred tip 201 during the transfer with air inflation collector assembly 150.When most advanced and sophisticated 201 were made by thermoplastic elastomer alloy such as Versaflex  CL30, the tip can evenly be expanded during elastomer made inflation.Shift during the inflation, tip region 210 and transition portion 212 leave (seeing Fig. 7 B) basically, make cell cluster on tip region 210 and the transition portion 212 finally basically on common plane, accept on the structure so that cell cluster is transferred to subsequently.This helps to keep the spatial relationship of cell mass concentrated cell.

After the transfer, can remove most advanced and sophisticated 201 and be placed on and contain preservative agent from managing 200 with the container of preserving all the other cell clusters on most advanced and sophisticated 201.Then, abandon pipe 200 or be connected to new tip 201 further to collect.If most advanced and sophisticated 201 do not need to preserve then discardable most advanced and sophisticated 201.

Fig. 7 A-K has shown the notion that adopts cell harvestor 150 to carry out the cell cluster transfer, has the coloured label and the marked fluid of the cell cluster of simulation collection.Fig. 7 A has shown the tip 201 of catcher, and its tip has coloured label 500 of the transition zone cell clusters of indication collection.Fig. 7 B has shown the tip 201 of inflation, and coloured label 500 is thin out but still as seen.Fig. 7 C has shown and has joined in the zone that comprises transition zone cell clusters the marking fluid 502 that shifts to help perusal.Fig. 7 D has shown that the tip 201 with inflation presses down on labelling and represents on the paper of microscope slide 504 actual sizes.Fig. 7 E has shown the trace of staying on the schematic microscope slide 504, the cell cluster that this trace representative is shifted.Fig. 7 F shows that most advanced and sophisticated 201 are contracted to its original size and shape.Fig. 7 G is most advanced and sophisticated 201 close-up view, the zone that show tags liquid (promptly representing cell cluster) shifts or do not shift.Shown in Fig. 7 H, most advanced and sophisticated 201 the tip region 210 and the bottom of transition region 212 have " cell cluster " of small size not shift.Key transition region " cell cluster " between tip region 210 and transition region 212 shifts fully.Fig. 7 I-K has shown the result after three independent transfers of adopting index liquid.

Fig. 8 has shown the example of cell cluster transfer equipment 704.In this example, the hole 322 on the pipe 200 of cervical cell collector 150 is as the orientation mark that aligns with correspondence markings on the transfer equipment 704, with directional collector on transfer equipment 150.Need to proofread and correct orientation, to keep based on the relation between any anomalous uterus neck cell of the anatomical location identification in the doubtful zone of its biological property and clusters of cells.

Catcher 150 is placed on the equipment 704 feasible most advanced and sophisticated 201 the structures of accepting towards coating microscope slide 703 forms that are positioned at transfer equipment 704 bottoms.Equipment 704 comprises pinch tube 200 and makes the pipe 200 clamp mechanisms 705 that are held in place.Transfer equipment 704 also comprises a cylinder group 701, and it is configured to air suction catcher 150 so that most advanced and sophisticated 201 inflations.Handle 702 is pivotally connected to transfer equipment 704, and bar 706 extends into cylinder group 701 from handle, is used for the piston of activated cylinders equipment 701.When the downward driving handle 702 of user, the piston in the activated cylinders equipment 701 enters catcher 150 and enters most advanced and sophisticated 201 so that most advanced and sophisticated inflation (seeing Fig. 7 B) by managing 200 to force air.

In case most advanced and sophisticated 201 inflations, the handle 708 that is connected in handle 704 rotates.The rotation of handle 708 causes the catcher installing mechanism, comprises the collector assembly 150 that is mounted thereon, and is similar to drilling machine and moves to microscope slide 703.Finally, the pointed end of inflation by being pressed on the microscope slide 703, is similar to mode shown in Fig. 7 D.Then, rotary handle 708 makes collector assembly 150 retractions, and release lever 702 is thought most advanced and sophisticated 201 aerofluxuss.

