US20040172014A1

US20040172014A1 - Device for the optically controlled micro-manipulation of biological objects

Info

Publication number: US20040172014A1
Application number: US10/484,913
Authority: US
Inventors: Andreas Maass
Original assignee: Eppendorf SE
Current assignee: Eppendorf SE
Priority date: 2001-07-27
Filing date: 2002-07-18
Publication date: 2004-09-02
Also published as: WO2003016463A3; DE10136572A1; AU2002355887A1; JP2005500056A; US20060274406A1; US7408704B2; DE10136572B4; WO2003016463A2

Abstract

The invention relates to a device for the optically controlled micromanipulation of biological objects, containing the following: at least one micro manipulator comprising at least one holder that is motor-displaceable by means of Control elements for a cytological instrument; and a microscope, which has at least one functional element that is motor-displaceable by means of a control element. The motor-displaceable holder is coupled to at least one motor-displaceable functional clement in such a way that a mutual adjustment or setting of the holder and an adjustment of the functional element(s) of the microscope can be carded out in a co-ordinated manner by means of a common control element (17, 18).

Description

BACKGROUND OF THE INVENTION

The invention relates to a device according to the superordinate concept of Claim 1. Analogous devices generally have at least one micro-manipulator, which has at least one motor-displaceable holder for a cytotechnical instrument, by means of which a biological specimen, generally a cell or a tissue, can be manipulated.

Cytotechnical instruments are, for example, capillary tubes or pipettes, with which cells or tissues can be held or manipulated. Typical instruments are holding, etching, biopsy or injection capillary tubes or fine puncturing or cutting instruments or electrodes. Using the motor-displaceable holder, the instrument can be moved in all three spatial axes (xyz-axes); in order to bring its free end into the working position relative to a biological specimen that is to be manipulated.

This type of device generally comprises two manipulators, each of which have at least one holder for cytotechnical instruments.

In addition, a microscope is provided in this type of device for optical control of the micro-manipulation operations. Both an inverted or an upright microscope can be used, whereby, in both instances, a transillumination arrangement is conventionally used for examining biological specimens. A number of motor-displaceable functional elements are also available on the microscope such as, for example, a microscope table that can be moved or rotated in the xy-direction, a height-displaceable z-drive, a mechanism for changing over the objective lens, etc.

A number of different control elements are provided that make it necessary for the operator to reach around or change position when operating the different functions of the motor-displaceable holder of the micro-manipulator and the displaceable functional elements of the microscope.

In the case of a micro-manipulator having two separate holders, DE 19740324.7 discloses providing a coupling between the two holders. When one of the holders is actuated in a specific fashion by means of a control element, the other holder automatically executes a preprogrammed, generally opposing, movement thereto. In this fashion, when working with a plurality of instruments, for example, exchanging instruments is simpler and more reliable.

The object of the invention is to provide a device that can be operated more easily than the known devices.

In this connection and according to the invention, at least one function of the at least one motor-displaceable holder of the micro-manipulator is coupled to at least one motor-displaceable functional element of the microscope in such a fashion that both can be actuated in a coordinated manner by means of a common control element.

The term “activated in a coordinated fashion” is understood to mean that the respective functions of the manipulator and the microscope are expediently coupled by means of a common control element. The displacement or adjustment of the micro-manipulator and a motor-displaceable functional element of the microscope can accordingly be done simultaneously or sequentially upon actuating a common control element.

The term “control element” as used in the following is intended to include all devices that are associated with a function of the manipulator and/or the microscope. If a function of the manipulator and of the microscope is activated in a coordinated fashion, then one refers to a common control element. Accordingly, in both cases, for example, these can be pushbutton or rotary knobs, switches or joysticks or the like.

Preferably, an operator console is provided, which accommodates the control elements for the microscope and/or the at least one manipulator. The control elements can easily be connected to a processor, for example the processor of the micro-manipulator, a defined interface between the processor and the microscope is assigned to the processor, so that activation of the micro-manipulator functions and the microscope according to the invention is essentially restricted to corresponding programming by means of a common control element and does not impose any problems or limitations relative to hardware.

In the context of the invention, therefore, principally all functions of the at least one motor-displaceable drive can be coupled to one or a plurality of the functional elements of the microscope, insofar as this results in a facilitation of operation.

A particularly preferred embodiment relates to the coupling of the covered range of movement of the cytotechnical instrument as a factor of the field of view included by the selected objective.

The field of view; that is, the respective work surface observed using the microscope, for example the surface of a Petri dish, decreases with increasing magnification. In order to assure that when processing cells the instrument operated by means of the micro-manipulator does not leave the field of view, its permissible range of movement must accordingly be adapted to the field of view.