Figure 16-19 has shown that cell cluster is transferred to and has accepted structural another embodiment.The cell harvestor assembly is slidably disposed on the hold-down arm 1613 that pulley 1604 is installed, as shown in figure 17.Hold-down arm 1613 hollows are so that the rear end that air can be by hold-down arm 1613 and enter catcher 150 so that most advanced and sophisticated 201 inflations.Align with the correspondence markings 1606 on the hold-down arm 1613 in hole 332, with committed cell catcher on arm 1613.Labelling 1606 is formed for cooperating catcher is fixed on the part of the locking piece on the hold-down arm 1613 with hole 332.

Pulley 1604 is installed is comprised turntable 1608, turntable 1608 has handle 1610 and is used to accept the area supported of microscope slide 1609.Adopt suitable fixed mechanism such as anchor clamps that microscope slide 1609 is on the throne in the area supported locking.Turntable 1608 is rotatably installed on the support plate 1611, thereby can use handle 1610 revolving-turrets 1608.Support arm 1607 is pivotally connected in plate 1611 by pivot 1612, and hold-down arm 1613 extends from support arm 1607.In addition, air pump 1650 is connected in support arm 1607 and is communicated with the rear end fluid of hold-down arm 1613, is used for air is pumped in the hold-down arm 1613 so that most advanced and sophisticated 201 inflations.Air pump 1650 can be motorized motions or user manual actuation.

After the collection, be installed to catcher on the hold-down arm 1613 and lock (Figure 16) on the throne.Microscope slide 1609 on the turntable 1608 is rotated down support arm 1607 (Figure 17) counterclockwise then.Before the contact microscope slide, air pump 1650 makes catcher tip 1601 be inflated to proper volume.As shown in figure 18, most advanced and sophisticated 201 accurately are oriented on the microscope slide 1609 with suitable angle, shift to realize cell cluster.

Figure 19 has shown another enforcement of air pump, wherein, adopts plunger 1901 and makes most advanced and sophisticated 201 inflations by the plunger cavity 1902 that piston body 1903 limits.Plunger cavity 1902 is communicated with the dorsal part fluid of hold-down arm 1613, make when support arm 1607 when turntable 1608 rotates counterclockwise, plunger 1901 and piston body 1902 compressions, force air to flow out and enter hold-down arm 1613 dorsal parts, thereby when microscope slide 1609 rotates, make most advanced and sophisticated 201 inflations in pointed end from plunger cavity 1902.

Be rotated downward to be when cooperating with microscope slide 1609 when most advanced and sophisticated 201, support arms 1607 contacts with microscope slide 1609 to keep tip 201.Use handle 1610 rotating tables 1608 then.One driving mechanism is connected between turntable 1608 and the hold-down arm 1613, and it is rotatably installed on the support arm 1607, so that hold-down arm 1613 rotates with the catcher 150 that is fixed in it.Driving mechanism is configured to make catcher tip 201 to turn round fully, and the spring in the turntable 1608 makes this mechanism get back to initial position.

Shown in Fig. 1 C, Fig. 8 and Figure 16-19, adopt microscope slide to accept structure as what transitional cell was trooped.Microscope slide preferably is configured to: (i) coating processing section or all surfaces so that cell and cell cluster be attached to microscope slide rather than still be attached to the surface of catcher; (ii) can be orientated uniquely with respect to the orientation mark on the catcher.These features can be by through spraying paint or etched finishing glass is realized, thereby identify patient and the corresponding catcher of record.

C. analyze

Fixing cell and the cell cluster of transferring to as shown in Figure 1 on the microscope slide 101.Fixative can be any fluid or the aerosol that can keep cervix cells shape and biochemical characteristics.Fixative can be to be used for fixing a kind of in the fluid of cytological samples or the aerosol at present, or the improved form of these preparations, and it promotes cyto-architectural preservation or rapidoprint to be used for other to use, for example with the ability of molecular probe reaction.An example of aerosol fixative is Shandon CytoFix.

For labeled cell and cell cluster, can use comprise can with the staining reagent of one or more molecular probes of abnormal development epithelium of cervix uteri characteristic biomarker reaction.Appreciable biomarker comprises protein, especially the modification or the activated form of the molecule of proliferative cell expression.Fig. 9 A-C has shown an example; wherein; handle cervix cells with the inhibitor M344 that causes the unbalance histone deacetylase of cell cycle in the newborn transformant; the protein phosphorylation ribosomal protein S6 (Fig. 9 A) and the broken cells keratin 18 (Fig. 9 B) of expressing in the dyeing proliferative cell, these two kinds of albumen are apoptotic specific markers.The a pair of label of expressing when this is cervix uteri abnormal development, but do not express in the same cell in pathological changes, shown in combined diagram (Fig. 9 C).Also can use other label right, comprise propagation and cell cycle inhibitor label.The example of propagation label has Ki-67 antigen and proliferating cell nuclear antigen (PCNA).Usually can in the active growth cell, not comprise p16, p21 and p27 by the cell cycle inhibitor of high level expression.Adopt screening technique as herein described, the right successful Application of any given label will depend on the concrete biological characteristics of institute's application organizes and unusual new things.

Spendable other biomarker comprises: express messenger RNA molecule, lipid and the protein of the gene that increases and the glycosylation form of lipid in nucleic acid, the abnormal development cervix cells.The effect of these target biological molecules in tissue and abnormal development cell (for example comprises the intracellular signal transduction receptor, the activated protein kinase of mitogen), structural protein (for example, cytokeratin) and nuclear breeding related gene product (for example, Ki-67).These protein expressions can be according to for example misgrowth or apoptosis.

The mode of using and detect staining reagent for the expression of determining these biomarkers can comprise: with fluorescein (for example FITC), reactive sign (for example, biotin) revises antibody and nucleic probe, perhaps direct and reporter molecules (for example horseradish peroxidase) coupling with these molecules.Can be intuitively (for example, by the irradiation of apparent fluorescence) by with enzyme reporter molecules (for example, the link coupled alkali phosphatase of streptavidin) and/or add precipitating substrate (for example blue and bromine chloro-indole based phosphates) and react and carry out colorimetric and read and detect these probes from azoles.

In order to discern the existence of the abnormal development groups of cells of indicating the epithelium of cervix uteri damage, can adopt redying of some modes.This can realize in the following manner: adopt to be used for immunocytochemistry and immunohistochemical reagent at present so that perusal cell (for example C.I. 42590 or hematoxylin), adopt the reagent (for example phalloidin) with main cell characteristic reaction, or be used for developing and be commonly referred to the painted reagent of Pap.

Then, how individual signal intensity and definite these signals ratio between collection and stained specimens of using scanning device to measure from the suitable detection probe changes.Scanning and analytical integration be near on the zone of minimum preneoplastic lesion, this zone concerning the clinician in the morphology obviously and can be by histology or immunohistochemistry confirmation.Scanning device can be automatically, and to realize analyzing a plurality of microscope slides, required analysis software can reside in the scanner or be present in the external computer.

Figure 10 has described to can be used for to read an example of the scanning device 1000 of specimen slide.Scanning device 1000 shown in Figure 10 is manual instruments.Manual instrument in this example comprises the conventional amplifier 1002 (for example, 3X or higher) of coupling on solid-state flat luminous device 1006.The example value in the amplifier visual field is 8 millimeters, but also can adopt other value according to the needs of user.

The manual platform 1010 of cantilevered two axial lines is connected with microscope slide keeper 1004, and microscope slide is positioned between amplifier and the luminous organ.Provide differential 4-connecting rod 1012 so that microscope slide is rough and precision positioning amplifier below.Connecting rod 1012 is connected in Platform Position Unit 1018, and Platform Position Unit comprises stick 1014 and locking piece 1016.Provide to comprise the slide block 1008 that excites and launch optical filter, can under white light and fluorescence, observing sample.Slide block 1008 is inserted between luminous organ and the microscope slide keeper.This manual equipment 1000 also can have focus head, to allow the resolution of user resonance-amplifier 1002.