In this connection, therefore, provision is made that when displacing the objective lens by means of a common control element, adaptation of the covered range of movement of the cytotechnical instrument using the holder is made to the new magnification or the accordingly covered field of view.

Generally, a control element that can be displaced in one or a plurality of spatial axes, for example a joystick, is provided for moving the motor-displaceable holder. The joystick can, by means of different transmission ratios, control the movement of the instrument in the xy-direction or in many cases in the z-direction, as well.

Accordingly, in the case of the cited preferred embodiment, upon actuation of a common control element, the objective is changed on the microscope and, for example, the covered range of movement of the cytotechnical instrument using the joystick adapted to the new field of view. Accordingly, the transmission ratio of the joystick is advantageously adapted so that regardless of the magnification, upon corresponding movement of the joystick the cytotechnical instrument; that is, its observed tip, executes a substantially consistent appearing movement within the field of view. The common control element can, if ergonomically possible, be integrated in the joystick, if appropriate. Generally, however, it is a separate control element.

According to a further advantageous embodiment provision is made that together with focussing the microscope objective a corresponding movement of the instrument or its free end is made in the z-direction. This is always important, for example, when the microscope table is shifted together with the Petri dish on it; for example, in order to change the cell to be processed. In this case it is advantageous if the free end of the instrument can be set as quickly as possible and with minimal control involvement to the optimal position relative to the z-axis for processing the new cell.

This is necessary, because as a rule the surface of Petri dishes is not flat or the cells lie in different planes. The new cell to be processed is therefore generally neither in the focus of the microscope objective nor in the correct position relative to the end of the instrument. In this preferred embodiment it is proposed that, upon actuation of a control element for focusing the microscope on the new cell, the position of the instrument relative to the z-axis is correspondingly changed in a coordinated fashion, so that upon fine adjustment of the cell the end of the instrument is again in the optimum processing height (position in the direction of the z-axis) relative to the cell.

According to a further advantageous embodiment, provision is made that upon moving the microscope table a corresponding positioning of the at least one cytotechnical instrument is effected by means of a common control element. This is always of interest, when, by positioning the microscope table, the position of a cell in the field of view of the microscope is to be changed and the cell is in processing engagement with one or a plurality of cytotechnical instruments. In this case, the instruments must be re-positioned relative to the positioning of the microscope table in order to remain in processing engagement with the cell or in order to re-establish the processing engagement. In this embodiment, upon actuation of a common control element, the required re-positioning of the instrument(s) is made in a coordinated fashion with the positioning of the microscope table, which represents a considerable facilitation of operation.

The invention is not limited to the aforesaid embodiments. A number of other possibilities are conceivable as to how the functions of the micro-manipulator and the individual or multiple functional elements of the microscope can be coupled to each other.

It is, for example, conceivable to store all relevant data on the microscope and manipulator settings in a specific location in the processor and to call them up again by means of a control element so that the microscope table moves in a coordinated fashion into the stored xy-position, the microscope objective is selected and correspondingly focussed, the manipulators move the held instruments into the corresponding xyz-positoins and, if applicable, sets the joystick to the desired transmission ratio. Obviously, also only single selected functions of the addressed functions can be activated with respect to the stored values.

The invention naturally includes devices that comprise not only one but a plurality of manipulators having a plurality of different instruments. In this connection, an advantageous embodiment provides for the fact that the holders of the plurality of manipulators comprising the device can be set or adjusted together by means of a common control element.