Can use battery or wall wart to power as luminous organ.The illumination that light-emitting component 1006 provides will be depended on the emissive porwer that excitating light strength that saturated used fluorogen is required and positive cell are trooped and produced.Exemplary value comprises absorption (exciting) peak value 495nm, emission peak 519nm, or absorb at 590nm, the dyestuff of 617nm emission.

Figure 11 has described to can be used for to read another example 1100 of the instrument of specimen slide.Instrument 1100 shown in Figure 11 is automatic units.This automatic unit adopts " contact image sensor " (CIS) 1112 to capture the microscope slide image, and a vacuum chuck is installed on the spherical microscope slide back and forth to transport microscope slide 1110 by the CIS1112 supply line between input lifters 1108 and the output lifters 1106.

Lifters

1106,1108 is driven by motor 1102 and gear 1104.

Motor 1116 drives tightens belt-type drive and driving screw to drive 1114 is can be with two examples of reciprocating conveyer device 1120.Moving back and forth conveyer device 1120 rides on the linear bearing 1118.Lifters the 1106, the 1108th, an example of moving belt design.In another example, lifters can be the design of capwise cross bar.Packing restriction and output/batch sizes requirement are depended in the selection of lifters.Depend on illumination level and used concrete CIS sweep time.

CIS also can be responsible for reading bar code data from each microscope slide.Bar code comprises the patient population data that can be printed in the report.Provide bar code data can reduce the error that manual operation causes.And positive ID is enforceable to the CLIA compliance.

Typical case CIS readout instrument can be captured bar code and be had decoding software (for example, 8-10 character of sign indicating number 128).Can use 200DPI CIS (for example, the PI216MC-DR of Peripheral Imaging company) in the native system.If there is the requirement of specific wavelength and gray level, then consider to use other cis module.Can obtain 200DPI and Geng Gao monochrome and colored cis module from many suppliers.When needing, can improve cis module to realize concrete application.For example, may need to add wavelength and select optical filter.Also may need to remove cover plate or cooperate fractional pitch grin lens bar.Also may need to use two monochromatic cis modules, one in each color, rather than in single color module, remove spectral response.Equally, the illumination that provides of CIS will be depended on the emissive porwer that excitating light strength that saturated used fluorogen is required and positive cell are trooped and produced.Exemplary value comprises absorption (exciting) peak value 495nm, emission peak 519nm, or absorb at 590nm, the dyestuff of 617nm emission.

In an example, can use to be become to be used for embedded system by particular design but not the single board computer (SBC) of desk-top/laptop application is controlled automatic unit.Exemplary SBC includes but not limited to: the SBC that Sharp, Atmel and Auron produce.SBC also can be responsible for data and obtain/handle and print.SBC will programme in known manner, to realize control automatic system and the concrete application of obtaining and handle the data of being accepted from CIS.Significant if desired user interface interaction effect for example shows the result of all samples in window, composite print or store initial data, the similar means that can adopt USB interface or transfer of data with transfer of data to personal computer or master computer.

The used power supply of automatic system can be many forms.In an example, use rechargeable battery.Power requirement under processor and the LCD display 5VDC is about 450mA.This power requirement can be satisfied by NiMH type battery.For example, can provide operation in 7 hours during the new battery of four 3500mAHr set of cells.If use the AA set of cells of 1500mAHr scope, can provide operation in 3 hours during then new battery.

At last, consider also can realize " lite " version automatic system.This lite version can comprise LCD display, single shaft platform, CIS pick off and scaled processing capacity.User can place microscope slide the CIS below.Then, user presses the button to obtain data, then video data on LCD display.