In the following, the invention will be more completely described with reference to the figures, which represent two exemplary embodiments, wherein: [0024]
FIG. 1: diagrammatically represents coupling of a joystick-transmission ratio of the manipulator with the objective adjustment of the microscope; [0025]
FIG. 2: likewise diagrammatically represents the possible coupling between focussing of the objective and z-position of an instrument.[0026]
FIG. 1 is broken down into two partial figures a and b, wherein in both cases a field of [0027] view 10 or 10′ onto a surface 11 of a Petri dish [not shown], for example, containing the cells 12, 13 to be processed.
In the represented example, the [0028] cell 12 is in the processing intervention position using the free end 14 of a cytotechnical instrument 15, which can be a capillary tube or a hollow needle, for example. For the sake of clarity, only a partial view of the instrument is represented. The holder holding the instrument or the manipulator is not shown.
The positioning of the [0029] instrument 15 in the xy-direction and, if applicable, also in the z-direction is done by means of a control element that can be shifted in the corresponding axes; in the case represented, a joystick is used.
The [0030] joystick 16 is accommodated along with other control elements 17, 18 in a operator console 18. The control elements 17, 18 can be optionally assigned functions. They can be configured as buttons, knobs or switches, etc.
A angular field is shown at [0031] 19, 19′, respectively, by means of which the instrument 15 can be moved in the direction of the x-axis using the joystick 16, without leaving the field of view 10 or 10′. In dependence on the set magnification, the angular field 19′ is appreciably less than the zone 19. The desired angular field can be correspondingly adjusted by means of joystick 16 transmission.
According to the invention, provision is made that the adjustment of the [0032] joystick 16 for a specific angular field 19, 19′ is done automatically using the adjustment of the corresponding magnification on the microscope [not shown] by means of the control element 17 (common control element), for example.
The advantage of the described embodiment resides in the fact that the [0033] joystick 16 is automatically offset in time upon actuation of the control element 17 for shifting the objective lens such that at all times a movement of the instrument 15 corresponding only to the currently available visual field 10, 10′ is possible. In this fashion the instrument 15 is prevented from moving outside of the field of view 10, 10′.
In the represented case, the corresponding limitation of the [0034] joystick 16 is represented only for the x-axis. Naturally, in practice, the displacement of the y-axis is adapted accordingly. Upon displacement of the instrument 15 in the z-axis, which can be effected by means of a rotation of the joystick 16, for example, no compulsory opposing limitation is required.
FIG. 2 represents a lateral view of a Petri dish [0035] 20 having a work surface 22, on which the cells 23 and 24 to be processed are placed. In addition, the operator console 28 of FIG. 1 is represented with the control elements 16, 17 and 18.
Processing of the [0036] cells 23 and 24 is done under visual control by means of a microscope [not shown], which is represented here only by an objective lens 25, 25′ in different focal positions.
Processing of the [0037] cells 23 and 24 is done in the represented case by means of a cytotechnical instrument 26, 26′ represented here in two different positions and whose tip 27, is in an optimal position of intervention relative to the cell 23 or 24, respectively.
Because of the fact that the [0038] work surface 22 of the Petri dish 20 is not flat, the position of the cells 23 and 24 deviates also relative to the z-axis.
With the transition of processing from the [0039] cell 23 to the cell 24, re-focussing is necessary and the position of the instrument 26 must be changed so that its tip 27 is again in the optimum position of intervention with the cell 24.
A possibility at the time of changing over of processing is to correspondingly shift the Petri dish [0040] 20 under the objective. There are also microscope tables on which the micro-manipulator is fixedly mounted. The xy - displaceable platform is designed so as to accommodate the microscope, so that the entire microscope can be shifted accordingly.
According to the invention, provision is made that when focussing the objective [0041] 25, 25′ on the cell 24, for example, a corresponding displacement of the instrument 26 in the z-direction occurs automatically. Thus the identical processing conditions are automatically adjusted as in the case of processing the cell 23.
Actuation of both functions can by done by means of the [0042] control element 18, for example.
Obviously, additional functions or settings of the manipulator can be coupled with the functions of the microscope without departing from the scope of the invention. [0043]

Claims

1. A device for optically controlled micro-manipulation of biological specimens having at least one micro-manipulator with at least one cytotechnical instrument holder that is motor-displaceable by means of control elements, and with a microscope, which has at least one functional element motor-displaceable by means of a control element, characterized in that the motor-displaceable holder is coupled with at least one motor-displaceable functional element of the microscope in such fashion that, by means of a common control element (17, 18), a common displacement or adjustment of the holder and a displacement of the at least one functional element of the microscope can be executed in a coordinated fashion.

2. The device according to claim 1, characterized in that upon changing the size of the field of view (10, 10′) by changing the microscope objective lens (25, 25′), the covered range of displacement of the cytotechnical instrument (15) using the holder is adapted to the new field of view.

3. The device according to claim 2, characterized in that for adapting the covered range of movement of the cytotechnical instrument (15) using the holder to the new size of the field of view, the transmission ratio of the control element (16) controlling the holder is correspondingly changed.

4. The device according to claim 1, characterized in that with the displacement of the microscope objective (25, 25′) for the purpose of focussing a displacement of the holder in the z-direction takes place.

5. The device according to claim 1, characterized in that with displacement of the microscope table or the microscope by means of a common control element, a corresponding displacement of at least one cytotechnical instrument of the at least one manipulator takes place.

6. The device according to claim 1, characterized in that specific stored settings of one or a plurality of motor-displaceable functional elements of the microscope and of the manipulator can be refined and readjusted by actuation of a common control element.

7. The device according to one of claims 1 - 6, characterized in that the control elements (16, 17, 18) for adjusting or displacing the at least one motor-displaceable holder and/or of the at least one motor-displaceable functional element of the microscope is provided on an operator console (28).

8. The device according to one of claims 1-7, characterized in that two micro-manipulators are provided, whose holders can be adjusted or displaced in common with a functional element of the microscope by means of a common control element