III. embodiment 2

With reference now to Figure 12 and 13,, shown, be used for another embodiment 10 in the cervical cell collector of cervical canal 100 collecting cells.In this example, cervical cell collector is made of assembly, this assembly comprises flexible cell sample zone 12 and the rigidity pusher 22 that adjoins, comprise second assembly in the rigidity pusher, second assembly comprises the point dilator 16 that is rotatably installed on the rigid core element 14, one stack features 31 of point dilator is meshed with the corresponding actuating feature 32 of core element 14, the matching characteristic of second stack features, 33 engagement pushers 34.The actuating feature 32 of core element 14 for example is constructed with the screw thread of suitable pitch.The lancet (stylette) 18 that is attached to core element 14 passes the opening 20 on the point dilator 16.

Cell sample zone 12 can be the elasticity elastic construction of being made by following suitable elastomeric material, such as micropore polyvinyl acetate, thermoplastic elastomer (TPE), nitrile rubber, nitrile foam, urethane foam, silicone rubber, latex rubber, polyurethane and have suitable low durometer, the high any material that stretches percentage ratio and surface quality.

Shown in Figure 13 A, 13B and 13C, cervical cell collector can be at extended state (Figure 13 A); Intermediateness (Figure 13 B); And change between the depressed state (Figure 13 C).The clinician is inducted into the desired degree of depth in the cervical canal 100 (with most advanced and sophisticated depth representing) with the tip of the cervical cell collector under the extended state 10, as shown in FIG. 13A.Under this state, pusher 22 retractions, cell sample spare 12 is roughly complied with the outer surface of point dilator 16.In case the clinician just advances pusher and core element 14 and lancet 18 maintenance transfixions towards cervical orifice (os) after the tip of cervical cell collector 10 is suitably located in cervical canal 100.When the feature 31 and 34 of pusher 22 during, advance pusher 22 that point dilator 15 is moved and around immobilized core element 14 rotations towards cervical orifice equally respectively with the individual features 32 of core element 14 and point dilator 16 and 33 engagements.Simultaneously, the propelling pair cell of pusher 22 sampling part 12 has applied compression stress, thereby causes its outer radial against cervical orifice outwards to be out of shape, shown in Figure 13 B and 13C.Point dilator 16 pushed in cell sample spare 12 most advanced and sophisticated the tip diameter of cell sample spare 12 is increased, thereby the outer surface of cell sample spare 12 is oppressed on the wall of cervical canal 100.Point dilator 16 helps point dilator with respect to rotatablely moving of cell sample spare 12 inner surfacies and enters, thus expansion cell sample spare.

Cell sample spare 12 can make the cervix cells that comes off be attached to the outer surface of cell sample spare against contacting with rotation of cervical orifice and pipeline 100.The retraction of pusher 22 causes point dilator 16 to withdraw from from the tip of cell sample spare 12, and makes cell sample spare can get back to its initial extended state.Then, can take out cervical cell collector 10 from cervical canal 100 and vagina, being collected in the lip-deep cell of cell sample spare is that follow-up evaluation is standby.

Can be used for estimating by the cell that several modes are prepared to be trapped on the cell sample zone 12.A kind of mode be with the cell harvesting surface impregnation to preserving in the medium and preferably it being stirred and preserve in the medium, the suspension of cell in preserving medium captured in preparation.The gained cell suspending liquid can be conventional the mode of cell monolayer preparation be deposited on microscope slide or the similar surfaces, and according to known method dyeing with estimate.Perhaps, available flow cytometer is estimated suspension cell.

Preparation is captured another kind of mode that cell is used to estimate schematically shown in Figure 14 and 15.In this mode, rigidity axle 114 is inserted cell sample zone 12, force the cell sample area part that is stained with cell to present the axle shape, as shown in figure 14.The keying feature 112 and 116 of coupling guarantees that the cell sample zone keeps predetermined orientation with respect to axle on cell sample zone 12 and the axle 114.This can be by making trace on the microscope slide corresponding to the signature on the catcher, thereby the mode of the orientation of reflection device realizes when device inserts cervical canal.These traces allow the clinician accurately to identify the zone of gathering cell.

As shown in figure 15, the cell surface that contains in cell sample zone can contact with the surface of microscope slide or similar suitable processing then, and the radian suitable in this treatment surface upper edge rolls so that the whole cell surface that contains in cell sample zone contacts with microscope slide.The cell surface that contains in cell sample zone makes cell transfer on the microscope slide from the cell sample surface with contacting of microscope slide.Then, according to the dyeing of the method set up with estimate these transitional cells.In the method, keep intercellular relative tertiary location, thereby can determine the approximate location of collecting cell on cervix uteri.Microscope slide has coverslip usually.Whether the material on the microscope slide can determine the composition of used sealing medium with some otherwise processed after checking cervix uteri analytical system result.

Use suitable illumination to observe the microscope slide of tool coverslip.Scrutiny determines whether there is signal framing in a cervix uteri sample area.Mark the position of lesion candidates with reference to the cervix uteri collection of illustrative plates of expression collecting cell position.

Use has the catcher of above-mentioned feature and gathers the inside and outside cell of cervix uteri.Can collect sample by internist or health care worker.Perhaps, can train women oneself and collect sample to realize the purpose of cervix uteri analytical system.

Though described the present invention in conjunction with the preferred embodiments, for a person skilled in the art clearly, can realize other purpose of the present invention and improvement and still in authority of the present invention and scope.

Various aspects of the present invention and described form are fit to reach other purpose of claiming and advantage very much.Described details is not regarded limitation of the present invention as.

Claims

1. system that in cervix uteri, detects abnormal structure, described system comprises:

Catcher is used for from the cell cluster of Cervical Exocervix zone and the collection space arrangement of interior cervix uteri zone, and described catcher is kept the spatial integrity that is collected in the described cell cluster on the described catcher;

Accept structure, be used to accept the cell cluster that shifts from described catcher, wherein, described structure and the described catcher accepted is configured to keep and transfers to the described spatial integrity of accepting the described cell cluster of structure;

Analytical reagent is used for preparing to transfer to the structural cell cluster of described acceptance so that check; And

Scanning device is used to detect the cell cluster by described analytical reagent preparation, thereby detects the unbalance of two or more cellular expression characteristics of whether existing in the demonstration abnormal development state under.

2. the system as claimed in claim 1 is characterized in that, described catcher and the described structure of accepting respectively comprise at least one orientation mark thereon, to help to keep respectively the spatial integrity of the cell of collecting and shifting.

3. the system as claimed in claim 1 is characterized in that, described catcher also comprises: main body; With the elastic surface that is positioned near described main body one end, described elastic surface has the texture that contacts that is fit to from Cervical Exocervix and interior cervix uteri zone clusters of cells, described elastic surface is made by the material that described elastic surface can evenly be expanded, and described elastic surface is rotatable

Wherein, when described elastic surface expansion and rotation, the contact texture of described elastic surface helps described elastic surface from Exocervix and interior cervix uteri zone clusters of cells.

4. system as claimed in claim 3 is characterized in that the material of described elastic surface comprises thermoplastic elastomer alloy.

5. system as claimed in claim 3 is characterized in that, described contact texture comprises MT-11010.

6. the system as claimed in claim 1, it is characterized in that, described analytical reagent comprises that also the cytology detects mixed liquor, and described mixed liquor comprises as first reagent of the first cellular expression attribute tags thing with as second reagent of the second cellular expression attribute tags thing.

7. system that detects abnormal structure, described system comprises:

Catcher is used for from may show the potential unbalance local organization of two or more cellular expression characteristics zone clusters of cells under the abnormal development state;

Accept structure, be used to accept the cell cluster that shifts from described catcher;

Scanning device is used to detect the cell cluster of described analytical reagent preparation, thereby detects the unbalance of two or more cellular expression characteristics of whether existing in the demonstration abnormal development state under.

8. method that in cervix uteri, detects abnormal structure, described method comprises:

(a) use catcher from Cervical Exocervix zone and interior cervix uteri zone clusters of cells, keep being collected in the spatial integrity of the cell cluster on the described catcher simultaneously;

(b) at least a portion cell cluster that described catcher is collected is transferred to and is accepted on the structure, keeps transferring to the spatial integrity of the structural cell cluster of described acceptance simultaneously;

(c) cytology is detected mixed liquor and be applied to transfer to the structural cell cluster of described acceptance; And

(d) analyze the unbalance of two or more cellular expression characteristics in the described cell cluster.

9. method as claimed in claim 8 is characterized in that, keeps the spatial integrity of the cell cluster of collecting and shifting respectively by described catcher and structural at least one orientation mark of described acceptance.

10. method as claimed in claim 8 is characterized in that, described collection step also comprises:

Troop at Exocervix and interior cervix uteri zone exposing cell, described cell cluster contacts with the elastic surface of catcher, and the described elastic surface with contact texture is fit to from Exocervix and interior cervix uteri zone clusters of cells;

Expand the described elastic surface of described catcher; And

Rotate described elastic surface with respect to Exocervix and interior cervix uteri zone;

Wherein, when described elastic surface expansion and rotation, the described contact texture of described elastic surface helps described elastic surface from Exocervix and interior cervix uteri zone clusters of cells.

11. method as claimed in claim 10 is characterized in that, described expansion step comprises the described catcher of mechanical expansion.

12. method as claimed in claim 10 is characterized in that, described method comprises the described elastic surface of manual rotation.

13. method as claimed in claim 10 is characterized in that, described method comprises the described elastic surface of machinery rotation.

14. method as claimed in claim 10 is characterized in that, described method comprises the about 20-30 degree of the described elastic surface of rotation.

15. method as claimed in claim 10 is characterized in that, described method is rotated described elastic surface after being included in the described elastic surface of expansion.

16. method as claimed in claim 8 is characterized in that, described transfer step also comprises pneumatically expands described catcher.

17. method as claimed in claim 16 is characterized in that, described catcher is expanded to the cell cluster collected from Exocervix and the interior cervix uteri zone degree on common plane basically that makes.

18. method as claimed in claim 8 is characterized in that, the step that described application cell is learned mixed liquor also comprises: use first reagent as the label of the first cellular expression characteristic with use the label of second reagent as the second cellular expression characteristic.

19. method as claimed in claim 18 is characterized in that, described application cell is learned the step that detects mixed liquor and is also comprised described first and second reagent are applied to cell cluster together.

20. method as claimed in claim 8 is characterized in that, the step that described analysis of cells is trooped comprises: scan described cell cluster and measure each signal intensity that is detected by analytical reagent and determine detected signal such as where changes between cell cluster.

21. a method that detects abnormal structure, described method comprises:

(a) with catcher collecting cell sample, described cell sample comprises the cell cluster in the regional area that can show the potential unbalance tissue of two or more cellular expression characteristics under the abnormal development state;

(b) at least a portion of the described cell cluster that will collect is transferred to and accepts structure;

(c) cytology being detected mixed liquor is applied to be transferred on the described described cell cluster of accepting structure; And

(d) two or more cellular expression characteristics unbalance in the described cell cluster that analyze to shift.

22. method as claimed in claim 21 is characterized in that, described application cell is learned the step that detects mixed liquor and is comprised: use first reagent as the first cellular expression attribute tags thing with use second reagent as the second cellular expression attribute tags thing.

23. method as claimed in claim 22 is characterized in that, described application cell is learned the step that detects mixed liquor and is comprised: the transitional cell that described first and second reagent is applied to together the individual cells sample.

24. method as claimed in claim 21 is characterized in that, described analytical procedure also comprises with scanning device and scans described cell cluster.

25. one kind is screened cell cluster and constitutes with indication and may exist before the tumor or the method that exists of the cell of the regional area part that the tumor sexually transmitted disease (STD) becomes, described method comprises:

In cell cluster, seek two or more biomarkers that between normal cell growth, growth and functional period, in same cell, do not take place usually.